UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

W ASHTNGTON, D.C. 20460 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: 

Subject: 

PC Code: 

Decision Nos.: 

Petition Nos.: 

22-SEP-2015 

Pyrimethanil. Human Health Risk Assessment for Proposed Uses on 

Greenhouse-Grown Cucumbers, Tomato Subgroup 8-IOA, Lemon Subgroup 10-

l OB, Orange Subgroup I 0-1 OA, Grapefruit Subgroup l 0-1 OC, Pome Fruit Group 

11-10, Stone Fruit Group 12- 12 Caneberry Subgroup 13-07 A, and Bushberry 

Subgroup l 3-07B. 

288201 

492391 & 493505 

4F8291 & 4E8302 

DP Barcode: 

Registration Nos.: 

Regulatory Action: 

0428262 

264-788 & 43813-32 

Section 3 

Risk Assessment Type: Single Chemical/Aggregate Assessment 

None 

Case No.: 7059 

TXR No.: 

MRID No.: 

From: 

Through: 

To: 

None 

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

CASNo.: 

40CFR 

53 112-28-0 

§ 180.5 18 

Jennifer R. Tyler, Chemist /} / 

Anwar Y. Dunbar, Ph.D., Pharmacologist ~ ~Y~ Risk Assessment Branch 1 (RAB I )/Health Effectffii ion (HED; 7509P) 

Thurston G. Morton, Acting Branch Chief !"'/}/ !~ /r 

RAB l/HED (7509P) ~V/)/'t / 

Hope Johnson/Cynthia Giles-Parker, RM 2 1 

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). The Interregional Research Project No. 4 (IR-4) and Bayer CropScience have 

submitted petitions for the use of pyrimethanil on cucumbers (greenhouse-grown), tomato 

subgroup 8-1 OA, lemon subgroup 10-1 OB, orange subgroup 10-1 OA, grapefruit subgroup 10-

l OC, pome fruit group l l-10, stone fruit group 12-1 2, caneberry subgroup 13-07 A, and 

bushberry subgroup l 3-07B. The risk assessment, residue chemistry review, and dietary 

exposure assessment were conducted by George Kramer (RABI); occupational/residential 

exposure assessment were provided by Jennifer Tyler (RABI); the hazard characterization by 

Anwar Dunbar (RAB I); and the drinking water assessment by James Wolf of the Environ.mental 

Fate and Effects Division (EFED). 

NOTE: A human health risk assessment was completed on 28-JAN-2015 by HED (Memo, J. 

Tyler el al. , D417167). In the present memo, dietary, occupational, and aggregate risks were rePage I of32 
Pyrimethanil Human Health Risk Assessment DP# 428262 

evaluated based on the addition of the proposed new uses to the pyrimethanil use pattern. 

Table of Contents 

1.0 Executive Summary 

2.0 HED Recommendations 

2.1 Data Deficiencies/Conditions of Registration 

2.2 Tolerance Considerations 

3.0 Introduction 

3.1 Chemical Identity 

3. 2 Physical/Chemical Characteristics 

3.3 Pesticide Use Pattern 

3.4 Anticipated Exposure Pathways 

3.5 Consideration of Environmental Justice 

4.0 Hazard Characterization and Dose Response Assessment 

4. 1 Summaty of Toxicological Effects 

4.2 Safetyfactorfor Infants and Children (FQPA Safety Factor) 

4.3 Toxicity Endpoint and POD Selections 

5.0 Dietary Exposure and Risk Assessment 

5.1 Residues of Concern Summ01y and Rationale 

5.2 Food Residue Profile 

5.3 Water Residue Profile 

5.4 Diet01y Risk Assessment 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization 

6.1 Spray Drift 

6.2 Residential Bystander Post-Application Inhalation Exposure 

7 .0 Aggregate Exposure/Risk Characterization 

7. 1 Acute Aggregate Risk 

7.2 Short- and Intermediate-Term Aggregate Risk 

7. 3 Chronic Aggregate Risk 

7. 4 Cancer Risk 

8.0 Cumulative Risk Characterization/Assessment 

9.0 Occupational Exposure/Risk Pathway 

9. 1 Handler Exposure and Risk Estimates 

9.2 Post-application Exposure and Risk Estimates 

9.3 Restricted-Entry Interval (REI) 

10.0 References 

Appendix A: Toxicity Profile Tables. 

Appendix B: Metabolism Assessment. 

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9 

9 

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10 

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JI 

12 

13 

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Pyrimethanil Human Health Risk Assessment DP# 428262

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1.0 Executive Summary

IR-4 has submitted a petition for the use of Scala® SC Fungicide (EPA Reg. No. 264-788), an 

aqueous suspension-concentrate (SC) formulation containing 5.0 lbs/gal of pyrimethanil on the 

cucumbers (greenhouse-grown), tomato subgroup 8-10A, lemon subgroup 10-10B, orange 

subgroup 10-10A, grapefruit subgroup 10-10C, pome fruit group 11-10, and stone fruit group 12-

12 (PP# 4E8302).. No new data were submitted to support tolerances on tomato subgroup 8-

10A, lemon subgroup 10-10B, pome fruit group 11-10, orange subgroup 10-10A, grapefruit 

subgroup 10-10C, and stone fruit group 12-12. The petitioner has requested that existing 

tolerances be expanded to their respective crop groups or crop subgroups. Bayer CropScience 

has submitted a petition for the use of Scala® SC Fungicide on caneberry subgroup 13-07A and 

bushberry subgroup 13-07B (PP# 4F8291). 

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 New Uses: The proposed new use on greenhouse-grown cucumbers is as a foliar 

application three times per season at 0.70 lbs ai/A with a maximum of 2.1 lbs ai/A/season and a 

preharvest interval (PHI) of 1 day. The proposed new use to caneberries and bushberries is as a 

foliar application 2-4 times per season at 0.35-0.70 lbs ai/A with a maximum of 1.4 lbs 

ai/A/season and a PHI of 1 day.

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 database 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 
Pyrimethanil Human Health Risk Assessment DP# 428262

Page 4 of 32

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

potential 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. 

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 high-performance liquid chromatography (HPLC) with 

tandem mass spectroscopy (MS/MS) Method 140/01/012. There are also adequate methods 

available to enforce tolerances for residues of pyrimethanil in/on crops. The submitted field trial 

residue data for the subject crops 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. 

Drinking Water Exposure and Risk: Surface and ground estimated drinking water concentrations 

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

were generated by EFED using the Surface Water Concentration Calculator (SWCC) and 

Pesticide Root Zone Model-Ground Water (PRZM-GW) models, respectively. In this 

assessment, the 1-in-10-year annual average surface water concentration (27.9 ppb) and the 1-in10-year acute peak surface water concentrations (156 ppb) were used for chronic and acute 

dietary exposure assessments, respectively.

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

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 for direct and 

indirect water sources. The resulting acute dietary risk estimates (food and drinking water) were 

≤40% 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 ≤80% of the chronic populationadjusted 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). 

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).
Pyrimethanil Human Health Risk Assessment DP# 428262

Page 5 of 32

Occupational Exposure/Risk: Based on the anticipated use patterns and current labeling, shortand intermediate-term dermal and inhalation exposures occupational handler exposures are 

expected from the proposed uses. A margin of exposure (MOE) ≥ 100 is adequate to protect 

occupational pesticide handlers from dermal and inhalation exposures. Risk estimates for all 

scenarios are not of concern at either baseline or with the addition of personal-protective 

equipment (PPE; up to and including label-prescribed PPE which includes chemical-resistant 

gloves and headgear), except for applying broadcast sprays via mechanically-pressurized 

handguns to greenhouse-grown cucumbers. For this scenario, risk estimates are not of concern 

assuming a double layer of clothing and chemical-resistant gloves are worn, which is the highest 

level of PPE for which exposure data are available for this scenario. Exposure data are not 

available to assess the impact of chemical-resistant headgear for handheld equipment. 

HED expects that post-application dermal exposure will occur since pyrimethanil is applied as a 

foliar spray. An occupational post-application dermal exposure assessment was conducted 

previously in conjunction with a request for the use of pyrimethanil on small fruit, vine climbing 

13-07F and low growing berry 13-07G (Memo, J. Tyler, 08-MAY-2012; D389987). The postapplication dermal exposures in the 08-MAY-2012 assessment were calculated for postapplication activities with the highest (i.e., most conservative) transfer coefficients (TCs) 

(girdling and turning of grapes). In addition, the proposed use pattern for caneberry crop group 

13-07A, bushberry crop subgroup 13-07B are identical to that of small fruit, vine climbing 13-

07F and low growing berry 13-07G. Therefore, the 5/8/2012 post-application dermal exposure 

assessment is adequate to cover the proposed uses on caneberry, crop group 13-07A, and 

bushberry, crop subgroup 13-07B. In that assessment, the short- and intermediate-term risk 

estimates are not of concern (i.e., MOEs ≥100) on the day of treatment (i.e., Day 0) for all postapplication exposure activities. 

For greenhouse cucumbers, the occupational post-application risk estimates are of concern (i.e., 

MOEs <100) on the day of application (12 hours after application) for high-contact activities 

such as hand harvesting, pinching, hand pruning, tying, etc. These activities are not of concern 

at 48 hours after application. For low-contact activities (such as transplanting and irrigation), 

risk estimates are not of concern on the day of application. 

Based on the Agency's current practices, a quantitative non-cancer occupational post-application 

inhalation exposure assessment was not performed for pyrimethanil at this time. If new policies 

or procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for pyrimethanil.

The Worker Protection Standard (WPS) for Agricultural Pesticides contains requirements for 

protecting workers from inhalation exposures during and after greenhouse applications through 

the use of ventilation requirements [40 CFR 170.110, (3) (Restrictions associated with pesticide 

applications)].

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 
Pyrimethanil Human Health Risk Assessment DP# 428262

Page 6 of 32

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 Agricultural Reentry 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

Pending submission of a revised Sections B and F, 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. 

2.1 Data Deficiencies/Conditions of Registration

No additional data are required to support the proposed use.

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)

Cucumber 1.5 1.5

Orange subgroup 10-10A 10 10 Harmonization with Canada.

Fruit, citrus, group 10-10 Lemon subgroup 10-10B 11

Grapefruit subgroup 10-10C 10

Fruit, pome, group 11-10 14 15 Harmonization with Codex.

Fruit, stone, group 12-12 10 10

Tomato, subgroup 8-10A 0.50 0.50

Caneberries subgroup 13-07A 15.0 15 Caneberry, subgroup 13-07A

Bushberries subgroup 13-07B 8.0 8.0 Bushberry, subgroup 13-07B
Pyrimethanil Human Health Risk Assessment DP# 428262

Page 7 of 32

Note to RD: With the establishment of these tolerances, the following tolerances should be 

removed from 40 CFR §180.518 (a)(1): "Fruit, citrus, group 10, except lemon, postharvest," 

"Lemon, preharvest and postharvest," "Fruit, pome, group 11 (pre-harvest and post-harvest)," 

"Fruit, stone, group 12," and "Tomato." Also, the tolerance in 40 CFR §180.518(a)(1) for 

residues of pyrimethanil in/on onion, bulb, subgroup 3-07A (2.0 ppm) does not match the 

recommended tolerance from a previous assessment (Memo, Tyler et al., 22-MAY-2013; 

D389923). HED recommended for a tolerance of 0.20 ppm for residues of pyrimethanil in/on 

onion, bulb, subgroup 3-07A.

2.2.3 Revisions to Petitioned-For Tolerances

For some commodities, the proposed tolerance levels differ slightly from those being 

recommended by HED. In the case of pome fruit, HED is recommending a higher tolerance 

level in order to harmonize with the established Canadian maximum residue limit (MRL). In the 

case of citrus fruit, HED is recommending for a single crop-group tolerance, instead of the 

individual subgroups in order to harmonize with the established Canadian MRL. In addition, 

HED is recommending a change in the numerical expression of the caneberry subgroup 13-07A 

tolerance value in order to conform to current HED policy on significant figures. 

2.2.4 International Harmonization

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

proposed tolerances for residues in/on caneberry, crop subgroup 13-07A and bushberry, crop 

subgroup 13-07B are harmonized with the established Canadian MRLs. The U.S. tolerance for 

residues in/on tomato (0.50 ppm for the tomato subgroup 8-10A) is harmonized with the 

Canadian MRL, while the Codex MRL is established at a higher level (0.7 ppm). However, 

Bayer CropScience has requested that EPA not harmonize with Codex in order to prevent the 

creation of a trade barrier with Canada. The U.S. and Codex tolerances/MRLs for residues of 

pyrimethanil in/on citrus are not harmonized. Residues in the U.S. residue trials (maximum of 

8.43 ppm) were higher than the Codex MRL of 7 ppm, precluding harmonization. The U.S. and 

Canadian tolerances/MRLs for residues of pyrimethanil in/on citrus are harmonized, except for 

the lemon subgroup 10-10B. In order to harmonize with Canada, HED recommends that the 

U.S. tolerance for residues in/on the lemon subgroup 10-10B be reduced from 11 to 10 ppm. As 

this value is the same as that recommended for the other citrus subgroups, a single tolerance of 

10 ppm is appropriate for residues in/on fruit, citrus, group 10-10. The U.S. and Codex 

tolerances/MRLs for residues of pyrimethanil in/on stone fruit are not harmonized. Residues 

were higher in the U.S. residue trials (maximum of 6.5 ppm) than the Codex MRLs of 2-4 ppm, 

precluding harmonization. The U.S. and Canadian tolerances/MRLs for residues of pyrimethanil 

in/on stone fruit are harmonized at 10 ppm. The U.S. and Codex tolerances/MRLs for residues 

of pyrimethanil in/on the pome fruit group are not harmonized. As the difference in values is 

minimal, HED recommends that the U.S. tolerance be increased from 14 to 15 ppm in order to 

harmonize with Codex. There are currently no established Codex, Canadian, or Mexican MRLs 

for pyrimethanil in/on cucumber. 

2.3 Label Recommendations

Short- and intermediate-term post-application risk estimates were not a concern on day 0 (12 

hours following application) for low-contact activities, such as transplanting and irrigation. 
Pyrimethanil Human Health Risk Assessment DP# 428262

Page 8 of 32

However, there were risk estimates of concern related to high-contact activities up until 48 hours 

after application; therefore, HED is recommending that the REI be revised on the label to address 

these concerns. In addition, there are risk estimates of concern for applicators 

mixing/loading/applying broadcast sprays via a mechanically-pressurized handgun to 

greenhouse-grown cucumbers assuming the label-prescribed PPE, which included chemicalresistant gloves and headgear. For this scenario, risk estimates are not of concern assuming a 

double layer of clothing and chemical-resistant gloves are worn. Even though the label also 

requires chemical-resistant headgear, there are no exposure data available to assess the reduction 

in exposure for handheld equipment. HED is thus recommending that the mechanicallypressurized handgun application scenario for greenhouse-grown cucumbers be revised on the 

label to address these concerns.

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.

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) Scala® SC Fungicide (EPA Reg. No. 264-788)
Pyrimethanil Human Health Risk Assessment DP# 428262

Page 9 of 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 new use patterns. Pyrimethanil is currently 

registered for use on tomato; citrus fruit, group 10, except lemon (postharvest); lemon 

(preharvest and postharvest); pome fruit group 11 (preharvest and postharvest); and stone fruit 

group 12 (preharvest and postharvest). The petitioner has requested that the existing uses be 

expanded to tomato subgroup 8-10A, lemon subgroup 10-10B, pome fruit group 11-10, orange 

subgroup 10-10A, grapefruit subgroup 10-10C, and stone fruit group 12-12. The existing 

directions for use for these crops are unchanged, other than the additional crops covered by the 

updated groups/subgroups. Detailed reviews of the directions for use for these crops can be 

found in previous HED reviews (D361363, 08-APR-2009, G. Kramer; D347247, 17-JUL-2008, 

G. Kramer; D369788, 08-DEC-2009, G. Kramer; and D284001, 12-JAN-2004, J. Morales and G. 

Kramer).

Table 3. Summary of Directions for Use of Pyrimethanil.

Applic. Timing, 

Type, and 

Equip.

Formulation

(EPA Reg. 

No.)

Applic. 

Rate

(lbs ai/A)

Max. No. 

Applic. per 

Season

Max. Seasonal 

Applic. Rate

(lbs ai/A)

PHI

(days)

Use Directions and 

Limitations

Cucumber

Greenhouse 

only

Scala® SC 

Fungicide 

(EPA Reg. No. 

264-788)

0.70 3 2.1 1

Retreatment interval: 7-14 

days.

Small Berries (caneberries and bushberries)

Ground or air 

Scala® SC 

Fungicide 

(EPA Reg. No. 

264-788)

0.35-0.70 4 1.4 0

Retreatment interval: 7-14 

days.

HED Conclusions: The submitted label is adequate to allow evaluation of the cucumber, 

caneberry, and bushberry residue data relative to the new proposed uses.
Pyrimethanil Human Health Risk Assessment DP# 428262

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3.4 Anticipated Exposure Pathways

RD has requested an assessment of human health risk to support the proposed new uses of 

pyrimethanil on cucumber, caneberry, and bushberry. 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 is not expected. In an occupational setting, applicators 

may be exposed while handling the pesticide prior to application, as well as during application. 

There is also a potential for post-application exposure for workers re-entering treated fields. 

This risk assessment considers all of the aforementioned exposure pathways based on the 

proposed new uses of pyrimethanil and considers the existing registered uses as well for the 

dietary and residential 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://epa.gov/compliance/ej/resources/policy/exec_order_12898.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 U.S. Department of 

Agriculture (USDA) under the National Health and Nutrition Examination Survey, What We Eat 

in America, (NHANES/WWEIA); 2003-2008 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 

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

The toxicology database for pyrimethanil is 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, 08-FEB-2013; TXR# 

0056470). 
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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 approximately

51%. 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 

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 mice 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 
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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 potential 

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 selected endpoints for pyrimethanil protect for any potential signs of neurotoxicity;

therefore, the concern for neurotoxicity is low. 

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.
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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 glutamyl 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 selected.

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 decreased body weights 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 for MOEs less than 100 (10X for inter-species extrapolation and 10X for 

intra-species extrapolation). This study protects for the effects in the pyrimethanil hazard 

database. It is appropriate for the route as well as the durations of exposure in occupational 

settings.

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 
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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 for MOEs less than 100 (10X for 

inter-species extrapolation and 10X for intra-species extrapolation). This study protects for the 

effects in the pyrimethanil hazard database. It is appropriate for the route as well as the durations 

of exposure in occupational settings.

Table 4.3.1. Summary of Toxicological Doses and Endpoints for Pyrimethanil for Use in Dietary Exposure 

Risk Assessments.

Exposure/

Scenario POD Uncertainty/FQPA Safety Factors

RfD, PAD, LOC for 

Risk Assessment Study and Toxicological Effects

Acute Dietary

(Females 13-

49 years of 

age)

NOAEL = 

45 

mg/kg/day

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/day

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/day

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) 

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment

(March 2005), the 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-2012).

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. 
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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 Uncertainty/FQPA Safety Factors

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%)

UFA = 10X

UFH = 10X

FQPA SF = 1X

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) 

Term Inhalation

Oral NOAEL = 

23.1 mg/kg/day 

(inhalation 

absorptionb = 

100%)

UFA = 10X

UFH = 10X

FQPA SF = 1X

Occupational 

LOC for MOE = 

100

Reproductive Toxicity - Rat:

LOAEL = 294 mg/kg/day based on 

decreased mean body weights and 

body-weight gains.

Cancer (oral, 

dermal, inhalation)

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

the 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-2012).

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. MOE = 

margin of exposure. LOC = level of concern. a= dermal-absorption factor, from MRID 46630101. b= Inhalationabsorption 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-2012). 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 
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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. 

5.0 Dietary Exposure and Risk Assessment

The residue chemistry data submitted in support of proposed uses were evaluated by HED 22-

SEP-2015 (Memo, G. Kramer; D421844). The drinking water assessment was completed by 

EFED on 14-MAY-2015 (Memo, J. Wolf; D422295). The dietary exposure assessment was 

completed in a HED memorandum dated 22-SEP-2015 (Memo, G. Kramer; D424861).

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

No new data were submitted to support tolerances on tomato subgroup 8-10A, lemon subgroup 

10-10B, pome fruit group 11-10, orange subgroup 10-10A, grapefruit subgroup 10-10C, and 

stone fruit group 12-12. The petitioner has requested that existing tolerances be expanded to 

their respective crop groups or crop subgroups. The residue data for caneberries and bushberries 

were previously submitted and reviewed under PP#8F7468 (Memo, W. Cutchin, 02-FEB-2010; 

D372647). 

The data-collection method used to generate the cucumber residue data was an HPLC-MS/MS 

Method 140/01/012. 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 

pyrimethanil tolerances on the subject crops. 

The cucumber samples analyzed in this study were held in frozen storage for a maximum of 139 

days prior to analysis of pyrimethanil residues. There are adequate concurrent storage stability 
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data to indicate that pyrimethanil residues are stable in/on cucumber for the duration of this 

study.

The submitted field trial residue data for greenhouse-grown cucumbers 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. Pertrial-average-residues of pyrimethanil ranged 0.07 ppm to 0.82 ppm in/on five cucumber trials 

with samples harvested at a 1-day PHI (highest individual residue of 0.83 ppm) from the five 

trials. Using the Organization for Economic Co-operation and Development (OECD) tolerancecalculation procedures for the residue data set indicates that the requested tolerance of 1.5 ppm 

for residues of pyrimethanil in/on cucumber is appropriate. 

There are no new uses proposed for crops with associated livestock food/feed items of regulatory 

concern; therefore, a discussion of livestock residues is not germane to these petitions.

Analytical standards for pyrimethanil, with an expiration date 13-JUL-2018, are currently 

available in the EPA National Pesticide Standards Repository. 

Adequate confined and limited field rotational crop trials are available and support the labelspecified 30-day plant-back interval (PBI) for crops without uses on the Scala® label. The 

available data indicate that tolerances are not currently required for rotational crops.

5.3 Water Residue Profile

EFED studies indicated that pyrimethanil is expected to be moderately persistent in the 

environment. Aerobic metabolism is expected to be the major route of degradation for 

pyrimethanil in the environment. The only major degradate is 2-amino-4,6-dimethylpyrimidine. 

Although it may be less toxic than the parent, 2-amino-4,6-dimethylpyrimidine is expected to be 

more mobile and more persistent in the environment than the parent. MARC recommended that 

parent and 2-amino-4,6-dimethylpyrimidine are the residues of concern for drinking water.

EFED provided EDWCs estimated with the SWCC and PRZM-GW using the maximum 

application rate and number of applications, as there are no monitoring data available for use in 

the human health risk assessment (J. Wolf, 14-MAY-2015; D422295). 

IR-4 has requested to expand the citrus, pome and stone fruit crops for the existing postharvest 

uses for PENBOTEC® 400 SC (EPA Reg. No. 43813-32). 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. 

The screening level drinking water concentrations for combined residues of pyrimethanil (parent 

+ 2-amino-4,6-dimethylpyrimidine) in surface water are not expected to exceed 156 μg/L for the 

peak 1-in-10-year concentration; 27.9 μg/L for the 1-in-10-year annual mean concentration; and, 

21.3 μg/L for the 30-year annual average concentration for the new uses or crop group expansion 

(assuming 2 crops per year1). The screening level drinking water concentrations for combined 

residues of pyrimethanil (parent + 2-amino-4,6-dimethylpyrimidine) in groundwater estimated 

 

1 1 crop per year – peak 68 μg/L; annual average = 18 μg/L, and 30 year average = 13 μg/L.
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with PRZM-GW are 128 μg/L for the highest daily value and 117 μg/L for the post-breakthrough average (Table 2). Current policy is for EFED to recommend the EDWCs for the water 

source with the highest EDWCs, which for pyrimethanil is surface water for acute exposure and 

groundwater for chronic exposure. However, due to generally low leaching (EDWCs and 

incomplete breakthrough) with 100-year simulation in groundwater, the surface water EDWCs 

are recommended for both acute and chronic exposure assessments. The EDWCs for the 

combined residues are presented below in Table 5.3.1. The models and their descriptions are 

available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/. 

Table 5.3.1. Surface Water and Groundwater EDWCs for Pyrimethanil Plus the Degradate (2-amino-4,6-

dimethylpyrimidine) for the Proposed New uses and Crop Group Expansions for Scala® SC Fungicide 

(EPA Reg No. 264-788) Assuming the Maximum Application Rate (3 or 6 applications @ 0.7 lb a.i./A/year).

Standard Scenarios Model Application Rate 1-in-10-Year 30-Year

Surface Water #/lb a.i./A

Peak Annual Mean Mean

(ug/L)

Multiple Scenarios1-6 SWCC 3 @ 0.7/7 per crop 

cycle/2 crop cycles 

1561 27.92 21.33

3 @ 0.7/7 per crop 

cycle/1 crop cycles

67.84 17.55 13.16

Groundwater 

Highest 

Daily Value Post-breakthrough Average

FL Citrus PRZM-GW 3 @ 0.7/7 per crop 

cycle/2 crop cycles

128 117

FL Potato 3 @ 0.7/7 per crop 

cycle/2 crop cycles

25.2 22.7

1 FL Strawberry (2 crop cycles).

2 PA Tomato (2 crops cycles).

3 CA Grape (2 crops cycles).

4 FL Strawberry (1 crop cycle).

5 PA Apple (1 crop cycle).

6 GA Peach (1 crop cycle).

In this assessment, the 1-in-10-year annual average surface water concentration (27.9 ppb) and 

the 1-in-10-year acute peak surface water concentrations (156 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 USDA’s 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 SWCC

surface water model. 
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5.4.2 Acute Dietary Risk Assessment

Using the DEEM-FCID software, dietary risk is estimated at 10% of the aPAD for the general 

U.S. population and 40% 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 15% of the cPAD for the general 

U.S. population and 80% 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.” 

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 0.105357 11 0.024977 15

N/A N/A

All Infants (<1 year old) 0.369251 37 0.090488 53

Children 1-2 years old 0.401904 40 0.136305 80

Children 3-5 years old 0.254739 25 0.082594 49

Children 6-12 years old 0.137476 14 0.038145 22

Youth 13-19 years old 0.065147 6.5 0.016025 9.4

Adults 20-49 years old 0.060961 6.1 0.014440 8.5

Adults 50-99 years old 0.063998 6.4 0.017030 10

Females 13-49 years old 0.063604 14 0.015479 9.1

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.

6.1 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a 
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potential source of exposure from the ground application methods (e.g., groundboom and 

airblast) employed for pyrimethanil. The agency has been working with the Spray Drift Task 

Force (a task force composed of various registrants which was developed as a result of a Data 

Call-In issued by EPA), 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 website for more information).2 The agency has also developed a policy on how to 

appropriately consider spray drift as a potential source of exposure in risk assessments for 

pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during 

the Registration Review process which ensures that all uses for that pesticide will be considered 

concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures 

For Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating 

Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification 

of indirect non-occupational exposure to drift. 

6.2 Residential Bystander Post-Application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

(FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report 

on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analysis is required for pyrimethanil.

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 pyrimethanil 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.

 

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
Pyrimethanil Human Health Risk Assessment DP# 428262

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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. 

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) 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, 21-SEP-2015, D429034).

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 

following scenarios: 1) open mixing/loading SC formulations for aerial, airblast, chemigation,

and groundboom applications; 2) applying sprays via aerial, airblast and groundboom equipment; 
Pyrimethanil Human Health Risk Assessment DP# 428262

Page 22 of 32

3) flagging to support aerial applications; and 4) open mixing/loading/applying SC formulations 

for applications via backpack, manually-pressurized handgun, and mechanically-pressurized 

handgun equipment.

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 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 long-sleeved shirt, long pants, 

shoes plus socks, chemical-resistant gloves made of waterproof material, chemical-resistant 

headgear for overhead exposure.

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

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

inhalation exposures. Risk estimates for all scenarios are not of concern at either baseline or 

with the addition of PPE (up to and including label-prescribed PPE which includes chemicalresistant gloves and headgear), except for applying broadcast sprays via mechanicallypressurized handguns to greenhouse-grown cucumbers. For this scenario, risk estimates are of 

not of concern assuming a double layer of clothing and chemical-resistant gloves are worn, 

which is the highest level of PPE for which exposure data are available for this scenario. 

Exposure data are not available to assess the impact of chemical-resistant headgear for handheld 

equipment. 
Page 23 of 32

Table 9.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Proposed Uses of Pyrimethanil.

Exposure Scenario Crop LOC

Dermal Unit 

Exposure

(μg/lb ai)1

Inhalation Unit 

Exposure

(μg/lb ai)1 Max. App. 

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation Total

Level of PPE Level of PPE Dose (mg/kg/day)4 MOE5 Dose 

(mg/kg/day)6 MOE7 MOE8

Mixer/Loader

Open Mixing/Loading 

Liquids for Aerial 

Applications/Chemigation

Small berries 

(caneberries and 

bushberries)

100

Baseline: 220

PPE-G: 37.6

Baseline: 0.219 0.7 lb ai/A

350 A

Baseline: 0.344

PPE-G: 0.0587

Baseline: 67

PPE-G: 390

Baseline: 

0.000671

Baseline: 

34,000

Baseline: 67

PPE-G: 390

Open Mixing/Loading for 

Airblast Applications

Blackberries, 

highbush 

blueberries, 

raspberries

40 A Baseline: 0.0393 Baseline: 590 Baseline: 

0.0000766

Baseline: 

300,000 Baseline: 590 

Open Mixing/Loading 

Liquids for 

Chemigation/Groundboom 

Applications

Greenhouse 

Cucumbers 60 A Baseline: 0.0589 Baseline: 390 Baseline: 0.000115

Baseline: 

200,000 Baseline: 390

Open Mixing/Loading 

Liquids for Groundboom 

Applications

Blackberries, 

highbush 

blueberries, 

raspberries

40 A Baseline: 0.0393 Baseline: 590 Baseline: 

0.0000766

Baseline: 

300,000 Baseline: 590

Lowbush 

blueberries 80 A Baseline: 0.0784 Baseline: 290 Baseline: 0.000154

Baseline: 

150,000 Baseline: 290

Applicator

Applying Sprays via 

Aerial Equipment

Small berries 

(caneberries and 

bushberries)

100

Eng. Control: 2.08 Eng. Control: 

0.049

0.7 lb ai/A

350 A Eng. Control: 

0.00325 Eng. Control: 7,100 Eng. Control: 0.000015

Eng. 

Control: 

1,500,00

0

Eng. Control: 

7,100

Applying Sprays via 

Airblast Equipment

Blackberries, 

highbush 

blueberries, 

raspberries

Baseline: 1770 

PPE-G: 1590 

PPE-DL/G: 1480

PPE-G/CRH: 215

Baseline: 4.71 40 A

Baseline: 0.316

PPE-G: 0.284

PPE-DL/G: 0.264

PPE-G/CRH: 

0.0384 

Baseline: 73

PPE-G: 81

PPE-DL/G: 88

PPE-G/CRH: 600

Baseline: 

0.0165

Baseline: 

14,000

Baseline: 73 

PPE-G: 81

PPE-DL/G: 87

PPE-G/CRH: 580
Pyrimethanil Human Health Risk Assessment DP# 428262

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Table 9.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Proposed Uses of Pyrimethanil.

Exposure Scenario Crop LOC

Dermal Unit 

Exposure

(μg/lb ai)1

Inhalation Unit 

Exposure

(μg/lb ai)1 Max. App. 

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation Total

Level of PPE Level of PPE Dose (mg/kg/day)4 MOE5 Dose 

(mg/kg/day)6 MOE7 MOE8

Applying Sprays via 

Groundboom Equipment

Greenhousegrown cucumbers

Baseline: 78.6 Baseline: 0.34 

60 A Baseline: 0.021 Baseline: 1,100 Baseline: 

0.0179

Baseline: 

130,000 Baseline: 1,100 

Blackberries, 

highbush 

blueberries, 

raspberries

40 A Baseline: 0.014 Baseline: 1,700 Baseline: 

0.000119

Baseline: 

190,000 Baseline: 1,700 

Lowbush 

blueberries 80 A Baseline: 0.0281 Baseline: 820 Baseline: 0.000238

Baseline: 

97,000 Baseline: 810 

Flagger

Flagger

Small berries 

(caneberries and 

bushberries)

100 Baseline: 11 Baseline: 0.35 0.7 lb ai/A 350 A Baseline: 0.0172 Baseline: 1,300 Baseline: 

0.00107 

Baseline: 

22,000 Baseline: 1,200 

Mixer/Loader/Applicator

Broadcast applications via 

backpack

Greenhousegrown cucumbers

Baseline: 13,200 

PPE-G: 11,200

Baseline: 140 

0.014 lb 

ai/gal 

solution

40 gal 

solution

Baseline: 0.0471 Baseline: 490 Baseline: 

0.00098

Baseline: 

24,000 Baseline: 480

Broadcast applications via 

manually pressurized 

handgun

Baseline: 100,000 

PPE-G: 430

Baseline: 30 Baseline: 0.357

PPE-G: 0.00154

Baseline: 65 

PPE-G: 15,00

Baseline: 

0.00021 

Baseline: 

110,000 

Baseline: 65 

PPE-G: 13,000

Broadcast applications via 

mechanically-pressurized 

handgun

Greenhousegrown cucumbers

Baseline: 3500

PPE-G: 2500

PPE-DL/G: 1600

Baseline: 120

1000 gal 

solution

Baseline: 0.312

PPE-G: 0.223

PPE-DL/G: 0.143

Baseline: 74

PPE-G: 100

PPE-DL/G: 160

Baseline: 

0.021

Baseline: 

1,100

Baseline: 69

PPE-G: 92

PPE-DL/G: 140

Blackberries, 

highbush 

blueberries, 

raspberries

Baseline: 1300 

PPE-G: 390

Baseline: 3.9 Baseline: 0.116 Baseline: 200 Baseline: 

0.000683

Baseline: 

34,000 Baseline: 200
Pyrimethanil Human Health Risk Assessment DP# 428262

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Table 9.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Proposed Uses of Pyrimethanil.

Exposure Scenario Crop LOC

Dermal Unit 

Exposure

(μg/lb ai)1

Inhalation Unit 

Exposure

(μg/lb ai)1 Max. App. 

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation Total

Level of PPE Level of PPE Dose (mg/kg/day)4 MOE5 Dose 

(mg/kg/day)6 MOE7 MOE8

Broadcast applications via 

mechanically-pressurized 

handgun

Lowbush 

blueberries 100

Baseline: 1300 

PPE-G: 390

Baseline: 3.9

0.047 lb 

ai/gal 

solution

1000 gal 

solution

Baseline: 0.39

PPE-G: 0.117

Baseline: 59 

PPE-G: 200

Baseline: 

0.00229

Baseline: 

10,000

Baseline: 59 

PPE-G: 200

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (May 2013); Level of PPE: Baseline = Long-sleeved 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. PPE-DL/G = Long-sleeved shirt, long pants, shoes plus socks, coveralls, and chemical-resistant gloves. PPE-G/CRH =

Long-sleeved shirt, long pants, shoes plus socks and chemical-resistant gloves and headgear for overhead exposure (*label-prescribed PPE). EC = enclosed cockpit (aerial applicators).

2 Based on registered or proposed label (Reg. No. 264-788).

3 HED ExpoSAC Policy 9.1.

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.
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9.2 Post-application Exposure and Risk Estimates

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as scouting for pests 

or harvesting. Post-application exposure levels vary over time and depend on such things as the 

type of activity, the nature of the crop or target that was treated, the type of pesticide application, 

and the chemical’s degradation properties. In addition, the timing of pesticide applications, 

relative to harvest activities, can greatly reduce the potential for post-application exposure.

Dermal: HED expects that post-application dermal exposure will occur since pyrimethanil is 

applied as a foliar spray. An occupational post-application dermal exposure assessment was 

conducted previously in conjunction with a request for the use of pyrimethanil on small fruit, 

vine climbing 13-07F and low growing berry 13-07G (Memo, J. Tyler, 08-MAY-2012; 

D389987). In that assessment, the short- and intermediate-term risk estimates are not of concern 

(i.e., MOEs ≥ 100) on the day of treatment (i.e., Day 0) for all post-application exposure 

activities. 

The post-application dermal exposures in the 08-MAY-2012 assessment were calculated for 

post-application activities with the highest (i.e., most conservative) TCs (girdling and turning of 

grapes). In addition, the proposed use pattern for caneberry crop group 13-07A, bushberry crop 

subgroup 13-07B are identical to that of small fruit, vine climbing 13-07F and low growing berry 

13-07G. Therefore, the 5/8/2012 post-application dermal exposure assessment is adequate to 

cover the proposed uses on caneberry crop group 13-07A and bushberry crop subgroup 13-07B. 

An assessment was conducted for post-application dermal exposure from applications to 

greenhouse-grown cucumbers. It is the policy of HED to use the best available data to assess 

post-application exposure. Sources of generic post-application data, used as surrogate data in the 

absence of chemical-specific data, are derived from ARTF exposure monitoring studies, and, as 

proprietary data, are subject to the data protection provisions of FIFRA. The standard values 

recommended for use in predicting post-application exposure that are used in this assessment, 

known as “transfer coefficients,” are presented in the “Science Advisory Council for Exposure 

(ExpoSAC) Policy 3” (http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, 

along with additional information about the ARTF data, can be found at 

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

Chemical-specific DFR data are available for pyrimethanil on greenhouse cucumbers (MRID# 

48823501). This study has been submitted to the Agency, and a detailed review is forthcoming. 

Based on a preliminary analysis of the data, it is proposed that predicted greenhouse cucumber 

DFR values calculated based on a linear regression of the measured data be used since the R2-

value is high (0.9762).

Table 9.2 provides a summary of the estimated post-application dermal exposures and risks to 

occupational pesticide workers. The short- and intermediate-term risk estimates are of concern 

(i.e., MOEs ≥ 100) on the day of application for high contact post-application exposure activities 

associated with greenhouse-grown vegetables. Risk estimates are not of concern for these 

activities after 48 hours. Low contact activities, such as transplanting and irrigation, are not of 

concern on the day of application.
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Table 9.2. Dermal Post-application Exposure and Risk Using Chemical-Specific Data.

Crop/Site

Transfer 

Coefficients 

(cm2/hr)

DAT1 Site

Predicted

DFR2 

(ug/cm2)

Chemical-Specific 

Dermal Dose3 

(mg/kg/day)

Chemical 

Specific 

MOE4

Greenhouse-grown 

Cucumbers

1,200

0

Greenhouse 

Cucumbers 4.681

0.282 82

1 0.247 93

2 0.217 110

230 0 0.054 430

1. DAT = Days after treatment.

2. Predicted DFR residues from chemical-specific study (MRID 48823501).

3. Chemical-Specific Dermal Dose = [DFR (ug/cm2) x Tc (cm2/hr) x 0.001 mg/ug x 8 hrs/day x DAF (51%)]  body weight (80 kg).

4. Chemical-Specific MOE = NOAEL (23.1 mg/kg/day)/Adjusted Dermal Dose (mg/kg/day).

Inhalation: There are multiple potential sources of post-application inhalation exposure to 

individuals performing post-application activities in previously treated fields. These potential 

sources include volatilization of pesticides and resuspension of dusts and/or particulates that 

contain pesticides. The agency sought expert advice and input on issues related to volatilization 

of pesticides from its FIFRA SAP in December 2009, and received the SAP’s final report on 

March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analysis is required for pyrimethanil.

In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the ARTF. Given these two efforts, the Agency will continue to 

identify the need for and, subsequently, the way to incorporate occupational post-application 

inhalation exposure into the agency's risk assessments.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.

The WPS for Agricultural Pesticides contains requirements for protecting workers from 

inhalation exposures during and after greenhouse applications through the use of ventilation 

requirements [40 CFR 170.110, (3) (Restrictions associated with pesticide applications)].

9.3 Restricted-Entry Interval (REI)

The proposed label specifies a 12-hour REI. Pyrimethanil is classified as Toxicity Category IV 

via the dermal route and Toxicity Category IV for skin irritation potential. It is not a skin 

sensitizer. Short- and intermediate-term post-application risk estimates were not a concern on 

day 0 (12 hours following application) for low contact activities, such as transplanting and 

irrigation. However, there were risk estimates of concern related to high contact activities up 

until 48 hours after application; therefore, HED is recommending that the REI be revised on the 
Pyrimethanil Human Health Risk Assessment DP# 428262

Page 28 of 32

label to address those concerns.

 

10.0 References

Previous Risk Assessments: J. Tyler et al., 28-JAN-2015; D417167. J. Tyler et al., 22-MAY2013; D389923. 

HASPOC Memo: J. Van Alstine, 08-FEB-2013; TXR# 0056470

Chemistry Memo: G. Kramer, 22-SEP-2015; D421844

Drinking Water Memo: J. Wolf, 14-MAY-2015; D422295

Dietary Memo: G. Kramer, 22-SEP-2015; D424861

Occupational and Residential Exposure Assessment Memo: J. Tyler, 21-SEP-2015; D429034

List of Appendices:

Appendix A. Toxicology Profile

Appendix B. Physical/Chemical Properties

Appendix C. Review of Human Research

cc: G. Kramer (RAB1)

RDI: RAB1 (7/22/15)

G.F. Kramer:S10957:PY-S:(703)305-5079:7509P:RAB1
Pyrimethanil Human Health Risk Assessment DP# 428262

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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
Pyrimethanil Human Health Risk Assessment DP# 428262

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Table A.3. Toxicity Profile for Pyrimethanil.

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.
Pyrimethanil Human Health Risk Assessment DP# 428262

Page 31 of 32

Table A.3. Toxicity Profile for Pyrimethanil.

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

Classification/Doses Results

870.5300

Gene Mutation

43301625 (1991);

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 clear evidence of biologically significant induction of 

mutant colonies over background.

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) 

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

Acceptable/Guideline

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])

Acceptable/Guideline

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

Immunotoxicity LOAEL is not established.
Pyrimethanil Human Health Risk Assessment DP# 428262

Page 32 of 32

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