FILE NAME: Valent.doc (July XX, 2014)

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE 

PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

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

Valent U.S.A. Corporation

[Insert petition number]

EPA has received a pesticide petition ([insert petition number]) from Valent U.S.A. 

Corporation, 1600 Riviera Avenue, Suite 200, Walnut Creek, CA 94596 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 import 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 commodity orange at 0.08 parts per million (ppm) and at 1.8 ppm in or on 

orange, oil. 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-. A gas chromatography with mass-selective detection (GC/MSD) 

enforcement analytical method has been submitted and determined by EPA to be acceptable for 

determination of etoxazole residues in citrus commodities. The method has been validated by an 

independent laboratory, and has been validated by the EPA Analytical Chemistry Laboratory as 

directed at 40 CFR 158.1410

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 (orange and orange, oil). 

The chronic dietary assessment included all etoxazole registered uses to date using DEEM-FCID 

version 2.03 and is the baseline for this assessment. Chronic dietary exposure to etoxazole on 

orange commodities was calculated using the most recent DEEM-FCID version 3.16 and the 

results for select subpopulations were combined with those of the previous dietary 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

The Codex Alimentarius Commission (Codex) has established maximum residue limits 

(MRLs) for etoxazole on citrus fruit at 0.1 ppm, as well as on several other commodities. In 

addition, MRL values have been established for etoxazole in the following countries: Australia, 

Brazil, Canada, European Union, Japan, South Korea, Israel, Norway, South Africa, Switzerland, 

Taiwan, and Turkey.

1U.S. Environmental Protection Agency (EPA). 2011. “Etoxazole. Chronic Dietary Exposure and Risk Assessment for the Section 3 

Registration Action on Field Corn and Pop Corn.” PC Code 107091. DP Barcode: D385941. From J. R. Tyler (HED) through M. Sahafeyan, A. 

Acierto (DESAC/HED) and G. F. Kramer (RAB1/HED) to A. Metzger, J. Hebert (RD). September 23.