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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

 POLLUTION PREVENTION

MEMORANDUM

Date: 28-JAN-2015

Subject: Pyrimethanil. Human Health Risk Assessment for Proposed Post-Harvest Use

on Pomegranates.

PC Code: 288201 DP Barcode: D417167

Decision No.: 484376 Registration No.: 43813-32

Petition No.: 3F8213 Regulatory Action: Section 3 

Risk Assessment Type: Single Chemical/Aggregate Assessment Case No.: 7059

TXR No.: None CAS No.: 53112-28-0

MRID No.: None 40 CFR §180.518

From: Jennifer R. Tyler, Chemist

Jaclyn Pyne, Biologist

Anwar Y. Dunbar, Ph.D., Pharmacologist

Risk Assessment Branch 1 (RAB1)/Health Effects Division (HED; 7509P)

Through: Charles W. Smith III, Branch Chief

George F. Kramer, Ph.D., Senior Chemist

RAB1/HED (7509P)

To: Hope Johnson/Cynthia Giles-Parker, RM 21

Registration Division (RD; 7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and 

exposure data and conduct dietary, occupational, residential and aggregate exposure assessments, 

as needed, to estimate the risk to human health that will result from proposed and currently 

registered uses of the active ingredient (ai) pyrimethanil (4,6-dimethyl-N-phenyl-2-

pyrimidinamine). Bayer CropScience has submitted a petition for the post-harvest use of 

pyrimethanil on pomegranates. The risk assessment and occupational/residential exposure 

assessment were provided by Jennifer Tyler (RAB1); the residue chemistry review and dietary

exposure assessment by Jaclyn Pyne (RAB1); the hazard characterization by Anwar Dunbar 

(RAB1); and the drinking water assessment by James Wolf of the Environmental Fate and 

Effects Division (EFED).

NOTE: A human health risk assessment was completed on 22-MAY-2013 by HED (Memo, J. 

Tyler et al., D389923). In the present memo, dietary, occupational, and aggregate risks were reevaluated based on the addition of pomegranates to the pyrimethanil use pattern.
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Table of Contents

1.0 Executive Summary 3

2.0 HED Recommendations 5

2.1 Data Deficiencies/Conditions of Registration 5

2.2 Tolerance Considerations 6

3.0 Introduction 6

3.1 Chemical Identity 7

3.2 Physical/Chemical Characteristics 7

3.3 Pesticide Use Pattern 7

3.4 Anticipated Exposure Pathways 8

3.5 Consideration of Environmental Justice 8

4.0 Hazard Characterization and Dose Response Assessment 9

4.1 Summary of Toxicological Effects 9

4.2 Safety factor for Infants and Children (FQPA Safety Factor) 10

4.3 Toxicity Endpoint and POD Selections 11

5.0 Dietary Exposure and Risk Assessment 14

5.1 Residues of Concern Summary and Rationale 14

5.2 Food Residue Profile 14

5.3 Water Residue Profile 15

5.4 Dietary Risk Assessment 16

6.0 Residential (Non-Occupational) Exposure/Risk Characterization 17

7.0 Aggregate Exposure/Risk Characterization 17

7.1 Acute Aggregate Risk 17

7.2 Short- and Intermediate-Term Aggregate Risk 17

7.3 Chronic Aggregate Risk 18

7.4 Cancer Risk 18

8.0 Cumulative Risk Characterization/Assessment 18

9.0 Occupational Exposure/Risk Pathway 18

9.1 Handler Exposure and Risk Estimates 18

9.2 Post-application Exposure and Risk Estimates 20

10.0 References 21

Appendix A: Toxicity Profile Tables. 22

Appendix B: Metabolism Assessment. 26
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1.0 Executive Summary

Bayer CropScience has submitted a petition for the post-harvest use of Penbotec®400 Soluble 

Concentrate (SC) (EPA Reg. No. 43813-32), a SC formulation containing 3.27 pounds (lb) 

ai/gallon (gal) [400 grams (g) ai/liter (L)] on pomegranates. The petitioner requests the 

establishment of a 5.0-ppm tolerance for residues of pyrimethanil in/on pomegranate.

Pyrimethanil is an amino acid synthesis inhibitor that inhibits the secretion of enzymes necessary

for fungal infection. Pyrimethanil is currently registered in the U.S. for use on several raw 

agricultural commodities (RACs). Permanent tolerances have been established for residues of 

pyrimethanil per se in/on plant commodities at levels ranging from 0.05 ppm in/on vegetable, 

tuberous and corm, subgroup 1C to 150 ppm in/on citrus oil [40 CFR §180.518(a)(1)]. 

Tolerances have also been established for pyrimethanil residues and its metabolite 4-[4,6-

dimethyl-2-pyrimidinyl)amino]phenol in fat (0.01 ppm), kidney (2.5 ppm) and byproducts 

(except kidney) (0.01 ppm) of cattle, goats, horses and sheep and in milk (0.05 ppm) [40 CFR 

§180.518(a)(2)]. There are no registered or proposed residential uses.

Proposed Use: The proposed use to the subject crops is as a single post-harvest application at 

0.82 lb ai/100 gal via in-line dip/drench wash tanks. Applications can be made to the fruit on the

same day as sold or consumed.

Toxicity Profile: Pyrimethanil is of low acute lethality by the oral, dermal, and inhalation routes. 

It is a slight eye irritant, is not irritating to the skin, and it is not a dermal sensitizer. A single 

oral dose of 1000 mg/kg produced a number of acute signs of neurotoxicity, including ataxia, 

dilated pupils, and decreases in motor activity, hind limb grip strength, and body temperature. 

However, there was no evidence of neurotoxicity with repeated dosing in a subchronic 

neurotoxicity study in rats. The major target organs of repeated oral exposure were the liver and 

the thyroid. These effects were accompanied by decreased body weight. Reproductive toxicity

was not observed, and developmental effects (e.g., decreased fetal weight, retarded ossification, 

extra ribs) were observed only at maternally toxic doses. Special short-term exposure studies 

demonstrated increased liver uridine diphosphate glucuronosyl transferase (UDPGT) activity 

leading to decreases in thyroid hormones (T3, T4) and compensatory increases in thyroidstimulating hormone (TSH) in adult rats. Thyroid adenomas were seen in rats following longterm exposure, and it was concluded that they were mediated via disruption of the 

thyroid/pituitary axis. There were no concerns for mutagenicity.

Dose-response and Food Quality Protection Act (FQPA) Assessment: The pyrimethanil risk 

assessment team has evaluated the hazard and exposure data; and, based on these data, 

recommended that the FQPA Safety Factor (SF) be reduced to 1X. The toxicological is 

complete and there is no evidence of increased offspring susceptibility. The exposure databases 

are sufficient to determine the nature/magnitude of the residue in food and dietary analyses are 

unlikely to underestimate risk of exposure from pyrimethanil. Although there is evidence of 

neurotoxicity in the acute neurotoxicity study, concern is low since effects were only seen at the 

limit dose, effects are well-characterized with clearly established no-observed adverse effect 

level/lowest observed adverse effect level (NOAEL/LOAEL) values, and the selected endpoints 

are protective for the observed effects. 
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Residue Chemistry: The qualitative nature of the pyrimethanil residue in plant commodities is 

adequately understood based on acceptable metabolism studies in lettuce, grapes, and tomatoes. 

The HED Metabolism Assessment Review Committee (MARC) has determined that for risk 

assessment and tolerance expression, parent only is the residue of concern. The data-collection 

method used to generate pomegranate residue data in conjunction with magnitude of the residue 

study associated with this petition was a gas chromatography method with mass-selective 

detection (GC/MSD). There are also adequate methods available to enforce tolerances for 

residues of pyrimethanil in/on pomegranate. The submitted field trial residue data for 

pomegranate are adequate. The field trial data reflect the proposed use pattern, an adequate 

number of trials were conducted, and samples were analyzed for the residue of concern using 

validated data-collection methods. Using the Organization for Economic Co-operation and 

Development (OECD) tolerance calculation procedures for the residue data set indicates that the 

requested tolerance of 5.0 ppm for residues of pyrimethanil in/on pomegranates is appropriate. 

For plant commodities, the U.S., Canadian, and Codex residue definitions are harmonized. 

There are currently no established Codex or Canadian MRLs for residues of pyrimethanil in/on 

pomegranates; therefore, harmonization is not an issue for this petition. 

Drinking Water Exposure and Risk: Based on the information provided, EFED considers the 

proposed post-harvest dip use of pyrimethanil as an indoor use that would pose minimal 

exposure to the environment, provided that release of the chemical and contaminated water are 

controlled. Therefore, EFED concluded that an updated drinking water assessment is not needed 

for the proposed use. HED used estimated drinking water concentrations (EDWCs) provided by

EFED in conjunction with the most-recent human health risk assessment. Surface and ground 

EDWCs were generated by EFED using the Pesticide Root Zone Modeling/Exposure Analysis 

Modeling System (PRZM/EXAMS) and the Screening Concentration in Ground Water Model 

(SCI-GROW) models, respectively. The EDWCs for the combined total residues (pyrimethanil 

+ 2-amino-4,6-dimethylpyrimidine) in ground water are not expected to exceed 4.8 μg/L based 

on the registered seasonal application rate of 2.1 lb ai/A on strawberry in Florida. The EDWCs 

for combined residues of pyrimethanil (parent + 2-amino-4,6-dimethylpyrimidine) in raw surface 

source water are not expected to exceed 86.5 μg/L for the peak 1-in-10-year concentration; and 

29.4 μg/L for the 1-in-10-year annual mean concentration. 

Dietary Exposure and Risk: Acute and chronic dietary exposure assessments were conducted 

using the using the Dietary Exposure Evaluation Model software with the Food Commodity

Intake Database (DEEM-FCID) Version 3.16. The acute and chronic dietary analyses assumed 

default processing factors (as necessary), empirical processing factors for orange and apple juice, 

tolerance-level residues, 100% crop treated (CT) for all commodities and EDWCs (acute 86.5 

ppb, chronic 29.4 ppb) for direct and indirect water sources. The resulting acute dietary risk 

estimates (food and drinking water) were ≤38% of the acute population-adjusted dose (aPAD)

and are not of concern to HED (<100% aPAD; children 1-2 years old were the most highly

exposed population subgroup). The resulting chronic dietary risk estimates (food and drinking 

water) were ≤76% of the chronic population-adjusted dose (cPAD) and are not of concern to 

HED (<100% cPAD; children 1-2 years old were the most highly exposed population subgroup). 

Residential Exposure: Currently, there are no registered/proposed uses of pyrimethanil that 

result in residential exposures. Therefore, a residential exposure assessment was not performed.

Aggregate Risk: The Agency conducts aggregate exposure assessments by summing dietary

(food and water) and residential exposures (residential or other non-occupational exposures). 
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Since there are no registered/proposed uses of pyrimethanil that result in residential exposures, 

the acute and chronic aggregate risk assessments are equal to the acute dietary and chronic 

dietary estimates (food and water only), respectively. The acute and chronic aggregate 

exposures to the general U.S. population and all other subpopulations from the uses of 

pyrimethanil do not exceed HED’s level of concern (LOC).

Occupational Exposure/Risk: Based on the anticipated use patterns and current labeling, dermal 

and inhalation exposure occupational pesticide handlers are expected to be mixer/loaders using 

open-pour loading of liquids for automated systems. Occupational handler dermal and inhalation 

risk estimates were calculated. An MOE ≥100 is adequate to protect occupational pesticide 

handlers from dermal and inhalation exposures. Dermal and inhalation risks for occupational 

handlers are above the LOC (100) with label-required personal-protective equipment (PPE) (i.e., 

long-sleeved shirt, long pants, shoes plus socks and chemical-resistant gloves); and, therefore, 

are not of concern.

Based on the proposed use pattern, HED expects post-application dermal and inhalation 

exposure for workers while sorting and packing treated pomegranates, as well as indirect 

inhalation exposure for workers present in the warehouse, but not directly involved in the 

treatment process. The short- and intermediate-term risk estimates are not of concern (i.e., 

MOEs ≥100) at baseline (i.e., t-shirt and no gloves and no respirator) for all post-application 

exposure activities.

Environmental Justice Considerations: Potential areas of environmental justice concerns, to the 

extent possible, were considered in this 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.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf.

Review of Human Research: This exposure/risk assessment relies in part on data from studies in 

which adult human subjects were intentionally exposed to a pesticide or other chemical. These 

data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 

1.1); the Outdoor Residential Exposure Task Force (ORETF) database; the Agricultural Re-entry

Task Force (ARTF) database, are subject to ethics review pursuant to 40 CFR 26, have received 

that review, and are compliant with applicable ethics requirements. For certain studies, that 

review may have included review by the Human Studies Review Board. Descriptions of data 

sources as well as guidance on their use can be found at 

http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

2.0 HED Recommendations

HED concludes that the toxicological, residue chemistry and occupational/residential databases 

support a Section 3 registration and establishment of the tolerances listed in Section 2.2.2. HED 

is not recommending for any additional data or label modifications in conjunction with this 

petition.

2.1 Data Deficiencies/Conditions of Registration

No additional data are required to support the proposed use.
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2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

A residue analytical method entitled “Analytical Method for the Determination of Residues of 

ZK 100309 in Vines, Strawberries, and Apples by HPLC” was submitted in conjunction with an 

earlier pyrimethanil petition, PP#4E4384, for the establishment of a tolerance on imported wine 

grapes. The method has been subjected to a successful petition method validation (PMV) by

Analytical Chemistry Branch (ACB)/Biological and Economics Analysis Division (BEAD) (DP# 

288256, E. Kolbe, 7/7/04). In addition, the QuEChERS method has been shown to adequately 

quantify residues of pyrimethanil (http://www.crlpesticides.eu/library/docs/fv/CRLFV_Multiresidue_methods.pdf).

2.2.2 Recommended Tolerances

Table 2.2.2. Tolerance Summary for Pyrimethanil.

Commodity

Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

40 CFR §180.518 (a)(1)

Pomegranate 5.0 5.0

2.2.3 Revisions to Petitioned-For Tolerances

HED is not recommending for any changes to the proposed tolerance.

2.2.4 International Harmonization

For plant commodities, the U.S., Canadian, and Codex residue definitions are harmonized. 

There are currently no established Codex or Canadian MRLs for residues of pyrimethanil in/on 

pomegranates; therefore, harmonization is not an issue for this petition. 

2.3 Label Recommendations

HED is not recommending for any changes to Penbotoc®400 SC (EPA Reg. No. 43813-32) 

label.

3.0 Introduction

Pyrimethanil is an anilinopyrimidine fungicide that inhibits the secretion of fungal enzymes that 

are required during the infection process. Pyrimethanil blocks the ability of the fungus to 

degrade and digest the plant tissues, thus stopping penetration and development of the disease. 

The precise mechanism of inhibition of enzyme secretion has not been fully established. Protein 

synthesis is not inhibited, and evidence suggests that extracellular enzymes accumulate inside the 

fungus, their release being blocked in the presence of the fungicide. Pyrimethanil penetrates 

rapidly into the plant tissues, where it stops the development of the disease, providing a 

significant curative action. In vitro, germ tube extension and mycelial growth are inhibited.
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Pyrimethanil does not exhibit cross-resistance to sterol-inhibitors, dicarboximides, 

benzimidazoles, quinone outside inhibitors, or phenylamides, but may exhibit cross-resistance in 

certain plant pathogenic fungi including anilinopyridine (AP) compounds such as cyprodinil and 

mepanipyrim.

3.1 Chemical Identity

Table 3.1. Test Compound Nomenclature.

Chemical structure

N

CH3 N N

CH3

H

Common name Pyrimethanil

IUPAC name N-(4,6-dimethylpyrimidin-2yl)aniline

CAS name 4,6-dimethyl-N-phenyl-2-pyrimidinamine

CAS # 53112-28-0

End-use product/(EP) Penbotoc®

400 SC (EPA Reg. No. 43813-32)

3.2 Physical/Chemical Characteristics

Table 3.2. Physicochemical Properties of the Technical Grade Test Compound.

Parameter Value References

Melting point 96oC

The Pest Manual. British Crop 

Protection Council. Twelfth 

Edition, Editor: C.D.S. Tomlin.

pH (water solution at 25oC) 6.1

Specific gravity at 20oC 1.15

Water solubility (g/l at 25oC) 0.121 

Solvent solubility (g/l at 20oC) acetone – 389, ethyl acetate – 617, 

methanol – 176, methylene chloride –

1000, n-hexane – 23.7, toluene – 412 

Vapor pressure at 25oC 2.2 mPa

Octanol/water partition coefficient log 

(KOW) 

2.84

UV/visible absorption spectrum No UV absorption above 290 nm Pest Management Regulatory 

Agency Health, Canada, 2006.

3.3 Pesticide Use Pattern

Table 3.3 provides a summary of the proposed use patterns. Penbotec®400SC is formulated as a 

SC, and is proposed at a maximum application rate of 32 fl oz formulation/100 gal water, waterwax, or wax-oil emulsion (0.82 lb ai/100 gal) via in-line dip/drench wash tanks to harvested 

pomegranates. A single post-harvest application is permitted. There is no post-treatment 

interval prior to human consumption. The product label requires applicators and other handlers 

to wear PPE which consists of long-sleeved shirt, long pants, shoes plus socks and chemicalresistant gloves.
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Table 3.3. Summary of Proposed Directions for Use of Pyrimethanil.1

Commodity Trade Name 

(EPA Reg. No.)

Application 

Timing, Type, 

Equipment

Application 

Rate

(lb ai/100 gal)

Maximum 

Seasonal 

Application 

Rate

(lb ai/100 gal)

PHI

(days)

RTI

(days)

Min. 

GPA

Pomegranate Penbotec®

400 

SC (43813-32)

In-line 

dip/drench 0.82 0.82 NA NA NA

1. PHI = preharvest interval; RTI = retreatment interval; GPA = gallons of water per acre; NA = not applicable.

HED Conclusions: The submitted label is adequate to allow evaluation of the residue data 

relative to the proposed post-harvest use on pomegranates.

3.4 Anticipated Exposure Pathways

RD has requested an assessment of human health risk to support the proposed new post-harvest 

use of pyrimethanil on pomegranates. Humans may be exposed to pyrimethanil in food and 

drinking water since pyrimethanil may be applied directly to growing crops, and applications 

may result in pyrimethanil reaching surface and ground water sources of drinking water. There 

are no registered residential uses of pyrimethanil; therefore, human exposure in residential or 

non-occupational settings are expected. In an occupational setting, workers may be exposed 

while handling the pesticide prior to application as well as when performing sorting and packing 

tasks. Additionally, there is a potential for indirect inhalation exposure for workers in the 

warehouse or packaging facility not directly involved in the automated treatment process.

A human health risk assessment was completed on 22-MAY-2013 by HED (Memo, J. Tyler et 

al., D389923). This risk assessment considers all of the aforementioned exposure pathways 

based on the proposed new use of pyrimethanil, but also considers the existing uses as well, 

particularly for the dietary exposure assessments. 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

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/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. 

Further considerations are currently in development as OPP has committed resources and 
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expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Characterization and Dose Response Assessment

Since the last risk assessment, the conclusions and study classification for the subchronic 

neurotoxicity study have been revised so that no LOAEL was observed, and so that it is now an 

acceptable/guideline study (Memo, A. Dunbar, 14-AUG-2014; TXR# 0057032). The toxicology

database for pyrimethanil is therefore now complete. The HED HASPOC looked at all existing 

hazard and exposure data, and current use patterns for pyrimethanil; and, using a weight-ofevidence (WOE) approach, concluded that subchronic inhalation and dermal toxicity studies are 

not required for pyrimethanil at this time (Memo, J. Van Alstine, 8-FEB-2013; TXR# 0056470). 

4.1 Summary of Toxicological Effects

Pyrimethanil is of low acute lethality by the oral, dermal, and inhalation routes. It is a slight eye 

irritant, is not irritating to the skin, and it is not a dermal sensitizer. 

Through the oral route, pyrimethanil was well absorbed from the gastrointestinal tract. 

Following a single oral dose of 10 mg/kg, pyrimethanil was eliminated within 24 hours, and the 

major route of elimination was via the urine (72%). Approximately 17-18% of the dose was 

eliminated via the feces. Detectable levels of pyrimethanil were found in the adrenals, blood, 

kidney, liver, spleen, and thyroid less than 24 hours post dosing. The chemical was detected 

only in the liver, kidney, thyroid, and blood at 24 hours post dose. Four days post-dose, 

detectable levels of the chemical were found only in the liver, kidney, and thyroid. Regarding 

the total detectable levels per tissue, the highest levels of the chemical were detected in the liver 

in both sexes. There were no significant sex differences in metabolites generated. 

Pyrimethanil was well absorbed through the dermal route. In a dermal penetration study, the 

compound was applied to the shaved dorsal skin of male Sprague Dawley rats. Total absorbed 

dose (based on the sum of urine, feces, cage wash, blood, carcass, and non-treated skin) for the 

low, intermediate, and high doses at 10 hours post-treatment were 37.22, 35.77, and 20.39%, 

respectively. The “potentially absorbable” dose (combined tape stripping excluding first two 

tape strips and treated skin after tape stripping) for low, intermediate, and high dose at 10 hours 

post-treatment was 13.95, 5.55, and 4.80%, respectively. Absorption increased with greater 

exposure time, and the percent of dose absorbed increased with lower doses. The value 

ultimately used for risk assessment was calculated by combining the absorbed dose (37.22%) 

with the potentially absorbable dose (13.95%) from the study, which would be equal to 51.2%. 

Use of the 51% dermal absorption value for dermal exposure assessment for human risk is 

considered conservative and protective.

By the oral route of exposure, the rat was the most sensitive species to pyrimethanil toxicity

followed by the dog and then the mouse. The major target organs of repeated oral exposure were 

the liver, kidney, and the thyroid, and effects observed were manifested as some clinical signs 

(vomiting, diarrhea, and salivation in the dog for example), changes in clinical chemical 

parameters (liver enzymes), changes in organ weights (mostly relative), and finally macroscopic 

and microscopic organ changes. There were also decreased body weights throughout the 

database. No reproductive toxicity was observed, and developmental effects (e.g., decreased 
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fetal weight, retarded ossification, extra ribs) were observed only at maternally toxic doses. 

There was no evidence of neurotoxicity in either of the acute or subchronic studies. There were 

no indicators of targeted effects on the immune system in the guideline Immunotoxicity study.. 

Special short-term exposure studies demonstrated increased liver UDPGT activity leading to 

decreases in thyroid hormones (T3, T4) and compensatory increases in TSH in adult rats. 

Thyroid adenomas were seen in rats following long-term exposure, and it was concluded that 

they were mediated via disruption of the thyroid/pituitary axis. In the newly submitted mouse 

carcinogenicity study, there was no evidence of thyroid tumors up to the highest dose tested. 

There are no concerns for mutagenicity.

The thyroid has been shown to be one of the target organs in adult animals for pyrimethanilinduced toxicity thus raising a potential concern for thyroid toxicity in the young. However, 

HIARC previously concluded that there is no concern for thyroid toxicity in the young based on 

the following weight of evidence considerations the effects seen on the thyroid and the liver in 

the database, while treatment-related, are not severe in nature; and in each of the studies that 

show an effect on thyroid hormone levels, as well as in all studies chosen for points of departure 

(PODs) selection, there is a wide dose spread (~10-fold difference between NOAELs and 

LOAELs) which provides a measure of protection for any potential effects linked to decreased 

thyroid hormone levels in offspring.

4.2 Safety factor for Infants and Children (FQPA Safety Factor)

The pyrimethanil risk assessment team has evaluated the hazard and exposure data; and, based 

on these data, recommended that the FQPA SF be reduced to 1X. The toxicological is complete 

and there is no evidence of increased offspring susceptibility. The exposure databases are 

sufficient to determine the nature/magnitude of the residue in food and dietary analyses are 

unlikely to underestimate risk of exposure from pyrimethanil. Although there is evidence of 

neurotoxicity in the acute neurotoxicity study, concern is low since effects were only seen at the 

limit dose, effects are well-characterized with clearly established NOAEL/LOAEL values, and 

the selected endpoints are protective for the observed effects.

4.2.1 Completeness of the Toxicology Database

The toxicology database for pyrimethanil is adequate for FQPA consideration. The following 

studies are available: Developmental toxicity studies in rats and rabbits, a two-generation 

reproduction toxicity study, and both acute and subchronic neurotoxicity studies. 

4.2.2 Evidence of Neurotoxicity

Clinical signs of neurotoxicity (ataxia, decreased motor activity, decreased body temperature, 

decreased hind limb grip strength in males, and dilated pupils) were observed in females in the 

acute neurotoxicity study in rats at the highest dose tested only (1000 mg/kg). Although the limit 

dose was not tested in the subchronic neurotoxicity study, no clinical signs, behavioral changes 

or neuropathology were seen at 1/2 limit dose (up to 430 mg/kg/day). In addition, no neurotoxic 

signs were seen in the rest of the database and the target organ for toxicity for pyrimethanil is the 

thyroid. The concern for neurotoxicity therefore is low. 
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4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence of qualitative or quantitative increased susceptibility following pre-/postnatal exposure to pyrimethanil in the developmental toxicity studies in rats and rabbits or in the 

two-generation reproduction study in rats.

4.2.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties with respect to exposure data. The dietary food exposure 

assessment utilizes tolerance-level residues (established or recommended) and 100% CT for all 

proposed/established commodities. By using these assumptions, the acute and chronic 

exposures/risks will not be underestimated. The dietary drinking water assessment utilizes water 

concentration values generated by models and associated modeling parameters that are designed 

to provide conservative, health-protective, high-end estimates of water concentrations that will 

not likely be exceeded. There are no residential uses.

4.3 Toxicity Endpoint and POD Selections

The selected toxicity endpoints are summarized in Tables 4.3.1 and 4.3.2.

Acute Dietary Endpoint (Females Age 13-49): The endpoint used for establishing the aPAD for 

females 13-49 years of age was selected from the prenatal developmental toxicity study in 

rabbits. An aPAD of 0.45 mg/kg/day was derived from a developmental NOAEL of 45 

mg/kg/day and a 100-fold factor that included 10X for inter-species extrapolations, 10X for 

intra-species variations, and 1X FQPA SF. The endpoint of concern is a developmental effect 

characterized as increases in fetuses with 13 thoracic vertebrae and 13 pairs of ribs observed at 

300 mg/kg (LOAEL). These developmental anomalies are presumed to be the result of a single 

oral dose following in utero exposure; and, therefore, are relevant to pregnant females.

Acute Dietary Endpoint (General U.S. Population): The endpoint used for establishing the 

aPAD for the general population including infants and children was selected from the acute 

neurotoxicity study in rats. An aPAD of 1.0 mg/kg/day was derived from a NOAEL of 100 

mg/kg/day and a 100-fold factor that included 10X for inter-species extrapolations, 10X for 

intra-species variations, and a 1X FQPA SF. Effects at the LOAEL of 1000 mg/kg (highest dose 

tested) included decreased motor activity, ataxia, decreased body temperature, hind limb grip 

strength, and dilated pupils. The effects were seen after a single oral dose and thus appropriate 

for this exposure scenario and the population of concern. 

Chronic Dietary Endpoint (All Populations): The endpoint used for deriving the cPAD was 

selected from a chronic toxicity study with rats. The cPAD was derived from a NOAEL of 17 

mg/kg/day and a 100-fold factor that included 10X for inter-species extrapolations, 10X for 

intra-species variations, and 1X FQPA SF. The LOAEL of 221 mg /kg/day is based on increased 

serum cholesterol and gamma glutanyl transferase (GGT), increased relative liver/body-weight 

ratios, necropsy, and histopathological findings in the liver and thyroid. The endpoint of concern 

was seen following repeated oral exposure in the most sensitive species; and, thus, is appropriate 

for assessing potential risk via chronic dietary exposure to pyrimethanil.

Incidental Oral [short (1-30 days) - and intermediate (1-6 months)-term]: There are no 

residential uses for pyrimethanil. Therefore, an incidental oral endpoint was not chosen.
Pyrimethanil Human Health Risk Assessment DP# 417167 

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Dermal [short (1-30 days) - and intermediate (1-6 months)-term]: The pyrimethanil database 

does not contain a dermal toxicity study. Therefore, the Agency has selected an oral NOAEL of 

23 mg/kg/day for short and intermediate term dermal risk assessments. The endpoint of concern 

is based on decreasedbody weight observed in the rat two-generation reproduction toxicity study

at the LOAEL of 294 mg/kg/day. Since an oral dose was selected a dermal absorption factor of 

51% should be used for route-to-route extrapolation which yields a dermal equivalent dose of 45 

mg/kg/day (23 mg/kg/day ÷ 0.51 DAF = 45 mg/kg/day). The LOC for occupational dermal 

exposures is 100 (10X for inter-species extrapolation and 10X for intra-species extrapolation).

Inhalation [short (1-30 days) - and intermediate (1-6 months)-term]: An inhalation toxicity

study was not submitted. The short- and intermediate-term inhalation endpoints are based upon 

the parental effect of decreased body weights observed in the two-generation reproduction 

toxicity study. The NOAEL is 23.1 mg/kg/day. This endpoint is appropriate for the duration of 

exposure and the populations of concern. Inhalation exposure is assumed to be equivalent to oral 

exposure. The LOC for occupational inhalation exposures is 100 (10X for inter-species 

extrapolation and 10X for intra-species extrapolation).

Table 4.3.1. Summary of Toxicological Doses and Endpoints for Pyrimethanil for Use in Dietary and NonOccupational Human Health Risk Assessments.

Exposure/

Scenario POD UFs/FQPA SF

RfD, PAD, 

LOC Study and Toxicological Effects

Acute Dietary

(Females 13-49 

years of age)

NOAEL 

= 45 

mg/kg/da

y

UFA = 10X

UFH = 10X

FQPA SF = 1X

Acute RfD = 

0.45 mg/kg/day

aPAD = 0.45 

mg/kg/day

Developmental Toxicity - Rabbit:

LOAEL = 300 mg/kg/day based on 

increases in fetuses with 13 thoracic 

vertebrae and 13 pairs of ribs.

Acute Dietary 

(General 

Population, 

including Infants 

and Children) 

NOAEL 

= 100 

mg/kg/da

y

UFA = 10X

UFH = 10X

FQPA SF = 1X

Acute RfD = 1 

mg/kg/day

Acute Neurotoxicity- Rat: LOAEL = 

1000 mg/kg/day based on decreased 

motor activity, ataxia, decreased body 

temperature, hind limb grip strength, 

and dilated pupils.

Chronic Dietary 

(All Populations)

NOAEL 

= 17 

mg/kg/da

y

UFA = 10X

UFH = 10X

FQPA SF = 1X

Chronic RfD = 

0.17 mg/kg/day

cPAD = 0.17 

mg/kg/day

Chronic Toxicity - Rat: 

LOAEL = 221 mg/kg/day based on 

decreased body-weight gains; 

increased serum cholesterol and GGT, 

increased relative liver/body weight 

ratios, necropsy and histopathological 

findings in the liver and thyroid.

Cancer (oral, 

dermal, 

inhalation) 

CARC Classification: “Not Likely To Be Carcinogenic To Humans At Doses That Do Not 

Alter Rat Thyroid Hormone Homeostasis”

Table 4.3.2. Summary of Toxicological Doses and Endpoints for Pyrimethanil for Use in Occupational 

Human Health Risk Assessments.

Exposure

Scenario POD LOC for Risk Assessment Study and Toxicological Effects

Short (1-30 days) and 

Intermediate (1- 6 months) 

Term Dermal

Oral NOAEL =

23.1 mg/kg/day

(dermal 

absorptiona= 

51%)

Occupational LOC 

for MOE = 100

Reproductive Toxicity - Rat

LOAEL = 294 mg/kg/day based on 

decreased mean body weights and 

body-weight gains.

Short (1-30 days) and 

Intermediate (1- 6 months) 

Oral NOAEL =

23.1 mg/kg/day

Occupational LOC 

for MOE = 100

Reproductive Toxicity - Rat

LOAEL = 294 mg/kg/day based on 
Pyrimethanil Human Health Risk Assessment DP# 417167 

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Table 4.3.2. Summary of Toxicological Doses and Endpoints for Pyrimethanil for Use in Occupational 

Human Health Risk Assessments.

Exposure

Scenario POD LOC for Risk Assessment Study and Toxicological Effects

Term Inhalation (inhalation 

absorptionb= 

100%)

decreased mean body weights and 

body-weight gains.

Cancer (oral, dermal, 

inhalation)

CARC Classification: “Not Likely To Be Carcinogenic To Humans At Doses That 

Do Not Alter Rat Thyroid Hormone Homeostasis”

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

(interspecies). FQPA SF = FQPA Safety Factor. PAD = population-adjusted dose (a = acute, c = chronic). RfD = reference 

dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. a= dermal-absorption factor, from MRID 

46630101. b= Inhalation-absorption factor assumed.

4.3.1 Recommendation for Combining Routes of Exposures for Risk Assessment

HED notes that the same oral toxicity study was selected for assessment of short-/intermediateterm dermal and inhalation exposures and thus the dermal and inhalation routes of exposure 

should be combined.

4.3.2 Cancer Classification and Risk Assessment Recommendation

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March 2005), 

the Cancer Assessment Review Committee (CARC) classified pyrimethanil as “Not Likely To 

Be Carcinogenic To Humans At Doses That Do Not Alter Rat Thyroid Hormone 

Homeostasis” (TXR#0056151, J. Rowland, 23-DEC-2011). This decision was based on the 

following:

i) Treatment-related increases in thyroid follicular cell tumors in male and female SpragueDawley rats at doses which were considered adequate to assess carcinogenicity;

ii) No treatment-related tumors were seen in male or female CD-1 mice at doses which were 

considered adequate to assess carcinogenicity;

iii) There is no mutagenicity concern and there is no evidence for thyroid carcinogenesis 

mediated through a mutagenic mode of action;

iv) The non-neoplastic toxicological evidence (i.e., thyroid growth, thyroid hormonal changes) 

indicated that pyrimethanil was inducing a disruption in the thyroid-pituitary hormonal 

status. The overall weight-of-evidence was considered sufficient to indicate that 

Pyrimethanil induced thyroid follicular tumors through an antithyroid mode of action; and

v) Rats are substantially more sensitive than humans are to the development of thyroid 

follicular cell tumors in response to thyroid hormone imbalance. 

Quantification of Carcinogenic Risk: Quantification of carcinogenic risk is not required. The 

CARC determined that the thyroid tumors arise through a non-linear mode of action and the 

NOAEL (17 mg/kg/day) established for deriving the cPAD is not expected to alter thyroid 

hormone homeostasis nor result in thyroid tumor formation. 
Pyrimethanil Human Health Risk Assessment DP# 417167 

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5.0 Dietary Exposure and Risk Assessment

The residue chemistry data submitted in support of proposed uses were evaluated by HED on 12-

AUG-2014 (Memo, J. Pyne; D416841). The drinking water assessment was completed by EFED 

on 26-SEP-2011 (Memo, J. Wolf; DP389925). The dietary exposure assessment was completed 

in a HED memorandum dated 12-AUG-2014 (Memo, J. Pyne; D417165).

5.1 Residues of Concern Summary and Rationale

The residues which are regulated in plant commodities are pyrimethanil, per se (40 CFR 

§180.518). For risk assessment purposes, the residues of concern are: 1) pyrimethanil for plant 

commodities; 2) in livestock, pyrimethanil + metabolite AEC614276 for ruminant muscle, fat 

and byproducts; and 3) pyrimethanil + metabolite AEC614277 for milk. In drinking water, 

residues of concern are pyrimethanil + Degradate 1 (2-amino-4,6-dimethylpyrimidine). 

Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance 

Expression.

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Plants Primary Crop Pyrimethanil, per se Pyrimethanil, per se

Rotational Crop Pyrimethanil, per se Pyrimethanil, per se

Livestock Ruminant Pyrimethanil + AEC614276 

for muscle, fat, and 

byproducts. For milk, 

pyrimethanil + AEC614277.

Pyrimethanil + AEC614276 

for muscle, fat, and 

byproducts. 

Pyrimethanil + AEC614277 

for milk.

Poultry Not Applicable Not Applicable

Drinking Water Parent (Pyrimethanil) + 

Degradate 1 (2-amino-4,6-

dimethylpyrimidine)

Not Applicable

5.2 Food Residue Profile

The data-collection method used to generate pomegranate residue data in conjunction with 

magnitude of the residue study associated with this petition was a GC/MSD method. The 

procedure derived from “Fruit and Vegetables: Analytical Method for the Determination of 

Residues (Improved Version), Pyrimethanil, Active Substance,” M.H. Peatman, 15/FEB/1999, 

and Morse Labs’ modifications to the analytical method dated 6/FEB/2012 and 10/FEB/2012. 

The lowest level of method validation (LLMV) was 0.05 ppm. This method was adequate for 

data collection. There are also adequate methods available to enforce tolerances for residues of 

pyrimethanil in/on pomegranate. 

The pomegranate samples analyzed in this study were held in frozen storage for a maximum of 

92 days for the whole fruits and 93 days for flesh prior to analysis of pyrimethanil residues. 

Acceptable storage stability data are available demonstrating that residues of pyrimethanil are 

stable under frozen storage conditions in: carrot, lettuce, and tomato for up to 12 months; in 

apples for up to 676 days (22.2 months); and peaches for up to 651-658 days (21.4-21.6 months) 

(refer to DP#s 284001 and 284870, J. Morales and G. Kramer, 1/12/04). The available storage 

stability data are adequate to support the storage conditions and durations for samples of 

pomegranate (whole fruit and flesh) from the submitted crop field trial study.
Pyrimethanil Human Health Risk Assessment DP# 417167 

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The submitted field trial residue data for pomegranate are adequate. The field trial data reflect 

the proposed use pattern, an adequate number of trials were conducted, and samples were 

analyzed for the residue of concern using validated data-collection methods. Two pomegranate 

field trials were submitted. Each field trial had four samples that were treated post-harvest with 

an SC formulation of pyrimethanil (Penbotec®400SC), with two samples treated at a 1X rate 

(1,000 ppm) and two samples treated at a 2X rate (2,000 ppm). Per-trial-average-residues of 

pyrimethanil in/on pomegranate, whole fruit ranged 1.51-1.66 ppm from the 1X trial and from 

2.50 to 3.01 ppm in the 2X trial. Residues were below the limit of quantitation (LOQ; <0.05 

ppm) in/on pomegranate flesh treated at a 1X rate.

The OECD tolerance-calculation procedures were used to determine the tolerance for residues of 

pyrimethanil in/on pomegranate. Per-trial-average-residues from the 1,000- and 2,000-ppm trials 

were used to calculate the tolerance. Since the label proposes applications of 1,000 ppm, 

proportionality was used for the 2,000-ppm trial residues. The OECD tolerance-calculation 

procedures for the residue data set indicates that the requested tolerance of 5.0 ppm for residues 

of pyrimethanil from a treatment solution of 1,000 ppm in/on pomegranate is appropriate. 

There are no livestock food/feed items of regulatory concern the pomegranate; therefore, a 

discussion of livestock residues is not germane to this petition.

5.3 Water Residue Profile

Based on the information provided, EFED considers the proposed post-harvest dip use of 

pyrimethanil as an indoor use that would pose minimal exposure to the environment, provided 

that release of the chemical and contaminated water are controlled. Therefore, an updated 

drinking water assessment is not needed for this new use (Memo, J. Wolfe, 30-JUN-2014; 

D416873). HED used EDWCs provided by EFED in conjunction with the most-recent human 

health risk assessment (Memos, J. Wolfe, 22-OCT-2003, D283999 and D290313; 08-JAN-2009, 

D353180). Tier I SCI-GROW screening concentration of combined total residues (pyrimethanil 

+ 2-amino-4,6-dimethylpyrimidine) in ground water for uses on small berries (caneberries and 

bushberries) are not expected to exceed 4.8 μg/L for previously estimated uses based on the 

registered seasonal application rate of 2.1 lb ai/A on strawberry in Florida

Tier II PRZM-EXAMS screening drinking water concentrations for combined residues of 

pyrimethanil (parent + 2-amino-4,6-dimethylpyrimidine) in raw surface source water are not 

expected to exceed 86.5 μg/L for the peak 1-in-10-year concentration; 29.4 μg/L for the 1-in-10-

year annual mean concentration; and, 17.9 μg/L for the 30-year annual average concentration. 

These EDWCs correspond to the FL/strawberries (acute) and NY/grapes (chronic) scenarios.

Table 5.3. Estimated Drinking Water Concentrations for Combined Total Residues, Parent 

(Pyrimethanil) Plus Major Degradate (2-amino-4,6-dimethylpyrimidine).

Chemical

Acute (peak) 

Surface Water 

Concentration 

(ppb)

Annual Average 

Surface Water 

Concentration

1-in-10-yr (ppb)

Average of Annual 

Average Surface 

Water Concentration 

(ppb)

Ground Water 

Concentration 

(ppb)

Pyrimethanil plus 

2-amino-4,6-

dimethylpyrimidine.

86.5 29.4 17.9 4.8
Pyrimethanil Human Health Risk Assessment DP# 417167 

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In this assessment, the annual average surface water concentration (29.4 ppb) and the acute peak 

surface water concentrations (86.5 ppb) were used for chronic and acute dietary exposure 

assessments, respectively.

5.4 Dietary Risk Assessment

Unrefined acute and chronic aggregate dietary (food and drinking water) exposure and risk 

assessments were conducted using DEEM-FCID Version 3.16. This software uses 2003-2008 

food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health 

and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA).

5.4.1 Description of Residue and Percent Crop Treated Data Used in Dietary Assessment

The acute and chronic dietary exposure assessment was unrefined, using tolerance-level residues 

and assuming 100% CT for all registered and proposed commodities. DEEM Version 7.81 

default processing factors were used to estimate residues in processed commodities, as available, 

and empirical processing factors were used for orange and apple juice. Drinking water was 

incorporated directly into the dietary assessment using the EDWCs generated by the 

PRZM/EXAMS surface water model. Based on the proposed use pattern for a postharvest dip 

treatment, a revised drinking water assessment was not required.

5.4.2 Acute Dietary Risk Assessment

Using the DEEM-FCID software, dietary risk is estimated at 9.8% of the aPAD for the general 

U.S. population and 38% of the aPAD for children 1-2 years old, the population subgroup with 

the highest estimated acute dietary exposure. Therefore, the acute dietary risk assessment shows 

that for all included commodities plus drinking water, the acute dietary risk estimates are below 

HED’s LOC for the general U.S. population and all population subgroups (i.e., <100% aPAD).

5.4.4 Chronic Dietary Risk Assessment

Using the DEEM-FCID software, dietary risk is estimated at 14% of the cPAD for the general 

U.S. population and 76% of the cPAD for children 1 to 2 years old, the population subgroup with 

the highest estimated chronic dietary exposure to pyrimethanil. The chronic dietary risk 

assessment shows that for all included commodities plus drinking water, the chronic dietary risk 

estimates are below HED’s LOC for the general U.S. population and all population subgroups 

(i.e., <100% cPAD).

5.4.5 Cancer Dietary Risk Assessment

A cancer dietary assessment was not conducted because pyrimethanil is classified as “Not Likely 

To Be Carcinogenic To Humans At Doses That Do Not Alter Rat Thyroid Hormone 

Homeostasis.” 
Pyrimethanil Human Health Risk Assessment DP# 417167 

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5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Pyrimethanil.

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD1

Dietary 

Exposure

(mg/kg/day)

% cPAD

Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population 0.97834 9.8 0.023739 14

N/A N/A

All Infants (<1 year old) 0.344534 34 0.085185 50

Children 1-2 years old 0.380589 38 0.128860 76

Children 3-5 years old 0.241219 24 0.078291 46

Children 6-12 years old 0.131512 13 0.036225 21

Youth 13-19 years old 0.059804 6.0 0.015366 9.0

Adults 20-49 years old 0.056534 5.6 0.013819 8.1

Adults 50-99 years old 0.058642 5.9 0.016149 9.5

Females 13-49 years old 0.058418 13 0.014775 8.7

1. Population subgroup with the highest exposure and risk is in bold type. The aPAD for Females 13-49 years of age is 0.45 mg/kg/day; aPAD 

for general U.S. population is 1 mg/kg/day.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

Currently, there are no registered/proposed uses of pyrimethanil that result in residential 

exposures. Therefore, a residential exposure assessment was not performed.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks 

from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure. In the case of pyrimethanil, aggregate risk assessments were performed for

acute aggregate exposure (food + drinking water) and chronic aggregate exposure (food + 

drinking water). A cancer aggregate risk assessment was not performed because imidacloprid is 

not carcinogenic. All potential exposure pathways were assessed in the aggregate risk 

assessment. 

7.1 Acute Aggregate Risk

No acute residential/recreational exposures are expected. In the case of pyrimethanil, the acute 

aggregate risk is composed of exposures to pyrimethanil residues in food and drinking water and 

is equivalent to the acute dietary risk discussed in Section 5.4.1. As shown in Table 5.4.6, the 

acute risk estimates do not exceed the HED’s LOC for the general U.S. population and all 

population subgroups.

7.2 Short- and Intermediate-Term Aggregate Risk

Pyrimethanil is not registered for residential uses. Therefore, short- and intermediate term 

residential exposures are not expected. 
Pyrimethanil Human Health Risk Assessment DP# 417167 

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7.3 Chronic Aggregate Risk

A long-term aggregate risk assessment was not performed, because long-term residential 

exposure to pyrimethanil (i.e., >6 months) is unlikely to occur based upon the use patterns. 

Specifically, in the case of pyrimethanil, the chronic aggregate risk is composed of exposures to 

pyrimethanil residues in food and drinking water and is equivalent to the chronic dietary risk 

discussed in Section 5.4.2. As shown in Table 5.4.6, the chronic risk estimates do not exceed the 

HED’s LOC for the general U.S. population and all population subgroups.

7.4 Cancer Risk

Pyrimethanil is classified as “Not Likely To Be Carcinogenic To Humans At Doses That Do Not 

Alter Rat Thyroid Hormone Homeostasis.” Therefore, a cancer aggregate risk assessment was 

not conducted. 

8.0 Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for 

pyrimethanil and any other substances, and pyrimethanil does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this action, therefore, EPA has 

assumed that pyrimethanil does not have a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Pathway

Based on the proposed application scenario and toxicological considerations, non-cancer 

occupational handler (dermal and inhalation) and occupational post-application (dermal and 

inhalation) risk assessments were conducted. The proposed new uses were evaluated in the cited 

memorandum and the resulting occupational exposure/risks were reviewed by the HED Science 

Advisory Council for Exposure (ExpoSAC; Memo, J. Tyler, 20-AUG-2014, D417166).

9.1 Handler Exposure and Risk Estimates

Based on the anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, occupational handler exposure is expected from the proposed uses. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

mixing/loading liquids for automated system exposure scenario. A separate applicator

assessment was not conducted as the application of pyrimethanil is mechanically automated for 

the in-line dip/drench wash tanks. A mixer/loader assessment was performed and is considered 

to result in a conservative estimate of handler risk.

HED classifies exposures from 1 to 30 days as short-term and exposures 30 days to six months 

as intermediate-term. Exposure duration is determined by many things, including the exposed 

population, the use site, the pest pressure triggering the use of the pesticide, and the cultural 
Pyrimethanil Human Health Risk Assessment DP# 417167 

Page 19 of 26

practices surrounding that use site. For most agricultural uses, it is reasonable to believe that 

occupational handlers will not apply the same chemical every day for more than a one-month 

time frame; however, there may be a large agribusiness and/or commercial applicators who may

apply a product over a period of weeks (e.g., completing multiple applications for multiple 

clients within a region). For pyrimethanil, based on the proposed use pattern, short- and 

intermediate-term exposures are expected. In addition, the short- and intermediate-term PODs 

are the same; therefore, estimates for short-term durations are protective of longer-term exposure 

durations. The average adult body weight of 80 kg was used for estimating dermal and 

inhalation doses. 

No chemical-specific handler exposure data were submitted in support of this Section 3 

registration. It is the policy of HED to use the best available data to assess handler exposure. 

Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, 

include PHED 1.1, the Agricultural Handler Exposure Task Force (AHETF) database, or other 

registrant-submitted occupational exposure studies. Some of these data are proprietary (e.g., 

AHETF data), and subject to the data protection provisions of the Federal Insecticide, Fungicide, 

and Rodenticide Act (FIFRA). The standard values recommended for use in predicting handler 

exposure that are used in this assessment, known as “unit exposures,” are outlined in the 

“Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” 

(http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with 

additional information on HED policy on use of surrogate data, including descriptions of the

various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposuredata.html.

Estimates of dermal and inhalation exposure were calculated for various levels of PPE. Results 

are presented for “baseline,” defined as a single layer of clothing consisting of a long sleeved 

shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline 

with various levels of PPE as necessary (e.g., gloves, respirator, etc). The pyrimethanil product 

labels direct mixers, loaders, applicators and other handlers to wear long-sleeved shirt, long 

pants, shoes plus socks and chemical-resistant gloves.

Table 9.1 provides a summary of the estimated exposures and risks to occupational pesticide 

handlers. An MOE ≥ 100 is adequate to protect occupational pesticide handlers from dermal and 

inhalation exposure. Dermal and inhalation risks for occupational handlers are above the LOC 

(100) with label-required PPE (i.e., wear long-sleeved shirt, long pants, shoes plus socks and 

chemical-resistant gloves).
Pyrimethanil Human Health Risk Assessment DP# 417167 

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Table 9.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Post-harvest Use on Pomegranates.

Exposure 

Scenario Crop LOC

Dermal 

Unit 

Exposure 

(μg/lb ai)1

Inhalation 

Unit 

Exposure 

(μg/lb ai)1

Max.

App. Rate 

(lb ai/gal 

solution)2

Amount 

Handled 

Daily 

(gal/day)3

Dermal Inhalation Total

Mitigation 

Level

Mitigation 

Level

Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 MOE8

Mixer/Loader

Open Mixing/

Loading 

Liquids for 

Automated 

System

Pomegranates 100

Baseline: 

220

PPE-G: 

37.6

Baseline: 

0.219 0.0082 25,000

Baseline: 

0.289

PPE-G: 

0.0494

Baseline: 

80

PPE-G: 

470

Baseline: 

0.000565

Baseline: 

41,000

Baseline: 

80

PPE-G: 

460

1. Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (May 2013); Level of mitigation: Baseline = Longsleeved shirt, long pants, shoes plus socks and no gloves (dermal); no respirator (inhalation). PPE-G = Long-sleeved shirt, long pants, shoes 

plus socks and chemical-resistant gloves.

2. Based on registered or proposed label (Reg. No. 43813-32).

3. HED ExpoSAC Policy/Guidance “Assessment of Occupational Exposure for Post-Harvest Commodity Pesticide Treatments.”

4. Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/gal) × Amount Handled 

(gal/day) × DAF (51%) ÷ BW (80 kg).

5. Dermal MOE = Dermal NOAEL (23.1 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6. Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/gal) × Amount Handled 

(gal/day) ÷ BW (80 kg).

7. Inhalation MOE = Inhalation NOAEL (23.1 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

8 Total MOE = NOAEL (23.1 mg/kg/day) ÷ Dermal Dose + Inhalation Dose.

9.2 Post-application Exposure and Risk Estimates

During automated treatments, dermal and inhalation exposure is anticipated for workers 

performing sorting and packing tasks. Since the workers experience exposure following the 

treatment, this is technically “post-application” exposure; however, unlike other post-application 

activities (e.g., harvesting, scouting, etc.), this treatment is not governed by the Worker 

Protection Standard (WPS) and potential restricted-entry intervals (REIs). Additionally, for 

workers in the warehouse or packaging facility not directly involved in the automated treatment 

process, there is potential for indirect inhalation exposure. Exposures for these various scenarios 

are assessed using HED ExpoSAC Policy/Guidance “Assessment of Occupational Exposure for 

Post-Harvest Commodity Pesticide Treatments” (M. Crowley, 23-MAR-2012).

HED classifies exposures from 1 to 30 days as short-term and exposures 30 days to six months 

as intermediate-term. For pyrimethanil, based on the proposed use pattern, short- and 

intermediate-term exposures are expected. In addition, the short- and intermediate-term PODs 

are the same; therefore, estimates for short-term durations are protective of longer-term exposure 

durations.

The short- and intermediate-term risk estimates are not of concern (i.e., MOEs ≥100) at baseline 

(i.e., t-shirt and no gloves and no respirator) for all post-application exposure activities.
Pyrimethanil Human Health Risk Assessment DP# 417167 

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Table 9.2.1. Occupational Post-application Non-Cancer Exposure and Risk Estimates for Pyrimethanil.

Crop/Site Activities

Max App. 

Rate

(% ai in 

solution)

Dermal Inhalation Combined 

Unit 

Exposure 

(μg/% ai)1 Dose

(mg/kg/day)2 MOE3

Unit 

Exposure 

(μg/% ai)1 Dose

(mg/kg/day)4 MOE5 MOE6

Mitigation 

Level

Mitigation 

Level

Pomegranates

Sorter

0.1

T-shirt/NG: 

21,600

T-shirt/NG: 

0.0139 1,700 NR 6,720 NR 0.0085 NR 2,700 T-shirt/NG and NR 1,000

Packer T-shirt/NG: 

15,300

T-shirt/NG: 

0.0098 2,400 NR 6,760 NR 0.0085 NR 2.700 T-shirt/NG and NR 1,300

1. Based on Table 2 in ExpoSAC Policy/Guidance “Assessment of Occupational Exposure for Post-Harvest Commodity Pesticide Treatments” 

(M. Crowley, 23-MAR-2012); Level of mitigation: T-shirt/NG = t-shirt and no gloves; NR = no respirator.

2. Dermal Dose = [Unit Exposure (μg/% ai) * Application Rate (% ai in solution) * Adjustment Factor (0.001 μg/mg)] ÷ Body Weight (80 kg).

3. Dermal MOE = Dermal POD (23.1 mg/kg/day)/Dermal Dose.

4. Inhalation Dose = [Unit Exposure (μg/% ai) * Application Rate (% ai in solution) * Adjustment Factor (0.001 μg/mg)] ÷ Body Weight (80 

kg).

5. Inhalation MOE = Inhalation POD (23.1 mg/kg/day)/Inhalation Dose.

6. Total MOE = NOAEL (23.1 mg/kg/day) ÷ (Dermal Dose + Inhalation Dose).

Table 9.2.2. Occupational Post-application Non-Cancer Indirect Inhalation Exposure and Risk Estimates for 

Pyrimethanil.

Crop/Site Max App. Rate

(% ai in solution)

Inhalation

Unit Exposure (μg/% ai)1

Inhalation Dose

(mg/kg/day)2 MOE3

Mitigation Level

Pomegranates 0.1 NR 307 NR 0.0004 NR 60,000

1. Based on Table 4 in ExpoSAC Policy/Guidance “Assessment of Occupational Exposure for Post-Harvest Commodity Pesticide Treatments” 

(M. Crowley, 23-MAR-2012); Level of mitigation: NR = no respirator.

2. Inhalation Dose = [Unit Exposure (μg/% ai) * Application Rate (% ai in solution) * Adjustment Factor (0.001 μg/mg)] ÷ Body Weight (80 

kg)].

3. Inhalation MOE = Inhalation POD (23.1 mg/kg/day)/Inhalation Dose.

10.0 References

 Toxicity Profile Tables.

 Metabolism Assessment.

RDI: G. Kramer (21-JUL-2014); RAB1 (23-JUL-2014); C. Smith (23-JUL-2014)

J. Tyler:S10943:PY1:(703)-851-5825(7509P)
Pyrimethanil Human Health Risk Assessment DP# 417167 

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Appendix A: Toxicity Profile Tables.

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food and non-food uses for pyrimethanil are in Table 

A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols 

were used.

Table A.1. Toxicological Data Requirements for Pyrimethanil.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation ..............................................

870.2600 Dermal Sensitization......................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

870.3150 Oral Subchronic (nonrodent).........................................

870.3200 21-Day Dermal ..............................................................

870.3250 90-Day Dermal ..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

no

no

no

yes

yes

no

no

no

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (nonrodent).............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200b Oncogenicity (mouse)....................................................

870.4300 Chronic/Oncogenicity (rat)............................................

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5100 Mutagenicity—Gene Reverse Mutation - bacterial .......

870.5300 Mutagenicity—Gene Mutation - mammalian................

870. 5395 Mutagenicity—Micronucleaus Assay in Bone Marrow

870. 5550 Mutagenicity—Unscheduled DNA Synthesis..............

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)...............................

870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotoxicity Screening Battery (rat) .................

870.6200b 90-Day Neurotoxicity Screening Battery (rat)...............

870.6300 Develop. Neurotoxicity .................................................

no

no

yes

yes

no

no

no

yes

yes

-

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity .............................................................

yes

yes

yes

yes

yes

yes

Table A.2. Acute Toxicity Profile – Pyrimethanil.

Guideline No./Study Type MRID No. Results Toxicity 

Category

870.1100/Acute oral toxicity

43345002

LD50 = 4149 mg/kg, M 5971 

mg/kg, F

III

870.1200/Acute dermal toxicity 43345003 LD50 >5000 mg/kg IV

870.1300/Acute inhalation toxicity 43301604 LC50 >1.98 mg/L III

870.2400/Primary eye irritation 43345004 slight eye irritant IV

870.2500/Primary dermal irritation 43345005 non irritant IV

870.2600/Dermal sensitization 43301605 not a sensitizer

Table A.3. Toxicity Profile for Pyrimethanil.
Pyrimethanil Human Health Risk Assessment DP# 417167 

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Guideline No./Study Type MRID, (year)/

Classification/Doses Results

870.3100(a)

90-Day Oral Toxicity (rat) 

43345006

43301608 (1990, 1992)/

acceptable/guideline

0, 80, 800, 8000 ppm

0/0, 5.4/6.8, 54.5/66.7, 

529.1/625.9 mg/kg/day [M/F]

NOAEL = 54.5 mg/kg/day [M], 66.7 mg/kg/day [F].

LOAEL = 529.1 mg/kg/day [M], 625.9 mg/kg/day [F] based on 

body weights (20%), body-weight gain(30%), food consumption, 

brown urine,  urinary protein;  abs. heart, adrenal, spleen, 

thymus weights;  rel. liver, kidney, gonad weights, liver, thyroid 

hypertrophy.

870.3100(b)

90-Day Oral Toxicity (mouse)

43301606 (1991)

acceptable/guideline

0, 80, 900, 10,000 ppm

0/0, 12/18, 139/203, 1864/2545 

mg/kg/day [M/F]

NOAEL = 139 [M] mg/kg/day, 203 [F] mg/kg/day.

LOAEL = 1864 [M] and 2545 [F] mg/kg/day based on  bodyweight gain (7-12%), cholesterol, bilirubin [F/M], dark thyroids, 

rel. liver weights, kidney, thyroid, bladder histopathology.

870.3150

90-Day Oral Toxicity (dog)

43301610 (1991)

acceptable/guideline

0, 6, 80, 1000/800 mg/kg/day 

[M/F]

NOAEL = 80 mg/kg/day.

LOAEL = 1000/800 mg/kg/day based on  water consumption, 

vomiting, diarrhea, salivation, hypoactivity.

870.3700(a)

Developmental Toxicity (rat)

43301617

43345018

43301619 (1991)

acceptable/guideline

0, 7, 85,1000 mg/kg/day

NOAEL = Maternal: 85 mg/kg/day.

Developmental: 85 mg/kg/day.

LOAEL = Maternal: 1000 mg/kg/day based on  body weight, and 

body-weight gain.

Developmental: LOAEL = 1000 mg/kg/day based on  in mean 

litter weight and mean fetal weight.

870.3700(b)

Developmental Toxicity (rabbit)

43301620

43301621

43301622 (1991)

acceptable/guideline

0, 7, 45, 300 mg/kg/day

NOAEL = Maternal: 45 mg/kg/day.

Developmental NOAEL = 45 mg/kg/day.

LOAEL = Maternal: 300 mg/kg/day based on deaths,  body wt, 

body-weight gain, food consumption, production, and size of fecal 

pellets.

Developmental: 300 mg/kg/day based on deaths,  body weight, 

body-weight gain, food consumption, production and size of fecal 

pellets fetal weight,  fetal runts, retarded ossification, 13 

thoracic vertebrae and pairs of ribs.

870.3800

Two-Generation Reproduction 

and Fertility Effects (rat)

43301623 (1993)

acceptable/guideline

0, 32, 400, or 5000 ppm

0/0,1.9/2.2,23.1/27.4, 294/343 

mg/kg/day [M/F]

NOAEL = Systemic: 23.1 [M] mg/kg/day, 27.4 mg/kg/day [F].

Repro: 294/343 mg/kg/day. 

Offspring: 23.1 mg/kg/day [M], 27.4 mg/kg/day [F].

LOAEL = Systemic: 294 mg/kg/day [M], 343 mg/kg/day [F] 

based on  body weight (11-13%), and body-weight gain (11-

17%).

Repro: >294/343 mg/kg/day.

Offspring: 294 mg/kg/day based on  pup body weights on PND 

21.

870.4100b

Chronic Toxicity (dog)

43345007

43301614 (1992)

acceptable/guideline

0, 2, 30, 400/250 mg/kg/day

NOAEL = 30 mg/kg/day.

LOAEL = 250 mg/kg/day based on  body weight, food & water 

consumption, food efficiency, neutrophils,  clotting time.

870.4200b

Carcinogenicity (mouse)

43301615 (1992)

unacceptable/guideline

0, 16, 160, 1600 ppm

0/0, 2/2.5, 20/24.9, 210.9/253 

mg/kg/day

[M/F]

NOAEL = 210.9 mg/kg/day [M], 253.8 mg/kg/day [F].

No toxicologically significant effects were found.

870.4200b

Carcinogenicity (mouse)

48046301 (2010)

acceptable/guideline

0 (2 groups), 3,500, or 7,000 

ppm (equivalent to 0, 0, 

477/594, 984/1217 mg/kg 

bw/day [M/F])

NOAEL = 477/594 mg/kg/day [M/F]. 

LOAEL = 984/ 1217 mg/kg/day based on increased livers weights 

(both absolute and relative) in both males and females and 

increased thyroid colloidal alteration mainly in males at the high 

dose. There were no compound related carcinogenic effects seen 

in this study. 

870.4300

Combined 

Chronic/Carcinogenicity (rat)

43301612-3 (1993)/

acceptable/guideline

0, 32, 400, 5000 ppm

0/0, 1.3/1.8, 17/22, 221/291 

mg/kg/day

[M/F]

NOAEL = 17 mg/kg/day [M], 22 mg/kg/day [F].

LOAEL = 221 mg/kg/day [M], 291 mg/kg/day [F] based on 

body-weight gain (5-15% [M]; 15-45% [F])

[10-15%@ 6 months], serum cholesterol, GGT, rel. liver weights; 

liver, thyroid histopathology [ thyroid adenomas].

870.5100

Gene Mutation

43301624 (1990);

0, 15, 50, 150, 500, or 1500 

μg/plate in the presence and 

absence of mammalian 

metabolic activation (S9-mix)

Acceptable/Guideline

There was no evidence of induced mutant colonies over 

background.

870.5300

Gene Mutation

43301625 (1991);

0, 15, 50, 150, 500, or 1500 

There was no clear evidence of biologically significant induction of 

mutant colonies over background.
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Table A.3. Toxicity Profile for Pyrimethanil.

Guideline No./Study Type MRID, (year)/

Classification/Doses Results

μg/plate in the presence and 

absence of mammalian 

metabolic activation (S9-mix)

Acceptable/Guideline

870.5375

Chromosome aberration

43301627 (1990);

0, 7.8, 31.3, or 62.5 μg/mL 

without metabolic activation 

(S9-mix) and to concentrations 

of 0, 31.3, 125, or 250, μg/mL 

with S9-mix. 

Acceptable/Guideline

There was no evidence of chromosome aberrations induced over 

background.

870.5395

Mammalian erythrocyte 

micronucleus test in mice

43301626 (1991); 

0, 225, 450, or 900 mg/kg body 

weight

Acceptable/Guideline

There was no statistically significant increase in the frequency of 

micronucleated polychromatic erythrocytes in mouse bone marrow 

at any dose or harvest time.

870.5550

Unscheduled DNA synthesis in 

mammalian culture

43301628 (1991)

0, 100, 300, or 1000 mg/kg 

body weight

Acceptable/Guideline

Negative in inducing unscheduled DNA synthesis in rat 

hepatocytes as a result of in vivo gastric intubation.

870.6200a

Acute-Neurotoxicity Screening 

Battery (rat)

45657221

45657220 (2001)

acceptable/guideline

0, 30, 100, 1000 mg/kg/day

NOAEL = 100 mg/kg/day [M], 100 mg/kg/day [F].

LOAEL = 1000 mg/kg/day [M], 1000 mg/kg/day [F] based on 

motor activity, ataxia, and body temperature in both sexes, 

hindlimb grip strength in males, and  dilated pupils in females on 

Day 1. 

870.6200b

Subchronic-Neurotoxicity 

Screening Battery (rat)

45657222 (1998)

Acceptable/Guideline

0, 60, 600, 6000 ppm

0/0, 4/4.6, 38.7/44.3, 

391.9/429.9 mg/kg/day [M/F]

The systemic NOAEL = 6000 ppm (391.9/429.9 mg/kg/day [M/F]) 

A LOAEL for systemic toxicity was not observed.

The neurotoxicity NOAEL is 6000 ppm (391.9/429.9 mg/kg/day 

[M/F]). 

A LOAEL for neurotoxicity was not observed.

870.7465

Metabolism and 

Pharmacokinetics

43301629 (1991), 

10 mg/kg (28 days consecutive 

days) [M]

acceptable/guideline

43345009 (1993), 

11.8 mg/kg or 800 mg/kg (single 

dose), 10 mg/kg/day (14 days 

repeated dosing) [M/F]

acceptable/guideline

43750101 (1995)

10 mg/kg [M/F] (single dose)

Acceptable/guideline

At a dose level of 10 mg/kg, pyrimethanil was eliminated within 24 

hours, and the major route of elimination was via the urine [72%]. 

Approximately 17-18% of the dose was eliminated via the feces. 

Radiolabel was detected only in the liver, kidney, and blood at study 

termination [24 hours post dose]. The highest residue was displayed 

in the liver in both sexes. There was no significant sex difference. 

The overall recovery of radiolabel was 91%. Detectable levels of 

radiolabel were found in the adrenals, blood, kidney, liver, spleen, and 

thyroid following exposure. Only the blood and liver displayed 

detectable levels of radiolabel after a single dose [24-hour sample]. 

Four days after the last dose, detectable levels of radiolabel were 

found only in the liver, kidney, and thyroids. It appears that the levels 

in the blood, kidney, and thyroid would continue to increase with 

increased exposure time, while the level in the adrenal appears to have 

reached a plateau, and that in the liver appears to be declining. The 

main pathways of metabolism involved oxidation to phenols in either 

or both aromatic rings, and the minor pathways involved oxidation of 

the methyl group to the corresponding alcohol. Minor differences 

were observed between the high- and low-dose exposures, the single 

low- and repeat low-dose exposures, and between the sexes, but none 

appear to be of any toxicological significance.

870.7600

Dermal Penetration

46630101 (2005)

Acceptable/guideline

0.6, 6.0, and 60 μg ai/cm2

The dermal-absorption value at 10 hours is 51.2%. This value is 

very similar to 60% absorption (57.20% absorbed dose plus 2.77% 

potentially absorbable dose) for which the skin site was washed 

after 10 hours, and which were sacrificed after 120 hrs. Therefore, 

using the 51% dermal absorption value for dermal exposure 

assessment for human risk is conservative and considered 

protective.

870.7800

Immunotoxicity

48263901 (2010)

0, 80, 800, or 8000 ppm (0, 6.9, 

69.5, or 652 mg/kg bw/day, 

respectively [F])

Immunotoxicity NOAEL = 8000 ppm (652 mg/kg/day).

Immunotoxicity LOAEL is not established.
Pyrimethanil Human Health Risk Assessment DP# 417167 

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Table A.3. Toxicity Profile for Pyrimethanil.

Guideline No./Study Type MRID, (year)/

Classification/Doses Results

Acceptable/Guideline
Pyrimethanil Human Health Risk Assessment DP# 417167 

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Appendix B: Metabolism Assessment.

Table B.1. Pyrimethanil Metabolites of Concern.

Common name/

ID No. Chemical name Chemical structure

AE C614276 4-[4,6-dimethyl-2-

pyrimidinyl)amino]phenol

AE C614277 4,6-dimethyl-2-(phenylamino)-5-

pyrimidinol

Degradate 1 2-amino-4,6-dimethylpyrimidine.

N

H

N

N CH3

CH3

HO

N

H

N

N CH3

CH3

OH

H2N

N

N CH3

CH3