Ethylene Thiourea Human Health Risk Assessment D383971 

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF 

PREVENTION, PESTICIDES 

AND TOXIC SUBSTANCES 

MEMORANDUM

DATE: November 16, 2010 

SUBJECT: Addendum to the Aggregate Human Health Risk Assessment of the Common 

Metabolite/Degradate Ethylene Thiourea (ETU) to Support New Tolerances on Imported 

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

Broccoli, Cabbage, Lettuce, and Peppers. 

PC Codes: 600016, 14504, 14505, 14601 DP Barcode: D383971 

Decision No.: 299414 Registration No.: NA 

Petition No.: PP# 9E6006 PP#4F4324 and 4F4333 Regulatory Action: New Tolerance 

Risk Assessment Type: Aggregate Case No.: NA 

TXR No.: NA CAS No.: 96-45-7; 8018-01-7; 12427-38-2; 9006-42-2 

MRID No.: NA 40 CFR: 180.176, 180.110, 180.217

REVIEWER: Christine L. Olinger, Chemist 

Risk Assessment Branch 7 

Health Effects Division (7509P) 

THROUGH: Michael S. Metzger, Chief 

Risk Assessment Branch 7 

Health Effects Division (7509P) 

TO: Cynthia Giles-Parker, Chief 

Fungicide Branch 

Registration Division (7505P) 

Introduction 

BASF Corporation has submitted a petition for tolerances on imported bananas and grapes for the 

fungicide metiram and Dow AgroSciences LLC has submitted petitions for tolerances on almonds, 

broccoli, cabbage, lettuce, and peppers for the fungicide mancozeb. BASF has since amended the grape 

petition to bananas and wine grapes only. Metiram and mancozeb are in the class of ethylene 

bisdithiocarbamate fungicides (EBDCs), which all produce the common metabolite and environmental 

degradate, ethylenethiourea (ETU). Maneb is the third fungicide registered for use in the United States 

that belongs to the EBDC group. HED has previously assessed the aggregate exposure to ETU, and 

most aggregate scenarios were below the level of concern, but there was some concern for the aggregate 

cancer assessment (T. Goodlow, D337241, 6/14/07). Since the proposed tolerance on bananas was the 
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most significant contributor to the risk, and the assessment reflected minimal refinement, the registrant 

submitted additional information regarding the proposed use on bananas. In addition the Mancozeb 

Task Force has submitted additional usage information in support of the mancozeb petition. The acute 

and chronic (non-cancer) assessment has not been modified, and will not be further discussed in this 

assessment. This addendum will only address the aggregate cancer assessment. A tabular summary of 

all memoranda discussed in this document and prepared in support of the proposed tolerances and 

registrations may be found at the end of this memo. 

Hazard Assessment 

No data pertinent to the hazard assessment has been submitted since the most recent risk assessment. 

This addendum updates only the cancer assessment, so only the cancer classification is presented herein. 

Treatment with ETU produced increases in tumor incidence in rodents. Various literature studies have 

shown increased incidence of thyroid tumors in two strains of rats as well as mice. The HED Cancer 

Assessment Review Committee evaluated the carcinogenicity potential of ETU and classified ETU as a 

probable human carcinogen, group B2. The cancer slope factor 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. Further discussion of the cancer studies/classification and hazard 

characterization may be found in the previous ETU risk assessment (cited above) as well as a memo by 

K. Farwell (5/28/03). 

Dietary Exposure/Risk Assessment

No additional residue data have been submitted since the most recent risk assessment, other than some 

clarifying information on the limits of quantification for the residue method used in the banana field 

trials. The petitioner provided further information on the proposed use of metiram on bananas, which 

has been reviewed by the Biological and Economic Analysis Division (BEAD) (A. Halvorson, 8/6/08). 

The updated mancozeb usage information was recently reviewed by BEAD (C. Chen and J. Alsadek, 

9/16/10, DP Barcode: 360397). The cancer dietary assessment has been updated to include the updated 

usage information and is described in detail in a memo currently in review (C. Olinger, 366141). The 

acute and chronic (non-cancer) dietary assessment is described in the previous risk assessment (T. 

Goodlow, D337241, 6/14/07). 

Exposure and risk estimates for the ETU dietary aggregate (food and drinking water) cancer assessment 

are presented in Table 1. HED is generally concerned when the cancer risk is no longer considered 

negligible, typically when the risk exceeds 10-6. The aggregate (food and water) cancer risk estimate 

associated with exposure to ETU from all EBDCs for food alone is 2.6 x 10-6 and food and water 

combined water is 2.8 x 10-6 for the general U.S. population. Although some inputs into this assessment 

are highly refined, other inputs are very conservative, as high-end field trial residues were used for some 

commodities, as well as the assumption of 100% crop treated for several commodities. The greatest 

contributors to the dietary exposure for the cancer assessment were leafy vegetables, Brassica 

vegetables, fruiting vegetables, and water. 
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Table 1. Results of Cancer Dietary Exposure Analysis for ETU from Mancozeb, Metiram, and Maneb 

Population Subgroup Exposure 

(mg/kg/day) Estimated Cancer Risk 

General U.S. Population – Food Only 0.000043 2.6 x 10-6

General U.S. Population – Food and Water 0.000047 2.8 x 10-6

Residential Exposure/Risk Assessment

The detailed assessment for residential exposures may be found in the most recent risk assessment; 

short and intermediate exposures are not of concern. Two uses could result in ETU exposure and were 

assessed for ETU cancer risk in the most recent assessment: home gardeners applying mancozeb to 

vegetables and golfers contacting mancozeb treated turf after application. The cancer risk to home 

gardeners and golfers is presented in Tables 2, 3, and 4. Further description of the assumptions and data 

used in the assessment may be found in the previous risk assessment. 

Table 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

Table 3. Mancozeb-derived ETU Postapplication Exposure and Risk for Adult Home Gardeners on Day 0 

Assuming Five Exposure Days per Year Over a Lifetime

Crop Group Application Rate 

(lb ai/acre)

Lifetime Average Daily Dose 

(LADD), (mg/kg/day) Cancer Risk 

Low 1 High 1 Low 1 High 1

Vegetable, cucurbit - 

West 2.4 2 3.1 x 10-8 1.6 x 10-7 5.16 x 10-7 2.66 x 10-6

Vegetable, cucurbit - 

East 2.4 2 2.7 x 10-8 1.3 x 10-7 4.49 x 10-7 2.16 x 10-6

1

 Exposures are shown for low and high contact activities for the commodity that might be found in a home garden and led to the highest 

exposure. 

2 Note – while the application rates are the same for west and east cucurbit, the dislodgeable foliar residues for east and west are different, 

leading to different exposures and risks from the same application rate. 

Table 4. 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
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Aggregate Risk Assessment

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 cancer slope factor. The existing and proposed uses of mancozeb, metiram, and 

mancozeb were considered for dietary exposure. ETU aggregate cancer results are shown in Table 5.

Table 5. ETU Aggregate Cancer Results 

Population 

Cancer Slope 

Factor 

(mg/kg/day)-1 

Average daily 

Food & Water 

Exposure1

(mg/kg/day) 

Residential 

Exposure 2

(LADD)

Aggregate 

Exposure(food, 

water and 

residential) 

(mg/kg/day)

Aggregate 

Cancer Risk 3

U.S. Population 6.01 x 10-2 4.7 x 10-5 4.1 x 10-6 5.1 x 10-5 3.1 x 10-6

1 From Table 1. 

2

 Handler LADD (low pressure handwand – highest exposure scenario) is 3.8 x10-7 from Table 2. Home garden post 

application LADD is 2.7 x10-6 from Table 3. Treated turf post app LADD is 1.0 x10-6 from Table 4. Total residential 

exposure is 4.1 x10-6. 3

 Aggregate cancer risks are for the U.S. Population and are calculated by multiplying the cancer slope factor (0.0601) by the 

total exposure. 

Risk Characterization

The aggregate cancer risk estimate associated with exposure to ETU from all EBDCs is 3.1 x 10-6 for the 

general U.S. population. HED is generally concerned when the cancer risk is no longer considered 

negligible, typically when the risk exceeds 3.16 x 10-6. Some aspects of this assessment can be 

considered highly refined; other parts of this assessment can be considered conservative. The 

uncertainties and conservatisms in the assessment are described below. 

The cancer risks in this assessment were quantified using a slope factor taken from a rat carcinogenicity 

study. This screening level approach is generally considered to be conservative because it assumes that 

any dose will lead to some probability of tumor formation, with conclusions on carcinogenicity drawn 

from studies in which animals were dosed at higher levels than those to which people would be exposed. 

The method ignores the body's ability to repair genetic damage when exposed to very low doses of 

toxicants, such as those generally found to pesticide residues in foods. However, further refinement is 

not possible for ETU because of the absence of adequate mechanistic data on tumor formation. 

However, it should also be noted that only rodent toxicity data are available for ETU, with resulting 

toxicity assumed to be similar in humans. While the assumption of a similar toxic response to toxicants 

across species this is generally considered to be a reasonable approach, there are no human 

epidemiological data to either support or refute this assumption. 

The dietary exposure assessment has been refined with the use of monitoring and usage data. 

Monitoring data are available on several commodities (see Table 6), but average field trial data were 

used for most. Generally monitoring data show considerably lower residues than field trials, indicating 

that the residue values used in the assessment are somewhat conservative. 
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Table 6. Comparison of Source of Residue Data for Dietary Risk Assessment 

Monitoring Data (Existing 

Uses Only) Field Trial Data 

Head Lettuce 

Tomatoes 

Cucumbers 

Meat 

Milk 

Potatoes 

Onion 

Corn 

Broccoli 

Dry Beans 

Grape Juice 

Wine 

Almond 

Apple 

Asparagus 

Banana 

Barley 

Sugar Beets 

Endive 

Cabbage 

Canistel 

Cantaloupe 

Carrot 

Cauliflower 

Celery 

Cherimoya 

Chickpea 

Chinese Waxgourd 

Chive 

Collards 

Cottonseed 

Cranberry 

Fig 

Flaxseed 

Garlic 

Ginseng 

Guar 

Honeydew 

Kale 

Kohlrabi 

Leek 

Leaf Lettuce 

Mango 

Mustard Greens 

Oats 

Papaya 

Peanut 

Pear 

Pepper 

Plantain 

Pumpkin 

Quince 

Rice 

Rye 

Safflower 

Sapote 

Shallot 

Sorghum 

Squash 

Sugar Apple 

Turnip Tops 

Walnut 

Watermelon 

Wheat 

Percent crop treated (PCT) information was used for most of the existing uses; however, such 

information was not available for many commodities, resulting in a conservative assessment. Percent 

Crop Treated for New uses (PCTn) data were used to refine the estimates for the proposed new uses of 

mancozeb. It is unlikely that actual PCT for mancozeb will exceed these estimates for mancozeb on 

each of these five crops during the next five years. 

HED assumed that no commodity would be treated with more than one EBDC fungicide, as there are 

label restrictions regarding treatment with multiple EBDCs. Therefore, if the total percent crop treated 

for all EBDCs for a given commodity exceeded 100%, the PCT for the EBDC that showed the lowest 

residues was reduced until the total equaled 100%. For example the PCTn for mancozeb on leaf lettuce 

was 62% and the PCT for maneb on leaf lettuce was 65%. Since the maneb field trials showed higher 

residues of ETU, HED assumed a PCT of maneb 65%, but reduced the PCTn for mancozeb to 35%. It 

is highly unlikely that all lettuce consumed in the US is treated with an EBDC. 

The assessment was highly refined with respect to consideration of the effect of consumer processing on 

residues. Extensive processing data have been submitted, showing the effect of peeling, cooking, 

washing, etc. on ETU residues. Processing factors were applied to every commodity in the assessment. 

The estimated drinking water concentration, 0.2 ppb, is based on a targeted ground water monitoring 

study. 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 

(Figure 3). 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 
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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. 

The assumptions for the residential golfer assessment are refined. The average golfer plays 19 rounds a 

year. However, it is unlikely that the course will have been treated with EBDCs before the rounds. 

Therefore, HED assumed that only one of the 19 rounds will be on an EBDC-treated course. Only tees 

and greens are treated with EBDCs, so HED assumed that only one hour of the round will be on EBDCtreated turf. HED also assumed that the golfer will play for 50 years out of his/her lifetime. 

Relative to other risk assessments completed by the Agency, exposure estimated for ETU overall should 

be considered highly refined, and hazard quantification unrefined, leading to an overall refined 

assessment of risk. In the absence of data showing the mechanism of tumor formation, we recommend 

that risk management decisions be made assuming this is a refined assessment of cancer risk. 

Regulatory Recommendation

Mancozeb 

Sufficient residue data are available to support the proposed uses and tolerances for mancozeb. The 

aggregate human health risks are below the level of concern for mancozeb and the common metabolite 

ETU. Therefore, HED recommends amending 40 CFR 180.176(a) to include the following tolerances: 

 Almond ............................................................................................ 0.1 ppm 

 Almond, hulls ...................................................................................... 4 ppm 

 Broccoli ............................................................................................... 7 ppm 

 Cabbage............................................................................................... 9 ppm 

 Lettuce, head .................................................................................... 3.5 ppm 

 Lettuce, leaf ....................................................................................... 18 ppm 

 Pepper ............................................................................................... 12 ppm 

Note that all of these recommendations, with the exception of almond, are different that the original 

tolerance petition. Since the original petitions, the registrant has altered the proposed use pattern and/or 

formulations, which affected the residues. In addition, HED has used the NAFTA MRL calculator for 

selecting the appropriate regulatory level, leading to additional changes. A discussion on international 

harmonization may be found in the residue reviews cited below. 

Metiram 

Sufficient residue data are available to support the proposed tolerances for metiram. The aggregate 

human health risks are below the level of concern for metiram and the common metabolite ETU. 

Therefore, HED recommends amending 40 CFR 180.217(a) to include the following tolerances: 

 Banana................................................................................................. 3 ppm 

 Grape, wine ......................................................................................... 5 ppm 

Since these tolerances apply only to imported commodities, there should be a footnote for these 
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commodities stating that there are no US registrations as of the publication date. 

Note that the residue definition in 180.217 (a) needs to modified to be in accordance with the 

Reregistration Eligibility Decision (June 2005) as well as the updated guidance on tolerance Definition 

(S. Knizner 5/27/09); the appropriate language follows: 

Tolerances are established for residues of a metiram (a 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), including its metabolites and degradates, in or on the commodities in the 

following table. Compliance with the tolerance levels specified in this paragraph is to be 

determined by measuring only those metiram residues convertible to and expressed in 

terms of the degradate carbon disulfide. 

The recommended tolerance levels are the same as in the revised petition. 

References 

Author Barcode Date Title 

C. Olinger D366141 11/16/10 

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. 

C. Olinger D347074 11/20/07 Clarification of FQPA Factor. 

T. Goodlow 

et. al. D337241 6/14/07 

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

Petition for the Establishment of Import Tolerances on Grapes and 

Bananas. 

T. Goodlow 

et. al. D337241 6/14/07 

Ethylenethiourea (ETU) from EBDCs: Health Effects Division 

(HED) Human Health Risk Assessment of the Common 

Metabolite/Degradate ETU 

D. Davis D327307; 

D327318 6/11/07 

Mancozeb: Human Health Risk Assessment to Support Proposed 

New Uses on Broccoli, Cabbage, Lettuce, Peppers and Almonds. 

PC Code: 014504, Petition No: PP# 4F4333 & PP#4F4324. 

C. Olinger 

D311550; 

D321530; 

D322230; 

D323877 

4/24/07 

Metiram. Petition for the Establishment of Import Tolerances on 

Grape and Banana. Summary of Analytical Chemistry and 

Residue Data. PP# 9E6006 

C. Olinger D326753 4/17/07 

PP# 9E6006 Metiram Acute, Chronic, and Cancer Dietary 

Exposure Assessments for New Tolerances on Imported Grapes 

and Bananas. 

C. Olinger D324878; 

D323879 4/17/07 

PP#4F4324 and 4F4333 Mancozeb Acute, Chronic, and Cancer 

Dietary Exposure Assessments for New Tolerances on Almonds, 

Broccoli, Cabbage, Lettuce, and Peppers 
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Author Barcode Date Title 

C. Olinger D337240 4/17/07 

PP# 9E6006 PP#4F4324 and 4F4333 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. 

C. Olinger D289183 4/5/07 Mancozeb on Almonds. Summary of Analytical Chemistry and 

Residue Data. 

C. Olinger D294203 4/3/07 Mancozeb on Broccoli, Cabbage, Lettuce, and Peppers. Summary 

of Analytical Chemistry and Residue Data. PP# 4F4333 

C. Olinger D283152 11/5/03 

Mancozeb: Anticipated Residues for Dietary Exposure 

Assessment to Support Reregistration. Chemical ID No. 014504. 

DP Barcode No. D283152. 

K. Farwell None 5/28/03 ETHYLENE THIOUREA. 3rd Report of the Hazard Identification 

Assessment Review Committee. TXR NO. 0051924