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 

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 

CFR part 180.

1. by establishing a tolerance for residues of

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

oxothiazolidine-3-carboxamide) in or on the raw agricultural commodity sorghum, grain

at 3 parts per million (ppm); sorghum, grain, forage at 5 ppm; and sorghum, grain, stover 

at 6 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

1. 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-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. Eight new field trials were conducted by Gowan 

Company in support of the proposed label amendments for sorghum (grain). The 

amendments include regional (Western US) use of hexythiazox on sorghum (grain). The 

results of these new trials support the proposed tolerance levels: sorghum, grain 3 ppm; 

sorghum, grain, forage 5 ppm; and sorghum, grain, stover 6 ppm.
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 body weight 

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 NOAEL was 36 mg/kg/day and the LOAEL was 215 

mg/kg/day. Effects were decreased body weight 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. Metabolite toxicology. There are no metabolites of toxicological concern based 

on a differential metabolism between plants and animals.

8. Endocrine disruption. No specific tests 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 occurring 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 

the proposed use results 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. 

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. U.S. 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 cPAD 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

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

those in the United States.