FILE NAME: Hexythiazox NOF 100812

Template Number P25 

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GOWAN COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE (August 12, 2010 ) EPA Registratio n Division contact: Mark Suarez , PM #13, telephone (703) 305
- 0120 TEMPLATE: EPA has received a pesticide petition (number not currently available) from Gowan Company , 370 South Main Street, Yuma, AZ 85364 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 amending the existing tolerances for residues of hexy thiazox ( 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 to remove the geographical restriction for existing field corn tolerances and establish a new tolerance for aspirated grain fractions. 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 e valuated the sufficiency

o f 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 t ea have been previously

reviewed by

the Agency . The Agency has determined that the residues of concern are hexy

thiazox and its metabolites containing the (4
- chlorophenyl)
- 4
- methyl
- 2
- oxo - 3
- thiazolidine moiety . The results of a new corn metabolism study (M RID 48081501, currently

in review) are consistent with the other plant metabolism data. 2. Analytical method . A practical analy tical method, high pressure liquid chromatography with a UV detector, which detects and measures residues of hexy thiazox and its metabolites as a common moiety , is available for enforcement purposes with a limit of2

detection that allows monitoring of food with residues at or above the levels set in this tolerance. 3. Magnitude of residues. Twenty new field trials were conducted by Go wan Company

in support of the proposed label amendments for field corn. The amendments include 1) removing the regional use restriction and 2) reducing the pre
- harvest interval to 30 days. The results of these new trials support the currently established tolerance levels of 0.02 ppm for field corn grain and 6.0 ppm for field corn forage. We propose to increase the tolerance for field corn stover to 6.0 ppm. 4. Magnitude of the Residue in Processed Food/Feed. Data on field corn processed commodities support the establishment of a new tolerance of 0.5 ppm for aspirated grain fractions. B. Toxicological Profile 1. Acute toxicity . A battery of acute toxicity

studies places technical grade hexy thiazox in Toxicity Category IV for acute oral LD50 (LD50 > 5,0 00 milligram/kilograms (mg/kg)), Category I II for dermal LD50 (LD50 >5,000 mg/kg), Category I II for inhalation L C50 (LC50 >2.0 mg/L), Category I II for primary

eye irritation (showed mild irritation (reddened conjunctiva)), Category IV for dermal irritation (non irritant). Hexy thiazox is a non - sensitizer. Acute toxicological studies place technical grade hexy thiazox in Toxicology

Category I II. 2. Genotoxicty. The following genotoxicity studies were all negative: Ames gene mutation, CHO gene mutation, CHO chr omosome aberration, mouse micronucleus and rat hepatocy te unscheduled DNA sy

nthesis. 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 Lo west - 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 devel opmental NOAELwas 1,080 mg/kg/day (HDT); the developmental L OAEL 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. Subch ronic toxicity. Ina 1
- month feeding study in dogs, the NOAEL was 1.75 mg/kg/day and the L OAEL was 12.5 mg/kg/day , based on increased liver and adrenal weights. 5. Chronic toxicity . In a 1
- ye ar 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, the3

NOAEL was 36 mg/kg/day and the L OAEL was 215 mg/kg/day . Effects were decreased body we ight in males and increased hepatocellular carcinomas and combined adenoma/carcinomas. Ina chronic feeding/carcinogenicity study in rats, the NOAEL(sy stemic) was 26 mg/kg/day

and the L OAEL (sy stemic) was 180 mg/kg/day based on decreased body weight gai n 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 establish ing 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 hexy thi azox. 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 Octobe r 16, 1998, [63.FR55540]. 6. Animal metabolism . The metabolism of hexy thiazox has been studied in goats, hens and rats. Metabolic pathways in the animal are similar to those in plants. 7. Metabolic toxicology . There are no metabolites of toxicological concern b ased on a differential metabolism between plants and animals. 8. Endocrine disruptions . No specific test have been conducted with hexy thiazox 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 multi
generational reproduction studies, which would suggest that hexy thiazox 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

( March 17, 2010, 75FR12691.) i. Acute Exposure . No acute endpoint has been i dentified in the toxicological studies for hexy

thiazox; 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 diet ary risk of not more than 0.3% of the chronic Population Adjusted Dose (cPAD) for any population The registrant has concluded that hexy thiazox use in field corn will not significantly contribute to this dietary

exposure . ii. Cancer. The Agency has previously determined that the chronic reference dose is sufficient to evaluate all chronic risk of hexy thiazox, including carcinogenic potential. iii. Dietary Exposure from drinking water. The Agency used screening level water exposure models in the dietary exposure ana ly sis and risk assessment for4 hexy thiazox in drinking water. Based on the Pesticide Root Zone Model /Exposure Analy sis Modeling Sy stem (PRZM/EXAMS) the estimated drinking water concentration (EDWC) of hexy thiazox for chronic exposures for non
cancer and c ancer 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

- die tary exposure. HED 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 EPA has not determined whether hexy thiazox has a common mechanism of toxicity w ith 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 , hexy thiazox does not share a toxic metabolite with other substances. F o r the purposes of this tolerance action, therefore, the registrant has not assumed that hexy thiazox has a common mechanism of toxicity

w ith other substances. F or purposes of this petition the potential risks of hexy thiazox in its aggregate exposure only

w ill be considered. E. Safety Determination 1. 1. US population

i. Acute risk. No adverse effect resulting from a single oral exposure to hexy thiazox has been identified, thus hexy thiazox is not expected to pose an acute risk. ii. Short

- and intermediate term r isk. 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 hexy thiazox is a MOE of 100 or below, these MOEs are not of conce rn. iii. Chronic risk. EPA previously concluded that chronic exposure to hexy thiazox from food and water will utilize no more than 49% of the cPAD for (children 1
- 2 years old) the population group receiving the greatest exposure. This assessment utilized exi sting tolerance values, assumed 100% crop treated and utilized default processing factors. The incremental additional potential dietary

exposure associated with the proposed use will utilize no greater than 0.3% of the cPAD. Chronic residential exposure to residues of hexy thiazox 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 dose5 will be protective for both chronic and carcinogenic risks. T here 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 h exy thiazox residues. F. International Tolerances No national or transnational maximum residue levels for hexy thiazox on field corn exist apart from those in the United States.