UNITED STA TES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: July 29, 2015 

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

male pubertal assay. 

PC Code: 059201 

Decision No.: 505081 

Petition No.: NIA 

Risk Assessment Type: NI A 

TXR No.: 0057291 

MRID No.: 49610501 

DP Barcode: D427337 

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. A_ - ff_ --- - Immediate Office '---7 0 

Health Effects Division (7509P) 

THROUGH: Jess Rowland ~~-:;. (;2...c5 ...,2------.. 

Deputy Director 

Health Effects Division 

TO: Joel Wolf 

Chemical Review Manager 

Risk Management and Implementation Branch II 

Pesticide Re-evaluation Division (7505P) 

I. CONCLUSION 

Yer.Apr. 20 10 

Based on the information provided in the test order recipient's rebuttal, the agency now 

considers the low dose in the male pubertal assay to be adequate with only the high dose 

showing evidence of overt toxicity. The EDSP WoE analysis for phosmet which includes 

data from the low dose in the male pubertal assay as well as data from other Tier 1 assays 

and OSRI, support a lack of potential interaction of phosmet with the androgen pathway and 

a potential interaction with the thyroid pathway in mammals. Therefore, a repeat of this 

assay is not required. 

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II. ACTION REQUESTED 

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

49610501) by Gowan Company regarding the deficiencies identified in the preliminary Data 

Evaluation Report (DER) for the male pubertal assay (MRID 48673003) and the agency's 

request to repeat this assay for phosmet. 

III.BACKGROUND 

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

pubertal assay (OCSPP 890.1500) for phosmet be repeated due to deficiencies identified in 

the study (MRID 48673003) as described in the preliminary DER. In response to the 

agency's email, the test order recipient submitted a rebuttal (MRID 49610501) providing 

additional information and rationale for not requiring a repeat of the male 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, post-dosing 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 486730038 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 1 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 androgen pathway and thyroid pathways. 

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V. DISCUSION 

In the Tier 1 male pubertal rat assay, tremors were seen at both doses (10 and 20 mg/kg/day) 

tested. The additional data submitted in the rebuttal show at the 10 mg/kg/day dose level, 

mild tremors were seen during one day only in 6/16 animals. In contrast, the severity of 

tremors at the 20 mg/kg/day dose level ranged from mild to moderate and were seen on 

multiple days in 11/16 animals. Based on this additional information, the low dose is now 

considered to be adequate with only the high dose showing evidence of overt toxicity. 

In this study, there were no effects on age or weight at preputial separation (PPS), hormone 

concentrations, or gross and microscopic pathology. Slight decreases in ventral prostate 

weights (NS; !9 and 15%) were observed in the low (10 mg/kg/day) and high-dose (20 

mg/kg/day) males, respectively. Serum T4 levels were increased by 48 and 43%, 

respectively, in the low (10 mg/kg/day)- and high-dose (20 mg/kg/day) groups, with no 

treatment-related effects noted for thyroid weight or TSH concentration. Marginal decreases 

in thyroid colloid area and increases in follicular cell height were observed in all animals. 

Overall based on the agency's WoE analysis, there is no convincing evidence for potential 

interaction of phosmet with the androgen pathway. While the Tier 1 androgen receptor 

binding assay was positive, the steroidogenesis assay was negative and there were no 

androgen-related effects were observed in the Tier 1 Hershberger or Fish Short Term 

Reproduction Assay (FSTRA) in the absence of overt toxicity. The only androgen-related 

effect observed in the mammalian Part 158 studies was an increase in the incidence of 

testicular atrophy in the mouse carcinogenicity study. 

T4 levels were increased and changes in thyroid histopathology (decreased colloid area and 

increases in follicular cell height) were observed at both doses in the male pubertal assay, 

although the effects at the high dose occurred in the presence of overt toxicity. Similarly, 

thyroid effects (increased T4 levels and histopathology) were observed in the Tier 1 female 

pubertal assay; however, both test doses were considered to be overtly toxic in this assay. In 

the Part 158 mammalian studies, histopathological changes in the thyroid were observed at 

10.9 mg/kg/day in the chronic rat study. In the amphibian metamorphosis assay (AMA), the 

observed developmental delays are likely not thyroid-mediated. 

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