EPA REGISTERED 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 tolerance petition 

documents. In cases where the outline element does not apply please insert "NARemove" and maintain the outline. The comment notes that appear on the left 

margin represent hidden typesetting codes designed to expedite the processing of the 

Federal Register document. Please do not remove or alter these comment notes or 

change the margins, font, or format in your document. Simply replace the 

instructions that appear in italics and brackets, i.e., "[insert company name]," with 

the information specific to your action.] 

[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) 

ofthe Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 

CFR part 180. 

(Options (pick one) 

1. by amending the regional restriction of a tolerance to include Arizona for 

residues of 

Hexythiazox (trans-5-( 4-chlorophenyll)-N-cyclohexyl-4-methyl-2-

oxothiazolidine-3-carboxamide) in or on the raw agricultural commodity cotton, gin 

byproduct at 3 parts per million (ppm) and cotton, undelinted seed at 0.2 parts per 

million (ppm). EPA has determined that the petition contains data or information 

regarding the elements set forth in section 408 ( d)(2) of the 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. 

A. Residue Chemistry 

I. Plant metabolism. The nature of the residues in plants is adequately 

understood for purposes of this tolerance. Metabolism studies in fruit crops, radish, 

tea and corn have been completed. The Agency has determined that the residues of 

concern are hexythiazox and its metabolites containing the ( 4-chlorophenyl)-4-
c 

methyl-2-oxo-3-thiazolidine moiety. 

2. Analytical method. A practical analytical method, high pressure liquid 

chromatography with a UV detector, which detects and measures residues of 

hexythiazox and its metabolites as a common moiety, is available for enforcement 

purposes with a limit of detection that allows monitoring of food with residues at or 

above the levels set in this tolerance. 

3. Magnitude of residues. Data on file with EPA supports the amendment to 

the cotton tolerance. 

B. Toxicological Profile 

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

hexythiazox in Toxicity Category IV for acute oral LD50 (LD50 > 5,000 

mi~ligramlkilograms (mglkg)), Category III for dermal LD50 (LD50 >5,000 mglkg), 

Category III for inhalation LC50 (LC50 >2.0 mg!L), Category III for primary eye 

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

irritation (non irritant). Hexythiazox is a non-sensitizer. Acute toxicological studies 

place technical grade hexythiazox in Toxicology Category III. 

2. Genotoxicty. The following genotoxicity studies were all negative: Ames 

gene mutation, CHO gene mutation, CHO chromosome aberration, mouse 

micronucleus and rat hepatocyte unscheduled DNA synthesis. 

3. Reproductive and developmental toxicity. In a developmental toxicity study 

in rats, the maternal No-Adverse-Effect-Level (NOAEL) was 240 mglkg/day and the 

maternal Lowest-Adverse-Effect-Level (LOAEL) was 720 mglkg/day based on 

increased ovarian weights and decreased bone ossification. In a developmental 

toxicity study in rabbits, the maternal NOAEL was 1,080 mglkg/day {HDT); the 

maternal LOAEL was not determined. The developmental NOAEL was 1,080 

mglkglday (HDT); the developmental LOAEL was not determined. In a 2-

generation reproduction study in rats, the parental NOAEL was 35 mglkglday and 

the parental LOAEL was 200 mglkglday based on decreased body weight gain, 

decreased food consumption and efficiency, and increased liver, kidney and ovarian 

weights. The reproductive NOAEL was 35 mglkg/day and the reproductive LOAEL 

was 200 mglkg/day based on decreased pup bwt during lactation, delayed hair 

growth and eye opening. 

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

1.75 mglkg/day and the LOAEL was 12.5 mglkg/day, based on increased liver and 

adrenal weights. 

5. Chronic toxicity. In a 1-year feeding study in dogs, the NOAEL was 2.5 

mglkg/day and the LOAEL was 12.5 mglkglday, 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 mglkg/day and the LOAEL was 

215 mglkglday. 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 

mglkglday and the LOAEL (systemic) was 180 mglkg/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 Code 128849, TXR 0055255) noted that the NOAEL of 2.5 mg/kglday, 

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/kglday) that 

induced tumors. Thus, the chronic RID 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. No specific test have been conducted with 

hexythiazox to determine whether the chemical may have any effect in humans that 

is similar to an effect produced by a naturally ocurring estrogen or other endocrine 

effects. However, there were no significant findings in other relevant toxicity tests, 

i.e., teratology and multi-generational reproduction studies, which would suggest 

that hexythiazox produces effects characteristic of the disruptions of hormones. 

C. Aggregate Exposure 

1. Dietary exposure. Dietary Exposure from food. A dietary risk assessment 

for all registered crops has been completed by the Agency (December 14, 2011, 

FR Doc No. 2011-32086) 

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. A tier 1 chronic risk assessment by Gowan Company indicates 

that registered uses as well as uses proposed in the meantime and still under 

evaluation result in a dietary risk of not more than 68.5% of the chronic Population 

Adjusted Dose (cPAD) for any population. 

ii. Drinking Water. The Agency used screening level water exposure models in 

the dietary exposure analysis and risk assessment for hexythiazox in drinking water. 
C .. 

... ~' 

Based on the Pesticide Root Zone Model/Exposure Analysis Modeling System 

(PRZM/EXAMS) the estimated drinking water concentration (EDWC) of 

hexythiazox for chronic exposures for non-cancer and cancer assessments is 

estimated to be 4.5 parts per billion (ppb) for surface water. Since surface water 

residue values greatly exceed groundwater EDWCs, surface water residues were 

used in the dietary risk assessment. 

2. Non-dietary exposure. HED has conducted a residential risk assessment to 

support approved uses on turf, ornamental landscape plantings, ornamental plants, 

orchids and residential fruit trees, nut trees and caneberries. The Agency concluded 

that there were no residential risks of concern associated with these uses (January 

28,2010 EPA Memo. PR Code: 128849, DP Barcode D372889.) 

D. Cumulative Effects 

EPA has not found that hexythiazox shares a common mechanism of toxicity with 

any other substance. 

E. Safety Determination 

1. US population. Acute 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 concluded the combined short-term 

food, water, and residential exposures result in aggregate MOEs of 14,000 for adults 

and 1,900 for children. Because EPA's level of concern for hexythiazox is a MOE of 

100 or below, these MOEs are not of concern. 

Chronic risk. Chronic exposure to hexythiazox from food and water will utilize no 

more than 68.5% of the cP AD for the population group receiving the greatest 

exposure (children 1-2 years old). This assessment utilized existing tolerance values, 

assumed 100% crop treated, and utilized default processing factors. Chronic 

residential exposure to residues of hexythiazox is not expected. 

2. Infants and children. 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. 

F. International Tolerances 

The European Union, Iceland, Norway, Israel, Russia, and Switzerland have 

established an MRL of 0.5 ppm for hexythiazox on cottonseed. Mexico and 

Honduras have established an MRL of 0.2 ppm for hexythiazox on cottonseed. 

Taiwan has established an MRL of 0.05 for hexythiazox on cottonseed. Turkey has 

established an MRL of 0.02 for hexythiazox on cottonseed.