Page 1 of 62 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES

Date: 6/11/07

MEMORANDUM

SUBJECT: Mancozeb: Human Health Ri sk Assessment to Support Proposed New Uses on Broccoli, Cabbage, Lettuce, Peppers and Almonds. PC Code: 014504, Petition No: PP# 4F4333 & PP#4F4324. DP Barcode: D327307 & D327318. Risk Assessment Type: Single Chemical Aggregate.

FROM: Donna Davis, Risk Assessor Reregistration Branch 1 Health Effects Division (7509P)

AND

Timothy C. Dole, CIH, Industrial Hygienist Kit Farwell, D.V.M. Christine L. Olinger, Chemist Reregistration Branch 1 Health Effects Division (7509P)

THROUGH: Whang Phang, Branch Senior Scientist Michael S. Metzger, Chief Reregistration Branch 1 Health Effects Division (7509P)

TO: Cynthia Giles-Parker, Branch Chief Mary Waller, Risk Manager Lisa Jones, Risk Manager Fungicide-Herbicide Branch Registration Division (7505P)

Attached please find the human health ri sk assessment for the active ingredient, mancozeb, to support requested new uses on broccoli, cabbage, lettuce, peppers and almonds. This document addresses risks fr om exposure to mancozeb and mancozebderived ethylenethiourea (ETU ) only. A separate assessment addressing risk from ETU derived from all ethylene bisdithiocarba mate (EBDC) pesticides is forthcoming.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 2 of 62 Table of Contents

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

2.0 Ingredient Profile .................................................................................................. 8 2.1 Summary of Registered/Proposed Uses .......................................................... 8 2.2 Structure and Nomenclature ........................................................................... 9 2.3 Physical and Chemical Properties ................................................................ 10

3.0 Hazard Characterization .................................................................................... 11 3.1 Toxicology Profile ........................................................................................... 11 3.2 Mancozeb: Recommendation for a Developmental Neurotoxicity Study and Rationale for UF DB ................................................................................ 16 3.3 Summary of Toxicological Doses a nd Endpoints for Mancozeb and ETU for Use in Human Risk Assessments ........................................................... 17 3.4 Endocrine Disruption ..................................................................................... 20

4.0 Public Health Data .............................................................................................. 20

5.0 Dietary Exposure/Risk Characterization ......................................................... 21 5.1 Pesticide Metabolism and Environmental Degradation .............................. 21 5.2 Dietary Exposure and Risk ............................................................................ 30

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................ 35 6.1 Residential Handler Exposures and Risks .................................................... 36 6.2 Residential Postapplication Exposure ........................................................... 38 6.3 Spray Drift ....................................................................................................... 43

7.0 Aggregate Risk Assessments and Risk Characterization ................................ 44 7.1 Acute Aggregate Risk ..................................................................................... 46 7.2 Short/Intermediate-Term Aggregate Risk ................................................... 46 7.3 Long-Term (Chronic) Aggregate Risk .......................................................... 51 7.4 Cancer Aggregate Risk ................................................................................... 51 7.5 ETU Aggregate Exposure from All Sources ................................................. 52

8.0 Cumulative Risk Characterization/Assessment ............................................... 52

9.0 Occupational Exposure/Risk Pathway .............................................................. 53 9.1 Occupational Handler Exposures and Risks ............................................... 53 9.2 Occupational Postapplication Exposures and Risks .................................... 56Mancozeb Human Health Risk Assessment D327307 & D327318

Page 3 of 62 10.0 Data Needs and Label Recommendations ........................................................ 59 10.1 Toxicology ........................................................................................................ 59 10.2 Residue Chemistry .......................................................................................... 59 10.3 Occupational and Residential Exposure ....................................................... 60

11.0 Environmental Justice .................................................................................... 60

12.0 Regulatory Recommendations ........................................................................... 60

References: ....................................................................................................................... 61Mancozeb Human Health Risk Assessment D327307 & D327318

Page 4 of 62 1.0 Executive Summary

Background Dow AgroSciences LLC has proposed to amend the use pattern for the 80% wettable powder (WP) formulation of mancozeb (Dithane® M45 Fungicide; EPA Reg. No. 62719-387) to include uses on broccoli, cabba ge, lettuce, peppers and almonds. In conjunction with the proposed new uses, Do w AgroSciences has proposed, in petitions PP#4F4333 (broccoli, cabbage, lettuce a nd peppers) and PP#4F4324 (almonds), the establishment of permanent tolerances for re sidues of mancozeb in/on the following raw agricultural commodities:

Broccoli.......................................................................13 ppm Cabbage.......................................................................10 ppm Lettuce........................................................................10 ppm Peppers........................................................................7 ppm Almond nuts........................................................................................0.1 ppm Almond hulls.................................................................10 ppm

Mancozeb Toxicology Considerations Mancozeb is not acutely toxic via the oral, dermal or inhala tion routes of exposure. Further, mancozeb is not a skin irritant nor is it a skin sensitiz er, although it does cause mild eye irritation. The findings in multiple studies demonstrate that the thyroid is a target organ for mancozeb. Thyroid toxicity was manifested as alternations in thyroid hormones, increased thyroid weight, and mi croscopic thyroid lesi ons (mainly thyroid follicular cell hyperplasia). In a subchroni c study in the rat, neuropathology was seen microscopically (injury to peripheral nerves) with associated clini cal sings (abnormal gait and limited use of rear legs) a nd loss of muscle mass. Deve lopmental defects in the rat developmental toxicity study included hydrocepha ly, skeletal system defects, and other gross defects. Abortions occurred in the rabbit developmental toxi city study at the high dose.

There is a data gap for a developmental neurotoxicity study with mancozeb. An additional uncertainty factor of 10X is applie d to account for this data gap. An acute neurotoxicity study has recently been received and is under review. Preliminary review indicates no concerns for neurotoxicity at the high dose of 2000 mg/kg.

Based on the lack of evidence of pre- and/ or postnatal susceptib ility resulting from exposure to mancozeb, and considering the la ck of residual uncerta inties, no additional FQPA Safety Factor beyond the 10X applie d to account for the missing studies is required.

Mancozeb doses and endpoints are summarized below.

Exposure Route, Duration Mancozeb Dose in mg/kg/day (study/effects) Acute dietary (females 13-49) NOAEL of 128 (Developmental rat/hydrocephaly, malformations) Acute dietary (gen. US pop.) No applicable endpoint/dose identified Chronic dietary (gen. US pop.) NOAEL of 4.83 (Rat chroni c/thyroid effects) Incidental oral, any duration NOAEL of 9.24 (Subchronic oral ra t/decreased thyroxine)Mancozeb Human Health Risk Assessment D327307 & D327318

Page 5 of 62 Dermal, short-, intermediate-term Quantitation not required (no toxicity at limit dose in dermal tox study) Dermal, long term NOAEL of 4.83 (Rat or al chronic/carcinogeni city/thyroid effects) Inhalation, any duration NOAEL of 21 (Sub chronic inhalation rat/thyroid hyperplasia and decreased thyroxine in females)

Combined Uncertainty factor s (UFs) for mancozeb dietary assessments are 1000X. The level of concern (LOC) for the residential and aggregate assessments is 1000. The LOC for the occupational risk assessment is 100. Mancozeb dermal absorption is 1%. Inhalation absorption is 100%.

ETU Toxicology Considerations In addition to assessing risk from exposure to mancozeb, this assessment also considers risks from exposure to mancozeb-deriv ed ETU, a degradate of mancozeb.

HED has relied on a combination of guidelin e data and several studies in the open literature to assess hazard for ETU. The thyroid is a targ et organ for ETU. Thyroid toxicity in subchronic and ch ronic rat, mouse, and dog studi es included decreased levels of T 4 , changes in T 3 levels, compensatory increases in levels of TSH, increased thyroid weight, and microscopic thyroi d changes, chiefly hyperplasia. Overt liver toxicity was observed in one chronic dog study. Developmen tal defects in the rat developmental toxicity study were similar to those seen with mancozeb, and included hydrocephaly and related lesions, skeletal system defects, and other gross defects

Due to the limited nature of the toxicol ogical database for ETU based on guideline studies as well as the need for a developm ental neurotoxicity study, and a comparative thyroid assay, HED applied a database uncer tainly factor of 10X to the dietary, residential and aggregate risk assessments for ETU. No additional FQPA safety factor beyond the 10X database uncertainty factor is required since teratogenic effects seen in the database are well characterized, the dose- response relationship is well characterized and the doses selected for risk assessment addr ess concerns for developmental toxicity.

ETU endpoints used for risk assessment are summarized below.

Exposure Route, Duration ETU Dose in mg/kg/day (study/effects) Acute dietary (females 13-49) NOAEL of 5 (Dev elopmental rat/developmental brain defects) Acute dietary (gen. US pop) No applicable endpoint/dose identified Chronic dietary (gen. US pop.) NOAEL of 0.18 (Chronic dog/thyroid toxicity) Incidental oral, any duration NOAEL of 7 (4-week Dog/thyroid toxicity) Oral, short/intermediate-term NOAEL of 5 (Dev elopmental rat/developmental brain defects) Dermal, short/intermediate-term Toddlers NOAEL of 7 (4-week Dog/thyroid toxicity) Dermal, short/intermediate- term Females 13-49 yrs NOAEL of 5 (Developm ental rat/developmental brain defects) Dermal, Long-Term NOAEL of 0.18 (Chronic dog/thyroid toxicity) Inhalation, Short/Int-Term NO AEL of 5 (Developmental rat/developmental brain defects) Inhalation, Long-Term NOAEL of 0.18 (Chronic dog/thyroid toxicity)

Combined UFs for dietary assessmen ts are 1000X. The level of concern (LOC) for ETU residential and aggregate assessments is 1000. The LOC for occupatio nal assessments is 100. 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 ex posure are similar for similar durations.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 6 of 62 Residue Chemistry Considerations Provided the requested label revisions are made to restrict the use of “U-boom” type devices and to omit the requirement for a surf actant as part of the almond use pattern, there are no residue chemistry deficiencies th at would preclude the establishment of the requested tolerances or granti ng of the requested registrations

. Analytical methods are available for the enforcement of toleran ces for the plant commodities which are the subject of this request. Adequate crop field trial data have been submitted to support the requested new uses of the WP formulation of mancozeb on brocco li, cabbage, lettuce, peppers and almonds. HED notes that the data submitted would not only support the use of the WP formulation as requested in this petition, but would also support the use of a dry flowable formulation on the same crops with the same use patterns and restrictions.

International Harmonization HED has recommended that all tolerances for the EBDC pesticides be expressed in terms of CS 2 , therefore, harmonizing the toleran ce definition with the Codex tolerance expression. However, the actua l tolerance levels for cabbage , head lettuce, leaf lettuce peppers and almond hulls cannot be harmoni zed with current Codex values either because U.S. field trial data values exceed ed the Codex MRL or because the Codex MRL was significantly higher than that recommended in the U.S.

Drinking Water Considerations Residues of mancozeb are not expected in ground or surface water. However, mancozeb’s metabolite, ETU, is highly water soluble and may reach both surface and ground water under some conditions. ETU su rface water estimated drinking water concentrations (EDWCs) were based bot h on PRZM-EXAMS modeling information and available monitoring data.

Dietary Risk Assessments Probabilistic acute dietary exposure and risk assessments were conducted for mancozeb and ETU incorporating maximum percent cr op treated or maximum projected percent crop treated information, field trial or monitoring data, and processing and cooking factors. No acute dietary risks of concer n were identified for either mancozeb or mancozeb-derived ETU.

The chronic dietary exposure and risk asse ssments (noncancer and cancer) for mancozeb and mancozeb-derived ETU incorporated average values based either on field trial data or monitoring data and average pe rcent crop treated data or av erage projected percent crop, as well as processing and cooking factors. No chronic noncancer risks of concern were identified for mancozeb or mancozeb-derived ETU. Further, the estimated cancer risk for food alone and aggregated food a nd water are not of concern.

Residential Exposure and Risk No new residential uses are bei ng added to the label as a resu lt of the actions that are the subject of these two petitions. However, in light of the reconsideration of the toxicity data requirements for mancozeb, the reside ntial exposures and risks for mancozeb and mancozeb-derived ETU were revisited. All residential exposure scenarios had MOEsMancozeb Human Health Risk Assessment D327307 & D327318

Page 7 of 62 that were above the level of concern of 1000, with the exception of in cidental oral risks for toddlers exposed to transplanted turf w ith a PHI of 3 days. Based on the current LOC, a PHI of 5 days would be required to a ssure that incidental oral risks to toddlers exceeded the LOC of 1000.

Aggregate Risk Assessments HED conducted acute, short a nd intermediate term and chronic non cancer aggregate assessments for mancozeb and mancozeb-der ived ETU, as well as a cancer aggregate assessment for mancozeb-derived ETU. A ssuming a 5-day PHI for the existing use on sod farm turf, there are no aggregate risks of concern for mancozeb or mancozeb-derived ETU.

Occupational Exposure and Risk HED conducted occupational exposure and risk assessments for the proposed new uses. Provided the WP label includes a requirement for a PF5 respirator, there are no risks of concern. HED notes that the occupational risks are significantly lower with the dry flowable (DF) formulation and that a resp irator would not be required for the DF formulation.

Environmental Justice Considerations Potential areas of environmental justice concer ns, to the extent possi ble, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898.

Review of Human Research This risk assessment does not rely on any da ta from studies in which human subjects were intentionally exposed to a pesticide or other chemical.

Data Gaps The following residue chemistry data needs have been identified and should be resolved with these new uses.

• The label should be amended to prohibit the use of a “U-boom” application device.

• The proposed use for almonds must be amended to remove the instruction to add a surfactant to the spray mixture

• The petitioner should provide amended Section Fs to express the tolerances as carbon disulfide, and change the proposed levels to broccoli, 7 ppm; cabbage, 9 ppm; head lettuce, 3.5 ppm; leaf lettuce, 18 ppm; pepper, 12 ppm: almond hulls, 4 ppm.
Additional data gaps for mancozeb and ETU we re identified in the RED are summarized in Section 10.0. Those data remain outstanding.

Regulatory Recommendations Provided the existing label for the sod farm turf use of mancozeb is revised to stipulate an 5-day PHI, there is nothing in this manco zeb specific risk assessment to preclude the establishment of the requested tolerances at the levels stipulated below.

Further, HED notes that the new uses that are the subject of th is action have beenMancozeb Human Health Risk Assessment D327307 & D327318

Page 8 of 62 included in the forthcoming ETU aggregat e risk assessment. The ETU aggregate assessment considers exposure and risk from ETU derived from all existing and pending uses of the EBDC pesticides. The addition of these new mancozeb uses does not result in aggregate ETU exposures or risks of concer n when considered with the existing and pending uses of EBDC pesticides.

Provided the requested label and Section F re visions are made as noted above under data gaps, HED recommends the following tolera nce levels based on the available data:

Broccoli................................................................................................................... 7.0 ppm Cabbage................................................................................................................... 9.0 ppm Lettuce, head ........................................................................................................... 3.5 pp m Lettuce, leaf.............................................................................................................. 18 ppm Pepper ...................................................................................................................... 12 ppm Almond.................................................................................................................... 0.1 ppm Almond, hulls.......................................................................................................... 4.0 ppm

2.0 Ingredient Profile

Mancozeb is a member of the EBDC group of fungicides and is currently registered for use on a variety of fruit, vegeta ble, nut, and field crops.

2.1 Summary of Registered/Proposed Uses

The petitioner is proposing to add uses on br occoli, cabbage, lettuce, pepper and almonds to the product label for the 80% WP (E PA Reg. No. 62719-387) formulation only. The proposed use directions for broccoli, ca bbage, lettuce, pepper and almonds are summarized in Table 2.1, below.

Table 2.1 Summary of Directions for New Uses of 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 (PP#4F4333)

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 (PP#4F4333)

Postemergence Broadcast 80% WP 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.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 9 of 62 Table 2.1 Summary of Directions for New Uses of 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

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 (PP#4F4333)

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. Postemergence Broadcast 80% WP

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. Almonds (PP#4F4324)

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. 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

The chemical structures and nomenclature for mancozeb and its major metabolite, ethylenethiourea (ETU) are pres ented in Table 2.2, below.

Table 2.2 Mancozeb and ETU Structures and Nomenclature

Chemical structure

N H S S

N H S Mn

S Zn

x y

Common name MancozebMancozeb Human Health Risk Assessment D327307 & D327318

Page 10 of 62 Table 2.2 Mancozeb and ETU Structures and Nomenclature Company experimental name Not applicable IUPAC name manganese ethylenebis(dithiocarba mate)(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 End-use product (EP) 80% WP (Dithane® M45 Fungicide; EPA Reg. No. 62719-387)
Chemical structure of ETU metabolite

N H NH S

Ethylenethiourea

2.3 Physical and Chemical Properties

Mancozeb is a coordination product of zi nc ion and maneb (manganese ethylenebisdithiocarbamate), which contains 20% manganese and 2.5% zinc. Technical mancozeb is a yellowish powder with a negligible vapor pressu re at 20 °C. Mancozeb is practically insoluble in water, and most organic solvents. Mancozeb decomposes in acid and alkaline conditions, with heat, and upon exposure to moisture and air. Other identifying codes and ch aracteristics include:

Empirical Formula: (C 4 H 6 MnN 2 S 4 ) x (Zn) y Molecular Weight: (265.3) x + (65.4) y CAS Registry No.: 8018-01-7 PC Code: 014504

The physicochemical properties of mancozeb are summarized in table 2.3, below.

Table 2.3 Physicochemical Properties of Mancozeb.

Parameter Value Reference Melting point/range Decomposes at 150 oC pH 6.5 (25% slurry in water) Density 0.41 g/cc (packed) Water solubility 1.1 μ g/mL at room temperature RCB No. 4368, 11/9/88, G. Makhijani

Solvent solubility Insoluble in most organic solvents DEB No. 4689, 12/16/88, G. Makhijani Vapor pressure Not applicable; negligible RCB No. 4368, 11/9/88, G. Makhijani Dissociation constant, pK a Not applicable; does not dissociate DEB No. 4750, 1/24/89, G. Makhijani Octanol/water partition coefficient, Log(K OW ) 3.24 at room temperature RCB No. 4368, 11/9/88, G. Makhijani UV/visible absorption spectrum Not availableMancozeb Human Health Risk Assessment D327307 & D327318

Page 11 of 62 3.0 Hazard Characterization

3.1 Toxicology Profile

D317371, 6/3/2005, K. Farwell D317369, 6/3/2005, K. Farwell

The hazard characterization for mancozeb and its major metabolite, ETU is discussed in detail in the document entitled Mancozeb. Health Effects Division (HED) Human Health Risk Assessment to Support Reregistration (D317371, K. Farwell, 6/3/2005). Revised mancozeb endpoints and data gaps are de scribed in a separate memo entitled Mancozeb Toxicity Endpoints for Risk Assessment (D317369, K. Farwell, 6/3/2005). The ETU data requirements and uncertainty factors outlined in the 6/3/2005 risk assessment remain unchanged. However, the data requirements and uncertainty factors for the mancozeb risk assessment document have been revised as noted in Section 3.1 below. The hazard characterizations for both mancozeb a nd ETU are briefly summarized below.

Mancozeb Mancozeb is not acutely toxic via the oral, dermal or inhala tion routes of exposure. Further, mancozeb is not a skin irritant nor is it a skin sensitiz er, although it does cause mild eye irritation. The findings in multiple studies demonstrate that the thyroid is a target organ for mancozeb. Thyroid toxicity was manifested as alternations in thyroid hormones, increased thyroid weight, and mi croscopic thyroid lesi ons (mainly thyroid follicular cell hyperplasia). These effects are due to the ETU metabolite. In a subchronic study in the rat, neuropathology was seen (inj ury to peripheral nerv es) microscopically with associated clinical sings (abnormal ga it and limited use of rear legs) and loss of muscle mass. An acute neurotoxicity study has recently been received and is under review. Preliminary review indicates no con cerns for neurotoxicit y at the high dose of 2000 mg/kg. Other toxicity included increases in bilateral retinopathy in the chronic rat study. Elevated cholesterol and a mild, regene rative, anemia occurr ed in subchronic and chronic dog studies.

Mancozeb is rapidly absorbed and eliminated in the urine. In oral rat metabolism studies with radiolabelled mancozeb and other EBDCs, an average 7.5% in vivo metabolic conversion of EBDC to ETU occurred, on a we ight-to-weight basis. Metabolism data indicate mancozeb does not bio-accumulate. Mancozeb has been tested in a series of in vitro and in vivo genotoxicity assays, which have s hown that it exhibits weak genotoxic potential.

Thyroid follicular cell adenomas and carcinom as were increased in high-dose males and females in the combined rat toxicity/carci nogenicity study with mancozeb. Doses in a mouse study were too low to assess carcinogeni city, and there were no treatment-related changes in tumor rates. Hist orically, mancozeb’s potential for carcinogenicity has been based on its metabolite ETU, which is clas sified as Group B2, with a cancer potency factor [Q 1 *, 0.0601 (mg/kg/day) -1 ] for risk assessment. Because mancozeb is known to be converted to ETU, it has also been classi fied as Group B2 for carcinogenicity, and theMancozeb Human Health Risk Assessment D327307 & D327318

Page 12 of 62 ETU cancer potency factor has been used in past and current risk assessments for assessing cancer risk associated with mancozeb uses.

There is a data gap for a developmental neurotoxicity study with mancozeb. An additional uncertainty factor of 10X is a pplied to account for this data gap.

Developmental defects in the rat developm ental toxicity study in cluded hydrocephaly, skeletal system defects, and other gro ss defects which occurred at a dose causing maternal mortality and did not indicate increased susceptibil ity of offspring. Abortions occurred in the rabbit developmental toxicity study at the high dose which also caused maternal mortality, and there was no indication of enhanced susceptibility of offspring in the rabbit. There was no evidence of reproductive toxicity in the 2-generation reproduction study in rats. Based on the lack of evidence of pre- and/or postnatal susceptibility resulting from exposure to manc ozeb, and considering the lack of residual uncertainties, no additional FQPA Safety Factor beyond the 10X applied to account for the missing studies is required.

ETU HED has relied on a combination of guidelin e data and several studies in the open literature to assess hazard for ETU . ETU is not acutely toxic via the dermal or inhalation routes of exposure. There is no data on acute oral toxicity. ETU is not a skin or eye irritant. The thyroid is a target organ for ETU. Thyroi d toxicity in subchronic and chronic rat, mouse, and dog studies included decreased levels of T 4 , changes in T 3 levels, compensatory increases in levels of TSH, increased thyroid weight, and microscopic thyroid changes, chiefly hyperplasia. Overt liver toxicity was observed in one chronic dog study. Developmental defects in the rat de velopmental study were similar to those seen with mancozeb, and included hydrocepha ly and related lesions, skeletal system defects, and other gross defects

Due to the limited nature of the toxicol ogical database for ETU based on guideline studies as well as the need for a developm ental neurotoxicity study, and a comparative thyroid assay, HED applied a database uncer tainly factor of 10X to the dietary, residential and aggregate risk assessments for ETU. No additional FQPA safety factor beyond the 10X database uncertainty factor is required since teratogenic effects seen in the database are well characterized, the dose- response relationship is well characterized and the doses selected for risk assessment addr ess concerns for developmental toxicity.

The results of acute toxicity testing for ma ncozeb are shown in Table 3.1.1, below. A toxicity profile for mancozeb technical is shown in Table 3.1.2, below.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 13 of 62 Table 3.1.1 Acute Toxicity Data for Mancozeb

Guideline No. Study Type MRID # Results Tox. Category

870.1100 Acute Oral 00142522 LD 50 > 5000 mg/kg IV

870.1200 Acute Dermal 00142522 LD 50 > 5000 mg/kg IV

870.1300 Acute Inhalation 00142522 LC 50 > 5.14 mg/L IV
870.2400 Eye Irritation 00142522 corneal involvement clearing in < 7 days III

870.2500 Skin Irritation 00142522 Negative IV
870.2600 Dermal Sensitization 40469501 Negative N/A
870.6100 acute delayed neurotox (hen) none
870.6200 acute neurotoxicity Study recently submitted & under review

Table 3.1.2. Toxicity Profile for Mancozeb Technical

Study Type [Guideline #] Doses MRID No. Results

Subchronic feeding - rat [870.3100] [males: 1.78, 3.49, 7.42, 14.98, 57.34 mg/kg/day] [females: 0, 2.20, 4.38, 9.24, 17.82, 74.64 mg/kg/day] 00261536/ Acceptable NOAEL=9.24/14.98 mg/kg/day in females/males LOAEL=17.82 in females/males based on decreased serum thyroxine. In males, body weight decrements, changes in thyroid hormones and liver enzymes, mi croscopic changes in liver and thyroids, increased absolute and relative thyroid weights, and increased relative liver weights were observed at the LOAEL of 57.34 mg/kg/day.
Subchronic Feeding - mouse [870.3100] [males: 0, 1.78, 18.13, 166.9, or 1662.5 mg/kg/day] [females: 0, 2.34, 21.68, 233.8, or 2160.2 mg/kg/day] 00259888 NOAEL=18.13/21.68 mg/kg/day in males/females LOAEL=166.9/233.8 mg/kg/day in males/females, based on microscopic lesions of thyroid follicular cell hypertrophy or hyperplasia in females and decreased liver MFO enzyme activity in males.

Subchronic Feeding - dog [870.3150] [males: 0, 0.29, 2.98, 28.62, 101.53 mg/kg/day] [females: 0, 0.32, 3.35, 28.91, 108.67 mg/kg/day] 00261537 NOAEL=2.98/3.35 mg/kg/day in males/females. LOAEL =28.62/28.91 mg/kg/day in males/females, based on dehydration, decreased body weights and food consumption, anemia, lymphoid depletion of the thymic cortex, elevated cholesterol and prostate hypogenesis.
28-Day Dermal Toxicity - rabbit [870.3200] [0, 10, 100, or 1000 mg/kg/day] 40588201 NOAEL ≥ 1000 mg/kg/day [HDT] in males and females.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 14 of 62 Table 3.1.2. Toxicity Profile for Mancozeb Technical

Study Type [Guideline #] Doses MRID No. Results

90-Day Inhalation Toxicity - rat [870.3465] [0, 0.018, 0.079, or 0.326 mg/L] 00159471 NOAEL=0.079 mg/L LOAEL=0.326 mg/L based upon body weight decrements in males, thyroid hyperplasia in females, and decreased thyroxine in females.
Subchronic Neuropathology - rat [870.6100] [males: 0, 1.35, 8.21, 49.7, or 339 mg/kg/day] [females: 0, 1.67, 10.5, 63.3, or 412 mg/kg/day] 42034101 NOAEL=8.21/10.5 mg/kg/day in males/females. LOAEL=49.7/63.3 mg/kg/day in males/females, based on microscopic evidence of peripheral nerve damage and decreased body weight gain in females.

Chronic Oral Toxicity - rat [870.4100] [males: 0, 0.77, 2.33, 4.83, or 30.9 mg/kg/day] [females: 0, 1.06, 3.06, 6.72, or 40.2 mg/kg/day] 41903601 NOAEL=4.83/6.72 mg/kg/day in males/females. LOAEL =30.9/40.2 mg/kg/day in males/females, based on changes in thyroid hormone levels, microscopic thyroid changes, changes in thyroid weights and bilateral retinopathy.
Chronic Oral Toxicity - dog [870.4100] [males: 0, 1.75, 7.26, 27.26, 53.52 mg/kg/day] [females: 0, 1.84, 7.02, 29.24, or 59.72 mg/kg/day] 41810501 NOAEL in males=1.75 mg/kg/day; LOAEL in males=7.26 mg/kg/day, based on decreased body weight gain. NOAEL in females=7.02 mg/kg/day, LOAEL in females=29.24 mg/kg/day, based on anemia.
Carcinogenicity - mouse [870.4200] 0, 30, 100, or 1000 ppm [males: 0, 4, 13, or 131 mg/kg/day] [females: 0, 5, 18, or 180 mg/kg/day] Much of the mancozeb degraded to ETU by weeks 52-80. 41981801 NOAEL for systemic toxicity=100 ppm. LOAEL=1000 ppm based on minor body weight decrements and changes in thyroid hormone levels. Instability of test material from weeks 52-80, when much of the mancozeb had degraded to ethylenethiourea (ETU). No treatment-related increase in tumors occurred. Dosing considered inadequate for assessing the carcinogenic potential due to minimal toxicity in the study. Classified unacceptable.
Developmental Toxicity - rat [870.3700] 0, 2, 8, 32, 128, or 512 mg/kg/day 00246663 Maternal NOAEL=32 mg/kg/day. Maternal LOAEL=128 mg/kg/day, based on decreased food consumption, body weight, and body weight gains.

Developmental NOAEL=128 mg/kg/day. Developmental LOAEL=512 mg/kg/day, based on hydrocephaly, gross developmental defects, skeletal defects, cryptorchidism, abortions, increased resorptions, and decreased fetal weight.
Developmental Toxicity - rabbit [870.3700] 0, 10, 30, or 80 mg/kg/day 40433001 Maternal NOAEL=30 mg/kg/day. Maternal LOAEL=80 mg/kg/day, based on abortions, mortality, and clinical signs.

Developmental NOAEL=30 mg/kg/day. Developmental LOAEL=80 mg/kg/day, based on abortions.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 15 of 62 Table 3.1.2. Toxicity Profile for Mancozeb Technical

Study Type [Guideline #] Doses MRID No. Results

2-Generation Reproduction - rat [870.3800] [males: 0, 1.73, 6.95, 68.90 mg/kg/day] [females: 0, 1.83, 7.47, or 79.37 mg/kg/day] 41365201 Parental NOAEL=6.95/7.47 mg/kg/day males/females Parental LOAEL=68.90/79.37 mg/kg/day males/females, based on body weight decrements, increased relative thyroid weights, and increased incidence of thyroid follicular cell hyperplasia.

Reproductive NOAEL ≥ 69.90/79.37 mg/kg/day [HDT] males/females. No adverse reproductive or offspring effects were attributed to mancozeb.
Chronic Toxicity/Carcinogenicity - rat [870.4100] 41903601 See chronic toxicity in rats, above.

Developmental Neurotoxicity - rat [870.6300] none N/A

Gene Mutation [870.5100, 870.5300] - Mutagenicity: Salmonella

- in vitro mammalian: CHO/HGPRT - mouse host-mediated 00259044 00259044 00259044 Negative with and without activation Negative with and without activation Negative
Cytogenetics/Structural Chromosomal Aberrations [870.5900, 870.5385] - CHO cells

- in vivo bone marrow cytogenetics - Mouse micronucleus assay 40810202 00259044 40788901 Positive (stronger respons e without activation) Negative Negative
Other Genotoxic Effects [870.5550] - Unscheduled DNA Synthesis- hepatocytes - Unscheduled DNA Synthesis- HeLa cells - SCE in CHO cells

- in vitro transformation 10T1/2 cell

- in vitro transformation/promotion10T1/2 cell - DNA damage in E. coli pol A 40611701 40810205 00259044 00259044 00259044 40810201 Negative Pos with/without activation, not concentration dependent Positive without activation, negative with activation Negative Negative Positive (stronger respons e without activation)

Metabolism [870.7485] 00262834 00262835 41656301 Rapidly absorbed after oral administration, highest accumulations in thyroid. No significant overall accumulation in the body in e ither rat or mouse study.

Dermal Penetration 870.7600 40955401 00250063 Dermal absorption = 1%

Domestic Animal Safety 870.7200 NoneMancozeb Human Health Risk Assessment D327307 & D327318

Page 16 of 62 3.2 Mancozeb: Recommendation for a Developmental Neurotoxicity Study and Rationale for UF DB
As part of the reevaluation of mancozeb to support the new uses that are the subject of this action, the uncertainty factors and need for a DNT study were reviewed for compliance with current policy. The proposed 158 Guidelines state that a DNT study should be required using a weight-of-the-ev idence approach when a pesticide causes neuropathology in adult animals.

Mancozeb had been evaluated by the Hazard Identification Assessment Review Committee (HIARC) in 1999, 2001, and 2003. At th e last meeting of the committee in 2003, the HIARC removed the requirement fo r a DNT study with mancozeb which had been levied in previous HIARC meeti ngs. In 2003, the HIARC removed the DNT requirement because the hydrocephaly occurr ing in the mancozeb developmental study was attributed to ETU, a mancozeb metabolite . Peripheral nerve injury which occurred in the subchronic neuropathology study with mancozeb was not considered sufficient indication for a developmental neurotoxi city with mancozeb at that time.

The EBDC team reconsidered the peripheral nerve injury observed in the subchronic neurotoxicity study with mancozeb as part of its reevaluation. The peripheral nerve injury is characterized as a myelinopa thy and included demyelination, myelin phagocytosis, Schwann cell proliferation, thicke ned myelin sheath, intrasheath ellipsoids, neurofibrillary degeneration, and myelin ovo ids, bubbles, and debris at the study LOAEL of 50 mg/kg/day. The NOAEL for the subchroni c neurotoxicity study was 8 mg/kg/day.

An acute neurotoxicity study has recently been received and is under review. Preliminary review indicates that there are no neuropath ology or FOB changes in this study; reduced motor activity on day one may be due to systemic toxicity and not due to neurotoxicity.

The EBDC team considered whether the DNT study required for ETU would adequately address any concerns for developmental neur otoxicity triggered by the peripheral nerve injury seen in the subchronic neurotoxicit y study. While ETU is the major mancozeb metabolite, accounting for 40% of the radioactivit y in urine, there are no reports of nerve injury from ETU. HED notes that the toxicity database for ETU is limited.

The EBDC team considered the possibility th at the myelinopathy seen in the mancozeb subchronic neurotoxicity study might be due to CS 2 . CS 2 is known to cause cause peripheral nerve injury. Given that a DNT fo r ETU was required, the team considered the possibility that a DNT conducted with ETU would address the potential hazard for peripheral nerve injury; that is, if the metabolic profile demonstrated that significant amounts of CS 2 could be expected as degradation products of ETU, then the potential for developmental neurotoxicity would be addr essed with the ETU DNT and no further study would be required. However, after consider ing the structure of ETU, as well as the metabolic profile for mancozeb, the team determined that generation of CS 2 from ETU was unlikely to be significant, but that greater amounts of CS 2 would likely be generated from breakdown of the parent mancozeb molecu le or other metabolites. Therefore, ifMancozeb Human Health Risk Assessment D327307 & D327318

Page 17 of 62 CS 2 was expected to be the cause of any deve lopmental neurotoxicity, that toxicity would not be measured in a study which dosed only with ETU.

After evaluating all the eviden ce, the EBDC Team concluded that a DNT study should be required for mancozeb and a 10X database uncer tainty factor to account for lack of this study should be applied in addition to a 100X for inter- and intra-species extrapolation when conducting the dietary, residential and aggregate risk assessments.

3.3 Summary of Toxicological Doses and Endpoints for Mancozeb and ETU for Use in Human Risk Assessments

Doses and endpoints for mancozeb and ETU are summarized in the Tables 3.3.1 and 3.3.2, respectively. As noted above, a detailed de scription of the toxicity database, as well as details on the selection of endpoint s and doses for risk assessment for both mancozeb and its degradate, ETU, are contai ned in the 6/3/2005 risk assessment. The only deviation from that assessment is the addition of a 10X UF DB for mancozeb which is detailed in Section 3.2 of this document.

Table 3.3.1 Summary of Toxicological Doses and Endpoints for Mancozeb

Exposure/Scenario Point of Departure Uncertainty/F QPA SF RfD, PAD, Level of Concern for RA Study & Toxic Effects Mancozeb Dietary Exposures

Acute Dietary (Females 13 – 49) NOAEL = 128 mg/kg/day UF A = 10 UF H = 10 UF DB =10 Acute RfD = 0.13 mg/kg/day

Acute PAD = 0.13 mg/kg/day Developmental Toxicity in the rat LOAEL = 512 mg/kg/day based on hydrocephaly and other malformations Acute Dietary (general population) No appropriate endpoint was identified from oral toxicity studies.

Chronic Dietary (all populations) NOAEL = 4.83 mg/kg/day UF A = 10 UF H = 10 UF DB =10 Chronic RfD = 0.005 mg/kg/day

Chronic PAD = 0.005 mg/kg/day Toxicity/Carcinogenicity in the rat LOAEL = 30.9 mg/kg/day based on changes in thyroid toxicity (changes in thyroid hormone levels, microscopic thyroid changes and changes in thyroid weights) Mancozeb Oral Exposures

Incidental Oral (Short- or Intermediate-Term) NOAEL = 9.24 mg/kg/day UF A = 10 UF H = 10 UF DB =10 Residential LOC = 1000 Subchronic Toxicity Study in the rat LOAEL = 17.82 mg/kg/day based on decreased thyroxine Mancozeb Dermal Exposures Dermal (Short-, and Intermediate-Term) Risk Assessment not required. No systemic toxicity via the dermal route at 1000 mg/kg/day and no developmental concerns.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 18 of 62 Table 3.3.1 Summary of Toxicological Doses and Endpoints for Mancozeb

Exposure/Scenario Point of Departure Uncertainty/F QPA SF RfD, PAD, Level of Concern for RA Study & Toxic Effects

Dermal (Long-Term) NOAEL = 4.83 mg/kg/day

DA = 1% UF A = 10 UF H = 10 UF DB =10 Residential LOC = 1000

Occupational LOC = 100 Toxicity/Carcinogenicity in the rat LOAEL = 30.9 mg/kg/day based on thyroid toxicity (changes in thyroid hormone levels, microscopic thyroid changes and changes in thyroid weights) Mancozeb Inhalation Exposures

Inhalation (Short-, Intermediate- or Long-Term) NOAEL = 0.079 mg/L [equivalent to 21 mg/kg/day] UF A = 10 UF H = 10 UF DB =10 Residential LOC = 1000

Occupational LOC = 100 Subchronic Inhalation in the rat LOAEL = 0.326 mg/L based on thyroid hyperplasia and decreased thyroxine (females) Mancozeb Cancer

Cancer Mancozeb’s potential for carcinogenicity is due to the formation of the metabolite ETU which is classified as a probable human carcinogen (B2). Mancozeb’s cancer risk is calculated by estimating exposure to mancozeb-derived ETU and using the ETU cancer potency factor (Q 1 * ) of 6.01 x 10 -2 (mg/kg/day) -1 to provide a quantitative estimate of risk.

Table 3.3.2 Summary of Toxicologi cal Doses and Endpoints for ETU

Exposure/Scenario Point of Departure Uncertainty/ FQPA SF RfD, PAD, Level of Concern for RA Study & Toxic Effects ETU Dietary Exposures

Acute Dietary (Females 13 – 49) NOAEL = 5 mg/kg/day UF A = 10 UF H = 10 UF DB =10 Acute RfD = 0.005 mg/kg/day

Acute PAD = 0.005 mg/kg/day Developmental Toxicity in the rat (Khera Study, MRID No. 45937601) LOAEL = 10 mg/kg/day based on developmental defects of the brain Acute Dietary (general population) No appropriate endpoint attributable to a single exposure (dose) was identified.

Chronic Dietary (all populations) NOAEL = 0.18 mg/kg/day UF A = 10 UF H = 10 UF DB =10 Chronic RfD = 0.0002 mg/kg/day

Chronic PAD = 0.0002 mg/kg/day Chronic Oral Toxicity in the dog. LOAEL = 1.99 mg/kg/day based on thyroid toxicity (increased thyroid weight and macroscopic changes in the thyroid – hypertrophy, follicular dilation)Mancozeb Human Health Risk Assessment D327307 & D327318

Page 19 of 62 Table 3.3.2 Summary of Toxicologi cal Doses and Endpoints for ETU

Exposure/Scenario Point of Departure Uncertainty/ FQPA SF RfD, PAD, Level of Concern for RA Study & Toxic Effects ETU Oral Exposures

Incidental Oral (Short- and Intermediate-Term) (Toddlers) NOAEL = 7 mg/kg/day UF A = 10 UF H = 10 UF DB =10 Residential LOC = 1000 4 week range-finding dog study LOAEL = 34 mg/kg/day based on thyroid toxicity (decreased levels of thyroid hormones, gross thyroid lesions)

Oral (Short-, and Intermediate-Term) (Females 13-49) NOAEL = 5 mg/kg/day UF A = 10 UF H = 10 UF DB =10 Residential LOC = 1000 Developmental Toxicity in the rat (Khera Study, MRID No. 45937601) LOAEL = 10 mg/kg/day based on developmental defects of the brain ETU Dermal Exposures

Dermal (Short-, Intermediate-Term) (Toddlers) NOAEL = 7 mg/kg/day UF A = 10 UF H = 10 UF DB =10 Residential LOC = 1000 4 week range-finding dog study LOAEL = 34 mg/kg/day based on thyroid toxicity (decreased levels of thyroid hormones, gross thyroid lesions)

Dermal (Short-, and Intermediate-Term) (Females 13-49) NOAEL = 5 mg/kg/day

DA = 26% UF A = 10 UF H = 10 UF DB =10 Residential LOC = 1000

Occupational LOC = 100 Developmental Toxicity in the rat (Khera Study, MRID No. 45937601) LOAEL = 10 mg/kg/day based on developmental defects of the brain

Dermal (Long-Term) NOAEL = 0.18 mg/kg/day

DA = 26% UF A = 10 UF H = 10 UF DB =10 Residential LOC = 1000

Occupational LOC = 100 Chronic Oral Toxicity in the dog LOAEL = 1.99 mg/kg/day based on thyroid toxicity (increased thyroid weight and macroscopic changes in the thyroid – hypertrophy, follicular dilation) ETU Inhalation Exposures

Inhalation (Short-and Intermediate-Term) NOAEL = 5 mg/kg/day

IA = 100% UF A = 10 UF H = 10 UF DB =10 Residential LOC = 1000

Occupational LOC = 100 Developmental Toxicity in the rat (Khera Study, MRID No. 45937601) LOAEL = 10 mg/kg/day based on developmental defects of the brainMancozeb Human Health Risk Assessment D327307 & D327318

Page 20 of 62 Table 3.3.2 Summary of Toxicologi cal Doses and Endpoints for ETU

Exposure/Scenario Point of Departure Uncertainty/ FQPA SF RfD, PAD, Level of Concern for RA Study & Toxic Effects

Inhalation (Long-Term) NOAEL = 0.18 mg/kg/day

IA = 100% UF A = 10 UF H = 10 UF DB =10 Residential LOC = 1000

Occupational LOC = 100 Chronic Oral Toxicity in the dog LOAEL = 1.99 mg/kg/day based on thyroid toxicity (increased thyroid weight and macroscopic changes in the thyroid – hypertrophy, follicular dilation) ETU Cancer

Cancer Q 1 * = 6.01 x 10 -2 (mg/kg/day) -1 ETU is classified as a Group B2 carcinogen with a linear lowdose extrapolation approach for human risk assessment based on liver tumors in female mice.

3.4 Endocrine Disruption

EPA is required under the FFDCA, as ame nded by FQPA, to develop a screening program to determine whether certain substanc es (including all pes ticide active and other ingredients) “may have an eff ect 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 there was a scientific basis for including, as part of the program, the androge n and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC’s recommendation that the Program include evaluations of potential effect s 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 th e science develops and res ources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program (EDSP).

When additional appropriate sc reening and/or testing protoc ols being considered under the Agency’s EDSP have been developed, mancozeb may be subjected to further screening and/or testing to better character ize effects related to endocrine disruption.

4.0 Public Health Data

D286184, J. Blondell, 10/16/02
HED previously reviewed incident reports in connection with the 6/3/05 human health risk assessment. Findings are summarized in the RED and detailed in the memorandum entitled Review of Mancozeb Incident Reports cited above

. Briefly, eleven incidentsMancozeb Human Health Risk Assessment D327307 & D327318

Page 21 of 62 were reported in the OPP Incident Data Sy stem (IDS) from 1992 to 2001 involving skin rashes and contact dermatitis with a few reports of dizziness and nausea. Forty four cases were reported in the California Pesticide illness Surveillance Program (1982 – 1999) in which mancozeb was judged to be responsiv e for the health effects reported. The majority of those cases involved workers developing rashes while tending grapes and occurred before the Special Review for mancozeb which resu lting in lowering the application rate on grapes.

5.0 Dietary Exposure/Risk Characterization

5.1 Pesticide Metabolism and Environmental Degradation

D294203; 4/3/07; C. Olinger D289183; 4/5/07; C. Olinger

5.1.1 Metabolism in Primary Crops

The qualitative nature of the residue in plants is adequately understood based on previously submitted plant metabolism studies with potato, soybean, sugar beet, tomato, and wheat. The metabolism studies indicated that the major metabolites are natural products (proteins, carbohydrates, lipids, and lignins) with minor amounts of mancozeb degradation products (ETU, ethyl eneurea, ethylene bisisocyan ate sulfide, Jaffe’s base, and ethylenediamine).

HED has concluded that the tolerance expres sions for mancozeb and the related EBDC active ingredients, metiram and maneb, shoul d be revised to include residues of the parent EBDC only, calculated as CS 2 . For risk assessment purposes, both parent and ETU residues must be considered.

5.1.2 Metabolism in Livestock

The qualitative nature of the residue in livestock is adequately understood based on previously submitted metabolism studies with goats and poultry. The residues of concern in livestock commodities are the parent mancozeb and ETU.

The residues of toxicological concern in meat and milk are mancozeb per se and ETU. HED has concluded that the tolerance expres sion for mancozeb should be revised to include residues of the parent EBDC only, calculated as CS 2 . For risk assessment purposes, both parent and ETU re sidues must be considered.

There are no poultry feed items associated w ith these requested new uses; therefore, a discussion of poultry metabolism is not relevant to this risk assessmentMancozeb Human Health Risk Assessment D327307 & D327318

Page 22 of 62 5.1.3 Rotational Crops

A confined rotational crop study was requi red in the mancozeb RED and remains outstanding. Product labels for existing uses of mancozeb do not in clude any plant-back restrictions. HED is not requiring the study as a condition of regist ration to support these new uses for the following reasons:

• the study was previously required in the RED

• proposed labels are consistent with existing product labels

• environmental fate data indicate that mancozeb is non-persistent in the environment (Patrick, Parker, and Ruhman, D205808, 10/20/04)

5.1.4 Analytical Methodology

Adequate methods are available for the en forcement of tolera nces for the plant commodities which are the subj ect of this request. The Pesticide Analytical Method (PAM) Vol. II lists Methods I, II, III, IV, a nd A for the determination of dithiocarbamate residues in/on plant commodities. The Keppel colorimetric method (Method III) is the preferred method for tolerance enforcement. The Keppel method determines EBDCs as a group by degradation to CS 2 . The analytical methodology for ETU is based on the original method published by Ol ney and Yip (JAOAC 54:165-169).

Enforcement methods for livestock commodities are not available. Prior to the RED, HED had concluded that tolerances were not required for animal commodities since there were not likely to be residue s in animal commodities as a result of exposur e to treated feed items for which there are existing toleranc es. However, in the RED, HED noted that a new ruminant feeding study conducted at highe r levels was required and the outcome of that study would determine if tolerances for animal commodities were required. Further, if tolerances are required, a method to enfo rce those tolerances would be required.

The only animal feed item associated with th ese new uses is almond hulls. Based on the available feeding study, HED does not believe th at there are likely to be detectable residues in meat and milk as a result of the proposed use on almonds, therefore; an enforcement method for livestock commodities is not required to support the new use on almonds.

Mancozeb is not recovered through any of the FDA Multiresidue Method Testing Protocols. There is small recovery (<50 %) of ETU using multiresidue Method 302, but ETU is not recovered using Methods 303 or 304.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 23 of 62 5.1.5 Environmental Degradation

D290057; 10/16/02; R. Parker

The Environmental Fate and Effects Division (EFED) provided information on the fate of the EBDC compounds in conjunction with th e RED as part of the drinking water assessment for mancozeb. Mancozeb, as well as the other EBDC compounds are short lived in soil and water.

The EBDC degradate, ETU has an aerobic so il half-life of 3 days, and an estimated aquatic aerobic metabolism half-life of si x days. The measured anaerobic aquatic metabolism half life is 149 days. ETU is highly water soluble; highly vulnerable to indirect photolysis; and is moderately mob ile. ETU has a relatively high vapor pressure, but the high solubility reduces the possibi lity of losses from surface water due to volatilization.

5.1.6 Pesticide Metabolites and Degradates of Concern

The residues of concern for risk assessment and the residues to be included in the tolerance expression for mancozeb are summarized in the table below.

Table 5.1.6 Summary of Metabolites and De gradates to be included in the Risk Assessment and Tolerance Expression

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression
Primary Crop Mancozeb & ETU Mancozeb, measured as CS 2 Plants
Rotational Crops No data are available. Identified as a data gap in the RED.
Livestock Ruminant Mancozeb & ETU Mancozeb, measured as CS 2 Drinking Water ETU only Not Applicable

5.1.7 Drinking Water Residue Profile

D290057, 8/26/2004, R. Parker D323143 and 323141, 8/11/2006, M. Ruhman

As noted above, mancozeb is short lived in soil and water and would, therefore; not be expected to remain in surface water long enough to reach a location that would supply water for human consumption whether from surface or ground water. However, mancozeb’s degradate, ETU, is highly water soluble and may reach both surface and ground water under some conditions; therefore, a drinking water assessment for ETU was conducted to support various EBDC pesticide uses for the RED. It should be noted that the assessment conducted for the RED comb ined ETU from all sources of EDBCMancozeb Human Health Risk Assessment D327307 & D327318

Page 24 of 62 pesticides, including mancozeb. After consider ation of the new application rates and use patterns in comparison to the maximum appli cation rates and use patterns used in the most recent drinking water assessment, as we ll as considering the appropriateness of extrapolating monitoring data to these new uses, EFED has determined that the previously derived EDWCs for ETU can be used in the human health risk assessment to support the proposed new uses on broccoli, lettuce, cabbage, pepper and almonds.

ETU surface water estimated drinking water concentrations were based both on PRZMEXAMS modeling information and available m onitoring data. The acute (peak) surface water EDWC ranged from 0.1 ppb from monitori ng data to 25.2 ppb as a model output. The chronic/cancer surface water valu e provided by EFED was 0.1 ppb based on monitoring data.

ETU ground water EDWC values were taken from a targeted monitoring study in Florida. EFED provided a value of 0.21 ppb from the mo nitoring data to be used in the acute, chronic and cancer risk assessments. Th is value represents the single highest concentration found in untreated water sample d from one of 84 sites over a period from 2001- 2004. No detectable residues of ETU were found in treated water at the 84 sites, including the two sites wh ere ETU residues were found in untreated water.

A more detailed summary of the ETU drinki ng water assessment conducted for the RED can be found in the human health risk assessment developed for the RED (D317371, 6/3/2005, K. Farwell) and a dditional details on the drinking water assessment are contained in the EFED drinking wa ter assessment memorandum entitled Revision No. 2: Estimated Drinking Water Concentration of Ethylenebisdithocarbamate (EBDC) Degradate Ethylenethiourea (ETU) for the Use in Human Health Risk Assessment cited above.

ETU estimated drinking water concentrations provided by EFED are summarized below.

Table 5.1.7 Summary of Estimated Surface Water and Ground Water Concentrations for ETU.

ETU from all EBDC pesticides including mancozeb Surface Water Conc., ppb a Ground water Conc., ppb b

Acute 0.1 – 25.2 0.21 Chronic (non-cancer) 0.1 0.21 Chronic (cancer) 0.1 0.21

a Surface water EDWCs were derived from both monitoring and modeling data. A range of acute surface water concentrations was provided. The lower end of the range was based on monitoring data and the upper end of the range was based on EPA PRZM and EXAMS models. Chronic/Cancer EDWCs were based on monitoring data.
b Ground water EDWCs were taken from a community well monitoring program and represent the single highest value found at any sampling for 84 sites.
Bolded values used in the dietary risk assessment.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 25 of 62 5.1.8 Food Residue Profile

D294203; 4/3/07; C. Olinger D289183; 4/5/07; C. Olinger

Application of mancozeb to food crops results primarily in surface residues. For the new uses that are the subject of these two petiti ons, crop field trial data were provided and are the basis for the recommended tolerance levels, as well as the basis for the information used for the dietary risk assessment.

Broccoli Previously submitted data for broccoli (D 198104, 9/6/96, R. Perfetti) represented three trials conducted in Zone 10 (CA) in whic h broccoli was harvested 7 days following the last of six applications of the 75% DF fo rmulation at 1.3-1.9 lb ai/A/application for a total seasonal rate of ~9.6 lb ai/A. Applications were made with 7- to 10-day retreatment intervals (RTIs). Residues of mancozeb we re 1.43 ppm - 12.23 ppm in/on these samples.

Additionally, five broccoli fiel d trials were conducted in the United States in Zones 6 (TX; 1 trial), 10 (CA; 3 trials), and 12 (OR; 1 trial) during the 1997 growing season. Maximum residues of mancozeb and ETU were, respectively, 2.65 ppm and 0.014 ppm in/on broccoli harvested 7-8 da ys following foliar treatment with the 75% DF formulation at a total rate of 9.4-9.7 lb ai/A.

The current broccoli crop field trial data in combination with the previously submitted crop field trial data are adequa te to satisfy data requireme nts and support use of the WP and DF formulations of mancozeb on broccoli. The available crop field trial data support a tolerance for residues of mancozeb, expressed in terms of CS 2 , in/on broccoli at 7.0
ppm.

Head Lettuce Previously submitted data represented 6 trials co nducted in CA (3 trials) and FL (3 trials). Head lettuce grown in CA was harvested 10 da ys following the last of 4 applications of the 75% DF formulation at 1.6 lb ai/A/applica tion for a total applic ation rate of 6.4 lb ai/A (1x the proposed maximum seasonal rate to lettuce grown in CA). Head lettuce grown in FL was harvested 10 days following the last of 6 applications of the 75% DF or 80% WP formulation at 1.5-1.6 lb ai/A/applicatio n for total applicati on rates of 9.5-9.6 lb ai/A (~1x the proposed maximum seasonal rate to lettuce grown in states other than CA). Applications were made with 6- to 10-day retreatment intervals (RTIs). Residues of mancozeb were 0.47-3.87 ppm in/on untrimmed head lettuce

Dow AgroSciences (as Rohm and Haas Company) has submitted field trial data for mancozeb on head lettuce. Two lettuce field tr ials were conducted in the United States in Zone 10 (CA) during the 1997 growing seas on. Maximum residues of mancozeb and ETU were, respectively, 0.608 ppm and 0.0085 ppm in/on head lettuce harvested 10 days following foliar treatment with the 4 lb/gal flowable concentrate formulation at a total rate of 9.6 lb ai/A.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 26 of 62 The submitted head lettuce crop field trial data combined with supporting information from the leaf lettuce data, are sufficient to establish a tolerance and to support the use of the WP and DF formulations on head lettuce. The available crop fi eld trial data would support a tolerance for residues of ma ncozeb, expressed in terms of CS 2 , in/on head lettuce at 3.5 ppm.

Leaf Lettuce Three lettuce field trials were conducted in the United States in Zones 1 (NY; 1 trial), 3 (FL; 1 trial), and 10 (CA; 1 trial) during the 1997 growing season. Maximum residues of mancozeb and ETU were, respectively, 10.2 ppm and 0.14 ppm in/on leaf lettuce harvested 10-11 days following foliar treatmen t with the 75% DF formulation at a total rate of 9.4-9.7 lb ai/A. Maximum residues of mancozeb and ETU were, respectively, 10.67 ppm and 0.058 ppm in/on leaf lettuce harv ested 14-15 days following treatment.

Five lettuce field trials were conducted in the United States in Zone 10; three trials were located along the coast (Monterey and Ventura Counties) and two trials were located in the Central Valley (Tulare and Madera Countie s) in CA. The trials were conducted during the 1999 growing season. Maximum residues of mancozeb and ETU were, respectively, 108 ppm and 0.600 ppm in/on l eaf lettuce harvested 10 days following foliar treatment with the 75% DF formulation at a total rate of 6.4-6.6 lb ai/A. Maximum residues of mancozeb and ETU were, re spectively, 97.4 ppm and 0.785 ppm in/on leaf lettuce harvested 14 days following treatment . Maximum residues of mancozeb and ETU were, respectively, 267 ppm and 0.385 ppm in/ on leaf lettuce harvested 10 days following foliar treatment with the 4 lb/gal Fl C (flowable concentrat e) formulation at a total rate of 6.4 lb ai/A. Maximum residue s of mancozeb and ETU were, respectively, 148 ppm and 0.694 ppm in/on leaf lettuce harves ted 14 days following treatment. The petitioner noted that residues in/on leaf lettuce from th e Madera County field trial (#98299-5) were much higher (>3x) than thos e in/on samples from the other CA field trials, most likely because of the method of application. At the Madera County trial, applications were made using a U-shaped boom, which applies the test substance around the whole plant including the underside of the leaves not typically exposed to sunlight and moisture. In addition, the Central Valley ar ea of CA is typically hotter and drier than other areas of CA, and the highest residues were observed in/on samples from the two trials conducted in the Central Valley.

The submitted leaf lettuce crop field trial data are adequate to satisfy data requirements to support use of the WP or DF formulations on leaf lettuce. Because the maximum observed residues in/on head lettu ce and leaf lettuce differ by mo re than 5x, the petitioner must propose separate toleran ces for head lettuce and leaf lettuce. The available crop field trial data would support a tolerance for residues of mancozeb, expressed in terms of CS 2 , in/on leaf lettuce at 18 ppm, provided that the label is modified to prohibit the use of a “U-shaped” boom.

Pepper Previously submitted data for pepper (DP Barcode D198104, 9/6/96, R. Perfetti) represented two trials conducted in CA and FL. At the CA trial, pe ppers were harvested 7 days following the last of six applicatio ns of the 75% DF formulation at 1.6 lbMancozeb Human Health Risk Assessment D327307 & D327318

Page 27 of 62 ai/A/application for a total seasonal rate of 9.6 lb a i/A (1x the proposed maximum seasonal rate to peppers grown west of the Mississippi River). At the FL trial, peppers were harvested 10 days following the last of six applications of th e 80% WP formulation at 2.4 lb ai/A/application fo r a total seasonal rate of 14.4 lb ai/A (1x the proposed maximum seasonal rate to peppers grown east of the Mississippi Ri ver). Applications were made with 7- to 10-day RTIs. Re sidues of mancozeb were 0.48 and 1.02 ppm in/on these samples.

Nine pepper field trials were conducted in the United States ; six trials were conducted on bell pepper in Zones 2 (GA and SC; 2 trials), 3 (FL; 1 trial), 5 (OH; 1 trial), 6 (OK; 1 trial), and 10 (CA; 1 trial), and three trials were conducted on non-bell pepper in Zones 1 (NY; 1 trial), 8 (NM; 1 trial), and 10 (C A; 1 trial) during th e 1997 growing season. For locations west of the Mississippi Rive r, maximum residues of mancozeb and ETU were, respectively, 5.95 ppm and 0.04 ppm in /on bell pepper, and 10.0 ppm and 0.09 ppm in/on non-bell pepper harvested 7 days follo wing foliar treatment with the 75% DF formulation at a total rate of 9.3-9.6 lb ai/A. For locations ea st of the Mississippi River, maximum residues of mancozeb and ETU were, respectively, 1.90 ppm and 0.06 ppm in/on bell pepper, and 1.87 ppm and 0.02 ppm in/on non-bell pepper harvested 7 days following foliar treatment with the 75% DF formulation at a to tal rate of 14.2-14.7 lb ai/A. For locations west of the Mississippi River, maximum residues of mancozeb and ETU were, respectively, 2.13 ppm and 0.03 ppm in/on bell pepper, and 10.1 ppm and 0.03 ppm in/on non-bell pepper harvested 7 da ys following foliar treatment with the 4 lb/gal FlC formulation at a total rate of 9.6-9.7 lb ai/A. For locations east of the Mississippi River, maximum residues of ma ncozeb and ETU were, respectively, 5.37 ppm and 0.05 ppm in/on bell pepp er harvested 7 days following foliar treatment with the 4 lb/gal FlC formulation at a total rate of 14.2-14.6 lb ai/A. No non-bell pepper trials were conducted east of the Mississippi Rive r with the 4 lb/gal FlC formulation.

The current pepper crop field trial data in combination with the previously submitted crop field trial data are adequate to satisfy geogr aphic representation data requirements for use of the WP or DF formulations on pepper. The available crop field trial data would support a tolerance for residues of ma ncozeb, expressed in terms of CS 2 , in/on pepper at 12 ppm.

Cabbage Previously submitted data for cabbage (D198104, 9/6/96, R. Perfetti) represented 9 trials conducted in CA, FL, MI, NC, NJ, NY, OH, TX , and WI in which cabbage was treated with 6 applications of the 75% DF or 80% WP formulation at 1.5- 1.8 lb ai/A/application for total application rates of 9.5-9.7 lb ai/A (~1x the proposed maximum seasonal rate). Applications were made with 6- to 11-day RTIs, and samples were harvested 10 days after treatment in FL and 7 days after treatmen t in all other states. Residues of mancozeb were 0.64-10.74 ppm in/on untrimmed cabbage.

The available data are adequate to satisf y geographic representation requirements and support establishment of a to lerance for the use of the WP or DF formulations onMancozeb Human Health Risk Assessment D327307 & D327318

Page 28 of 62 cabbage. The data would support a toleran ce for residues of mancozeb, expressed in terms of CS 2 , in/on cabbage at 9.0 ppm.

Almonds Previously, the petitioner had submitted crop fi eld trial data for almonds reflecting five field trials conducted in CA (M RID 43018401; DP Barcodes D201278 and D206514, 9/16/94, R. Perfetti); at each tr ial, almonds were treated with 3 applications of the 80% WP or 75% DF formulation at 4.8 lb ai/A/app lication, with retreatmen t intervals of 8-19 days, for a total seasonal rate of 14.4 lb ai/A (1x the proposed maximum seasonal rate). Samples were harvested 136-161 days following the final application and were stored frozen for 238-285 days (7.8-9.4 months) prior to analysis. Residues of mancozeb and ETU were below the LOQ (<0.05 and <0.01 ppm , respectively) in/on all samples of almond nutmeat, and were 4.64-5.98 ppm and 0.107-0.471 ppm, respectively, in/on almond hulls.

Dow AgroSciences (as Rohm and Haas Company) has submitted field trial data for mancozeb on almonds. Six almond field tria ls were conducted in the United States in Zone 10 (CA) during the 1996 growing season. E ach field test consisted of one untreated plot and four treated plots. Six or se ven foliar spray applications of a 75% DF formulation of mancozeb were made to al mond trees at ~6.4 lb ai/A/application for a total rate of ~38.4 or ~44.8 lb ai/A (2.7x or 3.1x the proposed maximum seasonal rate for almonds). Applications were started at th e popcorn to full bloom growth stage, and subsequent applications were ma de at 14- to 33-day retreatmen t intervals; at most trials, all applications except the first one or two were made postbloom. Applications were made using ground equipment. Two plots were treated with concentrate spray volumes (<50 gal/A) and two plots were treated w ith dilute spray volumes (>100 gal/A); an adjuvant was added to all of the spray mixt ures. Samples of almonds were harvested 15- 17 days after the last applic ation (DALA) from one dilute and one concentrate treated plot, and samples of mature almonds we re harvested 59-60 DALA from the other concentrate and dilute treated plots. Alm onds were separated into nutmeats and hulls.

No significant differences were observed in the mancozeb and ETU residues in/on almond nutmeat and hulls harvested 59-60 days following foliar applications made with concentrate (<50 gallons per acre (GPA)) vers us dilute (>100 GPA) spray volumes in exaggerated rate studies. Using concentr ate spray volumes, the maximum residues of mancozeb and ETU, respectively, were 0.163 ppm and <0.01 ppm (LOQ) in/on nutmeat, and 38.6 ppm and 1.55 ppm in/on almond hulls . Using dilute spray volumes, the maximum residues of mancozeb and ETU, respectively, were 0.129 ppm and <0.01 ppm (LOQ) in/on nutmeat, and 32.9 ppm and 1.05 ppm in/on almond hulls. Overall, the maximum residues of mancozeb and ETU, respectively, were 0.163 ppm and <0.01 ppm in/on almond nutmeat, and 38.6 ppm and 1.55 ppm in/on almond hulls. No significant differences were observed in the mancozeb and ETU residues in/on almond nutmeat and hulls harvested 15-17 days following foliar ap plications made with concentrate (<50 GPA) versus dilute (>100 GPA) spray volum es. Using concentrate spray volumes, the maximum residues of mancozeb and ETU, respectively, were 0.117 ppm and <0.01 ppmMancozeb Human Health Risk Assessment D327307 & D327318

Page 29 of 62 (LOQ) in/on nutmeat, and 49.0 ppm and 1.32 ppm in/on almond hulls. Using dilute spray volumes, the maximum residues of ma ncozeb and ETU, respectively, were 0.133 ppm and <0.01 ppm (LOQ) in/on nutmeat , and 47.9 ppm and 1.48 ppm in/on almond hulls. Overall, the maximum residues of mancozeb and ETU, respectively, were 0.133 ppm and <0.01 ppm in/on almond nutmeat , and 49.0 ppm and 1.48 ppm in/on almond hulls. In general, residues of manco zeb and ETU in/on nutmeat and hull samples harvested at the 15- to 17-day PHI declined (or remained below the LOQ) at the 59/60- day PHI.

HED concludes that adequate crop field tria l data have been submitted to support the proposed use of mancozeb on almonds. The available data would support a tolerance for residues of mancozeb, expressed in terms of CS 2 , in/on almond nutmeat at 0.03 ppm (LOQ) and almond hulls at 4.0 ppm.

5.1.9 International Residue Limits

There are no established or proposed Codex maximum resi due limits for residues of mancozeb per se ; however, Codex limits for dimet hyldithiocarbamates fungicides are grouped under dithiocarbamates. Codex MR Ls for dithiocarbamates have been established for the following commodities: head cabbages at 5 ppm (based on mancozeb and maneb data); Cos lettuce at 10 ppm (bas ed on maneb data); head lettuce at 10 ppm (based on mancozeb, maneb, and metiram data); sweet peppers at 1 ppm (based on mancozeb and maneb data); almonds at 0.1 ppm and almond hulls at 20 ppm (based on maneb and ziram data). The MRLs are currently expressed as ppm CS 2 . Canadian MRLs have been established for ethylenebi sdithiocarbamate fungicides and are expressed in terms of manganese and zinc ethylenebi s (dithiocarbamate) (polymeric); MRLs have been established for broccoli, cabbage, lett uce, and peppers at 7 ppm. No Mexican MRLs have been established for residues of mancozeb in the requested crops.

HED has recommended that all tolerances for the EBDC pesticides be expressed in terms of CS 2 , therefore, harmonizing the toleran ce definition with the Codex tolerance expression. However, for the reasons indicated below, the recommended tolerance levels are not harmonized with Codex.

• Based on the calculations in the toleran ce spreadsheet, the appropriate tolerance level for cabbage is 9.0 ppm. The tole rance level cannot be harmonized with Codex; the highest residue level in the crop field trials (6.0 ppm in CS 2 equivalents) is greater than the Codex MRL for cabbage.

• The available data indicate that the appropr iate tolerance level for head lettuce is 3.5 ppm. The tolerance level cannot be harmonized with Codex; the highest residue level in the crop fi eld trials (2.2 ppm in CS 2 equivalents) is considerably less than the Codex MRL of 10 ppm for head lettuce.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 30 of 62 • The available data indicate that the appropr iate tolerance level for leaf lettuce is 18 ppm. The tolerance level cannot be harmonized with Codex; the highest residue level in the crop fi eld trials (14 ppm in CS 2 equivalents) is greater than the Codex MRL for Cos lettuce.

• The appropriate tolerance le vel for pepper is 12 ppm. The tolerance level cannot be harmonized with Codex as the Codex MRL has been established for sweet pepper only.

• The appropriate tolerance le vel for almond hulls is 4 ppm. This value can not be harmonized with Codex as it is signifi cantly below the Codex MRL of 20 ppm.

5.2 Dietary Exposure and Risk

D323878 and D323879, 4/17/07, C. Olinger
Acute and chronic dietary risk assessments for mancozeb and acute, chronic and cancer dietary risk assessments for mancozeb-der ived ETU were conducted using the Dietary Exposure Evaluation Model (DEEM-FCIDTM, Version 2.03) which uses food consumption data from the U.S. Department of Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998.

The acute, chronic, and cancer assessments can be considered somewhat refined. Residue estimates were refined using cons umer processing factors (washing, cooking), commercial processing, percent crop treated factors, and monitoring data for several commodities. Crop field trial data were used for all of the proposed new uses and several existing uses, which are likely to provid e higher estimates than actual exposures.

Since mancozeb per se is not expected in ground or su rface water, the acute and chronic exposure and risk assessments for the pare nt compound consider contribution from food residues only. Additionally, since mancozeb’s po tential for carcinogenicity is due to the formation of the metabolite ETU, which is classified as a probable human carcinogen (B2), mancozeb’s cancer risk is calculated by estimating exposure to mancozeb-derived ETU and using the ETU cancer potency factor to provide a quantitative estimate of risk.

Details of the dietary exposure and risk assessment are contained in the memorandum entitled PP#4F4324 and 4F4333 Mancozeb Acute, Chronic and Cancer Dietary Exposure Assessments for New Tolerances on Almonds, Broccoli, Cabbage, Lettuce and Peppers
, which is referenced above.

5.2.1 Acute Dietary Exposure/Risk

A probabilistic acute dietary exposure a nd risk analysis was conducted for both mancozeb and for mancozeb-derived ETU to support the proposed new uses of mancozeb. Maximum estimated percent crop treated information for the existing uses, asMancozeb Human Health Risk Assessment D327307 & D327318

Page 31 of 62 well as maximum projected percent crop trea ted information for the new uses were incorporated into the acute dietary assessmen ts. For commodities which are considered partially blended, or not blende d, the entire distributions of residue data from field trials or monitoring data from a market basket survey were used to generate residue distribution files (RDFs). Where HED had only field trial data for a partially blended or non blended commodity, the adjustment for per cent crop treated is in corporated into the RDF via addition of zero residue values corresponding to the pe rcent of crop not treated. For partially blended or not blended commod ities where monitoring data from a market basket survey are available, the maximum percent crop treated data were used to determine what percent of the non-detects shoul d be treated as zeros and what percentage should be incorporated into the RDF as half the limit of quantitation (1⁄2 LOQ). The only exception is the wine RDF which used the enti re distribution of monitoring data with no further adjustment for percent of crop treated. For commodities considered to be blended where either field trial data or monitoring data were available, the average residue incorporating the likely maximum estimated percent crop treated was used as a point estimate. Processing and cooking factors from st udies with mancozeb as well as with the other EBDC pesticides were incorporated into the analysis.

An acute endpoint was selected for the subpopul ation, females 13 – 49 years of age only. No acute endpoint was selected for the general population. For mancozeb per se , females 13 – 49 years of age have an exposure from food th at is equivalent to an estimated risk of 6.9% of the mancozeb aPAD at the 99.9 th percentile. HED is not concerned with risks that do not exceed 100% of the aPAD, therefor e; HED has no concern for acute risks to females 13 – 49 yrs, the subgroup of concern, resulting from exposure to mancozeb per

se from the existing and new uses of mancozeb.

For mancozeb-derived ETU, females 13 – 49 yrs of age have an exposure from food only that is equivalent to 24% of the ETU aPAD at the 99.9 th percentile. For mancozebderived ETU, females 13 – 49 years of age have an exposure from food and water that is equivalent to 71% of the ETU aPAD at the 99.9 th percentile. HED is generally not concerned with risks that do not exceed 100% of the aPAD, therefore; HED has no concern for acute risks to females 13 – 49 yr s, the subgroup of concern, resulting from exposure to mancozeb-derived ETU through f ood and water resulting from the existing and new uses of mancozeb.

Exposures and risks for both mancozeb and ma ncozeb-derived ETU at select percentiles are summarized in Table 5.2.1, below.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 32 of 62 Table 5.2.1 Results of Acut e Dietary Exposure and Risk Assessment for Mancozeb and ETU
95 th Percentile 99 th Percentile 99.9 th Percentile Population Subgroup aPAD (mg/kg/day) Exposure (mg/kg/day) % aPAD Exposure (mg/kg/day) % aPAD Exposure (mg/kg/day) % aPAD

Mancozeb

Females 13 – 49 yrs Food Only 0.13 0.000216 0.17 0.0126 0.97 0.008926 6.9

ETU

Females 13 - 49 yrs Food Only 0.005 0.0001 2.0 0.000351 7.0 0.00123 24

Females 13 - 49 yrs
Food and Water 0.005 0.00128 26 0.0021 42 0.00356 71

5.2.2 Chronic Dietary Exposure/Risk

Chronic anticipated residues were calculated from field trial or monitoring data for mancozeb and ETU. Averages of the field trial residue values were used for the new tolerances, while either field trial or market basket survey data were used for established uses. Both average percent crop treated information for the existing uses as well as estimates of average projected percent crop tr eated for the new uses were incorporated into the chronic dietary risk assessments. Additionally, residue es timates were further refined using consumer processing f actors (washing, cooking) and commercial processing factors.

For mancozeb per se , the general U.S. population has an estimated exposure from food that is equivalent to 1.5% of the mancozeb cPAD. The most highly exposed subgroup is children 1 – 2 years of age with an estimated exposure from food that is equivalent to 3.3% of the mancozeb cPAD. HED is genera lly not concerned with risks that do not exceed 100% of the cPAD, therefore; HED has no concern for chronic risks to the general population or any regulated subgr oup, resulting from exposure to mancozeb per

se from the existing and new uses of mancozeb.

For mancozeb-derived ETU, the general U.S. population has an estimated exposure from food only that is equivalent to 14% of the ETU cPAD. The most highly exposed subgroup is children 1 – 2 years of age with an estimated exposure from food that is equivalent to 32% of the ETU cPAD. For mancozeb-derived ETU, the general population has an estimated exposure from food and water that is equivalent to 16% of the ETU cPAD. The most highly exposed subgr oup is children 1 – 2 ye ars of age with anMancozeb Human Health Risk Assessment D327307 & D327318

Page 33 of 62 estimated exposure from food that is equiva lent to 36% of the ETU cPAD. HED is generally not concerned with risks that do not exceed 100% of the cPAD, therefore; HED has no concern for chronic risks to the ge neral population or any regulated subgroup, resulting from dietary exposure to manco zeb-derived ETU from the existing and new uses of mancozeb.

Chronic dietary exposures and risks for bot h mancozeb and mancozeb-derived ETU for the U.S. population and all regulated s ubgroups are summarized in Tables 5.2.4.1, 5.2.4.2 and 5.2.4.3, below.

5.2.3 Cancer Dietary Risk

Cancer anticipated residues were calculated from either fiel d trial or monitoring data for mancozeb-derived ETU. Averages of the fiel d trial residue values were used for the new tolerances, while field trial or market basket survey data were used for established uses. Both average percent crop treated information fo r the existing uses as well as estimates of average projected percent crop treated information for the ne w uses were incorporated into the cancer dietary risk assessment. Additionally, residue estimates were further refined using consumer processing f actors (washing, cooking) and commercial processing factors.

Exposure and risk estimates for the ETU cancer assessment are presented in Tables 5.2.4.2 and 5.2.4.3, below. Because of the uncertainties regarding estimation of cancer potency and human exposure, risk estimates ranging from 1 x10 -6 to 3 x10 -6 are generally considered indistinguishable. The estimated cancer risk for food alone and aggregated food and water are within this range and are not of concern.

5.2.4 Summary of Dietary Exposure and Risk for Mancozeb and ETU

Tables 5.2.4.1, 5.2.4.2 and 5.2.4.3 provide a summary of the dietary exposure and risk for mancozeb and mancozeb-derived ETU.

Table 5.2.4.1 Summary of Dietary Ex posure and Risk for Mancozeb Food Only

Acute Dietary (99.9th Percentile) Chronic Dietary Cancer

Population Subgroup Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk

General U.S. Population 0.000073 1.5

All Infants (< 1 year old) N/A

0.000058 1.2 Mancozeb’s potential for carcinogenicity is due to

the formation of theMancozeb Human Health Risk Assessment D327307 & D327318

Page 34 of 62 Table 5.2.4.1 Summary of Dietary Ex posure and Risk for Mancozeb Food Only

Acute Dietary (99.9th Percentile) Chronic Dietary Cancer

Population Subgroup Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk

Children 1-2 years old 0.000167 3.3

Children 3-5 years old 0.0000133 2.7

Children 6-12 years old 0.00008 1.6

Youth 13-19 years old 0.000051 1.0

Adults 20-49 years old 0.000068 1.4

Adults 50+ years old 0.000066 1.3

Females 13-49 years old 0.008926 6.9 0.000071 1.4 metabolite ETU which is classified as a probable human carcinogen (B2). Mancozeb’s cancer risk is calculated by estimatingexposure to mancozebderived ETU and using the ETU cancer potency factor (Q 1 * ) of 6.01 x 10 -2 (mg/kg/day) -1 to provide a

quantitative estimate of risk.

Table 5.2.4.2 Summary of Dietary Exposu re and Risk for Mancozeb-Derived ETU Food Only

Acute Dietary (99.9th Percentile) Chronic Dietary Cancer

Population Subgroup Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk

General U.S. Population 0.000028 14 0.000028 1.7 x 10 -6

All Infants (< 1 year old) 0.000028 14

Children 1-2 years old 0.00065 32

Children 3-5 years old 0.000051 26

Children 6-12 years old 0.000033 16

Youth 13-19 years old 0.000019 9.5

Adults 20-49 years old 0.000025 12

Adults 50+ years old N/A

0.000025 13

Females 13-49 years old 0.00123 24 0.000024 12 N/AMancozeb Human Health Risk Assessment D327307 & D327318

Page 35 of 62 Table 5.2.4.3 Summary of Dietary Exposu re and Risk for Mancozeb-Derived ETU

Food and Water

Acute Dietary (99.9th Percentile) Chronic Dietary Cancer

Population Subgroup Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk

General U.S. Population 0.000032 16 0.000032 1.9 x 10 -6

All Infants (< 1 year old) 0.000042 21

Children 1-2 years old 0.000071 36

Children 3-5 years old 0.000057 29

Children 6-12 years old 0.000037 18

Youth 13-19 years old 0.000022 11

Adults 20-49 years old 0.000029 14

Adults 50+ years old N/A

0.000030 15

Females 13-49 years old 0.00356 71 0.000028 14 N/A

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

D317368, 05/31/05, T. Dole

No new residential uses are bei ng added to the mancozeb label as a result of this action, however there are existing resi dential uses registered.

The document entitled Mancozeb: 2 nd Revised Occupational and Residential Exposure Assessment and Recommendations for the Rere gistration Eligibility Decision Document cited above provides a detailed summary of the exposure and risk assessment for the existing residential uses of mancozeb. Subsequent to the completion of that memorandum, the EBDC Team, revisited th e toxicological data requirements for mancozeb and concluded that a DNT was require d and that a database uncertainty factor to account for the lack of that study should be applied to the mancozeb risk assessments. As a result of that decision, the level of c oncern for the residential risk assessments was revised from 100 to 1000.

All residential exposure scenarios previously evaluated had MOEs that were above the LOC of 1000, with the exception of incident al oral risks for toddlers exposed to transplanted turf treated on a sod farm with a PHI of 3 day. Based on the current LOC, a PHI of 5 days would be required to assure that incidental oral risk s to toddlers exceeded an LOC of 1000.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 36 of 62 Exposures and risks from the various reside ntial scenarios are briefly summarized here since those values are required for the aggreg ate risk assessment to support the new uses that are the subject of this action.

6.1 Residential Handler Exposures and Risks

The existing residential handler scenario identi fied for mancozeb is for the application of mancozeb in home gardens. The anticipa ted use patterns and current labeling indicate that backpack and low pressure handwand sp rayers 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. Residential scenarios are consid ered 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, tu rf 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.

Since the endpoints selected fo r the short- and intermediate -term assessment are identical, short- and intermediate-term risk assessments yield the same MOEs and a single value is shown in the tables below. Risks from both mancozeb and mancozeb-derived ETU are calculated. 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.

Mancozeb A mancozeb dermal risk assessment is not required since a dermal endpoint was not selected based on lack of systemic toxicity at the limit dose of 1000 mg/kg/day in the 28- day dermal toxicity study. Inhalation exposur e and risks were calculated for residential handlers applying mancozeb by either bac kpack sprayer or low pressure handwand sprayer. For both scenarios, inhalation MO Es far exceeded the level of concern of 1000 for mancozeb; therefore, HED has no concern for short- and intermediate-term inhalation risks from mancozeb per se to residential handlers from the existing home garden use. Short/Intermediate-term inhalation exposures and risks for mancozeb per se are summarized in Table 6.1.1, below.

Table 6.1.1 Home Gardener Handler Exposure and Short/Intermediat e-Term Risks for Mancozeb

Exposure Scenario Application Rate (lb ai/acre) Area Treated (Acre/Day) Absorbed Daily Dose (mg/kg/day) Inhalation MOE 1

Backpack 2.4 x 10 -5 890000

Low Pressure Handwand 2.4 0.023 (1000 ft 2 ) 7.1 x 10 -6 3000000

1 NOAEL is 21 mg/kg/day; 100% IA.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 37 of 62 ETU Both dermal and inhalation exposures and risks for mancozeb-derived ETU were calculated for residential handlers. Sin ce the short/intermediate-term dermal and short/intermediate-term inhalation endpoints we re taken from the same study, dermal and inhalation exposures were adde d 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 risks for residential handlers using both backpack spraye rs and low pressure handwand sprayers far exceeded the LOC of 1000; th erefore, HED has no concern short- and intermediate-term risks to residential ha ndlers exposed to mancozeb-derived ETU. Short- and intermediate-term dermal and i nhalation exposures and combined risk for residential handlers are summar ized in Table 6.1.2, below.

Table 6.1.2 Home Gardener Handler Exposure a nd Short/Intermediate- Term Risks for Mancozeb-Derived ETU

Absorbed ETU Daily Dose (mg/kg/day) Exposure Scenario

Dermal Inhalation Combined Absorbed ETU Daily Dose (mg/kg/day) ETU MOE 1

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

Cancer 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 handw and sprayers had an estimated cancer risk of 2.3 x 10 -8

.

HED has no concern for cancer risks to residential handlers as a result of exposure to mancozeb-derived ETU from the existing home garden use. Cancer risks for home garden handlers are summarized in the table below.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 38 of 62 Table 6.1.3 Home Garden Handler Exposure and Cancer Risk for ETU from Mancozeb

Exposure Scenario Application Rate (lbs ai/acre) Absorbed Daily Dose (mg/kg/day) a Lifetime Average Daily Dose b Cancer Risk c

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

Notes a. ADD = Absorbed Daily Dose from dermal and inhalation exposure b. LADD = Lifetime Average Daily Dose = ADD * (5 exposure day per year/365 days per year)*(50 years of exposure/70 years of life) c. LADD * Q 1 * where Q 1 * = 0.0601 mg/kg/day

6.2 Residential Postapplication Exposure

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 w ith treated turf (golfer scenario)

• youth (ages 10 – 12) dermal exposure from working in treated home gardens

• toddler’s incidental oral exposure from ha nd-to-mouth transfer of residues, objectto-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 assessments are detailed in the 5/31/05 ORE (occupational and reside ntial exposure) memorandum cited under section 6.0. Results of the residential postapplication exposure and risk assessment are briefly summarized below.

6.2.1 Home Garden Postapplication Scenarios

Mancozeb Dermal toxicity is not expected to result fr om exposure to mancozeb; therefore, a dermal endpoint for mancozeb has not been selecte d. An assessment of dermal exposure and risk for mancozeb per se from postapplication exposure for adults and youth to treated home gardens is not required.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 39 of 62 ETU Table 6.2.1.1, below summarizes the postapplic ation 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 a nd 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 significantly exceed the LOC of 1000 a nd, therefore; are not of concern.

Table 6.2.1.1 Mancozeb-derived ETU Postapplication Short/Intermediate-Term Exposure and Risks for Adult and Youth Home Gardeners

ETU MOE on Day 0 (Adults/Youth)

Crop Group Application Rate (lb ai/acre) Low Medium High Very High

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

Vegetable, cucurbit - West Vegetable, cucurbit - East 2.4

2.4 80000/150000 94000/170000 27000/49000 31000/57000 16000 / 29000* 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

Low, medium and High refer to low, medium and high c ontact activities Note – while the application rates are the same for west and east cucurbit, the dislodgeable foliar residue values used for eas t and west are different, which explains the different exposures and risks from the same application rate. The highest exposure/risk scenario is shown in bold. * 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 Cancer risks from exposure to mancozeb-d erived ETU from home garden exposure scenarios are summarized in Table 6.2.1.2, belo w. As in the table above, the scenario with the highest risk is shown in bold. Can cer risks are shown for low, medium and high contact activities and also for representative commodities that might be found in a home garden. Postapplication cancer risks for adult home gardeners for all scenarios are not of

concern.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 40 of 62 Table 6.2.1.2 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 Applicatio n Rate (lb ai/acre) Low* Medium* High* Very High*

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

Vegetable, cucurbit - West Vegetable, cucurbit - East 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 *Note – 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.

6.2.2 Treated Turf Postapplication Scenarios for Toddlers

Toddlers can be exposed to mancozeb and its metabolite ETU when in contact with treated turf. Incidental oral exposures and risks are shown below. HED notes that there are no direct homeowner applica tions of mancozeb to turf; ho wever, there is a registered use to permit treatment of sod on sod farm s with subsequent transplantation to a residential setting. In calculating treated tu rf 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 fa rm and exposure in a re sidential setting.

Since there are no direct home lawn uses fo r 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 further since the installation process includes watering-in wh ich will tend to increase the dissipation of residues, HED considers risks to toddlers expo sed to treated lawns to be of short-term duration only.

In assessing risks to toddlers from incident al oral exposure, HED sums the total exposure from residue transfer from hand-to-m outh, object-to-mouth and soil ingestion.

Mancozeb Mancozeb exposures and risks resulting from exposure to treated turf were calculated using a 7-day average TTR value. The dose wa s averaged since the e ffect of concern, an alteration of thyroid hormone, is not consider ed an acute affect a nd would not likely be seen after one or two days of exposure.

The level of concern for the mancozeb inci dental oral risk assessment is 1000. MOEsMancozeb Human Health Risk Assessment D327307 & D327318

Page 41 of 62 which exceed 1000 are not of concern.

At a 3-day PHI, mancozeb MOEs for oral exposures from hand-to-mouth transfer of residues and for total incident al oral exposure ar e below 1000 and are of concern. Based on information on residue dissipation, HED calcula tes that an interval of 7 days between treatment and first toddler expos ure to transplanted turf is required to allow residues to dissipate sufficiently to generate combined oral incidental risks that exceed the minimum required MOE of 1000 for toddlers. Assuming tw o days are required to harvest, ship and install the treated sod, a PHI of 5-days would be needed fo r combined incidental oral MOEs to exceed HED’s level of concern of 1000. Table 6.2.2.1, below shows the TTR values and exposures from hand-to-mout h, object-to-mouth and soil ingestion for toddlers exposed to residential turf from day 0 through day 13, as well as MOEs for 3- day and 5-day PHIs. Table 6.2.2.2, below shows the combined exposures and risks for 3- day and 5-day PHIs.

Table 6.2.2.1 Summary of Mancozeb TTR values , Doses and MOEs at 0 to 13 Days After Treatment for Turf

Hand-to-Mouth 3 Object-to-Mouth 4 Soil Ingestion 5

DAT TTR (ug/cm 2 ) Dose (mg/kg/day) MOE TTR (ug/cm 2 ) Dose (mg/kg/day) MOE TTR (ug/g) Dose (mg/kg/day) MOE Aggregate MOE 6

0 9.76 39.0 130.8 1 6.60 26.4 88.4 2 4.46 17.8 59.7 3 3.01 12.0 40.4 4 2.03 8.1 27.3 5 1.37 5.5 18.4 6 0.93 3.7 12.4 7 0.63 2.5 8.4 8 0.42 1.7 5.7 9 0.29 1.1 3.8 10 0.19 0.8 2.6 11 0.13 0.5 1.8 12 0.09 0.4 1.2 13 0.06 0.2 0.8 3-day PHI 1 0.57 0.015 610 2.3 0.0038 2400 7.6 0.00005 180000 490
5-day PHI 2 0.26 0.0069 1300 1.0 0.0017 5400 3.5 0.00002 400000 1100

1 Listed TTR value is averaged over a seven day period begi nning on DAT 5 to account for a 3 day PHI and 2 days for harvesting, shipping and installation.
2 Listed TTR value is averaged over a seven day period begi nning on DAT 7 to account for a 5 day PHI and 2 days for harvesting, shipping and installation.
3 HTM Dose = [(TTR * Saliva extraction factor (0.5) * Surface area of hands (20 cm 2 ) * Frequency (20 hand to mouth contacts per hour) * Exposure Duratio n (2 hours) * 0.001 mg/ug)] / [BW (15 kg)]
4 OTM Dose = [(TTR * Ingestion rate for mouthing grass (25 cm 2 /day) * 0.001 mg/ug)] / [BW (15 kg)]
5 Soil Ingestion Dose = [(Soil Concentration (ug/gm)* Soil i ngestion rate (100 mg/day) * 0.001 mg/ug)] / [BW (15 kg)] 6 Aggregate MOE refers to total MOE for hand-to-mouth, objec t-to-mouth and soil ingestion and does not include food residues.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 42 of 62 Table 6.2.2.2 Summary of Mancozeb Incide ntal Oral Exposures and Risks for Toddlers Exposed to Treated Turf

Exposure Pathway 3-Day PHI Mancozeb

TTR* 3-Day PHI Dose (mg/kg/day) 3-Day PHI Incidental Oral MOE 5-Day PHI Mancozeb

TTR** 5-Day PHI Dose (mg/kg/day) 5-Day PHI Incidental Oral MOEHand-toMouth 0.57 ug/cm 2 0.015 610 0.26 ug/cm 2 0.0069 1300Object-tomouth 2.3 ug/cm 2 0.0038 2400 1.0 ug/cm 2 0.0017 5400

Soil Ingestion 7.6 ppm 0.00005 180000 3.5 ppm 0.00002 400000

Total 0.019 490 0.0086 1100 * Based on a 3-day PHI and including an additional 2 days to account for harvesting, shipping and installation, resulting in 5 days between trea tment and residential exposure. ** At PHI noted plus two days for harves ting/shipping/installing, MOE exceeds 1000.

Since there were no dermal endpoints selected for mancozeb, a short-term dermal risk assessment for toddlers as a result of cont act with trea ted turf is not required.

ETU The calculations for the ETU MOEs were not updated from the Mancozeb ORE Assessment for the RED (D286871 of 5/15/2003) b ecause they indicated that there was no risk concern with a PHI of 3 days.

The level of concern for the ETU incidental oral and dermal risk assessments is 1000.

Mancozeb-derived ETU incidental oral exposur es and risks to toddl ers 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 not of concern. Incidental oral exposures and risk are summarized in Table 6.2.2.3, below.

Table 6.2.2.3 Summary of ETU Incidental Oral Exposures and Risks for Toddlers Exposed to Treated Turf Exposure Pathway ETU TTR* Dose (mg/kg/day) MOE Hand-to-Mouth 0.0085 ug/cm 2 0.0030 2300 Object-to-Mouth 0.034 ug/cm 2 0.00075 9300 Soil Ingestion 0.11 ppm 0.00001 700000 Total 0.00376 1900 * Based upon the existing PHI of 3 days and including an additional 2 days to account for harvesting, shipping and installation.

The short-term dermal exposures and risks fo r toddlers exposed to treated, transplanted turf are summarized in the table below. Short- term dermal risk to toddlers in contact with treated turf with a 3-day PHI was above 1000 and was; therefore, not of concern.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 43 of 62 Table 6.2.2.4 Summary of ETU Short-Term Dermal Exposures and Risks for Toddlers Exposed to Treated Turf Exposure Pathway ETU TTR* Dose (mg/kg/day) MOE Dermal 0.0085 ug/cm 2 0.0022 3100 * Based upon the existing PHI of 3 days and including an additional 2 days to account for harvesting, shipping and installation

.

6.2.3 Treated Turf Postapplication Scenario for Adults

Mancozeb The only postapplication scenario for adults in contact with treated tu rf is via the dermal route of exposure. Since no dermal endpoints were selected for mancozeb, a risk assessment for this scenario is not required.

ETU Adults may be exposed to mancozeb-derived ETU through dermal contact with turf. The MOE for short/intermediate-term dermal risk for the adult golfer exposed to ETU from contact with mancozeb treated golf courses exceeded 1000 and was; therefore, not of concern. Exposure and risk for adult golfe rs is summarized in the table below.

Table 6.2.3.1 ETU Short/Intermediate-Term D ermal Postapplicatio n Risks for Adults Exposed to Turf

Activity Application Rate (lb ai/acre) Mancozeb TTR (ug/cm 2 ) ETU TTR (ug/cm2) Transfer Coefficient

(cm 2 /hr) Hours per Day Exposure ETU Dose (mg/kg/day) MOE

Golf 17.4 9.76 0.060 500 4.0 0.00076 6600

Cancer Cancer risk to adult golfers from exposure to mancozeb-derived ETU is shown in the table below. Postapplication cancer risk for adult golfers is well below 3 x10 -6 and is not of concern.

Table 6.2.3.2 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 6 x 10 -8

6.3 Spray Drift

Spray drift is always a potential source of exposure to resident s nearby to spraying operations. This is particular ly the case with aerial appl ication, but, to a lesser extent,Mancozeb Human Health Risk Assessment D327307 & D327318

Page 44 of 62 could also be a potential source of expos ure from the ground application method employed for mancozeb. 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 pr actices. 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 Ag ency 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 assessmen ts 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 mana gement practices to re duce off-target drift with specific products with sign ificant risks associat ed with drift. It is noted that the application rate for turf was modeled to es timate postapplication residential exposure of toddlers. As this rate is highe r than many of agricultural appli cation rates, this scenario is protective of any exposure of farm children via spray drift from agricu ltural applications.

7.0 Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, HE D must consider and aggregate 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 NOAE L or PAD), or the risks themselves can be aggregated. When aggregating exposur es and risks from various sources, HED considers both the route and duration of exposure.

Based on the existing and newly proposed uses of mancozeb, exposure to mancozeb and to mancozeb-derived ETU can occur both fr om dietary sources (food and water) and in residential settings. The mancozeb uses in home gardens result in handler exposure for adults and postapplication exposure to adu lts and youth working in the garden. The mancozeb turf uses result in postapplication exposure to t oddlers playing on treated turf and adults participating in activities such as golf.

Mancozeb’s potential for carci nogenicity is due to the formation of the metabolite ETU; therefore, aggregate cancer ri sks are calculated based on exposure to mancozeb-derived ETU, using the cancer potency factor for ETU.

The aggregate risk assessments are intended to be representative of exposures that are likely to co-occur. For the purpose of th is risk assessment, HED only aggregated scenarios that they believed are likely to co-occur.

Mancozeb Residues of mancozeb per se are not expected in drinki ng water, so aggregate risk assessments for mancozeb are limited to combined food and residential pathways. Additionally, an endpoint was not selected fo r dermal risk assessment since there was no systemic toxicity observed at the highest dos e tested in the dermal studies; therefore exposure from the dermal route is not in cluded in the mancozeb aggregate riskMancozeb Human Health Risk Assessment D327307 & D327318

Page 45 of 62 assessments.

At the RED negotiated PHI of 3 days for sod fa rm use of mancozeb, incidental oral risks to toddlers are below the minimum required MO E of 1000; therefore si nce those risks are already of concern an aggr egate risk assessment can not be conducted. HED also conducted an aggregate risk assessment for toddl ers in contact with treated turf assuming an 5-day PHI, the PHI required for risks from incidental oral exposure to exceed 1000.

The following aggregate risk assessments were conducted for mancozeb per se to support the proposed new uses:

• Mancozeb Acute Aggregate which considers acute exposure to mancozeb per se from food only

• Mancozeb Short/Intermediate-Ter m Home Garden Aggregate (Adult) which considers residential handler exposures (i nhalation) to adult a pplicators combined with average food exposures

• Mancozeb Short/Intermediate-Term Treated Turf Aggregate (Toddler) which considers residential incident al oral exposures to toddl ers combined with average food exposures

• Mancozeb Long-Term (Chronic, Non-Cancer) Aggregate which considers chronic exposure to mancozeb per se from food only

ETU The following aggregate risk assessments were conducted for mancozeb-derived ETU to support the proposed new uses:

• ETU Acute Aggregate which considers acute exposur e to mancozeb-derived ETU from food and water

• ETU Short/Intermediate-Term Home Garden Aggregate which combines handler exposures (inhalation and dermal) and posta pplication garden exposures (dermal) plus food and water exposures for adults and postapplication garden exposures (dermal) plus food and water exposures for youth

• ETU Short-Term Treated Turf Aggregate (Toddlers) which combines treated turf postapplication exposures (incidental or al and dermal) plus food and water exposures for toddlers

• ETU Short/Intermediate-Term Treated Turf Aggregate (Adults “Golfers”) which considers short-term reside ntial exposures (dermal) pl us food and water exposures for adults participating in activities such as golf on treated turf

• ETU Long-Term (Chronic, Non Cancer) Aggregate which considers exposure from food and water only

• ETU Cancer Aggregate which combines handler home garden exposures (dermal and inhalation), postapplication home gard en exposures (dermal), postapplication treated turf exposures (dermal) a nd chronic food and water for adultsMancozeb Human Health Risk Assessment D327307 & D327318

Page 46 of 62 7.1 Acute Aggregate Risk

7.1.1 Mancozeb Acute Aggregate Risk

HED has calculated the acute dietary risk fo r females 13-49 years of age in Section 5.2.1 of this risk assessment. Since food is the only source contributing to the acute aggregate risk assessment, the acute aggregate risk as sessment for mancozeb is equivalent to the acute dietary risk assessment detailed in Section 5.2.1. HED has no concern for acute aggregate risks to females 13 – 49 yrs, the s ubgroup of concern, resu lting from exposure to mancozeb per se from the existing and new uses of mancozeb.

7.1.2 ETU Acute Aggregate Risk

HED has calculated the acute dietary risk for females 13 – 49 years of age from mancozeb-derived ETU in Section 5.2.1 of th is risk assessment. Since HED considers only dietary (food and water) contributions to the ETU acute aggregate risk, the ETU acute aggregate risk assessment is equivalent to the ETU acute di etary (food and water) risk assessment for ETU detailed in S ection 5.2.1. HED has no concern for acute aggregate risks to females 13 – 49 yrs, the s ubgroup of concern, resu lting from exposure to mancozeb-derived ETU through food and wa ter resulting from the existing and new uses of mancozeb.

7.2 Short/Intermediate-Term Aggregate Risk

7.2.1 Mancozeb Short/Intermediate-Te rm Aggregate Risk Assessments

7.2.1.1 Mancozeb Short/Intermediate-Te rm Home Garden Aggregate (Adult)

Since there are no dermal endpoints selected for mancozeb, the home garden aggregate risk assessment does not include dermal exposur e. Further, since residues of mancozeb are not expected in drinking water, only manc ozeb food residues are considered. This assessment combines residential handler exposur es (inhalation) to ad ult applicators plus average food exposures. The exposure valu e used for food represents the highest exposure found from all adult populations in the mancozeb chronic dietary exposure
assessment.

Aggregate short/intermediate-term home garden risk for adults far exceeds the level of concern of 1000 for this risk assessmen t and is not of concern. Mancozeb short/intermediate-term home garden aggregat e (adult) risk calculations are summarized in the table below.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 47 of 62 Table 7.2.1.1 Mancozeb Short/Intermediate -Term Home Garden Aggregate (Adult) Risk Calculations

Short/Intermediate-Term Scenario

Population LOC for Aggregate Risk 1 MOE food 2 MOE oral 3 MOE dermal 4 MOE inhalation 5 Aggregate MOE (food and residential) 6

Adult 1000 130000 N/A N/A 890000 110000

1 The LOC is based on UF A = 10, UF H = 10, UF DB = 10
2 MOE food = [(short/intermed iate-term oral NOAEL)/(chronic dietary exposure)]. ST/IT oral NOAEL = 9.24 mg/kg/day; Chronic food exposure = 0.000071 mg/ kg/day from Table 5.2.4.1 (highest exposed adult subgroup)
3 N/A is “not applicable” since oral expos ures are not expected for adult populations.
4 N/A is “not applicable” sin ce a dermal endpoint was not sele cted for mancozeb based on lack of systemic toxicity at the high dose tested in the 28-day dermal study.
5 Inhalation MOE from Table 6.1.1 (backpack sprayer scenario)
6 Aggregate MOE (food and residential) = 1

 / [(1/MOE food) + (

 1/MOE oral) + (1/MOE derm al) + (1/MOE inhalation)]

7.2.1.2 Mancozeb Short-Term Treate d Turf Aggregate (Toddler)

Since there are no dermal endpoi nts selected for mancozeb and no likelihood of residues in drinking water, the mancozeb short-term treated turf aggregate risk assessment for toddlers combines residential incidental oral exposures with average food residues. The exposure value used for food represents the highest exposure found from all child populations in the mancozeb chronic dietary exposure assessment.

HED calculated incidental oral exposures a nd risks to toddlers based on the assumption that the sod farm use labels would reflect a 3- day PHI. At that PHI, estimated risks to toddlers were below 1000 and were of concern. Because the individu al incidental oral risks at a 3-day PHI were below the level of concern, no further aggregation could be conducted.

HED calculated the PHI needed to bring the MOE for incidental oral risk to toddlers from exposure to mancozeb from treated turf a bove 1000. At a PHI of 5-days, assuming an additional 2 days for harvest, shipping and in stallation, MOEs for toddl er incidental oral risk exceed 1000, and are no longer of concern. The aggregate risk assessment provided in this section assumes mancozeb exposures based on a PHI of 5-days for sod farm use of mancozeb.

At a 5-day PHI for the sod farm use, mancozeb short-term aggregate risks for toddlers exposed to treated turf the aggregate risk is greater than 1000 and is not of concern. Mancozeb short-term treated tu rf aggregate risk calculations for toddlers are shown in the table below.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 48 of 62 Table 7.2.1.2 Mancozeb Short-Term Treated Tu rf Aggregate (Toddler) Aggregate Risk Calculations

Short-Term Scenario

Population NOAEL mg/kg/day LOC 1 Max Allowable Exposure 2 mg/kg/day Average Food 3 mg/kg/day Residential Exposure 4 mg/kg/day Aggregate MOE (food and residential) 5

Toddler 9.24 1000 0.00924 0.000167 0.0086 1100

1 The LOC is based on UF A = 10, UF H = 10, UF DB = 10
2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC
3 Average food residue is for most highly exposed chil d subpopulation from the chronic dietary assessment from Table 5.2.4.1
4 Residential Exposure = hand-to- mouth + object-to-mouth + soil ingestion exposur e from Table 6.2.2.2. 5 Aggregate MOE = [(NOAEL

 / (Avg Food & Water Exposure + Residential Exposure)]

7.2.2 ETU Short-Term Risk Assessments

7.2.2.1 ETU Short/Intermediate-T erm Home Garden Aggregate

The ETU short/intermediate-term home gard en aggregate combines handler inhalation and dermal exposures and postapplication gard en dermal exposures plus average food and water exposures for adults exposed to ma ncozeb-derived ETU. For youth exposed to mancozeb-derived ETU, the assessment co mbines postapplication garden dermal exposures with average food and water exposures. Average food and water exposure values reflect the most highly exposed a dult or youth subpopulation from the chronic dietary assessment.

The mancozeb-derived ETU short/intermediat e-term home garden aggregate MOEs for adults and youth exceed 1000, the level of concer n for this risk assessment and are not of concern. Aggregate risk calculations are shown in the table below.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 49 of 62 Table 7.2.2.1 ETU Short/Intermed iate-Term Home Garden A ggregate Risk Calculations

Short/Intermediate-Term Scenario

Population NOAEL mg/kg/day LOC 1 Max Allowable Exposure 2 mg/kg/day Average Food & Water Exposure 3 mg/kg/day Residential Exposure 4 mg/kg/day Aggregate MOE (food and residential) 5

Adults 5 1000 0.005 0.000030 0.000363 13000

Youth 7 1000 0.007 0.000071 0.000240 22000

1 The LOC is based on UF A = 10, UF H = 10, UF DB = 10
2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC
3 Average food and water exposure taken from most highl y exposed adult or youth subpopulation from the chronic dietary exposure assessm ent in Table 5.2.4.3.
4 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure] . Combined dermal and inhalation exposure for adult handlers is 4.5 x 10 -5 mg/kg/day (Table 6.1.2). Dermal post application exposure for adults is 3.1 x 10 -4 mg/kg/day (Table 6.2.1.1). Dermal pos tapplication exposure for youth is 2.4 x 10 -4 mg/kg/day (Table 6.2.1.1)
5 Aggregate MOE = [NOAEL /(Avg Food & Water Exposure + Residential Exposure)]

7.2.2.2 ETU Short-Term Treated Turf Aggregate (Toddlers)

The short-term treated turf aggregate risk assessment combines treated turf postapplication incidental oral and dermal exposures with average food and water exposures for toddlers. Average food and wa ter exposure values reflect the most highly exposed child subpopulation from the chronic di etary assessment. Since incidental oral risks for toddlers from mancozeb-derived ETU were not of concern at a 3-day PHI, those values were used for this aggregate risk a ssessment. Increasing the PHI for the sod farm use to 5 days would result in less risk than shown below.

The mancozeb-derived ETU short-term treated turf aggregate MOE for toddlers exceeds 1000, the level of concern for this risk assessm ent and is not of concern. Aggregate risk calculations are shown in the table below.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 50 of 62 Table 7.2.2.2 ETU Short-Term Treated Turf (Toddlers) Aggregate Risk Calculations

Short-Term Scenario

Population NOAEL mg/kg/day LOC 1 Max Allowable Exposure 2 mg/kg/day Average Food & Water Exposure 3 mg/kg/day Residential Exposure 4 mg/kg/day Aggregate MOE (food and residential) 5

Toddlers 7 1000 0.007 0.000071 0.00596 1200

1 The LOC is based on UF A = 10, UF H = 10, UF DB = 10
2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC
3 Average food and water exposure taken from most hi ghly exposed child subpopulation from the chronic dietary exposure assessment in Table 5.2.4.3.
4 Residential Exposure = incidental oral exposure + dermal exposure. Incide ntal oral exposure is 0.00376 mg/kg/day (Table 6.2.2.3). Dermal exposure is 0.0022 mg/kg/day (Table 6.2.2.4)
5 Aggregate MOE = [NOAEL /(Avg Food & Water Exposure + Residential Exposure)]

7.2.2.3 ETU Short/Intermediate-Term Treate d Turf Aggregate (Adults “Golfers”)

The short/intermediate-term treated turf a ggregate risk assessment combines dermal exposures for adults participating in activiti es such as golf on treated turf exposed to mancozeb-derived ETU with chroni c food and water exposures.

The mancozeb-derived ETU short-term treated turf aggregate MOE for adults (“golfers”) exceeds 1000, the level of concern for this ri sk assessment, and is not of concern. Aggregate risk calculations ar e shown in the table below.

Table 7.2.2.2 ETU Short/Intermediate-Ter m Treated Turf (Adults “Golfers”) Aggregate Risk Calculations

Short-Term Scenario

Population NOAEL mg/kg/day LOC 1 Max Allowable Exposure 2 mg/kg/day Average Food & Water Exposure 3 mg/kg/day Residential Exposure 4 mg/kg/day Aggregate MOE (food and residential) 5

Adults (Golfers) 5 1000 0.005 0.000030 0.00076 6300

1 The LOC is based on UF A = 10, UF H = 10, UF DB = 10
2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC
3 Average food and water exposure taken from most hi ghly exposed adult subpopulation from the chronic dietary exposure assessment in Table 5.2.4.3.
4 Residential Exposure = Dermal e xposure. Adult dermal exposure is 0.00076 mg/kg/day (Table 6.2.3.1)
5 Aggregate MOE = [NOAEL/(Avg Food & Wat er Exposure + Residential Exposure)]Mancozeb Human Health Risk Assessment D327307 & D327318

Page 51 of 62 7.3 Long-Term (Chronic) Aggregate Risk

7.3.1 Mancozeb Chronic (Non -Cancer) Aggregate Risk

There are no long-term reside ntial exposure scenar ios for mancozeb and there is not likely to be residues of mancozeb in drinking water. Therefore, the long-term or chronic (non-cancer) aggregate risk for mancozeb in cludes contribution from dietary (food only) exposure alone. The chronic (non-cancer) a ggregate risk assessment for mancozeb is equivalent to the mancozeb chronic dietary risk assessment conduction in Section 5.2.2 of this document. HED has no concern for ch ronic (non-cancer) aggregate risks to the general population or any regulated subgr oup, resulting from exposure to mancozeb per

se from the existing and new uses of mancozeb.

7.3.2 ETU Chronic (Non-Can cer) Aggregate Risk

The long-term or chronic (non-cancer) aggr egate risk for mancozeb-derived ETU includes contribution from di etary (food and water) exposure alone. The chronic (noncancer) aggregate risk assessment for manco zeb-derived ETU is equivalent to the mancozeb-derived ETU chronic dietary ri sk assessment conduction in Section 5.2.2 of this document. HED has no concern for ch ronic (non-cancer) aggregate risks to the general population or any regulated subgr oup, resulting from exposure to mancozebderived ETU from the existing and new uses of mancozeb.

7.4 Cancer Aggregate Risk

For the aggregate cancer risk assessment, HED combined residential handler and postapplication exposures for adults exposed to mancozeb-derived ETU from the home garden uses, as well as postapplication exposures to adults from cont act with treated turf during activities such as golf. The combined residential exposure was then aggregated with dietary exposure to mancozeb-derived ETU from food and water and compared to the ETU Q 1 *

.

Because of the uncertainties re garding estimation of cancer potency and human exposure, risk estimates ranging from 1 x10 -6 to 3 x10 -6 are generally considered indistinguishable. Additionally, HED generall y has no concern for cancer risk estimates which do not exceed 3 x10 -6 . Mancozeb-derived ETU aggregate cancer risk for the U.S Population does not exceed 3 x 10 -6 and is; therefore not of concern. ETU aggregate cancer calculations are shown in table 7.5, below.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 52 of 62 Table 7.5 ETU Aggregate Cancer Calculations

Population Q 1 * (mg/kg/day) -1 Negligible Risk Level 1 Chronic Food & Water Exposure 2 (mg/kg/day) Residential Exposure 3

(LADD) Aggregate Cancer Risk (food, water and residential) 4

U.S. Pop 6.01 x 10 -2 3 x10 -6 3.2 x10 -5 3.98 x 10 -6 2.2 x 10 -6

1 Because of the uncertainties regarding estimation of cancer potency and human exposure, risk estimates ranging from 1 x10 -6 to 3 x10 -6 are generally considered indistinguishable. Additionally, HED generally has no concern for cancer risk estimates which do not exceed 3 x10 -6

2 From Table 5.2.4.3
3 Handler LADD (low pressure handwand – highest exposure scenario) is 3.8 x10 -7 from Table 6.1.3. Home garden postapplication LADD is 2.6 x10 -6 from Table 6.2.1.2 (risk/ Q 1 * = exposure). Treated turf post app LADD is 1.0 x10 -6 from Table 6.2.3.2. Total re sidential exposure is 3.98 x10 -6

. 4 Aggregate Cancer Risk is (total LADD plus chronic food exposure) x Q 1 *

7.5 ETU Aggregate Exposure from All Sources D337241, 42005, T. Goodlow

ETU aggregate exposure and risk assessm ents were conducted to support the new mancozeb uses that are the subject of this action, as well as to support new use of the EBDC, metiram. The acute, chronic and cancer aggregate assessments for ETU considered food, water and residential expos ures resulting from current and proposed uses of metiram, mancozeb and maneb; only mancozeb and maneb are used in residential settings. Acute and chronic risks from all s ources of ETU were not of concern; however, the ETU aggregate cancer risk exceed s HED’s level of concern (3.8 x 10 -6 ). HED conducted sensitivity analyses and determined the greatest contribu tors to ETU exposure are bananas, leaf lettuce, water, turnip green s, grape juice and mangoe s. If the proposed metiram import tolerance in/on bananas (from metiram applications) is removed from the aggregate assessment, then the aggregate cancer risk does not exceed HED’s level of concern (3.2 x 10 -6 ). All other sensitivity analyses re sult in aggregate risks exceeding the level of concern. Note that the metiram-deriv ed ETU residue values from crop field trials used in the aggregate assessment are consider ed to be overestimates. Projected percent crop treated information was not available, so percent imported information was used (virtually 100%) and it is hi ghly unlikely that all bananas wi ll be treated. In general, monitoring data available for other commoditie s show much lower residues than field trial data, so the actual expos ure is likely to be lower. For these reasons, HED is requiring the submission of monitoring data for metiram and ETU on bananas.

8.0 Cumulative Risk Char acterization/Assessment

Unlike other pesticides for which EPA has fo llowed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to mancozeb and any other s ubstances. Mancozeb does produce a toxic metabolite, ETU, which is produced by other EBDC compounds. Ri sks from combinedMancozeb Human Health Risk Assessment D327307 & D327318

Page 53 of 62 exposures to ETU from all EB DC compounds are addressed in a separate ETU aggregate risk assessment. For the pur poses of this tolerance acti on EPA has not assumed that mancozeb has a common mechanism of toxici ty with other substances. For information regarding EPA’s efforts to determine whic h chemicals have a common mechanism of toxicity and to evaluate the cumulative e ffects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures fo r cumulating effects from substances found to have a common mechan ism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Pathway

D317368, 5/31/2005, T. Dole

9.1 Occupational Handler Exposures and Risks

Handler Exposure Scenarios Based upon the label instructions for the proposed new uses of Dithane M-35 it is assumed that aerial and airblast applications would be made to almonds and that aerial, chemigation and groundboom applications w ould be made to the vegetable crops (broccoli, cabbage, lettuce and peppers). Although Dithane M-35 is a wettable powder (WP) formulation, scenarios for Dithane DF, which is a dry flowable formulation (DF) are also considered because the existing re sidue chemistry data support use of the DF formulation and because the DF formulati on is less hazardous to handle. Although flagger scenarios are normally considered for aerial application, they are not considered for mancozeb because the RED prohi bits the use of human flaggers.

Calculation Methods The proposed new uses of mancozeb are similar to the existing uses that were included in the Mancozeb ORE Assessment for the RED (D317368, T. Dole, 5/31/2005) and the same calculation methods were used. Only inhalation MOEs were calculated for mancozeb exposures because no effects were observed in the mancozeb 28-day dermal toxicity study. In the case of ETU, howeve r, both inhalation and dermal exposures were considered for both noncancer and cancer risk assessments. The level of concern (LOC) for both the mancozeb and ETU occupational risk assessments is for MOEs below 100. The level of concern for occ upational cancer risks is 1 x 10 -4 to 1 x 10 -6 as discussed in the Dan Barolo memo of August 14, 1996. According to this memo “In considering applications for new registrations with non-di etary cancer risks, OPP carefully examines those uses with potential risks in the 10 -6 to 10 -4 range to seek ways of reducing those risks before registration occurs”.

Assumptions Used for Calculat ing Occupational Handler Risks The following assumptions and exposure factors were used:

• A body weight of 70 kg was used for assess ing mancozeb inhalation non-cancer risks and ETU cancer risks because the en dpoints were not gender specific.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 54 of 62 • A body weight of 60 kg was used for assessing ETU non-cancer risks because the ETU endpoint is specific to females.

• The amount of mancozeb that converts to ETU is 0.1 percent during mixing and 0.2 percent during loading based upon 1989 Ta nk Mix Data as discussed in the Mancozeb ORE Assessment for the RED.

• The dermal absorption factors are 1.0 per cent for mancozeb and 26 percent for ETU.

• The maximum proposed application rates were used.

• The daily acres treated per day are fro m the Health Effects Division Science Advisory Committee on Exposure Policy 9: Standard Values for Daily Acres Treated in Agriculture which was completed on July 5, 2000. The following values were used: - Aerial Application: 350 acres per day for almonds

- Chemigation: 350 acres per day for vegetables;

- Groundboom: 80 acres per day treated for vegetables;

- Airblast: 40 acres per day for almonds;

• The cancer risks were assessed using thirty days per year as was done in Mancozeb ORE Assessment for the RED for the existing uses.

• Flagging exposures were not assessed becau se the Mancozeb RED prohibits human flagging. This is consistent with the fact that Global Positioning Satellite technology is now predominantly used as indicate d by the 2003 National Agricultural Aviation Association (NAAA) survey.

• Baseline PPE includes typical work cl othing (i.e., a long-sleeved shirt, long pants, shoes, socks, and no respiratory protection). It does not include chemical-resistant gloves

.

• Single Layer PPE includes chemical-resistant gloves in addition to ba seline clothing.

• PF5 Respirator : is a respirator with a protecti on factor of 5 (i.e., it provides 80 percent inhalation protection). A PF5 resp irator is a filtering facepiece respirator (i.e. a dust mask) that provides dust/mist filtering only.

• It was assumed that that aerial applica tion would be done using closed cockpit aircraft as required by the RED.

• It was assumed that groundboom and airblast application would be done using open cab tractors because closed cab tr actors are not required by the RED.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 55 of 62 Unit Exposure Data Sources All of the unit exposure values used in this assessment are from the PHED Surrogate Guide of August 1998. This guide is a series of tables of standard unit exposure values for many occupational scenarios that can be utilized to ensure c onsistency in exposure
assessments.

Occupational Handler Risk Summary The handler risks for the mixing and loadi ng of mancozeb for the new use crops are shown in Table 9.1.1. The mancozeb inhala tion MOEs for mixing/ loading WP without respirators are below the level of concern of 100. If PF5 respirators are added, the inhalation MOEs range from 100 to 300 which exceed the level of concern. If the DF formulation is used, however, the inhala tion MOEs range from 1100 to 3400 without respirators. The ETU MOEs for mixing load ing WP are also less than the ETU MOEs for mixing/loading DF. The cancer ri sks for mixing/loading WP are in 10 -4 range if respirators are not worn, how ever, they are in the 10 -5 range if PF5 respirators are worn. The cancer risks for mixing/loading DF are in 10 -6 range, however, even if respirators are
not worn.

Table 9.1.1: Occupational Handler Risks for Mixi ng/Loading Mancozeb for the Proposed New Uses

Crops Treated lb ai per

acre acres per day Mancozeb Inhalation MOE without

Respirator Mancozeb Inhalation MOE with

PF5 2 Respirator ETU MOE with Single Layer PPE 3 ETU MOE with Single Layer PPE and PF5

Respirator ETU Cancer Risk with Single Layer PPE ETU Cancer Risk with Single Layer PPE and PF5

Respirator

Mixing Loading WP (Dithane M-45)

almonds peppers (east) other vegetables 1 4.8 2.4 1.6 350 350 350 20 41 61 100 200 300 52 100 160 220 430 650 2 x 10-4 1 x 10-4 7 x 10-5 5 x 10-5 2 x 10-5 2 x 10-5 Mixing/Loading DF (Dithane DF-45)

almonds peppers (east) other vegetables 1 4.8 2.4 1.6 350 350 350 1,100 2,300 3,400 not needed 1,400 2,900 4,300 not needed 7 x 10-6 4 x 10-6 3 x 10-6 not needed

1. Includes broccoli, cabbage, lettuce and peppers 2. A PF5 respirator is a filte ring facepiece respirator (i.e. a dustmask) that reduces inhalation exposur e by a factor of 5. 3. Single layer PPE includes standard work clothing (i.e. l ong pants, long sleeve shirts) a nd chemical resistant gloves.

* MOES in bold font do not exce ed the target MOE of 100 for mancozeb or ETU and are of concern.

The risks of mixing/loading WP were r ecognized in the Mancozeb RED and the following mitigation was adopted: "To mitigat e handler risks from this use, the WP labels must require the following personal pr otective equipment PPE: single layer with gloves and a PF 5 dust-mist respirator. The Ag ency believes that these measures will mitigate handler risk concerns to the extent feasible. Cancer risk estimates for handlers wearing single layer PPE, gloves and a PF 5 respirator are in the range of 1 x 10 -6 for groundboom, airblast, and hand a pplication (e.g. handwand). Fo r aerial application and chemigation, cancer risks are in the 10 -5 range and the chronic MOE for small grains, cotton, and cucurbits is 89 with the PPE descri bed above. EPA believes that the respirator requirement for the WP formulation will ha ve a positive effect in reducing potential exposures, resulting in a gradual shift in th e industry to the safer DF formulation."Mancozeb Human Health Risk Assessment D327307 & D327318

Page 56 of 62 The handler risks for the app lication of mancozeb to the new use crops are shown in Table 9.1.2, below. The mancozeb and ETU MOEs exceed 100 with baseline PPE and are not of concern. The cancer risks are in the 10-6 range and are also not of concern.

Table 9.1.2: Occupational Ha ndler Risks for Applying Mancozeb for the Proposed New Uses

Crops Treated lb ai per

acre acres per day Mancozeb Inhalation MOE without

Respirator Mancozeb Inhalation MOE with

PF5 2 Respirator ETU MOE with Baseline PPE 3 ETU MOE with Single Layer PPE ETU Cancer Risk with Baseline

PPE ETU Cancer Risk with Single Layer PPE

Aerial Application (Closed Cockpit Aircraft)

almonds peppers (east) other vegetables 1 4.8 2.4 1.6 350 350 350 13,000 39,000 26,000 Not needed 15,000 31,000 46,000 Not needed 7 x 10-7 3 x 10-7 2 x 10-7 Not needed

Groundboom Application (Open Cab Tractors) peppers (east) other vegetables 1 2.4 1.6 350 350 10,000 16,000 Not needed 21,000 63,000 Not needed 5 x 10-7 3 x 10-7 Not needed Airblast Application (Open Cab Tractors)
almonds 4.8 40 1,700 Not needed 1,900 Not needed 5 x 10-6 4 x 10-6 1. Includes broccoli, cabbage, lettuce and peppers 2. Baseline PPE includes standard work clothi ng (i.e. long pants and long sleeve shirts). 3. Single layer PPE includes standard work clothing and chemical resistant gloves.

* MOES in bold font do not exce ed the target MOE of 100 for mancozeb or ETU and are of concern.

9.2 Occupational Postapplication Exposures and Risks

Exposure Scenarios The mancozeb new uses incl ude the following crop groups:

• Trees, Nut, (Almond)

• Vegetable, Brassica (Broccoli and Cabbage)

• Vegetable, fruiting (Pepper)

• Vegetable, leafy (Lettuce);

Within each agronomic group, a variety of cultu ral practices are requi red to maintain the included crops. These practices are varied and typically involv e light contact with immature plants as well as heavy contact with more mature plants. The exposures scenarios and transfer coeffici ents for the new use crops are listed in Table 9.2.1, below:

Table 9.2.1 - Post Application Exposu re Scenarios and Transfer Coefficients

Crop Group (Specific Crops) Post Application Exposure Scenarios Transfer Coefficient

(cm 2 /hr)

Tree, Nut (Almonds) Low - Irrigation, scouting, thinning, weeding Medium – N/A High – Pruning (Not assessed, done in winter) 400 N/A N/A
Vegetable, Brassica Low - Irrigation, scouting, thinning weeding immature plants Medium - Irrigation and scouting mature plants 2000 4000Mancozeb Human Health Risk Assessment D327307 & D327318

Page 57 of 62 Table 9.2.1 - Post Application Exposu re Scenarios and Transfer Coefficients

Crop Group (Specific Crops) Post Application Exposure Scenarios Transfer Coefficient

(cm 2 /hr) (Broccoli and Cabbage) High - Hand harvesting, pruning, topping, tying mature plants 5000

Vegetable, fruiting (Pepper) Low - Irrigation, scouting, thinning, weeding immature plants Medium - Irrigation and scouting mature plants High - Hand harvesting, pruning, staking, tying 500 700 1000

Vegetable, leafy (Lettuce) Low - Irrigation, scouting, thinning weeding immature plants Medium - Irrigation and scouting mature plants High - Hand harvesting, pruning, and thinning mature plants 500 1500 2500

Data Used for Occupational Post application Exposure Scenarios Eight dislodgeable foliar residue (DFR) studies were submitted in support of the reregistration of mancozeb and these were reviewed in Mancozeb ORE Assessment for the RED. The DFR studies were conduc ted on apples, grapes and tomatoes using airblast and groundboom applica tion of Dithane DF dry flowable fungicide. The DFR studies were extrapolated to the new use cr ops as shown in Table 1 below by considering the effects of application method, crop mo rphology and climate. Where two or more studies were available for the same crop type and climate the study with the best data quality was selected to represent that scen ario. Typically the more recent studies had better data quality because the field fortifica tion levels were usually more representative of the measured DFR levels, the field rec overy was less variable and the limits of quantification were lower. In the case of Florida field toma toes, however, an older study was used because a substantial rain event (7.4 inches) occurred on DAT 3 of the more recent study.

Table 9.2.2 - Assignment of Mancozeb DFR Study Data to the New Use Crops

Crop Group (Labeled Crops) Region Study Used (MRID) Parameters Matched

Trees, Nut, (Almond) West WA Airblast Apple (449596-02) application method, climate

Vegetable, Brassica (Broccoli and Cabbage) East

West Florida Groundboom Tomato (425602-01) California Groundboom Tomato (449596-02) application method, climate application method, climate Vegetable, fruiting (Pepper) East West Florida Groundboom Tomato (425602-01) California Groundboom Tomato (449596-02) crop, application method, climate crop, application method, climate Vegetable, leafy (Lettuce) East West Florida Groundboom Tomato (425602-01) California Groundboom Tomato (449596-02) crop, application method, climate crop, application method, climate

Exposure Assumptions, factors and Transfer Coefficients A series of assumptions, factors and transf er coefficients served as the basis for completing the occupational postapplication wo rker risk assessments. Each assumption and factor is detailed below.

• The body weights, dermal absorption fact ors and toxicological endpoints are the same as those used for the occupational handler assessments.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 58 of 62 • Only maximum application rates were us ed for the postapplic ation assessments

• All postapplication cancer risk were b een assessed using 30 days per year.

• Risks were calculated using the transfer coe fficients that are listed in Table 1. These transfer coefficients were generally taken from HED’s revised policy entitled Policy 003.1 Science Advisory Council For Expos ure Policy Regarding Agricultural Transfer Coefficients (August 7, 2000) and are subject to further revision as more data becomes available.

Calculation Methods Because a dermal endpoint was not selected for mancozeb, post application exposures were assessed only for ETU and the specific ca lculation methods are detailed in the ORE Assessment for the RED. The level of con cern for the ETU postapplication occupational risk assessment is for MOEs below 100. The ETU exposure was calculated by adding the ETU dose absorbed from the leaf surface to th e ETU that is metabolically converted from absorbed mancozeb.

Occupational Postapplication Risk Estimates The occupational postapplication risks are summarized in Table 9.2.3. Current label requirements specify a 24 hour Restricted Entr y Interval (REI). Th e non-cancer risks are not of concern at the current REI with MOEs that exceed the level of concern of 100. The cancer risks are also less than 1x10 -4 for all of the scenarios and are not of concern.

Table 9.2.3 - ETU from Mancozeb Occupational Post Application Risks Short/Intermediate Term MOE on Day 1 Crop Group Application Rate (lb a.i./acre) Low Exposure Scenarios* Medium Exposure Scenarios* High Exposure Scenarios* ETU from Mancozeb Non-Cancer Risks (i.e. MOEs) Almonds 4.8 3600 N/A N/A Brassica (Broccoli and Cabbage) - West Brassica (Broccoli and Cabbage) - East 1.6 1.6 2900 2300 1500 1100 1200 920 Leafy Vegetables (Lettuce) - West Leafy Vegetables (Lettuce) - East 1.6 2.4 12000 9200 3900 3100 2400 1800 Vegetable, fruiting (Pepper ) - West Vegetable, fruiting (Pepper) - East 1.6 2.4 10000 7200 7200 5200 5000 3600 ETU from Mancozeb Cancer Risks Almonds 4.8 3 x 10-6 N/A N/A Brassica (Broccoli and Cabbage) - West Brassica (Broccoli and Cabbage) - East 1.6 1.6 4 x 10-6 5 x 10-6 7 x 10-6 1 x 10-5 9 x 10-6 1 x 10-5 Leafy Vegetables (Lettuce) - West Leafy Vegetables (Lettuce) - East 1.6 2.4 9 x 10-7 1 x 10-6 3 x 10-6 4 x 10-6 5 x 10-6 6 x 10-6 Vegetable, fruiting (Pepper ) - West Vegetable, fruiting (Pepper) - East 1.6 2.4 9 x 10-7 1 x 10-6 1 x 10-6 2 x 10-6 2 x 10-6 3 x 10-6 *Task descriptions for each crop and exposure scenario are included in Table 9.2.1.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 59 of 62 10.0 Data Needs and Label Recommendations

10.1 Toxicology

The following toxicology data gaps have b een identified either in previous risk assessments or in this assessment. 10X database uncertainty factors for mancozeb and ETU were applied to account for missing data . Because thyroid toxicity seen with mancozeb is due to ETU, a comparative thyroi d toxicity study is re quired for ETU only.

Mancozeb

• An acute neurotoxicity study

• A developmental neurotoxicity study

ETU

• A developmental toxicity study in rabbits

• A 2-generation reproduction study in rats

• A comparative thyroid study in adults and offspring

• A developmental neurotoxicity study

10.2 Residue Chemistry

The following residue chemistry data needs have been identified specific to this new use action and are required to suppor t the requested new uses.

• One leaf lettuce trial employed use of a “U-boom” application device (which applies the material to the undersides of the plant as well as over the top), resulting in considerably higher residues than the remaining trials. The proposed label must be amended to specifically prohi bit use of such a device. Alternatively the petitioner should submit a full set of trials reflecting this application technique.

• The proposed use for almonds must be amended to remove the instruction to add a surfactant to the spray mixture unless th e petitioner provides confirmation that a surfactant was used in the spray mixtures at the crop field trials used to establish the almond tolerance.

• The petitioner should provide amended Sec tion Fs to express the tolerances as carbon disulfide, and change the proposed levels to broccoli, 7 ppm; cabbage, 9 ppm; head lettuce, 3.5 ppm; leaf lettuce, 18 ppm; pepper, 12 ppm: almond hulls, 4
ppm.

The following data were required in the RED and remain outstanding.

• Ruminant feeding study

• Analytical method for ruminant commodities

• Confined rotational crop studyMancozeb Human Health Risk Assessment D327307 & D327318

Page 60 of 62 • Various crop field trial data to support existing uses

10.3 Occupational and Residential Exposure

No additional data are required with respect to occupational or residential exposure and risk.

11.0 Environmental Justice

Potential areas of environmental justice concer ns, to the extent possi ble, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmenta l 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-es tablished 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 water consumption, and activities in and around the home that involve pesticide use in a re sidential setting. Ex tensive data on food consumption patterns are compiled by the Un ited 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 appr opriate, non-dietary e xposures based on home use of pesticide products and associated risks for adult ap plicators and for toddlers, youths, and adults entering or playing on treated areas pos tapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized so ftware and models that consider exposure to bystanders and farm workers as well as lif estyle and traditional dietary patterns among specific subgroups.

12.0 Regulatory Recommendations

Provided the existing label for the sod farm turf use of mancozeb is revised to stipulate an 5-day PHI, there is nothing in this manco zeb specific risk assessment to preclude the establishment of the requested tolerances at the levels stipulated below.

Further, HED notes that the new uses that are the subject of th is action have been included in the forthcoming ETU aggregat e risk assessment. The ETU aggregate assessment considers exposure and risk from ETU derived from all existing and pending uses of the EBDC pesticides. The addition of these new mancozeb uses does not result in aggregate ETU exposures or risks of concer n when considered with the existing and pending uses of EBDC pesticides.Mancozeb Human Health Risk Assessment D327307 & D327318

Page 61 of 62 Provided the residue chemistry data needs specific to these new uses listed in Section 10.2 of this risk assessment are addres sed, HED recommends in favor of the establishment of tolerances at the le vels noted in Table 12.l, below.

Table 12.1 New Tolerance Summary for Mancozeb

Crop Commodity Proposed Tolerance

(ppm) Recommended Tolerance

(ppm) Comments ( Correct commodity definition ) Tolerances needed under §180.176 (a) Broccoli 13 7.0 Broccoli Cabbage 10 9.0 Cabbage 3.5 Lettuce, head Lettuce 10 18 Lettuce, leaf Peppers 7 12 Pepper Almond nuts 0.1 0.1 Almond Almond Hulls 10 4.0 Almond, hulls

References:

Mancozeb. Heath Effects Division (HED) Human Health Risk Assessment to Support Reregistration. D317371, K. Farwell, 6/3/05

Mancozeb Toxicity Endpoints for Risk Assessment D317369, K. Farwell, 6/3/2005

Mancozeb: Residue Chemistry Chapter of the Reregistration Eligibility Decision D305815, C. Olinger, 6/14/05

Review of Mancozeb Incident Reports D286184, J. Blondell, 10/16/02

Mancozeb on Broccoli, Cabbage, Lettuce, and Peppers. Summary of Analytical Chemistry and Residue Data. PP# 4F4333. D294203, C. Olinger, 4/3/07

Mancozeb on Almonds. Summary of Anal ytical Chemistry and Residue Data. PP#4F4324. D289183, C. Olinger, 4/5/07

Revision No. 2: Estimated Drinking Water C oncentration of Ethylen ebisdithiocarbamate (EBDC) Degrated Ethylenethiourea (ETU ) for the Use in Human Health Risk Assessment D290057, R. Parker, 8/26/2004Mancozeb Human Health Risk Assessment D327307 & D327318

Page 62 of 62 Estimated Drinking Water Concentrations of ETU (Ethylene-thio-u rea, degradate of mancozeb, and common degradate of EBDCs “E thene-bis-dithio-carbamates”) for Use in Human Health Risk Assessment. D323143 and D323141, M. Ruhman, 8/11/2006

PP#4F4324 and 4F4333 Mancozeb Acute, Chronic, and Cancer Dietary Exposure Assessments for New Tolerances on Almonds, Broccoli, Cabbage, Lettuce, and Peppers. D323878 and D323879, C. Olinger, 4/17/07

Mancozeb: 2 nd Revised Occupational and Reside ntial Expsoure Assessment and Recommendations for the Reregistra tion Eligibility Decision Document D317368, T. Dole, 5/31/2005

Reregistration Eligibility Decision for Mancozeb D. Edwards, 9/20/05

Ethylenethiourea (ETU) from EBDCs: Health Effects Division (HED) Human Health Risk Assessment of the Co mmon Metabolite/Degradate ETU D33724, T. Goodlow, 2007