Ethaboxam Human Health Risk Assessment DP No. 396490 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: May 21, 2013 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

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 

Risk Assessment 

Middleton, 

Branch 

Toxicologist 

II I' 

~ 

' f - Health Effects Division (7509P) 

THROUGH: Michael 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 

Registration Division (7505P) 

TO: Dominic Schulerffony Kish, RM Team 22 

Fungicide Branch 

Registration Division (7505P) 

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Ethaboxam Human Health Risk Assessment DP No. 396490 

1.0 Executive Summary .......................................................................................................... 4 

2.0 RED Recommendations ................................................................................................... 7 

2.1 

2.2 

2.2.3 

2.3 

Data Deficiencies/Conditions of Registration .............................................................. 7 

Tolerance Considerations .............................................................................................. 7 

International Harmonization ......................................................•.............................. 7 

Label Recommendations .................................................................•.............................. 7 

3.0 

3.1 

3.2 

3.3 

3.4 

3.5 

Introduction ....................................................................................................................... 7 

Chemical Identity" ........................................................................................................... 7 

Physical/Chemical Properties ........................................................................................ 8 

Pesticide Use Pattern ...................................................................................................... 9 

Anticipated Exposure Pathways ................................................................................. 10 

Consideration of Environmental Justice .......................................•............................ 10 

4.0 

4.1 

4.2 

4.2.1 

4.3 

4.4 

4.4.1 

4.4.2 

4.4.3 

4.4.4 

4.5 

4.5.1 

4.5.2 

4.5.3 

4.5.3 

Hazard Characterization and Dose-Response Assessment ............•............................ 11 

Toxicology Studies Available for Analysis ....................................•............................ 11 

Absorption, Distribution, Metabolism, & Elimination (ADME) ............................. 11 

Dermal Absorption ................................................................................................... 12 

Toxicological Effects .................................................................................................... 12 

Safety" Factor for Infants and Children (FQPA Safety" Factor) ..•............................ 14 

Completeness of the Toxicology Database .............................................................. 14 

Evidence of Neurotoxicity" ......................................................................................... 14 

Evidence of Sensitivicy/Susceptibilicy in the Developing or Young Animal. ....... 15 

Residual Uncertainty" in the Exposure Database ................................................... 15 

Toxicity" Endpoint and Point of Departure Selections .............................................. 15 

Dose-Response Assessment ...................................................................................... 15 

Recommendation for Combining Routes of Exposures for Risk Assessment ..... 16 

Cancer Classification and Risk Assessment Recommendation ............................ 17 

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

Asse.ssment ............................................................................................................................... 18 

5.0 

5.1 

5.1.1 

5.1.2 

5.1.3 

5.1.4 

5.2 

5.3 

5.4 

5.4.1 

5.4.2 

5.4.3 

5.4.4 

5.4.5 

5.4.6 

6.0 

6.1 

7.0 

Dietary Exposure and Risk Assessment ........................................................................ 19 

Metabolite/Degradate Residue Profile ....................................................................... 19 

Summary of Plant and Animal Metabolism Studies ............................................. 19 

Summary of Environmental Degradation .................................•............................ 20 

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

Residues of Concern Summary and Rationale ...................................................... 22 

Food Residue Profile .................................................................................................... 23 

Water Residue Profile .................................................................................................. 24 

Dietary Risk Assessment .............................................................................................. 25 

Description of Residue Data Used in Dietary Assessment .................................... 25 

Percent Crop Treated Used in Dietary Assessment .............................................. 25 

Acute Dietary Risk Assessment ............................................................................... 25 

Chronic Dietary Risk Assessment ........................................................................... 25 

Cancer Dietary Risk Assessment ............................................................................. 26 

Summary Table ......................................................................................................... 26 

Residential (Non-Occupational) Exposure/Risk Characterization ............................ 26 

Spray Drift .................................................................................................................... 26 

Aggregate Exposure/Risk Characterization ....................................•............................ 27 

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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 Profile and Executive Summaries .................................................. 33

Appendix B. Review of Human Research ................................................................................ 43
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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 inhibit mycelia growth and sporulation of P. infestans. It also 

weakly inhibits germination of zoospores or cysts. 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 mammalian 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 rice, and the rapeseed subgroup (20-A). Ethaboxam is not currently 

registered for use in the United States; however, there 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. Based on the proposed use pattern, there is the 

potential for occupational exposure to ethaboxam when treating and planting seeds. 

Occupational exposures are expected for short- and intermediate-term durations. 

HED has new information to suggest that in commercial 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 conduct 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 facilities operating over longer 

durations. HED also notes that it would be unlikely for a single chemical to be used 

continuously, even in high throughput facilities, over long term durations. Using conservative 

assumptions, the short- and intermediate-term scenarios are considered protective of longer-term 

exposure and risk. 

The toxicity database is considered to be complete. Toxicological studies with rats, mice, 

rabbits, and dogs show varying effects in the different 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 reproductive toxicity, observed as 

reductions in mating and decreases in the fertility index. Furthermore, ethaboxam has been 

classified as having “suggestive evidence of carcinogenic potential” 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 susceptibility 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 normal 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 liver effects were not observed in studies with rabbits or dogs. 
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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 assessment, the endpoint was effects on male reproductive 

organs (testes, epididymides, prostate, and seminal vesicles) selected from the carcinogenicity 

study in rats. 

For short- and intermediate-term dermal risk assessment, 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 toxicity study was not available, so HED selected the inhalation 

endpoint (male reproductive and lung effects) from a 13-week rat feeding study to assess both 

short- and intermediate-term inhalation exposure and risk. Since inhalation absorption data are 

not available, toxicity by the inhalation route is considered to be equivalent to the estimated 

toxicity by the oral route of exposure. 

Ethaboxam is classified as having “Suggestive Evidence 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 quantification of cancer risk using a non-linear approach 

would adequately account for all chronic toxicity (including carcinogenicity) resulting from 

ethaboxam exposures. 

HED recommends that the 10X Food Quality Protection 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 neurotoxicity, 3) the endpoints 

and doses selected for risk assessment are protective 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 result in residential exposure. Although a route-specific inhalation study is 

not available, HED has used weight-of-evidence considerations to conclude that the study is not 

needed, and therefore no additional uncertainty factors 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 interspecies (10X) and intraspecies (10X) 

uncertainty factors. For dietary assessments, the combined uncertainty factors of 100 were 

incorporated into the chronic population adjusted dose (cPAD), and HED would be concerned if 

dietary risk estimates exceeded 100% of the cPAD. 

The exposure pathways expected for ethaboxam are dietary exposure from imported grapes, as 

well as from drinking water, and occupational exposures via the dermal and inhalation routes. 

There are no registered or proposed residential uses, and residential exposure is not expected 

from the commercial use of this product. To assess dietary exposure, HED has used the Dietary 

Exposure Evaluation Model with the Food Commodity Intake Database (DEEM-FCIDTM) 

Version 3.16 with highly health-protective assumptions regarding the level and prevalence of 
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ethaboxam residues in grapes and processed grape commodities. In addition, estimated drinking 

water concentrations (EDWCs) resulting from the seed treatment use were incorporated directly 

into the dietary exposure assessment. 

The EDWCs for ethaboxam were modeled using the Tier 1 models, and using very conservative 

assumptions for the new seed treatment use. These assumptions include the use of the maximum 

treatment and seeding rates, that ethaboxam is stable to all routes of degradation, and that all 

ethaboxam applied to the seeds ends up in drinking water. Using these conservative 

assumptions, the predicted drinking water concentrations were in the low ppb range, with surface 

water estimates higher than ground water estimates. Even with the conservative assumptions 

used for both food and drinking water, the dietary risk estimates are below HED’s level of 

concern for all population subgroups, including those comprised of infants and children. 

For all proposed uses, occupational handler dermal and inhalation risk estimates are not of 

concern. Short- and intermediate-term primary handler (seed treater) MOEs ranged from 14,000 

for dermal exposure resulting from multiple activities while treating legume vegetable seeds to 

410,000 for inhalation exposure resulting from treating rapeseed. Short- and intermediate-term 

secondary handler (loader/planter) risk estimates ranged from a dermal MOE of 39,000 for cereal 

grains to an inhalation MOE of 7.8 x 106 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 there 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 required for exposure to treated seeds that have 

already been planted. Therefore, the labeling properly states the exception to the Agricultural 

Use Requirements restricted entry 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. These data, which include studies from 

Standard Operating Procedures (SOPs) for Seed Treatment, Policy 14, 15, and 15.1 are (1) 

subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are 

compliant with applicable ethics requirements. For certain studies, the ethics review may have 

included review by the Human Studies 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/science/post-app-exposure-data.html. 
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2.0 HED Recommendations 

There are no data deficiencies that would preclude registering the seed treatment uses for 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). 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 qualify 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 review in Canada, and since Canada considers seed 

treatment to be a food use, it might establish limit 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 feed soybean forage or hay to livestock.” 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 and nomenclature of ethaboxam are presented in 

Table 3.1, and the physicochemical properties of the technical grade of ethaboxam are presented 

in Table 3.2. 

 
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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, pKa 3.6 

Octanol/Water Partition 

Coefficient, Log(KOW) 

2.73 at pH 4; 2.89 at pH 7; 2.91 at pH 10 

UV/Visible Absorption 

Spectrum 

Solvent System 1 λmax (nm) Absorbance Є (dm3/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

CH3CH2NH

CN

CH2CH3
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Comments: Ethaboxam has a Log (Kow) less than 3, suggesting that it will not bioconcentrate. 

Environmental fate data are currently under review in the Agency, 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, especially for the proposed seed treatment uses. 

 

3.3 Pesticide Use Pattern

Valent is proposing a single end-use product (EP) for 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. ethaboxam 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 specifies that the fungicide should be pre-tested in tank mixtures with 

other seed treatment products to evaluate formulation compatibility and to ensure proper physical 

compatibility of products. The proposed Restricted Entry Interval (REI) is 12 hours for all crops. 

 

The Personal Protective Equipment (PPE) statement on the proposed label requires applicators 

and other handlers to wear long-sleeved shirt and long pants, socks, shoes, and chemical-resistant 

gloves. The proposed use directions are summarized in Table 3.3. 

Table 3.3. Summary of Directions for Use of Ethaboxam. 

Application 

Timing, Type, 

and Equipment 

Formulation1 

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 NS2

Pre-test tank mixtures with other 

seed treatment products. 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 

0.005-0.00653

 1 0.0065 

NS 

Pre-test tank mixtures with other 

seed treatment products. Do not 

tank mix with any products that 

contain a prohibition on tank 

mixing. 

0.005-0.00754 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 products. Do not 

tank mix with any products that 

contain a prohibition on tank 

mixing. 
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1 EPA Reg. No. 59639-RIL. 

2 NS = Not specified on the label. 

3

 For barley, buckwheat, pearl millet, 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 directions for the application 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 ai/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 result 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 existing, pending, or requested commercial or residential 

registrations that would result in exposure from use in a residential setting. In a commercial or 

on-farm seed treatment site, there is potential for handlers to be exposed while treating and 

planting seeds. However, potential for post-application exposure is expected to be negligible, 

since there will be no residue on foliage which could result in exposures from contact once plants 

are grown. 

The existing use on imported grapes 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 justice concerns, to the extent possible, were considered in this 

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

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

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the U.S. Department of 

Agriculture’s National Health and Nutrition Examination 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 categorized by subgroups based on age, season of the 

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

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

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

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

and adults entering or playing on treated areas post-application are evaluated. Further 
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considerations are currently in development as OPP has committed resources and expertise to the 

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

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

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis 

The toxicology database for ethaboxam is complete at this time. A subchronic inhalation 

toxicity study has not been submitted. However, 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 inhalation toxicity of ethaboxam; (3) 

effects on the male reproductive system are the 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 include: subchronic oral toxicity 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); developmental and reproduction studies in rats and a 

developmental study in rabbits; subchronic dermal toxicity and dermal penetration studies in 

rats; and an immunotoxicity study in rats. There is also a metabolism study in the rat, a complete 

mutagenicity battery, rat neurotoxicity (acute and subchronic), and acute lethality studies. 

4.2 Absorption, Distribution, Metabolism, & 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 excreted 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 dose group (83-92%). Biliary excretion of thiazole 

radiolabeled ethaboxam was similar to the percentages observed in the feces, indicating biliary 

excretion was the primary source of fecal radioactivity. Approximately 79-94% of the 

compound was absorbed after 48 hours, depending upon the dose. Minimal amounts (<1% of 

the dose) of the radiolabeled compound were retained in the tissues up to 120 hours post dosing. 

The thyroid generally contained the highest concentration of the thiazole label, but only minimal 

amounts of the thiophene label. 

Pharmacokinetic studies found minimal differences between the thiazole or thiophene label. 

Except for the elimination half-life (t1/2) (blood cell t1/2 ~ 69-162 hours; plasma t1/2 ~ 31-41 

hours), blood cell pharmacokinetic values were generally comparable to or lower than plasma 

values. Differences were noted between the low- and high-dose pharmacokinetics. The t1/2 was 

similar following single administration of both the low- and high-dose, while the Cmax, tcmax, and 

the area under the curve (AUC120) were higher following the high-dose compared to the low-
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dose. However, the increases were not proportional 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 compound 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 radioactive 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 metabolites 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 available where ethaboxam (technical) was applied 

to the skin of 12 male Sprague Dawley rats, dose at low (2 μg/cm2

) and high (1 mg/cm2) 

concentrations. The test material was allowed to remain in contact with the skin for six hours 

after application, after which residual 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 (absorbable dose) decreased over time. The absorbed 

and absorbable doses (from treated skin, stratum corneum, and skin surrounding dose site) were 

combined and, due to the variability 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 ethaboxam, with alterations to the male reproductive 

organs as well as functional effects on male reproduction observed in several oral subchronic and 

chronic rat studies. In 90-day feeding studies in rats, there were severe testicular alterations at 

650 and 2000 ppm. Effects observed were small testes, decreased testicular 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 vesicle 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. Effects observed were decreased epididymal and 

seminal vesicle weights, seminiferous tubule atrophy, small/flaccid testes and epididymides, 

abnormal spermatogenic cells in the epididymal duct, absent sperm, epididymal vacuolation, and 

reduced colloid in the prostate. Fine vacuolation of the adrenal zona glomerulosa was also 

observed in both sexes in the rat studies, along with decreased body weight in females. 

Decreased body weight and body weight gains were also noted in a dermal toxicity study in rats. 

However, no effects on male reproductive organs were observed in the study. There were no 
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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 findings were limited to increases in liver weight 

and centrilobular hepatocyte hypertrophy at 450 ppm (males) and 1000 ppm (females); these 

findings were considered adaptive responses. There 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/involution, and hematopoiesis of the spleen were 

also observed at 100 mg/kg/day. No treatment-related 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/day. Effects observed in the study 

were limited to decreased body weight gain and food consumption at the high dose. 

Ethaboxam was not neurotoxic in the available studies. Post-dose salivation was observed in a 

developmental rat study at 300 and 1000 mg/kg/day. However, in another developmental rat 

study and a developmental rat range-finding study, post-dose salivation was not observed. 

Additionally, no treatment-related neurotoxic effects were observed in the neurotoxicity studies. 

In the acute neurotoxicity study, no treatment-related effects were observed at doses up to 2000 

mg/kg/day. In the subchronic neurotoxicity study, decreased body weight, body weight gain, 

and food consumption were observed at 122 mg/kg/day. 

No evidence of increased quantitative or qualitative susceptibility was seen in the developmental 

toxicity studies in rats and rabbits. In two developmental rat studies, there were incidences of 

abnormal liver lobation observed at ≥100 mg/kg/day; however, the incidences were within 

historical control range. No treatment-related developmental or maternal effects were noted in 

the first rat developmental study. In the second developmental rat study, thin diaphragm with 

liver protrusion, decreased fetal body weight, misshapen pituitary, diaphragmatic hernia, and 

skeletal anomalies were seen at the limit dose of 1000 mg/kg/day. These effects were seen in the 

presence of comparable maternity toxicity. Maternal effects seen included increased salivation, 

decreased body weight (15%) and body weight gain (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 susceptibility 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 offspring 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 observed in the male reproductive organs similar to those seen in 

subchronic and chronic rat studies, as well as impaired sperm motility and reduced fertility in 

males. 
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Ethaboxam has been classified as having “suggestive evidence of carcinogenic potential,” based 

on an increased incidence of benign Leydig cell tumors in male rats. Although there is evidence 

of benign Leydig Cell tumors, 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 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 chronic toxicity, including 

carcinogenicity, that could result from exposure to ethaboxam. 

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

Although the currently proposed seed treatment uses are considered to be non-food, the existing 

use pattern (import tolerance on grapes) for ethaboxam will result in the potential for dietary 

exposure to infants and children. Further, the new seed treatment uses may result in the potential 

for exposure through drinking water. Thus, FQPA hazard and exposure considerations were 

addressed in HED’s evaluation of the database. HED recommends that the 10x FQPA Safety 

Factor (for the protection of infants 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 toxicity, including the required immunotoxicity and 

neurotoxicity studies, 2) there is no evidence of neurotoxicity, and HED has determined that the 

developmental neurotoxicity study is not required, 3) the endpoints and doses selected for risk 

assessment are protective 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 

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 children. Acceptable/guideline developmental toxicity 

studies in rats and rabbits and reproduction study in rats are all available for FQPA assessment. 

4.4.2 Evidence of Neurotoxicity 

There is no evidence that ethaboxam is neurotoxic. Post-dose salivation was observed in a 

developmental rat study at 300 and 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 rat range-finding study, post-dose salivation was 

not observed. Additionally, no treatment-related neurotoxic effects were observed in the 

neurotoxicity studies. In the acute neurotoxicity study, no treatment-related effects were 

observed at doses up to 2000 mg/kg/day. In the subchronic neurotoxicity 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 other species or toxicology studies. 
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4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal 

No evidence of increased quantitative or qualitative 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 susceptibility in the reproduction study, there 

are no residual uncertainties with regard to pre- and/or postnatal 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 selected for risk assessment, the degree of concern 

for the effects observed in the study is low based on the following: the offspring effects observed 

in the study are well characterized and clear NOAELs/LOAELs have been identified in the study 

for the effects of concern. Additionally, the points 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 uncertainties with respect to dietary and occupational exposure. The 

dietary exposure assessment is based on high-end health protective residue levels (that account 

for parent and metabolites of concern), and processing factors. Furthermore, very conservative, 

upper-bound assumptions were used to determine 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 the toxicity studies used for selecting 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 exposure 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 effects observed in offspring 

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 variability (± 2 days). Therefore, the endpoint in the absence of other potential single 

dose effects was not considered appropriate for acute dietary risk assessment. 
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For chronic dietary exposure and risk assessment, a NOAEL of 5.5 mg/kg/day was selected from 

the carcinogenicity study in rats based on effects seen in the male 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 database 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 higher dose (35.8 mg/kg/day), 

effects in the chronic mouse study (117 mg/kg/day) and systemic, reproductive, and offspring 

effects seen in the 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. 

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 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 weights, congestion, and alveolar septal 

congestion and focal alveolar hemorrhage) were seen in a 13-week oral study with a lower point 

of departure (PoD). However, these effects were adequately measured in the 28 day dermal 

toxicity study, and no reproductive effects were seen. 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 quantitative susceptibility. The 

study is appropriate for both the route and duration of exposure. 

For short- and intermediate-term inhalation exposure, 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 reproductive 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 effects 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 are no other uncertainty 

factors needed to account for missing data or the lack of a NOAEL. Therefore, for the chronic 

dietary risk assessment, a total 100X uncertainty factor was used (interspecies 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) and intraspecies (10X) 

uncertainty factors. 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment 

When there are potential occupational and residential exposures to a pesticide, the risk 

assessment must address exposures from three major sources: oral, dermal, and inhalation. It 

must be determined whether or not the individual exposures have the same toxicological effects. 
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If they do, then they can be combined. For ethaboxam, dermal and inhalation exposures were 

not combined since the toxicological effects for each route were not the same. 

4.5.3 Cancer Classification and Risk 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,” and concluded that potential human Leydig cell tumorigenesis is 

not expected at exposure levels that do not cause tumors in rats. The Agency has determined that 

quantification of cancer risk using a non-linear approach would adequately account for all 

chronic toxicity, including carcinogenicity, 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 tumors (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 highest 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 mutagen; however, the clastogenic potential of 

this compound cannot be determined at this time. Although the weight-of-evidence does 

not support a mutagenicity concern, 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 cell function (testosterone production). Thus, 

a nonlinear dose-response approach should 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, investigating reproductive hormone levels, exposure to 

ethaboxam resulted in a decrease in testosterone, and a slight increase in luteinizing 

hormone (LH). However, the data presented did not support a consistent pattern of 

decreased testosterone or increased LH and cannot be linked with 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 relevance of this tumor finding. Additional 
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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 Toxicity 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 

UFA= 10X 

UFH=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 point that is derived from observed dose-response data and 

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

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

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

sensitivity among members of the human population (intraspecies). PAD = population adjusted dose (a = acute, c = 

chronic). RfD = reference dose. 

 
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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 

UFA=10X 

UFH=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.] 

UFA=10X 

UFH=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 expected for the proposed seed treatment use. 

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

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

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

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

sensitivity among members of the human population (intraspecies). 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 previously to support the grape 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 thiophene 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 only major metabolite identified in plants was 

LGC-35523, a keto carboxylic acid derivative of thiophene labeled ethaboxam, which the 

petitioner stated is identical to a photodegradate present in an aqueous photolysis study. LGC-
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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 fruit. Metabolite LGC-35523 was not detected in potatoes. 

The propensity for translocation of ethaboxam residues in/on grapes and tomatoes was 

investigated by covering branches and/or trusses prior to applications of the test substance. 

When the total radioactive residue (TRR) of covered versus uncovered 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 petitioner expand their requests for ethaboxam 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/anaerobic conditions to carbon dioxide, nonextractable bound residues, minor metabolites (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-life was 108 days. In laboratory aerobic 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 20o

C. A water-sediment study 

demonstrated that ethaboxam rapidly dissipates 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 rats, 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 submitted data pertaining to environmental fate 

and environmental degradates. Preliminary information 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 excretion was in feces (approximately 70% of the 
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S

N

H

O

CN

HO

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 occurred at the low dose (10 mg/kg for 14 days). 

The nature of the residue in plants is adequately 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 plant metabolism studies. However, the extent of 

ethaboxam metabolism varied quantitatively among the crops tested. In grapes, the metabolite 

LGC-35523 also comprised a significant portion (up to 18%) of the total radioactive residue 

(TRR). 

Metabolism of ethaboxam appears to be quite different in plants and rats based on the available 

data. Although in all tested species the major residue is ethaboxam, the primary metabolite in 

rats, LGC-32801, was not observed in plants. Similarly, 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. Reported 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

H2N

CH2CH3

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

NH2

N

N

S

H3CH2CHN

CH2CH3

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

CH3CH2NH

CN

CH2CH3
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Table 5.1.3. Tabular Summary of Metabolites and Degradates. Reported data are ranges across 

all PHIs. 

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

thiophen-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

H2N

CH2CH3

O

N CN

HO3S 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

H3CH2C

CH2CH3

O

HO3S

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 ring or the thiophene ring. Ranges of residues found in grape, 

tomato, and potato are due to decreasing 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 noted above, ethaboxam and LGC-35523 were the only 

significant residues found in the grape metabolism study. Although it occurred at a significant 

portion of the applied radioactivity in grapes, 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 D332315, M. Doherty, Sept 8, 2006, Attachment 1): 

1. LGC-35523 is a very polar compound that is likely to undergo rapid excretion with very 

little biochemical transformation in mammals. It is not likely to engage in interactions 

that might lead to microsomal enzyme induction, inhibition of mitochondrial respiration, 

or endocrine disruption, as the much less polar parent will do. 

2. The following 28-day rat dietary studies indicate that LGC-35523 is less toxic than the 

parent: 
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 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 and a LOAEL of 13,000 ppm (with 

relatively benign treatment-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 toxicity resulting in growth retardation. At 

higher doses liver and thyroid weights were increased. 

EFED conducted a screening-level assessment of potential ethaboxam residues in surface and 

ground water sources of drinking water. This screening 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 Degradates 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 submitted 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 commodities, 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 rates, residues were below 5 ppb in seeds and 

pods in all samples (both labels). Residues ranged from <5 ppb to 25 ppb in soybean forage and 

hay. However, the label contains a feeding restriction 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 determined that the proposed uses qualify as nonfood uses. 
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Valent U.S.A. Corporation submitted adequate field trial data for residues of ethaboxam on 

soybean seed. Three field trials were conducted in the United States during the 2010 growing 

season in NAFTA Growing Zone 5 (Illinois, Missouri, 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 treatment 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 ethaboxam 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 that 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 radiotracer 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 submitted 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 residues in grapes. For the dietary assessment, HED 

used tolerance level residues and assumed 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 “water, direct, all sources” and “water, indirect, all 

sources.” 

Estimated drinking water concentrations (EDWCs) for ethaboxam were modeled using 

conservative assumptions for the proposed seed treatment uses. The highest use rate of 0.6 fl 

oz/100 lb seed is for legume vegetables (crop group 6) of which garden pea has the highest seed 

rate of 411 lbs seed/A. Given that the product is 3.2 lbs active ingredient per gallon, the 

maximum application rate is 0.062 lb/A. The water solubility of ethaboxam is 12.4 ppm (at 

25o

C). For the purpose of the drinking water screen, ethaboxam is assumed stable to all routes of 

metabolism and degradation due to the in-review status of the supporting environmental fate 

data. This is a very conservative assumption. Ethaboxam EDWCs were modeled with EFED’s 

Tier 1 surface water model (FIRST) and Tier 1 groundwater model (SCIGROW) 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 results from the surface water model are the highest 

estimates and were used in the dietary assessment. In addition, there is no acute dietary 
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endpoint, but HED has incorporated the peak surface 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 the applied fungicide ends up in drinking water. 

The models and their descriptions are available 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 (the only food commodities in the assessment). 

Empirical data indicate that residues of ethaboxam 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 incorporation of estimated ethaboxam residues in 

drinking water for the proposed non-food, seed treatment uses. For water, the EFED assumed 

no degradation, and provided the highest estimate from conservative models. 

5.4.2 Percent Crop Treated Used in Dietary Assessment 

HED has assumed 100% of imported grape commodities (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 health, 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% of 
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the cPAD (children 1-2 years old). Generally, HED is concerned when dietary risk estimates 

exceed 100% of the PAD; therefore, the chronic dietary 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 and 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, including those of infants and children. 

5.4.5 Cancer Dietary Risk Assessment 

Ethaboxam is classified as having “suggestive evidence of carcinogenicity,” and HED has 

concluded that assessments using 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 yrs1 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 highest 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 exposure 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 fields. The seed is previously treated with pesticides in a seed 

treatment facility either on farm or elsewhere. Therefore exposure potential resulting from spray 

drift is expected to be negligible. 

 
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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 aggregate risk estimates are 

below HED’s level of concern. 

8.0 Cumulative Exposure/Risk Characterization

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

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

to ethaboxam and any other substances, and ethaboxam does not appear to produce a toxic 

metabolite produced by other substances. For the purposes 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 determine which chemicals have a common mechanism 

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

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

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

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

9.0 Occupational Exposure/Risk Characterization

9.1 Short- and Intermediate-Term Handler Risk 

D409850, M. Collantes, April 30, 2013 

The registrant, Valent, is proposing a new use for V-10208 3.2 FS as a commercial and on-farm 

seed treatment for legumes vegetable seed, cereal grain seed and rapeseed. Although the 

proposed product is for on-farm use, the label specifies that seed should 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 routes. The quantitative exposure/risk assessment 

developed for occupational handlers treating seeds with ethaboxam 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 using surrogate data in the absence of chemicalspecific data, which include the Standard Operating Procedures (SOPs) for Seed Treatment 

(Policy 14), “Amount of Seed Treated or Planted per Day” (Policy 15), and Interim Guidance 

“Amount of Commercial Seed Treated Per Day” (Policy 15.1).
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Treatment of the proposed seeds is expected to result in short- and intermediate-term exposure. 

The AHETF survey reports that corn commercial facilities operate 240 days per year (50th

percentile; range 150 to 270 days), canola commercial facilities operate 180 days per year (50th

percentile: range 90 to 210 days) and 39% of soybean is treated downstream for a duration of 49 

days (50th percentile; range 4 to 150 days), while soybean commercial facilities operate 210 days 

per year (50th 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 that the same chemical is used consecutively 

for a long-term duration. Therefore, chronic occupational handler exposure for seed treatment 

was not assessed. Furthermore, the dermal and inhalation unit exposure values specified in 

Policy 14 are based on open-pour systems, whereas the majority of the seed 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 conservative estimates of exposure. 

Note that although both short- and intermediate-term durations of exposure are expected, the 

endpoints/doses for the respective dermal and inhalation short- and intermediate-term risk 

assessments are the same. Therefore, only short-term exposure and risk have been 

quantitatively assessed, and are considered protective of intermediate-term exposure and risk. 

The Personal Protective Equipment (PPE) statement on the proposed label requires applicators 

and other handlers to wear the following: 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 gloves 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 Exposure 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 resulting from multiple activities while treating 

legume vegetables to 410,000 for inhalation exposure resulting from treating canola. The 

loader/planter exposure and risk estimates ranged from a dermal MOE of 39,000 for cereal 

grains to an inhalation MOE of 7.8 x 106

 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 processed seed from other sources such as seed producers, seed 
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breeders and growers. They include seed and chemicals dealerships, distributors, retailers and 

agricultural cooperatives. Treatment may include custom treating of untreated seed or added 

treatments (i.e. adding fungicide to seed all ready treated 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 downstream facilities which may potentially treat 

legume seeds. Likewise, commercial seed treatment 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-Term 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 pesticide (also referred to as reentry exposure). The potential for dermal and inhalation post-application exposures following 

the planting of ethaboxam-treated seeds is unlikely because sustained levels of contact with 

treated seed after it has been placed in the soil or other planting media would not be expected. 

There is no routine cultural practice 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 exception to the Agricultural 

Use Requirements (for seed treatments), and has a restricted entry interval (REI) of 12 hours. 
Ethaboxam Human Health Risk Assessment DP No. 396490 

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Table 9.1. Short- and Intermediate-term Occupational Seed-Treatment Handlers Exposure and Risk Estimates for Ethaboxam 

Use Site PPE 

Dermal Unit 

Exposure a 

(mg/lb ai) 

Inhalation 

Unit 

Exposurea

(mg/lb ai) 

Application 

Rate b 

(lb ai/lb seed) 

Amount 

Treatedc

(lb seed/ 

day) 

Dermal 

Dose d 

(mg/kg/day) 

Daily 

Inhalation 

Dosee 

(mg/kg/day)

Derm

MOE

Loader/Applicator 

Legume 

Vegetables 

(surrogate – 

soybeans) Single 

Layer, 

Gloves 0.023 0.00034 

0.00015 281,250 0.012 0.000179 25,00

Cereal Grains 

(surrogate – 

wheat) 0.000065 360,000 0.0067 0.000099 45,00

Field Corn 

0.000075 

339,500 0.0073 0.00010 41,00

Canola and 

Rapeseed 125,000 0.0027 0.000039 110,0

Multiple Activities 

Legume 

Vegetables 

(surrogate – 

soybeans) Single 

Layer, 

Gloves 0.042 0.0016 

0.00015 281,250 0.022 0.00084 14,00

Cereal Grains 

(surrogate – 

wheat) 

0.000065 360,000 0.012 0.000468 24,00

Field Corn 

0.000075 

339,500 0.0133 0.00050 22,00

Canola and 

Rapeseed 125,000 0.0049 0.000187 61,00

a. Unit Exposures are based on Policy 14: Standard Operating Procedures for Seed Treatment. b. Application Rate is based on Proposed Label for V-10208 3.2 FS (EPA Reg No. 59639-185). c. Amount of Seed Treated is based 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 (lb ai/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 (16.3 mg/kg/day) ÷ inhalation dose (mg/kg/day). 
Ethaboxam Human Health Risk Assessment DP No. 396490 

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Table 9.2 Handler-Seed Planters Exposure and Risk Estimates for Ethaboxam Use Site Mitigation 

Level 

Dermal Unit Exposurea(mg/lb ai) 

Inhalation Unit Exposurea(mg/lb ai) 

Application Rateb (lb ai lb seed) 

Amount Plantedc

Dermal Dosed(mg/kg/day) 

Dermal MOEe Inhalat

Dosef(mg/kg

Legume 

Vegetables 

(surrogate – 

soybeans)

 Single 

Layer, 

Gloves 

0.25 0.0034 

0.00015 10,640 0.005 60,000 0.000

Cereal Grains (surrogate – wheat)

0.000065 37,500 0.0076 39,000 0.00

Field Corn

0.000075 

6,000 0.0014 210,000 0.000

Canola and Rapeseed 1645 0.00039 780,000 0.000

 a. Unit Exposures are based on Policy 14: Standard Operating Procedures for Seed Treatment. Note: the dermal unit exposure reflects handl

loading treated seed into hopper while using gloves, but reflects the driver operating the tractor without gloves, and this is considered approp

agricultural practices. 

 b. Application Rate is based on proposed label for V-10208 3.2 FS (EPA Reg. No. 59639-185).  c. Amount planted is based on information provided in the HED Reviewer’s Aid to Calculating Occupational Exposures from Activities Rel

 to Agricultural Seed Treatment (November 29, 2012) and the BEAD Acres Planted per Day and Seeding Rates of Crops Grown in the Un 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 (lb ai/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 (16.3 mg/kg/day) /inhalation dose (mg/kg/day). 
Ethaboxam Human Health Risk Assessment DP No. 396490 

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10.0 References

Ethaboxam. Petition for the Establishment of Tolerances without a U.S. Registration on Grape 

and its Processed Commodities. Summary of Analytical 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 Analytical 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, Cereal Grains (Crop Group 15) except Rice and 

Wild Rice, and the Rapeseed Subgroup (20-A). D411091, D. McNeilly, 4/30/2013. 

Ethaboxam: Occupational and Residential Exposure/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 Memo (D411925, 2013), A. Shelby 

MRID 46824211. EU Plant Protection Product Dossier 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 Commercial 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 Research 

 
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Appendix A. Toxicology Profile and Executive Summaries 

A.1 Toxicology Data Requirements 

The requirements (40 CFR 158.340) for food use (tolerances on imported commodities only) and 

non-food uses of ethaboxam are in Appendix Table A.1. Use of the new guideline numbers does 

not imply that the new (1998) guideline protocols were used. 

Appendix Table A.1. Toxicology 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 ........... Developmental Toxicity (rodent) 

870.3700b ........... Developmental Toxicity (nonrodent) 

870.3800 ............. Reproduction 

yes 

yes 

yes 

yes 

yes 

yes 

870.4100a ........... Chronic Toxicity (rodent) 

870.4100b ........... Chronic Toxicity (nonrodent) 

870.4200a ........... 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—Structural Chromosomal Aberrations 

870.5395 ............. Mutagenicity—Erythrocyte 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 Council (HASPOC) concluded (TXR# 0056543) that a subchronic inhalation study is not needed for 

ethaboxam at this time. 

 
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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 LD50 Males and females >

5,000 mg/kg 

LD50 Combined >5,000 mg/kg 

IV 

870.1200 Acute-dermal 48535632 LD50 Males and females >

5,000 mg/kg 

IV 

870.1300 Acute-inhalation 48535633 LC50 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 Other 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. 
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Table A.2.b. Subchronic, Chronic and Other 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 spermatids/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. 
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Table A.2.b. Subchronic, Chronic and Other 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 (incomplete 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 determined 
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Table A.2.b. Subchronic, Chronic and Other 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 F0 and F1 generation adult males (10.5-

22% and 10.7-14.5%, respectively), decreased 

premating body weight of the F1 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 spermatogenic 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 F1 pups (13.1-

15.7%), and decreased viability of the F1 (14%) 

and F2 (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, decreased 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) 
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Table A.2.b. Subchronic, Chronic and Other 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/Guideline 46378529 

 

Negative 

870.5300 (2001) 

IN VITRO

MAMMALIAN CELL 

GENE MUTATION 

TEST 

Acceptable/Guideline 46378530 Negative 

870.5375 (2001) 

-IN VITRO

MAMMALIAN CELL 

CHROMOSOME 

ABERRATION TEST 

Unacceptable/Guideline 46378531 Induced significant increases 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. 
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Table A.2.b. Subchronic, Chronic and Other Toxicity Studies Ethaboxam Technical

Guideline/ 

Type of Study

Study Title/ 

Classification /Doses

MRID Results 

870.5395 (2001) 

MAMMALIAN 

ERYTHROCYTE 

MICRONUCLEUS 

TEST (XDE-750) 

Acceptable/Guideline 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 excretion combined accounted 

for 96-104% of the administered 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/cm2 or 1 mg/cm2

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. 
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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 exposure is expected with the registered and 

proposed uses. 

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

Acute reference doses for the general population and females, 13-49 have not been established. 

There were no appropriate studies that demonstrated evidence of toxicity 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 variability (± 2 days). 

Therefore, the endpoint in the absence of other potential acute 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 extrapolation, 10x intraspecies variability, 1x FQPA 

Safety Factor) 

Study/Endpoint/Uncertainty Factors: A combined chronic/carcinogenicity study in rats was 

selected to establish the cRfD of 0.055 mg/kg/day. The NOAEL of 5.5 mg/kg/day and the 

LOAEL of 16.4 mg/kg/day were based 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 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 higher 

dose (35.8 mg/kg/day), effects in the chronic mouse study (117 mg/kg/day) and systemic, 

reproductive, and offspring effects seen in the 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 = 

100 (UF )

5.5 mg/kg/day = 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 extrapolation, 10x intraspecies variability, 1x FQPA 

Safety Factor) 
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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 weights, congestion, and alveolar septal congestion and focal 

alveolar hemorrhage) were seen in a 13-week oral study with a lower point of departure (PoD). 

However, these effects were adequately measured in the 28 day dermal toxicity study, and no 

reproductive or lung effects were seen. 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 quantitative susceptibility. 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 extrapolation, 10x intraspecies 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 effects 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 appropriate 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 developmental/reproduction studies. For risk assessment, 

inhalation toxicity was assumed to be equivalent to toxicity 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 extrapolation, 10x intraspecies variability, 1x FQPA 

Safety Factor). 

Study/Endpoint/Uncertainty Factors: The 2-generation reproduction study was selected for 

the incidental oral endpoint. The study is appropriate for the population of concern (children). 

The dose/endpoint is also protective of effects seen in the 13 week rat and developmental studies. 

Based on the current use pattern, there is no concern for incidental oral. 
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Residential Dermal/Inhalation Exposure (Short-Term-Intermediate-Term) 

The Occupational endpoints/PoDs selected are applicable to residential exposures via dermal and 

inhalation routes; however, residential exposure is not expected for the proposed seed treatment 

use. 

Occupational/ Residential Dermal 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 extrapolation, 10x intraspecies 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 LOAEL of 16.4 mg/kg/day 

were based on effects observed on the male reproductive organs. 

The dermal toxicity study in rats was also considered 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. Therefore, the combined chronic/carcinogenicity study 

in rats with male reproductive effects was selected for long-term dermal exposure. The study is 

also protective of the Leydig cell tumors 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 the 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. Since an oral toxicity study was used for 

dermal exposure, a dermal absorption factor of 7.5% was used. 

Occupational/Residential Inhalation 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 extrapolation, 10x intraspecies 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 LOAEL of 16.4 mg/kg/day 

were based on effects observed on the male reproductive organs. This study is appropriate for 

the population of concern and the exposure duration. In the rat study, reproductive effects, as 

well as lung effects were seen in the male reproductive organs the (target for ethaboxam). The 

study is also protective of the Leydig cell tumors 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 the 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. 
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A.4 EXECUTIVE SUMMARIES FOR NEW AND REVISED TOXICOLOGY 

 STUDIES 

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

EXECUTIVE SUMMARY: In a 28-day oral toxicity 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 diet 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 mortality, clinical signs, organ weights, or gross 

pathology. Histopathology was not evaluated. A statistically significant decrease in mean body 

weight gain was seen in males in the 13000 ppm group; overall mean food efficiency in this 

group was reduced 12% (not statistically evaluated). Both sexes in the 13000 ppm group had a 

significantly increased blood albumin level. Males in the 13000 ppm group had a significantly 

decreased mean corpuscular volume (MCV); in the absence of other hematological changes, the 

decreased MCV count in males is unlikely to be treatment-related. Minor hematology and blood 

chemistry changes were recorded for animals receiving 13000 ppm. Females in the 13000 ppm 

group showed increases in mean total white blood cell, lymphocyte, monocyte, basophil, and 

large unstained cell counts, and in blood cholesterol 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 toxicity 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 toxicity 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 (equivalent 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 mortality. At 200 ppm, there were a few statistically 

significant effects on hematology and clinical chemistry parameters; in the absence of correlating 

pathology, the toxicological significance 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 ducts), 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, there were no effects on absolute body weight and no 

corresponding liver histopathology. A few statistically significant changes in hematology and 

clinical chemistry parameters, of questionable toxicological significance, were also noted in both 

sexes at 650 ppm. At 2000ppm, decreased mean absolute body weight in both sexes (up to 
Ethaboxam Human Health Risk Assessment DP No. 396490 

Page 44 of 53 

21%) , a statistically significant decreased in mean body weight gain in both sexes (Weeks 0-13), 

decreased total food consumption in males, increased mean adjusted liver weights with a 

correlating increase in trace centrilobular hepatocyte hypertrophy in both sexes, an increased 

incidence of fine vacuolation of the zona glomerulosa in the adrenals in females, decreased mean 

absolute or adjusted testes weight with correlating severe testicular atrophy (all animals), 

increased incidence of trace-minimal interstitial cell hyperplasia of the testes, decreased mean 

absolute prostate weight, and decreased mean absolute epididymides weight with a correlating 

absence of spermatozoa (all animals) and increased incidence of abnormal spermatogenic cells in 

occasional ducts. Changes in hematological and clinical chemistry parameters also were found in 

both sexes at 2000 ppm, some of which (e.g., increased 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 observed in females at 2000 ppm. 

The LOAEL is 650 ppm (equivalent to 49.7 and 58.0 mg/kg/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). The NOAEL is 200 ppm 

(equivalent to 16.3 and 17.9 mg/kg/day in males and females, respectively). 

This 90-day oral toxicity study in the rat is Acceptable/Guideline and satisfies the guideline 

requirement for a 90-day oral 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 controls and treated groups in food and water 

consumption, ophthalmology, and urinalysis parameters that were considered toxicologically 

significant. There were three premature sacrifices (40 and 100 mg/kg/day groups) done for 

humane reasons, one male dog had meningitis and 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 (adjusted 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 were 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 weights comparable with controls. However, the 

body weight gains were decreased and ranged from 78 to 81% of the control in the 40 and 100 

mg/kg/day groups. The body weights for females in the 40 and 100 mg/kg/day groups were 

decreased to 87 and 83% of control, respectively, 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 than other dose groups. The body weight gain of 
Ethaboxam Human Health Risk Assessment DP No. 396490 

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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 toxicity study in dogs is Acceptable/Guideline and satisfies the guideline 

requirement (OPPTS 870.3150; OECD 409) for a 90-day oral toxicity 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 shaved skin of 5 rats of the Sprague-Dawley [(Crl: 

CD) BR VAF PLUS strain]/sex/dose at dose 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 mortality, clinical signs, chemistry, or organ weights. 

Food intake was variable in both sexes but not considered 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. There was dermal irritation reported at 300 and 

1000 mg/kg/day in males and delineated by microscopic 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/day in male rats, based on decreasing body 

weight and weight gains without a significant loss of food intake. The NOAEL is 300 

mg/kg/day. 

The LOAEL for dermal irritation is 300 mg/kg/day in male rats based on histopathological 

changes of epithelial hyperplasia, hyperkeratosis, 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 toxicity 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% methylcellulose. On GD 20, all females were killed by CO2

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 and stained for skeletal examination. 
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Fur loss/alopecia was observed on seven animals 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: control: 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 intake (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 (litters) 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, respectively. Pre-implantation loss for the 100- 

and 300-mg/kg/day groups was significantly greater than that of the control (13.5% and 11.6%, 

respectively, compared to 7.9% for the controls), but no effects were observed on the mean 

number of implantations or mean number of live fetuses. The distribution of dams showing total 

resorption (1 control and 2 at 30 mg/kg/day) did not suggest a relationship to treatment. The 

fetal sex ratio was unaffected by treatment. Fetal body weight was similar between the treated 

and control groups. 

No treatment-related external or skeletal malformations/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 fetuses (litters) with abnormal 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 lobation was within the historical 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 study 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 toxicity 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 CO2 asphyxiation and subjected to macroscopic post mortem 

examination. The following observations were recorded: pregnancy status, number of corpora 

lutea, number and distribution of live young and embryofetal deaths, individual fetal weights, 

and gross fetal abnormalities. 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 and stained for skeletal examination. 
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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 control level throughout the treatment period 

resulting in final body weight of the high-dose group 85% of the control 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 beginning 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/day based on post dose salivation. The 

maternal NOAEL is 100 mg/kg/day. 

Three high-dose and one control dam had complete litter resorption. The mean number of 

corpora lutea, implantations, and live fetuses and 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), respectively. In the high-dose group, six fetuses from 

2 litters had misshapen pituitary and seven fetuses from four litters had diaphragmatic hernia 

compared with none of the controls. Other treatment-related findings in the control, low-, mid-, 

and high-dose fetuses(litters) included thin diaphragm with protrusion 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 thoracic 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(litters), 1(1), 5(3), 5(5), and 9(7), respectively; However, the 

incidences were within historical control range. 

The developmental toxicity LOAEL for LGC-30473 in rats is 1000 mg/kg/day, based on 

thin diaphragm with liver protrusion, decreased fetal body weight (21%), misshapen 

pituitary, diaphragmatic hernia, and skeletal anomalies (incomplete or irregular 

ossification of the pelvic girdle, digits, sternebrae, and thoracic vertebral centra).The 

developmental toxicity NOAEL is 300 mg/kg/day. 

ACUTE NEUROTOXICITY STUDY- RAT; OPPTS 870.6200A 

EXECUTIVE SUMMARY: In an acute neurotoxicity study (MRID 48535643), groups of male 

and female (aged 41-42 days) (Sprague-Dawley Crl:CD (SD strain) (rat species) (10/sex/dose) 

were given a single oral dose of Ethaboxam (98.9 a.i., batch # AS2293b) in 1% aqueous 

carboxymethyl cellulose via gavage at doses of 0, 300, 1000, or 2000 mg/kg/day and observed 
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for 14 days. Neurobehavioral assessment (functional observational battery and motor activity 

testing) was performed in 10 animals/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 changes. Of the perfused animals, 5/sex/dose from 

the control and 2000 mg/kg/day dose levels were subjected to histopathological evaluation of 

brain, CNS and peripheral nervous system tissues. Body weight gains 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, clinical signs, brain weight, gross or histologic 

pathology or neuropathology. 

The treatment of the top two doses (1000, 2000 mg/kg/day) caused a slight drop in food intake in 

the first week of the study which gradually returned to near control 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 were 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 palatability since changes were seen during the first week of 

treatment and dissipated by week two. Therefore, in the absence of other treatment related effects 

the decrease in body weight gain alone 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 neurotoxicity 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 activity testing) was performed on all animals at 

pretest (Week -1) and Weeks 1, 3, 7 and 12. Opthamology exams were conducted prior to dosing 

and at the end of the study. Hematology and clinical chemistry parameters along with organ 

weights and gross histopathologyobservations were also determined. At study termination, all 

surviving animals were euthanized and perfused in situ for neuropathological examination; fixed 

brain weights and brain dimensions 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 evaluation 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 observations, ophthalmology, FOB findings, or locomotor 

activity pattern (ambulatory and total motor activity counts) at any dietary concentration level in 
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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 was 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 observed during the weekly body weight evaluations. 

Treatment-related effects on body weights and cumulative body weight gains were evident at the 

dietary concentration level of 1,500 ppm in males 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 significant differences in body weights were noted at 

dietary concentration levels of 250 and 600 ppm in males and females and at 1,500 ppm in 

females. Mean body weight gains were significantly 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 gain (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-related 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 differences in body weight (10% increases at 600 ppm during Weeks 6, 7, 

and 8) and food consumption compared to controls in the female dose groups during the study 

period, these were transient and did not show dose response relationships. In addition, there were 

no statistically significant decreases in body weight gains, cumulative body weight gains or 

decreases in body weight in the female exposed groups throughout the study. On this basis, it 

was concluded that the inconsistent 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 alterations observed in brain weights or measurements, 

gross histopathology observations or microscopic neurohistopathology findings in the 1,500 ppm 

(high dose) male and female groups compared to controls 

It is concluded that Ethaboxam did not exhibit neurotoxic effects in this subchronic neurotoxicity 

feeding study at dietary concentration levels of 250, 600 and 1,500 ppm, based on the lack of 

altered behavior in the FOB parameters, no changes in locomotor activity, and no effects on 

brain weights and measurements, or the macroscopic 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 characterized by decreased body weights, decreased 

cumulative body weight gains and significant reductions in food consumption. 

 

The NOAEL is 600 ppm (equivalent to 43 mg/kg 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. 
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The study is classified as Acceptable/Guideline and satisfies the guideline requirement (OPPTS 

870.6200b) for a subchronic neurotoxicity study in rats. 

IN VITRO MAMMALIAN CELL MICRONUCLEUS ASSAY; OPPTS 870.5550 

In an in vitro mammalian cell micronucleus assay (MRID 46989601), 24-and 48-hr 

phytohemagglutinin (PHA)-stimulated human lymphocyte cultures from male donors were 

exposed to LGC-30473 (99.7% a.i, Batch # P980622) prepared in dimethyl 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 harvested 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 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. 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 nonactivated test level for centromeric staining, using 

fluorescent in situ hybridization (FISH), revealed that the mechanism for this induction was 

aneugenicity rather than clastogenicity. Since positive 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 demonstrated 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 PENETRATION STUDY-RAT; 870.7600 

EXECUTIVE SUMMARY: In a dermal penetration study (MRID 48535712), LGC-30473 

unlabeled and radiolabeled at the 4-ethyl site (purity 99.3%, Batch No. P980622 unlabeled, and 

purity >97%, Batch No. P341 radiolabeled) was applied to groups of 12 male Sprague Dawley 

rats/dose at concentrations of 2 μg/cm2

 or 1 mg/cm2 skin. The test material was allowed to 

remain in contact with the skin for six hours after application. During the treatment period, the 

rats were placed in glass metabolism cages. After six hours, residual test material was removed 

by washing the skin. Four rats/time interval/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. 
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Recovery of the radiolabel for the study was excellent, being >99.4% at 2 μg/cm2

 and >98.8% at 

1 mg/cm2 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, indicating 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 0.08% at the high dose, and 0.24 to 0.95% at the 

low dose) remained in the viable epidermis, and 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 level 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 absorbable dose (the amount remaining in treated 

skin, stratum corneum, and around the dose site) was 6.43% at 6hrs, 3.46% at 72 hours, and 

3.29% at 120 hrs. For risk assessment purposes, the absorbed and absorbable doses (from treated 

skin, stratum corneum, and skin surrounding dose site) were combined and due to the variability 

in the absorbable dose, the 6 hour time point resulted in the greatest total 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 appropriate for risk assessment. 

This study is Acceptable/Guideline and satisfies the guideline requirement for a dermal 

penetration study (870.7600) in rats. 

IMMUNOTOXICITY STUDY-RAT; OPPTS 870.7800 

EXECUTIVE SUMMARY: In an immunotoxicity study (MRID # 48535655), Ethaboxam 

(98.9% a.i., Batch/Lot LGC- 30473) was administered to male Sprague-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 days. The positive control group consisting of female rats was 

administered cyclophosphamide 50 mg/kg (dose volume 10 mL/kg b.w) by intraperitoneal 

injection on Day 27. During the study, clinical condition, bodyweight, food and water 

consumption, organ weight, macropathology were evaluated. On Day 25, all animals in all 

groups received a single intravenous dose of 1 mL/animal, sheep red blood cells (SRBC, 

2x108

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 forming 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 groups 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. 
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The systemic toxicity NOAEL was 250 ppm (equivalent 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/106

 viable cells), total activity 

(PFC/spleen) or cellularity (cells/spleen) in all treated groups. High inter-individual 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 distribution that would 

demonstrate significant suppression of anti-SRBC antibody response. Animals in positive control 

group showed a statistically significant (p< 0.001) decrease of the PFC response. This confirmed 

the ability of the test system to detect immuno-suppressive effects and confirmed the validity of 

the study design. 

The Natural Killer (NK) cells activity was not evaluated in this study. The toxicology database of 

Ethaboxam did not indicate immunotoxicity. The overall weight of evidence suggests that the 

chemical does not directly target 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 for acute neurotoxicity study (MRID 48535687), groups 

of non-fasted, young adult Sprague-Dawley Crl:CD(SD) 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 assessment (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 macroscopic pathology in males or females at any dose level. 

On day 4, slight body weight loss was observed 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 gain during the latter half of the observation 

period. Overall (Day 1-7) mean body weight gain was low in the 1,000 mg/kg group females and 

2,000 mg/kg group males. The lower body weight gains in these animals were consistent with 

the low body weight gain and body weight loss that were noted between Day 1 and Day 4. 
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No test substance-related effects on neurobehavioral assessments, including home cage, arena, 

manipulation and in-the-hand observations. Bright yellow urine was observed during the arena 

observations and occasionally during manipulation observations 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 Sprague-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 Tmax was 

6 hours after dosing, that was principally selected based on a previous rat metabolism study. In 

addition, this study establishes suitable 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 Database 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-entry 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 exposed to a pesticide or other chemical were used in this risk 

assessment.