I 

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 not apply, please insert "NA-Remove" and 

maintain the outline. Please do not change the margins, font, or format 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 has received a pesticide petition ([insert petition number]) 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 

CFRpart 180. 

(Options (pick one) 

1. by establishing a tolerance 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 information regarding the elements set forth 

in section 408 (d)(2) of 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. .,,, 

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A. Residue Chem is try !•••!• 

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1. Plant metabolism. The nature of the residues in plants is adequately • t * I 

understood for purposes of this tolerance petition. Metabolism studies in fruit crops? • '' J * * I 

radish, tea and corn have been completed. The Agency has determined that the 

residues of concern are hexythiazox and its metabolites containing the . ..I..* 

(4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety calculated as the 

stoichiometric equivalent of hexythiazox. * 

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2. Analytical method. The basic analytical method was previously reviewed by 

the Agency in association with the establishment of the current tolerances with 

registrations of multiple commodities. The methods used in a new cotton raw 

agricultural commodities study are described fully in the study report which is 

submitted concurrently with this petition. 

3. Magnitude of residues. The Agency previously has reviewed Magnitude of 

the Residue data supporting tolerances with regional registrations for cotton 

commodities (MRID 44574703). Tolerances of 0.2 ppm 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 of proposed increased tolerances and full national registrations for 

hexythiazox in cotton. The results from these trials show that after one application 

of Onager® IE Miticide at 0.1563 lb ai/A (0.1752 kg ai/ha) residues of hexythiazox 

ranged from <LOD (0.007 ppm) to 0.175 ppm (mean ± standard deviation = 0.0647 

± 0.0596 ppm) on eighteen undelinted seed RAG samples collected 34 to 36 DAA. 

Residues of hexj thiazox ranged from 1.96 to 5.70 ppm (mean ± standard deviation = 

4.02 ± 1.61 ppm) on six gin byproduct RAG samples collected 34 to 36 DAA. 

B. Toxicological Profile 

1. Acute toxicity. A battery of acute toxicity studies places technical grade 

hex} thiazox in Toxicity' Category IV for acute oral toxicity (LD50 > 5,000 mg/kg). 

Category III for acute dermal toxicity (LD50 >5,000 mg/kg). Category III for acute 

inhalation toxicity (LC50 >2.0 mg/L), Category III for primary eye irritation 

(showed mild irritation (reddened conjunctiva) and Category IV for dermal 

irritation (non irritant). Hexy thiazox is a non-sensitizer. 

2. Genotoxicity. A number of mutagenicity studies were conducted. These are 

a mammalian ery throcy te micronucleus test [MRID 45480101], a mammalian cell 

forward gene mutation assay [MRID 00155154], a rat primary hepatocyte 

unscheduled DNA sy nthesis 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 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 twogeneration 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 NOIJiL.»t 

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4. Subchronic toxicity. In a 1-month feeding study in dogs, the NOAEL was 

1.75 mg/kg/day and the LOAEL was 12.5 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 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 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) was 180 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 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 (RfD) is approximately 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 (Ql*) 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 bet^veen plants and animals. 

8. Endocrine disruption. Information concerning possible endocrine effects of 

hexy thiazox similar to effects produced by a naturally occurring estrogen, or other 

endocrine effects is available from the tw o-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 hexy thiazox induces estrogenic or other ,***! 

endocrine effects. J 

C. Aggregate Exposure 

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 

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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 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 national use of hexythiazox in cotton will not add appreciably to 

dietary risk. A tier 1 chronic assessment shows a negligible percentage of the 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) 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 substances. 

E. Safety Determination 

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 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). Th^***« 

proposed increase in tolerances for cotton will utilize negligible percentage of thg***, 

cPAD. Chronic residential exposure to the residues of hexythiazox is not expecttSJ.  

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2. Infants and children. EPA previously has determined that reliable data • • • • • 

• • show the safety of infants and children would be adequatelv protected if the 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, or to infants and children from aggregate exposure to hexythiazox 

residues. * 

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F. International Tolerances 

Apart from the US tolerances no other transnational maximum residue levels 

for hexythiazox in cotton are available. 

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