UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

MEMORANDUM

Date: May 21, 2013 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

SUBJECT: lprodione. Response to Comments on lprodione Registration Review PWP.

PC Code: 109801 DP Barcode: 0410176 Decision No.: 468700 Registration No.: NA Petition No.: NA Regulatory Action: Registration Review RiskAssessment Type: NA Rereltistration Case No.: NA TXRNo.: 0056669 CAS No.: 36734-19-7 MRIDs:NA 40 CFR: §180.399



### FROM: Linda 

### Taylor, Ph.D

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Risk Assessment ranch VII HealthEffec ts Division 7509P

THROUGH: Michael Metzger
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Risk Assessment Branch VII 

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TO: James Parker, Chemical Review Manager Risk Management and Implementa tion Branch I Pesticide Re-Evaluation Division (7508P)

INTRODUCTION: The first public comment period for the iprodione registration review (docket number EPA-HQ-OPP

-2012-0392) has ended. Three sets ofcomments pertinent to the Human Health Scoping Document and proposed risk assessment were received from FMC Corpora tion Agricultural Products Group, Physicians Committ ee for Responsible Medicine (PCRM), and Bayer CropScience.

I. ACTION REQUESTED: The Pesticide Re-Evaluation Division requested HED Risk Assessment Branch VII (RAB VII) to respond to the comments received during the iprodione registration reviewPr eliminary WorkPlan (PWP) open commentperiod.

D. BACKGROUND:

The FMC Corporation Agricultural Products Group comment pertinent to the HED requests clarification on the new rationale for changes in the low dose linear extra polation Q,

## *based

Page I of3on Leydig cell tumors. The PCRM comment argues against the requirement ofa 2-generation reproduction**study~** citing available studies. If a study is still required, PCRM suggests the registrant use the OECD TG 443 Extended One-Generation Reproductive Toxicity Study (EOGRTS) instead of the EPA guideline 870.3800 Two-Generation Reproduction Study. This request stems mainly from the fact that the OECD study utilizes fewer animals. Bayer CropScience comments argue against the data requirements for 870.3800 (2-generation reproduction study) and 870.3465 (28-day inhalation toxicity study) and request clarification

on the new rationale for the changes from the mouse liver tumors to Leydig cell tumors as the source ofthe low-dose linear extrapolation Q1

## *for cancer risk assessment.

III. RESULTS/DISCUSSION: (1) low-dose linear extrapolation 01*, based on Leydig cell
tumors: It is Agency policy that cancer classification and the basis of the linear low-dose extrapolation are the purview of the Cancer Assessment Review Committee (CARC). The 1998 CARC cancer classification ofiprodione and***~** based on the more sensitive Leydig cell tumors, is the official Agency position (TXR# 0012523, 02/26/1998). The CARC concluded that the available mode ofaction (MOA) data do not provide a sufficient basis for establishing an MOA for iprodione for either tumortype (Leydig cell or liver). In2007, anad hoc committee recommended a change in the method of quantification of cancer risk for iprodione and not the CARC. The adhoc committee's recommendation was based on draft guidance on the use ofmode ofaction data for Leydig cell tumors ("Draft Guidance on the Cancer Hazard Assessment of Pesticides that Induce Leydig Cell Tumors in Rats"). That draft guidance has not been finalized. Since no new MOA data have been submitted to the**Agency~** the CARC has not reconsidered iprodione's cancer classification or the basis ofthe low-dose extrapolation. In order for the cancer classification to be reconsidered, additional support for a mode ofaction for either tumor type would need to be submitted to the CARC with a request for reconsideration of the cancer classification. A copy ofthe 1998 CARC report, as requested by Bayer CropScience, is appendedto this memo.

(2) data requirement for a 2-generation reproduction study: Since the potential for interaction with the androgenic pathway has been demonstrated following oral administration of iprodione, infonnation regarding testosterone levels at various lifestages following exposure to iprodione is essential in determining whether exposure during mating,**gestation~ lactation~**  and/or postnatally results in lower effect levels than those currently available. Androgendependent processes, anogenital distance (AGD at 120 and 250 mglkg/day; NOAEL 20 mg/kg/day) and preputial separation (PPS at 100 and 200 mglkg/day), have been shownto be adversely affected following iprodione exposure (gavage), and PPS was correlated with decreased testosterone levels, which were observed at the same and lower (50 mglkg/day) dose levels. Testosterone levels were not measured in the rat chronic dietary study, where an increased incidence ofinterstitial cell hyperplasia, reduced spermatozoa in the**epididymides~** and reduced secretion of the seminal vesicles were observed at 12 mglkg/day and 69 mglk:g/day (NOAEL 6.1 mg/kg/day) or in the existing 2-generation reproduction study, which did not identify any effects in the male reproductive organs at dose levels 18.5, 61.4, and 154.8 mglk:g/day, which are similar to and greater than those in the chronic study. Currently, the Point of Departure for iprodione is based on decreased testosterone levels (endpoint ofconcern) at 

### 50 mglk:glday (LOAEL-NOAEL 

### = 5 mg/kg/day) from a gavage study (33 days ofdosing).

Page 2 of3Based on the arguments raised in the comments and the issues addressed, HED will present iprodione to the Agency Hazard and Science Policy Council for consideration ofwhether the 2-generation reproduction study or another more focused study is appropriate to satisfy the residual uncertainties/concerns with respect to iprodione's effects on testosterone at various lifestages following dietary exposure. The requirement for a new 2-generation reproduction study will be evaluated by HED's Hazard and Science Policy Council (HASPOC) with a weight ofevidence approach inthe near future.

(3) data requirement for an inhalation toxicity study: For some exposure scenarios (e.g., mixing/loading wettable powder iprodione for application to golfcourse turf), occupational inhalation exposure MOEs (WP formulations) using an oral endpoint are below the level of

concern (LOC of 1 000) at baseline PPE (no respirator). Since the potential for interaction with the androgenic pathway has been demonstrated following oral administration of iprodione, information regarding testosterone levels following inhalation exposure to iprodione is necessary to determine whether the inhalation route of exposure is more sensitive. This is based on (1) the fact that inhaled chemicals enter the circulation before many ofthe detoxification processes associated with oral exposure occur (first pass effect) and (2) chemicals in the respiratory tract enter the blood stream more readily than chemicals in the gastrointestinal tract. Assessing testosterone levels following inhalation exposure will provide a route-specific measure ofthe endpoint ofconcern for use in the inhalation exposure risk assessments. It is particularly important to properly assess inhalation risks for iprodione because there is high inhalation exposure for workers applying the dust product, and because ofthe toxic endpoint (reducedtestosterone levels).

IV. SUMMARY CONCLUSIONS: 

### In 2007, an 

### ad hoc committee recommended a change in the method ofquantification ofcancer risk for iprodione. Since no new mode ofaction (MOA) data have been submitted to the Agency, the CARC has not reconsidered iprodione's

cancer classification or the basis of the low-dose extrapolation. In order for the cancer classification to be reconsidered, additional support for a mode of action for either tumor type would need to be submitted with a request for reconsideration of the cancer classification.

Based on the arguments raised in the comments and the issues addressed, the Agency's Hazard and Science Policy Council will, in the near future, consider whether the 2-generation reproduction study or another more focused study is appropriate to satisfy the residual uncertainties/concerns with respect to iprodione's effects ontestosterone at various lifestages following dietary exposure.

A waiver of the inhalation study cannot be granted based on concern for some inhalation exposure scenarios.

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