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TEMPLATE:

[ Janssen PMP, a Division of Janssen Pharmaceutica NV ]

[ Pesticide P etition number 3F8213 ]

EPA has received a pesticide petition ( [insert petition number] ) from [J anssen PMP, a Division of J anssen Pharmaceutica NV , located at 1125 Trenton

Harbourton 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 b y establishing a tolerance for r esidues of [ p yrimethanil (4,6

- dimethyl

- N

phenyl

- 2

- pyrimidinamine) ] in or on the raw agricultural commodit y [ pomegran a te ] at [ 5 .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 Che mistry

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 C6 14276, AE C614277, AE C614278, and AE C621312) being released after acid hydrolysis. Analysis of the foliage fromapples and carrots confirmed that the metabolism of pyrimethanil in plants proceeded primarily via hydroxylation of the aromatic ring structur es 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 e xtracted from apples by homogenization with aceto ne. An aliquot of the extract wa s 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 pomegranate as a postharvest dip/drench treatment . Trials were conducted in CA (Region 10), wher e 99% of the pomegranates are produced in t he United States . The trials were conducted 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 ora l (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 neurotox icity study , g roups 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 subs tantial 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 as say 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 overgestation 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 emacia tion. 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, de layed skeletal ossification and incidence of fetuses with 13 thoracic vertebrae and ribs. The d evelopmental NOAEL was 45 mg/kg/ day.

iii. Two

- generation reproduction

— Rat . Three groups of 30 Sprague

- Dawley rats per sex received dietary exposure to pyrimetha nil 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 weanin g, 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 differe nt 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 di etary

- 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 weig ht 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

wa s 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 centrilo bular 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 signif icant decreases in relative liver weights (females), pigmentation of thyroid follicles, urolithiasis, moderate urothelial hyperplasia in urinary bladder, and slight kidney tubular degeneration (females). The NO EL 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 hy perplasia 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 NO A EL was 80

m g/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 fin dings 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.

vi i

. Dermal tox icity 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 imm unotoxic 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 month s. 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 weightgain 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 co lloid 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 i ncreased 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 s econdary 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 roden t 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 rece ived 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 Carcinogenicit y 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 rea sonable 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 wer e the ur ine (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

. [ 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 fro m 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 d ose 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 fertili ty 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 resi due 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

- FCID TM (Ver 3.15), adding pomegranate at 5 ppm (proposed tolerance) to existing commodities. Tolerance level residues with 100% crop treated were used to calcul ate the estimates. The aPAD dose for the general population is 1 mg/kg/day; however the aPAD for Females 13

- 49 years of age is 0.45 mg/kg/day. The resulting acute food and drink risk estimates are <100% aPAD for the total US population at the 95 th percen tile 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 populat ion subgroup is also children 1

- 2 years old (76% of cPAD). It should be noted that this version of DEEM

- FCID uses the new consumption data (NHANES 2003

- 2008).

ii. Drinking Water

. [EPA drinking water values (2011) were used in the assessment. EDWCs we re 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 μ g/L. The maximum estimated annual mean non

- cancer chronic exposure concentration for the combined residues (adjusted for reg ional percent cropped area) is 29.4 μ g/L. These estimates are well below the Drinking Water Levels of Comparison (DWLOC) for all subpopulations. The aDWLOC is 22608, 31413 and 6851 μ g/L for Females 13

- 49, the US Population and Children 1

- 2 ( the most high ly exposed subpopulation ), respectively. The cDWLOC is 5899 and 1624 μ g/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
p otential 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 wa ter. ]

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 substanc es. ]

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 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 cPAD represents the level at or below which daily aggregate exposure over a lifetime will not pose app reciable 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. 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 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 inf ants 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

[ MRLs have neither been established in any countr y , n or CODE X 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. ]