Document ID: EPA-HQ-OPP-2017-0273-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2017-10-23T04:00Z

EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR PESTICIDE PETITION 

FILE NAME: NOF ETOXAZOLE 10/27/16 Valent Word doc (October, 2016)

Docket ID Number: EPA-HQ-OPP-2017-0273

EPA Registration Division contact: Venus Eagle (703-308-8045)

Interregional Research Project No. 4 (IR-4)

[Insert petition number]

	EPA has received a pesticide petition (7E8559) from Interregional Research Project Number 4 (IR-4), Rutgers, The State University of New Jersey, 500 College Road East, Suite 201 W, Princeton, NJ 08540 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 by 

 Establishing a tolerance for residues of etoxazole, 2-(2,6-difluorophenyl)-4-[4-(1,1-dimethylethyl)-2-ethoxyphenyl]-4,5-dihydrooxazole, in or on the raw agricultural commodities [Corn, sweet, kernel plus cob with husks removed] at [0.01] parts per million (ppm); [Corn, sweet, forage] at [1.5] ppm; [Corn, sweet, stover] at [5.0] ppm; [Fruit, pome, group 11-10] at [0.20] ppm; [Nut, tree, group 14-12] at [0.01] ppm; [Fruit, stone, group 12-12] at [1.0] ppm and [Cottonseed subgroup 20C] at [0.05] ppm.  

 Remove established tolerances for residues of etoxazole,  2-(2,6-difluorophenyl)-4-[4-(1,1-dimethylethyl)-2-ethoxyphenyl]-4,5-dihydrooxazole, in or on the raw agricultural commodities [Fruit, pome, group 11] at [0.20] ppm, [Fruit, stone, group 12, except plum] at [1.0] ppm, [Nut, tree, group 14] at [0.01] ppm, [Cotton, undelinted seed] at [0.05] ppm, [Pistachio] at [0.01] ppm, [Plum] at [0.15] ppm and [Plum, prune, dried] at [0.30] 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 qualitative nature of etoxazole 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 the sweet corn commodity.  GC/NPD enforcement methodology is also available to enforce proposed livestock commodity tolerances.

  3. Magnitude of residues. Crop field trial data and processing residue data are enclosed which will support the requested tolerances.

B. Toxicological Profile

	1. Acute toxicity.  The acute toxicity of technical grade etoxazole is low by all routes. The battery of acute toxicity 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 irritant 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 aberration assay, a micronucleus assay, and an
unscheduled DNA synthesis (UDS) assay. Etoxazole produced a positive result in the mouse lymphoma gene mutation assay but only 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 increased 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 presacral vertebrae with 13th ribs). In the two-generation reproduction study conducted with rats, offspring toxicity was more severe (pup mortality) than parental toxicity (increased liver 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, increased liver weights and centrilobular hepatocellular swelling in the liver were observed. 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 severity. In a 90 - day toxicity study in mice, hepatotoxicity (increased relative liver weight, liver enlargement, and centrilobular hepatocellular swelling) was observed at high doses. Similar effects were observed at the high dose in a mouse carcinogenicity study. Subchronic and chronic toxicity studies in rats produced similar effects (increased liver weights, centrilobular hepatocellular swelling, etc.) to those seen in mice and dogs. In addition, slight increases in thyroid weights and incisors were observed in subchronic and chronic toxicity studies in rats at high doses and at terminal stages of the study. There is no evidence 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 inadequate dosing, benign interstitial cell tumors (testis) and pancreas benign islet cell adenomas were observed (in females) at the high dose. These effects were not observed in a second acceptable carcinogenicity study in rats at higher doses. In special mechanistic male rat studies there were no observable changes in serum hormone levels (estradiol, luteinizing hormone (LH), prolactin and testosterone) or reproductive effects (interstitial cell proliferation or spermatogenesis) noted. EPA classified etoxazole as ``not likely 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-tbutylphenyl and 14C-oxazole-etoxazole 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 for etoxazole is current and complete. The database includes a thorough evaluation of the potential effects on reproduction and development, and the pathology of the endocrine 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 defines NOAEL/LOAEL values.  

C. Aggregate Exposure

	1. Dietary exposure.  A Tier I chronic dietary exposure assessment was conducted using tolerance-level residues, 100% crop treated, and default processing factors for processed commodities lacking supporting residue data.  Only a chronic assessment was conducted as EPA has determined that there is no effect of concern that would result from acute dietary intake, and that no quantitative assessment of acute exposure is required.

	i. Food.  Input data for the chronic dietary exposure assessment included tolerances supporting currently registered crops and those proposed in this petition. The chronic dietary assessment included all etoxazole registered uses to date using DEEM-FCID version 2.03 and is the baseline for this assessment. 

  	ii. Drinking water.  EPA-estimated drinking water concentrations (EDWCs) using the First Index Reservoir Screening Tool (FIRST) were included as part of the dietary exposure assessment as described in EPA's 2011 dietary 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 application rate of 0.36 lb ai/Acre.

	2. Non-dietary exposure.  There are no residential or proposed residential non-food 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 cumulative 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 indicating that etoxazole shares a common mechanism of toxicity with any other substance.  Only the aggregate exposure of etoxazole has been considered in this risk assessment.

E. Safety Determination 

	1. U.S. population. As no acute toxicity endpoint 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 uncertainty factor of 100X to account for inter- and intra-species variability.  Based on currently registered uses, and uses proposed in this petition, total chronic aggregate exposure to etoxazole is conservatively estimated to be 2.8% 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, for 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 toxicological database for evaluating prenatal and postnatal toxicity for etoxazole is complete with respect to current data requirements, and there are no special prenatal or postnatal toxicity 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, and uses proposed in this petition, total chronic aggregate exposure to etoxazole is conservatively estimated to be 11.5% for children aged 1-2 years (the most highly exposed subpopulation).  Chronic aggregate exposure below 100% of the cPAD is generally considered to represent a reasonable certainty of no harm to exposed populations.
 
F. International Tolerances

	Maximum residue limits (MRLs) values have been established for etoxazole for sweet corn in the following locations: Canada, and European Union. The Codex Alimentarius Commission (Codex) has established MRLs for etoxazole on sweet corn.