EPA REGISTRATION DIVISION COMPANY 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 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: 

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 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 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 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 corn raw and processed commodities. GC/NPD enforcement methodology is also 

available to enforce proposed livestock commodity tolerances.
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 3. Magnitude of residues. Crop field trial data and processing residue data have 

been submitted which adequately 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 
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(testis) and pancreas benign islet cell adenomas were observed (in females) at the high 

dose. These effects were not observed in an 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-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 for etoxazole is current and 

complete, with the exception of an immunotoxicity study, acute and subchronic 

neurotoxicity studies, which are currently in progress (initiated March 2010). 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. As EPA has determined that 

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

assessment of acute dietary exposure is required. Chronic dietary exposures to etoxazole 

were calculated using Dietary Exposure Evaluation Model DEEM-FCIDTM, Version 2.16. 

 i. Food. Input data for the chronic dietary exposure assessment included 

tolerances supporting currently registered crops and those proposed 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 (including African eggplant; Bell pepper; Eggplant; Martynia; 

Nonbell pepper; Okra; Pea eggplant; Pepino; Roselle; Scarlet eggplant; cultivars, 
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varieties, and/or hybrids of these). The dietary assessment 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 concentrations (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 application 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 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, uses 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, 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, uses 

pending registration with the Agency and uses proposed in this petition, total chronic 

aggregate exposure to etoxazole is conservatively estimated to be 7.7% of the cPAD for 
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infants, 10.6% for children aged 1-2 years (the most highly exposed subpopulation), and 

7.0% for children aged 3-5 years. 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

Presently there are no Codex maximum residue limits (MRL) for etoxazole, but 

a proposal for establishment of Codex MRLs has been submitted to the JMPR for 

evaluation in 2010. In addition, MRL values have been established for etoxazole in the 

following countries: Australia, Brazil, Canada (proposed but not published), European 

Union (harmonized), Japan, South Korea, Israel, Norway, South Africa, Switzerland, 

Taiwan.and Turkey.