Document ID: EPA-HQ-OPP-2019-0383-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2019-08-30T04:00Z

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:

Tea Association of the USA, Inc.

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from Tea Association of the USA, Inc. 362 5th Ave - Suite 1002 New York, NY 10001 requesting, 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 Hexythiazox, (trans-5-(4-chlorophenyl)-N-cyclohexyl-4-methyl-2-oxothiazolidine-3-carboxamide)

	
in or on the raw agricultural commodity tea at 15 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 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 adequately understood 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.

	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 2011 JMPR evaluations for tea are based on the residue trial data from India.  The JMPR Evaluation and Report and provided in place of the actual residue reports, are included under the EPA pilot to use JMPR reviews or national reviews to set US import tolerances.  The methods used for tea is summarized in the JMPR evaluations. 
	3. Magnitude of residues. Field trial data have been generated for hexythiazox on tea.  Eight trials were conducted in India on tea during the 2008 and 2009 growing season.
Residue Levels in RAC Samples
The results from these trials show that after two applications of Maiden EC at 25 g ai/ha, 14 days between applications and a zero day PHI, maximum residue of hexythiazox was 5.2 ppm (median  -  4.55 ppm) on eight green and black tea samples collected 0 DAA.   
Residue Levels in Product as consumed
The 2011 JMPR evaluations for hexythiazox/tea are based on the residue trial data, including processing data from India.  The JMPR Evaluation and report are provided with this submission in place of the actual residue reports, and are included under the EPA pilot to use JMPR reviews or national reviews to set US import tolerances.  The data indicate that the transfer factor from tea to brewed tea was 0.04 for green tea and 0.03 for fermented (black) tea.
B. Toxicological Profile

	1. Acute toxicity.  In the most recent risk assessment for hexythiazox completed in 2017, the Agency noted that the toxicology database for hexythiazox is complete. Hexythiazox has low acute toxicity via the oral, dermal, or inhalation route of exposure (Category IV). It is a mild eye irritant (Toxicity Category III), but not a skin irritant or a skin sensitizer.

	2. Genotoxicty.  Hexythiazox is not considered to be a mutagen. Mutagenicity studies that have been conducted include a mammalian erythrocyte micronucleus test [MRID 45480101], a mammalian cell forward gene mutation assay [MRID 00155154], a rat primary hepatocyte unscheduled DNA synthesis assay [MRID 00156893], a clastogenic evaluation in an in vitro cytogenetic assay measuring chromosomal aberration in Chinese hamster ovary cells [MRID 00156894], and an Ames study with Salmonella [MRID 44955710]. All mutagenicity tests were negative.

	3. Reproductive and developmental toxicity.  .  Hexythiazox is not considered to be a reproductive or developmental neurotoxic or immunotoxic chemical. 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 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. In a subchronic toxicity study in rats, increased liver and adrenal weights, as well as adrenal histopathology (fatty degeneration of the adrenal zona fasciculata) were seen. In the chronic feeding/carcinogenicity studies in rats and mice, effects included decreased body weight gain and increased liver 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 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].

	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. 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, 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, Vol. 82, No. 208, Monday, October 30, 2017, Pages 50084-50089).

	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. The Agency comprehensively evaluated potential dietary exposure resulting from the currently registered uses of hexythiazox in the October 30, 2017 Federal Register. The Agency concluded that chronic exposure to hexythiazox from food and water will utilize 93% of the cPAD (for children 1-2 years old). The Agency's assessment employed tolerance residue values, the assumption of 100% crop treated, and default processing factors.
   
	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 assessment was estimated to be 4.31 parts per billion (ppb). (Federal Register, Vol. 82, No. 208, Monday, October 30, 2017, Pages 50084-50089)

	2. Non-dietary exposure. EPA has previously determined that potential residential exposures to hexythiazox are not expected.

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 toxic effects attributable to a single dose of hexythiazox has been identified, thus hexythiazox 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 of the risk for all applicable crops, including the tolerance on tea, and water sources, shows no more than 93% of the cPAD for any population subgroup.  

	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 1X. 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
	There exists a CODEX maximum residue limit (MRL) of 15 ppm and a European Union (EU) MRL of 15 ppm hexythiazox on tea.