

[Federal Register: September 12, 2007 (Volume 72, Number 176)]
[Notices]               
[Page 52108-52125]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr12se07-84]                         

-----------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

[OPP-2004-0292; FRL-8144-4]

 
Pyraclostrobin; Order Denying Objections to Issuance of 
Tolerances

AGENCY: Environmental Protection Agency (EPA).

ACTION: Order.

-----------------------------------------------------------------------

SUMMARY: The Natural Resource Defense Council (``NRDC'') filed 
objections with EPA to a final rule under section 408 of the Federal 
Food, Drug, and Cosmetic Act (``FFDCA''), (21 U.S.C. 346a), 
establishing tolerances for the pesticide pyraclostrobin on various 
food commodities. NRDC argues that EPA has unlawfully removed the 
additional safety factor for the protection of infants and children 
required by Food Quality Protection Act of 1996. This order denies the 
objections for the reasons stated herein.

FOR FURTHER INFORMATION CONTACT: Tony Kish, Registration Division 
(7505P), Office of Pesticide Programs, Environmental Protection Agency, 
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone 
number: (703) 308-9443; e-mail address: kish.tony@epa.gov.

SUPPLEMENTARY INFORMATION:

Response to NRDC Objections

Table of Contents
I. General Information
A. Does This Action Apply to Me?
B. How Can I Get Additional Information, Including Copies of this 
Document and Other Related Documents?
II. Introduction
A. What Action Is the Agency Taking?
B. What Is the Agency's Authority for Taking This Action?
III. Statutory and Regulatory Background
A. Statutory Background
B. Setting Tolerances Under the FFDCA
 1. In general
 2. Choosing a tolerance value
 3. The safety determination--risk assessment

[[Page 52109]]

 a. Levels of concern and risk assessment
 (i) Threshold Effects
 (ii) Non-threshold effects
 b. Estimating human exposure
C. Children's Safety Factor Policy
IV. The Challenged Tolerance Decision
V. NRDC Objections
A. Children's Safety Factor
 1. Legal Requirements for Imposing the Children's Safety Factor and 
the Standard for Choosing a Different Safety Factor
 2. Pre-natal Sensitivity
 3. Inadequate and Missing Data
 a. Immunotoxicity Data
 b. Two-generation Reproduction Study
 c. Other Data Deficiencies
B. Arbitrary and Capricious
VI. Public Comment
A. In General
B. BASF Corporation
C. NRDC
VII. Response to Objections
A. Children's Safety Factor
 1. Legal Interpretation of the Children's Safety Factor Provision
 a. Children's Safety Factor Provision
 b. Operation of the Children's Safety Factor Provision
 i. Data Gaps
 ii. Increased Sensitivity in the Young
 c. The Standard for Choosing a Different Safety Factor
 2. Individual Factual Findings Bearing on the Children's Safety Factor
 a. Pre-Natal Sensitivity
 i. Rat Developmental Study
 ii. Rabbit Developmental Study
 b. Immunotoxicity
 c. Two-generation Reproduction Study
 d. Other Data Deficiencies
 e. Conclusion With Regard to NRDC's Factual Allegations
B. NRDC's Claim that EPA's Tolerance Decision was Arbitrary and 
Capricious
C. Conclusion on Objections
VIII. Response to Comments
IX. Regulatory Assessment Requirements
X. Submission to Congress and the Comptroller General

I. General Information

A. Does This Action Apply to Me?

    In this document EPA denies objections to a tolerance actions filed 
by the Natural Resources Defense Council (``NRDC''). This action may 
also be of interest to agricultural producers, food manufacturers, or 
other pesticide manufacturers. Potentially affected categories and 
entities may include, but are not limited to:
     Crop Production (NAICS code 111).
     Animal Production (NAICS code 112).
     Food Manufacturing (NAICS code 311).
     Pesticide Manufacturing (NAICS code 32532).
    This listing is not intended to be exhaustive, but rather provides 
a guide for readers regarding entities who may be interested in today's 
action.

B. How Can I Get Additional Information, Including Copies of this 
Document and Other Related Documents?

    An electronic copy of this Federal Register document and all other 
documents included in the rulemaking docket for this action may be 
accessed through the EPA's electronic docket. EPA has established a 
docket for this action under docket identification (ID) number EPA-HQ-
OPP-2004-0292. To access the electronic docket, go to http://www.regulations.gov
, select ``Advanced Search,'' then ``Docket 

Search.'' Insert the docket ID number where indicated and select the 
``Submit'' button. Follow the instructions on the regulations.gov web 
site to view the docket index or access available documents. All 
documents in the docket are listed in the docket index available in 
regulations.gov. Although listed in the index, some information is not 
publicly available, e.g., Confidential Business Information (CBI) or 
other information whose disclosure is restricted by statute. Certain 
other material, such as copyrighted material, is not placed on the 
Internet and will be publicly available only in hard copy form. 
Publicly available docket materials are available in the electronic 
docket at http://www.regulations.gov,or, if only available in hard 

copy, at the OPP Regulatory Public Docket in Rm. S-4400, One Potomac 
Yard (South Building), 2777 S. Crystal Drive, Arlington, VA. The Docket 
Facility is open from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays. The Docket telephone number is (703) 305-
5805.You may also access this Federal Register document electronically 
through the EPA Internet under the Federal Register'' listings at 
http://www.epa.gov/fedrgstr.


II. Introduction

A. What Action Is the Agency Taking?

    On June 5, 2006, the Natural Resource Defense Council (``NRDC'') 
filed objections with EPA to a final rule under section 408 of the 
Federal Food, Drug, and Cosmetic Act (``FFDCA''), (21 U.S.C. 346a), 
establishing tolerances for the pesticide pyraclostrobin on various 
food commodities. (Ref. 1). NRDC makes two main claims in its 
objections: (1) that EPA has unlawfully removed the additional safety 
factor for the protection of infants and children; and (2) that EPA's 
decision to promulgate the tolerances was arbitrary and capricious 
because EPA made its decision in the absence of data that EPA had 
determined were necessary to evaluate pyraclostrobin's safety. NRDC did 
not exercise the option provided in section 408(g)(2) to request a 
hearing on its objections. This Order responds to those objections.
    EPA published notice of the objections in the Federal Register, (71 
FR 41015 (July 19, 2006)), and held a 60-day public comment period.
    The body of this document contains the following sections. First, 
there is a background section which explains the applicable statutory 
and regulatory provisions, EPA risk assessment practices, and the 
relevant EPA science policy documents. Second, EPA describes the 
objected-to tolerance action. Third, there is a section setting forth 
in greater detail the substance of the objections. Fourth, a summary of 
the public comment is presented. Finally, EPA's announces its response 
to the objections.

B. What Is the Agency's Authority for Taking This Action?

    The procedure for filing objections to tolerance actions and EPA's 
authority for acting on such objections is contained in section 408(g) 
of the FFDCA and regulations at 40 CFR Part 178. (21 U.S.C. 346a(g)).

III. Statutory and Regulatory Background

A. Statutory Background

    EPA establishes maximum residue limits, or ``tolerances,'' for 
pesticide residues in food under section 408 of the FFDCA. (21 U.S.C. 
346a). Without such a tolerance or an exemption from the requirement of 
a tolerance, a food containing a pesticide residue is ``adulterated'' 
under section 402 of the FFDCA and may not be legally moved in 
interstate commerce. (21 U.S.C. 331, 342). Monitoring and enforcement 
of pesticide tolerances are carried out by the U.S. Food and Drug 
Administration (``FDA'') and the U. S. Department of Agriculture 
(``USDA'').
    A pesticide tolerance may only be promulgated by EPA if the 
tolerance is ``safe.'' (21 U.S.C. 346a(b)(2)(A)(i)). ``Safe'' is 
defined by the statute to mean

[[Page 52110]]

that ``there is a reasonable certainty that no harm will result from 
aggregate exposure to the pesticide chemical residue, including all 
anticipated dietary exposures and all other exposures for which there 
is reliable information.'' (21 U.S.C. 346a(b)(2)(A)(ii)). Section 408 
directs EPA, in making a safety determination, to ``consider, among 
other relevant factors- . . . .available information concerning the 
aggregate exposure levels of consumers (and major identifiable 
subgroups of consumers) to the pesticide chemical residue and to other 
related substances, including dietary exposure under the tolerance and 
all other tolerances in effect for the pesticide chemical residue, and 
exposure from other non-occupational sources.'' (21 U.S.C. 
346a(b)(2)(D)(vi)). Other provisions address in greater detail exposure 
considerations involving ``anticipated and actual residue levels'' and 
``percent of crop actually treated.'' (See 21 U.S.C. 346a(b)(2)(E) and 
(F)). Section 408(b)(2)(C) requires EPA to give special consideration 
to risks posed to infants and children. This provision directs that 
``an additional tenfold margin of safety for the pesticide chemical 
residue and other sources of exposure shall be applied for infants and 
children to take into account potential pre- and post-natal toxicity 
and completeness of the data with respect to exposure and toxicity to 
infants and children.'' (21 U.S.C. 346a(b)(2)(C)). EPA is permitted to 
``use a different margin of safety for the pesticide chemical residue 
only if, on the basis of reliable data, such margin will be safe for 
infants and children.'' (Id.) [The additional safety margin for infants 
and children is referred to throughout this notice as the ``children's 
safety factor.''] These provisions establishing the detailed safety 
standard for pesticides were added to section 408 by the Food Quality 
Protection Act of 1996 (``FQPA''), an act that substantially rewrote 
this section of the statute.
    Tolerances are established by rulemaking under the unique 
procedural framework set forth in the FFDCA. Generally, the rulemaking 
is initiated by the party seeking the tolerance by means of filing a 
petition with EPA. (See 21 U.S.C. 346a(d)(1)). EPA publishes in the 
Federal Register a notice of the petition filing along with a summary 
of the petition, prepared by the petitioner. (21 U.S.C. 346a(d)(3)). 
After reviewing the petition, and any comments received on it, EPA may 
issue a final rule establishing the tolerance, issue a proposed rule, 
or deny the petition. (21 U.S.C. 346a(d)(4)). Once EPA takes final 
action on the petition by either establishing the tolerance or denying 
the petition, any affected party has 60 days to file objections with 
EPA and seek an evidentiary hearing on those objections. (21 U.S.C. 
346a(g)(2)). Objections must state with ``particularity'' their basis. 
(40 C.F.R. 178.25(a)(2)). EPA's final order on the objections is 
subject to judicial review. (21 U.S.C. 346a(h)(1)).
    EPA also regulates pesticides under the Federal Insecticide, 
Fungicide, and Rodenticide Act (``FIFRA''), (7 U.S.C. 136 et seq). 
While the FFDCA authorizes the establishment of legal limits for 
pesticide residues in food, FIFRA requires the approval of pesticides 
prior to their sale and distribution, (7 U.S.C. 136a(a)), and 
establishes a registration regime for regulating the use of pesticides. 
FIFRA regulates pesticide use in conjunction with its registration 
scheme by requiring EPA review and approval of pesticide labels and 
specifying that use of a pesticide inconsistent with its label is a 
violation of federal law. (7 U.S.C. 136j(a)(2)(G)). In the FQPA, 
Congress integrated action under the two statutes by requiring that the 
safety standard under the FFDCA be used as a criterion in FIFRA 
registration actions as to pesticide uses which result in dietary risk 
from residues in or on food, (7 U.S.C. 136(bb)), and directing that EPA 
coordinate, to the extent practicable, revocations of tolerances with 
pesticide cancellations under FIFRA. (21 U.S.C. 346a(l)(1)).

B. Setting Tolerances Under the FFDCA

    1. In general. The process EPA follows in setting tolerances under 
the FFDCA includes two steps. First, EPA determines an appropriate 
residue level value for the tolerance taking into account data on 
levels that can be expected in food. Second, EPA evaluates the safety 
of the tolerance relying on toxicity and exposure data and guided by 
the statutory definition of ``safe'' and requirements concerning risk 
assessment. Only on completion of the second step can EPA make a 
decision on whether a tolerance may be established. Below, EPA explains 
in detail, the reasons for this approach.
    2. Choosing a tolerance value. In the first step of the tolerance 
setting process (choosing a tolerance value), EPA evaluates data from 
experimental crop field trials in which the pesticide has been used in 
a manner, consistent with the draft FIFRA label, that is likely to 
produce the highest residue in the crop in question (e.g., maximum 
application rate, maximum number of applications, minimum pre-harvest 
interval between last pesticide application and harvest). (Refs. 2 and 
3). These crop field trials are generally conducted in several fields 
at several geographical locations. (Ref. 3 at 5, 7 and Tables 1 and 5). 
Several samples are then gathered from each field and analyzed. (Id. at 
53). Generally, the results from such field trials show that the 
residue levels for a given pesticide use will vary from as low as non-
detectable to measurable values in the parts per million (``ppm'') 
range with the majority of the values falling at the lower part of the 
range. EPA uses a statistical procedure to analyze the field trial 
results and identify the upper bound of expected residue values. This 
upper bound value is used as the tolerance value. (Ref. 4). (As 
discussed below, the safety of the tolerance value chosen is separately 
evaluated.)
    There are three main reasons for closely linking tolerance values 
to the maximum value that could be present from maximum label usage of 
the pesticide. First, EPA believes it is important to coordinate its 
actions under the two statutory frameworks governing pesticides. (See 
The Pesticide Coordination Policy; Response to Petitions, (61 FR 2378, 
2379; January 25, 1996)). It would be illogical for EPA to set a 
pesticide tolerance under the FFDCA without considering what action is 
being taken under FIFRA with regard to registration of that pesticide 
use. (Cf. 40 CFR 152.112(g) (requiring all necessary tolerances to be 
in place before a FIFRA registration may be granted)). In coordinating 
its actions, one basic tenet that EPA follows is that a grower who 
applies a pesticide consistent with the FIFRA label directions should 
not run the risk that his or her crops will be adulterated under the 
FFDCA because the residues from that legal application exceed the 
tolerance associated with that use. To prevent such an outcome, crop 
field trials require application of the pesticide in the manner most 
likely to produce maximum residues. Second, choosing tolerance values 
based on FIFRA label rates helps to ensure that tolerance levels are 
established no higher than necessary. If tolerance values were selected 
solely in consideration of health risks, in some circumstances, 
tolerance values might be set so as to allow much greater application 
rates than necessary for effective use of the pesticide. This could 
encourage misuse of the pesticide. Finally, closely linking tolerance 
values to FIFRA labels helps EPA to police compliance with label 
directions by growers because detection of an

[[Page 52111]]

overtolerance residue is indicative of use of a pesticide at levels, or 
in a manner, not permitted on the label.
    3. The safety determination - risk assessment. Once a tolerance 
value is chosen, EPA then evaluates the safety of the pesticide 
tolerance using the process of risk assessment. To assess risk of a 
pesticide, EPA combines information on pesticide toxicity with 
information regarding the route, magnitude, and duration of exposure to 
the pesticide.
    In evaluating a pesticide's potential hazards (e.g., liver effects, 
carcinogenicity), EPA examines both short-term (e.g., ``acute'') and 
longer-term (e.g., ``chronic'') adverse effects from pesticide 
exposure. (Ref. 2 at 8-10). EPA also considers whether the ``effect'' 
has a threshold - a level below which exposure has no appreciable 
chance of causing the adverse effect. For non-threshold effects, EPA 
assumes that any exposure to the substance increases the risk that the 
adverse effect may occur. At present, EPA only considers one adverse 
effect, the chronic effect of cancer, to potentially be a non-threshold 
effect. (Ref. 2 at 8-9). Not all carcinogens, however, pose a risk at 
any exposure level (i.e., ``a non-threshold effect or risk''). Advances 
in the understanding of carcinogenesis have increasingly led EPA to 
conclude that some pesticides that cause carcinogenic effects only 
cause such effects above a certain threshold of exposure. EPA has 
traditionally considered adverse effects on the endocrine system to be 
a threshold effect; that determination is being reexamined in 
conjunction with the endocrine disruptor screening program.
    Once EPA identifies a hazard for a durational scenario, EPA must 
determine the toxicological level of concern and then compare estimated 
human exposure to this level of concern. This comparison is done 
through either calculating a safe dose in humans (incorporating all 
appropriate safety factors) and expressing exposure as a percentage of 
this safe dose (the reference dose (``RfD'') approach) or dividing 
estimated human exposure into an appropriately protective dose from the 
relevant studies (the margin of exposure (``MOE'') approach). How EPA 
determines the level of concern and assesses risk under these two 
approaches is explained in more detail below. EPA's general approach to 
estimating exposure is also briefly discussed.
    a. Levels of concern and risk assessment--i. Threshold effects. In 
assessing the risk from a pesticide's threshold effects, EPA evaluates 
an array of toxicological studies on the pesticide. In each of these 
studies, EPA attempts to identify the lowest observed adverse effect 
level (``LOAEL'') and the next lower dose at which there are no 
observed adverse affect levels (``NOAEL''). Generally, EPA will use the 
lowest NOAEL from the available studies, taking into account the route 
and duration of exposure, as a starting point in estimating the level 
of concern for humans for a given exposure scenario (e.g., acute oral 
exposure). This selected NOAEL is usually referred to as the Point of 
Departure. In estimating and describing the level of concern, however, 
the Point of Departure is at times manipulated differently depending on 
whether the risk assessment addresses dietary or non-dietary exposures. 
(Refs. 2 at 3-8; 5 at 8, 52-52; and 6).
    For dietary risks, EPA uses the Point of Departure to calculate a 
safe dose or RfD. The RfD is calculated by dividing the Point of 
Departure by applicable safety or uncertainty factors. Typically, a 
combination of safety or uncertainty factors providing a hundredfold 
(100X) margin of safety is used: 10X to account for uncertainties 
inherent in the extrapolation from laboratory animal data to humans and 
10X for variations in sensitivity among members of the human population 
as well as other unknowns. Further, to account for deficiencies in the 
database or the results seen in the database, EPA has traditionally 
applied additional safety factors on a case-by-case basis. The FQPA 
amendments to FFDCA section 408 require an additional safety factor of 
10X to protect infants and children (to address data completeness and 
pre- and post-natal toxicity concerns), unless reliable data support 
selection of a different factor.
    In implementing FFDCA section 408, EPA's Office of Pesticide 
Programs, also calculates a variant of the RfD referred to as a 
Population Adjusted Dose (``PAD''). A PAD is the RfD divided by any 
portion of the FQPA children's safety factor that does not correspond 
to one of the traditional additional safety factors used in general 
Agency risk assessment. (Ref. 5 at 13-16). The reason for calculating 
PADs is so that other parts of the Agency, which are not governed by 
FFDCA section 408, can, when evaluating the same or similar substances, 
easily identify which aspects of a pesticide risk assessment are a 
function of the particular statutory commands in FFDCA section 408. 
Today, RfDs and PADs are generally calculated for both acute and 
chronic dietary risks although traditionally a RfD or PAD was only 
calculated for chronic dietary risks. Throughout this document general 
references to EPA's calculated safe dose are denoted as a RfD/PAD.
    To quantitatively describe risk using the RfD/PAD approach, 
estimated exposure is expressed as a percentage of the RfD/PAD. Dietary 
exposures lower than 100 percent of the RfD/PAD are generally not of 
concern.
    For non-dietary, and often for combined dietary and non-dietary, 
risk assessments of threshold effects, the toxicological level of 
concern is not expressed as a safe dose or RfD/PAD but rather as the 
margin of exposure (MOE) that is necessary to be sure that exposure to 
a pesticide is safe. To calculate the MOE for a pesticide for a given 
exposure scenario, the expected human exposure to the pesticide is 
divided into the dose identified as the Point of Departure. A safe MOE 
is generally considered to be a margin at least as high as the product 
of all applicable safety factors for a pesticide. For example, if a 
pesticide needs a 10X factor to account for interspecies differences, a 
10X factor for intraspecies differences, and a 10X FQPA children's 
safety factor, the safe or target MOE would be a value of at least 
1,000. In contrast to the RfD/PAD approach, the higher the MOE, the 
safer the pesticide. Accordingly, if the target MOE is 1,000, MOEs 
exceeding 1,000 would generally not be of concern. Like RfD/PADs, 
specific MOEs are calculated for exposures of different durations. For 
non-dietary exposures, EPA typically examines short-term, intermediate-
term, and long-term exposures. Additionally, non-dietary exposure often 
involves exposures by various routes including dermal, inhalation, and 
oral.
    The RfD/PAD and MOE approaches are fundamentally equivalent. For a 
given risk and given exposure of a pesticide, if the pesticide were 
found to be safe under a RfD/PAD analysis it would also pass under the 
MOE approach, and vice-versa.
    ii. Non-threshold effects. For risk assessments for non-threshold 
effects, EPA does not use the RfD/PAD or MOE approach. Rather, EPA 
calculates the slope of the dose-response curve for the non-threshold 
effects from relevant studies using a model that assumes that any 
amount of exposure will lead to some degree of risk. The slope of the 
dose-response curve can then be used to estimate the probability of 
occurrence of additional adverse effects as a result of exposure to the 
pesticide. For non-threshold cancer risks, EPA generally is concerned 
if the probability of increased cancer cases exceed the range of 1 in 1 
million. Because NRDC's petition concerns the children's safety factor 
and

[[Page 52112]]

the children's safety factor is only applicable to threshold risks, no 
further discussion of non-threshold risk assessment is included here.
    b. Estimating human exposure. Equally important to the risk 
assessment process as identifying hazards and determining the 
toxicological level of concern is estimating human exposure. Under 
FFDCA section 408, EPA is concerned not only with exposure to pesticide 
residues in food but also exposure resulting from pesticide 
contamination of drinking water supplies and from use of pesticides in 
the home or other non-occupational settings. (See 21 U.S.C. 
346a(b)(2)(D)(vi)). There are two critical variables in estimating 
exposure in food: (1) The types and amount of food that is consumed; 
and (2) the residue levels in those foods. Consumption is estimated by 
EPA based on scientific surveys of individuals' food consumption in the 
United States conducted by the U.S. Department of Agriculture. (Ref. 2 
at 12). Information on residue levels comes from a range of sources 
including crop field trials, data on pesticide reduction due to 
processing and other practices, information on the extent of usage of 
the pesticide, and monitoring of the food supply. (Id. at 17).
    In assessing exposure from pesticide residues in food, EPA, for 
efficiency's sake, follows a tiered approach in which it, in the first 
instance, conducts an initial, screening-level exposure assessment 
using the worst case assumptions that 100 percent of the crop in 
question is treated with the pesticide and 100 percent of the food from 
that crop contains pesticide residues at the tolerance level. (Id. at 
11). When such an assessment shows no risks of concern, EPA's resources 
are conserved because a more complex risk assessment is avoided and 
regulated parties are spared the cost of any additional studies that 
may be needed. If, however, a first tier assessment suggests there 
could be a risk of concern, EPA then attempts to refine its exposure 
assumptions to yield a more realistic picture of residue values through 
use of data on the percent of the crop actually treated with the 
pesticide and data on the level of residues that may be present on the 
treated crop. These latter data are used to estimate what has been 
traditionally referred to by EPA as ``anticipated residues.'' Use of 
percent crop treated data and anticipated residue information is 
appropriate because EPA's worst case assumptions of 100 percent 
treatment and residues at tolerance value significantly overstate 
residue values. (71 FR 43906, 43909-43910 (August 2, 2006)).
    In estimating pesticide exposure levels in drinking water, EPA most 
frequently uses mathematical water exposure models rather than 
pesticide-specific monitoring data. (69 FR 30042, 30058 (May 26, 2004). 
EPA's models are based on extensive monitoring data and detailed 
information on soil properties, crop characteristics, and weather 
patterns. These models calculate estimated environmental concentrations 
of pesticides using laboratory data that describe how quickly the 
pesticide breaks down to other chemicals and how it moves in the 
environment (i.e., does it bind to the soil or is it highly water 
soluble). Although computer modeling provides an indirect estimate of 
pesticide concentrations, these concentrations can be estimated 
continuously over long periods of time, and for places that are of most 
interest for any particular pesticide. Modeling is a useful tool for 
characterizing vulnerable sites, and can be used to estimate peak 
concentrations from infrequent, large storms. Whether EPA assesses 
pesticide exposure in drinking water through monitoring data or 
modeling, EPA uses the higher of the two values from surface and ground 
water in assessing overall exposure to the pesticide. In most cases, 
pesticide residues in surface water are significantly higher than in 
ground water.
    Generally, in assessing residential exposure to pesticides, EPA 
relies on its Residential Standard Operating Procedures (``SOPs'')(Ref. 
7). The SOPs establish models for estimating application and post-
application exposures in a residential setting where pesticide-specific 
monitoring data is not available. SOPs have been developed for many 
common exposure scenarios including pesticide treatment of lawns, 
garden plants, trees, swimming pools, pets, and indoor surfaces 
including crack and crevice treatments. The SOPs are based on existing 
monitoring and survey data including information on activity patterns, 
particularly for children. Where available, EPA relies on pesticide-
specific data in estimating residential exposures.

C. Children's Safety Factor Policy

    As part of implementation of the major changes to FFDCA section 408 
included in the FQPA, EPA has issued a number of policy guidance 
documents addressing critical science issues. On January 31, 2002, EPA 
released its science policy guidance on the children's safety factor. 
(Ref. 5) [This policy is hereinafter referred to as the ``Children's 
Safety Factor Policy'']. The Children's Safety Factor Policy emphasizes 
throughout that EPA interprets the children's safety factor provision 
as establishing a presumption in favor of application of an additional 
10X safety factor for the protection of infants and children. (Id. at 
4, 11, 47, A-6). Further, the policy notes that the children's safety 
factor provision permits a different safety factor to be substituted 
for this default 10X factor only if reliable data are available to show 
that the different factor will protect the safety of infants and 
children. (Id.). Given the wealth of data available on pesticides, 
however, the policy indicates a preference for making an individualized 
determination of a protective safety factor if possible. (Id. at 11). 
The policy states that use of the default factor could under- or over-
protect infants and children due to the wide variety of issues 
addressed by the children's safety factor. (Id.). Further, the policy 
notes that ``[i]ndividual assessments may result in the use of 
additional factors greater or less than, or equal to 10X, or no 
additional factor at all.'' (Id.).
    In making pesticide-specific assessments regarding the magnitude of 
the children's safety factor, the policy stresses the importance of 
focusing on the statutory language that ties the children's safety 
factor to concerns regarding potential pre- and post-natal toxicity and 
the completeness of the toxicity and exposure databases. (Id. at 11-
12). As to the completeness of the toxicity database, the policy 
recommends use of a weight-of-the-evidence approach which considers not 
only the presence or absence of data generally required under EPA 
regulations and guidelines but also the availability of ``any other 
data needed to evaluate potential risks to children.'' (Id. at 20). The 
policy indicates that the principal inquiry concerning missing data 
should center on whether the missing data would significantly affect 
calculation of a safe exposure level. (Id. at 22; accord 67 FR 60950, 
60955 (September 27, 2002) (finding no additional safety factor 
necessary for triticonazole despite lack of developmental neurotoxicity 
(``DNT'') study because the ``DNT [study] is unlikely to affect the 
manner in which triticonazole is regulated.'')). When the missing data 
are data above and beyond general regulatory requirements, the policy 
states that the weight of evidence would generally only support the 
need for an additional safety factor where the data ``is being required 
for `cause,' that is, if a significant concern is raised

[[Page 52113]]

based upon a review of existing information, not simply because a data 
requirement has been levied to expand OPP's general knowledge.'' (Ref. 
5 at 23).
    As to potential pre- and post-natal toxicity, the Children's Safety 
Factor Policy lists a variety of factors that should be considered in 
evaluating the degree of concern regarding any identified pre- or post-
natal toxicity. (Id. at 27-31). As with the completeness of the 
toxicity database, the policy emphasizes that the analysis should focus 
on whether any identified pre- or post-natal toxicity raises 
uncertainty as to whether the RfD/PAD is protective of infants and 
children. (Id. at 31). Once again, the presence of pre- or post-natal 
toxicity, by itself, is not regarded as determinative as to the 
children's safety factor. Rather, the policy stresses the importance of 
evaluating all of the data under a weight of evidence approach focusing 
on the safety of infants and children. (Id.).
    In evaluating the completeness of the exposure database, the policy 
explains that a weight-of-the-evidence approach should be used to 
determine the confidence level EPA has as to whether the exposure 
assessment ``is either highly accurate or based upon sufficiently 
conservative input that it does not underestimate those exposures that 
are critical for assessing the risks to infants and children.'' (Id. at 
32). EPA describes why its methods for calculating exposure through 
various routes and aggregating exposure over those routes generally 
produce conservative exposure estimates - i.e. health-protective 
estimates due to overestimation of exposure. (Id. at 40-43). 
Nonetheless, EPA emphasizes the importance of verifying that the 
tendency for its methods to overestimate exposure in fact were 
adequately protective in each individual assessment. (Id. at 44).

IV. The Challenged Tolerance Decision

    On April 5, 2006, EPA promulgated a final rule establishing 
tolerances for the fungicide pyraclostrobin on shelled succulent beans; 
foliage in the legume crop group; mangoes; and papayas. (71 FR 17014 
(April 5, 2006)). Pyraclostrobin is a synthetic analog of a natural 
antifungal substance which inhibits spore germination, mycelial growth, 
and sporulation of the fungus on the leaf surface. (Ref. 8 at 4). The 
tolerances were requested in petitions from the pyraclostrobin 
registrant, BASF Corporation, and the Interregional Research Project 
Number 4 (``IR-4''). The IR-4 is a program sponsored by the U.S. 
Department of Agriculture and land grant universities and directed 
toward obtaining regulatory approval for pesticide uses on minor and 
speciality food crops that are not likely to be supported by private 
sector companies. EPA evaluated the petitions in a joint effort with 
the Pest Management Regulatory Agency of Canada.
    Given pyraclostrobin's exposure pattern and toxicological 
characteristics, EPA determined that pyraclostrobin potentially 
presented acute, chronic, short-term, and cancer risks and EPA 
quantitatively assessed these risks in making its safety determination. 
(71 FR at 17018-17019; 69 FR 63083, 93093-63095 (October 29, 2004); 
Ref. 8 at 31-32). All of these risks were found to be below the 
Agency's level of concern. (Id.). EPA concluded that there were 
reliable data supporting its determination that the additional 
children's safety factor was not needed to protect the safety of 
children. In making this determination EPA considered the completeness 
of the toxicity and exposure database and data bearing on pre- and 
post-natal toxicity. (71 FR at 17018; 69 FR 63092-63093). EPA found 
that there was adequate toxicity and exposure data. Although there was 
some evidence of qualitative and quantitative increased sensitivity in 
the young from the developmental study in rabbits and reproduction 
study in rats, respectively, EPA concluded using a weight-of-the-
evidence test that residual concerns for increased sensitivity in the 
young were low. (69 FR at 63093); (Ref. 9 at 8).

V. NRDC Objections

    In its objections, NRDC cites various allegedly inadequate studies 
and pre-natal toxic effects of pyraclostrobin as grounds for claiming 
it was unlawful for EPA to remove the children's safety factor and 
EPA's overall decision was arbitrary and capricious.

A. Children's Safety Factor

    NRDC argues that EPA should have retained the children's safety 
factor for two separate reasons: (1) pyraclostrobin demonstrated pre-
natal toxicity; and (2) there were inadequacies in the submitted 
toxicity data on pyraclostrobin and additional toxicity and exposure 
data are needed. NRDC claims that EPA's decision to remove the 
children's safety factor violates the FFDCA; however, NRDC does not 
allege that retention of the children's safety factor would result in 
the pyraclostrobin tolerances exceeding the FFDCA section 408 safety 
standard. NRDC expanded on its objections in comments it submitted on 
its own objections. These comments principally argued that EPA had 
wrongly interpreted the children's safety factor provision. (Ref. 10).
    1. Legal requirements for imposing the children's safety factor and 
the standard for choosing a different safety factor. NRDC describes the 
children's safety factor provision as requiring that the additional 
children's safety factor ``shall be applied'' to ``take into account'' 
(1) ``potential pre- and post-natal toxicity;'' (2) ``completeness'' of 
toxicity data; and (3) ``completeness'' of the exposure data. With 
regard to the reference to pre- and post-natal toxicity, NRDC argues 
that this statutory language ``mandates application of the safety 
factor to account for any potential for pre- or post-natal toxicity.'' 
(Ref. 10 at 2). As to completeness of the data, NRDC takes a similarly 
rigid position: ``Where studies identified by EPA as necessary to 
ensure safety have never been conducted or reviewed - or have been 
determined to be inadequate - EPA by definition cannot find that there 
is a `reasonable certainty' that `no harm will result' to children, as 
required by law[,]'' and therefore, cannot modify the children's safety 
factor. (Id.).
    NRDC acknowledges that EPA may apply a factor different than 
presumptive tenfold children's safety factor but stresses that a 
different factor may be applied only if there is reliable data showing 
the different factor is safe. EPA, NRDC claims, has applied a different 
standard in the pyraclostrobin tolerance decision - requiring that 
there be merely adequate data on pyraclostrobin toxicity and exposure 
and that there be no substantial evidence of increased sensitivity of 
infants and children to the pesticide. (Id.).
    2. Pre-natal sensitivity. In discussing evidence on pre-natal 
sensitivity, NRDC references both the developmental studies in rats and 
in rabbits. NRDC asserts that the developmental rat study shows 
qualitative increased sensitivity in the rat fetuses because the 
effects in the rat fetuses (dilated renal pelvis and cervical ribs with 
no cartilage) were more severe than the effects in adults (reduced body 
weight, body weight gain, food intake, and food efficiency). (Ref. 1 at 
7). Qualitative increased sensitivity is seen in the rabbit 
developmental study, according to NRDC, again because the effects in 
the fetuses were more severe than the effects in the adults (increased 
resorption and post-implantation loss versus reduced body weight, body 
weight gain, food intake, and food efficiency). (Id.). NRDC argues that 
EPA erred by looking beyond the question of whether the animal studies 
show fetuses to be qualitatively more sensitive than

[[Page 52114]]

maternal animals to examine whether it was safe to remove or reduce the 
factor despite a finding of qualitative increased sensitivity. 
According to NRDC, because the studies show qualitative increased 
sensitivity in pre-natal animals as compared to adult animals, ``EPA 
must retain the full tenfold safety factor . . . .'' (Id. at 5).
    3. Inadequate and missing data--a. Immunotoxicity data. NRDC argues 
that, because EPA has not required immunotoxicity data on 
pyraclostrobin, EPA cannot explain the differential immunotoxic results 
between males and females in the pyraclostrobin studies. Due to this 
lack of understanding, NRDC claims that immunotoxicity ``should be 
considered a serious potential risk of pyraclostrobin . . . [and] EPA 
must retain the full tenfold safety factor as a result.'' (Id. at 6-7). 
NRDC cites four studies in support of this argument. First, it 
references a 90-day oral toxicity mouse study in which females 
allegedly showed immunotoxic effects at a dose at which males only 
showed more generalized toxicity (e.g., reduced body weight). Second, 
NRDC points to a 90-day oral toxicity study in dogs in which NRDC 
claims females suffered body weight loss, reduced food intake, and 
reduced food efficiency in addition to the gastrointestinal effects 
that occurred in both sexes. Third, NRDC cites two neurotoxicity 
studies in which males were shown to be significantly more sensitive 
than females. NRDC claims that these studies demonstrate that males and 
females respond differently to pyraclostrobin and that EPA should be 
particularly concerned about the immunotoxic effects in females because 
there is ``substantial data demonstrating that females are more likely 
than males to develop autoimmune diseases in response to environmental 
stressors.'' (Id. at 6).
    b. Two-generation reproduction study. NRDC asserts that the two-
generation rat reproduction study with pyraclostrobin relied upon by 
EPA is ``invalid'' and that EPA cannot rehabilitate it by combining it 
with a one-generation rat reproduction study because that study 
produced results which contradict the two-generation study. (Id. at 7-
8). The two-generation study is invalid, according to NRDC, because it 
showed no adverse effects at any of the doses tested. NRDC states that 
such a study ``must be considered invalid because it is unknown whether 
the study failed to find an effect because there really was no effect, 
or if it was due to a lack of statistical power, poor study design, or 
an endless number of potential fatal weaknesses (e.g., the test agent 
could have degraded through poor storage conditions; the endpoint 
measurements could have been reported in error; treated and control 
animals could have been mis-categorized, etc.).'' (Id. at 8). NRDC 
argues that the one-generation study contradicts the two-generation 
study because the former identified adverse effects at a dose lower 
than a dose in the two-generation study that showed no effects. NRDC 
concludes that ``EPA must retain the full tenfold safety factor in 
light of these invalid and deficient studies.'' (Id.)
    c. Other data deficiencies. NRDC briefly mentions several other 
alleged data gaps or deficiencies: (1) data on anticipated 
pyraclostrobin residues which EPA has required to be submitted; (2) a 
missing 28-day inhalation toxicity study; (3) a deficient chronic 
toxicity study in rats due to failure to show adverse effects; (4) a 
deficient mouse cancer study due to failure to show adverse effects; 
and (5) an unacceptable dermal penetration study due to problems in 
administration of the test dose. Categorizing these deficiencies as 
``significant,'' NRDC argues EPA must retain the children's safety 
factor to address them. (Id. at 8-10).

B. Arbitrary and Capricious

    NRDC also argues that the tolerance decision was arbitrary and 
capricious ``because EPA never received or reviewed information that 
the agency considered necessary to review the pesticides' safety 
(listed above), and because EPA failed to explain adequately its 
departure from the required children's safety factor.'' (Id. at 10).

VI. Public Comment

A. In General

    On July 19, 2006, EPA published a notice in the Federal Register 
calling attention to and requesting comments on the NRDC Objections. 
(71 FR 41015 (July 19, 2006)). The notice included a short summary of 
the objections and referenced readers to EPA's electronic docket for a 
full copy of the objections. EPA received three comments on the 
objections. Other than NRDC's comments on its own objections, the only 
significant comment EPA received was from BASF Corporation, the 
registrant under FIFRA for pyraclostrobin.

B. BASF Corporation

    BASF Corporation has registered pyraclostrobin for use as a 
pesticide under FIFRA and petitioned for several of the tolerances that 
are subject to the present objections. As to the potential for 
pyraclostrobin to impact differently on males and females, BASF argues 
in its comments that differential effects on the sexes are noted in 
toxicology studies and taken into account in setting the RfD. (Ref. 
11). Any uncertainty regarding the sensitivities of these two groups is 
addressed, according to BASF, by the tenfold uncertainty factor used to 
account for variable sensitivities in humans. Further, BASF argues that 
the ``issue of differential sensitivity between sexes is not relevant 
for evaluating the need to apply the FQPA safety factor'' because that 
safety factor only addresses potential differences in sensitivities 
between adults and children. (Id. at 1).
    BASF challenges NRDC's assertion that qualitative sensitivity was 
demonstrated in the rat and rabbit developmental studies. BASF claims 
that the fetal effects seen in the rat study (dilated renal pelvis and 
cervical ribs with no cartilage) were not due to treatment. This is 
evidenced, according to BASF, by the fact that the incidence of these 
effects was within the historical control range for the experimental 
animal. As to the effects on rabbit fetuses (increased resorption and 
post-implantation loss), BASF argues these effects are a result of the 
severe effects that pyraclostrobin had on the maternal animals as 
opposed to any direct toxic effect on the fetuses. According to BASF, 
``maternal body weight gain during the treatment period was reduced by 
a dramatic 77% at the high dose and 39% at the mid dose compared to 
controls. This substantial effect to the maternal animals would be 
expected to affect the dam's ability to deliver full-term fetuses and 
does not reflect a direct action of the test material on the fetus.'' 
(Id. at 2).
    With regard to the two-generation reproduction study in rats, BASF 
contends that the results from this study are not inconsistent with the 
one-generation reproduction study. BASF claims that body weight changes 
were seen in the highest dose tested in the two-generation reproduction 
study. Although the body weight changes in the two-generation study 
were small, BASF argues that ``the effects at this dose fits along a 
dose-response curve with the two doses in the range-finding [one-
generation] study.'' (Id. at 3).
    BASF disputes NRDC's claims regarding data gaps and deficiencies. 
First, BASF asserts that a 28-day inhalation study has been submitted 
to EPA. Second, BASF contends that subsequent data submitted to EPA led 
EPA to conclude that the rat and mouse carcinogenicity studies were 
conducted at sufficiently high doses. Finally, BASF

[[Page 52115]]

states that a repeat dermal penetration study was conducted. (Id. at 
4).

C. NRDC

    In its comments, NRDC expands on its legal argument that EPA must 
retain the children's safety factor when data are absent. According to 
NRDC, when data EPA has determined are ``necessary to evaluate safety'' 
are not available, EPA ``by definition'' may not remove the 10X 
children's safety factor. (Ref. 10 at 2). NRDC also cites general 
statements that children can be more vulnerable than adults to 
pesticides and that children may have greater relative exposure to 
pesticides than adults and argues that this means that the children's 
safety factor must be retained for pyraclostrobin. (Id. at 3). Finally, 
NRDC listed various documents that it claims support its objections. 
(Id. at 4).

VII. Response to Objections

    As summarized above, NRDC's objections pertain primarily to EPA's 
decision on the children's safety factor - in brief, NRDC's argument is 
that, due to evidence on pre-natal toxicity and immunotoxicity, and 
data deficiencies, EPA erred in removing the children's safety factor. 
NRDC also recasts these same allegations to claim that EPA acted 
arbitrarily and capriciously in promulgating the pyraclostrobin 
tolerances. These arguments are addressed separately below.

A. Children's Safety Factor

    NRDC objects to the pyraclostrobin tolerances on the ground that it 
was unlawful for EPA to remove the children's safety factor. Although 
not stated, presumably NRDC believes that EPA should have denied the 
petition seeking the pyraclostrobin tolerances for this reason. A 
decision on the children's safety factor, however, is not outcome 
determinative with regard to whether a petitioned-for tolerance meets 
the safety standard for establishing tolerances. Retention of the 
children's safety standard would generally result in a tenfold lowering 
of the pesticide's RfD/PAD, thus decreasing by a factor of ten the 
amount of aggregate exposure to the pesticide that would not exceed the 
RfD/PAD; it would not, however, bar the establishment of the tolerance. 
EPA has established many tolerances for which the children's safety 
factor has been retained. (See, e.g., 71 FR 56369, 56372 (September 27, 
2006); 70 FR 14535, 14541-14542 (March 23, 2005)). Similarly, EPA has 
recently denied a petition to revoke tolerances which claimed that EPA 
should have retained the children's safety factor where it was clear 
that EPA could make the reasonable certainty of no harm finding with or 
without retention of the additional safety factor. (72 FR 39318, 39323-
39324 (July 18, 2007)). For pyraclostrobin, EPA's exposure assessment, 
which is partially refined, suggests that retention of the children's 
safety factor may raise safety concerns for the pesticide. Because it 
is unclear whether further refinement of the exposure assessment would 
render the decision on the children's safety factor irrelevant to the 
ultimate safety decision, EPA has chosen to address the merits of the 
argument presented by NRDC.
    NRDC makes two different types of arguments as to why the 
children's safety factor should be retained. First, citing various 
issues regarding pre-natal toxicity and data completeness, NRDC 
essentially argues that the overall weight-of-evidence does not support 
EPA's conclusion that there is reliable data showing it will be safe 
for children to use a hundredfold margin of safety rather than a 
thousand-fold margin. Second, NRDC argues that each of the individual 
issues it raises ``compel'' EPA to retain the children's safety factor. 
This second argument is more fully made in the legal contentions 
presented in NRDC's comments on its objections.
    In responding to NRDC's arguments, EPA first addresses the legal 
contention that various findings ``compel'' the retention of the 
children's safety factor. In this section, EPA explains why it 
fundamentally disagrees with NRDC's approach to the safety factor 
provision. Second, EPA examines the merits of the various factual 
allegations made by NRDC concerning pre-natal toxicity and data 
deficiencies. As EPA makes clear below, in most instances NRDC is 
mistaken in its factual allegations. Finally, EPA addresses whether the 
totality of the claims raised by NRDC alter EPA's conclusion regarding 
removal of the children's safety factor.
    1. Legal interpretation of the children's safety factor provision. 
In its objections and its comments on its objections, NRDC claims that 
(1) EPA is legally compelled to retain the children's safety factor 
when there is a data gap; (2) EPA is legally compelled to retain the 
children's safety factor when there is evidence showing that the young 
are more sensitive to the effects of a pesticide or a pesticide causes 
pre- or post-natal toxicity; and (3) EPA has applied an incorrect 
standard in evaluating whether the presumptive tenfold children's 
safety factor may be modified. Following a summary of the statutory 
language on the children's safety provision, EPA explains why each of 
these assertions are incorrect.
    a. Children's safety factor provision. The statutory requirements 
pertaining to the children's safety factor are contained in two 
sentences in section 408(b)(2)(C). The first sentence commands that as 
to ``threshold effects, for the purposes of [making the reasonable 
certainty of no harm finding], an additional tenfold margin of safety 
for the pesticide chemical residue and other sources of exposure shall 
be applied for infants and children.'' (21 U.S.C. 346a(b)(2)(C)). This 
sentence also explains that the purpose for this additional safety 
factor is ``to take into account potential pre- and post-natal toxicity 
and completeness of the data with respect to exposure and toxicity to 
infants and children.'' (Id.). Switching course, the second sentence 
then countermands the mandatory language in the first sentence (``shall 
be applied'') and makes clear that EPA has the authority to deviate 
from the requirement to apply an additional 10X safety factor. The 
second sentence reads ``[n]othwithstanding such requirement for an 
additional margin of safety, the Administrator may use a different 
margin of safety for the pesticide chemical residue only if, on the 
basis of reliable data, such a margin will be safe for children.'' 
(Id.).
    b. Operation of the children's safety factor provision. EPA has 
interpreted the children's safety factor provision as containing a 
presumption in favor of retaining an additional tenfold safety factor 
for the protection of infants and children. That presumption may be 
overcome, however, when EPA has reliable data showing that use of a 
different safety factor will protect the safety of infants and 
children. Such a different safety factor may be lower or higher than 
the default 10X value. In making decisions about whether it has 
reliable data supporting a different safety factor, EPA has looked at 
the totality of the evidence bearing on the safety of infants and 
children and carefully weighed the strength of that evidence in 
determining whether a different safety factor would be safe. That was 
the approach followed with pyraclostrobin.
    NRDC appears to interpret the children's safety factor provision 
quite differently. Repeatedly in its objections, NRDC argues that EPA 
``must'' retain the children's safety factor due to some data 
deficiency or because of the identification of increased sensitivity in 
the young. NRDC affirms this view in its comments stating that the 
statute ``mandates application of the safety factor to account for any 
potential for pre- or post-natal toxicity'' and, that

[[Page 52116]]

where necessary studies are missing, ``EPA, by definition'' cannot make 
the safety finding needed to choose a different safety factor. Under 
NRDC's interpretation, the children's safety factor operates in a rigid 
and automatic fashion: upon identification of a data gap or of 
sensitivity in the young, EPA loses all discretion to choose a 
different safety factor.
    i. Data gaps. EPA has previously rejected NRDC's interpretation as 
it applies to data gaps noting that the interpretation fails to take 
into account the entire children's safety factor provision. In 
responding to other tolerance objections filed by NRDC, EPA stated its 
disagreement with the view ``that the mere absence of a required 
[developmental neurotoxicity] study should, by itself, conclusively bar 
EPA from applying a different additional safety factor than the 10X 
default value.'' (70 FR at 46723). EPA pointed out that the statute 
``expressly authorizes'' EPA to choose a different safety factor based 
solely on whether EPA determined that a different factor was safe and 
that EPA's policy of making children's safety factor decisions on a 
case-by-case basis examination of all of the data on a pesticide is in 
accord with this statutory provision. (Id.). EPA concluded that NRDC's 
outcome-determinative approach to data gaps and the children's safety 
factor simply did not address the statute's grant of discretion to EPA 
to choose a different safety factor.
    In its comments on its objections, NRDC now offers the following 
argument as to why, when data on pesticide safety are lacking, EPA does 
not have the authority to choose a different safety factor. NRDC claims 
that, when needed safety data are missing, EPA, ``by definition,'' 
cannot make the reasonable certainty of no harm (i.e. safety) finding 
necessary to choose a different safety factor. NRDC's logic seems to be 
as follows: if EPA determines it needs additional data on safety, EPA 
has necessarily concluded that such data are ``necessary to ensure 
safety,'' and if data that are ``necessary to ensure safety'' are 
lacking, EPA cannot make the safety finding required to apply a 
different children's safety factor.
    The main problem with this argument is that it ignores the plain 
language of the statute. As noted above, section 408(b)(2)(C) contains 
two sentences regarding application of an additional safety factor for 
the protection of infants and children. The first sentence requires EPA 
to apply an additional 10X safety factor to address, among other 
things, data completeness issues. Importantly, the data completeness 
issue mentioned by the statute is data bearing on toxicity and exposure 
- i.e., data on safety. In the very next sentence, however, the statute 
provides that ``notwithstanding such requirement'' to apply a safety 
factor to address safety data completeness issues, EPA may choose a 
different factor so long as that factor is safe for children. If there 
is any definitional reading of this language, it is that EPA has the 
authority to choose a different safety factor when safety data are 
incomplete. NRDC's interpretation would read EPA's grant of authority 
to choose a different factor when there are safety data completeness 
issues out of the statute.
    In addition to ignoring the plain language of the children's safety 
provision, NRDC's argument also is inconsistent with the statutory 
structure in at least two ways. First, NRDC's interpretation renders 
the children's safety factor provision, itself, mere surplusage if data 
completeness issues arise. If, as NRDC has argued, a request for data 
means that the data are necessary to ensure safety, then EPA, in those 
circumstances, not only cannot make the safety (reasonable certainty of 
no harm) finding necessary to remove the children's safety factor but 
EPA cannot make the safety (reasonable certainty of no harm) finding 
necessary to grant the tolerance. In other words, under NRDC's 
argument, the entire children's safety provision becomes irrelevant if 
EPA has requested data, because that request, by itself, conclusively 
bars EPA from establishing the tolerance. NRDC has not explained why it 
is rational to assume that Congress drafted a provision addressing data 
completeness issues but made the provision inoperative if data 
completeness issues arise.
    Second, NRDC's elevation of an EPA requirement for additional 
safety data to a determination that a tolerance is unsafe (i.e. that a 
safety determination cannot be made) is inconsistent with the structure 
of section 408 that permits EPA to require additional safety data on 
existing tolerances while at the same time commanding that tolerances 
that do not meet the safety standard be revoked. Under section 408(f), 
EPA is authorized to require the submission of data ``to support the 
continuation of a tolerance . . . .'' (21 U.S.C. 346a(f)). The sole 
criterion for the continuation of a tolerance is whether it continues 
to meet the reasonable certainty of no harm standard. (21 U.S.C. 
346a(b)(2)(A)(i)). Thus, Congress contemplated that EPA could require 
safety data on existing tolerances. Yet, under NRDC's interpretation it 
is difficult to see how EPA could ever require submission of safety 
data on existing tolerances. NRDC has argued that if data bearing on 
the reasonable certainty of no harm finding are needed (which is the 
finding necessary to request data under section 408(f)), then the 
reasonable certainty of no harm finding cannot be made. Thus, if EPA 
were to determine that additional safety data are needed on an existing 
tolerance, it would also be concluding that that tolerance is unsafe. 
The statute, however, commands EPA to revoke unsafe tolerances, not 
request more safety data concerning them. (21 U.S.C. 
346a(b)(a)(2)(A)(ii)). In other words, under NRDC's approach, if EPA 
determines that data were needed to support the continuation of a 
tolerance, EPA would have to revoke the tolerance rendering moot any 
decision to require submission of additional data to support the 
tolerance. Presumably, Congress would not have enacted such a self-
defeating provision.
    The underlying flaw in NRDC's argument is that it equates an EPA 
decision to seek additional safety data with the proposition that EPA 
has necessarily determined that a safety finding cannot be made in the 
absence of such data. NRDC does not take into account that there are 
many types of safety data and that the varying types of safety data 
have varying degrees of importance to the ultimate reasonable certainty 
of no harm finding. For example, the five core required toxicology 
studies would generally be of greater importance to the children safety 
factor determination than conditionally-required toxicology studies or 
special studies, for instance, to determine mechanism of toxicity. 
Similarly, as to pesticide exposure data, residue data on major crops 
will be of more significance than data on minor crops, and even for 
major crops the importance of the first 15 geographically-distributed 
residue studies will be of more value than the next five such studies. 
Further, not only are some studies more important or necessary to the 
safety determination than others, but, in the absence of a study, 
information from one study, or a group of studies, or the assumptions 
made to compensate for the missing study, may significantly diminish 
any uncertainty raised by the study's absence. For example, in the 
absence of dermal absorption data, EPA generally assumes 100 percent of 
a pesticide is dermally absorbed. Given all of these considerations and 
the range of data that can be required, it is apparent that a request 
for additional data is not synonymous with a determination that

[[Page 52117]]

a safety finding cannot be me made. Thus, it is reasonable not to adopt 
NRDC's absolutist approach but to evaluate on a case-by-case basis 
whether the safety data that are available on a pesticide show that a 
different safety factor is safe.
    At bottom, the decision on the children's safety factor turns on 
whether a safety finding can be made, not on whether any particular 
study is available. If data are absent, EPA may still examine the 
existing reliable data to determine if a factor different than 10X is 
safe. NRDC is incorrect to the extent it argues that EPA is statutorily 
barred from making this inquiry.
    ii. Increased sensitivity in the young. In the current objections, 
NRDC also argues that EPA ``must'' retain the children's safety factor 
because ``[j]uveniles are qualitatively more sensitive than adults to 
pyraclostrobin toxicity.'' (Ref. 1 at 7). NRDC criticizes EPA for 
examining whether there is ``substantial evidence'' of sensitivity. 
(Id. at 5). Presumably, NRDC's view is that any evidence of sensitivity 
automatically requires EPA to retain the children's safety factor.
    This rigid interpretation of the children's safety provision, 
however, fails for the same reason NRDC's argument for automatic 
retention of the children's safety factor for data deficiencies fails - 
it is not in accord with the plain language of the statute. The statute 
does direct EPA to consider ``susceptibility of infants and children'' 
to pesticides. (21 U.S.C. 346a(b)(2)(C)(i)(II)). It also states that an 
additional safety factor to protect infants and children shall be 
applied ``to take into account potential pre- and post-natal toxicity . 
. . .'' (21 U.S.C. 346a(b)(2)(C)). Nonetheless, in clear and 
unmistakable language, Congress decreed that, ``[n]otwithstanding such 
requirement for an additional margin of safety'' to take into account 
potential pre- and post-natal toxicity, EPA is authorized to choose a 
different safety factor if EPA has reliable data showing a different 
factor is safe. (Id.). Interpreting the statute as creating a rigid, 
per se rule that the identification of sensitivity in the young removes 
EPA's discretion to choose a different safety factor is inconsistent 
with this language and the flexibility granted to the Agency. On the 
other hand, EPA's policy, and the approach it followed with 
pyraclostrobin, of examining the entire database to determine if, 
despite a finding of sensitivity, there are reliable data showing a 
different factor to be safe, is in full accord with the statutory 
provision.
    c. The standard for choosing a different safety factor. 
Alternatively, NRDC argues that even if the statutory language does not 
compel EPA to retain the children's safety factor whenever there is a 
data gap or evidence of sensitivity in the young, EPA's interpretation 
of the standard for choosing a different safety factor ``frustrates 
congressional policy.'' (Ref. 10 at 2). NRDC asserts that the language 
EPA offered in summarizing its decision to remove the children's safety 
factor demonstrates the unlawfulness of EPA's interpretation: ``[EPA] 
has concluded that there are reliable data to support reducing the FQPA 
SF [safety factor] to 1X for all potential pyraclostrobin exposure 
scenarios because the toxicity and exposure databases are adequate, 
there are no residual uncertainties for pre- or postnatal toxicity, and 
there is no substantial evidence of increased sensitivity of infants 
and children to pyraclostrobin.'' (Id.). NRDC claims that ``requiring 
`substantial evidence' of `increased sensitivity of infants and 
children,' along with merely `adequate' data regarding toxicity and 
exposure'' is not true to the reasonable certainty of no harm standard. 
(Id.).
    NRDC's view here is not well-founded. Contrary to NRDC's argument, 
EPA does not apply the reasonable certainty of no harm standard in some 
sort of formalistic fashion using fixed rules that provide minimal 
protection to children. Rather, EPA applies the reasonable certainty of 
no harm standard in the children's safety factor provision, just as it 
does with the overall reasonable certainty of no harm provision for 
tolerances, using a comprehensive, weight-of-the-evidence approach that 
is designed to protect fully the safety of children.
    EPA, as well as FDA, has applied a reasonable certainty of no harm 
standard in administering various provisions of the FFDCA for many 
years. Since its enactment in 1958, the ``safety'' standard in FFDCA 
section 409 has been interpreted by FDA as imposing a reasonable 
certainty of no harm standard. (21 C.F.R. 170.3(i)). EPA was governed 
by this standard in implementing section 409 as to pesticides in 
processed foods for the period between 1970 and 1996. In 1996, when 
Congress enacted the FQPA, the reasonable certainty of no harm safety 
standard was codified in section 408. (7 U.S.C. 346a(b)(2)(A)(ii)). In 
brief, EPA has applied that standard using a complex risk assessment 
process which involves careful weighing of scientific evidence at each 
step along the way. (62 FR 62961, 62962-62963 (November 26, 1997)). 
First, a thorough evaluation of hazard and exposure data is conducted 
to determine the adequacy of that data to address the potential risks 
posed by a pesticide and the significance of any data gaps that are 
identified. Hazard data are examined using a weight-of-the-evidence 
approach for the purpose of identifying a safe dose for humans. 
Derivation of a safe dose generally requires use of safety factors to 
address any uncertainties in knowledge. Exposure data are carefully 
weighed in estimating potential human exposure. Finally, human exposure 
estimates are compared to the safe dose to determine if there is a 
reason for concern. (Ref. 2; 5; and 6).
    A similar, if slightly more narrowly focused, inquiry is involved 
in determining if there are reliable data showing that a safety factor 
different than the presumptive 10X factor will ensure that there is a 
reasonable certainty of no harm to children. (Ref. 5 at 8-18; 50-53). 
This inquiry examines the risks to children guided by the three factors 
mentioned in the statute - completeness of the toxicity database; 
completeness of the exposure database; and the potential for pre- and 
post-natal toxicity. (21 U.S.C. 346a(b)(2)(C)). In other words, EPA 
focuses on the completeness or adequacy of the databases regarding the 
hazard a pesticide poses to children and children's potential exposure 
to that pesticide. This completeness inquiry identifies and evaluates 
the significance of any data gaps. It also examines evidence bearing on 
pre- and post-natal toxicity with particular emphasis on whether there 
is evidence indicating that children may be more sensitive than adults 
to the toxic effects of a pesticide. (21 U.S.C. 346a(b)(2)(C)(i)(II)). 
As in the broader reasonable certainty of no harm evaluation, the 
children's safety factor determination involves an examination of 
uncertainties and a determination as to whether these uncertainties are 
addressed by adequate safety factors or other aspects of the risk 
assessment such as the levels that adverse effects occur in adults. 
Each step involves a careful weighing of the scientific evidence and a 
characterization of what the data show. That is precisely what was done 
with pyraclostrobin - examining the adequacy of the hazard and exposure 
data; and evaluating the evidence on pre- and post-natal toxicity, the 
evidence on increased sensitivity in the young, and the degree to which 
any pre- or post-natal toxicity was addressed by basing safety 
determinations on effects seen at similar or lower doses in adults. EPA 
did not apply any rigid tests in

[[Page 52118]]

determining if there was reasonable certainty of no harm supporting the 
removal of the additional safety factor for pyraclostrobin but rather 
considered all of the relevant data and weighed its significance to the 
safety of children. This approach is consistent with (1) the statutory 
language itself - reasonable certainty of no harm; (2) EPA's historic 
interpretation and implementation of that language; and (3) protection 
of infants and children.
    The language from the pyraclostrobin decision cited by NRDC 
(adequate safety data and no substantial evidence of sensitivity) was 
intended as a summary of EPA's weight-of-the-evidence evaluation in 
making its reasonable certainty of no harm finding on the children's 
safety factor. Considerations of data adequacy and the substantiality 
of evidence on harmful effects are a routine part of the weight-of-the-
evidence analysis used to make reasonable certainly of no harm 
determinations. Surely, Congress did not intend to remove EPA's 
discretion to choose a different safety factor when data on infants and 
children are adequate to evaluate safety and evidence of sensitivity in 
the young is insubstantial.
    Accordingly, EPA denies NRDC's objection to the extent they rely on 
these flawed interpretations of the statute or a misreading of EPA's 
tolerance decision.
    2. Individual factual findings bearing on the children's safety 
factor--a. Pre-natal sensitivity. As indicated above, NRDC relies on 
evidence of qualitative pre-natal sensitivity (i.e., effects more 
severe in the young as compared to adults) as grounds for retaining the 
children's safety factor for pyraclostrobin. NRDC's objections appear 
to argue that the mere indication of increased qualitative sensitivity 
requires EPA, as a legal matter, to retain the children's safety 
factor. That legal interpretation is without merit as explained above. 
NRDC may, however, have been asserting that the evidence bearing on 
pre-natal sensitivity for pyraclostrobin is so significant to the 
evaluation of the safety of pyraclostrobin that EPA erred in concluding 
that there was reliable data to determine that removing the children's 
safety factor would be protective of the safety of children.
    NRDC claims two pyraclostrobin studies show that pyraclostrobin 
causes increased qualitative pre-natal sensitivity: the developmental 
study in rats and the developmental study in rabbits. The developmental 
study in rats found that pre-natally exposed fetuses had adverse 
effects at 50 milligrams/kilogram of body weight/day (mg/kg/day) and 
that the maternal animals had adverse effects at the lower dose of 25 
mg/kg/day. The NOAELS in fetuses and maternal animals respectively were 
25 mg/kg/day and 10 mg/kg/day. (Refs. 9 at 4; and 12 ). NRDC contends 
that the study showed qualitative pre-natal sensitivity because the 
effects in the fetuses (incidences of dilated renal pelvis and cervical 
ribs with no cartilage) were more severe than the effects in the 
maternal animals (reduced body weight, reduced body weight gain, food 
intake, and food efficiency). The developmental study in rabbits showed 
adverse effects in fetuses and the maternal animals at the same level 
(LOAEL - 10 mg/kg/day; NOAEL - 5 mg/kg/day). (Refs. 9 at 5-6; and 13). 
NRDC asserts that effects in the fetuses (increased resorption and 
post-implantation loss) however, are more severe than in the maternal 
animals. (Ref. 1 at 7).
    BASF in its comments disputes NRDC's claims of qualitative 
sensitivity. First, BASF claims that effects seen in the rat fetuses 
were not caused by exposure to pyraclostrobin. To support this 
assertion BASF argues that adverse effects were within the level to be 
expected based on historical information on this species of rat. 
Second, BASF claims that the rabbit developmental study does not 
evidence qualitative sensitivity because the effects in the fetuses 
were derivative of the effects on the maternal animals. Noting that 
decreased weight gain in the maternal animals was dramatic (39% at the 
LOAEL and 77% and the next higher dose), BASF argues that it is to be 
expected that ``the dam's ability to deliver full-term fetuses [would 
be affected] and does not reflect a direct action of the test material 
on the fetus.'' (Ref. 11 at 2).
    In the pyraclostrobin rulemaking, EPA characterized the effects in 
the rabbit, but not the rat, study as evidencing qualitative 
sensitivity in the young. EPA further determined that there was a low 
degree of concern as to the sensitivity seen in the rabbit study 
because the effects in the rabbit fetuses occurred at the same dose 
that adverse effects occurred in the maternal animals and a clear NOAEL 
for the effects seen in the fetuses was identified and taken into 
account in assessing potential risk to humans. In light of NRDC's 
objections and BASF's comments, however, EPA has re-examined its 
earlier conclusions both as to the presence or absence of qualitative 
sensitivity in the rat and rabbit fetuses and the degree of concern 
raised by the studies regarding the protection of infants and children.
    i. Rat developmental study. To recap, in the rat developmental 
study, pyraclostrobin exposure resulted in dilated renal pelvis and 
cervical ribs with no cartilage in the rat fetuses at 50 mg/kg/day 
(with a NOAEL of 25 mg/kg/day) and reduced body weight in the maternal 
animals at the lower dose of 25 mg/kg/day (with a NOAEL of 10 mg/kg/
day). EPA does not believe that these findings support retention of the 
children's safety factor for four reasons.
    First, there is substantial evidence indicating that the effects 
seen at the high dose in the fetuses (dilated renal pelvis and cervical 
ribs with no cartilage present) were not treatment-related. These 
effects occur with some frequency in rats. Historical data from the lab 
conducting the study showed that, for rat controls in other studies, 
dilated renal pelvis was seen in between 8.8 and 28.8 percent of rat 
fetuses, and cervical ribs with no cartilage present was seen in 
between 0.5 and 6.6 percent of rat fetuses. (Ref. 14 at 2-3). In the 
pyraclostrobin rat study, dilated renal pelvis was detected in 18.8 
percent of the fetuses and cervical ribs with no cartilage present was 
found in 5.1 percent. (Id.). Because these effects appeared at a rate 
consistent with those seen in control groups, this study outcome 
carries little weight.
    Second, the effects in fetuses are not more severe than the reduced 
body weight seen in maternal animals. Dilated renal pelvis and cervical 
ribs with no cartilage present are relatively common effects in rat 
fetuses and are regarded as reversible developmental variations in that 
they often disappear as the animal matures. Dilated renal pelvis 
involves an enlargement of the portion of the kidney referred to as the 
pelvis. The renal pelvis is a funnel-shaped region that collects urine 
before it is discharged through the ureter. When the renal pelvis 
becomes dilated or enlarged there may be difficulties in discharging 
urine. As the historical control data cited above shows, this is a 
fairly common event in rats. The enlargement is related to rapid renal 
growth late in the gestation period and it generally is resolved 
following birth so long as no other abnormalities are present in the 
kidney. (Ref. 15). A cervical rib without cartilage is a supernumerary 
(or extra) rib that commonly disappears after birth as ossification of 
the bone is unlikely to occur in the absence of cartilage. Because 
these effects are generally reversible post-natally, were seen with 
pyraclostrobin at the high dose only, and were within the range of 
historical controls, it was reasonable for EPA not to treat them as a 
severe effect. On the

[[Page 52119]]

other hand, reduced body weight, while not one of the more severe 
effects seen in animal studies, is nonetheless a sign of generalized 
toxicity that merits concern. Thus, the effects in the fetuses are not 
properly characterized as more severe than the effects in maternal 
animals.
    Third, reduced body weight in the maternal animals was found at a 
lower dose than the dose which resulted in dilated renal pelvis and 
cervical ribs with no cartilage present in the fetuses. Thus, on a 
quantitative basis, adult animals proved more sensitive than the 
fetuses.
    Fourth, and probably most important, a clear NOAEL was identified 
for the effects seen in the fetuses. That NOAEL was taken into 
consideration in setting the RfD/PAD for pyraclostrobin as EPA examined 
all of the NOAELs from relevant studies to identify the lowest NOAEL. 
Accordingly, the RfD/PAD for pyraclostrobin was set at least 100-fold 
(10X for inter-species sensitivity and 10X for intra-species 
variability) below the safe level (NOAEL) for rat fetuses in the rat 
developmental study. In fact, as to the NOAEL for the fetal effects 
seen in the rat developmental study, there was a greater than 100-fold 
margin because the NOAEL in the rat developmental study for maternal 
animals was lower than the fetal NOAEL, and a still lower NOAEL from 
another study was used to set the RfD/PAD. (Ref. 8 at 12-13).
    Accordingly, after re-evaluating the rat developmental study, EPA 
concludes that (1) the study does not show increased qualitative 
sensitivity in rat fetuses; and (2) given the results of the study and 
the manner in which those results were incorporated into EPA's risk 
assessment for infants and children, there is reliable data to show, 
with regard to developmental effects in rats, that it is safe to remove 
the children's safety factor.
    ii. Rabbit developmental study. As noted above, the findings in the 
rabbit developmental study were that, at the same dose level, 
pyraclostrobin caused reduced body weight and reduced body weight gain 
in maternal animals, and increased resorption of fetuses. EPA concluded 
that, because fetal resorptions were more serious than body weight 
effects, this study shows increased qualitative sensitivity in rabbit 
fetuses; however, EPA concluded that the traditional safety factors 
provide sufficient protection for infants and children. (Ref. 9 at 7). 
NRDC argues that because the study shows qualitative sensitivity the 
children's safety factor must be retained. Taking a different tack, 
BASF does not contend that fetal resorptions are not more serious than 
body weight effects but instead claims that the resorptions are 
derivative of the effects on the maternal animals and thus not evidence 
of qualitative sensitivity.
    EPA disagrees with BASF that the fetal resorptions are derivative 
of the body weight effects. To the extent either effect is derivative 
of the other, it is the decreased body weights in maternal animals that 
is the result of the fetal resorptions, not the other way around. Body 
weight decreases in the maternal animals were due, in large part, to 
decreases in the weight of the gravid uterus (a uterus containing a 
fetus or fetuses). In turn, weight loss in the gravid uterus was a 
result of the fetal resorptions. (Ref. 14 at 7). In light of this 
finding, as well as the other evidence of gestational effects (e.g. 
blood in the bedding), EPA concludes there is insufficient evidence to 
classify the resorptions as a derivative effect.
    EPA, however, also disagrees with NRDC regarding the significance 
of the finding of qualitative sensitivity based on fetal resorptions 
and reaffirms its conclusion that there is low concern that traditional 
safety factors are not protective of the fetal effects seen in the 
rabbit developmental study. Not only were the fetal effects seen at the 
same quantitative levels as the maternal effects but clear NOAELs were 
identified for both the fetal and maternal effects in that study. These 
NOAELs (which were identical) formed the basis for the RfD/PAD for 
pyraclostrobin. Specifically, EPA used the NOAELs in establishing the 
RfD/PAD by dividing the NOAELs by 10X safety factors for inter- and 
intra-species variability (total of 100X). Having clearly defined the 
threshold for the qualitatively more sensitive effects in the young, 
and applied a 100X safety factor to the NOAEL below the threshold, EPA 
concludes it is safe for infants and children not to retain an 
additional 10X factor.
    b. Immunotoxicity . NRDC claims various studies show that males and 
females have different levels of sensitivity to pyraclostrobin. 
According to NRDC, some of the studies indicated males were more 
sensitive and others indicated females were more sensitive. NRDC calls 
particular attention to alleged heightened female sensitivity to 
immunotoxic effects in the 90-day oral toxicity study in the mouse and 
claims that this sensitivity ``is supported by substantial data 
demonstrating that females are more likely than males to develop 
autoimmune diseases in response to environmental stressors.'' (Ref. 1 
at 6). Based on this alleged sensitivity of females to immunotoxic 
results, NRDC then argues that ``[b]ecause EPA does not routinely test 
pesticides for immunotoxicity, the full repercussions of these results 
for female mortality and morbidity (i.e. autoimmune disease, 
compromised immune response, etc.) should be considered a serious 
potential risk of pyraclostrobin'' and merits retention of the 
children's safety factor. EPA interprets this argument as essentially a 
claim that EPA cannot remove the children's safety factor because it 
has inadequate data on the immunotoxic effects of pyraclostrobin.
    BASF responds to NRDC by asserting that the children's safety 
factor was not intended to address differential sensitivities between 
males and females. Further, BASF asserts that any differences in 
sensitivity are taken into account in the risk assessment because the 
lowest NOAEL from male or female is used in selecting a safe dose and, 
in addition, a tenfold safety factor is applied to this NOAEL to 
address any lingering uncertainty as to differential male/female 
sensitivity.
    While EPA agrees generally with BASF's comments, EPA does not 
believe that they address NRDC's core concern here which is the 
adequacy of the data pertaining to pyraclostrobin's immunotoxic 
potential. EPA has identified the immune system as a target of 
pyraclostrobin; however, EPA believes that pyraclostrobin's immunotoxic 
effects have been well-characterized and that no additional data is 
needed to protect against immunotoxic risks.
    Currently, EPA does not routinely require that pesticides be tested 
specifically for immunotoxicity. Toxicology data requirements for a 
food-use pesticide, however, typically contain data that provide 
information for evaluating potential hazard to the immune system. For 
example, examination (in varying degrees) of the macro- and/or 
microscopic structural anatomy of immune system organs and tissues is 
performed in a number of toxicity studies, including the 90-day 
subchronic studies in multiple species, the chronic and carcinogenicity 
studies, the prenatal developmental toxicity studies (rats and 
rabbits), acute inhalation toxicity study, and the two-generation 
reproduction and fertility effects study. Additionally, non-specific 
indicators of a diseased state in the animal (e.g., clinical behavior 
which is evaluated by detailed observations throughout the conduct of 
all guideline animal studies) can also be useful in discerning 
perturbations in immune system function. If these toxicity studies show 
findings indicative of possible

[[Page 52120]]

immunotoxicity, they are given due consideration in the risk 
assessment. (Ref. 16 at 3).
    EPA is considering requiring specific immunotoxicity testing for 
pesticides in the future. If the toxicity studies are inconclusive 
regarding immunotoxicity, there is concern, depending on the pesticide, 
that potential immunotoxic effects may not have been identified. 
Accordingly, the Agency has proposed that the pesticide toxicity data 
requirements be amended to require adult immunotoxicity testing for all 
pesticides. (70 FR 12277 (March 11, 2005). The proposed immunotoxicity 
testing would improve the likelihood that pesticides which have 
potential immunotoxic effects will be identified. If these proposed 
amendments are adopted, EPA will have to make determinations as to the 
timing of requiring these tests for existing pesticides and what the 
implications are for application of the children's safety factor of 
this new data requirement. The Children's Safety Factor policy 
recommends that this safety factor is more appropriate in situations 
when a study is requested ``for cause'' as opposed to a request based 
on more general considerations. EPA is likely to apply a similar 
approach to broadly-imposed new data requirements for immunotoxicity 
testing: although the requirements may apply to all pesticides, only 
those pesticides for which immunotoxicity is a specific concern would 
require retention of the children's safety factor. Important 
considerations in this analysis are likely to be the sensitivity of any 
immunotoxicity effects seen in the existing database (i.e., is the RfD/
PAD based on the immunotoxic responses or do such effects only occur at 
higher doses), the degree to which any immunotoxicity effects are seen 
across studies and across species, and the nature and severity of the 
immunotoxic effects.
    For pyraclostrobin, EPA's analysis of the existing data identified 
the immune system as a target organ but not the primary target. Effects 
were seen in the thymus, an important gland in the immune system, in 
terms of thymus atrophy and lymph node apoptosis. The thymus effects 
were seen in the 90-day study in mice at high doses (NOAEL/LOAEL of 
30.4/119 mg/kg/day in males and NOAEL/LOAEL of 12.9/40.4 mg/kg/day in 
females). In a chronic/carcinogenicity study in mice, these effects 
were not seen at the highest dose tested (17.2 mg/kg/day for males and 
32.8 mg/kg/day for females). Similar findings were not seen in 
available data with rats and dogs. Although decreased thymus weights 
were found at the highest dose (29-36 mg/kg/day) in the pups in the 
two-generation rat reproduction study, EPA does not interpret this 
effect as an immunotoxic response because total pup weights were 
reduced and ``relative'' thymus weights (the ratio of thymus weight/
body weight) was normal. (Ref. 16 at 2). Similarly, in a recently 
submitted inhalation study, apparent thymus weight effects were seen, 
but again EPA concluded this was not an immunotoxic response given the 
lack of any confirming histopathological findings in the thymus and the 
excessively toxic level of the dose at which the thymus effects were 
seen. (Refs. 16 at 2 and 17).
    EPA believes that the immunotoxic potential of pyraclostrobin has 
been well-characterized; that no additional data is needed taking into 
account all of the evidence bearing on potential immunotoxic effects; 
and that identification of immunotoxic effects in the 90-day mouse 
study does not support retention of the children's safety factor to 
protect the safety of infants and children. Most important to these 
findings are the facts that (1) immunotoxic effects were only seen at 
high doses in one study in the mouse - no immunotoxic effects were seen 
in other mouse studies or in studies in other species; and (2) 
combining the data from the 90-day mouse study and the chronic/cancer 
study in mice shows a NOAEL for immunotoxic effects for both male and 
female mice (30.4 mg/kg/day for males from the 90-day mouse study and 
32.8 mg/kg/day for females in the chronic/cancer study) that is 
approximately 10X higher than the NOAEL used to set the RfD/PAD (3.4 
mg/kg/day from the rat chronic study).
    Although EPA has required the submission of developmental 
immunotoxicity data for two pesticides, those pesticides have a 
markedly different toxicological profile than pyraclostrobin. The two 
pesticides in question, clothianidin and dinotefuran, caused 
immunotoxic effects in multiple studies and species, and rat pups in 
the two generation rat reproduction study appeared to be more sensitive 
to these immunotoxic effects than adult animals. Further, the 
immunotoxic effects for these pesticides were the most sensitive 
effects seen in the database and were used to set the RfD/PAD for the 
pesticides. These circumstances are markedly different from 
pyraclostrobin where an immunotoxic effect was seen at a high dose in 
only one study.
    c. Two-generation reproduction study. NRDC claims that the two-
generation reproduction study in rats is invalid because it did not 
show adverse effects at any dose and that it cannot be rehabilitated by 
reference to the one-generation reproduction study because that study 
is contradictory in that it showed adverse effects at levels below 
levels tested in the two-generation study. BASF disputes NRDC's 
contention, arguing that the two-generation study did show some adverse 
effects at the highest dose tested and these effects were consistent 
with the one-generation study and ``fit along a dose-response curve 
with the two doses in the [one-generation] range-finding [reproduction] 
study.'' (Ref. 11 at 3.)
    EPA disagrees with NRDC. An examination of all of the data from the 
two reproduction studies indicates that the reproduction effects of 
pyraclostrobin have been adequately characterized and no further data 
is needed.
    The two-generation reproduction study and the one-generation 
reproduction study both tested the same strain of male and female 
Wistar rats from the same source. Using the same batch and purity of 
pyraclostrobin (BAS 500 F; Batch No. J.-No. 27882/199/b or /c; 98.7%), 
the two-generation study tested 0, 25, 75 or 300 ppm and the one-
generation study tested 200, 400 and 600 ppm of Pyraclostrobin. This 
corresponds to 0, 2.5/2.6, 7.4/7.8 and 29.0/30.4 mg/kg/day (males/
females (``M/F'')) for the two-generation reproduction study and 0, 
20.5/21.3, 39.9/42.5 and 59.1/60.4 mg/kg/day (M/F) for the one-
generation reproduction study. (Ref. 14 at 7-8).
    In evaluating the results of these studies, EPA concluded that the 
one-generation reproduction study resulted in statistically 
significant, adverse body weight effects in parental animals at the mid 
(39.9/42.5 mg/kg/day) and high (59.1/60.4 mg/kg/day) doses and in pups 
at the low (20.5/21.3 mg/kg/day) as well as the mid and high doses. On 
the other hand, EPA determined that none of the doses used in the two-
generation reproduction study (2.5/2.6, 7.4/7.8 and 29.0/30.4 mg/kg/
day) caused statistically significant adverse effects in the parental 
animals or the offspring. Further, EPA initially classified the two-
generation reproduction study as unacceptable due to its failure to 
identify statistically significant adverse effects and indicated that 
the study should be repeated at higher doses.
    Upon reevaluation, EPA concluded that, when taken together, the two 
reproduction studies fulfilled the requirement for a two-generation 
reproduction study and a second reproduction study did not have to be 
conducted. Importantly, the two-generation study did show treatment-

[[Page 52121]]

related effects on body weight; these effects, however, were not judged 
significant enough to be considered adverse. Body weight decrements of 
5 percent or less were consistently seen in both maternal and paternal 
animals at the high dose in the two-generation study and slightly 
greater weight decrements were seen in the first and second generation 
pups. (Refs. 14 at 8; 18). Specifically, the first and second 
generation pups of the high dose group (29.0/30.4 mg/kg/day) had 
decreased body weights on days 14 and 21 and on day 7 as well in second 
generation pups. The decreases were slightly more pronounced in the 
second generation (9 to 13%) than in the first (4 to 10%). In the one-
generation study, the body weight decrease in pups between days 7 and 
21 for the low (20.5/21.3 mg/kg/day), mid (39.9/42.5 mg/kg/day), and 
high (59.1/60.4 mg/kg/day) doses groups pups were 7 to 14 percent, 11 
to 20 percent, and 24 to 37 percent, respectively. (Ref. 14 at 8). As 
Table 1 indicates, a comparison of the percentage weight loss from the 
pups in the two studies shows that the studies are complementary 
because the dose response curve when comparing the lowest two doses in 
the one-generation study with the highest dose in the two-generation 
study only slightly deviates from what might be expected. EPA concludes 
that this slight deviation in the dose response curve is likely due to 
normal variability in mammalian response and variability in human and 
instrumental measurements rather than any defect in the two-generation 
study.

  Table 1.--Body Weight Loss in Pups in the One- and Two-Generation Rat
                          Reproduction Studies
------------------------------------------------------------------------
   Dose (mg/kg/day) for Males/                         Weight Loss (days
             Females                     Study               7-12)
------------------------------------------------------------------------
20/21                             One-generation      7-14%
------------------------------------------------------------------------
29/30                             Two-generation      4-10% (first
                                                       generation)*
                                                      9-13% (second
                                                       generation)
------------------------------------------------------------------------
40/42                             One-generation      11-20%
------------------------------------------------------------------------
*Days 14 - 21 only.

    The consistency of effect and response from the two studies refute 
NRDC's claims regarding the contradictory nature of the findings from 
the two studies.
    Moreover, although the body weight effects seen at the highest dose 
in the two-generation reproduction study were not significant enough to 
be judged adverse, a new study would not provide any additional data 
for risk assessment purposes. The concern with that study is not that 
it did not test at a low enough dose, but the opposite. Repeating the 
two-generation study at doses similar to and above 29 mg/kg/day (the 
highest dose tested in the two-generation study) is very unlikely to 
change the Point of Departure for pyraclostrobin which is currently a 
NOAEL of 3.4 mg/kg/day from the rat chronic/carcinogenicity study. The 
conclusion not to request a repeat study is in accord with the 
decisions made by the Agency's Pesticide Rejection Rate Analysis - 
Toxicology which states that a study should not be rejected provided 
that NOAELs are established in other studies that can be used to 
estimate a reference dose. (Ref. 19). In the case of pyraclostrobin, 
acute and chronic reference doses for dietary risks as well as doses 
for non-dietary risks were based on other studies.
    d. Other data deficiencies. NRDC also claims there are several 
other significant data deficiencies which necessitate retention of the 
children's safety factor. For the reasons explained below, EPA does not 
find merit in this contention.
    i. Anticipated residue data. NRDC notes that EPA is issuing a data 
call-in for information bearing on anticipated residues and asserts 
that this means there is a database deficiency. NRDC cites to page 
17016 of the Federal Register to support this assertion. In fact, 
however, there is no data deficiency. If EPA relies on anticipated 
residue information in establishing a tolerance, it must require, 
pursuant to section 408(f)(1), that data be provided five years after 
the tolerance is established demonstrating that the residue levels in 
food are not above the levels anticipated. 21 U.S.C. 346a(b)(2)(E). 
Page 17016 of the pyraclostrobin Federal Register notice merely notes 
that EPA is subject to this obligation with regard to pyraclostrobin 
because it did rely on anticipated residue data in setting the 
tolerance.
    ii. 28-day inhalation study. NRDC notes that in 2004 a 28-day 
inhalation study in rats was outstanding and argues that this is a 
significant data gap. The 28-day inhalation study, however, is used to 
assess worker risk in connection with application of pyraclostrobin. 
Inhalation is not a significant exposure pathway for residential post-
application exposure due to pyraclostrobin's very low volatility. In 
any event, this study has now been submitted and reviewed. The study 
established a NOAEL of 0.001 milligrams/liter (mg/L) based on 
hyperplasia of the duodenum, alveolar histiocytosis in the lungs, and 
olfactory atrophy/necrosis in the nasal tissues at 0.030 mg/L (LOAEL). 
(Ref. 17). This endpoint will be taken into account in the future in an 
updated occupational risk assessment for pyraclostrobin.
    iii. Rat chronic toxicity study. NRDC claims the chronic toxicity 
study in rats was unacceptable due to failure to test at a dose high 
enough to produce significant toxicity. NRDC cites an October 2004 
rulemaking for pyraclostrobin, (67 FR 63083, 63086 (October 29, 2004)), 
in support of this claim. The October 2004 Federal Register statement, 
however, was an error because EPA had determined in 2003 that the 
dosing in the rat chronic study was adequate. Specifically, EPA 
concluded in an October 2003 memorandum that ``[u]pon reevaluation at 
the September 10, 2003 meeting, the [Cancer Assessment Review 
Committee] concluded that female rats were tested adequately at the top 
dose of 200 ppm.'' (Ref. 20 at 23). The re-evaluation was based on 
additional data and statistical analysis bearing on the rat chronic 
study. EPA found that ``[t]here was a statistically significant 
decrease in cumulative body weight gain compared to controls across 
study intervals from Day 147 to study termination in the 200 ppm group 
females.'' (Id.). It had been previously determined that male rats were 
tested at a high enough dose. (Id. at 22).
    iv. Mouse carcinogenicity study. NRDC claims the mouse 
carcinogenicity study was unacceptable due to failure to test at a dose 
high enough to produce significant toxicity. EPA originally concluded 
that this study had to be re-conducted at a higher dose; however, based 
on interim reports from a second study, using a higher dose, EPA found 
the dosing in the first mouse carcinogenicity study to be adequate. 
(Ref. 21). The second study involved a dose of 360 ppm which is double 
the high dose in the first study. Within a short period the study 
evidenced severe reductions in body weight and body weight gain at the 
360 ppm dose. (Ref. 22). After 6 months of the study, EPA agreed that 
the 360 ppm dose was excessive and permitted the study to be terminated 
concluding that based on both studies, it had sufficient information to 
determine that the dosing in the first study was high enough to 
adequately characterize any cancer potential of pyraclostrobin. 
Following formal submission of the data, EPA confirmed that, compared 
to control

[[Page 52122]]

animals, there was a large decrease in the body weight/ body weight 
gain of female mice at 360 ppm up to the end of the study. Mean body 
weight of treated females was significantly decreased by 4-24% compared 
with that of controls during the study and was 21% less than that of 
controls when the study was terminated at 7 months. Weight gain, 
relative to controls, was reduced by 37% (p< =0.01) during the first 91 
days of the study and by 40% (p< =0.01) over the entire study. (Ref. 
23).
    v. Dermal absorption study. NRDC claims the dermal absorption study 
was inadequate. NRDC notes that EPA described the study as unacceptable 
but nonetheless used it to calculate the percentage of dermal 
absorption by pyraclostrobin. EPA acknowledges that there were 
difficulties with the dermal absorption study; however, EPA was 
ultimately able to use the data obtained from this study to calculate 
pyraclostrobin's dermal absorption rate. (Ref. 9 at 15-16). The 
difficulty with the study was that most of the pyraclostrobin intended 
to be applied to the skin of the animal, remained in the dressing used 
to cover the skin where pyraclostrobin was applied. Because, however, 
the amount of pyraclostrobin that remained in the dressing was 
measured, it was possible to calculate what amount of pyraclostrobin 
was applied to the skin and hence, by comparing this amount to the 
amount absorbed by the animal, to derive the dermal absorption rate. In 
the underlying science memorandum, EPA initially characterized the 
study as unacceptable without expressly noting that its ability to 
derive a dermal absorption rate despite the flaws in the study made the 
study acceptable. EPA's initial characterization of the study was 
mistakenly cited in the 2004 Federal Register notice relied upon by 
NRDC. EPA notes that BASF claims to have submitted a new dermal 
absorption study but EPA has not received such a study from BASF.
    e. Conclusion with regard to NRDC's factual allegations. For the 
reasons described above, EPA rejects each of NRDC's claims regarding 
the need for additional data or alleged deficiencies in submitted data.

B. NRDC's Claim that EPA's Tolerance Decision was Arbitrary and 
Capricious

    NRDC also claims that it was arbitrary and capricious for EPA to 
establish the challenged pyraclostrobin tolerances because EPA did not 
review needed safety data and because ``EPA failed to explain 
adequately its departure from the required children's safety factor.'' 
(Ref. 1 at 10). As to the first contention, NRDC relies on its prior 
allegations regarding missing or deficient data. Because EPA has above 
rejected each of these claims regarding missing or deficient data, EPA 
also disagrees that its tolerance decision was arbitrary or capricious 
due to a failure to consider needed data.
    NRDC provides no further elaboration with regard to its claim that 
EPA did not provide an adequate explanation of its decision on the 
children's safety factor. EPA explained its reasoning in both the 
preamble to the final rule promulgating the challenged pyraclostrobin 
tolerances, (71 FR at 17018), and in an earlier tolerance rulemaking on 
pyraclostrobin, (69 FR at 63092-63093), that was cross-referenced in 
the later action. EPA's regulations require that the basis for 
objections be stated with ``particularity,'' (40 C.F.R. 178.25(a)(2)), 
and NRDC's failure to provide any basis for its lack of explanation 
contention is alone grounds for denial of this objection. Nonetheless, 
EPA reiterates below its reasoning for removal of the children's safety 
factor.
    In determining whether there are reliable data showing that a 
different safety factor would be safe for evaluating the risks of 
pyraclostrobin to infants and children, EPA has focused primarily on 
three issues: (1) The completeness of the toxicity database; (2) the 
completeness of the exposure database; and (3) what the data show with 
regard to pre- and post-natal toxicity.
    This analysis did not occur in isolation but in the context of the 
overall risk assessment for pyraclostrobin. Before it makes any 
children's safety factor decision, EPA analyzes the toxicity and 
exposure databases. EPA's process with regard to toxicity data is 
described in its Children's Safety Factor policy:
    Before any decisions are made on the appropriate FQPA safety 
factor applied to ensure the safety of infants and children from the 
use of a particular pesticide, all of the relevant submitted data 
for the pesticide should be assembled and reviewed by Agency 
scientists. The toxicology database is evaluated to identify 
potential adverse effects, to determine the adequacy of the 
available data to characterize potential human risks, and to analyze 
the relationship between dose and response, that is, the levels at 
which the chemical causes adverse effects in test animals. The 
assessment of the potential for adverse health effects in infants 
and children is part of the overall hazard and dose-response 
assessment for a chemical. Available data pertinent to children's 
health risks are evaluated along with data on adults and the NOAEL 
(no-observed-adverse-effect-level) or benchmark dose (BMD) for the 
most sensitive critical effect(s) based on consideration of all 
health effects. By doing this, protection of the health of children 
will be considered along with that of other sensitive populations. 
(Ref. 5 at 7).

    A similar process is undertaken to estimate exposure for all 
exposed population subgroups. Once these toxicity and exposure analyses 
are complete, EPA turns to the three critical factors pertaining to the 
children's safety factor described above and conducts a weight-of-the-
evidence analysis to identify any concerns regarding the safety of 
infants and children. Finally, each of these factors are considered 
together in ``an integration step wherein the weight-of-evidence 
analyses for the completeness of the toxicity database, the degree of 
concern for pre- and postnatal toxicity, and results of the exposure 
assessments are combined by decisionmakers in evaluating whether the 
presumptive 10X safety factor should be retained or reliable data 
justify a different factor that could range from a level of 1X to 10X, 
and possibility greater than 10X.'' (Id. at 50).
    In assessing the completeness of the toxicity database, EPA 
considers first whether the core five toxicology studies are available 
(chronic toxicity study in two species, two-generation reproduction 
study, and developmental toxicity study in two species) and next 
whether there are data gaps for any other studies, ``particularly those 
that pertain to evaluating risk to children and other sensitive 
subpopulations.'' (Id. at 24.) If data gaps are identified, then ``the 
risk assessor should consider the general, overall value of the 
particular type of study to the risk assessment.'' For pyraclostrobin, 
the toxicity database was adequate because no data gaps pertaining to 
infants and children have been identified. As explained in Unit 
VII.A.2., EPA disagrees with each of NRDC's claims regarding the 
existence of data gaps or data deficiencies.
    In assessing the completeness of the exposure database, EPA uses a 
weight-of-the-evidence approach to ``address all important sources, 
routes, and pathways of exposure for the pesticide and include both the 
expected exposure duration as a consequence of each use and the 
expected pathway(s) of exposure.'' (Id. at 36). The object of this 
analysis is to determine the level of confidence that ``the assessment 
is either highly accurate or based upon sufficiently conservative input 
that it does not underestimate those exposures that are critical for 
assessing the risks to infants and children.'' (Id.). For 
pyraclostrobin, there is high confidence that the exposure assessment 
does not

[[Page 52123]]

underestimate exposure. EPA examined three pathways of exposure: food, 
drinking water, and exposure from use on residential turf. As explained 
in Unit III.B.3.b., EPA follows a tiered approach in estimating 
pesticide residues in food, first conducting a simple, very 
conservative assessment (assuming all registered crops contain 
tolerance level residues) that grossly overestimates exposure from 
residues in food and then refining that analysis in steps if needed. 
For pyraclostrobin, EPA conducted a slightly refined analysis. For the 
acute exposure assessment, EPA assumed all pyraclostrobin-registered 
crops were treated with pyraclostrobin and that 65 of 73 crops had 
residues at the tolerance level. For the other crops (various leafy 
greens and dried beans), EPA assumed residues would be at the highest 
average value from residue field trials designed to produce maximum 
residues. For the chronic exposure assessment, EPA used data on percent 
crop treated for most of the registered crops and assumed tolerance 
level residues for all registered crops other than apple and pear. For 
apple and pear, EPA used the average value from residue field trials 
designed to produce maximum residues. Although these exposure 
assessments are somewhat refined, they remain very conservative in 
comparison to estimates based on monitoring data gathered from food 
distribution channels. To estimate exposure to pyraclostrobin through 
residues in drinking water and from treated residential turf EPA used 
exposure models that incorporate pesticide specific information and are 
designed to produce high-end estimates of exposure. (Ref. 8 at 30; 69 
FR at 30058-30064). Because of this conservative approach to estimating 
exposure, EPA has very high confidence that its exposure assessment 
does not underestimate exposure to pyraclostrobin. In all likelihood, 
it substantially overestimates exposure.
    Finally, in examining a pesticide's potential pre- and post-natal 
toxicity, EPA also conducts a weight-of-the-evidence analysis focusing 
on whether data show increased sensitivity in the young, how well the 
dose-response relationship of any pre- or post-natal effects are 
understood, and, to the extent available, information on a pesticide's 
toxicokinetics and mode of action. For pyraclostrobin, the key studies 
on pre- and post-natal toxicity were the rat and rabbit developmental 
toxicity studies and the one and two generation rat reproduction 
studies. The rat developmental study showed no increased sensitivity in 
the rat fetuses (see discussion in Unit VII.A.2.a.i.) and, in any 
event, the effects seen in the fetuses occurred at higher doses than 
the effects in maternal animals. Qualitatively more severe effects were 
seen in the fetuses in the rabbit developmental study (fetal 
resorptions compared to body weight effects); however, these effects 
occurred at the same dose as the adverse effects in the maternal 
animals and a clear NOAEL level was identified for both the maternal 
and fetal effects. Finally, the one generation rat reproduction study 
indicated that rat pups may be quantitatively more sensitive than 
parental animals in that marginal body weight effects were seen at a 
lower dose in pups than in parental animals. The two generation rat 
reproduction study, however, failed to replicate this quantitative 
sensitivity instead showing that marginal body weight effects occurred 
in both pups and parental animals at the same dose (see discussion in 
Unit VII.A.2.c.). Moreover, the two generation study established a 
clear NOAEL for the body weight effects in both pups and parental 
animals. Based on this evidence, EPA concluded that the effects on the 
young were well understood/characterized and that there were no 
residual concerns that reliance on the traditional 10X intra-species 
safety factor, when applied to the NOAELs for effects in fetuses and 
pups, would not be protective of infants and children. (71 FR 17014, 
17018 (April 5, 2006); 69 FR 63083, 63092-63093 (October 29, 2004)).
    Taking into account that (1) there is a complete toxicity database; 
(2) the exposure estimate is a likely overestimate of pyraclostrobin 
exposure; and (3) pyraclostrobin's pre- and post-natal effects are 
well-defined by the database and there are no residual concerns 
regarding potential increased sensitivity - EPA concludes that it has 
reliable data showing that it is safe for infants children to conduct 
its risk assessment using a 100-fold safety factor without use of the 
additional 10X children's safety factor.

C. Conclusion on Objections

    For the reasons stated above, all of the NRDC's objections are 
hereby denied.

VIII. Response to Comments on NRDC's Objections

    In comments on its own objections, NRDC made two additional 
arguments. First, NRDC cited general statements that children can be 
more vulnerable than adults to pesticides and that children may have 
greater relative exposure to pesticides than adults. These two points, 
according to NRDC, make it ``especially important that EPA apply the 
required FQPA safety factor for pyraclostrobin.'' (Ref. 10 at 3). EPA 
does not believe that this general information is particularly helpful 
in making the specific determination for pyraclostrobin under the 
children's safety provision. Concerns about children's vulnerability 
and exposure led to passage of the children's safety factor provision; 
yet that provision expressly allows EPA to choose a factor different 
than the presumptive additional 10X safety factor if such different 
factor is safe for children. NRDC's argument here essentially reads 
EPA's authority to choose a different factor out of the statute not 
just for pyraclostrobin but for all pesticides. Further, EPA would note 
that it has taken into account, in making a decision on the children's 
safety factor for pyraclostrobin, data estimating children's exposure 
to pyraclostrobin and data evaluating the relative sensitivity of the 
young vis-a-vis adults to pyraclostrobin.
    An additional claim included in NRDC's comments is that its 
objections are supported by six documents referenced in the objections. 
These documents include a letter to EPA, a report from EPA's Office of 
Inspector General, several law review articles, and the National 
Academy of Sciences' 1993 report on pesticides and children. Other than 
listing the documents, NRDC did not explain how these documents support 
its objections. All of the documents address, at least in part, 
application of an additional safety factor for the protection of 
children. None of the documents, however, mentions pyraclostrobin. EPA 
does not believe that the mere listing of documents, particularly such 
general documents as these, trigger any obligation upon the Agency to 
respond to the substance of the documents. Further, the failure of NRDC 
to offer any substantive explanation as to why these documents were 
included in its comments means that NRDC has not presented or exhausted 
any issues, questions, or conclusions contained in these documents 
before the Agency. The reason for the exhaustion requirement in section 
408 as to tolerance issues is so that EPA may make a full record on an 
issue and bring its experience to bear on it. (Nader v. EPA, 859 F.2d 
747, 754 (9th Cir. 1988)). Because NRDC has not presented any issues, 
questions, or conclusions contained in these documents to EPA, it 
cannot, should it challenge this Order in court, cite matters in these 
documents to the court as supporting its objections. For the

[[Page 52124]]

same reason, EPA will not include these documents in the record for 
this action.

IX. Regulatory Assessment Requirements

    As indicated previously, this action announces the Agency's final 
order regarding objections filed under section 408 of FFDCA. As such, 
this action is an adjudication and not a rule. The regulatory 
assessment requirements imposed on rulemaking do not, therefore, apply 
to this action.

X. Submission to Congress and the Comptroller General

    The Congressional Review Act, (5 U.S.C. 801 et seq.), as added by 
the Small Business Regulatory Enforcement Fairness Act of 1996, does 
not apply because this action is not a rule for purposes of 5 U.S.C. 
804(3).

XII. References

    1. Natural Resources Defense Council, ``Objection to the 
Establishment of Tolerances for the Pesticide Chemical Residues of 
Pyraclostrobin'' Docket Id No. EPA-HQ-OPP-2004-0292 (June 5, 2006).
    2. Office of Pesticide Programs, U.S. EPA, Available Information on 
Assessing Pesticide Exposure From Food: A User's Guide (June 21, 2000).
    3. U.S. EPA, Residue Chemistry Test Guidelines: OPPTS 860.1500 Crop 
Field Trials (August 1996).
    4. Office of Pesticide Programs, U.S. EPA and Pest Management 
Regulatory Agency, ``Health Canada, NAFTA Guidance Document for 
Guidance for Setting Pesticide Tolerances Based on Field Trial Data'' 
(September 28, 2005).
    5. Office of Pesticide Programs, U.S. EPA, ``Determination of the 
Appropriate FQPA Safety Factor(s) in Tolerance Assessment'' (January 
31, 2002).
    6. Office of Pesticide Programs, U.S. EPA, ``The Use of Data on 
Cholinesterase Inhibition for Risk Assessments of Organophosphorous and 
Carbamate Pesticides'' (August 18, 2000).
    7. Office of Pesticide Programs, U.S. EPA, Versar Corporation, 
``Standard Operating Procedures (SOPs) for Residential Exposure 
Assessments'' (Draft, December 19, 1997).
    8. Office of Prevention, Pesticides, and Toxic Substances, U.S. 
EPA, Memorandum from Barry O'Keefe to John Bazuin/Cynthia Giles-Parker, 
``Pyraclostrobin Human Health Risk Assessment to Account for Revised 
Tolerances on Succulent Beans, Dried Shelled Peas and Beans, and 
Strawberries, and to Establish Tolerances on Mangos and Papayas'' 
(November 30, 2005).
    9. Office of Prevention, Pesticides, and Toxic Substances, U.S. 
EPA, Memorandum from Ghazi Dannan to William Wassell, ``PYRACLOSTROBIN 
- 3rd Report of the Hazard Identification Assessment Review Committee'' 
(February 10, 2003).
    10. Natural Resources Defense Council, Re: ``Objection to the 
Establishment of Tolerances for Pesticide Chemical Residues of 
Pyraclostrobin,'' Docket ID No. EPA-HQ-OPP-2004-0292 (September 9, 
2006).
     11. BASF Corporation, Docket ID [EPA-HQ-OPP-2004-0292; FRL-8076-81 
``Pyraclostrobin; Objections to Pesticide Tolerances; Notice of 
Availability;'' Federal Register, Vol 71, No. 138, July 19, 2006 
(September 12, 2006).
    12. Health Effects Division, Office of Pesticide Programs, U.S. 
EPA, Data Evaluation Record (TXR: 0051615): ``Prenatal 
Developmental Toxicity Study'' (Teratology); Species: Rat; Guideline: 
OPPTS 870.3700; OPP 83-3a; ``Pyraclostrobin'' (April 29, 2003).
    13. Health Effects Division, Office of Pesticide Programs, US EPA, 
``Data Evaluation Record (TXR: 0051615): Prenatal 
Developmental Toxicity Study'' (Teratology); Species: Rabbit; 
Guideline: OPPTS 870.3700; OPP 83-3b; ``Pyraclostrobin'' (April 29, 
2003).
    14. Office of Prevention, Pesticides, and Toxic Substances, U.S. 
EPA, Memorandum from Ghazi Dannan to Cynthia Giles-Parker/Tony Kish, 
``HED Response to NRDC Objection to the Establishment of Tolerances for 
Pesticide Chemical Residues of Pyraclostrobin.'' Docket ID No. EPA-HQ-
OPP-2004-0292. (PC Code 099100) (July 16, 2007).
    15. Woo, David C. and Hoar, Richard M., ```Apparent Hydronephrosis' 
as a Normal Aspect of Renal Development in the Late Gestation of Rats: 
The Effect of Methyl Salicylate'' (Teratology; 1972 Oct;6(2):191-6).
    16. Office of Prevention, Pesticides, and Toxic Substances, U.S. 
EPA, Memorandum from Yung Yang to Cynthia Giles-Parker/Tony Kish,``HED 
Response to NRDC Objection to the Establishment of Tolerances for 
Pesticide Chemical Residues of Pyraclostrobin.'' Docket ID No. EPA-HQ-
OPP-2004-0292. TXR  0054635, DP Barcode: D341293, PC Code: 
099100. (July 24, 2007).
    17. Health Effects Division, Office of Pesticide Programs, US EPA, 
Data Evaluation Record: Subchronic Inhalation Toxicity - [rat]; OPPTS 
870.3465 [82-4]; OECD 413. ``Pyraclostrobin; methyl [2-[[[1-(4-
chlorophenyl)-1H-pyrazol-3-yl]methyl] phenyl]methoxycarbamate'' (August 
21, 2007).
    18. Office of Pesticide Programs, U.S. EPA, Data Evaluation Record, 
Multigeneration Reproductive Toxicity Species: Rat; Guideline: OPPTS 
870.3800; OPP 83-4; EPA MRID No. 45118327, EPA Pesticide Chemical Code: 
099100, EPA DP Barcode D269669, D267732, EPA Submission No. S583112, 
HED TXR:0051615, Test Material: BAS 500 F (January 16, 2003).
    19. Office of Pesticide Programs, U.S. EPA, ``Pesticide Rejection 
Rate Analysis Toxicology,'' 738-R-93-005, pp. 82-83, (July 1993).
    20. Office of Prevention, Pesticides, and Toxic Substances, U.S. 
EPA, Memorandum from Jessica Kidwell to Ghazi Dannan and Barry O'Keefe, 
``PYRACLOSTROBIN: Report of the Cancer Assessment Review Committee 
(Second Evaluation);'' PC Code: 099100 (October 22, 2003).
    21. Office of Prevention, Pesticides, and Toxic Substances, U.S. 
EPA, Memorandum from Jessica Kidwell to Ghazi Dannan and Paula 
Deschamp, ``PYRACLOSTROB IN: Third Report of the Dose Adequacy Review 
Team (DART)'' (July 19, 2005).
    22. Office of Prevention, Pesticides, and Toxic Substances, U.S. 
EPA, Memorandum from Jessica Kidwell to Ghazi Dannan, ``PYRACLOSTROBIN: 
Second Report of the Dose Adequacy Review Team (DART)'' (March 7, 
2005).
     23. Office of Prevention, Pesticides, and Toxic Substances, U.S. 
EPA, Memorandum from Jessica Kidwell to Ghazi Dannan and Barry O'Keefe, 
PYRACLOSTROBIN: Report of the Cancer Assessment Review Committee (Third 
Evaluation); PC Code: 099100 (February 15, 2007).

[[Page 52125]]

List of Subjects

    Environmental protection, Pesticides and pests.


    Dated: September 4, 2007.
Debra Edwards,
Director, Office of Pesticide Programs.
[FR Doc. E7-18025 Filed 9-11-07; 8:45 am]

BILLING CODE 6560-50-S
