EPA REGISTRATION DIVISION CO MPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: John Hebert (703-308-6249)

INSTRUCTIONS: Please utilize this outline in p reparing the pesticide petition. In

cases where the outline element does not apply, please insert “NA-Remove” and

maintain the outline. Please do not chan ge 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:

Valent U.S.A. Corporation

[0F7783]

EPA has received a pesticide petition ([0F7783]) from Valent U.S.A. Corporation

, 1600 Riviera Avenue, Suite 200, Walnut Creek, CA 94596 proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosme tic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishi ng a tolerance for residues of etoxazole, 2-(2,6- difluorophenyl)-4-[4-(1,1-dimethylet hyl)-2-ethoxyphenyl]-4,5-dihydrooxazole, in or on the raw agricultural commodity corn, field, grain at 0.01 ppm, corn, field, forage at 0.6

ppm, corn, field, stover at 2.5 ppm, corn, field, refined oil at 0.03 ppm, corn, pop, grain at
0.01 ppm, corn, pop, stover at 2.5 ppm, poultry, fat at 0.01 ppm, and poultry, liver at 0.02 ppm. EPA has determined that the petition contains data or info rmation 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 qualitative nature of etox azole residues in plants is adequately understood based upon the plant metabolism studies on cotton, eggplant, apple and orange. Parent compound etoxazole is the major residue formed in all crops

studied.

2. Analytical method. Adequate enforcement methodology (GC/MSD) for detecting and measuring levels of etoxazole is available to enforce proposed tolerances in/on corn raw and processed commodities. GC/NPD enforcement methodology is also available to enforce proposed livestock commodity tolerances.2

3. Magnitude of residues. Crop field trial data and pr ocessing residue data have been submitted which adequately support the requested tolerances.

B. Toxicological Profile

1. Acute toxicity. The acute toxicity of technica l grade etoxazole is low by all routes. The battery of acute to xicity studies place etoxazole in Toxicity Category III. The oral LD50 in the rat is greater than 5 grams/ kilogram (g/kg), the dermal LD50 is greater than 2.0 g/kg, and the inhalation LC50 in the rat is greater than 1.09 milligrams/liter (mg/L). Technical grade etoxazole is not an i rritant to eyes or skin and is not a skin

sensitizer.

2. Genotoxicity. Etoxazole was evaluated and found to be negative in an Ames reverse mutation assay, a chromosome abe rration assay, a micronucleus assay, and an unscheduled DNA synthesis (UDS) assay. Etoxa zole produced a positive result in the mouse lymphoma gene mutation assay but onl y in the presence of metabolic activation. Etoxazole does not present a genetic hazard.

3. Reproductive and developmental toxicity. The toxicology data for etoxazole provides no indication of increase d susceptibility, as compared to adults, of rat and rabbit

fetuses to in utero exposure in developmental studies. The rabbit developmental toxicity study included maternal toxic effects (liver enlargement, decreased weight gain, and decreased food consumption) at the same dose as developmental effects (increased incidences of 27 presacral vertebrae and 27 pr esacral vertebrae with 13th ribs). In the two-generation reproduction study conducted with rats, offspring toxicity was more severe (pup mortality) than pare ntal toxicity (increased live r and adrenal weights) at the same dose, indicating increased qualitative susceptibility.

4. Subchronic toxicity. The liver is the main target organ in mice, rats and dogs. In a 90–day toxicity study in dogs, incr eased liver weight s and centrilobular hepatocellular swelling in the liver were obser ved. Similar effects were observed in a chronic toxicity study in dogs at similar doses , indicating that systemic effects (mainly liver effects) occur at similar dose levels following short- through long-term exposure without increasing in severi ty. In a 90–day toxicity study in mice, hepatotoxicity (increased relative liver we ight, liver enlargement, a nd centrilobular hepatocellular swelling) was observed at high doses. Similar e ffects were observed at the high dose in a mouse carcinogenicity study. Subchronic and chr onic toxicity studies in rats produced similar effects (increased liver weights, centrilobular hepatocellu lar swelling, etc.) to those seen in mice and dogs. In addition, slight increases in thyroid weights and incisors

were observed in subchronic and chronic toxici ty studies in rats at high doses and at terminal stages of the study. There is no eviden ce of immunotoxicity or neurotoxicity in any of the submitted studies.

5. Chronic toxicity. See summary in section B.4 above. Two studies in mice showed no evidence of carcinogenicity up to the HDT. In a rat carcinogenicity study, which was deemed unacceptable due to inadeq uate dosing, benign interstitial cell tumors3

(testis) and pancreas benign islet cell adenom as were observed (in females) at the high

dose. These effects were not observed in an acceptable carcinogenici ty study in rats at higher doses. In special mechanistic male rat studies there were no observable changes in serum hormone levels (estradi ol, luteinizing hormone (LH), prolactin and testosterone) or reproductive effects (inter stitial cell proliferation or spermatogenesis) noted. EPA

classified etoxazole as ‘‘not lik ely to be carcinogenic to humans.’’ The toxicity endpoint for chronic dietary exposure is derived from the NOAEL from a chronic oral toxicity study in dogs.

6. Animal metabolism. The metabolism of 14C-tbut ylphenyl and 14C-oxazoleetoxazole has been studied in rats. For both labels, following a single oral dose at 5 mg/kg or 500 mg/kg, the majority of etoxazole is excreted within 7 days, primarily in the

feces.

7. Metabolite toxicology

. Parent compound is the only residue of concern in agricultural commodities for tolerance enforcement purposes.

8. Endocrine disruption

. The toxicology database fo r etoxazole is current and complete, with the exception of an im munotoxicity study, acute and subchronic neurotoxicity studies, which are currently in progress (initiated March 2010). The database includes a thorough evaluation of the potential effect s on reproduction and development, and the pathology of the endocri ne organs following short- and long-term exposure. The battery of tests included in support of this petition fully characterizes potential endocrine-related in vivo effects and clearly defi nes NOAEL/LOAEL values.

C. Aggregate Exposure

1. Dietary exposure. A Tier I chronic dietary ex posure assessment was conducted using tolerance-level residues, 100% crop tr eated, and default processing factors for processed commodities lacking supporting resi due data. As EPA has determined that

there is no effect of concern that would resu lt from acute dietary intake, no quantitative

assessment of acute dietar y exposure is required. Chronic dietary exposures to etoxazole were calculated using Dietary E xposure Evaluation Model DEEM-FCID TM , Version 2.16.

i. Food. Input data for the chronic di etary exposure assessment included tolerances supporting currently re gistered crops and those propos ed in this petition (field corn grain; poultry liver/fat), as well as crops/commodities included in a tolerance petition submitted by IR-4 on December 23, 2009 (PP 9E7675) and currently under evaluation by the Agency. The December 2009 petition includes the following crops and subcrop groups: caneberry (Crop Subgroup 13-07A); berry, low growing (Crop Subgroup 13-07G); fruit, small, vine climbing except fuzzy kiwifruit (Subgroup 13-07F); vegetables, cucurbit (Crop Subgroup 9B); pepper; eggplant; avocado, mango, and papaya,. An amendment submitted January 29, 2010 expanded peppers and eggplants to proposed crop subgroups for peppers (including bell and non bell, chili, cooking, pimento and sweet) and eggplants (inc luding African eggplant; Bell pepper; Eggplant; Martynia; Nonbell pepper; Okra; Pea eggplant; Pepino; Roselle; Scarlet eggplant; cultivars,4

varieties, and/or hybr ids of these). The dietary asse ssment supporting this petition does not include popcorn, however given the conservative exposure assumptions and assessment results it is not expected that addition of this commodity will result in exposure exceeding toxicity endpoints of concern.

ii. Drinking water. EPA estimated drinking water c oncentrations (EDWCs) using the First Index Reservoir Screening Tool ( FIRST) were included as part of the dietary exposure assessment. The EDWC in surface water was estimated to be 4.761 ppb, based on the application of etoxazole to mint at a maximum seasonal applica tion rate of 0.36 lb

ai/Acre.

2. Non-dietary exposure

. There are no residential or proposed residential nonfood uses for etoxazole, therefore there is no non-dietary component to the estimate of

aggregate exposure..

D. Cumulative Effects

FFDCA Section 408(b)(2)(D)(v) requires that the Agency must consider “available information'' concerning the cumula tive effects of a particular pesticide's

residues and ``other substances'' that have a common mechanism of toxicity. There are currently no available data or other reliable information indica ting that etoxazole shares a common mechanism of toxicity with any othe r substance. Only the aggregate exposure

of etoxazole has been consider ed in this risk assessment.

E. Safety Determination

1. U.S. population. As no acute toxicity endpo int has been identified for etoxazole, no assessment of acute aggregate exposure is required. The chronic population adjusted dose (cPAD) of 0.046 mg /kg/day has been calculated from the chronic toxicity endpoint using an uncertain ty factor of 100X to account for inter- and intra-species variability. Based on currently registered uses, us es pending registration with the Agency and uses proposed in this petition, total chronic aggregate exposure to etoxazole is conservatively estimated to be 2.5% of the cPAD for the U.S. Population. Chronic aggregate exposure below 100% of the cPAD is generally considered to represent a reasonable certainty of no harm to exposed populations.

2. Infants and children

. FFDCA section 408 provides that EPA shall apply an additional margin of safety, up to ten-fold, fo r added protection for infants and children in the case of threshold effects, unless EPA determines that a different margin of safety will

be safe for infants and children. The toxicol ogical database for evaluating prenatal and postnatal toxicity for etoxazole is complete wi th respect to current data requirements, and there are no special prenatal or postnatal toxi city concerns for infants and children. EPA has concluded that reliable data support reduction of the FQPA Safety Factor for protection of infants and children to 1X. Based on currently registered uses, uses pending registration with the Agency and uses proposed in this petition, total chronic aggregate exposure to etoxazole is conservati vely estimated to be 7.7% of the cPAD for5

infants, 10.6% for children aged 1-2 years (t he most highly exposed subpopulation), and 7.0% for children aged 3-5 years. Chroni c aggregate exposure below 100% of the cPAD is generally considered to represent a r easonable certainty of no harm to exposed populations.

F. International Tolerances

Presently there are no Codex maximum re sidue limits (MRL) for etoxazole, but a proposal for establishment of Codex MR Ls has been submitted to the JMPR for evaluation in 2010. In addition, MRL values ha ve been established for etoxazole in the following countries: Australia, Brazil, Canada (proposed but not published), European Union (harmonized), Japan, South Korea, Is rael, Norway, South Africa, Switzerland, Taiwan.and Turkey.