### Iprodione Registration Review Human Health Scoping Document

Page 2 of 29 (D233218, C. Scheltema, 7/31/1998) , as well as u pdated dietary (D392706, D. Davis, 3/15/12) and occupational and residential (D389181, M. Lloyd, 3/7/12) exposure and risk assessments

were considered as part of this scoping exercise.

Based on the current ly registered uses, exposures to iprodione can be expected to occur via the dietary (food and drinking water), occupational (handler and post

- application), and residential (handler and pos t

- application) exposure pathways for iprodione and through the oral, dermal, and inhalation routes of exposure.

Iprodione is a systemic fungicide use d on a wide variety of agricultural crops, as well as on institutional turf, including sod farms, commerci al lawns, golf courses, sports fields, etc

. Iprodione shares a common metabolite, 3,5

- dichloroanil in e (3,5

- DCA), with the active ingredients vinclozolin and procymidone. Ther efore, risks need to be considered not only for parent and other regulated metab olites, but also for aggregate 3,5

- DCA resulting from application of iprodione, procymidone and vinclozoli n.

The toxicity data base for iprodione is incomplete , but is adequate for assessing risk with

reten tion of the FQPA safety factor. A 2

- generation reproduction study (870.3800) and an inhalation toxicity study (870.3465) are required for registration review

. Once those data have been received and reviewed, their impact on the regulatory endpoints, points of departure (PoDs)

and uncerta inty factors/safety factors (UF/SFs) will need to be evaluated.

T he residue chemistry database for iprodione is incomplete

. A n adequate enforcement method

for livestock commodities is required and a residue decline study in rice water is required. The

r egistrant was informed of both these deficiencies in the Registration Eligibility Decision Document (RED). The tolerance expression in the 40CFR should be updated to reflect current policy.

The Agency recently updated the drinking water assessment for ip rodione and conducted highly refined acute, chronic and cancer dietary (food and water) risk assessments. No acute or chronic (non

- cancer) dietary risks of concern were identified. Iprodione estimated cancer risk from drinking water alone is 1.7 x 10 - 5



### . Iprodione estimated cancer risk from the currently registered

food uses is 7.8 x 10 - 6 

### . The estimated 3,5

- DCA cancer risk for water alone from the registered

turf use is 3.9 x 10 - 5 

### . The estimated 3,5

- DCA cancer risk from food (imported wine grapes only)

is 5.6 x 10 - 7 

### . These dietary assessments reflect all available refinements and were conducted in compliance with current scientific policies and practices; therefore, a new assessment will be required only if new data are provided which impact the PoDs, UF/SFs, or drinking water

residues used in this assessment.

The residential exposure database is complete. A revised residential exposure assessment may be required under registration review that in cludes post

- application exposure to adults and children playing on commercially treated turf. This assessment should incorporate, as necessary, the additional toxicology studies that have been submitted to HED as well as the recently updated Health Effect

s Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment

.

### Iprodione Registration Review Human Health Scoping Document

Page 3 of 29 An updated aggregate risk assessment may be required to support the registration review which incorporates any new PoDs, UF/SFs, any revisions to the drinking w ater assessment, as well as the findings from the updated non

- occupational (residential) assessment.

The occupational exposure database is complete. Updated occu pational handler exposure

assessments may be required under registration review based upon revisions to the Agency’s

s cenario

- specific surrogate handler exposure data and updated commercial seed treatment methodology. An occupational post

- application assessment may be required under registration

review which incorporates recently received dislodgeable foliar residue (DFR) data

.

Introduction

HED has evaluated the most recent complete human health risk assessment for iprodione conducted in 1998 in conjunction with the R ED , as well as recently conducted dietary risk

assessments , t o determine if sufficient data are available and if updates are needed to support registration r eview. HED has also c o nsidered updates to its toxicity, exposure and usage databases, and the latest Agency science policy and risk assessment methodologies.

Iprodione is a contact and/or locally systemic fungicide registered for use on a variety of field, fruit, and vegetable crops in agricultural settings. Iprodione is currently registered for use on institutional turf, including sod farms, commercial lawns, golf courses, sports fields, etc

. Iprodione is restricted from use on residential turf/lawns.

Information on the chemical identify of iprodione is included in Attachment 1.

Hazard Identification/ Toxicology

The toxicity database for iprodione is incomplete but sufficient for assessing risk with retention of the FQPA safety factor.

Iprodione is associated with toxicity of the liver, adrenals, and male and female reproductive organs in animal studies. Iprod ione has been shown to alter anogenital distances in male fetuses following exposure during late gestation, to delay male sexual maturation and decrease testosterone levels in immature male rats, and there is evidence of toxicity to the male reproductive o rgans in chronic studies in rats, as evidenced by increased interstitial cell hyperplasia, reduced epididymidal spermatozoa, and reduced secretion of the seminal vesicles. Reproductive function was not affected in the 2

- generation reproduction study perfor med under the old protocol. The prenatal developmental toxicity study in rabbits, a special prenatal study in rats, and the two

- generation reproduction study in rats showed no indication of increased susceptibility to in utero and/or postnatal exposure to iprodione. Iprodione does not pose a genotoxic hazard , but has been classified as a “Likely” human carcinogen based on an increased incidence of liver tumors in both sexes of the mouse and an increase incidence of Leydig cell

tumors in male rats. The pr oposed mode of action (MOA) of iprodione for Leydig cell tumors is disruption of testosterone biosynthesis ; however

, sufficient information is not available to

### Iprodione Registration Review Human Health Scoping Document

Page 4 of 29 delineate a definitive MOA for either tumor type ; therefore, the Agency is regulating carcinogenicity using a linearized low dose extrapolation model (Q1* approach) based on the

L eydig cell tumors

. Iprodione does not appear to be a frankly neurotoxic chemical. There is no concern for immunotoxicity.

The iprodione metabolite, 3,5

- DCA, is assumed to pose a potential cancer hazard based on its structural similarity to para

- chloroaniline (PCA). 3,5

- DCA is a common metabolite of iprodione, vinclozolin, and procymidone; therefore, a separate aggregate canc er risk assessment considering this metabolite is required. The established Q 1 

### * of 6.38 x 10 - 2 

### (mg/kg/day) - 1 

### for PCA was used in this assessment as the Agency believes that the use of the PCA Q 1 

### * represents a reasonable upper bound risk estimate.

Acute a nd subchronic neurotoxicity studies in rats, which are required in accordance with new data requirements for conventional pesticide registration (40 CFR Part 158), have not been

submitted. However, based on a weight

- of

- evidence (WOE) approach, considering all the available iprodione hazard and exposure information, the HED Hazard and Science Policy Council (HASPOC) concluded that the acute and subchronic neurotoxicity studies are not required for iprodione at this time ( TXR No. 0056453 , 10/16/12 ). Based o n current policies, a repeat dose inhalation toxicity study in rats is required due to the potential for repeated inhalation exposure to aerosol ized formulations of iprodione. The HASPOC determined that a 28

- day inhalation toxicity study is required for i prodione to better estimate risk for occupational inhalation exposure

.

Previously, HED concluded that an assessment of effects on the male reproductive system following pre

- and/or postnatal exposure was required, and these aspects could be assessed by conducting a 2

- generation reproduction study, as described in OCSPP 870.3800. However, t hese data were never formally requested. Th ese data are still necessary to fully characterize iprodione hazard and should be required.

The most recent dietary risk assessment for iprodione was conducted in 2012 (D392706 , D. Davis, 3/15/12 ) and included review of the available toxicity data for iprodione, consideration of current policies, and a re

- evaluation of endpoints for risk assessment. N ew acute and chronic

t oxicological points of departure (PODs) were selected for dietary risk assessment, and new endpoints were selected for occupational and non

- occupational short and intermediate term dermal and inhalation exposure scenarios

. The toxicity profile tables for iprodione are included

as Attachment 2. The iprodione endpoints, points of departure (PoD s), and uncertainty/safety factors (UF/SFs) are summarized in Attachment 3

.

The most sensitive endpoint in the iprodione database is the reduction of testosterone. The point of departure (POD) used for all exposure risk assessments was selected from a male rat pubertal assay, based on reduced serum levels of testosterone

. An uncertainty factor of 1000X wa s applied to the endpoint selected for all routes and durations of exposure (10X for interspecies extrapolation, 10X for intraspecies variation, 10X FQPA SF ). The FQPA safety factor accounts

for the lack of a NOAEL in the testosterone data ( UF LOAEL→NOAEL 

### ) and for the lack of the guideline studies (reproduction study, 870.3800 and 28

- day inhalation toxicity study, 870.3465)

. Since testosterone is the b asis of the acute and chronic risk assessments and is considered the

### Iprodione Registration Review Human Health Scoping Document

Page 5 of 29 endpoint that is protective of all other downstream effects in males or females and further, s ince testosterone levels would be affected before, and at a dose level equal to or lower than , any other potential effects that may occur following repeat exposure, there are no residual concerns

.

Conclusion s The following toxicity studies are required for registration review: a 2

- generation reproduction study (870.3800) and an inhalat ion toxi city study (870.3465). For both studies, serum

testosterone measurements should be included. A protocol for each study should be provided to the Agency for review pr ior to undertaking the studies. These two studies have not been previously formally requ ested of the registrant and should be called

- in in connection with registration review. Once these studies have been received and reviewed, the impact of this data on the endpoints for regulation, PoDs, and UFs will need to be reevaluated.

Dietary Exposure The residue chemistry database for iprodione is in complete . A n adequate enforcement method

for livestock commodities and data on r esidue decline in rice water have not been provided

.

The nature of the residue in plants and animals is adequatel y understood. The residues of concern for both tolerance setting and risk assessment purposes in plants are iprodione, its RP

30228 isomer, and its RP

- 32490 metabolite. The residues of concern for both tolerance setting and risk assessment purposes in li vestock are iprodione, its RP

- 30228 isomer, and metabolites

RP

- 25040 and RP

- 44227. Additionally, the iprodione 3,5

- DCA metabolite, which is also a common metabolite of vinclozolin and procymidone , poses a potential cancer concern and a separate risk asses sment is required for this metabolite. The residue of concern in rotational crops is not adequately understood at this time. However, c urrently, iprodione labels limit rotation only to those crops for which there is a primary use ; therefore no additional data are required with respect to rotational crops.

An adequate analytical method for enforcing tolerance in plant matrices is available. The HED Chapter of the RED for Iprodione (D233218, C. Scheltema, 7/31/1998) noted that an adequate method for the detection of all the regulated residues in livestock was not available. The registrant, Bayer CropScience, formerly Aventis CropScience, met with the Agency on February 8, 2000 to present a new method for the determination of residues in livestock commodities. The Agency recommended that the registrant submit the method, along with an independent method validation (ILV) for Agency review (D262 487, W. Smith, 6/7/2000). There is no record that the method was ever submitted for Agency review. Requirements for multi

- residue method testing have been satisfied for iprodione.

Field trial data generated using acceptable data collection methods and s upported by adequate storage stability data are available for all registered crops. Adequate processing studies are available. Adequate livestock feeding studies have been submitted for iprodione.

T he RED indicated that a decline study in rice water was required and that the registrant committed to conduct a study. No record is available to indicate that th e s e data were received and reviewed. Therefore, this data remain an outstanding data gap.

### Iprodione Registration Review Human Health Scoping Document

Page 6 of 29 A drinking water assessment (D359480, C. Peck, 2012) was conducted by the Environmental

Fate and Effects Division which modeled separately the estimated drinking water concentrations (EDWCs) for iprodione residues of concern (iprodione and the three degradates RP30228, RP35606, and RP 32490) and 3,5

- DCA in surfa ce water and groundwater. 3

, 5

- DCA was assessed separately because the toxicity endpoint for 3,5

- DCA is different from that of iprodione. EFED has concluded that p ending receipt and review of additional environmental fate and toxicity data for iprodione and it s degradates, or changes in labeled use rates, the drinking water assessment will be reevaluated. However, if no new, relevant data regarding the environmental fate, toxicity, or use of iprodione or its degradates are submitted, the EDWCs from the 2 012 drinking water assessment will be used in the registration review risk assessment.

The Agency conducted highly refined acute probabilistic, chronic, and cancer risk assessments for iprodione and its regulated metabolites and a separate cancer dietary risk assessment for 3,5

- DCA from iprodione, vinclozolin and procymidone. Refinements to the dietary assessment included the use of monitoring data, percent crop treated information, empirical processing factors, and modeled drinking water values. Iprodio ne acute and chronic (non

- cancer) dietary (food and water) risks were not of concern. Iprodione estimated cancer risk from drinking water

alone is 1.7 x 10 - 5 

### . Iprodione estimated cancer risk from the currently registered food uses is 7.8

x 10 - 6 

### . The est imated 3 ,5

- DCA cancer risk for water alone from the registered turf use is 3.9 x

10 - 5 

### . The estimated 3,5

- DCA cancer risk from food (imported wine grapes only) is 5.6 x 10 - 7



### .

Conclusions The residue chemistry database is incomplete. A livestock enforcement method and submission

of a residue decline study in rice water are required . These data have been previously requested. All other residue chemistry data requirements have been adequat ely addressed.

Should the required toxicology data impact the PoDs or UF/SFs for risk assessment, or should the registrant provide additional data which may be used to refine the drinking water assessment, the Agency may need to update the dietary risk a ssessment for iprodione and 3,5

- DCA. In the absence of new information; the referenced assessment reflects all available refinements and current science policy and practices and would not need to be updated for registration review.

Residential Exposure and Risk

As noted above, iprodione is currently registered for use on institutional turf, including sod farms, commercial lawns, golf courses, sports fields, etc . Iprodione is restricted from use on residential turf/lawns. Based on these uses, adults a nd children may experience exposure to iprodione as a result of contacting commercially treated turf (i.e., residential post

- application exposure).

In accordance with the updated Part 158 data requirements (2007), a turf transferable r esidue ( TTR ) study is required for all occupational (e.g., sod farms, golf courses, parks, and recreational

ar eas) or residential turf uses, and that TTR data are available for iprodione.

### Iprodione Registration Review Human Health Scoping Document

Page 7 of 29 The 1998 RED addressed mitigations involving residential exposure. Specifically, the RED addressed cancelling residential uses of iprodione on small gardens, home ornamentals, and the residential uses of iprodione on turf. Since the 1998 RED, additional toxicology studies have been submitted to HED, registered use sites have changed, and the Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment have recently been updated . A March 2012 assessment ( D3891 81) for proposed new agricultural uses of iprodione partially reassessed aggregate exposure and risk. Specifically, the assessment evaluated iprodione dermal post

- application exposure (cancer and non

- cancer) for casual golfers using the updated iprodione PoDs and UF/ SFs, the 2012 SOPs, and available turf transferable residue (TTR) data. Non

- cancer post

- application dermal golfer risk estimates are not of concern.

Post

- application cancer risk estimates range from 3.2 x10 - 6 

### to 1.8x10 - 5



### .

Spray Drift Spray dri ft is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employe d for iprodione . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift websi te 1 

### . On a chemical

- by

- chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT ® 

### computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic

methods. After the policy is in place, the Agency may impose further refinements in spray

- drift

management practices to reduce off

- target drift with specific products with significant risks

associated with drift.

Conclusions The residential exposure database is adequate to support the registration review process for iprodione. A revised residential exposure assessment (cancer and non

- cancer) may be required under registration review that includes post

- application exposure to adults and children playing on commercially treated turf. This assessment should incorporate, as necessary, the additional toxicology studies that have been submitted to HED, updated human factors (e.g., body weight) assumptions, and the 2012 Revised Resi dential SOPs.

Aggregate Risk Assessment

The most recently completed aggregate risk assessment was conducted in connection with the

1998 RED. As indicated above, additional toxicity data is required which may impact the PoDs

and UF/SFs for use in risk a ssessment. Additionally, an updated non

- occupational (residential)

assessment may be required. Lastly it is possible that additional data may be provided with

1 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm

### Iprodione Registration Review Human Health Scoping Document

Page 8 of 29 which to update the drinking water assessment. Consequently, a revised aggregate risk

assessme nt for iprodione may be required for registration review

.

Occupational E xpos ur e

As noted above, i prodione is registered for use on a variety of field, fruit, and vegetable crops, including almonds, grapes, peaches, potatoes, rice, berries, onions, peanuts, lettuce, and is also registered for use on golf courses, commercial turf

, and ornamentals

. The Agency has determined that there is a potential for occupational handler and post

- application exposures

resul ting from the registered uses of iprodione.

Occupational Handlers

T he 1998 RED evaluated a number of occupational handler scenarios that represent ed the major iprodione occupational handler scenarios based on application equipment and formulation type

. Th at assessment indicated that occupational handler scenarios resulted in inhalation risk estimates of concern for some exposure scenarios (e.g., high acreage aerial/chemigation applications, belly grinder mix/load/apply applications). Risk mitigation mea sures mentioned in the RED included additional personal protective equipment for a number of occupational handler

scenarios

. Additionally, the RED indicated data gaps for iprodione handler commercial seed treatment exposure scenarios. Since the RED, HED has reevaluated the hazard database for iprodione, there have been changes to the registered use pattern, and there is new unit exposure data available to assess occupational handler scenarios. Because of these changes, HED will likely reevaluate the occup ational handler assessment for iprodione.

Occupational Post

- application The 1998 RED addressed occupational post

- application exposures with default dislodgeable

foliar residue (DFR) data. Based on this assessment, t he restricted

- entry interval was set to 48

- hours for use of iprodione on grapes and ornamentals, and to 24

- hours for all other iprodione

uses. Technical iprodione is currently classified as toxicity category II I/IV for acute dermal toxicity, primary eye, and skin irritation.

In accordance with the updated Part 158 data requirements (2007), one or more DFR studies are required when a pesticide has residential or occupational uses that could result in post

application dermal exposure. Since the RED, t hree DFR studies (on lettuce, peaches, a nd grapes) have been submitted for iprodione. Review of the lettuce DFR study is complete and review of the peach and grape study is under way. Screening assessments of the primary DFR

studies indicate that they are suitable for use in human health risk assessment.

Conclusions for Occupational Exposure and Risks The occupational exposure database is complete

. Updated occu pational handler exposure

assessments may be required under registration review based upon revisions to the Agency’ s

s cenario

- specific surrogate handler exposure data 2 

### and exposure methodology relating to

commercial seed treatment

. Additionally, a n updated occupational seed treatment assessment and occupational post

- application assessment (cancer and non

- cancer) for f oliar applications of

2

- Available: http://www.epa.gov/pesticides/science/handler

- exposure

- table.pdf

### Iprodione Registration Review Human Health Scoping Document

Page 9 of 29 iprodione to agricultural crops (using the newly available DFR study data) may be required under registration review

.

Public Health and Pesticide Epidemiology Data

The Agency has reviewed the available incident data for iprodione (D404146, S. Recore, 7/31/12) and concludes that based on the low frequency and severity of incident cases reported for iprodione, there does not appear to be a concern at this time that wou ld warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk assessment.

Tolerance Assessment and International Harmonization

Tolerances for iprodione are established under 40 CFR §180.399 for the combined residues of iprodione, its isomer RP30228 (3

- 1

- methylethyl)

- N

- (3,5

- dichlorophenyl)

- 2,4

- dioxo

- 1

- imidazolidine

- carboxamide) and its metabolite RP32490 (3

- (3,5

- dichlorophenyl)

- 2,4

- dioxo

- 1

- im idazolidine

- carboxamide) in/on a variety of plant commodities. Tolerances for livestock

commodities are established for the combined residues of iprodione, its isomer RP30228, and its metabolites RP32490 and RP36114 ([ N

- (3,5

- dichloro

- 4

- hydroxyphenyl)

- urei do

- carboxamide]).

According to HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner), the tolerance expression for iprodione on plant commodities should be revised to state:

“Tolerances are established for residues of iprodione, includi ng its metabolites and degradates, in or on the commodities in the tables below. Compliance with the tolerance levels specified below is to be determined by measuring the sum of iprodione [3

- (3,5

- dichlorophenyl)

- N

- (1

- methylethyl)

- 2,4

- dioxo

- 1

- imidazolidi necarboxamide], its RP

30228 isomer [3

- (1

- methylethyl)

- N

- (3,5

- dichlorophenyl)

- 2,4

- dioxo

- 1

- imidazolidinecarboxamide], and its RP

- 32490 metabolite [3

- (3,5

- dichlorophenyl)

- 2,4

- dioxo

- 1

- imidazolidine

- carboxamide].

The appropriate tolerance expression for li vestock will be determined when an acceptable

enforcement method has been submitted.

At this time, there are no pending requests for the establishment of new tolerance for iprodione.

The International Residue Limit Status Sheet is attached to this document as Attachment 4

.

There are no Codex, Canadian, or Mexican Maximum Residue Limits (MRLs) established for livestock commodities; therefore a discussion of harmonization of livestock tolerance expression or levels is not required for this active ingredient. There are no Mexican MRLs for iprodione on plant commodities. The U.S. plant residue definition is harmonized with Canada, but is not

harmonized with Codex. Both the U.S. and Can ada include the iprodione isomer and a metabolite in their tolerance expression, while Codex regulates on parent only. Despite the residue definition discrepancy, levels are harmonized between Codex and the U.S. on several

### Iprodione Registration Review Human Health Scoping Document

Page 10 of 29 commodities including succulent beans, broccoli, leaf lettuce, and rice grain. However, b ecause of the inclusion of only the parent in Codex MRLs, it may not be possible to harmonize with

Codex values that are lower than the current U.S. tolerance s since the Codex MRL may not be adequat e to cover the regulated residues in the U.S. (almonds, dry beans, cherries, grapes, kiwifruit, head lettuce, bulb onions, peaches, and strawberry). For those commodities where Codex has established a higher tolerance, despite the residue definition discr epancy, it is possible that levels can be harmonized (caneberries, and carrots). U.S. tolerances and Canadian MRLs are harmonized for carrots only. For most commodities Canadian MRLs are significantly lower

than the U.S. tolerances (apricot

- 20 ppm vs. 3 ppm, dry bean

- 2 ppm vs. 0.3 ppm, caneberries

– 25 ppm vs. 10 ppm for Canadian raspberries, cherries

– 20 ppm vs. 5 ppm, grape

– 60 ppm vs. 10 ppm, raisins 300 ppm vs. 60 ppm, kiwifruit

– 10 ppm vs. 0.5 ppm, lettuce 25 ppm vs. 15 ppm,

nectarine

– 20 ppm vs. 10 ppm, peach 20 ppm vs. 10 ppm, plum 20 ppm vs. 2 ppm, prune 20 ppm vs. 2 ppm, and raspberry 15 ppm vs. 10 ppm) suggesting that the current Canadian MRL levels would not be sufficient to cover residues resulting from the U.S. use patterns.

Environm ental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Popu lations and Low

- Income Populations," http://www.eh.doe.gov/nepa/tools/guidance/Volume1/2

- 6

- EO_12898envjustice.pdf ). The Office of Pesticide Programs (OPP) typically considers the highest potential exposures from the legal use of a pesticide when conducting human health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets

withi n the U.S., and people who may be exposed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure

that the risk estimates are based on the best available information.

Cumulative

EPA has not , at this time, made a determination as to whether iprodione shares a common mechanism of toxicity with any other substances

.

### Iprodione Registration Review Human Health Scoping Document

Page 11 of 29 Human Studies

The previous i prodione risk assessments rel ied in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. Studies such as the Pesticide Handlers Exposure Database

, Outdoor Residential Exposure Task Force , and Agricultural Handler Exposure T ask Force have been reviewed by the Agency and found on the basis of available evidence to have been neither fundamentally unethical nor significantly deficient relative to standards of ethical research conduct prevailing when they were conducted.

There i s no barrier in EPA's "Protection of Human Subjects" R egulation to reliance on these

studies.

Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively , these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine in fluence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute te sts and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its most recent registration decision, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessm ent scenarios from the existing hazard database. However, as required by FFDCA section 408(p), iprodione is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether cert ain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP empl oys a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal sys tems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Iprodione

was included on that list a nd has been issued an order to conduct the Tier 1 testing. Once all required Tier 1 and Tier 2 data have been received and reviewed, the endpoints and safety factors used for risk assessment purposes will be examined and a new risk assessment performed if necessary. For further information on the status of the EDSP, the policies and

### Iprodione Registration Review Human Health Scoping Document

Page 12 of 29 procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: htt p://www.epa.gov/endo/

.

Data Requirements

The following toxicity studies are required to support the registration review of iprodione:

2

- generation reproduction study (870.3800)

inhala tion toxicity study (870.3465) For both studies, serum testosterone measurements should be included. A protocol for each study should be provided to the Agency for review prior to undertaking the studies.

The following residue chemistry data are required to support the registration re view of iprodione: An analytical enforcement method for livestock

Residue decline in rice water

References

Table 1 : HED Memoranda Relevant to Registration Review

Author Barcode/TXR # Date Title

C.

Scheltema D233218 07/31/1998 The HED Chapter of the Reregistration Eligibility Decision Document (RED) for Iprodione (PC Code: 109801, List A Case No. 2335, DP Barcode: D233218).

D. Davis D392706 3/15/12 Iprodione

. Acute Probabilistic, Chronic and Cancer Aggregate (Food and Drinking Water) Dietary Exposure and Risk Assessments for Parent and 3,5

- DCA to Support New Section 3 Registration Actions on Cucurbits (Crop Group 9) and Fruiting Vegetables (Crop Group 8

- 10)and to Support a Tolerance for Imported Canola. K. Rury TXR# 0056453 10/16/12 IPRODIONE: Summary of Hazard and Science Policy Council (HASPOC) Meetings:

Recommendations on the need for the inhalation, and acute and subchronic neurotoxicity studies.

S. Recore D404146 08/01/2012 Iprodione : Review of Human

Incidents

### Iprodione Registration Review Human Health Scoping Document

Page 13 of 29 Table 1 : HED Memoranda Relevant to Registration Review

Author Barcode/TXR # Date Title

T.

Goodlow D 381906 12/15/2010 Iprodione: Proposed Label

Amendment for Use on Peanuts.

T. Dole D338091 01/04/2008 Occupational Risk Assessment for the Proposed Deletion of the Water Soluble Bag Requirement for

Wettable Powder Formulations of Iprodione Applied Via Chemigation

to Ornamentals M. Lloyd D389181 03/07/2012 Iprodione: Occupational Exposure

and Risk Assessment for the Proposed New Uses on Cucurbits, Fruiting Vegetables (includes Updated Non

- Occupational Cancer Assessment).

Attachment s

Attachment 1. Chemical Identity Attachment 2. Toxicity Profile Tables Attachment 3. Endpoint Tables

Attachment 4 . Iprodione International Residue Limits Table

### Iprodione Registration Review Human Health Scoping Document

Page 14 of 29 Attachment 1. Iprodione Chemical Identity

Table A1.1. Iprodione Nomenclature.

Compound

Common name Iprodione

Company experimental name CPD

- 20

IUPAC name 3

- (3,5

- dichlorophenyl)

- N

- isopropyl

- 2,4

- dioxoimidazolidine

- 1

- carboxamide

CAS name 3

- (3,5

- dichlorophenyl)

- N

- (1

- methylethyl)

- 2,4

- dioxo

- 1

- imidazolidinecarboxamide

CAS registry number 36734

- 19

- 7

End

- use products (EP) EnclosureTM Flowable Fungicide and Nematicide (4.0 lb/gal FlC)

Chemical structure of isomer;

RP

- 30228; isoiprodione

3

- (1

- methylethyl)

- N

- (3,5

- dichlorophenyl)

- 2,4

- dioxo

- 1

- imidazolidinecarboxamide

Chemical structure of metabolite;

RP

- 32490; iprodione amide

3

- (3,5

- dichlorophenyl)

- 2,4

- dioxo

- 1

- imidazolidine

- carboxamide

### Iprodione Registration Review Human Health Scoping Document

Page 15 of 29 Table A1.2. Physicochemical Properties of the Technical Grade of Iprodione.

Parameter Value Reference

Melting point ~128 °C Product Chemistry Chapter to Iprodione RED (DP# 234629, 3/26/97, J. Abbotts) pH Not applicable since the T/TGAI is not dispersible in water

Density 1.0 g/mL at 20 °C DP# 233155, 2/19/97, J. Abbotts

Water solubility Iprodione is practically insoluble in water (13 mg/L). Product Chemistry Chapter to Iprodione RED (DP# 234629, 3/26/97, J. Abbotts)

Solvent solubility Iprodione is soluble in dichloromethane (45 g/100 mL), acetone (34 g/100 mL), ethyl acetate (23 g/100 mL), acetonitrile (17 g/100 mL), and toluene (15 g/100 mL)

Vapor pressure <1 x 10
- 7 mm Hg (25 °C) DP# 233154, 2/19/97, J. Abbotts

Dissociation constant, pK

a Not applicable since the T/TGAI is not dispersible in water

Octanol/water partition coefficient, Log(K OW ) K OW average of 974.7 at pH 3;

K OW average of 1006 at pH 5 DP# 189210, 6/4/93, F. Toghrol

UV/visible absorption spectrum Not available

### Iprodione Registration Review Human Health Scoping Document

Page 16 of 29 Attachment 2. Toxicity Profile Tables

Table A2.1 Acute Toxicity Profile

– Iprodione

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] 42306301 LD 50 = 4468 mg/kg III

870.1200 Acute dermal [rabbit] 40567601 LD 50 > 2000 mg/kg III

870.1300 Acute inhalation [rat] 42946101 LC 50 > 5.16 mg/L IV

870.2400 Acute eye irritation [rabbit] 41867301 Mild irritant III

870.2500 Acute dermal irritation [rabbit] 41867302 Not an irritant IV

870.2600 Skin sensitization [guinea pig] 40567602

42524601 Not a dermal sensitizer

-



### Table A2.2 Subchronic, Chronic and Other Toxicity Profile

– Iprodione

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day oral toxicity

(rat)

TXR No.010747 42960701 (1993)

0, 1000, 2000, 3000, or 5000 ppm (diet)

Acceptable/non

- guideline Males: 0, 78, 151, 252, or 355 mg/kg/day Females: 0, 89, 189, 266, or 408 mg/kg/day NOAEL = 1000 ppm ( males 78 / females 89

mg / kg/day LOAEL = 2000 ppm (males 151/females 189 mg/kg/day), based on decreased body weight/gain, decreased food consumption/food utilization, organ weight effects (decreased ovary weight) and microscopic lesions in the sex organs (testicular interstitial cell hype rplasia, uterine atrophy, decreased number of corpora lutea) and adrenals (enlargement of cells of zona glomerulosa, fine vacuolation of zona fasciculate). At HDT, decreased absolute brain, decreased relative ovary, uterus, pituitary, and adrenal weights

870.3100 90

- Day oral toxicity

(mouse) 48125502 (1989)

0, 1500, 3000, 6000, or 12000 ppm (diet) Acceptable/non

- guideline

Males: 0, 260, 509, 1066, or 2130 mg/kg/day Females: 0, 327, 659, 1303, or 2608 mg/kg/day NOAEL

– 1500 ppm, 260/327 mg/kg/day

LOAEL = 3000 ppm, 509/659 mg/kg/day, increased adrenal weight, and microscopic adrenal findings

### Iprodione Registration Review Human Health Scoping Document

Page 17 of 29 Table A2.2 Subchronic, Chronic and Other Toxicity Profile

– Iprodione

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3150 90

- Day oral toxicity

(dog) MRID 00157377 (1976)

MRID 00157378 (1977) MRID 00232702 (1976)

Unacceptable; 2 dogs/sex

0, 800, 2400, or 7200 ppm

0, ≈ 60, 180, 270 mg/kg/day

(0.075 conversion) NOAEL = 2400 ppm (≈180 mg/kg/day). LOAEL = 7200 ppm (≈270 mg/kg/day), based on liver hypertrophy and increased alkaline phosphatase.

870.3200 21

- Day dermal

toxicity (rabbit) 42023201(1991)

424468401 (1992)

Acceptable/guideline

0, 100, 500, or 1000 mg/kg/day (21 days) NOAEL = 1000 mg/kg/day LOAEL =no deaths, clinical signs of toxicity, no adverse effects on BW, FC, the skin, liver, or kidneys.

870.3465 90

- Day inhalation

toxicity (species) Not available Waived by HASPOC; TXR#0056453, 10/16/12

870.3700a Prenatal

developmental in Sprague

- Dawley rats

Sex differentiation study

TXR No. 012400 44365001 (1997)

Acceptable/non

- guideline

0, 20, 120, or 250 mg/kg/day

GD 6

- 19 Maternal NOAEL = 20 mg/kg/day. LOAEL = 120 mg/kg/day, based on decreased BWG and decreased food efficiency. 7 dams had enlarged adrenals (bilateral). At 250 mg/kg/day, there were 9 out of 25 deaths and 20 dams had enlarged adrenals. Developmental NOAEL = 20 mg/kg/day

LOAEL = 120 mg/kg/d ay based on decreased anogenital distance (AGD) in the male pups.

870.3700a Prenatal

developmental in

Crl:CD®BR/VAF/P

LUS rats

TXR No. 006359

TXR No. 007008 MRID 00162983 (1986)

MRID 00162984 (1986)

MRID 40514901 (1987)

MRID 40514909 (11987)

Acceptable/guideline

0, 40, 90, or 2000 mg/kg/day

GD 6

- 15 Maternal NOAEL = 200 mg/kg/day (maternal toxicity not observed)

LOAEL = Developmental NOAEL = 90 mg/kg/day LOAEL = 200 mg/kg/day based on delayed fetal developmental (slightly reduced fetal body weight and increased incidences of space between the body wall and organs in the

fetuses.

### Iprodione Registration Review Human Health Scoping Document

Page 18 of 29 Table A2.2 Subchronic, Chronic and Other Toxicity Profile

– Iprodione

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3700a Prenatal

developmental in (Sprague

- Dawley rat) 0071324 (1976)

Unacceptable/non

guideline

does not appear to provide

a robust evaluation of fetal effects following in

utero exposure

0, 100, 200, or 400 mg/kg/day

GD 5

- 15 Materna l NOAEL = 200 mg/kg/day LOAEL = 400 mg/kg/day based on slightly decreased BWG and significantly decreased

food consumption. Developmenta l NOAEL = 200 mg/kg/day

LOAEL = 400 mg/kg/day based on decreased implantation sites.

870.3700b Prenatal

developmental in (New Zealand rabbit)

TXR No. 005214 MRID 00155469 (1985)

Acceptable/guideline

0, 20, 60, or 200 mg/kg/day

GD6

- 18 Materna l NOAEL = 20 mg/kg/day LOAEL = 60 mg/kg/day based on decreased body weight gain. At 200 mg/kg/day, there was an increased rate of abortions (7 does; GD 17

- 23), body weight loss, decreased food consumption, decreased defecation and

urination in females that aborted. Developmenta l NOAEL = 60 mg/kg/day LOAEL = 200 mg/kg/day based on abortions

, and increased incidence of skeletal variations (13 th full rib, malaligned sternebrae, and/or 27 presacral vertebrae, with or without delayed

oss ification.

870.3800 Reproduction and

fertility effects (rat)

TXR No.009695 MRID 00162983 (1986)

MRID 41871601 (1991)

acceptable/guideline*

0, 300, 1000, or 3000/2000 ppm

males: 0, 18.5, 61.4, 154.8 mg/kg/day

females: 0, 22.5, 76.2, or

201.2 mg/kg/day

*sperm parameters not assessed; new 870.3800 required (1998) Parental/Systemic NOAEL = 300 ppm, 18.5/22.5 mg/kg/day LOAEL = 1000 ppm, 61.4/76.2 mg/kg/day based on decreased body weight, body weight gain, and food consumption in both sexes.

At the highest dose tested, increase in number of pups found dead, cannibalized or missing (F1a phase); 1 control and 11 high

- dose dams sacrificed (LD 1

- 25) following death of entire

litter. Reproductive N OAEL = 3000/2000 (155/201 mg/kg/day (HDT) Offspring N OAEL = 1000 ppm, 61/76 mg/kg/day

LOAEL = 2000/3000 ppm, 155/201 mg/kg/day

based on decreased pup viability and pup body weight, increased incidence of clinical signs (smallness of size, reduced mobility, unkempt appearance, hunching, or tremors) in pups

du ring lactation period.

### Iprodione Registration Review Human Health Scoping Document

Page 19 of 29 Table A2.2 Subchronic, Chronic and Other Toxicity Profile

– Iprodione

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.4100a Chronic toxicity

(Sprague

- Dawley rat)

TXR No. 010570 MRID 42637801 (1992)

MRID 42787001 (1993)

0, 150, 300, or 1600 ppm

Acceptable/guideline

Males: 0, 6.1, 12.4, or 69 mg/kg/day

Females: 0, 8.4, 16.5, or

95 mg/kg/day NOAEL = 6.1/8.4 mg/kg/day. LOAEL = 12.4/16.5 mg/kg/day, based on increases in generalized enlargement of the cells of the zona glomerulosa in males and females, in fine vacuolation of the zona fasciculata and in generalized fine vacuolation

of t he zone reticularis in males in the adrenal cortex, an increased incidence of interstitial cell hyperplasia, reduced spermatozoa in the epididymides, reduced secretion of the seminal vesicles, increased hemosiderosis in the spleen in females, and increased liver weight.

Tumors: increased incidence of both unilateral and bilateral benign interstitial cell tumors in the testes of males at the 1600 ppm dose level.

870.4100a Chronic toxicity

(Charles River CD rat) MRID 00071997 (1978)

MRID 00164249 (1978)

MRID 00128931 (1983)

Unacceptable

0, 125, 250, or 1000 ppm

0, 6.25, 12.5, or 50 mg/kg/day NOAEL = 50 mg/kg/day.

LOAEL = not identified.

Incidence of testicular interstitial cell tumors was 2, 2, 4, 5 out of 60 rats/group.

870.4100b Chronic toxicity

(dog) MRID 42211101 (1991)

0, 200, 300, 400, or 600

ppm
Acceptable/non

- guideline

Males: 0, 7.8, 12.4, 17.5, or 24.6 mg/kg/day

Females: 9, 9.1, 13.1, 18.4, or 26.4 mg/kg/day NOAEL = 17.5/18.4 mg/kg/day LOAEL = 24.6/26.4 mg/kg/day, based on a

decrease in red blood cell (RBC, HGB, HCT)

values.

870.4100b Chronic toxicity

(dog)

TXR No. 005882 MRID 00144391 (1984)

MRID 41327001 (1989)

Acceptable/guideline

0, 100, 600, 3600 ppm

Males: 0, 4.1, 24.9, or145.3 mg/kg/day

Females: 0, 4.3, 28.3, or

152.5 mg/kg/day NOAEL = 4.1/4.3 mg/kg/day LOAEL = 24.9/28.3 mg/kg/day, based on decreased prostate weight and an increased incidence of erythrocytes with Heinz bodies

.

### Iprodione Registration Review Human Health Scoping Document

Page 20 of 29 Table A2.2 Subchronic, Chronic and Other Toxicity Profile

– Iprodione

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.4200 Carcinogenicity

(rat)

TXR No. 010570 MRID 42637801 (1992)

MRID 42787001 (1993)

0, 150, 300, or 1600 ppm

Acceptable/guideline

Males: 0, 6.1, 12.4, or 69 mg/kg/day

Females: 0, 8.4, 16.5, or 95 mg/kg/day NOAEL = 6.1/8.4 mg/kg/day. LOAEL = 12.4/16.5 mg/kg/day, based on increases in generalized enlargement of the

cells of the zona glomerulosa in males and females, in fine vacuolation of the zona fasciculata and in generalized fine vacuolation

of the zone reticularis in males in the adrenal cortex, an increased incidence of interstitial cell hyperplasia, reduced spermatozoa in the

e pididymides, reduced secretion of the seminal vesicles, increased hemosiderosis in the spleen in females, and increased liver weight. At HDT, atrophy of seminiferous tubules in testes, with atrophy of prostate and absence of spermatozoa in epididymides ; increased incidence of tubular hyperplasia in ovaries and increased sciatic nerve fiber degeneration in

females
evidence of carcinogenicity: increased incidence of both unilateral and bilateral benign

interstitial cell tumors in the testes at the 1600

ppm

.

870.4300 Carcinogenicity

(mouse)

TXR No. ? MRID 42825002 (1993)

0, 160, 800, or 4000 ppm

Acceptable/guideline

Males: 0, 23, 115, or 604 mg/kg/day

Females: 0, 27, 138, 793 mg/kg/day NOAEL = 23/27 mg/kg/day LOAEL = 115/138 mg/kg/day, based on the increased incidence of centrilobular hepatocyte enlargement in females and the increased incidence of generalized vacuolation/ hypertrophy of the interstitial cells in the testes

of males. At the highest dose tested

, increase in the incidence of benign ovarian tumors [luteoma] in females compared to the control incidence, which was accompanied by an increase in luteinization of the interstitial cells, corpora lutea absent, and prominent granulosa cells.

evidence of carcinogenicity: increased incidence of hepatocellular tumors in both

sexes

870.4300 Carcinogenicity

(mouse) MRID 00070963 (1978)

Unacceptable

0, 200, 500, or 1250 ppm

0, 30, 75, or 187.5 mg/kg/day NOAEL = 187.5 mg/kg/day

LOAEL = not identified.

No evidence of carcinogenicity

### Iprodione Registration Review Human Health Scoping Document

Page 21 of 29 Table A2.2 Subchronic, Chronic and Other Toxicity Profile

– Iprodione

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

Gene

Mutation

870.5100 Salmonella

typhimurium

TA98, TA100, TA1535, Ta1537,

Ta1538 41604106 (1990)

Acceptable/guideline Negative with and without metabolic activation; reductions in mean numbers of

revertants and background lawn at highest dose

– S9; precipitate at dose ≥250 μg/plate ±S9

Mammalian

cell

forward

gene mutation

assay

870.5300 CHO/HGPRT 00148206 (1985)

Acceptable/guideline Did not induce mutation with or without

metabolic activation.

In vitro

chromosom

al

aberration

assay

870.5375 Chinese hamster

ovary (CHO) cells (+/

- S9) 00148207 (1985)

Acceptable/guideline

0, 40, 150, 400 μg/mL

+S9

0, 15, 75, 150 μg/mL

– S9 Negative +/

- S9; precipitation at ≥150 μg/mL

In vivo

mouse micronucle

us assay

870.5395 CD

- 1 mouse 43535001 (1994)

Acceptable/guideline

0, 750, 1500, or 3000 mg/kg (one dose) No evidence of a clastogenic or aneugenic effect at any dose level or harvest time.

Other

Effects

870.5500 DNA damage in

Bacillus subtilis MRID 00148208 (1985)

Acceptable/guideline Positive with and without metabolic activation

Other

Effects

870.5900

sister

chromatid exchange

assay Chinese hamster

ovary cells 00148209 (1985)

Acceptable/guideline Negative both with and without metabolic

activation

870.6200a Acute neurotoxicity

screening battery Not available Waived by HASPOC; TXR#0056453, 10/16/12

870.6200b Subchronic

neurotoxicity screening battery Not available Waived by HASPOC; TXR#0056453, 10/16/12

870.6300 Developmental

neurotoxicity Not available Conditionally required

870.7485 Metabolism and

pharmacokinetics (species) MRID 42984101

MRID 41346701

MRID 43484901 (1994)

### Iprodione Registration Review Human Health Scoping Document

Page 22 of 29 Table A2.2 Subchronic, Chronic and Other Toxicity Profile

– Iprodione

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

Levels of iprodione in testes and plasma

TXR No. 013804 MRID 44750701 ()

Acceptable/non

- guideline Iprodione and metabolites reach target organ (testes)

870.7600 Dermal penetration

(rat, male)

(TXR No. 011645) MRID 43535003 (1994)

Acceptable/guideline

Single dose: 0.4, 4.0, 40 mg/rat for 0.5, 1, 2, 4, 10,

or 24 hours Skin residues increased with duration of

exposure to 5

- 10% of applied dose; absorption appears saturated at 4 and 40 mg/rat; following

a 10

- hour exposure, ≈5% is absorbed; following 24

- hour exposure, ≈15% is absorbed.

870.7800 Immunotoxicity

Sprague

- Dawley

female rat MRID 48649101 (2010)

Acceptable/Guideline No evidence of immunotoxicity was observed in female Sprague

- Dawley rats at 225 mg/kg/day, the highest dose tested.

Pubertal toxicity study (Sprague

Dawley male rat) MRID 48279201 (2007)

Toxicology Letters 174:

74

- 81, 2007. NOAEL = not identified for testosterone effect. LOAEL = 50 mg/kg/day, based on significant,

dose

- related reductions in serum testosterone levels (↓73%)

. NOAEL = 50 mg/kg/day LOAEL = 100 mg/kg/day, based on a delay in preputial separation (PPS)

Special mechanistic study

Immature pocine cultured Leydig

cells MRID 44171901 (1996)

Acceptable/non

- guideline

In vitro Iprodione and its metabolites (RP36115 and RP36112) appear to modulate Leydig cell steroidogenesis by interfering at the level of cholesterol transport and/or steroidogenic enzyme activity.

Special mechanistic study

Male CD® Sprague

Dawley rats

TXR No. 012192 MRID 44171903 (1996)

Acceptable/non

- guideline

In vitro Endocrine Challenge Test (ECT) using human chorionic gonadotropin (hCG)

In vivo (prior exposure via diet for 14 days at 3000 ppm)

Testicular sections incubated with 0, 1, 10, or 100 μg/mL iprodione for

1 hour Dose

- related reduction in testosterone secret ion

from testicular sections incubated in vitro with iprodione, with and without hCG stimulation; prior exposure of rats in vivo for 14 days appeared to have little effect on secretion of testosterone, with and without hCG stimulation

from testicular secti ons incubated in vitro other than a slight increase initially.

### Iprodione Registration Review Human Health Scoping Document

Page 23 of 29 Table A2.2 Subchronic, Chronic and Other Toxicity Profile

– Iprodione

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

Special mechanistic study

Sprague

- Dawley

male rat

TXR No. 012192 44171904 (1996)

Acceptable/non

- guideline

Human chorionic gonadotropin (hCG) Endocrine Challenge Test (ECT)

In vivo diet exposure for 2, 7, or 14 days at 3000

ppm Iprodione did not produce alterations in testicular function following dietary exposure at 3000 ppm for 14 days.

Special mechanistic study

Male rat

TXR No. 011645 MRID 43535002 (1994)

MRID 44203401 (1996)

Acceptable/non

- guideline Iprodione has poor binding affinity to androgen receptor following exposure;

Marked increase in adrenal weights was accompanied by histopathological lesion (vacuolation) indicative of an alteration of steroidogenesis following 30 day exposure.

Special mechanistic study

Male rat MRID 44729201 (1998)

Acceptable/non

- guideline

0, 70, 300 mg/kg (gavage)

Single dose Decreased testosterone concentration at 2hours (↓59%** @ 70/↓75%** @ 300 mg/kg) and at 4 hours (↓29% @ 70/↓59%* @ 300 mg/kg); increased luteinizing hormone concentration at 2 hours (↑24% @ 70/↑33%* @ 300 mg/kg) and at 4 hours (↑36%* @ 70/↑55%** @ 300 mg/kg)

Special mechanistic study

Male rat MRID 45859601 (2001)

Acceptable/non

- guideline

0, 70, 300 mg/kg (gavage)

Single dose Decreased testosterone concentration at 30 minutes (↓48%** @ 70/↓49%** @ 300 mg/kg), at 1 hour (↓49%** @ 70/↓67%** @ 300 mg/kg), at 2 hours (↓64%** @ 70/↓56%** @ 300 mg/kg), and at 4 hours (↓35% @ 70/↓54%** @ 300 mg/kg); increased luteinizing hormone concentration at 4 hours (↑10% @ 70/↑30%** @ 300 mg/kg)

Special mechanistic study

Male rat

TXR No. 0052725 MRID 45859602 (2002)

Acceptable/non

- guideline

0, 6, 70, 300 mg/kg/day (gavage for 14 days) Dose

- related increase in mean BrdU labeling index at 70 (↑36%) and 300 (↑74%) mg/kg/day during 2 nd week assessment. At 6 mg/kg/day there was a slight (↑10%) increase. Demonstrates an increase in Leydig cell proliferation in the testis.

### Iprodione Registration Review Human Health Scoping Document

Page 24 of 29 Table A2.2 Subchronic, Chronic and Other Toxicity Profile

– Iprodione

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

Special mechanistic study

Male rat

TXR No. 0052725 MRID 45859603 (2002)

Acceptable/non

- guideline

0, 6, 70, 300 mg/kg/day (gavage for 14 days) Decreased testosterone concentration at 1 hour (↓17% @ 6/26% @ 70/↓36%* @ 300 mg/kg), at 2 hour (↓9% @ 6/↓44%* @ 70/↓37%* at 300 mg/kg), at 4 hours (↓48%** @ 300 mg/kg), and recovery at 24 hours.

Increased luteinizing hormone concentration at 2 hours (↑3 2% @ 70/↑39%** @ 300 mg/kg) and at 4 hours (↑24% @ 70/↑54% @ 300 mg/kg/day.

Special mechanistic study

Cultured Leydig

cells

TXR No.011907 MRID 43830601 (1995)

Acceptable/non

- guideline

1

- 10 μg/mL (3

- hour exposure) Inhibited gonadotrophin

- stimulated testosterone secretion; not related to Leydig cell damage because removal of iprodione from culture medium resulted in recovery of cells’ ability to secrete testosterone following hCG stimulation.

Special mechanistic study

CD

- 1 mouse (male) MRID 44171902 (1996)

Acceptable/non

- guideline

3

- and 14

- day oral

exposure
0, 4000 ppm (696 mg/kg/day) or 12000 ppm (2138 mg/kg/day) Iprodione, at dose levels 5

- and 15

- fold greater

than the LOEL for liver effects observed in the

mo use carcinogenicity study, induces (1) liver cell proliferation, (2) increased microsomal enzyme activities, (3) an increase in total cytochrome P

- 450 content, and (4) centrilobular hypertrophy, which most closely resemble the pattern of liver effects obse rved following phenobarbital exposure.

### Iprodione Registration Review Human Health Scoping Document

Page 25 of 29 Attachment 2

. Iprodione and 3,

- 5

- DCA Endpoints

T able A 2 .1. Summary of Toxicological Doses and Endpoints for Iprodione for Use in Dietary

Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD/PAD Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children) No acute endpoint was identified in the database. It is noted that a decline in testosterone for a

short time period (repeat exposure) during puberty could potentially result in delayed puberty as well as other adverse effects, but a delay in puberty or other adverse outcomes would not be expected from an acute (single) exposure. A transient decline for a few hours in an adult or young animal would not likely cause any adverse, permanent effects. Acute Dietary (Females 13

- 49 years of age) LOAEL = 50

mg/kg/day UF A 10x

UF H 10x

FQPA: UF LOAEL

→ N OAEL = 10x

Total UF: 1000 aRfD = 0.05

mg/kg

aPAD = 0.05 mg/kg Male pubertal toxicity study (rat)

MRID 48279201 LOAEL = 50 mg/kg/day, based on significant , dose

- related reductions in

serum testosterone levels (↓73%) ; delay in PPS at 100 mg/kg/day

Developmental t oxicity s tudy (r ats )

MRID 44365001 LOAEL = 120 mg/kg/day based on decreased AGD in male pups (single dose effect) Chronic Dietary (All Populations) LOAEL = 50

mg/kg/day UF A 10x

UF H 10x

FQPA: UF LOAEL

→ N OAEL = 10x

Total UF: 1000 cRfD = 0.05

mg/kg/day

cPAD = 0.05 mg/kg/day Co

- critical studies: Chronic oral toxicity

(rat) and Male pubertal toxicity study (rat)

Chronic Oral Toxicity: MRID

42637801/42787001 NOAEL = 6.1 mg/kg/day. LOAEL = 12.4 mg/kg/day, based on increases in generalized enlargement of th e cells of the zona glomerulosa in males and females, in

fine vacuolation of the zona fasciculata and in generalized fine vacuolation of the zone reticularis in males in the adrenal cortex,

an increased incidence of interstitial cell hyperplasia, reduced s permatozoa in the epididymides, reduced secretion of the seminal vesicles, increased hemosiderosis in the spleen in females, and increased liver weight.

Male pubertal toxicity (rat)

MRID 48279201 LOAEL = 50 mg/kg/day, based on significant , dose

- related re ductions in

serum testosterone levels (↓73%)

Point of Departure (Po D) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivit y among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose.

### Iprodione Registration Review Human Health Scoping Document

Page 26 of 29 Table A 2

. 2. Summary of Toxicological Doses and Endpoints for Iprodione for Use in Non

Occupational Human Health Risk Assessments (Dermal and Inhalation)

Exposure/

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Dermal and

Inhalation (short

- and

intermediate

- term) LOAEL =

50 mg/kg/day UF A 10x

UF H 10x

FQPA: UF LOAEL→

LOAEL = 10x

Total UF: 1000 LOC for MOE

< 1000 Co

- critical studies: Chronic oral toxicity

(rat) and Male pubertal toxicity study (rat)

Chronic Oral Toxicity: MRID

42637801/42787001 NOAEL = 6.1 mg/kg/day. LOAEL = 12.4 mg/kg/day, based on increases in generalized enlargement of the cells of the zona glomerulosa in males and females, in

fine vacuolation of the zona fasciculata and in generalized fin e vacuolation of the zone reticularis in males in the adrenal cortex,

an increased incidence of interstitial cell hyperplasia, reduced spermatozoa in the epididymides, reduced secretion of the seminal vesicles, increased hemosiderosis in the spleen in fema les, and increased liver weight.

Male pubertal toxicity (rat)

MRID 48279201 LOAEL = 50 mg/kg/day, based on significant , dose

- related reductions in

serum testosterone levels

. Point of Departure (Po D) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adver se effect level.

LOAEL = lowest observed adverse effect level. U F = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor. LOC = Level of Concern.



### Cancer Assessment

I prodione has been classified as a “Likely” human carcinogen, based on the increased incidence

of liver tumors in both sexes of the mouse and the increased incidence of L eydig cell tumors in male rats. The regist rant previously submitted mode of action (MOA) data; however, the Cancer Assessment Review Committee (CARC) determined that the MOA data do not provide a sufficient basis for establishing an MOA for iprodione for either tumor type. Therefore the Agency ha s determined that it is appropriate to quantify cancer dose response using the linearized low dose extrapolation model (Q 1 

### * ap proach), and the Leydig cell tumor Q 1 

### * of

4.39 x 10 - 2 

### was c hosen for human health risk assessment as the most sensitive endpoint.

The only concern identified for 3,5

- DCA is a potential carcinogenicity concern. A surrogate Q 1 

### * was used to obtain the carcinogenic risk estimate for 3,5

- DCA. Since 3,5

- DCA is not a registered pesticide; there are no toxicology data for this compound. Consequently, the established Q 1 

### * of 6.38 x 10 - 2 

### (mg/kg/day) - 1 

### for p

- chloroaniline (PCA) was used in this assessment because of the structural similarities between 3,5

- DCA and PCA. HED believes that

the use of the PCA Q 1 

### * represents a reasonable upper bound risk estimate.

### Iprodione Registration Review Human Health Scoping Document

Page 27 of 29 Attachment 3 . Iprodione International Residue Limits Table

Table A 3

. Summary of US and International Tolerances and Maximum Residue Limits for Iprodione Residue Definition : US 40 CFR 180.399:

Plant: combined residues of the fungicide iprodione [3

- (3,5

- dichlorophenyl)

- N

- (1

- ethylethyl)

- 2,4

- dioxo

- 1

- imidazolidinecarboxamide], its isomer 3

- (1

- methylethyl)

- N

- (3,5

- dichlorophenyl)

- 2,4

- dioxo

- 1

- imidazolidinecarboxamide, and its metabolite 3

- (3,5

- dichlorophenyl)

- 2,4

- dioxo

- 1

- imidazolidine

- carboxamide

Livestock: combined residues of iprodione [3

- (3,5

- dichlorophenyl)

- N

- (1

- methylethyl)

- 2,4

- dioxo

- 1

- imidazolidinecarboxamide], its isomer [3

- (1

- methylethyl)

- N

- (3,5

- dichlorophenyl)

- 2,4

- dioxo

- 1

- i midazolidinecarboxamide, and its metabolites [3

- (3,5

- dichlorophenyl)

- 2,4

- dioxo

- 1

- imidazolidine

- carboxamide] and [ N

- (3,5

- dichloro

- 4

- hydroxyphenyl)

- ureido

- carboxamide], all expressed as iprodione equivalents



### Canada Plant: 3

- (3,5

- dichlorophenyl)

- N

- isoprop yl

- 2

- 4

- dioxoimidazolidine

- 1

- carboxamide, including

the metabolites 3

- isopropyl

- N

- (3,5

- dichlorophenyl)

- 2,4

- dioxoimidazolidine

- 1

- carboxamide and

3

- (3,5

- dichlorophenyl)

- 2,4

- dioxoimidazolidine

- 1

- carboxamide



### Mexico 1



### Codex 2 Plant: Iprodione



### Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 

### Codex 2

Plant Commodities with U.S. Tolerances
Almond, hulls 2.0

Almond 0.3 0.2

Apricot 20.0 3.0 Bean, dry, seed 2.0 0.3 beans 0.1 beans (dry) Bean, forage 90.0
Bean, succulent 2.0 2 common bean (pods and/or immature seeds) Blueberry 15.0 Boysenberry 15.0

Broccoli 25.0 25 Caneberry subgroup 13A 25.0 10 raspberries 30 blackberries, raspberries, red,

black
Carrot, roots 5.0 5.0 10 Po Cherry, sweet, postharvest 20.0 5.0 cherries 10 cherries Cherry, tart 20.0
Cotton, undelinted seed 0.10 Cowpea, hay 90.0

Currant 15.0

Garlic 0.1 Ginseng 2.0 Ginseng, dried root 4.0 Grape 60.0 10 10 Grape, raisin 300 60 raisins

Kiwifruit 10.0 0.5 (edible portion) 5

### Iprodione Registration Review Human Health Scoping Document

Page 28 of 29 Table A 3

. Summary of US and International Tolerances and Maximum Residue Limits for Iprodione

Lettuce 25.0 15 10 lettuce, head

25 lettuce leaf Nectarine, postharvest 20.0 10 peaches/nectarines
Onion, bulb 0.5 0.2 Peach, postharvest 20.0 10 peaches/nectarines 10 peach

Peanut 0.5 Peanut, hay 150.0 Plum, postharvest 20.0 2.0 plums Plum, prune 20.0 2.0 prunes

Potato 0.5 Raspberry 15.0 10 raspberries
Rice, bran 30.0 Rice, grain 10.0 10 rice husked
Rice, hulls 50.0
Rice, straw 20.0 Strawberry 15.0 5.0 10

Plant Commodities with International MRLs and NO US Tolerance Barley 2 Common bean (pods and/or immature seeds) 2

Cucumber 0.5 2

Leeks 13

Pome fruits 5 Po Rapeseed (canola) 1.0 0.5 Sugar beet 0.1 (*)

Sunflower seed 0.5

Tomatoes 0.5 5 Witloof chicory (sprouts) 1

Wine 5.0

Livestock Commodities
Cattle, fat 0.5 Cattle, kidney 3.0
Cattle, liver 3.0
Cattle, meat 0.5 Cattle, meat byproducts, except kidney and liver 0.5

Egg 1.5
Goat, fat 0.5
Goat, kidney 3.0
Goat, liver 3.0
Goat, meat 0.5 Goat, meat byproducts, except kidney and liver 0.5

Hog, fat 0.5 Hog, kidney 3.0 Hog, liver 3.0 Hog, meat 0.5 Hog, meat byproducts, except kidney and liver 0.5

Horse, fat 0.5 Horse, kidney 3.0
Horse, liver 3.0

### Iprodione Registration Review Human Health Scoping Document

Page 29 of 29 Table A 3

. Summary of US and International Tolerances and Maximum Residue Limits for Iprodione

Horse, meat 0.5 Horse, meat byproducts, except kidney and liver 0.5

Milk 0.5 Poultry, fat Poultry, liver 5.0 Poultry, meat 1.0 Poultry, meat byproducts, except liver 1.0

Sheep, fat 0.5 Sheep, kidney 3.0 Sheep, liver 3.0 Sheep, meat 0.5 Sheep, meat byproducts, except kidney and liver 0.5

Completed: M. Negussie; 08/21/2012

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MR Ls indicated as proposed have not been finalized by the CCPR and the CAC.