FILE NAME: Hexythiazox NOF 100812

Template Number P25

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GOWAN COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE

(August 12, 2010)

EPA Registration Division contact: Mark Suarez, PM #13, telephone (703) 305-0120

TEMPLATE:

EPA has received a pesticide petition (number not currently available) from Gowan 

Company, 370 South Main Street, Yuma, AZ 85364 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

by amending the existing tolerances for residues of hexythiazox (trans-5-(4-chlorophenyl)-Ncyclohexyl-4-methyl-2-oxothiazolidine-3-carboxamide) and its metabolites containing the (4-

chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety to remove the geographical restriction for 

existing field corn tolerances and establish a new tolerance for aspirated grain fractions. EPA has 

determined that the petition contains data or information regarding the elements set forth in section 

408(d)(2) of the FFDCA; 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 

 

1. Plant metabolism. The nature of the residues in plants is adequately understood for 

purposes of this tolerance. Metabolism studies in fruit crops, radish and tea have been 

previously reviewed by the Agency. 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. The results of a new corn metabolism study (MRID 

48081501, currently in review) are consistent with the other plant metabolism data.

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 
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detection that allows monitoring of food with residues at or above the levels set in this 

tolerance. 

3. Magnitude of residues. Twenty new field trials were conducted by Gowan Company in 

support of the proposed label amendments for field corn. The amendments include 1) 

removing the regional use restriction and 2) reducing the pre-harvest interval to 30 days. 

The results of these new trials support the currently established tolerance levels of 0.02 

ppm for field corn grain and 6.0 ppm for field corn forage. We propose to increase the 

tolerance for field corn stover to 6.0 ppm.

4. Magnitude of the Residue in Processed Food/Feed. Data on field corn processed 

commodities support the establishment of a new tolerance of 0.5 ppm for aspirated grain 

fractions.

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 milligram/kilograms (mg/kg)), 

Category III for dermal LD50 (LD50 >5,000 mg/kg), 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 mg/kg/day and the maternal 

Lowest-Adverse-Effect-Level (LOAEL) was 720 mg/kg/day based on increased ovarian 

weights and decreased bone ossification. In a developmental toxicity study in rabbits, the 

maternal NOAEL was 1,080 mg/kg/day (HDT); the maternal LOAEL was not determined. 

The developmental NOAEL was 1,080 mg/kg/day (HDT); the developmental LOAEL was 

not determined. In a 2-generation reproduction study in rats, the parental NOAEL was 35 

mg/kg/day and the parental LOAEL was 200 mg/kg/day based on decreased body weight 

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

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

200 mg/kg/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 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 
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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 (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 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 (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. Metabolic toxicology. There are no metabolites of toxicological concern based on a 

differential metabolism between plants and animals.

8. Endocrine disruptions. 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 multigenerational reproduction studies, which would suggest that hexythiazox produces effects 

characteristic of the disruptions of hormones.

C. Aggregate Exposure

1. Dietary Exposure from food. A dietary risk assessment for all registered crops has been 

recently completed by the Agency ( March 17, 2010, 75FR12691.)

i. Acute Exposure. No acute endpoint has been identified in the toxicological 

studies for hexythiazox; therefore, a quantitative acute dietary exposure 

assessment is unnecessary.

i. Chronic Exposure. A tier 1 chronic risk assessment indicates that the 

proposed use results in an incremental additional dietary risk of not more than 

0.3% of the chronic Population Adjusted Dose (cPAD) for any population The 

registrant has concluded that hexythiazox use in field corn will not significantly

contribute to this dietary exposure.

ii. Cancer. The Agency has previously determined that the chronic reference 

dose is sufficient to evaluate all chronic risk of hexythiazox, including 

carcinogenic potential.

iii. Dietary Exposure from drinking water. The Agency used screening level 

water exposure models in the dietary exposure analysis and risk assessment for 
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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 exposures for noncancer and cancer assessments is estimated to be 4.1 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 (July

14, 2010 75FR40741).

2. From non-dietary exposure. HED has conducted a residential risk assessment to support 

recently approved uses on turf, ornamental landscape plantings, ornamental plants, orchids 

and residential fruit trees, nut trees and caneberries. The Agency concludes that there are

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 determined whether hexythiazox has a common mechanism of toxicity with other 

substances or how to include this pesticide in a cumulative risk assessment. Unlike other pesticides 

for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, 

hexythiazox does not share a toxic metabolite with other substances. For the purposes of this 

tolerance action, therefore, the registrant has not assumed that hexythiazox has a common mechanism 

of toxicity with other substances. For purposes of this petition the potential risks of hexythiazox in its 

aggregate exposure only will be considered.

E. Safety Determination

1. 1. US population

i. 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.

ii. Short-and intermediate term risk. EPA has concluded the combined shortterm food, water, and residential exposures result in aggregate MOEs of 

16,000 for adults and 2,000 for children. Because EPA's level of concern for 

hexythiazox is a MOE of 100 or below, these MOEs are not of concern.

iii. Chronic risk. EPA previously concluded that chronic exposure to 

hexythiazox from food and water will utilize no more than 49% of the cPAD 

for (children 1-2 years old) the population group receiving the greatest 

exposure. This assessment utilized existing tolerance values, assumed 100% 

crop treated and utilized default processing factors. The incremental additional 

potential dietary exposure associated with the proposed use will utilize no 

greater than 0.3% of the cPAD. Chronic residential exposure to residues of 

hexythiazox is not expected.

iv. Cancer risk As discussed in the Federal Register of March 17, 2010, (75 

FR 12691), EPA concluded that regulation based on the chronic reference dose 
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will be protective for both chronic and carcinogenic risks. There are no chronic 

risks of concern.

v. 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

No national or transnational maximum residue levels for hexythiazox on field corn exist apart from 

those in the United States.