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 

Risk Assessment Type: NA Rereltistration Case No.: NA 

TXR No.: 0056669 CAS No.: 36734-19-7 

MRIDs:NA 40 CFR: §180.399 

FROM: Linda Taylor, Ph.D . .- ~~ C 

Risk Assessment ranch VII 

Health Effects Division 7509P 

THROUGH: Michael Metzger, Branch Chi#J J ;J p (} 1~ / 

Risk Assessment Branch VII 'tL! ~ K# r c:;:::::r 

Health Effects Division 7509 

TO: James Parker, Chemical Review Manager 

Risk Management and Implementation 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 of comments pertinent to 

the Human Health Scoping Document and proposed risk assessment were received from 

FMC Corporation Agricultural Products Group, Physicians Committee 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 review Preliminary Work Plan (PWP) open comment period. 

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 extrapolation Q, * based 

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on Leydig cell tumors. The PCRM comment argues against the requirement of a 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 of the 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 of iprodione 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 of action (MOA) data do not provide a sufficient basis for 

establishing an MOA for iprodione for either tumor type (Leydig cell or liver). In 2007, an ad 

hoc committee recommended a change in the method of quantification of cancer risk for 

iprodione and not the CARC. The ad hoc committee's recommendation was based on draft 

guidance on the use of mode of action 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 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 to the CARC 

with a request for reconsideration of the cancer classification. A copy of the 1998 CARC 

report, as requested by Bayer CropScience, is appended to 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 shown to 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 of interstitial 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 of concern) at 50 mglk:glday (LOAEL-NOAEL = 5 mg/kg/day) from a gavage 

study (33 days of dosing). 

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Based 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 of 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 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 of evidence approach in the near future. 

(3) data requirement for an inhalation toxicity study: For some exposure scenarios (e.g., 

mixing/loading wettable powder iprodione for application to golf course 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 of the 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 of the endpoint of concern 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 

of the toxic endpoint (reduced testosterone levels). 

IV. SUMMARY CONCLUSIONS: In 2007, an ad hoc committee recommended a change 

in the method of quantification of cancer risk for iprodione. Since no new mode of action 

(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 on testosterone 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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