### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , 

## D.C. 20460

OFFI C E O F C HEMI CA L SA FET Y A ND POLLUTI O N PRE V ENTION



### MEMORAN D UM

Date

Sub j ect:

From: 29

- September-2015



### Etoxazo l e: 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
Decis i on No.: 493877 Reg i st r at i on Nos.: not applicable
Petit i o n No.: 4 £ 8304 Reg u lato r y Act i o n : tolerance without U.S. r eg istration
R i sk Assessme n t Type: s in g le chemical / ag g re g ate Case No.: 7616
TXR N o.: 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 Effec ts 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 est i mate the risk to human health that will resu l t from all reg i ste r ed 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 ri sk assessment
, dietary risk assessment
, and r esidue 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 Melende z of the E nvironme n tal Fate and Effects Division ( EFED).

Page I of21Etoxazole Hum an Health Ri sk Assessment D422673



### Tab l e o f C onte n t s

I

. 0 Executive Summary

..... .. .. .. . .. .. .. . ............ . ... .. .. .. .. ................. ....................... .. ...... .............. ... ..... ..... . .. . .. . .. .. .... .......... 3

2 .1 Da t a D eficiencie s/ Da t a Needs

......... . ................................................................................................................. 4 2.2 To lerance Co n s id e rati o n s

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

............................................................................................................... 4 2.2.2 Recomm e nd ed T o l e r a nce s

.............. .. .. ................ .................... ............................................ ........ . . .. . ......... 5 2.2.3 Re visions to Pe titi one d-For Toleranc es

................................. ..... ............................... ... .......... ..... . . ............ 5 2.2.4 Int e rn a ti onal Hannon i zat i on

...................................................................................................................... 5 2.3 Label R eco mm endations

.............. .. .. .. .......................................... .... ... .. ........................................ .......... .......... 5

3.0 Introduction

............................................................................................................................................................ 6

3. 1 Chemical Id e ntit y .

.. .. .. ............. ................... .. .. ... . ................. .. .. .. . ........... .. .. ............................ ............... ..... . ....... 6 3.2 P es t ic i de U se Patt e rn / Directions

.. .. .. .............. ... . ...... ............ .. ............... .......... . ...... ............... ..... . . .. . .. . . .............. 6 3.3 Antic ipated Expo s ur e Pathways

. .. . .. ...... . ... .. .. .. .. ... ... . .............. . .. . . . ......... . ... . . ... . ...... . ... ............... . ... . .................... 7 3 .4 Consideratio n of Environmental Just i ce

........................................................................................................... 7

4 .0 Hazard Characterization a nd Do se- R es pon se Assessment

....... ... ...... ....... . .. .. .. ....................... . ...... . . .. . ........... ........ 

### 8

4.1 To x icol ogy Studies Available for Analysis

....................................................................................................... 8 4.2 Absorption, Di strib uti on. Metabolism, & E l imin ation (ADM E )

...................................................................... 8 4.2. I D ermal Absorption

............ ............... ............................. .. . ............... .............................. .. . ........... .............. 9 4.3 T ox icol og ical Effec t s

................. .......... ... . .. .. ... .. ................. . ....... .. . ... . ... ... . . ...... ............................... ........... ........ 9 4.4 Safety fa cto r for In fa nt s and Children (FQ PA Safe t y Factor)

........................................................................... 9 4.4.1 Complet e n ess of the Toxicology D ataba se

... ....... .. ... .. . . . ... . ... .. .. . ... . ........ . ... .. . ..... .. .. .. . ..... . .. . . . .. . . .. .. . ........... 1 0 4.4.2 Evidence ofNeu r otoxicity

. .. ... ......... . ... ... .. .. .. ...... ........... . .. . .... . ... . ............ .. .. . .. .. .. . .. .. . .. .......... . . .. .. . ...... . .. . .. . . 10 4.4.3 Evidence of Sensi ti vit y / Suscept i bi l ity in th e Develop in g or Young Anima l

.. . ...... . .. ............. . .. . ...... . ..... .. 10 4.4.4 Residual Uncertainty in the Exposure D a taba se

...... ....... ... .......... .. . ... . ...... . .. . ... . .. ........................ . .. . .. . .. ..... I 0 4 .5 Toxicity Endpoint a nd Point of Departure Se lecti o n s

..... ..... .... .. .. ... . .. .. .. ......... .. ................... .............. .............. I 0 4.5.1 D ose -Re sponse Assessment

..................................................................................................................... 1 0 4

. 5

. 2 Recomm en d a ti on for Co mbinin g R o ut es of Exposu r es for Ri sk Assessment..

........................................ I I 4.5.3 Cancer Classificat i o n and Ri sk Assessment R ecomme ndation

..... ... ....................................... . .. . ............. I I 4.5.4 Summary of Points of Departure**~d** . Toxicity Endpo int s Use d in Human Risk Assessment..

................ I I

5.0 Dietary Exposure and Ri sk Assessment

................................................................................................................ I 2



### 5. I Metabo li te / D eg rada t e R es idu e Profile

...................................... . ................................................. . .. . .. . ......... .. . . . 1 2 5.2 Food R esidue Profil e

.. .. ............ . .. ... .. .. .. . .. . ... .. ... . ... .. ... . ........ . . . . . . . ... .. .. .. .. .. .. . ... .. .................................................. 1 2 5.3 Dr i n k i n g Wat e r R es i du e Profile

....................................................................................................................... 1 2 5.4 D i etary (Foo d + Drinking Water ) Ri s k A ssess m e nt

...... ................. . .. ........................................... ........... ........ 1 3

6.0 Re s idential (No n- Occ upati ona l ) Exposu re/Ri s k Character i zation

........................................................................ 1 3

6.1 Re side n tial B ys t ande r Post-Application I nhalation Exposu r e

. ... .. ... . ......................................... ........... ........... 13 6.2 Spray Drift

.................... . ....... ... . ....... . .. ................................. .......................... ................................ .... .............. 14

7.0 Aggregate Exposure / Ri s k C h arac t e rization

.......... ... . ........... ... ... . ... ... . ... .. . ........................................ ........ . ..... ....... 14

8.0 C umu l at i ve E x po s ur e / Ri s k C haracter i zat i on

... .. .. .......................... .................. .................. ......... .. ........... . .. . .. . .. .... 1 4

9

. 0 Occupat i onal Exposure / Ri s k C h arac t e r ization

......... .. .. ....... .. .. .......... . ............ .. .. .. . .. .. .. . .. ..... .. .. . ........ . . . ... .. .. . .. . ..... . 1 4

Appendix A: Tox ico l ogy Profil e and Executive S umm a ri es

...................................................................................... 1 5 Appendix B: Exposure t o E t oxazo l e in Fish/Shellfish a t Cons umption L evels Associa t ed with Subsiste nce F i shing

.

...................................................... . ............................................... ....... ................................. .. . . ..... ....... ........... 19
Appe ndix C: Ph ys ical / Chemica l Properties

.. .. .. ... ... ............................................................................. . .. ................. ... 21

P age 2 of2 IEtoxazole Human Health Risk Assessment D4 22673

Page 3 of 21 

### 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 toler ances 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, hepatoc ellular swelling and histopathological indicators)

, and the severity does not appear to increase with time. In rats only, there w ere effect s on incisors (elongation, whitening, and partial loss of upper and/or lower incisor s ). 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 susceptibilit ies w ere observed following i n utero exposure to rats or rabbits in the developmental studies ; however, o ffspring 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.

F Q PA Safety Factor (

SF ) Decision: The RAB1 risk assessment team has evaluated the available hazard and exposure data for etoxazole, and recommend s that the FQPA SF be reduced to 1X. The recommendation is based upon; 1) the completeness of the hazard databa se; 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 ri sk assessment was conducted using the Dietary Exposure Evaluation Model

- Food Consumption Intake Database (DEEM

- FCID, ve r. 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 carcinogen ic 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, andEtoxazole Human Health Risk Assessment D4 22673

Page 4 of 21 

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

. In addition, b ased 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 ( L OC; ≤ 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 resid ential 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 ri sk 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 carcinoge n ic to humans

. Occupational Exposure and Risk Assessment: Since the proposed us e 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 h uman health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Lo w

- Income Populations.”

2.0 HED Recommendations

Provided the petitioner submits a revised Section F, HED concludes that the toxicological and residue chemistry database s 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/nitrogen

phosphorus detector (NPD)) are available for enforcing the current plant and livestock tolerances including the currently established tangerine tolerance (D303628, J. Tyle r, 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 D4 22673

Page 5 of 21 

### 2.2.2 Recommended Tolerances

Table 2.2.2.1 is a summary of t he 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) HED

Recommended 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 D4 22673

Page 6 of 21 

### 3.0 Introduction

3.1 Chemical Identity

The chemical structure and nomenclature of etoxazole is presented in Table 3.1.1. The physi c ochemical 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. T able 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 scenar io. 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 D4 22673

Page 7 of 21 

### 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 e toxazole appear s to have a high potential to bioaccumulate (≤1600x for edible tissues; D311941, J. Meléndez, 31

- May

2005) . B ased on th e EFED assessment, HED included residues in fish/shellfish in the dietary exposure analysis (D426228, T. Bloem, 29

- Sep

- 20 15). 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 patter ns 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 a nd 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 dev elopment 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 etoxazo le 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 perfor med 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 D4 22673

Page 8 of 21 

### 4.0 Hazard Characterization and Dose

- Re sponse 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

- d oses (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 high

dose groups (15.2

- 19.1% dose).

For the single low

- dose groups, maximum concentrations in the plasma (C max 

### ) 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, C max 

### was 15.8

- 16.4 μg Eq/g for mal es and 5.3

- 5.6 μg Eq/g for females. Though m aximum 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

- the

c urve ( 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. C oncent rations 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 accumulatio n.Etoxazole Human Health Risk Assessment D4 22673

Page 9 of 21 

### 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 o n 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

N o 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. Additiona lly, 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 w ere effect s on incisors (elongation, whitening, and partial loss of upper and/or lower incisor s ). There is no evidence of neurotoxicity or immunot oxicity. 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 susceptibilit ies w ere observed following in utero exposure to rats or rabbits in the devel opmental studies ; however, o ffspring 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 susceptib ility

.

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 recommend s 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 p otential inhalation exposure and subsequent risk assessment which would trigger a 10x database UF, due the absence of the required route specific study

.Etoxazole Human Health Risk Assessment D4 22673

Page 10 of 21 

### 4.4.1 Completeness of the Toxicology Database
The toxicological database is adequate for FQPA asses sment. 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 Neurotoxici ty

There is no evide nce 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 fo r 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 n o

- o bservable a dverse

- e ffect l evel ( NOAEL ) ; 2) the selected en d points 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 adjus ted 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 exposu re. In addition, r esidential 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 sub popul ation 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

- o bservable adverse

- e ffect l evel ( 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 subpopula tion 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 sele ct the endpoint for establishing the c hronic r eference d ose ( 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 swe lling in the liver at the LOAEL of 23.5 mg/kg/day. Although the NOAEL in the chronic rat study is lower, it was notEtoxazole Human Health Risk Assessment D4 22673

Page 11 of 21 

### 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 protect ed 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, t his study and these effects are appropriate for the durati on 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 com bining 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 Asse ssment
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 f ro m 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 Non

Occupational 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 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, increased liver weights, liver enlargement (females), and incidences of centrilobular hepatocellular swelling in the l iver. 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 d eparture (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 adv erse

- 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). 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 D4 22673

Page 12 of 21 

### 5.0 Dietary Exposure and Risk Assessment
D4 24375 , T. Bloem, 29

- Sep

- 201 5 (residue chemistry summary ) D4 26228 , T. Bloem, 29

- Sep

- 201 5 (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 assessmen t 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 hull 1 etoxazole

etoxazole primary crops

- cotton gin byproducts and almond hull 1 etoxazole and R

- 3 poultry tissue (except liver) 2 etoxazole egg and poultry liver 2 etoxazole and R

- 16 milk and ruminant muscle/fat 2 etoxazole ruminant liver/kidney 2 etoxazole and metabolite 1
water 3 Parent, R

- 8, and R

- 13

-- rotational crops 4 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

- 20 03

. 2 D283737, J. Tyler, 31

- Jul

- 2003; D289666, J. Tyler, 17

- Jun

- 2003; D289666, J. Tyler, 17

- Jun

- 20 03

. 3 D289666, J. Tyler, 17

- Jun

- 20 03

. 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 re duce 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 f

ield trial and processing data

, and when considering international MRLs

, HED

con cludes 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 ( D 426353, J. Meléndez

, 3 1

- Mar

- 2015 ; Tier 1 assessment ). The assessment was based on the esta blished 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, R

8

, 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 : E DWCs 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 0.36 lb ai/acre/season. Ground Water (PRZM_GW)

-- -- -- <0.1Etoxazole Human Health Risk Assessment D4 22673

Page 13 of 21 

### 5.4 Dietary (Food + Drinking Water) Risk Assessment

A chronic dietary risk assessment was conducted using the DEEM

- FCID ( ve r. 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 carcinogen ic 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, b ased 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 exp osure 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 Decembe r 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 Scree ning Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

2014

- 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 forEtoxazole Human Health Risk Assessment D4 22673

Page 14 of 21 

### 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 method s (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 e valuated 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 Assessmen t (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 consider s and aggregate s 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 dos e were not identified and etoxazole is classified as not likely to be carcinogen ic 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 to xicity, 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 ha s 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 th e 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 us e is for a tolerance without an U.S. registration, occupational exposure assessment is unnecessary.

RDI: RAB1 ( 20

- May

- 201 5 )

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 D4 22673

Page 15 of 21 

### 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 Yes 1 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 A berrations 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# 005 6977

.

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/AEtoxazole Human Health Risk Assessment D4 22673

Page 16 of 21 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 weig hts, 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 swel ling.

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 13 th ribs in the fetuses.Etoxazole Human Health Risk Assessment D4 22673

Page 17 of 21 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 F 1 males and increased adrenal weights in the P females Offspring/Sys temic 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 (femal es), 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 R everse 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 D4 22673

Page 18 of 21 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 m ales = 15000 ppm (858 mg/kg/day). The systemic LOAEL for males was not established. Neurotoxicity NOAEL = 15000 ppm (858 mg/kg/day). A n eurotoxicity 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 [ 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 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 14 C

labels, but c oncentrations 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 within 120 ho urs 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 D4 22673

Page 19 of 21 

### 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 estimate s for fish/shellfish. However, th e s e analys e s d id not consider fish/shellfish consumption rates associated with subsistence fishing. To account for these consumption rates, the assessment summarized below was conducted.

C onsumption rates associated wi th subsistence fishing were attained from the Fish Consumption Rates Technical Support Document (ver. 2.0 ) from the State of Washington Department of Ecology ( https://fortres s.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

o n the consumption rates from this document

, and the fish/shellfish r esidue estimate, exposure estimates were calculated and added to the DEEM

- F C ID estimates (see Table C .1). T he resulting total exposure estimates are less than HED’s LOC.

It is noted th at t he 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 d emonstrated 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 contr ast to lindane, etoxazole is anticipated
to a ffect 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 t he lindane analysis were not applicable to the current assessment.Etoxazole Human Health Risk Assessment D4 22673

Page 20 of 21 Table B .1 : Summary of Subsistence Dietary Input s and Risks.

Population Fish/Shellfish Residue

Estimate 1 (ppm) Body

Weight (kg) Subsistence DEEM

- FCID Exposure 4 combined %PAD 5

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 7 0 214 0.0000153 0.001278 3
Adult Females 6 0 214 0.0000178 0.001171 3

1 Tolerances for residues of etoxazole in/on fish/shellfish have not been established. The USDA PDP monitored etoxazole residu es 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 )

. T he 113 g/day consumption figure for children 6

- 12 years old was derived by adjusting the adult
consump tion 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, E ditors. United States Atomic Energy Commission. pp. 1109

- 1111.
3 E xposure = consumption (g/day) ÷ body weight x fish residues (ppm) x (1 mg/1000 μg)

. 4 See Table 5.4.1.
5 C ombine d %PAD = (subsistence exposure + DEEM

- FCID exposure) ÷ c PAD (cPAD = 0.0 4 6 mg/kg/day)

.Etoxazole Human Health Risk Assessment D4 22673

Page 21 of 21 

### 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 K ow 

### .

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/cm 3

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 (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.