Document ID: EPA-HQ-OPP-2012-0357-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-08-22T04:00Z

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.