EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER
EPA Registration Division contact: [Richard (iebkin, PM 10, (703) 305-6701] INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In cases where the outline element does not apply, please insert"NA-Remove" and maintain the outline. Please do notchange the margins, 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] EPAhasreceived a pesticidepetition ([insert petition number]) from Gowan Company, LLC,P.O. Box 556 Yuma, AZ85366 proposing,pursuant to section 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 a tolerance forresidues of
Hexythiazox, (trans-5-(4-chlorophenyI)-N-cyclohexyl-4-methyl-2- oxothiazolidine-3-carboxamide) in or ontheraw agricultural commodity alfalfa, forage at 20 ppm and alfalfa, hay at 60ppm. EPAhas determined that thepetition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPAhas not fully evaluated the sufficiency ofthe submitted data at this timeor whether the data supports granting ofthepetition. Additional data maybe neededbefore EPArules on thepetition.
A.Residue Chemistry • • •••• •• • I • • I.Plant metabolism. The nature ofthe residues in plants is adequately • understood for purposes ofthis tolerance petition. Metabolism studies in fruit crqpj,,;, radish, tea and corn have been completed. The Agency has determined that the residues ofconcern are hex\'thiazox and its metabolites containing the (4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety calculated as the stoichiometric equivalent ofhexjthiazox. • •

• • • ••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 alfalfa raw agricultural commodities study aredescribed fully in the study report which is submitted concurrently with this petition.
3.Magnitude ofresidues. The Agency previously has reviewed Magnitude of the Residuedata supporting tolerances with regional registrations for alfalfa commodities (MRID 48643602). Tolerances of 15 ppm and30 ppm currently are established for residues of hexvThiazox in alfalfa, forage and alfalfa, hay, respectively. New field trials were conducted in regions 7 and 8 by Gowan Company in support ofproposed increased tolerances and regional expansion for hex>'thiazox in alfalfa. The results from these trials show thatafter one application ofOnager® IE Miticide at 0.1875 lbai/A (0.210kg ai/ha) residues of hexythiazox ranged from 3.64 to 11.0 ppm (mean = 7.80ppm ± 3.22) on 6 alfalfa forage samples collected 14 DAA for the first cutting and from 11.9 to 33.3 ppm (mean = 23.7ppm ± 9.21) on 6 alfalfa hay samples collected 14 DAA. Residues ofhexythiazox ranged from <0.007 to 0.153 ppm (mean = 0.0431 ppm ± 0.0607) on 6 alfalfa forage samples collected 42 DAA for the second cutting and from 0.0237 to 0.294ppm (mean = 0.122ppm ± 0.116) on 6 alfalfa hay samples for the second cutting at 42 DAA. Residues ofhexythiazox ranged from <0.007 to <0.02ppm (mean = <0.02 ppm ± 0.00758) on 6 alfalfa forage samples collected 68-71 DAA for the third cutting and from <0.007 to 0.0336 ppm (mean = 0.0203 ppm ± 0.0109) on 6 alfalfa hay samples for the third cutting at68-71 DAA.
B. ToxicologicalProfile 1.Acutetoxicity. Abatteiy ofacute toxicity studies places technical grade hexj'thiazox in Toxicity- Category IV for acuteoral toxicity* (LDso > 5,000 mg/kg). Category IIIfor acute dermal toxicity' (LDso >5,000 mg/kg). Category nifor acute inhalation toxicity- (LCso >2.0 mg/L), Category IIIfor primary eye irritation (showed mild irritation (reddened conjunctiva) and Category IV for dermal irritation (non irritant). Hexythiazox is a non-sensitizer. 2. Genotoxicity.A number ofmutagenicity studies were conducted.These are a mammalian erythrocyte micronucleus test [NIRID 45480101], a mammalian cell forward gene mutation assay [MRID 00155154], a rat primary hepatocyte unscheduled DNA synthesis assay [MRID 00156893], a clastogenicevaluation in aym in vitro cytogenetic assay measuring chromosomal aberration in Chinese hamster ,, ovary cells [NIRID 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 NOEL was 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 I, toxicity was observed at the highest dose tested, 1080 mg/kg/day. In a two- • ••• • • •generation 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 chronicNOEL.

4. Subchronic toxicity.In a 1-month feeding study 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 feeding study in dogs, the NOAEL was 2.5 mg/kg/day and the LOAEL was 12.5 mg/kg/day, based on increased alkaline phosphatase, increased adrenal and liver weights, and liver and adrenal lesions. In a carcinogenicitystudy in mice, the NOAEL was 36 mg/kg/day and the LOAEL was 215 mg/kg/day. Effects were decreased bodj-weight in males and increased hepatocellular carcinomas and combined adenoma/carcinomas.
In a chronic feeding/carcinogenicity study inrats, the NOAEL (systemic) was 26 mg/kg/day and the LOAEL (systemic) was 180 mg/kg/day based on decreased body weight 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 (RID) is approximately 65-fold lower than the lowest dose (163 mg/kg/day) that induced tumors. Thus, thechronic RfD of0.025 mg/kg/day would be protective of all chronic effects including potential carcinogenicity ofhexythiazox. TheCARC concluded that the evidence asa whole was not strongenough to warrant the use of 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 hexvthiazox 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 between plants and animals. •••• • « •••• 8. Endocrine disruption. Information concerning possible endocrine effects of**•* hexythiazox similar to effects produced by a naturally occurring estrogen, or other * endocrine effects is availablefrom the two-generation rat reproduction study, th»***! rat and rabbit developmental studies and the rat and dog chronic studies. There is, no evidence from these studies that hexythiazox induces estrogenicor other • • • • • •••••

» •• • • • »• •• ••••• • i endocrine effects. • • •
• ••• • • • •• •C.AggregateExposure 1. Dietaryexposure. Dietary Exposure from food. Adietary risk assessment for all registered crops has been completed by the Agency (Federal Register, July 17, 2013, pages 42693-42699).
1.Food. Acute Exposure. No acute endpoint has been identified in the toxicological studies for hexv'thiazox; therefore, a quantitative acute dietaiy exposure assessment is unnecessary. Chronic Exposure. The proposed regional expansion of hexvthiazox in alfalfa will not add to dietary risk. A tier 1chronic assessmentshows employing tolerance residue values,the assumption of 100% croptreated and default processing factors shows that the maximally exposed subpopulation (children 1-2 years old) utilized 93.4% ofthe cPAD. ii.Drinking water. The Agency has previously used screening level surface water exposure models in dietaiy exposure analysis and risk assessment for hex\'thiazox in drinking water.Based on the Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS), theestimated drinking water concentration (EDWC) of hex\'thiazox 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 are below 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 hexythiazox has been identified, thus hex\'thiazox is not expected to pose an acute risk. Short-and intermediate term risk. EPA has previously concluded that thereare no short term or intermediate term risks ofconcern from exposure to hexythiazox. •••• Chronic risk. A tier 1chronic assessment shows that no more than 93.4yo ofthe •••• cPAD would be utilized by all population subgroups following the proposed use ip**,*, alfalfa commodities. Chronic residential exposure to the residues ofhex\'thiazox is ^ not expected. • • • • • • •••••• 2. Infantsandchildren. EPA previously has determined that reliable data , , •,,* show the safety ofinfants and children would be adequately protected if the FQPiV**** **J", SFwere reduced to IX. Based on these risk assessments, it can be concluded • that there is a reasonable certainty that no harm will resnlt to the general • •
• ••• K • • •• •

### population, or to infantsand children from aggregate exposuretohexjthiazox

residues. F.International Tolerances There areno codexmaximumresidue levelsestablished forhexythiazox on alfalfa other than the UStolerances.

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