BACKGROUND

In a submission via Federal eRulemaking Portal da ted August 24, 2009, Gowan Company submitted preliminary comments on several documen ts included in the June 2009 initial docket for the Registration Review of phosmet. This response is limited to comments on documents which are the purview of the Heal th Effects Division (HED). Th e specific comments for which HED is providing response were id entified as comments 1.4, 1.5 and 2.1.

RESPONSE TO COMMENTS

Registrant Comment 1.4 The FQPA safety factor of 10X was retained by the Agency for women of child-bearing age because of the lack of the gestational compone nt of the comparative cholinesterase assay.

Gowan points to the Agency’s previous conclusi on that the guideline developmental toxicity study on phosmet did not identify any adverse fe tal effect (2004 letter from EPA to Gowan Company), and that exposure to th e fetus during gestation is less th an to the dam. Gowan asserts that potential bioavailability of phosmet to the fetus following substantial maternal exposure is quite limited, and therefore, no additional FPQA safety factor for women of child-bearing age is

warranted.

Agency Response

HED concurs that as stated in the referenced EP A letter, the developmental toxicity study did not identify any adverse fetal effects; however, HED notes that this st udy did not include an assessment of the endpoint of concern, cholinesterase inhibition, in either the dam or the fetus. Further, HED notes that the full context of th e referenced 2004 EPA le tter cited also includes EPA’s position that Gowan Company could defer initiation of the DNT until the Agency had completed an analysis of DNT studies conduc ted on other organophosphate chemicals. This deferral was additionally predic ated on the submission of acu te and repeat-dose relative sensitivity studies.

Subsequent to the cited EPA letter, Gowa n submitted acute (3/19/2007) and repeat-dose (3/6/2009) comparative cholines terase assays on phosmet. Having reviewed the recently submitted acute and repeat-dose comparative cho linesterase sensitivity studies, the Agency concluded that the FQPA SF could be removed for infants and childre n since the new data adequately characterized the risk to that group. These data provided sufficient information to assure that selected endpoints are protective of adverse effects for these population subgroups.

The Agency has reviewed epidemiological da ta from other organophosphates which indicates that the pregnant animal may be more sensitiv e than the non-pregnant animal. Therefore, the key issue which dictates retention of the FQPA SF for women of child bearing years is based on concern that the pregnant animal may be more sensitive to phosmet exposure. In the absence of

Page 2 of 3a DNT on phosmet which would have provided the gestational component needed to address the concern that pregnant animals a nd/or the fetus may be more sensitive, and in light of the information gleaned from the analysis of data on other organophosphates, the Agency maintains

that there is not sufficient evid ence to support removal of the FQPA safety factor for women of child bearing years at this time for phosmet.

Registrant Comment 1.5 Gowan Company has cited an Agency comment that the results of recent epidemiology studies in mothers and children highlight the importance of c onsidering gestational e xposure, but notes that the Agency hasn’t provided rationale explai ning why epidemiology studies with other compounds are relevant to phosmet, particularly to the assignment of phosmet-specific FQPA safety factor.

Agency Response

The Agency considers the epidemiology studi es on other organophosphate chemicals to be relevant to phosmet to the extent that they rais e a potential concern that pregnant animals may be more sensitive to the adverse effects of orga nophosphates than non pregnant animals. Given the similar toxicity profile among the organophosphate s this evidence suggest s a concern. That concern must be addressed either through an uncer tainty factor or with actual data since FQPA requires the Agency to retain the FQPA SF unless there is sufficient data to remove it. In light of the sensitivity seen in closely related compounds, and since the Ag ency is lacking data with a gestational component which would have come fro m a DNT, the Agency continues to maintain that an FQPA SF for females of child bearing years must be retained.

Registrant Comment 2

. 1 The registrant notes that additi onal information was requested in a meeting with HED and SRRD on August 3, 2009. Gowan requested these documents (see below) in order to prepare an adequate response to both the Human Health Assessment Scoping Document [EPA-HQ-OPP2009-0316-004] and to the Revision To the Occupa tional Postapplication Exposure and Risk Calculations for Phosmet [EPA-HQ-OPP-2009-0316-007].

Agency Response The 2009 ToxSac meeting notes for phosmet were transmitted to Gowan on August 26, 2009. A formal and detailed response to the Gowan January 19, 2009 letter was completed on September 1, 2009 (TXR No. 0055254) and transmitted to Gowan on September 18, 2009. The BMD analysis, which was part of the July 30 post-appl ication risk assessment, was also transmitted to Gowan on September 18, 2009.

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