EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: [Richard (iebkin, 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-chlorophenyI)-N-cyclohexyl-4-methyl-2-

oxothiazolidine-3-carboxamide) in or on the raw agricultural commodity alfalfa, forage 

at 20 ppm and alfalfa, hay at 60 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 

• • 

• ••• 

• • • 

I • • 

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

understood for purposes of this tolerance petition. Metabolism studies in fruit crqpj,,;, 

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

residues of concern are hex\'thiazox and its metabolites containing the 

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

stoichiometric equivalent of hexj thiazox. 

• • 

• • 

• • • 
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 alfalfa 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 alfalfa 

commodities (MRID 48643602). Tolerances of 15 ppm and 30 ppm currently are 

established for residues of hexvThiazox in alfalfa, forage and alfalfa, hay, 

respectively. New field trials were conducted in regions 7 and 8 by Gowan 

Company in support of proposed increased tolerances and regional expansion for 

hex>'thiazox in alfalfa. The results from these trials show that after one application 

of Onager® IE Miticide at 0.1875 lb ai/A (0.210 kg ai/ha) residues of hexythiazox 

ranged from 3.64 to 11.0 ppm (mean = 7.80 ppm ± 3.22) on 6 alfalfa forage samples 

collected 14 DAA for the first cutting and from 11.9 to 33.3 ppm (mean = 23.7 ppm 

± 9.21) on 6 alfalfa hay samples collected 14 DAA. Residues of hexythiazox ranged 

from <0.007 to 0.153 ppm (mean = 0.0431 ppm ± 0.0607) on 6 alfalfa forage samples 

collected 42 DAA for the second cutting and from 0.0237 to 0.294 ppm (mean = 

0.122 ppm ± 0.116) on 6 alfalfa hay samples for the second cutting at 42 DAA. 

Residues of hexythiazox ranged from <0.007 to <0.02 ppm (mean = <0.02 ppm ± 

0.00758) on 6 alfalfa forage samples collected 68-71 DAA for the third cutting and 

from <0.007 to 0.0336 ppm (mean = 0.0203 ppm ± 0.0109) on 6 alfalfa hay samples 

for the third cutting at 68-71 DAA. 

B. Toxicological Profile 

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

hexj'thiazox in Toxicity- Category IV for acute oral toxicity* (LDso > 5,000 mg/kg). 

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

inhalation toxicity- (LCso >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 erythrocyte micronucleus test [NIRID 45480101], a mammalian cell 

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

unscheduled DNA synthesis assay [MRID 00156893], a clastogenic evaluation in aym 

in vitro cytogenetic assay measuring chromosomal aberration in Chinese hamster ,, 

ovary cells [NIRID 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 I, 

toxicity was observed at the highest dose tested, 1080 mg/kg/day. In a two- • • • • • • • 
generation 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 

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 bodj-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 (RID) 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 hexv thiazox 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, th»***! 

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 

• • • 

• • 

• •••• 

» • • 

• • • 

»• •• ••••• 

• i 

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). 

1. Food. Acute Exposure. No acute endpoint has been identified in the 

toxicological studies for hexv'thiazox; therefore, a quantitative acute dietaiy 

exposure assessment is unnecessary. 

Chronic Exposure. The proposed regional expansion of hexv thiazox in alfalfa will 

not add to dietary risk. A tier 1 chronic assessment shows employing tolerance 

residue values, the assumption of 100% crop treated and default processing factors 

shows that the maximally exposed subpopulation (children 1-2 years old) utilized 

93.4% of the cPAD. 

ii. Drinking water. The Agency has previously used screening level surface 

water exposure models in dietaiy exposure analysis and risk assessment for 

hex\'thiazox in drinking water. Based on the Pesticide Root Zone Model /Exposure 

Analysis Modeling System (PRZM/EXAMS), the estimated drinking water 

concentration (EDWC) of hex\'thiazox 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 hex\'thiazox 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. A tier 1 chronic assessment shows that no more than 93.4yo of the •••• 

cPAD would be utilized by all population subgroups following the proposed use ip**,*, 

alfalfa commodities. Chronic residential exposure to the residues of hex\'thiazox 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 FQPiV**** ** J", 

SF were reduced to IX. Based on these risk assessments, it can be concluded • 

that there is a reasonable certainty that no harm will resnlt to the general • • 

• ••• 

K • • 

• • • 
population, or to infants and children from aggregate exposure to hexj thiazox 

residues. 

F. International Tolerances 

There are no codex maximum residue levels established for hexythiazox on 

alfalfa other than the US tolerances. 

• ••• 

» • 

»• • • • 

»• • 

• • • • 

• •••••• 

• • 

• • 

• • • •• •• •••! 

• ••• 

» • • 

• • •