I 

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: [Richard Gebkin, 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 

CFR part 180. 

(Options (pick one) 

1. by establishing a tolerance for residues of 

Hexjthiazox, (trans-5-(4-chlorophenyl)-N-cyclohex>l-4-methyl-2-

oxothiazolidine-3-carboxamide) in or on citrus group 10, fruit at 0.6 ppm, citrus, 

dried pulp at 0.6 ppm, and citrus, oil at 26 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 adequatelyunderstood 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 calculated as the 

stoichiometric equivalent of hexythiazox. • • 

• • • 

• • 

• • • • 4 

• • 
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 citrus 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 citrus 

commodities (MRID 45898701, MRID 46330602, and MRID 46977001). Tolerances 

of 0.35 ppm, 0.60 ppm, and 24 ppm currently are established for residues of 

hexythiazox in citrus group 10, fruit, citrus dried pulp, and citrus oil, respectively. 

New field trial data have been generated for hexythiazox on citrus. Four orange 

trials were conducted in EPA Regions 6 (one trial) and 10 (three trials) in 2013 and 

2014. Three grapefruit trials were conducted in Regions 6 (one trial) and 10 (two 

trials) in 2013 and 2014. Five lemon trials were conducted in Region 10 in 2013 and 

2014. Side-by-side plots testing concentrate and dilute spray volumes were also 

established at one orange and one grapefruit trial in Region 6 where only one trial is 

required. The results from these trials show that after one application of 

Onager®lE Miticide at 0.1875 lb ai/A (0.210 kg ai/ha) ± 5% residues of hexythiazox 

ranged from 0.0392 to 0.0891 ppm (mean = 0.0631 ppm ± 0.0161) on ten orange 

RAC samples collected 7 DAA and from 0.0222 to 0.0798 ppm (mean = 0.0484 ppm 

± 0.0182) on ten orange RAC samples collected 14 DAA from the concentrated and 

dilute spray mixture applications. Residues of hexythiazox ranged from <0.02 

(LOQ) to 0.0853 ppm (mean = 0.0488 ppm ± 0.0268) on eight grapefruit RAC 

samples collected 7 DAA and from <0.02 (LOQ) to 0.0572 ppm (mean = 0.0377 ppm 

± 0.0168) on eight grapefruit RAC samples collected 14 DAA from the concentrated 

and dilute spray mixture applications. Residues of hexj thiazox ranged from 0.102 

to 0.257 ppm (mean = 0.184 ppm ± 0.0504) on ten lemon RAC samples collected 7 

DAA and from 0.100 to 0.264 ppm (mean = 0.177 ppm ± 0.0483) on ten lemon RAC 

samples collected 14 DAA from the concentrated and dilute spray mixture 

applications. 

B. Toxicological Profile 

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

hexythiazox in Toxicity Category IV for acute oral toxicitj' (LDso > 5,000 mg/kg), * * * * 

Categoiy III for acute dermal toxicity (LDso >5,000 mg/kg). Category III for acute,,*,; 

inhalation toxicity (LCso >2.0 mg/L), Categorj- III for primaiy- 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 ar"[* 

a mammalian erythrocyte micronucleus test [NIRID 45480101], a mammalian cell . 

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

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

in vitro cy togenetic 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 

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 carcinogenicitj' study in mice, the NOAEL was 36 mg/kg/day and the LOAEL was 

215 mg/kg/day. Effects were decreased bodweight in males and increased 

hepatocellular carcinomas and combined adenoma/carcinomas. 

In a chronic feeding/carcinogenicit\' 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 carcinogenicitj- of hexythiazox. The CARC 

concluded that the evidence as a whole was not strong enough to warrant the use pf*' 

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 hexj thiazox has been studied in * 

1 

plants. 

goats, hens and rats. Metabolic pathways in the animal are similar to those in I • • • ••• 

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 
hexj'thiazox similar to effects produced by a naturally occurring estrogen, or other 

endocrine effects is available from the two-generation rat reprodnction 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). 

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

toxicological studies for hexj thiazox; therefore, a quantitative acute dietary 

exposure assessment is unnecessarj'. 

Chronic Exposure. The Agency comprehensively evaluated potential dietary 

exposnre resnlting from the cnrrently registered uses of hexy thiazox 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 citrus will not add appreciably to dietary risk. 

A tier 1 chronic assessment shows a 2.1% of the cPAD will be utilized by any 

population subgronp for the proposed use in citrus. 

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

water exposure models in dietary exposnre 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 toxidt\i.!. 

• • • • 

• • 

with any other substances. * 

E. Safety Determination 

• •• 

• • • ••••• 

•••• • i 

• • • • • 

• • •••••• 

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 I 

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 hexj thiazox. 

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 increase in tolerances for citrus will utilize no more than an additional 

2.1% 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 IX. 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 hexv'thiazox residues. 

F. International Tolerances 

The following maximum residue levels for hexy thiazox on citrus commodities 

have been established. 

Country Commodity Hexythiazox 

Tolerance 

(ppm) 

Codex Citrus, Fruit 0.5 

EU Citrus Fruits, Grapefruit, 

Oranges, Lemons, Limes, 

Mandarins, Others 

1.0 

Japan Citrus (NATSUDAIDAL, 

whole). Lemon 

Orange (including navel 

orange). Grapefruit, Lime, 

Other citrus fruits 

2.0 

Taiwan 

Citrus (including whole Taiwan 

crop group for citrus) 1.0 

• ••• 

• • 

» • • 

• • •• 

• •• 

• • • • ••• 

• • 

• • • 

• • 

•••••• 

• • 

• • 

• •••• 

• • 

• ••• 

» • • 

• • •