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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: [ Mark Suarez, PM 13, (703) 305

- 0120 ]

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 not change the margins, font, or format in your pesticide petition. Simply re place the instructions that appear in green , i.e., “ [ insert

company name ] ,” with the information specific to your action.

TEMPLATE:

Gowan Company

[ D

- 495616 ]

EPA has received a pesticide petition ( [ D

- 495616 ] ) from Gowan Company, LLC, P.O. Box 556 Yuma, AZ 85366 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.

( Options (pick one)

1. by establishing a tolerance for residues of

Hexythiazox

, (trans

- 5

- (4

- c hlorophenyl )

- N

- cyclohexyl

- 4

- methyl

- 2

- oxothiazolidine

- 3

- carboxamide) in or on the raw agricultural commodity Wheat
, wheat forage at 6.0 ppm , wheat hay at 30 ppm , wheat straw at 8.0 ppm and wheat grain at 0.02 ppm . EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted d a ta at this time or whether the data
supports gran ting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. The nature of the residues in plants is adequately understood for purposes of this tolerance petition . Metabolism studies in fruit crops, radish, tea and corn have been com p leted. The Agency has determined that the residues of concern are hexythiazox and its metabolites containing the (4

- chlorophenyl)

- 4

- methyl

- 2

- oxo

- 3

- thiazolidine moiety.2

2. Analytical method. The Agency previously determined (DP # 396862, June 18, 2012) that the methods described in MRID 48643601 were acceptable for determining residues of hexythiazox in wheat raw agricultural commodities. The

methods used in a new wheat processing/AGF study are similar and are described fully in the study report which is submitted concurrently with the wheat petition.

3. Magnitude of residues. Three field trials conducted by Gowan Company in support of the propose d tolerances and regi onal registration for use of hexythiazox

in wheat have been reviewed previously by the Agency (MRID 48643601) . The results of these trials support the proposed tolerance levels (ppm): wheat forage 3.0, wheat hay 30, wheat grain 0.02, and wheat straw 6.0. New d ata also have been generated for hexythiazox on w heat aspirated grain fractions (AGF) and processed commodities (PC)

. The results from the aspirated grain fraction (AGF) trial show

that mean residues of hexythiazox in AGF was 0.170 p pm. These data show that no changes to the currently established tolerance of 5 ppm for AGF will be necessitated by the proposed use in wheat. The results from the processing study show that the

mean residues of hexythiazox collected 74 DAA were < 0.02 ppm in/on wheat grain, <0.02 ppm for germ, <0.007 ppm for flour, <0.007 ppm for middlings, <0.02 ppm for bran and <0.007 ppm for shorts.

B. Toxicological Profile

1. Acute toxicity. A battery of acute toxicity studies place s technical grade hexythiazox in Toxicity Category IV for acute oral toxicity (LD 50 > 5,000 mg/kg), Category III for acute dermal toxicity (LD 50 >5,000 mg/kg), Category III for acute
inhalation toxicity (LC 50 >2.0 mg/L), Category III for primary eye irritation (showed mild irritation (reddened conjunctiva ) and Category IV for dermal irritation (non irritant). Hexythiazox is a non

- sensitizer.

2. Genotoxic i ty. A number of mutagenicity studies were conducted

. These are 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 t hese mutagenicity tests were negative.

3. Reproductive and developmental 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 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 2400 ppm 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 NOEL.

4. Subchronic toxicity. In a 1

- month feeding study in dogs, the NOAEL was3

1.75 mg/ kg/day and the LOAEL was 12.5 m g/kg/da y, 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 carcinogenicity study in mice, the NOAEL was 36 mg/kg/day and the LOAEL was 215 mg/kg/day. Effects were decreased bodyweight in males and increased hepatocellular carcin omas and combined adenoma/carcinomas.

In a chronic feeding/carcinogenicity study in rats, 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 20 09 report from the Cancer Assessment Review Committee (CARC) (September 02, 2009, PC Code 128849, TXR 0055255) noted that the NOAEL of 2.5 mg/kg/day, from the one year toxicity study in dogs, used in establishing the chronic reference dose (Rf D) is approxi mately 65

- fold lower than the lowest dose (163 mg/kg/day) that induced tumors. Thus, the chronic RfD of 0.025 mg/kg/day would be protective of all chronic effects including potential carcinogenicity of hexythiazox. The CARC concluded that the evidence as a whole was not strong enough to warrant the use of a linear low dose extrapolation model applied to the animal data (Q1*) for a quantitative estimation of human 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 similar to those in plants.

7. Metabolite toxicology

. There are no metabolites of toxicological 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 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.

C. Aggregate Exposure

1. Dietary exposure. D ietary Exposure from food. A dietary risk assessment for all registered crops has been completed by the Agency (Federal Register, July 17, 2013, pages 42693

- 42699).

i. Food. Acute Exposure . No acute endpoint has been identified in the toxicological studies for hexythiazox; therefore, a quantitative acute dietary4

exposure assessment is unnecessary. Chronic Exposure

. The Agency comprehensively evaluated potential dietary exposure resulting fr om the currently registered uses of hexythiazox 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% of the 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 use of hexythiazox in wheat will not add appreciably to dietary risk.

A tier 1 chronic assessment shows than no more than 0.3% of the cPAD will be utilized by any population subgroup for the proposed use in wheat.

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 est imated drinking water concentration (EDWC) of hexythiazox 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 of concern.

D. Cumulative Effects

EPA has not found that hexythiazox shares a common mechanism of toxicity with any other substance s

.

E. Safety Determination

1. U.S. population. A cute risk . No adverse effect resulting from a single oral exposure to hexythiazox has been identified, thus hexythiazox is not expected to pose

an acute risk.

Short

- and intermediate term risk . EPA has previously concluded that there are no

short term or intermediat e term risk of concern from exposure to hexythiazox.

Chronic risk

. The agency previously concluded that no more than 82% of the cPAD would be utilized from the currently registered uses ( food and water )

. The proposed

new use in wheat w ill utilize no more than an additional 0.3% of the cPAD. Chronic residential exposure to the residues of hexythiazox is not expected.

2. Infants and children

. EPA previously has determined that reliable data show the safety of infants and children woul d be adequately protected if the FQPA

SF were reduced to 1X. Based on these risk assessments, it can be concluded that there is a reasonable certainty that no harm will result to the general population, or to infants and children from aggregate exposure to hexythiazox

residues.5

F. International Tolerances No national or transnational maximum residue levels for hexythiazox in

wheat are available

.