EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITION 

Docket ID Number: EPA-HQ-OPP-2012-0357

EPA Registration Division contact: Sidney Jackson (703) 305-7610 

Interregional Research Project Number 4 

Pesticide Petition Number: PP 2E8016

EPA has received a pesticide petition (PP 2E8016) from Interregional Research 

Project Number 4 (IR-4), IR-4 Project Headquarters, Rutgers, The State University of 

New Jersey, 500 College Road East, Suite 201W, 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 by establishing a tolerance for residues of

hexythiazox (4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety) in or on the raw 

agricultural commodities Pepper/Eggplant subgroup 8-10B at 1.5 parts per million (ppm), 

Fruit, pome, group 11-10 at 0.25 ppm, Caneberry subgroup 13-07A at 1.0 ppm, Fruit, 

small, vine climbing, except fuzzy kiwifruit, subgroup 13-07F at 1.0 ppm, and Berry, low 

growing, subgroup 13-07G at 3.0 ppm. Further, this petition proposes to delete existing 

tolerances established in 40 CFR 180.448 for hexythiazox for Pome Fruit Crop Group 11, 

Caneberry Subgroup 13A, grape, and strawberry once the proposed tolerances have been 

established since the proposed new tolerances will supersede the existing tolerances. 

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 support 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. 

2. Analytical method. A practical analytical method, high pressure liquid 

chromatography with a ultra violet (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. Seven field trials and three greenhouse trials on bell 
pepper and an additional three field trials on nonbell peppers were conducted under the 

IR-4 Project in support of the proposed label amendment (national use) for 

Pepper/Eggplant subgroup 8-10B. The results of these trials support the proposed 

tolerance level of 1.5 ppm in/on pepper/eggplant subgroup 8-10B.

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 as 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-Observed-Adverse-Effect-Level (NOAEL) was 240 mg/kg/day and 

the maternal Lowest-Observed-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, [63FR55540].

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 (at the time of the assessment) has been completed by the Agency 

(March 17, 2010, 75FR12691.)

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 indicates 

that the proposed use results in a dietary risk of not more than 65.4% 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 4.1 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. 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 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

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 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. Chronic risk. Chronic exposure to hexythiazox 

from food and water will utilize no more than 65.4% of the cPAD for (children 1-2 years 

old) the population group receiving the greatest exposure. 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 (MRLs) for hexythiazox exist apart 

from those in the United States.