Ethylene Thiourea Human H ealth Risk Assessment D383971

Page 1 of 8 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 Huma n Health Risk Assessment of the Common Metabolite/Degradate Ethylen e 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 T XR 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 fungi cide mancozeb. BASF has since amended the grape petition to bananas and wine gr apes 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 regist ered for use in the United States that belongs to the EBDC group. HED has previous ly assessed the aggregate exposure to ETU, and most aggregate scenarios were belo w the level of concern, but there wa s some concern for the aggregate cancer assessment (T. Goodlow, D337241, 6/14/07). Si nce the proposed toleran ce on bananas was theEthylene Thiourea Human H ealth Risk Assessment D383971

Page 2 of 8 most significant contributor to the risk, and the asse ssment reflected minimal refinement, the registrant submitted additional information regarding the propos ed use on bananas. In addition the Mancozeb Task Force has submitted additional usage informati on in support of the mancozeb petition. The acute and chronic (non-cancer) assessment has not been modi fied, and will not be further discussed in this assessment. This addendum will only address the a ggregate cancer assessment. A tabular summary of all memoranda discussed in this document and pr epared 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 classifica tion is presented herein.

Treatment with ETU produced increases in tumor incide nce 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 carcinogeni city 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 th e cancer studies/classif ication and hazard characterization may be found in the previous ETU ri sk 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 informati on 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 recen tly reviewed by BEAD (C. Chen and J. Alsadek, 9/16/10, DP Barcode: 360397). The cancer dietary asse ssment 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 aggr egate (food and drinking water) cancer assessment are presented in Table 1. HED is generally concer ned when the cancer risk is no longer considered negligible, typically when the risk exceeds 10 -6 . The aggregate (food and wa ter) 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. Alt hough some inputs into this assessment are highly refined, other inputs are ve ry conservative, as high-end field trial residues were used for some commodities, as well as the assumption of 100% crop treated for several comm odities. The greatest contributors to the dietary exposur e for the cancer assessment we re leafy vegetables, Brassica vegetables, fruiting vegetables, and water.Ethylene Thiourea Human H ealth Risk Assessment D383971

Page 3 of 8 Table 1. Results of Cancer Dietary Exposure Anal ysis 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 concer n. 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 descri ption 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 Dose 2 Cancer Risk 3

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 exposu re days per year/365 days per year)*(50 years of exposure/70 years of life)

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

Table 3. Mancozeb-derived ETU Po stapplication 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 ri sks from the same application rate.

Table 4. Summary of ETU Postapplicatio n Cancer Risks for Adults Exposed to Turf

Activity Application Rate (lb ai/acre) Mancozeb TTR (ug/cm2) ETU TTR (ug/cm2) Transfer Coefficient

(cm 2 /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 -8Ethylene Thiourea Human H ealth Risk Assessment D383971

Page 4 of 8 Aggregate Risk Assessment For the aggregate cancer risk assessment, HED co mbined residential handler and post application exposures for adults exposed to ETU from the home ga rden uses, as well as post application exposures to adults from contact with treated turf during ac tivities such as golfing. The combined residential exposure was then aggregated with dietary e xposure to ETU from food and drinking water and multiplied by the ETU cancer slope factor. The ex isting 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

Exposure 1 (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 multip lying the cancer slope f actor (0.0601) by the total exposure.

Risk Characterization The aggregate cancer risk estimate associated wi th exposure to ETU from all EBDCs is 3.1 x 10 -6 for the general U.S. population. HED is ge nerally 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 conclusion s on carcinogenicity drawn from studies in which animals were dosed at higher levels than those to whic h people would be exposed. The method ignores the body's ability to repair geneti c 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 th at 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 appr oach, there are no human epidemiological data to either s upport or refute this assumption.

The dietary exposure assessment has been refined with the use of monito ring and usage data. Monitoring data are available on se veral commodities (see Table 6), bu t average field trial data were used for most. Generally monitoring data show cons iderably lower residues than field trials, indicating that the residue values used in the assessment are somewhat conservative.Ethylene Thiourea Human H ealth Risk Assessment D383971

Page 5 of 8 Table 6. Comparison of Source of Re sidue 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 exis ting 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 ma ncozeb will exceed these estimates for mancozeb on each of these five crops during the next five years.

HED assumed that no commod ity would be treated with more than one EBDC fungicide, as there are label restrictions regarding treatmen t 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 PC Tn 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 wi th respect to consideration of th e 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 we re 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 wa s 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 con tinuously 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 de tected 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 allEthylene Thiourea Human H ealth Risk Assessment D383971

Page 6 of 8 the other 117 sites. Such higher gr oundwater concentration values, found in private areas in rural areas, are very rare and are unli kely to represent ground water ETU concen trations 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 wi ll 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 assume d 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 th e Agency, exposure estimated for ETU overall should be considered highly refined, and hazard quantific ation unrefined, leading to an overall refined assessment of risk. In the absence of data show ing the mechanism of tumor formation, we recommend that risk management decisions be made assumi ng this is a refined assessment of cancer risk.

Regulatory Recommendation Mancozeb Sufficient residue data are availa ble to support the proposed uses a nd 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 CF R 180.176(a) to include th e 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 alte red the proposed use pattern and/or formulations, which affected the residues. In ad dition, HED has used the NAFTA MRL calculator for selecting the appropriate re gulatory level, leading to additional changes. A discussion on international harmonization may be found in the residue reviews cited below.

Metiram Sufficient residue data are availa ble to support the proposed tolerances for metiram. The aggregate human health risks are below the level of c oncern for metiram and the common metabolite ETU. Therefore, HED recommends am ending 40 CFR 180.217(a) to include the following tolerances:

Banana................................................................................................. 3 ppm Grape, wine ......................................................................................... 5 ppm

Since these tolerances apply only to imported co mmodities, there should be a footnote for theseEthylene Thiourea Human H ealth Risk Assessment D383971

Page 7 of 8 commodities stating that ther e 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 (d ithiocarbamato)] zinc with 1 part by weight ethylenebis [dithiocarbamic acid] bimolecular and trimolecular cyclic anhydrosulfides and disulfides), including its metabolites and degr adates, in or on the commodities in the following table. Compliance with the tolerance le vels 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 th e 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, Ch ronic, 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 PeppersEthylene Thiourea Human H ealth Risk Assessment D383971

Page 8 of 8 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