### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460OFFIC E OF CHEM ICAL SAFETY AND POLLUTION PR EVENTION



### MEMORANDUM DATE: 8/22/2014 SUBJECT: Thiophanate-Methyl (TM)/Carbendazim (MBC). Response to Registrants ' Comments on Registration Review Preliminary Workplan (Docket ID No. EPAOPP-2014-0004) PC Code: 10200 l (Thiophanate-Methyl) DP Barcode: D420917, 420919 128872 (Carbendazim) Decision No.: 492147,492148 Petition No.: N/A Registration No.: N/A Regulatory Action: Registration Review Case No.: 2680 Risk Assessment Type: N/A TXR No.: N/A 

### CAS No.: 23564-05-8 (Thiophanate

-Methyl) 10605

-21-7 (Carbendazirn) 

### MRID No.: N/A 

### 40 C.FR: 180.371 (Thiophanate-Methyl) 

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. }/ &t::...c?..t Risk Assessment Branch II Health Effects Division (7509P)/Office ofPesticide Programs Nathan Mottl, Biologist 

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## Chief**(~~~-~~- /!:__"'**  Risk Assessment Branch li ..:,:/ Health Effects Division (7509P)/Office ofPesticide Programs TO: Carissa Cyran, Chemical Review Manager, PM Team 51 Thomas Moriarty, RM Team 51 Pesticide Re-Evaluation Division (7508P)/Of tice ofPesticide ProgramsBACKGROUND The Agency recently prepared a human health risk assessment seeping document for registration review ofthiophanate-methyl (TM) and its metabolite carbendazim (MBC)(D413079 , M. Collantes, et al., 3/20 / 20 14). The Thiophanate-Methyl and Carbendazim Task Fo rce submitted comments on the Agency's preliminary workplan and anticipated data requirements for TM and MBC (Docket ID No. EPA - HQ

- OPP - 2014 - 0004). These comments related to several toxicit y study requirements requested by the Health Effects Division (HED) and exposure study requirements requested by the Antimicrobials Division (AD). In this memorandum, the Agency is responding to the comments from the TMIMBC T ask Force regarding these data requirements , as well as a number of exposure-related data requirements identified by AD . CONCLUSIONS In p r eparation of the seeping document , the Agency identified the following as data requirements to support registration review of TM and MBC: ( 1) a rat subchronic inhalation toxicit y study (OPPTS 870.3265) on TM , (2) a rat developmental thyroid toxicity study on TM (no guideline number) and (3) an immunotoxicity study (OPPTS 870.7800) on MBC . The fo llowing comments from the TM / MBC Task Force on these r equirements are addressed b y HED and AD: ( 1) Submission of a 28-day inhalation tox icitv studv on TM instead of a 90 - day study: The Task Force noted that EPA would accept a rat 28-day inhalation toxicity study on TM in

lieu of a 90-day inhalation toxicity study. The Agency requested i nclusion of thyroid measures in this study and review of the study protocol prior to in i tiation of the study. E PA Response: EPA concurs that a rat 28- d ay inhalation toxicity study with assessment of thyroid parameters will satisfy the guideline requirement for a subchronic inhalation toxicity study, and that the study protocol should be submitted for review. A 90-day inhalation study is not required at this time . (2) Need for the rat developmental thyroid toxicity studv for TM: The Task Force r equested that the Agency reser ve the requirement for a developmental thyroid study on TM pending review of the rat extended one-generation reproductive toxicity study on MBC. This request is based on the following rationale : the extended one-generation study wi ll assess both neurolog i cal parameters and thy r oid weight, pa t hology , and parental and pup thyroid hormone levels. As TM is rapidly metabolized to MBC, the Task Force proposes that the MBC study will adequately assess potential thyroid toxicity from TM, and that the requirement for a developmental thyroid study on TM should be held in reserve pending its review. EPA Response: Although TM is metabol i zed to MBC, i t has been shown t o affect the liver and thyroid. Effects on the thyroid are observed in several species exposed to TM,

but the available studies on MBC do not show toxicity to the thyroid . There rema i n uncertainties regarding the relative sensitivity to effects from TM during early deve l opment, for example, due to d i fferences in metabolic capacity in the liver. Page 2 of3Examination ofthe thyroid in offspring in the rat two-generation reproductive toxicity study (MRIDs 42899101-05 and 43624401) was not performed until postnatal week 8, which does not address the developmental window ofconcern. Because thyroid effects can result in permanent developmental effects, this study is required to support registration review ofTM. (3) Need for an immunotoxicitv studv on MBC : The Task Force requested that the Agency reserve the requirement for an immunotoxicity study on MBC pending review ofthe rat extended one-generation reproductive toxicity study on MBC, which includes evaluation of several parameters relevant to immunotoxicity (white blood cell count, spleen and thymus weight, and histopathology). EPA Response: The Agency will reserve the requirement for an immunotoxicity study pending review ofthe extended one-generation reproductive toxicity study. Upon consideration ofthat data, the requirement for an immunotoxicity study will be determined. (4) Need for exposure data for MBC: The Agency has required exposure data to assess occupational and residential handler exposures (dermal and inhalation) associated with the use ofan airless sprayer, low pressure handwand, and brush/roller; various pouring/mixing activities for liquid and solid materials (paints/stains and slurries); and indoor surface residue dissipation data for plastic toys and textiles. The Task Force has indicated the exposure data requirement will be satisfied through its membership in the American Chemistry Council's (ACC) Antimicrobial Exposure Assessment Task Force II (AEATF Il). For the textiles and toys, the Task Force is reassessing the role ofMBC in the textile market, and intends to limit the use ofMBC in plastics to articles that are not toys. Pending a final decision with respect to MBC in textiles and plastics, the Task Force has requested the Agency hold the residue dissipation requirement in reserve. EPA Response: The Agency considers the proposed use ofthe AEATF II data to be an acceptable approach to providing the additional occupational and residential exposure information for MBC. With respect to the impregnated toys, no data would be required if these products are removed from the market. Likewise, no data would be required 

### if textiles containing MBC are no longer marketed.

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