Docket ID #: EPA-HQ-OPP-2010-0916

COMPANY NOTICE OF FILING FOR HEXYTHIAZOX TOLERANCE PETITION

EPA Registration Division contact: Sidney Jackson, 703-305-7610 

Interregional Research Project Number 4 (IR-4) and Gowan Company

PP# 0E7787

EPA has received a pesticide petition (PP 0E7787) from the Interregional Research Project, 

No. 4 (IR-4), 500 College Road East, Suite 201 W, Princeton, NJ 08540 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 180.448, by establishing a tolerance for residues of hexythiazox (trans-5-(4-

chlorophenyl)-N-cyclohexyl-4-methyl-2-oxothiazolidine-3-carboxamide) and its metabolites 

containing the (4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety in or on tomato at 0.50 parts 

per million (ppm). 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 

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

tolerance. 

3. Magnitude of residues. Five new greenhouse trials were conducted by IR4 in support of 

the proposal to add greenhouse tomatoes to the label. The results of these new trials 

support the proposed tolerance levels of 0.50 ppm.

4. Magnitude of the Residue in Processed Food/Feed. Tomatoes grown in greenhouses are 

intended for the fresh market, not for processing commodities. Processing studies are not 

required. Greenhouse tomatoes are not rotated to other crops.

B. Toxicological Profile
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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 

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 EPA 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].
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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. EPA has previously determined that the residues of concern in plant 

and animal commodities are hexythiazox and its metabolite containing the (4 

chlorophenyl)-4-methyl-2oxo-3-thiazolidine moiety. 

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 (July 14, 2010, 75FR40741).

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 

8% of the chronic Population Adjusted Dose (cPAD) for any population 

subgroup. The registrant has concluded that hexythiazox use in greenhouse 

tomatoes will not significantly contribute to 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 

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. EPA 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
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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 in the July 14, 2010, 75FR40741 

that chronic exposure to hexythiazox from food and water will utilize no more 

than 49% of the cPAD for the population group receiving the greatest 

exposure (children 1-2 years old). The current assessment evaluated all 

registered crops, pending tolerance actions and the proposed new tolerance for 

tomatoes. This assessment utilized the proposed tolerance value for tomatoes, 

assumed 100% crop treated and utilized default processing factors. The 

additional potential dietary exposure associated with the proposed use, using a 

conservative Tier 1 assessment for all tomatoes, not just limited to greenhouse 

grown tomatoes, will now utilize 57% of the cPAD. Actual exposure will be 

considerably less. 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 

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

According to the Codex alimentarius website (http://www.codexalimentarius.net/mrls/) a 0.1 ppm 

MRL has been established by Codex.
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