Document ID: EPA-HQ-OPP-2012-0044-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-05-02T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Mary Waller, (703)-308-9354

TEMPLATE:

United Phosphorus, Inc.

Petition Number:  

	EPA has received a pesticide petition ([1F7935]) from United Phosphorus, Inc., 630 Freedom Business Center, King of Prussia, PA 19406, requesting, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance for residues of
mancozeb in or on the raw agricultural commodity walnuts at 0.75 parts per million (ppm) of carbon disulfide equivalents.  EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of  FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism.  The plant metabolism of mancozeb is understood.  Plant metabolism has been evaluated in five diverse crops, including potato, soybean, sugar beet, tomato, and wheat.  These studies demonstrate that mancozeb is extensively metabolized to natural products (proteins, carbohydrates, lipids, lignins, etc.) with minor amounts of degradation products including ethylenethiourea (ETU), ethyleneurea, ethylene bisisocyanate sulfide, and ethylenediamine.

	2. Analytical method.  Residues of mancozeb are determined by decomposing the residue with a strong acid to release carbon disulfide (CS2).  The CS2 can be measured by gas chromatography or by absorbance of a colored copper dithiocarbamate complex formed by sweeping the CS2 through a trap and into a reaction tube containing a solution of copper acetate and an amine.  Adequate methodology for enforcement is available in the Pesticide Analytical Manual (PAM), Volume II, Methods II and III.

	3. Magnitude of residues.  Residue field trials in California demonstrated that the highest residue in mancozeb equivalents was 0.67 ppm, which translates to 0.40 ppm of mancozeb in CS2 equivalents.  The highest residue will be less than the proposed tolerance of 0.75 ppm of mancozeb in CS2 equivalents.  

B. Toxicological Profile

	1. Acute toxicity.   Mancozeb is not acutely toxic, with Category IV toxicity for the oral, dermal, and inhalation routes.  Mancozeb is not a skin irritant (Category IV) and it is not a skin sensitizer.  Mancozeb is classified as Category III for eye irritation. 

	2. Genotoxicty.   A weight of the evidence evaluation demonstrates that mancozeb is not genotoxic in mammalian systems.   

	3. Reproductive and developmental toxicity. i. Developmental toxicity in the rat.  In the developmental study in rats, the maternal (systemic) no observed adverse effect level (NOAEL) was 32 mg/kg/day, with a maternal lowest observed effect level (LOAEL) of 128 mg/kg/day. The developmental NOAEL was 128 mg/kg/day and the developmental LOAEL was 512 mg/kg/day.  The effects at the LOAEL occurred only at doses that produced significant maternal toxicity, including mortality, and are not considered relevant for human risk assessment.  There were no developmental effects at doses below those which were maternally toxic, so mancozeb was not uniquely toxic to the conceptus.
	ii. Developmental toxicity in the rabbit.  In the developmental study in rabbits, the maternal (systemic) NOAEL was 30 mg/kg/day and the maternal LOAEL was 80 mg/kg/day based on reduced feed intake, weight loss, mortality, and clinical signs.  The developmental NOAEL was greater than 80 mg/kg/day because no effects were seen without severe maternal toxicity.  Mancozeb was not developmentally toxic in this study.
	iii. Reproductive toxicity.  In the 2-generation reproduction study in rats, the maternal (systemic) NOAEL was 6.95/7.47 mg/kg/day males/females and the parental LOAEL was 68.90/79.37 mg/kg/day males/females.  The reproductive NOAEL is greater than or equal to 69.90/79.37 mg/kg/day males/females (the highest dose tested).  There were no adverse reproductive or offspring effects.  Mancozeb does not show reproductive toxicity.  In conclusion, mancozeb is not a reproductive toxicant and developmental effects occurred only at doses that were maternally toxic and the effects are secondary to excessive maternal toxicity. 

	4. Subchronic toxicity.  i. Rat 90-day feeding study.  A subchronic feeding study in rats conducted for 13 weeks had a NOAEL of 9.24/14.98 mg/kg/day in females/males and a LOAEL of 17.82/57.34 mg/kg/day in females/males.  In males, the LOAEL was 57.34 mg/kg/day.  
	ii. Mouse 90-day feeding study.  A 90-day subchronic study resulted in a NOAEL of 18.13/21.68 mg/kg/day in males/females and a LOAEL of 166.9/233.8 mg/kg/day in males/females.
	iii. Dog 90-day feeding study.  A subchronic feeding study in dogs conducted for three months had a NOAEL of 2.98/3.35 mg/kg/day in males/females and a LOAEL of 28.62/28.91 mg/kg/day in males/females.
	iv. Rat 28-day dermal study.  No toxicity, including no changes in thyroid hormones, was seen at the limit dose of 1000 mg/kg/day.  The NOAEL is greater than 1000 mg/kg/day.
	v. Rat 90 day neuropathology study.  A subchronic feeding study in rats conducted for three months had a NOAEL of 8.2 mg/kg/10.5 mg/kg in males/females and a LOAEL of 49.7/63.3 mg/kg in males/females.

	5. Chronic toxicity. . i. Rat.  A 24-month chronic/carcinogenicity study in male and female rats was conducted at 20, 60, 125, or 750 ppm of mancozeb.  The NOAEL was 125 ppm (4.83/6.72 mg/kg/day in males/females) with a LOAEL of 750 ppm (30.9/40.2 mg/kg/day in males/females).  
	ii. Mouse.  A 78-week chronic/oncogenicity study was conducted in male and female mice dosed at 0, 30, 100, or 1000 ppm.  The NOAEL was 100 ppm (13/18 mg/kg/day in males/females) and a LOAEL of 1000 ppm (131/180 mg/kg/day in males/females).  There was no evidence of carcinogenicity.
	iii. Dog.  A 1-year feeding study in dogs resulted in a NOAEL of 50 ppm (1.75 mg/kg/day) for males and 200 ppm (7.02 mg/kg/day) for females.  The LOAEL was 200 ppm (7.26 mg/kg/day) in males and 800 ppm (29.24 mg/kg/day) in females.

	6. Animal metabolism. .  The absorption, distribution, excretion, and metabolism of mancozeb in rats, goats, and hens were investigated.  Following oral administration, mancozeb was rapidly and essentially completely excreted.  The bulk of the residue is incorporated into natural products.  

	7. Metabolite toxicology. The mancozeb metabolite of toxicological concern is ethylenethiourea (ETU).  ETU is classified as a B2 carcinogen with a Q* of 0.06 (mg/kg/day)-1 based on mouse liver tumors and (3/4) scaling factor.  The non-cancer chronic toxicity of ETU is based on a NOAEL of 0.18 mg/kg/day in a chronic dog study.  Using a 1000X safety factor (100X based on inter- and intra-species uncertainty and 10X database uncertainty factor), the cPAD is 0.0002 mg/kg/day.  The acute endpoint is based on a rat developmental study with a NOAEL of 5 mg/kg/day, resulting in an aPAD of 0.005 mg/kg/day with a 1000X safety factor.   The ETU developmental effects are species-specific.  ETU is not developmentally toxic in rabbits, guinea pigs or cats and has equivocal effects in mice and hamsters.

	8. Endocrine disruption. The endocrine system includes the reproductive hormones estrogen and androgens as well as the thyroid hormone system.  Mancozeb and ETU are not known to interfere with reproductive hormones and mancozeb and ETU do not have reproductive toxicity.  While thyroid effects were seen in testing in rodents, it is well known and accepted that rats are more sensitive to thyroid effects than humans.  Mancozeb and ETU are not expected to show thyroid effects at the levels of human or environmental exposure.  Additionally, the chronic risk assessments are based on thyroid effects and the %cPAD is substantially below the level of concern.

C. Aggregate Exposure

	1. Dietary exposure.   The acute and chronic dietary food exposures utilized anticipated residue values from a market basket survey for ethylenebisdithiocarbamates (EBDCs) and ETU and field trial and food processing data when market basket survey data were not available. Field trial data were used for walnuts.  The acute and chronic exposure assessments for mancozeb and ETU derived from mancozeb uses described in this Notice of Filing are from an April 17, 2007 EPA memorandum titled "PP#4F4324 and 4F4333 Mancozeb Acute, Chronic, and Cancer Dietary Exposure Assessments for New Tolerances on Almonds, Broccoli, Cabbage, Lettuce, and Peppers, from Christina L. Olinger to Cynthia Giles-Parker, DP Number 323878 and 323879.  The assessments for ETU from all EBDCs used in this Notice of Filing are described in EPA's April 17, 2007 memorandum titled:  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, from Christine L. Olinger to Cynthia Giles-Parker, DP Barcode: D337240.  The petitioned-for tolerance and the existing mancozeb tolerances in 40 CFR 180.176 were included in EPA's assessments.  EPA used 1% crop treated for mancozeb and 30% crop treated for maneb.  Future exposures will come from 31% crop treated with mancozeb and 0% crop treated for maneb.  Incorporation of this change and use of all of the walnut data described in this petition will not impact the conclusions in the aforementioned EPA documents or the risk assessments described herein.    Numerous refinements can be made with actual percent of crop treated data for some crops and corrections to anticipated residue calculations.  These adjustments will lead to considerable reduction of the acute and chronic exposures.  

	i. Food. Dietary exposure assessments for mancozeb and ETU from mancozeb were conducted using the Dietary Exposure Evaluation Model (DEEM) software with the Food Commodity Intake Database (DEEM-FCID(TM) , Version 1.3), which incorporates consumption data from USDA's Continuing Survey of Food Intakes by Individuals (CSFII), 1994-1996 and 1998.  The exposure and risk assessments described in this Notice of Filing include all crops currently on the mancozeb labels plus walnuts.  For the purposes of this Notice of Filing, exposures calculated by EPA in the above-mentioned documents have been used to describe the acute and chronic exposures.  
	a.  Acute dietary exposure.  Mancozeb.  The acute exposure for mancozeb is for females 13-49 years of age, the only population group of concern.  The acute risk assessment is based only on residues in food because mancozeb residues are not expected in drinking water.  EPA calculated that the exposure to mancozeb in food including all of the crops on the current label and walnuts with 1% crop treated would be only 0.008926 mg/kg/day at the 99.9th percentile.  This is 6.9% of the aPAD.  (76 Fed. Reg. 18912, April 6, 2011)  As described above, use of 31% crop treated for walnuts will not change the overall assessment..
	ETU.  The acute risk assessment for ETU is a risk from food and water for females 13-49 years of age.  For ETU from mancozeb uses, including all crops currently on the mancozeb label and walnuts with 1% crop treated, EPA calculated that the exposure from food only would be 0.00123 mg/kg/day, or 25% of the aPAD.   The ETU exposure for females 13-49 years old from food and water is 0.00356 mg/kg/day, or 71% aPAD. 

	b.  Chronic dietary exposure.  The chronic reference dose for mancozeb is based on a NOAEL of 4.83 mg/kg/day and an uncertainty factor of 1000, resulting in a cPAD of 0.005 mg/kg/day.  The cPAD for ETU is 0.0002 mg/kg/day based on a NOAEL of 0.18 mg/kg/day and an uncertainty factor of 1000, which includes an extra 10X database uncertainty factor.  For food only, the mancozeb chronic (non-cancer) dietary exposure to the general U.S. population is 0.000073 mg/kg/day, or 1.5% cPAD.  For children 1-2 years old, the most highly exposed group, the exposure is 0.000167 mg/kg/day, or 3.3% cPAD.  For ETU derived from mancozeb, the food exposure is 0.00028 mg/kg/day, or 14% cPAD for the U.S. population and 0.000065 mg/kg/day, or 32% cPAD for children 1-2 years old, the most sensitive subgroup.   For food and water, the ETU exposures are 0.000032 mg/kg/day, or 16% cPAD for the U.S. population and 0.000071 mg/kg/day, or 36% cPAD for children 1-2 years old.  

	c.  Cancer dietary exposure.  The theoretical cancer dietary exposure is based on ETU, with a Q* of 0.06 (mg/kg/day)[-1].  The relevant population is the general U.S. population.  The aggregate theoretical cancer risk is from food and drinking water exposures from the general U.S. population and the lifetime average daily dose for golfers, home gardeners and athletes.   EPA calculated a theoretical cancer risk of approximately 3 X 10[-6] for ETU from mancozeb and other EBDC uses.  This risk is in the negligible risk range.  (76 Fed. Reg. 18913, April 6, 2011). EPA also stated that "even if it is assumed that all walnuts in the US are treated, the cancer risk from walnuts is in the range of 1-3 X 10[-9], which is considerably below the level of concern".  (EPA Memorandum July 16, 2009, Christina L. Olinger to Libby Pemberton, DB Barcode D366095).  Therefore, the ETU cancer risk will not increase with establishment of the mancozeb tolerance.    EPA's theoretical cancer risk number includes all of the crops on the maneb label.  All maneb registrations have been cancelled, therefore it is appropriate to calculate the theoretical cancer risk without the maneb crops.  Deletion of the crops only on the maneb label reduces the theoretical cancer risk to 2.2 X 10[-6].  

	ii. Drinking water. i. Mancozeb.  Mancozeb is very short-lived in soil and water and therefore humans are not exposed to mancozeb from either surface water or ground water sources.  
	ii. ETU.  ETU residues were measured in a surface water and ground water monitoring study conducted by the EBDC/ETU Task Force.   From this survey, the estimated ground water concentration (EDWC) for chronic exposure was 0.21 ppb.  The EDWC for chronic surface water exposures was 0.1 ppb.  Based on PRZM/EXAMS modeling, the EDWC of ETU acute exposure was estimated to be 25.5 ppb.  The water concentration of 0.21 ppb was used to estimate the theoretical cancer risk from ground water exposure.       

	2. Non-dietary exposure. i.  Mancozeb.  The registered residential uses of mancozeb are home gardens, golf courses, and sod farms.  EPA aggregated chronic exposure through food with short-and intermediate-term residential exposures to mancozeb (76 Fed. Reg. 18911, April 6, 2011) to determine the short- and intermediate-term risks.  There is no drinking water exposure to mancozeb and there are no long-term residential exposure scenarios for mancozeb.  Therefore, the chronic aggregate risk for mancozeb is only for food.  The mancozeb short and intermediate-term MOEs for adults and toddlers are greater than 1000, thus the MOEs do not raise risk concerns. (76 Fed. Reg. 18913, April 6, 2011).
	ii. ETU.  ETU aggregate exposure sources are from food, drinking water, home gardening, and golfing.  EPA's scenarios for aggregate exposures from these applications have been described (id.).  The chronic ETU exposures are from food and water only because golfing and toddler exposures are short-term.  The aggregate chronic exposure to ETU from food and water is 58% of the cPAD for children 1-2 years old, the most sensitive subpopulation.  The MOE's for ETU short and intermediate-term risks for adults and toddlers are greater than 1000, thus the MOEs do not raise risk concerns. (id.)

D. Cumulative Effects

	The cumulative effects from mancozeb and the other EBDC chemicals are from ETU.  EPA concluded that mancozeb does not share a common mechanism of toxicity with other substances.  EPA calculated the acute and chronic aggregate, cumulative dietary assessment for ETU in an April 17, 2007 document, titled 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, from Christine L. Olinger to Cynthia Giles-Parker.  The ETU cumulative aggregate dietary risk from food and water is 87% of the aPAD.  The aggregate cumulative chronic risk estimate is 83% of the cPAD for food alone and 86% for food and water combined for the most sensitive subgroup, children ages 1-2.  For the general U.S. population, the ETU exposure is 28% of the cPAD for food alone and 30% cPAD for food and water.  As described above, the aggregate, cumulative theoretical cancer risk is in the negligible risk range.  Mancozeb is the only EBDC with registrations that have residential exposures.  Thus, the risks for short/intermediate exposures from mancozeb are also the cumulative exposures for residential uses.  

E. Safety Determination

	1. U.S. population. Based on the risks described above, there is a reasonable certainty that no harm will result to the general population from aggregate exposures to mancozeb and aggregate cumulative exposures to ETU.  The MOEs for short and intermediate term exposures do not raise a risk concern.

	2. Infants and children. The risk assessments demonstrate that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to mancozeb residues or from cumulative aggregate exposure to ETU residues.  

F. International Tolerances

	The Codex Alimentarius tolerances are established for the dithiocarbamate group rather than for mancozeb.  There are no proposed or established Codex tolerances for walnuts in the dithiocarbamate group.