Docket ID #: EPA - HQ - OPP - 2010 - 09 1 6

COMPANY NOTICE OF FILIN G 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 rece ived 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 e stablishing a tolerance 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 moi ety 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 e valuated the sufficiency

of the submitted data at this time or whether the data support s 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 i s 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 hexy

thiazox 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 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 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 propos ed toleranc e levels of 0.50 ppm . 4. Magnitude of the Residue in Processed Food/Feed. Tomatoes grown in greenhouses are i ntended for the fresh market, not for processing commodities. Processing studies are not required. Greenhouse tomatoes are not rotated to other crops. B. Toxi cological Profile2

1. Acute toxicity . A battery of acute toxicity

studies places technical grade hexy thiazox in Toxicity Category IV for acute oral LD50 (LD50 > 5,000 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 technica l grade hexy thiazox in Toxicology

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

nthesis. 3. Reproduc tive 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 decrea sed 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 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 reprod

uctive 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. Ina 1
- month feeding study in dogs, the NOAEL was 1.75 mg/kg/day and the L OAE L 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, the NOAEL was 36 mg/kg/day and the L OAEL was 215 mg/kg/day . Effects were decreased body weight 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 gain and increased liver weights in both sexes. A 2009 report from the EPA Cancer Assessment Rev iew 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 hexy thiazox. 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].3

6. Animal metabolism . The metabolism of hexy thiazox has been studi ed in goats, hens and rats. Metabolic pathway s 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 hexy thiazox and its metabolite containing the (4 chlorophenyl)
- 4
- methyl
- 2oxo
- 3
- thiazolidine moie ty . 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 th e 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 identifie d 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 dietary risk of not more than 8 % of the chronic Population Adjusted Dose (cPAD) for any population subgroup. The registrant has concluded that hexy thiazox use in greenhouse tomatoes will not signif

icantly contribute to dietary

exposure . ii. Cancer. The Agency has previo usly

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 analy sis and risk assessment for 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 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. E PA 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 Effects4

EPA has not determined whether hexy thiazox has a common mechanism of toxicity w ith other substance s 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. For 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 on ly

will 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 te rm 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 hexy thiazox is a MOE of 100 or below, these MOEs are not of c oncern. iii. Chronic risk. EPA previously concluded in the July

14, 2010, 75FR40741 that chronic exposure to hexy thiazox from food and water will utilize no more than 49 % of the cPAD for the population group receiving the greatest exposure (children 1
- 2 year s old)
. The current assessment evaluated all registered crops, pending tolerance actions and the proposed new tolerance for tomatoes. T his assessment utilized the proposed tolerance value for tomatoes , assumed 100% crop treated and utilized default proce ssing 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 exp osure will be c onsiderably

less. 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 dose will be protec tive 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 i nfants and children from aggregate exposure to hexy thiazox residues. F. International Tolerances According to the Codex a limentarius website (http://www.codexalimentarius.net/mrls/ ) a 0.1 ppm MRLhas been established by Codex.5