Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 3 of 36

Table of Contents

1.0 EXECUTIVE SUMMARY ..................................................................................... 4

2.0 INGREDIENT PROFILE..................................................................................... 10

2.1 SUMMARY OF PROPOSED USES..................................................................................................10

2.2 STRUCTURE AND NOMENCLATURE ..............................................................................................11

2.3 PHYSICAL AND CHEMICAL PROPERTIES ....................................................................................11

3.0 HAZARD CHARACTERIZATION/ASSESSMENT ........................................ 12

3.1 HAZARD AND DOSE-RESPONSE CHARACTERIZATION...............................................................12

3.2 FQPA CONSIDERATIONS ..............................................................................................................14

3.3 DOSE-RESPONSE ASSESSMENT..................................................................................................15

4.0 DIETARY EXPOSURE/RISK CHARACTERIZATION ................................. 18

4.1 PESTICIDE METABOLISM AND ENVIRONMENTAL DEGRADATION.............................................18

4.2 DIETARY EXPOSURE AND RISK .................................................................................................22

5.0 RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK 

CHARACTERIZATION ............................................................................................... 23

5.1 OTHER (SPRAY DRIFT, ETC.)......................................................................................................23

6.0 AGGREGATE RISK ASSESSMENT AND RISK CHARACTERIZATION. 23

6.1 ACUTE AGGREGATE RISK..........................................................................................................24

6.2 SHORT- AND INTERMEDIATE-TERM AGGREGATE RISK.............................................................24

6.3 LONG-TERM AGGREGATE RISK.................................................................................................24

6.4 CANCER RISK.............................................................................................................................24

7.0 CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT ................... 24

8.0 OCCUPATIONAL EXPOSURE/RISK PATHWAY......................................... 24

8.1 HANDLER EXPOSURE AND RISK ESTIMATES .............................................................................25

8.2 POST-APPLICATION EXPOSURE AND RISK ESTIMATES ..............................................................29

8.3 RESTRICTED ENTRY INTERVAL (REI) .......................................................................................30

9.0 DATA NEEDS AND LABEL RECOMMENDATIONS.................................... 30

9.1 TOXICOLOGY .............................................................................................................................30

9.2 RESIDUE CHEMISTRY.................................................................................................................30

9.3 OCCUPATIONAL AND RESIDENTIAL EXPOSURE.........................................................................31

APPENDIX A: TOXICITY PROFILE TABLES....................................................... 32

APPENDIX B: METABOLISM ASSESSMENT. ...................................................... 35

APPENDIX C: TOLERANCE SUMMARY FOR PYRIMETHANIL..................... 36
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 4 of 36

1.0 Executive Summary

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

aqueous SC formulation containing 5.0 lbs/gal of pyrimethanil. The petitioner requests that the 

following tolerances be established as a result of the proposed uses for the residues of 

pyrimethanil (4,6-dimethyl-N-phenyl-2-pyrimidinamine) in/on:

Ginseng ................................................................................................................................ 2.5 ppm

Onion, bulb, subgroup 3-07A............................................................................................... 0.10 ppm

Onion, green, subgroup 3-07B ............................................................................................. 2.0 ppm

Berry and small fruit, small fruit vine climbing subgroup, except fuzzy kiwifruit 13-07F.. 5.0 ppm

Berry and small fruit, low growing berry subgroup 13-07G ................................................ 3.0 ppm

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

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

almonds, pome fruit, citrus fruit, stone fruit (except cherry), bananas, grapes, onions, pistachios, 

strawberries, tomatoes, and tuberous and corm vegetables. 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 Uses: The proposed use to the subject crops is as a foliar application three times at 

0.35-0.70 lb ai/A with a maximum of 1.4-2.1 lb ai/A/season and a preharvest interval (PHI) of 1-

30 days. 

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. Exposure to pyrimethanil in oral toxicity studies primarily resulted in 

decreased body weights and body-weight gain, often accompanied by decreases in food 

consumption. The major target organs of repeated oral exposure were the liver and the thyroid. 

No reproductive toxicity was observed, and developmental effects (e.g., decreased fetal weight, 

retarded ossification, extra ribs) were observed only at maternally toxic doses. Special shortterm exposure studies demonstrated increased liver uridine diphosphate glucuronosyl transferase 

(UDPGT) activity leading to decreases in thyroid hormones (T3, T4) and compensatory 

increases in thyroid-stimulating hormone (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. There were no concerns for mutagenicity.

Dose-response and Food Quality Protection Act (FQPA) Assessment: The toxicity database for 

pyrimethanil is adequate for risk assessment and tolerance setting. Appropriate endpoints were 

identified for exposures to pyrimethanil. The identified endpoints for pyrimethanil are as 

follows:
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 5 of 36

The Agency has selected the no-observed-adverse-effect level (NOAEL) of 100 mg/kg/body 

weight for the acute dietary risk assessment for the general population including infants and 

children. The endpoint of concern is neurotoxicity (decreased motor activity, ataxia, decreased 

body temperature, hind-limb grip strength, and dilated pupils) observed in an acute neurotoxicity 

study at 1000 mg/kg/day [lowest-observed-adverse-effect level (LOAEL)].

The Agency has selected the developmental NOAEL of 45 mg/kg/day for the acute dietary risk 

assessment for pregnant females (13-49). The endpoint of concern is skeletal variations 

(increases in fetuses with 13 thoracic vertebrae and 13 pairs of ribs) observed in a pre-natal 

developmental toxicity study in rabbits at 300 mg/kg/day (LOAEL). The in utero effects are the 

most sensitive endpoint for this sub-population (potentially pregnant females). 

The Agency has selected the NOAEL of 17 mg/kg/day for chronic dietary risk assessment for 

general population including infants and children. The endpoint of concern is systemic toxicity 

manifested as decreased body-weight gains; increased serum cholesterol and gamma-glutamyl 

transferase (GGT), increased relative liver/body-weight ratios, necropsy and histopathological 

findings in the liver and thyroid observed in a chronic toxicity/carcinogenicity study in rats at 221 

mg/kg/day (LOAEL).

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 decreases in body weight and body-weight gain

observed in the two-generation reproduction study in rat at 294 mg/kg/day (LOAEL). The use of 

this NOAEL will also address the concern for the toxicity seen in the target organs (liver and 

thyroid) seen at a comparable dose (221 mg/kg/day) in the chronic toxicity/carcinogenicity study 

in rats as well as the developmental toxicity study in rabbits. Since an oral dose was selected a 

dermal-absorption factor of 51% should be use for route-to-route extrapolation which yields a 

dermal-equivalent dose of 45 mg/kg/day (23 mg/kg/day ÷ 0.51 dermal-absorption factor = 45 

mg/kg/day).

The pyrimethanil database does not contain an inhalation 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 decreases in body weight and body-weight gain

observed in the two-generation reproduction study in rat at 294 mg/kg/day (LOAEL). Since an 

oral dose was selected, a 100% absorption factor (i.e., equivalent to oral absorption) should be 

use for route-to-route extrapolation.

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 

recommendation is based on the following:

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.

There are no residual uncertainties concerning pre- and post-natal toxicity.

A guideline immunotoxicity study has been submitted; and, there is no evidence for 

immunotoxicity due to pyrimethanil treatment. Evidence of neurotoxicity was observed at a very 

high dose (the limit dose) in the acute neurotoxicity study in rats. However, the study has a clear 

NOAEL, which is being utilized as the point of departure (POD) for the acute dietary exposure 

scenario; and, there was no evidence of neurotoxicity observed in the subchronic neurotoxicity 

study in rats.

A developmental neurotoxicity (DNT) study is not required. 

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. The Hazard 

Identification Assessment Review Committee (HIARC), however, concluded that there is no 

concern for thyroid toxicity in the young based on the following weight of evidence 

considerations: the effects seen on the thyroid and the liver in the database, while treatment-
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 6 of 36

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 endpoint 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. In addition, the 

decrease in thyroid hormone in the special 14-day study was relatively mild (≤24%), statistically 

significant at only one time point, observed at a high dose (379 mg/kg./day), and compensated for 

by an increase in TSH. Any possible decrease in thyroid hormone levels at the PODs chosen for 

risk assessment would be undetectable. There was no indication of any offspring toxicity in 

offspring, except for decreased body weight, in the two-generation reproduction toxicity study.

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

assessment utilizes tolerance-level residues (established or recommended) and 100% crop treated 

(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, 

which are designed to provide conservative, health-protective, high-end estimates of water 

concentrations that will not likely be exceeded. There are no residential uses.

Pyrimethanil was reclassified as “Not Likely To Be Carcinogenic to Humans at Doses That Do 

Not Alter Rat Thyroid Hormone Homeostasis.” Therefore, quantification of carcinogenic risk is 

not required. The Cancer Assessment Review Committee (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 chronic reference dose (cRfD) is not expected to alter thyroid hormone homeostasis 

nor result in thyroid tumor formation.

Residue Chemistry: No new data were submitted to support tolerances on onion, bulb, subgroup 

3-07A; onion, green, subgroup 3-07B; low-growing berry 13-07G crop subgroup; or small fruit 

vine climbing subgroup 13-07F, except fuzzy kiwifruit. The petitioner has requested that 

existing tolerances be expanded to their respective crops or crop groups.

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 ginseng residue data in conjunction with the 

magnitude of the residue study associated with this petition was gas chromatography/massselective detector (GC/MSD) 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 submitted field trial residue data for ginseng are adequate. The field trial data reflect the 

proposed use pattern, an adequate number of trials were conducted in the appropriate geographic 

regions, and samples were analyzed for the residue of concern using validated data-collection 

methods. Per-trial-average-residues of pyrimethanil residues ranged from 0.099 to 0.585 ppm 

in/on three ginseng trials with samples harvested at a 29-day PHI (highest individual residue of 

0.69 ppm) from the three trials. Using the Organization for Economic Co-operation and 

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

requested tolerance of 2.5 ppm for residues of pyrimethanil in/on ginseng is too high; a tolerance 

of 1.5 ppm is appropriate. A revised Section F is requested.
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 7 of 36

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

U.S. and Codex tolerances/maximum residue limits (MRLs) for residues of pyrimethanil in/on 

the bulb onion subgroup 3-07A, green onion subgroup 3-07B, and grapes (small vine climbing 

fruit subgroup 13-07F) are not harmonized. For grapes, the European PHI is 21 days; the U.S., 7 

days. Residues were thus higher in U.S. residue trials, necessitating a higher tolerance, and 

precluding harmonization. For the bulb onion subgroup 3-07A and green onion subgroup 3-07B, 

HED recommends that the U.S. tolerances be increased in order to harmonize with Codex; bulb 

onion subgroup 3-07A from 0.10 to 0.20 ppm and green onion subgroup 3-07B from 2.0 to 3.0 

ppm. The U.S. tolerances and Codex MRLs for strawberries (low-growing berry subgroup 13-

07G) are harmonized. There are currently no established Codex, Canadian, or Mexican MRLs 

for pyrimethanil in/on ginseng. 

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

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

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

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

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

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

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

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

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

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

using the Dietary Exposure Evaluation Model - Food Consumption Intake Database (DEEMFCID , ver. 2.03), which incorporates consumption data from the United States Department of 

Agriculture (USDA) Continuing Survey of Food Intake by Individuals (CSFII; 1994-1996 and 

1998). A cancer dietary assessment was not conducted because pyrimethanil is classified as “not 

likely to be carcinogenic to humans.” 

The acute and chronic dietary analyses assumed DEEM-FCIDTM (ver. 7.81) default processing 

factors (as necessary), empirical processing factors for orange and apple juice, tolerance-level 

residues, 100% CT for all commodities and EDWCs (acute 86.5 ppb, chronic 29.4 ppb) for direct 

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

were ≤35% of the acute population-adjusted dose (aPAD) and are not of concern to HED 

(<100% aPAD; all infants <1 year old were the most highly exposed population subgroup). The 

resulting chronic dietary risk estimates (food and drinking water) were ≤64% of the chronic 

population-adjusted dose (cPAD) and are not of concern to HED (<100% cPAD; children 1-2 

years old were the most highly exposed population subgroup). 

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

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

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

(food and water) and residential exposures (residential or other non-occupational exposures). 

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

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

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

to the U.S. population and all other subpopulations from the uses of pyrimethanil does not 

exceed HED’s level of concern (LOC).
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 8 of 36

Occupational Exposure/Risk: Based on the proposed new uses, the most highly exposed 

occupational pesticide handlers are expected to be mixer/loaders using open-pour loading of 

liquids in support of aerial and groundboom applications, aerial applicators, applicators using 

open-cab ground boom equipment, and flaggers. Occupational handler dermal and inhalation 

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

handlers from dermal and inhalation exposures. Airblast applicator dermal MOEs are >100 with 

a baseline protection plus gloves and headgear. All other estimated dermal and inhalation MOEs 

are >100 with baseline protection, and these proposed uses are not of concern for HED. The 

proposed label requires applicators and other handlers to wear a long-sleeved shirt and long 

pants, shoes plus socks, and chemical-resistant gloves. The label should be amended to specify 

the use of chemical-resistant headgear for overhead exposure. RD should ensure the appropriate 

personal-protective equipment (PPE) is listed on the label.

HED expects that post-application dermal exposure will occur since pyrimethanil is applied postemergence as a foliar spray. HED has determined that 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. Based on the Agency's current practices, a quantitative 

occupational post-application inhalation exposure assessment was not performed for 

pyrimethanil at this time.

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.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food consumption. Extensive data on food consumption patterns are compiled by the 

USDA under the CSFII and are used in pesticide risk assessments for all proposed/registered

food uses/tolerances 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. Further considerations are currently in 

development as OPP has committed resources and expertise to the development of specialized 

software and models that consider exposure from traditional dietary patterns among specific 

subgroups.

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

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

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

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

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

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

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

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

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

http://www.epa.gov/pesticides/science/post-app-exposure-data.html.
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 9 of 36

Regulatory Recommendations and Data Deficiencies

Recommendations

Pending submission of revised Sections B and F as specified below, the residue chemistry, 

toxicology, and occupational exposure databases support conditional registration and 

establishment of permanent tolerances as listed below.

Ginseng........................................................................................................... 1.5 ppm

Onion, bulb subgroup 3-07A.........................................................................0.20 ppm

Onion, green subgroup 3-07B ........................................................................ 3.0 ppm

Fruit, small, vine climbing, subgroup 13-07F, except fuzzy kiwifruit........... 5.0 ppm

Low growing berry subgroup 13-07G............................................................ 3.0 ppm

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

strawberry; grape; onion, bulb; and onion, green.

In accordance with current Agency practice to describe more clearly the measurement and scope 

or coverage of tolerances, HED recommends for the following revisions to the pyrimethanil 

tolerance expressions:

40 CFR §180.518 (a)(1) “Tolerances are established for residues of the fungicide pyrimethanil, 

including its metabolites and degradates, in or on the commodities in the table below. 

Compliance with the tolerance levels specified below is to be determined by measuring only 

pyrimethanil (4,6-dimethyl-N-phenyl-2-pyrimidinamine).”

40 CFR §180.518 (a)(2) “Tolerances are established for residues of the fungicide pyrimethanil, 

including its metabolites and degradates, in or on the commodities in the table below. 

Compliance with the tolerance levels specified below is to be determined by measuring is to be 

determined by measuring only the sum of pyrimethanil and its metabolite 4-[4,6-dimethyl-2-

pyrimidinyl)amino]phenol, calculated as the stoichiometric equivalent of pyrimethanil.”

40 CFR §180.518 (a)(3) “Tolerances are established for residues of the fungicide pyrimethanil, 

including its metabolites and degradates, in or on the commodities in the table below. 

Compliance with the tolerance levels specified below is to be determined by measuring is to be 

determined by measuring only the sum of pyrimethanil and its metabolite 4,6-dimethyl-2-

(phenylamino)-5-pyrimidinol, calculated as the stoichiometric equivalent of pyrimethanil.”

Data Deficiencies/Requirements

Toxicology: 

A 90-day inhalation study (870.3465)

Residue Chemistry: 

Adjuvants were not used in any of the submitted residue field trials. Since adjuvants 

were not used in the submitted residue field trials, the label should prohibit such uses on 

ginseng; onion, bulb, subgroup 3-07A; onion, green, subgroup 3-07B; low-growing berry 

13-07G crop subgroup; or small fruit vine climbing subgroup 13-07F, except fuzzy 

kiwifruit.
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 10 of 36

A summary of the recommended tolerances along with recommendations for commodity 

definitions are presented in Appendix C. The petitioner is required to submit a revised 

Section F to reflect the recommendations in Appendix C.

ORE:

The label should be amended to specify the use of chemical-resistant headgear for 

overhead exposure. RD should ensure the appropriate PPE is listed on the label.

2.0 Ingredient Profile

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.

2.1 Summary of Proposed Uses

Table 2.1 provides a summary of the proposed use patterns. ScalaTM SC is formulated as a SC, 

and is proposed at a maximum application rate of 0.70 lb ai/A via ground and aerial applications 

to ginseng, bulb vegetables 03-07A and 03-07B, small fruit, vine climbing 13-07B, and lowgrowing berry 13-07G. The proposed PHIs range from 1 to 30 days. The label requires 

applicators and other handlers to wear a long-sleeved shirt and long pants, shoes plus socks, and 

chemical-resistant gloves. The proposed label specifies a 12-hour restricted-entry interval (REI).
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 11 of 36

Table 2.1. Summary of Directions for Use of Pyrimethanil.1

Applic. Timing, 

Type, and 

Equip.

Formulation

(EPA Reg. No.)

Applic. 

Rate

(lb ai/A)

Max. No. 

Applic. 

per Season

Max. Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Bulb Vegetables Do not apply this product 

for more than 2 sequential 

applications before 

rotating to a fungicide 

from a different functional 

group.

Minimum application 

volume: 50 GPA ground 

and 15 GPA aerial for 

vine crops, and 15 GPA 

ground and 5 GPA aerial 

for field crops.

RTI: 7-14 days.

PBI: 30 days for all nonlabeled crops.

Ground, air, or 

chemigation

ScalaTM SC Fungicide 

(264-788) 0.35-0.70 3-6 2.1 7

Ginseng

Ground, air, or 

chemigation

ScalaTM SC Fungicide 

(264-788) 0.70 3 2.1 30

Small Fruit Vine-Climbing Subgroup Except Fuzzy Kiwifruit

Ground, air, or 

chemigation

ScalaTM SC Fungicide 

(264-788) 0.35-0.70 2-4 1.4 7

Low-Growing Berry Subgroup

Ground, air, or 

chemigation

ScalaTM SC Fungicide 

(264-788) 0.35-0.70 3-6 2.1 1

1. PHI = preharvest interval. GPA = gallons per acre. RTI = retreatment interval. PBI = plantback interval.

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

relative to the proposed uses. Adjuvants were not used in any of the submitted residue field trials 

(48421101.der.doc, 45657111.der.wpd, 45657112.der.wpd, and 45657123.der.wpd). Since 

adjuvants were not used in the submitted residue field trials, the label should prohibit such 

uses on ginseng; onion, bulb, subgroup 3-07A; onion, green, subgroup 3-07B; low-growing 

berry 13-07G crop subgroup; or small fruit vine climbing subgroup 13-07F, except fuzzy 

kiwifruit. In addition, RD should ensure the appropriate PPE is listed on the label.

2.2 Structure and Nomenclature

Table 2.2. 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) ScalaTM SC Fungicide (EPA Reg. No. 264-788)

2.3 Physical and Chemical Properties

Table 2.3. 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 
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 12 of 36

Table 2.3. Physicochemical Properties of the Technical Grade Test Compound.

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.

3.0 Hazard Characterization/Assessment

3.1 Hazard and Dose-Response Characterization

3.1.1 Adequacy of the Toxicity Database and Hazard Profile

The toxicology database for pyrimethanil is complete. Since the completion of the previous risk 

assessment, the previously requested guideline mouse carcinogenicity study has been submitted 

(Memo, J. Kidwell, 24-APR-2003, TXR# 0050408), and the cancer classification has been 

changed (Memo, J. Rowland, 23-DEC-2011, TXR#0056151). A guideline immunotoxicity 

study has also been submitted. HED’s Hazard Assessment and Policy Committee (HASPOC), 

looked at all existing hazard and exposure data, and current use patterns for pyrimethanil, and 

used a weight-of-evidence approach to require a 90-day inhalation study and to not require a 28-

day dermal toxicity study (Memo, D. Smegal, 23-FEB-12, TXR# 0054040). This weight-ofevidence approach for the inhalation study considered all of the available hazard and exposure 

information including: (1) the use of an oral POD that results in MOEs as low as 110 (the 

lowest MOE) for risk via the inhalation route resulting from occupational and residential 

exposures; (2) the physical/chemical properties; (3) the toxicological profile of pyrimethanil; and 

(4) there is repeated inhalation exposure based on the use pattern and method of application (i.e., 

greenhouses). The committee further concluded that under the current uses, a 28-day dermal 

study is not required pending the use of headgear in occupational scenarios of concern. This 28-

day study is required for any future residential uses, and the registrant is welcome to submit a 

study to further refine dermal risk assessments. 

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 study termination 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 
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 13 of 36

dose 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 (combine tape stripping excluding first 

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

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

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

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

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

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

considered conservative and protective.

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

followed by the dog and then the mouse. Subchronic and chronic exposure to pyrimethanil in

oral toxicity studies primarily resulted in decreased body weights and body-weight gain, often 

accompanied by decreases in food consumption. 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. No reproductive toxicity was observed, and 

developmental effects (e.g., decreased fetal weight, retarded ossification, extra ribs) were 

observed only at maternally toxic doses. Pyrimethanil was not immunotoxic. 

There are currently no dermal or inhalation toxicity studies available for pyrimethanil.

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

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

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

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

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

There are no concerns for mutagenicity.

3.1.2 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 was seen at 1/2 limit dose (430 mg/kg/day) in the subchronic neurotoxicity 

study. In addition, no neurotoxic signs were seen in the rest of the database and the target organ 

for toxicity for pyrimethanil is the thyroid; therefore, neurotoxicity is not a primary concern. 

3.1.2.1 Determination of Susceptibility

There is no evidence for increased susceptibility following in utero exposure in the rat and rabbit 

or following pre- and post-natal exposure in the 2-generation reproduction study in rats.

3.1.2.2 Degree-of-Concern Analysis

There are no concerns or residual uncertainties for pre- and/or postnatal toxicity following 

exposure to pyrimethanil.
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 14 of 36

3.1.3 Recommendation for a DNT Study

There are no neurotoxicity concerns and no evidence for increased susceptibility; therefore, there 

is no concern for potential neurodevelopmental effects from exposure to pyrimethanil. A 

developmental neurotoxicity study is not required.

3.2 FQPA Considerations

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 study,

Acute and subchronic (unacceptable) neurotoxicity studies,

An immunotoxicity study.

Based on previous HIARC conclusions (2003) and the pyrimethanil risk assessment team’s reevaluation of the hazard and exposure data, the FQPA SF can be reduced to 1X. The 

recommendation is based on the following:

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.

There are no residual uncertainties concerning pre- and postnatal toxicity.

A guideline immunotoxicity study has been submitted, and there is no evidence for 

immunotoxicity due to pyrimethanil treatment. Evidence of neurotoxicity was observed at a 

very high dose (the limit dose) in the acute neurotoxicity study in rats. However, the study has a 

clear NOAEL, which is being utilized as the POD for the acute dietary exposure scenario, and 

there was no evidence of neurotoxicity observed in the subchronic neurotoxicity study in rats up 

to the highest dose tested in that study (430 mg/k/day).

A DNT study is not required.

Thyroid has been shown to be one of the target organs in adult animals for pyrimethanil-induced 

toxicity thus raising a potential concern for thyroid toxicity in the young. HIARC, however, 

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

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

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

on thyroid hormone levels, as well as in all studies chosen for 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.

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.

The FQPA SF recommended by the pyrimethanil review team assumes that the exposure 

databases (dietary food, drinking water, and residential) are complete and that the risk 

assessment for each potential exposure scenario includes all metabolites and/or degradates of 

concern and does not underestimate the potential risk for infants and children.
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 15 of 36

3.3 Dose-Response Assessment

3.3.1 Acute Population-Adjusted Dose (aPAD) - 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.

3.3.2 Acute Population-Adjusted Dose (aPAD) - General 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 interspecies 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. 

3.3.3 Chronic Population-Adjusted Dose (cPAD) 

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 decreased body-weight gains, increased serum cholesterol and 

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.

3.3.4 Incidental Oral Exposure (Short- and Intermediate-Term) 

There are no residential uses for pyrimethanil. Therefore, an incidental oral endpoint was not 

chosen.

3.3.5 Dermal Absorption

A dermal-absorption study was submitted (MRID No. 46630101) and reviewed (Memo, P.V. 

Shah, 23-FEB-2009, D322065). A dermal-absorption factor of 51% was chosen based on results 

from the in vivo dermal-absorption study in rats. Previously, HED used a dermal-absorption 

factor of 37.2% (Memo, K. Lowe, 04-JAN-2007, D322065). This dermal-absorption factor was 

based on preliminary review of the MRID 46630101; however, subsequent to a detailed review 

HED concluded that the dermal-absorption factor of 51% is more appropriate for this dermal 

exposure assessment. 
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 16 of 36

3.3.6 Dermal Exposure (Short- and Intermediate-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 decreases in body weight and body-weight gain

observed in the two-generation reproduction study in rat at 294 mg/kg/day (LOAEL). The use of 

this NOAEL will also address the concern for the toxicity seen in the target organs (liver and 

thyroid) seen at a comparable dose (221 mg/kg/day) in the chronic toxicity/carcinogenicity study 

in rats as well as the developmental toxicity study in rabbits. Since an oral dose was selected a 

dermal-absorption factor of 51% should be use for route-to-route extrapolation which yields a 

dermal-equivalent dose of 45 mg/kg/day (23 mg/kg/day ÷ 0.51 dermal-absorption factor = 45 

mg/kg/day). 

3.3.7 Inhalation Exposure (Short- and Intermediate-Term) 

An inhalation toxicity study was not submitted. The short- and intermediate-term inhalation 

endpoints are based upon the parental effects observed in the 2-generation reproduction study. 

The NOAEL is 23.1 mg/kg/day. The effect observed at the LOAEL of 294 mg/kg/day was 

decreased parental mean body weights and body-weight gains. This endpoint is appropriate for 

the duration of exposure and the populations of concern. The Agency has assumed that 

absorption via the inhalation route is complete (100%). The LOC for occupational dermal 

exposure is a MOE <100.

3.3.8 Level of Concern for Margin of Exposure

The target MOEs for occupational and non-dietary residential exposure risk assessments are as 

follows:

Table 3.3.8. Summary of LOCs for Risk Assessment.

Route Duration

Short-Term (1-30 days) Intermediate-Term (1-6 Months)

Occupational (Worker) Exposure

Dermal 100 100

Inhalation 100 100

Residential (Non-Dietary) Exposure

Oral NA NA

Dermal NA NA

Inhalation NA NA

3.3.9 Classification of Carcinogenic Potential

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-2011). This decision was based on the following:

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

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

considered adequate to assess carcinogenicity;
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 17 of 36

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 to the development of thyroid follicular 

cell tumors in response to thyroid hormone imbalance. 

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

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

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

hormone homeostasis nor result in thyroid tumor formation. 

3.3.10 Recommendation for Aggregate Exposure Risk Assessments

As per FQPA, 1996, when there are potential residential exposures to the pesticide, aggregate 

risk assessment must consider exposures from three major sources: oral, dermal and inhalation 

exposures. An aggregated exposure risk assessment is not required since there are no residential 

uses for pyrimethanil at this time. 

3.3.11 Summary of Toxicological Doses and Endpoints for Pyrimethanil for Use in Human 

Health Risk Assessments

The selected toxicity endpoints are summarized in Tables 3.3.11.a and 3.3.11.b.

Table 3.3.11.a. Summary of Toxicological Doses and Endpoints for Pyrimethanil for Use in Dietary and NonOccupational Human-Health Risk Assessments.

Exposure/

Scenario

Point of 

Departure

Uncertainty/FQ

PA Safety 

Factors

RfD, PAD, 

LOC 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-2011).
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 18 of 36

Table 3.3.11.b. Summary of Toxicological Doses and Endpoints for Pyrimethanil for Use in Occupational 

Human-Health Risk Assessments.

Exposure

Scenario

Dose Used in Risk 

Assessment, UF 

FQPA SF and LOC 

for Risk Assessment Study and Toxicological Effects

Short (1-30 days) and 

Intermediate (1- 6 

months) Term 

Dermal

Oral NOAEL =

23.1 mg/kg/day

(dermal absorptiona= 

51%)

Occupational LOC for 

MOE = 100

Reproductive Toxicity - Rat

LOAEL = 294 mg/kg/day based on 

decreased mean body weights and 

body-weight gains.

Short (1-30 days) and 

Intermediate (1- 6 

months) Term 

Inhalation

Oral NOAEL =

23.1 mg/kg/day

(inhalation 

absorptionb= 100%)

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-2011).

Point of departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark 

the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = 

no-observed adverse-effect level. LOAEL = lowest-observed adverse-effect level. UF = uncertainty factor. UFA = extrapolation 

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

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

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

46630101. b= Inhalation absorption factor assumed.

4.0 Dietary Exposure/Risk Characterization

The residue chemistry data submitted in support of proposed uses were evaluated by HED on 08-

MAY-2012 (Memo, G. Kramer; D389985). The drinking water assessment was completed by 

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

completed in a HED memorandum dated 08-MAY-2012 (Memo, G. Kramer; D389986).

4.1 Pesticide Metabolism and Environmental Degradation

4.1.1 Metabolism in Crops

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 MARC has 

determined that for risk assessment and tolerance expression, parent only is the residue of 

concern. Future new uses on root crops whose tops are significant food/feed items will require 

the analysis of samples for metabolite AEC614278.

4.1.2 Metabolism in Livestock

None of the subject crops have livestock food/feed items of regulatory interest; therefore, issues 

pertaining to livestock metabolism, analytical methods and storage stability data for and residues 

in livestock commodities are not addressed in the current petition.

4.1.3 Analytical Methodology

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 
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 19 of 36

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).

4.1.4 Environmental Degradation

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 

(degradate 1). Although it may be less toxic than the parent, degradate 1 is expected to be more 

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

and degradate 1 are the residues of concern for drinking water.

4.1.5 Comparative Metabolic Profile

The major route of dissipation for pyrimethanil is expected to be aerobic metabolism for both 

aqueous and terrestrial environments. Pyrimethanil partitions into the sediment, but is stable to 

anaerobic (total system) degradation in both soil and sediment systems. Pyrimethanil is stable to 

both hydrolysis and aqueous photolysis at environmental pHs, but is susceptible to photolysis in 

soil.

In plants, pyrimethanil is the only significant residue ranging from essentially all of the total 

radioactive residues (TRR) in carrots and tomatoes to 44% in lettuce. Limited metabolism of 

pyrimethanil occurs with minor amounts (less than 10%) of the phenyl and pyrimidyl 

hydroxylated metabolites (AE C614276, AE C614277, AE C614278, and AE C621312) being 

released after acid hydrolysis. Analysis of the foliage from apples and carrots confirmed that the 

metabolism of pyrimethanil in plants proceeded primarily via hydroxylation of the aromatic ring 

structures as well as the methyl groups.

In livestock, pyrimethanil is rapidly metabolized and excreted from lactating dairy cows. The 

observed total radioactive residues in edible tissues and milk were as follows: milk maximum 

residue of 0.069 ppm; liver - 0.363 ppm; kidney 0.249 ppm, and muscle 0.017 ppm. The 

metabolic pathway is similar to that of plants involving hydroxylation of the phenyl and 

pyrimidine rings as well as hydroxylation of the methyl substituents. Further metabolic reactions 

occur including cleavage of the phenyl ring to produce substituted pyrimidines. The major 

metabolite was AE C614276 (46% of the kidney residues, 63% of the milk residues resulting 

from hydroxylation of the phenyl ring). Hydroxylation of the pyrimidinyl ring of pyrimethanil 

resulted in formation of minor amounts of AE C614277. Hydroxylation of the methyl groups of 

pyrimethanil resulted in formation of minor amounts of AE C614278. Hydroxylation of the 

methyl groups of AE C614276 resulted in formation of minor amounts of AE C614800.

In rats, when pyrimethanil was administered orally, it was absorbed rapidly and eliminated 

within 24 hours. The major routes of elimination were the urine (approximately 72% of the 

administered dose), and the feces (17-18% of the administered dose). The main pathways of 

metabolism involved oxidation to phenols in either or both aromatic rings. The minor pathways 

of metabolism involved oxidation of the methyl group to the corresponding alcohol.
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 20 of 36

4.1.6 Toxicity Profile of Major Metabolites and Degradates

The primary residue of concern in both crop and animal commodities is pyrimethanil. In the 

animal metabolism, since major metabolites are produced following the oral administration of 

pyrimethanil, toxicology data for metabolites are completely supported by data obtained for 

pyrimethanil.

4.1.7 Pesticide Metabolites and Degradates of Concern

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 4.1.7. 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

4.1.8 Drinking Water Residue Profile

EFED reassessed pyrimethanil for the proposed new uses presented in this memo. Tier I SCIGROW screening concentration of combined total residues (pyrimethanil + 2-amino-4,6-

dimethylpyrimidine) in ground water for uses on small berries (caneberries and bushberries) are 

not expected to exceed 4.8 μg/L for previously estimated uses based on the registered seasonal 

application rate of 2.1 lb ai/A on strawberry in Florida (Memos, 22-OCT-2003, D283999 and 

D290313; 08-JAN-2009, D353180). 

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

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

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

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

These EDWCs correspond to the FL/strawberries (acute) and NY/grapes (chronic) scenarios.
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 21 of 36

Table 4.1.8. Estimated Drinking Water Concentrations for Combined Total Residues, Parent 

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

Chemical

Acute (peak) 

Surface Water 

Concentration 

(ppb)

Annual Average 

Surface Water 

Concentration

1-in-10-yr (ppb)

Average of Annual 

Average Surface 

Water Concentration 

(ppb)

Ground Water 

Concentration 

(ppb)

Pyrimethanil plus 

2-amino-4,6-

dimethylpyrimidine.

86.5 29.4 17.9 4.8

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

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

assessments, respectively.

4.1.9 Food Residue Profile

No new data were submitted to support tolerances on onion, bulb, subgroup 3-07A; onion, green, 

subgroup 3-07B; low-growing berry 13-07G crop subgroup; or small fruit vine climbing 

subgroup 13-07F, except fuzzy kiwifruit. The petitioner has requested that existing tolerances be 

expanded to their respective crops or crop groups.

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

magnitude of the residue study associated with this petition was GC/MSD Method 140/01/012. 

The 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 ginseng samples analyzed in this study were held in frozen storage for a maximum of 259 

days prior to analysis of pyrimethanil residues. There are adequate concurrent storage stability 

data to indicate that pyrimethanil residues are stable in/on ginseng for the duration of this study.

The submitted field trial residue data for ginseng are adequate. The field trial data reflect the 

proposed use pattern, an adequate number of trials were conducted in the appropriate geographic 

regions, and samples were analyzed for the residue of concern using validated data-collection 

methods. Per-trial-average-residues of pyrimethanil residues ranged from 0.099 to 0.585 ppm 

in/on three ginseng trials with samples harvested at a 29-day PHI (highest individual residue of 

0.69 ppm) from the three trials. Using the OECD tolerance calculation procedures for the 

residue data set indicates that the requested tolerance of 2.5 ppm for residues of pyrimethanil 

in/on ginseng is too high; a tolerance of 1.5 ppm is appropriate. A revised Section F is 

requested.

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 ScalaTM label. The 

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

4.1.10 International Residue Limits

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

U.S. and Codex tolerances/MRLs for residues of pyrimethanil in/on the bulb onion subgroup 3-

07A, green onion subgroup 3-07B, and grapes (small vine climbing fruit subgroup 13-07F) are 

not harmonized. For grapes, the European PHI is 21 days; the U.S., 7 days. Residues were thus 
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 22 of 36

higher in U.S. residue trials, necessitating a higher tolerance, and precluding harmonization. For 

the bulb onion subgroup 3-07A and green onion subgroup 3-07B, HED recommends that the 

U.S. tolerances be increased in order to harmonize with Codex; bulb onion subgroup 3-07A from 

0.10 to 0.20 ppm and green onion subgroup 3-07B from 2.0 to 3.0 ppm. The U.S. tolerances and 

Codex MRLs for strawberries (low-growing berry subgroup 13-07G) are harmonized. There are 

currently no established Codex, Canadian, or Mexican MRLs for pyrimethanil in/on ginseng.

4.2 Dietary Exposure and Risk

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

assessments were conducted using DEEM-FCIDTM, Version 2.03 which uses food consumption 

data from the USDA’s CSFII from 1994-1996 and 1998.

4.2.1 Acute Dietary Exposure/Risk

The unrefined acute assessment assumed that pyrimethanil residues are present in all 

commodities at tolerance levels and that 100% of all crops are treated. DEEM-FCIDTM Version 

7.81 default processing factors were used as necessary when empirical processing factors were 

not available. Drinking water was incorporated directly into the dietary assessment using the 

EDWCs generated by the PRZM/EXAMS water model.

The resulting acute dietary risk estimates for food and water combined are below HED’s LOC

(i.e., <100% of the aPAD) for the general U.S. population and all population subgroups at the 

95th percentile of the exposure distribution. Using the DEEM-FCIDTM software, dietary risk is 

estimated at 9.9% of the aPAD for the general U.S. population; 35% of the aPAD for all infants 

<1 years old, the population subgroup with the highest estimated acute dietary exposure to 

pyrimethanil; and 13% of the aPAD for the females 13-49 years of age population subgroup. 

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).

4.2.2 Chronic Dietary Exposure/Risk

The unrefined chronic assessment assumed that pyrimethanil residues are present in all 

commodities at tolerance levels and that 100% of all crops are treated. DEEMTM Version 7.81 

default processing factors were used to estimate residues in all commodities as appropriate when 

empirical processing factors are not available. As in the acute scenario, drinking water was 

incorporated directly into the chronic dietary assessment using the EDWC values generated by 

the PRZM/EXAMS water model.

The resulting chronic dietary risk estimates for food and water combined are well below HED’s 

LOC (i.e., <100% of the cPAD) for the overall U.S. population and all population subgroups. 

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

U.S. population and 64% 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).
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 23 of 36

Table 4.2. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Pyrimethanil.

Population

Subgroup

Acute Dietary1

95th Percentile Chronic Dietary1

aPAD 

(mg/kg/day)

Dietary 

Exposure

(mg/kg/day)

% aPAD cPAD 

(mg/kg/day)

Dietary 

Exposure

(mg/kg/day)

% cPAD

U.S. Population (total)

1.0 mg/kg 

bw/day

0.098872 9.9

0.17 mg/kg 

bw/day

0.023155 14

All Infants (<1 year old) 0.349561 35 0.092221 54

Children 1-2 years old 0.349561 34 0.108087 64

Children 3-5 years old 0.246781 25 0.074796 44

Children 6-12 years old 0.129627 13 0.034198 20

Youth 13-19 years old 0.061678 6.2 0.013698 8.1

Adults 20-49 years old 0.054748 5.5 0.012575 7.4

Adults 50+ years old 0.064706 6.5 0.017041 10

Females 13-49 years old 0.45 mg/kg 

bw/day

0.059322 13 0.013724 8.1

1

Population subgroups with the highest exposure and risk are in bold type.

4.2.3 Cancer Dietary Risk

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.” 

5.0 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.

5.1 Other (Spray Drift, etc.)

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for pyrimethanil. 

The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices. On a chemical-by-chemical basis, the Agency is now requiring interim 

mitigation measures for aerial applications that should be placed on product labels/labeling. The 

Agency has completed its evaluation of the new database submitted by the Spray Drift Task 

Force, a membership of U.S. pesticide registrants, and is developing a policy on how to 

appropriately apply the data and the AgDRIFT®computer model to its risk assessments for 

pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in 

place, the Agency may impose further refinements in spray-drift-management practices to reduce 

off-target drift with specific products with significant risks associated with drift.

6.0 Aggregate Risk Assessment and Risk Characterization

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 exposure, the acute and chronic 
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 24 of 36

aggregate risk assessments are equal to the acute dietary and chronic dietary estimates (food and 

water only), respectively (see Table 4.2).

6.1 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 4.2. As shown in Table 4.2, the acute 

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

subgroups.

6.2 Short- and Intermediate-Term Aggregate Risk

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

residential exposures are not expected. 

6.3 Long-Term 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 4.2. As shown in Table 4.2, the chronic risk estimates do not exceed the 

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

6.4 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. 

7.0 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/.

8.0 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 
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 25 of 36

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

Council for Exposure (ExpoSAC; Memo, J. Tyler, 08-MAR-2012, D389987).

8.1 Handler Exposure and Risk Estimates

Potential occupational handler exposure scenarios include: 1) mixing/loading liquids in support 

of aerial, airblast and groundboom applications; 2) applicators using open-cab airblast 

equipment; 3) aerial applicators; 4) applicators using open-cab ground boom equipment; and 5) 

flaggers. 

Handler exposure is expected to be short- and intermediate-term based on information provided 

on proposed labels (i.e., maximum of three sprays per season at a maximum rate of 0.70 lb ai/A). 

Typically, HED completes short- and intermediate-term assessments for occupational scenarios 

in all cases because these kinds of exposures are likely and acceptable use/usage data are not 

available to justify deleting intermediate-term scenarios. Based on use data and label 

instructions, HED believes that occupational exposures may occur over a single day or up to 

weeks at a time for many of the use-patterns and that intermittent exposure over several weeks 

may also occur. Some applicators may apply these products over a period of weeks, because 

they are commercial applicators who are completing multiple pesticide applications for multiple 

clients. Long-term exposures are not expected; therefore, a long-term assessment was not 

conducted. 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, the 

ORETF database, or other registrant-submitted occupational exposure studies. Some of these 

data are proprietary (e.g., AHETF data), and subject to the data protection provisions of the

Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). The standard values 

recommended for use in predicting handler exposure that are used in this assessment, known as 

“unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate 

Reference Table” (http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, 

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

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

For pesticide handlers, it is HED’s standard practice to present estimates of dermal exposure for 

“baseline”; that is, for workers wearing a single layer of work clothing consisting of a longsleeved shirt, long pants, shoes plus socks and no protective gloves, as well as for “baseline” and

the use of protective gloves or other PPE as might be necessary. The ScalaTM SC label requires 

applicators and other handlers to wear a long-sleeved shirt and long pants, shoes plus socks, and 

chemical-resistant gloves. 

Table 8.1 provides a summary of the estimated exposures and risks to occupational pesticide 

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

inhalation exposures. All estimated dermal and inhalation MOEs are >100 with baseline 

protection, except for airblast applicators. Airblast applicator dermal MOEs are >100 only with 

a baseline protection plus gloves and headgear. The proposed label requires applicators and 
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 26 of 36

other handlers to wear a long-sleeved shirt and long pants, shoes plus socks, and chemicalresistant gloves. The label should be amended to specify the use of chemical-resistant headgear 

for overhead exposure. RD should ensure the appropriate PPE is listed on the label. 
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 27 of 36

Table 8.1. Short- and Intermediate-term Exposure & Risk to Occupational Handlers From Applying Pyrimethanil to the Proposed New Use Sites.

Crop or Target Unit Exposure1

(mg ai/lb handled)

Applic. Rate2

(lb ai/A)

Units Treated3

(A/day)

Avg. Daily Dose4

(mg ai/kg bw/day) MOE5 Combined MOEs7

Mixer/Loader –Liquids –Aerial Applications

Ginseng, bulb vegetables, small 

fruit vine climbing, low-growing

berry

Dermal

Baseline6: 0.220

PPE-G

6

: 0.0376 0.70 350

Dermal

Baseline: 0.34

PPE-G: 0.059

Dermal

Baseline: 67

PPE-G: 390

PPE-G dermal + 

Baseline inhalation: 

Inhal. 390

Baseline: 0.000219

Inhal.

Baseline: 0.00067

Inhal.

Baseline: 34,000

Mixer/Loader –Liquids –Groundboom Applications

Ginseng, bulb vegetables, small 

fruit vine climbing, low-growing

berry

Dermal

Baseline: 0.220

0.70 80

Dermal

Baseline: 0.079

Dermal

Baseline: 290 Baseline dermal + 

inhalation:

290 Inhal.

Baseline: 0.000219

Inhal:

Baseline: 0.00015

Inhal.

Baseline: 150,000

Mixer/Loader –Liquids –Airblast Applications

Small fruit vine climbing

Dermal

Baseline: 0.220 0.70 40

Dermal

Baseline: 0.039

Dermal

Baseline: 590 Baseline dermal + 

inhalation:

590 Inhal.

Baseline: 0.000219

Inhal:

Baseline: 0.000077

Inhal:

Baseline: 300,000

Applying Sprays via Aerial Equipment

Ginseng, bulb vegetables, small 

fruit vine climbing, low-growing

berry

Dermal

Eng. Cont9: 0.005 0.70 350

Dermal

Eng. Cont: 0.0078

Dermal

Eng. Cont: 3,000 Eng. Control dermal 

+ inhalation:

2,900

Inhal.

Eng. Cont: 

0.000068

Inhal.

Eng. Cont: 0.00021

Inhal.

Eng. Cont: 110,000

Applying Sprays via Groundboom Equipment

Ginseng, bulb vegetables, small 

fruit vine climbing, low-growing

berry

Dermal

Baseline: 0.0786 0.70 80

Dermal

Baseline: 0.028

Dermal

Baseline: 820 Baseline dermal + 

inhalation:

820

Inhal.

Baseline: 0.00034

Inhal.

Baseline: 0.00024

Inhal.

Baseline: 97,000

Applying Sprays via Airblast Equipment

Small fruit vine climbing

Dermal

Baseline: 1.77

PPE-G

6

: 1.59

PPE-G, HG6: 0.22 0.70 40

Dermal

Baseline: 0.32

PPE-G: 0.28

PPE-G, HG: 0.039

Dermal

Baseline: 73

PPE-G: 81

PPE-G, HG: 590

PPE-G, HG dermal + 

Baseline inhalation:

570 Inhal.

Baseline: 0.00471

Inhal.

Baseline: 0.0016

Inhal.

Baseline: 14,000
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 28 of 36

Table 8.1. Short- and Intermediate-term Exposure & Risk to Occupational Handlers From Applying Pyrimethanil to the Proposed New Use Sites.

Crop or Target Unit Exposure1

(mg ai/lb handled)

Applic. Rate2

(lb ai/A)

Units Treated3

(A/day)

Avg. Daily Dose4

(mg ai/kg bw/day) MOE5 Combined MOEs7

Flagger

Ginseng, bulb vegetables, small 

fruit vine climbing, low-growing 

berry

Dermal

Baseline: 0.011 0.70 350

Dermal

Baseline: 0.017

Dermal

Baseline: 1,300 Baseline dermal + 

Inhal. inhalation: 1,300

Baseline: 0.00035

Inhal.

Baseline: 0.0011

Inhal.

Baseline: 22,000

1. Unit Exposures are taken from the Occupational Pesticide Handler Unit Exposure Surrogate Reference Table, September 2011. Inhal. = Inhalation. Units = mg ai/pound of ai handled. 

2. Applic. Rate. = Taken from ScalaTM SC label. 

3. Units Treated are taken from “Standard Values for Daily Acres Treated in Agriculture”; ExpoSAC SOP No. 9.1. Revised September 2001.

4. Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated * Absorption factor (dermal only = 51%) 80 kg Body Weight. 

5. MOE = Margin of Exposure = NOAEL ADD. NOAEL = 23.1 (dermal and inhalation) mg/kg bw/day.

6. Baseline = Long-sleeve shirt, long pants, and no gloves (dermal); no respirator (inhalation). PPE-G = Long-sleeve shirt, long pants, and gloves. PPE-G, HG = Long-sleeve, shirt, long pants, plus gloves and chemical-resistant hat.

7. Combined MOEs= NOAEL (mg/kg/day) / Combined dermal + inhalation dose (mg/kg/day).
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 29 of 36

8.2 Post-application Exposure and Risk Estimates

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

a foliar spray. Post-application exposure is expected to be short- and intermediate-term based on 

information provided on proposed labels (i.e., maximum of 3 sprays per season with a RTI of 1-2 

weeks). Only short-term exposure was assessed; however, the assessment is protective of 

intermediate-term exposures since the dermal endpoints are the same for both durations.

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 chemicalspecific 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/postapp-exposure-data.html.

Chemical-specific dislodgeable foliar residue (DFR) data were available for pyrimethanil on 

apples, grapes, and strawberries. Since DFR data are not available for the root vegetable crops, 

the available data were used as surrogates. Based on a review of the available data, it was 

decided that the DFR data for grapes would be used to estimate post-application exposure for the 

vine trellis crop group, and the strawberry DFR data would be used to estimate post-application 

exposure for the low-growing berry and root vegetable groups. 

Even though there are no data specifically for the root vegetable crops, it is believed that the 

strawberry data are representative of the root vegetable crops for the following reasons: (1) the 

data represents DFR data collected in the field, and (2) the application method, rate, and timing 

are similar between the DFR study and the proposed use sites. One caveat is the leaf texture of 

strawberries does not match the root vegetable crops.

Based on an analysis of the data, it is proposed that predicted grape and strawberry DFR values 

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

(0.900 for grape, and 0.808-0.883 for strawberries).

All agricultural crop scenarios resulted in MOEs greater than 100 on day 0, and are not of 

concern.

Table 8.2. Dermal Post-application Exposure and Risk Using Chemical Specific Data.

Crop Group Proposed Crop

Transfer 

Coefficients 

(cm2/hr)

DAT1Site

Predicted

DFR2 

(ug/cm2)

ChemicalSpecific 

Dermal Dose3 

(mg/kg/day)

ChemicalSpecific 

MOE4

Berry, low Low-growing 

berries 1,900 (irrigation) 0

CA 0.77 0.075 310

NY 0.38 0.037 630

Vegetable, 

root

Bulb vegetables, 

ginseng

4,200 (hand 

weeding) 0

CA 0.77 0.16 140

NY 0.38 0.081 250

Vine trellis Small fruit, vine 

climbing

19,300 (girdling, 

turning)

0

CA 0.21 0.21 110

1 0.17 0.17 140

1. DAT = Days after treatment

2. Predicted DFR residues
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 30 of 36

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

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

Inhalation: Based on the Agency's current practices, a quantitative occupational post-application 

inhalation exposure assessment was not performed for pyrimethanil at this time primarily 

because it has a low acute inhalation toxicity (Toxicity Category IV), has a low vapor pressure 

(<1 x 10-7 torr at 25oC), and is applied at a low use rate (0.70 lb ai/A). However, there are 

multiple potential sources of post-application inhalation exposure to individuals performing postapplication activities in previously treated areas. 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 

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 is in the process of evaluating the SAP report as well as available post-application 

inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and 

procedures, to identify the need for and, subsequently, the way to incorporate occupational postapplication inhalation exposure into the Agency's risk assessments. 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.

8.3 Restricted Entry Interval (REI)

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

following application) for all post-application activities, except for girdling, tying, and turning 

table grapes. For all other applications, the REI is based on the acute toxicity of pyrimethanil. 

Pyrimethanil is of low acute toxicity by oral, dermal, and inhalation routes (Acute Toxicity 

Categories III and IV), a slight eye irritant, not irritating to the skin, and not a dermal sensitizer. 

Acute Toxicity Category III and IV chemicals via these routes are supported by a 12-hour REI 

under the Worker Protection Standard (WPS).

9.0 Data Needs and Label Recommendations

9.1 Toxicology

A 90-day inhalation study (870.3465)

9.2 Residue Chemistry

Adjuvants were not used in any of the submitted residue field trials. Since adjuvants 

were not used in the submitted residue field trials, the label should prohibit such uses on 

ginseng; onion, bulb, subgroup 3-07A; onion, green, subgroup 3-07B; low-growing berry 

13-07G crop subgroup; or small fruit vine climbing subgroup 13-07F, except fuzzy 

kiwifruit.

A summary of the recommended tolerances along with recommendations for commodity 

definitions are presented in Appendix C. The petitioner is required to submit a revised 

Section F to reflect the recommendations in Appendix C.
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 31 of 36

9.3 Occupational and Residential Exposure

The label should be amended to specify the use of chemical-resistant headgear for 

overhead exposure. RD should ensure the appropriate PPE is listed on the label.

Appendix A: Toxicity Profile Tables.

Appendix B: Metabolism Assessment.

Appendix C: Tolerance Summary for Pyrimethanil.

RDI: RAB1 review (11-JAN-2012); G. Kramer (09-JAN-2012); D. Vogel (11-JAN-2012)

J. Tyler:S10943:PY1:(703)-851-5825(7509P)
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 32 of 36

Appendix A: Toxicity Profile Tables.

Table A.1. Acute Toxicity Profile – Pyrimethanil.

Guideline No./Study Type MRID No. Results Toxicity 

Category

870.1100/Acute oral toxicity

43345002

LD50 = 4149 mg/kg, M 5971 

mg/kg, F

III

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

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

870.2400/Primary eye irritation 43345004 slight eye irritant IV

870.2500/Primary dermal irritation 43345005 non irritant IV

870.2600/Dermal sensitization 43301605 not a sensitizer

Table A.2. 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 

weight, 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.
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 33 of 36

Table A.2. Toxicity Profile for Pyrimethanil.

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

Classification/Doses Results

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 mos],

serum cholesterol, GGT, rel. liver weights; liver, thyroid 

histopathology [ thyroid adenomas].

870.5100

Gene Mutation

43301624 (1990);

0, 15, 50, 150, 500 or 1500 

μg/plate in the presence and 

absence of mammalian 

metabolic activation (S9-mix)

Acceptable/Guideline

There was no evidence of induced mutant colonies over 

background.

870.5300

Gene Mutation

43301625 (1991);

0, 15, 50, 150, 500 or 1500 

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)

acceptable/guideline

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

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

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

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

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

Day 1.

870.6200b

Subchronic-Neurotoxicity 

Screening Battery (rat)

45657222 (1998)

unacceptable/Guideline 

(inadequate dosing)

0, 60, 600, 6000 ppm

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

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

NOAEL = 44.3 mg/kg/day [F]

LOAEL = 429.9 mg/kg/day [F], >391.9 mg/kg/day [M] based on 

body weight (8%), body weight gain (21%), food consumption (9-

15%) [F]. No effects in males.
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 34 of 36

Table A.2. Toxicity Profile for Pyrimethanil.

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

Classification/Doses Results

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# 389923

Page 35 of 36

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
Pyrimethanil Human-Health Risk Assessment DP# 389923

Page 36 of 36

Appendix C: Tolerance Summary for Pyrimethanil.

Tolerance Summary for Pyrimethanil.

Commodity Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

40 CFR §180.518 (a)(1)

Ginseng 2.5 1.5

Onion, bulb, subgroup 3-07A 0.10 0.20

Onion, green, subgroup 3-

07B

2.0 3.0

Berry and small fruit, small 

fruit vine climbing subgroup, 

except fuzzy kiwifruit 13-07F

5.0 5.0 Fruit, small, vine climbing, subgroup 

13-07F, except fuzzy kiwifruit

Berry and small fruit, low 

growing berry subgroup 13-

07G

3.0 3.0 Low growing berry subgroup 13-

07G