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<SPAN STYLE="color:#000000;background-color:#ffffff;position:absolute;left:72.00pt;top:72.00pt;z-index:2;"><IMG WIDTH=188 HEIGHT=65 style="width:90pt;height:30pt;" SRC="outputfile562637297.htm_files\outputfile562637297_p0.png"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:176.40pt;top:72.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">United States</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:176.40pt;top:81.35pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Environmental Protection</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:176.40pt;top:90.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Agency</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:319.95pt;top:72.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Prevention, Pesticides</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:319.95pt;top:81.35pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">and Toxic Substances</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:319.95pt;top:90.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">(7101)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:472.45pt;top:72.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">EPA 740-C-09-002</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:491.60pt;top:81.35pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">October 2009</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:182.05pt;top:113.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 34.02pt">Endocrine Disruptor</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:182.05pt;top:152.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 34.02pt">Screening Program</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:182.05pt;top:191.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 34.02pt">Test Guidelines</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:102pt;width:478pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:182.05pt;top:240.10pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 34.02pt">OPPTS 890.1100:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:182.05pt;top:279.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 34.02pt">Amphibian</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:182.05pt;top:318.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 34.02pt">Metamorphosis (Frog)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:290.10pt;top:744.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 1</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:0.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile562637297.htm_files\outputfile562637297_background0.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:792.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:285.25pt;top:891.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">NOTICE</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:916.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">This guideline is one of a series of test guidelines established by the Office of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:929.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">Prevention, Pesticides and Toxic Substances (OPPTS), United States Environmental Protection</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:941.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">Agency for use in testing pesticides and chemical substances to develop data for submission to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:954.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">the Agency under the Toxic Substances Control Act (TSCA) (15 U.S.C. 2601, </FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 10.98pt">et seq.</FONT></i><FONT STYLE="font-size: 10.98pt">), the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:967.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) (7 U.S.C. 136, </FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 10.98pt">et seq.</FONT></i><FONT STYLE="font-size: 10.98pt">), and section</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:979.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">408 of the Federal Food, Drug and Cosmetic (FFDCA) (21 U.S.C. 346a).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1005.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">The OPPTS test guidelines serve as a compendium of accepted scientific</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1017.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">methodologies and protocols that are intended to provide data to inform regulatory decisions</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1030.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">under TSCA, FIFRA, and/or FFDCA.  This document provides guidance for conducting the test,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1043.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">and is also used by EPA, the public, and the companies that are subject to data submission</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1055.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">requirements under TSCA, FIFRA and/or the FFDCA.  As a guidance document, these</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1068.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">guidelines are not binding on either EPA or any outside parties, and the EPA may depart from</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1080.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">the guidelines where circumstances warrant and without prior notice.  The procedures contained</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1093.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">in this guideline are strongly recommended for generating the data that are the subject of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1106.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">guideline, but EPA recognizes that departures may be appropriate in specific situations. You</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1118.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">may propose alternatives to the recommendations described in these guidelines, and the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1131.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">Agency will assess them for appropriateness on a case-by-case basis.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1156.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">For additional information about OPPTS harmonized test guidelines and to access the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1169.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">guidelines electronically, please go to </FONT></FONT><FONT COLOR="0000ff"><FONT STYLE="font-size: 10.98pt">http://www.epa.gov/oppts </FONT></FONT><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">and select “Test Methods &</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1182.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">Guidelines” on the left side navigation menu.  You may also access the guidelines in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1194.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><u><i><FONT COLOR="0000ff"><FONT STYLE="font-size: 10.98pt">http://www.regulations.gov </FONT></FONT></i></u><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">grouped by Series under Docket ID #s: EPA-HQ-OPPT-2009-0150</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1207.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">through EPA-HQ-OPPT-2009-0159, and EPA-HQ-OPPT-2009-0576.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:877pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:877pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:877pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:878pt;width: 1pt;height:367pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:1245pt;width:478pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:878pt;width: 1pt;height:367pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:1245pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;left:71.76pt;top:1584.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1656.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">OPPTS 890.1100:  Amphibian Metamorphosis (Frog).</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:1683.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(a)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1683.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Scope</FONT></b><FONT STYLE="font-size: 12.00pt">.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1711.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(1)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:143.95pt;top:1711.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Applicability. </FONT></b><FONT STYLE="font-size: 12.00pt">This guideline is intended to meet testing requirements of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1725.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the Toxic Substances Control Act (TSCA) (15 U.S.C. 2601, </FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">et seq.</FONT></i><FONT STYLE="font-size: 12.00pt">), the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1739.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) (7 U.S.C.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1752.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">136, </FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">et seq.</FONT></i><FONT STYLE="font-size: 12.00pt">), and the Federal Food, Drug, and Cosmetic Act (FFDCA) (21</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1766.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">U.S.C. 346a).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:1794.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(2)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1794.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Background. </FONT></b><FONT STYLE="font-size: 12.00pt">The Endocrine Disruptor Screening Program (EDSP)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1808.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">reflects a two-tiered approach to implement the statutory testing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1821.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">requirements of FFDCA section 408(p) (21 U.S.C. 346a).  In general, EPA</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1835.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">intends to use the data collected under the EDSP, along with other</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1849.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">information, to determine if a pesticide chemical, or other substances, may</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1863.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">pose a risk to human health or the environment due to disruption of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1877.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">endocrine system.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1904.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">This test guideline is intended to be used in conjunction with other</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1918.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">guidelines in the OPPTS 890 series that make up the full screening</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1932.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">battery under the EDSP to identify substances that have the potential to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1946.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">interact with the estrogen, androgen, or thyroid hormone (Tier 1</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1959.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">“screening”).  The determination will be made on a weight-of-evidence</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1973.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">basis taking into account data from the Tier 1 assays and other</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:1987.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">scientifically relevant information available.  The fact that a substance may</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2001.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">interact with a hormone system, however, does not mean that when the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2015.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">substance is used, it will cause adverse effects in humans or ecological</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2028.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">systems.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2056.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Chemicals that go through Tier 1 screening and are found to have the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2070.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">potential to interact with the estrogen, androgen, or thyroid hormone</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2084.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">systems will proceed to the next stage of the EDSP where EPA will</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2097.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">determine which, if any, of the Tier 2 tests are necessary based on the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2111.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">available data.  Tier 2 testing is designed to identify any adverse</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2125.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">endocrine-related effects caused by the substance, and establish a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2139.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">quantitative relationship between the dose and that endocrine effect.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2166.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(3)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2166.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Source. </FONT></b><FONT STYLE="font-size: 12.00pt">OPPTS developed this guideline through a process of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2180.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">harmonization with Test Guideline 231 published by the Organization for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2194.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Economic Cooperation and Development (OECD) (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 1</FONT></b><FONT STYLE="font-size: 12.00pt">).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2222.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(b)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2222.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Purpose. </FONT></b><FONT STYLE="font-size: 12.00pt">The Amphibian Metamorphosis Assay (AMA) is a screening assay</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2235.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">intended to empirically identify substances which may interfere with the normal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2249.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">function of the hypothalamic-pituitary-thyroid (HPT) axis.  The AMA represents a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2263.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">generalized vertebrate model to the extent that it is based on the conserved</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2277.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">structures and functions of the HPT axis.  It is an important assay because</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2291.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">amphibian metamorphosis provides a well-studied, thyroid-dependent process</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:290.10pt;top:2328.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 3</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:2376.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2448.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">which responds to substances active within the HPT axis, and it is the only</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2462.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">existing assay that detects thyroid activity in an animal undergoing morphological</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2475.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">development.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2503.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(c)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:107.95pt;top:2503.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Introduction. </FONT></b><FONT STYLE="font-size: 12.00pt">The need to develop and validate an assay capable of detecting</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2517.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">substances active in the thyroid system of vertebrate species originates from</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2531.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">concerns that environmental levels of chemicals may cause adverse effects in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2544.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">both humans and wildlife.  The Amphibian Metamorphosis Assay (AMA)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2558.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">underwent an extensive validation program which included intra- and inter-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2572.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">laboratory studies demonstrating the relevance and reliability of the assay (</FONT></FONT><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Ref.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2586.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">2, Ref. 3</FONT></b><FONT STYLE="font-size: 12.00pt">).  Subsequently, the validation of the assay was subject to peer-review</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2600.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">by a panel of independent experts (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 4</FONT></b><FONT STYLE="font-size: 12.00pt">).  This Test guideline is the outcome of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2613.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the experience gained during the validation studies for the detection of thyroid</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2627.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">active substances</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2655.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(d)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2655.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">General Experimental Design</FONT><FONT COLOR="000000"><i></FONT><FONT STYLE="font-size: 12.00pt">. </FONT></i></b><FONT STYLE="font-size: 12.00pt">The general experimental design entails</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2669.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">exposing stage 51 </FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">Xenopus laevis </FONT></i><FONT STYLE="font-size: 12.00pt">tadpoles to a minimum of three different</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2682.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">concentrations of a test chemical and a dilution water control (and solvent</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2696.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">control, if necessary) for 21 days.  There are four replicates for each test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2710.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">treatment.  Larval density at test initiation is 20 tadpoles per test tank for all</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2724.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">treatment groups.  The observational endpoints are hind limb length, snout to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2738.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">vent length (SVL), developmental stage, wet weight, thyroid histology, and daily</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2751.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">observations of mortality.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:2779.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(e)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2779.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Description of the Method</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2807.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(1)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2807.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Test Species</FONT></b><FONT STYLE="font-size: 12.00pt">.  </FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">Xenopus laevis </FONT></i><FONT STYLE="font-size: 12.00pt">is routinely cultured in laboratories</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2820.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">worldwide and is easily obtainable through commercial suppliers.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2834.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Reproduction can be easily induced in this species throughout the year</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2848.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">using human chorionic gonadotropin (hCG) injections and the resultant</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2862.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">larvae can be routinely reared to selected developmental stages in large</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2876.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">numbers to permit the use of stage-specific test protocols.  It is preferred</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2889.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that larvae used in the assay are derived from in-house adults.  As an</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2903.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">alternative although this is not the preferred procedure, eggs or embryos</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2917.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">may be shipped to the laboratory performing the test and allowed to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2931.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">acclimate; the shipping of larval stages for use in the test is unacceptable.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:2958.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(2)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2958.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Equipment and Supplies. </FONT></b><FONT STYLE="font-size: 12.00pt">The following equipment and supplies are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:2972.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">needed for the conduct of this assay:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3000.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(i)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:3000.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Exposure system (see description below);</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3014.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(ii)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:3014.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Glass or stainless steel aquaria (see description below);</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3027.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(iii) Breeding tanks</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3041.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(iv)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:179.95pt;top:3041.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Temperature controlling apparatus (e.g., heaters or coolers</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:3055.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(adjustable to 22° ± 1°C));</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3069.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(v) Thermometer;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3083.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(vi)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:179.95pt;top:3083.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Binocular dissection microscope;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:290.10pt;top:3120.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 4</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:3168.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3240.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(vii)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:3240.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Digital camera with at least 4 megapixel resolution and micro</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:3254.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">function;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3267.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(ix)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.05pt;top:3267.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Image digitizing software;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3281.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(x)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:3281.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Petri dish (e.g. 100 x 15 mm) or transparent plastic chamber of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:3295.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">comparable size;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3309.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(xi)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.05pt;top:3309.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Analytical balance capable of measuring to 3 decimal places (mg);</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3323.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(xii)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.05pt;top:3323.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Dissolved oxygen meter;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3336.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(xiii) pH meter;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3350.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(xiv)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.05pt;top:3350.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Light intensity meter capable of measuring in lux units;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3364.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(xv) Miscellaneous laboratory glassware and tools;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3378.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(xvi)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:179.95pt;top:3378.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Adjustable pipetters (10 to 5,000 μL) or assorted pipettes of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:3392.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">equivalent sizes;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3405.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(xvii)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.05pt;top:3405.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Test chemical in sufficient quantities to conduct the study,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:3419.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">preferably of one lot #; and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3433.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(xviii)  Analytical instrumentation appropriate for the chemical on test or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:3447.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">contracted analytical services.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3474.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(3)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3474.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Chemical Testability. </FONT></b><FONT STYLE="font-size: 12.00pt">The AMA is based upon an aqueous exposure</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3488.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">protocol whereby test chemical is introduced into the test chambers via a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3502.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">flow-through system.  Flow-through methods however, introduce</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3516.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">constraints on the types of chemicals that can be tested, as determined by</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3530.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the physicochemical properties of the compound.  Therefore, prior to using</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3543.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">this protocol, baseline information about the chemical should be obtained</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3557.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that is relevant to determining the testability, and the OECD Guidance</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3571.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Document on Aquatic Toxicity Testing of Difficult Substances and Mixtures</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3585.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should be consulted (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 5</FONT></b><FONT STYLE="font-size: 12.00pt">).  Characteristics which indicate that the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3599.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">chemical may be difficult to test in aquatic systems include: high octanol</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3612.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">water partitioning coefficients (log K</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:333.35pt;top:3617.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">ow</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:343.55pt;top:3612.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">), high volatility, susceptibility to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3626.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">hydrolysis, and susceptibility to photolysis under ambient laboratory</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3640.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">lighting conditions.  Other factors may also be relevant to determining</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3654.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">testability and should be determined on a case by case basis.  If a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3668.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">successful test is not possible for the chemical using a flow-through test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3681.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">system, a static renewal system may be employed.  If neither system is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3695.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">capable of accommodating the test chemical, then the default is to not test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3709.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">it using this protocol.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:3737.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(4)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3737.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Exposure System.  </FONT></b><FONT STYLE="font-size: 12.00pt">A flow-through diluter system is preferred, when</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3750.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">possible, over a static renewal system.  If physical and/or chemical</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3764.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">properties of any of the test substances are not amenable to a flow-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3778.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">through diluter system, then an alternative exposure system (e.g., static-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3792.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">renewal) can be employed.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3819.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The system components should have water-contact components of glass,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3833.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stainless steel, and/or Teflon®.  However, suitable plastics can be utilized</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3847.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">if they do not compromise the study.  Exposure tanks should be glass or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3861.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stainless steel aquaria, equipped with standpipes that result in an</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:3875.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">approximate tank volume between 4.0 and 10.0 L and minimum water</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:290.10pt;top:3912.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 5</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:3960.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4032.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">depth of 10 to 15 cm.  The system should be capable of supporting all</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4046.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">exposure concentrations and a control, with four replicates per treatment.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4059.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The flow rate to each tank should be held constant in consideration of both</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4073.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the maintenance of biological conditions and chemical exposure (e.g.  25</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4087.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">mL/min).  The treatment tanks should be randomly assigned to a position</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4101.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">in the exposure system in order to reduce potential positional effects,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4115.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">including slight variations in temperature, light intensity, etc.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4142.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Fluorescent lighting should be used to provide a photoperiod of 12 hr light:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4156.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">12 hr dark at an intensity that ranges from 600 to 2,000 lux (lumens/m ) at</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:514.20pt;top:4154.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">2</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4170.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the water surface.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4197.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Water temperature should be maintained at 22° ± 1°C, pH maintained</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4211.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">between 6.5 to 8.5, and the dissolved oxygen (DO) concentration > 3.5</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4225.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">mg/L (> 40% of the air saturation) in each test tank.  As a minimum water</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4239.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">temperature, pH and dissolved oxygen should be measured weekly;</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4253.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">temperature should preferably be measured continuously in at least one</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4266.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">test vessel. Total hardness and alkalinity should be measured in the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4280.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">control vessels and one vessel at the highest concentration at least once</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4294.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">per week.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4322.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Appendix 1 outlines the experimental conditions under which the protocol</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4335.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should be executed.  For further information on setting up flow-through</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4349.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">exposure systems and/or static renewal systems, please refer to the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4363.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">ASTM Standard Guide for Conducting Acute Toxicity Tests on Test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4377.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Materials with Fishes, Macroinvertebrates, and Amphibians (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 6</FONT></b><FONT STYLE="font-size: 12.00pt">) and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4391.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">general aquatic toxicology texts.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4418.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(i)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4418.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Water quality. </FONT></b><FONT STYLE="font-size: 12.00pt">Any water that is locally available (</FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">e.g. </FONT></i><FONT STYLE="font-size: 12.00pt">springwater</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4432.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">or charcoal-filtered tap water) and permits normal growth and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4446.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">development of </FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">X. laevis </FONT></i><FONT STYLE="font-size: 12.00pt">tadpoles could be used. Because local</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4460.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">water quality can differ substantially from one area to another,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4473.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">analysis of water quality should be undertaken, particularly, if</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4487.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">historical data on the utility of the water for raising </FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">Xenopus </FONT></i><FONT STYLE="font-size: 12.00pt">is not</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4501.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">available.  Special attention should be given that the water is free of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4515.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">copper, chlorine and chloramines, all of which are toxic to frogs and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4529.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">tadpoles. It is further recommended to analyze the water</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4542.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">concerning background levels of fluoride, perchlorate and chlorate</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4556.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(by-product of drinking water disinfection) as all of these anions are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4570.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">substrates of the iodine transporter of the thyroid gland and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4584.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">elevated levels of each of these anions may confound the study</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4598.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">outcome. Analysis should be performed before testing begins and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4611.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the testing water should normally be free from these anions.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:4639.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(ii)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4639.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Iodide Concentration in Test Water. </FONT></b><FONT STYLE="font-size: 12.00pt">In order for the thyroid gland</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4653.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to synthesize TH, sufficient iodide needs to be available to the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4667.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">larvae through a combination of aqueous and dietary sources.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:290.10pt;top:4704.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 6</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:4752.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4824.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Currently, there are no empirically derived guidelines for minimal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4838.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">iodide concentrations.  However, iodide availability may affect the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4851.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">responsiveness of the thyroid system to thyroid active agents and is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4865.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">known to modulate the basal activity of the thyroid gland, an aspect</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4879.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that deserves attention when interpreting the results from thyroid</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4893.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">histopathology.  Likewise, excessive iodide concentrations could</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4907.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">potentially mask the effects of thyroid active substances.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4920.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Therefore, measured aqueous iodide concentrations from the test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4934.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">water should be reported.  Based on the available data from the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4948.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">validation studies, the protocol has been demonstrated to work well</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4962.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">when test water iodide (I ) concentrations ranged between 0.5 and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:310.10pt;top:4960.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4976.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">10µg/L.  Ideally, the minimum iodide concentration in the test water</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:4989.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should be 0.5μg/L.  If the test water is reconstituted from deionized</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5003.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">water, iodine must be added at a minimum concentration of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5017.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">0.5μg/L.  Iodide supplementation is only needed if the concentration</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5031.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">is naturally below 0.5 μg/L in the test water; then, the iodide</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5045.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">supplementation should not exceed 2 μg/L.  Any supplementation</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5058.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of the test water with iodine or other salts must be noted in the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5072.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">report.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:5100.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(5)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5100.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Holding of Animals.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5127.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(i)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5127.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Adult Care and Breeding. </FONT></b><FONT STYLE="font-size: 12.00pt">Adult care and breeding is conducted</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5141.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">in accordance with standard guidelines (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 7</FONT></b><FONT STYLE="font-size: 12.00pt">) and the reader is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5155.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">directed to the standard guide for performing FETAX for more</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5169.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">detailed information.  Such standard guidelines provide an example</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5183.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of appropriate care and breeding methods, but strict adherence is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5196.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">not required.  To induce breeding, pairs (3-5) of adult females and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5210.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">males are injected with human chorionic gonadotropin (hCG).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5224.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Female and male specimens are injected with approximately 800</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5238.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">IU-1000 IU and 600 IU-800 IU, respectively, of hCG dissolved in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5252.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">0.6-0.9% saline solution.  Breeding pairs are held in large tanks,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5265.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">undisturbed and under static conditions to promote amplexus.  The</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5279.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">bottom of each breeding tank should have a false bottom of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5293.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stainless steel or plastic mesh which permits the egg masses to fall</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5307.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to the bottom of the tank.  Frogs injected in the late afternoon will</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5321.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">usually deposit most of their eggs by mid morning of the next day.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5334.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">After a sufficient quantity of eggs are released and fertilized, adults</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5348.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should be removed from the breeding tanks.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:5376.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(ii)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5376.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Larval Care and Selection.  </FONT></b><FONT STYLE="font-size: 12.00pt">After the adults are removed from the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5390.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">breeding tanks, the eggs are collected and evaluated for viability</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5403.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">using a representative sub-set of the embryos from all breeding</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5417.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">tanks.  The best individual spawn(s) (2-3 recommended to evaluate</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5431.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the quality of the spawns) should be retained based upon embryo</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5445.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">viability and the presence of an adequate number (minimum of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5459.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1500) of embryos.  All the organisms used in a study must originate</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:290.10pt;top:5496.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 7</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:5544.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5616.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">from a single spawning event (</FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">i.e.</FONT></i><FONT STYLE="font-size: 12.00pt">, the spawns should not be co-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5630.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">mixed).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5657.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The embryos are transferred into a large flat pan or dish and all</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5671.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">obvious dead or abnormal eggs (see definition in (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 6</FONT></b><FONT STYLE="font-size: 12.00pt">)) are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5685.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">removed using a pipette or eyedropper.  The sound embryos from</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5699.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">each of the three spawns are transferred into three separate</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5712.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">hatching tanks.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5740.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Four days after being placed in the hatching tanks, the best spawn,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5754.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">based on viability and hatching success, is selected and the larvae</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5768.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">are transferred into an appropriate number of rearing tanks at 22°</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5781.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">±1°C.  In addition, some additional larvae are moved into extra</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5795.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">tanks for use as replacements in the event that mortalities occur in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5809.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the rearing tanks during the first week.  This procedure maintains</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5823.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">consistent organism density and thereby reduces developmental</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5837.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">divergence within the cohort of a single spawn.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5864.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">All rearing tanks should be siphoned clean daily. As a precaution,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5878.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">vinyl or nitrile gloves are preferred to latex gloves.  Mortalities</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5892.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should be removed daily and replacement larvae should be added</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5906.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">back to maintain the organism density during the first week.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5919.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Feeding must occur at least twice per day.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5947.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">During the pre-exposure phase, tadpoles are acclimated to the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5961.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">conditions of the actual exposure phase including; the type of food,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5975.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">temperature, light-dark cycle, and the culture medium.  Therefore, it</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:5988.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">is recommended that the same culture/dilution water be used</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6002.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">during the pre-exposure phase and the exposure phase.  If a static</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6016.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">culture system is used for maintaining tadpoles during the pre-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6030.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">exposure phase, the culture medium should be replaced completely</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6044.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">at least twice per week.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6071.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Crowding, caused by high larval densities during the pre-exposure</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6085.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">period, should be avoided because such effects could markedly</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6099.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">affect tadpole development during the subsequent testing phase.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6113.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Therefore, the rearing density should not exceed approximately</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6126.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">four tadpoles/L culture medium (static exposure system) or 10</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6140.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">tadpoles/L culture medium (with </FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">e.g. </FONT></i><FONT STYLE="font-size: 12.00pt">50 mL/min flow rate in the pre-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6154.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">exposure or culturing system).  Under these conditions, tadpoles</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6168.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should develop from stages 45/46 to stage 51 within twelve days.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6195.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Representative tadpoles of this stock population should be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6209.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">inspected daily for developmental stage in order to estimate the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6223.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">appropriate time point for initiation of exposure.  Care should be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6237.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">used to minimize stress and trauma to the tadpoles, especially</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6251.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">during movement, cleaning of aquaria, and manipulation of larvae.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:290.10pt;top:6288.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 8</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:6336.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6408.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Stressful conditions/activities should be avoided such as loud</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6422.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and/or incessant noise, tapping on aquaria, vibrations in the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6435.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">aquaria, excessive activity in the laboratory, and rapid changes in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6449.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">environmental media (light availability, temperature, pH, DO, water</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6463.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">flow rates, etc.)  If tadpoles do not develop to stage 51 within 17</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6477.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">days after fertilization, excessive stress should be considered as a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6491.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">potential culprit.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:6518.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(iii)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6518.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Larval Culture and Feeding. </FONT></b><FONT STYLE="font-size: 12.00pt">Tadpoles are fed with Sera Micron®</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6532.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(Sera GmbH, Heinsberg, Germany) throughout the pre-exposure</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6546.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">period (after NF stage 45/46) and during the entire test period of 21</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6560.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">days, or other diet that has demonstrated to allow equal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6573.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">performance of tadpoles within the AMA when using Sera Micron®.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6587.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The feeding regime during the pre-exposure period should be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6601.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">carefully adjusted to meet the demands of the developing tadpoles.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6615.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">That is, small portions of food should be provided to the newly</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6629.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">hatched tadpoles several times per day (at least twice).  Excess</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6642.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">food should be avoided i) to maintain water quality and ii) to prevent</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6656.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the clogging of gill filters with food particles and detritus.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6684.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">For Sera Micron®, the daily food rations should be increased along</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6698.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">with tadpole growth to approximately 30 mg/animal/day shortly</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6711.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">before test initiation.  Sera Micron®, a commercially available</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6725.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">tadpole food that has been shown in the validation studies to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6739.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">support proper growth and development of </FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">X. laevis </FONT></i><FONT STYLE="font-size: 12.00pt">tadpoles, is a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6753.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">fine particulate that stays suspended in the water column for a long</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6767.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">period of time and is subject to washing out with the flow.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6780.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Therefore, the total daily amount of food should be divided into</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6794.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">smaller portions and fed at least twice daily.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6822.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">For Sera Micron®, the feeding regime is outlined in Table 1.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6836.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Feeding rates must be recorded.  Sera Micron® can be fed dry or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6849.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">as a stock solution prepared in dilution water.  Such a stock</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6863.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">solution should be freshly prepared every other day and stored at</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:6877.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">4°C when not in use.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6905.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Table 1. </FONT></b><FONT STYLE="font-size: 12.00pt">Feeding Regime for </FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">X. laevis </FONT></i><FONT STYLE="font-size: 12.00pt">Tadpoles During the In-life Portion of the AMA in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:6918.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Flow-through Conditions.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:139.40pt;top:6939.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Study Day</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:306.25pt;top:6939.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Food ration (mg Sera Micron/animal/day)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:6932pt;width:194pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:67pt;top:6933pt;width:193pt;height: 1pt;background-color:#dbe4f0;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:261pt;top:6932pt;width:283pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:261pt;top:6933pt;width:283pt;height: 1pt;background-color:#dbe4f0;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:544pt;top:6932pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:156.55pt;top:6958.35pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">0-4 30</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:67pt;top:6955pt;width:193pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:261pt;top:6955pt;width:283pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:156.55pt;top:6972.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">5-7 40</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:67pt;top:6969pt;width:193pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:261pt;top:6969pt;width:283pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:153.70pt;top:6985.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">8-10 50</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:67pt;top:6983pt;width:193pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:261pt;top:6983pt;width:283pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:150.95pt;top:6999.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">11-14 70</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:67pt;top:6997pt;width:193pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:261pt;top:6997pt;width:283pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:150.95pt;top:7013.35pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">15-21 80</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:67pt;top:7010pt;width:193pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:261pt;top:7010pt;width:283pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:7024pt;width:194pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:261pt;top:7024pt;width:283pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:544pt;top:7024pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:290.10pt;top:7080.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 9</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:6336.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile562637297.htm_files\outputfile562637297_background8.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:7128.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:7200.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(6)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7200.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Analytical Chemistry. </FONT></b><FONT STYLE="font-size: 12.00pt">Prior to conducting a study, the stability of the test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7214.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">compound should be evaluated using existing information on its solubility,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7227.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">degradability, and volatility.  Test solutions from each replicate tank at</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7241.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">each concentration should be sampled for analytical chemistry analyses at</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7255.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">test initiation (day 0), and weekly during the test for a minimum of four</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7269.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">samples.  It is recommended that each test concentration be analyzed</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7283.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">during system preparation, prior to test initiation, to verify system</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7296.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">performance.  In addition, it is recommended that stock solutions be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7310.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">analyzed when they are changed, especially if the volume of the stock</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7324.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">solution does not provide adequate amounts of chemical to span the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7338.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">duration of routine sampling periods.  In the case of chemicals which</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7352.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">cannot be detected at some or all of the concentrations used in a test,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7365.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stock solutions should be measured and system flow rates recorded to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7379.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">calculate actual concentrations.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:7407.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(7)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7407.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Chemical Delivery. </FONT></b><FONT STYLE="font-size: 12.00pt">The method used to introduce the test chemical to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7421.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the system can vary depending on its physicochemical properties. Water</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7434.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">soluble compounds can be dissolved in aliquots of test water at a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7448.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">concentration which allows delivery at the target test concentration in a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7462.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">flow-through system.  Chemicals which are liquid at room temperature and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7476.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sparingly soluble in water can be introduced using liquid:liquid saturator</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7490.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">methods. (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 8</FONT></b><FONT STYLE="font-size: 12.00pt">)  Chemicals which are solid at room temperature and are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7503.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sparingly soluble in water can be introduced using glass wool column</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7517.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">saturators (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 8</FONT></b><FONT STYLE="font-size: 12.00pt">).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7545.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The preference is to use a carrier-free test system, however different test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7559.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">chemicals will possess varied physicochemical properties that will likely</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7572.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">require different approaches for preparation of chemical exposure water.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7586.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">It is preferred that effort be made to avoid solvents or carriers because: i)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7600.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">certain solvents themselves may result in toxicity and/or undesirable or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7614.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">unexpected endocrinological responses, ii) testing chemicals above their</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7628.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">water solubility (as can frequently occur through the use of solvents) can</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7641.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">result in inaccurate determinations of effective concentrations, and iii) the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7655.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">use of solvents in longer-term tests can result in a significant degree of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7669.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">“biofilming” associated with microbial activity.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7697.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">For difficult to test substances, a solvent may be employed as a last</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7710.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">resort, and the OECD Guidance Document on aquatic toxicity testing of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7724.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">difficult substances and mixtures should be consulted (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 5</FONT></b><FONT STYLE="font-size: 12.00pt">) to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7738.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">determine the best method.  The choice of solvent will be determined by</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7752.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the chemical properties of the substance.  Solvents which have been</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7766.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">found to be effective for aquatic toxicity testing include acetone, ethanol,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7779.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">methanol, dimethyl formamide and triethylene glycol.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7807.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In case a solvent carrier is used, solvent concentrations should be below</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7821.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the chronic No Observed Effect Concentration (NOEC); the OECD</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7835.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guidance Document recommends a maximum of 100µl/L; a recent review</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:7872.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 10</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:7920.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:7992.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">recommends that solvent concentrations as low as 20µl/L of dilution water</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:8006.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">be used (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 13</FONT></b><FONT STYLE="font-size: 12.00pt">).  If solvent carriers are used, appropriate solvent</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:8019.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">controls (clean water) must be evaluated in addition to non-solvent</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:8033.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">controls.  If it is not possible to administer a chemical via the water, either</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:8047.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">because of physicochemical characteristics (low solubility) or limited</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:8061.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">chemical availability, introducing it via the diet may be considered.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:8075.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Preliminary work has been conducted on dietary exposures; however, this</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:8088.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">route of exposure is not commonly used. The choice of method should be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:8102.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">documented and analytically verified.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:8130.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(8)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:8130.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Selection of Test Concentrations</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:8157.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(i)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8157.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Establishing the High Test Concentration. </FONT></b><FONT STYLE="font-size: 12.00pt">For the purposes of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8171.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">this test, the high test concentration should be set by the solubility</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8185.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">limit of the test substance; the maximum tolerated concentration</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8199.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(MTC) for acutely toxic chemicals; or 100 mg/L, whichever is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8213.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">lowest.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8240.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The MTC is defined as the highest test concentration of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8254.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">chemical which results in less than 10% acute mortality.  Using this</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8268.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">approach assumes that there are existing empirical acute mortality</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8282.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">data from which the MTC can be estimated.  Estimating the MTC</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8295.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">can be inexact and typically requires some professional judgment.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8309.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Although the use of regression models may be the most technically</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8323.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sound approach to estimating the MTC, a useful approximation of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8337.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the MTC can be derived from existing acute data by using 1/3 of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8351.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the acute LC</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:248.05pt;top:8356.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">50</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:260.20pt;top:8351.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">value.  However, acute toxicity data may be lacking</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8364.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">for the species on test.  If species specific acute toxicity data are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8378.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">not available, then a 96-hour LC</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:350.75pt;top:8383.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">50</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:362.95pt;top:8378.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">test can be completed with</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8392.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">tadpoles that are representative (</FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">i.e.</FONT></i><FONT STYLE="font-size: 12.00pt">, same stage) of those on test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8406.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">in the AMA.  Optionally, if data from other aquatic species are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8420.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">available (</FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">e.g. </FONT></i><FONT STYLE="font-size: 12.00pt">LC</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:273.40pt;top:8425.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">50</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:285.60pt;top:8420.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">studies in fish or other amphibian species), then</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8433.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">professional judgment may be used to estimate a likely MTC based</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8447.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">on inter-species extrapolation.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8475.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Alternatively, if the chemical is not acutely toxic and is soluble</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8489.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">above 100 mg/L, then 100 mg/L should be considered the highest</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8502.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">test concentration (HTC), as this concentration is typically</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8516.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">considered “practically non-toxic.”</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8544.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Although not the recommended procedure, static renewal methods</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8558.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">may be used where flow-through methods are inadequate to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8571.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">achieve the MTC.  If static renewal methods are used, then the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8585.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stability of the test chemical concentration must be documented</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8599.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and remain within the performance criteria limits.  Twenty-four hour</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8613.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">renewal periods are recommended. Renewal periods exceeding 72</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8627.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">hours are not acceptable.  Additionally, water quality parameters</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:8664.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 11</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:8712.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8784.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(</FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">e.g. </FONT></i><FONT STYLE="font-size: 12.00pt">DO, temperature, pH, etc.) must be measured at the end of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8798.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">each renewal period, immediately prior to renewal.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:8825.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(ii)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8825.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Test Concentration Range. </FONT></b><FONT STYLE="font-size: 12.00pt">There is a required minimum of three</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8839.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">test concentrations and a clean water control (and vehicle control if</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8853.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">necessary). The minimum test concentration differential between</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8867.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the highest and lowest should be about one order of magnitude.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8880.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The maximum dose separation is 0.1 and the minimum is 0.33.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:8908.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(f)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:8908.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Procedure.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:8936.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(1)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:8936.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Test Initiation and Conduct.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:8963.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(i)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8963.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Day 0. </FONT></b><FONT STYLE="font-size: 12.00pt">The exposure should be initiated when a sufficient number</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8977.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of tadpoles in the pre-exposure stock population have reached</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:8991.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">developmental stage 51, according to Nieuwkoop and Faber (</FONT></FONT><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Ref</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9005.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">9</FONT></b><FONT STYLE="font-size: 12.00pt">), and which are less than or equal to 17 days of age post</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9018.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">fertilization.  For selection of test animals, healthy and normal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9032.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">looking tadpoles of the stock population should be pooled in a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9046.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">single vessel containing an appropriate volume of dilution water.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9060.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">For developmental stage determination, tadpoles should be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9074.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">individually removed from the pooling tank using a small net or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9087.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">strainer and transferred to a transparent measurement chamber</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9101.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(</FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">e.g.</FONT></i><FONT STYLE="font-size: 12.00pt">, 100 mm Petri dish) containing dilution water.  For stage</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9115.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">determination, it is preferred not to use anesthesia, however one</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9129.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">may individually anesthetize the tadpoles using 100 mg/L tricaine</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9143.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">methanesulfonate (</FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">e.g. </FONT></i><FONT STYLE="font-size: 12.00pt">MS-222), appropriately buffered with</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9156.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sodium bicarbonate (pH 7.0), before handling.  If used,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9170.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">methodology for appropriately using MS-222 for anesthesia should</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9184.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">be obtained from experienced laboratories and reported with the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9198.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">test results.  Animals should be carefully handled during this</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9212.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">transfer to minimize handling stress and to avoid any injury.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9239.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The developmental stage of the animals is determined using a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9253.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">binocular dissection microscope.  To reduce the ultimate variability</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9267.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">in developmental stage, it is important that this staging be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9281.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">conducted as accurately as possible.  According to Nieuwkoop and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9294.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Faber (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 9</FONT></b><FONT STYLE="font-size: 12.00pt">), the primary developmental landmark for selecting</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9308.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stage 51 organisms is hind limb morphology.  The morphological</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9322.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">characteristics of the hind limbs should be examined under the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9336.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">microscope.  While the complete Nieuwkoop and Faber (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 9</FONT></b><FONT STYLE="font-size: 12.00pt">)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9350.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">guide should be consulted for comprehensive information on</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9363.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">staging tadpoles, one can reliably determine stage using prominent</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9377.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">morphological landmarks.  The following table can be used to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9391.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">simplify and standardize the staging process throughout the study</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9405.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">by identifying those prominent morphological landmarks associated</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9419.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">with different stages, assuming that development is normal.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:9456.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 12</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:9504.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:9576.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Table 2. </FONT></b><FONT STYLE="font-size: 12.00pt">Prominent Morphological Staging Landmarks Based on N&F Guidance.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:319.20pt;top:9590.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Developmental Stage</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:9589pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:9589pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:9589pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:9590pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:194pt;top:9590pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:9590pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:105.65pt;top:9590.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Prominent</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:96.25pt;top:9602.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Morphological</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:103.70pt;top:9613.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Landmarks</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:199.60pt;top:9613.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">51</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:221.60pt;top:9613.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">52</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:243.50pt;top:9613.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">53</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:265.45pt;top:9613.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">54</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.40pt;top:9613.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">55</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:309.35pt;top:9613.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">56</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:331.30pt;top:9613.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">57</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:353.30pt;top:9613.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">58</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:375.20pt;top:9613.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">59</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:397.15pt;top:9613.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">60</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:419.10pt;top:9613.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">61</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:441.05pt;top:9613.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">62</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:463.00pt;top:9613.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">63</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:485.00pt;top:9613.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">64</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:506.90pt;top:9613.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">65</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:528.85pt;top:9613.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">66</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:9601pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:194pt;top:9601pt;width:351pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:9602pt;width: 1pt;height:22pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:194pt;top:9602pt;width: 1pt;height:22pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:215pt;top:9602pt;width: 1pt;height:22pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:237pt;top:9602pt;width: 1pt;height:22pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:259pt;top:9602pt;width: 1pt;height:22pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:281pt;top:9602pt;width: 1pt;height:22pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:303pt;top:9602pt;width: 1pt;height:22pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:325pt;top:9602pt;width: 1pt;height:22pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:347pt;top:9602pt;width: 1pt;height:22pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:369pt;top:9602pt;width: 1pt;height:22pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:9602pt;width: 1pt;height:22pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:413pt;top:9602pt;width: 1pt;height:22pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:435pt;top:9602pt;width: 1pt;height:22pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:457pt;top:9602pt;width: 1pt;height:22pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:479pt;top:9602pt;width: 1pt;height:22pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:501pt;top:9602pt;width: 1pt;height:22pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:523pt;top:9602pt;width: 1pt;height:22pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:9602pt;width: 1pt;height:22pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:110.95pt;top:9625.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Hindlimb</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:201.75pt;top:9625.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">X X X X X X X</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:9624pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:9625pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:194pt;top:9625pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:215pt;top:9625pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:237pt;top:9625pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:259pt;top:9625pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:281pt;top:9625pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:303pt;top:9625pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:325pt;top:9625pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:347pt;top:9625pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:369pt;top:9625pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:9625pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:413pt;top:9625pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:435pt;top:9625pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:457pt;top:9625pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:479pt;top:9625pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:501pt;top:9625pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:523pt;top:9625pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:9625pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:110.95pt;top:9637.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Forelimb</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:311.50pt;top:9637.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">X X X X X</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:9636pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:9637pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:194pt;top:9637pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:215pt;top:9637pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:237pt;top:9637pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:259pt;top:9637pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:281pt;top:9637pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:303pt;top:9637pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:325pt;top:9637pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:347pt;top:9637pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:369pt;top:9637pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:9637pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:413pt;top:9637pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:435pt;top:9637pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:457pt;top:9637pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:479pt;top:9637pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:501pt;top:9637pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:523pt;top:9637pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:9637pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:83.10pt;top:9649.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Craniofacial structure</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:399.30pt;top:9649.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">X X X X</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:9648pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:9649pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:194pt;top:9649pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:215pt;top:9649pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:237pt;top:9649pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:259pt;top:9649pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:281pt;top:9649pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:303pt;top:9649pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:325pt;top:9649pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:347pt;top:9649pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:369pt;top:9649pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:9649pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:413pt;top:9649pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:435pt;top:9649pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:457pt;top:9649pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:479pt;top:9649pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:501pt;top:9649pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:523pt;top:9649pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:9649pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:96.50pt;top:9661.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Olfactory nerve</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:104.30pt;top:9672.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">morphology</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:421.35pt;top:9667.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">X</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:443.30pt;top:9667.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">X</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:465.25pt;top:9667.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">X</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:9660pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:9661pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:194pt;top:9661pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:215pt;top:9661pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:237pt;top:9661pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:259pt;top:9661pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:281pt;top:9661pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:303pt;top:9661pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:325pt;top:9661pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:347pt;top:9661pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:369pt;top:9661pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:9661pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:413pt;top:9661pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:435pt;top:9661pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:457pt;top:9661pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:479pt;top:9661pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:501pt;top:9661pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:523pt;top:9661pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:9661pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:9684.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Tail length</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:465.15pt;top:9684.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">X X X X</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:9684pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:9684pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:9696pt;width:127pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:194pt;top:9684pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:194pt;top:9696pt;width:21pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:215pt;top:9684pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:216pt;top:9696pt;width:21pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:237pt;top:9684pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:238pt;top:9696pt;width:21pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:259pt;top:9684pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:260pt;top:9696pt;width:21pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:281pt;top:9684pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:282pt;top:9696pt;width:21pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:303pt;top:9684pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:304pt;top:9696pt;width:21pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:325pt;top:9684pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:326pt;top:9696pt;width:21pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:347pt;top:9684pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:348pt;top:9696pt;width:21pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:369pt;top:9684pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:370pt;top:9696pt;width:21pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:391pt;top:9684pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:392pt;top:9696pt;width:21pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:413pt;top:9684pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:413pt;top:9696pt;width:21pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:435pt;top:9684pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:435pt;top:9696pt;width:21pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:457pt;top:9684pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:457pt;top:9696pt;width:21pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:479pt;top:9684pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:479pt;top:9696pt;width:21pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:501pt;top:9684pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:501pt;top:9696pt;width:21pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:523pt;top:9684pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:523pt;top:9696pt;width:21pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:9684pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:9696pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9710.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">For test initiation, all tadpoles must be at stage 51.  The most</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9724.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">prominent morphological staging landmark for that stage is hind</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:9738.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">limb morphology, which is demonstrated in Figure 1.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:9766.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Figure 1. </FONT></b><FONT STYLE="font-size: 12.00pt">Hind Limb Morphology of a Stage 51 Tadpole.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;background-color:#ffffff;position:absolute;left:72.00pt;top:9779.60pt;z-index:2;"><IMG WIDTH=976 HEIGHT=147 style="width:468pt;height:70pt;" SRC="outputfile562637297.htm_files\outputfile562637297_p1.jpg"></SPAN>
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<SPAN STYLE="color:#000000;background-color:#ffffff;position:absolute;left:72.00pt;top:9990.00pt;z-index:2;"><IMG WIDTH=976 HEIGHT=147 style="width:468pt;height:70pt;" SRC="outputfile562637297.htm_files\outputfile562637297_p4.jpg"></SPAN>
<SPAN STYLE="color:#000000;background-color:#ffffff;position:absolute;left:72.00pt;top:10060.15pt;z-index:2;"><IMG WIDTH=976 HEIGHT=146 style="width:468pt;height:69pt;" SRC="outputfile562637297.htm_files\outputfile562637297_p5.jpg"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10144.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In addition to the developmental stage selection, an optional size</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10157.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">selection of the experimental animals may be used.  For this</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10171.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">purpose, the whole body length (not SVL) should be measured at</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10185.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">day 0 for a sub-sample of approximately 20 NF stage 51 tadpoles.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10199.35pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">After calculation of the mean whole body length for this group of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10213.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">animals, minimum and maximum limits for the whole body length of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:10248.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 13</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:9504.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile562637297.htm_files\outputfile562637297_background12.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:10296.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10368.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">experimental animals can be set by allowing a range of the mean</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10382.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">value ± 3 mm (mean values of whole body length range between</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10395.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">24.0 and 28.1 mm for stage 51 tadpoles).  However, developmental</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10409.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">staging is the primary parameter in determining the readiness of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10423.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">each test animal. Tadpoles exhibiting grossly visible malformations</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10437.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">or injuries should be excluded from the assay.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10464.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Tadpoles that meet the stage criteria described above are held in a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10478.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">tank of clean culture water until the staging process is completed.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10492.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Once the staging is completed, the larvae are randomly distributed</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10506.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to exposure treatment tanks until each tank contains 20 larvae.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10520.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Each treatment tank is then inspected for animals with abnormal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10533.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">appearance (</FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">e.g.</FONT></i><FONT STYLE="font-size: 12.00pt">, injuries, abnormal swimming behavior, etc.).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10547.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Overtly unhealthy looking tadpoles should be removed from the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10561.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">treatment tanks and replaced with larvae newly selected from the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10575.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">pooling tank.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10602.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(ii)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10602.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Observations. </FONT></b><FONT STYLE="font-size: 12.00pt">For more in-depth information on test termination</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10616.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">procedures and processing of tadpoles, refer to the OECD</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10630.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guidance Document on Amphibian Thyroid Histology (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 10</FONT></b><FONT STYLE="font-size: 12.00pt">).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10658.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(iii)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10658.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Day 7 Measurements. </FONT></b><FONT STYLE="font-size: 12.00pt">On day 7, five randomly chosen tadpoles</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10671.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">per replicate are removed from each test tank.  The random</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10685.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">procedure used must give each organism on test equal probability</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10699.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of being selected.  This can be achieved by using any randomizing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10713.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">method but requires that each tadpole be netted.  Tadpoles not</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10727.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">selected are returned to the tank of origin and the selected tadpoles</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10740.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">are humanely euthanized in 150 to 200 mg/L MS-222, appropriately</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10754.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">buffered with sodium bicarbonate to achieve pH 7.0.  The</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10768.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">euthanized tadpoles are rinsed in water and blotted dry, followed by</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10782.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">body weight determination to the nearest milligram.  Hind limb</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10796.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">length, snout to vent length, and developmental stage (using a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10809.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">binocular dissection microscope) are determined for each tadpole.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:10837.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(iv)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10837.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Day 21 Measurements (Test Termination). </FONT></b><FONT STYLE="font-size: 12.00pt">At test termination</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10851.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(day 21), the remaining tadpoles are removed from the test tanks</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10865.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and humanely euthanized in 150 to 200 mg/L MS-222,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10878.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">appropriately buffered with sodium bicarbonate to pH 7.0, as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10892.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">above.  Tadpoles are rinsed in water and blotted dry, followed by</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10906.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">body weight determination to the nearest milligram.  Developmental</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10920.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stage, SVL, hind limb length and wet body weight are measured for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10934.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">each tadpole.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10961.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">All larvae are placed in Davidson’s fixative for 48 to 72 hours either</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10975.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">as whole body samples or as trimmed head tissue samples</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:10989.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">containing the lower jaw for histological assessments.  For</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11003.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">histopathology, a total of five tadpoles should be sampled from</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:11040.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 14</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:11088.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11160.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">each replicate tank.  Since follicular cell height is stage dependent</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11174.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 11</FONT></b><FONT STYLE="font-size: 12.00pt">), the most appropriate sampling approach for histological</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11187.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">analyses is to use stage-matched individuals, whenever possible.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11201.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In order to select stage-matched individuals, all larvae must first be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11215.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">staged prior to selection and subsequent processing for data</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11229.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">collection and preservation.  This is necessary because normal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11243.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">divergence in development will result in differential stage</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11256.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">distributions within each replicate tank.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11284.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Animals selected for histopathology (n=5 from each replicate)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11298.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should be matched to the median stage of the controls (pooled</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11312.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">replicates) whenever possible.  If there are replicate tanks with</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11325.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">more than five larvae at the appropriate stage, then five larvae are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11339.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">randomly selected.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11367.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">If there are replicate tanks with fewer than five larvae at the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11381.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">appropriate stage, then randomly selected individuals from the next</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11394.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">lower or upper developmental stage should be sampled to reach a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11408.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">total sample size of five larvae per replicate.  Preferably, the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11422.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">decision to sample additional larvae from either the next lower or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11436.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">upper developmental stage should be made based on an overall</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11450.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">evaluation of the stage distribution in the control and chemical</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11463.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">treatments.  That is, if the chemical treatment is associated with a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11477.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">retardation of development, than additional larvae should be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11491.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sampled from the next lower stage. In turn, if the chemical</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11505.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">treatment is associated with an acceleration of development, then</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11519.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">additional larvae should be sampled from the next upper stage.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11546.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In cases of severe alterations of tadpole development due to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11560.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">treatment with a test chemical, there might be no overlap of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11574.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stage distribution in the chemical treatments with the calculated</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11588.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">control median developmental stage. In only these cases, the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11601.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">selection process should be modified by using a stage different</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11615.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">from the control median stage to achieve a stage-matched</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11629.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sampling of larvae for thyroid histopathology.  Furthermore, if</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11643.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stages are indeterminate (</FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">i.e.</FONT></i><FONT STYLE="font-size: 12.00pt">, asynchrony), then 5 tadpoles from</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11657.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">each replicate should be randomly chosen for histological analysis.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11670.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The rationale underlying sampling of any larvae that are not at a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11684.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stage equivalent to the control median developmental stage should</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:11698.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">be reported.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:11726.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(2)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11726.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Determination of Biological Endpoints. </FONT></b><FONT STYLE="font-size: 12.00pt">During the 21 day exposure</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11739.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">phase, measurement of primary endpoints is performed on days 7 and 21,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11753.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">however daily observation of test animals is necessary.  Table 3 provides</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11767.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">an overview of the measurement endpoints and the corresponding</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11781.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">observation time points.  More detailed information for technical</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11795.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">procedures for measurement of apical endpoints and histological</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:11832.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 15</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:11880.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11952.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">assessments is available in the OECD Guidance Document on Amphibian</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:11966.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Thyroid Histopathology (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 10</FONT></b><FONT STYLE="font-size: 12.00pt">).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:11993.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Table 3. </FONT></b><FONT STYLE="font-size: 12.00pt">Observation Time Points for Primary Endpoints in the AMA.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:139.30pt;top:12014.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Apical Endpoints</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:321.65pt;top:12014.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Daily</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:402.90pt;top:12014.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Day 7</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:486.25pt;top:12014.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Day 21</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:12009pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:12009pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:12009pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:12010pt;width: 1pt;height:17pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:293pt;top:12010pt;width: 1pt;height:17pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:372pt;top:12010pt;width: 1pt;height:17pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:459pt;top:12010pt;width: 1pt;height:17pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:12010pt;width: 1pt;height:17pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:94.50pt;top:12030.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Mortality</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:330.55pt;top:12030.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">●</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:12027pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:12028pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:293pt;top:12028pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:372pt;top:12028pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:459pt;top:12028pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:12028pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:94.50pt;top:12046.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Developmental Stage</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:413.20pt;top:12046.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">●</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:499.30pt;top:12046.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">●</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:12043pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:12044pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:293pt;top:12044pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:372pt;top:12044pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:459pt;top:12044pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:12044pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:94.50pt;top:12062.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Hind Limb Length</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:413.20pt;top:12062.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">●</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:499.30pt;top:12062.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">●</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:12059pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:12060pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:293pt;top:12060pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:372pt;top:12060pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:459pt;top:12060pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:12060pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:94.50pt;top:12078.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Snout-Vent Length</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:413.20pt;top:12078.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">●</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:499.30pt;top:12078.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">●</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:12075pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:12076pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:293pt;top:12076pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:372pt;top:12076pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:459pt;top:12076pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:12076pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:94.50pt;top:12094.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Wet Body Weight</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:413.20pt;top:12094.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">●</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:499.30pt;top:12094.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">●</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:12091pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:12092pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:293pt;top:12092pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:372pt;top:12092pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:459pt;top:12092pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:12092pt;width: 1pt;height:15pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:94.10pt;top:12110.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Thyroid Gland Histology</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:499.30pt;top:12110.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">●</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:12107pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:12108pt;width: 1pt;height:16pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:12123pt;width:227pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:293pt;top:12108pt;width: 1pt;height:16pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:294pt;top:12123pt;width:78pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:372pt;top:12108pt;width: 1pt;height:16pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:373pt;top:12123pt;width:85pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:459pt;top:12108pt;width: 1pt;height:16pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:459pt;top:12123pt;width:85pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:12108pt;width: 1pt;height:16pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:12123pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12138.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Developmental stage, hind limb length, SVL and wet weight are the apical</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12152.10pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">endpoints of the AMA, and each is briefly discussed below.  Further</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12165.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">technical information for collecting these data is available in the OECD</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12179.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guidance Document on Amphibian Thyroid Histopathology (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 10</FONT></b><FONT STYLE="font-size: 12.00pt">)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12193.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">including procedures for computer-assisted analysis which are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12207.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">recommended for use.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12234.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(i)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12234.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Developmental Stage. </FONT></b><FONT STYLE="font-size: 12.00pt">The developmental stage of </FONT></FONT><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">X. laevis</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12248.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">tadpoles is determined using the staging criteria of Nieuwkoop and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12262.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Faber (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 9</FONT></b><FONT STYLE="font-size: 12.00pt">).  Developmental stage data are used to determine if</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12276.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">development is accelerated, asynchronous, delayed or unaffected.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12290.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Acceleration or delay of development is determined by making a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12303.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">comparison between the median stage achieved by the control and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12317.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">treated groups.  Asynchronous development is reported when the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12331.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">tissues examined are not malformed or abnormal, but the relative</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12345.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">timing of the morphogenesis or development of different tissues is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12359.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">disrupted within a single tadpole.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12386.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(ii)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12386.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Hind Limb Length. </FONT></b><FONT STYLE="font-size: 12.00pt">Differentiation and growth of the hind limbs</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12400.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">are under control of thyroid hormones and are major developmental</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12414.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">landmarks already used in the determination of developmental</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12428.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stage.  Hind limb development is used qualitatively in the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12441.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">determination of developmental stage, but is considered here as a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12455.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">quantitative endpoint.  Therefore, hind limb length is measured as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12469.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">an endpoint to detect effects on the thyroid axis (Figure 2).  For</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12483.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">consistency, hind limb length is measured on the left hind limb.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12497.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Hind limb length is evaluated both at day 7 and at day 21 of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12510.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">test.  On day 7, measuring hind limb length is straightforward, as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12524.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">illustrated in Figure 2.  However, measuring hind limb length on day</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12538.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">21 is more complicated due to bends in the limb.  Therefore,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12552.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">measurements of hind limb length at day 21 should originate at the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12566.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">body wall and follow the midline of the limb through any angular</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12579.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">deviations.  Changes in hind limb length at day 7, even if not</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12593.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">evident at day 21, are still considered significant for potential</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:12624.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 16</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:11880.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile562637297.htm_files\outputfile562637297_background15.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:12672.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12744.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">thyroid activity.  Length measurements are acquired from digital</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12758.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">photographs using image analysis software as described in the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12771.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">OECD Guidance Document on Amphibian Thyroid Histopathology</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12785.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 10</FONT></b><FONT STYLE="font-size: 12.00pt">).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:12813.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(iii)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12813.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Body Length and Wet Weight. </FONT></b><FONT STYLE="font-size: 12.00pt">Determinations of snout to vent</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12827.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">length (SVL) (Figure 2) and wet weight are included in the test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12840.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">protocol to assess possible effects of test substances on the growth</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12854.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">rate of tadpoles in comparison to the control group and are useful in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12868.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">detecting generalized toxicity to the test compound.  Because the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12882.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">removal of adherent water for weight determinations can cause</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12896.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stressful conditions for tadpoles and may cause skin damage,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12909.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">these measurements are performed on the day 7 sub-sampled</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12923.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">tadpoles and all remaining tadpoles at test termination (day 21).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12937.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">For consistency, use the cranial aspect of the vent as the caudal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12951.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">limit of the measurement.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12978.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Snout to vent length (SVL) is used to assess tadpole growth as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:12992.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">illustrated in Figure 2.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:13020.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Figure 2. </FONT></b><FONT STYLE="font-size: 12.00pt">(A) Types of Body Length Measurements and (B) Hind Limb Length</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:13034.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Measurements for </FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">X. laevis </FONT></i><FONT STYLE="font-size: 12.00pt">Tadpoles (1).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;background-color:#ffffff;position:absolute;left:72.00pt;top:13047.60pt;z-index:2;"><IMG WIDTH=640 HEIGHT=480 style="width:468pt;height:170pt;" SRC="outputfile562637297.htm_files\outputfile562637297_p6.jpg"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:13231.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(iv)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13231.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Thyroid Gland Histology. </FONT></b><FONT STYLE="font-size: 12.00pt">While developmental stage and hind</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13245.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">limb length are important endpoints to evaluate exposure-related</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13259.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">changes in metamorphic development, developmental delay</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13273.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">cannot, by itself, be considered a diagnostic indicator of anti-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13287.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">thyroidal activity.  Some changes may only be observable by</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13300.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">routine histopathological analysis.  Diagnostic criteria include</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13314.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">thyroid gland hypertrophy/atrophy, follicular cell hypertrophy,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13328.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">follicular cell hyperplasia, and as additional qualitative criteria:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13342.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">follicular lumen area, colloid quality and follicular cell height/shape.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13356.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Severity grading (4 grades) should be reported.  Please refer to the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13369.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">OECD Guidance Document on Amphibian Thyroid Histopathology</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13383.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 10</FONT></b><FONT STYLE="font-size: 12.00pt">) for information on morphologic and histological</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:13416.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 17</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:13464.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13536.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">preparation of samples, and for performing histologic analyses on</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13550.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">tissue samples.  Further information regarding the normal thyroid</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13563.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">gland architecture during metamorphic development and more</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13577.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">photomicrographic examples of the core diagnostic criteria with</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13591.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">associated severity grades can be obtained in “Thyroid</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13605.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Histopathology Assessments for the Amphibian Metamorphosis</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13619.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Assay to Detect Thyroid-active Substances” in </FONT></FONT><i><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Toxicologic</FONT></FONT></i></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13632.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">Pathology </FONT></i><FONT STYLE="font-size: 12.00pt">(2009) (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 15</FONT></b><FONT STYLE="font-size: 12.00pt">).  Laboratories performing the assay for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13646.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the first time(s) should seek advice from experienced pathologists</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13660.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">for training purposes prior to undertaking histological analysis and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13674.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">evaluation of the thyroid glands.  Overt and significant changes in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13688.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">apical endpoints indicating developmental acceleration or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13701.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">asynchrony may preclude the necessity to perform</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13715.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">histopathological analysis of the thyroid glands.  However, absence</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13729.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of overt morphological changes or evidence of developmental delay</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13743.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">warrants histological analyses.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:13770.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(v)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13770.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Mortality. </FONT></b><FONT STYLE="font-size: 12.00pt">All test tanks should be checked daily for dead tadpoles</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13784.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and the numbers recorded for each tank.  The date, concentration</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13798.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and tank number for any observation of mortality should be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13812.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">recorded.  Dead animals should be removed from the test tank as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13826.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">soon as observed.  Mortality rates exceeding 10% may indicate</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13839.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">inappropriate test conditions or toxic effects of the test chemical.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:13867.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(vi)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13867.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Additional Observations. </FONT></b><FONT STYLE="font-size: 12.00pt">Cases of abnormal behavior and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13881.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">grossly visible malformations and lesions should be recorded.  The</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13895.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">date, concentration and tank number for any observation of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13908.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">abnormal behavior, gross malformations, or lesions should be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13922.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">recorded.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13950.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Normal behavior is characterized by the tadpoles being suspended</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13964.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">in the water column with tail elevated above the head, regular</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13977.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">rhythmic tail fin beating, periodic surfacing, operculating, and being</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:13991.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">responsive to stimulus.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14019.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Abnormal behavior would include, for example, floating on the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14033.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">surface, lying on the bottom of the tank, inverted or irregular</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14046.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">swimming, lack of surfacing activity, and being nonresponsive to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14060.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stimulus.  In addition, gross differences in food consumption</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14074.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">between treatments should be recorded.  Gross malformations and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14088.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">lesions could include morphological abnormalities (</FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">e.g.</FONT></i><FONT STYLE="font-size: 12.00pt">, limb</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14102.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">deformities), hemorrhagic lesions, bacterial or fungal infections, to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14115.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">name a few.  These determinations are qualitative and should be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14129.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">considered akin to clinical signs of disease/stress and made in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14143.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">comparison to control animals.  If the occurrence or rate of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14157.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">occurrence is greater in exposed tanks than in the controls, then</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14171.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">these should be considered as evidence for overt toxicity.  Similar</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:14208.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 18</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:14256.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14328.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">lesions manifested across all groups, including the control group,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14342.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should be considered as evidence of inappropriate testing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14355.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">conditions.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:14383.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(g)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:14383.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Data and Reporting.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:14411.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(1)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:14411.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Data Collection. </FONT></b><FONT STYLE="font-size: 12.00pt">All data should be collected using electronic or manual</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:14424.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">systems which conform to good laboratory practices (GLP).  Study data</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:14438.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should include:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:14466.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">•</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14466.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Test substance</FONT></u><FONT STYLE="font-size: 12.00pt">:  Name and CAS number.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:14486.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">•</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14486.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Characterization of the test substance</FONT></u><FONT STYLE="font-size: 12.00pt">:  Physical-chemical</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14499.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">properties; information on stability and biodegradability.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:14519.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">•</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14519.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Chemical observations and data</FONT></u><FONT STYLE="font-size: 12.00pt">:  Method and frequency of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14533.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">preparation of dilutions.  Test chemical information includes actual</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14547.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and nominal concentrations of the test chemical, and in some</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14561.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">cases, non-parent chemical, as appropriate.  Test chemical</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14574.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">measurements may be required for stock solutions as well as for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14588.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">test solutions.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:14608.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">•</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14608.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Solvent (if other than water)</FONT></u><FONT STYLE="font-size: 12.00pt">:  Justification of the choice of solvent,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14622.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and characterization of solvent (nature, concentration used).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:14649.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Test conditions:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:14677.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">•</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14677.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Operational records</FONT></u><FONT STYLE="font-size: 12.00pt">:  These consist of observations pertaining to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14691.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the functioning of the test system and the supporting environment</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14705.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and infrastructure.  Typical records include: ambient temperature,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14718.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">test temperature, photoperiod, status of critical components of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14732.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">exposure system (</FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">e.g. </FONT></i><FONT STYLE="font-size: 12.00pt">pumps, cycle counters, pressures), flow</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14746.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">rates, water levels, stock bottle changes, and feeding records.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14760.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">General water quality parameters include: pH, DO, conductivity,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14774.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">total iodine, alkalinity, and hardness.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:14793.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">•</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14793.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Deviations from the test method</FONT></u><FONT STYLE="font-size: 12.00pt">:  This information should include</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14807.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">any information or narrative descriptions of deviations from the test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14821.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">method.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:14849.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Results:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:14876.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">•</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14876.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Biological observations and data</FONT></u><FONT STYLE="font-size: 12.00pt">:  These include daily observations</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14890.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of mortality, food consumption, abnormal swimming behavior,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14904.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">lethargy, loss of equilibrium, malformations, lesions, etc.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14918.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Observations and data collected at predetermined intervals include:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14931.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">developmental stage, hind limb length, snout vent length, and wet</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:14945.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">weight.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:15000.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 19</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:15048.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15120.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">•</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:15120.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Statistical analytical techniques and justification of techniques used</FONT></u><FONT STYLE="font-size: 12.00pt">:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:15134.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Results of the statistical analysis preferably in tabular form,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:15147.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">methods for determining whether outliers exist, and justification for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:15161.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">not using outliers.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15181.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">•</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:15181.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Histological data</FONT></u><FONT STYLE="font-size: 12.00pt">:  These include narrative descriptions, as well as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:15195.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">graded severity and incidence scores of specific observations, as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:15209.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">detailed in the histopathology guidance document.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15228.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">•</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:15228.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><u><FONT STYLE="font-size: 12.00pt">Ad hoc observations</FONT></u><FONT STYLE="font-size: 12.00pt">:  These observations should include narrative</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:15242.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">descriptions of the study that do not fit into the previously described</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:15256.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">categories.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:15290.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(2)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15290.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Data reporting. </FONT></b><FONT STYLE="font-size: 12.00pt">Appendix 2 contains daily data collection spreadsheets</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15303.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that can be used as guidance for raw data entry and for calculations of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15317.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">summary statistics.  Additionally, reporting tables are provided that are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15331.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">convenient for communicating summaries of endpoint data.  Reporting</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15345.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">tables for histological assessments can be found in Appendix 2.  Similar</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15359.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">electronic templates for the AMA can be accessed on EPA’s OPPTS</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15372.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Harmonized Test Guidelines website and in the public docket (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 14</FONT></b><FONT STYLE="font-size: 12.00pt">).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:15400.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(3)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15400.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Guidance on Performance Criteria for Optimal Data Quality.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15414.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Generally, gross deviations from the test method will likely result in sub-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15428.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">optimal data for interpretation or reporting.  Therefore, the following criteria</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15441.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">in Table 4 have been developed as guidance for determining the quality of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:15455.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the test performed, and the general performance of the control organisms.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:15483.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Table 4. </FONT></b><FONT STYLE="font-size: 12.00pt">Performance Criteria for the AMA.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:154.25pt;top:15500.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Criterion</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:375.30pt;top:15500.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Acceptable limits</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15496pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15496pt;width:483pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15496pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15497pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15497pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15497pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:15521.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Test concentrations</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.00pt;top:15516.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Maintained at ≤ 20% CV (variability of measured test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:339.40pt;top:15527.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">concentration) over the 21 day test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15515pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15515pt;width:207pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15515pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:279pt;top:15515pt;width:274pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15515pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15516pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15516pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15516pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:15545.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Mortality in controls</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:286.90pt;top:15540.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">≤10% - mortality in any one replicate in the controls should</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:367.50pt;top:15551.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">not exceed 2 tadpoles</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15539pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15539pt;width:207pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15539pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:279pt;top:15539pt;width:274pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15539pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15539pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15539pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15539pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:15563.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Minimum median developmental stage of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:15575.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">controls at end of test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:410.90pt;top:15569.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">57</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15562pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15562pt;width:207pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15562pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:279pt;top:15562pt;width:274pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15562pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15563pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15563pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15563pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:15587.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Spread of development stage in control</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:15599.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">group</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:289.80pt;top:15587.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">The 10</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:320.95pt;top:15585.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 6.48pt"><s>th</s></FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:329.10pt;top:15587.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">and the 90</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:376.40pt;top:15585.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 6.48pt"><s>th</s></FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:384.55pt;top:15587.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">percentile of the development stage</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:304.40pt;top:15599.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">distribution should not differ by more than 4 stages</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15586pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15586pt;width:207pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15586pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15586pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15587pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15587pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15587pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:15611.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Dissolved Oxygen</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:370.10pt;top:15611.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">≥ 40% air saturation*</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15610pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15610pt;width:207pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15610pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:279pt;top:15610pt;width:274pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15610pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15611pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15611pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15611pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:15630.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">pH</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:298.30pt;top:15624.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">pH should be maintained between 6.5-8.5.  The inter-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:285.00pt;top:15636.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">replicate/inter-treatment differentials should not exceed 0.5.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15623pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15623pt;width:207pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15623pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:279pt;top:15623pt;width:274pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15623pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15624pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15624pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15624pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:15654.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Water temperature</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:291.35pt;top:15649.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">22º</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:308.95pt;top:15648.25pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">±</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:317.20pt;top:15649.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">1ºC - the inter-replicate/inter-treatment differentials</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:360.65pt;top:15660.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">should not exceed 0.5 ºC</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15647pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15647pt;width:207pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15647pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:279pt;top:15647pt;width:274pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15647pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15648pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15648pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15648pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:15672.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Test concentrations (non-control) without</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:15684.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">overt toxicity</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:409.50pt;top:15678.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">≥ 2</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15672pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15672pt;width:207pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15672pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:279pt;top:15672pt;width:274pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15672pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15672pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15672pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15672pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:15697.35pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Replicate performance</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:305.05pt;top:15697.35pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">≤ 2 replicates across the test can be compromised</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15695pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15695pt;width:207pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15695pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:279pt;top:15695pt;width:274pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15695pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15696pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15696pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15696pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:286.10pt;top:15710.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">If a carrier solvent is used, both a solvent control and clean</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:310.55pt;top:15721.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">water control must be used and results reported</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15709pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15709pt;width:207pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15709pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:279pt;top:15709pt;width:274pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15709pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15710pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15710pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15710pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:15733.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Special conditions for use of a solvent</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:288.05pt;top:15734.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Statistically significant differences between solvent control</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.75pt;top:15745.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">and water control groups are treated specially.  See below</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:371.70pt;top:15757.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">for more information</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15733pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15733pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:279pt;top:15733pt;width:274pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15733pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15733pt;width: 1pt;height:35pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15768pt;width:207pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15733pt;width: 1pt;height:34pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15768pt;width:275pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15733pt;width: 1pt;height:35pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15768pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:15792.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 20</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:15048.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile562637297.htm_files\outputfile562637297_background19.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:15840.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:154.25pt;top:15915.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Criterion</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:375.30pt;top:15915.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Acceptable limits</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15912pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15912pt;width:483pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15912pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15912pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15912pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15912pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:285.00pt;top:15931.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Representative chemical analyses before and after renewal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:378.60pt;top:15942.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">must be reported</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15930pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15930pt;width:207pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15930pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:279pt;top:15930pt;width:274pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15930pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15931pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15931pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15931pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:293.35pt;top:15957.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Ammonia levels must be measured immediately prior to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:398.90pt;top:15968.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">renewal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15954pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15954pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:279pt;top:15954pt;width:274pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15954pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15955pt;width: 1pt;height:27pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15955pt;width: 1pt;height:27pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15955pt;width: 1pt;height:27pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:286.40pt;top:15984.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">All water quality parameters listed in Table 1 of Appendix 1</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:311.10pt;top:15995.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">must be measured immediately prior to renewal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15982pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15982pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:279pt;top:15982pt;width:274pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15982pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:15982pt;width: 1pt;height:25pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:15982pt;width: 1pt;height:25pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:15982pt;width: 1pt;height:25pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:15982.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Special conditions for static renewal system</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:322.75pt;top:16009.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Renewal period must not exceed 72 hours</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:16008pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:16008pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:279pt;top:16008pt;width:274pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:16008pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:16008pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:16008pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:16008pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:287.75pt;top:16022.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Appropriate feeding schedule (50% of the daily food ration</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:377.15pt;top:16033.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">of Sera Micron ®)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:16021pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:16021pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:279pt;top:16021pt;width:274pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:16021pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:16022pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:16045pt;width:207pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:16022pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:278pt;top:16045pt;width:275pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:16022pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:553pt;top:16045pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:16045.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">*</FONT><FONT STYLE="font-size: 10.98pt">Aeration of water can be maintained through bubblers.  It is recommended to set bubblers at</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:16059.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">levels that do not create undue stress on the tadpoles.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:16086.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(4)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16086.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Test Validity. </FONT></b><FONT STYLE="font-size: 12.00pt">Achieving the following goals will likely deem a test to be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16099.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">considered acceptable/valid:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16127.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(i)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:16127.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Valid experiment in a test determined to be negative for</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:16141.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">thyroid activity:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:16161.05pt;z-index:3;"><FONT FACE ="Wingdings" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">…</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:207.00pt;top:16161.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">For any given treatment (including controls), mortality should</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:207.35pt;top:16174.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">not exceed 10%.  For any given replicate, mortality should not</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:207.35pt;top:16188.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">exceed three tadpoles, otherwise the replicate may be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:207.35pt;top:16202.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">considered compromised.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:16222.25pt;z-index:3;"><FONT FACE ="Wingdings" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">…</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:207.00pt;top:16222.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">At least two treatment levels, with all four uncompromised</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:207.35pt;top:16236.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">replicates, should be available for analysis.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:16255.85pt;z-index:3;"><FONT FACE ="Wingdings" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">…</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:207.00pt;top:16255.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">At least two treatment levels without overt toxicity should be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:207.35pt;top:16269.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">available for analysis.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16297.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(ii)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:16297.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Valid experiment in a test determined to be positive for thyroid</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:16311.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">activity:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:16330.85pt;z-index:3;"><FONT FACE ="Wingdings" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">…</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:16330.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Mortality of no more than two tadpoles/replicate in the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:16344.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">control group should occur.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:16372.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(5)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16372.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Decision logic for the conduct of the AMA. </FONT></b><FONT STYLE="font-size: 12.00pt">Decision logic was</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16386.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">developed for the AMA to provide logical assistance in the conduct and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16399.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">interpretation of the results of the bioassay (see flow chart in Figure 3).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16413.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The decision logic, in essence, weighs the endpoints in that advanced</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16427.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">development, asynchronous development, and thyroid histopathology are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16441.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">weighed heavily, while delayed development, snout-vent length and wet</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16455.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">body weight, parameters that can potentially be affected by general</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:16468.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">toxicity, are weighted less heavily.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:16584.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 21</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:15840.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile562637297.htm_files\outputfile562637297_background20.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:16632.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:16704.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Figure 3. </FONT></b><FONT STYLE="font-size: 12.00pt">Decision Logic for the Conduct of the AMA.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:95.35pt;top:16734.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Conduct AMA</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:257.10pt;top:16728.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">High Quality</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:259.00pt;top:16739.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Experiment</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:270.70pt;top:16980.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Likely</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:246.85pt;top:16992.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Thyroid Inactive:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:273.25pt;top:17003.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Stop</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.70pt;top:16910.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Remarkable Histological Effects</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:343.45pt;top:16721.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">NO</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:265.90pt;top:16883.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">NO</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:231.95pt;top:16797.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Advanced Development</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:356.60pt;top:16791.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">YES*</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:265.10pt;top:16825.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">NO</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:223.40pt;top:16854.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Asynchronous Development</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:258.10pt;top:16769.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">YES</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:402.95pt;top:16796.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Likely Thyroid Active</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:266.65pt;top:16943.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">NO</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:365.00pt;top:16847.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">YES*</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:414.20pt;top:16853.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Likely Thyroid Active</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:372.60pt;top:16901.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">YES</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:418.30pt;top:16908.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Likely Thyroid Active</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:410.45pt;top:16739.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Repeat Study</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:17042.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">*Histology may be required by some regulatory authorities despite significant differences in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:17054.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">advanced and asynchronous development.  The entity performing this test is encouraged to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:17067.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">consult the necessary authorities prior to the performing the test to determine which endpoints</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:17079.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">are required.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:17106.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(i)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17106.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Advanced development (determined using developmental</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17120.10pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">stage, SVL and HLL).  </FONT></b><FONT STYLE="font-size: 12.00pt">Advanced development is only known to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17133.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">occur through effects which are thyroid hormone related.  These</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17147.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">may be peripheral tissue effects such as direct interaction with the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17161.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">thyroid hormone receptor (such as with T4) or effects which alter</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17175.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">circulating thyroid hormone levels.  In either case, this is considered</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17189.10pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sufficient evidence to indicate that the chemical has thyroid activity.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17202.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Advanced development is evaluated in one of two ways.  First, the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17216.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">general developmental stage can be evaluated using the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17230.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">standardized approach detailed in Nieuwkoop and Faber (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 9</FONT></b><FONT STYLE="font-size: 12.00pt">).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17244.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Second, specific morphological features may be quantified, such as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17258.10pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">hind limb length, at both days 7 and 21, which is positively</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17271.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">associated with agonistic effects on the thyroid hormone receptor.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17285.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">If statistically significant advances in development or hind limb</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17299.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">length occur, then the test indicates that the chemical is likely</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17313.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">thyroid active.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:17376.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 22</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:16632.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile562637297.htm_files\outputfile562637297_background21.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:17424.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17496.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The evaluation of test animals for the presence of accelerated</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17510.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">development relative to the control population will be based on</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17523.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">results of statistical analyses performed for the following four</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17537.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">endpoints:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17551.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:17551.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">hind limb length (normalized by SVL) on study day 7</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17565.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:17565.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">hind limb length  (normalized by SVL) on study day 21</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17579.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:17579.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">developmental stage on study day 7</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17592.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:216.00pt;top:17592.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">developmental stage on study day 21</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17620.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Statistical analyses of hind limb length should be performed based</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17634.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">on measurements of the length of the left hind limb.  Hind limb</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17648.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">length is normalized by taking the ratio of hind limb length to snout-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17661.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to-vent length of an individual.  The means of the normalized values</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17675.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">for each treatment level are then compared.  Acceleration of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17689.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">development is indicated by a significant increase in the mean hind</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17703.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">limb length (normalized) in a chemical treatment group compared to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17717.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the control group on study day 7 and/or study day 21 (see</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17730.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Appendix 3).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17758.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Statistical analyses of developmental stage should be performed</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17772.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">based on determination of developmental stages according to the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17786.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">morphological criteria described by Nieuwkoop and Faber (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 8</FONT></b><FONT STYLE="font-size: 12.00pt">).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17799.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Acceleration of development is indicated when the multi-quantal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17813.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">analysis detects a significant increase of developmental stage</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17827.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">values in a chemical treatment group compared to the control group</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17841.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">on study day 7 and/or study day 21.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17868.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In the AMA test method, a significant effect on any of the four</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17882.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">endpoints mentioned above is regarded sufficient for a positive</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17896.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">detection of accelerated development.  That is, significant effects</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17910.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">on hind limb length at a specific time point do not require</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17924.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">corroboration by significant effects on hind limb length at the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17937.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">alternative time point, nor by significant effects on developmental</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17951.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stage at this specific time point.  In turn, significant effects on</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17965.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">developmental stage at a specific time point do not require</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17979.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">corroboration by significant effects on developmental stage at the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:17993.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">alternative time point, nor by significant effects on hind limb length</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18006.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">at this specific time point.  The weight of evidence for accelerated</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18020.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">development will nevertheless increase if significant effects are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18034.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">detected for more than one endpoint.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:18062.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(ii)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18062.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Asynchronous development (determined using developmental</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18075.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">stage criteria). </FONT></b><FONT STYLE="font-size: 12.00pt">Asynchronous development is characterized by</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18089.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">disruption of the relative timing of the morphogenesis or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18103.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">development of different tissues within a single tadpole.  The</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18117.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">inability to clearly establish the developmental stage of an organism</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18131.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">using the suite of morphological endpoints considered typical of any</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:18168.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 23</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:18216.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18288.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">given stage indicates that the tissues are developing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18302.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">asynchronously through metamorphosis.  Asynchronous</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18315.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">development is an indicator of thyroid activity.  The only known</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18329.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">modes of action causing asynchronous development are through</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18343.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">effects of chemicals on peripheral thyroid hormone action and/or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18357.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">thyroid hormone metabolism in developing tissues such as is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18371.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">observed with deiodinase inhibitors.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18398.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The evaluation of test animals for the presence of asynchronous</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18412.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">development relative to the control population is based on gross</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18426.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">morphological assessment of test animals on study day 7 and study</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18440.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">day 21.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18467.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The description of normal development of </FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">X. laevis </FONT></i><FONT STYLE="font-size: 12.00pt">by Nieuwkoop</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18481.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and Faber (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 9</FONT></b><FONT STYLE="font-size: 12.00pt">) provides the framework for identifying a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18495.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">sequential order of normal tissue remodelling.  The term</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18509.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">“asynchronous development” refers specifically to those deviations</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18522.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">in tadpole gross morphological development that disallow the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18536.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">definitive determination of a developmental stage according to the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18550.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">criteria of Nieuwkoop and Faber (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 9</FONT></b><FONT STYLE="font-size: 12.00pt">) because key</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18564.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">morphological landmarks show characteristics of different stages.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18591.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">As implicated by the term “asynchronous development”, only cases</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18605.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">showing deviations in the progress of remodelling of specific</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18619.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">tissues relative to the progress of remodelling of other tissues</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18633.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should be considered.  Some classical phenotypes include delay or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18647.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">absence of fore limb emergence despite normal or advanced</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18660.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">development of hind limbs and tail tissues, or the precocious</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18674.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">resorption of gills relative to the stage of hind limb morphogenesis</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18688.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and tail resorption.  An animal will be recorded as showing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18702.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">asynchronous development if it cannot be assigned to a stage</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18716.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">because it fails to meet a majority of the landmark developmental</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18729.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">criteria for a given Niewkoop and Faber stage (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 9</FONT></b><FONT STYLE="font-size: 12.00pt">), or if there is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18743.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">extreme delay or acceleration of one or more key features (</FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">e.g.</FONT></i><FONT STYLE="font-size: 12.00pt">, tail</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18757.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">completely resorbed, but forelimbs not emerged).  This assessment</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18771.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">is performed qualitatively and should examine the full suite of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18785.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">landmark features listed by Nieuwkoop and Faber (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 9</FONT></b><FONT STYLE="font-size: 12.00pt">).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18798.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">However it is not necessary to record the developmental stage of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18812.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the various landmark features of animals being observed.  Animals</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18826.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">recorded as showing asynchronous development are not assigned</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18840.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to a Nieuwkoop and Faber (</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 9</FONT></b><FONT STYLE="font-size: 12.00pt">) development stage.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18867.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Thus, a central criterion for designating cases of abnormal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18881.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">morphological development as “asynchronous development” is that</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18895.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the relative timing of tissue remodelling and tissue morphogenesis</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18909.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">is disrupted whereas the morphology of affected tissues is not</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:18923.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">overtly abnormal.  One example to illustrate this interpretation of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:18960.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 24</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:19008.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19080.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">gross morphological abnormalities is that retarded hind limb</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19094.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">morphogenesis relative to development of other tissues fulfills the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19107.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">criterion of “asynchronous development” whereas cases showing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19121.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">missing hind limbs, abnormal digits (</FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">e.g.</FONT></i><FONT STYLE="font-size: 12.00pt">, ectrodactyly, polydactyly),</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19135.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">or other overt limb malformations should not be considered as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19149.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">“asynchronous development”.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19176.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In this context, the major morphological landmarks that should be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19190.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">evaluated for their coordinated metamorphic progress should</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19204.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">include hind limb morphogenesis, fore limb morphogenesis, fore</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19218.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">limb emergence, the stage of tail resorption (particularly the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19232.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">resorption of the tail fin), and head morphology (</FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">e.g.</FONT></i><FONT STYLE="font-size: 12.00pt">, gill size and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19245.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stage of gill resorption, lower jaw morphology, protrusion of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19259.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Meckel’s cartilage).</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19287.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Dependent on the mode of chemical action, different gross</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19301.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">morphological phenotypes can occur. Some classical phenotypes</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19314.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">include delay or absence of fore limb emergence despite normal or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19328.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">advanced development of hind limbs and tail tissues, precocious</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19342.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">gill resorption relative to hind limb and tail remodelling.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:19370.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(iii)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19370.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Histopathology. </FONT></b><FONT STYLE="font-size: 12.00pt">If the chemical does not accelerate development</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19383.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">or cause asynchronous development, then histopathology of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19397.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">thyroid glands is evaluated using the available guidance document</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19411.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(</FONT></FONT><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Ref. 10</FONT></b><FONT STYLE="font-size: 12.00pt">).  Developmental retardation, in the absence of toxicity, is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19425.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">a strong indicator of anti-thyroid activity, but the developmental</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19439.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stage analysis is less sensitive and less diagnostic than the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19452.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">histopathological analysis of the thyroid glands.  Therefore,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19466.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">conducting histopathological analyses of the thyroid glands is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19480.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">required in this case.  Effects on thyroid gland histology have been</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19494.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">demonstrated in the absence of developmental effects.  If changes</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19508.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">in thyroid histopathology occur, then the chemical is considered to</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19521.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">be thyroid active.  If no developmental delays or histological lesions</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19535.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">are observed in the thyroid glands, then the chemical is considered</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19549.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to be thyroid inactive.  The rationale for this decision is that the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19563.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">thyroid glands are under the influence of TSH and any chemical</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19577.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">which alters circulating thyroid hormone sufficiently to alter TSH</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19590.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">secretion will result in histopathological changes in the thyroid</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19604.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">glands.  Various modes and mechanisms of action can alter</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19618.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">circulating thyroid hormone.  So, while thyroid hormone level is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19632.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">indicative of a thyroid related effect, it is insufficient to determine</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19646.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">which mode or mechanism of action is related to the response.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19673.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Because this endpoint is not amenable to basic statistical</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19687.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">approaches, the determination of an effect associated with</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19701.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">exposure to a chemical shall be made through expert opinion by a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19715.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">pathologist.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:19752.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 25</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:19800.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:19872.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(iv)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19872.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Delayed development (determined using developmental stage,</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19886.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">HLL, BW, SVL). </FONT></b><FONT STYLE="font-size: 12.00pt">Delayed development can occur through anti-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19899.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">thyroidal mechanisms and through indirect toxicity.  Mild</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19913.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">developmental delays coupled with overt signs of toxicity likely</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19927.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">indicate a non-specific toxic effect.  Evaluation of non-thyroidal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19941.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">toxicity is an essential element of the test to reduce the probability</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19955.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of false positive outcomes.  Excessive mortality is an obvious</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19968.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">indication that other toxic mechanisms are occurring.  Similarly,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19982.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">mild reductions in growth, as determined by wet weight and/or SVL</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:19996.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">length, also suggest non-thyroidal toxicity.  Apparent increases in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:20010.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">growth are commonly observed with compounds that negatively</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:20024.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">affect normal development.  Consequently, the presence of larger</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:20037.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">animals does not necessarily indicate non-thyroidal toxicity.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:20051.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">However, growth should never be solely relied upon to determine</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:20065.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">thyroid toxicity.  Rather, growth, in conjunction with developmental</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:20079.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stage and thyroid histopathology, should be used to determine</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:20093.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">thyroid activity.  Other endpoints should also be considered in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:20106.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">determining overt toxicity including edema, hemorrhagic lesions,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:20120.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">lethargy, reduced food consumption, erratic/altered swimming</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:20134.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">behavior, etc.  If all test concentrations exhibit signs of overt</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:20148.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">toxicity, the test compound must be re-evaluated at lower test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:20162.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">concentrations before determining whether the compound is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:20175.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">potentially thyroid active or thyroid inactive.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:20203.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Statistically significant developmental delays, in absence of other</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:20217.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">signs of overt toxicity, indicate that the chemical is thyroid active</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:20231.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(antagonistic).  In the absence of strong statistical responses, this</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:20244.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">outcome may be augmented with results from thyroid</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:20258.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">histopathology.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:20286.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(6)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20286.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Statistical analyses. </FONT></b><FONT STYLE="font-size: 12.00pt">Statistical analyses of the data should preferably</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20300.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">follow procedures described in the document Current Approaches in the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20313.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Statistical Analysis of Ecotoxicity Data: A Guidance to Application (</FONT></FONT><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Ref</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20327.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">12</FONT></b><FONT STYLE="font-size: 12.00pt">).  For all continuous quantitative endpoints (HHL, SVL, wet weight)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20341.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">consistent with a monotone dose-response, the Jonckheere-Terpstra test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20355.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should be applied in step-down manner to establish a significant treatment</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20369.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">effect.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20396.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">For continuous endpoints that are not consistent with a monotone dose-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20410.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">response, the data should be assessed for normality (preferably using the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20424.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Shapiro-Wilk or Anderson-Darling test) and variance homogeneity</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20438.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(preferably using the Levene test).  Both tests are performed on the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20451.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">residuals from an ANOVA.  Expert judgment can be used in lieu of these</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20465.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">formal tests for normality and variance homogeneity, though formal tests</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20479.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">are preferred.  Where non-normality or variance heterogeneity is found, a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20493.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">normalizing, variance stabilizing transformation should be sought. If the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20507.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">data (perhaps after a transformation) are normally distributed with</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:20544.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 26</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:20592.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:21336.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 27</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20664.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">homogeneous variance, a significant treatment effect is determined from</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20678.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Dunnett’s test.  If the data (perhaps after a transformation) are normally</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20691.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">distributed with heterogeneous variance, a significant treatment effect is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20705.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">determined from the Tamhane-Dunnett or T3 test or from the Mann-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20719.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Whitney-Wilcoxon U test.  Where no normalizing transformation can be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20733.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">found, a significant treatment effect is determined from the Mann-Whitney-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20747.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Wilcoxon U test using a Bonferroni-Holm adjustment to the p-values.  The</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20760.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Dunnett test is applied independently of any ANOVA F-test and the Mann-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20774.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Whitney test is applied independently of any overall Kruskall-Wallis test.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20802.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Significant mortality is not expected but should be assessed from the step-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20816.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">down Cochran-Armitage test where the data are consistent with dose-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20829.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">response monotonicity, and otherwise from Fisher’s Exact test with a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20843.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Bonferroni-Holm adjustment.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20871.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A significant treatment effect for developmental stage is determined from</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20885.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the step-down application of the Jonckheere-Terpstra test applied to the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20898.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">replicate medians. Alternatively, and preferably, the multi-quantal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20912.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Jonckheere test from the 20</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:292.75pt;top:20910.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">th</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:302.70pt;top:20912.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">to the 80</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:349.45pt;top:20910.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">th</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:359.40pt;top:20912.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">percentile should be used for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20926.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">effect determination, as it takes into account changes to the distribution</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20940.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">profile.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20967.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The appropriate unit of analysis is the replicate so the data consist of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20981.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">replicate medians if the Jonckheere-Terpstra or Mann-Whitney U test is</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:20995.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">used, or the replicate means if Dunnett’s test is used.  Dose-response</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:21009.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">monotonicity can be assessed visually from the replicate and treatment</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:21023.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">means or medians or from formal tests such as previously described (</FONT></FONT><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Ref.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:21036.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">12</FONT></b><FONT STYLE="font-size: 12.00pt">).  With fewer than five replicates per treatment or control, the exact</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:21050.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">permutation versions of the Jonckheere-Terpstra and Mann-Whitney tests</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:21064.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">should be used if available. The statistical significance of all tests</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:21078.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">indicated is judged at the 0.05 significance level.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:21105.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Please see Figure 4 for a flow chart for performing statistical tests on</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:21119.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">continuous data.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:21384.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:286.50pt;top:21496.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Flow-Chart for Continuous Response</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:249.05pt;top:21529.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Are data consistent with monotone dose-response?</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:161.30pt;top:21562.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Yes</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:587.95pt;top:21562.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">No</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:103.45pt;top:21614.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Apply step-down Jonckheere-Terpstra test to</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:93.25pt;top:21627.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">determine effects. With <5 reps per concentration</FONT></FONT><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">,</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:127.25pt;top:21640.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">use exact version of test if available.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:472.25pt;top:21604.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Are data normally distributed</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:468.00pt;top:21618.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">(possibly after transformation)?</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:447.10pt;top:21660.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Yes</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:628.75pt;top:21660.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">No</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:153.80pt;top:21727.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Are variances homogeneous</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:145.85pt;top:21739.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">(possibly after transformation)?</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:120.40pt;top:21782.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Yes</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:334.80pt;top:21782.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">No</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:104.80pt;top:21832.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Use Dunnett test to</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:104.80pt;top:21844.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 10.02pt">determine effects</FONT></b><FONT STYLE="font-size: 12.00pt">.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:317.10pt;top:21851.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Use Tamhane-Dunnett</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:324.60pt;top:21864.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">(T3) test if available</FONT></FONT><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:314.40pt;top:21877.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Otherwise follow arrow</FONT></FONT><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:523.90pt;top:21732.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Use Mann-Whitney test with</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:515.80pt;top:21745.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Bonferroni-Holm adjustment to</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:507.65pt;top:21758.35pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">determine effects. With <5 reps per</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:504.90pt;top:21771.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">concentration, use exact version of</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:555.95pt;top:21784.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">test if available.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:36.00pt;top:21456.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Figure 4. </FONT></b><FONT STYLE="font-size: 12.00pt">Flowchart for Statistical Approaches for Continuous Response Data.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:359.35pt;top:21948.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 28</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:21384.00pt;z-index:-1;"><img style="width:792pt;height:612pt;" src="outputfile562637297.htm_files\outputfile562637297_background27.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:21996.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22068.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(7)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22068.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Special Data Analysis Considerations.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22095.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(i)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22095.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Use of compromised treatment levels. </FONT></b><FONT STYLE="font-size: 12.00pt">Several factors are</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22109.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">considered when determining whether a replicate or entire</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22123.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">treatment demonstrates overt toxicity and should be removed from</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22137.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">analysis.  Overt toxicity is defined as >2 mortalities in any replicate</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22151.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">that can only be explained by toxicity rather than technical error.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22164.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Other signs of overt toxicity include hemorrhage, abnormal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22178.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">behaviors, abnormal swimming patterns, anorexia, and any other</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22192.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">clinical signs of disease.  For sub-lethal signs of toxicity, qualitative</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22206.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">evaluations may be necessary, and should always be made in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22220.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">reference to the clean water control group.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22247.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(ii)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22247.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Solvent controls. </FONT></b><FONT STYLE="font-size: 12.00pt">The use of a solvent should only be considered</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22261.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">as a last resort, when all other chemical delivery options have been</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22275.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">considered.  If a solvent is used, then a clean water control must be</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22289.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">run in concert.  At the termination of the test, an evaluation of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22302.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">potential effects of the solvent must be performed.  This is done</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22316.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">through a statistical comparison of the solvent control group and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22330.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the clean water control group.  If statistically significant differences</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22344.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">are detected in these endpoints between the clean water control</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22358.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">and solvent control groups, then best professional judgment should</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22371.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">be used to determine if the validity of the test is compromised.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:144.00pt;top:22399.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(iii)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22399.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Treatment groups achieving developmental stage 60 and</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22413.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">above. </FONT></b><FONT STYLE="font-size: 12.00pt">After stage 60, tadpoles show a reduction in size and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22427.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">weight due to tissue resorption and reduction of absolute water</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22440.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">content.  Thus, measurements of wet weight and SVL cannot</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22454.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">appropriately be used in statistical analyses for differences in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22468.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">growth rates.  Therefore, wet weight and length data from</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22482.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">organisms >NF60 must be censored and cannot be used in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22496.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">analyses of replicate means or replicate medians.  Two different</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22509.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">approaches could be used to analyze these growth-related</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22523.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">parameters.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22551.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">One approach is to consider only tadpoles with developmental</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22565.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stages lower or equal to stage 60 for the statistical analyses of wet</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22578.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">weight and/or SVL.  This approach is believed to provide sufficiently</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22592.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">robust information about the severity of possible growth effects as</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22606.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">long as only a small proportion of test animals are removed from</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22620.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the analyses (≤20%).  If an increased number of tadpoles show</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22634.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">development beyond stage 60 (≥20%) in one or more nominal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22647.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">concentration(s), then a two-factor ANOVA with a nested variance</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22661.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">structure should be undertaken on all tadpoles to assess growth</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22675.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">effects due to chemical treatments while taking into account the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:22740.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 29</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:22788.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22860.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">effect of late stage development on growth.  Appendix 3 provides</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:180.00pt;top:22874.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">guidance on the two-factor ANOVA analysis of weight and length.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:22901.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(h)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:108.00pt;top:22901.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">References.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:22929.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">1.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.05pt;top:22929.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">OECD (2009).  Amphibian Metamorphosis Assay.  OECD Guideline for the Testing</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:22943.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of Chemicals.  No. 231.  Paris, France.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:22970.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:22970.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">OECD (2004).  Report of the Validation of the Amphibian Metamorphosis Assay for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:22984.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the Detection of Thyroid Active Substances:  Phase 1 – Optimization of the Test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:22998.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Protocol.  Environmental Health and Safety Publications.  Series on Testing and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23012.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Assessment.  No. 77.  Paris, France.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:23039.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">3.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23039.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">OECD (2007).  Final Report of the Validation of the Amphibian Metamorphosis</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23053.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Assay: Phase 2 - Multi-chemical Interlaboratory Study. Environmental Health and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23067.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Safety Publications. Series on Testing and Assessment.  No. 76.  Paris, France.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:23094.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">4.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23094.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">OECD (2008).  Report of the Validation Peer Review for the Amphibian</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23108.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Metamorphosis Assay and Agreement of the Working Group of the National</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23122.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Coordinators of the Test Guidelines Programme on the Follow-up of this Report.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23136.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Environmental Health and Safety Publications. Series on Testing and Assessment.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23150.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">No. 92.  Paris, France.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:23177.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">5.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23177.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">OECD (2000).  Guidance Document on Aquatic Toxicity Testing of Difficult</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23191.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Substances and Mixtures.  Environmental Health and Safety Publications. Series</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23205.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">on Testing and Assessment.  No. 23.  Paris, France.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:23232.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">6.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23232.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">ASTM (2002).  Standard Guide for Conducting Acute Toxicity Tests on Test</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23246.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Materials with Fishes, Macroinvertebrates, and Amphibians.  American Society for</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23260.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Testing and Materials, ASTM E729-96(2002), Philadelphia, PA.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:23288.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">7.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23288.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">ASTM (2004).  Standard Guide for Conducting the Frog Embryo Teratogenesis</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23301.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Assay - </FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">Xenopus </FONT></i><FONT STYLE="font-size: 12.00pt">(FETAX).  E 1439-98.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:23329.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">8. Kahl,M.D., Russom,C.L., DeFoe,D.L. & Hammermeister,D.E. (1999). Saturation</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23343.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Units for Use in Aquatic Bioassays.  Chemosphere 39, pp. 539-551.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:23370.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">9.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23370.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Nieuwkoop,P.D. & Faber,J. (1994).  Normal Table of Xenopus Laevis. Garland</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23384.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Publishing, New York.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:23412.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">10.  OECD (2007).  Guidance Document on Amphibian Thyroid Histology.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23426.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Environmental Health and Safety Publications.  Series on Testing and</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23439.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Assessment.  No. 82.  Paris, France.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:23467.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">11.  Dodd,M.H.I. & Dodd,J.M. (1976).  Physiology of Amphibia.  Lofts,B. (ed.),</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23481.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Academic Press, New York, pp. 467-599.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:23532.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 30</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:23580.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:23666.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">12.  OECD (2006).  Current Approaches in the Statistical Analysis of Ecotoxicity Data:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23679.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">A Guidance to Application.  Environmental Health and Safety Publications.  Series</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23693.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">on Testing and Assessment.  No. 54.  Paris, France.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:23721.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">13.  Hutchinson TH, Shillabeer N, Winter MJ, Pickford DB (2006).  Acute and Chronic</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23735.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Effects of Carrier Solvents in Aquatic Organisms: A critical Review. Review.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23748.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Aquatic Toxicology, 76, pp.69–92.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:23776.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">14.  EPA.  OPPTS Harmonized Test Guidelines.  Available on-line at:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23790.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><u><FONT COLOR="0000ff"><FONT STYLE="font-size: 12.00pt">http://www.epa.gov/oppts </FONT></FONT></u><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">(select “Test Methods & Guidelines” on the left side</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23804.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">navigation menu).  You may also access the guidelines in</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23817.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><u><i><FONT COLOR="0000ff"><FONT STYLE="font-size: 12.00pt">http://www.regulations.gov </FONT></FONT></i></u><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">grouped by Series under Docket ID #s: EPA-HQ-OPPT-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23831.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">2009-0150 through EPA-HQ-OPPT-2009-0159, and EPA-HQ-OPPT-2009-0576.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:23859.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">15. Grim KC </FONT></FONT><FONT COLOR="000000"><i><FONT STYLE="font-size: 12.00pt">et al</FONT></i><FONT STYLE="font-size: 12.00pt">. (2009). Thyroid Histopathology Assessments for the Amphibian</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23873.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Metamorphosis Assay to Detect Thyroid-active Substances.  Toxicologic Pathology</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.00pt;top:23886.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">37, pp 415-424.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.35pt;top:24324.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Page 31</FONT></FONT></FONT></SPAN>
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<SPAN STYLE="color:#000000;position:absolute;left:273.65pt;top:24444.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Appendix 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24471.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.98pt">Table 1.  Experimental Conditions for the 21-day Amphibian Metamorphosis Assay.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24488.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Test Animal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24488.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><i><FONT STYLE="font-size: 10.02pt">Xenopus laevis </FONT></i><FONT STYLE="font-size: 10.02pt">larvae</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24484pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24484pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24484pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24484pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24484pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24484pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24506.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Initial Larval Stage</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.80pt;top:24506.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Nieuwkoop and Faber stage 51</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24502pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24503pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24503pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24503pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24525.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Exposure Period</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.75pt;top:24525.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">21 days</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24521pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24521pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24521pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24521pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24543.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Larvae Selection Criteria</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.65pt;top:24543.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Developmental stage and total length (optional)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24539pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24540pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24540pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24540pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24558.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Minimum of 3 concentrations spanning approximately one</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24570.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">order of magnitude</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24564.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Test Concentrations</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24558pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24558pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24558pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24558pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24585.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Exposure Regime</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24585.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Flow-through (preferred) and/or static-renewal</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24581pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24582pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24582pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24582pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24604.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Test System Flow-Rate</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24604.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">25 mL/min (complete volume replacement ca. every 2.7 h)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24600pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24600pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24600pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24600pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24622.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Mortality Daily</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24618pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24619pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24619pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:424pt;top:24619pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24619pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24641.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Developmental Stage</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:430.10pt;top:24641.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">D 7 and 21</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24637pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24637pt;width:281pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24637pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24637pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:424pt;top:24637pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24637pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24659.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Hind Limb Length</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:430.10pt;top:24659.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">D 7 and 21</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24655pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24655pt;width:281pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24656pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24656pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:424pt;top:24656pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24656pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24678.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Snout-Vent Length</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:430.15pt;top:24678.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">D 7 and 21</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24674pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24674pt;width:281pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24674pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24674pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:424pt;top:24674pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24674pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24668.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Primary Endpoints / Determination Days</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24696.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Wet Body Weight</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:430.15pt;top:24696.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">D 7 and 21</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24692pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24692pt;width:281pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24693pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24693pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:424pt;top:24693pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24693pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24715.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Thyroid Histology</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:430.10pt;top:24715.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">D 21</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24711pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24711pt;width:281pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24711pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24711pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:424pt;top:24711pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24711pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24730.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Dechlorinated tap water (charcoal-filtered) or the equivalent</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24741.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">laboratory source</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24736.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Dilution Water / Laboratory Control</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24729pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24730pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24730pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24730pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24757.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Larval Density</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24757.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">20 larvae / test vessel (5 / L)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24753pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24753pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24753pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24753pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24772.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">4-10 L (10-15 cm minimum water) / Glass or Stainless Steel</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24783.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">test vessel (e.g., 22.5 cm x 14 cm x 16.5 cm)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24778.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Test Solution / Test Vessel</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24771pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24772pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24772pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24772pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24799.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Replication</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.65pt;top:24799.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">4 replicate test vessels / test concentration and control</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24795pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24795pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24795pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24795pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24817.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Acceptable Mortality Rate in Controls</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24817.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">≤ 10% per replicate test vessel</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24813pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24814pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24814pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24814pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:204.95pt;top:24832.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Number</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:204.95pt;top:24844.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Fixed</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24838.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">All tadpoles (5/replicate are evaluated initially)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24832pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24832pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:199pt;top:24832pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24832pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24832pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:204.95pt;top:24859.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Region</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.65pt;top:24859.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Head or whole body</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24855pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:199pt;top:24855pt;width:346pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24856pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:199pt;top:24856pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24856pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24856pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24859.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Thyroid Fixation</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:204.95pt;top:24874.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Fixation</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:204.95pt;top:24886.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Fluid</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24880.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Davidson’s fixative</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24874pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:199pt;top:24874pt;width:346pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24874pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:199pt;top:24874pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24874pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24874pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:204.95pt;top:24901.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Food</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24902.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Sera Micron</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:323.60pt;top:24901.05pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">®</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:334.25pt;top:24902.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">or equivalent</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24897pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24898pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:199pt;top:24898pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24898pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24898pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24913.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Feeding</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:204.95pt;top:24916.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Amount /</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:204.95pt;top:24928.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Frequency</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24922.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">See Table 1 for feeding regime using Sera Micron</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24916pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:199pt;top:24916pt;width:346pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24916pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:199pt;top:24916pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24916pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24916pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:204.95pt;top:24943.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Photoperiod</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24943.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">12 h Light : 12 h dark</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24939pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24940pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:199pt;top:24940pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24940pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24940pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24952.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Lighting</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:204.95pt;top:24962.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Intensity</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.75pt;top:24962.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">600 to 2000 lux (Measured at Water Surface)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24958pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:199pt;top:24958pt;width:346pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24958pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:199pt;top:24958pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24958pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24958pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24980.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Water Temperature</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:24981.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">22º</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:287.25pt;top:24980.05pt;z-index:3;"><FONT FACE ="Symbol" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">±</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:295.55pt;top:24981.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">1ºC</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24976pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24977pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24977pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24977pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:24999.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">pH</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.65pt;top:24999.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">6.5 – 8.5</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24995pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:24995pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:24995pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:24995pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:25017.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Dissolved Oxygen (DO) Concentration</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.70pt;top:25017.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">>3.5 mg/L (>40% Air Saturation)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:25013pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:25014pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:25014pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:25014pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:25036.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Analytical Chemistry Sample Schedule</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:269.65pt;top:25036.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Once / Week (4 Sample Events / Test)</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:25032pt;width:479pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:25032pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:25050pt;width:197pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:25032pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:264pt;top:25050pt;width:280pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:25032pt;width: 1pt;height:18pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:545pt;top:25050pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:295.45pt;top:25116.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">A - 1</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:25164.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:273.65pt;top:25236.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Appendix 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:161.00pt;top:25250.10pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Reporting Tables for Raw Data and Summary Data.</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:25277.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Table 1. </FONT></b><FONT STYLE="font-size: 12.00pt">General Test Chemical Information.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:25295.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Reporting Organization:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:359.65pt;top:25297.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Chemical Name:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:25311.10pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Study Title:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:359.65pt;top:25313.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">CAS Number:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:25326.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Report Name:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:359.65pt;top:25329.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Purity</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:25342.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Date of report:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:359.65pt;top:25345.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Stability</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:25358.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Report filename:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:359.65pt;top:25358.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Octanol:Water Coefficient (K</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:475.45pt;top:25358.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">):</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:468.50pt;top:25362.10pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 4.98pt">ow</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:359.65pt;top:25374.10pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Chemical volatility</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:359.65pt;top:25392.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Other Chemical Constituents:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:359.65pt;top:25408.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Solvent (if applicable):</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:246.60pt;top:25436.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Value Units</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:25454.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Nominal Dose 1:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:25474.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Nominal Dose 2:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:25491.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Nominal Dose 3:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:25509.35pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Nominal Dose 4:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:25547.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Date (day 0)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:311.65pt;top:25547.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Enter date (mm/dd/yy)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:25565.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Date (day 7)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:25581.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Date (day 14)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:25594.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Date (day 21)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:295.45pt;top:25908.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">A - 2</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:25164.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile562637297.htm_files\outputfile562637297_background32.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:25956.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:26028.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Table 2</FONT></b><FONT STYLE="font-size: 12.00pt">.  Study Descriptors.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26043.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Chemical Name:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:208.70pt;top:26043.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26056.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">CAS #:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:208.70pt;top:26056.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26069.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Assay:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:208.65pt;top:26069.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Amphibian Metamorphosis</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:117.30pt;top:26110.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Descriptor Value</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26123.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Test Species</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26139.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Source of larvae</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26154.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Number Larvae/Replicate</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26170.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Number Replicates/Dose</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26186.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Larval stage (NF) at initial</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26195.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">dosing</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26211.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Exposure system (flow-</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26221.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">through/static renewal)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26242.10pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Test-system flow rate (ml/min)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26262.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Dilution water/Laboratory</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26272.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">control source</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26289.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Water contaminants</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26298.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">concentrations (flouride,</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26307.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">chlorates, etc.)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26325.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Test vessel (steel/glass)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26340.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Diet type</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26356.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Diet amount</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26372.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Diet frequency</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26388.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Light/dark cycle (hours)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26403.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Light intensity (lux)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26419.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Iodine concentration (μg/L)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:295.45pt;top:26700.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">A - 3</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:25956.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile562637297.htm_files\outputfile562637297_background33.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:26748.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:295.45pt;top:27492.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">A - 4</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:26820.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Table 3</FONT></b><FONT STYLE="font-size: 12.00pt">.  Raw Test Conditions.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26834.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Chemical</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26843.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Name: 0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:26854.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">CAS #:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:123.05pt;top:26854.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:327.90pt;top:26866.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Temperature (°C)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:211.40pt;top:26879.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:304.20pt;top:26879.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:397.00pt;top:26879.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:489.80pt;top:26879.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:187.15pt;top:26892.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:280.00pt;top:26892.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:372.85pt;top:26892.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:465.60pt;top:26892.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:77.80pt;top:26906.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Test Day</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:137.55pt;top:26906.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Date</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:184.10pt;top:26906.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:26901pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:26901pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:26901pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:26901pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:26903pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:26903pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:197pt;top:26903pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:221pt;top:26903pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:244pt;top:26903pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:290pt;top:26903pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:313pt;top:26903pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:337pt;top:26903pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:383pt;top:26903pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:406pt;top:26903pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:429pt;top:26903pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:476pt;top:26903pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:499pt;top:26903pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:522pt;top:26903pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:91.70pt;top:26917.10pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">0 01/00/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:26915pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:26915pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:26915pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:26915pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:26916pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:26916pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:91.70pt;top:26930.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">7 01/07/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:26928pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:26928pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:26928pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:26928pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:26929pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:26929pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:88.85pt;top:26943.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">14 01/14/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:26941pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:26941pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:26941pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:26941pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:26943pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:26943pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:88.85pt;top:26957.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">21 01/21/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:26955pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:26955pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:26955pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:26955pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:26956pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:26956pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:26968pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:26968pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:26968pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:312.40pt;top:26983.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Dissolved Oxygen (mg/L)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:211.40pt;top:26997.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:304.20pt;top:26997.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:397.00pt;top:26997.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:489.80pt;top:26997.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:187.15pt;top:27010.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:280.00pt;top:27010.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:372.85pt;top:27010.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:465.60pt;top:27010.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:77.80pt;top:27023.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Test Day</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:137.55pt;top:27023.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Date</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:184.10pt;top:27023.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27019pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27019pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27019pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27019pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27020pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27020pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:197pt;top:27020pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:221pt;top:27020pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:244pt;top:27020pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:290pt;top:27020pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:313pt;top:27020pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:337pt;top:27020pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:383pt;top:27020pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:406pt;top:27020pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:429pt;top:27020pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:476pt;top:27020pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:499pt;top:27020pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:522pt;top:27020pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:91.70pt;top:27034.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">0 01/00/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27032pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27032pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27032pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27032pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27034pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27034pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:91.70pt;top:27048.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">7 01/07/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27046pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27046pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27046pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27046pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27047pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27047pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:88.85pt;top:27061.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">14 01/14/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27059pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27059pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27059pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27059pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27060pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27060pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:88.85pt;top:27074.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">21 01/21/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27072pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27072pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27072pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27072pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27074pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27074pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27085pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27085pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27085pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:355.10pt;top:27101.35pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">pH</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:211.40pt;top:27114.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:304.20pt;top:27114.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:397.00pt;top:27114.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:489.80pt;top:27114.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:187.15pt;top:27128.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:280.00pt;top:27128.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:372.85pt;top:27128.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:465.60pt;top:27128.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:77.80pt;top:27141.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Test Day</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:137.55pt;top:27141.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Date</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:184.10pt;top:27141.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27137pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27137pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27137pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27137pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27138pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27138pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:197pt;top:27138pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:221pt;top:27138pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:244pt;top:27138pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:290pt;top:27138pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:313pt;top:27138pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:337pt;top:27138pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:383pt;top:27138pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:406pt;top:27138pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:429pt;top:27138pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:476pt;top:27138pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:499pt;top:27138pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:522pt;top:27138pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:91.70pt;top:27152.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">0 01/00/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27150pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27150pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27150pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27150pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27151pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27151pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:91.70pt;top:27165.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">7 01/07/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27163pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27163pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27163pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27163pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27165pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27165pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:88.85pt;top:27178.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">14 01/14/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27176pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27176pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27176pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27176pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27178pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27178pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:88.85pt;top:27192.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">21 01/21/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27190pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27190pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27190pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27190pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27191pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27191pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27203pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27203pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27203pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:239.15pt;top:27218.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Total hardness</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:211.40pt;top:27232.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:304.20pt;top:27232.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:187.15pt;top:27245.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:280.00pt;top:27245.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:77.80pt;top:27258.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Test Day</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:137.55pt;top:27258.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Date</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:184.10pt;top:27258.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">1 2 3 4 1 2 3 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27254pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27254pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27254pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27254pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27256pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27256pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:197pt;top:27256pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:221pt;top:27256pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:244pt;top:27256pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:290pt;top:27256pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:313pt;top:27256pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:337pt;top:27256pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:91.70pt;top:27269.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">0 01/00/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27267pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27267pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27267pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27267pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27269pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27269pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:91.70pt;top:27283.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">7 01/07/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27281pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27281pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27281pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27281pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27282pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27282pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:88.85pt;top:27296.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">14 01/14/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27294pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27294pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27294pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27294pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27296pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27296pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:88.85pt;top:27309.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">21 01/21/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27307pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27307pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27307pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27307pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27309pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27309pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27321pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27321pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27321pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:249.85pt;top:27336.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Alkalinity</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:211.40pt;top:27349.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:304.20pt;top:27349.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:187.15pt;top:27363.10pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:280.00pt;top:27363.10pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:77.80pt;top:27376.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Test Day</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:137.55pt;top:27376.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Date</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:184.10pt;top:27376.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">1 2 3 4 1 2 3 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27372pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27372pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27372pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27372pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27373pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27373pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:197pt;top:27373pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:221pt;top:27373pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:244pt;top:27373pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:290pt;top:27373pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:313pt;top:27373pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:337pt;top:27373pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:91.70pt;top:27387.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">0 01/00/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27385pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27385pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27385pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27385pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27387pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27387pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:91.70pt;top:27400.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">7 01/07/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27398pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27398pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27398pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27398pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27400pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27400pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:88.85pt;top:27414.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">14 01/14/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27412pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27412pt;width:46pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27412pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27412pt;width:56pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:71pt;top:27413pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:117pt;top:27413pt;width: 1pt;height:11pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:88.85pt;top:27427.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">21 01/21/00</FONT></FONT></FONT></SPAN>
<span style="position:absolute;font-size:0;left:71pt;top:27425pt;width: 1pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:71pt;top:27425pt;width:46pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:117pt;top:27425pt;width: 1pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:117pt;top:27425pt;width:56pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:71pt;top:27426pt;width: 1pt;height:12pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:71pt;top:27438pt;width:46pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:117pt;top:27426pt;width: 1pt;height:12pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:117pt;top:27438pt;width:56pt;height: 1pt;background-color:#000000;"></span><span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:26748.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile562637297.htm_files\outputfile562637297_background34.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:27540.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:295.45pt;top:28284.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">A - 5</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:27612.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Table 4</FONT></b><FONT STYLE="font-size: 12.00pt">.  Mortality Data.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:18.70pt;top:27626.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Chemical</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:18.70pt;top:27635.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Name: 0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:18.70pt;top:27646.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">CAS #:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:87.90pt;top:27646.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:173.75pt;top:27670.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:190.15pt;top:27670.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:278.80pt;top:27670.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:295.20pt;top:27670.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:383.90pt;top:27670.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:400.25pt;top:27670.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:488.95pt;top:27670.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:505.30pt;top:27670.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:142.25pt;top:27684.35pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:247.30pt;top:27684.35pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:352.35pt;top:27684.35pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:457.35pt;top:27684.35pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Replicate Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:31.25pt;top:27700.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Test Day</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:98.75pt;top:27700.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Date  1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27695pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27695pt;width:69pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27695pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27695pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27697pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27697pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:158pt;top:27697pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:184pt;top:27697pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:210pt;top:27697pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:263pt;top:27697pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:289pt;top:27697pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:315pt;top:27697pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:368pt;top:27697pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:394pt;top:27697pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:420pt;top:27697pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:473pt;top:27697pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:499pt;top:27697pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:525pt;top:27697pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:45.10pt;top:27711.35pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">0 01/00/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27709pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27709pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27709pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27709pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27710pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27710pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:45.10pt;top:27724.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">1 01/01/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27722pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27722pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27722pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27722pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27724pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27724pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:45.10pt;top:27738.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">2 01/02/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27736pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27736pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27736pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27736pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27737pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27737pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:45.10pt;top:27752.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">3 01/03/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27749pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27749pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27749pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27749pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27751pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27751pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:45.10pt;top:27765.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">4 01/04/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27763pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27763pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27763pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27763pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27764pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27764pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:45.10pt;top:27779.10pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">5 01/05/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27776pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27776pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27776pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27776pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27778pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27778pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:45.10pt;top:27792.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">6 01/06/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27790pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27790pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27790pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27790pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27791pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27791pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:45.10pt;top:27806.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">7 01/07/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27804pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27804pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27804pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27804pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27805pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27805pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:45.10pt;top:27819.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">8 01/08/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27817pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27817pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27817pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27817pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27819pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27819pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:45.10pt;top:27833.35pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">9 01/09/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27831pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27831pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27831pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27831pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27832pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27832pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:42.30pt;top:27846.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">10 01/10/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27844pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27844pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27844pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27844pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27846pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27846pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:42.30pt;top:27860.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">11 01/11/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27858pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27858pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27858pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27858pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27859pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27859pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:42.30pt;top:27873.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">12 01/12/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27871pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27871pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27871pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27871pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27873pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27873pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:42.30pt;top:27887.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">13 01/13/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27885pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27885pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27885pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27885pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27886pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27886pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:42.30pt;top:27901.10pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">14 01/14/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27898pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27898pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27898pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27898pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27900pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27900pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:42.30pt;top:27914.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">15 01/15/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27912pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27912pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27912pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27912pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27913pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27913pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:42.30pt;top:27928.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">16 01/16/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27925pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27925pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27925pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27925pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27927pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27927pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:42.30pt;top:27941.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">17 01/17/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27939pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27939pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27939pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27939pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27941pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27941pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:42.30pt;top:27955.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">18 01/18/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27953pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27953pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27953pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27953pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27954pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27954pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:42.30pt;top:27968.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">19 01/19/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27966pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27966pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27966pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27966pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27968pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27968pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:42.30pt;top:27982.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">20 01/20/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27980pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27980pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27980pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27980pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27981pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27981pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:42.30pt;top:27995.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">21 01/21/00</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27993pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27993pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27993pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27993pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:27995pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:27995pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:18.70pt;top:28008.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Replicate</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:18.70pt;top:28020.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Count</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:142.55pt;top:28020.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:28007pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:28007pt;width:68pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:28007pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:28007pt;width:48pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:132pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:158pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:184pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:210pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:237pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:263pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:289pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:315pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:342pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:368pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:394pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:420pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:447pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:473pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:499pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:525pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:552pt;top:28008pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:18.70pt;top:28032.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Treatment</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:18.70pt;top:28043.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Count</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:182.00pt;top:28043.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">0 0 0 0</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:13pt;top:28031pt;width:539pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:13pt;top:28032pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:82pt;top:28032pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:132pt;top:28032pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:237pt;top:28032pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:342pt;top:28032pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:447pt;top:28032pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:552pt;top:28032pt;width: 1pt;height:23pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:18.70pt;top:28055.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Percent</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:18.70pt;top:28067.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Mortality</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:167.75pt;top:28067.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">#DIV/0! #DIV/0! #DIV/0! #DIV/0!</FONT></FONT></b></FONT></SPAN>
<span style="position:absolute;font-size:0;left:13pt;top:28055pt;width:539pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:13pt;top:28055pt;width: 1pt;height:23pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:13pt;top:28078pt;width:69pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:82pt;top:28055pt;width: 1pt;height:23pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:82pt;top:28078pt;width:49pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:132pt;top:28055pt;width: 1pt;height:23pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:132pt;top:28078pt;width:104pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:237pt;top:28055pt;width: 1pt;height:23pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:237pt;top:28078pt;width:104pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:342pt;top:28055pt;width: 1pt;height:23pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:342pt;top:28078pt;width:104pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:447pt;top:28055pt;width: 1pt;height:23pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:447pt;top:28078pt;width:104pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:552pt;top:28055pt;width: 1pt;height:23pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:552pt;top:28078pt;width: 1pt;height: 1pt;background-color:#000000;"></span><span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:27540.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile562637297.htm_files\outputfile562637297_background35.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:28332.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:295.45pt;top:29076.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">A - 6</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:28404.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Table 5.  </FONT></b><FONT STYLE="font-size: 12.00pt">Day 7 Raw Endpoint Data.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:28421.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Chemical Name:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:153.20pt;top:28421.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:28434.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">CAS #:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:153.20pt;top:28434.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:28447.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Date (Day 7):</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:153.20pt;top:28447.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">01/00/00</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:93.80pt;top:28493.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Nominal</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:82.45pt;top:28502.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Concentration</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:153.20pt;top:28493.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:155.90pt;top:28502.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:199.60pt;top:28493.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Individual</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:201.35pt;top:28502.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Identifier</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:250.50pt;top:28493.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Developmental</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:268.10pt;top:28502.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Stage</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:323.20pt;top:28503.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Late Stage?</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:387.85pt;top:28484.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Hindlimb</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:391.60pt;top:28493.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Length</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:395.15pt;top:28503.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">(mm)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:441.35pt;top:28475.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Snout to</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:448.90pt;top:28484.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Vent</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:444.30pt;top:28493.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Length</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:447.85pt;top:28503.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">(mm)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:501.70pt;top:28475.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Whole</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:495.05pt;top:28484.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Organism</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:491.95pt;top:28493.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Wet Weight</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:505.10pt;top:28503.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">(mg)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28518.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28513pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28534.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28527pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28527pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28527pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28529pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28550.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28543pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28543pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28543pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28545pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28565.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28559pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28559pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28559pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28560pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28581.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28575pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28575pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28575pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28576pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28597.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28592pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28613.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28606pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28606pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28606pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28608pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28628.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28622pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28622pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28622pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28623pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28644.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28638pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28638pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28638pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28639pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28660.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28653pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28653pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28653pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28655pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28676.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28671pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28691.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28685pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28685pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28685pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28686pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28707.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28701pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28701pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28701pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28702pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28723.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28716pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28716pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28716pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28718pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28739.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28732pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28732pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28732pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28734pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28754.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28749pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28770.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28764pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28764pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28764pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28765pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28786.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28779pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28779pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28779pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28781pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28802.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28795pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28795pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28795pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28797pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28817.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28811pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28811pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28811pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28812pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28833.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28828pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28849.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28842pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28842pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28842pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28844pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28865.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28858pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28858pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28858pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28860pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28880.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28874pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28874pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28874pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28875pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28896.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28890pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28890pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28890pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28891pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28912.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28907pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28928.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28921pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28921pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28921pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28923pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28943.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28937pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28937pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28937pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28938pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28959.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28953pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28953pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28953pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28954pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28975.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:28968pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28968pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:28968pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28970pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:28991.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:147pt;top:28986pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29006.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29000pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29000pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29000pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29001pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29022.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29016pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29016pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29016pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29017pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29038.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<span style="position:absolute;font-size:0;left:71pt;top:29031pt;width:75pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:147pt;top:29031pt;width: 1pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:148pt;top:29031pt;width:45pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:70pt;top:29047pt;width:77pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:147pt;top:29033pt;width: 1pt;height:14pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:148pt;top:29047pt;width:45pt;height: 1pt;background-color:#000000;"></span><span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:28332.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile562637297.htm_files\outputfile562637297_background36.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:29124.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:295.45pt;top:29868.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">A - 7</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:29199.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Chemical Name:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:153.20pt;top:29199.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:29212.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">CAS #:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:153.20pt;top:29212.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:29225.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Date (Day 7):</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:153.20pt;top:29225.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">01/00/00</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:93.80pt;top:29271.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Nominal</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:82.45pt;top:29281.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Concentration</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:153.20pt;top:29271.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:155.90pt;top:29281.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:199.60pt;top:29271.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Individual</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:201.35pt;top:29281.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Identifier</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:250.50pt;top:29271.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Developmental</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:268.10pt;top:29281.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Stage</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:323.20pt;top:29281.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Late Stage?</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:387.85pt;top:29262.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Hindlimb</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:391.60pt;top:29271.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Length</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:395.15pt;top:29281.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">(mm)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:441.35pt;top:29253.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Snout to</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:448.90pt;top:29262.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Vent</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:444.30pt;top:29272.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Length</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:447.85pt;top:29281.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">(mm)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:501.70pt;top:29253.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Whole</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:495.05pt;top:29262.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Organism</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:491.95pt;top:29272.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Wet Weight</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:505.10pt;top:29281.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">(mg)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29295.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29290pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29311.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29305pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29326.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29320pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29320pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29320pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29321pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29342.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29335pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29335pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29335pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29337pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29358.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29351pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29351pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29351pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29353pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29374.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29367pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29367pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29367pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29368pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29389.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29384pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29405.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29398pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29398pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29398pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29400pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29421.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29414pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29414pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29414pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29416pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29437.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29430pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29430pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29430pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29431pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29452.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29446pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29446pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29446pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29447pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29468.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29463pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29484.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29477pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29477pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29477pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29479pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29500.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29493pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29493pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29493pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29494pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29515.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29509pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29509pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29509pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29510pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29531.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29524pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29524pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29524pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29526pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29547.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29542pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29563.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29556pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29556pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29556pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29557pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29578.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29572pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29572pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29572pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29573pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29594.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29587pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29587pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29587pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29589pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29610.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29603pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29603pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29603pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29605pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29626.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29620pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29641.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29635pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29635pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29635pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29636pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29657.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29650pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29650pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29650pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29652pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29673.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29666pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29666pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29666pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29668pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29689.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29682pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29682pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29682pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29683pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29704.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29699pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29720.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29713pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29713pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29713pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29715pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29736.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29729pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29729pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29729pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29731pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29752.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29745pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29745pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29745pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29746pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29767.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 1</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29761pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29761pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29761pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29762pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29783.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29778pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29799.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29792pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29792pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29792pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29794pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29815.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:29808pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29808pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:29808pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:29809pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:29830.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<span style="position:absolute;font-size:0;left:71pt;top:29824pt;width:75pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:147pt;top:29824pt;width: 1pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:148pt;top:29824pt;width:45pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:70pt;top:29839pt;width:77pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:147pt;top:29825pt;width: 1pt;height:14pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:148pt;top:29839pt;width:45pt;height: 1pt;background-color:#000000;"></span><span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:29124.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile562637297.htm_files\outputfile562637297_background37.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:29916.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:295.45pt;top:30660.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">A - 8</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:29991.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Chemical Name:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:153.20pt;top:29991.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:30004.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">CAS #:</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:153.20pt;top:30004.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.70pt;top:30017.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Date (Day 7):</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:153.20pt;top:30017.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">01/00/00</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:93.80pt;top:30063.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Nominal</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:82.45pt;top:30073.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Concentration</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:153.20pt;top:30063.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Replicate</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:155.90pt;top:30073.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Number</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:199.60pt;top:30063.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Individual</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:201.35pt;top:30073.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Identifier</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:250.50pt;top:30063.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Developmental</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:268.10pt;top:30073.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Stage</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:323.20pt;top:30073.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Late Stage?</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:387.85pt;top:30054.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Hindlimb</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:391.60pt;top:30063.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Length</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:395.15pt;top:30073.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">(mm)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:441.35pt;top:30045.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Snout to</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:448.90pt;top:30054.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Vent</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:444.30pt;top:30064.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Length</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:447.85pt;top:30073.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">(mm)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:501.70pt;top:30045.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Whole</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:495.05pt;top:30054.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Organism</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:491.95pt;top:30064.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">Wet Weight</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:505.10pt;top:30073.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">(mg)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:30087.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 2</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:147pt;top:30082pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:30103.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:147pt;top:30097pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:30118.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:30112pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:30112pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:30112pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:30113pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:30134.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:30127pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:30127pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:30127pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:30129pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:30150.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:30143pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:30143pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:30143pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:30145pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:30166.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:30159pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:30159pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:30159pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:30160pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:30181.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:147pt;top:30176pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:30197.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:30190pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:30190pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:30190pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:30192pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:30213.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:30206pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:30206pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:30206pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:30208pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:30229.15pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:71pt;top:30222pt;width:75pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:30222pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:148pt;top:30222pt;width:45pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:147pt;top:30223pt;width: 1pt;height:14pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:107.30pt;top:30244.90pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 7.98pt">0 4</FONT></FONT></b></FONT></SPAN>
<span style="position:absolute;font-size:0;left:71pt;top:30238pt;width:75pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:147pt;top:30238pt;width: 1pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:148pt;top:30238pt;width:45pt;height: 1pt;background-color:#000000;"></span><span style="position:absolute;font-size:0;left:147pt;top:30239pt;width: 1pt;height:14pt;background-color:#000000;"></span><span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:29916.00pt;z-index:-1;"><img style="width:612pt;height:792pt;" src="outputfile562637297.htm_files\outputfile562637297_background38.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:30708.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:367.45pt;top:31272.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">A - 9</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:36.00pt;top:30780.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Table 6.  </FONT></b><FONT STYLE="font-size: 12.00pt">Day 7 Summary Endpoint Data.</FONT></FONT></FONT></SPAN>
<span style="color:#000000;background-color:#ffffff;position:absolute;left:0.00pt;top:30708.00pt;z-index:-1;"><img style="width:792pt;height:612pt;" src="outputfile562637297.htm_files\outputfile562637297_background39.png"></span>
<SPAN STYLE="position:absolute;left:71.76pt;top:31320.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:31392.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Table 7.  </FONT></b><FONT STYLE="font-size: 12.00pt">Day 21 Raw Endpoint Data.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;background-color:#ffffff;position:absolute;left:72.00pt;top:31405.80pt;z-index:2;"><IMG WIDTH=785 HEIGHT=1270 style="width:468pt;height:621pt;" SRC="outputfile562637297.htm_files\outputfile562637297_p7.png"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:292.60pt;top:32064.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">A - 10</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:32112.00pt"> </SPAN>
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<SPAN STYLE="color:#000000;position:absolute;left:364.60pt;top:35052.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">A - 14</FONT></FONT></FONT></SPAN>
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<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:35172.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Table 9.  </FONT></b><FONT STYLE="font-size: 12.00pt">Chemistry Data.</FONT></FONT></FONT></SPAN>
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<SPAN STYLE="color:#000000;position:absolute;left:292.60pt;top:36636.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">A - 16</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:35975.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Table 10. </FONT></b><FONT STYLE="font-size: 12.00pt">Histopathology Reporting Tables for Core Criteria.</FONT></FONT></FONT></SPAN>
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<SPAN STYLE="color:#000000;position:absolute;left:331.10pt;top:36112.85pt;z-index:3;"></SPAN>
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<SPAN STYLE="color:#000000;position:absolute;left:331.10pt;top:36088.95pt;z-index:3;"></SPAN>
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STYLE="position:absolute;font-size:0;left:206pt;top:36119pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:236pt;top:36119pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:266pt;top:36119pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:295pt;top:36119pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:334pt;top:36119pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:373pt;top:36119pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:405pt;top:36119pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:437pt;top:36119pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN 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STYLE="position:absolute;font-size:0;left:236pt;top:36132pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:266pt;top:36132pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:295pt;top:36132pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:334pt;top:36132pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:373pt;top:36132pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:405pt;top:36132pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:437pt;top:36132pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:467pt;top:36132pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:497pt;top:36132pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:70pt;top:36145pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:108pt;top:36145pt;width:158pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:295pt;top:36145pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:334pt;top:36145pt;width:163pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:70pt;top:36145pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:108pt;top:36145pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:146pt;top:36145pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:176pt;top:36145pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:206pt;top:36145pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:236pt;top:36145pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:266pt;top:36145pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:295pt;top:36145pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:334pt;top:36145pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:373pt;top:36145pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:405pt;top:36145pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:437pt;top:36145pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:467pt;top:36145pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:497pt;top:36145pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:70pt;top:36158pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:108pt;top:36158pt;width:158pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:295pt;top:36158pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:334pt;top:36158pt;width:163pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:70pt;top:36158pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:108pt;top:36158pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:146pt;top:36158pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:176pt;top:36158pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:206pt;top:36158pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:236pt;top:36158pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:266pt;top:36158pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:295pt;top:36158pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:334pt;top:36158pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:373pt;top:36158pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:405pt;top:36158pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:437pt;top:36158pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:467pt;top:36158pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:497pt;top:36158pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:70pt;top:36171pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:108pt;top:36171pt;width:158pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:295pt;top:36171pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:334pt;top:36171pt;width:163pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:70pt;top:36172pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:108pt;top:36172pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:146pt;top:36172pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:176pt;top:36172pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:206pt;top:36172pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:236pt;top:36172pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:266pt;top:36172pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:295pt;top:36172pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:334pt;top:36172pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:373pt;top:36172pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:405pt;top:36172pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:437pt;top:36172pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:467pt;top:36172pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:497pt;top:36172pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:87.85pt;top:36188.90pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:87.85pt;top:36131.10pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.65pt;top:36188.60pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.65pt;top:36150.80pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.65pt;top:36145.80pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:99.65pt;top:36129.15pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:307.45pt;top:36183.05pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:307.45pt;top:36160.80pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:307.45pt;top:36139.70pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:319.25pt;top:36180.85pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:331.10pt;top:36179.15pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:331.10pt;top:36160.30pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:331.10pt;top:36155.25pt;z-index:3;"></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:70pt;top:36184pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:108pt;top:36184pt;width:158pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:295pt;top:36184pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:334pt;top:36184pt;width:163pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:70pt;top:36185pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:108pt;top:36185pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:146pt;top:36185pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:176pt;top:36185pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:206pt;top:36185pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:236pt;top:36185pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:266pt;top:36185pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:295pt;top:36185pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:334pt;top:36185pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:373pt;top:36185pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:405pt;top:36185pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:437pt;top:36185pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:467pt;top:36185pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:497pt;top:36185pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:78.40pt;top:36200.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Total:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:304.35pt;top:36200.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Total:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:70pt;top:36198pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:70pt;top:36198pt;width:38pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:108pt;top:36198pt;width:158pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:295pt;top:36198pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:295pt;top:36198pt;width:39pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:334pt;top:36198pt;width:163pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:146pt;top:36198pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:176pt;top:36198pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:206pt;top:36198pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:236pt;top:36198pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:266pt;top:36198pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:373pt;top:36198pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:405pt;top:36198pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:437pt;top:36198pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:467pt;top:36198pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:497pt;top:36198pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:146pt;top:36211pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:146pt;top:36211pt;width:30pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:176pt;top:36211pt;width:30pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:206pt;top:36211pt;width:30pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:236pt;top:36211pt;width:30pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:266pt;top:36211pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:266pt;top:36211pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:373pt;top:36211pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:373pt;top:36211pt;width:32pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:405pt;top:36211pt;width:32pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:437pt;top:36211pt;width:30pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:467pt;top:36211pt;width:30pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:497pt;top:36211pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:497pt;top:36211pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:159.80pt;top:36277.70pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:159.80pt;top:36233.75pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:171.60pt;top:36273.85pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:171.60pt;top:36257.75pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:171.60pt;top:36226.00pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:189.80pt;top:36277.70pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:189.80pt;top:36233.75pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:201.60pt;top:36264.15pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:201.60pt;top:36235.70pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:219.80pt;top:36276.30pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:219.80pt;top:36245.15pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:231.60pt;top:36273.85pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:231.60pt;top:36257.75pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:231.60pt;top:36226.00pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:249.80pt;top:36276.30pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:249.80pt;top:36245.15pt;z-index:3;"></SPAN>
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<SPAN STYLE="position:absolute;font-size:0;left:70pt;top:36407pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:108pt;top:36407pt;width:158pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:295pt;top:36407pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:334pt;top:36407pt;width:163pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:70pt;top:36407pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:108pt;top:36407pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:146pt;top:36407pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:176pt;top:36407pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:206pt;top:36407pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:236pt;top:36407pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:266pt;top:36407pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:295pt;top:36407pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:334pt;top:36407pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:373pt;top:36407pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:405pt;top:36407pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:437pt;top:36407pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:467pt;top:36407pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:497pt;top:36407pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:78.40pt;top:36422.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Total:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:304.35pt;top:36422.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Total:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:70pt;top:36420pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:70pt;top:36420pt;width:38pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:108pt;top:36420pt;width:158pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:295pt;top:36420pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:295pt;top:36420pt;width:39pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:334pt;top:36420pt;width:163pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:146pt;top:36421pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:146pt;top:36433pt;width:30pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:176pt;top:36421pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:177pt;top:36433pt;width:29pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:206pt;top:36421pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:207pt;top:36433pt;width:29pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:236pt;top:36421pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:237pt;top:36433pt;width:29pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:266pt;top:36421pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:266pt;top:36433pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:373pt;top:36421pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:373pt;top:36433pt;width:32pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:405pt;top:36421pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:406pt;top:36433pt;width:31pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:437pt;top:36421pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:438pt;top:36433pt;width:29pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:467pt;top:36421pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:468pt;top:36433pt;width:29pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:497pt;top:36421pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:497pt;top:36433pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;left:71.76pt;top:36684.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:36756.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Table 11.  </FONT></b><FONT STYLE="font-size: 12.00pt">Additional Histopathology Criteria.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:36775.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Date:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:139.00pt;top:36775.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Chemical:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:246.95pt;top:36775.55pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Pathologist:</FONT></FONT></FONT></SPAN>
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<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:36993pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:103pt;top:36993pt;width:90pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:241pt;top:36993pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:280pt;top:36993pt;width:90pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:36994pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:103pt;top:36994pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:133pt;top:36994pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:163pt;top:36994pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:193pt;top:36994pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:241pt;top:36994pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:280pt;top:36994pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:310pt;top:36994pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:340pt;top:36994pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:370pt;top:36994pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:73.20pt;top:37008.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Total:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:250.20pt;top:37008.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Total:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:37006pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:37006pt;width:37pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:103pt;top:37006pt;width:90pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:241pt;top:37006pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:241pt;top:37006pt;width:39pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:280pt;top:37006pt;width:90pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:133pt;top:37007pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:163pt;top:37007pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:193pt;top:37007pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:310pt;top:37007pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:340pt;top:37007pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:370pt;top:37007pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:133pt;top:37020pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:133pt;top:37020pt;width:30pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:163pt;top:37020pt;width:30pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:193pt;top:37020pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:193pt;top:37020pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:310pt;top:37020pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:310pt;top:37020pt;width:30pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:340pt;top:37020pt;width:30pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:370pt;top:37020pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:370pt;top:37020pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:146.30pt;top:37096.85pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:146.30pt;top:37065.75pt;z-index:3;"></SPAN>
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<SPAN STYLE="color:#000000;position:absolute;left:158.10pt;top:37092.15pt;z-index:3;"></SPAN>
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<SPAN STYLE="color:#000000;position:absolute;left:176.30pt;top:37096.85pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:176.30pt;top:37065.75pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:176.30pt;top:37037.95pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:188.10pt;top:37093.80pt;z-index:3;"></SPAN>
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<SPAN STYLE="color:#000000;position:absolute;left:323.30pt;top:37096.85pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:323.30pt;top:37065.75pt;z-index:3;"></SPAN>
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<SPAN STYLE="color:#000000;position:absolute;left:335.10pt;top:37092.15pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:335.10pt;top:37061.55pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:335.10pt;top:37042.05pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:353.30pt;top:37096.85pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:353.30pt;top:37065.75pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:353.30pt;top:37037.95pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:365.10pt;top:37093.80pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:365.10pt;top:37065.50pt;z-index:3;"></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:365.10pt;top:37046.05pt;z-index:3;"></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:133pt;top:37033pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:133pt;top:37033pt;width:30pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:163pt;top:37033pt;width:30pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:193pt;top:37033pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:193pt;top:37033pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:310pt;top:37033pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:310pt;top:37033pt;width:30pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:340pt;top:37033pt;width:30pt;height: 1pt;background-color:#000000;"></SPAN><SPAN 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STYLE="position:absolute;font-size:0;left:241pt;top:37134pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:280pt;top:37134pt;width:90pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:37135pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:103pt;top:37135pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:133pt;top:37135pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:163pt;top:37135pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:193pt;top:37135pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:241pt;top:37135pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN 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STYLE="position:absolute;font-size:0;left:340pt;top:37148pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:370pt;top:37148pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:76.85pt;top:37158.75pt;z-index:3;"></SPAN>
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<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:37226pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:103pt;top:37226pt;width:90pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:241pt;top:37226pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:280pt;top:37226pt;width:90pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:37226pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:103pt;top:37226pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:133pt;top:37226pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:163pt;top:37226pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:193pt;top:37226pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:241pt;top:37226pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:280pt;top:37226pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:310pt;top:37226pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:340pt;top:37226pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:370pt;top:37226pt;width: 1pt;height:12pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:73.20pt;top:37241.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Total:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:250.20pt;top:37241.30pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Total:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;font-size:0;left:66pt;top:37239pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:66pt;top:37239pt;width:37pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:103pt;top:37239pt;width:90pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:241pt;top:37239pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:241pt;top:37239pt;width:39pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:280pt;top:37239pt;width:90pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:133pt;top:37239pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:133pt;top:37252pt;width:30pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:163pt;top:37239pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:163pt;top:37252pt;width:29pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:193pt;top:37239pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:193pt;top:37252pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:310pt;top:37239pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:310pt;top:37252pt;width:30pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:340pt;top:37239pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:340pt;top:37252pt;width:29pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:370pt;top:37239pt;width: 1pt;height:13pt;background-color:#000000;"></SPAN><SPAN STYLE="position:absolute;font-size:0;left:370pt;top:37252pt;width: 1pt;height: 1pt;background-color:#000000;"></SPAN><SPAN STYLE="color:#000000;position:absolute;left:292.60pt;top:37428.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">A - 17</FONT></FONT></FONT></SPAN>
<SPAN STYLE="position:absolute;left:71.76pt;top:37476.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:37548.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><b><FONT STYLE="font-size: 12.00pt">Table 12. </FONT></b><FONT STYLE="font-size: 12.00pt">Narrative Descriptions for Histopathological Findings.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.90pt;top:37563.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Date:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.90pt;top:37575.95pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Chemical:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:76.90pt;top:37588.75pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Pathologist:</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:300.35pt;top:37601.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">Narrative description</FONT></FONT></FONT></SPAN>
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<SPAN STYLE="position:absolute;left:71.76pt;top:38268.00pt"> </SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:270.30pt;top:38354.10pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">APPENDIX 3</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:73.30pt;top:38381.70pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Alternative Analysis of Weight and Length in the Case of Late Stage Development</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:145.80pt;top:38395.50pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><b><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">Exceeding 20% of Tadpoles in One Or More Concentration(s)</FONT></FONT></b></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38423.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">If an increased number of tadpoles show development beyond stage 60 (≥20%) in one</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38436.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">or more nominal concentration(s), then a two-factor ANOVA with a nested variance</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38450.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">structure should be undertaken on all tadpoles to assess growth effects due to chemical</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38464.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">treatments while taking into account the effect of late stage development on growth.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38492.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">The proposal is to use all data but take into account the effect of late stage</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38505.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">development. This can be done with a two-factor ANOVA with a nested variance</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38519.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">structure.  Define LateStage=’Yes’ for an animal if its developmental stage is 61 or</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38533.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">greater.  Otherwise, define LateStage=’No’. Then a two-factor ANOVA with</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38547.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">concentration and LateStage and their interaction can be done, with Rep(Conc) a</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38561.05pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">random factor and Tadpole(Rep) another random effect.  This still treats the rep as the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38574.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">unit of analysis and gives essentially the same results as a weighted analysis of</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38588.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">rep*latestage means, weighted by the number of animals per mean.  If the data violate</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38602.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the normality or variance homogeneity requirements of ANOVA, then a normalized</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38616.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">rank-order transform can be done to remove that objection.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38643.85pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">In addition to the standard ANOVA F-tests for the effects of CONC, LateStage, and their</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38657.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">interactions, the interaction F-test can be “sliced” into two additional ANOVA F-tests,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38671.45pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">one on the mean responses across concentrations for LateStage=’No’ and another on</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38685.25pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">the mean responses across concentrations for LateStage=’Yes.’  Further comparisons</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38699.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">of treatment means against controls are done within each level of LateStage.  A trend-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38712.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">type analysis can be done using appropriate contrasts or simple pairwise comparisons</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38726.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">can be done if there is evidence of non-monotone dose-response within a level of the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38740.40pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">LateStage variable.  A Bonferroni-Holm adjustment to the p-values is made only if the</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38754.20pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">corresponding F-slice is not significant.  This can be done in SAS and, presumably,</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38768.00pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">other statistical software packages.  Complications can arise when there are no late</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38781.80pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">stage animals in some concentrations, but these situations can be handled in a straight-</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:72.00pt;top:38795.60pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 12.00pt">forward fashion.</FONT></FONT></FONT></SPAN>
<SPAN STYLE="color:#000000;position:absolute;left:292.60pt;top:39012.65pt;z-index:3;"><FONT FACE ="Arial" style = "font-size: 12.00pt"><FONT COLOR="000000"><FONT STYLE="font-size: 10.02pt">A - 19</FONT></FONT></FONT></SPAN>
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