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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

 

 OFFICE OF 

 PREVENTION, PESTICIDES 

 AND TOXIC SUBSTANCES 

June 14, 2007 

MEMORANDUM

SUBJECT: Ethylenethiourea (ETU) from EBDCs: Health Effects Division (HED) 

Human Health Risk Assessment of the Common Metabolite/Degradate 

ETU 

 PC Code : 600016, DP Barcode: D337241. 

 Regulatory Action: Registration Action

 Risk Assessment Type: Aggregate 

 

FROM: Toiya Goodlow, Risk Assessor 

 Christine Olinger, Risk Assessor 

 Donna Davis, Risk Assessor 

 Reregistration Branch 1 

 Health Effects Division (7509P) 

THROUGH: Michael S. Metzger, Branch Chief 

 Whang Phang, Senior Scientist 

 Reregistration Branch 1 

 Health Effects Division (7509P) 

TO: Cynthia Giles-Parker, Branch Chief 

 Fungicide-Herbicide Branch 

 Registration Division (7505P) 

The attached human health risk assessment is for ethylene thiourea (ETU), which is the 

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

mancozeb, maneb and metiram. Several new uses for mancozeb and metiram have been 

proposed, requiring an update of the most recent ETU aggregate assessment conducted 

by Christine Olinger (D317416, 6/8/05) in support of the reregistration of the EBDCs. 

This risk assessment summarizes human health risks from exposure to ETU resulting 

from all registered and proposed uses of the parent EBDCs and supersedes all previous 

assessments. 
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Table of Contents

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

2.0 Ingredient Profile.................................................................................................. 9 

2.1 Summary of Registered/Proposed Uses.................................................. 9 

2.2 Structure and Nomenclature ................................................................. 12 

3.0 Hazard Characterization/Assessment............................................................... 14 

3.1 Hazard and Dose-Response Characterization...................................... 14 

3.1.1 Database Summary..................................................................... 14 

3.1.2 Toxicological Effects................................................................... 14 

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)................ 17 

3.3 FQPA Considerations............................................................................. 18 

3.3.1 Recommendation for a Developmental Neurotoxicity Study.. 19 

3.3.2 Safety Factor for Infants and Children .................................... 19 

3.4 Hazard Identification and Toxicity Endpoint Selection...................... 19 

3.4.1 Acute Reference Dose (aRfD) - Females age 13-49.................. 19 

3.4.2 Acute Reference Dose (aRfD) - General Population................ 19 

3.4.3 Chronic Reference Dose (cRfD)................................................. 20 

3.4.4 Incidental Oral Exposure (Short- and Intermediate-Term)... 20 

3.4.5 Oral Exposure (Short- and Intermediate-Term) .................... 20 

3.4.6 Dermal Absorption ..................................................................... 20 

3.4.7 Dermal and Inhalation Exposure (Short- and IntermediateTerm) ....................................................................................................... 21 

3.4.8 Dermal and Inhalation Exposure (Long-Term)....................... 21 

3.4.9 Classification of Carcinogenic Potential ................................... 21 

3.5 Endocrine Disruption ............................................................................. 23 

4.0 Public Health and Pesticide Epidemiology Data.............................................. 24 

5.0 Dietary Exposure/Risk Characterization ......................................................... 24 

5.1 Environmental Degradation .................................................................. 24 

5.1.1 Surface Water.............................................................................. 24 

5.1.2 Ground Water ............................................................................. 26 

5.2 Dietary Exposure and Risk .................................................................... 27 

5.2.1 Anticipated Residue Information.............................................. 28 

5.2.2 Acute Dietary Exposure/Risk..................................................... 29 

5.2.3 Chronic Dietary Exposure/Risk................................................. 29 

5.2.4 Cancer Dietary Risk ................................................................... 29 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................ 31 

6.1 Residential Handler Exposures and Risks............................................ 32 

6.2. Residential Postapplication Exposure................................................... 33 

6.2.1 Residential Postapplication Exposure – Mancozeb ................. 33 

6.2.1.1 Home Garden Postapplication Scenarios .................. 34 

6.2.1.2 Treated Turf Postapplication Scenarios for Toddlers.. 

 ........................................................................................ 34 

6.2.1.3 Treated Turf Postapplication Scenario for Adults... 35 

6.2.2 Residential Postapplication Exposure - Maneb ....................... 36 

6.3 Other (Spray Drift, etc.)......................................................................... 37 
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7.0 Aggregate Risk Assessments and Risk Characterization................................ 38 

7.1 Acute Aggregate Risk ............................................................................. 39 

7.2 Short- and Intermediate-Term Aggregate Risk................................... 39 

7.2.1 ETU Short- and Intermediate-Term Home Garden Aggregate

 ....................................................................................................... 39 

7.2.2 ETU Short-Term Treated Turf Aggregate (Toddlers).......... 40 

7.2.3 ETU Short- and Intermediate-Term Treated Turf Aggregate 

(Adult “Golfers”) .................................................................................... 41 

7.3 Long-Term (Chronic) Aggregate Risk.................................................. 42 

7.5 Cancer Aggregate Risk........................................................................... 42 

8.0 Cumulative Risk Characterization/Assessment............................................... 44 

9.0 Occupational Exposure/Risk Pathway.............................................................. 44 

10.0 Data Needs and Label Recommendations ........................................................ 44 

References........................................................................................................................ 45 
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1.0 Executive Summary

Use Profile 

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

(EBDC) fungicides mancozeb, maneb and metiram. The EBDCs are used on agricultural 

crops such as vegetables, fruits and nuts, on turf including golf courses and sod farms, 

and on ornamentals including cut flowers. The EBDCs are broad spectrum contact 

fungicides used to prevent a variety of fungal diseases. 

Updated human health risk assessments have been conducted for mancozeb and metiram 

to account for proposed new uses. The proposed Section 3 uses for mancozeb are for use 

on almonds, broccoli, cabbage, lettuce (head and leaf), and pepper (bell and non-bell). 

Import tolerances on bananas and grapes were proposed for metiram. No new uses for 

maneb have been proposed; therefore, an updated risk assessment for maneb is not 

necessary at this time. The mancozeb and metiram risk assessments include exposures 

and risks from ETU derived from the individual EBDC. 

The purpose of this assessment is to provide information on aggregate exposure and risk 

from ETU as a result of all EBDC usage, to describe risks from all three EBDCs in broad 

terms, and to identify significant sources of exposure and risk. 

Sources of ETU 

Crops treated with EBDCs may contain both 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. Therefore, both EBDC and ETU 

residues may be consumed in the diet. During application of EBDCs, workers may be 

exposed to ETU residues which form during degradation of the tank mix over a typical 

workday, and the Agency has data to reflect these potential exposures. Additional 

exposure to both EBDCs and ETU may occur during activities conducted in and around 

growing crops following treatment with EBDCs. Metabolic conversion of absorbed 

EBDC to ETU occurs and has been accounted for in calculating ETU doses. 

Hazard Assessment 

The toxicology database for ETU is limited based on guideline studies, and HED has 

relied on a combination of guideline data and several studies in the open literature to 

assess hazard for ETU. The thyroid and the nervous system are targets for ETU. Thyroid 

toxicity in subchronic and chronic rat, mouse, and dog studies included decreased levels 

of T4 (serum thyroxin), increases or decreases in T3 (triiodothyronine), compensatory 

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

and microscopic thyroid changes, chiefly hyperplasia. Overt liver toxicity was observed 

in one chronic dog study. Developmental defects in the rat developmental study included 

hydrocephaly and related lesions, skeletal system defects, and other gross defects. These 

defects showed increased susceptibility of the fetuses because they occurred at a dose that 

caused minimal maternal toxicity (decreased food consumption and body weight gain). 
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Although the data provided evidence for increased susceptibility to fetuses following 

dosing with ETU, HED determined that the degree of concern or uncertainty for the 

qualitative susceptibility is low because the developmental effects were well 

characterized in numerous studies in the published literature, as well as in a guideline 

study submitted by the registrant. In addition, the dose-response relationship was well 

characterized, and doses selected for overall risk assessments addressed concerns for 

developmental and thyroid toxicity. 

The submitted data do not support the reduction or removal of the 10X Food Quality 

Protection Act safety factor (FQPA SF) due to the absence of required toxicological 

studies. HED has retained a 10X FQPA safety factor for ETU dietary, residential and 

aggregate risk assessments. 

The doses and endpoints used for ETU are listed below. For acute ETU exposures, 

developmental effects were selected as the most sensitive endpoint. This same endpoint 

was also used for short and intermediate term exposures. For chronic exposures, the 

endpoint was based upon thyroid effects that were observed in the chronic dog study. 

ETU was classified as a probable human carcinogen based upon liver tumors observed in 

female mice and a unit risk value, Q1*, of 0.0601 (mg/kg/day)-1 was used for risk 

assessment. 

Exposure Route, Duration ETU Dose in mg/kg/day (study/effects) 

Acute dietary (females 13-49) NOAEL of 5 (Developmental rat/developmental brain defects) 

Chronic dietary (gen. U.S. pop.) NOAEL of 0.18 (Chronic dog/thyroid toxicity) 

Incidental oral, short/int.-term (toddlers) NOAEL of 7 (4-week Dog/thyroid toxicity) 

Oral, short/int.-term (females 13-49) NOAEL of 5 (Developmental rat/developmental brain defects) 

Dermal, short/int.-term (toddlers) NOAEL of 7 (4-week Dog/thyroid toxicity) 

Dermal, short/int.-term (females 13-49) NOAEL of 5 (Developmental rat/developmental brain defects) 

Dermal, long-term NOAEL of 0.18 (Chronic dog/thyroid toxicity) 

Inhalation, short/int.-term NOAEL of 5 (Developmental rat/developmental brain defects) 

Inhalation, long-term NOAEL of 0.18 (Chronic dog/thyroid toxicity) 

[NOAEL= No observed adverse effect level. Combined Uncertainty factors (UFs) for ETU occupational 

assessments are 100x; combined UFs for residential and dietary assessments are 1000x. Dermal absorption 

for ETU is 26%, while inhalation absorption is 100%. Dermal and inhalation exposures can be combined, 

since the toxic effects from these two routes of exposure are similar for similar durations.]

Drinking Water Exposure 

The OPP Environmental Fate and Effects Division (EFED) prepared a drinking water 

exposure assessment for ETU. The parent EBDC fungicides are very short-lived in soil 

and water and would not reach water used for human consumption whether from surface 

water or ground water. However, ETU is highly water soluble, and may reach both 

surface and ground water under some conditions. 

The ETU surface water estimated drinking water concentrations (EDWCs) were 

generated using a combined monitoring/modeling approach. The monitoring data were 

from a targeted surface water monitoring study conducted by the ETU Task Force, in 

which none of the tested water samples had concentrations above the limit of detection of 

0.1 ppb. A ground water EDWC was selected from a targeted ground water monitoring 
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study conducted in a known EBDC use area in Florida. Acute surface water estimates 

were reported as a range of 0.1 ppb (monitoring) to 25.2 ppb (modeling) and 

chronic/cancer surface water estimates were 0.1 ppb (monitoring). Ground water 

estimates were 0.21 ppb (monitoring) for all durations of exposure. 

Dietary Exposure and Risk Analysis 

Both EBDC and ETU residues may be consumed in the diet. In this assessment the ETU 

food residues from each of the EBDCs are aggregated. For the acute, chronic and cancer 

dietary assessments, field trial or monitoring data from the EBDC/ETU Market Basket 

Survey, percent crop treated information, and extensive processing study results were 

used for existing uses. Dietary inputs for the proposed new uses and tolerances included 

field trial data, processing factors, projected percent crop treated information (for the 

proposed mancozeb new uses), and percent imported information (for the proposed 

metiram tolerances). 

A probabilistic acute aggregate dietary assessment was conducted for ETU derived from 

metiram, mancozeb, and maneb uses. Aggregated acute dietary exposure and risk 

estimates for food alone and food and drinking water are below HED’s level of concern. 

The refined chronic risk estimates are below the HED’s level of concern for aggregate 

exposure to ETU for the general U.S. population and all population subgroups for food 

alone and food and drinking water. 

The aggregate cancer risk estimate associated with exposure to ETU from all EBDCs for 

both food alone and food and drinking water combined is 3.3 x 10-6 and 3.6 x 10-6, 

respectively, for the general U.S. population. The greatest contributors to the dietary 

exposure for the cancer assessment were bananas and leaf lettuce. 

Residential and Recreational Exposures and Risks 

No new residential uses were added to the label as part of the current Section 3 requests. 

There is a potential for home gardener exposure during and after applications to home 

garden vegetables from the existing uses of the EBDCs. There is also a potential for 

golfer and toddler post application exposure on golf course turf and transplanted lawns. 

The agricultural application rates were used because the rates given on the two home 

garden product labels for mancozeb conflicted with one another and were generally 

higher than the agricultural rates. The residential handler Margins of Exposure (MOEs) 

for ETU from use of mancozeb in gardens were not of concern because they greatly 

exceed the target MOE of 1000. The cancer risks were also not of concern because they 

were less than 1x10-6. 

The post application risks were also assessed for adult and youth-aged home gardeners. 

The ETU MOEs exceeded the target MOE of 1000 for both adult and youth home 

gardeners. The cancer risk for adult home gardeners was less than 1x10-6. 
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For the ETU aggregate assessment, the turf exposures were assessed for toddlers by 

assuming the application conditions from the mancozeb and maneb Reregistration 

Eligibility Decision (RED) documents. Assuming a three day Pre-Harvest Interval (PHI) 

and two days to harvest, transport and install the turf, all MOEs exceeded 1000 and were 

not of concern. 

Mancozeb is the only EBDC registered for use on golf courses. The turf exposures were 

assessed for golfers by using the day 0 Turf Transferable Residues (TTR) for short term 

exposures and the 7 day average TTR for lifetime exposures. The ETU MOE for golfers 

exceeded the target MOE of 1000 and is not of concern. The golfer cancer risk was 

6 x 10-9 assuming that golfers played an average of 1 day per year on mancozeb treated 

turf. 

Aggregate Risks 

The aggregate exposures for adults included food, drinking water, golfing, and home 

gardening, while the aggregate exposures for toddlers include playing on turf, food and 

drinking water. 

Acute aggregate risks were calculated for females 13-49 years old only because an 

appropriate endpoint for this exposure duration was not identified for other populations. 

The acute aggregate exposures including food and drinking water were not of concern as 

the exposure resulted in a risk that was equivalent to 89% of the aPAD at the 99.9th

percentile of exposure. 

The short term aggregate risks were calculated for adults by aggregating average daily 

food exposure, chronic drinking water exposure, and the residential exposures. The short 

term MOEs ranged from 6,100 to 13,000, which are not of concern. For youth gardeners, 

aggregate risks are not of concern. The aggregate risks for toddlers playing on turf, food, 

and drinking water are also not of concern. 

The chronic aggregate risks were calculated using average food and drinking water 

exposures and were below HED's level of concern (<100% cPAD). The most highly 

exposed population subgroup was children 1-2 years old, with aggregate risks of 86% of 

the cPAD. 

The cancer risks were aggregated using the average daily food, drinking water and 

residential exposures. The aggregate cancer risk for the U.S. population is 3.8 x 10-6, 

which exceeds HED’s level of concern. HED conducted sensitivity analyses to 

determine the commodities that provided the most contribution to the ETU exposure. 

The commodities that are the greatest contributors to ETU exposure are bananas, leaf 

lettuce, drinking water, turnip greens, grape juice and mangoes. If the proposed tolerance 

in/on bananas (from metiram applications) is removed from the aggregate, then the 

aggregate cancer risk does not exceed HED’s level of concern. Note that the metiramderived ETU residue values from crop field trials used in the aggregate assessment are 

considered to be overestimates. Projected percent crop treated information was not 

available, so percent imported information was used and it is highly unlikely that all 
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bananas will be treated. In general, monitoring data on other commodities show much 

lower residues than field trial data, so actual exposure is likely to be lower. 

Occupational Exposure 

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

of the EBDC fungicides in the risk assessments of the parent compound. 

Environmental Justice Considerations 

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

in this human health risk assessment, in accordance with U.S. Executive Order 12898, 

"Federal Actions to Address Environmental Justice in Minority Populations and LowIncome Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf). 

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED 

estimates risks to population subgroups from pesticide exposures that are based on 

patterns of that subgroup’s food and drinking water consumption, and activities in and 

around the home that involve pesticide use in a residential setting. Extensive data on 

food consumption patterns are compiled by the United States Department of Agriculture 

(USDA) under the Continuing Survey of Food Intake by Individuals (CSFII) and are used 

in pesticide risk assessments for all registered food uses of a pesticide. These data are 

analyzed and categorized by subgroups based on age, season of the year, ethnic group, 

and region of the country. Additionally, OPP is able to assess dietary exposure to 

smaller, specialized subgroups and exposure assessments are performed when conditions 

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

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

youths, and adults entering or playing on treated areas postapplication are evaluated. 

Further considerations are currently in development as OPP has committed resources and 

expertise to the development of specialized software and models that consider exposure 

to bystanders and farm workers as well as lifestyle and traditional dietary patterns among 

specific subgroups. 

Review of Human Research

This risk assessment does not rely on any data from studies in which human subjects 

were intentionally exposed to a pesticide or other chemical. 

Data Gaps 

The data gaps for each individual EBDC and the corresponding exposures to ETU are 

discussed in the risk assessments for each parent compound. The data gaps for ETU, 

which were previously identified in the 2005 human health risk assessment for the RED, 

include the following: 

Toxicology

 

• Guideline 870.3800 2-generation reproduction, rat 

• Guideline 870.3700 Developmental toxicity, rabbit 
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• Guideline 870.6300 Developmental neurotoxicity 

• Non-guideline Comparative study for thyroid toxicity in adults and 

 offspring 

2.0 Ingredient Profile

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

fungicides, metiram, maneb and mancozeb. Technical ethylenethiourea 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 soluble in water, with a water solubility of 20,000 ppm 

at 30 °C, but it is also slightly soluble in methanol, ethanol, ethylene glycol, pyridine, 

acetic acid and naphtha. When ETU is heated to decomposition, nitrogen and sulfur 

oxides are emitted. 

2.1 Summary of Registered/Proposed Uses 

The EBDC fungicides are used on numerous agricultural crops, including vegetables, 

fruit and nut trees, field and forage crops, and grapes; for seed treatment; on turf, 

including golf courses, and sod farms; and on ornamental trees, shrubbery, perennials and 

annuals. The EBDCs are broad spectrum contact fungicides used to prevent a variety of 

fungal diseases, including downy mildews, anthracnose, rusts, leaf spots, blights, crown 

rot, molds, cankers, seed rot and seedling damping off. EBDC end-use products are 

available as wettable powder (WP), dry flowable (DF), dust (D), emulsifiable concentrate 

(EC), and ready-to-use formulations. 

Mancozeb and maneb have the most food uses, while metiram food uses are limited to 

apples and potatoes, with proposed import tolerances on bananas and grapes. In terms of 

annual production and uses, mancozeb is the most significant of the EBDCs, with over 6 

million pounds of total domestic usage; crops with the largest market in terms of pounds 

active ingredient (ai) are potatoes, fresh tomatoes and apples. Maneb domestic use is 

estimated to be over 2 million pounds ai annually; crops with the largest markets in 

pounds ai are potatoes, peppers (bell and nonbell), and lettuce. Metiram domestic use is 

estimated at over 600,000 pounds annually, with two-thirds of the production volume 

applied to apples, and one-third of the production volume applied to potatoes. 

Summary Tables 2.1 and 2.3 show the proposed new uses for metiram, and mancozeb, 

respectively. Table 2.2 shows the future harmonization pattern for grapes grown in 

Europe. 
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Table 2.1 Summary of Proposed Uses for Metiram on Bananas and Grapes 1

Application 

Timing; 

Equipment 

Type 2 

Formulation Applic. 

Rate 3 

Max. No. 

Applic/ 

Season 

Max. 

Seasonal 

Applic. Rate 

(lb ai/A) 

PHI 

(days) 

Use Directions and 

Limitations 

Bananas (For Use in Central and South America) 

Broadcast spray 

to established 

banana crops 

Polyram® 80 

WG 

2.0-2.5 

kg/ha 

Not 

specified 

(NS) 

NS 7 Spray mix is to be prepared 

by adding 0.4 L/ha of Nu 

Film (surfactant) to water 

(spray volume not 

specified) and Polyram® 

80 WG. Initial application 

may be made when disease 

symptoms first appear and 

repeated at 8-15 day 

intervals. 

Grapes (For Use in Italy)

Broadcast spray 

to established 

grape orchards 

Polyram® DF 

Fungicide 

150-400 

g/100 L 

water 

NS NS 28 When mixed with other 

formulations, the longest 

waiting period must be 

observed. The following 

varieties may be sensitive 

to Polyram® DF: Butirra 

d’Estate, Conference, 

Coscia, Gentil Bianca, S. 

Maria and Spadona. 

Grapes (For Use in France)

Broadcast spray 

to established 

grape orchards 

Polyram® DF 

Fungicide 

2.0-3.5 

kg/ha 

NS NS NS 

Grapes (For Use in Germany)

Broadcast spray 

to established 

grape orchards 

Polyram® 

WG 

0.8-3.2 

kg/ha 

8 NS 56 Do not apply more than 8 

applications in producing 

plantings, of which 

maximally 4 with decaying 

flowers until start of 

maturing (vine stages 68-

81, BBCH Code) 

1 Information included in table excerpted directly from proposed label. 

2 Type of application equipment is not specified on the labels. 

3

 It could not be determined if the application rates were in terms of product or the active ingredient. 
Page 11 of 46 

Table 2.2 Label Directions for the Use of Metiram on Grapes Grown in Europe1

Country Product 

Name 

Growth 

Stage & 

Season 

BBCH 

No. 

Applic. 

per 

Season2 

Single Applic. 

Rate 

Implied Max. 

Seasonal Rate 

PHI 

(days) 

Germany3 Polyram® DF 15-79 6 2.24 kg ai/ha 

(2.0 lb ai/A) 

13.44 kg ai/ha 

(12.0 lb ai/A) 

56 

EU (N+S-EU)4 Polyram® DF 15-79 3 1.1 kg ai/ha 

(1.0 lb ai/A) 

3.3 kg ai/ha 

(2.9 lb ai/A) 

56 

EU (N+ S-EU)5 Polyram® DF 15-79 3 1.8 kg ai/ha 

(1.6 lb ai/A) 

5.4 kg ai/ha 

(4.8 lb ai/A) 

56 

France (N + SEU) 518 01F 60-80 3 1.1 kg ai/ha 

(1.0 lb ai/A) 

3.3 kg ai/ha 

(2.9 lb ai/A) 

35 

1

 Information included in table excerpted directly from proposed label. 

2

 Minimum retreatment interval is 12 days 

3

 Exemplarily listed for a national label direction. 

4

 Minimum use rate for metiram in grapes (supports also use of mix formulations) 

5

 Future EU harmonized GAP. 

Table 2.3 Summary of Proposed Uses for Mancozeb. 

Applic. 

Timing, Type, 

and Equip. 

Formulation 

Applic. 

Rate 

(lb ai/A) 

[kg 

ai/ha]

Max. No. 

Applic. 

per Season 

Max. 

Seasonal 

Applic. Rate 

(lb ai/A) 

[kg ai/ha] 

PHI 

(days) 

Use Directions and 

Limitations 

Broccoli and Cabbage 

Postemergence 

Broadcast 

80% WP 1.6 6 (implied) 9.6 7 Applications are to be 

made as soon as disease 

is present. A minimum 

retreatment interval 

(RTI) of 7 days is 

specified. 

Lettuce 

1.6 6 (implied) 9.6 10 Applications are to 

begin when disease 

appears. Use limited to 

all states except CA. A 

minimum RTI of 7 days 

is specified. 

Postemergence 

Broadcast 

80% WP 

1.6 4 (implied) 6.4 14 Applications are to 

begin when disease 

appears. Use limited to 

CA. A minimum RTI of 

7 days is specified. 

Pepper 

Postemergence 

Broadcast 

80% WP 1.6 6 (implied) 9.6 7 Applications are to 

begin when disease 

appears. Use limited to 

west of the Mississippi 

River. A minimum RTI 

of 7 days is specified. 
Page 12 of 46 

Table 2.3 Summary of Proposed Uses for Mancozeb. 

Applic. 

Timing, Type, 

and Equip. 

Formulation 

Applic. 

Rate 

(lb ai/A) 

[kg 

ai/ha]

Max. No. 

Applic. 

per Season 

Max. 

Seasonal 

Applic. Rate 

(lb ai/A) 

[kg ai/ha] 

PHI 

(days) 

Use Directions and 

Limitations 

2.4 6 (implied) 14.4 7 Applications are to 

begin when disease 

appears. Use limited to 

east of the Mississippi 

River. A minimum RTI 

of 7 days is specified. 

Almond 

Postemergence 

Broadcast 

Ground or aerial 

80% WP 4.8 3 (implied) 14.4 

Last 

applic. 

to be 

made no 

later 

than 5 

weeks 

after 

petal fall 

Applications are to 

begin at the dormant to 

popcorn growth stages 

and continue with a 

minimum 7-day 

retreatment interval. A 

non-ionic surfactant or 

spreader sticker is to be 

added to the spray 

solution. Aerial 

applications are to be 

made in a minimum of 

10 gal/A. The grazing 

of livestock in treated 

areas is prohibited. 

2.2 Structure and Nomenclature 

Table 2.4 ETU Test Compound Nomenclature

Compound 

Common name Ethylenethiourea (ETU) 

Empirical formula C3H6N2S 

Molecular weight 102.2 

CAS registry number 96-45-7 
Page 13 of 46 

Table 2.5 Metiram Test Compound Nomenclature

Compound 

HN S

HN

Zn

S

S

S

HN S

HN

S

S

S

3 x

Empirical Formula (C16H33N11S16Zn3)x

Common name Metiram 

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

CAS name mixture of 5.2 parts by weight of ammoniates of 

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

[dithiocarbamic acid] bimolecular and trimolecular cyclic anhydrosulfides and 

disulfides 

CAS registry number 9006-42-2 

Table 2.6. Mancozeb Test Compound Nomenclature

Chemical structure 

N

H

S

S

N

H

S

Mn

S

Zn

x

y

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 2.7 Maneb Test Compound Nomenclature

Chemical structure 

Common name Maneb 

IUPAC name Manganese ethylenebis (dithiocarbamate) (polymeric) 

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

CAS registry number 12427-38-2 
Page 14 of 46 

3.0 Hazard Characterization/Assessment 

3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary

The ETU toxicology database is considered incomplete; however by using a combination 

of guideline and literature information and including an additional uncertainty factor; 

sufficient information was available to select endpoints for ETU. 

Guideline toxicological data gaps include a 2-generation reproduction studies in rats, a 

developmental study in rabbits, developmental neurotoxicity study and a comparative 

study for thyroid toxicity in adults and offspring. 

 

3.1.2 Toxicological Effects

Acute toxicity: The acute toxicity profile for ETU is shown in Table 3.1, below. Acute 

oral and dermal sensitization studies with ETU were not available. 

Table 3.1 Acute Toxicity of ETU

Guideline No. Study Type MRID Nos. Results Toxicity 

Category

870.1100 Acute Oral – rat N/A N/A N/A 

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

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

870.2400 Primary Eye Irritation 458881-04 No irritation 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).

Subchronic/Chronic toxicity: The thyroid is a target organ for ETU. Thyroid toxicity 

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

thyroid hormone T4 (serum thyroxin), changes in the thyroid hormone T3 

(triiodothyronine), compensatory increases in levels of thyroid stimulating hormone 

(TSH), increased thyroid weight, and microscopic thyroid changes, chiefly hyperplasia. 

Anemia occurred in the subchronic and chronic dog studies. Increased liver weight and 

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

limited to the chronic dog study in which hepatocellular necrosis was seen. 

Carcinogenicity: Treatment with ETU produced increases in tumor incidence in 

rodents. Thyroid follicular cell adenomas and carcinomas were increased in a study with 

F344 rats. Thyroid follicular cell adenomas and pituitary adenomas were also increased 

in a study with SD rats. Thyroid follicular cell adenomas and carcinomas, hepatocellular 

adenomas and carcinomas, and pituitary adenomas were increased in a study with 

B6C3F1 mice. 
Page 15 of 46 

The HED Cancer Assessment Review Committee evaluated the carcinogenicity potential 

of ETU and classified ETU as a probable human carcinogen, group B2, (Bill Sette, Ph.D., 

4/16/90). The Q1* for ETU, using a 3⁄4 scaling factor, was determined to be 0.0601 

(mg/kg/day)-1 based upon female mouse liver tumors in a National Toxicology Program 

(NTP) study (Bernice Fisher and Hugh Pettigrew, 2/24/95). 

Developmental/Reproductive toxicity: The nervous system is a target for ETU. The 

developmental defects seen in the rat developmental study with ETU included 

exencephaly, 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, incomplete cranial ossification, wide cranial sutures, curved 

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

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

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

caudal vertebrae, abnormal pelvic limb posture, oligodactyl, agnathia, cleft palate, cleft 

lip, club limb, stubby tail, forelimb flexure, kinked tail, cryptorchidism (abnormal 

descending of the testes), ectopic kidneys, agenesis of the kidneys, hydronephrosis, 

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

atresia (closure). 

Developmental defects in the rat developmental study indicated increased qualitative 

susceptibility since numerous and severe developmental defects occurred at a dose which 

only caused decreased maternal food consumption and body weight gain. These 

developmental defects were similar to defects seen in an accompanying developmental 

toxicity study with mancozeb; however, ETU was considered a more severe 

developmental toxicant than mancozeb because: (a) a smaller dose of ETU (50 

mg/kg/day) was needed to cause developmental defects than did mancozeb (512 

mg/kg/day); (b) many of the same developmental defects occurred with greater 

frequency with ETU than with mancozeb; (c) more types of developmental defects 

occurred with ETU than with mancozeb; and (d) developmental defects which occurred 

with ETU were accompanied by minimal maternal toxicity whereas developmental 

defects that occurred with mancozeb were accompanied by more severe maternal 

toxicity. 

A developmental study in rabbits was not submitted. No reproductive toxicity was 

attributed to treatment in the 2-generation reproduction study in rats. 

Neurotoxicity: Neurotoxicity studies for ETU are not available. 

The toxicity profile of ETU is shown in Table 3.2. 
Page 16 of 46 

Table 3.2 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) 

00261536/1986 

Acceptable 

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) 

00259888/1985 

Unacceptable 

NOAEL = 1.72 mg/kg/day 

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

thyroid hypertrophy/hyperplasia. 

% purity, feed concentrations were not reported. 

At the high dose, more microscopic thyroid changes 

and increases in thyroid and liver weight occurred. 

Unacceptable because dietary concentrations were 

not reported. 

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 

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) 

In high dose group: mortality, anemia, decreased 

activity, decreased thyroid hormone levels, increased 

thyroid weight microscopic thyroid hyperplasia. 

Chronic 

tox/carcinogenicity - rat 

[870.4100] 

 0, 0.5, 2.5, 5.0, or 125 ppm 

42607801/1992 

Unacceptable 

Concentration of ETU in feed varied widely and 

doses could not be determined. 

Microscopic thyroid hyperplasia occurred in the lowdose group. At higher doses, changes in thyroid 

hormone and TSH levels, increased thyroid weight, 

and grossly enlarged livers, occurred. Increases in 

thyroid follicular adenomas and pituitary adenomas 

in high-dose males. 

Unacceptable because ETU concentrations varied 

widely. 

Chronic (24-Month) 

Feeding - mouse (NTP) 

NA 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.

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 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 Rangefinding - 

Dog 

0, 196, 980, 4900 ppm 

(males: 0, 7.0, 34, or 172 

41863401/1989 

Acceptable 

NOAEL = 7 mg/kg/day 

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

of thyroid hormones, gross thyroid lesions. 
Page 17 of 46 

Table 3.2 Toxicity Profile of ETU

Study Type 

[Guideline No.] 

MRID No./ 

Classification 

Results 

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

36, or 197 mg/kg/day) 

Developmental tox. - rat 

[870.3700] 

50 mg/kg/day 

00246663/1980 

Acceptable/nonguideline 

Maternal NOAEL = <50 mg/kg/day 

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

decreased body weight gain. 

Developmental NOAEL = <50 mg/kg/day 

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

gross developmental defects, central nervous system 

defects, skeletal defects, cryptorchidism, and 

decreased fetal weight. 

Only one dose was included in the study. 

Developmental tox. - rat 

[870.3700] 

 0, 5, 10, 20, 40, or 80 

mg/kg/day 

4593760/1973 

[Khera, K.S. 1973. 

Teratology 7:243-252] 

Acceptable nonguideline 

Maternal NOAEL = 40 mg/kg/day 

Maternal LOAEL = 80 mg/kg/day, based on 

mortality. 

Developmental NOAEL = 5 mg/kg/day 

Developmental LOAEL = 10 mg/kg/day based on 

central nervous system and gross developmental 

defects of the brain including exencephaly, dilated 

ventricles and hypoplastic cerebellum. 

2-Generation 

reproduction - rat 

[870.3800] 

0, 2.5, 25, 125 ppm 

42391701/1992 

Unacceptable 

Doses on a 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 with test 

material and poor record keeping. 

Dermal absorption - rat 

[870.7600] 

40312001/1987 

Acceptable 

Dermal absorption = 26% 

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)

Metiram, mancozeb and maneb degrade and/or are metabolized to ETU. In oral rat 

metabolism studies with radiolabelled 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, 

including the dietary exposure assessment as well as dermal and inhalation assessments. 

There is inherent uncertainty in assuming the metabolic conversion occurs following 

dermal and inhalation dosing, since dermal and inhalation exposure do not involve the GI 

tract. In addition to ETU, other identified decomposition products are ethylenethiuram, 

ethylene-bis-isothiocyanate sulfide (EBIS), carbon disulfide (CS2), and elemental sulphur 

(the latter 3 being known inhibitors of mono-oxygenases). Metabolism data indicate that 

the EBDCs do not bioaccumulate. 
Page 18 of 46 

3.3 FQPA Considerations 

HED has evaluated the toxicology database for ETU and reviewed the potential for 

increased susceptibility of infants and children from exposure to ETU in accordance with 

the February 2002 OPP 10X guidance document. Studies available for FQPA 

consideration included several developmental toxicity studies from the literature, one 

unacceptable guideline developmental toxicity study in rats where only one dose was 

administered, and a 2-generation reproduction toxicity study in rats. 

There is concern for prenatal toxicity resulting from exposure to ETU due to the effects 

seen in developmental studies. There was evidence of quantitative and qualitative 

susceptibility to fetuses in several developmental studies in rats: 

• In a 1973 literature study (Khera), developmental defects of the brain in the fetuses 

occurred at a dose significantly lower than the dose at which maternal toxicity was 

observed; 

• In a 1979 literature study (Chernoff, et. al.), the maternal toxicity NOAEL was twice 

the developmental LOAEL, at which hydrocephalus occurred. The maternal LOAEL 

was four times higher than the developmental LOAEL, and the effect consisted of 

reduced body weight gain and mortality; 

• In a 1978 literature study (Teramoto, et. al.), developmental toxicity (dilated 

ventricle of the brain was seen at the lowest dose tested (10 mg/kg/day) in the 

absence of maternal toxicity; 

• In a 1991 literature study (Saillenfait, et. al.), severe developmental effects (dilated 

ventricles of the brain, hydroureter, short/kinky tail, and dilated ureters) were seen at 

a dose (25 mg/kg/day) that only induced decreases in body weight gain in the dams. 

Evidence of susceptibility in rabbits could not be ascertained due to the missing prenatal 

study in this species. The 2-generation reproduction study in rats was not adequate to 

evaluate susceptibility. 

Since there is evidence of increased susceptibility of fetuses following exposure to ETU 

in the rat developmental studies, HED evaluated the level of concern for the effects 

observed when considered in the context of all available toxicity data. In addition, the 

database was examined to determine if there were residual uncertainties after establishing 

toxicity endpoints and uncertainty factors to be used in the ETU risk assessment. HED 

determined that the degree of concern for the susceptibility seen in ETU developmental 

studies was low because: 

• The developmental effects have been well-characterized in numerous studies in the 

published literature, as well as in a guideline study submitted by the registrant; 

• There is a clear NOAEL for these effects and the dose-response relationship, although 

steep, it is well characterized in the numerous developmental studies in rats. 

• The developmental endpoint with the lowest NOAEL was selected for deriving the 

acute reference dose. 
Page 19 of 46 

• The target organ toxicity (thyroid toxicity) was selected for deriving the chronic 

reference dose as well as endpoints for non-dietary exposures (incidental oral, dermal, 

and inhalation). 

3.3.1 Recommendation for a Developmental Neurotoxicity Study 

HED concluded that a developmental neurotoxicity study for ETU was required, based 

on severe central nervous system defects observed in the developmental toxicity study in 

rats including: exencephaly, 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, and meningoencephalocele. A comparative thyroid toxicity study in 

adults and offspring was also required. 

3.3.2 Safety Factor for Infants and Children 

Although there are no residual uncertainties for pre- and/or post-natal toxicity, the FQPA 

Safety Factor of 10X was retained due to database uncertainties for ETU. In addition to 

the required DNT study, there are data gaps for a developmental toxicity study in rabbits, 

a 2-generation reproduction study in rats and a study evaluating the comparative thyroid 

toxicity in adults and offspring. HED determined that the FQPA SF must be retained to 

account for the lack of these studies, since the available data provide no basis to support 

reduction or removal of the factor. 

3.4 Hazard Identification and Toxicity Endpoint Selection 

HED evaluated the toxicology database of ETU and selected the doses and endpoints for 

risk assessment based on a variety of exposure pathways resulting from use of the EBDC 

fungicides. These doses and endpoints are summarized in Table 3.4. 

3.4.1 Acute Reference Dose (aRfD) - Females age 13-49 

The ETU acute dietary endpoint for females 13-49 years old was selected from a nonguideline developmental toxicity study in rats (Khera, K.S.; Teratology 7:243-252, 1973, 

MRID No. 45937601). The LOAEL was 10 mg/kg/day based on developmental effects 

of the brain, including exencephaly, dilated ventricles and hypoplastic cerebellum. The 

NOAEL for the study was 5 mg/kg/day. Application of the combined standard 10X UFs 

to account for intraspecies variability and interspecies extrapolation as well as the FQPA 

10X database uncertainty factor (UFDB) results in an acute reference dose of 0.005 

mg/kg/day. The acute population adjusted dose is equal to the acute RfD, 0.005 

mg/kg/day. 

3.4.2 Acute Reference Dose (aRfD) - General Population 

HED concluded that an acute reference dose for the general population is not needed, 

since there was no appropriate endpoint attributable to a single dose in the available 

toxicity studies. 
Page 20 of 46 

3.4.3 Chronic Reference Dose (cRfD) 

The ETU chronic reference dose for the general population was selected from a chronic 

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

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

at the LOAEL of 1.99 mg/kg/day. The combined 1000X UF (standard 100X and an 

additional FQPA 10X UFDB) results in a chronic reference dose, RfD, of 0.0002 

mg/kg/day. The cPAD of 0.0002 mg/kg/day is equivalent to the chronic RfD. 

3.4.4 Incidental Oral Exposure (Short- and Intermediate-Term) 

A non-guideline 4-week range-finding toxicity study conducted in dogs was used to 

select incidental oral endpoints and doses for risk assessment. The NOAEL was 7 

mg/kg/day based on gross thyroid lesions and decreased thyroid hormone levels at the 

LOAEL of 34 mg/kg/day. The endpoint is appropriate for the population 

(infants/children) and the short- term duration of exposure (up to 30 days). In addition, 

the study can be used for intermediate-term incidental oral risk assessment, since it is also 

supported by a subchronic toxicity study in dogs in which the NOAEL for thyroid effects 

was similar, at 6 mg/kg/day. The combined UF applied to both short- and intermediateterm incidental oral risk assessments is 1000X, based on the standard 100X UF, as well 

as the FQPA 10X UFDB. An additional uncertainty factor to extrapolate from a shorterto a longer-term study was not needed, since the NOAEL for thyroid effects in the 

subchronic dog study was similar to that observed in the 4-week dog study.

3.4.5 Oral Exposure (Short- and Intermediate-Term) 

The ETU oral endpoint for females 13-49 years old was selected from a non-guideline 

developmental toxicity study in rats (Khera). The study NOAEL was 5 mg/kg/day based 

on developmental effects of the brain, including exencephaly, dilated ventricles, and 

hypoplastic cerebellum, observed at the LOAEL of 10 mg/kg/day. The target MOE for 

residential exposures is 1000, which includes the standard 100X combined UFs, as well 

as the 10X FQPA UFDB. 

3.4.6 Dermal Absorption 

Dermal Absorption Factor: 26%. 

The ETU dermal absorption factor is 26%, from a dermal absorption study in rats. The 

value of 26% dermal absorption was determined at the lowest dermal dose after 10 hours 

of exposure followed by washing of the skin. ETU residues were detected in organs at all 

three dermal doses, and were highest in the thyroid. 
Page 21 of 46 

3.4.7 Dermal and Inhalation Exposure (Short- and Intermediate-Term) 

Females 13-49 years old, dermal and inhalation exposure 

In the absence of adequate dermal and inhalation toxicity studies for ETU, the nonguideline oral study in rats (Khera) was used to select endpoints for short- and 

intermediate-term dermal and inhalation risk assessments. The study NOAEL was 5 

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

ventricles, and hypoplastic cerebellum, observed at the LOAEL of 10 mg/kg/day; the 

endpoint is considered applicable for females 13-49 years old. Because an oral toxicity 

study was chosen, the 26% dermal absorption factor (relative to oral absorption) for ETU 

should be used in the dermal exposure assessment, and 100% absorption should be 

assumed for calculating inhalation exposure and risk, i.e. inhalation absorption is 

equivalent to oral absorption. The target MOE for residential exposures is 1000, which 

includes the standard 100X combined UFs, as well as the 10X FQPA UFDB. The target 

MOE for occupational assessments is 100. 

Toddlers, dermal exposure 

The non-guideline 4-week range-finding toxicity study conducted in dogs was also used 

to select short- and intermediate-term dermal endpoints for risk assessment for 

infants/children. The study NOAEL was 7 mg/kg/day based on gross thyroid lesions and 

decreased thyroid hormone levels at the LOAEL of 34 mg/kg/day. The combined UF 

applied to both short- and intermediate-term dermal risk assessments is 1000X, based on 

the standard 100X UF, as well as the FQPA 10X UFDB. An additional uncertainty factor 

to extrapolate from a shorter- to a longer-term study was not needed, since the NOAEL 

for thyroid effects in the subchronic dog study (6 mg/kg/day) was similar to that observed 

in the 4-week dog study.

3.4.8 Dermal and Inhalation Exposure (Long-Term) 

The long-term dermal and inhalation endpoints were selected from the chronic toxicity 

study in dogs. The NOAEL is 0.18 mg/kg/day based on decreased body weight gain, 

increased thyroid weight, and microscopic changes in the thyroid at the LOAEL of 1.99 

mg/kg/day. Since an oral study was selected, estimated dermal exposure should be 

adjusted by 26%, the ETU dermal absorption factor (relative to oral absorption). For 

calculating inhalation risks, a 100% oral equivalent absorption factor should be used. For 

residential exposures, the target MOE for ETU is 1000, based on the combined UFs of 

100X for intra-species variability and interspecies extrapolation, and an additional FQPA 

10X UFDB for an incomplete database. For occupational exposures, the long-term target 

MOE for dermal and inhalation exposures is 100. 

3.4.9 Classification of Carcinogenic Potential 

The HED Cancer Assessment Review Committee evaluated the carcinogenicity potential 

of ETU and classified ETU as a probable human carcinogen, group B2, (Bill Sette, Ph.D., 

4/16/90). The Q1* for ETU, using a 3⁄4 scaling factor, was determined to be 0.0601 

(mg/kg/day)-1 based upon female mouse liver tumors in a National Toxicology Program 
Page 22 of 46 

study (Bernice Fisher and Hugh Pettigrew, 2/24/95.

3.4.10 Summary of Toxicological Doses and Endpoints for ETU for Use in Human 

Risk Assessments 

Table 3.4 ETU Toxicological Doses and Endpoints for Use in Human Health Risk Assessment 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty/FQPA 

Safety Factors 

RfD, PAD, Level of 

Concern for Risk 

Assessment 

Study and Toxicological 

Effects 

Dietary Exposure 

Acute Dietary 

(General 

Population, 

including Infants 

and Children) 

There was no appropriate endpoint attributable to a single dose in the available toxicity 

studies. 

Acute Dietary 

(Females 13-49 

years old) 

NOAEL= 5 

mg/kg/day 

UFA= 10x 

UFH=10x 

FQPA SF=10x,UFDB

Acute RfD = 0.005 

mg/kg/day 

aPAD = 0.005 

mg/kg/day 

Developmental Rat 

Toxicity 

(Khera Study, MRID No. 

45937601) 

LOAEL = 10 mg/kg/day, 

based on developmental 

defects of brain 

Chronic Dietary 

(All Populations) 

NOAEL= 0.18 

mg/kg/day 

UFA= 10x 

UFH=10x 

FQPA SF= 10x,UFDB

Chronic RfD = 

0.0002 

mg/kg/day 

cPAD = 0.0002 

mg/kg/day 

Dog Chronic Oral 

Toxicity 

LOAEL= 1.99 mg/kg/day 

based on thyroid toxicity 

Oral Exposure 

Incidental Oral 

Short-Term (1-30 

days) 

IntermediateTerm (1-6 

months) 

(Toddlers) 

NOAEL= 7 

mg/kg/day 

UFA= 10x 

UFH=10x 

FQPA SF= 10x,UFDB

Residential MOE = 

1000 

Occupational MOE = 

N/A 

4-week range-finding dog 

study 

LOAEL= 34 mg/kg/day 

based thyroid toxicity 

Oral (Short-Term 

(1-30 days) 

IntermediateTerm (1-6 

months) 

(Females 13-49 

years old) 

NOAEL= 5 

mg/kg/day 

UFA= 10x 

UFH=10x 

FQPA SF= 10x,UFDB 

Residential MOE = 

1000 

Occupational MOE = 

N/A 

Developmental Rat 

Toxicity 

(Khera Study, MRID No. 

45937601) 

LOAEL = 10 mg/kg/day, 

based on developmental 

defects of brain 

Dermal Exposure 

Dermal ShortTerm (1-30 days) 

IntermediateTerm (1-6 

months) 

(Toddlers) 

NOAEL= 7 

mg/kg/day 

UFA= 10x 

UFH=10x 

FQPA SF= 10x,UFDB

Residential MOE = 

1000 

Occupational MOE = 

N/A 

4-week range-finding dog 

study 

LOAEL= 34 mg/kg/day 

based thyroid toxicity 

Dermal Short- NOAEL= 5 UFA= 10x Residential MOE = Developmental Rat 
Page 23 of 46 

Table 3.4 ETU Toxicological Doses and Endpoints for Use in Human Health Risk Assessment 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty/FQPA 

Safety Factors 

RfD, PAD, Level of 

Concern for Risk 

Assessment 

Study and Toxicological 

Effects 

Term (1-30 days) 

IntermediateTerm (1-6 

months) 

(Females 13-49 

years old) 

mg/kg/day UFH=10x 

FQPA SF= 10x,UFDB 

DA= 26% 

1000 

Occupational MOE = 

100 

Toxicity 

(Khera Study, MRID No. 

45937601) 

LOAEL = 10 mg/kg/day, 

based on developmental 

defects of brain 

Dermal LongTerm (>6 months) NOAEL= 0.18 

mg/kg/day 

UFA= 10x 

UFH=10x 

FQPA SF= 10x,UFDB 

DA= 26% 

Residential MOE = 

1000 

Occupational MOE = 

100 

Dog Chronic Oral 

Toxicity 

LOAEL= 1.99 mg/kg/day 

based on thyroid toxicity 

Inhalation Exposure 

Inhalation ShortTerm (1-30 days) 

IntermediateTerm (1-6 

months) 

NOAEL=5 

mg/kg/day 

UFA= 10x 

UFH=10x 

FQPA SF= 10x,UFDB

Residential MOE = 

1000 

Occupational MOE = 

100 

Developmental Rat 

Toxicity 

(Khera Study, MRID No. 

45937601) 

LOAEL = 10 mg/kg/day, 

based on developmental 

defects of brain. 

Inhalation LongTerm (>6 months) NOAEL=0.18

mg/kg/day 

UFA= 10x 

UFH=10x 

FQPA SF= 10x,UFDB

Residential MOE = 

1000 

Occupational MOE = 

100 

Dog Chronic Oral 

Toxicity 

LOAEL= 1.99 mg/kg/day 

based on thyroid toxicity 

Cancer 

Cancer (oral, 

dermal, 

inhalation) 

Q1* = 6.01x10-2 (mg/kg/day)-1 ETU is classified as a probable human carcinogen, 

Group B2, with a low-dose extrapolation approach 

for human risk assessment, based on liver tumors 

in female mice. 

Note: Separate short- and intermediate-term oral and dermal endpoints were selected for toddler and adult 

(females 13-49 years old) population subgroups. 

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

data and used to mark the beginning of extrapolation to determine risk associated with lower 

environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest 

observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human 

(interspecies). UFH = potential variation in sensitivity among members of the human population 

(intraspecies). 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. DA = dermal absorption. N/A = not applicable. 

3.5 Endocrine Disruption 

EPA is required under the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended 

by FQPA, to develop a screening program to determine whether certain substances 

(including all pesticide active and other ingredients) “may have an effect in humans that 

is similar to an effect produced by a naturally occurring estrogen, or other such endocrine 

effects as the Administrator may designate.” Following recommendations of its 

Endocrine Disruptor and Testing Advisory Committee (EDSTAC), EPA determined that 
Page 24 of 46 

there was a scientific basis for including, as part of the program, the androgen and thyroid 

hormone systems, in addition to the estrogen hormone system. EPA also adopted 

EDSTAC’s recommendation that the Program include evaluations of potential effects in 

wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in 

wildlife may help determine whether a substance may have an effect in humans, FFDCA 

authority to require the wildlife evaluations. As the science develops and resources 

allow, screening of additional hormone systems may be added to the Endocrine Disruptor 

Screening Program (EDSP). 

When additional appropriate screening and/or testing protocols being considered under 

the Agency’s EDSP have been developed, ETU may be subjected to further screening 

and/or testing to better characterize effects related to endocrine disruption. 

4.0 Public Health and Pesticide Epidemiology Data 

See the parent EBDC compound risk assessments for public health data, as incident data 

are not available for the degradate, ETU. 

5.0 Dietary Exposure/Risk Characterization 

5.1 Environmental Degradation 

Reference: 

Estimated Drinking Water Concentrations of ETU (Ethylene-thio-urea, degradate of mancozeb, and 

common degradate of EBDCs “Ethene-bis-dithio-carbamates”) for Use in Human Health Risk Assessment. 

D323143 and D323141. August 11, 2006. M.A. Ruhman and Ronald Parker. 

The EBDC metabolite/degradate ETU has an aerobic soil half-life of about 3 days; in the 

absence of data, the aquatic aerobic metabolism half-life was assumed to be about 6 days, 

or double the soil half life. The measured anaerobic aquatic metabolism half-life, 

however, is substantially longer (149 days) possibly leading to the periodic detections in 

ground water. ETU is soluble in water (20,000 ppm); highly vulnerable to indirect 

photolysis (half-life = 1 day), and moderately mobile (288 L/kg). It also has a relatively 

high vapor pressure but high solubility, reducing the possibility of losses from surface 

water due to volatilization. 

5.1.1 Surface Water 

Water Monitoring: The EBDC/ETU Task Force conducted a national surface water 

monitoring survey from 2001-2003. A total of 22 sites were chosen to represent 

vulnerable and high EBDC-use sites. Surface water sites were sampled twice monthly 

for three months during each application season and quarterly for the three remaining 

quarters of each year for a period of 2 years. There were no detections of ETU in surface 

water during this period at a limit of quantitation of 0.1 ppb. 
Page 25 of 46 

The Agency has been unable to locate any other surface water monitoring data for the 

EBDC fungicides or for ETU. The EBDCs and ETU were not included in the U.S. 

Geological Survey (USGS) National Water Quality Assessment (NAWQA) sampling 

program because EBDC/ETU test methods were incompatible with NAWQA test 

methods. The USGS is currently planning to begin method development and limited 

EBDC/ETU monitoring. 

Water Modeling: The ETU surface water estimates were calculated using the linked 

USEPA PRZM (Pesticide Root Zone Model) and EXAMS (Exposure Analysis Model 

System) simulation models. This type of modeling provides high-end estimates for 

surface water pesticide concentrations. Calculation includes pesticide-specific properties, 

multiple years of actual weather variations, and crop-specific information. In addition to 

runoff from the field, the model takes into account surface water residues resulting from 

spray drift (aerial or ground). Conservative assumptions included the use of a vulnerable 

drinking water reservoir surrounded by a runoff-prone watershed, maximum use rate, 

lowest application intervals, and no buffer zone. Modeling was done for 22 crop 

scenarios. 

The highest one-in-ten year acute surface water EDWC was 25.2 ppb and the lowest 

value was 4.5 ppb. These values were calculated using the national default percent 

cropped area (PCA) value of 0.87. If the maximum regional PCA value (0.56 California 

PCA) is used, then the highest acute surface water EDWC was 13.9 ppb and the lowest is 

1.4 ppb. 

The highest chronic concentration value was 1.9 ppb and the lowest value was 0.2 ppb 

using the national maximum PCA. 

Acute Surface Water EDWCs: The ETU surface water estimated drinking water 

concentrations were generated using a combined monitoring/modeling approach. The 

targeted ETU monitoring found no surface water concentrations above the detection limit 

of 0.1 ppb. Because samples were taken every 14 days during the application season and 

acute values may have been missed, a range of acute surface EDWCs was established 

with a lower limit based on monitoring and an upper limit based on PRZM/EXAMS 

modeling. 

The range of acute EDWCs was 0.1 ppb (monitoring) and the upper limit was 25.2 ppb. 

The values were adjusted by the national maximum default percent cropped area value of 

0.87. 

Chronic Surface Water EDWC: The chronic EDWC is 0.1 ppb from the targeted ETU 

monitoring program mentioned above. No surface water concentrations were found 

above the detection limit of 0.1 ppb and the Agency believes that monitoring 

demonstrates that long-term average chronic values would not exceed the detection limit. 
Page 26 of 46 

5.1.2 Ground Water 

Water Monitoring: A monitoring program of community ground water systems was 

conducted by the EBDC Task Force from 2001-2003. Untreated and associated treated 

ground water was sampled for a period of two years in 84 sites chosen to represent high 

EBDC-use sites. ETU was detected above the detection limit intermittently in untreated 

water from two ground water sites. The highest concentration was 0.21 ppb in untreated 

water in Florida. There were no detections in treated water in any of the 84 community 

water sites, including those two sites where ETU was detected in the untreated water. 

A monitoring program of private wells was conducted by the EBDC Task Force from 

2001-2003. Raw ground water was sampled monthly for a period of two years in 125 

sites chosen to represent high EBDC-use sites. ETU was detected in the range of 0.10 to 

0.25 ppb continuously at 2 sites in Florida and intermittently at six sites: three in Florida 

and one each in New York, Illinois and Maine. The highest detected ETU concentration 

measured for a private well near an EBDC treated field was 0.57 ppb in an apple growing 

region of New York. No detection of ETU was observed in all the other 117 sites. Such 

higher groundwater concentration values, found in private areas in rural areas, are very 

rare and are unlikely to represent ground water ETU concentrations expected in drinking 

water relevant for use in a national assessment. 

In 25 years of monitoring in California, there has been only one ETU detection (0.75 

ppb). Additionally, ground water monitoring in Holland, resulted in only 8 positive 

samples with a maximum concentration of 1.5 ppb. 

Water Modeling: The ETU EDWCs in ground water, derived from the industry's 

targeted ground water monitoring study, were evaluated by comparing them to 

concentrations predicted by the SCI-GROW model. This is a screening model used to 

estimate pesticide concentrations in vulnerable ground water. The SCI-GROW estimate 

is based on environmental fate properties of the pesticide, maximum application rate, and 

existing data from small-scale prospective ground water monitoring studies at sites with 

sandy soils and shallow ground water (i.e., exceptionally vulnerable ground water). 

Pesticide concentrations estimated by SCI-GROW represent conservative or high-end 

exposure values and in most cases, use areas will have groundwater that is less vulnerable 

to contamination than the areas used to derive the SCIGROW estimate. The SCI-GROW 

modeling indicates that the upper level ETU concentrations from the targeted monitoring 

study are unlikely to be exceeded even under the most vulnerable conditions. 

Ground Water EDWCs (acute and chronic): For ETU, the EDWC value for both acute 

and chronic exposure is 0.21 ppb. This value is from monitoring untreated water in 

Florida. 
Page 27 of 46 

Table 5.1 Summary of Estimated Surface Water and Ground Water Concentrations for ETU

Exposure Duration ETU 

Surface Water Conc. 1 

 (ppb)

Groundwater Conc. 1

(ppb)

Acute 0.1-25.2 0.21 

Chronic (non-cancer) 0.1 0.21

Chronic (cancer) 0.1 0.21

1 Bolded values represent drinking water estimates included in the aggregate dietary assessment. 

5.2 Dietary Exposure and Risk 

Reference: 

Aggregate Dietary 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. DP Barcode: D337240. April 17, 2007. Christine 

Olinger. 

Separate dietary exposure assessments were conducted for each EBDC parent compound. 

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. These documents 

are listed below: 

• Metiram: Acute, Chronic, and Cancer Dietary Exposure Assessments for New 

Tolerances on Imported Grapes and Bananas. PP# 9E6006. D326753. April 17, 2007. 

Christine Olinger. 

• Mancozeb Acute, Chronic, and Cancer Dietary Exposure Assessments for New 

Tolerances on Almonds, Broccoli, Cabbage, Lettuce, and Peppers. PP#4F4324 and 

4F4333. D323878. April 17, 2007. Christine Olinger. 

• Maneb and Ethylenethiourea: Revised Acute/Probabilistic, Chronic, and Cancer 

Dietary Exposure Assessments for the Reregistration Eligibility Decision; DP 

Barcode: D295410; June 2005; F. Fort. 

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

aggregated. ETU aggregate acute, chronic and cancer dietary risk assessments were 

conducted using the Dietary Exposure Evaluation Model (DEEM-FCIDTM), Version 2.03, 

which used food consumption data from the United States Department of Agriculture’s 

(USDA’s) Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 

and 1998. 

The ETU aggregate acute, chronic, and cancer assessments can be considered somewhat 

refined. Residue estimates were refined using consumer processing factors (washing, 

cooking), commercial processing (winemaking, juice), percent crop treated factors 

(existing domestic uses only), and market basket survey (monitoring) data for several of 

the existing uses. Projected percent crop treated information was used to refine the 
Page 28 of 46 

estimates for the proposed new uses of mancozeb. Projected percent crop treated 

information is not available for the uses on imported crops (bananas and grapes), so 

residue estimates were refined slightly using percent imported factors. Crop field trial 

data were used for several of the existing uses as well as all of the proposed new uses, 

which are likely to provide higher estimates than actual exposures. 

5.2.1 Anticipated Residue Information 

Crops treated with EBDCs may contain both 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. Therefore, both EBDC and ETU 

residues may be consumed in the diet. In this assessment the ETU food residues from 

each of the EBDCs were aggregated. 

When possible, market basket survey (MBS) data, generated by the ETU Task Force, 

were used to calculate anticipated residues. MBS data are available on the following 

foods: green beans (raw, frozen, canned, and baby food), dry beans (dry and canned), 

broccoli (raw and frozen), celery, sweet corn (raw, frozen, canned), cucumbers, lettuce, 

meat, milk, onion (dry bulb), potato (raw, frozen), and tomato (raw, juice, ketchup, paste, 

puree). 

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

data from field trials or monitoring data were used to generate residue distribution files 

(RDFs) for commodities which were considered to be not blended or partially blended. 

For commodities considered to be blended in this analysis, the average residues 

incorporating the likely maximum estimated PCT was used as a point estimate. Different 

approaches were taken for for commodities on which more than one EBDC might be 

registered, depending upon the source of the residue data. It was assumed that 

commodities would not be treated with more than one EBDC in a season, as there were 

no data available to determine the relative amount of crops treated with more than one 

EBDC. Only data for the individual chemicals were available. When more than one 

EBDC was registered on any crop and the MBS data were used for the assessment, then 

the percent crop treated values for the individual EBDC were summed and an RDF was 

created in which zeroes were added proportionately. For a few commodities mancozeb 

field trial data were used for both mancozeb and maneb. Those commodities were 

treated similarly to the commodities using MBS. RDFs were created with a proportionate 

number of values from the relative percent crop treated for each chemical. For example, 

the percent crop treated for mancozeb, maneb, and metiram on apples is 35, 5, and 25, 

respectively. Therefore, an RDF where 35% of the values representing treated 

commodities were from mancozeb field trials, 5% from maneb field trials, and 25% from 

metiram field trials was created. 

Chronic anticipated residues were also calculated from field trial or monitoring data for 

ETU. Averages of the field trial and MBS residue data were used. In determining the 

average residue when two or more EBDCs were used on a crop, the following equation 

was used. 
Page 29 of 46 

(ETU from Mancozeb Residue x Mancozeb PCT/100) 

 + (ETU from Maneb residue x Maneb PCT/100) 

 + (ETU from Metiram residue x Metiram PCT/100)

 = Chronic AR for ETU

If the sum of the PCT values for all three EBDCs exceeded 100% then the PCT values 

were adjusted so that the sum equaled 100%. 

5.2.2 Acute Dietary Exposure/Risk

Acute dietary exposure and risk for ETU are below HED’s level of concern. For females 

13-49 years old, estimated dietary exposure (food only) was 0.002799 mg/kg/day, which 

utilized 56% of the aPAD at the 99.9th percentile. For food and water, the acute dietary 

exposure was 0.004437 mg/kg/day which utilized 89% of the aPAD at the 99.9th

percentile of exposure. The results of the acute dietary exposure assessments for ETU 

are shown in Summary Table 5.2. 

5.2.3 Chronic Dietary Exposure/Risk 

The chronic risk estimates are below the HED’s level of concern for aggregate exposure 

to ETU for the general U.S. population and all population subgroups. The most highly 

exposed population subgroup was children ages 1-2 for food alone and food and water 

assessments. For food only, the chronic dietary exposure was 0.000166 mg/kg/day which 

utilized 83% of the cPAD. For food and water combined, the chronic dietary exposure 

was 0.000173 mg/kg/day, which utilized 86% of the cPAD. The results of the chronic 

dietary exposure assessments for ETU are shown in Summary Table 5.2. 

5.2.4 Cancer Dietary Risk

The cancer risk assessment for ETU was based on the same anticipated residues derived 

for the chronic dietary exposure assessment. The estimated chronic dietary exposure for 

the general U.S. population corresponds to a cancer risk of 3.3 x 10-6 for food alone and 

3.6 x 10-6 for food and water combined. The results of the cancer dietary exposure 

assessments for ETU are shown in Summary Table 5.2. 
Page 30 of 46 

Table 5.2 Result of Acute and Chronic Dietary Exposure and Risk Estimates for ETU Using 

DEEM-FCIDTM

Population Subgroup ETU (food only) ETU (food and water) 

Exposure, 

mg/kg/day 

% PAD Exposure, 

mg/kg/day 

%PAD 

Acute Dietary Estimates (99.9th Percentile of Exposure) 

Females 13-49 yrs 0.002799 56 0.004437 89 

Chronic Dietary Estimates 

U.S. Population 0.000055 28 0.000060 30 

All infants (< 1 yr) 0.000073 37 0.000088 44 

Children 1-2 yrs 0.000166 83 0.000173 86 

Children 3-5 yrs 0.000112 56 0.000118 59 

Children 6-12 yrs 0.000057 29 0.000061 31 

Youth 13-19 yrs 0.000034 17 0.000037 19 

Adults 20-49 yrs 0.000045 22 0.000049 25 

Adults 50+ yrs 0.000056 28 0.000061 30 

Females 13-49 yrs 0.000046 23 0.000050 25 

Cancer Dietary Estimate 

U.S. Population 0.000055 3.3 x 10-6 0.000060 3.6 x 10-6

The dietary cancer risk including food and water is 3.6 x 10-6, which exceeds HED’s 

level of concern. Therefore, HED conducted a critical commodity contribution analysis 

for the cancer assessment and sensitivity analyses for several scenarios. The greatest 

contributors to the dietary exposure are bananas (approximately 17% of the exposure) 

and leaf lettuce (approximately 10% of the exposure). Other commodities contributing 

more than 3% of the total exposure were turnip greens, water, mangoes, and grape juice. 

The results of the critical commodity analysis and aggregate sensitivity analyses may be 

found in Tables 5.3 and 5.4, respectively. 

Table 5.3 Summary of Commodities Contributing Greater than 3% of Total Dietary 

Exposure to the Chronic/Cancer Exposure Assessment 

Commodity Exposure, 

mg/kg bw/day 

Individual Cancer 

Risk 

Percent 

Contribution to 

Total Exposure 

Bananas, uncooked1 0.000010 6.2 x 10-7 17 

Lettuce, Leaf 0.0000061 3.7 x 10-7 10 

Water (direct and indirect 

sources) 

0.0000044 2.7 x 10-7 7.4 

Turnip Greens 1 0.0000041 2.5 x 10-7 6.8 

Grape Juice (cooked and 

uncooked) 

0.0000028 1.6 x 10-7 4.6 

Mangoes, uncooked1 0.000002 1.2 x 10-7 3.3 1

Note that this exposure value reflects the assumption of 100% crop treated. 
Page 31 of 46 

Table 5.4 Sensitivity Analyses 

Scenario Exposure, 

mg/kg bw/day 

Estimated Cancer Risk 

Aggregate Food and Water, excluding 

proposed tolerance for metiram on 

bananas 

0.00005 3.0 x 10-6

Aggregate Food and Water, excluding 

mancozeb proposed use on leaf lettuce 

0.000059 3.5 x 10-6

Aggregate Food and Water, assuming 

1% crop treated for Turnip Greens 

0.000056 3.4 x 10-6

6.0 Residential (Non-Occupational) Exposure/Risk Characterization 

Mancozeb: 2nd Revised ORE Assessment for the RED. D317368. May 31, 2005. Timothy Dole. 

Maneb: 2nd Revised ORE Assessment for the RED. D295411. June 8, 2005. Timothy Dole. 

No new residential uses are being added to the mancozeb or maneb labels as a result of 

this action, however there are existing residential uses registered. There are no uses of 

metiram that will result in exposure in residential settings. 

The document entitled Mancozeb: 2nd Revised Occupational and Residential Exposure 

Assessment and Recommendations for the Reregistration Eligibility Decision Document

cited above provides a detailed summary of the exposure and risk assessment for the 

existing residential uses of mancozeb. The document entitled Maneb: 2nd Revised 

Occupational and Residential Exposure Assessment and Recommendations for the 

Reregistration Eligibility Decision Document cited above provides a detailed summary of 

the exposure and risk assessment for the existing residential uses of maneb. 

Exposures and risks from the various residential scenarios are briefly summarized here 

since those values are required for the ETU aggregate risk assessments. 

The existing residential handler scenario identified for mancozeb is for the application of 

mancozeb in home gardens. The anticipated use patterns and current labeling indicate 

that backpack and low pressure handwand sprayers could be used by the homeowner to 

make mancozeb applications. Residential risks are assumed to be of short-term and 

intermediate-term in duration for home garden scenarios and for adults on treated turf. 

HED notes that there are no direct homeowner applications of mancozeb to turf; 

however, there is a registered use to permit treatment of sod on sod farms with 

subsequent transplantation to a residential setting. Residential scenarios are considered to 

be of short-term duration for toddlers on treated turf since it is unlikely that sod would be 

installed more than once per year and since subsequent to installation, turf is watered 

which would contribute to a more rapid dissipation of residues. There are no long-term 

residential exposure scenarios associated with mancozeb at this time. In the previous 

aggregate assessment, exposure to athletes from treated playing fields was considered. 

However, the application to athletic field has been voluntarily cancelled, so is not 

considered in this assessment. 
Page 32 of 46 

Maneb is used on sodfarms and the labels currently state “Do not use on residential, 

pasture or range grasses”. The registrants have agreed to modify the label to include a 

statement such as “For Use on Sodfarms Only” which will eliminate the possibility that 

maneb would be applied to turf in such areas as parks and golf courses where residential 

exposures might occur. The only remaining exposure scenario occurs after the treated 

turf is transplanted from the sod farms to areas such as residential lawns. Therefore, the 

only residential scenario considered for maneb is toddlers playing on turf transplanted 

from sod farms. 

6.1 Residential Handler Exposures and Risks

There are no residential handler scenarios for maneb. 

The existing residential handler scenario identified for mancozeb is for the application of 

mancozeb in home gardens. The anticipated use patterns and current labeling indicate 

that backpack and low pressure handwand sprayers could be used by the homeowner to 

make mancozeb applications. Since the endpoints selected for the short- and 

intermediate-term assessment are identical, short- and intermediate-term risk assessments 

yield the same MOEs; one value is shown in the tables below for each application 

method. Based on tank mix studies, it was assumed that 0.2% of the mancozeb would 

convert to ETU, additionally; a 7.5% in vivo conversion of mancozeb to ETU was also 

considered in the exposure calculations. 

Both dermal and inhalation exposures and risks for mancozeb-derived ETU were 

calculated for residential handlers. Since the short/intermediate-term dermal and 

short/intermediate-term inhalation endpoints were taken from the same study, dermal and 

inhalation exposures were added to calculate a combined absorbed mancozeb-derived 

ETU daily dose. That dose was then compared to the NOAEL from the rat 

developmental toxicity study. Short/intermediate-term combined dermal and inhalation 

MOEs for residential handlers using both backpack sprayers and low pressure handwand 

sprayers far exceeded the level of concern (LOC) of 1000; therefore, HED has no 

concern short-term risks to residential handlers exposed to mancozeb-derived ETU. 

Short-term dermal and inhalation exposures and combined risk for residential handlers 

are summarized in Table 6.1, below. 

Table 6.1 Home Gardener Handler Exposure and Short/Intermediate-Term Risks for 

Mancozeb-Derived ETU

Absorbed ETU Daily Dose 

Exposure Scenario (mg/kg/day)

Dermal Inhalation

Combined Absorbed ETU Daily 

Dose (mg/kg/day)

ETU 

MOE1 

Backpack 5.9 x 10-6 2.1 x 10-6 8.1 x 10-6 620000 

Low Pressure Handwand 4.4 x 10-5 6.4x 10-7 4.5 x 10-5 110000 

1 NOAEL is 5 mg/kg/day

As previously noted, mancozeb’s potential for carcinogenicity is due to the formation of 

the metabolite ETU. Cancer risks from exposure to ETU as a result of application of 
Page 33 of 46 

mancozeb are calculated by estimating exposure to mancozeb-derived ETU and using the 

ETU Q1

*

 of 0.0601 (mg/kg/day)-1 to provide a quantitative estimate of risk. Residential 

handler estimated cancer risks were calculated for applicators using a backpack sprayer 

and a low pressure handwand sprayer. For applicators using backpack sprayers the 

estimated cancer risk from mancozeb-derived ETU was 4.1 x 10-9. Residential handlers 

using low pressure handwand sprayers had an estimated cancer risk of 2.3 x 10-8. 

Because of the uncertainties in the cancer hazard quantification methodology, risk 

estimates ranging from 1 x10-6 to 3 x10-6 are generally considered indistinguishable. 

Generally, cancer risk estimates which do not exceed 3 x10-6 are below HED’s level of 

concern. Therefore, cancer risks to residential handlers as a result of exposure to 

mancozeb-derived ETU from the existing home garden use are not of concern. Cancer 

risks for home garden handlers are summarized in Table 6.2 below. 

Table 6.2 Home Garden Handler Exposure and Cancer Risk for ETU from Mancozeb

Exposure Scenario 

Application 

Rate 

(lbs ai/acre)

Absorbed Daily 

Dose (mg/kg/day)1

Lifetime 

Average Daily 

Dose2

Cancer Risk3

Backpack 2.4 6.9 x 10-6 6.8 x 10-8 4.1 x 10-9

Low Pressure 

Handwand 2.4 3.7 x 10-5 3.8 x 10-7 2.3 x 10-8

1

 ADD = Absorbed Daily Dose from dermal and inhalation exposure 

2

 LADD = Lifetime Average Daily Dose = ADD * (5 exposure days per year/365 days per year)*(50 years 

 of exposure/70 years of life) 

3

 Risk = (LADD * Q1*), where Q1* = 0.0601 (mg/kg/day)-1

6.2. Residential Postapplication Exposure 

6.2.1 Residential Postapplication Exposure – Mancozeb 

Mancozeb can be used in areas that can be frequented by the general population including 

residential areas (e.g., home lawns and gardens) and golf courses. As a result, individuals 

can be exposed by entering these areas if the areas have been previously treated. The 

residential postapplication exposure and risk assessments conducted included the 

following: 

• Adult dermal exposure from contact with treated home gardens

• Adult dermal exposure from contact with treated turf (golfer scenario) 

• Youth (ages 10 - 12) dermal exposure from working in treated home gardens 

• Toddler incidental oral exposure from hand-to-mouth transfer of resides, object-to- 

 mouth transfer of residues and soil ingestion from contact with treated turf 

• Toddler dermal exposure from contact with treated turf 

The residential postapplication exposure and risk assessment are detailed in the 

mancozeb ORE (occupational and residential exposure) memorandum. Results of the 

residential postapplication exposure and risk assessment are summarized in the 

subsequent sections. 
Page 34 of 46 

6.2.1.1 Home Garden Postapplication Scenarios 

Table 6.3, below summarizes the post application risks from mancozeb-derived ETU for 

adults and youth exposed to treated home gardens on Day 0 (the day of application). 

Exposures are shown for low, medium and high contact activities and also for 

representative commodities that might be found in a home garden. The scenario with the 

greatest risk is shown in bold. MOEs for all scenarios for both subpopulations on Day 0 

exceed the LOC of 1000 and, therefore; are not of concern. 

Table 6.3 Mancozeb-derived ETU Postapplication Short/Intermediate-Term Exposure and Risks

for Adult and Youth Home Gardeners

ETU MOE on Day 0 (Adults/Youth)1 Crop Group Application Rate 

(lb ai/acre) Low Medium High2 Very High

Cut Flowers 1.2 53000/97000 33000/61000 19000/35000 N/A 

 Vegetable, cucurbit – 

West3

Vegetable, cucurbit – 

East3

2.4 

2.4 

80000/150000 

94000/170000 

27000/49000 

31000/57000 

16000/290004

19000/34000 

N/A 

N/A 

Vegetable, fruiting - West 

Vegetable, fruiting - East 

1.6 

2.4 

120000/220000 

87000/160000 

86000/160000 

62000/110000 

60000/110000 

43000/79000 

N/A 

N/A 

1 Low, medium and High refer to low, medium and high contact activities. 2 The highest exposure/risk scenario is shown in bold. 3 While the application rates are the same for west and east cucurbit, the dislodgeable foliar residue values used for east 

and west are different, which explains the different exposures and risks from the same application rate. 4

The adult dose for this scenario = 3.1 x 10-4 mg/kg/day and the youth dose for this scenario = 2.4 x 10-4 mg/kg/day 

taken from the ORE chapter cited above. 

Cancer risks from exposure to mancozeb-derived ETU from home garden exposure 

scenarios are summarized in Table 6.4, below. As in the table above, the scenario with 

the highest risk is shown in bold. Postapplication cancer risks for adult home gardeners 

are not of concern. 

Table 6.4 Mancozeb-derived ETU Postapplication Cancer Risks for Adult Home Gardeners

Cancer Risk on Day 0 Assuming Five Exposure Days per Year 

Over a Lifetime

Crop Group Application 

Rate 

(lb ai/acre) Low Medium High2 Very High

Cut Flowers 1.2 4.7 x 10-8 7.5x 10-8 1.3 x 10-7 NA 

 Vegetable, cucurbit – 

West1

Vegetable, cucurbit - East1

2.4 

2.4 

3.1 x 10-8 

2.7 x 10-8 

9.4 x 10-8 

8.0 x 10-8 

1.6 x 10-7 

1.3 x 10-7 

NA 

NA 

Vegetable, fruiting - West 

Vegetable, fruiting – East 

1.6 

2.4 

2.1 x 10-8 

2.9 x 10-8 

2.9 x 10-8 

4.1 x 10-8

4.2 x 10-8 

5.8 x 10-8 

NA 

NA 1

 While the application rates are the same for west and east cucurbit, the dislodgeable foliar residues for east and west 

are different, which explains the different exposures and risks from the same application rate. 2 The highest exposure/risk scenario is shown in bold.

6.2.1.2 Treated Turf Postapplication Scenarios for Toddlers 

Toddlers can be exposed to ETU when in contact with turf treated with mancozeb. 

Incidental oral exposures and risks are shown below. HED notes that there are no direct 
Page 35 of 46 

homeowner applications of mancozeb to turf; however, there is a registered use to permit 

treatment of sod on sod farms with subsequent transplantation to a residential setting. In 

calculating treated turf risks for mancozeb and its metabolite, ETU, HED used the 

outcome of the RED risk mitigation negotiations which provides for a 3-day PHI and 

includes an additional two days for harvesting, shipment and installation for a total of 5 

days between treatment on a sod farm and exposure in a residential setting. 

Since there are no direct home lawn uses for mancozeb, toddlers would only be exposed 

to mancozeb in a residential setting from turf transplanted from a sod farm. Since it is 

unlikely that sod would be installed more than once per year, and the installation process 

includes watering-in which will tend to increase the dissipation of residues, HED 

considered risks to toddlers exposed to treated lawns to be of short-term duration only. 

To assess risks to toddlers from incidental oral exposure, HED summed the total 

exposure from residue transfer from hand-to-mouth, object-to-mouth and soil ingestion. 

The level of concern for both the ETU incidental oral and dermal risk assessments is 

1000. 

Mancozeb-derived ETU incidental oral exposures and risks to toddlers in contact with 

treated turf were calculated based on a 3-day PHI for sod farm turf. The MOE for 

combined oral incidental risk to toddlers in contact with treated turf subsequent to 

installation exceeds 1000 and is therefore, not of concern. Incidental oral exposures and 

risk are summarized in Table 6.5, below. 

Table 6.5 Summary of ETU Incidental Oral Exposures and Risks for Toddlers Exposed to 

Turf Treated with Mancozeb

Exposure Pathway ETU TTR1 Dose (mg/kg/day) MOE

Hand-to-Mouth 0.0085 ug/cm2 0.0030 2300 

Object-to-Mouth 0.034 ug/cm2 0.00075 9300 

Soil Ingestion 0.11 ppm 0.00001 700000 

Total 0.00376 1900 

1 Based upon the existing PHI of 3 days and including an additional 2 days to account for harvesting, shipping and 

installation.

Short-term dermal risk to toddlers in contact with treated turf with a 3-day PHI was 

above 1000 and is not of concern. Short-term dermal exposures and risks for toddlers 

exposed to treated grass are summarized in Table 6.6, below. 

Table 6.6 Summary of ETU Short-Term Dermal Exposures and Risks for Toddlers 

Exposed to Turf Treated with Manzozeb

Exposure Pathway ETU TTR1 Dose (mg/kg/day) MOE

Dermal 0.0085 ug/cm2 0.0022 3100 1

 Based upon the existing PHI of 3 days and including an additional 2 days to account for harvesting, shipping and 

installation. 

6.2.1.3 Treated Turf Postapplication Scenario for Adults

Adults may be exposed to mancozeb-derived ETU through dermal contact with turf 
Page 36 of 46 

treated directly with mancozeb. The MOE for short/intermediate-term dermal risk for the 

adult golfer exposed to ETU from contact with mancozeb treated golf courses exceeds 

1000 and is not of concern. Exposure and risk for adult golfers is summarized in the 

table below. 

Table 6.7 ETU Short/Intermediate-Term Dermal Postapplication Risks for Adults Exposed to 

Turf

Activity Application 

Rate 

(lb ai/acre)

Mancozeb 

TTR 

(ug/cm2

)

ETU TTR 

(ug/cm2)

Transfer 

Coefficient 

(cm2/hr)

Hours per 

Day 

Exposure

ETU Dose 

(mg/kg/day)

MOE

 Golf 17.4 9.76 0.060 500 4.0 0.00076 6600 

The cancer risk to adult golfers from exposure to mancozeb-derived ETU is summarized 

in Table 6.8. Postapplication cancer risks for adult golfers are not of concern. 

 Table 6.8 Summary of ETU Postapplication Cancer Risks for Adults Exposed to Turf

Activity

Application 

Rate 

(lb ai/acre)

Mancozeb 

TTR 

(ug/cm2)

ETU TTR 

(ug/cm2)

Transfer 

Coefficient 

(cm2

/hr)

Hours per 

Day 

Exposure

Days Per 

Year 

Exposure

Years of 

Exposure 

per 

Lifetime

LADD 

(mg/kg/day)

Cancer 

Risk

Golf 10.5 3.2 0.020 500 1.0 1 50 1.0 x 10-6 6x10-8

 

6.2.2 Residential Postapplication Exposure - Maneb

Like mancozeb, toddlers can be exposed to ETU when in contact with turf treated with 

maneb. Incidental oral exposures and risks are shown below. HED notes that there are 

no direct homeowner applications of maneb to turf; however there is a registered use to 

permit treatment of sod on sod farms with subsequent transplantation to a residential 

setting. In calculating treated turf risks for maneb-derived ETU, HED used the outcome 

of the RED risk mitigation negotiations which provides for a lower application rate (8.7 

lb ai/A) and a 3-day PHI, which includes an additional two days for harvesting, shipment 

and installation, for a total of 5 days between treatment on a sod farm and exposure in a 

residential setting. 

Since there are no direct home lawn uses for maneb, toddlers would only be exposed to 

maneb in a residential setting from turf transplanted from a sod farm. Since it is unlikely 

that sod would be installed more than once per year, and the installation process includes 

watering-in which will tend to increase the dissipation of residues, HED considers risks 

to toddlers exposed to treated lawns to be of short-term duration only. 

To assess risks to toddlers from incidental oral exposure, HED summed the total 

exposure from residue transfer from hand-to-mouth, object-to-mouth and soil ingestion 

The level of concern for both the ETU incidental oral and dermal risk assessments is 

1000. 

Maneb-derived ETU incidental oral exposures and risks to toddlers in contact with 

treated turf were calculated based on a 3-day PHI for sod farm turf. The MOE for 

combined oral incidental risk to toddlers in contact with treated turf subsequent to 
Page 37 of 46 

installation exceeds 1000 and is not of concern. Incidental oral exposures and risk are 

summarized in Table 6.9, below. 

Table 6.9 Summary of ETU Incidental Oral Exposures and Risks for Toddlers Exposed to 

Turf Treated with Maneb

Exposure Pathway ETU TTR1 Dose (mg/kg/day) MOE

Hand-to-Mouth 0.0151 ug/cm2 0.0014 5000 

Object-to-Mouth 0.0605 ug/cm2 0.00044 16000 

Soil Ingestion 0.203 ppm 0.000066 110000 

Total 0.0019 3700 

1 Based upon the existing PHI of 3 days and including an additional 2 days to account for harvesting, shipping and 

installation.

Short-term dermal risk to toddlers in contact with treated turf with a 3-day PHI exceeds 

1000 and is not of concern. Short-term dermal exposures and risks for toddlers exposed 

to treated grass are summarized in Table 6.10. 

Table 6.10 Summary of ETU Short-Term Dermal Exposures and Risks for Toddlers 

Exposed to Turf Treated with Maneb

Exposure Pathway ETU TTR1 Dose (mg/kg/day) MOE

Dermal 0.0151 ug/cm2 0.0034 2000 1 Based upon the existing PHI of 3 days and including an additional 2 days to account for harvesting, shipping and 

installation. 

6.3 Other (Spray Drift, etc.)

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 ground application method 

employed for the 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. On a chemical by chemical 

basis, the Agency is now requiring interim mitigation measures for aerial applications 

that must be placed on product labels/labeling. The Agency has completed its evaluation 

of the new database submitted by the Spray Drift Task Force, a membership of U.S. 

pesticide registrants, and is developing a policy on how to appropriately apply the data 

and the AgDRIFT computer model to its risk assessments for pesticides applied by air, 

orchard airblast and ground hydraulic methods. After the policy is in place, the Agency 

may impose further refinements in spray drift management practices to reduce off-target 

drift with specific products with significant risks associated with drift. It is noted that the 

application rate for turf was modeled to estimate postapplication residential exposure of 

toddlers. As this rate is higher than many of agricultural application rates, this scenario is 

protective of any exposure of farm children via spray drift from agricultural applications. 
Page 38 of 46 

7.0 Aggregate Risk Assessments and 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. 

The proposed new uses of mancozeb and tolerances of metiram can result in exposures to 

ETU from food and drinking water. The existing uses of metiram, mancozeb and maneb 

may result in exposures to ETU from food, water, and residential sources. The mancozeb 

uses in home gardens result in handler exposure for adults and postapplication uses to 

adults and youth working in the garden. The mancozeb and maneb sod farm turf uses 

could result in postapplication exposure to toddlers playing on treated turf. The use of 

mancozeb on golf courses could result in postapplication exposures to golfers. 

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 they believed are likely to co-occur. 

The ETU surface and ground water monitoring data are considered adequate to generate 

quantitative surface and ground water drinking water chronic exposure estimates. The 

surface water monitoring data, combined with PRZM-EXAMs modeling, indicate a 

concentration of 0.1 ppb should be used to calculate aggregate chronic and cancer 

exposure and risk. The ETU ground water concentration (0.21 ppb) was taken from a 

targeted monitoring study; use of this value to calculate aggregate risk provides an upper 

bound estimate of exposure through drinking water from ground water sources. 

The following aggregate risk assessments have been completed: 

• ETU Acute Aggregate which considers acute exposure to ETU from food and 

drinking water 

• ETU Short/Intermediate-Term Home Garden Aggregate which combines handler 

exposures (inhalation and dermal) and post application garden exposures (dermal) 

plus average daily food and drinking water exposure for adults and post application 

garden exposures (dermal) plus average daily food and drinking water exposure for 

youth 

• ETU Short-Term Treated Turf Aggregate (Toddlers) which combines treated turf 

post application exposures (incidental oral and dermal) plus average daily food and 

drinking water exposure for toddlers 

• ETU Short/Intermediate-Term Treated Turf Aggregate (Adults “Golfers”) which 

considers short-term residential exposures (dermal) plus average daily food and 

drinking water exposure for adults participating in activities such as golfing on treated 

turf 

• ETU Long-Term (Chronic, Non-Cancer) Aggregate which considers chronic 
Page 39 of 46 

exposure from food and drinking water only 

• ETU Cancer Aggregate which combines handler garden exposures (dermal and 

inhalation), post application garden exposures (dermal), post application treated turf 

exposures (dermal) and average daily food and drinking water exposure for adults 

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 5.2.2. 

7.2 Short- and Intermediate-Term Aggregate Risk

7.2.1 ETU Short- and Intermediate-Term Home Garden Aggregate 

The ETU short/intermediate-term home garden aggregate combines handler inhalation 

and dermal exposures and post application garden dermal exposures plus average daily 

food and drinking water for adults exposed to ETU. For youth exposed to ETU, the 

assessment combines post application garden dermal exposures with average food and 

drinking water. Only mancozeb is registered for use in home garden settings. Average 

food and drinking water exposure values reflect the most highly exposed adult or youth 

subpopulation from the average daily dietary assessment, and consider ETU derived from 

mancozeb, metiram, and maneb applications. The existing and proposed food uses were 

included in the food and drinking water exposure estimates. 

The ETU short/intermediate-term home garden aggregate MOEs for adults and youth 

exceed 1000, the level of concern for this risk assessment, and are not of concern. 

Aggregate risk results are shown in Table 7.1. 
Page 40 of 46 

Table 7.1 ETU Short/Intermediate-Term Home Garden Aggregate Risk Results 

Short/Intermediate-Term Scenario 

Population NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day 

Average 

Food & Water 

Exposure3 

mg/kg/day 

Residential 

Exposure4

mg/kg/day 

Aggregate 

MOE 

(food, water 

and 

residential)5

Adults – handler 

and postapplication 

5 1000 0.005 0.000061 0.000318 13000 

Youth – postapplication 7 1000 0.007 0.00017 0.000240 17000 

1

 The LOC is based on UFA = 10, UFH = 10, UFDB = 10 (Table 3.4). 2

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

3

 Average food and drinking water exposure taken from most highly exposed adult or youth subpopulation 

from the chronic dietary exposure assessment in Table 5.2. Food and drinking water consider ETU derived 

from existing and proposed uses of mancozeb, metiram, and maneb. 

4

 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. Combined dermal and 

inhalation exposure for adult handlers is 8.1 x 10-6 mg/kg/day (Table 6.1). Dermal postapplication 

exposure for adults is 3.1 x 10-4 mg/kg/day (Table 6.3). Dermal postapplication exposure for youth is 2.4 x 

10-4 mg/kg/day (Table 6.3). Only mancozeb is registered for use in home garden settings. 5

 Aggregate MOE = [NOAEL / (Avg Food & Drinking water Exposure + Residential Exposure)] 

7.2.2 ETU Short-Term Treated Turf Aggregate (Toddlers) 

The short-term treated turf aggregate risk assessment combines treated turf post 

application incidental oral and dermal exposures with average daily food and drinking 

water exposure for toddlers. Maneb and mancozeb are both registered for applications to 

sod farms. Average food and drinking water exposure values, including all sources of 

ETU, reflect the most highly exposed children’s subpopulation from the chronic dietary 

assessment. 

The ETU short-term treated turf aggregate MOE for toddlers exceeds 1000, the level of 

concern for this risk assessment, and is not of concern. Aggregate risk results are shown 

in Table 7.2. 
Page 41 of 46 

Table 7.2 ETU Short-Term Treated Turf (Toddlers) Aggregate Risk Results 

Short-Term Post-Application Scenario 

Population NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day 

Average 

Food & 

Water 

Exposure3 

mg/kg/day 

Residential 

Exposure4

mg/kg/day 

Aggregate MOE 

(food and 

residential)5

Toddlers – 

mancozeb 

derived ETU 

7 1000 0.007 0.00017 0.00596 1100 

Toddlers – 

maneb derived 

ETU 

7 1000 0.007 0.00017 0.00531 1280 

1

 The LOC is based on UFA = 10, UFH = 10, UFDB = 10 2

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

3

 Average food and drinking water exposure taken from most highly exposed child subpopulation from the 

chronic dietary exposure assessment in Table 5.2. 4

 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. For mancozeb, 

incidental oral exposure is 0.00376 mg/kg/day (Table 6.5). Dermal exposure is 0.0022 mg/kg/day (Table 

6.6). For maneb, incidental oral exposure is 0.0019 mg/kg/day (Table 6.9). Dermal exposure is 0.0034 

mg/kg/day (Table 6.10). 

5

 Aggregate MOE = [(NOAEL / (Avg Food & Drinking water Exposure + Residential Exposure)] 

7.2.3 ETU Short- and Intermediate-Term Treated Turf Aggregate (Adult 

“Golfers”) 

The short/intermediate-term treated turf aggregate risk assessment combines dermal 

exposures for adults participating in activities such as golfing on treated turf exposed to 

ETU with average daily food and drinking water exposures. Only mancozeb uses are 

relevant for this scenario. 

The ETU short-term treated turf aggregate MOE for adults (“golfers”) exceeds 1000, the 

level of concern for this risk assessment and is; therefore, not of concern. Aggregate risk 

results are shown in Table 7.3. 
Page 42 of 46 

Table 7.3 ETU Short/Intermediate-Term Treated Turf (Adults “Golfers”) Aggregate Risk 

Results 

Short-Term Scenario 

Population NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day 

Average 

Food & 

Water 

Exposure3 

mg/kg/day 

Residential 

Exposure4

mg/kg/day 

Aggregate MOE 

(food and 

residential)5

Adults 

(Golfers) 

5 1000 0.005 0.000061 0.00076 6100 

1

 The LOC is based on UFA = 10, UFH = 10, UFDB = 10 2

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

3

 Average food and drinking water exposure taken from most highly exposed adult subpopulation from the 

chronic dietary exposure assessment in Table 5.2. Food and drinking water consider ETU derived from 

existing and proposed uses of mancozeb, metiram, and maneb. 

4

 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. Adult dermal 

exposure is 0.00076 mg/kg/day for mancozeb treated turf (Table 6.7) 

5

 Aggregate MOE = [(NOAEL ) / (Avg Food & Drinking water Exposure + Residential Exposure)] 

7.3 Long-Term (Chronic) Aggregate Risk 

As noted above, there are no long-term residential exposure scenarios for the existing and 

proposed uses on the EBDCs which would result in long term residential 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 (noncancer) aggregate risk assessment for ETU is equivalent to the ETU chronic dietary risk 

assessment discussed in Section 5.2.3 of this document. 

7.5 Cancer Aggregate Risk 

For the aggregate cancer risk assessment, HED combined residential handler and post 

application exposures for adults exposed to ETU from the home garden uses, as well as 

post application exposures to adults from contact with treated turf during activities such 

as golfing. The combined residential exposure was then aggregated with dietary 

exposure to ETU from food and drinking water and multiplied by the ETU Q1

*

. The 

existing and proposed uses of mancozeb, metiram, and mancozeb were considered for 

dietary exposure. The maneb residential use was not aggregated because the mancozeb 

residential uses will result in much higher exposures than the maneb sod farm use and 

exposure to an individual from sod farm uses of both chemicals is considered unlikely. 

ETU aggregate cancer results are shown in Table 7.4.
Page 43 of 46 

Table 7.4 ETU Aggregate Cancer Results 

Population Q1* 

(mg/kg/day)-1

Negligible 

Risk Level1 

Average daily 

Food & Water 

Exposure2

(mg/kg/day) 

Residential 

Exposure 3

(LADD)

Aggregate 

Cancer Risk 

(food, water 

and 

residential)4

U.S. Population 6.01 x 10-2 3 x10-6 6.0 x10-5 4 x 10-6 3.8 x 10-6

1 Because of the uncertainties in the hazard quantification methodology, risk estimates ranging from 1 x10-6

to 3 x10-6 are generally considered indistinguishable. Generally, cancer risk estimates which do not exceed 

3 x10-6 are below HED’s level of concern. 2 From Table 5.2. 

3

 Handler LADD (low pressure handwand – highest exposure scenario) is 3.8 x10-7 from Table 6.2. Home 

garden post application LADD is 2.6 x10-6 from Table 6.4 (risk/ Q1* = exposure). Treated turf post app 

LADD is 1.0 x10-6 from Table 6.8. Total residential exposure is 3.98 x10-6. 4

 Aggregate cancer risks are for the U.S. Population and are calculating the Q1* (0.0601) by the total 

exposure. 

The aggregate cancer risk is approximately 3.8 x 10-6, which exceeds HED’s level of 

concern. In fact, the aggregate food and drinking water risk also exceeds HED’s level of 

concern, before aggregation with residential exposures. Therefore, HED conducted 

sensitivity analyses to determine the commodities that provided the most contribution to 

the ETU exposure. The commodities that are the greatest contributors to ETU exposure 

are bananas, leaf lettuce, drinking water, turnip greens, grape juice and mangoes (Table 

5.3). The results of the aggregate sensitivity analyses may be found in Table 7.5. If the 

proposed tolerance in/on bananas (from metiram applications) is removed from the 

aggregate, then the aggregate cancer risk does not exceed HED’s level of concern. All of 

the other sensitivity analyses resulted in risks exceeding the level of concern. Note that 

the metiram-derived ETU residue values from banana field trials used in the aggregate 

assessment are considered to be overestimates. Projected percent crop treated 

information was not available, so percent imported information was used, and it is highly 

unlikely that all imported bananas will be treated. In general, monitoring data on other 

commodities show much lower residues than field trial data, so actual exposure is likely 

to be lower. 
Page 44 of 46 

Table 7.5 Sensitivity Analyses for ETU Aggregate Cancer Results 

Scenario Negligible 

Risk Level1 

Average daily 

Food & 

Water 

Exposure2

(mg/kg/day) 

Residential 

Exposure 3

(LADD)

Aggregate 

Cancer Risk 

(food, water 

and 

residential)4 

Food, Water, Residential, all 

proposed uses 3 x10-6 6.0 x10-5 4 x 10-6 3.8 x 10-6

Food, Water, Residential, excluding 

proposed banana tolerance 3 x10-6 5.0 x10-5 4 x 10-6 3.2 x 10-6

Food, Water, Residential, excluding 

proposed use of mancozeb on leaf 

lettuce 

3 x10-6 5.9 x10-5 4 x 10-6 3.8 x 10-6

Food, Water, Residential, all 

proposed uses, assuming 1% crop 

Treated for turnip greens 

3 x10-6 5.6 x10-5 4 x 10-6 3.6 x 10-6

1 Because of the uncertainties in the hazard quantification methodology, risk estimates ranging from 1 x10-6

to 3 x10-6 are generally considered indistinguishable. Generally, cancer risk estimates which do not exceed 

3 x10-6 are below HED’s level of concern. 2 From Table 5.2. 

3 Handler LADD (low pressure handwand – highest exposure scenario) is 3.8 x10-7 from Table 6.2. Home 

garden post application LADD is 2.6 x10-6 from Table 6.4 (risk/ Q1* = exposure). Treated turf post app 

LADD is 1.0 x10-6 from Table 6.8. Total residential exposure is 3.98 x10-6. 4

 Aggregate cancer risks are for the U.S. Population and are calculating the Q1* (0.0601) by the total 

exposure. 

8.0 Cumulative Risk Characterization/Assessment 

Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering whether to 

establish, modify, or revoke a tolerance, the Agency consider "available information” 

concerning the cumulative effects of a particular pesticide's residues and "other 

substances that have a common mechanism of toxicity.” 

No determination of a common toxic effect or mechanism of toxicity has been made for 

acute or chronic non-cancer risks from EBDCs. 

9.0 Occupational Exposure/Risk Pathway 

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

of the EBDC fungicides in the risk assessments of the parent compound. 

10.0 Data Needs and Label Recommendations

The data gaps for each individual EBDC and the corresponding exposures to ETU are 

discussed in the risk assessments for each parent compound. The data gaps for ETU, 

which were previously identified in the 2005 human health risk assessment, include the 

following: 
Page 45 of 46 

Toxicology

 

• Guideline 870.3800 2-generation reproduction, rat 

• Guideline 870.3700 Developmental toxicity, rabbit 

• Guideline 870.6300 Developmental neurotoxicity 

• Non-guideline Comparative study for thyroid toxicity in adults and 

 offspring 

References 

Davis, Donna. DP Barcode: D327307 & D327318. June 2007. Mancozeb: Human 

Health Risk Assessment to Support Proposed New Uses on Broccoli, Cabbage, Lettuce, 

Peppers and Almonds. 

Dole, Timothy. DP Barcode: D317368. May 31, 2005. Mancozeb: 2nd Revised ORE 

Assessment for the RED. 

Dole, Timothy. DP Barcode: D295411. June 8, 2005. Maneb: 2nd Revised ORE 

Assessment for the RED. 

Goodlow, Toiya. DP Barcode: D267866. June 2007. Metiram: Human Health Risk 

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

Grapes and Bananas. 

Olinger, Christine. DP Barcode: D317416. June 8, 2005. ETU from EBDCs: Health 

Effects Division (HED) Human Health Risk Assessment of the Common 

Metabolite/Degradate ETU to Support Reregistration. 

Olinger, Christine. DP Barcodes: D267866 and D322230. Metiram: Petition for the 

Establishment of Import Tolerances on Grape and Banana. Summary of Analytical 

Chemistry and Residue Data. PP# 9E6006. 

Olinger, Christine. DP Barcode: D289183. April 5, 2007. Mancozeb on Almonds. 

Summary of Analytical Chemistry and Residue Data. PP#4F4324. 

Olinger, Christine. DP Barcode: D294203. April 3, 2007. Mancozeb on Broccoli, 

Cabbage, Lettuce, and Peppers. Summary of Analytical Chemistry and Residue Data. 

PP# 4F4333. 

Olinger, Christine. DP Barcode: D337240. April 17, 2007. Aggregate Dietary 

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. 
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Parker, Ronald and Ruhman, Mohammed. DP Barcodes: D323143 and D323141. August 

11, 2006. Estimated Drinking Water Concentrations of ETU (Ethylene-thio-urea, 

degradate of mancozeb, and common degradate of EBDCs “Ethene-bis-dithiocarbamates”) for Use in Human Health Risk Assessment.