UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date 

Subject: 

From: 

29-September-2015 

Etoxazole: Human Health Risk Assessment in Support of the Proposed Tolerances for 

Residues in/on Imported Oranges and Orange Oil. 

PC Code: 107091 DP Barcode: 0422673 

Decision No.: 493877 Registration Nos.: not applicable 

Petition No.: 4£ 8304 Regulatory Action: tolerance without U.S. registration 

Risk Assessment Type: single chemical/aggregate Case No.: 7616 

TXR No.: not applicable CAS No.: 153233-91-1 

MRIO No: not applicable 40 CFR: 180.593 

Tom Bloem, Ch~~ , /} / 

Anwar Y. Dunb~:u;~harmacologist ~ ltJ. v~ Risk Assessment Branch I/Health Effects Division ~lfHED; 

To: Venus Eagle/Rita Kumar RMOl 

Registration Division (RD; 7505P) 

HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. RD of OPP has requested that HED evaluate hazard and 

exposure data and conduct dietary, occupational, residential, and aggregate exposure 

assessments, as needed, to estimate the risk to human health that will result from all registered 

and proposed uses of etoxazole (2-(2,6-difluorophenyl)-4-(4-(1,1-dimethylethyl)-2-

ethoxyphenyl]-4,5-dihydrooxazole). A summary of the findings and an assessment of the hwnan 

health risk resulting from the registered and proposed uses are provided in this document. The 

risk assessment, dietary risk assessment, and residue chemistry data review were provided by 

Tom Bloem (RABI), the hazard characterization was provided by Anwar Dunbar (RABI), and 

the drinking water assessment by Jose Melendez of the Environmental Fate and Effects Division 

(EFED). 

Page I of21 
Etoxazole Human Health Risk Assessment D422673 

Table of Contents 

I .0 Executive Summary ............................................................................................................................................... 3 

2.1 Data Deficiencies/Data Needs ........................................................................................................................... 4 

2.2 Tolerance Considerations .................................................................................................................................. 4 

2.2.1 Enforcement Analytical Method ............................................................................................................... 4 

2.2.2 Recommended Tolerances ........................................................................................................................ 5 

2.2.3 Revisions to Petitioned-For Tolerances ..................................................................................................... 5 

2.2.4 International Hannon ization ...................................................................................................................... 5 

2.3 Label Recommendations ................................................................................................................................... 5 

3.0 Introduction ............................................................................................................................................................ 6 

3. 1 Chemical Identity .................................................................. ............................................................................ 6 

3.2 Pesticide Use Pattern/Directions ....................................................................................................................... 6 

3.3 Anticipated Exposure Pathways ........................................................................................................................ 7 

3.4 Consideration of Environmental Justice ........................................................................................................... 7 

4.0 Hazard Characterization and Dose-Response Assessment .................................................................................... 8 

4.1 Toxicology Studies Available for Analysis ....................................................................................................... 8 

4.2 Absorption, Distribution. Metabolism, & Elimination (ADME) ...................................................................... 8 

4.2. I Dermal Absorption .................................................................................................................................... 9 

4.3 Toxicological Effects ........................................................................................................................................ 9 

4.4 Safety factor for Infants and Children (FQPA Safety Factor) ........................................................................... 9 

4.4.1 Completeness of the Toxicology Database ................. ............................................................................. 10 

4.4.2 Evidence ofNeurotoxicity ........................................................................................................................ 10 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ........................................... 10 

4.4.4 Residual Uncertainty in the Exposure Database ....................................................................................... I 0 

4.5 Toxicity Endpoint and Point of Departure Selections ...................................................................................... I 0 

4.5.1 Dose-Response Assessment ..................................................................................................................... 10 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment.. ........................................ I I 

4.5.3 Cancer Classification and Risk Assessment Recommendation ................................................................ I I 

4.5.4 Summary of Points of Departure ~d .Toxicity Endpoints Used in Human Risk Assessment.. ................ I I 

5.0 Dietary Exposure and Risk Assessment ................................................................................................................ I 2 

5. I Metabolite/Degradate Residue Profile ............................................................................................................. 12 

5.2 Food Residue Profile ........................................................................................................................................ 12 

5.3 Drinking Water Residue Profile ....................................................................................................................... 12 

5.4 Dietary (Food + Drinking Water) Risk Assessment ........................................................................................ 13 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ........................................................................ 13 

6.1 Residential Bystander Post-Application Inhalation Exposure ......................................................................... 13 

6.2 Spray Drift ....................................................................................................................................................... 14 

7.0 Aggregate Exposure/Risk Characterization .......................................................................................................... 14 

8.0 Cumulative Exposure/Risk Characterization ........................................................................................................ 14 

9.0 Occupational Exposure/Risk Characterization ..................................................................................................... 14 

Appendix A: Tox icology Profile and Executive Summaries ...................................................................................... 15 

Appendix B: Exposure to Etoxazole in Fish/Shellfish at Consumption Levels Associated with Subsistence Fishing . 

......................................................................................................................................................................... 19 

Appendix C: Physical/Chemical Properties ................................................................................................................ 21 

Page 2 of2 I 
Etoxazole Human Health Risk Assessment D422673

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1.0 Executive Summary

Etoxazole [2-(2,6-difluorophenyl)-4-[4-(1,1-dimethylethyl)-2-ethoxyphenyl]-4,5-dihydrooxazole] is a 

contact acaricide/ovicide that is currently registered in the U.S. for the control of mites on various raw

agricultural commodities (RACs). Permanent tolerances have been established for residues of 

etoxazole in/on plant commodities, ranging from 0.01 ppm for tree nuts to 20 ppm for peppermint 

and spearmint oils [40 CFR §180.593(a)]. Tolerances have also been established for residues of 

etoxazole in fat (0.02 ppm) and liver (0.01 ppm) of ruminants and in milk fat (0.01 ppm). Valent® 

U.S.A. Corporation has submitted a petition proposing tolerances, without a U.S. registration, for 

residues of etoxazole in/on orange, whole fruit (0.08 ppm) and orange, oil (1.8 ppm). 

Hazard Assessment: The hazard database for etoxazole is adequate for both Food Quality 

Protection Act (FQPA) and dose-response evaluation. The effects in the etoxazole database 

show liver toxicity in all species tested (enzyme release, hepatocellular swelling and 

histopathological indicators), and the severity does not appear to increase with time. In rats only, 

there were effects on incisors (elongation, whitening, and partial loss of upper and/or lower 

incisors). There is no evidence of neurotoxicity or immunotoxicity. No toxicity was seen at the 

limit dose in a 28-day dermal toxicity study in rats. Etoxazole was not mutagenic. No increased 

quantitative or qualitative susceptibilities were observed following in utero exposure to rats or 

rabbits in the developmental studies; however, offspring toxicity was more severe (increased pup 

mortality) than maternal toxicity (increased liver and adrenal weights) at the same dose (158.7 

mg/kg/day) in the rat reproduction study indicating increased qualitative susceptibility. 

Etoxazole was categorized has having low acute toxicity (Toxicity Categories III and IV) via the 

oral, dermal, and inhalation routes. It is not an eye or dermal irritant or a dermal sensitizer. 

FQPA Safety Factor (SF) Decision: The RAB1 risk assessment team has evaluated the 

available hazard and exposure data for etoxazole, and recommends that the FQPA SF be reduced 

to 1X. The recommendation is based upon; 1) the completeness of the hazard database; 2) the 

lack of neurotoxicity; 3) the lack of residual concern for pre- and postnatal susceptibility; and 4) 

the lack of residual uncertainty in the exposure database. A detailed discussion of these 

conclusions can be found in Section 4.4. Table 4.5.4.1 is a summary of the toxicological points 

of departure (PODs) relevant to the current assessment. 

Residue Chemistry and Drinking Water Assessments: Adequate residue chemistry data have 

been submitted to support the establishment of tolerances, without an U.S. registration, in/on 

orange and orange oil. In addition, adequate data are available for the generation of the modeled 

estimated drinking water concentrations (EDWCs). 

Dietary Risk Estimates (Food + Drinking Water): A chronic dietary risk assessment was 

conducted using the Dietary Exposure Evaluation Model - Food Consumption Intake Database 

(DEEM-FCID, ver. 3.16) which incorporates food consumption data from the United States 

Department of Agriculture (USDA) National Health and Nutrition Examination Survey, What 

We Eat in America (NHANES/WWEIA; 2003-2008). Acute and cancer analyses were not 

conducted as toxicological effects attributable to a single dose were not identified and etoxazole 

is classified as not likely to be carcinogenic to humans. 

The chronic analysis assumed 100% crop treated, tolerance-level residues or tolerance-level 

residues adjusted to account for the residues of concern, modeled drinking water estimates, and 
Etoxazole Human Health Risk Assessment D422673

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in the absence of empirical data, DEEM (ver. 7.81) default processing factors. In addition, based 

on EFED’s conclusion that etoxazole has a high potential to bioaccumulate, residue estimates for 

fish/shellfish were included. The resulting chronic exposure estimates do not exceed HED's 

level of concern (LOC; ≤15% chronic population-adjusted dose (cPAD); children 1-2 years old 

were the most highly exposed subpopulation).

Residential (Non-Occupational) Exposure and Risk Assessment: There are no proposed or 

registered etoxazole products that result in residential exposure. Therefore, a residential 

exposure assessment was not performed.

Aggregate-Risk Estimates: Based on the proposed/registered uses, aggregate exposure consists 

of only dietary exposure. As indicated above, the unrefined chronic dietary risk assessment 

resulted in exposure estimates which are not of concern to HED. Acute and cancer analyses 

were not conducted as toxicological effects attributable to a single dose were not identified and 

etoxazole is classified as not likely to be carcinogenic to humans. 

Occupational Exposure and Risk Assessment: Since the proposed use is for a tolerance without 

an U.S. registration, occupational exposure assessment is unnecessary. 

Environmental Justice Considerations: Potential areas of environmental justice concerns, to 

the extent possible, were considered in this human health risk assessment, in accordance with 

U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority 

Populations and Low-Income Populations.”

2.0 HED Recommendations

Provided the petitioner submits a revised Section F, HED concludes that the toxicological and 

residue chemistry databases support the establishment of the permanent tolerances listed in Section 

2.2.2. 

2.1 Data Deficiencies/Data Needs

Toxicology/Residue Chemistry/ORE: None

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate methods (gas chromatography/mass-selective detector (GC/MSD) or GC/nitrogenphosphorus detector (NPD)) are available for enforcing the current plant and livestock tolerances 

including the currently established tangerine tolerance (D303628, J. Tyler, 30-Mar-2005). Based on 

the similarity of tangerines and oranges, HED concludes that the current tolerance-enforcement 

methods are adequate to enforce the tolerances recommended herein. 
Etoxazole Human Health Risk Assessment D422673

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2.2.2 Recommended Tolerances

Table 2.2.2.1 is a summary of the proposed and HED-recommended tolerances for residues of 

etoxazole per se. A revised Section F is requested. 

Table 2.2.2.1: Tolerance Summary.

Commodity Proposed 

Tolerance (ppm)

HEDRecommended 

Tolerance (ppm)1

Comments

40 CFR 180.629(a)

orange, whole fruit 0.08 0.10 The commodity definition should be “orange” and a tolerance of 0.10 

ppm recommended to harmonize with the Codex MRL. 

orange, oil 1.8 1.0 Based on the orange RAC HAFT of 0.048 ppm and the median orange oil 

processing factor of 20x, a tolerance of 1.0 ppm is recommended.

1

 Tolerance without an U.S. registration.

2.2.3 Revisions to Petitioned-For Tolerances

See the comments column of Table 2.2.2.1. 

2.2.4 International Harmonization

There are no Canadian or Mexican maximum residue limits (MRLs) in/on the proposed commodities. 

There is a Codex MRL for residues in/on citrus (0.10 ppm). Although the Organization for Economic 

Co-operation and Development (OECD) tolerance-calculation procedure indicated that a 0.08-ppm 

tolerance for residues in/on orange is appropriate, a tolerance for residues in/on orange of 0.10 ppm is 

recommended for purposes of harmonization. 

2.3 Label Recommendations

None.
Etoxazole Human Health Risk Assessment D422673

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3.0 Introduction

3.1 Chemical Identity

The chemical structure and nomenclature of etoxazole is presented in Table 3.1.1. The 

physicochemical properties for etoxazole are presented in Appendix C. 

Table 3.1.1: Structure and Nomenclature of Etoxazole.

Compound

Common name etoxazole

Company experimental names S-1283, V-1283, YI-5301

IUPAC name (RS)-5-tert-butyl-2-[2-(2,6-difluorophenyl)-4,5-dihydro-1,3-oxazol-4-yl]phenetole

CAS name 2-(2,6-difluorophenyl)-4-[4-(1,1-dimethylethyl)-2-ethoxyphenyl]-4,5-dihydrooxazole

CAS # 153233-91-1

End-use products/EP Zeal® WP Miticide (72% WDG)

3.2 Pesticide Use Pattern/Directions

Valent® submitted a translated copy of a Brazilian label which includes instructions for 

application to orange trees. Table 3.2.1 is a summary of the end-use products and target pests 

and Table 3.2.2 is a summary of the Brazilian orange application scenario. The Brazilian 

application scenario is supported by the available residue chemistry data. 

Table 3.2.1: Summary of End-Use Product.

Trade Name Conc. Formulation Label Date Target Crops Target Pests

Smite (Brazilian label) 110 g ai/L SC not provided orange trees flat mite (Tetranychus urticae)

Table 3.2.2: Summary of Brazilian Orange Application Scenario.1

App. Timing; 

Type; and Equip. Formulation

Single App. 

Rate; g ai/ha

(lb ai/acre)

Max. # App. 

per Season

Max. Seasonal 

App. Rate; g ai/ha

(lb ai/acre)

PHI

(days) Use Directions and Limitations

beginning of 

infestation; broadcast 

foliar spray using a 

Turbo Atomizer

SC

(110 g ai/L)

89-99

(0.08-0.09) 2

198

(0.18) 14

-Label indicates a spray solution of 45 

ml/100 L (4.95 g ai/100 L)

-spray volumes are 1800-2000 L/ha (192-

214 gal/acre); 5-10 L/tree (1.3-2.6 gal/tree)

-RTI is not specified; label indicates that 

etoxazole should be applied at the 

beginning of infestation when the juvenile 

forms of the pest are present (etoxazole 

does not control adult mites)

1

 It is noted that the label specifies "citrus (oranges)." PHI = preharvest interval; RTI = retreatment interval. 
Etoxazole Human Health Risk Assessment D422673

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3.3 Anticipated Exposure Pathways

Based on the proposed/registered application scenarios, etoxazole residues may be found in 

drinking water and crop/livestock commodities. Based on results of a fish accumulation study 

and the high octanol/water partition coefficient, EFED indicated that etoxazole appears to have a 

high potential to bioaccumulate (≤1600x for edible tissues; D311941, J. Meléndez, 31-May2005). Based on the EFED assessment, HED included residues in fish/shellfish in the dietary 

exposure analysis (D426228, T. Bloem, 29-Sep-2015). None of the proposed/registered uses are 

expected to result in residential exposure. 

3.4 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf). As a part of every 

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to 

well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water 

consumption, and activities in and around the home that involve pesticide use in a residential 

setting. Extensive data on food consumption patterns are compiled by the USDA’s 

NHANES/WWEIA, are used in pesticide risk assessments for all registered food uses of a 

pesticide. These data are analyzed and categorized by subgroups based on age, season of the 

year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas post-application are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise to the 

development of specialized software and models that consider exposure to bystanders and farm 

workers as well as lifestyle and traditional dietary patterns among specific subgroups.

It is noted that, based on an assessment by EFED which concluded that etoxazole has a high 

potential to bioaccumulate, the dietary risk assessment conducted in support of the current uses 

included residue estimates for fish/shellfish. The resulting exposure estimates were all less than 

HED’s LOC (see Section 5.4). HED also performed a separate analysis for exposure to 

etoxazole in fish/shellfish at the consumption level associated with subsistence fishing; the 

resulting exposure estimates were also less than HED’s LOC (see Appendix B). 
Etoxazole Human Health Risk Assessment D422673

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4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The hazard database for etoxazole is adequate for both FQPA and dose-response evaluation. 

Etoxazole was evaluated for toxicity through the oral, and dermal routes of exposure, and for the 

potential for carcinogenicity in the following acceptable studies:

(1) Subchronic and chronic oral toxicity in rats, mice and dogs; 

(2) Subchronic dermal toxicity in rats; 

(3) Developmental toxicity in rats and rabbits; 

(4) Reproductive and postnatal toxicity in rats; 

(5) Carcinogenicity in mice and rats;

(6) Acute and subchronic neurotoxicity in rats;

(7) Immunotoxicity in rats; 

(8) Genotoxicity and mutagenicity studies toxicology studies; and 

(9) Metabolism in rats 

Considering all available hazard and exposure data for etoxazole, HED’s Hazard Science and 

Policy Council (HASPOC) used a weight-of-evidence approach to require a 90-day inhalation 

study for etoxazole (TXR # 0056977). Appendix A includes a summary of the etoxazole 

toxicological database. 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

The absorption, distribution, metabolism, and elimination (ADME) for etoxazole was 

investigated using low- and high-doses (50 and 500 mg/kg), in addition to single and repeated 

oral dosing regimens. Oral absorption was rapid, with the time to peak plasma concentration 

levels (Tmax) being 2-4 hours for the low-dose groups and 4-6 hours for the high-dose groups. 

Based on the recovery of radioactivity in the urine and bile of the bile-duct cannulated rats, 

greater absorption occurred in the low-dose groups (48.2-67.5% dose) in comparison to the highdose groups (15.2-19.1% dose).

For the single low-dose groups, maximum concentrations in the plasma (Cmax) were 0.961-1.51 

μg Eq/g for males and 0.631-0.646 μg Eq/g for females. For the single high-dose groups, Cmax

was 15.8-16.4 μg Eq/g for males and 5.3-5.6 μg Eq/g for females. Though maximum plasma 

concentrations were 7-18x higher in the high-dose versus the low-dose rats, the increase was not

proportional to the 100-fold increase in the dose level indicating saturation. Area-under-thecurve (AUC) values confirm this effect.

Excluding the gastrointestinal (G.I.) tract, concentrations of radioactivity over time were 

generally highest in liver, lymph nodes, thyroids, and fat, and were lowest in brain for both sexes 

in each dose group. Concentrations in tissues of males were generally 1.5-2x higher than in 

females from the same group. Consistent with plasma levels, with the exception of the G.I. tract, 

the ~20x increase in tissue concentrations in the high-dose groups did not reflect the 100x 

increase in the dose level. Repeated dosing of rats indicated some potential for accumulation.
Etoxazole Human Health Risk Assessment D422673

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Unchanged parent accounted for 17.8-29.1% of the dose in feces from the low-dose groups and 

74.7-80.2% of the dose in feces from the high-dose groups. Based on the analyses of excreta, 

bile, and liver, the biotransformation of etoxazole in rats primarily involves the hydroxylation of 

the 4,5-dihydrooxazole ring, followed by cleavage of the parent molecule, and hydroxylation of 

the tertiary-butyl side chain.

In the low-dose groups, 77.1-88.3% of the dose was recovered in the feces and 7.6-16.6% of the 

dose was recovered in the urine. In the high-dose groups, 90.9-93.8% of the dose was recovered 

in the feces and 1.6-3.2% of the dose was recovered in the urine. For all dose groups, 

radioactivity recovered in exhaled air accounted for 0.05% of the dose, and radioactivity 

remaining in tissues and the residual carcass by 168 hours post-dose accounted for 0.06-0.76% of 

the dose.

4.2.1 Dermal Absorption

No dermal absorption study was submitted; however, a quantitative dermal assessment is not 

needed for etoxazole since no effects were seen up to the limit dose in the guideline dermal 

toxicity study and there is no concern for quantitative susceptibility. Additionally, the current 

action is for an import tolerance and does not require evaluation of dermal risk.

4.3 Toxicological Effects

The effects in the etoxazole database show liver toxicity in all species tested (enzyme release, 

hepatocellular swelling and histopathological indicators), and the severity does not appear to 

increase with time. In rats only, there were effects on incisors (elongation, whitening, and partial 

loss of upper and/or lower incisors). There is no evidence of neurotoxicity or immunotoxicity. 

No toxicity was seen at the limit dose in a 28-day dermal toxicity study in rats. Etoxazole was 

not mutagenic. 

No increased quantitative or qualitative susceptibilities were observed following in utero

exposure to rats or rabbits in the developmental studies; however, offspring toxicity was more 

severe (increased pup mortality) than maternal toxicity (increased liver and adrenal weights) at 

the same dose (158.7 mg/kg/day) in the rat reproduction study indicating increased qualitative 

susceptibility. 

Etoxazole was categorized as having low acute toxicity (Toxicity Categories III and IV) via the 

oral, dermal, and inhalation routes. It is not an eye or dermal irritant or a dermal sensitizer. 

4.4 Safety factor for Infants and Children (FQPA Safety Factor)

The RAB1 risk assessment team has evaluated the available hazard and exposure data for 

etoxazole, and recommends that the FQPA SF be reduced to 1x for all exposure scenarios 

relevant to the current assessment. The recommendation is based upon; 1) the completeness of 

the hazard database; 2) the lack of neurotoxicity; 3) the observed qualitative postnatal 

susceptibility is protected for by the selected endpoints; 4) the lack residual uncertainty in the 

exposure database; and 5) the lack of potential inhalation exposure and subsequent risk

assessment which would trigger a 10x database UF, due the absence of the required route 

specific study. 
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4.4.1 Completeness of the Toxicology Database

The toxicological database is adequate for FQPA assessment. The following acceptable studies are 

available for evaluation: developmental toxicity studies in rats and rabbits, a two-generation 

reproduction study in rats, and acute and subchronic neurotoxicity studies in rats.

4.4.2 Evidence of Neurotoxicity

There is no evidence of neurotoxicity in the etoxazole database including guideline acute and 

subchronic neurotoxicity studies. 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There are no residual uncertainties for pre-/post-natal toxicity. There is evidence of increased 

qualitative offspring susceptibility in the rat reproduction study (see Section 4.3), but the concern is 

low since: 1) the effects in pups are well-characterized with a clear no-observable adverse-effect 

level (NOAEL); 2) the selected endpoints are protective of the doses where the offspring toxicity is 

observed; and 3) offspring effects occur in the presence of parental toxicity. 

4.4.4 Residual Uncertainty in the Exposure Database

Adequate data are available to determine the nature and magnitude of the residue in all 

proposed/registered crops and in livestock. The current dietary exposure analysis assumed 100% 

crop treated, tolerance-level residues or tolerance level residues adjusted to account for the residues 

of concern, modeled drinking water estimates, and in the absence of empirical data, DEEM (ver. 

7.81) default processing factors. Therefore, the dietary exposure analysis are conservative and 

unlikely to underestimate exposure. In addition, residential exposure as a result of the 

proposed/registered uses is not anticipated. 

4.5 Toxicity Endpoint and Point of Departure Selections

The endpoints for etoxazole have not been changed since the last risk assessment. 

4.5.1 Dose-Response Assessment

Acute Dietary Endpoint (All populations): An endpoint of concern attributable to a single oral dose 

was not identified for either the general U.S. population (including infants and children) or the 

females 13-49 years old subpopulation for etoxazole. HED evaluated the suitability of a 

developmental toxicity study in rabbits (MRID 45090003) in which the developmental NOAEL of 

200 mg/kg/day is based upon increased incidences of 27 presacral vertebrae and 27 presacral 

vertebrae with 13th ribs (skeletal variations) in the fetuses at the lowest-observable adverse-effect 

level (LOAEL) of 1000 mg/kg/day (limit dose). Although these developmental effects may be 

attributed to a single dose and this endpoint is appropriate for the subpopulation females 13-49

years old, HED concluded that these effects are minor in magnitude and were observed only at the 

limit dose (1000 mg/kg/day). 

Chronic Dietary Endpoint for the General Population: The chronic toxicity study in the dog was 

used to select the endpoint for establishing the chronic reference dose (cRfD). The NOAEL of 4.62 

mg/kg/day is based upon increased alkaline phosphatase activity, increased liver weights, liver 

enlargement (females), and incidences of centrilobular hepatocellular swelling in the liver at the 

LOAEL of 23.5 mg/kg/day. Although the NOAEL in the chronic rat study is lower, it was not 
Etoxazole Human Health Risk Assessment D422673

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selected because the lower NOAEL is thought to be an artifact of the dose selection, resulting in a 

100- fold difference between the NOAEL (2.05 mg/kg/day) and the LOAEL (208 mg/kg/day), 

which is protected for by the NOAEL from the chronic dog study. The cPAD which is 0.0462 

mg/kg/day, was derived from a NOAEL of 4.62 mg/kg/day and a total 100-fold UF factor that 

included a 10X for inter-species extrapolations, a 10X for intra-species variations, and a 1X FQPA 

SF. While the effects in study are considered highly conservative by current policy, this study and 

these effects are appropriate for the duration of exposure and is protective of the general population.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

There are no incidental oral or dermal endpoints considered in this action; thus, there are no 

recommendations for combining routes.

4.5.3 Cancer Classification and Risk Assessment Recommendation

HED’s Hazard Identification Assessment Review Committee (HIARC) classified etoxazole as “not 

likely” to be carcinogenic. This decision was based on weight of evidence such as the lack of 

carcinogenicity in two studies in mice, lack of carcinogenicity in one study in rats, and the lack of 

hormonal and reproductive effects in special studies. 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.5.4.1 is a summary of the toxicological endpoints used in the current assessment. It is 

noted that since the current proposal pertains to an import tolerance (no occupational exposure for 

workers in the U.S.) and since residential exposure is not anticipated from the proposed/registered 

uses, only dietary toxicological endpoints are listed in Table 4.5.4.1. 

Table 4.5.4.1: Summary of Toxicological Doses and Endpoints for etoxazole for Use in Dietary and NonOccupational Human Health Risk Assessments.

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, LOC for 

Risk Assessment Study and Toxicological Effects

Acute Dietary (All 

populations)

N/A N/A N/A

A dose and endpoint attributable to a single 

dose were not identified in the database 

including the hazard database. An acute 

dietary assessment was not performed.

Chronic Dietary 

(All Populations)

NOAEL = 

4.62 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

cPAD = cRfD = 

0.046 mg/kg/day

Chronic Oral Toxicity Study- Dog

LOAEL = 23.5 mg/kg/day based upon 

increased alkaline phosphatase activity, 

increased liver weights, liver enlargement 

(females), and incidences of centrilobular 

hepatocellular swelling in the liver.

Cancer (oral, 

dermal, 

inhalation)

HED classified etoxazole as “not likely to be carcinogenic to humans” according to EPA Proposed 

Guidelines for Carcinogen Risk Assessment (April 10, 1996).

Point of departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no-observed adverse-effect level. LOAEL = lowest-observed adverse-effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population-adjusted dose (a = acute, c = chronic). RfD = reference dose. N/A = not applicable.
Etoxazole Human Health Risk Assessment D422673

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5.0 Dietary Exposure and Risk Assessment

D424375, T. Bloem, 29-Sep-2015 (residue chemistry summary)

D426228, T. Bloem, 29-Sep-2015 (dietary exposure analysis)

5.1 Metabolite/Degradate Residue Profile

Based on the available cotton, eggplant, orange, apple, poultry, and ruminant metabolism studies, the 

confined rotational crop studies, and the environmental fate data, HED concludes that the residues of 

concern for tolerance enforcement and risk assessment are as defined in Table 5.1.1. 

Table 5.1.1: Summary of Metabolites and Degradates of Concern for Risk Assessment and Tolerance Enforcement.

Matrix Residues of Concern

Risk Assessment Tolerance Enforcement

primary crops - except cotton gin byproducts and almond hull1etoxazole

etoxazole

primary crops - cotton gin byproducts and almond hull1etoxazole and R-3

poultry tissue (except liver)2etoxazole

egg and poultry liver2etoxazole and R-16

milk and ruminant muscle/fat2etoxazole

ruminant liver/kidney2etoxazole and metabolite 1

water3 Parent, R-8, and R-13 --

rotational crops4 no decision no decision

1

 D283737, J. Tyler, 31-Jul-2003; D303628, J. Tyler, 30-Mar-2005; D307178, J. Tyler, 6-Apr-2005; D289666, J. Tyler, 17-Jun-2003.

2

 D283737, J. Tyler, 31-Jul-2003; D289666, J. Tyler, 17-Jun-2003; D289666, J. Tyler, 17-Jun-2003.

3

 D289666, J. Tyler, 17-Jun-2003.

4

 D283737, J. Tyler, 31-Jul-2003; D307178, J. Tyler, 6-Apr-2003; D353394, D. Rate, 18-Nov-2008.

5.2 Food Residue Profile

The number and geographical representation of the submitted field trial data are adequate. In 

addition, the petitioner submitted adequate orange processing data which indicated that the residues 

of concern concentrate in orange oil and reduce in orange juice and dried orange pulp. All samples 

were analyzed using adequately validated methods and sufficient storage stability data are available. 

Based on these field trial and processing data, and when considering international MRLs, HED 

concludes that the tolerances listed in Table 2.2.2.1, for residues of etoxazole per se, are appropriate. 

A revised Section F is requested. 

5.3 Drinking Water Residue Profile

The EFED provided EDWCs of etoxazole and the metabolites of concern (R-8 and R-13) in 

surface and ground water using the FQPA Index Reservoir Screening Tool (FIRST) and 

Pesticide Root Zone Model - Ground Water (PRZM-GW) models, respectively (D426353, J. 

Meléndez, 31-Mar-2015; Tier 1 assessment). The assessment was based on the established mint 

use which has a maximum proposed seasonal application rate of 0.36 lb ai/acre. EFED 

calculated the 1-in-10-year estimated annual mean non-cancer chronic EDWCs for etoxazole, R8, and R-13 in surface and ground water of 4.761 ppb and 0.746 ppb, respectively. Table 5.3.1 is 

a summary of the EDWCs provided by EFED.

Table 5.3.1: EDWCs for Etoxazole and Metabolites for Chronic Analysis 

Source Etoxazole (ppb) R-8 (ppb) R-13 (ppb) Total (ppb) Application Scenario

Surface Water (FIRST) 0.618 4.08 0.063 4.761 One application to mint at 

Ground Water (PRZM_GW) -- -- -- <0.1 0.36 lb ai/acre/season.
Etoxazole Human Health Risk Assessment D422673

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5.4 Dietary (Food + Drinking Water) Risk Assessment

A chronic dietary risk assessment was conducted using the DEEM-FCID (ver. 3.16) which 

incorporates food consumption data from the USDA NHANES/WWEIA (2003-2008). Acute and 

cancer analyses were not conducted as toxicological effects attributable to a single dose were not 

identified and etoxazole is classified as not likely to be carcinogenic to humans. The chronic analysis 

assumed 100% crop treated, tolerance-level residues or tolerance level residues adjusted to account for 

the residues of concern, modeled drinking water estimates, and in the absence of empirical data, 

DEEM (ver. 7.81) default processing factors. In addition, based on EFED’s conclusion that etoxazole 

has a high potential to bioaccumulate, residue estimates for fish/shellfish were included. The resulting 

chronic exposure estimates do not exceed HED's LOC (≤15% cPAD; children 1-2 years old were the 

most highly exposed subpopulation). Table 5.4.1 is a summary of the dietary exposure/risk estimates. 

Table 5.4.1: Summary of Chronic Dietary (food and water) Exposure and Risk Estimates.

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) %cPAD

general U.S. Population

0.0249

0.001650 4

all Infants (<1 year old) 0.003650 8

children 1-2 years old 0.006865 15

children 3-5 years old 0.004616 10

children 6-12 years old 0.002216 5

youth 13-19 years old 0.001107 2

adults 20-49 years old 0.001209 3

adults 50+ years old 0.001278 3

females 13-49 years old 0.001171 3

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no proposed or registered etoxazole products that result in residential exposure. 

Therefore, a residential exposure assessment was not performed.

6.1 Residential Bystander Post-Application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to individuals 

nearby pesticide applications. The agency sought expert advice and input on issues related to 

volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 

2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP2014-0219). During Registration Review, the agency will utilize this analysis to determine if data 

(i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for
Etoxazole Human Health Risk Assessment D422673

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6.2 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential 

source of exposure from the ground application methods (e.g., groundboom and airblast) employed 

for etoxazole. The agency has been working with the Spray Drift Task Force (a task force 

composed of various registrants which was developed as a result of a Data Call-In issued by EPA), 

EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop 

the best spray drift management practices (see the agency’s Spray Drift website for more 

information; http://www.epa.gov/opp00001/factsheets/spraydrift.htm). The agency has also 

developed a policy on how to appropriately consider spray drift as a potential source of exposure in 

risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for 

each pesticide during the Registration Review process, which ensures that all uses for that pesticide 

will be considered concurrently. The approach is outlined in the revised (2012) Standard 

Operating Procedures For Residential Risk Assessment (SOPs) - Residential Exposure Assessment 

Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines 

the quantification of indirect non-occupational exposure to drift. 

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED considers and aggregates pesticide exposures and risks from 

dietary (food and water) and residential (dermal, inhalation, and/or incidental oral) sources. 

Based on the proposed/registered uses, aggregate exposure consists of only dietary exposure. As 

indicated above, the unrefined chronic dietary risk assessment resulted in exposure estimates 

which are not of concern to HED. Acute and cancer analyses were not conducted as 

toxicological effects attributable to a single dose were not identified and etoxazole is classified as 

not likely to be carcinogenic to humans. 

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to etoxazole and any other substances and etoxazole does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that etoxazole has a common mechanism of toxicity with other substances. 

For information regarding EPA’s efforts to determine which chemicals have a common 

mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy 

statements released by EPA’s Office of Pesticide Programs concerning common mechanism 

determinations and procedures for cumulating effects from substances found to have a common 

mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Since the proposed use is for a tolerance without an U.S. registration, occupational exposure 

assessment is unnecessary. 

RDI: RAB1 (20-May-2015)

Appendix A. Toxicology Profile and Executive Summaries.

Appendix B: Exposure to Etoxazole in Fish/Shellfish at Consumption Levels Associated with Subsistence Fishing.

Appendix C: Physical/Chemical Properties.
Etoxazole Human Health Risk Assessment D422673

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Appendix A: Toxicology Profile and Executive Summaries

The requirements (40 CFR 158.340) for a food use and non-food use for etoxazole are in Table A.1. 

Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1. Study Requirements for Food Uses for Etoxazole.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

870.1200 Acute Dermal Toxicity

870.1300 Acute Inhalation Toxicity

870.2400 Primary Eye Irritation

870.2500 Primary Dermal Irritation

870.2600 Dermal Sensitization

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

870.3100 Oral Subchronic (rodent)

870.3150 Oral Subchronic (nonrodent)

870.3200 21-Day Dermal

870.3465 90-Day Inhalation

Yes

Yes

Yes

Yes1

Yes

Yes

Yes

No

870.3700a Developmental Toxicity (rodent)

870.3700b Developmental Toxicity (nonrodent)

870.3800 Reproduction

Yes

Yes

Yes

Yes

Yes

Yes

870.4100a Chronic Toxicity (rodent)

870.4100b Chronic Toxicity (nonrodent)

870.4200b Oncogenicity (mouse)

870.4300 Chronic/Oncogenicity (rat)

No

Yes

Yes

Yes

-

Yes

Yes

Yes

870.5100 Mutagenicity—Gene Mutation - bacterial

870.5300 Mutagenicity—Gene Mutation - mammalian

870.5375 Mutagenicity—Structural Chromosomal Aberrations

870.5385 Mutagenicity— Bone marrow Chrom. Ab

870.5395 Mutagenicity-In vivo Mouse micronucleus assay......

870.5395 Mutagenicity-In vivo Rat micronucleus assay............

870.5450 Mutagenicity-Dominant lethal assay in mice............

870.5550 Mutagenicity-In vitro unscheduled DNA synthesis......

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

870.6100a Acute Delayed Neurotoxicity (hen)

870.6100b 90-Day Neurotoxicity (hen)

870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90-Day Neurotoxicity Screening Battery (rat)

870.6300 Develop. Neurotoxicity

No

No

Yes

Yes

No

-

-

Yes

Yes

-

870.7485 General Metabolism

870.7600 Dermal Penetration

870.7800 Immunotoxicity

Yes

No

Yes

Yes

-

Yes

1 Study is required at this time based upon weight-of-evidence decisions by the HASPOC. Decisions are discussed in detail in TXR# 

0056977.

Table A.2: Acute Toxicity of Etoxazole Technical Grade Active Ingredient (TGAI).

Guideline No. /Study Type MRID No. Results Toxicity Category

870.1100 / Acute Oral 45089919 LD50 >5000 mg/kg IV

870.1200 / Acute Dermal 45089921 LD50 >2000 mg/kg II

870.1300 / Acute Inhalation 45089923 LC50 >1.09 m/L III

870.2400 / Primary Eye Irritation 45089925 Not an eye irritant IV

870.2500 / Primary Dermal Irritation 45089927 Not a dermal irritant IV

870.2600 / Dermal sensitization 45089929 Not a dermal sensitizer N/A
Etoxazole Human Health Risk Assessment D422673

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Table A.3: Subchronic, Chronic, and Other Toxicity Profile

Guideline 

No. Study Type MRID No. (year)/ Classification/Doses Results

870.3100 90-Day oral toxicity 

(rat)

45089935, 45089934 (1995)

Acceptable/guideline

0, 100, 300, 1000, or 3000 

ppm

M: 0, 6.12, 18.28, 61.8, or 

183.7 mg/kg/day 

F: 0, 6.74, 20.50, 69.0, or 

204.8 mg/kg/day

NOAEL = 61.8/69.0 mg/kg/day (M/F).

LOAEL = 183.7/204.8 mg/kg/day (M/F), based upon 

increases in hepatic enzyme levels, increased liver 

weights and centrilobular hepatocellular swelling in 

both sexes and liver enlargement in females only.

870.3100 90-Day oral toxicity 

(rat)

45089931 (1998)

Acceptable/guideline

0, 5000, or 10000 ppm

M: 0, 300.4, or 610 

mg/kg/day 

F: 0, 336.6, or 692 

mg/kg/day

NOAEL = not determined.

LOAEL = 300.4/336.6 mg/kg/day (M/F), based upon 

clinical signs, clinical chemistry, increased liver 

weights, and histopathology.

870.3100 90-Day oral toxicity 

(mouse)

45089936 (1994), 45089938 

(1992)

Acceptable/guideline

0, 100, 400, 1600 or 6400 

ppm

M: 0, 13.42, 55.13, 213.6, or 

878.4 mg/kg/day 

F: 0, 15.15, 62.00, 250.5, or 

994.5 mg/kg/day

NOAEL = 213.6/250.5 mg/kg/day (M/F).

LOAEL = 878.4/994.5 mg/kg/day (M/F), based upon 

periportal hepatocellular necrosis, increased alkaline 

phosphatase levels, accompanied by increased 

relative liver weight, liver enlargement, and 

centrilobular hepatocellular swelling.

870.3150 90-Day oral toxicity 

(dog)

45089933 (1995), 45089932 

(1992)

Acceptable/guideline

0, 200, 2000, or 10000 ppm

M: 0, 5.33, 53.7, or 268 

mg/kg/day

F: 0, 5.42, 55.9, or 277 

mg/kg/day

NOAEL = 5.33/5.42 mg/kg/day (M/F).

LOAEL = 53.7/55.9 mg/kg/day (M/F), based upon 

clinical signs (vomiting foamy fluid and mucous 

stool), clinical chemistry, increased liver weights, 

and centrilobular swelling in the liver and acinar cell 

atrophy in the prostate.

870.3200 21/28-Day dermal 

toxicity (rabbit)

45089941 (1999)

Acceptable/guideline

M & F: 0 or 1000 mg/kg/day

NOAEL = 1000 mg/kg/day (M/F).

LOAEL = not determined.

No systemic effects noted.

870.3700a Prenatal 

developmental in 

(rat)

45090005 (1994), 45090004 

(1993)

Acceptable/guideline

F: 0, 40, 200, or 1000 

mg/kg/day

Maternal NOAEL = 1000 mg/kg/day.

LOAEL = not determined.

Developmental NOAEL = 1000 mg/kg/day.

LOAEL = not determined.

870.3700b Prenatal 

developmental in 

(rabbit)

45090003, 45090002 (1994) 

Acceptable/guideline

F: 0, 40, 200, or 1000 

mg/kg/day

Maternal NOAEL = 200 mg/kg/day

LOAEL = 1000 mg/kg/day based upon liver 

enlargement and decreased body weight gains and 

food consumption.

Developmental NOAEL = 200 mg/kg/day

LOAEL = 1000 mg/kg/day based upon increased 

incidences of 27 presacral vertebrae and 27 presacral 

vertebrae with 13th ribs in the fetuses.
Etoxazole Human Health Risk Assessment D422673

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Table A.3: Subchronic, Chronic, and Other Toxicity Profile

Guideline 

No. Study Type MRID No. (year)/ Classification/Doses Results

870.3800 Reproduction and 

fertility effects

(rat)

45090007 (1996), 45090006 

(1993)

Acceptable/guideline

0, 80, 400, or 2000 ppm

M/F: 0, 5.59/6.59, 

28.17/33.37, or 139.1/158.7 

mg/kg/day

Parental/Systemic NOAEL = 28.17/33.37 

mg/kg/day

LOAEL = 139.1/158.7 mg/kg/day (M/F), based 

upon increased liver weights in the P and F1 males 

and increased adrenal weights in the P females

Offspring/Systemic NOAEL = 28.17/33.37 

mg/kg/day

LOAEL = 139.1/158.7 mg/kg/day (M/F), based upon 

pup mortality.

Reproductive NOAEL = 139.1/158.7 mg/kg/day.

LOAEL = not determined.

870.4100b Chronic toxicity

(dog)

45089942 (1996)

Acceptable/guideline

0, 200, 1000, or 5000 ppm

M: 0, 4.62, 23.5, or 116 

mg/kg/day

F: 0, 4.79, 23.8, or 117 

mg/kg/day

NOAEL = 4.62/4.79 mg/kg/day (M/F).

LOAEL = 23.5/23.8 mg/kg/day (M/F), based upon 

increased alkaline phosphatase activity, increased 

liver weights, liver enlargement (females), and 

incidences of centrilobular hepatocellular swelling in 

the liver.

870.4200b Carcinogenicity

(mouse)

45571801 (2001)

Acceptable/guideline

0, 2250, 4500 ppm

M/F: 0/0, 242/243, 484/482 

mg/kg/day

NOAEL = 242/243 (M/F).

LOAEL = 484/482 (M/F), based on a slight increase 

in the incidence of a fatty change in the centrilobular 

hepatocytes in males.

870.4200b Carcinogenicity

(mouse)

45090001 (1996)

Unacceptable/guideline

0, 15, 60, or 240 ppm 

M: 0, 15.1, 60.1, or 241 

mg/kg/day

F: 0, 15.1, 60.5, or 243 

mg/kg/day

NOAEL = 241/243 mg/kg/day (M/F).

LOAEL = not determined.

No evidence of carcinogenicity.

870.4300 Chronic/ 

Carcinogenicity

(rat)

45250903, 45089937 (1996)

Unacceptable/guideline

0, 4, 16, or 64 mg/kg/day 

nominal 

M: 0, 4.01, 16.1, or 64.4 

mg/kg/day

F: 0, 4.03, 16.1, or 64.5 

mg/kg/day

NOAEL = 64 mg/kg/day (M/F).

LOAEL = not determined.

Equivocal evidence of carcinogenicity.

870.4300 Chronic/ 

Carcinogenicity

(rat)

45571802 (2001)

Acceptable/guideline

0, 50, 5000, 10000 ppm

M/F: 0/0, 1.83/2.07, 

187/216, 386/445 mg/kg/day

NOAEL = 1.83/2.07 mg/kg/day (M/F).

LOAEL = 187/216 (M/F), based upon effects on the 

incisors including abnormal amelogenesis.

No evidence of carcinogenicity.

870.5100 Reverse gene 

mutation assay in 

bacteria

45250905 (1992)

Acceptable/guideline

When tested up to cytotoxic levels, there was no 

evidence of induced mutant colonies over 

background.

870.5100 Reverse gene 

mutation assay in 

bacteria

45090015 (1999)

Acceptable/non-guideline

When tested up to cytotoxic levels, there was no 

evidence of induced mutant colonies over 

background.

870.5300 in vitro forward 

gene mutation assay 

in mouse lymphoma 

cells

45090013 (1996)

Acceptable

When tested up to cytotoxic levels, mutagenic in the 

presence of S9 activation and equivocal for 

mutagenicity in the absence of S9 activation.

870.5375 in vitro mammalian 

cytogenetics assay

45250904 (1994)

Acceptable/guideline

When tested up to cytotoxic levels, not clastogenic in 

the presence or absence of S9 activation.
Etoxazole Human Health Risk Assessment D422673

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Table A.3: Subchronic, Chronic, and Other Toxicity Profile

Guideline 

No. Study Type MRID No. (year)/ Classification/Doses Results

870.5395 bone marrow 

micronucleus assay

45090010 (1996)

Acceptable

There was no significant increase in the frequency of 

micronucleated polychromatic erythrocytes in bone 

marrow after any treatment time.

870.6200a Acute neurotoxicity 

screening battery 

(rat)

48769402 (2011)

Acceptable/guideline

0, 100, 500, or 2000 mg/kg 

bw

Systemic NOAEL = 2000 mg/kg bw.

A Systemic toxicity LOAEL was not observed. 

Neurotoxicity NOAEL = 2000 mg/kg bw.

A neurotoxicity LOAEL was not observed. 

870.6200b Subchronic 

neurotoxicity 

screening battery 

(rat)

48769403 (2011)

Acceptable/guideline

0, 1500, 5000, or 15000 ppm 

(0, 84.6/101.4, 282/334, 

858/1034 mg/kg bw/day 

[M/F])

Systemic NOAEL = 15000 ppm (858 mg/kg/day 

[F]). 

Systemic toxicity LOAEL = 15000 ppm (1034

mg/kg/day [F]) based upon decreased absolute body 

weights and abnormalities of incisor, elongation, 

whitening, and partial loss of upper and/or lower 

incisor. 

The systemic NOAEL for males = 15000 ppm (858 

mg/kg/day). 

The systemic LOAEL for males was not established.

Neurotoxicity NOAEL = 15000 ppm (858 

mg/kg/day). 

A neurotoxicity LOAEL was not observed. 

870.7485 Metabolism and 

pharmacokinetics

(rat)

45090016 (1996)

Acceptable

50, 500 mg/kg

Within 168 hours of administering a single oral dose 

of [14C-butylphenyl]- or [14C-oxazole]-etoxazole at 5 

or 500 mg/kg, 92.0-97.6% of the administered dose 

was recovered from male and females rats. [14C]-

Etoxazole was rapidly absorbed from the G.I. tract of 

rats following oral dosing. Maximum concentrations 

of radioactivity in plasma were observed within 2-4 

hours of dosing for the low-dose groups and within 

4-6 hours of dosing for the high-dose groups. 

Excluding the G.I. tract, concentrations of 

radioactivity over time were generally highest in 

liver, lymph nodes, thyroids, and fat, and were 

lowest in brain for both sexes in each dose group. 

For each tissue, the actual concentrations of 

radioactivity were similar between the two 14Clabels, but concentrations in tissues of males were 

generally 1.5-2x higher than in females from the 

same group. For both low- and high-dose rats, fecal 

excretion was the primary route of elimination and 

excretion of the 14C-dose was essentially complete 

within 120 hours of dosing. 

870.7800 Immunotoxicity

(rat)

48769406 (2011)

Acceptable/guideline

0, 1500, 5000, or 15000 ppm 

(0, 82.2, 418, 1211 mg/kg 

bw/day [F])

Systemic NOAEL =toxicity 15000 ppm (1211 mg/kg 

bw/day).

A systemic toxicity LOAEL was not observed. 

Immunotoxicity NOAEL = 15000 ppm (1211 mg/kg 

bw/day).

An immunotoxicity LOAEL was not observed. 

Non-guideline Effect on 

proliferative activity 

of testicular 

interstitial cells in 

rat

45089939 (1996)

Acceptable/non-guideline

0 or 3000 ppm

Test performed in 

conjunction with subchronic 

oral toxicity test in rats 

(MRID 45089935)

A toxic level of the test substance did not affect the 

proliferative activity of testicular interstitial cells.
Etoxazole Human Health Risk Assessment D422673

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Appendix B: Exposure to Etoxazole in Fish/Shellfish at Consumption Levels Associated 

with Subsistence Fishing.

Based on an assessment by EFED which concluded that etoxazole has a high potential to 

bioaccumulate, the dietary risk assessment conducted in support of the current uses included 

residue estimates for fish/shellfish. However, these analyses did not consider fish/shellfish 

consumption rates associated with subsistence fishing. To account for these consumption rates, 

the assessment summarized below was conducted. 

Consumption rates associated with subsistence fishing were attained from the Fish Consumption 

Rates Technical Support Document (ver. 2.0) from the State of Washington Department of 

Ecology (https://fortress.wa.gov/ecy/publications/publications/1209058.pdf). The report 

addresses fish consumption in the State of Washington among the general population, tribal 

populations, and other groups such as Asian and Pacific Islanders and recreational anglers. Based 

on the consumption rates from this document, and the fish/shellfish residue estimate, exposure 

estimates were calculated and added to the DEEM-FCID estimates (see Table C.1). The resulting 

total exposure estimates are less than HED’s LOC. 

It is noted that the lindane subsistence diet exposure analysis (D282455, T. Morton, 17-Apr-2002) 

utilized consumption data from the Alaska Department of Fish and Game - Division of 

Subsistence - Community Profile Database (ver. 3.11; 27-Mar-2001). Based on lindane’s

demonstrated properties for long-range transport and the documented concentrations in terrestrial, 

freshwater, and marine habitats, the lindane analysis selected the three Alaskan communities with 

the highest consumption of seal, whale, or walrus. In contrast to lindane, etoxazole is anticipated 

to affect only water bodies in the vicinity of the application site (long range transport is not 

anticipated; D311941, J. Meléndez, 31-May-2005). Therefore, it was concluded that the 

consumption estimates used in the lindane analysis were not applicable to the current assessment. 
Etoxazole Human Health Risk Assessment D422673

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Table B.1: Summary of Subsistence Dietary Inputs and Risks.

Population Fish/Shellfish Residue 

Estimate1(ppm)

Body 

Weight (kg)

Subsistence

DEEM-FCID Exposure4combined %PAD5

Consumption (g/day)

2 Exposure (mg/kg/day)3

Acute Chronic Acute Chronic Acute Chronic Acute Chronic

Children 1-2 years old

0.005

10

acute 

assessment is 

unnecessary

25

acute 

assessment is 

unnecessary

0.0000125

acute 

assessment is 

unnecessary

0.006865

acute 

assessment is

unnecessary

15

Children 3-5 years old 20 25 0.0000062 0.004616 10

Children 6-12 years old 30 113 0.0000188 0.002216 5

Adults 70 214 0.0000153 0.001278 3

Adult Females 60 214 0.0000178 0.001171 3

1

 Tolerances for residues of etoxazole in/on fish/shellfish have not been established. The USDA PDP monitored etoxazole residues in catfish (2008, 2009, and 2010) and salmon (2013) with no 

residues detected (LOD = 0.001-0.005 ppm). Based on this information, residues in fish/shellfish were assumed to be at the LOD for the PDP data (0.005 ppm). 

2

 Consumption rates derived from the Fish Consumption Rates Technical Support Document (ver. 2.0; https://fortress.wa.gov/ecy/publications/publications/1209058.pdf) from the State of 

Washington Department of Ecology. The adult consumption figures were taken from Table 1 and the children (<6 years old) consumption figures were taken from Table A.1. The 

referenced document did not include consumption figures for children (6-12 years old). The 113 g/day consumption figure for children 6-12 years old was derived by adjusting the adult 

consumption figure by 0.53 with the 0.53 factor based on the following reference: Heller, C., 1966. Meat Consumption at Three Northern Eskimo Villages. Environment of the Cape 

Thompson Region, Alaska. Wilimovsky, Norman, & Wolfe, John, Editors. United States Atomic Energy Commission. pp. 1109-1111.

3

 Exposure = consumption (g/day) ÷ body weight x fish residues (ppm) x (1 mg/1000 μg).

4

 See Table 5.4.1. 

5

 Combined %PAD = (subsistence exposure + DEEM-FCID exposure) ÷ cPAD (cPAD = 0.046 mg/kg/day).
Etoxazole Human Health Risk Assessment D422673

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Appendix C: Physical/Chemical Properties

Table C.1 is a summary of the physical/chemical properties for etoxazole. Etoxazole has a low 

water solubility and a high Log Kow.

Table C.1: Physicochemical Properties of Etoxazole (TGAI).

Melting range 101.5-102.5C

46018505.der.wpd

pH 6.2

Density 1.2389 g/cm3

Water solubility 

3.99 x 10-5 g/L at 10C

7.04 x 10-5 g/L at 20C

6.69 x 10-5 g/L at 30C

Solvent solubility (g/L at 20C)

acetone: 309 1,2-dichloroethane: 402

ethyl acetate: 249 n-heptane: 18.7

methanol: 104 xylene: 252

Vapor pressure at 25C 7.0 x 10-6 pascals

Dissociation constant (pKa) no measurable pKa

Octanol/water partition coefficient Log(KOW) 5.52 ± 0.58 at 20C

UV/visible absorption Not available.