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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 replace 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-chlorophenyl)-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 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 petition. 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.
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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 proposed tolerances and regional 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 data also have been 

generated for hexythiazox on wheat 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 ppm. 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 places technical grade

hexythiazox 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). Hexythiazox is a non-sensitizer.

2. Genotoxicity. 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 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 NOEL. 

4. Subchronic toxicity. In a 1-month feeding study in dogs, the NOAEL was
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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 (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. 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. Dietary 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 dietary
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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 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 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 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 intermediate 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 will 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 would 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.
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F. International Tolerances

No national or transnational maximum residue levels for hexythiazox in 

wheat are available.