### 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 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: NIA 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 Divis ion (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 ofovert toxicity. The EDSP WoE analysis for phosmet which includes data from the low dose in the male p ubertal assay as well as data from other Tier 1 assays and OSRI , support a lack ofpotential interaction ofphosmet with the androgen pathway and a potential interaction with the thyroid pathway in mammal s . Therefore , a repeat ofthis assay i s 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 ofthe male pubertal assay. 

### IV. EVALUATION OF THE REGISTRANTS RESPONSE In the rebuttal , the test order recipient concluded:

" Administration ofphosmet 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 ofclinical 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 da y s ofdosing

. When seen, post-dosing clinical signs were typically mild and did not persist. The high dose of20 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 ofthe 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 ofthe Agency's weight-of-the-evidence evaluation ofthe 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 ofEvidence (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-do se (20 mg/kg/day) males , re spectively. 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 ofphosmet 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 ofovert 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 thi s 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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