EPA Registration Division contact: Andrew Ertman; (703) 308-9367 

IR-4

PP 1E7861 

 EPA has received a pesticide petition (1E7861) from IR-4, IR-4 Project 

Headquarters, Rutgers, The State University of NJ, 500 College Road East, Suite 201 W, 

Princeton, NJ 08540 proposing, pursuant to section 408(d) of the Federal Food, Drug, 

and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by 

establishing a tolerance for residues of pyrimethanil (4,6-dimethyl-N-phenyl-2-

pyrimidinamine) in or on the raw agricultural commodities onion, bulb, subgroup 03-

07A at 0.1 parts per million (ppm), onion, green, subgroup 03-07B at 2.0 ppm, berry and 

small fruit, small fruit vine climbing subgroup, except fuzzy kiwifruit 13-07F at 5.0 ppm, 

berry and small fruit, low growing berry subgroup 13-07G at 3.0 ppm and ginseng at 2.5 

ppm. EPA has determined that the petition contains data or information regarding the 

elements set forth in section 408 (d)(2) of the FDDCA; however, EPA has not fully 

evaluated the sufficiency of the submitted data at this time or whether the data supports 

granting of the petition. Additional data may be needed before EPA rules on the petition. 

A. Residue Chemistry

 1. Plant metabolism. The metabolic profile of pyrimethanil has been investigated 

following application to five different crops (apple, carrots, grapes, lettuce and tomatoes) 

and is well understood. 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. 

 2. Analytical method. The plant metabolism studies demonstrated that analysis for 

the parent compound, pyrimethanil is sufficient to enable the assessment of the relevant 

residues in crop commodities. Pyrimethanil was extracted from apples by 

homogenization with acetone. An aliquot of the extract was diluted with a mixture of 

acetonitrile and water with subsequent residue determination by HPLC-MS/MS. The 

method allows the detection and measurement of residues in or on agricultural 

commodities at or above the proposed tolerance level. 

 3. Magnitude of residues. Magnitude of residue trials were conducted for 

pyrimethanil on bulb onion as a representative of the bulb onion subgroup 03-07A, on 

green onions as a representative for the green onion subgroup 03-07B, on grapes as a 

representative for the small fruit vine climbing except fuzzy kiwifruit subgroup 13-07F, 
on strawberries as a representative for the low growing berry subgroup 13-07G, and on 

ginseng. Trials were conducted in the various required regions across the United States in 

accordance with EPA guidance for crop field trials under OPPTS 860.1500. 

B. Toxicological Profile

 1. Acute toxicity. Pyrimethanil is of low toxicity by the oral (toxicity category 

III), inhalation (toxicity category III), and dermal (toxicity category III) routes. It is 

slightly irritating to the eyes and non-irritating to the skin in rabbit studies. Pyrimethanil 

is not a dermal sensitizer. In an acute neurotoxicity study, groups of 10 rats/sex/group 

were dosed once by oral gavage at dose levels of 0, 30, 100, 

1,000 mg of pyrimethanil/kg bodyweight. On the day of dosing, high dose animals 

experienced transient behavioral effects attributable to receipt of a substantial bolus dose 

of test substance. No histopathological lesions accompanied these transient behavioral 

changes. The NOAEL was 100 mg/kg due to reduced body temperature for males. 

 2. Genotoxicty. Pyrimethanil is not mutagenic or genotoxic in any assay in either 

the presence or absence of metabolic activation.

 3. Reproductive and developmental toxicity. Pyrimethanil is not a developmental 

or reproductive toxicant. 

i. Developmental—Rat. Thirty Sprague Dawley rats/group received doses of 0, 7, 85, 

1,000 mg/kg/day of pyrimethanil by gavage from gestation days 6–15. At the highest 

dose tested (HDT), reduced maternal body weight gain was observed during gestation 

days 6–15, along with a slight but statistically significant decrease in food consumption, 

hair loss, hunched posture, slight emaciation, and slightly reduced mean fetal body 

weight. The maternal and developmental no observed adverse effect level (NOAEL) was 

85 mg/kg/day. 

ii. Developmental —Rabbit. Groups of at least 18 time-mated New Zealand white rabbits 

received oral gavage doses of 0, 7, 45 or 300 mg/kg/day pyrimethanil over gestation days 

7–19. At the HDT, there was a decrease in body weight gain, production of feces and 

food consumption. Three females were euthanized due to severe emaciation. The HDT, 

300 mg/kg/day exceeded the maternal maximum tolerated dose (MTD). The maternal 

NOAEL was 45 mg/kg/day due to reduced fecal production in 1/3 of the animals. The 

HDT resulted in reduced mean fetal body weight, increased incidence of runts, delayed 

skeletal ossification and incidence of fetuses with 13 thoracic vertebrae and ribs. The 

developmental NOAEL was 45 mg/kg/day. 

iii. Two-generation reproduction—Rat. Three groups of 30 Sprague-Dawley rats per sex 

received dietary exposure to pyrimethanil at levels of 0, 1.7, 20.9 or 266.7 mg/kg/day. In 

the parental generation at the highest dose tested there was a statistically significant 

decrease in mean body weight gain in both sexes. Mean pup weights, observed on 

postnatal day (PND1) through weaning, were reduced, though were within the range of 

historical controls. In the F1 generation at the HDT, mean body weights and mean food 

consumption were reduced. Though the mean score for the combined sexes was the same 
as the controls, a marginally different air-righting reflex at PND11 associated with 

reduced body weight was seen in high dose male pups. The NOAEL for maternal and 

developmental toxicity was 20.9 mg/kg/day. The reproductive NOAEL was 266.7 mg/kg/ 

day.

 4. Subchronic toxicity. i. 28–day dietary - Rat. Five Sprague-Dawley

rats/sex/group received dietary exposure to pyrimethanil for 28 days at 0, 844, 1,161, 

1,500, and 2,710 mg/kg/ day. All doses exceeded the maximum tolerated dose. Severe 

emaciation was observed at all dose levels. Body weight gains and food consumption 

were reduced. Liver and thyroid histopathology were observed, along with reduced 

hemoglobin, Maxium Concentration Volume (MCV), and Mean Corpuscular Hematocrit 

(MCH). Kidney, adrenal and liver weights were altered. No NOAEL was achieved.

ii. 90–Day dietary—Rat. Ten Sprague- Dawley rats/sex/group received pyrimethanil in 

the diet at dose levels of 0, 5.4–6.8, 54.5–66.7, 545–667 mg/kg/ day (males and females, 

respectively). High dose animals had reduced body weight gain and food consumption, 

increased urinary protein in males, colored urine (not blood or bilirubin) and minimal 

hepatocellular hypertrophy. The NOAEL in males was 54.5–66.7 (males and females, 

respectively) due to colored urine and a low incidence of minimal centrilobular 

hepatocellular hypertrophy. 

iii. 28–Day dietary—Mouse. Five CD- 1 mice/sex/group received dietary doses of 0, 

167–236, 567–667, 1,960–2,357 mg/kg/day males and females respectively, for 28 days 

(all the mice in one additional high dose group, 30,000 ppm, died within the first week of 

the study). At 1,960–2,357 mg/kg/day, animals experienced body weight loss (females), 

decreased body weight gain during the first 2 weeks (males), a statistically significant 

decrease in cholesterol, statistically significant decreases in relative liver weights 

(females), pigmentation of thyroid follicles, urolithiasis, moderate urothelial hyperplasia 

in urinary bladder, and slight kidney tubular degeneration (females). The NOEL was 

167–236 mg/kg/day. 

iv. 90–Day dietary—Mouse. Twenty CD-1 mice/sex/group received pyrimethanil diet 

exposure at dose levels of 0, 12–18, 139–203, 1,864–2,545 mg/kg/day males-females for 

90 days. At the high dose, animals had decreased body weight and increased food 

consumption, cholesterol and total bilirubin. High dose females had increased relative 

liver weights. Histopathology in the high dose animals was found in the kidneys, liver, 

thyroid and urinary bladder. High dose males had slight urinary tract tubular dilation and 

slight to moderate hyperplasia of bladder epithelium. Based on mild hepatic glycogen 

depletion, the NOAEL was 139–203 mg/kg/day (males and females, respectively). 

v. 90–Day dietary—Dog. Four beagle dogs/sex/group received pyrimethanil by gavage 

for 90 days at doses of 0, 6, 80, 1,000 mg/kg/day. The high dose was lowered to 800 

mg/kg/day on day 7 due to frequent and consistent vomiting. Decreased body weight, 

food and water consumption were observed. Males had a significant reduction in 

phosphate, while females experienced a slight reduction in sodium, anion gap and total 

protein. At 80 mg/kg/day, infrequent vomiting after dosing and decreased water 
consumption were observed. After 4 weeks of dosing at 80 mg/kg/day, males had 

significantly reduced phosphate. The NOAEL was 80 mg/kg/day. 

vi. Subchronic Neurotoxicity – rat. Groups of 12 Sprague-Dawley rats per sex were 

treated for 13 weeks with pyrimethanil via the diet at 0, 4, 38.7-44.3, 391.9-429.9 

mg/kg/d (males and females, respectively). There were no treatment-related findings in 

behavioral assessments, neuropathology or brain morphometrics. The NOAEL was 44.3 

mg/kg/day in females based upon decreased body weight and food consumption in the 

high dose group. There were no treatment related effects in males. 

vii. Dermal toxicity evaluation. No dermal studies have been conducted for pyrimethanil. 

vii. Pyrimethanil was evaluated for immunotoxic potential in female rats following 28 

consecutive days of treatment by dietary administration. This study revealed no evidence 

of immunotoxic potential at dose levels up to and including 652 mg/kg/day, the highest 

dose tested. 

 5. Chronic toxicity. i. Chronic toxicity—Dog. Four beagle dogs/sex/ group 

received pyrimethanil by gavage at levels of 0, 2, 30, or 250 mg/kg/day for 12 months. 

The high dose was reduced from 400 to 250 mg/kg/day on day 8 of treatment due to 

excessive vomiting during the first week of treatment. At the high dose, there was a 

decrease in mean body weight gain and mean consumption of food and water. The 

NOAEL for the study was 30 mg/kg/day. 

ii. Combined chronic toxicity/ oncogenicity—Rat. Seventy Sprague- Dawley 

rats/sex/group received pyrimethanil by diet at levels of 0, 1.3–1.8, 17–22, 221–291 

mg/kg/day (males and females, respectively) for 2 years. At the HDT, body weight gain 

and food consumption were decreased. Absolute liver weights were increased.

Histopathology revealed centrilobular hepatocyte hypertrophy, increased incidence of 

eosinophilic foci (males), thyroid follicular hyperplasia, hypertrophy and colloid 

depletion, and the presence of a brown pigment, identified as lipofuscin in thyroid

follicular cell epithelium. There was a statistically significant, dose-dependent increase in 

the incidence of benign thyroid follicular cell adenomas. There was no increased 

incidence in any malignant tumor or increase in tumor multiplicity as a result of daily 

dietary ingestion of pyrimethanil at any dose level. The results of special studies,

discussed below, demonstrate that the benign thyroid tumors are likely a secondary result 

of a disruption of thyroid-pituitary homeostasis, a well known, threshold-mediated 

mechanism. The NOAEL was 17 mg/kg/day (males) and 22 mg/kg/day (females). 

iii. Oncogenicity—Mouse. Two oncogenicity studies were conducted using CD-1 mice 

continually exposed to pyrimethanil by administration in the diet. These lifetime feeding 

studies demonstrated no evidence of oncogenic potential at dose levels up to and 

including 1000 mg/kg/day, the highest dose tested. 

iv. Special studies. Since rodent thyroid tumors are fairly common, and since the EPA has 

established that five lines of evidence are required to prove the thyroid-pituitary 

disruption mode of action for rodent thyroid tumors, special studies were undertaken. 
a)Thyroid mechanistic study (14–day). Sprague Dawley rats received 378.5 mg/ kg/day 

of pyrimethanil for 14 days to study the effects of pyrimethanil on the thyroid and liver 

microsomal enzymes. An increase in the levels of UDPGT and a corresponding 

statistically significant increase in liver weight were observed. Thyroid hormones T4 and 

T3 were decreased, while TSH levels were significantly increased. All effects were 

shown to be reversible. b) Dietary thyroid function test using perchlorate discharge (7–

day). Sprague Dawley rats received 509 mg/kg/day pyrimethanil or 177 mg/kg/day 

propylthiouracil, or 109 mg/kg/day phenobarbital in order to study the function of the 

thyroid gland. The animals fed pyrimethanil had 43% decreased body weight gain, 21% 

decreased food consumption and a 150% increase in uptake of iodine-125. There was no 

significant discharge of radioactive iodine from the thyroid after administration of 

perchlorate. The required five lines of evidence to support the threshold mode of action 

for thyroid pituitary disruption and rat thyroid tumors are satisfied in the pyrimethanil 

studies. EPA’s final rule establishing a tolerance for pyrimethanil in wine stated that 

‘‘The Agency’s Carcinogenicity Peer Review Committee (CPRC) chose a non-linear 

approach MOE based on a NOAEL of 17 mg/kg/ day for increased incidences of thyroid 

tumors in rats. The MOE methodology was selected because of thyroid tumors associated 

with administration of pyrimethanil in the rat, which may be due to a disruption in the 

thyroid pituitary status. This chemical has been classified as a Group C chemical 

(possible human carcinogen) and a nonlinear methodology MOE was applied for the 

estimation of human cancer risk. The estimated MOE does not exceed the Agency’s level 

of concern and therefore, EPA has a reasonable certainty that no harm will result from 

exposures to residues of pyrimethanil.” 

 6. Animal metabolism. When pyrimethanil was orally administered to rats, 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 (1 7-1 8% of the 

administered dose). The main pathways of metabolism involved oxidation to phenols in 

either or both aromatic rings. The minor pathway of metabolism involved oxidation of 

the methyl group to the corresponding alcohol. 

 7. Metabolite toxicology. Not applicable. The primary residue of concern in both 

crop and animal commodities is pyrimethanil. 

 8. Endocrine disruption. Chronic, life span, and multi-generational bioassays in 

mammals and acute and subchronic studies on aquatic organisms and wildlife did not 

reveal endocrine effects. 

C. Aggregate Exposure

 1. Dietary exposure. For dietary analysis, an acute reference dose (aRfD) of 0.45 

mg/kg/day was derived for females 13 - 50 from an NOAEL of 45 mg/kg/day in the 

rabbit developmental study, based on an increased incidence of fetuses with 13 thoracic 

vertebrae and ribs, and an uncertainty factor of 100. For the general population including 

infants and children, the acute reference dose is 1 mg/kg/day from on an NOAEL of 100 

mg/kg/day in the acute rat neurotoxicity study, based on transient behavioral effects, and 

an uncertainty factor of 100. A chronic reference dose (cRfD) of 0.17 mg/kg/day for all 
populations was derived from the chronic toxicity study in the rat, based on decreased 

body weight gain and food consumption, increased liver weights and histopathological 

changes, and an uncertainty factor of 100. EPA has evaluated the potential for increased 

susceptibility of infants and children from exposure to pyrimethanil and has determined 

there was no quantitative or qualitative evidence of increased susceptibility following 

prenatal exposure (in rats and rabbits), or postnatal exposure (in rats). There were no 

effects on fertility or reproduction in the two-generation reproduction study in rats. The 

special FQPA SF has been reduced to 1X based on toxicological considerations, the 

nature of the assumptions used 

in the dietary exposure risk assessments, the completeness of the residue chemistry and 

environmental fate databases, and the lack of the potential for residential exposures. 

Acute and chronic Population Adjusted Doses (aPAD and cPAD) are, therefore, the same 

as the reference doses for the populations and subpopulations of interest. 

 i. Food. Dietary exposure to pyrimethanil was estimated from potential residues 

on food using CARES Version 3.0 software for dietary analyses. The acute Tier One 

assessments used 100% crop treated and tolerance level residue values. The chronic Tier 

2 assessment is based on tolerances, average residue values for key crops and percent 

crop treated values for key crops from the 2004 EPA assessment. All registered uses, 

pending uses on caneberry and bushberry subgroups, and new proposed uses on ginseng 

and the bulb onion, green onion, small fruit vine climbing except fuzzy kiwifruit, and low 

growing berry subgroups were included in the assessment. Acute exposure utilizes 

16.3% of the aPAD for Females 13-49 and 10.3% and 31.5% of the aPAD for the US 

Population and Children 1-2 respectively. Chronic exposure utilizes 1.0% for the US 

Population and 4.7% for Children 1-2, the most highly exposed subpopulation. These are 

conservative estimates and actual exposures are likely to be much less. 

 ii. Drinking Water. EPA drinking water values (2004) were used in the 

assessment. EDWCs were calculated for use on strawberries (the scenario resulting in 

the highest drinking water exposure), and included pyrimethanil and its major metabolite 

(2-amino-4,6-dimethylpyrimidine). The surface water estimated drinking water 

concentrations (EDWCs) were determined using PRZM/EXAMS (Pesticide Root Zone 

Model/Exposure Analysis Modeling System). Ground water EDWCs, calculated using 

SCI-GROW (Screening Concentration in Ground Water), model were lower than the 

surface water EDWCs. For surface water, the maximum estimated peak acute 

concentration of the combined residues is 37.8 μg/L. The maximum estimated annual 

mean non-cancer chronic exposure concentration for the combined residues (adjusted for 

regional percent cropped area) is 5.1 μg/L. These estimates are well below the Drinking 

Water Levels of Comparison (DWLOC) for all subpopulations. The aDWLOC is 22608, 

31413 and 6851 μg/L for Females 13-49, the US Population and Children 1-2 (the most 

highly exposed subpopulation), respectively. The cDWLOC is 5899 and 1624 μg/L for 

the US Population and Children 1-2 (the most highly exposed subpopulation), 

respectively. 
These conservative estimates indicate there is no concern for dietary exposures from 

potential residues of pyrimethanil in food and drinking water.

 2. Non-dietary exposure. Pyrimethanil is not registered for use on any sites that 

would result in residential exposure. Therefore, the aggregate risk is the sum of the risk 

from food and water. 

D. Cumulative Effects

 Section 408(b)(2)(D)(v) requires that, when considering whether to establish, 

modify, or revoke a tolerance, the Agency consider “available information” concerning 

the cumulative effects of a particular pesticide’s residues and “other substances that have 

a common mechanism of toxicity.” EPA has not made a common mechanism of toxicity 

finding as to pyrimethanil and any other substances and pyrimethanil does not appear to 

produce a toxic metabolite produced by other substances. 

E. Safety Determination

 1. U.S. population. Risk assessments for pyrimethanil are based on a complete 

and reliable toxicity data package and highly conservative assumptions. Chronic dietary 

(food) exposure will utilize 1% of the cPAD for the US Population. The chronic EDWC 

is more than 1000 fold lower than the cDWLOC. EPA generally has no concern for 

exposures below 100% of the cPAD because the cPAD represents the level at or below 

which daily aggregate exposure over a lifetime will not pose appreciable risk to human 

health. Acute dietary (food) exposure for females 13-49, representing the most sensitive 

subpopulation of the overall U.S. adult population, utilizes only 10.3% of the aPAD using 

highly conservative assumptions and the aEDWC is more than 500 fold lower than the 

aDWLOC. Therefore, there is a reasonable certainty that no harm will occur to the US 

Population from aggregate exposure (food, drinking water and non-dietary) to residues of 

pyrimethanil. 

 2. Infants and children. EPA has determined that the toxicology database for 

pyrimethanil regarding potential pre- and post-natal effects in children is complete and 

does not indicate any particular developmental or reproductive concerns. The special 

FQPA SF has been reduced to 1X. Using the conservative assumptions described in the 

exposure section above, chronic dietary exposure to residues of pyrimethanil in food for 

Children 1-2 (the most highly exposed sub group) is less than 5% of the cPAD. The 

chronic EDWC is more than 300 fold lower than the cDWLOC. Acute dietary exposure 

to residues of pyrimethanil in food for Children 1-2 (the most highly exposed sub group) 

is 31.5% of the aPAD. The chronic EDWC is more than 180 fold lower than the 

cDWLOC. There are no non-dietary concerns for infants and children. Therefore, there is 

a reasonable certainty that no harm will occur to infants and children from aggregate 

exposure to residues of pyrimethanil.

F. International Tolerances

 Codex MRLs have been established for pyrimethanil on bulb onions at 0.2 ppm. 
Codex MRLs have not been established for pyrimethanil on ginseng and the bulb onion, 

green onion, small fruit vine climbing except fuzzy kiwifruit, and low growing berry 

subgroups. Codex MRLs are established on grapes at 4.0 ppm and strawberries at 3.0 

ppm. In addition, MRLs have been established for onions and strawberries in the EU at 

0.1 ppm and 5.0 ppm, respectively.