UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: July 29, 2015 

SUBJECT: Phosmet: Response to the Test Order recipient's rebuttal for a repeat of the 

female pubertal assay. 

PC Code: 059201 

Decision No.: 505080 

Petition No.: NI A 

Risk Assessment Type: NI A 

TXR No.: 0057292 

MRID No.: 49610502 

DP Barcode: D427336 

Registration No.: NI A 

Regulatory Action: NI A 

Case No.: NI A 

CAS No.: 732-11-6 

40 CFR: NIA 

FROM: Greg Akerman, Ph.D. _L)~ /1~--- Immediate Office 

Health Effects Division (7509P) 

THROUGH: Jess Rowland ~~Q-S2--­ Deputy Director 

Health Effects Division 

TO: Joel Wolf 

Chemical Review Manager 

Risk Management and Implementation Branch II 

Pesticide Re-evaluation Division (7505P) 

I. CONCLUSION 

Ver.Apr. 2010 

The assay does not satisfy the EDSP Tier I Test Order requirements for a female pubertal 

assay since overt toxicity was seen at both doses tested. However, a new assay is not 

required at this time since the results from a repeat assay would have no impact on the risk 

assessment. The point of departure (PoD) for the phosmet risk assessment is based on 

cholinesterase inhibition at substantially lower doses than the ones tested in this assay. For 

additional information see the EDSP Tier 1 Weight of Evidence Analysis for Phosmet (TXR 

0057145). 

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II. ACTION REQUESTED 

The Pesticide Re-evaluation Division (PRD) requested a review of the rebuttal (MRID 

49610502) by Gowan Company regarding the deficiencies identified in the preliminary DER 

for the female pubertal assay (MRID 48673003) for phosmet and the agency's request to 

repeat the study. 

III.BACKGROUND 

In an October 30, 2014 email to the test order recipient, the agency requested that the female 

pubertal assay (OCSPP 890.1450) for phosmet be repeated due to deficiencies identified in 

the study (MRID 48673003) as described in the preliminary data evaluation record (DER). 

In response to the agency's email, the test order recipient submitted a rebuttal (MRID 

49610502) providing additional information and rationale for not requiring a repeat of the 

female pubertal assay. 

IV. EVALUATION OF THE REGISTRANTS RESPONSE 

In the rebuttal, the test order recipient concluded: 

"Administration of phosmet to intact juvenile/peripubertal male rats at treatment levels of 

10 and 20 mg/kg/day did not cause any effects suggesting disruption in pubertal 

development or thyroid function. Testing at lower treatment levels would not be expected 

to produce a different result. The pattern and lack of severity of clinical signs observed 

in the test animals indicates that the high dose was well tolerated by the test animals 

throughout the course of study. No clinical signs were observed pre-dosing (i.e. about 24 

hours after the previous dose) at any time in the study. No post-dosing clinical signs 

occurred during the first two days or the last eleven days of dosing. When seen, postdosing clinical signs were typically mild and did not persist. The high dose of 20 

mg/kg/day produced toxic effects, as required by the guideline. However, this treatment 

level was not excessive and was well tolerated by the test animals over the course of the 

study. We consider MRID 48673003B to be a valid and negative study. Accordingly, we 

do not believe that the Agency's requirement that we repeat the study is justified. 

Notwithstanding, completion of the Agency's weight-of-the-evidence evaluation of the 

entire phosmet Tier I EDSP battery should be fundamental to inform any request for 

further work." 

The agency evaluated the registrant's rebuttal along with the findings in the other EDSP Tier 

1 assays and other scientifically relevant information (OSRI) considered in the agency's 

Weight of Evidence (WoE) analysis (TXR 0057149) on the potential for phosmet to interact 

with the estrogen pathway and thyroid pathways. 

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V. DISCUSION 

In the female pubertal assay, persistent tremors were seen at both doses (10 and 20 

mg/kg/day) tested, and body weight losses (9-10%) were seen at the high dose (20 

mg/kg/day) indicating overt toxicity. The submitted additional information in rebuttal show 

that tremors were seen in 10116 rats at the 10 mg/kg/day dose level (during 10 days) and all 

animals at the 20 mg/kg/day dose (during 18 days). The severity of the tremors ranged from 

"not characterized to moderate." Upon review of these data, the agency reaffirms its previous 

conclusion that both doses tested in this assay were excessive. 

Although both doses were considered to be overtly toxic, it is noted that there were no 

treatment-related effects on vaginal opening, cycle status at necropsy, mean age at first 

estrus, mean cycle length, percent cycling, percent regularly cycling or histopathological 

changes in the ovaries or uterus. Serum T4 concentrations were increased by 24 and 38%, 

respectively, in the low- and high-dose groups, but no treatment-related effects were noted 

for thyroid weight or TSH concentration. 

In the agency's WoE analysis for phosmet, the available data do not suggest that phosmet has 

the potential to act as an estrogen agonist based on the in vitro and uterotrophic studies. 

Additionally, while the in vitro aromatase assay was positive which could indicate a potential 

decrease in estradiol production, the in vitro steroidogenesis was negative and the results of 

both the female pubertal and Fish Short Term Reproduction Assay (FSTRA), do not support 

an anti-estrogenic effect. Thyroid effects (increased T4 levels and histopathology) were 

observed in the female pubertal assay; however, both test doses were considered to be overtly 

toxic. 

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