COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE 

EPA Registration Division contact: Hope Johnson; (703) 305-5410

Bayer CropScience

4F8291

EPA has received a pesticide petition (4F8291) from Bayer CropScience, 2 T.W. 

Alexander Drive, Research Triangle Park, NC 27709 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

berries and small fruit: caneberry (crop subgroup 13-07A) at 15.0 parts per million 

(ppm) and berries and small fruit: bushberry (crop subgroup 13-07B) at 8.0 parts per 

million (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 crops by homogenization with acetone. An aliquot of the extract was 

diluted with a mixture of acetonitrile and water with subsequent residue 
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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 blackberry/raspberry as representative of the caneberry (Crop 

Subgroup 13-07 A) and blueberry as a representative of bushberry (Crop Subgroup 

13-07B). 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 shows low toxicity by the oral (toxicity 

category III), inhalation (toxicity category III), and dermal (toxicity category IV) 

routes. It is slightly irritating to the eyes and non-irritating to the skin in rabbit 

studies. Pyrimethanil is not a dermal sensitizer. Acute neurotoxicity of pyrimethanil 

in the rat was assessed, the NOAEL was 100 mg/kg due to reduced body 

temperature in males, and transient behavioral effects observed at the high dose 

tested (HDT).

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. An oral developmental toxicity study in the 

Sprague Dawley rat did not reveal any evidence of teratogenic potential. The 

maternal and developmental NOAEL was 85 mg/kg/day. An oral developmental 

toxicity study in New Zealand rabbits did not reveal any evidence of teratogenic 

potential and the NOAEL was 45 mg/kg/day. The maternal and developmental 

LOAEL was 300 mg/kg/day due to reduced body weights, reduced fecal production, 

and food consumption in the dams and decreased mean body weight, body weight 

gain, food consumption, and an increased incidence of fetuses with 13 thoracic 

vertebrae and ribs. A two-generation reproduction study in the Sprague-Dawley 

rats did not indicate any disruption of reproductive function. The NOAEL for 

maternal and developmental toxicity was 20.9 mg/kg/day due to reduced body 

weights at higher dose levels, and the reproductive NOAEL was 266.7 mg/kg/day, 

the HDT.

4. Subchronic toxicity. A 28–day dietary toxicity study was conducted in CD- 1 

mice established a NOAEL of 202 mg/kg/day. A 90-day dietary toxicity study in 

Sprague-Dawley rats showed a NOAEL of 54.5 and 66.7, in males and females, 

respectively. A 90-day dietary toxicity study was conducted in CD-1 mice and 

demonstrated a NOAEL of 139 and 203 mg/kg/day in males and females, 

respectively, based on changes found in the kidney, liver, thyroid, and urinary 

bladder at higher dose levels. A 90-day oral toxicity study in dogs showed a

NOAEL of 80 mg/kg/day due to decreased body weight and food consumption and 
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changes in clinical chemistry endpoints at 800 mg/kg/day. A subchronic 

neurotoxicity study in Sprague-Dawley rats indicated no treatment-related findings 

in behavioral assessments, neuropathology or brain morphometrics. The NOAEL 

was 44.3 mg/kg/day in females based upon decreased mean body weight, body 

weight gain and food consumption at 429.9 mg/kg/day. There were no treatment 

related effects in males at any dose level up to 391.9 mg/kg/day. A 28-day 

immunotoxicity study conducted in female Sprague-Dawley rats revealed no 

evidence of immune suppression at dose levels up to and including 652 mg/kg/day, 

the HDT.

5. Chronic toxicity. A 12-month chronic toxicity study in the dog 

demonstrated a NOAEL of 30 mg/kg/day due to a decrease in mean body weight 

gain and mean consumption of food and water at higher dose levels. 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 

984 mg/kg/day (males) and 1217 mg/kg/day (females), the HDT. A 2-year combined 

chronic toxicity/oncogenicity study conducted in the Sprague-Dawley rat showed a 

NOAEL of 17 mg/kg/day (males) and 22 mg/kg/day (females) due to decreased body 

weight gain and food consumption, and effects on the liver and thyroid at 221 

mg/kg/day (males) and 291 mg/kg/day (females). The results of mechanistic studies, 

demonstrate that the thyroid effects are likely secondary due to induction of 

enzymes in the liver involved in metabolism of thyroid hormones, a well 

characterized, threshold-mediated mechanism.

6. Animal metabolism. Metabolism and pharmacokinetic studies in the rat 

show rapid absorption and elimination within 24-hours of pyrimethanil 

administration. 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 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. There is no evidence to suggest that pyrimethanil has 

any potential primary endocrine disruption. Chronic, life span, and multigenerational bioassays in mammals and acute and subchronic studies on aquatic 

organisms and wildlife did not reveal any potential endocrine effects. Changes in the 

thyroid are secondary to induction of metabolic enzymes in the liver, and not due to 

a direct effect on endocrine mediated functions.

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 – 49 yrs. from an NOAEL of 45
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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 twogeneration reproduction study in rats. The special FQPA safety factor 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 DEEM-FCID Ver. 3.16 software for dietary analyses. 

Consumption data used in this program were taken from NHANES WWEIA 2003-

2008. The acute Tier 1 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 plus proposed uses on the caneberries and 

bushberries crop subgroups were included in the assessment. Acute exposure (95th

percentile) for food only utilizes 12.5% of the aPAD for Females 13-49 yrs. old and 

9.6% and 34% of the aPAD for the US Population and Children 1-2 yrs. old 

respectively. Chronic exposure utilizes 13.5% for the US Population and 75% for 

Children 1-2 yrs. old, 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 (2011) 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 86.5 g/L. The 

maximum estimated annual mean non-cancer chronic exposure concentration for 

the combined residues (adjusted for regional percent cropped area) is 29.4 g/L. 
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The addition of the acute estimated drinking water concentration (EDWC) of 86.5

ppb resulted in 9.8% of the aPAD utilized for the US Population, 13% of the aPAD 

utilized for females 13-49 yrs. old, and 38% utilized for Children 1-2 yrs. old, the 

most highly exposed subpopulation. The addition of the chronic EDWC of 29.4 ppb 

utilized 13.8% of the cPAD for the US Population and 76% of the cPAD for 

Children 1-2 yrs. old, the most highly exposed subpopulation. In conclusion, the 

results of these conservative acute and chronic estimates (including drinking water) 

are acceptable for all population subgroups examined. Therefore, there is a 

reasonable certainty that no harm will result from exposure to 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 

aggregate dietary (food and water) exposure will utilize about 14% of the cPAD for 

the US Population. Acute aggregate dietary exposure (food and water) for the U.S. 

population, utilizes 10% of the aPAD. Therefore, there is a reasonable certainty 

that no harm will occur to the US Population from aggregate exposure (food and 

drinking water) 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 and water for Children 1-2 yrs. old (the most highly exposed 

sub group) is about 76% of the cPAD. Acute aggregate dietary exposure to residues 

of pyrimethanil in food and water for Children 1-2 yrs. old (the most highly exposed 

sub group) is 38% of the aPAD. 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.
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F. International Tolerances

Codex tolerances are currently not available for pyrimethanil on caneberries 

or bushberries. Tolerances have been established for caneberries and bushberries in 

the EU at 10 ppm and 5 ppm, respectively.