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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: [Richard Gcbkin, PM 10, (703) 305-6701] INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In . cases where the outline element does notapply, please insert "NA-Remove"and maintain the outline. Please do not change themargins, font, orformat in your pesticide petition. Simply replace the instructions that appear in green, i.e., "[insert company name],"with the information specific to your action. TEMPLATE: Gowan Company [Insert petition number] EPA hasreceived a pesticidepetition ([insert petition number]) from Gowan Company, LLC,P.O. Box556 Yuma, AZ85366 proposing,pursuant tosection 408(d) ofthe Federal Food, Drug, and Cosmetic Act(FFDCA), 21 U.S.C. 346a(d),to amend 40 CFRpart 180. (Options (pick one) 1. by establishing atolerance for residues of
Hexythiazox, (trans-5-(4-chlorophenyl)-N-cyclohexyl-4-methyl-2- oxothiazolidine-3-carboxamide) in or on the raw agricultural commodity cotton, undelinted seed at 0.5 ppm and cotton, gin byproducts at 15 ppm. EPA has determined that the petition contains data or informationregarding the elementsset forth in section 408 (d)(2) of FDDCA; however, EPA has not fullyevaluated the sufficiency ofthe submitted data at thistime or whether the data supports granting ofthe petition. Additional data maybe neededbefore EPArules on thepetition. .,,, • • •••• A. Residue Chemistry !•••!• # •••••• 1.Plant metabolism. The nature ofthe residues in plants is adequately • t * I understood for purposes ofthis tolerance petition. Metabolism studies in fruit crops?• ''J**I radish, tea and corn have been completed. The Agency has determined that the residues ofconcern are hexythiazox and its metabolites containing the . ..I..* (4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety calculated as the stoichiometric equivalent ofhexythiazox. * • • •2. Analytical method.The basic analytical method was previously reviewed by

the Agency in association with the establishment ofthe current tolerances with registrations ofmultiple commodities. The methods used in a new cotton raw agricultural commodities study aredescribed fully in the study report which is submitted concurrently with this petition. 3.Magnitude ofresidues. The Agencypreviously has reviewed Magnitude of the Residue datasupporting tolerances with regional registrations for cotton commodities (MRID 44574703). Tolerances of0.2ppm and 3 ppm currently are established for residues of hexythiazox in cotton, undelinted seed and cotton, gin byproducts, respectively. Nine new field trials were conducted by Gowan Company in support ofproposed increased tolerances and full national registrations for hexythiazox in cotton. The results from these trials show that after one application ofOnager® IE Miticide at 0.1563 lb ai/A (0.1752kg ai/ha) residues ofhexythiazox ranged from <LOD (0.007 ppm) to 0.175 ppm (mean ± standard deviation = 0.0647 ± 0.0596ppm) on eighteen undelinted seed RAG samples collected 34 to 36 DAA. Residues ofhexjthiazox ranged from 1.96 to 5.70 ppm (mean ± standard deviation = 4.02 ± 1.61ppm) on six gin byproduct RAG samples collected 34 to 36 DAA.
B. ToxicologicalProfile 1. Acutetoxicity. Abattery ofacute toxicity studies places technical grade hex}thiazox in Toxicity' Category IV for acuteoral toxicity (LD50> 5,000 mg/kg). Category III for acutedermal toxicity (LD50>5,000 mg/kg). Category IIIfor acute inhalation toxicity (LC50 >2.0 mg/L), Category III for primary eyeirritation (showed mild irritation (reddened conjunctiva) and Category IV for dermal irritation (non irritant). Hexythiazox is a non-sensitizer. 2. Genotoxicity. A number of mutagenicity studies were conducted.These are a mammalian erythrocyte micronucleus test [MRID 45480101], a mammalian cell forward gene mutation assay [MRID 00155154], a rat primary hepatocyte unscheduled DNA synthesis assay [MRID 00156893], a clastogenic evaluation in an in vitro cytogenetic assay measuring chromosomal aberration in Chinese hamster ovary cells [MRID 00156894], and an Ames study with Salmonella [MRID 44955710]. All these mutagenicity tests were negative. 3. Reproductive anddevelopmental toxicity.In a developmental toxicity study***^ with rats [MRID 00147578], the fetotoxicity NOELwas 240 mg/kg/day, and the compound was not embryotoxic at the highest dose tested, 2160 mg/kg/day. In a; developmental toxicity study with rabbits [MRID 00146555], no developmental toxicity was observed at the highest dose tested, 1080 mg/kg/day. In a twogeneration reproduction study with rats [MRID 00147578 and 00151360], no reproductive effects were observed at 2400ppm in the diet (^110 and >139 mg/kg/day, males and females, respectively). It is concluded that the NOEL for developmental and reproductive effects is greater than 10 times the chronic NOIJiL.»t •• • • • • •• •• • • • •• • • •

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• ••• • • • •• •4. Subchronic toxicity.In a 1-month feedingstudy in dogs, the NOAEL was

1.75 mg/kg/day and the LOAEL was12.5 mg/kg/day, based on increased liver and adrenal weights. 5. Chronic toxicity. In a 1-year feedingstudy in dogs, the NOAEL was2.5 mg/kg/day and the LOAEL was12.5 mg/kg/day, based on increased alkaline phosphatase, increased adrenal and liverweights, and liver and adrenal lesions.In a carcinogenicity study in mice, the NOAEL was 36 mg/kg/day and the LOAEL was 215 mg/kg/day. Effects weredecreased bodyweight in males and increased hepatocellular carcinomas and combined adenoma/carcinomas.
In a chronic feeding/carcinogenicity study in rats, the NOAEL (systemic) was 26 mg/kg/day and the LOAEL (sy stemic) was180 mg/kg/day based on decreased bodyweight gain and increased liver weights in both sexes. A 2009 report from the Cancer Assessment Review Committee (CARC) (September 02, 2009, PC Code128849, TXR 0055255) noted that the NOAEL of2.5 mg/kg/day, from the one year toxicity study in dogs, used in establishing the chronic reference dose (RfD) is approximately 65-fold lower than the lowest dose (163 mg/kg/day) that induced tumors. Thus, the chronic RfDof0.025 mg/kg/day would be protective of all chronic effects including potential carcinogenicity ofhexythiazox. The CARC concluded that the evidence as a whole was not strong enough to warrant the useof a linear low dose extrapolation model applied to the animal data (Ql*) for a quantitative estimation ofhuman risk, as had been previously assessed in October 16,1998, [63.FR55540].
6. Animal metabolism. The metabolism of hexythiazox has been studied in goats, hens and rats. Metabolic pathways in the animal are similarto those in plants.7. Metabolite toxicology. There are no metabolites oftoxicological concern based on a differential metabolism bet^veen plants and animals. 8. Endocrine disruption.Information concerning possible endocrine effects of hexythiazox similarto effects produced by a naturally occurring estrogen, or other endocrine effects is available from the two-generation rat reproduction study, the rat and rabbit developmental studies and the rat and dog chronic studies.There.is***, no evidence from these studies that hexythiazox induces estrogenic or other ,***! endocrine effects. J C.AggregateExposure
I.Dietary exposure. Dietary Exposure from food. A dietary risk assessmeift.*. for all registered crops has been completed by the Agency (Federal Register, July 17, 2013, pages 42693-42699). " • • • • • • • • •

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i. Food. Acute Exposure. No acute endpoint has been identified in the • ••• » • • •• •toxicological studies for hexythiazox; therefore,a quantitative acute dietary

exposure assessment is unnecessary. Chronic Exposure.The Agency comprehensively evaluated potential dietary exposure resulting from the currently registered uses ofhexythiazox in the July 17, 2013 Federal Register.The Agency concluded that chronic exposure to hexythiazox from food and water will utilize no more than 82% ofthe cPAD (for children 1-6 years old). The Agency's assessment employed tolerance residue values, the assumption of 100% crop treated and default processing factors. The proposed national use ofhexythiazox in cotton will not add appreciably to dietary risk. A tier 1chronic assessment shows a negligible percentage ofthe cPAD will be utilized by any population subgroup for the proposed use in cotton. ii. Drinking water. The Agency has previously used screening level surface water exposure models in dietary exposure analysis and risk assessment for hexythiazox in drinking water.Based on the Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS),the estimated drinking water concentration (EDWC) ofhexythiazox for chronic assessment was estimated to be 4.31 parts per billion (ppb). (Federal Register, July 17, 2013, pages 42693-42699) 2. Non-dietary exposure. EPA has previously determined that potential residential exposures to hexythiazox arebelow levels ofconcern. D. CumulativeEffects
EPA has not found that hexythiazox shares a common mechanism of toxicity with any other substances.
E. SafetyDetermination 1. U.S.population. Acute risk. No adverse effect resulting from a single oral exposure to hex>Jhiazox has heen identified, thus hex>Jhiazox is not expected to pose an acute risk. Short-and intermediate term risk. EPA has previously concluded that there are no short term or intermediate term risks ofconcern from exposure to hexythiazox. Chronic risk. The Agency previously concluded that no more than 82% ofthe cPAD would be utilized from the currently registered uses (food and water). Th^***« proposed increase in tolerances for cotton will utilize negligible percentage ofthg***, cPAD. Chronic residential exposure to the residues ofhexythiazox is not expecttSJ.  • 2. Infantsand children. EPA previously has determined that reliable data • • • • • •• show the safety ofinfants and children would be adequatelv protected ifthe FQPA **  SF were reduced to IX. Based on these risk assessments, it can be concluded that there is a reasonable certainty that no harm will result to the general • population, orto infants and children from aggregateexposure to hexythiazox residues. *• ••• 9 9 9 99 9F.International Tolerances Apart from the US tolerances noother transnational maximum residue levels for hexythiazox in cotton areavailable.

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