### UNITED STATES ENV IR ONMENTAL PROTECTION AGENCY WASHINGTON, D

. C. 20460



### MEMORANDUM

Date: 26-JUNE-20 14 OFFI CE OF CHEMICAL SAFETY AND
POLLUTION PR EVENTION



### SUBJECT: Etoxa zole. Human-Health Assessment Scoping Document in Support of Registration
Review

.

PC Cod e: 1 0709 1 DP Barcode: D418224
Decision No.: 488002 Registration No.: N / A
Petition No .: N / A Regulatory Action: Registration Review Scoping Document
Risk Assessment Type: 

### N / A Case N o.: 76 1 6

TXR No.: N / A CAS No.: 15 3233-91

- 1

MRID No

. : N/A 40 CFR: § 180 .593

FROM : Jennife r Tyler

,

# hemi**s· J.** **~ 1\** **~T~** JaclynPyne

, Bio1ogist 

# o i**~~** 4"7 /


### Anwar Y. Dunba r , Ph.D

., harmac 6fogist

## ~frt/' 

# -%--**Z/W~** Risk Assessment Branch 1 (RAB 1 )/Hea lth Effectffl i vision (HED; 7509P)

THROUGH: Charles W. Smith II I

, Br anch C hie f

## c:=-~**~** Geo rge F. Kramer, Ph.D.

, Seni or**Chemis ~~-.---=::::;;~IS-** **----­** 

### RABl! H ED (7509 P)

TO: Julia S to kes
Pesticide Re-Evaluation Division ( PRD ) (7508P)

Attache d is H ED's human-health ri sk assessment scoping document for etoxazole [2-(2,6- difluorophenyl)-4-[ 4

- ( 1

, 1-dimethylethyl)-2-ethoxyphenyl]-4

, 5 -d ihydrooxazole] to su pp ort Registration Review.

Page 1 of21Etoxazole**Registrat~on** Review Human-Health**AssessmentJ oping**  Document



### Table of Contents



### Execut iv e Summary

.................................................................. ........ .. .. .......................................... 3
1.0 Intr o duction

.......................................................................................................................... 4
2.0 Ha zard Tdentification!foxicology

........................................................................................ 4
3.0 R esidue C hemistry

........................................................ ................. . .. ................................... 6
4.0 D i etary Ex posure

................................................................................................................. 7
5.0 Residential Exposure

......... ...... ............................................................................ .. .............. 7
6.0 Aggregate Risk Assessment.

................................................................................................ 8
7.0 Occupational Exposu re

........................................................................... . ............................ 8
8.0 Pub li c Health and Pesticide Epidemiology Data

................................................. ....... ....... 10
9.0 To l erance Assessment and In te rna tiona l H a rmonization

................................ .................. I 0
10.0 Environmental Justice

......................................... ......... ...................................................... 10
11.0 Cumu l ative

...... ......................................... . ...... ..... ... .................... .. . ................... .. .. .. ....... .... 10
12.0 Human Studies

........................................................................................ . .......................... 11
13.0 Ri s k-A ssess ment Updates, Data Deficienci es, and Labe l Revisions

................................. 11
14.0 References

.......................................................................................................................... 12
Attachment 1: Chemica l Identity Tables

................................................................ .. ................... 13
Attachment 2: Etoxazole Acute, Subchronic

, and Chronic Toxicity Profile

.......... .. .. ................ . 14
Attachment 3: Etoxazo le E ndpoint Selection Table s

................................................................... 18
Attachment 4: Summary of Registered Uses

. .............................................................................. 19
Attachment 5: Etoxazole IRLS Sheet.

................. .. ..... .................................... ............................. 20

Page 2 of21Etoxazole Registration Review Human

- Health Assessment Scoping Document

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Page 3 of 21 

### Executive Summary

HED has prepared a scoping document to support Registration Review of etoxazole

. Etoxazole
is a contact acaricide/ovicide and is a member of the diphenyloxazoline class of
insecticide/miticide

. It is formulated as wettable powders (WPs)

, water

- dispersible g ranules (WDGs)

, emulsifiable concentrates (ECs) , pressurized liquids

, and pressurized gases. Etoxazole is currently registered for use on a var iety of crops and ornamentals as well as for use in commercial greenhouses. The current registrations include S pecial Local Need (SLN) registrations on carrots and alfalfa. There are no pending PRIA actions for etoxazole. The most recent quantitative human

- health risk assessment was performed in 2011, and was for the use of
etoxazole on field corn and popcorn ( Me mo, J. Tyler et al. , 23

- SEP

- 2011; D439804).

HED has evaluated the status of the human

- health risk assessments for etoxazole to determine whether sufficient data are available and whether any updates are needed to support Registration
Review. HED has co nsidered all available data and human

- health risk assessments for etoxazole with respect to its toxicity, exposure, and usage databases, and the most updated Agency science policy and risk assessment methodologies to determine the scope of work necessary t o support Registration Review.

The toxicity database for etoxazole is adequate for risk assessment as specified by the revised 2007 40CFR Toxicology Data Requirements , with the exception of a subchronic inhalation toxicity study

. During Registration R evi ew, the endpoints, points of departure (PODs) , and safety factors (SFs) used in the most recent human health risk assessments will be reconsidered based on current HED policy, the newly submitted data, and any identified data gaps.

The residue chemistry d atabase is adequate to support current Registration Review requirements. Adequate metabolism (crops, livestock, and rotational crops), storage stability, magnitude of the residue, and processing data are available to support the registered uses. Adequate methods are available for enforcement of the currently established tolerances.

The dietary

- exposure database is adequate to support current registration requirements. In the most recent risk assessment, chronic dietary exposures were not of concern to HED. However, as part of Registration Review, a revised dietary exposure analysis may be required to reflect the most recent dietary exposure models, potential revised estimated drinking water concentrations ( EDWCs ) , and/or changes to the toxicological P ODs.

There are no proposed or current registrations for products containing etoxazole that allow
residential use . Therefore, residential handler and conventional residential post

- application
exposure assessment s will not be needed during R egistration R ev iew. A residential bystander
risk assessment will be conducted

.

There is sufficient information available to assess aggregate exposure. However, a new aggregate risk assessment will be required during Registration Review to incorporate revised dietary e xposure analyses and/or residential exposure assessments.

The occupational exposure database is adequate to support the Registration Review process for etoxazole. The most recent occupational handler and post

- application exposure assessments are

not re flective of current exposure policies and data, and did not identify risks of concern. HED has conducted occupational handler assessments for most of the occupational handler scenarios anticipated for the registered uses of etoxazole . However, during Reg istration Review, updatedEtoxazole Registration Review Human

- Health Assessment Scoping Document

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Page 4 of 21 

### occupational assessments will be conducted to reflect all currently registered uses, using current occupational/residential exposure ( ORE ) policies and/or updated if toxicological PODs as
needed.

The following d a ta deficiency w as identified for etoxazole :

 Toxicology: OCSPP Guideline # 870.3465

, Subchronic Inhalation Toxicity Study.

In addition, EPA anticipates conducting the following risk assessment updates during Registration Review:

 Toxicology:

o Review of the submitted immunotoxicity, acute neurotoxicity, and subchronic neurotoxicity studies.

o Reevaluation of toxicity endpoint/dose selection, along with the Food Quality Protection Act (FQPA ) SF based on current HED policy.

 Residue Chemistry:

o None.

 Dietary Exposure:

o R ev ised dietary exp osure analysis to reflect the most recent dietary exposure models, potential revised EDWCs , and/or changes to the toxicological PODs

.

 Aggregate Exposure:

o New aggregate risk assessment to incorporate revised dietary exposure analyses
and/o r residential exposure assessments.

 Occupational/Residential Exposure:

o Revised occupational handler inhalation assessments to reflect all potential exposure scenarios, as well as updated policies and exposure data.

o A spray drift assessment for bystanders will be conducted. A screen will be
conducted so that the need for a volatilization assessment can be determined.

o Assessments for all uses may be updated if toxicological PODs are revised.

1.0 Introduction

Etoxazole is a contact acaricide/ovicide and i s a member of the diphenyloxazoline class of
insecticide/miticide

. It is formulated as WPs packaged in WSPs

, WDG s , ECs , pressurized liquids, and pressurized gases. It is currently registered for use on a variety of crops and
ornamentals as well as for us e in commercial greenhouses. The current registrations include SLN registrations on carrots and alfalfa. There are no pending PRIA actions for etoxazole. The most recent quantitative human

- health risk assessment was performed in 2011, and was for the

us e of etoxazole on field corn and popcorn ( Memo, J. Tyler et al. , 23

- SEP

- 2011; D439804).

2.0 Hazard Identification/Toxicology

Etoxazole was rapidly absorbed from the G.I. tract of rats following oral dosing. Maximum
concentrati ons of radioactivity in p lasma were observed within 2

- 4 hours of dosing for the low

dose group (5 mg/kg) and within 4

- 6 hours of dosing for the high

- dose group (500 mg/kg). The
half

- life of etoxazole was longer in females at the low dose in comparison to males (88.8 compared to 7 1.4 hours). In the high

- dose groups, the half

- life was longer in males in comparison to females (44.4 compared to 28.2 hours). Excluding the G.I. tract, concentrations ofEtoxazole Registration Review Human

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Page 5 of 21 

### 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 both low

- and high

- dose rats, fecal excretion was the primary route of elimination and excretion was essentially complete within 120 hours of dosing for both groups. With the exception of minor urinary metabolites, the metabolite profile in excreta was qualitatively similar between the sexes, and etoxazole was eliminated primarily in the feces as parent compound.

The liver is the target organ in mice, rats, and dogs through the oral ro ute. 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 the systemic effect s (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, such as increased relative liver weight, liver enlargement, and centrilobu lar hepatocellular swelling , were observed at high doses.

Similar effects were observed at the high dose in a mouse carcinogenicity study. Subchronic and chronic toxicity studies in rats also produced similar effects (increased liver weights,
centrilobul ar hepatocellular swelling, etc.) as 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.

No quantitativ e or qualitative evidence of increased susceptibility was seen following in utero exposure to rats or rabbits in developmental studies. Offspring toxicity was qualitatively more severe (pup mortality) than parental toxicity (increased liver and adrenal we ights) at the same dose in the rat reproduction study.

No toxicity was seen at the limit dose in a 28

- day dermal toxicity study in rats. There is no evidence of immunotoxicity or neurotoxicity in any study reviewed thus far

.

HED’s Hazard Identific ation 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. Etoxazole was not mutagenic.

Etoxazole has 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.

In the last risk assessment, three toxicity data gaps were identified: (1) an immunotoxicity study; (2) an acute neurotoxicity study; and (3) a subchronic neurotoxicity study. All three studies have been submitted to the agency and are pen ding formal review. Preliminary review suggests that they will not impact the endpoints for risk assessment. There is no repeated

- dose inhalation study available for etoxazole . The agency granted a waiver for this study ( Memo, A. Dunbar et al ., 21

- APR

- 2 010 ; D388416 ). To be consistent with current practices, the Hazard Science and

Po licy Council (HASPOC) was asked to re

- evaluate the need for a repeated

- dose inhalation toxicity study for etoxazole. Using a weight of evidence approach, the HASPOC conclude d that
a subchronic inhalatio n study is required at this time , although HED recommends that in the absence of such information, a requirement for handlers of the Zeal ® 

### WDG Miticide product to

use PF5 respirator s may be adequate to address concerns about in halation exposure (Memo, U. Habiba; TXR # 0056977 )

.Etoxazole Registration Review Human

- Health Assessment Scoping Document

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Page 6 of 21 

### Conclusions: The toxicity database for etoxazole is adequate for risk assessment as specified by
the revised 2007 40 CFR Toxicology Data Requ irements , with the exception of a subchronic inhalation study . During Registration R eview, the previously submitted immunotoxicity, acute neurotoxicity, and subchronic neurotoxicity studies will be reviewed and the endpoints, PODs

, and SF s used in the most recent human

- health risk assessments will be reconsidered b ased on current HED policy, the newly submitted data, and any identified data gaps.

3.0 Residue Chemistry

Permanent tolerances are established for residues of etoxazole in/on a variety of crops and
livestock commodities at levels ranging from 0.01 ppm to 20 ppm (40 CFR §180.593 (a)). There are currently no tolerances established for etoxazole for indirect/inadvertent residues in rotational

crops.

Adequate methods are available for enforcing the current plant and livestock tolerances. In all
available m agnitude of the residue and processing studies, samples were analyzed using either the current enforcement methods or a slightly modified version of current enforcement methods.
All enforcement methods have been forwarded to the Analytical Chemistry Labor atory ( ACL ) for Agency petition method validations ( PMVs ) (Memos, J. Tyler, 6/17/03; D290912 and D290914). These methods were deemed adequate by ACL for tolerance enforcement (personal communication, C. Stafford to D. Vogel, 11/5/07). Food and Drug Admin istration (FDA) multiresidue methods (MRMs) may be used to determine residues of etoxazole in fatty and non

fatty matrices and to determine residues of Metabolite R

- 3 in nonfatty matrices. The results of the MRM testing were forwarded to the FDA for inclu sion in the Pesticide Analytical Method (PAM) Vol. I (Memo, J. Tyler, 6/17/03; D290919).

The nature of the residue in plants and livestock is adequately understood based on available
metabolism studies. The HED Metabolism Assessment Review Committee (MAR C) concluded that only parent should be included in the tolerance expression for all plant commodities (Memo, J. Tyler, 4/23/03; D288817). For risk assessment purposes, only parent will be considered for most plant commodities; however, Metabolite R

- 3 ( N

- (2,6

- difluorobenzoyl)

- 4

- tert

- butyl

- 2

- ethoxybenzamide) should also be included in the risk assessment for cotton gin byproducts and almond hulls (Memo, J. Tyler, 07/29/2003; DP#291694 and Memo, J. Tyler, 11/06/2007; DP#346200). For livestock commodities, t he HED MARC concluded that, for ruminant muscle, fat, and milk, the residue of concern for tolerance expression and risk assessment is parent only. For ruminant liver and kidney, the residue of concern for tolerance expression is parent only, but both par ent and Metabolite 1 (2

- amino

- 2

- (2

- ethoxy

- 4

- (1 

- hydroxycarbonyl

- 1 

- methylethyl)phenyl) ethanol) should be included in the risk assessment. For poultry, the MARC
concluded that Metabolite R

- 16 (2

- methyl

- 2

- {3

- ethoxy

- 4

- [2

- (2,6

- difluorophenyl)

- 4,5

- dihydro

1,3

- oxazol

- 4

- yl] phenyl}propionic acid) will likely to have similar toxicity to the parent; and, therefore, should be included in the risk assessment for liver and egg whites. Parent only is needed for tolerance expression.

Adequate field trial and processi ng data are available to support the use of etoxazole on the registered crops. An adequate number of trials were conducted in the appropriate geographical regions using the appropriate formulation applied at the maximum use rate. Registration requirement s for magnitude of the residue in meat, milk, poultry, and eggs are fulfilled. These studies are also supported by adequate storage stability data.Etoxazole Registration Review Human

- Health Assessment Scoping Document

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Page 7 of 21 

### Adequate confined and field rotational crop data are available to support the registered uses of

etoxazo le. HED previously concluded that the residue of concern in rotated crops is etoxazole (Memos, J. Tyler, 9/23/11; D385940; J. Tyler, 7/31/03; D283737; J. Tyler et al, 8/7/03; D292548 and J. Tyler, 4/6/05; D307178)

.

Conclusions : The residue chemistry d atabase is adequate to support current Registration Review data requirements. Adequate metabolism (crops, livestock, and rotational crops), storage stability, magnitude of the residue, and processing data are available to support the registered
uses. Ade quate methods are available for enforcement of the currently established tolerances.

4.0 Dietary Exposure

In conjunction with the most recent human

- health risk assessment, a chronic dietary exposure
assessment was conducted for t he general U.S. populat ion and various population subgroups using the Dietary Exposure Evaluation Model software with the Food Commodity Intake
Database DEEM

- FCID, Version 2.03 that incorporates consumption data from USDA’s Continuing Surveys of Food Intakes by Individuals (CSFI I), 1994

- 1996 and 1998. The assessment was unrefined, using HED

- calculated residues of concern (parent and metabolites of concern) for livestock commodities and HED

- recommended tolerance

- level residues for all other commodities; 100% crop treated (CT) inf ormation for all commodities; empirical processing factors for apple juice, grape juice and raisins and 1.0x or the DEEM

- FCID (ver 7.81) default
factors were assumed for all other processed commodities

.

The HED MARC concluded that the residue of concern i n drinking water is the parent and two major metabolites, R

- 8 and R

- 13 (HED MARC, 23

- APR

- 2003, DP D288817). Other metabolites identified were present at low levels, and are not expected to be more toxic than the parent. The Environmental Fate and Effects Division (EFED) provided Tier 1 EDWCs of etoxazole and the metabolites of concern (R

- 8 and R

- 13) in surface and ground water using t he FQPA Index Reservoir Screening Tool (FIRST) and Screening Concentration in Ground Water (SCI

- GROW) models, respectively (Memo, A. Metzger, 1/31/11; DP#386080). Drinking water was incorporated directly in the dietary assessment using the chronic concentration for surface

water.

The chronic dietary exposure estimates are not of concern to HED (<100% cPAD) for the general U. S. population (2.7% cPAD) and all population subgroups (the most highly exposed population subgroup is children 1

- 2 years old at 11% cPAD).

Conclusions : The dietary

- exposure database is adequate to support current registration requirements. In the most recent risk assessment, chronic dietary exposures were not of concern to HED. However, as part of Registration Review, a revised dietary exposure analysis may be required to reflect the most recent dietary exposure models, potential revised EDWCs, and/or changes to the toxicological PODs.

5.0 Residential Exposure

There are no proposed or registered products containing etoxazole that would result in residential exposure. Therefore, a residential exposure assessment was not performed.

Spray Drift and Vo latilization : Residential bystander exposures resulting from off

- site transport (e.g., spray drift or volatilization) may occur as a result of applications of etoxazole

. TheEtoxazole Registration Review Human

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Page 8 of 21 

### potential for spray drift will be quantitatively evaluated for each pesticide du ring the Registration
Review process that 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

. In terms of volatilization, the agency has developed a Volatilization Screening T ool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219 ). During Registration Review, the agency will ut ilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for specific chemicals.

Conclusions : There are no proposed or current registrations for products containing eto xazole that allow residential use. Therefore, residential handler and conventional residential post

application exposure assessments will not be needed during Registration Review. A residential bystander risk assessment will be conducted

.

6.0 Aggregate Risk Assessment

The most recent aggregate

- risk assessment was performed in conjunction with the 2011 HED
human

- health risk assessment ( Memo, J. Tyler et al. , 23

- SEP

- 2011; D385745 ). A chronic aggregate (food + drinking water) risk assessment was conducted . An acute aggregate risk assessment was not performed because an endpoint of concern attributable to a single oral dose was not selected for any population subgroup (including infants and children). Short

- and
intermediate

- term aggregate risk assessment s were not performed because there are no registered

or proposed residential non

- food uses. A cancer aggregate risk assessment was not performed because etoxazole is not carcinogenic. The chronic aggregate (food + drinking water) exposure
and risk estima tes did not exceed HED's level of concern (LOC).

Conclusions : There is sufficient information available to assess aggregate exposure. However, a new aggregate risk assessment will be required during Registration Review to incorporate revised dietary exp osure analyses and/or residential exposure assessments.

7.0 Occupational Exposure

Occupational handler and post

- application exposures are expected based on the registered agricultural uses of etoxazole. Attachment 4 provides a summary of the occupati onal use
pattern. Current formulations include WPs

, WDGs

, ECs , pressurized liquids

, and pressurized

gases . The maximum ap plica tion rate is 0.18 lb ai/A, and applicatio ns can b e made using aerial, groundboom, airblast, fogger, or handheld equipment, depen ding on the use site

.

Based on these uses, there is a potential for exposure to etoxazole in occupational scenarios from handling etoxazole products during the application process (i.e., mixer/loaders, applicators, and mixer/loader/applicators). In addit ion, there is a potential for post

- application worker exposure from entering into areas previously treated with etoxazole.

Occupational Handlers : There is the potential for inhalation exposure to occupational handlers from the currently registered use pa ttern of etoxazole. In the most recent exposure assessment for etoxazole, assessments were conducted for mixers/loaders, applicators

, and flaggers for aerial and groundboom applic ations of a wettable powder formulation (packaged in water

- soluble packets ) (Memo, A. Nowotarski, 15

- AUG

- 2011, D385939). The assessment was based anEtoxazole Registration Review Human

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Page 9 of 21 

### application rate of 0.135 lb ai/A , and maximum area treated per day or gallons handled for the proposed uses. Handler's exposure and risk were calculated at baseline (long pants, a long

sleeved shirt, no chemical

- resistant gloves, and no respirator) and with personal

- protective equipment (PPE) when necessary (e.g., chemical

- resistant gloves, respirators, and engineering controls). I nhalation risk estimates were not of concern (i.e., MOEs ≥ 100) with baseline protection

.

Based on a review of the registered labels for etoxazole for this scoping docume nt, HED has
conducted occupational handler assessment s for most of the occupational handler scenarios anticipated for the registere d use s of etoxazole

. However, during Registration Review, updated occupational assessments will be conducted to reflect all currently registered uses, using current ORE policies and/or updated if toxicological PODs as needed.

Occupational Post

- Application

De rmal : Typically, it is possible for agricultural workers to have post

- application exposure to pesticide residues during the course of typical agricultural activities. However the Agency did not identify a dermal toxicological endpoint; therefore, an asse ssment for dermal post

- application exposure was not conducted.

Inhalation : Based on the Agency's current practices, a quantitative occupational post

- application inhalation exposure assessment was not performed for etoxazole at this time primarily becau se it
has a low acute inhalation toxicity (Toxicity Category III), a low vapor pressure (<1.0 x 10

- 8 

### mmHg), and is applied at a low use rate (0.135 lb ai/A)

. However, there are multiple potential sources of post

- application inhalation exposure to individu als performing post

- application activities in previously treated areas. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issue s 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/2 009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force (ARTF) and may, as appropriate, develop policies and procedu res, to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, then the Agency may revisit the need for a quan titative occupational post

- application inhalation exposure assessment for etoxazole.

Conclusions : The occupational exposure database is adequate to support the Registration Review process for etoxazole . The most recent occupational handler and post

- appl ication

e xposure assessments are not reflective of current exposure policies and data, and did not identify risks of conce rn. HED has conducted occupational handler assessments for most of the occupational handler scenarios anticipated for the registered uses of etoxazole. However, d uring Registration Review, updated occupational assessments will be conducted to reflect all currently registered uses , using current ORE policies and/or updated i f toxicological PODs as needed

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Page 10 of 21 

### 8.0 Public Health and Pesti cide Epidemiology Data

The Agency has reviewed the available incident data for etoxazole (Memo, E. Evans and S.

Recore , 08

- APR

- 2014; D418223) and concluded that based on the low frequency and low severity of incident cases of etoxazole reported to either the OPP Incident Data System (IDS) or Sentinel Event Notification System for Occupational Risk (SENSOR)

- Pesticides, there does not appear to be a concern at this time that would warrant further investigation. The Agency will
continue to monitor the incid ent information and if a concern is triggered, additional analysis
will be included in the risk assessment.

9.0 Tolerance Assessment and International Harmonization

U.S. permanent tole rances (listed in 40 CFR 180.593 ) and Canadian, Mexic an, and Codex

Max imum Residue Limits (MRLs) are summarized in Attachment 5

. Canada and Codex have
established M RLs for residues of etoxazole in/on several raw agricultural and livestock commodities, but several are not harmonized with U

. S

. tolerances (commodities with dif ferent
tolerance are bolded in the table ). There are no Mexican MRLs for etoxazole. The U.S. residue
definition is harmonized with Canad a and Codex

. During Registration Review, HED may look into the possibility of harmonizing with Canada and Codex for t he commodities with differing
tolerances.

10.0 Environmental Justice

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

most recent etoxazole 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 1 

### .” The OPP typically considers the highest potential exposures from the legal use of a pesticide when conducting human

- health risk assessment s, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., and people who may be exposed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to
ensure that the risk estimates are based on the best available information.

11.0 Cumulative

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a
common mechani sm of toxicity, EPA has not made a common mechanism of toxicity finding for etoxazole and any other substances; and etoxazole does not appear to produce a toxic metabolite produced by other subst ances. For the purposes of this tolerance action, therefore, EPA has assumed that etoxazole does not have 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 che micals, 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/pestic ides/cumulative/.

1 http://www.epa.gov/compliance/envir onmentaljustice/resources/policy/exec_order_12898.pdfEtoxazole Registration Review Human

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Page 11 of 21 

### 12.0 Human Studies

Past etoxazole risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine thei r dermal and inhalation exposure. Many such studies, involvi ng exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED), the Outdoor Residential Exposure Task Force (ORETF) Database, and the ARTF Database. EPA has
reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing a t the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on these studies.

13.0 Risk

- A ssessment Updates, Data Deficiencies, and Label Revisions

The following data deficiency was identified for etoxazole:

 Toxicology: OCSPP Guideline # 870.3465, Subchronic Inhalation Toxicity Study.

In addition, EPA anticipates conducting the following risk assessment updates during Registration Review:

 Toxicology:

o Review of the submitted immunotoxicity, acute neurotoxicity, and subchronic neurotoxicity studies.

o Reevaluation of toxicity endpoint/dose selection, along with the FQPA SF based

on current H ED policy.

 Residue Chemistry:

o None.

 Dietary Exposure:

o Revised dietary exposure analysis to reflect the most recent dietary exposure models, potential revised EDWCs, and/or changes to the toxicological PODs.

 Aggregate Exposure:

o New aggregate risk asses sment to incorporate revised dietary exposure analyses and/or revised residential exposure assessments.

 Occupational/Residential Exposure:

o Revised occupational handler inhalation assessments to reflect all potential exposure scenarios, as well as updated policies and exposure data.

o Assessments for all uses may be updated if toxicological PODs are revised.

o A spray drift assessment for bystanders will be conducted. A screen will be
conducted so that the need for a volatilization assessment can be determined

.Etoxazole Registration Review Human

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Page 12 of 21 

### 14.0 References

HED Memoranda Relevant to Registration Review.

Author Barcode Date Title

M. Dow D273223 10

- JUL

- 2002 ETOXAZOLE

- Exposure/Risk Assessment for Pesticide Handlers and Agricultural Workers from the Use of Etoxazole on Ornamental Plants I n Greenhouses, Lath and Shadehouses J. Tyler D283737 31

- JUL

- 20 03 Etoxazole. Registration for Use on Cotton, Pome fruits, Strawberries and Imported Oranges.

M. Dow D288816 5

- AUG

- 2003 ETOXAZOLE

- Exposure and Risk Assessment for Pesticide Handlers and Agr icultural Workers from the Use of Etoxazole On Cotton, Pome Fruit and Strawberry. J. Tyler D292548 7

- AUG

- 20 03 PP#: 2F6420. Etoxazole in/on Cotton, Strawberry, Pome Fruit and Imported Mandarin Oranges

. M. Dow D313939 3

- MAR

- 2005 ETOXAZOLE

- Exposure/Risk A ssessment for the Proposed Use of Etoxazole on Grape and Tree Nuts Including Pistachio.

J. Tyler D330258 30

- MAR

- 20 05 Etoxazole. Registration for Use on Grapes and Tree Nuts, including
Pistachios J. Tyler D307178 6

- APR

- 20 05 Etoxazole in/on Cotton, Pome f ruits, Strawberries and Imported Oranges. Review of Amendment Dated 6/18/04 Submitted in Response to the Health Effects Division’s (HED’s) Memo of 7/31/03 (D283737).

M. Dow D341212 2

- JUL

- 2007 ETOXAZOLE

- Occupational Exposure/Risk Assessment for the Prop osed Uses of Etoxazole on Cherry, Melon and Hops. J. Tyler D335334 15

- AUG

- 20 07 PP#: 6E7150. Etoxazole in/on Cherries, Hops, and Melon Subgroup 9A. S. Levy D346199 14

- NOV

- 20 07 PP# 6E7150. Etoxazole. REVISED: Registration for Use on Cherries, Hops, and Melon Subgroup 9A.

M. Dow D353080 24

- JUN

- 2008 ETOXAZOLE

– Occupational Exposure/Risk Assessment for the Proposed Use of Etoxazole on Greenhouse Tomato, Cucumber, Peach,
Plum and Mint.

D. Rate D387610 18

- NOV

- 20 08 Etoxazole; Petition for Tolerances and Use s on Stone Fruits, Cucumber, Tomato, and Mint.

M. Dow D367031 22

- JUL

- 2009 ETOXAZOLE

– Human, Occupational Exposure/Risk Assessment for the Proposed Use of Etoxazole in Total Release Greenhouse Fogger. J. Tyler D339039 31

- JUL

- 20 09 Etoxazole in/on Grapes a nd Tree Nuts, including Pistachios. Review of Waiver Request for Grape Processing Study Submitted in Response to Residue Chemistry Deficiencies Identified in D303628 (J. Tyler, 3/30/05).

D. Rate D378452 4

- AUG

- 20 10 Petition for Tolerances and Uses on Peppe rs (Bell and Non

- bell); Squash/Cucumbers (Subgroup 9B); Avocado; Tropical and Subtropical Fruits (Inedible Peel); Caneberry Subgroup 13

- 07A; Small Fruit Vine Climbing, Except Kiwifruit, Subgroup 13

- 07F; Low

- growing Berry, Subgroup 13

- 07G; and Tea.

W. Wa ssell D380307 20

- OCT

- 2010 PP# 6E7150. Etoxazole. Registration for Use on Cherries, Hops, and Melon Subgroup 9A.

A. Nowotarski D378458 10

- NOV

- 2010 (Revised) Etoxazole: Exposure/Risk Assessment for IR

- 4 Requested Registration of Etoxazole on Peppers/Egg plant, Low Growing Berry Subgroup (13

- 07G), Small Fruit Vine Climbing Subgroup (13

- 07F), Squash/Cucumber Subgroup (9B), Tropical Fruits and Tree Fruits, Caneberry Subgroup (13

- 07A).

D. Rate D373916 2

- DEC

- 2010 Etoxazole; Human Health Risk Assessment for Pr oposed Tolerances and Uses on Peppers (Bell and Non

- bell); Squash/Cucumbers (Subgroup 9B); Avocado; Tropical and Subtropical Fruits (Inedible Peel); Caneberry Subgroup 13

- 07A; Small Fruit Vine Climbing, Except Kiwifruit, Subgroup
13

- 07F; Low

- growing Berry, Subgroup 13

- 07G; and Tea. J. Tyler D387610 13

- MAY

2011 Etoxazole in/on Stone Fruits, Cucumber, Tomato, and Mint

.

Review of Plum Processing Study Submitted in Response to Residue Chemistry Deficiencies Identified in D353394 (D. Rate, 18

- NOV

- 2008 ).
A. Nowotarski D385939 15

- AUG

- 2011 Etoxazole: Occupational and Residential Exposure/Risk Assessment for Proposed Uses on Field Corn and Popcorn. J. Tyler D385940 23

- SEP

- 2011 Etoxazole. Human

- Health Risk Assessment for Proposed Uses in/on Field
Corn and P op Corn.

cc: J. Tyler (RAB1), J. Pyne (RAB1), A. Dunbar (RAB1) RDI: RAB1 ( 5 / 21/14), C. Smith (5/21 /14) J. Tyler : S10943 :PY

- S:(703) 305

- 5564 :7509P:RAB1Etoxazole Registration Review Human

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Page 13 of 21 

### Attachment 1: Chemical Identity Tables.

Table A. 1.1. 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

Table A. 1.2. Physicochemical Properties of Etoxazole (Technical Grade Active Ingredient (TGAI)).

Parameter Value References Melting range 101.5

- 102.5  C

46018505.der.wpd pH 6.2 Density 1.2389 g/cm 3 Water solubility 3.99 x 10

- 5 a t 10  C

7.04 x 10

- 5 at 20  C

6.69 x 10

- 5 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 (pK a ) no measurable pK a Octanol/water partition coefficient Log(K OW ) 5.52 ± 0.58 at 20  C UV/visible absorption Not available.Etoxazole Registration Review Human

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Page 14 of 21 

### Attachment 2: Etoxazole Acute, Subchronic, and Chronic Toxicity Profile.

2.1 Toxicology Data Requirements.

The requirements (40 CFR 158.340) for food and non

- food uses 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.2.1. Toxicological Data Requirements 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
ye s
yes yes

yes
yes
yes
yes
yes 870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 28

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes
yes
yes
yes
yes yes

yes
yes
yes

no 870.3700a Developmen tal 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)

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity ( mouse)

................................ .................... 870.4300 Chronic/Oncogenicity

................................ .................... yes
yes
yes
yes
yes yes

yes
yes
yes
yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other Genotoxic Effects

....................... 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 Screenin g Battery (rat)

............... 870.6300 Develop. Neurotoxicity

................................ ................. no

no
yes
yes

no n o

no in review
in review

no 870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

no
yes y es

no in review Special Studies for Ocular Effects

Acute Oral (rat)

................................ ........................... Subchronic Oral (rat)

................................ .................. Six

- month Oral (dog)

................................ .................. no

no

no no

no

noEtoxazole Registration Review Human

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Page 15 of 21 

### 2.2 Toxicity Profiles.

TABLE A.2. 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 Derma l Irritation 45089927 Not a dermal irritant IV

870.2600 / Dermal sensitization 45089929 Not a dermal sensitizer N/A

TXR# 0051659 , P. Shah, 19/MAR/2003.

TABLE A.2. 3 . Subchronic, Chronic, and Geno

- Toxicity Profile for Etoxazole.

Guideline No./ Study Ty pe MRID No. (year)/Classification/Doses Results

870.3100
90

- Day oral toxicity rodents (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 rodents (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 chemi stry, increased liver weights, and histopathology.

870.3100
90

- Day oral toxicity rodents (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 cent rilobular hepatocellular swelling.

870.3150
90

- Day oral toxicity in nonrodents (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 toxicity in rodents (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 toxicity in nonrodents (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 13 th ribs in the fetuses.

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 F 1 males and increased adrenal weights in the P fem ales

. 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.

870.4300 45 250903, 45089937 (1996) NOAEL = 64 mg/kg/day (M/F).Etoxazole Registration Review Human

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Page 16 of 21 TABLE A.2. 3 . Subchronic, Chronic, and Geno

- Toxicity Profile for Etoxazole.

Guideline No./ Study Ty pe MRID No. (year)/Classification/Doses Results

Combined chronic toxicity/ carcinogenicity rodents (rat) 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 LOAEL = not determined.

Equivocal evidence of carcinogenicity.

870.4300
2

- Year feed/carcinogenic (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 amelog enesis.

No evidence of carcinogenicity

. 870.4100b Chronic toxicity nonrodents (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).
LOA EL = 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.

78

- Week Carcinogenic

Mouse 45571801 (2001)

Acce ptable/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.

Non

- guideline
13

- week study:
Effe ct 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.

Gene Mutation
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 o ver background.

Gene Mutation

Non

- guideline

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.

Gene Mutation
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.

Cytogenetics
870.5375

in v itro mammalian cytogenetics assay 45250904 (1994)

Acceptable/guideline When tested up to cytotoxic levels, not clastogenic in the presence or absence of S9 activation.

870.5395
bone marrow micronucleus assay 45090010 (1996)

Acceptable There was no signi ficant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any treatment time.Etoxazole Registration Review Human

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Page 17 of 21 TABLE A.2. 3 . Subchronic, Chronic, and Geno

- Toxicity Profile for Etoxazole.

Guideline No./ Study Ty pe MRID No. (year)/Classification/Doses Results

870.5550
unscheduled DNA synthesis in primary rat hepatocytes/
mammalian cell
cultures 45090014 (1997)

Acceptable When tested up to cyt otoxic levels, there was no evidence that unscheduled DNA synthesis was induced by the test substance.

870.6200a
Acute Neurotoxicity (Rat) 48769402 (2011)

Classification Pending ; data in review 0, 100, 500, 2000 mg/kg Systemic NOAEL = 2000 mg/kg

. Systemic LOAEL was not established

. Neurotoxicity NOAEL 2000 mg/kg

. Neurotoxicity LOAEL was not established

. 870.6200b
Subchronic Neurotoxicity (Rat) 48769403 (2012)

Classification Pending ; data in review 0, 1500, 5000 and 15000 ppm (0, 84.6/101.4, 282/334, 858/1 034 mg/kg/day [M/F]) Systemic NOAEL = 858/1034 mg/kg/day [M/F]

. Systemic LOAEL was not established

. Neurotoxicity NOAEL = 858/1034 mg/kg/day [M/F]

. Neurotoxicity LOAEL was not established

.

870.7485 Metabolism and pharmacokinetics 45090016 (1996)

Acceptab le 50, 500 mg/kg Within 168 hours of administering a single oral dose of [ 14 C

- butylphenyl]

- or [ 14 C

- oxazole]

- etoxazole at 5 or 500 mg/kg, 92.0

- 97.6% of the administered dose was recovered from male and females rats. [ 14 C]

- Etoxazole was rapidly absorbed fr om 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, concent rations of radioactivity over time were generally highest in liver, lymph nodes, thyroid, 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 14 C

- lab els, 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 14 C

dose was essentially complete wit hin 120 hours of dosing.

870.7800 28

- Day Immunotoxicity (Rat) 48769406 (2011)

Classification Pending ; data in review 0, 1000, 5000 and 15000 ppm (0, 82.2, 418, 1211 mg/kg/day [F]) Systemic NOAEL = 1211 mg/kg/day

. Systemic LOAEL was not established

. Immu notoxicity NOAEL = 1211 mg/kg/day

. Immunotoxicity LOAEL was not established

.Etoxazole Registration Review Human

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Page 18 of 21 

### Attachment 3: Etoxazole Endpoint Selection Tables.

Table A.3.1. Summary of Toxicological Doses and Endpoints for Etoxazole for Use in Human

- Health Risk
Assessments.

Expos ure Scenario Point of Departure Uncertainty/ FQPA

Safety Factors RfD, PAD, LOC
for Risk
Assessment Study and Toxicological Effects

Acute Dietary (General population, including infants and children) N/A N/A N/A A dose and endpoint attributable to a single dose were not identified in the database including the developmental toxicity studies. Acute Dietary (Females 13

- 49 years of age) N/A N/A N/A A dose and endpoint attributable to a single dose were not identified in the database including the developmental toxicity studies. Chronic Dietary (All populations) NOAEL = 4.62 mg/kg/day UF A = 10X

UF H = 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,
increa sed liver weights, liver enlargement (females), and incidences of centrilobular hepatocellular swelling in
the liver.
Inhalation
Short

- (1

- 30 days),
Intermediate

- (1

- 6 months), and Long

Term (>6 months) NOAEL = 4.62 mg/kg/day

( inhalation

absorption rate = 100%) UF A = 10X

UF H = 10X FQPA SF = 1X Residential/

Occupational
LOC for MOE =
100 Chronic Oral Toxicity Study

- Dog

LOAEL = 23.5 mg/kg/day based upon increased alkaline phosphatase activity, increased liver weights, liver enlargement (females), and inci dences 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).

Po int 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

- obse rved adverse

- effect level.
LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). F QPA SF = FQPA Safety Factor. PAD = population

adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.Etoxazole Registration Review Human

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Page 19 of 21 

### Attachment 4: Summary of Registered Uses.

Table A.4.1. Summary o f Registered Uses for Etoxazole.

Crop/Use Site Product (Formulation) Application

Method Maximum

App Rate (lb/ai/A) REI

(hours)

A gricultural Crops Apple EC Ground 0.11 24 Caneberry subgroup 13

- 07A DF/WDG, WP Ground 0.135 12 Corn, field and pop DF/WDG, WP Ground, aerial 0.135 12

Cotton DF/WDG, WP Ground, aerial 0.045 12

EC 24
Cucumber (greenhouse) PRL Fogger 0.056 2 Cucurbit vegetables (Crop Group 9) DF/WDG, WP Ground, aerial 0.135 12 Eggplant (greenhouse) PRL Fogger 0.056 2 Hops DF/WDG, WP Gro und 0.18 12 Low growing berry (subgroup 13

- 07G) DF/WDG, WP Ground 0.135 12 Mint (peppermint and spearmint) DF/WDG, WP Ground, aerial 0.18 12 Mint (peppermint and spearmint; greenhouse) PRL Fogger 0.056 2 Pepper and Eggplant (Subgroup 8

- 10B) DF/WDG, WP Ground 0.135 12

Pear EC Ground 0.11 24 Pepper (greenhouse) PRL Fogger 0.056 2 Pome fruit (Crop group 11) DF/WDG, WP Ground 0.135 12 Pome fruit (apple and pear; greenhouse ) PRL Fogger 0.056 2 Pumpkin (greenhouse) PRL Fogger 0.056 2
Small fruit vin e climbing, except fuzzy kiwifruit (Subgroup 13

- 07F) DF/WDG, WP Ground 0.135 12

Squash (greenhouse) PRL Fogger 0.056 2 Stone fruit (Crop Group 12) DF/WDG, WP Ground 0.135 12 Stone fruit (except plum; greenhouse) PRL Fogger 0.056 2 Strawberry EC Groun d 0.11 24 Tree nuts (Crop Group 14) DF/WDG, WP Ground 0.135 12 Tree nuts (almonds and pecans; greenhouse) PRL Fogger 0.056 2 Tropical and Sub

- tropical Fruit (Inedible Peel) DF/WDG, WP Ground, aerial 0.135 12 Tomato (Greenhouse

- grown) DF/WDG Boom spra yer, handwand (high and low pressure), backpack 0.125 12

PRL Fogger 0.056 2

Non

- agricultural Crops
Christmas trees DF/WDG, WP Ground, aerial 0.135 12

Non

- bearing fruit trees DF/WDG, WP Ground 0.135 12 Ornamentals (greenhouse) PRGS Aerosol, fog or
fum igation 24

PRL Total release 0.056 2

WDG Ground 0.1 12 24(c)
Alfalfa WP Ground, aerial 0.135 12 Carrot (including tops) WP Ground, aerial 0.135 12Etoxazole Registration Review Human

- Health Assessment Scoping Document

______________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _________________________________________________________________________ _____________________________________________________________________________________________________________________________ ___________________________________________________________________________________________

Page 20 of 21 

### Attachment 5: Etoxazole IRLS Sheet.

Table A.5.1. Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 

### Codex 2



### 40 CFR 180.593: (a) General. Etoxazole (2

- (2,6

- difluorophenyl)

- 4

- [4

- (1,1

- dimethylethyl)

- 2

- ethoxyphenyl]

- 4,5

- dihydrooxazole) 2

- (2,6

- difluorophenyl)

- 4

- [4

- (1,1

- dimethylethyl)

- 2

- ethoxyp henyl]

- 4,5

- dihydrooxazole etoxazole. The
residue is fat
soluble.



### Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 

### Codex 2

Almond, hulls 2.0 3 Apple, wet pomace 0.50

Avocado 0.20 Berry, low growing, subgroup 13

- 07G 0.50 0.5 strawberries Caneberry subgroup 13

- 07A 1.5

Canistel 0.20 Cattle, fat 0.02 Cattle, liver 0.01 0.01 (*) edible
offal (mammalian) Corn, field, forage 0.80 Corn, field, grain 0.01 Corn, field, refined oil 0.03 Corn, fiel d, stover 4.0 Corn, pop, grain 0.01 Corn, pop, stover 4.0 Cotton, gin byproducts 1.0 Cotton, undelinted seed 0.05 0.05 Fruit, pome, group 11 0.20 0.2 apples, Asian pears, crabapples, loquats, mayhaws, pears, quinces 0.07 pome
fruit s

Fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F 0.50 0.5 grapes 0.5

Fruit, stone, group 12, except plum 1.0 Goat, fat 0.02 Goat, liver 0.01 0.01 (*) edible
offal (mammalian) Grape, raisin 1.5 1.5 Hop, dried cones 7 .0 15 hops dry Horse, fat 0.02 Horse, liver 0.01 Mango 0.20 Melon subgroup 9A 0.20 Milk, fat 0.01 0.01 (*) Nut, tree, group 14 0.01 0.01 almond nuts, beechnuts, black walnuts, Brazil nuts, butternuts, cashew nuts, chestnuts, chin quapin nuts, English walnuts, hazelnuts (filbert), hickory nuts, macadamia nuts, pecan nuts, pistachio nuts 0.01

Papaya 0.20 Pepper/eggplant subgroup 8

- 10B 0.20 Peppermint, oil 20 Peppermint, tops 10 15 mintsEtoxazole Registration Review Human

- Health Assessment Scoping Document

______________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _________________________________________________________________________ _____________________________________________________________________________________________________________________________ ___________________________________________________________________________________________

Page 21 of 21 

### Table A.5.1. Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 

### Codex 2

Pistachio 0.01 0.01 (*) tre e

nuts
Plum 0.15 Plum, prune, dried 0.30 Sapodilla 0.20 Sapote, black 0.20 Sapote, mamey 0.20 Sheep, fat 0.02 Sheep, liver 0.01 0.01 (*) edible
offal (mammalian) Spearmint, oil 20 Spearmint, tops 10 15 mints Squash/cucu mber subgroup 9B 0.02 0.02 cucumber Star apple 0.20 Tangerine 1 0.10 Tea, dried* 15 15 tea, green, black (black
fermented and dried)

Tomato 0.20



### MRLs with NO US Equivalent

Citrus fruits 0.1 Meat (from mammals other than marine mammals) 0.01 (*) (fat)



### Completed: M. Negussie; 04/14/2014

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicate d as proposed have not been finalized by the CCPR and the CAC.