Ethylene Thiourea Human Health Risk Assessment DP No. D411820 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: May 23,2013 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Ethylene Thiourea (ETU); Aggregate Human Health Risk Assessment of the 

Common Metabolite/Degradate Ethylene Thiourea (ETU) to Support Proposed New Section 3 

Use on Walnuts and Tolerance for Imported Tangerines 

PC Codes: 014504,014601, and 600016 

Decision No.: 467111 

Petition No.: 1F7935, 2E8062 

Risk Assessment Type: Aggregate 

TXRNo.:NA 

MRIDNo.: NA 

DP Barcode: 411820 

Registration No.: NA 

Regulatory Action: Section 3; New Tolerance 

Case No.: NA 

CAS No.: 8018-01-7,9006-42-2, and 96-45-7 

40 CFR: §180.176 and §180.217 

FROM: Danette Drew, Chemist/Risk Asses~~---~ -

Ana Rivera-Lupianez, Chemist ~-t--"0 -

Linda 

Pete Savoia, 

Taylor, 

Chemist 

Ph.D., Toxicolo 

L~

· 

: 

~~~~? 

- J ~ 

c.--

Risk Assessment Branch V an II 

Health Effects Division (7509P) ~ 

THROUGH: Michael Metzger, Branch Chief U j' ~ Risk Assessment Branch V and Vi 

'l ' 

Health Effects Division (7509P) 

TO: Tamue Gibson, Risk Manager 

Heather Garvie, Risk Manager 

Fungicide Branch 

Registration Division (7505P) 

Attached please find the human health risk assessment for ethylene thiourea (ETU), which is the 

common metabolite/degradate of the registered ethylene bisdithiocarbamate (EBDC) fungicides 

mancozeb and metiram. This document supersedes the 4115/13 document D405592, Aggregate 

Human Health Risk Assessment of the Common Metabolite/Degradate Ethylene Thiourea (ETU) 

to Support Proposed New Section 3 Use on Walnuts and Tolerance for Imported Tangerines. 

Page 1 of38 
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New uses are proposed for the use of mancozeb on walnuts and for tolerances for mancozeb on 

imported tangerines. This aggregate risk assessment summarizes human health risks from 

combined exposure to ETU resulting from all registered and proposed uses of the parent EBDCs 

(mancozeb and metiram).
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1.0 Executive Summary............................................................................................................. 4

2.0 Data Deficiencies................................................................................................................. 7

3.1 Chemical Identity ............................................................................................................. 7

3.2 Physical/Chemical Characteristics................................................................................... 8

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

3.4 Anticipated Exposure Pathways....................................................................................... 9

3.5 Consideration of Environmental Justice .......................................................................... 9

4.0 Hazard Characterization and Dose-Response Assessment................................................ 10

4.1 Summary of Toxicological Effects ................................................................................ 10

4.2 Safety Factor for Infants and Children (FQPA Safety Factor)....................................... 12

4.2.1 Completeness of the Toxicology Database............................................................. 12

4.2.2 Evidence of Neurotoxicity ...................................................................................... 13

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ......... 13

4.2.4 Residual Uncertainty in the Exposure Database..................................................... 13

4.3 Toxicity Endpoint and Point of Departure Selections.................................................... 13

5.0 Dietary Exposure and Risk Assessment ............................................................................ 18

5.1 Food Residue Profile...................................................................................................... 18

5.2 Water Residue Profile .................................................................................................... 18

5.3 Dietary Risk Assessment................................................................................................ 19

5.3.1 Description of Residue Data Used in Dietary Assessment..................................... 20

5.3.2 Percent Crop Treated Used in Dietary Assessment ................................................ 20

5.3.3 Acute Dietary Risk Assessment.............................................................................. 21

5.3.4 Chronic Dietary Risk Assessment .......................................................................... 21

5.3.5 Cancer Dietary Risk Assessment............................................................................ 21

5.3.6 Summary Table....................................................................................................... 21

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .................................... 22

6.1 Residential Risk Estimates for Use in Aggregate Assessment ...................................... 22

6.2 Residential Bystander Post-application Inhalation Exposure ........................................ 24

6.3 Spray Drift...................................................................................................................... 24

7.0 Aggregate Exposure/Risk Characterization....................................................................... 25

7.1 Acute Aggregate Risk .................................................................................................... 26

7.2 Short-Term Aggregate Risk ........................................................................................... 26

7.3 Intermediate-Term Aggregate Risk................................................................................ 27

7.4 Chronic Aggregate Risk................................................................................................. 27

7.5 Cancer Aggregate Risk................................................................................................... 27

8.0 Cumulative Exposure/Risk Characterization..................................................................... 27

9.0 Occupational Exposure/Risk Characterization .................................................................. 28

10.0 References.......................................................................................................................... 28

Appendix A. Toxicology Profile and Executive Summaries....................................................... 30

A.1 Toxicity Profiles............................................................................................................. 30

A.2 Executive Summaries....................................................................................................... 33

Appendix B. Review of Human Research ................................................................................... 38
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1.0 Executive Summary

Background

Ethylene thiourea (ETU) is a common degradate/metabolite of the ethylene bisdithiocarbamate 

(EBDC) fungicides mancozeb and metiram; these are the only currently registered EBDCs. A 

third EBDC, maneb, is no longer registered for use and maneb tolerances expired in December 

2012. The EBDCs are broad spectrum contact fungicides used in agriculture, professional turf 

management, and horticulture. In terms of usage (total lbs. active ingredient applied), mancozeb 

is the more significant of the two registered EBDCs. Mancozeb is used on a wide variety of 

agricultural food crops, on turf, including golf courses and sod farms, and on home vegetable 

gardens. There are current petitions proposing new uses for mancozeb on walnuts and imported 

tangerines (PP#1F7935 and PP# 2E8062) and a human health risk assessment has been recently 

performed for mancozeb and ETU derived from mancozeb only to support the new uses

(D411742, 5/13/13, Mancozeb: Human Health Risk Assessment to Support Proposed New 

Section 3 Uses on Walnuts and Tolerances for Imported Tangerines). Metiram uses are limited 

to the crops apples and potatoes, with import tolerances on bananas and grapes; there are no 

residential uses of metiram. The most recent metiram risk assessment, including ETU from 

metiram only, was performed in 2007 (D267866, 6/14/07, Metiram: Human Health Risk 

Assessment for PP#9E6006. Petition for the Establishment of Import Tolerances on Grapes and 

Bananas). The most recent risk assessment for ETU combined from multiple EBDCs was 

performed in 2010 (D383971, 11/16/10, Addendum to the Aggregate Human Health Risk 

Assessment of the Common Metabolite/Degradate Ethylene Thiourea (ETU) to Support New 

Tolerances on Imported Grapes and Bananas for Metiram and for New Tolerances for 

Mancozeb on Almonds, Broccoli, Cabbage, Lettuce, and Peppers). 

Crops treated with mancozeb or metiram may contain both the parent EBDC and ETU residues; 

in addition, cooking and/or processing may result in conversion of EBDC residues to ETU, or in 

concentration or reduction of existing ETU residues. ETU is the residue of concern in drinking 

water from the use of EBDCs. Therefore, ETU residues may be consumed in the diet through 

food or drinking water. Residential handler exposure to ETU may occur during application of 

mancozeb to home gardens. Residential post-application exposures to ETU may also occur to 

adults and youth entering mancozeb-treated golf courses and home gardens. There are no 

residential uses of the EBDC metiram. In addition, in vivo metabolic conversion of absorbed 

EBDC to ETU occurs and has been accounted for in calculating ETU doses for oral, dermal and 

inhalation routes of exposure. This aggregate risk assessment summarizes human health risks 

from combined exposure to ETU resulting from all existing and proposed uses of mancozeb 

along with the established uses of metiram. 

Hazard and Toxicology

The toxicology database for the EBDCs and ETU is sufficient for characterizing toxicity and 

hazard. HED has relied on a combination of guideline data and several studies in the open 

literature to assess hazard for ETU. The thyroid is a target organ for ETU. Thyroid toxicity in 

subchronic and chronic rat, mouse, and dog studies included decreased levels of T4, changes in 

T3 levels, compensatory increases in levels of TSH, increased thyroid weight, and microscopic 
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thyroid changes, chiefly hyperplasia. Overt liver toxicity was observed in one chronic dog study.

Developmental defects in the rat developmental toxicity study were similar to those seen with 

mancozeb, and included hydrocephaly and related lesions, skeletal system defects, and other 

gross defects.

Toxicology data gaps for ETU include a 2-generation reproduction study in rats, a developmental 

neurotoxicity study in rats, and a developmental thyroid toxicity study in rats. These three data

gaps will be addressed with the ongoing extended one generation reproduction toxicity (EOGRT) 

study on ETU. The data gaps being addressed in the EOGRT study could affect women of 

childbearing age or the developing young, and, consequently, the ETU FQPA SF of 10X is 

retained for females 13-49 years of age and for children less than 6 years of age. The FQPA 

safety factor for ETU is reduced to 1X for other lifestages (children > 6 years, females > 49 

years, and adult males), for which the thyroid is largely developed and there are applicable 

thyroid data. Although there was fetal sensitivity for malformations in the ETU developmental 

rat studies, the endpoints that were selected are protective of these effects. 

The recently submitted immunotoxicity study on ETU did not show any immunotoxicity 

potential.

The HED Cancer Assessment Review Committee classified ETU as a probable human 

carcinogen, Group B2, with a cancer potency factor [Q1*, 0.0601 (mg/kg/day)-1] for risk 

assessment. 

Dietary Risk Assessments

Refined probabilistic acute dietary exposure and risk assessments were conducted for ETU from 

EBDC uses and incorporated maximum percent crop treated or maximum projected percent crop 

treated information, field trial or monitoring data, and processing and cooking factors. There are 

no acute dietary (food and drinking water) risk estimates of concern for females 13-49 years old 

(the only population for which an acute toxicity endpoint was identified for ETU).

The chronic dietary exposure and risk assessments (non-cancer and cancer) for ETU were also 

refined and incorporated average values based either on field trial data or monitoring data and 

average percent crop treated data or average projected percent crop, as well as processing and 

cooking factors. Chronic non-cancer dietary (food and water) risk estimates for ETU from 

EBDC uses are below HED’s level of concern for the general U.S. population and all population 

subgroups. The cancer dietary risk was estimated to be 2 x 10-6for the general U.S. population.

The acute, chronic and cancer dietary estimated exposures to ETU were primarily a result of the 

registered and proposed mancozeb uses; the metiram dietary contribution to total ETU was 

minimal.

Residential Exposure and Risk

Home Gardens
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Residential handler risk estimates (combined dermal and inhalation) were assessed for ETU as a 

result of adults applying mancozeb to home gardens. Short-term and cancer assessments were 

performed. There are no short-term handler risk estimates of concern. The cancer risk for 

residential handlers was estimated in the 10-8range.

Residential post-application risk estimates for ETU were assessed for home gardeners (adults 

and youth) harvesting vegetables from mancozeb treated gardens. A dermal post-application 

assessment (short-term and cancer) was performed for ETU. Inhalation exposures are not 

expected for the post-application activities. There are no short-term risk estimates of concern for 

adults or youth entering treated home gardens. Post-application ETU cancer risk for adult home 

gardeners is estimated at 9 x 10-7.

Turf (Golf Courses)

Residential post-application risk estimates for ETU were assessed for adult and youth golfers 

contacting mancozeb treated turf after application. A dermal post-application assessment (shortterm and cancer) was performed for ETU. Inhalation exposures are not expected for the postapplication golfing activities. There are no short-term risk estimates of concern for adults or 

youth golfing on treated turf. The cancer risk to adult golfers is estimated at 3 x 10-8.

Aggregate Risk Assessments

HED conducted acute, short- term, chronic, and cancer aggregate assessments for ETU from the 

EBDC uses. The aggregate assessments combined the highest estimated residential exposures 

with food and drinking water exposures. The garden scenarios resulted in higher postapplication exposures than the golfing scenarios; aggregate assessments using the garden 

scenario are protective of any post-application exposures to adult and youth golfers. 

The acute and chronic (non-cancer) aggregate assessments include only dietary (food and 

drinking water) exposures. There are no acute or chronic aggregate risk estimates of concern.

The short-term aggregate assessment for ETU combined adult residential handler exposures and 

dietary (food and water) exposures. There are no short-term aggregate risk estimates of concern 

for adults applying the EBDC mancozeb to gardens.

A short-term aggregate assessment was performed for ETU for adults and youth entering treated 

gardens. Post-application exposures to ETU were combined with dietary (food and water) 

exposures. There are no short-term aggregate risk estimates of concern for adults or youth 

entering treated gardens.

The cancer aggregate assessment for ETU includes contributions from residential and dietary 

(food and water) exposures. Cancer aggregate risk estimates for adults applying mancozeb to 

gardens or entering treated gardens are estimated at 2 x 10 -6and 3 x 10-6, respectively.

Occupational Exposure and Risk
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The occupational aspect of ETU human health risk assessment has been completed for each of 

the EBDC fungicides in the most recent risk assessments of the parent compound. For details of 

the ETU occupational assessments see D411769, 5/14/13, Mancozeb: Revised Occupational and 

Residential Risk Assessment to Support Request for Section 3 Registrations on Walnuts and 

D337241, 6/14/07, Ethylenethiourea (ETU) from EBDCs: Health Effects Division (HED) Human 

Health Risk Assessment of the Common Metabolite/Degradate ETU..

Environmental Justice Considerations

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

human health risk assessment, in accordance with U.S. Executive Order 12898. Refer to Section 

3.5 of this document.

Review of Human Research

(See Appendix B of this document.)

2.0 Data Deficiencies

The data gaps for each individual EBDC (mancozeb and metiram) and the corresponding 

exposures to ETU are discussed in the risk assessments for each parent compound. Toxicology 

data gaps for ETU include a 2-generation reproduction study in rats, a developmental 

neurotoxicity study in rats, and a developmental thyroid toxicity study in rats. These data gaps 

will be addressed with an extended one-generation reproductive toxicity study on ETU, which is

currently in progress. 

3.0 Introduction

3.1 Chemical Identity

Table 3.1.1 ETU Test Compound Nomenclature

Compound

Common name Ethylenethiourea (ETU)

Empirical formula C3H6N2S

Molecular weight 102.2

CAS registry number 96-45-7
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Table 3.1.2 Mancozeb Test Compound Nomenclature

Chemical structure

Common name Mancozeb

IUPAC name manganese ethylenebis(dithiocarbamate)(polymeric) complex with zinc salt

CAS name [[1,2-ethanediylbis[carbamodithioato]](2-)]manganese mixture with [[1,2-

ethanediylbis[carbamodithioato]](2-)]zinc

CAS registry number 8018-01-7

Table 3.1.3 Metiram Test Compound Nomenclature

Compound

Empirical Formula (C16H33N11S16Zn3)x

Common name Metiram

IUPAC name zinc ammoniate ethylenebis(dithiocarbamate)-poly(ethylenethiuram disulfide)

CAS name mixture of 5.2 parts by weight of ammoniates of 

[ethylenebis(dithiocarbamato)]zinc with 1 part by weight ethylenebis 

[dithiocarbamic acid] bimolecular and trimolecular cyclic anhydrosulfides and 

disulfides

CAS registry number 9006-42-2

3.2 Physical/Chemical Characteristics

ETU is a metabolite, environmental degradate, and cooking byproduct of the EBDC fungicides, 

metiram and mancozeb. Technical ethylene thiourea is a crystalline solid with a white to pale 

green color, and a faint amine odor. It has a melting point of 203-204 C. ETU is considered 

highly soluble in water, with a water solubility of 20,000 ppm at 30 C, but it is also slightly 

soluble in methanol, ethanol, ethylene glycol, pyridine, acetic acid and naphtha. When ETU is 

heated to decomposition, nitrogen and sulfur oxides are emitted.

ETU is highly vulnerable to indirect photolysis, and is moderately mobile. ETU has an aerobic 

soil half-life of 3 days, and an estimated aquatic aerobic metabolism half-life of six days. The 

measured anaerobic aquatic metabolism half life is 149 days. ETU has a relatively high vapor 

pressure, but the high solubility reduces the possibility of losses from surface water due to 

volatilization.

N

H

S

S

N

H

S

Mn

S

Zn

x

y

HN

S

HN

Zn

S

S

S

HN

S

HN

S

S

S

3

x
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3.3 Pesticide Use Pattern

The EBDCs are broad spectrum contact fungicides used in agriculture, professional turf 

management, and horticulture. EBDC end-use products are available as wettable powder (WP), 

dry flowable (DF), dust (D), emulsifiable concentrate (EC), and ready-to-use formulations.

The currently registered EBDC fungicides are mancozeb and metiram. Mancozeb is used on a 

wide variety of agricultural food crops, on turf, including golf courses and sod farms, and on 

home vegetable gardens. There are current petitions proposing new uses for mancozeb on 

walnuts and imported tangerines (1F7935, 2E8062). Metiram uses are limited to apples and 

potatoes, with import tolerances on bananas and grapes. In terms of usage, mancozeb is the 

more significant of the two EBDCs; for mancozeb, the largest estimated usage in terms of 

pounds active ingredient (ai) are potatoes (2,500,000), apples (1,200,000) and fresh tomatoes 

(600,000). For metiram, estimated usage in terms of pounds active ingredient (ai) is 300,000 for 

potatoes and 300,000 for apples.

3.4 Anticipated Exposure Pathways

Crops treated with mancozeb or metiram may contain both the parent EBDC and ETU residues; 

in addition, cooking and/or processing may result in conversion of EBDC residues to ETU, or in 

concentration or reduction of existing ETU residues. ETU is the residue of concern in drinking 

water from the use of EBDCs. Therefore, EBDC and/or ETU residues may be consumed in the 

diet through food or drinking water. During application of EBDCs, workers may be exposed to 

ETU residues which form during degradation of the tank mix over a typical workday, and the 

Agency has data to reflect these potential exposures. Exposure to both EBDCs and ETU may 

also occur during activities conducted in and around growing crops (or turf) following treatment 

with EBDCs. In addition, residential exposure may occur to EBDCs and ETU in postapplication scenarios involving the use of EBDCs on golf courses and in home gardens (only 

mancozeb has residential uses; there are no residential or golf course uses for metiram). 

Metabolic conversion of absorbed EBDC to ETU occurs and has been accounted for in 

calculating ETU doses.

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 USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and/or the CDC under the 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 
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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 

postapplication are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

Since the last comprehensive ETU risk assessments (6/14/07, D337241 and 11/16/10, D383971), 

the interspecies uncertainty factor is reduced from 10X to 3X because of toxicodynamic 

differences in adult thyroid function that result in greater sensitivity of the adult rat to 

hypothyroidism compared to adult humans. The 3X toxicodynamics part of the 10X interspecies

factor is removed in those assessments that are based on rat thyroid toxicity endpoints, leaving 

the 3X portion for toxicokinetic interspecies differences (Hazard Science Policy guidance). 

Additionally, a 10X FQPA UFDB was applied previously to all assessments due to the data gaps

for a 2-generation reproduction study in rats, a rat developmental neurotoxicity study, and a rat 

developmental thyroid toxicity study for ETU. Because these data gaps could affect women of 

childbearing age or the developing young, the FQPA SF is retained for females 13-49 years of 

age and for children less than 6 years of age. The FQPA SF is reduced to 1X for all other 

population groups, including children greater than 6 years who have a thyroid system similar to 

adults, because any endpoints from the extended one generation study will not affect those 

population groups, and risk assessment based on currently available data will not underestimate 

risks (children > 6 years, females > 49 years, and adult males). 

4.1 Summary of Toxicological Effects

The toxicology database on ETU is sufficient for assessing the toxicity and characterizing the 

hazard of ETU. There are acceptable subchronic oral studies in rats and dogs, several rat 

developmental toxicity studies from the open literature, a rabbit developmental toxicity study, 

and a dermal absorption study in rats. Data gaps for ETU include a 2-generation reproduction 

study in rats, a developmental neurotoxicity study in rats, and a developmental thyroid toxicity 

study in rats. These data gaps will be satisfied with an extended one-generation reproduction 

study on ETU, which is in progress. 

The toxicity profile of ETU shows that the thyroid is a major target organ for ETU.

Thyroid toxicity: The thyroid is a target organ for ETU because ETU inhibits the enzyme, 

thyroid peroxidase. Thyroid toxicity in subchronic and chronic rat, mouse, and dog studies 

includes decreased levels of the thyroid hormone T4 (serum thyroxin), variable changes in T3, 

compensatory increases in levels of thyroid stimulating hormone (TSH), increased thyroid 

weight, and microscopic thyroid changes, chiefly hyperplasia. 
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Developmental toxicity: Fetal malformations occurred mainly in rats, although hydrocephaly 

and domed head were observed in a rabbit developmental study with ETU. The malformations 

in rats occurred throughout the body. Hydrocephaly occurred in the absence of maternal toxicity 

after treatment with a single dose of ETU. There was a steep dose-response for the 

malformations in rats. 

Malformations in rat developmental studies (repeat oral dosing) with ETU included 

hydrocephaly and related malformations (exencephaly, atrophy of brain tissue, cranial edema, 

compression and/or hemorrhages of the spinal cord, deficiency of tissue in the olfactory bulb, 

meningoencephalocele), incomplete cranial ossification and wide cranial sutures, curved 

clavicle, fused sternebrae, absent caudal or sacral vertebrae, fused and/or thickened ribs, wavy 

ribs, misshapen or incomplete ossification of hindlimb long bones, ribs and pelvis, kyphosis 

(abnormal spine curvature), reduced number of ribs, fused lumbar, sacral, or caudal vertebrae, 

abnormal pelvic limb posture, oligodactyl, agnathia, cleft palate, cleft lip, club limb, stubby tail, 

forelimb flexure, kinked tail, cryptorchidism, ectopic kidneys, agenesis of the kidneys, 

hydronephrosis, reduced stomach with thickened wall, edematous fat pads, syndactyl digits, and 

anal atresia. Hydrocephaly and microphthalmia occurred in rats after treatment with a single oral 

dose. 

Post implantation loss was observed in a developmental rabbit study with ETU, in addition to 

hydrocephaly and domed head described above. 

Neurotoxicity: Neurotoxicity studies for ETU are not available; however, no neurotoxicity was 

observed in any of the studies. Although the available studies are inadequate in their assessment 

of behavioral effects and do not use optimal methods to evaluate the potential toxicity to the 

nervous tissue structure and function, the toxicity profile of ETU shows that the principal toxic 

effects are on the thyroid.

Carcinogenicity: Thyroid follicular cell adenomas and carcinomas were increased in an ETU

study with F344 rats conducted by the National Toxicology Program (NTP). Thyroid follicular 

cell adenomas and pituitary adenomas were also increased in an ETU study with SD rats

submitted by the registrant. Thyroid follicular cell adenomas and carcinomas, hepatocellular 

adenomas and carcinomas, and pituitary adenomas were increased in an ETU study with 

B6C3F1 mice conducted by the NTP. The rat carcinogenicity study with ETU was classified 

unacceptable; the Cancer Assessment Review Committee did not recommend that this study be 

repeated because tumors were found in the other studies at lower doses, though the requirement 

was reserved (txr# 013554). 

The HED Cancer Assessment Review Committee classified ETU as a probable human 

carcinogen, Group B2. The Q1* for ETU, using a 3/4 scaling factor is 0.0601 (mg/kg/day)-1

based upon female mouse liver tumors in a National Toxicology Program study. 

Other toxicity: Anemia occurred in the subchronic and chronic dog studies. Increased liver 

weight and hepatocellular hypertrophy occurred in several studies; however, overt liver toxicity 

was limited to the chronic dog study in which hepatocellular necrosis was seen. An 
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immunotoxicity study has recently been submitted and is under review. Preliminary review of 

this study did not show any concerns for immunotoxicity. 

Approximately 91% of an oral dose of ETU is absorbed. The plasma t1/2 is approximately 0.2 or 

0.3 hours (12-18 minutes) after a single oral dose or i.v. dose. Excretion of radioactivity was 

essentially complete within 3-4 days, the majority being excreted in urine (75%-83%) and 

approximately 5%-7% in feces following oral or i.v. dosing. ETU residues were highest in the 

thyroid.

The ETU dermal absorption factor is 26%, based on a dermal absorption study in rats. This 

value was determined at the lowest dermal dose after 10 hours of exposure followed by washing 

of the skin. ETU residues were highest in the thyroid.

ETU is the main metabolite of the ethylenebisdithiocarbamates (EBDCs) mancozeb, metiram,

and maneb. In oral rat metabolism studies with radiolabeled EBDCs, an average 7.5% in vivo

metabolic conversion of EBDC to ETU occurred, on a weight-to-weight basis. This metabolic 

conversion has been taken into consideration in the human health risk assessment. 

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

HED recommends that the 10X FQPA Safety Factor be retained for all ETU exposure 

assessments for females 13-49 years of age and for children less than 6 years of age because of 

data gaps for a developmental thyroid study, a reproduction study, and a developmental 

neurotoxicity (DNT) study. These data gaps are being addressed by an ongoing extended onegeneration reproductive toxicity study. The developing brain is very sensitive to perturbations in 

thyroid hormones; however, results from the developmental thyroid study will not affect points 

of departure for children greater than 6 years of age, who have a thyroid system similar to 

adults1, adult females greater than 49 years of age (assumed to be beyond typical child-bearing 

age), or adult males since thyroid data for those populations are already available. Additionally, 

endpoints from the other segments of the extended one-generation study will not affect these 

latter populations, and the FQPA SF is reduced to 1X for these populations. 

The developmental malformations described above have been well-characterized in numerous 

studies. Although the NOAELs varied to some extent between the different studies, the studies 

were conducted by different laboratories in different years using different strains of rats. 

However, the individual studies each showed clear NOAELs. There was generally a steep doseresponse for the malformations. The developmental study with the lowest NOAEL was selected 

for the acute dietary assessment for women of childbearing age and is therefore protective of the 

developmental malformations. 

4.2.1 Completeness of the Toxicology Database

The toxicology database for ETU, while incomplete, is sufficient for assessing the toxicity and 

characterizing the hazard of ETU. Studies available for FQPA consideration included several 

developmental toxicity studies in rats from the literature and a guideline developmental toxicity 

 

1 Kevin Crofton, personal communication.
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study in rabbits. A reproduction study with ETU was classified unacceptable and is a data gap. 

A developmental neurotoxicity study is required because hydrocephaly and related 

malformations were reported in rat developmental toxicity studies. A developmental thyroid 

study is required because ETU causes thyroid toxicity, and neural development is regulated by 

thyroid hormone. The ongoing extended one-generation reproductive toxicity study on ETU 

should satisfy these data gaps. An immunotoxicity study on ETU is available.

4.2.2 Evidence of Neurotoxicity

Neurotoxicity was not noted in toxicity studies with ETU. Although the existing studies are 

inadequate in their assessment of behavioral effects and do not use optimal methods to evaluate 

the potential toxicity to the nervous tissue structure and function, the toxicity profile for ETU 

shows that the principal toxic effects occur in the thyroid. The endpoints that were selected are 

based on thyroid or developmental effects and would be protective of any potential 

neurotoxicity. Developmental malformations of the brain, as described previously, occurred in 

one rabbit and several rat developmental toxicity studies with ETU. 

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

There is evidence of increased susceptibility following in utero exposure to ETU in the rat 

developmental toxicity studies. Several developmental toxicity studies with ETU in the open 

literature demonstrate quantitative and qualitative fetal sensitivity. In one study (Khera, 1973) 

developmental toxicity [brain malformations (exencephaly, dilated ventricles, and hypoplastic 

cerebellum)] was observed at a dose level considerably lower than the dose causing maternal 

toxicity (mortality). In another study (Teramoto, et al., 1978), developmental toxicity (dilated 

ventricle of the brain) was seen in the absence of maternal toxicity. Additionally, 

developmental effects (dilated ventricles of the brain, hydroureter, short/kinky tail, and dilated 

ureters) were seen in another study (Saillenfait, et al., 1991) at a dose that only induced 

decreases in body weight gain in the dams. See the Appendix A.2 (Executive Summaries) of this 

document for citations to these articles. 

4.2.4 Residual Uncertainty in the Exposure Database

HED has used refined assumptions in the food portion of the dietary exposure assessment, 

including the use of percent crop treated estimates and monitoring residue values for several 

commodities including some major contributors to the dietary risk such as milk and corn 

commodities. Modeling and monitoring data were used to derive estimated drinking water 

concentrations. The residential exposure assessment was conducted such that residential 

exposure and risk will not be underestimated. The aggregate exposure and risk estimates 

presented in this assessment are not expected to underestimate actual exposure and risk expected 

based on the current and proposed use patterns.

4.3 Toxicity Endpoint and Point of Departure Selections

A detailed description of the toxicity studies used for selecting toxicity endpoints and points of 

departure for various exposure scenarios is presented in Appendix A. The doses and endpoints 
Ethylene Thiourea Human Health Risk Assessment DP No. D411820

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are summarized below and in Tables 4.3.1 and 4.3.2 which also provide the appropriate safety 

factors.

Acute dietary, females 13-49 years: The ETU acute dietary endpoint for females 13-49 years old 

was selected from a non-guideline developmental toxicity study in rats. The LOAEL was 10 

mg/kg/day, based on developmental malformations of the brain, including exencephaly, dilated 

ventricles and hypoplastic cerebellum. The NOAEL was 5 mg/kg/day. 

Acute dietary, general population, including infant and children: No hazard or appropriate acute 

endpoint attributable to a single exposure was identified from the available oral toxicity 

database; therefore, no acute dietary risk is expected following acute exposure to ETU. 

Chronic dietary, all populations: The ETU chronic reference dose was selected from a chronic 

oral toxicity study in dogs. The study NOAEL was 0.18 mg/kg/day, based on decreased body 

weight gain, increased thyroid weight, and microscopic changes in the thyroid observed at the 

LOAEL of 1.99 mg/kg/day. 

Short-term oral, children <6 years: The incidental oral endpoint for children less than 6 years of 

age was selected from a non-guideline 4-week range-finding oral toxicity study conducted in 

dogs. The NOAEL was 7 mg/kg/day, based on gross thyroid lesions and decreased thyroid 

hormone levels at the LOAEL of 34 mg/kg/day. The endpoint is supported by a subchronic oral 

toxicity study in dogs in which the NOAEL for thyroid effects was similar (6 mg/kg/day). 

Short and intermediate-term dermal, all populations other than females 13-49 years: In the 

absence of a dermal toxicity study for ETU, toxic effects from the non-guideline 4-week rangefinding study conducted in dogs was used for short- and intermediate-term dermal endpoints for 

all population groups other than females 13-49 years of age. The NOAEL was 7 mg/kg/day 

based on gross thyroid lesions and decreased thyroid hormone levels at the LOAEL of 34 

mg/kg/day. Because an oral toxicity study was chosen, the 26% dermal absorption factor for 

ETU was used in the dermal exposure assessment. 

Short and intermediate-term dermal, females 13-49 years: In the absence of a dermal toxicity 

study for ETU, toxic effects observed in the non-guideline oral developmental study in rats were

used as the endpoint for short- and intermediate-term dermal risk assessments for females 13-49 

years of age. The study NOAEL was 5 mg/kg/day, based on developmental malformations of 

the brain, including exencephaly, dilated ventricles, and hypoplastic cerebellum, observed at the 

LOAEL of 10 mg/kg/day. Because an oral toxicity study was chosen, the 26% dermal 

absorption factor for ETU was used in the dermal risk assessment. 

Long-term dermal, all populations: The long-term dermal endpoint for all populations is selected 

from the chronic toxicity study in dogs. The NOAEL is 0.18 mg/kg/day based on decreased 

body weight gain, increased thyroid weight, and microscopic changes in the thyroid at the 

LOAEL of 1.99 mg/kg/day. Since an oral study was selected, estimated dermal exposure was

adjusted by 26%, the ETU dermal absorption factor. 
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Short and intermediate-term inhalation, all populations other than females 13-49 years: In the 

absence of an inhalation toxicity study for ETU, toxicity observed in the non-guideline 4-week 

range-finding toxicity study conducted in dogs was used for the short- and intermediate-term 

inhalation endpoints for all population groups other than females 13-49 years of age. The 

NOAEL was 7 mg/kg/day based on gross thyroid lesions and decreased thyroid hormone levels 

at the LOAEL of 34 mg/kg/day. Because an oral toxicity study was chosen, it will be assumed 

that inhalation absorption is equivalent to oral absorption. 

Short and intermediate-term inhalation, females 13-49 years: In the absence of an inhalation

toxicity study for ETU, toxicity observed in the non-guideline oral study in rats was used as an 

endpoint for short- and intermediate-term inhalation risk assessments for females 13-49 years of 

age. The study NOAEL was 5 mg/kg/day based on developmental malformations of the brain, 

including exencephaly, dilated ventricles, and hypoplastic cerebellum, observed at the LOAEL 

of 10 mg/kg/day. Because an oral toxicity study was chosen, it will be assumed that inhalation 

absorption is equivalent to oral absorption. 

Long-term inhalation, all populations: The long-term inhalation endpoint for all populations is 

from the chronic toxicity study in dogs. The NOAEL is 0.18 mg/kg/day based on decreased 

body weight gain, increased thyroid weight, and microscopic changes in the thyroid at the 

LOAEL of 1.99 mg/kg/day. Because an oral toxicity study was chosen, it will be assumed that 

inhalation absorption is equivalent to oral absorption. 

Cancer: The HED Cancer Assessment Review Committee classified ETU as a probable human 

carcinogen, Group B2, with a cancer potency factor [Q1*, 0.0601 (mg/kg/day)-1] for risk 

assessment. 

Table 4.3.1 Summary of Toxicological Doses and Endpoints for ETU for Use in Dietary and Non-Occupational Human 

Health Risk Assessments 

Exposure PoD Safety Factors RfD, PAD, LoC Study and Tox

ETU Acute Dietary Exposure

Acute Dietary 

(General Pop, 

including Infants 

and Children)

N/A N/A N/A A study with acute toxicity applicable 

to the general population was not 

identified.

Acute Dietary

(Females 13-49 

years old)

NOAEL= 5 

mg/kg/day

UFA= 10x

UFH = 10x

FQPA UFDB = 

10x

Acute RfD = 0.005 

mg/kg/day

aPAD = 0.005 

mg/kg/day

Developmental Rat Toxicity

MRID No. 45937601 (1973)

LOAEL = 10 mg/kg/day, based on 

hydrocephaly and other malformations

ETU Chronic Dietary Exposure

Chronic Dietary 

(Females 13-49 

years of age and 

Children < 6 

years)

NOAEL= 0.18 

mg/kg/day

UFA= 10x

UFH = 10x

FQPA UFDB = 

10x

Chronic RfD = 0.00018

mg/kg/day

cPAD = 0.00018 

mg/kg/day

Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

Chronic Dietary 

(Adult Males, 

Females >49 

years, Children ≥ 

6 years)

NOAEL= 0.18 

mg/kg/day

UFA= 10x

UFH = 10x

FQPA SF = 1x

Chronic RfD = 0.0018

mg/kg/day

cPAD = 0.0018 

mg/kg/day

Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity
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Table 4.3.1 Summary of Toxicological Doses and Endpoints for ETU for Use in Dietary and Non-Occupational Human 

Health Risk Assessments 

Exposure PoD Safety Factors RfD, PAD, LoC Study and Tox

ETU Incidental Oral Exposure

Short -

Term Oral 

(Children < 6 

years of age)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based on 

thyroid toxicity

ETU Residential Dermal Exposure

Dermal Short and

IntermediateTerm (Children` < 

6 years of age)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based on 

thyroid toxicity

Dermal Short and

IntermediateTerm (Adult 

Males, Females 

>49 years, 

Children ≥ 6 

years)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

LOC = 100 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based on 

thyroid toxicity

Dermal Short and 

IntermediateTerm (Females 

13-49 years old)

NOAEL= 5 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973)

LOAEL = 10 mg/kg/day, based on 

hydrocephaly and other malformations

Dermal LongTerm 

(Females 13-49 

years of age and 

Children < 6 

years)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

Dermal LongTerm 

(Adult Males, 

Females >49 

years, Children ≥ 

6 years)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

LOC = 100 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

ETU Residential Inhalation Exposure

Inhalation Short 

and IntermediateTerm (Children < 

6 years of age)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based thyroid 

toxicity

Inhalation Short 

and IntermediateTerm (Adult 

Males, Females 

>49 years, 

Children ≥ 6 

years)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

LOC = 100 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based thyroid 

toxicity

Inhalation Short 

and IntermediateTerm (Females 

13-49 years old)

NOAEL= 5 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973)

LOAEL = 10 mg/kg/day, based on 

hydrocephaly and other malformations

Inhalation LongTerm (Females 

13-49 years of age 

and Children < 6 

years)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity
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Table 4.3.1 Summary of Toxicological Doses and Endpoints for ETU for Use in Dietary and Non-Occupational Human 

Health Risk Assessments 

Exposure PoD Safety Factors RfD, PAD, LoC Study and Tox

Inhalation LongTerm (Adult 

Males, Females 

>49 years, 

Children ≥ 6 

years)

NOAEL=

0.18mg/kg/da

y

UFA= 10x

UFH=10x

FQPA SF= 1x

LOC = 100 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

ETU Cancer

Cancer (all routes) Q1

*

= 6.01 x 

10 -2

(mg/kg/day)-1

ETU is classified as a Group B2 carcinogen with a linear low-dose extrapolation 

approach for human risk assessment based on liver tumors in female mice.

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). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c 

= chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table 4.3.2 Summary of Toxicological Doses and Endpoints for ETU for Use in Occupational Human Health Risk 

Assessments 

Exposure PoD Safety 

Factors RfD, PAD, LoC Study and Tox

ETU Occupational Dermal Exposure

Dermal Short and

Intermediate-Term 

(Adult Males, 

Females >49 

years)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

LOC = 100 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based on 

thyroid toxicity

Dermal Short and 

Intermediate-Term 

(Females 13-49 

years old)

NOAEL= 5 

mg/kg/day

UFA= 10x

UFH=10x

UFDB = 10x

LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973)

LOAEL = 10 mg/kg/day, based on 

hydrocephaly and other malformations

Dermal LongTerm 

(Females 13-49 

years of age)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH=10x

UFDB = 10x

LOC = 1000 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

Dermal LongTerm 

(Adult Males, 

Females >49 

years)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH=10x

LOC = 100 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

ETU Occupational Inhalation Exposure

Inhalation Short 

and IntermediateTerm (Adult 

Males, Females 

>49 years)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

LOC = 100 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based thyroid 

toxicity

Inhalation Short 

and IntermediateTerm (Females 

13-49 years old)

NOAEL= 5 

mg/kg/day

UFA= 10x

UFH=10x

UFDB = 10x

LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973)

LOAEL = 10 mg/kg/day, based on 

hydrocephaly and other malformations

Inhalation LongTerm (Females NOAEL= 

0.18 

UFA= 10x

UFH=10x

LOC = 1000 Dog Chronic Oral Toxicity

MRID 42338101 (1992)
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Table 4.3.2 Summary of Toxicological Doses and Endpoints for ETU for Use in Occupational Human Health Risk 

Assessments 

Exposure PoD Safety 

Factors RfD, PAD, LoC Study and Tox

13-49 years of 

age)

mg/kg/day UFDB = 10x LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

Inhalation LongTerm (Adult 

Males, Females 

>49 years)

NOAEL=

0.18mg/kg/da

y

UFA= 10x

UFH=10x

LOC = 100 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

ETU Cancer

Cancer (all routes) Q1

*

= 6.01 x 

10 -2

(mg/kg/day)-1

ETU is classified as a Group B2 carcinogen with a linear low-dose extrapolation 

approach for human risk assessment based on liver tumors in female mice.

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). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c 

= chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

5.0 Dietary Exposure and Risk Assessment 

5.1 Food Residue Profile

Crops treated with EBDCs may contain both the parent EBDC and ETU residues. As a 

metabolite, there are no separate tolerances for residues of ETU in food but it is considered a 

residue of concern and is assessed separately since ETU has its own hazard and toxicity 

database. Residues of ETU are measured in the field trials for metiram and mancozeb using 

adequate data collection methods. Residues of ETU are stable in frozen tangerine at least four 

months and frozen walnuts for at least ten months. 

Cooking and/or processing of EBDC-treated foods may result in conversion of EBDC residues to 

ETU, or in concentration or reduction of existing ETU residues. Therefore, both EBDC and 

ETU residues may be consumed in the diet. In this assessment only exposures to ETU are being 

considered; the dietary contribution of ETU from the each of the EBDCs was combined 

(aggregated). Market basket survey (MBS) data, generated by the ETU Task Force, were used to 

calculate anticipated residues in several foods for use in the risk assessment (corn, cucumber, 

onion, pumpkin, potato, squash, starfruit, tomato, meat, and milk commodities). 

5.2 Water Residue Profile

ETU is highly water soluble and may reach both surface and ground water under some 

conditions. A drinking water assessment for ETU was conducted to support various EBDC 

pesticide uses for the 2005 Reregistration Eligibility Decision (RED) (D286871, 5/15/03). ETU 

surface water estimated drinking water concentrations were based both on PRZM-EXAMS 
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modeling information and available monitoring data. The acute (peak) surface water EDWC 

ranged from 0.1 ppb from monitoring data to 25.2 ppb as a model output. The chronic/cancer 

surface water value provided by EFED was 0.1 ppb based on monitoring data.

ETU ground water EDWC values were taken from a targeted monitoring study in Florida. EFED 

provided a value of 0.21 ppb from the monitoring data to be used in the acute, chronic and cancer 

risk assessments. This value represents the single highest concentration found in untreated 

water sampled from one of 84 sites over a period from 2001- 2004. No detectable residues of 

ETU were found in treated water at the 84 sites, including the two sites where ETU residues 

were found in untreated water. 

A more detailed summary of the ETU drinking water assessment can be found in the EFED 

drinking water assessment memorandum entitled Revision No. 2: Estimated Drinking Water 

Concentration of Ethylenebisdithocarbamate (EBDC) Degradate Ethylenethiourea (ETU) for the 

Use in Human Health Risk Assessment, D323143 and 323141, 8/11/06, M. Ruhman.

ETU estimated drinking water concentrations provided by EFED are summarized below.

Table 5.2 Summary of Estimated Surface Water and Ground Water Concentrations for 

ETU.

ETU from all EBDC pesticides including mancozeb

Surface Water Conc., ppb a Ground water Conc., ppb b

Acute 0.1 – 25.2 0.21

Chronic (non-cancer) 0.1 0.21

Chronic (cancer) 0.1 0.21

a

Surface water EDWCs were derived from both monitoring and modeling data. A range of acute surface water 

concentrations was provided. The lower end of the range was based on monitoring data and the upper end of the 

range was based on EPA PRZM and EXAMS models. Chronic/Cancer EDWCs were based on monitoring data.

b Ground water EDWCs were taken from a community well monitoring program and represent the single highest 

value found at any sampling for 84 sites.

Bolded values used in the dietary risk assessment.

5.3 Dietary Risk Assessment

Separate dietary exposure assessments have been previously conducted for each EBDC parent 

compound (mancozeb and metiram). In each of these assessments, human dietary exposure and 

health risk associated with the active ingredient were estimated, as well as dietary exposure and 

risk resulting from consumption of ETU residues derived from each EBDC individually. 

For this assessment, ETU dietary residues from each of the individual EBDCs were aggregated

(for combined ETU dietary assessment details see D405592, 4/8/13, Aggregate Dietary 

Assessment of the Common Metabolite/Degradate Ethylene Thiourea (ETU) Resulting from the 

Combined Uses of the Ethylene Bisdithiocarbamate Fungicides (EBDCs) to Support the New 

Use of Mancozeb on Walnuts and the Establishment of a Tolerance on Imported Tangerines for 

Section 3 Registration).
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ETU acute, chronic, and cancer aggregate dietary food and drinking water exposure and risk 

assessments were conducted using the Dietary Exposure Evaluation Model software with the 

Food Commodity Intake Database (DEEM-FCID) Version 3.16. This software uses 2003-2008 

food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health 

and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). 

5.3.1 Description of Residue Data Used in Dietary Assessment

Field trial or monitoring data from the EBDC/ETU Market Basket Survey, percent crop treated 

information, and processing/cooking study results were used in the refined dietary assessments.

Modeling estimates (PRZM/EXAMS) for surface water (mancozeb almond use scenario) were 

used for ETU EDWCs in the acute assessment and well monitoring data were used for ETU

EDWCs for ground water for the chronic and cancer assessments. 

For the probabilistic acute dietary exposure analysis, the entire distributions of residue data from 

field trials or monitoring data were used to generate residue distribution files (RDFs) for 

commodities that are considered to be not blended or partially blended. For commodities 

considered to be blended in this analysis, the average residues incorporating the likely maximum 

estimated % CT was used as a point estimate. 

5.3.2 Percent Crop Treated Used in Dietary Assessment

The following percent crop treated estimates were provided by BEAD and were used in the ETU 

assessment:

ETU from Mancozeb

The following maximum percent crop treated estimates were used in the acute dietary risk 

assessment for the following crops that are currently registered for mancozeb: almonds: 2.5%; 

apples: 45%; asparagus: 30%; barley: 2.5%; broccoli: 9%; cabbage: 47%; cantaloupes: 15%; 

carrots: 2.5%; celery: 2.5%; cherries: 2.5%; corn: 2.5%; cranberries: 20%; cucumbers: 50%; 

grapes: 20%; lettuce, head: 66%; lettuce, other: 61%; oats: 1%; onions: 70%; peanuts: 2.5%; 

pears: 50%; peppers: 48%; potatoes: 65%; pumpkins: 15%; rice: 2.5%; spinach: 2.5%; squash: 

30%; sugar beets: 2.5%; sweet corn: 15%; tomatoes: 50%; watermelons: 50%; and wheat: 2.5%. 

The following average percent crop treated estimates were used in the chronic and cancer dietary 

risk assessments for the following crops that are currently registered for mancozeb: almonds: 

1%; apples: 40%; asparagus: 15%; barley: 1%; broccoli: 7%; cabbage: 42%; cantaloupes: 5%; 

carrots: 1%; celery: 1%; cherries: 1%; corn: 1%; cranberries: 20%; cucumbers: 25%; grapes: 

10%; lettuce, head: 58%; lettuce, other: 59%; oats: 1%; onions: 60%; peanuts: 2.5%; pears: 40%; 

peppers: 43%; potatoes: 55%; pumpkins: 10%; rice: 1%; spinach: 1%; squash: 20%; sugar beets: 

1%; sweet corn: 5%; tomatoes: 25%; watermelons: 40%; and wheat: 1%. A percent import 

statistic value of 99% was used for banana in both the acute, chronic, and cancer dietary risk 

assessments. 
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A maximum percent crop treated estimate of 50% for walnuts and a maximum percent import 

consumption value of 35% for tangerines were used in the acute dietary risk assessment to 

support the current mancozeb registration actions. An average percent crop treated estimate of 

40% for walnuts as well as an average percent imported commodity in domestic consumption

value of 29% for tangerines were likewise used in the chronic and cancer dietary risk 

assessments. As a further refinement, the commodity having the highest %CT results with 

livestock feed uses had these values applied to meat and milk (potato; 65% CT maximum for 

acute and 65% CT average for chronic).

ETU from Metiram

Maximum percent crop treated estimate of 15% for apples and 10% for potatoes were used in the 

acute dietary risk assessment for these crops registered for metiram. Average percent crop 

treated estimates of 10% for apples and 5% for potatoes were used in the chronic and cancer 

dietary risk assessments for these crops currently registered for metiram. In regard to imported 

wine grapes for metiram, a 31% percent imported commodity in domestic consumption was 

used. 

5.3.3 Acute Dietary Risk Assessment

Acute dietary (food and water) risk estimates are below HED’s level of concern for ETU from 

EBDC uses. Acute dietary risk for females 13-49 years old (the only population subgroup with 

an identified acute dietary toxicological endpoint) are estimated at 59% of the aPAD.

See Table 5.3.6 for a summary of the acute dietary exposure and risk estimates.

5.3.4 Chronic Dietary Risk Assessment

Chronic dietary (food and water) risk estimates for ETU from EBDC uses are below HED’s level 

of concern for the general U.S. population and all population subgroups. The most highly 

exposed population subgroup is children ages 1-2 with an estimate of 58% of the cPAD.

See Table 5.3.6 for a summary of the chronic dietary exposure and risk estimates.

5.3.5 Cancer Dietary Risk Assessment

The cancer risk estimate associated with exposure to ETU in food and water, as a result all 

EBDC uses, is 2 x 10-6for the general U.S. population.

See Table 5.3.6 for a summary of the cancer dietary exposure and risk estimates.

5.3.6 Summary Table
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Table 5.3.6 Summary of Dietary (Food and Water) Exposure and Risk for ETU (derived from 

EBDCs mancozeb and metiram)

Population Subgroup

Acute Dietary

(99.9th Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD*

Dietary 

Exposure

(mg/kg/day)

% cPAD*

Dietary 

Exposure

(mg/kg/day

)

Risk

General U.S. Population

NA NA

0.000034 1.9 0.000031 2 x 10-6

All Infants (<1 year old) 0.000051 28

NA NA

Children 1-2 years old 0.000104 58

Children 3-5 years old 0.000069 38

Children 6-12 years old 0.000036 2.0

Youth 13-19 years old 0.000023 1.3

Adults 20-49 years old 0.000030 1.7

Adults 50-99 years old 0.000030 1.7

Females 13-49 years old 0.002962 59 0.000031 17

*The values for the highest exposed population is bolded

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

No new residential uses are being added to the mancozeb labels as a result of the new requests, 

however there are existing mancozeb residential uses registered for home gardens and on turf 

(golf courses). There are no uses of metiram that will result in exposure in residential settings. 

Currently, the only EBDC registered for uses resulting in residential exposures is mancozeb. 

Residential exposures to mancozeb-derived ETU, as a result of the current mancozeb home 

garden and golf course uses, have been recently assessed in D411769, 5/14/13, Mancozeb: 

Revised Occupational and Residential Risk Assessment to Support Request for Section 3 

Registrations on Walnuts. A summary of the residential risk estimates for use in the non-cancer 

(only short-term duration) and cancer aggregate ETU assessments is presented below. See 

D411769 for details of the residential risk assessment for mancozeb-derived ETU.

6.1 Residential Risk Estimates for Use in Aggregate Assessment

HED combines risk values resulting from separate exposure scenarios when it is likely they can 

occur simultaneously based on the use pattern and the behavior associated with the exposed 

population. For home garden scenarios a combined (dermal plus inhalation) residential exposure 

assessment for handlers was conducted for ETU exposures. The residential handler scenario 

identified for use in performing a short-term aggregate exposure assessment for ETU was for 

adults treating home gardens with mancozeb formulations (mixing/loading/application) utilizing 

a backpack sprayer. A summary of short-term residential handler exposure and risk estimates for 

ETU combined (dermal and inhalation) exposures, for use in the aggregate assessment, is 

presented in Table 6.1.1.
Ethylene Thiourea Human Health Risk Assessment DP No. D411820

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For residential post-application, the garden scenario represents the most conservative exposure 

estimates (compared to golfing) and was used in the short-term aggregate assessment. The only 

route of exposure for treated garden post-application scenarios is through the dermal route 

(inhalation exposures are not expected). A summary of short-term residential post-application 

exposure and risk estimates for ETU from mancozeb for use in performing short-term postapplication aggregate exposure assessment is presented in Table 6.1.2.

The garden scenarios were also selected for use in the ETU aggregate since cancer risk estimates 

were higher for garden activities than for golfing. A summary of residential handler and postapplication exposures and cancer risk estimates for ETU are presented in Tables 6.1.3 and 6.1.4.

See D411769, 5/14/13, for details regarding assumptions and calculations used in the residential 

assessment.

Table 6.1.1 Residential Exposures and Risks for the ETU (from Mancozeb) Short-Term Aggregate 

Assessment (Residential Handler/Garden Use)

Lifestage Handler Exposure Scenario Dose (mg/kg/day) LOC MOEs

Adult

(Female 13-49 

years old)

M/L/A

Backpack 

sprayer

Combined

(Inhalation + 

Dermal)

Home Garden Activities 0.000153 1000 32,700

Adult (Male, 

female >49 years 

old)

M/L/A

Backpack 

sprayer

Combined

(Inhalation + 

Dermal)

Home Garden Activities 0.000132 100 37,900

Table 6.1.2 Residential Exposures and Risks for the ETU (from Mancozeb) Short-Term Aggregate 

Assessment (Post-Application Exposures/Garden Use)

Lifestage Post-application Exposure Scenario Dose (mg/kg/day) LOC MOEs

Adult

(Female 13-49 years 

old) Liquid 

sprays

Dermal Home Garden 

Activities

0.0019 1000 2,700

Child 6 < 11 years old 0.0012 100 5,800

Child 11 < 16years 

old 0.0022 100 3,100

Table 6.1.3 Residential Exposures and Risks for the ETU (from Mancozeb) Aggregate Cancer 

Assessment (Residential Handler /Garden Use). 

Crop or Target

Total Absorbed Dose

ADD

(mg/kg/day)

Total LADD

(mg/kg/day)

Residential Handler

Cancer Risk Estimate

Mixer/Loader/Applicator (Liquid concentrate – Backpack Sprayer)

Home Gardens

(Vegetables) 0.000132 1.16 x 10 -6

7 x 10 -8
Ethylene Thiourea Human Health Risk Assessment DP No. D411820

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Table 6.3.4 Residential Exposures and Risks for the ETU (from Mancozeb) Aggregate Cancer 

Assessment (Post-Application Exposures/Garden Use)

Activity

ADD

Total ETU absorbed Dose

(mg/kg/day)

LADD (mg/kg/day) Cancer Risk 

Home Garden Activities 0.0019 1.41 x 10-59 x 10-7

6.2 Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for ETU since exposures are expected to be insignificant. 

However, volatilization of pesticides may be a potential source of post-application inhalation 

exposure to individuals nearby to pesticide applications. The Agency sought expert advice and 

input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and 

Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009. The Agency 

received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, developing policies and 

procedures, to identifying the need for and, subsequently, the way to incorporate post-application 

inhalation exposure into the Agency's risk assessments. If new policies or procedures are put 

into place, the Agency may revisit the need for a quantitative post-application inhalation 

exposure assessment for ETU.

6.3 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the airblast application method employed for EBDCs. The 

Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information2. The 

Agency has completed its evaluation of the new database submitted by the Spray Drift Task 

Force, a membership of U.S. pesticide registrants, and is developing a policy on how to 

appropriately apply the data and the AgDRIFT computer model to its risk assessments for 

pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in 

place, the Agency may impose further refinements in spray drift management practices to reduce 

off-target drift with specific products with significant risk estimates associated with drift.

Furthermore, turf (golfer scenario) and home garden uses were quantitatively assessed as part of 

this risk assessment; ETU risk estimates addressed in the golfer turf assessment provide the 

highest estimate of potential exposure from spray drift. It is noted that the 17.4 lb ai/acre 

application rate for turf was modeled to estimate post-application residential exposures (i.e., 

 

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
Ethylene Thiourea Human Health Risk Assessment DP No. D411820

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adults and youth 6 to 16 years old). As this rate is equal to or higher than the agricultural 

application rates, this scenario is protective of any ETU exposure via spray drift from 

agricultural EBDC applications.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure.

Based on the (existing and proposed) uses of the EBDCs mancozeb and metiram, exposure to 

ETU can occur both from dietary sources (food and water) and in residential settings. For the 

aggregate ETU assessments, both mancozeb and metiram uses are considered for dietary 

exposure assessment. However, since there are no residential uses of metiram, only mancozebderived ETU is considered in the residential component of the aggregate assessments. The 

mancozeb uses in home gardens may result in handler ETU exposure for adults and postapplication ETU exposure to adults and youth working in the garden. The mancozeb golf course 

turf use may result in post-application ETU exposure for adults and youth playing golf. For 

residential post-application exposure, the garden scenario has the highest exposure estimates and 

was used in the short-term aggregate assessment.

The aggregate risk assessments are intended to be representative of exposures that are likely to 

co-occur. For the purpose of this risk assessment, HED only aggregated scenarios that are 

believed likely to co-occur. The lifestages selected for the aggregate assessments represent the 

population subgroups expected to be the most highly exposed for each scenario. For more 

information on the exposure scenarios selected for aggregate assessment, see Section 6.1 above.

The following aggregate risk assessments were conducted for ETU:

ETU Acute Aggregate which considers acute exposure from food and water.

ETU Short-Term Aggregate (Adult and Youth) which considers 1) handler exposures 

(inhalation and dermal) plus food and water exposures for adults treating home gardens

and 2) post-application exposures (dermal) plus food and water for adults and youth 

entering the garden after treatment.

ETU Long-Term or Chronic (Non Cancer) Aggregate which considers exposure from 

food and water only.

ETU Cancer Aggregate which combines adult handler home garden exposures (dermal 

and inhalation) and chronic food and water and 2) post-application exposures (dermal) 

plus food and water for adults entering the garden after treatment.

Summaries of the aggregate risk assessments can be found below in Sections 7.1 through 7.5.
Ethylene Thiourea Human Health Risk Assessment DP No. D411820

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7.1 Acute Aggregate Risk

The acute aggregate risk assessment for ETU considers acute exposure from food and drinking 

water. An acute endpoint was selected only for the subpopulation, females 13-49 years old, so 

an acute aggregate assessment is required only for this subpopulation. Since HED usually 

considers only dietary (food and drinking water) contributions to ETU acute aggregate risk, the 

ETU acute aggregate risk assessment is equivalent to the ETU acute dietary (food and drinking 

water) risk assessment detailed in Section 5.3 of this document.

7.2 Short-Term Aggregate Risk

The short-term aggregate assessment for ETU combined adult residential handler exposures and 

dietary (food and water) exposures. There are no short-term aggregate risk estimates of concern 

for adults applying mancozeb to gardens (Tables 7.2.1).

A short-term aggregate assessment was performed for ETU for adults and youth entering treated 

gardens. Post-application exposures to ETU were combined with dietary (food and water) 

exposures. There are no short-term aggregate risk estimates of concern for adults or youth 

entering treated gardens (Table 7.2.2).

Table 7.2.1 ETU (derived from EBDCs) Short-Term Aggregate Risk Calculations

(Residential Handler/ Home Garden Use)

Population

Short-Term Scenario

NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

Aggregate 

MOE (food, 

water, and 

residential)5

Adult Male (and 

Females >49 yrs) 7 100 0.07 0.000034 0.000132 0.000166 42,000

Adult Female 

(13-49 yrs) 5 1000 0.005 0.000031 0.000153 0.000184 27,000

1 LOC = 10x inter-species UF, 10x intra-species UF; and for females (13-49 yrs) the 10x FQPA SF is retained.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = [Dermal exposure + Inhalation Exposure]. (Section 6.1).

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure)

5

Table 7.2.2 ETU (derived from EBDCs) Short-Term Aggregate Risk Calculations

(Residential Post-Application/ Home Garden Use)

Population

Short-Term Scenario

NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

Aggregate 

MOE (food, 

water, and 

residential)5

Adult Female 

(13-49 yrs) 5 1000 0.005 0.000031 0.0019 0.001931 2600

Youth 

(11- <16 yrs) 7 100 0.07 0.000023 0.0022 0.002223 3100

1 LOC = 10x inter-species UF, 10x intra-species UF; and for females (13-49 yrs) the 10x FQPA SF is retained.
Ethylene Thiourea Human Health Risk Assessment DP No. D411820

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2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = [Dermal exposure]. (Section 6.1).

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure)

5

7.3 Intermediate-Term Aggregate Risk

There are no intermediate-term residential exposure scenarios for mancozeb (and ETU), and no 

residential uses for metiram, therefore an intermediate-term aggregate assessment is not 

performed.

7.4 Chronic Aggregate Risk

There are no long-term residential exposure scenarios for the uses of the EBDCs which would 

result in long term residential exposures to ETU. Therefore, the long-term or chronic (noncancer) aggregate risk for ETU includes contribution from dietary (food and drinking water) 

exposure alone. The chronic aggregate risk assessment for ETU is equivalent to the ETU 

chronic dietary risk assessment discussed in Section 5.3 of this document. 

7.5 Cancer Aggregate Risk

The cancer aggregate assessment for ETU from EBDC uses includes contributions from 

residential and dietary (food and water) exposures. Handler and post-application ETU aggregate 

cancer risk estimates are 2 x 10-6and 3 x 10-6, respectively, for the general U.S. population.

Table 7.5.1 ETU (derived from EBDCs) Aggregate Cancer Risk Estimates

(Residential Handler/Garden Use)

Population Cancer Slope 

Factor (Q1*)

Food and Water 

Exposure 

(mg/kg/day)

Residential 

Exposure (LADD -

mg/kg/day1

Aggregate Cancer 

Risk (food, water, 

residential)2

US Population 6.01 x 10 -23.1 x 10 -51.16 x 10 -62 x 10 -6

1 Residential exposure values used in aggregate assessment: Section 6.1

2 Aggregate Cancer Risk = (Q1*) (Food & Water Exposure + LADD)

Table 7.5.2 ETU (derived from EBDCs) Aggregate Cancer Risk Estimates

(Residential Post-application/Garden Use)

Population Cancer Slope 

Factor (Q1*)

Food and Water 

Exposure 

(mg/kg/day)

Residential 

Exposure (LADD -

mg/kg/day1

Aggregate Cancer 

Risk (food, water, 

residential)2

US Population 6.01 x 10 -23.1 x 10 -51.41 x 10-53 x 10-6

1 Residential exposure values used in aggregate assessment: Section 6.1

2 Aggregate Cancer Risk = (Q1*) (Food & Water Exposure + LADD)

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 ETU and any other substances. Risks from combined exposures to ETU from all EBDC 

compounds are addressed in this ETU aggregate risk assessment. For information regarding 
Ethylene Thiourea Human Health Risk Assessment DP No. D411820

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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

The occupational aspect of ETU human health risk assessment has been completed for each of 

the EBDC fungicides in the most recent risk assessments of the parent compound. For details of 

the ETU occupational assessments see D397268, 11/14/12 and D337241, 6/14/07.

10.0 References

D. Drew, 5/13/13, D411742, Mancozeb: Human Health Risk Assessment to Support Proposed 

New Section 3 Uses on Walnuts and Tolerances for Imported Tangerines.

A. Rivera-Lupiáñez, 5/14/13, D411769, Mancozeb: Revised Occupational and Residential Risk 

Assessment to Support Request for Section 3 Registrations on Walnuts.

P. Savoia, 4/8/13, D404217, Mancozeb. Section 3 Registration for Establishing a Tolerance on 

Imported Tangerines. Summary of Analytical Chemistry and Residue Data. 

P. Savoia, 4/8/13, D402042, Mancozeb. Section 3 Registration Adding the Use of Mancozeb on 

Walnuts. Summary of Analytical Chemistry and Residue Data. 

P. Savoia, 4/8/13, D405592, Aggregate Dietary Assessment of the Common 

Metabolite/Degradate Ethylene Thiourea (ETU) Resulting from the Combined Uses of the 

Ethylene Bisdithiocarbamate Fungicides (EBDCs) to Support the New Use of Mancozeb on 

Walnuts and the Establishment of a Tolerance on Imported Tangerines for Section 3 

Registration. 

P. Savoia, 4/8/13, D402043 and D405277, Mancozeb. Acute, Chronic, and Cancer Dietary 

Exposure Assessments of Food and Drinking Water to Support the New Use of Mancozeb on

Walnuts and the Establishment of a Tolerance on Imported Tangerines for Section 3 

Registration. 

M. Ruhman, 7/3/12, D397306, Estimated Drinking Water Concentrations of ETU Degradate 

(Ethylene-thio-urea degradate) of Mancozeb from its Proposed New Use on Walnuts for Use in 

Human Health Risk Assessment.

Olinger, C., 11/16/10, D383971, Addendum to the Aggregate Human Health Risk Assessment of 

the Common Metabolite/Degradate Ethylene Thiourea (ETU) to Support New Tolerances on 
Ethylene Thiourea Human Health Risk Assessment DP No. D411820

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Imported Grapes and Bananas for Metiram and for New Tolerances for Mancozeb on Almonds, 

Broccoli, Cabbage, Lettuce, and Peppers.

Goodlow, T. 6/14/07, D337241, Ethylenethiourea (ETU) from EBDCs: Health Effects Division 

(HED) Human Health Risk Assessment of the Common Metabolite/Degradate ETU

Goodlow, T. 6/14/07, D267866, Metiram: Human Health Risk Assessment for PP#9E6006. 

Petition for the Establishment of Import Tolerances on Grapes and Bananas. 

M. Ruhman, 8/11/06, D323143 and 323141, Revision No. 2: Estimated Drinking Water 

Concentration of Ethylenebisdithocarbamate (EBDC) Degradate Ethylenethiourea (ETU) for the 

Use in Human Health Risk Assessment.
Ethylene Thiourea Human Health Risk Assessment DP No. D411820

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicity Profiles

Table A.1.1 Acute Toxicity of ETU

Guideline No. Study Type MRID Nos. Results Toxicity 

Category

870.1100 Acute Oral – rat N/A N/A N/A

870.1200 Acute Dermal - rabbit 458881-01 LD50 > 2000 mg/kg III

870.1300 Acute Inhalation - rat 458881-02 LC50 > 10.4 mg/L IV

870.2400 Primary Eye Irritation 458881-04 No irritation 1IV

870.2500 Primary Skin Irritation 458881-03 No irritation IV

870.2600 Dermal Sensitization N/A N/A N/A

1 The primary eye irritation study was classified unacceptable because a UV light was not observed with 

fluorescein staining, however, another study is not required (M. Lewis, 4/30/03, D289726).

Table A.1.2 Toxicity Profile of ETU

Study Type

[Guideline No.]

MRID No./

Classification

Results

Subchronic (13-week)

feeding - rat

[870.3100]

250 ppm (males: 14.28 

mg/kg/day; females: 17.81 

mg/kg/day)

000160704/1986

Acceptable/nonguideline

NOAEL = <14.28 mg/kg/day

LOAEL = 14.28 mg/kg/day, based on reduced body weight, 

changes in thyroid hormone and TSH levels, increased thyroid and 

liver weight, microscopic thyroid hyperplasia and liver 

hypertrophy.

Subchronic (13-Week)

feeding - mouse

[870.3100]

0, 1, 10, 100, 1,000 ppm 

(males: 0, 0.16, 1.72, 18.18, 

168.2 mg/kg/day; females: 0, 

0.22, 2.38, 24.09, 231.1 

mg/kg/day)

00154192/1985

Unacceptable/

Guideline

NOAEL = 1.72 mg/kg/day

LOAEL = 18.18 mg/kg/day, based on microscopic thyroid 

hypertrophy/hyperplasia.

At the high dose, more microscopic thyroid changes and increases 

in thyroid and liver weight occurred. 

Unacceptable because ETU concentrations varied widely.

Subchronic (13-Week)

feeding - dog

[870.3100]

0, 10, 150, 2000 ppm (males: 

0, 0.39, 6.02, 66.23 

mg/kg/day; females: 0, 0.42, 

6.51, 71.62 mg/kg/day)

42174201/1991

Acceptable/

Guideline

NOAEL = 0.39 mg/kg/day

LOAEL = 6.02 mg/kg/day, based on elevated cholesterol. (Note: 

this endpoint was not considered robust enough for use in risk 

assessment)

At 6.02 mg/kg/day, thyroid effects were observed.

In high dose group: mortality, anemia, decreased activity, 

decreased thyroid hormone levels, increased thyroid weight,

microscopic thyroid hyperplasia.

Chronic

tox/carcinogenicity - SD rat

[870.4100]

0, 0.5, 2.5, 5.0, or 125 ppm

Males: 0, 0.04, 0.17, 0.37, 

8.91 mkd

Females: 0, 0.05, 0.25, 0.49, 

42607801/1992

Unacceptable/

Guideline

Concentration of ETU in feed varied widely and doses could not 

be determined. Microscopic thyroid hyperplasia occurred in the 

low-dose group. At higher doses, changes in thyroid hormone and 

TSH levels, increased thyroid weight, and grossly enlarged livers. 

Increases in thyroid follicular adenomas and pituitary adenomas in 

high-dose males. 
Ethylene Thiourea Human Health Risk Assessment DP No. D411820

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Table A.1.2 Toxicity Profile of ETU

Study Type

[Guideline No.]

MRID No./

Classification

Results

13.57 mkd

Chronic (24-Month)

Feeding – B6C3F1 mouse 

(NTP)

45924403/1992

Fund. Appl. Tox. 

18: 405-417

w/ and w/out 

perinatal 

exposure

This study was used to determine the Q1* for ETU of 6.01 x 10-2

(mg/kg/day)-1based upon female mouse liver adenomas and/or 

carcinomas. Thyroid follicular cell adenomas and carcinomas, 

hepatocellular adenomas and carcinomas, and pituitary adenomas 

were increased. 

Chronic (24-Month)

Feeding – Fischer 344 rat 

(NTP)

45924403/1992

Fund. Appl. Tox. 

18: 405-417

w/ and w/out 

perinatal

Thyroid follicular cell adenomas and pituitary adenomas were 

observed.

Chronic (1-year) oral

toxicity - dog

[870.4100]

0, 5, 50, or 500 ppm

(males: 0, 0.18, 1.99, 20.13 

mg/kg/day; females: 0, 0.19, 

1.79, or 20.15 mg/kg/day)

42338101/1992

Acceptable/

Guideline

NOAEL = 0.18 mg/kg/day

LOAEL = 1.99 mg/kg/day, based on increased thyroid weight and 

microscopic changes in thyroid (hypertrophy, follicular dilatation).

At the high dose, mortality, anemia, and microscopic 

hepatocellular necrosis.

4-Week Range-finding -

Dog

0, 196, 980, 4900 ppm 

(males: 0, 7.0, 34, or 172 

mg/kg/day; females: 0, 8.0, 

36, or 197 mg/kg/day)

41863401/1989

Acceptable/nonguideline

NOAEL = 7 mg/kg/day

LOAEL = 34 mg/kg/day, based on decreased levels of thyroid 

hormones, gross thyroid lesions.

Developmental toxicity

SD BR rat

[870.3700]

50 mg/kg/day

(distilled water)

GD 6-15

00093929/1980

Acceptable/nonguideline

Maternal NOAEL = <50 mg/kg/day

Maternal LOAEL = 50 mg/kg/day, based on decreased body 

weight gain (↓36%).

Developmental NOAEL = <50 mg/kg/day

Developmental LOAEL = 50 mg/kg/day, based on numerous 

central nervous system defects (hydrocephaly and related 

malformations); gross developmental defects; skeletal defects, 

and decreased fetal weight (↓13%).

Only one dose group was included in the study.

Developmental toxicity

Wistar rat

[non-guideline]

0, 5, 10, 20, 40, 80 

mg/kg/day

45937601/1973

[Khera, K.S. 

1973. Teratology

7:243-252]

Maternal NOAEL = 40 mg/kg/day

Maternal LOAEL = 80 mg/kg/day, based on mortality (9 of 

11after 7-8 days).

Developmental NOAEL = 5 mg/kg/day

Developmental LOAEL = 10 mg/kg/day based on exencephaly, 

dilated ventricles, and hypoplastic cerebellum. At 20 mg/kg/day, 

hydrocephalus, encephalocele, meningocele, micrognathia, 

abnormal flexion of ankle, kinky or twisted tail; at ≥40 mg/kg/day: 

oligodactyl, domed head, retarded ossification of the skull 

occurred; at 80 mg/kg/day: coloboma of the eyelids, hemimelia, 

syndactyl, cleft palate, ectopic kidney, rudimentary calvarium, 

short tail, scoliosis and several types of skeletal anomalies 

occurred. Decreased fetal weight was noted at 40 mg/kg/day in 

group I (↓10%) and group III (↓21%) and at 80 mg/kg/day in 
Ethylene Thiourea Human Health Risk Assessment DP No. D411820

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Table A.1.2 Toxicity Profile of ETU

Study Type

[Guideline No.]

MRID No./

Classification

Results

group II (↓44%). Fetuses at 40 mg/kg/day in group II had weights 

comparable to controls. Number of live fetuses and corpora lutea 

were comparable to controls in all groups. 

Developmental toxicity

SD rat

(1) 0, 5, 10, 20, 30, 40, or 80 

mg/kg/day from GD 7-21.

(2) 0, 20, 25, or 30 

mg/kg/day from GD 7 to 

PND 15

45924404/1979

[Chernoff, et al., 

J. Toxicol. Env. 

Health 5: 821-

834]

Maternal NOAEL = 40 mg/kg/day (or lower).

Maternal LOAEL = 80 mg/kg/day, based on reduced body weight 

and 25% maternal mortality.

Gestational exposure only:

Developmental NOAEL = 10 mg/kg/day (↓7% fetal BW)

Developmental LOAEL = 20 mg/kg/day, based on hydrocephalus 

(12 fetuses/5 litters).

Decreased ossification was also observed at 30 mg/kg/day and 

above; at 40 mg/kg/day, encephalocele, kyphosis, and digit defects 

(oligodactyl, syndactyl) were also observed. At 80 mg/kg/day, 

fetal mortality was increased and there were increases in cleft 

palate, limb defects (micromelia, hemimelia), edema, and 

micrognathia. 

Gestational and postnatal exposure:

Postnatal toxicity at

30 mg/kg/day included hydrocephalus, dome-shaped heads, and 

pup mortality. 

Developmental toxicity

Wistar rat

[non-guideline]

0, 15, 30, 45 mg/kg

Dams received a single oral 

dose on gestation day 15.

MRID 48985801

[Khera and 

Tryphonas 

Tox Appl Pharm 

42:85-97. 1977]. 

Maternal NOAEL/LOAEL not reported

Developmental NOAEL = 15 mg/kg

Developmental LOAEL = 30 mg/kg based on postnatal mortality, 

hydrocephaly, microphthalmia, cerebellar dysplasia, cerebral 

atrophy, and in survivors, motor defects and dome-shaped head.

Developmental toxicity 

Wistar rat

0 or 240 mg/kg

Dams received a single dose 

on one gestation day between 

GD 6-21

No MRID 

[Ruddick and 

Khera. 

Teratology 

12:277-282, 

1975]

No maternal toxicity observed.

Teratogenic effects in fetuses from GD 10-21; greatest frequency 

of defects between GD 12-15; no defects before GD 10; ETU 

affected development of brain, kidney, eye, and axial and 

appendicular systems

Developmental toxicity 

SD rat

0, 15, 25, or 35 mg/kg/day 

from GD 6-20

No MRID 

[Saillenfait, et 

al., Fund. Appl. 

Toxicol. 17: 300-

408, 1991]

Maternal NOAEL

Maternal LOAEL = 15 mg/kg/day, based on decreased body 

weight gain

Developmental NOAEL = 15 mg/kg/day

Developmental LOAEL = 25 mg/kg/day, based on dilated 

ventricles of the brain, hydroureter, short/kinky tail, and dilated 

ureters. At 35 mg/kg/day, hydrocephaly, anencephaly, 

meningocele, meningorrhea, hyrdronephrosis, dilated renal pelvis, 

and vertebral abnormalities were observed.

Developmental toxicity 

Wistar-Imamichi rats

0, 10, 20, 30, 40, 50 

mg/kg/day 

GD 6-15.

45924405/1978

[Teramoto, et al., 

Congenital 

Anomalies 18: 

11-17, 1978]

Developmental NOAEL <10 mg/kg/day

Developmental LOAEL = 10 mg/kg/day, based on dilated brain 

ventricles. At higher doses, fetal death, meningocele, 

micrognathia, hydronephrosis, renal agenesis, uterine hypoplasia, 

skeletal anomalies, short/kinky tail, and scoliosis were observed. 

Developmental 

New Zealand White Rabbit

[870.3700]

0.5% aqueous 

methylcellulose

0, 5, 15, 50 mg/kg/day

47976403/2010

Acceptable/

Guideline

Maternal NOAEL = 5 mg/kg/day

Maternal LOAEL = 15 mg/kg/day based on increased 

postimplantation loss

Developmental NOAEL = 5 mg/kg/day 

Developmental LOAEL = 15 mg/kg/day based on increased 
Ethylene Thiourea Human Health Risk Assessment DP No. D411820

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Table A.1.2 Toxicity Profile of ETU

Study Type

[Guideline No.]

MRID No./

Classification

Results

GD 7-29 postimplantation loss

At 50 mg/kg/day, postimplanation loss, decreased fetal BW 

(↓10%), hydrocephaly (1), and domed head (2) were observed.

Developmental toxicity 

Syrian Golden hamsters

0, 90, 270, 810 mg/kg/day 

from GD 6-13.

45924405/1978

[Teramoto, et al., 

Congenital 

Anomalies 18: 

11-17, 1978]

Developmental NOAEL = 90 mg/kg/day

Developmental LOAEL = 270 mg/kg/day, based on skeletal 

malformations and short/kinky tail. At 810 mg/kg/day, fetal 

deaths, dilated brain ventricles, cleft palate, micrognathis, and anal 

atresia were observed.

Developmental toxicity 

JCL-ICR mouse

0, 200, 400, or 800 

mg/kg/day.

GD 7-15

45924405/1978

[Teramoto, et al., 

Congenital 

Anomalies 18: 

11-17, 1978]

No maternal or developmental toxicity was observed.

2-Generation

reproduction – SpragueDawley rat

[870.3800]

0, 2.5, 25, 125 ppm

42391701/1992

Unacceptable/

Non-guideline

42391801/1992

ETU content data

Doses on mg/kg/day basis could not be determined.

Parental: microscopic thyroid hyperplasia/hypertrophy in mid 

and/or high-dose groups.

No reproductive effects attributed to treatment.

Unacceptable because of stability problems (mkd could not be 

calculated) with test material and poor record keeping.

Dermal absorption – SD 

COBS CD rat

[870.7600]

40312601/1987

Acceptable

Dermal absorption = 26%

Immunotoxicity - rat

[870.7800]

48794502/2012

Acceptable/

Guideline

Negative for Immunotoxicity

A.2 Executive Summaries

Developmental Toxicity in Rats

(1) Khera, KS. National Health and Welfare, Canada. Teratology 7: 243-247, 1973 (MRID 

45937601). ETU (% a.i. and lot # not provided) was administered to Wistar rats by gavage at 

doses of 0, 5, 10, 20, 40, or 80 (group II only) mg/kg/day. There were 3 treatment groups: 

Group I was treated from 21-42 days before mating until gestation day (GD) 15; Group II was 

treated from GD 6-15; and Group III was treated from GD 7-20. No maternal toxicity was noted 

in this study.

The NOAEL for maternal toxicity is 80 mg/kg/day, the highest dose tested. The LOAEL 

for maternal toxicity was not determined. 

Similar developmental defects occurred at generally the same doses in groups that were treated at 

different times of gestation. At 10 mg/kg/day and above, defects included: exencephaly, dilated 

ventricles, and hypoplastic cerebellum; at 20 mg/kg/day and above: hydrocephalus, 

encephalocele, meningocele, micrognathia, abnormal flexion of ankle, kinky or twisted tail; at 
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40 mg/kg/day and above: oligodactyl, domed head, retarded ossification of the skull occurred; 

and at 80 mg/kg/day: coloboma of the eyelids, hemimelia, syndactyl, cleft palate, ectopic 

kidney, rudimentary calvarium, short tail, scoliosis and several types of skeletal anomalies 

occurred. Decreased fetal weight was noted at 40 mg/kg/day in group I (↓10%) and group III 

(↓21%) and at 80 mg/kg/day in group II (↓44%). Fetuses at 40 mg/kg/day in group II had 

weights comparable to controls. Number of live fetuses and corpora lutea were comparable to 

controls in all groups. 

The NOAEL for developmental toxicity is 5 mg/kg/day, and the LOAEL is 10 mg/kg/day 

based on developmental defects of the brain (exencephaly, dilated ventricles, and 

hypoplastic cerebellum).

In a developmental toxicity study (MRID 00093929; 1980), 50 mg/kg/day ethylene thiourea 

(ETU, 99%), was administered to a single dose group of pregnant SD BR rats (26/dose group) by 

gavage from days 6-15 of gestation. Separate dose groups received mancozeb (results not 

reported here). Doses were calculated on day 6 and not adjusted for weight changes during the 

study. No data on the stability of ETU were reported. 

Maternal survival and body weights in the 50 mg/kg/day ETU group were comparable to 

controls while food consumption was increased in comparison to controls. Body weight gains 

were decreased in the ETU group (↓36%) compared to controls during the treatment period. 

The ETU group (50 mg/kg/day) had decreased mean fetal body weight (↓13% compared to 

controls). The number of implants, resorptions, and litter size were all similar to control values. 

Developmental abnormalities attributed to treatment in the ETU group included abnormalities of 

the central nervous system: atrophy of brain tissue, cranial edema, dilated ventricles of the 

brain, compression and/or hemorrhages of the spinal cord, deficiency of tissue in the olfactory 

bulb, meningoencephalocele, exencephaly; abnormalities of the skeletal system: incomplete 

cranial ossification, wide cranial sutures, curved clavicle, fused sternebrae, absent caudal or 

sacral vertebrae, fused and/or thickened ribs, incomplete ossification of ribs, less than 13 ribs, 

wavy ribs, misshapen or incomplete ossification of hindlimb long bones, kyphosis, incomplete 

ossification or misshapen pelvis, abnormal pelvic limb posture, fused lumbar, sacral, or caudal 

vertebrae; gross defects: ectopic kidneys, agenesis of the kidneys, hydronephrosis, reduced 

stomach with thickened wall, anal atresia, agnathia, cleft palate, cleft lip, club limb, stubby tail, 

forelimb flexure, kinked tail, edematous fat pads, oligodactyl, syndactyl, webbed digits; and 

cryptorchidism. 

Maternal and developmental NOAELs for ETU were not determined because only 1 dose 

of ETU was used and adverse effects were observed. The maternal LOAEL for ETU was 

50 mg/kg/day, based on decreased body weight gain. The developmental LOAEL for ETU 

was 50 mg/kg/day, based on numerous central nervous system defects, gross developmental 

defects, skeletal defects, and decreased fetal weight.

Chernoff, N., et al. Health Effects Research Laboratory, EPA. J. Toxicol. Environ. Health 5: 

821-834 (1979). MRID 45924404. ETU (% a.i. and lot # not provided) was administered to SD 

rats by gavage at doses of 0, 5, 10, 20, 30, 40, or 80 mg/kg/day from gestation day (GD) 7-21. 
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Postnatal toxicity in pups was also evaluated in separate groups of dams treated at 0, 20, 25, or 

30 mg/kg/day from GD 7 to postnatal day (PND) 15. The only maternal toxicity reported was 

reduced body weight gain and 25% maternal mortality at 80 mg/kg/day. Although the NOAEL 

for maternal toxicity in this study appears to be 40 mg/kg/day, the actual maternal NOAEL may 

have been lower because the article did not describe observations for maternal toxicity. Fetal 

toxicity at 10 mg/kg/day was limited to decreased fetal weight (↓7%). At 20 mg/kg/day, 

hydrocephalus occurred (12 fetuses and 5 litters). At 30 mg/kg/day, there was also decreased 

ossification. At 40 mg/kg/day, there was also encephalocele, kyphosis, and digit defects 

(oligodactyl, syndactyl). At 80 mg/kg/day, fetal mortality was increased and there were 

increases in cleft palate, limb defects (micromelia, hemimelia), edema, and micrognathia. 

Postnatal toxicity at 30 mg/kg/day included hydrocephalus, dome-shaped heads, and pup 

mortality. The NOAEL for developmental toxicity was 10 mg/kg/day and the LOAEL was 

20 mg/kg/day based on hydrocephalus. 

Khera and Tryphonas (Toxicol. Appl. Pharm. 42: 85-97. 1977) tested ETU in Wistar rats at 

doses of 0, 15, 30, or 45 mg/kg. Dams received a single dose on gestation day (GD) 15. The 

NOAEL for developmental toxicity was 15 mg/kg/day and the LOAEL was 30 mg/kg/day, based 

on postnatal mortality, hydrocephalus, microphthalmia, cerebellar dysplasia, cerebral atrophy, 

and in survivors, motor defects and dome-shaped head. A cross-fostering study of survivors 

found that developmental toxicity was due to in utero exposure and not to exposure in milk. 

Maternal effects were not reported.

Ruddick and Khera (Teratology 12: 277-282. 1975) tested ETU in Wistar rats. Dams received a 

single oral dose of 240 mg/kg. Different groups received the single dose on one day between 

GD 6-21. No maternal toxicity was noted. Teratogenic effects occurred in fetuses from 

treatment days GD10-21, the greatest frequency of defects occurred between GD 12-15, and no 

defects occurred before GD 10. ETU affected development of the brain, kidney, eye, and axial 

and appendicular systems as occurred in other developmental studies in rats. 

Saillenfait, et al., (Fund. Appl. Toxicol. 17: 399-408. 1991) tested ETU in SD rats at 0, 15, 25, or 

35 mg/kg/day from GD 6-20. The only maternal toxicity noted was decreased body weight gain 

at 15 mg/kg/day and above. The NOAEL for developmental toxicity was 15 mg/kg/day and 

the LOAEL was 25 mg/kg/day based on dilated ventricles of the brain, hydroureter, 

short/kinky tail, and dilated ureters. Developmental toxicity at higher doses included 

hydrocephaly, anencephaly, meningocele, meningorrhea, hyrdronephrosis, dilated renal pelvis, 

and vertebral abnormalities. 

Teramoto, et al., (Congenital Anomalies 18: 11-17. 1978), tested ETU in Wistar-Imamichi rats at 

doses of 0, 10, 20, 30, 40, or 50 mg/kg/day from GD 6-15. No maternal toxicity was noted. The 

NOAEL for developmental toxicity in rats was < 10 mg/kg/day, the lowest dose tested; the 

LOAEL in rats was 10 mg/kg/day based on dilated brain ventricles. Developmental toxicity 

at higher doses included fetal death, meningocele, micrognathia, hydronephrosis, renal agenesis, 

uterine hypoplasia, skeletal anomalies, short/kinky tail, and scoliosis. ETU was also tested in 

Syrian Golden hamsters: the NOAEL for developmental toxicity in hamsters was 90 mg/kg/day 

and the LOAEL in hamsters was 270 mg/kg/day based on skeletal malformations and 

short/kinky tail; at 810 mg/kg/day, fetal death, dilated brain ventricles, cleft palate, micrognathia, 
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and anal atresia also occurred (GD 6-13). ETU was tested in JCL-ICR mice: no maternal 

toxicity was noted and no clear developmental toxicity was noted at dose levels up to 800 

mg/kg/day (GD 7-15). 

In the Chernoff, et al., (1979) article cited in the developmental toxicity section above, ETU was 

also tested in CD mice at 0, 100, or 200 mg/kg/day. One fetus in each of the two treatment 

groups had encephalocele. There was increased incidence of supernumery ribs at 200 

mg/kg/day. ETU was also tested in hamsters (300 mg/kg/day) and guinea pigs (100 mg/kg/day), 

but developmental toxicity did not occur. (J. Toxicol. Environ. Health, 5:821-834. 1979)

In the Khera, 1973 article reported in the Developmental Toxicity section above, testing of ETU 

in NZW rabbits was also reported. Rabbits were tested at doses of 0, 10, 20, 40, or 80 

mg/kg/day. Resorption sites and dead fetuses were reportedly increased in the 2 higher dose 

groups. Brain weight may have been reduced in the high dose group, but it was not clear if this 

was a treatment related effect. Degeneration of proximal convoluted tubules of the kidneys was 

seen in the high dose group. No treatment related skeletal abnormalities were seen. Teratogenic 

effects similar to those in rats were not noted in this study, however, the reporting on methods 

used and results in rabbits in this article was inadequate for a critical analysis of the data. 

Doerge and Takazawa (Chem. Res. Toxicol. 3: 98-101. 1990) reported that ETU is a directacting thyroid toxicant which acts by inhibiting thyroid peroxidase enzyme. The enzyme 

oxidizes ETU but does not permanently bind to ETU. 

Systemic Toxicity in Dogs

Chronic dog study: In a chronic oral toxicity study (MRID 42338101), Beagle dogs 

(4/sex) received ethylene thiourea (98.0%) at dietary concentrations of 0, 5, 50, or 500 ppm 

(males: 0, 0.18, 1.99, 20.13 mg/kg/day; females: 0, 0.19, 1.79, or 20.15 mg/kg/day) for 52 weeks. 

Analytical concentrations of test material in feed were variable, but acceptable for this study. 

Two males (days 47 and 113) and 1 female (day 37) in the 500 ppm group died or were 

sacrificed moribund. Death was attributed to treatment-induced anemia (hemoglobin values 

were reduced approximately ↓80% to ↓90%. Other toxicity in the dead/moribund dogs included 

anorexia, weight loss, subdued behavior, dyspnea, tachycardia, reduced level of thyroid 

hormones, increased bilirubin, and microscopic liver necrosis. Body weight gain was depressed 

in 50 ppm males (↓27%) and in 500 ppm males (↓27%) and females (↓50%) for weeks 0-13. 

Among survivors, body weights at termination were reduced in comparison to controls in 50 

ppm males (↓8%), 500 ppm males (↓15%) and 500 ppm females (↓16%). 

The 2 surviving 500 ppm males had pale mucous membranes; one male had a responding 

anemia (decreased red blood cell parameters and reticulocytosis). Serum cholesterol was 

elevated in 500 ppm males (↑50%) and females (↑50%), but not with statistical significance. 

Calculated values for serum globulins were elevated in 500 ppm dogs but are of uncertain 

toxicological significance. 

Thyroid toxicity was manifested as increased thyroid weights and microscopic changes in 

50 and 500 ppm animals. Absolute thyroid weights were increased in 50 ppm females (↑50%), 

in 500 ppm males (↑270%) and in 500 ppm females (↑72%); relative-to-body thyroid weights 

were increased in 50 ppm females (↑49%), in 500 ppm males (↑336%), and in 500 ppm females 
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(↑97%). Microscopic changes in the thyroid were observed only at the 2 higher dose levels. 

Follicular hypertrophy and follicular dilatation/colloid in males were observed in males and 

females. An increased number of thyroid follicles were observed microscopically in males and 

females. Although thyroid hormones were slightly decreased in treated animals in comparison to 

controls, there was no statistical significance or dose response relationship with the possible 

exception of thyroxine in males. 

The NOAEL is 5 ppm (males: 0.18; females: 0.19 mg/kg/day) and the LOAEL is 50 ppm 

(males: 1.99; females: 1.79 mg/kg/day), based upon decreased body weight gain, increased 

thyroid weight, and microscopic changes in the thyroid. Also occurring at 500 ppm were 

mortality, severe anemia, clinical signs, and microscopic liver necrosis. This study is classified 

acceptable and satisfies the guideline requirement for a chronic toxicity study with ethylene 

thiourea in dogs. 

Rangefinding dog study: In a 4-week rangefinding toxicity study (MRID 41863401), 

Beagle dogs (2/sex/dose) received ethylene thiourea (98.0%) in the diet for 4 weeks. Target 

dietary concentrations were 0, 200, 1000, and 5000 ppm. Dietary concentrations corrected for 

purity of the technical grade ethylene thiourea were 0, 196, 980, or 4900 ppm (males: 

approximately 0, 7.0, 34, or 172 mg/kg/day; females: approximately 0, 8.0, 36, or 197 

mg/kg/day). Homogeneity and stability results of test material mixed with food were variable, 

but acceptable for this study. 

There were no deaths, and clinical signs were comparable among groups. Body weight 

decrements in the two 4900 ppm females (↓13% at termination) and reduced body weight gain 

(↓95% at termination) were accompanied by decreased food consumption and decreased feed 

efficiency. Body weights and body weight gains of the males and low- and mid-dose females 

were unaffected by treatment. Hematology parameters were unaffected by treatment. 

Thyroid toxicity was noted as decreases in thyroid hormones and gross pathology; 

histopathological examination and organ weight determination were not performed. 

Triiodothyronine was depressed in males and females in the 980 ppm group (↓45%) and in the 

4900 ppm group (greater than ↓75%). Thyroxine was depressed in males and females in the 980 

ppm group (↓69%) and in the 4900 ppm group (greater than ↓94%). Thyroids in males and 

females in the 980 and 4900 ppm groups were found to be enlarged and dark on gross necropsy. 

The NOAEL is 196 ppm (males: 7.0 mg/kg/day; females: 8.0 mg/kg/day) and the 

LOAEL is 980 ppm (males: 34 mg/kg/day; females: 36 mg/kg/day), based on gross thyroid 

lesions and decreased thyroid hormones. This rangefinding study is classified acceptable/nonguideline. 
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Appendix B. Review of Human Research

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 

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; the Agricultural Re-entry Task Force (ARTF) database; and other registrantsubmitted studies; (1) are 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 that 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 the Agency website.3

 

3

http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html