UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES, AND

TOXIC SUBSTANCES

TXR No:	0053177

MEMORANDUM

DATE:	March 7, 2005

SUBJECT:	PYRACLOSTROBIN: Second Report of the Dose Adequacy Review Team
(DART)  	

PC code: 099100

FROM:	Jessica Kidwell, Executive Secretary

Dose Adequacy Review Team

Health Effects Division (7509C)

THROUGH:	Jess Rowland, Chair			

Dose Adequacy Review Team

Health Effects Division (7509C)

TO:		Ghazi Dannan, Toxicologist

Registration Action Branch 3

Health Effects Division (7509C)

John Bazuin/Cynthia Giles-Parker, PM Team 22

Fungicide Branch

Registration Division (7505C)

	

On February 23, 2005 the DART met to discuss BASF’s request to
terminate a supplemental female mouse carcinogenicity study.  Attached
please find the DART’s final report and recommendations.

Team Members in Attendance at the February 23, 2005 DART Meeting:
(Signature indicates concurrence with report unless otherwise noted:)

Karl Baetcke						____________________________________

William Burnam					____________________________________

Jessica Kidwell (Executive Secretary)	
____________________________________

Jess Rowland						____________________________________

Other Attendees: Ghazi Dannan (HED/RAB3), Kelly O’Rourke
(HED/RAB3),Stephen Dapson (HED/RAB3), Gerome Burke (HED/RAB3), Paula
Deschamp (HED/RAB3)

Attendees at the March 4, 2005 conference call with Health Canada’s
Pesticide Management Regulatory Agency (PMRA): William Burnam, Karl
Baetcke, Paula Deschamp, Jessica Kidwell, Catherine Adcock (PMRA)				

On February 23, 2005 the DART met to discuss BASF’s request to
terminate a supplemental female mouse carcinogenicity study.  HED had
previously requested that this study be conducted to meet guideline
requirements based on the concern that dosing in female mice at the high
dose of 180 ppm in the main carcinogenicity study was not adequate.  In
2004, BASF sent a proposal to the DART with the proposed dose level for
the carcinogenicity study in female mice.  The DART recommended that a
supplemental study be conducted at a dose of 360 ppm (2x the original
high dose) (See DART memo, 5/26/04, TXR # 0052548).  

The supplemental study was initiated in September 2004 and the
Registrant presented data obtained from study days 0 through 119.  BASF
is currently requesting the DART’s concurrence that the dose of 360
ppm be terminated due to a body weight gain decrease of 48% compared to
controls at day 119, and which, according to the registrant, appears to
be an excessive dose.  Since a dose of 180 ppm (½ the required dose of
360 ppm) was previously tested in the original mouse carcinogenicity
study, the registrant proposes that no further testing is needed.

The DART reviewed the registrant’s submission and considered their
request.  The DART agrees that there was a variable, but substantial,
decrease in body weight and body weight gain, with body weights
diverging from controls after day 56.  At day 91 there was a 12%
decrease in body weight and a 37% decrease in body weight gain. Food
efficiency was decreased by 56% compared to controls, however, no
information was provided on food spillage.  At day 119, there was a 20%
decrease in body weight and 48% decrease in body weight gain (over a 2
week period).  No mortality was reported and no other signs of toxicity
were seen. 

The Registrant made the argument that the body weight/body weight gain
decreases with accompanying decreases in food efficiency at the dose of
360 ppm greatly exceeds the requirement using the criteria set forth in
the HED Interim Guidance Document (#G2003.02) Rodent Carcinogenicity
(July 1, 2003) which states: “...for the selection of carcinogenicity
study doses, a decrease in body weight gain approaching 10% compared to
controls over the duration of a study of at least 90 days is sufficient
evidence that an adequate high dose has been identified.” and the
Interim Guidance Document #G2003.01 Interpretation of Body Weight Data
which states: “Other factors should be considered such as food
efficiency to see if [body weight] changes are secondary to other
effects.”  The DART acknowledges the substantial decreases in body
weight/body weight gain, however, this supplemental study is being
conducted to assess the carcinogenic potential of pyraclostrobin at a
single dose greater than 180 ppm.  The interim guidance documents, on
the other hand, apply to selection of doses for a study and/or
evaluation of a carcinogenicity study that employed multiple dose
levels.  These criteria do not apply to this situation since the
supplemental study is a bridging study. 

Therefore, it is the DART’s recommendation that the Registrant
continue this study for a total of 6 months to see if the decreases in
body weight/body weight gain and food efficiency are temporary or if the
body weight divergence is sustained.  At this time, the Registrant
should contact the DART for further evaluation of the body weight/body
weight gain effects, as well as other toxic effects seen, to determine
the adequacy of the dose.  (Note: The DART discussed this issue with
Health Canada’s PMRA on 3/4/05 and they agreed with the DART’s
recommendation for continuing the study.)					

 Dose Adequacy Review Team Report                       

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