![](media/image1.png){width="0.8152777777777778in"
height="0.9027777777777778in"}Number range CHAPTER UNITED STATES
ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

TXR: 0054626

**[MEMORANDUM]{.underline}**

**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:** Number range CHAPTERRobert 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 Number range CHAPTERNumber range
CHAPTER(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 UF~DB~ 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 UF~DB~ 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 UF~DB~ 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.