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[JanssenPMP, a Division ofJanssen PharmaceuticaNV] [Insertpetition number]

EPA has received a pesticide petition ([insert petition number]) f rom (Janssen PMP, a Division ofJanssen Pharmaceutica NV, located at 1125 TrentonHarbourton Road, Titusville, NJ08560] proposing, pursuant to section408(d) ofthe Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C

. 346a(d), to amend 40CFR part 180 by establishing a tolerance for residues of [pyrimethanil (4,6-dimethyl-Nphenyl-2-pyrimidinamine)] in oron 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) ofthe FDDCA; however, EPA has not fully evaluated the sufficiency ofthe submitted data at this time or whether the data**~upport~** granting ofthe petition

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

A. Residue Chemistry

1 Plantmetaho/isrn. [The metabolic profile ofpyrimethanil hasbeen investigated following application tofive differentcrops (apple,carrots, grapes, lettuce and tomatoes) and is weU understood. In plants, pyrimetbanil is the only significant residue ranging from essentially all oftheTotal RadioactiveResidues (TRR) in carrots andtomatoes to44% in lettuce. Limited metabolism of pyrimethanil occurs with minoramounts (less than 10%)ofthe phenyl and pyrimidyl hydroxylated metabolites (AE C614276, AE C614277, AE C614278, and AE C621312) being released after acid hydrolysis. Analysis ofthe foliage fromapples 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 overgestation days 7-19. Atthe HDT, there was a decrease in body weight gain, production offeces and food consumption. Threefemales were euthanized due to severeemaciation. The HDT, 300 mg/kglday exceeded the maternal maximum tolerated dose (MTD). Thematernal NOAEL was 45 mg/kglday due to reduced fecal production in 1/3 ofthe animals. The HDT resulted in reduced mean fetal body weight, increased incidenceofrunts, 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 groupsof30 Sprague-Dawley ratsper sex received dietary exposuretopyrimethanil atlevels of0, 1.7, 20.9 or266.7 mg/kglday. In the parentalgeneration atthe highest dose tested there was a statisticaiJy significantdecrease in mean body weightgain in both sexes. Mean pup weights, observed on postnatal day (PND1) through weaning, were reduced,though
were within the range ofhistorical controls. In theF1 generation atthe HOT, mean body weights and mean food consumption were reduced. Though the mean score for the combined sexes was thesame as the controls, a marginally different air-righting reflex atPND11 associated with reduced body weight was seen in high dose male pups. TheNOAEL for maternal and developmental toxicity was 20.9 mglkglday. Thereproductive NOAEL was 266.7 mg/kgl day.]
4. Subcllronic toxicity. [i. 28-day dietary- Rat. FiveSprague-Dawley rats/sex/group received dietary exposure to pyrimethanilfor 28 days at0, 844, 1,161, 1,500, and 2,710 mg/kgl day. All doses exceeded the maximum tolerated dose

. Severe emaciation was observed atall 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 werealtered. No NOAEL
was achieved.

ii.90-Daydietary-Rat. Ten Sprague- Dawley rats/sex/group received pyrimethanil in the dietat dose levels of0, 5.4-6.8, 54.5-66.7,545-'-667 mglkgl day (males and females, respectively). High dose animals had reduced body weightgain andfood consumption, increased urinaryproteinin males,colored urine (not blood or bilirubin) and minimal hepatocellular hypertrophy. TheNOAEL in males was 54.5- 66.7 (males and females, respectively) due tocolored urineand a low incidenceof minimal centrilobularhepatoceiJularhypertrophy.

iii.28-Day dietary-Mouse. Five CD- 1 mice/sex/groupreceived dietary doses of0, 167-236,567-667, 1,960-2,357 mg/kglday males andfemales respectively, for 28 days (all the mice in one additional high dose group,30,000 ppm, died within the first week ofthe study). At 1,960-2,357 mg/kglday, animals experienced body weight loss (females), decreased body weight gain during the rrrst2 weeks (males), a statistically significantdecrease in cholesterol, statistically significantdecreases in relative liver weights (females), pigmentation ofthyroid follicles, urolithiasis, moderate urothelial hyperplasia in urinarybladder,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 weightgainandfood consumption were decreased. Absolute liver weights were increased. Histopathology revealed centrilobularhepatocyte hypertrophy,increased incidence ofeosinophilic foci (males), thyroid follicular hyperplasia, hypertrophy and colloid depletion, andthe presenceofa brown pigment, identified aslipofuscin in thyroid foUicular cell epithelium. There was a statistically significant,dose-dependent increase in the incidence ofbenign thyroid follicular cell adenomas. Therewas no increased incidence in any malignant tumororincrease in tumor multiplicity as a resultofdaily dietary ingestion ofpyrimethanil at any dose level. The resultsof special studies, discussed below, demonstrate thatthe benign thyroid tumors are likely a secondaryresultofa disruption ofthyroid-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 usingCD-1 mice continually exposed to pyrimethanil byadministration in the diet. These lifetime feeding studies demonstrated no evidence ofoncogenic potential atdose levels up toand including 1000 mglkg/day, the highest dose tested.



### iv. Special studies. Since rodentthyroid tumors arefairly common, andsince the EPAbas established thatfive lines ofevidence arerequiredto prove thethyroidpituitary disruption modeofaction for rodentthyroid tumors, special studies were undertaken. a)Thyroid mechanistic study (14-day). SpragueDawley ratsreceived 378.5 mg/kg/day ofpyrimetbanil for 14 days to study theeffects ofpyrimethanil on the thyroid andlivermicrosomal enzymes. An increase in the levels ofUDPGT and
a correspondingstatistically significantincrease inliver weight were observed. Thyroid hormonesT4 andT3 were decreased, whileTSHlevels were significantly increased. All effects were shown to be reversible. b)Dietary thyroid function test using perchlorate discharge (7-day). SpragueDawley ratsreceived 509 mglkg/day pyrimethanil or 177 mglkglday propylthiouracil,or 109 mglkg/day phenobarbital 

### in ordertostudy thefunction ofthe thyroid gland. Theanimals fed pyrimethanil had 43% decreased body weight gain, 21% decreased food consumption and a 150% increase in uptakeofiodine-125. There was no significant dischargeof radioactive iodine from thethyroid after administration ofperchlorate. Therequired five lines ofevidence to supportthethreshold mode ofaction for thyroid pituitarydisruption and ratthyroid tumors aresatisfied in the pyrimethanil studies. EPA'sfinal rule establishing a tolerance for pyrimethanil in wine statedthat "TheAgency's Carcinogenicity Peer Review Committee (CPRC) chose a non-linear approach MOE based on a NOAEL of 17 mglkg/day for increased incidences ofthyroid tumors in rats. The MOE methodology was selected becauseofthyroid tumors associated with administration ofpyrimethanil in the rat, which may bedue to a disruption in the thyroid pituitary status.This chemical hasbeen classified as a Group C chemical (possible human carcinogen) and a nonlinear methodology MOE was applied for the estimation ofhuman cancer risk. Theestimated MOE does not exceed the Agency's level ofconcern andtherefore, EPA basa reasonablecertainty that no harm will 

### result from exposures to residues ofpyrirnethanil."]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 alsochildren 1-2 years old (76% of cP AD). Itshould be noted that this version ofDEEM-FCIDuses the new consumption data (NHANES 2003-2008).

ii Drinkmg Wotcr. [EPA drinking water values (2011) were used in the assessment. EDWCs were calculated forthe combined residues ofpyrimethanil (parent+ 2-amino-4,6-dimethylpyrimidine)from useon strawberries (acute) and grapes (chronic) which were the scenarios resulting in thehighest drinking water exposure. The surface water estimated drinkingwater concentrations (EDWCs) weredetermined usingTierIIPRZM!EXAMS (Pesticide RootZone Model/Exposure Analysis ModelingSystem). Ground waterEDWCs,calculated usingTierI SCI-GROW (Screening Concentration in GroundWater) model, were lower than thesurface waterEDWCs. Forsurface water, the maximum estimated peak acute concentration ofthe combined residues is 86.5 )lg!L. Themaximum estimated annual mean non-cancer chronicexposure concentration for the combined residues (adjusted for regional percentcropped area)is 29.4 )lg!L. These estimates are well below theDrinkingWaterLevels ofComparison (DWLOC)for all subpopulations. The aDWLOC is 22608, 31413 and 6851 )lgiL forFemales 13- 49, the US Population and Children 1-2 (the most highly exposed subpopulation), respectively. ThecDWLOC is 5899 and 1624 )lgiL forthe 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 ofpyrimethanil in food and drinking water.]

2 Non-dietary npo.wre [Pyrimethanilis not registered for use on any sites that would resultin residential exposure. Therefore,the aggregate risk is thesum of the risk from food and water.]

D. Cumulative 

### E.fl'ecl

. \ '
[Section 408(b)(2)(D)(v) requires that, when consideringwhetherto establish, modify, orrevoke a tolerance, the Agency consider "availableinformation" concerning thecumulativeeffects ofa particularpesticide's residues and "other substancesthathave a common mechanism oftoxicity." EPAhas not made a common mechanism oftoxicity fmding as topyrimethanil and any othersubstances and pyrimethanil doesnot appear to produce a toxic metabolite produced by other substances.]

E. SqfetyDetermination

I U.S. population [Riskassessments for pyrimethanil arebased on a complete and reliable toxicity data package and highly conservative assumptions. Chronic dietary (food) exposure 

### will utilize 13.9% ofthe cPAD for the US Population. ThechronicEDWCis more than 1000fold 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.]