Ethaboxam Human Health Risk Assessment DP No. 396490

UNITED STATES ENVIRONMENTAL PROTECT I ON AGENCY

WASHINGTON

, D

. C

. 20 4 60



### MEMORANDUM

Date: May 21, 2013 O F FICE OF CHEMICAL SAF E TY A ND POLLUT I ON PREVE N T I O N



### SUBJECT: Ethaboxam. Human Health Risk Assessment for Non-food Seed Treatment.

PC Code: 090205 DP Barcode: 0396490 Registration No: 59639-RIL Regulatory Action: Section 3
Case No.: 7053 Decision No: 456065
Petition : N/A
Risk Assessment Type: Single chemical, aggregate
TXRNo.: NA
MRIDNo.: NA



### FROM: CAS No.: 162650-77-3
40 CFR: § 180.622

Dennis McNeilly, Risk Assessor 

# -& --::;- 

# .t:}::_VYf**~___,_** Margarita Collantes

, Biologist 

### .ro'**~** 

### '-'·-,-- "1 Douglas Dotson, Ph.D.,

### Chemist).~~ Karlyn Middleton, Toxicologist**~** Risk Assessment Branch II I' ' 

## f

- Health Effects Division (7509P)



### THROUGH: M ichael Doherty

, Ph.D., Senior

# Ch~emist**~ ··**  Linnea Hanson, Ph.D., Toxicologist

.

### (4--1 Christina Swartz, Branch Chief

. Risk Assessment Branch II

Health Effects Division (7509P)
Office of Pesticide Programs
and Jeffrey L. Dawson, Chemist
Senior Scientist
Health Effects Division (7509P)

P.V. Shah, Ph.D., Toxicologist Chief, Inert Ingredients Assessment Br
R egistration Di visi on (7505 P)



### TO: Dominic Schulerffony Ki s h

, 

### RM Team 

### 22 Fungicide Branch Registration Division (7505P)

Page 1 of 53Etha b oxam H u man Health Risk Assessmen t DP No

. 39 6490

1.0 Executive Summary

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2.0 RED Recommendations

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2. 3 Data Deficiencies/Conditi o ns of Registration

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Tolerance Considerations

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Label Recommendations

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3 .5 Introduction

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Chemical Identity"

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Pesticide Use Pattern

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Consideration of Environmental Justice

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. 3 Hazard Characterizat i on and Dose-Response Assessment

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.. . ... .. .. .. .. .. ... . ....... 11 Absorption, Distribution, Meta b o l ism, & Elimination (ADME)

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Dermal Absorption

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Evidence of Neurotoxicity"

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Evidence of Sens i tivicy/Susceptibilicy in th e Developing or Y o ung Animal.

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Residual Uncert ai nty" i n the Exposure Database

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Dose

- Response Assessment

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Recommendation for Combining Routes of Exposure s for Risk Assessment

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Cancer Classification and Risk Assessment Recommendation

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Asse

. ssment

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6.0
6.1 

### 7.0 Dietary Exposure and Risk Assessment

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M e tabolite/Degradate Residue Pro fi le

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.... .. ...... . .. . ... .. .. .. ... 20 Comparison of Metabolic Pathways

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Residues of Concern Summary and Ra t ionale

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Food Residue Profile

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Water Residue Profile

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D i etary Risk Assessment

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Percent Crop Treated Used in Dietary Assessment

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Acute Dietary Risk Assessment

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Chronic Dietary Risk Ass e ssment

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Spray Drift

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Page 2 of 53Ethaboxam Human Health Risk Assessment DP No. 396490

Page 3 of 53 8.0 Cumulative Exposure/Risk Characterization .............................................................. 27
9.0 Occupational Exposure/Risk Characterization ........................................................... 27
9.1 Short- and Intermediate-Term Handler Risk ........................................................... 27
9.2 Short- and Intermediate-Term Post-Application Risk ............................................. 29
10.0 References .................................................................................................................... .... 32 Appendix A. Toxicology Profil e and Executive Summaries .................................................. 33 Appendix B. Review of Human Research ................................................................................ 43Ethaboxam Human Health Risk Assessment DP No. 396490

Page 4 of 53 1.0 Executive Summary

Ethaboxam ( N -(cyano-2-thienylmethyl)-4-ethyl-2-(ethylamino)-5-thiazolecarboxamide) is a thiazole carboxamide fungicide that controls various diseases caused by oomycetes. Ethaboxam is reported to have preventive, curative, systemic , and residual activity. It inhibits penetration on the plant surface and is reported to inhi bit mycelia growth and sporulation of P. infestans. It also weakly inhibits germination of zoospores or cyst s. Ethaboxam is believed to have multiple sites of action as it inhibits migration of nuclei from the growing germ tube and mycelia, and appears to inhibit oxygen consumption by mitochondria. The fungicidal mode of action is not fully
understood at this time. The mamm alian mode of action is not known.

Valent U.S.A. Corporation proposed the first US uses of ethaboxam as a seed treatment on legume vegetables (crop group 6) except cowpea and field pea, cereal grains (crop group 15) except rice and wild ri ce, and the rapeseed subgroup (20- A). Ethaboxam is not currently registered for use in the United States; however, th ere is a tolerance without U.S. registration for grapes at 6.0 ppm. The requested uses are being proposed as non-food uses; therefore, no tolerances are being proposed. HED has determined that the proposed uses do qualify as nonfood uses, and no tolerances are required. Ba sed on the proposed use pattern, there is the potential for occupational exposure to etha boxam when treating and planting seeds. Occupational exposures are expected for short- and intermediate-term durations.

HED has new information to suggest that in co mmercial seed treatment facilities with high throughput for various seed types (e.g., corn or soybean), the durations of exposure for occupational handlers might exceed those typically considered in short- and intermediate-term assessments. However, HED decided not to con duct a long-term exposure assessment due to the conservative nature of the unit exposures which are based on open-pour systems rather than the closed and/or automated systems that would be used in larger facili ties operating over longer
durations. HED also notes that it would be unlikely for a single chemical to be used continuously, even in high throughp ut facilities, over long term dur ations. Using conservative assumptions, the short- and intermediate-term s cenarios are considered protective of longer-term exposure and risk.

The toxicity database is consid ered to be complete. Toxicolo gical studies with rats, mice, rabbits, and dogs show varying effects in the diffe rent species tested, with rats being the most sensitive of the four. In male rats, ethaboxam exposure results in adverse effects on the testes, epididymides, prostate, and seminal vesicles. It also results in reproductiv e toxicity, observed as reductions in mating and decreases in the fert ility index. Furthermore, ethaboxam has been classified as having “suggestiv e evidence of carcinogenic potentia l” based on Leydig cell tumors
observed in male rats. There was indication of qualitative susceptibility in the 2-generation reproduction study; however, there was no susceptib ility seen in a developmental rabbit study.
Administration of ethaboxam to mice resulted in mild effects on the liver. A developmental toxicity study in rats suggests that ethaboxam may affect norma l liver development. In dogs, exposure to ethaboxam resulted in decreases in body weight and body weight gain. Treatmentrelated effects on male reproductive organs were not observed in studies with mice, rabbits, or dogs; similarly, treatment-related li ver effects were not observed in studies with rabbits or dogs.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 5 of 53 As a result of the fact that the rat was the most sensitive species tested, HED has based this risk
assessment on effects observed in the rat studies.

An acute dietary risk assessment (all populations) was not conducted since there were no studies
with relevant effects that could be attributed to a single dose.

For chronic dietary exposure and risk assessmen t, the endpoint was eff ects on male reproductive organs (testes, epididymides, prostate, and semi nal vesicles) selected from the carcinogenicity study in rats.

For short- and intermediate-term dermal risk as sessment, HED selected the endpoint (decreased body weight, and body weight gains) from the route- specific 28-day dermal study in the rat. A route-specific inhalation toxic ity study was not available, so HED selected the inhalation endpoint (male reproductive and lu ng effects) from a 13-week rat feeding study to assess both short- and intermediate-term inhalation exposure a nd risk. Since inhalation absorption data are not available, toxicity by the inhalation route is considered to be equi valent to the estimated toxicity by the oral route of exposure.

Ethaboxam is classified as having “Suggestive Ev idence of Carcinogenicity.” However, potential human Leydig cell tumorigenesis is not expected at exposure levels that do not cause tumors in rats. The Agency has determined that quantific ation of cancer risk using a non-linear approach would adequately account for all chronic toxicity (including carc inogenicity) resulting from ethaboxam exposures.

HED recommends that the 10X Food Quality Prot ection Act (FQPA) Safety Factor (for the protection of infants and children) be reduced to 1X. This conclusion was based on 1) the completeness of the toxicity database, 2) there is no evidence of neurot oxicity, 3) the endpoints and doses selected for risk assessment are protecti ve of the qualitative susceptibility observed in the reproduction study, and the degree of concern for the susceptibility is low, and 4) exposure will not be underestimated because the dietary assessment used tolerance levels and high-end drinking water estimates, assumed that 100% of imported grapes are treated, and because there
are no uses that could resu lt in residential exposure. Although a route-specifi c inhalation study is not available, HED has used weight-of-evidence c onsiderations to conclude that the study is not needed, and therefore no additional uncertainty fa ctors are needed to account for missing data. Therefore, the level of concern (LOC) for dermal and inhalation risk assessments is a margin of exposure (MOE) of 100, based on the combined in terspecies (10X) and intraspecies (10X) uncertainty factors. For dietary assessments, the combined uncertainty factors of 100 were incorporated into the chronic population adjusted dose (cPAD), a nd HED would be concerned if dietary risk estimates exceeded 100% of the cPAD.

The exposure pathways expected for ethaboxam ar e dietary exposure from imported grapes, as well as from drinking water, and occupational ex posures via the dermal and inhalation routes. There are no registered or propos ed residential uses, and reside ntial exposure is not expected from the commercial use of this product. To assess dietary exposure, HE D has used the Dietary Exposure Evaluation Model with the Food Commodity Intake Database (DEEM-FCID TM ) Version 3.16 with highly health-p rotective assumptions regardi ng the level and prevalence ofEthaboxam Human Health Risk Assessment DP No. 396490

Page 6 of 53 ethaboxam residues in grapes and processed grap e commodities. In addition, estimated drinking water concentrations (EDWCs) resulting from the s eed treatment use were incorporated directly into the dietary exposure assessment.

The EDWCs for ethaboxam were modeled using the Tier 1 models, and usi ng very conservative assumptions for the new seed treatment use. Th ese assumptions include the use of the maximum treatment and seeding rates, that ethaboxam is stab le to all routes of degradation, and that all ethaboxam applied to the seeds ends up in dr inking water. Using these conservative assumptions, the predicted drinking water concentr ations were in the lo w ppb range, with surface water estimates higher than gr ound water estimates. Even with the conservative assumptions used for both food and drinking water, the diet ary risk estimates are below HED’s level of concern for all population subgroups, includi ng those comprised of infants and children.

For all proposed uses, occupational handler derm al and inhalation risk estimates are not of concern. Short- and intermediate-term primar y handler (seed treate r) MOEs ranged from 14,000 for dermal exposure resulting from multiple activi ties while treating legume vegetable seeds to 410,000 for inhalation exposure resulting from treati ng rapeseed. Short- and intermediate-term secondary handler (loader/planter) risk estimates ranged from a dermal MOE of 39,000 for cereal grains to an inha lation MOE of 7.8 x 10 6 for rapeseed. All exposure estimates were calculated with baseline clothing (long sleeved shirt, long pants, socks and shoes) and gloves.

Occupational Post-Application Exposure and Risk Estimates A quantitative post-application exposure assessment is not required for seed treatment as exposure is expected to be negligible, since th ere will be no residue on foliage which could result in exposures from contact once the plants are grown.

Restricted Entry Interval No quantitative post-application assessment is re quired for exposure to treated seeds that have already been planted. Therefore, the labeling properly states the exception to the Agricultural Use Requirements restricted entr y interval (REI) of 12 hours.

Environmental Justice Potential areas of environmental justice were considered in this assessment. The potential for impact is not considered likely for seed treatment applications.

Human Studies Review This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. Thes e data, which include studies from Standard Operating Procedures (SOPs) for Seed Treatment, Policy 14, 15, and 15.1 are (1) subject to ethics review pursu ant to 40 CFR 26, (2) have receiv ed that review, and (3) are compliant with applicable ethics requirements. For certain studies, the et hics review may have included review by the Human Stud ies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at http://www.epa.gov/pesticides /science/handler-exposuredata.html and http://www.epa.gov/pesticides/sci ence/post-app-exposure-data.html

.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 7 of 53 2.0 HED Recommendations

There are no data deficiencies th at would preclude registering th e seed treatment uses for legume vegetables (crop group 6) except cowpea and field pea, cereal grains (cro p group 15) except rice and wild rice, and the rapeseed subgroup (20-A) . The requested uses are being proposed as nonfood uses. HED has determined that the proposed uses qualify as non-food uses, and no
tolerances are needed.

2.1 Data Deficiencies/Conditions of Registration

None.

2.2 Tolerance Considerations

HED has determined that the proposed uses qua lify as non-food uses and no tolerances are
needed.

2.2.3 International Harmonization

No Codex or Canadian maximum residue limits (MRLs) have been established for ethaboxam. The same seed treatment use pattern is under revi ew in Canada, and since Canada considers seed treatment to be a food use, it might establish li mit of quantitation tolerances (LOQ) for these uses. Mexico has not established MRLs for the proposed uses.

2.3 Label Recommendations

None.

(NOTE: HED assumes the feeding restrictions on the proposed labels for the livestock feed items are implemented on the final approved label. The proposed label contains the following restriction: “Do not graze or f eed soybean forage or hay to li vestock.” There are no rotational crop restrictions on the label and none are needed for this non-food use.)

3.0 Introduction

3.1 Chemical Identity

Ethaboxam is a thiazole carboxamide fungicide that controls various diseases caused by oomycetes. It is registered in South Korea and has been submitted for registration in many European countries. The chemical structure a nd nomenclature of ethaboxam are presented in Table 3.1, and the physicochemical properties of th e technical grade of ethaboxam are presented
in Table 3.2.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 8 of 53 Table 3.1. Ethaboxam Nomenclature.
Compound

Common name Ethaboxam Company experimental

name LGC-30473

IUPAC name (RS)- N -( α -cyano-2-thienyl)-4-ethyl-2-(ethylamino)-1,3-thiazole-5-
carboxamide

CAS name N -(cyano-2-thienylmethyl)-4-ethyl-2-(ethylamino)-5-
thiazolecarboxamide CAS registry number 162650-77-3 End-use product (EP) V-10208 3.2 FS (3.2 lbs/gallon ethaboxam)

3.2 Physical/Chemical Properties

Table 3.2. Physicochemical Properties of the Technical Grade Test Compound:
Ethaboxam.

Parameter Value Reference Melting Point/Range decomposes on melting at 185oC MRID 46378504 pH 6.8 (1% w/v suspension) MRID 46378502 Density 1.28 at 24°C Water Solubility 12.4 mg /L at 25°C MRID 46378508 Solvent Solubility at 20°C Solvent Solubility MRID 46378502 n-Heptane 0.00039 g/L

Xylene 0.14 g/L n-Octanol 0.37 g/L 1,2-Dichloroethane 2.9 g/L

Ethyl Acetate 11 g/L

Methanol 18 g/L Acetone 40 g/L Vapor Pressure at 25oC 6.1 x 10 -7 mm Hg (8.1 x 10 -5 Pascals) MRID 46378504 Dissociation Constant, pK

a 3.6
Octanol/Water Partition Coefficient, Log(K OW ) 2.73 at pH 4; 2.89 at pH 7; 2.91 at pH 10

UV/Visible Absorption Spectrum Solvent System 1 λ max (nm) Absorbance Є (dm 3 /mol/cm) Water:ACN 231 (shoulder) 0.696 11,200 311 1.144 18,400 0.125M HCl:ACN 235 0.794 12,800 284 1.006 16,200 0.125M NaOH:ACN 252 0.678 10,900 262 (shoulder) 0.622 10,000 289 0.647 10,400 335 1.098 17,700 No absorption maxima at wavelengths >400 nm

1 ACN = acetonitrile; all ratios were 4:1, v:v. S N H

S N

O CH 3 CH 2 NH CN CH 2 CH 3Ethaboxam Human Health Risk Assessment DP No. 396490

Page 9 of 53 Comments: Ethaboxam has a Log (K
ow ) less than 3, suggesting that it will not bioconcentrate.
Environmental fate data are curre ntly under review in the Agenc y, and indicate that ethaboxam is moderately to slightly mobile as tested in five soils. The vapor pressure is low and suggests that volatilization will not be an issue, especia lly for the proposed seed treatment uses.

3.3 Pesticide Use Pattern

Valent is proposing a single end-use product (EP) fo r the seed treatment use of ethaboxam. This product is V-10208 3.2 FS (flowable concentrate for seed treatment), and its EPA file symbol (registration number) is 59639-RIL. It contains 3.2 lb. ethaboxa m per gallon, or 0.025 lb ai per
fluid ounce.

This product may be used for commercial and on-farm seed treatments. The proposed product label for the FS formulation specifies that seed should be treated using mechanical, slurry, or mist-type seed treating equipment but that seed may not be treated in hopper or planter boxes at planting. The label further specifie s that the fungicide should be pr e-tested in tank mixtures with other seed treatment products to evaluate formula tion compatibility and to ensure proper physical compatibility of products. The proposed Restrict ed Entry Interval (REI) is 12 hours for all crops.

The Personal Protective Equipment (PPE) statem ent on the proposed label requires applicators and other handlers to wear long-sl eeved shirt and long pants, socks, shoes, and chemical-resistant gloves. The proposed use directio ns are summarized in Table 3.3.

Table 3.3. Summary of Directi ons for Use of Ethaboxam.

Application Timing, Type, and Equipment Formulation 1 Applic. Rate (lb ai/100 lb seed) Max. No. Applic. per Season Max. Seasonal Applic. Rate (lb ai/100 lb seed) PHI (days) Use Directions and
Limitations

Crop Group 6: Legume Vegetables (Succulent or Dried), except Cowpea and Field Pea

Use mechanical, slurry, or mist-type seed treating equipment. V-10208 3.2 FS 0.0075-0.015 1 0.015 NS 2 Pre-test tank mixtures with other seed treatment pr oducts. Do not tank mix with any products that contain a prohibition on tank mixing.

Crop Group 15: Cereal Grains, except Rice and Wild Rice

Use mechanical, slurry, or mist-type seed treating equipment. V-10208 3.2 FS 0.005-0.0065 3 1 0.0065

NS Pre-test tank mixtures with other seed treatment pr oducts. Do not tank mix with any products that contain a prohibition on tank mixing. 0.005-0.0075 4 1 0.0075

Crop Group 20-A: Rapeseed Subgroup

Use mechanical, slurry, or mist-type seed treating equipment. V-10208 3.2 FS 0.005-0.0075 1 0.0075 NS Pre-test tank mixtures with other seed treatment pr oducts. Do not tank mix with any products that contain a prohibition on tank mixing.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 10 of 53 1 EPA Reg. No. 59639-RIL.

2 NS = Not specified on the label.

3 For barley, buckwheat, pearl mi llet, proso millet, oats, rye, teosinte, triticale, and wheat, the single application rate is
0.005-0.0065 lb ai/100 lb seed.

4 For field corn, sweet corn, popcorn, and grain sorghum (milo), the single application rate is 0.005-0.0075 lb ai/100 lb
seed.

Conclusions: The registrant submitted adequate use di rections for the app lication of ethaboxam as a seed treatment to legumes, cereal grains, and the Rapeseed subgroup. The application rates range from 5-15 g ai/100 kg seed (0.005-0.015 lb a i/100 lbs of seed). HED is not recommending any changes to the proposed label.

3.4 Anticipated Exposure Pathways

The requested seed treatment uses might resu lt in human exposure to ethaboxam and/or its metabolites in drinking water only since the uses are considered to be non-food. The existing use on imported grapes might result in human exposure to ethaboxam and/or its metabolites in/on food. At this time, there are no existi ng, pending, or requested commercial or residential registrations that would result in exposure from use in a residentia l setting. In a commercial or on-farm seed treatment site, there is potential for handlers to be e xposed while treating and planting seeds. However, potential for post-appli cation exposure is expect ed to be negligible,
since there will be no residue on fo liage which could result in expos ures from contact once plants

are grown.

The existing use on imported gr apes might result in human exposure to ethaboxam and/or its metabolites in/on food. However, as there is no US registration for grapes, there is no potential for occupational exposure resulting from the use on grapes.

3.5 Consideration of Environmental Justice

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions
to Address Environmental Just ice in Minority Populations an d Low-Income Populations," ( http://www.eh.doe.gov/oepa/ guidance/justice/eo12898.pdf . As a part of every pesticide risk assessment, OPP considers a large variety of c onsumer subgroups according to well-established procedures. In line with O PP policy, HED estimates risks to population subgroups from pesticide exposures that are ba sed on patterns of that subgrou p’s food and water consumption,
and activities in and around th e home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s National Health and Nutrition Ex amination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categ orized 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-diet ary exposures based on home use of pesticide products and associated ri sks for adult applicators and for toddlers, youths, and adults entering or playing on treated ar eas post-application are evaluated. FurtherEthaboxam Human Health Risk Assessment DP No. 396490

Page 11 of 53 considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditi onal dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database for ethaboxam is comple te at this time. A subchronic inhalation toxicity study has not been submitted. Howeve r, the Hazard Science Policy Council (HASPOC) concluded (TXR# 0056543) that a subchronic inhalation study is not needed for ethaboxam at this time based on a weight of evidence approach. This approach considered all of the available hazard and exposure information, including: (1) the physical/chemical properties and low vapor pressure of ethaboxam (8.1 x10 -5 Pa); (2) the low acute inhala tion toxicity of ethaboxam; (3) effects on the male reproductive system are th e primary toxicological effects of concern following repeated exposure to ethaboxam; and (4) the use of an oral POD that results in inhalation MOEs >19,000 for all current and proposed uses of ethaboxam.

The available toxicity studies for ethaboxam incl ude: subchronic oral toxi city studies in rats, mice, and dogs; a chronic oral toxicity study in dogs ; carcinogenicity studies in rats and mice and mode of action data (Leydig cell tumors); deve lopmental and reproduction studies in rats and a developmental study in rabbits; s ubchronic dermal toxicity and de rmal penetration studies in rats; and an immunotoxicity study in rats. There is also a metabo lism study in the rat, a complete mutagenicity battery, rat neurot oxicity (acute and subchronic), and acute lethality studies.

4.2 Absorption, Distribution, Metab olism, & Elimination (ADME)

In a metabolism study in rats with radiolabeled thiazole or thiophene (10 or 150 mg/kg), the majority of the radiolabeled compound was excret ed in the feces or urine within 48 hours of administration, regardless of radiolabel, dose, or sex. For both radiolabels, combined fecal and urinary excretion accounted for 96- 104% of the administered dose. The main route of excretion was feces (66-74%), followed by urine (23-30 %), with a slightly greater proportion of radioactivity excreted in the feces of the high dos e group (83-92%). Biliary excretion of thiazole radiolabeled ethaboxam was similar to the percen tages observed in the feces, indicating biliary excretion was the primary sour ce of fecal radioactivity. Ap proximately 79-94% of the compound was absorbed after 48 hours, dependi ng upon the dose. Minimal amounts (<1% of the dose) of the radiolabeled compound were reta ined in the tissues up to 120 hours post dosing. The thyroid generally contained th e highest concentration of the th iazole label, but only minimal amounts of the thiophene label.

Pharmacokinetic studies found mini mal differences between the thi azole or thiophene label. Except for the elimination half-life (t 1/2 ) (blood cell t 1/2 ~ 69-162 hours; plasma t 1/2 ~ 31-41 hours), blood cell pharmacokinetic values were ge nerally comparable to or lower than plasma
values. Differences were noted between the low- and high-dose pharmacokinetics. The t 1/2 was similar following single administration of both the low- and high-dose, while the C
max , t cmax , and the area under the curve (AUC 120 ) were higher following the hi gh-dose compared to the low-Ethaboxam Human Health Risk Assessment DP No. 396490

Page 12 of 53 dose. However, the increases were not propor tional to dose suggesting a limited capacity for absorption.

Minimal quantitative differences were noted within the metabolic profiles of urine, feces, or bile
from rats administered the same doses of co mpound with the thiazole or thiophene label, following single or repeated oral administration of the low-dose of the thiazole label, or between sexes. The major urinary radi oactive components were derived by hydrolysis of the amide (7- 10% low-dose and 3% of high-dose) , and oxidation of the thiazole sulfur (< 3% of dose). The major fecal residues were the parent compound (5-18% low-dose and 47-68% of high-dose) and hydrolysis or conjugation products. The major meta bolites identified in the bile were obtained by hydrolysis of the amide (2-6%) and an N-deethylation of the parent (4-6%).

4.2.1 Dermal Absorption

An in vivo dermal absorption study in rats is avai lable where ethaboxam (technical) was applied to the skin of 12 male Sprague Da wley rats, dose at low (2 μg/cm 2 ) and high (1 mg/cm 2 )
concentrations. The test material was allowed to remain in contact with the skin for six hours after application, after which re sidual test material was removed by washing the skin. In the study, the total amount absorbed (absorbed dose) increased over time, while the amount in the treated skin, skin fur, and stratum corneum (absor bable dose) decreased over time. The absorbed and absorbable doses (from treat ed skin, stratum corneum, and skin surrounding dose site) were combined and, due to the variabil ity in the absorbable dose, the 6 hour time point resulted in the greatest total absorption. The 6 hour time point is also the most relevant time point for occupational exposure; thus, the total absorption of 7.5% after 6 hours is considered the most appropriate for risk assessment.

4.3 Toxicological Effects

The male reproductive system is a target for etha boxam, with alterations to the male reproductive organs as well as functional effects on male repr oduction observed in seve ral oral subchronic and chronic rat studies. In 90-day f eeding studies in rats, there were severe testicular alterations at 650 and 2000 ppm. Effects observed were small te stes, decreased testicul ar weight and atrophy, abnormal spermatids in the testes, and interstitial cell hyperplasia. In the epididymides, there were small epididymides, decreased epididymal weights, abnormal spermatogenic cells, and absent spermatozoa. Decreased seminal vesicl e and prostate weights were also observed.

A combined chronic/carcinogenicity study in rats also demonstrated adverse effects in the male reproductive system at 300 and 650 ppm. Effect s observed were decreased epididymal and seminal vesicle weights, seminiferous tubule atrophy, small/flaccid testes and epididymides, abnormal spermatogenic cells in the epididymal duc t, absent sperm, epididymal vacuolation, and reduced colloid in the prostate. Fine vacuolation of the adre nal zona glomerulosa was also observed in both sexes in the rat studies, al ong with decreased body weight in females.

Decreased body weight and body weight gains were also noted in a de rmal toxicity study in rats. However, no effects on male reproductive organs were observed in the study. There were noEthaboxam Human Health Risk Assessment DP No. 396490

Page 13 of 53 treatment-related male reproductive effects observed in mice, but there were mild effects seen in
the liver.

In a carcinogenicity study in mice, liver effects were seen at 900 ppm in the form of increased liver weights associated with centrilobular hypertrophy and liver histopathology (eosinophilic foci). In a 90-day feeding study in mice, liver fi ndings were limited to in creases in liver weight and centrilobular hepatocyte hypertrophy at 450 ppm (males) and 1000 ppm (females); these findings were considered adaptive responses. Th ere were no treatment-related male reproductive or liver effects observed in dogs. However, decreased body weight and body weight gain were seen in females in all treatment groups ( 15, 40, and 100 mg/kg/day) in the 90-day dog study. Decreased thymus weights and thymus atrophy/invol ution, and hematopoiesis of the spleen were also observed at 100 mg/kg/day. No treatment-rela ted effects were observed in the chronic dog study up to the highest dose tested of 30 mg/kg/day.

Although spleen and thymus effects were seen in dogs, no evidence of immunotoxicity was seen in an immunotoxicity study in rats at doses up to 121 mg/kg/da y. Effects observed in the study were limited to decreased body weight gain and food consumption at the high dose.

Ethaboxam was not neurotoxic in th e available studies. Post-dose salivation was observed in a developmental rat study at 300 a nd 1000 mg/kg/day. However, in another developmental rat study and a developmental rat range-finding stud y, post-dose salivation was not observed. Additionally, no treatment-related ne urotoxic effects were observed in the neurotoxicity studies. In the acute neurotoxicity st udy, no treatment-related effects we re observed at doses up to 2000 mg/kg/day. In the subchronic neurotoxicity study, decrease d body weight, body weight gain, and food consumption were obs erved at 122 mg/kg/day.

No evidence of increased quantit ative or qualitative susceptibility was seen in the developmental toxicity studies in rats and rabbi ts. In two developmental rat st udies, there were incidences of
abnormal liver lobation observed at ≥ 100 mg/kg/day; however, the incidences were within historical control range. No tr eatment-related developmental or ma ternal effects were noted in the first rat developmental study. In the second developmental ra t study, thin diaphragm with liver protrusion, decreased fetal body weight, mi sshapen pituitary, diaphragmatic hernia, and
skeletal anomalies were seen at the limit dose of 1000 mg/kg/day. These eff ects were seen in the presence of comparable maternity toxicity. Ma ternal effects seen included increased salivation, decreased body weight (15%) and body weight ga in (37-72%). In a developmental toxicity study in rabbits, there were no developmental effects observed up to 125 mg/kg/day. At 125 mg/kg/day, inappetence (2 animals sacrificed ), decreased food consumption (70%), and body weight loss (-73g vs. -16 controls) were seen in maternal animals.

There was indication of increased qualitative su sceptibility in a 2-generation reproduction study. In the 2-generation reproduction study, decreased body weight (up to 15%), decreased viability, and delayed sexual maturation were seen in offs pring animals at 52.6 mg/kg/day, with parental effects limited to decreased body weight and body weight gain in both sexes. There were adverse reproductive effects observe d in the male reproductive organs similar to those seen in subchronic and chronic rat studies, as well as im paired sperm motility and reduced fertility in
males.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 14 of 53 Ethaboxam has been classified as having “sugges tive evidence of carcin ogenic potential,” based on an increased incidence of benign Leydig cell tumo rs in male rats. Although there is evidence of benign Leydig Cell tumors, the NOAEL used (5.5 mg/kg/day) for es tablishing the chronic reference dose is approximately 6-fold lower th an the lowest dose that induced tumors (35.8 mg/kg/day, highest dose tested). The Agency has determined that quantification of cancer risk using a non-linear approach would adequately account for all chroni c toxicity, including carcinogenicity, that could resultfrom exposure to ethaboxam.

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

Although the currently proposed seed treatment us es are considered to be non-food, the existing use pattern (import tolerance on grapes) for etha boxam will result in the potential for dietary exposure to infants and children. Fu rther, the new seed treatment us es may result in the potential for exposure through drinking water. Thus, FQ PA hazard and exposure considerations were
addressed in HED’s evaluation of the database. HED recomme nds that the 10x FQPA Safety Factor (for the protection of in fants and children) be reduced to 1x. This recommendation is supported by the following considerations: 1) the toxicological database for ethaboxam is complete with regard to pre-and postnatal toxi city, including the requ ired immunotoxicity and neurotoxicity studies, 2) there is no evidence of neurotoxicity, a nd HED has determined that the developmental neurotoxicity study is not required, 3) the endpoint s and doses selected for risk assessment are protective of th e qualitative susceptibility obser ved in the reproduction study and the degree of concern for the sus ceptibility is low, and 4) exposure will not be underestimated because the dietary assessment used tolerance levels and high-end drinking water estimates, assumed that 100% of imported grapes are trea ted, and because there are no uses that could result in residential exposure.

4.4.1 Completeness of the Toxicology Database

The available toxicity studies are adequate for assessing and characterizing potential pre- and/or post-natal susceptibility for infants and childre n. Acceptable/guideline developmental toxicity
studies in rats and rabbits and re production study in rats are all av ailable for FQPA assessment.

4.4.2 Evidence of Neurotoxicity

There is no evidence that ethaboxam is neurot oxic. Post-dose salivation was observed in a developmental rat study at 300 a nd 1000 mg/kg/day, and is the only effect observed in the database that could potentially be associated with neurotoxicity. However, in another developmental rat study and a developmental ra t range-finding study, post-dose salivation was not observed. Additionally, no treatment-relate d neurotoxic effects were observed in the neurotoxicity studies. In th e acute neurotoxicity study, no tr eatment-related effects were observed at doses up to 2000 mg/ kg/day. In the subchronic ne urotoxicity study, decreased body weight, body weight gain, and food consumption were observed at 122 mg/ kg/day. No signs of neurotoxicity were observed in any ot her species or toxicology studies.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 15 of 53 4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

No evidence of increased quantitative or qualita tive susceptibility was seen in developmental toxicity studies in rats and rabbits. However, there was evidence of increased qualitative susceptibility in a reproduction study in rats. Decreased pup weights and viability in both generations, and delayed sexual maturation were seen, with maternal toxicity limited to decreased body weight and body weight gains. In paternal animals, adverse effects were observed in the male reproductive organs of both generations, and there was decreased fertility in
F1 adult males.

Although there is evidence of increased qualitative susceptib ility in the reproduction study, there are no residual uncertainties with regard to pre- and/or postnat al toxicity following in utero exposure of rats or rabbits and pre and/or post- natal exposures of rats. Considering the overall toxicity profile and the doses and endpoints sele cted for risk assessment, the degree of concern for the effects observed in the study is low base d on the following: the offspring effects observed in the study are well characterized and clear NOA ELs/LOAELs have been identified in the study for the effects of concern. Additionally, the poi nts of departure (PoDs) selected for risk assessment are protective of potential offspring effects.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainti es with respect to dietary a nd occupational exposure. The dietary exposure assessment is based on high-end health protective residue levels (that account for parent and metabolites of c oncern), and processing factors. Furthermore, very conservative, upper-bound assumptions were used to determin e exposure through drinking water, such that these exposures have not been underestimated. Actual risk from exposure to ethaboxam will likely be much lower than HED’s risk estimates for the proposed and existing uses.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

The detailed descriptions of th e toxicity studies used for sele cting toxicity endpoints and points of departure for various exposure scenarios are presented in Appendix A.3 of this assessment. Although residential endpoints/PoDs for incidental oral, dermal, and inhalation exposures have been selected, only dietary and occupational expo sure are expected with the registered and proposed uses. The male reproductive organs are a primary target for ethaboxam and the endpoints selected are mainly based on these effects.

An acute dietary risk assessment (all populations) was not conducted since there were no studies
with relevant effects that could be attributed to a single dose. The eff ects observed in offspring in the reproduction study were considered for acute dietary ex posure (females 13-49) based on delays in sexual maturation (pre putial separation and vaginal opening) observed at the LOAEL of 52.6 mg/kg/day. However, the delays were mild (2.4 and 2.1 days) and within normal biological variability (± 2 days). Therefore, the endpoint in the absence of other potential single dose effects was not considered appropria te for acute dietary risk assessment.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 16 of 53 For chronic dietary exposure and risk assessmen t, a NOAEL of 5.5 mg/kg/day was selected from the carcinogenicity study in rats based on effects seen in the ma le reproductive organs (testes, epididymides, prostate, and seminal vesicles) at the LOAEL of 16.4 mg/kg/day. The NOAEL in the rat is the lowest dose in the toxicity databa se for chronic durations. The chronic rat study is therefore considered to be the most appropriate for chronic dietary dose and endpoint selection. It is also protective of the Leydig cell tumors observed in rats at a hi gher dose (35.8 mg/kg/day),
effects in the chronic mouse study (117 mg/kg/day) and system ic, reproductive, and offspring effects seen in the reproduction study (56.1 mg/kg/day). No effect s were seen in the chronic dog study up to the high dose of 30 mg/kg/day.

For short-and intermediate-term dermal exposure, the 28-day dermal toxicity study in the rat was
selected for risk assessment. The NOAEL of 300 mg/kg/day was ba sed on decreased body weight and body weight gains observed at the LOAEL of 1000 mg/kg/da y. Male reproductive effects (abnormal spermatids in the testes , and abnormal spermatogenic cells in the epididymides) and lung effects (increased l ung weights, congestion, and alveolar septal congestion and focal alveolar hemo rrhage) were seen in a 13-week oral study with a lower point of departure (PoD). However, these effects we re adequately measured in the 28 day dermal toxicity study, and no reproductive effects were s een. Additionally, the dermal equivalent dose for the 13 week oral study, based on the LOAEL of 49.7 mg/kg/day and a 7.5% dermal absorption factor is 663mg/kg/ day. Therefore, the NOAEL of 300 mg/kg/day is protective of effects seen in the study. Furthermore, there is no concern for quantitat ive susceptibility. The study is appropriate for both the r oute and duration of exposure.

For short- and intermediate-term inhalation exposu re, the 13 week rat study was selected for risk assessment. The NOAEL of 16 mg/kg/day was based on male reproductive and lung effects observed at the LOAEL of 49.7 mg/ kg/day. Unlike dermal exposure, a route-specific study is not available to confirm whether male reproductiv e or lung effects are observed after inhalation exposure. Therefore, to protect for these effects, the oral 13-week dog study in rats was selected. The 13 week dog with a similar NOAEL was also considered; however, the rat was a more appropriate choice since effects in the study were seen in the target organ. Additionally, the PoD in the rat is protective of effect s seen in the dog study. For risk assessment, inhalation toxicity was assumed to be equivalent to toxicity via the oral route.

As stated above, the FQPA SF was reduced to 1X; in addition, there ar e no other uncertainty
factors needed to account for missi ng data or the lack of a NOAEL. Therefore, for the chronic dietary risk assessment, a total 100X uncertainty f actor was used (interspec ies factor of 10X and intraspecies factor of 10X). For dermal and inhalation risk assessments, the level of concern (LOC) is a MOE of 100, based on the combined interspecies (10X) a nd intraspecies (10X) uncertainty factors.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential occupational and resi dential exposures to a pesticide, the risk assessment must address exposures from three ma jor sources: oral, dermal, and inhalation. It
must be determined whether or not the individual exposures have the same toxicological effects.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 17 of 53 If they do, then they can be combined. For et haboxam, dermal and inhalation exposures were not combined since the toxicological e ffects for each route were not the same.

4.5.3 Cancer Classification and Ri sk Assessment Recommendation

In accordance with EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), the Cancer Assessment Review Committee (CARC) classified ethaboxam as having “Suggestive Evidence of Carcinogenicity,” a nd concluded that potential huma n Leydig cell tumorigenesis is not expected at exposure levels th at do not cause tumors in rats. The Agency has determined that quantification of cancer risk using a non-linear approach w ould adequately account for all chronic toxicity, including carci nogenicity, that could result from exposure to ethaboxam. The NOAEL used (5.5 mg/kg/day) for establishing the chronic reference dose is approximately 6-
fold lower than the lowest dose that induced tu mors (35.8 mg/kg/day). This determination was based on the following weight-of- evidence considerations:

 There was a treatment-related increase in only one tumor type (benign Leydig cell tumors of the testes), only at the hi ghest dose tested (650 ppm), and in only one species (Sprague Dawley rat).

 There were no treatment-related tumors seen in female rats or in male or female mice.

 Ethaboxam does not appear to be a gene muta gen; however, the clas togenic potential of this compound cannot be determined at this time. Although the weight-of-evidence does not support a mutagenicity concer n, the CARC recommended that the in vitro cytogenetic assay be repeated to clarify the earlier results. Additional mutagenicity data, including an

in vitro cytogenetics assay, have been submitted to the Agency; however, the new data have not been reviewed as part of the current risk assessment.

 It is well accepted that rat Leydig cell tumors are typically the result of disruption of the endocrine and paracrine control of Leydig ce ll function (testosterone production). Thus, a nonlinear dose-response approach shoul d be used for non-mutagenic compounds causing Leydig tumors by a hormonal mode of action. Leydig cell tumor induction in rats is of potential concern to humans unless the human relevance can be ruled out by the mode of action (Clegg et al ., 1997; Cook et al ., 1999).

 In a mode-of-action study in rats, investiga ting reproductive hormone levels, exposure to
ethaboxam resulted in a decrease in testoste rone, and a slight incr ease in luteinizing hormone (LH). However, the data presente d did not support a consistent pattern of
decreased testosterone or incr eased LH and cannot be linked w ith increases in Leydig cell adenomas. In other rat studies, there were adverse reproductive effects and marked testicular damage observed, effects indicative of a decrease in testosterone and testicular toxicity. The hormonal data and overall male reproductive effects observed are suggestive of a hormonally-mediated pathway; however, the data are inadequate to delineate a sequence of key events leading to tumor formation. Thus, the available data
are insufficient to characterize the human re levance of this tumor finding. AdditionalEthaboxam Human Health Risk Assessment DP No. 396490

Page 18 of 53 mode of action data have been submitted by the registrant; however, the data have not been evaluated as part of the current risk assessment.

4.5.3 Summary of Points of Departure and T oxicity Endpoints Used in Human Risk
Assessment

Table 4.5.3.a. Toxicological Doses and Endpoints for Ethaboxam for Use in Dietary Human Health Risk
Assessments

Exposure/
Scenario Point of Departure Uncertainty/ FQPA Safety
Factors RfD, PAD, Level of
Concern for Risk
Assessment Study and Toxicological Effects

Acute Dietary (All populations) No appropriate endpoint attributable to a single dose identified.

Chronic Dietary (All Populations) NOAEL=
5.5 mg/kg/day UF A = 10X
UF H =10X FQPA SF=1X Chronic RfD =0.055 mg/kg/day

cPAD = 0.055 mg/kg/day Combined Chronic/Carcinogenicity-Rat LOAEL (mg/kg/day): 16.4, based
on effects observed in the male reproductive organs (testes, epididymides, prostate, seminal vesicles). Cancer (oral, dermal, inhalation) Classification: “Suggestive Evidence of Carcinogenicity ”, based on an increased incidence of Leydig
Cell tumors in males.

Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. NOAEL = no observed 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). PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 19 of 53 Table 4.5.3.b. Summary of Toxicological Doses and Endpoints for Ethaboxam for Use in Occupational
Human Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty/ FQPA Safety
Factors Level of Concern for
Risk Assessment Study and Toxicological Effects

Dermal
Short-Term (1-30 days)
IntermediateTerm (1-6 months) NOAEL =300 mg/kg/day UF A =10X
UF H =10X Occupational LOC for
MOE = 100 28-day dermal toxicity -Rat LOAEL (mg/kg/day): 1000 mg/kg/day, based on decreased body weight (up to 10%) and body weight gains (41%).

Inhalation
Short-Term (1-30 days);
IntermediateTerm (1-6 months) NOAEL 16.3 mg/kg/day

[Inhalation toxicity is
assumed to be equivalent to toxicity via the oral route.] UF A =10X
UF H =10X Occupational LOC for
MOE = 100 13 week –Rat (MRIDs 46387805; 48535644) LOAEL (mg/kg/day): 49.7/58.0 mg/kg/day, based on testicular/epididymal effects in males (abnormal spermatids in the testes, and abnormal spermatogenic cells in the epididymides), lung effects (increased lung weights, congestion, and alveolar septal congestion and focal alveolar hemorrhage). Cancer (oral, dermal, inhalation) Classification: “Suggestive Evidence of Carcinogenicity ”, based on an increased incidence of Leydig
Cell tumors in males.

Note: The Occupational endpoints/PoDs selected are applicable to residential exposures via dermal and inhalation routes; however, residential exposure is not e xpected for the proposed seed treatment use. Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. NOAEL = no observed 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 (intrasp ecies). LOC = level of concern. MOE = Margin of Exposure.

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

Plant metabolism studies were submitted previous ly to support the grap e tolerances (without a US registration), and included studies in grapes , tomatoes and potatoes. These studies were considered to be acceptable, and demonstrated that the majority of the radioactivity was found as parent in both grapes (27 - 63%) and tomatoes ( 29 - 64%), regardless of whether the radiolabel was in the thiazole or thiophe ne portion of the compound. In contrast, very little parent was identified in potato tubers (<3%), with a significant portion of the radioactivity incorporated into carbohydrates such as glucose and starch. The on ly major metabolite identified in plants was LGC-35523, a keto carboxylic acid derivative of thiophene la beled ethaboxam, which the petitioner stated is identical to a photodegradate present in an aqueous photolysis study. LGC-Ethaboxam Human Health Risk Assessment DP No. 396490

Page 20 of 53 35523 accounted for up to 18% of the total radioactive residues in grapes, and up to 4% of the radioactivity in tomato fr uit. Metabolite LGC-35523 was not detected in potatoes.

The propensity for translocation of ethaboxa m residues in/on grapes and tomatoes was investigated by covering branches and/or trusses prior to applicat ions of the test substance.
When the total radioactive resi due (TRR) of covered versus unc overed matrices is compared, approximately 2-13% TRR was translocated into covered tomatoes and 12.3-25.6% TRR was translocated into covered grapes.

Data depicting metabolism of ethaboxam in livestock are not available, nor are they required at this time. Should the petitione r expand their requests for et haboxam to include significant livestock feed items, then a livestock metabolism study will be required.

5.1.2 Summary of Environmental Degradation

Ethaboxam degrades in soil under aerobic/an aerobic conditions to carbon dioxide, nonextractable bound residues, minor metabolite s (LGC-32533, 5.2%; and LGC-32525, 2.5%), and a major metabolite, i.e., 2-thiophene carboxylic acid (13.9%, split between the overlying water and sediment) in anaerobic soil only. No major metabolites were formed under aerobic
conditions.

In laboratory aerobic soil studies , the half-life for ethaboxam ranged from 0.6 – 6.1 days. Under
anaerobic conditions the half-lif e was 108 days. In laboratory aer obic aquatic studies, the total system half-life for ethaboxam ranged from 29-52 days. Ethaboxam is moderately to slightly
mobile as tested in five soils.

Ethaboxam is stable to hydrolysis over the pH range of 4–9 at 20 o C. A water-sediment study demonstrated that ethaboxam rapidly dissipate s from the water phase with a half-life of ≤ 6 days over the initial 7 days, and then the half- life increased to ≤ 29 days for the total system. Ethaboxam degrades under aerobic conditions to carbon dioxide (max 47.2%) bound residues (max 43.3%), and minor metabolites (LGC-32525 (max 2.4%) and LGC-32533 (max 4.9%).

No metabolite accounted for >10% of the anticipated residue in either the water or sediment phase.

5.1.3 Comparison of Metabolic Pathways

Data depicting the metabolism of ethaboxam in ra ts, grapes, potatoes, and tomatoes have been submitted to the Agency. Studies of metabolism in rotational crops and livestock are not required based on the non-food use pattern for the seed treatment uses. The Environmental Fate and Effects Division (EFED) is evaluating the su bmitted data pertaining to environmental fate and environmental degradates. Preliminary informa tion from the fate review is adequate for the purpose of HED’s risk assessment.

In rats dosed with radiolabeled ethaboxam, nearly 100% of the dose was excreted within 48 hours of administration. The primary route of ex cretion was in feces (approximately 70% of theEthaboxam Human Health Risk Assessment DP No. 396490

Page 21 of 53 S N H

O CN O H O administered dose); excretion in urine accounted for up to 30% of the administered dose. In feces, ethaboxam was identified as the major compound, followed by LGC-32801, which was the major compound identified in rat urine (Table 5.1.3). A comparison of low- and high-dose results from the metabolism study indicates that at the high dose (150 mg/kg for 14 days) uptake
of ethaboxam was less than that which occurr ed at the low dose (10 mg/kg for 14 days).

The nature of the residue in plants is ade quately understood based on acceptable metabolism studies conducted on grape, potato, and tomato. For the purposes of this petition, the residue of concern is the parent compound. Generally, ethaboxam was readily metabolized in the studied plants and incorporated into natural products (primarily sugars). Ethaboxam was the major residue component identified in all reviewed pl ant metabolism studies. However, the extent of ethaboxam metabolism varied quantitatively among th e crops tested. In grapes, the metabolite LGC-35523 also comprised a signif icant portion (up to 18%) of th e total radioactive residue (TRR).

Metabolism of ethaboxam appears to be quite differe nt in plants and rats based on the available data. Although in all tested sp ecies the major residue is etha boxam, the primary metabolite in rats, LGC-32801, was not observed in plants. Si milarly, the primary metabolite in grape and tomato, LGC-35523, was not formed during metabolism in the rat.

Table 5.1.3. Tabular Summary of Metabolites and Degradates. Repor ted data are ranges across
all PHIs.

Chemical Name Commodity Percent TRR (ppm) Structure Thiazole Label Thiophene Label

Ethaboxam

N

-(cyano-2- thienylmethyl)-4- ethyl-2- (ethylamino)-5-
thiazolecarboxamide Rat - Feces Low Dose – 10% High Dose – 68% Low Dose – 14% High Dose – 54%

Rat - Urine Not Found Not Found Grape 29-55 (0.16-1.0) 27-52 (0.23-0.82) Tomato 49-64 (0.20-0.85) 58-63 (0.40-0.92)
Potato Not Found 3 (0.001)

LGC-35523

N

-(Cyano-thiophen2-yl-methyl)-
oxalamic acid Rat - Feces N/A Not Found
Rat – Urine N/A Not Found Grape N/A 11-18 (0.17) Tomato N/A 2-4 (0.02-0.05)
Potato N/A Not Found

LGC-32800 2-Amino-4-ethyl-1-
oxo-1H-1l4-
thiazole-5- carboxylic acid (cyano-thiophen-2- yl-methyl)-amide Rat - Feces Not Found Not Found N

S H 2 N CH 2 CH 3

O H N CN

S O Rat – Urine Low Dose – 3 High Dose – 2 Low Dose – 3 High Dose – 2 Grape Not Found Not Found
Tomato Not Found Not Found

Potato Not Found Not Found

LGC-32801

2-[(4-Ethyl-2-ethylamino-thiazol5-yl)-hydroxymethylimino]-2- Rat - Feces Low Dose – 5 High Dose – 2 Low Dose – 5 High Dose – 2

S O

NH 2 N N

S H 3 CH 2 CHN CH 2 CH 3

OH Rat – Urine Low Dose – 10 High Dose – 3 Low Dose – 9 High Dose – 3 Grape Not Found Not Found

Tomato Not Found Not Found S N H

S N

O CH 3 CH 2 NH CN CH 2 CH 3Ethaboxam Human Health Risk Assessment DP No. 396490

Page 22 of 53 Table 5.1.3. Tabular Summary of Metabolites and Degradates. Repor ted data are ranges across
all PHIs.

Chemical Name Commodity Percent TRR (ppm) Structure Thiazole Label Thiophene Labelthiophen-2-ylacetamide Potato Not Found Not Found

LGC-32802

Sulfuric acid mono-{(2-amino-4-ethylthiazol-5-yl)- [(cyano-thiophen-2- yl-methylene)- amino]-methyl}

ester Rat - Feces Low Dose - 11 High Dose - 5 Low Dose - 10 High Dose - 4 N

S H 2 N CH 2 CH

3

O N CN

S HO

3 S Rat – Urine Not Found Not Found Grape Not Found Not Found
Tomato Not Found Not Found

Potato Not Found Not Found

LGC-32803

Sulfuric acid mono- [[(cyano-thiophen-2- yl-methylene)- amino]-(4-ethyl-2-ethylamino-thiazol5-yl)-meth yl] ester Rat - Feces Low Dose - 6 High Dose - 4 Low Dose - 6 High Dose - 4 N

S N H H 3 CH 2 C CH 2 CH 3

O

HO 3 S N CN

S Rat – Urine Not Found Not Found Grape Not Found Not Found

Tomato Not Found Not Found

Potato Not Found Not Found

All studies included separate investigation of radiolabel located in the thiazole ri ng or the thiophene ring. Ranges of residu es found in grape, tomato, and potato are due to decreasi ng residue levels with increasing PHI. Grape : MRID No. 46668301, 46378507; Total Application Rate: 1.12 lb a.i./A (1.25X); 0, 5, 10, 14-day PHIs.
Tomato : MRID No. 46378508; Total Application Rate: 0.535 lb a.i./A; 0, 3, 7, 14, 21-day PHIs.
Potato : MRID No. 46378506; Total Application Rate : 1.1 or 1.2 lb a.i./A; 14-day PHI.
Rat : MRID No. 46378533; dosing level: 10 or 150 mg/kg for 14 days

5.1.4 Residues of Concern Summary and Rationale

The proposed non-food seed treatment uses do not affect HED’s previous conclusions regarding the residues of concern in plants. As not ed above, ethaboxam and LGC-35523 were the only significant residues found in the grape metabo lism study. Although it occurred at a significant portion of the applied radioactivity in grap es, LGC-35523 was not found in the rat metabolism study, thereby making it a potential residue of concern for risk assessment. However, LGC35523 is expected to be significantly less toxic than the parent and to have different toxicity than ethaboxam for the following reasons (see D332 315, M. Doherty, Sept 8, 2006, Attachment 1):

1. LGC-35523 is a very polar compound that is li kely to undergo rapid excretion with very
little biochemical transformation in mammals. It is not likely to enga ge in interactions that might lead to microsomal enzyme i nduction, inhibition of mitochondrial respiration, or endocrine disruption, as the much less polar parent will do.

2. The following 28-day rat dietary studies indica te that LGC-35523 is less toxic than the parent:Ethaboxam Human Health Risk Assessment DP No. 396490

Page 23 of 53  LGC-35523 . In a rat dietary study conducted at levels of 650, 2000 or 13,000 ppm, LGC-35523 had a NOAEL of 2000 ppm a nd a LOAEL of 13,000 ppm (with relatively benign treatme nt-related effects).

 Ethaboxam. In a rat dietary study conducted at levels of 500, 1000, 3000, or 5000 ppm, parent ethaboxam had a NOAEL of 500 ppm and a LOAEL of 1000 ppm attributable to reduced food intake plus toxi city resulting in growth retardation. At higher doses liver and thyroid weights were increased.

EFED conducted a screening-level assessment of potential ethaboxam re sidues in surface and ground water sources of drinking water. This scre ening level assessment, assumes stability, i.e. no degradation, and is an upper bound estimate of likely residues in drinking water resulting from the proposed non-food seed treatment uses.

Table 5.1.4 Summary of Metabolites and De gradates to be included in the Risk Assessment and Tolerance Expression

Matrix Residues included in Risk
Assessment Residues included in Tolerance Expression

Plants Primary Crop Ethaboxam Ethaboxam

Rotational Crop Not Applicable Not Applicable

Livestock Ruminant Not Applicable Not Applicable

Poultry Not Applicable Not Applicable

Drinking Water Total ethaboxam related residues - assuming no degradation Not Applicable

5.2 Food Residue Profile D398681, D. Dotson, 4/30/2013

For the seed treatment uses, the registrant s ubmitted an adequate seed radiotracer study on canola, corn, sorghum, soybeans, and wheat. Canola, corn, sorghum, and wheat seed were treated at a 1x application rate. Soybeans were treated at either a 0.67x or 1x rate. TRR were below 5 ppb in samples of canola, corn co mmodities, sorghum commodities, and wheat commodities (with the exception of one wheat forage sample that had a residue of 6 ppb). In the soybean samples treated at both the 0.67x and 1x ra tes, residues were below 5 ppb in seeds and pods in all samples (both labels). Residues rang ed from <5 ppb to 25 ppb in soybean forage and hay. However, the label contains a feeding rest riction that prohibits the feeding of soybean forage and hay to livestock. Although one wheat forage sample had a residue of 6 ppb, this sample was taken at a 22-day PHI. Grazing of wheat forage doesn’t normally begin until a PHI of 40-60 days. For these reasons, HED has dete rmined that the proposed uses qualify as nonfood uses.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 24 of 53 Valent U.S.A. Corporation submitted adequate field trial data for residues of ethaboxam on soybean seed. Three field trials were conducte d in the United States during the 2010 growing season in NAFTA Growing Zone 5 (Illinois, Miss ouri, and Minnesota). One control plot and two treatment plots were established at each site. The treatment plots were planted with soybean seeds that were treated with a 3.2 lb ai/gal FS formulation of ethaboxam (V-10208 3.2 FS), at a rate of 7.5 g ai/100 kg of seed (0.0075 lb ai/100 lb seed, 0.5x tr eatment plot) and 37.5 g ai/100 kg seed (0.0375 lb ai/100 lb seed, 2.5x treatment plot ). Only samples from the exaggerated rate treatment plot were analyzed. Residues of et haboxam were below the LOD of 5 ppb in/on all samples of soybean seed harvested 109 to 147 DAP , using soybean seed treated at 37.5 g ai/100 kg seed (a 2.5x treatment rate). The label contains a feeding restriction th at prohibits the feeding of forage or hay to livestock. As a result, no field trial data were submitted for forage or hay,
and none are needed.

As a result of the fact that in the radiotrace r study residues were below 5 ppb in edible portions of the crop and there are feeding restrictions on the livestock feed items, the soybean field trial data are considered to be supplemental. For this reason, the three subm itted field trials are considered adequate. Under normal circumstances, 20 trials would be requested for soybeans if quantifiable residues are present in the samples, or 15 trials (a 25% reduction) if no samples contain quantifiable residues.

The proposed seed treatment uses do not affect dietary exposure through food, which comes entirely from the existing tolerances for residue s in grapes. For the dietary assessment, HED
used tolerance level residues and assu med that all grapes are treated.

5.3 Water Residue Profile

There is a potential for drinking water exposure associated with the proposed seed treatment uses. The drinking water residues used in these dietary risk assessments were provided by EFED (memo, A. Shelby, D411925), and incorporated directly into the DEEM-FCIDTM dietary assessments via entry into the food categories “wat er, direct, all sources” a nd “water, indirect, all
sources.”

Estimated drinking water concentrations (E DWCs) for ethaboxam were modeled using conservative assumptions for the proposed seed tr eatment uses. The high est use rate of 0.6 fl oz/100 lb seed is for legume vegetables (crop gr oup 6) of which garden pea has the highest seed rate of 411 lbs seed/A. Given that the produc t is 3.2 lbs active ingr edient per gallon, the maximum application rate is 0.062 lb/A. The water solubility of ethaboxam is 12.4 ppm (at
25 o C). For the purpose of the drinking water scree n, ethaboxam is assumed stable to all routes of metabolism and degradation due to the in-revie w status of the supporting environmental fate data. This is a very conser vative assumption. Ethaboxam EDWC s were modeled with EFED’s Tier 1 surface water model (FIRST) and Tier 1 groundwater model (SCIGR OW) with the results
shown in Table 5.3.

Typically, HED uses the higher of the surface or groundwater estimates for each duration when assessing dietary risk. For ethaboxam, the resu lts from the surface water model are the highest estimates and were used in the dietary assessment. In addition, there is no acute dietaryEthaboxam Human Health Risk Assessment DP No. 396490

Page 25 of 53 endpoint, but HED has incorporated the peak su rface water estimate into the chronic dietary exposure and risk assessment. This assessment is considered to be very conservative, it assumes no degradation, abiotic or biotic, and assumes all th e applied fungicide ends up in drinking water.

The models and their descriptions are availabl e at the EPA internet website via the web link, http://www.epa.gov/oppefed1/models/water/

.

Table 5.3 Summary of Estimated Surface Water and Groundwater Concentrations
for Ethaboxam.

Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b
Peak concentration EDWC = 3.3 ppb EDWC = 0.09 ppb

a From the Tier 1 surface water model (FIRST)

b From the SCI-GROW model.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment D411091, D. McNeilly, April 30, 2013

Very conservative assumptions were made concerning ethaboxam residues in/on food commodities and drinking water. The chronic dietary analysis is based on the tolerance-level residues of 6 ppm for all grape commodities (t he only food commodities in the assessment). Empirical data indicate that residues of et haboxam in processed grape commodities are not expected to exceed the tolerance level for grapes; therefore, no concentration factor was used in the analysis.

The chronic dietary analysis included direct in corporation of estimated ethaboxam residues in drinking water for the proposed non-food, seed treat ment uses. For water, the EFED assumed no degradation, and provided the highes t estimate from conservative models.

5.4.2 Percent Crop Treated Used in Dietary Assessment

HED has assumed 100% of imported grape comm odities (the only food commodities in the assessment) are treated with ethaboxam.

5.4.3 Acute Dietary Risk Assessment

No appropriate endpoint attributable to a single dose was identified.

5.4.4 Chronic Dietary Risk Assessment

Using assumptions considered to be highly protective of human h ealth, the chronic dietary risk estimates associated with the foreign use of ethaboxam on grapes range from approximately 3% of the chronic population-adjusted dose (cPAD; youth 13-19 years old) to approximately 35% ofEthaboxam Human Health Risk Assessment DP No. 396490

Page 26 of 53 the cPAD (children 1-2 years old) . Generally, HED is concerned when dietary risk estimates exceed 100% of the PAD; therefore, the chronic diet ary risk estimates associated with the use of ethaboxam on imported grapes as well as the non -food, seed treatment uses of ethaboxam in/on legume vegetables (crop group 6) except cowpea a nd field pea, cereal grains (crop group 15) except rice and wild rice, and the rapeseed subgroup (20-A) are below HED’s level of concern (LOC) for all population subgroups, incl uding those of infants and children.

5.4.5 Cancer Dietary Risk Assessment

Ethaboxam is classified as having “suggestiv e evidence of carcinogenicity,” and HED has
concluded that assessments usi ng a non-linear approach (e.g., a chronic RfD-based assessment) will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to ethaboxam. Chronic dietary risk estimates are below HED’s level of concern; therefore, potential cancer risk is also below HED’s level of concern.

5.4.6 Summary Table D411091, D. McNeilly, April 30, 2013

Table 5.4.6. Summary of Estimated Dietary (Food + Drinking Water) Exposures
and Risk for Ethaboxam.

Population Subgroup cPAD, mg/kg/day Chronic Estimates

Exposure, mg/kg/day Risk,
% cPAD
U.S. Population

0.055 mg/kg/day 0.003503 6.4 All infants (< 1 year) 0.006954 13 Children 1-2 yrs 1 0.019334 35 Children 3-5 yrs 0.011694 21 Children 6-12 yrs 0.004728 8.6 Youth 13-19 yrs 0.001569 2.9 Adults 20-49 yrs 0.002309 4.2 Adults 50-99 yrs 0.002660 4.8 Females 13-49 yrs 0.002422 4.4
1 The population subgroup with the high est estimated exposure/risk is bolded.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are currently no existing or proposed residential uses associated with ethaboxam. Therefore, an assessment for residential handler and post-application expo sure is not required.

6.1 Spray Drift

A quantitative post-application exposure assessment is not required since there will be no application of pesticides in the fi elds. The seed is previously tr eated with pesticides in a seed treatment facility either on farm or elsewhere. Therefore exposure potential resulting from spray drift is expected to be negligible.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 27 of 53 7.0 Aggregate Exposure/Risk Characterization

As there are no registered or requested residential uses of ethaboxam, aggregate exposure is equivalent to the dietary exposure discussed in Section 5.4.6. All aggreg ate risk estimates are
below HED’s level of concern.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has fo llowed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to ethaboxam and any other substances, and ethaboxam does not appear to produce a toxic metabolite produced by other substances. For the pur poses of this action, therefore, EPA has not
assumed that ethaboxam has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determ ine which chemicals have a common mechanism of toxicity and to evaluate th e cumulative effects of such chem icals, see the policy statements released by EPA’s Office of Pesticide Program s concerning common mechanism determinations and procedures for cumulating effects from s ubstances found to have a common mechanism on EPA’s website at http://www.ep a.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

9.1 Short- and Intermediate-Term Handler Risk D409850, M. Collantes, April 30, 2013

The registrant, Valent, is pr oposing a new use for V-10208 3.2 FS as a commercial and on-farm seed treatment for legumes vegetable seed, ce real grain seed and rapeseed. Although the proposed product is for on-farm use, the label specifies that seed s hould be treated using mechanical, slurry, or mist-type seed treating equipment and not applied in hopper or planter boxes at planting.

Based on the anticipated use patterns and current labeling, as well as the types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses, for both dermal and inhalation rout es. The quantitative exposure/risk assessment developed for occupational handl ers treating seeds with ethab oxam is based on the following
scenarios:

 Mixing, loading, applying liquid formulations for commercially and on-farm treated seeds;

 Multiple activities, and

 Loading and planting treated seed.

Commercial and on-farm exposure was assessed usi ng surrogate data in the absence of chemicalspecific data, which include the Standard Oper ating Procedures (SOPs) for Seed Treatment (Policy 14), “Amount of Seed Treated or Plante d per Day” (Policy 15), and Interim Guidance
“Amount of Commercial Seed Treated Per Day” (Policy 15.1).Ethaboxam Human Health Risk Assessment DP No. 396490

Page 28 of 53 Treatment of the proposed seeds is expected to re sult in short- and intermediate-term exposure. The AHETF survey reports that corn commercial facilities op erate 240 days per year (50 th percentile; range 150 to 270 days), canola commercia l facilities operate 1 80 days per year (50 th percentile: range 90 to 210 days) and 39% of s oybean is treated downstream for a duration of 49 days (50 th percentile; range 4 to 150 days), while s oybean commercial facili ties operate 210 days per year (50 th percentile; range 1 to 270 days). While these durations would be considered to potentially exceed the typical intermediate -term duration used in HED’s occupational assessments, HED had no information to indicate th at the same chemical is used consecutively for a long-term duration. Theref ore, chronic occupational handler exposure for seed treatment was not assessed. Furthermore, the dermal a nd inhalation unit exposure values specified in Policy 14 are based on open-pour systems, whereas the majority of the se ed treatment facilities with large throughputs are equipped with fully or partially automated closed mixing and loading systems. Therefore, HED concluded that a chronic exposure assessment for ethaboxam seed treatment would result in overly cons ervative estimates of exposure.

Note that although both short- and intermediate -term durations of exposure are expected, the endpoints/doses for the respective dermal and i nhalation short- and intermediate-term risk assessments are the same. Therefore, only short-term exposure and risk have been quantitatively assessed, and are c onsidered protective of intermed iate-term exposure and risk.

The Personal Protective Equipment (PPE) statem ent on the proposed label requires applicators
and other handlers to wear the fo llowing: long-sleeved shirt and long pants, socks, shoes, and chemical-resistant gloves. All handler and loader /planter scenarios were assessed using baseline clothing and PPE (i.e., gloves). HED notes that for loader/planter scenarios, the dermal unit exposures reflect the use of glove s for occupational workers loading the seed into the hopper, but not while driving the tractor during planting; this is considered to reflect typical agricultural practices.

Combining Exposures/Risk Estimates:

Dermal and inhalation exposure estimates were not combined since these routes of exposure
result in different toxicities.

Summary of Occupational Handler Non-Cancer Expos ure and Risk Estimates

Occupational handler dermal and inhalation risk estimates are not of concern (LOC = MOE > 100) for all proposed uses assessed. Short-term dermal and inhalation handler (seed treatment) MOEs ranged from 14,000 for dermal exposure resu lting from multiple activities while treating legume vegetables to 410,000 for inhalation expo sure resulting from treating canola. The loader/planter exposure and risk estimates ranged from a dermal MOE of 39,000 for cereal grains to an inha lation MOE of 7.8 x 10 6 for rapeseed. A summary of the handler planter exposure and risk estimates is provided in Tables 9.1 and 9.2.

HED assumes that the commercial seed treatment risk assessment is protective of downstream
seed treatment risk assessments. Downstream treaters do not produce their own seed but obtain cleaned and ready-for-planting pr ocessed seed from other sources such as seed producers, seedEthaboxam Human Health Risk Assessment DP No. 396490

Page 29 of 53 breeders and growers. They include seed and ch emicals dealerships, distributors, retailers and agricultural cooperativ es. Treatment may include custom tr eating of untreated seed or added treatments (i.e. adding fungicide to seed all ready treate d with insecticide) to treated seed. These facilities generally treat smaller batches of seed than the commercial facilities. Therefore, a separate risk assessment is not required for dow nstream facilities which may potentially treat legume seeds. Likewise, commercial seed treatme nt risk assessments are protective of on-farm seed treatment because the equipment is similar, but the on-farm throughput is significantly less, and a separate risk assessment is not required.

9.2 Short- and Intermediate-T erm Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pe sticide (also referred to as reentry exposure). The potential for dermal a nd inhalation post-applica tion exposures following the planting of ethaboxam-treated seeds is unlikel y because sustained levels of contact with treated seed after it has been pl aced in the soil or other planti ng media would not be expected. There is no routine cultural pr actice required for the production of agricultural commodities involving such an activity, as defined in the no /low contact criteria in the Worker Protection Standard (WPS). Therefore, no quantitative post- application assessment is required for exposure to treated seeds that have already been planted. The label states the excep tion to the Agricultural Use Requirements (for seed treatments), and has a restricted entry inte rval (REI) of 12 hours.Ethaboxam Human Health RiskAssessment DP No. 396490Page 30 of 53Table 9.1. Short- and Intermediate-term Occupational Seed-Treatment Handlers Exposure and Risk Estimates for EthaboxamUse SitePPEDermal UnitExposurea(mg/lb ai)InhalationUnitExposurea(mg/lb ai)ApplicationRateb(lb ai/lb seed)AmountTreatedc(lb seed/day)DermalDosed(mg/kg/day)DailyInhalationDosee(mg/kg/day)DermalMOEfInhalationMOEgLoader/ApplicatorLegumeVegetables(surrogate –soybeans)SingleLayer,Gloves0.0230.000340.00015 281,250 0.012 0.000179 25,000 91,000Cereal Grains(surrogate –wheat)0.000065360,000 0.0067 0.000099 45,000 160,000Field Corn0.000075339,500 0.0073 0.00010 41,000 150,000Canola andRapeseed125,000 0.0027 0.000039 110,000 410,000Multiple ActivitiesLegumeVegetables(surrogate –soybeans)SingleLayer,Gloves0.0420.00160.00015 281,250 0.022 0.00084 14,000 19,000Cereal Grains(surrogate –wheat)0.000065 360,000 0.012 0.000468 24,000 35,000Field Corn0.000075339,500 0.0133 0.00050 22,000 32,000Canola andRapeseed125,000 0.0049 0.000187 61,000 87,000a. Unit Exposures are based on Policy 14: Standard Operating Procedures for Seed Treatment.b. Application Rate is based on ProposedLabel for V-10208 3.2 FS (EPA Reg No. 59639-185).c. Amount of Seed Treated isbased on information provided in the HED Interim Guidance SOP 15.1:Amount of Commercial Seed Treated Per Day (November 14, 2012).d. Dermal Dose (mg/kg/day) = (unit exposure (mg/lb ai) × application rate (lb ai/lb seed) × daily amounts treated ÷ body weight (80 kg).e. Inhalation Dose (mg/kg/day) = (unit exposure (mg/lb ai) × application rate (lbai/lb seed) × daily amounts treated ÷ body weight (80 kg).f. Short- term Dermal MOE = NOAEL (300 mg/kg/day) ÷ dermal dose (mg/kg/day).g. Short-term Inhalation MOE = NOAEL (16.3mg/kg/day) ÷ inhalation dose (mg/kg/day).Ethaboxam Human Health RiskAssessment DP No. 396490Page 31 of 53Table 9.2 Handler-Seed Planters Exposure and Risk Estimates for EthaboxamUse SiteMitigationLevelDermalUnitExposurea(mg/lb ai)InhalationUnitExposurea(mg/lb ai)ApplicationRateb(lb ai lbseed)AmountPlantedcDermalDosed(mg/kg/day)DermalMOEeInhalationDosef(mg/kg/day)InhalationMOEgLegumeVegetables(surrogate –soybeans)SingleLayer,Gloves0.250.00340.00015 10,6400.005 60,000 0.00069 240,000CerealGrains(surrogate –wheat)0.000065 37,5000.0076 39,000 0.0001 160,000Field Corn0.0000756,0000.0014 210,000 0.000019 850,000Canola andRapeseed16450.00039 780,000 0.000002 7,800,000a. Unit Exposures are based on Policy 14:Standard Operating Procedures for Seed Treatment. Note: the dermal unit exposure reflects handlers’ exposure resulting fromloading treated seed into hopper while usinggloves, but reflects the driver operatingthe tractor without gloves, and this isconsidered appropriate based on typicalagricultural practices.b. Application Rate is based on proposedlabel for V-10208 3.2 FS (EPA Reg. No. 59639-185).c. Amount planted is based on information provided in the HEDReviewer’s Aid to Calculating Occupational Exposures from Activities Relatedto Agricultural Seed Treatment(November 29, 2012) and the BEAD AcresPlanted per Day and Seeding Rates ofCrops Grown in the United States,Appendix B, Table B-1.d. Dermal Dose (mg/kg/day) = (unit exposure (mg/lb ai) × application rate (lb ai/lb seed) × daily amounts treated / body weight (80 kg).e. Inhalation Dose (mg/kg/day) = (unit exposure (mg/lb ai) × application rate (lbai/lb seed) × daily amounts treated / body weight (80 kg).f. Short- term DermalMOE = NOAEL (300 mg/kg/day)/ dermal dose (mg/kg/day).g. Short-term Inhalation MOE = NOAEL (16.3 mg/kg/day) /inhalation dose (mg/kg/day).Ethaboxam Human Health Risk Assessment DP No. 396490

Page 32 of 53 10.0 References

Ethaboxam. Petition for the Esta blishment of Toleran ces without a U.S. Registration on Grape and its Processed Commodities. Summary of An alytical Chemistry and Residue Data. PP# 4E6863. D313733. M. Doherty. 04/27/06.

Ethaboxam. Request for Seed Treatment Use on Legume Vegetables (Crop Group 6) except Cowpea and Field Pea, Cereal Grains (Crop Group 15) except Rice and Wild Rice, and the Rapeseed Subgroup (20-A). Summary of Analy tical Chemistry and Residue Data. D398681, D. Dotson, 4/30/2013.

Ethaboxam. Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk
Assessments for the Non-food Use of Ethaboxam as a Seed Treatment for Legume Vegetables (Crop Group 6) except Cowpea and Field Pea, Ce real Grains (Crop Group 15) except Rice and Wild Rice, and the Rapeseed Subgro up (20-A). D411091, D. McNeilly, 4/30/2013.

Ethaboxam: Occupational and Residential Expos ure/Risk Assessment of Ethaboxam for Seed Treatment Uses on Legume Vegetables, Cereal Grains (except Rice and Wild Rice) and Rapeseed. D409850; May 2l, 2013.

Ethaboxam Drinking Water Me mo (D411925, 2013), A. Shelby

MRID 46824211. EU Plant Protection Product Dossi er According to 91/414/EEE Annex II/IIIA
– Active Substances Tier 3 Overall Assessment and Conclusions – Document N. September 2003. 82 p.

Standard Operating Procedure (SOP) Policy 14 for Seed Treatment; May 1, 2003.

Interim Guidance for Policy 15: Amount of Comm ercial Seed Treated Per Day (Updated March 21, 2013).

Reviewer’s Aid to Calculating Occupational Exposures from Activities Related to Agricultural Seed Treatment; Revised November 29, 2012.

Attachments:

Appendix A. Toxicology Profile and Executive Summaries Appendix B. Review of Human ResearchEthaboxam Human Health Risk Assessment DP No. 396490

Page 33 of 53 Appendix A. Toxicology Prof ile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use (t olerances on imported commodities only) and non-food uses of ethaboxam are in Appendix Tabl e A.1. Use of the new guideline numbers does not imply that the new (1998) gui deline protocols were used.

Appendix Table A.1. Toxi cology Data Requirements

Test 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 870.3250 90-Day Dermal 870.3465 28/90-Day Inhalation yes
yes
yes

no *no yes
yes
yes

-

- 870.3700a ........... Developmenta l Toxicity (rodent) 870.3700b ........... Developmental Toxicity (nonrodent) 870.3800 ............. Reproduction yes
yes
yes yes
yes
yes

870.4100a ........... Chronic Toxicity (rodent)
870.4100b ........... Chronic Toxi city (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 870.5375 ............. Mutagenicity—Structu ral Chromosomal Aberrations 870.5395 ............. Mutagenicity—Erythro cyte Micronucleus-mammalian 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 Developmental Neurotoxicity no

no
yes
yes

no -

- yes
yes

- 870.7485 ............. General Metabolism
870.7600 ............. Dermal Penetration
870.7600 ............. Immunotoxicity yes

no

yes yes
yes

yes

*The Hazard Science Policy Coun cil (HASPOC) concluded (TXR# 0056543) that a s ubchronic inhalation study is not needed for

ethaboxam at this time.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 34 of 53 A.2. Toxicity Profile Tables for Ethaboxam

Table A.2.a Acute Toxicity Profile for Ethaboxam
Guideline
Number Study Type
Classification MRID
Number Results Toxicity Category

870.1100 Acute-oral 46378518 LD 50 Males and females > 5,000 mg/kg

LD 50 Combined > 5,000 mg/kg IV

870.1200 Acute-dermal 48535632 LD 50 Males and females > 5,000 mg/kg IV

870.1300 Acute-inhalation 48535633 LC 50 Males and females> 4.89 mg/L IV

870.2400 Acute-eye
irritation-rabbit 48535634 No corneal involvement or iritis observed. No positive conjuctival irritation in 1/3 rabbits at 24 hrs. (a score of 1 for redness) All irritation cleared by 48
hours. IV

870.2500 Acute-dermal
irritation-rabbit 48535635 Not a dermal irritant IV

870.2600 Skin sensitization - guinea pig 48535636 Not a skin sensitizer Negative

Table A.2.b. Subchronic, Chronic and Oth er Toxicity Studies Ethaboxam Technical

Guideline/

Type of Study Study Title/

Classification /Doses MRID Results

870.3100

28-day study in rats

(metabolite) ppm = 0, 650, 2000,
13000 mg/kg/day = M: 0, 56.5, 170.9,
or1104.1

F: 0, 56.5, 70.7, or
1155.8

Acceptable/nonguideline 48535691 The NOAEL=13000 ppm (1104/ 1156 mg/kg/day).

LOAEL is not determined.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 35 of 53 Table A.2.b. Subchronic, Chronic and Oth er Toxicity Studies Ethaboxam Technical

Guideline/

Type of Study Study Title/

Classification /Doses MRID Results

870.3100 (2003)

13 WEEK FEEDINGRAT ppm = 0, 200, 650, 2000 mg/kg/day = M: 0, 16.3, 49.7, 154

F: 0, 17.9, 58, 164 Acceptable/Guideline 48535644
46387805 The NOAEL is 200 ppm (equivalent to 16.3 and 17.9 mg/kg bw/day in males and females, respectively).

The LOAEL is 650 ppm (equivalent to 49.7 and 58.0 mg/kg bw/day in males and females, respectively), based on decreased mean absolute epididymides weight in males with correlating histopathology, increased incidence of abnormal spermatids in occasional tubules of the testes in males, and lung effects (increased lung weights, congestion, and alveolar septal congestion and focal alveolar hemorrhage). At 2000 ppm (154/164 mg/kg/day), decreased body weight (up to 21%)/body weight gain in both sexes, decreased testicular and prostate weight, testicular atrophy and interstitial hyperplasia, abnormal sp ermatids/absent sperm.
Adrenal vacuolation in females.

870.3100 (2002)

13 WEEK FEEDINGMOUSE ppm = 0, 200, 450, 1000 mg/kg/day = M: 0, 33, 74, 163, 405 F: 0, 41, 93, 195, 483
Acceptable/Guideline 46387802 NOAEL =450/483 mg/kg/day

LOAEL is not determined

870.3150 (2001)

13 WEEK FEEDINGDOG mg/kg/day = 0, 15, 40, 100
Acceptable/Guideline 46387803 NOAEL =15 mg/kg/day

LOAEL= 40 mg/kg/day, based on decreased body weight (14%) and body weight gain (48%) seen in females.
At 100 mg/kg/day, decreased body weight (15%) and body weight gain (59%) in females, decreased thymus weights, and thymus atrophy/involution, and hematopoiesis of the spleen observed.

870.3200

28-day dermal toxicity
in rats mg/kg/day =

0, 100, 300, or 1000

Acceptable/Nonguideline 48535645 NOAEL = 300 mg/kg/day

LOAEL=1000 mg/kg/day, based on decreased body weight (up to 10%) and body weight gains (41%).

At 300 mg/kg/day, dermal irritation in the form of hyperkeratosis, scabbing, and dermal inflammation at the application site was also
observed.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 36 of 53 Table A.2.b. Subchronic, Chronic and Oth er Toxicity Studies Ethaboxam Technical

Guideline/

Type of Study Study Title/

Classification /Doses MRID Results

870.3700 (1997)

DEVELOPMENTAL
TOXICITY-RAT mg/kg/day = 0, 10, 30, 100, 300
Acceptable/guideline

mg/kg/day = 0, 100, 300, 1000
Acceptable/guideline 46387808

46488701 First study Maternal: NOAEL = 300 mg/kg/day
Maternal LOAEL is not determined.

Developmental: NOAEL= 300 mg/kg/day Developmental LOAEL is not determined Second study Maternal: NOAEL = 100 mg/kg/day Maternal LOAEL = 300 mg/kg/day, based on increased salivation. At 1000 mg/kg/day, salivation and decreased body weight (15%) and body weight gain (37-72%) were observed.

Developmental: NOAEL= 300 mg/kg/day Developmental LOAEL = 1000 mg/kg/day, based on thin diaphragm with liver protrusion (6 fetuses/4 litters), decreased fetal body weight (21%), misshapen pituitary (6 fetuses/2 litters), diaphragmatic hernia (7 fetuses/4 litters), and skeletal anomalies (inc omplete or irregular ossification of the pelvic girdle, digits, sternebrae, and thoracic vertebral centra).

870.3700 (1997)

DEVELOPMENTAL
TOXICITY-RABBIT mg/kg/day = 0, 25, 75, 125

Acceptable/Guideline 46490401 Maternal NOAEL= 75 LOAEL = 125 mg/kg/day, based on inappetence (2 animals sacrificed), decreased food consumption (70%), and body weight loss (-73g vs. -16 controls).

Developmental NOAEL= 125 mg/kg/day
LOAEL is not determinedEthaboxam Human Health Risk Assessment DP No. 396490

Page 37 of 53 Table A.2.b. Subchronic, Chronic and Oth er Toxicity Studies Ethaboxam Technical

Guideline/

Type of Study Study Title/

Classification /Doses MRID Results

870.3800 (2002)

2-GENERATION
REPRODUCTIONRAT ppm = 0, 65, 200, 650

mg/kg/day = M: 0, 5.2, 16.2, 52.6 F: 0, 5.7, 17.6, 56.1

Acceptable/Guideline 46387804 Parental: NOAEL=16.2/17.6 mg/kg/day. LOAEL = 52.6/56.1mg/kg/day, based on decreased premating body weight gain
of the F 0 and F 1 generation adult males (10.5- 22% and 10.7-14.5%, re spectively), decreased premating body weight of the F 1 adult males and females (10.3-17.45 and 7-12.9%, respectively).

Reproductive : NOAEL (mg/kg/day) M: 16.2, F: 56.1 LOAEL (mg/kg/day): M: 52.6, based on small epididymides and testes, abnormal sperma togenic cells in the epididymal ducts, impaired sperm mobility, abnormal sperm, and reduced fertility in males.

Offspring : NOAEL (mg/kg/day)
M/F: 16.2/17.6 LOAEL (mg/kg/day): M/F: 52.6/56.1, based on decreased body weight in male and female F 1 pups (13.1- 15.7%), and decreased viability of the F 1 (14%)
and F 2 (17%) males during lactation. Delay in
sexual maturation.

870.4300 (2002)

104 WEEK
COMBINED
CHRONIC
TOXICITY/CARCINO
GENICITY-RAT ppm = 0, 100, 300, 650

mg/kg/day = M: 0, 5.5, 16.4, 35.8 F: 0, 7, 21, 45.5
Acceptable/Guideline 46387811 NOAEL = 5.5/7 mg/kg/day

LOAEL = 16.4/21 mg/kg/day:
based on adverse effects seen in the male reproductive organs, d ecreased epididymal weight, seminiferous tubule atrophy, abnormal spermatogenic cells in epididymal duct, absent

sperm.

At 35.8/45.5 mg/kg/day adverse effects seen in the male reproductive organs, decreased epididymal and seminal vesicle weight, seminiferous tubule atrophy, small/flaccid testes and epididymides, abnormal spermatogenic cells in epididymal duct, absent sperm, epididymal vacuolation, and reduced colloid in the prostate. Decreased body weight (12%) seen in females.

Evidence of carcinogenicity Interstitial/Leydig cell adenoma at the highest dose tested (35.8/45.5 mg/kg/day)Ethaboxam Human Health Risk Assessment DP No. 396490

Page 38 of 53 Table A.2.b. Subchronic, Chronic and Oth er Toxicity Studies Ethaboxam Technical

Guideline/

Type of Study Study Title/

Classification /Doses MRID Results

870.4100 (2001)

52 WEEK FEEDINGDOG mg/kg/day = 0, 5, 10, 30
Acceptable/Nonguideline 46387809 NOAEL =30 mg/kg/day
LOAEL is not determined

870.4200 (2003)

52 WEEK
CARCINOGENICITYMICE ppm = 0, 100, 300, 900

mg/kg/day = M: 0, 12, 35, 117 F: 0, 14, 44, 135
Acceptable/Guideline 46235628 NOAEL= 35/44mg/kg/day

LOAEL = 117/135mg/kg/day): based on decreased body weight (9%), body weight gain (20%) and food efficiency (16- 19%) in both sexes, and liver toxicity in males.

No evidence of carcinogenicity

870.5100 (2004)

BACTERIAL
REVERSE
MUTATION ASSAY Acceptable/Guid eline 46378529 Negative

870.5300 (2001)

IN VITRO
MAMMALIAN CELL
GENE MUTATION
TEST Acceptable/Guid eline 46378530 Negative

870.5375 (2001)

- IN VITRO
MAMMALIAN CELL
CHROMOSOME
ABERRATION TEST Unacceptable/Guideline 46378531 Induced significant incr eases in chromosome
aberrations and a marked increase in the mitotic index at a concentration of 250 μg/mL (-S9) after a 3 hour exposure and at 100 μg/mL after 19 hours of continuous exposure.

870.5550 (2006)

In Vitro Micronucleus
Test in Cultured Human Lymphocytes 0, 25, 50, 75, 100, 125, 150, 175, 200, 250, 500,

800 or 1000  g/mL

Acceptable/Guideline 46989601 Induced a positive and significant (p< 0.01 - 0.001) response in the absence of S9 activation in lymphocytes stimulated with PHA for 24
hours.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 39 of 53 Table A.2.b. Subchronic, Chronic and Oth er Toxicity Studies Ethaboxam Technical

Guideline/

Type of Study Study Title/

Classification /Doses MRID Results

870.5395 (2001)

MAMMALIAN
ERYTHROCYTE
MICRONUCLEUS TEST (XDE-750) Acceptable/Guid eline 46378532 Negative

870.6200 (2011)

Acute Neurotoxicity in

Rats mg/kg/day=0, 300, 1000,
or 2000

Acceptable/guideline 48535643 The NOAEL is 2000 mg/kg/bw and the
LOAEL is not determined.

870.6200 (2009)

Subchronic Neurotoxicity in Rats ppm=250, 600, or 1,500

mg/kg/day=0, 18.0/21.0, 43.0/50.0, 106.0/122.0 mg/kg bw/day [M/F],

Acceptable/guideline 48535646 The NOAEL = 600 ppm (43/50 mg/kg/day)

LOAEL is 1,500 ppm (122 mg/kg body weight/day), based on reduction in body weights (9-12%), body weight gains and food consumption in males.

870.7485 (2003)

METABOLISM AND
PHARMOKINETICSRAT Thiazole or Thiophene
radiolabeled

mg/kg/day =
Low dose: 10 High dose: 150

Thiazole radiolabeled

Mg/kg/day = 10 Daily for 14 days

Acceptable/Guideline 46378533 Excretion-Majority of the radiolabeled compound was excreted in the feces or urine within 48 hours of administration, regardless of radiolabel, dose, or sex. For both radiolabels, fecal and urinary excre tion combined accounted
for 96-104% of the ad ministered dose. The main route of excretion was feces (66-74% of single or repeated administered low-dose), followed by urine (23-30% of the administered low-dose).

870.7600 (2003)

Dermal Penetration in

Rats 2 μg/cm 2 or 1 mg/cm 2

skin for 6 hrs

Acceptable/Guideline 48535712 Total absorption (absorbed and absorbable dose) was 7.5% after 6 hours

870.7800 (2011)

Immunotoxicity in Rats ppm=0, 250, 650, or
1500

mg/kg/day=0, 21, 52, or 121 mg/kg/day

Acceptable/Guideline 48535688

48535655 The systemic toxicity NOAEL = 250 ppm (equivalent to 21 mg/kg/day).

LOAEL is 650 ppm (equivalent to 52 mg/kg/day) based on reduced body weight gain (19%) and food consumption. At 1500 ppm (121 mg/kg/day), reduced body weight gain (42%) and food consumption were seen. The NOAEL for immunotoxicity was 1500 ppm (equivalent to 121 mg/kg bw/day), the highest dose tested; the LOAEL for immunotoxicity was not established.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 40 of 53 A.3. Hazard Identification and Endpoint Selection

Although residential endpoints/PoDs for incidental oral, dermal, and inhalation exposures have been selected, only dietary and occupational expo sure is expected with the registered and proposed uses.

Acute Reference Dose (aRfD) - Gen eral Population and Females age 13-49

Acute reference doses for the general population a nd females, 13-49 have not been established. There were no appropriate studies th at demonstrated evidence of t oxicity attributable to a single dose for these populations. The effects observed in the reproduction study were considered for acute dietary exposure (females 13-49) based on delays in sexual maturation (preputial separation and vaginal opening) observed at the LOAEL of 52.6 mg/kg/day. However, the delays were mild (2.4 and 2.1 days) and within normal biological variab ility (± 2 days). Therefore, the endpoint in the absence of other potential acut e effects was not considered appropriate for risk assessment.

Chronic Reference Dose (cRfD)

Study Selected: Combined Chronic/Carcinogenicity -Rat
MRID No: 46387811 Dose and Endpoint for Risk Assessment : NOAEL= 5.5 mg/kg/day

Uncertainty Factor: 100x (10x interspecies ex trapolation, 10x intraspeci es variability, 1x FQPA Safety Factor)

Study/Endpoint/Uncertainty Factors: A combined chronic/carcinogenicity study in rats was
selected to establish the cR fD of 0.055 mg/kg/day. The NO AEL of 5.5 mg/kg/day and the LOAEL of 16.4 mg/kg/day were ba sed on effects observed on the male reproductive organs.
The NOAEL in the rat is the lowest dose in the toxicity database for chronic durations. The chronic rat study is therefore cons idered to be the most appropri ate for chronic dietary dose and endpoint selection. It is also protective of the Leydig cell tumors observed in rats at a higher dose (35.8 mg/kg/day), effects in the chroni c mouse study (117 mg/kg/day) and systemic, reproductive, and offspring effects seen in th e reproduction study (56.1 mg/ kg/day). No effects were seen in the chronic dog study up to the high dose of 30 mg/kg/day.

Chronic RfD = ) UF ( 100 mg/kg/day 5

. 5 = 0.055 mg/kg/day

Occupational Dermal Exposure (Short- and Intermediate-Term)

Study Selected: 28-day Dermal -Rat
MRID No: 48535645 Dose and Endpoint for Risk Assessment : NOAEL= 300 mg/kg/day

Uncertainty Factor: 100x (10x interspecies ex trapolation, 10x intraspeci es variability, 1x FQPA Safety Factor)Ethaboxam Human Health Risk Assessment DP No. 396490

Page 41 of 53 Study/Endpoint/Uncertainty Factors: The 28-day dermal toxicity study in the rat was selected for risk assessment. The NOAEL of 300 mg/ kg/day was based on decreased body weight and body weight gains observed at the LOAEL of 1000 mg/kg/day. Male reproductive effects (abnormal spermatids in the testes , and abnormal spermatogenic cells in the epididymides) and lung effects (increased lung we ights, congestion, and alveolar septal congestion and focal alveolar hemorrhage) were seen in a 13-week oral study with a lo wer point of departure (PoD). However, these effects were adequately measur ed in the 28 day dermal toxicity study, and no reproductive or lung effects were seen. Additiona lly, the dermal equivalent dose for the 13 week oral study, based on the LOAEL of 49.7 mg/kg/day and a 7.5% de rmal absorption factor, is 663mg/kg/day. Therefore, the NOAEL of 300 mg/kg/day is protec tive of effects seen in the study. Furthermore, there is no concern for quan titative susceptib ility. The study is appropriate for both the route and duration of exposure.

Occupational Inhalation Exposure (Short- and Intermediate -Term)

Study Selected: 13 Week Toxicity -Rat
MRID No: 46387805; 48535644 Dose and Endpoint for Risk Assessment : NOAEL= 16.3

Uncertainty Factor: 100x (10x interspecies ex trapolation, 10x intraspeci es variability, 1x FQPA Safety Factor) Inhalation absorption: 100%

Study/Endpoint/Uncertainty Factors: The 13 week rat study was selected for risk assessment. The NOAEL of 16 mg/kg/day was based on male reproductive and lung effects observed at the LOAEL of 49.7mg/kg/day. Unlike dermal exposure, a route-specific study is not available to confirm whether male reproductive or lung e ffects are observed after inhalation exposure. Therefore, to protect for these effects, the oral 13-week study in rats was selected for both shortand intermediate-term inhalation exposure. The 13 week dog study with a similar NOAEL was also considered; however, the rat was a more appr opriate choice since effects in the study were seen in the target organ. Additionally, the PoD in the rat is protective of effects seen in the dog study, as well as effects observed in developmen tal/reproduction studies. For risk assessment, inhalation toxicity was assumed to be equivalent to toxic ity via the oral route.

FOR FUTURE USES (NOT FOR CURRENT RISK ASSESSMENT)

Incidental Oral (Short-Term)

Study Selected: 2-Generation Reproduction Study in Rats
MRID No.: 46387804 Dose and Endpoint for Risk Assessment : Offspring NOAEL = 16.2 mg/kg/day. Offspring LOAEL = 52.6 mg/kg/day Uncertainty Factor: 100x (10x interspecies ex trapolation, 10x intraspeci es variability, 1x FQPA Safety Factor). Study/Endpoint/Uncertainty Factors: The 2-generation reproduction study was selected for the incidental oral endpoint. The study is appr opriate for the population of concern (children). The dose/endpoint is also protectiv e of effects seen in the 13 week rat and developmental studies. Based on the current use pattern, there is no concern for incidental oral.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 42 of 53 Residential Dermal/Inhalation Exposu re (Short-Term-Intermediate-Term)

The Occupational endpoints/P oDs selected are appli cable to residential ex posures via dermal and inhalation routes; however , residential exposure is not expect ed for the proposed seed treatment

use.

Occupational/ Residential D ermal Exposure (Long-Term)

Study Selected: Combined Chronic/Carcinogenicity -Rat
MRID No: 46387811 Dose and Endpoint for Risk Assessment : NOAEL= 5.5 mg/kg/day

Uncertainty Factor: 100x (10x interspecies ex trapolation, 10x intraspeci es variability, 1x FQPA Safety Factor) Dermal absorption factor (DAF): 7.5%

Study/Endpoint/Uncertainty Factors: A combined chronic/carcinogenicity study in rats was
selected for risk assessment. The NOAEL of 5.5 mg/kg/day and the L OAEL of 16.4 mg/kg/day were based on effects observed on the male reproductive organs.

The dermal toxicity study in rats was also cons idered for risk assessment. However, since the dermal study was only conducted for 28 days it was considered appropriate for short-and intermediate-term dermal exposure only. Theref ore, the combined chronic/carcinogenicity study in rats with male reproductive effects was select ed for long-term dermal exposure. The study is also protective of the Leydig cell tumors observe d in the rat at a higher dose (35.8 mg/kg/day), the effects seen in the chronic mouse study ( 117 mg/kg/day) and system ic, reproductive, and offspring effects seen in the re production study (56.1 mg/kg/day). No effects were seen in the chronic dog study up to the high dose of 30 mg/kg/day. Since an oral toxicity study was used for dermal exposure, a dermal absorp tion factor of 7.5% was used.

Occupational/Residential Inha lation Exposure (Long-Term)

Study Selected: Combined Chronic/Carcinogenicity -Rat
MRID No: 46387811 Dose and Endpoint for Risk Assessment : NOAEL= 5.5 mg/kg/day

Uncertainty Factor: 100x (10x interspecies ex trapolation, 10x intraspeci es variability, 1x FQPA Safety Factor) Inhalation Absorption: 100%

Study/Endpoint/Uncertainty Factors: A combined chronic/carcinogenicity study in rats was
selected for risk assessment. The NOAEL of 5.5 mg/kg/day and the L OAEL of 16.4 mg/kg/day were based on effects observed on the male repr oductive organs. This study is appropriate for the population of concern and the exposure durati on. In the rat study, reproductive effects, as well as lung effects were seen in the male re productive organs the (target for ethaboxam). The study is also protective of the Leydig cell tumo rs observed in the rat at a higher dose (35.8 mg/kg/day), the effects seen in the chronic mouse study ( 117 mg/kg/day) and systemic, reproductive, and offspring effects seen in th e reproduction study (56.1 mg/ kg/day). No effects were seen in the chronic dog study up to the high dose of 30 mg/kg/day.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 43 of 53 A.4 EXECUTIVE SUMMARIES FOR NEW AND REVISED TOXICOLOGY
STUDIES

28 DAY Oral Subchronic Toxicity St udy (Metabolite)-Rat; OPPTS 870.3100

EXECUTIVE SUMMARY : In a 28-day oral toxici ty study (MRID 48535691) ethaboxam metabolite, LGC-35523 (92.6% a.i., Batch #PO30325) was administered to Crl:CD (SD)IGS BR rats (10/sex/dose) in the di et at dose levels of 0, 650, 2000, or 13000 ppm (equivalent to 0, 56.5, 170.9, or1104.1 mg/kg/dayin males; 0, 56.5, 70.7, or 1155.8 mg/kg/day in females).

There were no treatment-related effects on morta lity, clinical signs, orga n weights, or gross pathology. Histopathology was not ev aluated. A statistically signifi cant decrease in mean body weight gain was seen in male s in the 13000 ppm group; overall mean food efficiency in this group was reduced 12% (not statistically evalua ted). Both sexes in the 13000 ppm group had a significantly increased blood albumin level. Ma les in the 13000 ppm group had a significantly decreased mean corpuscular volume (MCV); in the absence of ot her hematological changes, the decreased MCV count in males is unlikely to be treatment-related. Minor hematology and blood chemistry changes were recorded for animal s receiving 13000 ppm. Females in the 13000 ppm group showed increases in mean total white bl ood cell, lymphocyte, monocyte, basophil, and large unstained cell counts, and in blood cholestero l levels. However, the changes in hematology were considered minor. Significant increases in mean motor activity (low and/or high beam)
scores were observed at one or more time point in all male treatment groups; mean total low beam scores were significantly increased for all treatment groups. In the absence of a clear doseresponse relationship, the findings for motor activity were not considered to be treatment-related.

The NOAEL is 13000 ppm (equivalent to 1104 mg/kg/day for males, 1156 mg/kg/day for females) and the LOAEL is not determined.

This 28-day oral toxic ity study in the rat is Acceptable/Non-Guideline and is appropriate for range-finding purposes.

90 DAY Oral Subchronic Toxicity Study-Rat; OPPTS 870.3100

EXECUTIVE SUMMARY : In a 90-day oral toxici ty study (MRID 48535644) LGC-30473 (Ethaboxam, 99.2% a.i., Batch # 6-1) was administered to Crl: CD BR rats (10/sex/dose) in the diet at dose levels of 0, 200, 650, or 2000 ppm (e quivalent to 0, 16.3, 49.7, or 154 mg/kg/day in males; 0, 17.9, 58.0, or 164 mg/kg/day in females).

There were no treatment-related effects on morta lity. At 200 ppm, there we re a few statistically significant effects on hematology a nd clinical chemistry parameters ; in the absence of correlating pathology, the toxicological si gnificance of these findings is questionable. At 650 ppm,
treatment-related effects were observed in the male reproductive organs. These included decreased mean absolute epididymides weight with correlating histopathology (increased incidence of abnormal spermatogenic cells in du cts), and an increased incidence of abnormal spermatids in occasional tubules of the testes. Decreased body weight gain and increased liver weights were seen at 650 ppm; however, ther e were no effects on absolute body weight and no corresponding liver histopathology. A few statis tically significant changes in hematology and clinical chemistry parameters, of questionable toxicological signifi cance, were also noted in both sexes at 650 ppm. At 2000ppm, decreased me an absolute body weight in both sexes (up toEthaboxam Human Health Risk Assessment DP No. 396490

Page 44 of 53 21%) , a statistically significant decreased in mean body weight ga in in both sexes (Weeks 0-13), decreased total food consumption in males, in creased mean adjusted liver weights with a correlating increase in trace centrilobular hepato cyte hypertrophy in both sexes, an increased
incidence of fine vacuolation of the zona glomerulosa in the adrena ls in females, decreased mean absolute or adjusted testes we ight with correlating severe te sticular atrophy (all animals),
increased incidence of trace-mini mal interstitial cell hyperplasia of the testes, decreased mean absolute prostate weight, and decreased mean ab solute epididymides weight with a correlating absence of spermatozoa (all animals) and increas ed incidence of abnormal spermatogenic cells in occasional ducts. Changes in hematological and c linical chemistry parameters also were found in both sexes at 2000 ppm, some of which (e.g., in creased alkaline phosphatase and cholesterol levels in both sexes) may have been related to altered hepatic function. An increased incidence of non-specific hair loss also was obs erved in females at 2000 ppm.

The LOAEL is 650 ppm (equivalent to 49.7 a nd 58.0 mg/kg/day in males and females, respectively), based on decreased mean absolu te epididymides weight in males with correlating histopathology, increased incidence of abnormal spermatids in occasional tubules of the testes in males, and lung e ffects (increased lung weights, congestion, and alveolar septal congestion and focal al veolar hemorrhage). The NOAEL is 200 ppm (equivalent to 16.3 and 17.9 mg/kg/day in males and females, respectively).

This 90-day oral toxic ity study in the rat is Acceptable/Guideline and satisfies the guideline requirement for a 90-day or al toxicity study (OPPTS 870.3100; OECD 408) in rats.

90 DAY Subchronic Toxicity Study-DOG; OPPTS 870.3150

EXECUTIVE SUMMARY : In a 90-day oral toxicity study (MRID 46387803), Ethaboxam (LGC-30473, 98% a.i.) was administered to four beagle dogs/sex/dose in a capsule daily at concentrations of 0, 15, 40, or 100 mg/kg/day.

There were no differences between the cont rols and treated groups in food and water consumption, ophthalmology, and urinalysis paramete rs that were considered toxicologically significant. There were thr ee premature sacrifices (40 a nd 100 mg/kg/day groups) done for humane reasons, one male dog had meningitis an d two females suffered from an anemic condition at necropsy. There were no clinical signs of toxicity noted for the surviving beagle dogs.

Treated dogs showed increases in absolute and relative (adjus ted for body weight) liver weights in the 40 and 100 mg/kg/day groups of both sexes. These changes were associated with the microscopic finding of hepatocyte hypertrophy. A slight involution/atrophy of the thymus and extramedullary hematopoiesis in the spleen we re detected in one dog of each sex in the 100 mg/kg/day group and one female in the 40 mg/kg/day group.

At termination, the treated male dogs had body wei ghts comparable with controls. However, the body weight gains were decrease d and ranged from 78 to 81% of the control in the 40 and 100 mg/kg/day groups. The body weights for female s in the 40 and 100 mg/kg/day groups were decreased to 87 and 83% of control, respectivel y, starting at Week 6 and remained similarly decreased through the remainder of the study and was 90% of control in the 15 mg/kg/day group at Week 13. The body weight decrease at 15 mg/kg/ day is not considered treatment related since animals at this dose started out weighing less th an other dose groups. The body weight gain ofEthaboxam Human Health Risk Assessment DP No. 396490

Page 45 of 53 the females was reduced in all groups (62%, 52% and 41% of control levels in the 15, 40, and 100 mg/kg/day groups, respectively).

The LOAEL is 40 mg/kg/day based on reduced body weight (14%) and body weight gain (48%) in females. The NOAEL is 15 mg/kg/day.

The 90-day oral toxic ity study in dogs is Acceptable/Guideline and satisfies the guideline requirement (OPPTS 870.3150; OECD 409) for a 90-day oral toxic ity study in dogs.

DERMAL TOXICITY STUDY-RAT; 870.3200

EXECUTIVE SUMMARY : In a 28-day dermal toxicity study (MRID48535645), Ethaboxam 97.5% a.i, (batch no.: 4-1) was applied to the shav ed skin of 5 rats of the Sprague-Dawley [(Crl: CD) BR VAF PLUS strain]/sex/dose at dos e levels of 0, 100, 300, or 1000 mg/kg/day, 6 hours/day for 5 days/week during a 28-day period.

There were no compound related effects on mortalit y, clinical signs, chemis try, or organ weights.
Food intake was variable in both sexes but not co nsidered toxicologically significant. There were shortened APTT values in 2 females at 1000 mg/ kg/day, but the changes were not accompanied by changes in hematology or histopathology. Ther e was dermal irritation reported at 300 and 1000 mg/kg/day in males and delineated by micr oscopic examination. There were decreased body weights and body weight gains in males at 1000 mg/kg/day.

The systemic toxicity LOAEL is 1000 mg/kg/d ay in male rats, based on decreasing body weight and weight gains without a signific ant loss of food intake. The NOAEL is 300 mg/kg/day.

The LOAEL for dermal irritation is 300 mg/kg/d ay in male rats based on histopathological changes of epithelial hyperplasia, hyperkeratosi s, scabbing and dermal inflammation. The NOAEL is 100 mg/kg/day.

This 28-day dermal toxicity study in the rat is Acceptable/Non-Guideline and satisfies the guideline requirement for a 28-day dermal toxi city study (OPPTS 870. 3200; OECD 410) in rat. This study was completed earlier than the 1998 guidelines and used only 5 animals per sex per dose while the guidelines now call for the use of 10 per sex per dose.

Developmental Toxicity Study-Rat; OPPTS 870.3700

EXECUTIVE SUMMARY : In a developmental toxicity study (MRID 46387808), Ethaboxam (LGC-30473, 97.5% a.i.) was administered to 25 female Crl:CD® BR VAF/Plus rats/dose by oral gavage at dose levels of 0, 10, 30, 100, or 300 mg/kg/day from gestation day (GD) 6 through 19, inclusive. The vehicle was 1% methylcellulo se. On GD 20, all females were killed by CO 2 asphyxiation and subjected to macroscopic post mortem examination. Half of the fetuses in each litter were preserved in Bouin’s solution for subsequent free-hand sectioning to discover visceral abnormalities; the remainder were fixed a nd stained for skeletal examination.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 46 of 53 Fur loss/alopecia was observed on seven animal s at 100 mg/kg/day and eight animals at 300 mg/kg/day compared with one control animal. Absolute body weight was similar between the treated and control groups throughout the study. Treatment at 300 mg/kg/day was associated with transient reductions in maternal body weight gain (GD 6-8: contro l: 9.2 g; 300 mg/kg/day: 4.1 g; GD 6-12: control: 41.3 g; 300 mg/kg/day: 35.3 g) and food inta ke (91% of control for GD 6-7). Increased water consumption was observed for all treated groups.

The maternal NOAEL is 300 mg/kg/day and the maternal LOAEL is not determined.

The number of fetuses (litte rs) examined was 232 (18), 311( 24), 268(23), 272(24), and 287(23) in the 0, 10, 30, 100, and 300 mg/kg/day groups, respec tively. Pre-implantation loss for the 100- and 300-mg/kg/day groups was significantly greate r than that of the control (13.5% and 11.6%, respectively, compared to 7.9% for the contro ls), but no effects were observed on the mean number of implantations or mean number of live fe tuses. The distribution of dams showing total resorption (1 control and 2 at 30 mg/kg/day) di d not suggest a relationship to treatment. The fetal sex ratio was unaffected by treatment. Fe tal body weight was similar between the treated and control groups.

No treatment-related external or skeletal malfor mations/variations were observed. The incidence of litters containing fetuses with abnormal liver lobation was higher than that of the control group at 100 and 300 mg/kg/day. The number of fe tuses (litters) with ab normal liver lobation was 2(2), 3(2), 2(2), 4(4), and 7(5), in the 0, 10, 30, 100, and 300 mg/kg/day groups, respectively. However, the abnormal liver loba tion was within the hist orical control range.
Increased incidences of abnormal liver lobation were also seen in another developmental study (MRID 46488701) at 100, 300, and 1000 mg/kg/day. These incidences were also within historical control range. Thin diaphragm with liver protrusion was also observed in the second developmental study at1000 mg/kg /day.

The developmental toxicity NOAEL is 300 mg /kg/day and the developmental toxicity
LOAEL is not determined.

The developmental toxicity st udy in the rat is classified Acceptable/Guideline and satisfies the guideline requirements (OPPTS 870.3700; OECD 414) for a developmental toxicity study in the

rat.

EXECUTIVE SUMMARY : In a developmental toxic ity study (MRID 46488701) LGC-30473 (97.5% a.i., batch 4-1) was administered to 25 time-mated Crl:CD® BR VAF/Plus rats/dose by oral gavage at dose levels of 0, 100, 300 or 1000 mg/kg/day from GD 6-19, inclusive. On GD 20, all dams were killed by CO 2 asphyxiation and subjected to macroscopic post mortem examination. The following observations were r ecorded: pregnancy stat us, number of corpora lutea, number and distribution of live young and em bryofetal deaths, indi vidual fetal weights, and gross fetal abnormalities. Half of the fetu ses in each litter were preserved in Bouin’s solution for subsequent free-hand sectioning to discover visceral abnormalities; the remainder
were fixed and stained for skeletal examination.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 47 of 53 All animals survived to scheduled sacrifice. Fur loss or alopecia was observed on 5, 9, 10, and 25 animals in the control, low-, mid-, and high- dose groups, respectively. Post-dosing salivation was seen on 3 mid-dose and 9 high-dose animals compared with none of the controls. Yellow staining was noted under the cages of the mid- and high-dose rats. No other treatment-related clinical signs were observed. Cumulative body weight gain by the high-dose group was reduced to 28-63% (p  0.01 for all intervals) of the contro l level throughout th e treatment period resulting in final body weight of the high-dose group 85% of the c ontrol level. The only other effect on body weight or body weight gain was a transient decrease in weight gain by the middose group for GD 6-12 (88% of control; p  0.05). Food consumption by the high-dose group
was 69-85% of the controls for GDs 6-11 and 18-19. Water consumption was significantly increased compared to the controls beginni ng on GD 8 for the mid-dose group and on GD 7 for the high-dose group.

The maternal toxicity LOAEL is 300 mg/kg/da y based on post dose salivation. The maternal NOAEL is 100 mg/kg/day.

Three high-dose and one contro l dam had complete litter reso rption. The mean number of corpora lutea, implantations, and live fetuses a nd the fetal sex ratio were similar between the treated and control groups. Fetal body weight for all treated groups was significantly less (p  0.01) than that of the control group; mean fetal weight for the control, low-, mid-, and high-dose groups was 3.78 g, 3.48 g, 3.51 g, and 3.00 g, respectively. Only the effect at the high dose is
considered treatment-related.

The number of fetuses (litters) examined in the control, low- , mid-, and high-dose groups was 269 (22), 276 (22), 284 (24), and 261 (21), respec tively. In the high-dose group, six fetuses from 2 litters had misshapen pituitary and seven fetu ses from four litters had diaphragmatic hernia compared with none of the controls. Other treat ment-related findings in th e control, low-, mid-, and high-dose fetuses(litters) in cluded thin diaphragm with protru sion of the liver in 2(2), 2(1), 2(2), and 6(4), respectively. An increase in the incidence of incomplete or irregular ossification of the pelvic girdle, digits, sternebrae, and t horacic vertebral centra was found in the high-dose group compared to the control group. Abnormal liver lobation was also seen in the control, low-, mid-, and high-dose fetuses(litter s), 1(1), 5(3), 5(5) , and 9(7), respectively; However, the
incidences were within historical control range.

The developmental toxicity LOAEL for LG C-30473 in rats is 1000 mg/kg/day, based on thin diaphragm with liver protrusion, decrea sed fetal body weight (21%), misshapen pituitary, diaphragmatic hernia, and skelet al anomalies (incomplete or irregular ossification of the pelvic girdle, digits, st ernebrae, and thoracic vertebral centra).The developmental toxicity NOAEL is 300 mg/kg/day.

ACUTE NEUROTOXICITY STU DY- RAT; OPPTS 870.6200A

EXECUTIVE SUMMARY : In an acute neurotoxicity study (MRID 48535643 ) , groups of male and female (aged 41-42 days) (Spr ague-Dawley Crl:CD (SD strain) (rat species) (10/sex/dose) were given a single oral dos e of Ethaboxam (98.9 a.i., ba tch # AS2293b) in 1% aqueous carboxymethyl cellulose via gavage at doses of 0, 300, 1000, or 2000 mg/kg/day and observedEthaboxam Human Health Risk Assessment DP No. 396490

Page 48 of 53 for 14 days. Neurobehavioral assessment (functi onal observational battery and motor activity testing) was performed in 10 an imals/sex/group at a pretest day, Day 1 (6hr post dosing) and at Day 8 and Day 15. Cholinesterase activity was not determined. At termination, 10 animals/sex/group were euthanized and perfused in situ for neuropathological examination, determination of brain weights and physical chan ges. Of the perfused animals, 5/sex/dose from the control and 2000 mg/kg/day dose levels were subjected to histopathol ogical evaluation of brain, CNS and peripheral nervous system tissues. Body weight ga ins were reduced in both sexes at 1000 and 2000 mg/kg/day doses in the first week. There were no weight change differences at 300 mg/kg/day in either sex compared to controls.

There were no treatment related changes in FOB parameters compared to controls. There were no treatment related effects on mortality, clinic al signs, brain weight, gross or histologic pathology or neuropathology.

The treatment of the top two dos es (1000, 2000 mg/kg/day) caused a slight drop in food intake in the first week of the study whic h gradually returned to near c ontrol values by week two. There were concomitant reductions in body weight gains both males and females at 1000 and 2000 mg/kg/day in the first week. However, there we re no changes in absolute body weight at any
dose in males or females. The decrease in food consumption and subsequent body weight gain is possibly related to decreased pa latability since changes were seen during the first week of treatment and dissipated by week tw o. Therefore, in the absence of other treatment related effects the decrease in body weight gain al one is not considered adverse.

The NOAEL is 2000 mg/kg/day and the LOAEL is not determined.

The study is classified as Acceptable/Guideline and satisfies the guideline requirement for an acute neurotoxicity study in rats (870.6200; OECD 424)

SUBCHRONIC NEUROTOXICITY STUDY- RAT; OPPTS 870.6200B

EXECUTIVE SUMMARY : In a subchronic neurotoxicit y oral (dietary) study (MRID 48535646), Ethaboxam (99.6% a.i., batch/lot # P 980622) was administered to Crl:CD(SD) rats (12/sex/group) at dose levels of 0, 250, 600, or 1,500 ppm (equivalent to 0, 18.0/21.0, 43.0/50.0, 106.0/122.0 mg/kg/day[M/F], respectively) for 13 weeks. Neurobehavioral assessment (functional observational battery and motor activit y testing) was performed on all animals at pretest (Week -1) and Weeks 1, 3, 7 and 12. Opth amology exams were conducted prior to dosing and at the end of the study. Hematology and c linical chemistry parame ters along with organ weights and gross histopathologyobs ervations were also determined. At study termination, all surviving animals were euthanized and perfused in situ for neuropathological examination; fixed brain weights and brain dimensi ons excluding olfactory bulb were recorded. Of the perfused animals, 6 animals/sex in the control and 1,500 ppm groups were subjected to microscopic histopathological evaluati on of brain and peripheral nervous system tissues.

All animals survived to the scheduled necropsy. No adverse, permanent treatment-related effects were observed on general clinical observati ons, ophthalmology, FOB findings, or locomotor activity pattern (ambulatory and to tal motor activity counts) at any dietary concentration level inEthaboxam Human Health Risk Assessment DP No. 396490

Page 49 of 53 males and females. During FOB physiological evaluations, significantly lower mean body weight was noted in the high-dose (1,500 ppm) group males on Week 7 ( ↓ 10% p ≤ 0.05) and Week 12 ( ↓ 9% p ≤ 0.05), but this decrease in body weight wa s not present in females. The effect on mean body weight in the 1,500 ppm males during the physiological evaluations was consistent with the lower body weight observe d during the weekly body weight evaluations.

Treatment-related effects on body we ights and cumulative body weight gains were evident at the dietary concentration level of 1,500 ppm in male s throughout the treatment period, but not in the females. Body weights were significantly (p ≤ 0.05) reduced by 9%-12% in the 1,500 ppm group males throughout the treatment period. No signifi cant differences in body weights were noted at dietary concentration levels of 250 and 600 pp m in males and females and at 1,500 ppm in females. Mean body weight gains were signif icantly reduced in the 1,500 ppm group males on Weeks 0-1 ( ↓ 28%; p ≤ 0.01), Week 6-7 ( ↓ 24%; p ≤ 0.01), and Week 8-9 ( ↓ 27%; p ≤ 0.05). In addition, mean cumulative body weight ga in (Weeks 0-13) was significantly (p ≤ 0.05) reduced by 18% in the 1,500 ppm group males when compared to the control group.

Treatment related-effects on food consumption were evident at 1,500 ppm in males throughout the exposure period. At 1,500 ppm, lower (p ≤ 0.05 or p ≤ 0.01) food consumption ranged from ↓ 10% to ↓ 17% on Week 0-1 through the end of the treatment period (Week 12-13) in males, when compared to the controls. No treatment-re lated effects on food consumption were observed at 250 and 600 ppm in males and females and at 1,500 ppm in females. Although there were statistically significant differen ces in body weight (10% increa ses at 600 ppm during Weeks 6, 7, and 8) and food consumption compared to contro ls in the female dose groups during the study period, these were transient and did not show dos e response relationships. In addition, there were no statistically significant decr eases in body weight gains, cu mulative body weight gains or decreases in body weight in the female exposed groups throughout the study. On this basis, it
was concluded that the inconsis tent body weight, body weight gain and food consumption effects
observed in females were not due to test substance exposure.

There were no test substance-associated alterati ons observed in brain weights or measurements, gross histopathology observations or microsc opic neurohistopathology findings in the 1,500 ppm (high dose) male and female groups compared to controls

It is concluded that Ethaboxam did not exhibit ne urotoxic effects in this subchronic neurotoxicity feeding study at dietary con centration levels of 250, 600 and 1,500 ppm, based on the lack of altered behavior in the FOB parameters, no ch anges in locomotor activity, and no effects on brain weights and measurements, or the macr oscopic and microscopic pathology of nervous system tissues. However, systemic toxicity of Ethaboxam was apparent in males in the 1,500 ppm group, but not in females. This was charac terized by decreased bod y weights, decreased cumulative body weight gains and significan t reductions in food consumption.

The NOAEL is 600 ppm (equivalent to 43 mg/k g body weight/day) and the LOAEL is 1,500 ppm (equivalent to 122 mg/kg body weight/day) , based on significant reduction in body weights, body weight gains and food consumption in males

.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 50 of 53 The study is classified as Acceptable/Guideline and satisfies the guide line requirement (OPPTS 870.6200b) for a subchronic neur otoxicity study in rats.

IN VITRO MAMMALIAN CELL MICRONUCL EUS ASSAY; OPPTS 870.5550

In an in vitro mammalian cell micronucleus assay (MRID 46989601), 24-and 48-hr phytohemagglutinin (PHA)-stimulated human ly mphocyte cultures from male donors were exposed to LGC-30473 (99.7% a.i, Ba tch # P980622) prepared in di methyl sulfoxide (DMSO) at concentrations of 0, 0.5, 1, 2.5, 5, 7.5, 10, 15 and 20  g/mL without metabolic activation for 20 hours. With S9 activation, cells were dosed for 3 hours with concentrations of 0, 25, 50, 75, 100, 125, 150, 175, 200, 250, 500, 800 or 1000  g/mL. Exposed lymphocytes were treated with the mitotic inhibitor, cytochalasin B and harves ted and scored for micronuclei in mononucleated,
binucleated and multinucleated cells. The S9 fraction was derived from the livers of Sprague Dawley rats induced with phenobarbitone/  -naphthoflavone and scored for structural chromosome aberrations. Mitomycin C (Mit C) and colchicine –S9 and cyclophosphamide (CP) +S9 served as positive controls.

Test material precipitation was seen at ≥ 500  g/mL+S9. LGC-30473 was tested to the highest concentrations (20  g/mL –S9; 75  g/mL +S9) causing adequate cytotoxicity (i.e., relative proliferative index that was 60% of the solvent control) and i nduced a positive and significant (p< 0.01 - 0.001) response in the absence of S9 ac tivation in lymphocytes stimulated with PHA for 24 hours. The response was obtained at three nonactivated test material concentrations (10,
15 and 20  g/mL) and in the presence of S9 activation at 75  g/mL. The subsequent analysis of cells treated with the highest positive nonactivat ed test level for centromeric staining, using
fluorescent in situ hybridization (FISH), revealed that the mechanism for this induction was aneugenicity rather than clastogenicity. Since po sitive activity was uncovered in cells stimulated for 24 hours in the short protocol , the 48-hour stimulated cells were not scored and the long protocol was not performed. The sensitivity of the test system to detect aneugenesis and clastogenesis was adequately demo nstrated by the results with the nonactivated and S9-activated positive controls. It was concluded: therefore, that LGC-30473 was positive in this human lymphocyte in vitro micronucleus assay.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for Test
Guideline OECD 487 for in vitro micronucleus data

DERMAL PENETRATIO N STUDY-RAT; 870.7600

EXECUTIVE SUMMARY : In a dermal penetration study (MRID 48535712), LGC-30473 unlabeled and radiolabeled at the 4-ethyl si te (purity 99.3%, Batch No. P980622 unlabeled, and purity >97%, Batch No. P341 radiolabeled) was a pplied to groups of 12 male Sprague Dawley rats/dose at concentrations of 2 μg/cm 2 or 1 mg/cm 2 skin. The test material was allowed to
remain in contact with the skin for six hours af ter application. During the treatment period, the rats were placed in glass metabolism cages. Af ter six hours, residual test material was removed by washing the skin. Four rats/time interva l/group were sacrificed 6, 72, and 120 hours after initiation of treatment. Urine, feces, treated skin, untreated skin, and carcass were collected for radioactivity determination.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 51 of 53 Recovery of the radiolabel for the stu dy was excellent, being >99.4% at 2 μg/cm 2 and >98.8% at 1 mg/cm 2 skin. Radiolabel recovered in the urine, feces, and carcass, indicators of absorption,
was <3.35% and <0.25% of the administered low- and high-dose, respectively, after 120 hours. Carcass radioactivity was <0.2% for both doses, i ndicating test material was rapidly metabolized
and excreted. The remainder of the radiolabel for both doses was associated with the skin. Radioactivity in the treated skin was generally associated with the fur and stratum corneum. Consequently only a small proportion (0.17 to 0.0 8% at the high dose, and 0.24 to 0.95% at the low dose) remained in the viable epidermis, a nd was available for absorption. The approximate ten-fold greater proportion absorbed after the low dose suggests the residual radioactivity on skin after washing at the high dose leve l was not available for absorption.

The amount absorbed (absorbed dose) increased with duration with 1.04% absorbed at 6 hrs, 2.69% at 72 hours, and 3.35 at 120 hours. The absorb able dose (the amount remaining in treated skin, stratum corneum, and around the dose si te) was 6.43% at 6hrs, 3.46% at 72 hours, and 3.29% at 120 hrs. For risk assessment purposes, th e absorbed and absorbab le doses (from treated skin, stratum corneum, and skin surrounding dose si te) were combined and due to the variability in the absorbable dose, the 6 hour time point re sulted in the greatest to tal absorption. Total absorption was 7.5% at 6hrs, 6.15% at 72 hrs, and 6.64% after 120 hours. The 6 hour time point is the most relevant time point for occupational exposure; thus, the total absorption of 7.5% after
6 hours is considered the most a ppropriate for risk assessment.

This study is Acceptable/Guideline and satisfies the guideline requirement for a dermal penetration study (870.7600) in rats.

IMMUNOTOXICITY ST UDY-RAT; OPPTS 870.7800

EXECUTIVE SUMMARY : In an immunotoxicity st udy (MRID # 48535655), Ethaboxam (98.9% a.i., Batch/Lot LGC- 30473) was administered to male Spra gue-Dawley rats (10/dose) in the diet at dose levels of 0, 250, 650, or 1500 ppm (equivalent to 0, 21, 52, or 121 mg/kg/day, respectively) for 28 consecutive da ys. The positive contro l group consisting of female rats was administered cyclophosphamide 50 mg/kg (dos e volume 10 mL/kg b.w) by intraperitoneal injection on Day 27. During the study, clin ical condition, bodyweight, food and water consumption, organ weight, macropathology were ev aluated. On Day 25, all animals in all groups received a single intravenous dose of 1 mL/animal, sheep red blood cells (SRBC,
2x10 8 cells/mL) in 0.9% saline. At sacrifice on Day 29, selected organs were removed and weighed (adrenals, spleen, and thymus). The anti-SRBC antibody response was measured with a modified plaque form ing cell (PFC) assay.

There were no premature deaths, and no treatment -related clinical signs. There was an overall reduction of weight gain about 19% and 42% at 650 and 1500 ppm, respectively. There was persistently low food consumption in these grou ps when compared to the vehicle control group. The macroscopic examination revealed no lesions attributable to treatment with Ethaboxam. The decreases in absolute weights of the thymus and the spleen at the high dose were considered to be due to the lower body weights as there was no effect on the relative body weights.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 52 of 53 The systemic toxicity NOAEL was 250 ppm (e quivalent to 21 mg/kg/day); the LOAEL was 650 ppm (equivalent to 52 mg/kg/day) based on reduced body weight gain and food consumption.

There were no statistically significant treatment -related effects on the specific anti-SRBC antibody response as measured by specific activity (PFC/10 6 viable cells), total activity (PFC/spleen) or cellularity (ce lls/spleen) in all treated groups . High inter-indivi dual variability was noted in all the treatment groups as well as in the control group. Evaluation of the individual animal data of this study did not show any trend or di stribution that would demonstrate significant suppressi on of anti-SRBC antibody response. Animals in positive control group showed a statistically signi ficant (p< 0.001) decrease of th e PFC response. This confirmed the ability of the test system to detect immuno- suppressive effects and co nfirmed the validity of the study design.

The Natural Killer (NK) cells activity was not eval uated in this study. The toxicology database of
Ethaboxam did not indicate immunot oxicity. The overall weight of evidence suggests that the chemical does not directly targ et the immune system. Under HED guidance a NK cell activity assay is not required at this time.

The NOAEL for immunotoxicity was 1500 ppm (equivalent to 121 mg/kg/day), the highest dose tested; the LOAEL for immunotoxicity was not established.

This immunotoxicity study is classified as Acceptable/Guideline and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in the rats

.

TIME TO PEAK EFFECT-RAT; NON-GUIDELINE

In a dose range and time of peak effect fo r acute neurotoxicity study (MRID 48535687), groups of non-fasted, young adult Sprague-Dawley Crl:CD(S D) rats (3/sex/dose) were given a single oral gavage dose of Ethaboxam (98.9% a.i., batch/lot # AS2293b) in aqueous methylcellulose [1% methylcellulose / 0.1% Tween 80] at doses of 300, 1000 or 2000 mg/kg (limit dose) and observed for 7 days. Neurobehavioral asse ssment (home cage, in-the-hand, arena, and manipulation observations) was performed in all 3 animals/sex/group prior to dosing, and at 1, 2, 4 and 6 hours after dosing. At study termination, all animals/sex/group were sacrificed and subjected to macroscopic pathology examination.

All animals survived to scheduled sacrifice. There were no test substance-related effects on clinical findings or macros copic pathology in males or fe males at any dose level.

On day 4, slight body weight loss was observe d in the 2,000 mg/kg group males and in the 1,000 mg/kg group females. In addition, these males and females showed low body weight gains on Day 1-4 followed by improvement of body weight ga in during the latter half of the observation period. Overall (Day 1-7) mean body weight ga in was low in the 1,000 mg/kg group females and 2,000 mg/kg group males. The lower body weight gain s in these animals we re consistent with the low body weight gain and body weight loss th at were noted between Day 1 and Day 4.Ethaboxam Human Health Risk Assessment DP No. 396490

Page 53 of 53 No test substance-related effects on neurobehavi oral assessments, including home cage, arena, manipulation and in-the-hand observations. Bright yellow urine was observed during the arena observations and occasionally during manipulation obs ervations at all dose levels in either sex. However, this finding was inconsistence, not treatment related and has no toxicological relevance. Also, the timing of it occurrence after dosing did not contribute towards determining the time to peak effect for the test substance.

In conclusion, the results demonstrate that Spragu e-Dawley Crl:CD(SD) rats can tolerate a single
acute oral administration of Ethaboxam at doses up to 2,000 mg/kg (limit dose) and the T
max was 6 hours after dosing, that was principally select ed based on a previous rat metabolism study. In addition, this study establishes su itable information that would be useful in designing a main acute neurotoxicity study.

The study is classified as Acceptable/Non-Guideline and is supplemental to the neurotoxicity screening battery study in rats.

Appendix B. Review of Human Research

Aside from the Pesticide Handlers Exposure Data base Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database , the Outdoor Residential Exposure Task Force (ORETF) database, and the Agricultural Re-ent ry Task Force (ARTF) database, which were described at the end of the Executive Summary, no data from studies in which adult human subjects were intentionally expos ed to a pesticide or other chem ical were used in this risk

assessment.