COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE 

EPA Registration Division contact: [Hope A. Johnson, Acting Product Manager, 

Team 21 (703) 308-9354] 

• INSTRUCTIONS: Please utilize this outline in preparing tolerance petition 

documents. In cases where the outline element does not apply please insert "NARemove" and maintain the outline. The comment notes that appear on the left 

margin represent hidden typesetting codes designed to expedite the processing of the 

Federal Register document. Please do not remove or alter these comment notes or 

change the margins, font, or format in your document. Simply replace the 

instructions that appear in italics and brackets, i.e., "[insert company name]," with 

the information specific to your action.] 

TEMPLATE: 

[Janssen PMP, a Division of Janssen Pharmaceutica NV] 

[Insert petition number] 

EPA has received a pesticide petition ([insert petition number]) from (Janssen 

PMP, a Division of Janssen Pharmaceutica NV, located at 1125 TrentonHarbourton Road, Titusville, NJ 08560] 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-Nphenyl-2-pyrimidinamine)] in or on the raw agricultural commodity[pomegranate] at 

[4.0] pans 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 ~upport~ granting of the petition. Additional data may be needed before 

EPA rules on the petition. 

A. Residue Chemistry 

1 Plant metaho/isrn. [The metabolic profile of pyrimethanil has been 

investigated following application to five different crops (apple, carrots, grapes, 

lettuce and tomatoes) and is weU understood. In plants, pyrimetbanil 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.J 

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(~{ residues. [Magnitude of residue trials were conducted for 

pyrimethanil on pomegranate as a postharvest dip/drench treatment. Trials were 

conducted in CA (Region 10), where 99% of the pomegranates are produced in the 

United States. The trials were conducted in accordance with EPA guidance for crop 

field trials under OPPTS 860.1500.] 

B. Toxicolo~ical Profile 

J Acute toxicity. I 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 pyrimethanillkg 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. Genotoxictv. (Pyrimethanil is not mutagenic or genotoxic in any assay in 

either the presence or absence of metabolic activation.( 

3 Reproductire and derelopmelllalwxicity. [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/kglday 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. Developmelltal-Rabbit. Groups of at least 18 time-mated New Zealand white 

rabbits received oral gavage doses of 0, 7, 45 or 300 mg/kglday 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/kglday exceeded the maternal maximum 

tolerated dose (MTD). The maternal NOAEL was 45 mg/kglday 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/kglday. 

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/kglday. In the parental generation at the highest dose tested there was a 

statisticaiJy 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 HOT, 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 mglkglday. 

The reproductive NOAEL was 266.7 mg/kgl day.] 

4. Subcllronic 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/kgl 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 mglkgl 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 hepatoceiJular 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/kglday 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/kglday, animals experienced body weight 

loss (females), decreased body weight gain during the rrrst 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 

deg~neration (females). The NOEL was 167-236 mg!kglday. 
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 mglkglday 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 mglkglday 

(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 mglkglday. The high dose was lowered 

to 800 mglkglday 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 mglkglday, infrequent vomiting after dosing and 

decreased water consumption were observed. After 4 weeks of dosing at 80 

mglkglday, males had significantly reduced phosphate. The NOAEL was 80 

mglkglday. 

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 

mglkgld (males and females, respectively). There were no treatment-related fmdings 

in behavioral assessments, neuropathology or brain morphometries. The NOAEL 

was 44.3 mglkglday 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 mglkglday, 

the highest dose tested.] 

5. Chronic ro.ncil\ [i. Chronic toxicity-Dog. Four beagle dogs/sex/ group 

received pyrimethanil by gavage at levels of 0, 2, 30, or 250 mg/kglday for 12 

months. The high dose was reduced from 400 to 250 mg/kglday 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/kglday. 

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!kglday (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 

foUicular 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 mglkglday (males) and 

22 mglkglday (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 mglkg/day, the highest dose tested. 

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

EPA bas established that five lines of evidence are required to prove the thyroidpituitary 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 pyrimetbanil 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 mglkg/day 

pyrimethanil or 177 mglkglday propylthiouracil, or 109 mglkg/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 mglkg/ 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 bas a reasonable certainty that no harm will 

result from exposures to residues of pyrirnethanil."] 
6 1ni111al mcwbo/i~m [When pyrimethanil was oraUy 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 maio 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 Metaholh rm icolog). [Not applicable. The primary residue of concern in 

both crop and animal commodities is pyrimethanil.] 

8. Ellll<'c'rint disruption I Chronic, life span, and multi-generational bioassays 

in mammals and acute and subchronic studies on aquatic organisms and wildlife did 

not reveal endocrine effects. I 

C. Aggregate E.\po.wre 

1 Dit rory < '.f>o.wre. [For dietary analysis, an acute reference dose (aRID) of 

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

from on an NOAEL of 100 mglkglday in the acute rat neurotoxicity study, based on 

transient behavioral effects, and an uncertainty factor of 100. A chronic reference 

dose (cRID) of0.17 mglkg/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 pyrimetbanil and bas 

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 effect~ on fertility or reproduction in the twogeneration reproduction study in rats. The special FQPA SF bas 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. [A revised acute and chronic exposure analyses were performed with 

DEEM-FCIDTM (Ver 3.15), adding pomegranate at 4 ppm (proposed tolerance) to 

existing commodities. Tolerance level residues with 100% crop treated were used to 

calculate the estimates. The aP AD dose for the general population is 1 mglkg/day; 

however the aPAD for Females 13-49 years of age is 0.45 mglkg/day. The resulting 

acute food and drink risk estimates are <100% aPAD for the total US population at 

the 95th percentile of the exposure distribution. The most exposed population 

subgroup is children 1-2 years of age (38% of the aPAD). The resulting chronic 

food and drinking water estimates are <100% cPAD for the US general population. 
The most highly exposed population subgroup is also children 1-2 years old (76% of 

cP AD). It should be noted that this version of DEEM-FCID uses the new 

consumption data (NHANES 2003-2008). 

ii Drinkmg Wotcr. [EPA drinking water values (2011) were used in the 

assessment. EDWCs were calculated for the combined residues of pyrimethanil 

(parent+ 2-amino-4,6-dimethylpyrimidine) from use on strawberries (acute) and 

grapes (chronic) which were the scenarios resulting in the highest drinking water 

exposure. The surface water estimated drinking water concentrations (EDWCs) 

were determined using Tier II PRZM!EXAMS (Pesticide Root Zone 

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

using Tier I 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 )lg!L. The maximum 

estimated annual mean non-cancer chronic exposure concentration for the 

combined residues (adjusted for regional percent cropped area) is 29.4 )lg!L. These 

estimates are well below the Drinking Water Levels of Comparison (DWLOC) for 

all subpopulations. The aDWLOC is 22608, 31413 and 6851 )lgiL for Females 13-

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

respectively. The cDWLOC is 5899 and 1624 )lgiL 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 npo.wre [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 E.fl'ecl.\' 

[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 fmding as to pyrimethanil and any other substances 

and pyrimethanil does not appear to produce a toxic metabolite produced by other 

substances.] 

E. Sqfety Determination 

I 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 13.9% 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 

cP AD 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 children, 1-2 years old, representing the most sensitive subpopulation 

of the overall U.S. adult population, utilizes only 38% 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 ln/mzt'i and lhildren [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 76% 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 38.03% 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. lnremational Tolerance:, 

[MRLs have neither been established in any country, nor CODEX for 

pyrimethanil on pomegranates. Codex MRLs have been established for 

pyrimethanil on bulb onions at 0.2 ppm. 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.]