UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460OFFICE OF CHEMICAL SAFETYAND POLLUTION PREVENTION



### MEMORANDUM Date: July 29, 2015 SUBJECT: Phosmet: Response to theTest Order recipient's rebuttal for a repeat ofthe 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.: NIA 

### 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 atthis time since the results from a repeat assay would have no impact on the risk assessment. The point ofdeparture (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 ofEvidence Analysis for Phosmet (TXR 0057145).

Page I of3II. ACTION REQUESTED The Pesticide Re-evaluation Division (PRD) requested a review ofthe 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). Inresponse to the agency's email, the test order recipient submitted a rebuttal (MRID 49610502) providing additional information and rationale for not requiring a repeat ofthe female pubertal assay.


### IV. EVALUATION OF THE REGISTRANTS RESPONSE In the rebuttal, the test order recipient concluded: "Administration ofphosmet to intactjuvenile/peripubertal male rats at treatment levels of 10 and 20 mg/kg/day did not cause any effects suggesting disruption inpubertal development orthyroid function. Testing at lower treatment levels would not be expected to produce a different result. The pattern and lack ofseverity ofclinical signs observed in the test animals indicates thatthe high dose was well tolerated by the test animals throughout the course ofstudy. 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 orthe last eleven days ofdosing. When seen, postdosing 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 48673003B to be a valid and negative study. Accordingly, we do notbelieve that the Agency's requirement that we repeat the study isjustified
. Notwithstanding, completion ofthe Agency's weight-of-the-evidence evaluation ofthe 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 ofEvidence (WoE) analysis (TXR 0057149) onthe 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 atthe high dose (20 mg/kg/day) indicating overt toxicity
. The submitted additional information inrebuttal 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 (dur ing 18 days). The severity ofthe tremors ranged from
"not characterized to moderate. " Upon review ofthese 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 orTSH concentration. Inthe 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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