Ethylene Thiourea Human Health Risk Assessment DP No. D411820

UNITED ST A TES ENVIRONMENTAL PROTEC TI ON AGENCY

WASHINGTON, D.C. 20460

MEMORANDUM

Date: May 23,2013 O FFI CE OF
CHEMICAL SA FETY AND
POLLUTION P REV ENTION

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

Common Metabolite/Degradate Ethy l ene Thiourea (ETU) to Sup po rt Proposed New Section 3

Use on Walnuts and Tolerance for Impo rted Tan gerines

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 Tolera nce 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, Chem ist

### ~-t--"0 

### - Pet e Savoia, Chemist**L~ :**  

### -**J ~**  Linda Taylor, Ph.D., Toxicolo ·

## ~~~~? 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 Regis tration Division (7505P)

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

common metabolite/degradate of the re giste red ethylene bisdithiocarbamate (EBDC) fun gicides

mancozeb and metiram. Thi s document supersedes th e 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 of38Ethylene Thiourea Human Health Risk Assessment DP No. D411820

Page 2 of 38 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).Ethylene Thiourea Human Health Risk Assessment DP No. D411820

Page 3 of 38 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

................................ ...... 2 2

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 Ca ncer 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 Append ix B. Review of Human Research

................................ ................................ ................... 38Ethylene Thiourea Human Health Risk Assessment DP No. D411820

Page 4 of 38 1.0 Executive Summary

Background

E thylene 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 EBDC s are broad spectrum contact fungicides us ed in agriculture, professional tur f management, and horticulture. In terms of usage (total lbs. active ingredient applied) , mancozeb

is the mo re significant of the two registered EBDCs. Mancozeb is used on a wide variety of agricultural food crops, on tu rf, 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 performe d for mancozeb and ETU derived from mancozeb only to support the new uses ( D 411742

, 5/13 /13

, Mancozeb: Human Health Risk Assessment to Support Proposed New Section 3 Uses on Walnuts and Tolerances for Imported Tangerines )

. M etiram 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 ( D 267866, 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 Hea lth 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 ).

C rops 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

- appl ication 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 m etabolic conversion of absorbed

EBDC to ETU occurs and has been a ccounted 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 e stablished 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 T 4 , changes in

T 3 levels , compensatory increases in levels of TSH, increased thyroid weight, and microscopicEthylene Thiourea Human Health Risk Assessment DP No. D411820

Page 5 of 38 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 relate d lesions, skeletal system defects, and other gross defects.

Toxicology d ata gaps for ETU i nclude 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 S F 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, G roup B2 , with a cancer potency factor [Q 1 *, 0.0601 (mg/kg/day) - 1 ] for risk

assessment.

Dietary Risk Assessments

Refined p robabilistic 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 pr ocessing and cooking factors. There are

n o 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 r isk 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

cooki ng 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 - 6 for 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 R isk

Home GardensEthylene Thiourea Human Health Risk Assessment DP No. D411820

Page 6 of 38 Residential handler risk estimates (combined dermal and inhalation) were assessed for ETU as a result of adults applying mancozeb to home gardens. S hort

- 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 - 8 range.

R esidential 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 gard ens. Post

- application ETU cancer risk for adult home gardeners is estimated at 9 x 10 - 7

.

Turf (Golf Courses)

R esidential post

- application risk estimates for ETU were assessed for adult and youth golfers contacting mancozeb treated turf after application

. A dermal post

- application assessment (short

term and cancer) was performed for ETU. Inhalation exposures are not expected for the post

application golfing activities. There are no short

- term risk estimates of concern for adults or youth golfing on tre ated 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 post

application exposures than the golfing scenarios; aggregate assessments using the garden scenario are protective of any post

- application e xposures 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 assessme nt 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 c ancer 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 - 6 and 3 x 10 - 6

, respectively

.

Occupational Exposure and RiskEthylene Thiourea Human Health Risk Assessment DP No. D411820

Page 7 of 38 The occupational aspect of ETU human health risk a ssessment has been completed for each of the EBDC fungicides in the most recent risk asse ssments of the parent compound. For details of the ETU occupational assessments see D4 11769, 5/14 /1 3

, 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 assessm ent, 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

d ata gaps for ETU i nclude 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 reproduct ive toxicity study on ETU, which is currently in progress.

3 .0 In troduction

3.1 Chemical Identity

Table 3.1.1 ETU Test Compound Nomenclature
Compound

Common name Ethylenethiourea (ETU) Empirical formula C 3 H 6 N 2 S Molecular weight 102.2 CAS registry number 96

- 45

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

Page 8 of 38 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 (C 16 H 33 N 11 S 16 Zn 3 )

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/Chem ical 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 decomp osition, nitrogen and sulfur oxides are emitted.

ETU is highly vu lnerable to indirect photolysis, and is m oderately mobile. ETU has an aerobic

soil half

- life of 3 days, and an estimated aquatic aerobic metabolism half

- life of six days. The

measured anaer obic 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

.Ethylene Thiourea Human Health Risk Assessment DP No. D411820

Page 9 of 38 3.3 Pesticide Use Pattern

The EBDC s 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 f or mancozeb on walnuts and imported tangerines ( 1F7935, 2E8062 ). M etiram uses are limited to apples and

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

mo re significant of the two EBDCs ; for mancozeb, t he larges t 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

C rops 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 existi ng 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 w hich form during degradation of the tank mix over a typical workday, and the Agency has data to reflect these potential exposures. E xposure 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 post

application 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 ris ks 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 pat terns 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 theEthylene Thiourea Human Health Risk Assessment DP No. D411820

Page 10 of 38 country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroup s 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 far m 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 UF DB was applied previously to all asses sments 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 yo ung, 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, becau se 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 devel opmental toxicity study, and a dermal absorption study in rats. D ata gaps for ETU i nclude 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 s atisfied 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

include s 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.Ethylene Thiourea Human Health Risk Assessment DP No. D411820

Page 11 of 38 Developmental toxicity: Fetal malformations occurred mainly in rats, although hydrocephaly

and domed head were observed in a rabbit deve lopmental 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.

Malf ormations 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 olfac t ory 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 hindlim b long b ones, 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 ta il, 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: Ne urotoxicity 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, t he toxicity profile of ETU shows that the principal toxic effects are on the thyroid.

Carcinogenicity: Thyroid follicular cell adenomas and carcinomas were increased in a n ETU study with F344 rats conducted by the National Toxicology Program (NTP) . Thyroid follicular

cell adenomas and pituitary adenomas were also increased in a n 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 a n ETU study with

B6C3F1 mic e 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 requ irement was reserved (txr# 013554 ).

The HED Cancer Assessment Review Committee classified ETU as a probable human carcinogen, G roup B2. The Q 1 * for ETU, using a 3/4 scaling factor is 0.0601 (mg/kg/day) - 1
based upon female mouse liver tumors in a Nation al 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 s tudy in which hepatocellular necrosis was seen. AnEthylene Thiourea Human Health Risk Assessment DP No. D411820

Page 12 of 38 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 absorbe d. The plasma t 1/2 i s 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

, m etiram,

and maneb. In oral r at 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 F actor 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 developme ntal thyroid study, a reproduction study

, and a developmental neurotoxicity ( DNT ) study

. T he se data gaps are being addressed by an ongoing extended one

generation reproductive toxicity study. The developing brain is very sensitive to perturbations in thy roid hormones ; however, r esults 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

adults 1 , 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,

e ndpoints 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 conducte d by different laboratories in different years using different strains of rats. However, the individual studies each showed clear NOAELs. There was generally a steep dose

response for the malformations. T he developmental study with the lowest NOAEL was s elected

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

4.2.1 Completeness o f the Toxicology Database

The toxicology database for ETU , while incomplete, is sufficient for ass essing 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.Ethylene Thiourea Human Health Risk Assessment DP No. D411820

Page 13 of 38 study in rabbits. A reproduction study wi th 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 ET U 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 N euro toxicity

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 tox ic 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 rabbi t and several rat developmental toxicity studies with ETU.

4.2.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r 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 hypop lastic 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 da ms. See the A ppendix A .2 (Executive Summaries) of this

document for citations to these articles.

4.2.4 Residual Uncertainty in the Exposure Datab ase

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 D eparture 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 endpointsEthylene Thiourea Human Health Risk Assessment DP No. D411820

Page 14 of 38 are summarized below and in Tables 4.3.1 and 4.3. 2 which also pro vide the appropriate safety

factors.

Acute d ietary, 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 developmenta l malformations of the brain, including exencephaly, dilated ventricles and hypoplastic cerebellum. The NOAEL was 5 mg/kg/day.

Acute d ietary, 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 d ietary, all populations : The ETU chronic reference dose was selected from a chronic

oral tox icity 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 o f 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 range

finding 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 w ere used as the endpoint for short

- and intermediate

- term dermal ri sk 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 or al 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. Th e 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.Ethylene Thiourea Human Health Risk Assessment DP No. D411820

Page 15 of 38 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 le sions 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 i s 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, incr eased 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 R eview Committee classified ETU as a probable human
carcinogen, G roup B2 , with a cancer potency factor [Q 1 *, 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

- Occupati onal 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 UF A = 10x

UF H = 10x FQPA UF DB = 10x Acute RfD = 0.0 0 5

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 UF A = 10x

UF H = 10x FQPA UF DB = 10x Chronic RfD = 0.00 0 18

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 UF A = 10x

UF H = 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 toxicityEthylene Thiourea Human Health Risk Assessment DP No. D411820

Page 16 of 38 Table 4.3.1 Summary of Toxicological Doses and Endpoints for ETU for Use in Dietary and Non

- Occupati onal 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 UF A = 10x

UF H =10x FQPA UF DB = 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

Intermediate

Term (Children` < 6 years of age) NOAEL= 7

mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 4

- week range

- finding dog study MRID 41863401 (1989) LOAEL= 34 mg/kg/day based on thyroid toxicity

Dermal Short and

Intermediate

Term (Adult Males, Females >49 years,
Children ≥ 6 years) NOAEL= 7

mg/kg/day UF A = 10x

UF H =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

Intermediate

Term (Females

13

- 49 years old) NOAEL= 5

mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 Developmental Rat Toxicity MRID No. 45937601 (1973) LOAEL = 10 mg/kg/day, based on hydrocephaly and other malformations Dermal Long

Term (Females 13

- 49 years of age and

Children < 6 years) NOAEL=

0.18 mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 Dog Chronic Oral Toxicity MRID 42338101 (1992) LOAEL= 1.99 mg/kg/day based on thyroid toxicity

Dermal Long

Term (Adult Males,

Females >49 years, Children ≥ 6 years) NOAEL=

0.18 mg/kg/day UF A = 10x

UF H =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 Intermediate

Term (Children < 6 years of age) NOAEL= 7

mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 4

- week range

- finding dog study MRID 41863401 (1989) LOAEL= 34 mg/kg/day based thyroid toxicity

Inhalation Short

and Intermediate

Term (Adult Males, Females >49 years, Children ≥ 6 years) NOAEL= 7

mg/kg/day UF A = 10x

UF H =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 Intermediate

Term (Females

13

- 49 years old) NOAEL= 5

mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 Developmental Rat Toxicity MRID No. 45937601 (1973) LOAEL = 10 mg/kg/day, based on hydrocephaly and other malformations Inhalation Long

Term (Females

13

- 49 years of age

and Children < 6 years) NOAEL=

0.18 mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 Dog Chronic Oral Toxicity MRID 42338101 (1992) LOAEL= 1.99 mg/kg/day based on thyroid toxicityEthylene Thiourea Human Health Risk Assessment DP No. D411820

Page 17 of 38 Table 4.3.1 Summary of Toxicological Doses and Endpoints for ETU for Use in Dietary and Non

- Occupati onal Human

Health Risk Assessments Exposure PoD Safety Factors RfD, PAD, LoC Study and Tox

Inhalation Long

Term (Adult Males, Females >49 years, Children ≥ 6 years) NOAEL=

0.18mg/kg/da

y UF A = 10x

UF H =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) Q 1 * = 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = 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 UF A = 10 x

UF H =10x LOC = 10 0 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 UF A = 10x

UF H =10x

UF DB = 10x LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973 ) LOAEL = 10 mg/kg/day, based on hydrocephaly and other malformations Dermal Long

Term (Females 13

- 49 years of age) NOAEL=

0.18 mg/kg/day UF A = 10 x

UF H =10x

UF DB = 10x LOC = 10 00 Dog Chronic Oral Toxicity MRID 42338101 (1992)
LOAEL= 1.99 mg/kg/day based on thyroid toxicity Dermal Long

Term (Adult Males,

Females >49 years) NOAEL=

0.18 mg/kg/day UF A = 10 x

UF H =10x LOC = 10 0 Dog Chronic Oral Toxicity MRID 42338101 (1992)
LOAEL= 1.99 mg/kg/day based on thyroid toxicity

ETU Occupational Inhalation Exposure

Inhalation Short

and Intermediate

Term (Adult Males, Females >49 years) NOAEL= 7

mg/kg/day UF A = 10 x

UF H =10x LOC = 10 0 4

- week range

- finding dog study MRID 41863401 (1989) LOAEL= 34 mg/kg/day based thyroid toxicity

Inhalation Short

and Intermediate

Term (Females

13

- 49 years old) NOAEL= 5

mg/kg/day UF A = 10x

UF H =10x

UF DB = 10x LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973 ) LOAEL = 10 mg/kg/day, based on hydrocephaly and other malformations Inhalation Long

Term (Females NOAEL=

0.18 UF A = 10 x

UF H =10x LOC = 10 00 Dog Chronic Oral Toxicity MRID 42338101 (1992)Ethylene Thiourea Human Health Risk Assessment DP No. D411820

Page 18 of 38 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 UF DB = 10x LOAEL= 1.99 mg/kg/day based on thyroid toxicity Inhalation Long

Term (Adult Males, Females >49 years) NOAEL=

0.18mg/kg/da

y UF A = 10 x

UF H =10x LOC = 10 0 Dog Chronic Oral Toxicity MRID 42338101 (1992) LOAEL= 1.99 mg/kg/day based on thyroid toxicity

ETU Cancer Cancer (all routes) Q 1 * = 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 ob served 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 f ield tr ials 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.

C ooking 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; t he dietary con tribution of ETU from the each of the EBDCs w as 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, pu mpkin, 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

condition s . 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

- EXAMSEthylene Thiourea Human Health Risk Assessment DP No. D411820

Page 19 of 38 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 monitor ing 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 o ver 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 m odels. 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 a ssessment, 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

C ombined 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 ).Ethylene Thiourea Human Health Risk Assessment DP No. D411820

Page 20 of 38 ETU a cute, 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 monitori ng data from the EBDC/ETU Market Basket Survey, percent crop treated information, and processing /cooking study results were us ed in the refined dietary assessments.

M odeling 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 tr ials 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 l ikely 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

T he 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: 4 5%; 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 t he 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 %; co rn: 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.Ethylene Thiourea Human Health Risk Assessment DP No. D411820

Page 21 of 38 A maximum percent crop treated estimate of 50% for walnuts and a maximum perc ent import consumption value of 35% for tangerines w ere 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 comm odity in domestic consumption value of 29% for tangerines w ere likewise used in the chronic and cancer dietary risk

assessment s. As a further refinement, the commodity having the highest %CT results with livestock feed uses had these values applied to mea t and milk (potato; 65% CT maximum for acute and 65% CT average for chronic).

ETU from Metiram

M aximum percent crop treated estimate of 15% for apples and 10% for potatoes were used in the acute dietary risk assessment for the se crops registered for meti ram. A verage percent crop
treated estimates of 10% for apples and 5% for potatoes were used in the chronic and cancer dietary risk assessments for the se 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 dieta ry (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 - 6 for 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 TableEthylene Thiourea Human Health Risk Assessment DP No. D411820

Page 22 of 38 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 0.0000 31 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 5 9 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 th e 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, t he 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 D4 11769, 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 assessment s is pres ented below. See

D 4 11769 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 associa ted with the exposed population. For home garden scenarios a combined (dermal plus inhalation) residential exposure

assessment for handlers was conducted for ETU exposures

. T he 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 shor t

- 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

Page 23 of 38 For residential post

- application, the g arden scenario represent s the most conserva tive 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 post

application aggregate exposure assessment is presented in Table 6. 1.2

.

The garden scenarios were also selected for use in the E TU aggregate since cancer risk estimates were higher for garden activities than for golfing. A summary of residential handler and post

application exposure s and cancer risk estimates for ETU are presented in Table s 6. 1.3 and 6.1.4

.

See D4 11769

, 5 /14/1 3

, 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 U se).

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

Page 24 of 38 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 - 5 9 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

- app lication 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 Advis ory 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 met hod 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 information 2 . 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 AgDR IFT 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 assessmen t 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.htmEthylene Thiourea Human Health Risk Assessment DP No. D411820

Page 25 of 38 adults and youth 6 to 16 years old). As this rate i s 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 us es of metiram, only mancozeb

derived 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 post

application 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

- te rm 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 lifestag es 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.

Summarie s 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

Page 26 of 38 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

- te rm 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 LOC 1 Max

Allowable Exposure 2
mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Total

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5

Adult Male (and Females >49 yrs) 7 100 0.07 0.00003 4 0.000132 0.00016 6 4 2 ,000

Adult Female (13

- 49 yrs) 5 1000 0.005 0.0000 31 0.000153 0.00018 4 2 7 ,000

1 LOC = 10 x 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 LOC 1 Max

Allowable Exposure 2
mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Total

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5

Adult Female (13

- 49 yrs) 5 1000 0.005 0.0000 31 0.0019 0.0019 31 2600

Youth (11

- <16 yrs) 7 100 0.07 0.00002 3 0.0022 0.00222 3 3 1 00

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

Page 27 of 38 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 residenti al exposures to ETU. Therefore, the long

- term or chronic (non

cancer) 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 dieta ry 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 a ggregate
cancer risk estimates are 2 x 10 - 6 and 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 (Q 1 *) Food and Water Exposure (mg/kg/day) Residential

Exposure (LADD

- mg/kg/day 1 Aggregate Cancer

Risk (food, water, residential) 2
US Population 6.01 x 10 - 2 3.1 x 10 - 5 1.16 x 10 - 6 2 x 10 - 6

1 Residential exposure values used in aggregate assessment : Section 6.1

2 Aggregate Cancer Risk = (Q 1 *) (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 (Q 1 *) Food and Water

Exposure (mg/kg/day) Residential

Exposure (LADD

- mg/kg/day 1 Aggregate Cancer

Risk (food, water, residential) 2
US Population 6.01 x 10 - 2 3.1 x 10 - 5 1.41 x 10 - 5 3 x 10 - 6

1 Residential exposure values used in aggregate assessment: Section 6.1

2 Aggregate Cancer Risk = (Q 1 *) (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 al l EBDC compounds are addressed in this ETU aggregate risk assessment. For information regardingEthylene Thiourea Human Health Risk Assessment DP No. D411820

Page 28 of 38 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 stateme nts 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 a ssessment has been completed for each of the EBDC fungicides in the most recent risk asse ssments of the parent c ompound . For details of the ETU occupational assessments see D 397268, 11/14/12 and D337241, 6/14/07

.

10.0 References

D. Drew, 5/ 13 / 13, D 411742, Mancozeb: Human Health Risk Assessment to Support Proposed

New Section 3 Uses on Walnuts and Tolerances for Imported Tangerines

.

A. Rivera

- Lupiáñez

, 5 /14/1 3 , D4 11769

, 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 t he Establishment of a Tolerance on Imported Tangerines for Section 3 Registration.

P. Savoia, 4/8/13

, D402043 and D405277, Man cozeb. 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 onEthylene Thiourea Human Health Risk Assessment DP No. D411820

Page 29 of 38 Imported Grapes and Bananas fo r 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/Degrada te ETU

Goodlow, T. 6/14/07

, D 267866

, Metiram : Human Health Risk Assessment for PP#9E6006.

Petition for the E stablishment 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

Page 30 of 38 A ppendix A

. Toxicology Profile and Executive Summaries

A. 1 Toxicity Profile s

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 LD 50 > 2000 mg/kg III

870.1300 Acute Inhalation

- rat 458881

- 02 LC 50 > 10.4 mg/L IV

870.2400 Primary Eye Irritation 458881

- 04 No irritation 1 IV

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) 00 0160704 /1986 Acceptable /non

guideline 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) 00 154192 /1985

Una cceptable/

G uideline 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 ad enomas and pituitary adenomas in high

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

Page 31 of 38 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) - 1 based 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

F und. 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 /non

guideline NOAEL = 7 mg/kg/day

LOAEL = 34 mg/kg/day, based on decreased levels of thyroid hormones, gross thyroid lesions.

Developmental tox icity

SD BR rat [870.3700] 50 mg/kg/day (distilled water)

GD 6

- 15 00 093929 /1980 Acceptable/non

guideline 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 decre ased fetal weight (↓13%)

.

Only one dose group was included in the study. Developmental tox icity

Wistar rat [ non

- guideline ] 0, 5, 10, 20, 40, 80 mg/kg/day 4593760 1 /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; a t 80 mg/kg/day: coloboma of the eyelids, hemimelia, syndactyl, cleft palate, ectopic ki dney, 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 inEthylene Thiourea Human Health Risk Assessment DP No. D411820

Page 32 of 38 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 i n 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 tox icity at 30 mg/kg/day included hydrocephalus, dome

- shaped heads, and pup mortality. Developmental tox icity

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, hydrocephal y , microphthalm i a, cerebellar dysplasia, cerebral atrophy, and in survivors, motor defec ts 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 MR ID [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, meningo r rhea, hyrdronephrosis, dilated renal pelvis,

and vertebral ab normalities 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

. Develo pmental

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 increasedEthylene Thiourea Human Health Risk Assessment DP No. D411820

Page 33 of 38 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 ta il. 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

– Sprague

Dawley 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 r ecord keeping. Dermal absorption

– SD

COBS CD rat [870.7600] 403126 01/1987 Acceptable Dermal absorption = 26%

Immunotoxicity

- rat [870.7800] 48794502/2012 Acceptable/

Guideline Negative for Immunotoxicity

A.2 E xecutive Summaries

D evelopmental 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; G roup 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.

Simi lar 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 abo ve: hydrocephalus, encephalocele, meningocele, micrognathia, abnormal flexion of ankle, kinky or twisted tail; atEthylene Thiourea Human Health Risk Assessment DP No. D411820

Page 34 of 38 40 mg/kg/day and above: oligodactyl, domed head, retarded ossification of the skull occurred; and at 80 mg/kg/day: coloboma of the eyelid s, 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/d ay 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

.

T he 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).

I n a developmental toxicity study (MRID 00093929; 1980), 50 mg/kg/day ethylene thiourea (ETU, 99%), was administered to a single dose gro up 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 stab ility 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 t o 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

cr anial 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 lon g 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 atr esia, 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 do se 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 developmenta l 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 gav age at doses of 0, 5, 10, 20, 30, 40, or 80 mg/kg/day from gestation day (GD) 7

- 21.Ethylene Thiourea Human Health Risk Assessment DP No. D411820

Page 35 of 38 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 toxi city 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 ob servations 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, t here 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) teste d 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, microphthalm ia, 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 r eported.

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 effec ts 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 ot her 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. N o 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, men ingocele, 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 LOAE L 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,Ethylene Thiourea Human Health Risk Assessment DP No. D411820

Page 36 of 38 and anal atresia also occurred (GD 6

- 13). ETU was tested in JCL

- ICR mice : no matern al 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/d ay. 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 tubu les 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 ar ticle was inadequate for a critical analysis of the data.

Doerge and Takazawa (Chem. Res. Toxicol. 3: 98

- 101. 1990) reported that ETU is a direct

acting 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.

A nalytical 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 (h emoglobin 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 necros is. 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 5 00 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 no t 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 femalesEthylene Thiourea Human Health Risk Assessment DP No. D411820

Page 37 of 38 ( ↑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 microsc opically 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

m ortality, 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 rang efinding 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 grad e 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 fo r 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 consumpti on 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 hormon es 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 depresse d 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/d ay; 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/non

guideline

.Ethylene Thiourea Human Health Risk Assessment DP No. D411820

Page 38 of 38 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 registrant

submitted studie s ; (1 ) are subj ect to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with a pplicable ethics requirements. For certain studies that review may have included review by t he Human Studies Review Board. Descriptions of data sources a s well as guidance on their use can be found at the Agency website. 3

3 http://www.epa.gov/pesticides/science/handler

- exposur e

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html