Iprodione Registration Review Human Health Scoping Document

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(D233218, C. Scheltema, 7/31/1998), as well as updated 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 currently 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 post-application) exposure pathways for iprodione and through the oral, dermal, and 

inhalation routes of exposure.

Iprodione is a systemic fungicide used on a wide variety of agricultural crops, as well as on 

institutional turf, including sod farms, commercial lawns, golf courses, sports fields, etc. 

Iprodione shares a common metabolite, 3,5-dichloroaniline (3,5-DCA), with the active 

ingredients vinclozolin and procymidone. Therefore, risks need to be considered not only for 

parent and other regulated metabolites, but also for aggregate 3,5-DCA resulting from 

application of iprodione, procymidone and vinclozolin.

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

retention 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 uncertainty factors/safety factors (UF/SFs) will need to be evaluated.

The residue chemistry database for iprodione is incomplete. An adequate enforcement method 

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

registrant 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 iprodione 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 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 as well as the recently 

updated Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide 

Exposure Assessment.
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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 water assessment, as well as 

the findings from the updated non-occupational (residential) assessment. 

The occupational exposure database is complete. Updated occupational handler exposure 

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

scenario-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 RED, as well as recently conducted dietary risk 

assessments, to determine if sufficient data are available and if updates are needed to support 

registration review. HED has also considered 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. Iprodione 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 organs 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 performed 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 proposed mode of action (MOA) of iprodione for Leydig cell tumors is 

disruption of testosterone biosynthesis; however, sufficient information is not available to 
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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 

Leydig 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 cancer risk assessment 

considering this metabolite is required. The established Q1* of 6.38 x 10-2(mg/kg/day)-1for 

PCA was used in this assessment as the Agency believes that the use of the PCA Q1* represents 

a reasonable upper bound risk estimate.

Acute and 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 on current policies, a 

repeat dose inhalation toxicity study in rats is required due to the potential for repeated inhalation 

exposure to aerosolized formulations of iprodione. The HASPOC determined that a 28-day 

inhalation toxicity study is required for iprodione 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, these 

data were never formally requested. These 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. New acute and chronic 

toxicological 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 (PoDs), 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 was 

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 (UFLOAEL→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 basis of the acute and chronic risk assessments and is considered the 
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endpoint that is protective of all other downstream effects in males or females and further, since

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. 

Conclusions

The following toxicity studies are required for registration review: a 2-generation reproduction 

study (870.3800) and an inhalation 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. These two studies have not been 

previously formally requested 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 incomplete. An adequate enforcement method 

for livestock commodities and data on residue decline in rice water have not been provided. 

The nature of the residue in plants and animals is adequately understood. The residues of 

concern for both tolerance setting and risk assessment purposes in plants are iprodione, its RP30228 isomer, and its RP-32490 metabolite. The residues of concern for both tolerance setting 

and risk assessment purposes in livestock 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 assessment is required for this metabolite. The residue of concern in rotational 

crops is not adequately understood at this time. However, currently, 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 (D262487, 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 supported 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.

The 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 these data were received 

and reviewed. Therefore, this data remain an outstanding data gap.
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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 surface 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 pending receipt and review of additional environmental fate and 

toxicity data for iprodione and its 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 2012 

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. Iprodione 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 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. 

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 adequately 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 assessment 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 and 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 residue 

(TTR) study is required for all occupational (e.g., sod farms, golf courses, parks, and recreational 

areas) or residential turf uses, and that TTR data are available for iprodione. 
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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 (D389181) 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 3.2x10-6to 1.8x10-5.

Spray Drift 

Spray drift 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 employed 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 website1. 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-driftmanagement 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 Residential 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 assessment. 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
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which to update the drinking water assessment. Consequently, a revised aggregate risk 

assessment for iprodione may be required for registration review. 

Occupational Exposure

As noted above, iprodione 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 

resulting from the registered uses of iprodione.

Occupational Handlers

The 1998 RED evaluated a number of occupational handler scenarios that represented the major 

iprodione occupational handler scenarios based on application equipment and formulation type. 

That 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 measures 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 occupational 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, the 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 III/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 postapplication dermal exposure. Since the RED, three DFR studies (on lettuce, peaches, and 

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 occupational handler exposure 

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

scenario-specific surrogate handler exposure data2and exposure methodology relating to 

commercial seed treatment. Additionally, an updated occupational seed treatment assessment 

and occupational post-application assessment (cancer and non-cancer) for foliar applications of 

 

2

- Available: http://www.epa.gov/pesticides/science/handler-exposure-table.pdf
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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 would 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-

imidazolidine-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)-ureido-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, including 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-imidazolidinecarboxamide], its RP30228 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 livestock 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 Canada 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 
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commodities including succulent beans, broccoli, leaf lettuce, and rice grain. However, because 

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. tolerances since the Codex MRL may not be 

adequate 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 discrepancy, 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.

Environmental 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 Populations 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 

within 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. 
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Human Studies

The previous iprodione risk assessments relied 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 Task 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 is no barrier in EPA's "Protection of Human Subjects" Regulation 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 influence, 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 tests 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 assessment 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 certain 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 employs 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 systems. 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 and 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 
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procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening 

battery, please visit our website: http://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)

inhalation 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 review 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
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Table 1: HED Memoranda Relevant to Registration Review

Author Barcode/TXR # Date Title

T. 

Goodlow

D381906 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). 

Attachments

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

N

O

O

N

H

O CH3

CH3

N

Cl

Cl

Cl

N Cl H

N

O

O

O

H3C N

CH3

N

O

O

O NH2

N

Cl

Cl
Iprodione Registration Review Human Health Scoping Document

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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, pKa Not applicable since the T/TGAI is not 

dispersible in water

Octanol/water partition coefficient,

Log(KOW)

KOW average of 974.7 at pH 3;

KOW 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

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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 LD50 = 4468 mg/kg III

870.1200 Acute dermal [rabbit] 40567601 LD50 > 2000 mg/kg III

870.1300 Acute inhalation [rat] 42946101 LC50 > 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 

hyperplasia, 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

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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/day 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

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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/nonguideline

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

Maternal NOAEL = 200 mg/kg/day

LOAEL = 400 mg/kg/day based on slightly 

decreased BWG and significantly decreased 

food consumption.

Developmental 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

Maternal 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.

Developmental NOAEL = 60 mg/kg/day

LOAEL = 200 mg/kg/day based on abortions, 

and increased incidence of skeletal variations 

(13th full rib, malaligned sternebrae, and/or 27 

presacral vertebrae, with or without delayed 

ossification.

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 NOAEL = 3000/2000 (155/201 

mg/kg/day (HDT) 

Offspring NOAEL = 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 

during lactation period.
Iprodione Registration Review Human Health Scoping Document

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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 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 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

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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 

epididymides, 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

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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

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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 (SpragueDawley 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® SpragueDawley 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 secretion 

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 sections incubated in vitro other 

than a slight increase initially.
Iprodione Registration Review Human Health Scoping Document

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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 2nd 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

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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 (↑32% @ 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 

mouse 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 observed 

following phenobarbital exposure.
Iprodione Registration Review Human Health Scoping Document

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Attachment 2. Iprodione and 3,-5-DCA Endpoints

Table A2.1. 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

UFA 10x

UFH 10x

FQPA:UFLOAEL

→NOAEL = 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 toxicity study (rats)

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

UFA 10x

UFH 10x

FQPA:UFLOAEL

→NOAEL = 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 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 

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 reductions in 

serum testosterone levels (↓73%)

Point of Departure (PoD) = 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. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among members of the human population (intraspecies). UFL = 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

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Table A2.2. Summary of Toxicological Doses and Endpoints for Iprodione for Use in NonOccupational 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

UFA 10x

UFH 10x

FQPA:UFLOAEL→

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 fine 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 females, 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 (PoD) = 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. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. 

FQPA SF = FQPA Safety Factor. LOC = Level of Concern.

Cancer Assessment

Iprodione 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 Leydig cell tumors in 

male rats. The registrant 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 has determined that it is appropriate to quantify cancer dose response using the 

linearized low dose extrapolation model (Q1* approach), and the Leydig cell tumor Q1* of 

4.39 x 10-2 was chosen 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 Q1* 

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 Q1* of 6.38 x 10-2(mg/kg/day)-1for 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 Q1* represents a reasonable upper bound risk estimate.
Iprodione Registration Review Human Health Scoping Document

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Attachment 3. Iprodione International Residue Limits Table

Table A3. 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-imidazolidinecarboxamide, 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-isopropyl-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

Mexico1

Codex2 Plant: Iprodione

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

US Canada Mexico1 Codex2

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
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Table A3. 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
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Table A3. 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. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.