  SEQ CHAPTER \h \r 1 		UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

TXR: 0054626

MEMORANDUM

Date:	June 21, 2007

Subject:	Fenamidone: Summary of HED Hazard Assessment and Policy
Committee (HASPOC) meeting of June 14, 2007

PC Code:		046679	

DP Barcode:		D335872

From:	  SEQ CHAPTER \h \r 1 Robert Mitkus, PhD, Toxicologist

	Registration Action Branch 1 (RAB1), Health Effects Division (HED;
7509P)

Thru:			Pv Shah, PhD, Acting Branch Chief

					RAB1, HED (7509P)

To:	HED HASPOC Members   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1
(7509P)

Meeting Attendees

HASPOC Members:  Tina Levine, Gino Scarano, Jess Rowland, Ray Kent

Others:  Robert Mitkus (presenter), Pv Shah, Kelly Lowe, Tom Bloem

Purpose of the Meeting

The HASPOC met on June 14, 2007 to discuss whether the Agency would
require Bayer Crop Science (BCS) to test the fungicide fenamidone in a
second DNT study, but using the Sprague Dawley rat.  The committee also
met to determine whether it was appropriate to retain the 10x UFDB for
lack of a DNT, since BCS had tested fenamidone under the DNT paradigm
using the Wistar rat.

 

Background

In the 2-generation reproduction study with fenamidone in Crl:CD(SD)BR
rats, absolute brain weight was decreased in adult F1 females at 1000
ppm/84.4 mg/kg/day (7%) and 5000 ppm/459.7 mg/kg/day (9%).  In F2 female
offspring, absolute brain weight was decreased at 1000 ppm (9%) and 5000
ppm (11%).  Decreased absolute brain weight (8%) was also observed in
adult male rats at 5000 ppm/392.3 mg/kg/day in the subchronic
neurotoxicity study with fenamidone in Crl:CDBR® rats.  Primarily for
these reasons, a DNT study was therefore required with fenamidone.  A
UFDB of 10X was applied to all exposure scenarios to account for the
lack of the DNT study with fenamidone.

Before the DNT study was performed, HED reviewed and agreed with the
doses proposed by Bayer Crop Science (BCS), except for the high dose. 
The DNT committee of 2004 recommended the use of a dose of 460 mg/kg/day
as the high dose with adjustment of dietary concentrations during
lactation, or the use of 5000 ppm as the highest dose without adjustment
of doses for increased food consumption in lactating females.  In
addition, EPA suggested that a preliminary dose range finding study
should be conducted, if the Crl:CD(SD)BR strain of rats were not
utilized in the DNT study, since the two-generation reproduction study
was conducted with this strain of rats.

BCS conducted the DNT study in Wistar rats without performing a
preliminary range finding study.  After review of the study in 2006, the
DNT Workgroup classified the study as Unacceptable/Guideline since it
was not possible to assess whether decreases in absolute brain weight
(as well as any possible changes in behavioral measures) would be
observed under the DNT testing paradigm using the Crl:CD(SD)BR strain of
rat, since decreases in absolute brain weight were observed in the F1
and F2 generations in the 2-generation reproduction study using the
Crl:CD(SD)BR strain of rat.

In response to the Agency’s rejection of the DNT study, BCS stated the
following: “The principal reason BCS chose to use the Wistar rat was
because all DNT studies performed at BCS have used only this rat
strain…. Using a strain other than Wistar was not a feasible option in
the absence of validation studies and historical control data for other
strains which might have been utilized.”

HASPOC Recommendations

The HazPoc decided to remove the 10x UFDB for lack of a DNT.  The
committee proposed that BCS perform a modified DNT study in the
Crl:CD(SD)BR strain of rat with measurement of the following endpoints:
brain weights and brain morphometry.  Doses were not proposed, but would
likely be similar to those recommended by the Agency previously.  It was
also suggested that the study report and DER for the 2-generation
reproductive toxicity study be given to David Miller’s branch to
determine whether statistical analysis was performed appropriately.

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