Mancozeb Human Health Risk Assessment OP Nos. 411742 and 411764



### UNITED ST A TES ENVIRONMENTAL PROTEC TI ON AGENCY

WASHINGTON, D.C. 20460

MEMORANDUM

Date: May 1 4, 2013 OFF I C E OF
CH EM I CAL SA FE TY AND

P O L LUTION PREVENTION



### SUBJECT: Mancozeb: Human Health Risk Assessment to Support Proposed New
Section 3 Uses on Walnu t s and Tolerances for Imported Tangerines

PC Code: 014504 DP Barcode: 0411742; 0411764

Dec ision No.:**~{,ft/1,** 

### /ff!OP1 Registration No.: 70506-185

, 70506-194,

70506

- 234, 70506-236

Petition No.: I F7935, 2E8062 Re2ulatorv Action: Section 3

Risk Assessment Type: Single Chemical Aggregate Case No.: 0643

TXRN o.: NA CAS No.: 8018-01-7

MRIDNo.:NA 40 CFR: 180 .176

... . 

### - FROM: Dane tte Drew, Chemist/Risk A p sss

..

## ~ Ana

# Rivera-Lupiafiez**~p emist** **~** Pete Savoia, Chemist 1 '_..l .'

_ 

### Linda Taylor, Ph.D., o xi colog i st

# ~/~~ (..._

Risk Assessment Branch V and VII

Health Effects Division (7509P)



### THROUGH: Michael Metzger, Branch Chi )

# {/~J**~f** R1sk Assessment Branch V an J<l...fi / {

Health Effects Division (7509P)

TO: Heather Garvie, Risk Manager

Tamue Gibson, Ri s k Manager Fungicide Branch Registration Division (7505P)

Attached please find the human h ealt h risk assess me n t for the active ingredien t mancozeb to support requested new uses on walnuts and to s upport import tolerances for the use on mandarin o rang es (tangerines). Th is doc ument supersedes the 4/10/13 document 0397268, Mancozeb: Human Health Risk

Assessment to Support Proposed New Section 3 Use s on Walnuts and Tolerances for Imported Tangerines. This document addresses risks from exposure to mancozeb and mancozeb-derived ethylenethiourea (ETU) o nly. A separate assessmen t addressing risk from ETU derived from all ethylene

bisdithiocarbamate (EBDC) pesticides is forthcoming.



### Page 1 

### of77Mancozeb Human Health Risk Assessment DP No s

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### Page 2 of 77 1.0 Executive Summary

................................ ................................ ................................ ............. 4

2.0 HED Recommendations

................................ ................................ ................................ ....... 9

2.1 Data Deficiencies

................................ ................................ ................................ ............. 9

2.2 Toleranc e Considerations

................................ ................................ ................................ . 9

2.2.1 Enforcement Analytical Method

................................ ................................ ............... 9

2.2.2 Recommended Tolerances

................................ ................................ ...................... 10

2.2.3 Revisions to Petitioned

- For Tolerances

................................ ................................ .. 10

2.2.4 International Harmonization

................................ ................................ ................... 11

2.3 Label Recommendations

................................ ................................ ................................ 11

2.3.1 Recommendations from Residue Reviews

................................ ............................. 11

2.3.2 Recommendations from Occupational Assessment

................................ ................ 11

2.3.3 Recommendations from Residential Assessment

................................ ................... 11

3.0 Introduction

................................ ................................ ................................ ........................ 12

3.1 Chemical Identity

................................ ................................ ................................ ........... 12

3.2 Physic al/Chemical Characteristics

................................ ................................ ................. 12

3.3 Pesticide Use Pattern

................................ ................................ ................................ ...... 12

3.4 Anticipated Exposure Pathways

................................ ................................ ..................... 14

3.5 Consideration of Environmental Justice

................................ ................................ ........ 14

4.0 Hazard Characterization and Dose

- Response Assessment

................................ ................ 15

4.1 Summary of Toxicological Effects

................................ ................................ ................ 15

4.2 Safety Factor for Infants and Children (FQPA Safety Factor)

................................ ....... 18

4.2.1 Completeness of the Toxicology Database

................................ ............................. 19

4.2.2 Evidence of Neurotoxicity

................................ ................................ ...................... 19

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

......... 19

4.2.4 Residual Uncertainty in the Exposure Database

................................ ..................... 20

4.3 Toxicity Endpoint and Point of Departure Selections

................................ .................... 21

5.0 Dietary Exposure and Risk Assessment

................................ ................................ ............ 28

5.1 Residues of Concern Summary and Rationale

................................ ............................... 28

5.2 Food Residue Profile

................................ ................................ ................................ ...... 29

5.3 Wate r Residue Profile

................................ ................................ ................................ .... 30

5.4 Dietary Risk Assessment

................................ ................................ ................................ 31

5.4.1 Description of Residue Data Used in Dietary Assessment

................................ ..... 31

5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ ................ 32

5.4.3 Acute Dietary Risk Assessment

................................ ................................ .............. 32

5.4.4 Chronic Dietary Risk Assessment

................................ ................................ .......... 33

5.4.5 Cancer Dietary Risk Assessment

................................ ................................ ............ 33

5.4.6 Summary Table

................................ ................................ ................................ ....... 33

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

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

6.1 Residential Handler Exposure

................................ ................................ ........................ 35

6.2 Post

- Application Exposure

................................ ................................ ............................. 41Mancozeb Human Health Risk Assessment DP No s

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### Page 3 of 77 6. 2.1 Home Garden Post

- application Scenarios

................................ .............................. 44

6.2.2 Treated Turf Post

- application Scenarios

................................ ................................ . 45

6.3 Residential Risk Estimates for Use in Aggregate Assessment

................................ ...... 47

6.4 Residential Bystander Post

- application Inhalation Exposure

................................ ........ 49

6.5 Spray Drift

................................ ................................ ................................ ...................... 49 7.0 Aggregate Exposure/Risk Characterization

................................ ................................ .......... 50

7.1 Acute Aggregate Risk

................................ ................................ ................................ .... 51

7.2 Short

- Term Aggregate Risk

................................ ................................ ......................... 51

7.3 Intermediate

- Term Aggregate Risk

................................ ................................ ................ 53

7.4 Long

- Term or Chronic Aggregate Risk

................................ ................................ ......... 53

7.5 Cancer Aggregate Risk

................................ ................................ ................................ ... 53 8.0 Cumulative Exposure/Risk Characterization

................................ ................................ ....... 54 9.0 Occupational Exposure/Risk Characterization

................................ ................................ ..... 54

9.1 Short

- and Intermediate

- Term and Cancer Handler Risk

................................ ............... 55

9.2 Short

- and Intermediate

- Term and Cancer Post

- Application Risk

................................ 65

9.2.1 Dermal Post

- Application Risk

................................ ................................ ................ 65

9.2.2 Inhalation Postapplication Risk

................................ ................................ .............. 67

10.0 References

................................ ................................ ................................ .......................... 68 Appendix A. Toxicology Profile and Executive Summaries

................................ ....................... 69 Appendix B. Physical/Chemical Properties

................................ ................................ ................. 76 Appendix C. Review of Human Research

................................ ................................ ................... 77Mancozeb Human Health Risk Assessment DP No s

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### Page 4 of 77 1.0 Executive Summary

Background

The Registration Division (RD) requested that the Health Effects Division (HED) conduct a

human health risk assessment to support 1) a petition for the proposed use of the fungicide mancozeb on walnuts (PP# 1F7935) and 2) a petition to support the establishment of a tolerance

for residues of mancozeb on imported tangerines (PP#2E806 2 ).

There are four United Phosphorus mancozeb end

- use products relevant to the petition for treating

walnuts

. These products are : Penncoze b 75DF (EPA Reg. No. 70506

- 185), Manzate Pro

- Stick Fungicide (EPA Reg. No. 70506

- 234), Penncozeb 4FL Flowable Fungicide (EPA Reg. No.

70506

- 194), and Manzate Flowable (EPA Reg. No. 70506

- 236). The Dow mancozeb product proposed fo r treating tangerines grow n in Korea is the Dithane® M45 Fungicide (EPA Reg. No.

62719

- 387)

.

Mancozeb is a coordination product of zinc ion and maneb (manganese ethylenebisdithiocarbamate) used as a broad

- spectrum fungicide in agriculture, professional turf management, and hortic ulture. In plants and livestock commodities, t he residues of concern for

risk assessment are mancozeb and its metabolite/degradate ethylenethiourea ( ETU ) . The residue of concern in drinking water is ETU only. Tolerances are currently established for res idues of

mancozeb including its metabolites and degradates ( measured as the degradate CS 2 

### ) on a number of crop and livestock commodities.

Mancozeb is a fungicide in the class of ethylenebis dithiocarbamates (EBDC), which also

includes the fungicides maneb and metiram; all of these compounds have a common metabolite/degradate, ethylenethiourea (ETU). Some of the more notable toxicity in the mancozeb studies was due to toxicity from its metabolite, ETU. Thyroid toxicity and developmental toxicity in rats w ere attributed to toxicity from ETU. Injury to peripheral nerves occurred in mancozeb toxicity studies but not in studies with ETU. Separate assessments are presented here in for 1) toxicity and exposure to parent mancozeb only and 2) toxicity and

exposur e to ETU derived from mancozeb, including combined exposures from both ETU as an environmental degradate and ETU as an in vivo metabolite

. A separate assessment addressing

risk from ETU derived from all ethylene bisdithiocarbamate (EBDC) pesticides, not just mancozeb, is forthcoming.

For residential, occupational and dietary exposures, including oral, dermal and inhalation routes of exposure, a 7.5% in vivo metabolic conversion of ab sorbed mancozeb to ETU has been used based on rat metabolism data, and has been accounted for in estimating total exposure ( in vivo metabolism and direct sources) to ETU.

Mancozeb Toxicology

The findings in multiple studies demonstrate that the thyroid is a target organ for mancozeb. Thyroid toxicity was manifested as alterations in thyroid hormones, increased thyroid weight,Mancozeb Human Health Risk Assessment DP No s

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### Page 5 of 77 and microscopic thyroid lesions (mainly thyroid follicular cell hyperplasia). In a subchronic study in the rat, neuropathology w as seen microscopically (injury to peripheral nerves) with associated clinical signs (abnormal gait and limited use of rear legs) and loss of muscle mass. Developmental defects in the rat developmental toxicity study included hydrocephaly, skeletal
system defects, and other gross defects. Abortions occurred in the rabbit developmental toxicity study at the high dose.

The database for mancozeb is extensive and is sufficient for characterizing toxicity and hazard. Although most of the mancozeb risk assess ment endpoints are of thyroid toxicity, a developmental thyroid toxicity study is not available. This datagap will be satisfied by an ongoing developmental thyroid toxicity study with ETU, which is part of an extended one

generation reproductive toxicity (EOGRT) study on ETU. For mancozeb, the FQPA SF (safety factor) of 10X is retained for women of childbearing age (13

- 49 years old) and for children less than 6 years old to account for the lack of data on the developing thyroid. The FQPA safety

factor i s reduced to 1X for other lifestages (children > 6 years, females > 49 years, and adult males), for which the thyroid is largely developed and there are applicable thyroid data.

The recently submitted immunotoxicity study has been reviewed and mancozeb di d not show any immunotoxicity potential.

ETU Toxicology

In addition to assessing risk from exposure to mancozeb, this assessment also considers risks from exposure to mancozeb

- derived ETU.

The toxicology database for mancozeb and ETU is sufficient for characterizing toxicity and

hazard. HED has relied on a combination of guideline data and several studies in the open literature to assess hazard for ETU. The thyroid is a target organ for ET U. Thyroid 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. Over t liver toxicity was observed in one chronic dog study. Developmental 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

.

Toxicology d ata gaps for ETU i nclude a 2

- generation reproduction study in rats, a developmental neurotoxicity study in rats, and a developmental thyroid toxicity study in rats

. These datagaps will be satisfied with the ongoing EOGRT study on ETU. The datagaps being addressed in the EOGRT study could affect women of childbearing age or the developing young, and the ETU FQPA SF of 10X is retained for females 13

- 49 years of age and for children less than 6 years of age. The FQPA safety factor for ETU is reduced to 1X for other lifestages (children > 6 years, females > 49 years, and adult males), for which the thyroid is largely developed and there are applicable thyroid data. Although there was fetal sensitivity for malformations in the ETU developmental rat studies, the endpoints that were selected are protective of these effects.Mancozeb Human Health Risk Assessment DP No s

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### Page 6 of 77 The recently submitted immunotoxicity study on ETU did not show any immunotoxicity potential

.

Cancer

Mancozeb’s potential for carcinogenicity (as well as that of the other EBDCs) is assessed by the metabolite, ETU, which is classified as a probable human carcinogen (B2), with a cancer potency factor (Q 1 * 

### ) of 0.0601 (mg/kg/day) - 1 

### for risk assessment. On this basis, mancozeb cancer risk has been calculated by estimating exposure to mancozeb

- derived ETU (including the metabolic conversion) and using the ETU cancer potency factor to provide a quantitative

estimate of risk.

Dietary Risk Assessments

Residues of manco zeb 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 surface water estimated drinking water concentrations (EDWCs) were

based both on PRZM

- EXAMS modeling information and available monitoring data.

Probabilistic acute dietary exposure and risk assessments were conducted for mancozeb and ETU incorporating maximum percent crop treated or maximum projected percent crop treated

info rmation, field trial or monitoring data, and processing and cooking factors. No acute dietary (food and drinking water) risks of concern were identified for either mancozeb or mancozeb

derived ETU.

The chronic dietary exposure and risk assessments (non

- cancer and cancer) for mancozeb and

mancozeb

- derived ETU incorporated average values based either on field trial data or monitoring data and average percent crop treated data or average projected percent crop treated estimates , as well as processing and c ooking factors. No chronic non

- cancer dietary (food and drinking water)

risks of concern were identified for mancozeb or mancozeb

- derived ETU. The cancer risk estimate associated with exposure to ETU in food and water, as a result of established and

propo sed mancozeb uses, is 2 x 10 - 6 

### for the general U.S. population.

Residential Exposure and Risk

No new residential uses are being added to the label as a result of the current actions ; however,

residential uses that could result in mancozeb and ETU exposure ( i.e., home gardeners applying mancozeb to vegetables or entering treated gardens, and golfers contacting mancozeb treated turf after application ) have been reassessed in this document to reflect updates to toxicology endpoint selections, updates to the Levels of Concern (LOCs), and updates to HED’s 2012 Residential

SOPs

.

Gardens

Residential handler risk estimates for adults applying mancozeb to gardens were assessed for mancozeb (inhalation only; dermal toxicity is not expected for mancozeb) and it’s degradateMancozeb Human Health Risk Assessment DP No s

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### Page 7 of 77 ETU (combined dermal and inhalation ). Non

- cancer short

- term assessments were performed for

both mancozeb and ETU. There are no handler risk estim ates of concern for adults applying mancozeb to home gardens. A cancer assessment was also performed for ETU. The cancer risk s for residential handler s are estimated in the 10 - 8 

### range

.

Residential post

- application risk estimates were assessed for home gardeners (adults and youth) harvesting vegetables from treated gardens. As no dermal hazard was identified for mancozeb, a quantitative dermal post

- application assessment (non

- cancer/shor t

- term and cancer) was only performed for its metabolite, ETU. Inhalation exposures are not expected for the post

application activities. There are no non

- cancer/short

- term risk estimates of concern for adults or youth enteri ng mancozeb treated home garde n. Post

- application cancer risk for adult home gardeners is estimated at 9 x 1 0 - 7



### .

Turf (Golf Courses)

R esidential post

- application risk estimates were assessed for adult and youth golfers contacting mancozeb treated turf after application

. As no dermal hazard was identified for mancozeb , a quantitative dermal post

- application assessment (non

- cancer/short

- term and cancer) was only performed for its metabolite, ETU. Inhalation exposures are not expected for the post

application golfing activities. There are no non

- cancer/short

- term risk estimates of concern for adults or youth golfing on treated turf. The cancer risk to adult golfers is estimated at 3 x 10 - 8



### .

Aggregate Risk Assessments

HED conducted acute, short

- term and chronic non

- cancer aggregate assessments for mancozeb

and mancozeb

- derived ETU, as well as a cancer aggregate assessment for mancozeb

- derived ETU. The aggregate assessments combined the residential scenarios that resulted in the highest estimated exposures with food and drinking wate r exposures. The garden scenarios resulted in higher post

- application exposures than the golfing scenarios; aggregate assessment s using the garden scenario are protective of any post

- application exposures to adult and youth golfers.

The acute and chroni c non

- cancer aggregate assessments include only dietary (food and drinking water) exposures. There are no acute or chronic aggregate risk estimates of concern.

The short

- term aggregate assessment for mancozeb and ETU combined adult residential handler

exp osures and dietary (food only for mancozeb; food and water for ETU) exposures. There are

no short

- term aggregate risk estimates of concern for adults applying mancozeb to gardens.

A short

- term aggregate assessment was performed for ETU for adults and yout h entering treated gardens. Post

- application exposures to ETU were combined with dietary (food and water) exposures. There are no short

- term aggregate risk estimates of concern for adults or youth entering treated gardens.

The cancer aggregate assessment for mancozeb

- derived ETU includes contributions from

residential and dietary (food and water) exposures

. The cancer aggregate risk estimates (han dlerMancozeb Human Health Risk Assessment DP No s

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### Page 8 of 77 and post

- application) for adults applying mancozeb to gardens or entering treated gardens are 2 x

10 - 6 

### and 3 x 10 - 6 

### , respectively.

Occupational Exposure and Risk

Occupational assessments were performed for the proposed U.S. walnut use. An occupational assessment was not performed for the proposed use on imported tangerines.

Handler (Non

- Cancer) Occupati onal handler non

- cancer ( short

- and intermediate

- term ) assessments were performed for

mancozeb and ETU exposures as a result of mancozeb applications to walnuts ( i.e. , during mixing, loading, and applying )

. A handler cancer assessment was also performed for ETU. O nly inhalation exposures were considered for mancozeb because no effects were observed at the limit

dose in a 28

- day dermal rat study. In the case of ETU, however, inhalation and dermal exposures were considered for both the non

- c ancer and cancer risk assessments.

All mixer/loader non

- cancer risk scenarios do not exceed HED’s level of concern ( i.e. , MOEs ≥ 300 for mancozeb exposures and MOEs ≥1000 for ETU exposures) at some level of ris k mitigation ( e.g., gloves

, respirators, or o ther engineering control measures). However, non

c ancer risks estimates for M/L scenarios using dry flowable (DF) formulations in support of aerial applications to walnuts exceed HED’s level of concern for females age 13

- 49 years ( i.e.,

MOE=260 for mancoze b inhalation exposures and MOE=750 for ETU exposures) at label PPE. It should be noted that no respiratory protection equipment or other engineering control measures are requested on the DF labels. With the addition of a respirator, MOE=1300 for mancozeb

i nhalation exposures and MOE=2900 for ETU exposures for females 13

- 49 mixing and loading the DF formulation for aerial application to walnuts.

A ll application non

- cancer risk scenarios do not exceed HED’s level of concern at some level of risk mitigation ( e.g
., gloves or other engineering control measures ). Aerial and airblast applicator risks do not exceed HED’s level of concern ( i.e. , MOEs ≥ 300 for mancozeb exposures and MOEs ≥1000 for ETU exposures) with engineering control ( i.e., enclosed cockpit

or c losed cab). Mixer/loader/ applicator s with mechanically pressurized handgun risks do not
exceed HED’s level of concern at label PPE ( i.e., gloves, no respirator).

Handler (Cancer)

The ETU cancer risks for all mix ing /loading (M/L) scenarios (all formulat ion types) for private

handlers are estimated in the 10 - 6 

### to 10 - 8 

### range at label PPE ( i.e., gloves, no respirator).

The ETU c ancer risks for commercial handlers M/L scenarios using dry flowable (DF) formulations in support of aerial applications ranged from 1 x10 - 5 

### at label specified PPE to 5 x 10 -

7 

### with the use of water soluble bags (WSB) as an engineering control measure ; the requested addition of a PF5 respirator to the DF labels would result in a cancer risk of 3 x10 - 6 

### for these M/L

handlers

. Cancer risks for commercial M/L scenarios using DF formulations in support of airblast applications ranged from 2 x10 - 6 

### at label PPE to 4 x 10 - 7 

### with the addition of the PF5 respirator.Mancozeb Human Health Risk Assessment DP No s

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### Page 9 of 77 Cancer risks for both private and commercial handlers M/L liquids in support of aerial and airblast applications are in the 10 - 7 

### to 10 - 8 

### range at label PPE.

For applicators, t he ETU cancer risks for applying to walnuts via airblast range from 10 - 6 

### (open cab, no respirator) to 10 - 8 

### (closed cab). The cancer risks for mixing/loading/application (M/L/A)

scenarios are estimated in the 10 - 7 

### range for both private and commercial handlers at label PPE.

Post

- Application (Non

- Cancer) All post

- application occupational exposure scenarios assessed resulted in short

- term/

interme diate term dermal MOEs that do not exceed HED's level of concern ( i.e.

, ETU MOEs ≥ 1000) at mancozeb current Restricted Entry Interval (REI) of 24 hours which is also proposed for walnut crops

.

Post

- Application (Cancer)

The ETU cancer risk estimates for walnut post

- application worker scenarios assessed are in the

10 - 7 

### to 10 - 8 

### range for private growers and 10 - 6 

### to 10 - 7 

### for commercial growers at Day 1 (at the 24 hour REI)

.

Environmental Justice Considerations

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898 . Refer to Section

3.5 of this document.

Review of Human Research ( S ee A ppendix C of this document.)

2.0 HED Recommendati ons

HED recommend s for registration and tolerance s for mancozeb uses on walnuts and imported tangerines provided the label modifications are made as outlined in Section 2.3 below. The specific tolerance recommendations are provided in Section 2.2 .2

.

2.1 Data Deficiencies

Toxicology d ata gaps for ETU i nclude a 2

- generation reproduction study in rats, a developmental neurotoxicity study in rats, and a developmental thyroid toxicity study in rats

. These datagaps and the mancozeb datagap of a developmental thyroid toxicity study in rats will be satisfied with

an extended one

- generation reproductive toxicity study on ETU, which is currently in progress.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical MethodMancozeb Human Health Risk Assessment DP No s

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### Page 10 of 77 T he residue of concern for tolerance enforcement is mancozeb measured as CS 2 

### . There are adequate methods available for the enforcement of crop tolerances with PAM Vol. II listing Methods I, II, II I , IV, and A for determining dithiocarbamate residues in/on plant commodities. The Keppel colo rimetric method (Method III) is preferred since this procedure determines EBDCs as a group by degradation to CS 2 

### . The analytical method for ETU is based on the methodology published by Olney and YIP (JAOAC 54:165

- 169). There are also adequate

enforcement methods available to perform the determination of residues in animal commodities developed by the registrant (DP No. D352531, C. L. Olinger, 07/16/2009). Mancozeb is not recovered through any of the FDA Multi

- Residue Method testing protocols.

Analytical standards for mancozeb are currently available in the EPA National Pesticide Standards Repository. The current stock of standards expired on 03/20/2013. Analytical

reference standards of mancozeb must be supplied and supplies replenished as re quested by the Repository. The reference standards should be sent to the Analytical Chemistry Lab, which is located at Fort Meade, to the attention of either Theresa Cole or Thuy Nguyen at the following

address:

USEPA

National Pesticide Standards Repository/Analytical Chemistry Branch/OPP 701 Mapes Road Fort George G. Meade, MD 20755

- 5350

(Note that the mail will be returned if the extended zip code is not used.)

2.2. 2 Recommended Tolerances

Pending revision s of Sections B (see Section 2.3.1 below) and F ( see Section 2.2.3 ) there are no deficiencies that preclude establishing permanent tolerance s for residues of mancozeb on walnut

and imported tangerines. The tolerance definition should be as follows:

Tolerances are established for residues of mancozeb (a coordination product of zinc ion and maneb (manganese ethylenebisdithiocarbamate)), including its metabolites and degradates, in or

on the commodities in the table below. Compliance with the tolerance levels specified below is

to be determi ned by measuring only those mancozeb residues convertible to and expressed as carbon disulfide , in or on the commodity

.

Table 2.2.2 Tolerance Summary for Mancozeb

Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments

Correct Commodity Definition

Walnut 0.75 0.7 0 Tangerine 10.0 10



### 2.2. 3 Revisions to Petitioned

- For TolerancesMancozeb Human Health Risk Assessment DP No s

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### Page 11 of 77 HED is recommending tolerance levels for mancozeb in walnuts that is only slightly different than what the petitioner is proposing. The newly submitted walnut data (converted to CS 2 

### equivalents ) were evaluated using by HED u sing the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures

. Based on the result of this statistical analysis, a tolerance of 0.7 0 ppm is rec ommended for walnuts. A revised Section F

should be submitted for the walnut petition (PP# 1F7935)

.

2.2. 4 International Harmonization

The mancozeb Codex and U.S. residue definition s are similar. Both definitions stipulate that the residue of concern is mancozeb, measured as carbon disulfide.



### There are no Codex, Canadian or Mexican MRLs established for mancozeb on walnuts. As a result, international harmonization is not an issue for the proposed use on walnuts. There is a

MRL o f 10 ppm established by Codex for the use of EBDC compounds on mandarins

. Using the

OECD tolerance calculation procedures, a U.S. tolerance of 8.0 ppm for residues of mancozeb on imported tangerines was calculated based on the submitted tangerine field tr ial data

. In order to harmonize with the established Codex MRL, a U.S. tolerance of 10 ppm is recommended.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

The use directions and product labeling specified in Section B ( PP # 1F7935) s hould be amended to delineate a maximum total seasonal rate for treating walnuts with mancozeb; t he instructions for the application rate and number of applications should be expanded to specify the “ maximum

allowed ” on e ach product label. In addition, the product labels should specify a re

- treatment
interval of 10 days between applications.

2.3.2 Recommendations from Occupational Assessment

Non

- cancer risks estimates for mixers/loaders scenarios using dry flowable formulations in support of aerial applications to walnuts exceed HED’s level of concern at label specified PPE (i.e. gloves, no respirator) but are not of concern when respirators are worn. It should be noted that no respiratory protection equipment or other engineering c ontrol measures are requested on the DF labels (EPA Reg.70506

- 234 and EPA Reg.70506

- 185 labels). The DF labels should be amended to stipulate the use of respirators for mixer/loaders.

2.3.3 Recommendations f rom Residential Assessment

None.Mancozeb Human Health Risk Assessment DP No s

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### Page 12 of 77 3.0 In troducti on

3.1 Chemical Identity

Table 3.1 Mancozeb Nomenclature

. Chemical structure

Common name Mancozeb

Company experimental name Not applicable

IUPAC name manganese ethylenebis(dithiocarbamate)(polymeric) complex with zinc salt

CAS name [[1,2

- ethanediylbis[carbamodithioato]](2

- )]manganese mixture with [[1,2

- ethanediylbis[carbamodithioato]](2

- )]zinc

CAS registry number 8018

- 01

- 7

End

- use product (EP) ( Dithane® M45 Fungicide; EPA Reg. No. 62719

- 387 ) ; (Penncozeb 75DF; EPA Reg. No. 70506

- 185); ( Penncozeb 4FL Flowable Fungicide;EPA Reg. No.

70506

- 194); ( Manzate Pro

- Stick Fungicide;EPA Reg. No. 70506

- 234); (Manzate Flowable; EPA Reg. No. 70506

- 236).

Chemical structure of ETU

metabolite

ethylenethiourea



### 3.2 Physical/Chemical Characteristics

Mancozeb is a coordination product of zinc ion and maneb (manganese ethylene

bisdithiocarbamate), which contains 20% manganese and 2.5% zinc. Technical mancozeb is a yellowish powder with a negligible vapor pressure at 20 °C. Mancozeb is practically inso luble in water, and most organic solvents. Mancozeb decomposes in acid and alkaline conditions, with heat, and upon exposure to moisture and air. Mancozeb is short lived in soil and water and would therefore not be expected to remain in surface water lon g enough to reach a location that would supply water for human consumption. However, mancozeb’s degradate ETU is highly water soluble, highly vu lnerable to indirect photolysis, and is m oderately mobile. ETU has an

aerobic soil half

- life of 3 days, and an estimated aquatic aerobic metabolism half

- life of six days. The measured anaerobic aquatic metabolism half life is 149 days. ETU has a relatively high vapor pressure, but the high solubility reduces the possibility of losses from surface water due to

v olatilization

. See Appendix B for a table of physicochemical properties of mancozeb.

3.3 Pesticide Use PatternMancozeb Human Health Risk Assessment DP No s

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### Page 13 of 77 There are four (4) United Phosphorus mancozeb end

- use products relevant to th e petition for treating walnuts (PP# 1F7935) . These products are Penncozeb 75DF (EPA Reg. No. 70506

- 185), Penncozeb 4FL Flowable Fungicide (EPA Reg. No. 70506

- 194), Manzate Pro

- Stick Fungicide (EPA Reg. No. 70506

- 234), and Manzate Flowable (EPA Reg. No. 70506

- 236). T h e proposed
pattern s of use for both formulations of mancozeb for treating walnuts are summarized below in

Table 3.3.1. Refer to Section 2.3 for recommended modifications to the proposed labels.

The Dow mancozeb product proposed for treating tangerines in Korea (PP# 2E806) is the Dithane® M45 Fungicide ( EPA Reg. No. 62719

- 387) which is a 75% wettable powder (WP) formulation. A copy of the Korean mancozeb label translated into English was provided by Dow

for assessment. T h e proposed pattern of use for this mancozeb product used for treating tangerines in Kor ea is summarized below in Table 3.3.2.

Tab le 3. 3.1 Summary of Directions for the Use of Mancozeb on Walnuts.

Crop Applic. Timing, Type, and Equip. Product Applic.

Rate (lb ai/A) Max. No.

Applic. per

Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Use Directions and Limitations

Walnuts Broadcast

foliar spray Penncozeb Technical

Manzate Pro

- Stick

Penncozeb 75DF

(water dispersible granule products)

1. 8 10 18.0 75 RTI: 10 days

Apply by ground in a minimum of 100 gal water/A, or by air in a

minimum of 10 gal water/A. Do not apply through any irrigation system. Begin applications at early pre

bloom prior to or when catkins are partially expanded. Make additional applications during bloom and early nutlet stage, or as needed if frequent rainfall occur s.

Restrictions: This product must be tank mixed with a fixed copper product (Cuprofix Ultra 40 Disperss) which is registered for

use on Walnuts. Manzate FL

Penncozeb 4FL

(liquid flowable products)Mancozeb Human Health Risk Assessment DP No s

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### Page 14 of 77 Tab le 3. 3.2 Summary of Directions for the Use of Mancozeb on Tangerines

Crop Applic. Timing,

Type, and Equip. Product Max. 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

Tangerines Korea:

Postemergence; ground equipment (boom sprayer) Dithane

M

- 45 (75% W P) 6.7

[7.5] 4 26.8 [ 30 ] 21 Applications to be made from

fruit set (early June) until fruit growth is completed (September); spray volume is 3,000

- 5,000 L/ha [321

- 535 gal/A], depending on tr ee size, with a concentration of 0.15 kg ai/hL [0.013 lb ai/gal]; may be

mixed with insecticides. A retreatment interval of 10 days is specified



### 3.4 Anticipated Exposure Pathways

Mancozeb is registered for use on numerous agricultural crops as well as on golf courses and in home vegetable gardens . Exposure to mancozeb, and its degradate ETU, may occur from ingestion of residues in/on foods and in drinking water, and via the dermal and inhalation routes for adults using mancozeb products in occupationa l and residential settings. In addition, both youth and adults may be exposed dermally to mancozeb and ETU in post

- application scenarios involving the use of mancozeb on golf courses and in home gardens. There is also a potential for
post

- application exp osure for workers re

- entering treated fields.

Risk assessments have been previously conducted for mancozeb; however, since the previous assessments toxicity points of departure and uncertainty factors have been revised. This risk

assessment considers the all of the aforementioned exposure pathways based on the proposed new uses of mancozeb, as well as the existing uses

.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were consider ed in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on pat terns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the 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 areMancozeb Human Health Risk Assessment DP No s

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### Page 15 of 77 performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated ri sks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of speci alized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Mancozeb is a fungicide in the class of ethylenebis dithiocarbamates (EBDC), which also includes maneb and metiram; all of these compounds have a common metabolite/degradate, ethylenethiourea (ETU). Some of the more notable toxicity in the mancozeb studies was due to toxicity from the metabo lite, ETU. As described in more detail below, thyroid toxicity and developmental toxicity in rats were both due to toxicity from ETU. Injury to peripheral nerves occurred in mancozeb toxicity studies but not in studies with ETU. Because of the overlap o f toxicity profiles, this hazard characterization includes some information on ETU. More details about the hazard profile for ETU are in a forthcoming separate ETU risk assessment.

Since the last comprehensive mancozeb/ETU risk assessment ( 6/11/07, D32 7307 & D327318)

, the interspecies uncertainty factor is reduced from 10X to 3X because of toxicodynamic differences in adult thyroid function that result in greater sensitivity of the adult rat to hypothyroidism compared to adult humans. The 3X toxicodyna mics part of the 10X interspecies factor is removed in those assessments that are based on rat thyroid toxicity endpoints, leaving the 3X portion for toxicokinetic interspecies differences (Hazard Science Policy guidance). Additionally, a 10X FQPA UF DB 

### wa s applied previously to all assessments due to the datagaps

for a 2

- generation reproduction study in rats, a rat developmental neurotoxicity study, and a rat developmental thyroid toxicity study for ETU. Because these datagaps could affect women of

childb earing age or the developing young, the FQPA SF is retained for females 13

- 49 years of age and for children less than 6 years of age. The FQPA SF is reduced to 1X for all other population groups, including children greater than 6 years who have a thyroid system similar to adults, because endpoints from the extended one generation study will not affect those population groups (children > 6 years, females > 49 years, and adult males).

4.1 Summary of Toxicological Effects

The database for mancozeb is ext ensive. There are acceptable subchronic oral studies in rats, mice, and dogs; a dermal toxicity study in rabbits; an inhalation toxicity study in rats; chronic toxicity studies in rats and dogs; carcinogenicity studies in rats and mice; acute neurotoxicit y, subchronic neurotoxicity, and developmental neurotoxicity studies in rats; developmental toxicity studies in rats and rabbits and a 2

- generation reproduction study in rats; a battery of mutagenicity studies; an immunotoxicity study in rats; and metabol ism studies. Although most of the mancozeb risk assessment endpoints are of thyroid toxicity, a developmental thyroid toxicity study is not available. This datagap will be satisfied by an ongoing developmentalMancozeb Human Health Risk Assessment DP No s

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### Page 16 of 77 thyroid study with ETU, which is part of an extended one

- generation reproductive toxicity study on ETU, described below.

The toxicology database on ETU is sufficient for assessing the toxicity and characterizing the hazard of ETU. There are acceptable subchronic oral studies in rats and dogs, sev eral rat developmental toxicity studies from the open literature, a rabbit developmental toxicity study, an immunotoxicity study in rats, and a dermal absorption study in rats. D ata gaps for ETU i nclude a

2

- generation reproduction study in rats, a developm ental neurotoxicity study in rats, and a developmental thyroid toxicity study in rats

. These datagaps will be satisfied with an extended

one

- generation reproductive toxicity study on ETU, which is in progress.

Thyroid toxicity in rat and dog studies wi th mancozeb was manifested as decreased thyroxine, increased thyroid weight, and microscopic thyroid lesions (mainly thyroid follicular cell hyperplasia), accompanied by increased thyroid stimulating hormone. These effects were due to inhibition of thyroi d peroxidase by the metabolite, ETU.

Fetal malformations in the rat developmental mancozeb study occurred throughout the body, at a

dose that was lethal to dams. Malformations in the head included hydrocephaly (increased cerebrospinal fluid in brain ventricles) and related lesions which included brain atrophy and edema, compressions and hemorrhages of the spinal cord, deficiency of tissue in the olfactory bulb, decreased ossification of the skull, and meningoencephalocele (meninges of the brain protruding through the skull). Defects throughout the skeletal system included curved clavicle, fused sternebrae, absent caudal or sacral vertebrae, fused and/or thickened ribs, wavy ribs,

mis shapen or incomplete ossification of hindlimb long bones, kyphosis, incomplete ossification or misshapen pelvis. G ross defects included agnathia ( small or absent lower jaw), cleft palate, cleft lip, club limb, stubby tail, forelimb flexure, kinked tail, an d cryptorchidism. The developmental malformations in the mancozeb developmental toxicity study did not indicate

increased sensitivity of fetuses relative to adults , because they were observed only at the dose

that was lethal to the dams. It is to be noted that t here were many ETU developmen t al studies with tight dose spacing , which was necessary because of the steep dose

- response for hydrocephaly. Several ETU studies clearly showed hydrocepahly in the absence of maternal toxicity. There is only one mancoze b developmental study. This study had wide dose spacing and the developmental toxicity occu rred at a dose that was lethal to d am s. If there had been

intermediate doses

, it is concluded that hydrocephaly likely would have been seen in the absence

of materna l toxicity. However, there was evidence of sensitivity in the developmental neurotoxicity study with mancozeb because decreased pup body weight occurred in the absence of maternal toxicity.

The developmental toxicity with mancozeb is attributed to ETU a nd the many literature studies with ETU help characterize the developmental hazard with mancozeb. The ETU studies showed a steep dose

- response for developmental toxicity and found that hydrocephaly occurred after treatment with a single dose of ETU in the absence of maternal toxicity. The malformations occurred in rats, but generally not in other species, although hydrocephaly and domed head were observed in a rabbit developmental study with ETU.

In the mancozeb rabbit developmental study, abortions oc curred at the same dose as did maternalMancozeb Human Health Risk Assessment DP No s

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### Page 17 of 77 mortality. In a 2

- generation reproduction study with mancozeb, there were no adverse reproductive or offspring effects; parental toxicity included body weight decrements and thyroid toxicity.

Microscopic injury t o peripheral nerves was seen in the rat subchronic neuropathology study, and at higher doses was accompanied by clinical signs (abnormal gait and limited use of rear legs) and loss of muscle mass. Females were more sensitive than males regarding clinical signs. Decreased motor activity occurred in the acute neurotoxicity study. In the developmental neurotoxicity study, there was no maternal toxicity and pup effects were limited to decreased body weight.

Other toxicity with mancozeb included increases in bilateral retinopathy in the chronic rat study. Elevated cholesterol and a mild, regenerative, anemia occurred in subchronic and chronic dog studies. Mancozeb is not acutely toxic with regard to lethality via the oral, dermal, or inhalation

routes of exposure (Tox Category IV). Mancozeb is not a skin irritant (Tox Category IV) nor is it a skin sensitizer although it did cause eye irritation (Tox Category III).

Thyroid follicular cell adenomas and carcinomas were increased in high

- dose males and femal es in the combined rat toxicity/carcinogenicity study with mancozeb. Doses in a mouse study were too low to assess carcinogenicity, and there were no treatment

- related changes in tumor rates.

Mancozeb’s potential for carcinogenicity (as well as that of the other EBDCs) is assessed by the metabolite, ETU, which is classified as a probable human carcinogen (B2), with a cancer potency factor (Q 1 * 

### ) of 0.0601 (mg/kg/day) - 1 

### for risk assessment. On this basis, mancozeb cancer risk has been calculated by estim ating exposure to mancozeb

- derived ETU (including the metabolic conversion) and using the ETU cancer potency factor to provide a quantitative

estimate of risk.

A developmental thyroid study with mancozeb is not available. Instead, the thyroid toxicity of mancozeb in offspring is being evaluated in an extended one

- generation reproductive toxicity study with ETU, which will also evaluate thyroid effects in the fetus and offspring. This study is presently being conducted. An immunotoxicity study with man cozeb and one with ETU have been submitted and reviewed. These studies did not show any concerns for immunotoxicity.

In the rat metabolism study, mancozeb was rapidly absorbed after oral administration with highest accumulation of radioactivity in the thyroid due to ETU residues; no parent compound was detected in the thyroid. There was no indication of significant overall accumulation of mancozeb and metabolites in the body. The majority of mancozeb was metabolized to ETU and

excreted in the urine. R adioactivity was rapidly absorbed into plasma with t 1/2 

### absorption times of 0.7 to 1.0 hour for the 1.5 mg/kg group and 1.7 hours for the 100 mg/kg group. Peak plasma concentrations were reached within 3 hours for the 1.5 mg/kg group and 6 hours for the 1 00 mg/kg group. The t 1/2 

### for the rapid phase of elimination was approximately 4

- 6 hours for both dose groups. The t 1/2 

### for the slow phase of elimination was 36.5 hours in the 1.5 mg/kg group and 25 hours in the 100 mg/kg group.Mancozeb Human Health Risk Assessment DP No s

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### Page 18 of 77 Mancozeb concentrated i n the liver and thyroids in comparison to whole blood concentrations. Peak liver concentrations of radioactivity were reached within 6 hours and were approximately 1.7x higher than whole blood concentrations after 1.5 mg/kg dosing and were approximately 6 x higher than whole blood after 100 mg/kg dosing. The thyroids had the highest mean residue concentration of any tissue, although individual thyroid concentrations varied as much as 30x within a group. Peak thyroid concentrations were reached within 6 ho urs after treatment with 1.5 mg/kg or within 24 hours after treatment with 100 mg/kg mancozeb. Peak thyroid concentrations of radioactivity were 42

- 45x higher than in whole blood after treatment with 1.5 mg/kg and were 6

- 16x higher than in whole blood aft er treatment with 100 mg/kg. The radioactivity levels in the thyroids decreased between 24 and 48 hours and then increased between 48 and 96 hours. Although radioactivity levels in the thyroids had increased after 48 hours, there was no indication of sig nificant overall accumulation of mancozeb and metabolites in the body. Average radioactivity residue levels in tissues 96 hours post

- dosing were < 4% of the dose. The area under the plasma concentration

- time curve (AUC) for ETU in males was

6.4% of the A UC for plasma radioactivity after dosing with 100 mg/kg radiolabeled mancozeb; the AUC for ETU in females was 3.1% of the AUC for plasma radioactivity . ETU had a plasma

t 1/2 

### of 3.9 hours in males and 4.7 hours in females.

In oral rat metabolism studies with radiolabelled mancozeb and other EBDCs, a pprox imately 20% of EBDC was converted to ETU on a molar basis, which equated to 7.5% conversion on a weight basis (Albin Kocialski memo, 9/12/89). While this metabolic conversion has been

included in the man cozeb and ETU risk assessment for all routes of exposure , there is some uncertainty in assuming the metabolic conversion occurs following dermal and inhalation dosing because absorption after dermal and inhalation dosing initially bypasses the liver.

The mancozeb dermal absorption factor is 1%, based on two non

- guideline dermal absorption studies, which together satisfy the guideline requirement for a dermal absorption study on mancozeb. This value is supported by comparison of NOAEL values between th e 28

- day dermal toxicity study in rats and the 13

- week rat feeding study (1000 mg/kg/day 9.25 mg/kg/day = 0.9% dermal absorption). The dermal absorption factor of 1% was also consistent with dermal absorption factors for the other EBDCs.

The ETU dermal absorption factor is 26%, based on a dermal absorption study in rats. This

value was determined at the lowest dermal dose after 10 hours of exposure followed by washing

of the skin. ETU residues were highest in the thyroid.

4. 2 Safety F ac tor for Infants and Children (FQPA Safety Factor)

For mancozeb, the FQPA SF (safety factor) of 10X is retained for women of childbearing age and for children less than 6 years old because of an inadequate database for the developing thyroid. Brain develo pment is very sensitive to perturbations in thyroid hormones and it is possible that the developmental thyroid study (being conducted with ETU) will result in lower NOAELs for these populations than are presently being used to assess risk.

Results from the developmental thyroid study will not affect endpoints for children over 6 years of age (for whom the thyroid system is more developed) or adults as thyroid data for thoseMancozeb Human Health Risk Assessment DP No s

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### Page 19 of 77 populations are already available. The database for toxicity studies affecting t hese populations is complete. Therefore, the FQPA safety factor is reduced to 1X for these populations.

For ETU, the datagaps being addressed in the extended one

- generation reproductive toxicity study could affect women of childbearing age or the devel oping young, and the FQPA SF of 10X

is retained for females 13

- 49 years of age and for children less than 6 years of age. The FQPA SF is reduced to 1X for all other population groups, including children greater than 6 years who have a thyroid system simil ar to adults, because endpoints from the extended one generation study will not affect those population groups (children > 6 years, females > 49 years, and adult males). Although there was fetal sensitivity for malformations in the ETU developmental rat

s tudies, the endpoints that were selected are protective of these effects.

4.2.1 Completeness o f the Toxicology Database

The toxicology database for mancozeb and ETU is sufficient for assessing the toxicity and characterizing the hazard of these chemica ls. There are guideline studies for developmental toxicity in rats and rabbits, reproductive toxicity in rats, acute neurotoxicity, subchronic neurotoxicity, immunotoxicity, and developmental neurotoxicity in rats for mancozeb. Thyroid toxicity in young r ats is being evaluated as part of an extended one

- generation reproductive toxicity study with ETU. The database for ETU is incomplete, but the extended one

- generation reproductive toxicity study on ETU will satisfy these datagaps. An immunotoxicity study on ETU is available.

4.2.2 Evidence of N eurotoxicity

Injury to peripheral nerves (demyelination, myelin phagocytosis, Schwann cell proliferation, thickened myelin sheath, intrasheath ellipsoids, neurofibrillary degeneration, and myelin ovoids, bubbles, and debris) was seen microscopically in the rat subchronic neuro toxicity study with associated clinical signs (abnormal gait and limited use of rear legs) and loss of muscle mass. Decreased motor activity was noted in an acute neurotoxicity study in rats with mancozeb. No neurotoxicity occurred in the mancozeb developmental neurotoxicity study in rats. Neurotoxicity was not noted in toxicity studies with ETU, but the toxicity profile for ETU shows that the principal toxic effects occur in the thyroid. The endpoints that were selected are based on thyroid effects and would be protective of any potential neurotoxicity following ETU exposure.

4.2.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

Developmental malformations in the mancozeb rat developmental toxicity study did not indicate sensitivity of offspring because they occurred at the same dose that caused maternal mortality. There was no indication of enhanced susceptibility of offspring i n the mancozeb rabbit developmental study because abortions occurred at the same dose that also caused maternal mortality. There was no evidence of sensitivity in the 2

- generation reproduction study with

mancozeb in rats. As noted above, the mancozeb deve lopmental toxicity study had wide dose spacing and developmental toxicity occu rred at a dose that was lethal to d am s. If there had beenMancozeb Human Health Risk Assessment DP No s

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### Page 20 of 77 intermediate doses

, it is concluded that hydrocephaly likely would have been seen in the absence of maternal toxicity. H owever , evidence of sensitivity was noted in the developmental neurotoxicity study with mancozeb, since decreased pup body weight occurred in the absence of maternal toxicity.

There is evidence of increased susceptibility following in utero exposure to ETU in the rat developmental toxicity studies. Several developmental toxicity studies with ETU in the open literature demonstrate quantitative and qualitative fetal sensitivity. In one study, developmental toxicity [brain malformations (exencephaly, dila ted ventricles, and hypoplastic cerebellum)] was observed at a dose level considerably lower than the dose causing maternal toxicity (mortality). In another study, developmental toxicity (dilated ventricle of the brain) was seen in the absence

of maternal toxicity. Additionally, developmental effects (dilated ventricles of the brain, hydroureter, short/kinky tail, and dilated ureters) were seen in another study at a dose that only induced decreases in body weight gain in the dams.

4.2.4 Residual Uncert ainty in the Exposure Database

HED has used refined assumptions in the food portion of the dietary exposure assessment, including the use of percent crop treated estimates and monitoring residue values for several commodities including some major contrib utors to the dietary risk such as milk and corn

commodities

. Modeling and monitoring data were used to derive estimated drinking water

concentrations. T he residential exposure assessment was conducted such that residential exposure and risk will not be u nderestimated. The aggregate exposure and risk estimates presented in this assessment are not expected to underestimate actual exposure and risk expected based on the current and proposed use patterns.

The database for mancozeb is extensive and is suffic ient for characterizing toxicity and hazard. Although most of the mancozeb risk assessment endpoints are of thyroid toxicity, a developmental thyroid toxicity study is not available. This datagap will be satisfied by an ongoing developmental thyroid toxicity study with ETU, which is part of an extended one

generation reproductive toxicity (EOGRT) study on ETU. For mancozeb, the FQPA SF (safety factor) of 10X is retained for women of childbearing a ge and for children less than 6 years old because of an inadequate database for the developing thyroid. Brain development is very sensitive to perturbations in thyroid hormones and it is possible that the developmental thyroid toxicity study (being conduc ted with ETU) will result in lower NOAELs for these populations than are presently being used to assess risk. The FQPA safety factor for mancozeb is reduced to 1X for other lifestages (children > 6 years, females > 49 years, and adult males), for which th e thyroid is largely developed and there are applicable thyroid data.

Toxicology d ata gaps for ETU i nclude a 2

- generation reproductive toxicity study in rats, a developmental neurotoxicity study in rats, and a developmental thyroid toxicity study in rats

. These datagaps will be satisfied with the ongoing EOGRT study on ETU. The datagaps being addressed in the EOGRT study could affect women of childbearing age or the developing young, and the FQPA SF of 10X is retained for females 13

- 49 years of age and for children less than 6 years of age. The FQPA safety factor for ETU is reduced to 1X for other lifestages. Although there was fetal sensitivity for malformations in the ETU developmental rat studies, the endpointsMancozeb Human Health Risk Assessment DP No s

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### Page 21 of 77 that were selected are protective of t hese effects.

4. 3 Toxicity Endpoint and Point of D eparture Selections

A detailed description of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios is presented in A ppendix A

. The doses and endpoints

are summarized below and in Tables 4.3.1 through 4.3.4 which also provide the appropriate safety factors.

Mancozeb Acute dietary, females 13

- 49 years of age : The acute dietary endpoint for females 13

- 49 years old was selected from a development al toxicity study in rats. The LOAEL was 512 mg/kg/day, based on hydrocephaly and other malformations. The NOAEL was 128 mg/kg/day. This endpoint is appropriate because hydrocephaly occurred after a single dose of ETU.

Acute dietary, general population : The acute dietary endpoint for the general population was

selected from an acute neurotoxicity study in rats. The LOAEL was 1000 mg/kg/day, based on decreased motor activity. The NOAEL was 500 mg/kg/day.

Chronic dietary : The chronic reference dose was selected from a chronic toxicity study in rats. The LOAEL was 30.9 mg/kg/day, based on thyroid toxicity (decreased thyroid hormones, microscopic thyroid changes, and increased thyroid weight). The NOAEL was 4.83 mg/kg/day.

Incidental oral exposure, children <6 years : The incidental oral endpoint for children less than 6 years of age was selected from a subchronic feeding study in rats. The LOAEL was 17.82 mg/kg/day, based on decreased thyroid hormone. The NOAEL was 9.24 mg/kg/day.

Dermal exposure, short

- and intermediate

- term : Risk assessment will not be quantified because no systemic toxicity was noted in a dermal toxicity study in rats at the limit dose. There are no developmental or reproductive concerns at doses that would occur from dermal exposure from registered uses considering the dermal absorption factor of 1%.

Dermal exposure, long

- term : The long

- term dermal endpoint was selected from a chronic oral toxicity study in rats. The LOAEL was 30.9 mg/kg/day, based on thyroid toxicity (decreased thyroid hormones, microscopic thyroid changes, and increased thyroid weight). The NOAEL was 4.83 mg/kg/day.

Inhalation exposure : The inhalation endpoint was selected from a subchronic inhalation study in

rats. The LOAEL was 0.326 mg/L, based on thyroid toxicity (thyroid hyperplasia and decreased thyroxine). The NOA E L was 0.079 mg/L.

ETU

Acute d ietary, females 13

- 49 years: The ETU acute dietary endpoint for females 13

- 49 years old

was selected from a non

- guideline developmental toxicity study in rats. The LOAEL was 10 mg/kg/day

, based on developmental malformations of the brain, including exencephaly, dilated ventricles and hypoplastic cerebellum. The NOAEL was 5 mg/kg/day.Mancozeb Human Health Risk Assessment DP No s

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### Page 22 of 77 Acute d ietary, general population , i ncluding infant and children : No hazard or appropriate acute endpoint attributable to a single exposure was identified from the available oral toxicity database; therefore, no acute dietary risk is expected following acute exposure to ETU.

Chronic d ieta ry, all populations : The ETU chronic reference dose was selected from a chronic

oral toxicity study in dogs. The study NOAEL was 0.18 mg/kg/day

, based on decreased body weight gain, increased thyroid weight, and microscopic changes in the thyroid observe d at the LOAEL of 1.99 mg/kg/day.

Short

- term o ral , children <6 years : The incidental oral endpoint for children less than 6 years of age was selected from a non

- guideline 4

- week range

- finding oral toxicity study conducted in dogs. The NOAEL was 7 mg/kg/day

, based on gross thyroid lesions and decreased thyroid hormone levels at the LOAEL of 34 mg/kg/day. The endpoint is supported by a subchronic oral toxicity study in dogs in which the NOAEL for t hyroid effects was similar (6 mg/kg/day ).

Short and intermediate

- term dermal , all populations other than females 13

- 49 years : In the

absence of a dermal toxicity study for ETU, the non

- guideline 4

- week range

- finding toxicity study conducted in dogs was used to select short

- and intermediate

- term dermal endpoints for all population groups other than females 13

- 49 years of age. The NOAEL was 7 mg/kg/day based on gross thyroid lesions and decreased thyroid hormone levels at the LOAEL of 34 mg/kg/day.

Becau se an oral toxicity study was chosen, the 26% dermal absorption factor for ETU should be used in the dermal exposure assessment.

Short and intermediate

- term dermal, females 13

- 49 years: In the absence of a dermal toxicity study for ETU, the non

- guideli ne oral developmental study in rats was used to select an endpoint

for short

- and intermediate

- term dermal risk assessments for females 13

- 49 years of age. The study NOAEL was 5 mg/kg/day

, based on developmental malformations of the brain, including

exenc ephaly, dilated ventricles, and hypoplastic cerebellum, observed at the LOAEL of 10 mg/kg/day. Because an oral toxicity study was chosen, the 26% dermal absorption factor for ETU should be used in the dermal exposure assessment.

Long

- term dermal, all p opulations : The long

- term dermal endpoint for all populations is selected from the chronic toxicity study in dogs. The NOAEL is 0.18 mg/kg/day based on decreased body weight gain, increased thyroid weight, and microscopic changes in the thyroid at the

LO AEL of 1.99 mg/kg/day. Since an oral study was selected, estimated dermal exposure should be adjusted by 26%, the ETU dermal absorption factor.

Short and intermediate

- term inhalation, all populations other than females 13

- 49 years : In the

absence of a n inhalation toxicity study for ETU, the non

- guideline 4

- week range

- finding toxicity study conducted in dogs was used to select short

- and intermediate

- term inhalation endpoints for all population groups other than females 13

- 49 years of age. The NOAEL was 7 mg/kg/day based on gross thyroid lesions and decreased thyroid hormone levels at the LOAEL of 34 mg/kg/day. Because an oral toxicity study was chosen, it will be assumed that inhalation absorption i s equivalent to oral absorption

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### Page 23 of 77 Short and intermediate

- term inhalation , females 13

- 49 years: In the absence of an inhalation toxicity study for ETU, the non

- guideline oral study in rats was used to select an endpoint for

short

- and intermediate

- term inhalation risk assessments for femal es 13

- 49 years of age. The study NOAEL was 5 mg/kg/day based on developmental malformations of the brain, including exencephaly, dilated ventricles, and hypoplastic cerebellum, observed at the LOAEL of 10 mg/kg/day. Because an oral toxicity study was cho sen, it will be assumed that inhalation absorption is equivalent to oral absorption

.

Long

- term inhalation , all populations : The long

- term inhalation endpoint for all populations is selected from the chronic toxicity study in dogs. The NOAEL is 0.18 mg /kg/day based on decreased body weight gain, increased thyroid weight, and microscopic changes in the thyroid at the LOAEL of 1.99 mg/kg/day. Because an oral toxicity study was chosen, it will be assumed that inhalation absorption is equivalent to oral ab sorption

.

Cancer

Thyroid follicular cell adenomas and carcinomas were increased in high

- dose males and females in the combined rat toxicity/carcinogenicity study with mancozeb. Doses in a mouse study were too low to assess carcinogenicity, and there w ere no treatment

- related changes in tumor rates. Mancozeb’s potential for carcinogenicity is assessed based on the metabolite, ETU, which is
classified as Group B2, with a cancer potency factor [Q 1 

### *, 0.0601 (mg/kg/day) - 1 

### ] for risk

assessment. Because man cozeb is known to be converted to ETU, it has also been classified as Group B2 for carcinogenicity, and after applying the metabolic conversion factor for EBDC to ETU (0.075), the ETU cancer potency factor is used for assessing cancer risk associated with

mancozeb uses.

Table 4.3.1 Summary of Toxicological Doses and Endpoints for MANCOZEB for Use in Dietary and Non

Occupational Human Health Risk Assessments
Exposure PoD Safety Factors RfD, PAD, LoC Study and Toxicity

Mancozeb Acute Dietary Exposure Acute Dietary (Adult Males, Females >49, and Children ≥ 6 years) NOAEL =

500 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Acute RfD = 5

mg/kg/day

Acute PAD = 5 mg/kg/day A cute neurotoxicity study in the rat LOAEL 1000 mg/kg/day based on decreased motor activity

Acute Dietary

(Children < 6 years) NOAEL =

500 mg/kg/day UF A = 10x

UF H = 10x FQPA UF DB = 10x Acute RfD =

5 mg/kg/day

Acute PAD = 0.5 mg/kg/day A cute neurotoxicity study in the rat LOAEL 1000 mg/kg/day based on

decreased motor activity

Acute Dietary

(Females 13

– 49 years) NOAEL =

128 mg/kg/day UF A = 10x

UF H = 10x FQPA UF DB = 10x Acute RfD = 1.3

mg/kg/day

Acute PAD = 0.13 mg/kg/day Developmental toxicity study in the

rat LOAEL = 512 mg/kg/day based on hydrocephaly and other

malformations Mancozeb Chronic Dietary ExposureMancozeb Human Health Risk Assessment DP No s

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### Page 24 of 77 Table 4.3.1 Summary of Toxicological Doses and Endpoints for MANCOZEB for Use in Dietary and Non

Occupational Human Health Risk Assessments
Exposure PoD Safety Factors RfD, PAD, LoC Study and Toxicity

Chronic Dietary

(Adult Males, Females >49, and Children ≥ 6 years) NOAEL =

4.83 mg/kg/day UF A = 3x

UF H = 10x FQPA SF = 1x Chronic RfD = 0.16

mg/kg/day

Chronic PAD = 0.16 mg/kg/day Toxicity/Carcinogenicity in the rat LOAEL = 30.9 mg/kg/day based on thyroid toxicity

Chronic Dietary

(Females 13

- 49 years and

Children < 6 years) NOAEL =

4.83 mg/kg/day UF A = 3x

UF H = 10x FQPA UF DB = 10x Chronic RfD = 0.16

mg/kg/day

Chronic PAD = 0.016 mg/kg/day Toxicity/Carcinogenicity in the rat LOAEL = 30.9 mg/kg/day based on thyroid toxicity

Mancozeb Incidental Oral Exposure

Short

- term Oral (Children < 6 years of age ) NOAEL =

9.24 mg/kg/day UF A = 3x

UF H = 10x FQPA UF DB = 10x LOC = 300 Subchronic Oral Toxicity Study in the rat. LOAEL = 17.82 mg/kg/day based on decreased thyroxine

Mancozeb Residential Dermal Exposure Dermal (Short

- , and Intermediate

Term, all pop. subgroups) Risk Assessment not required. No systemic toxicity via the dermal route at 1000 mg/kg/day and there

are no developmental or reproductive concerns at systemic doses which would occur as a result of dermal exposures from registered uses (dermal absorption = 1%)

Dermal (Long

Term) (Adult Males, Females >49 years,

Ch ildren ≥ 6 years) NOAEL =

4.83 mg/kg/day

DA = 1% UF A = 3x

UF H = 10x FQPA SF = 1x LOC = 30 Toxicity/Carcinogenicity in the rat. LOAEL = 30.9 mg/kg/day based on thyroid toxicity

Dermal (Long

Term) (Females

13

- 49 years and

Children < 6 years) NOAEL =

4.83 mg/kg/day

DA = 1% UF A = 3x

UF H = 10x FQPA UF DB = 10x LOC = 300 Toxicity/Carcinogenicity in the rat. LOAEL = 30.9 mg/kg/day based on thyroid toxicity

Mancozeb Residential Inhalation Exposure (all durations)

Inhalation (Adult Males,

Females >49

years, and Children ≥ 6 years) NOAEL =

0.079 mg/L ( 21 mg/kg/day ) UF A = 3x

UF H = 10x FQPA SF = 1x LOC = 30 Subchronic Inhalation in the rat LOAEL = 0.326 mg/L based on thyroid toxicity

Inhalation (Females 13

- 49 years and

Children < 6 years) NOAEL =

0.079 mg/L (21 mg/kg/day) UF A = 3x

UF H = 10x FQPA UF DB = 10x LOC = 300 Subchronic Inhalation in the rat LOAEL = 0.326 mg/L based on thyroid toxicity

Mancozeb Cancer Cancer (all routes) 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 quantitate risk.

Point of De parture (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL

= no observed adve rse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term riskMancozeb Human Health Risk Assessment DP No s

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### Page 25 of 77 assessment. UF DB = to account for the absence of key data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table 4.3. 2 Summary of Toxicological Doses and Endpoints for MANCOZEB for Use in Occupational

Human Health Risk Assessments
Exposure PoD Safety Factors RfD, PAD, LoC Study and Toxicity

Mancozeb Occupational Dermal Exposure Dermal (Short

- , and

Intermediate

- Term, all pop. subgroups) Risk Assessment not required. No systemic toxicity via the dermal route at 1000 mg/kg/day and there are no developmental or reproductive concerns at systemic doses which would occur as a result of dermal exposures from registered uses Dermal (Long

- Term)

(Adult Males, Females >49 years) NOAEL = 4.83 mg/kg/day

DA = 1% UF A = 3x

UF H = 10x LOC = 30 Toxicity/Carcinogenicity in the rat. LOAEL = 30.9 mg/kg/day

based on thyroid toxicity

Dermal (Long

- Term)

(Females 13

- 49 years) NOAEL = 4.83 mg/kg/day

DA = 1% UF A = 3x

UF H = 10x

UF DB = 10x LOC = 300 Toxicity/Carcinogenicity in the rat. LOAEL = 30.9 mg/kg/day

based on thyroid toxicity

Mancozeb Occupational Inhalation Exposure (all durations)

Inhalation

(Adult Males, Females >49 years) NOAEL = 0.079 mg/L [21 mg/kg/day] UF A = 3x

UF H = 10x LOC = 30 Subchronic Inhalation in the rat LOAEL = 0.326 mg/L based on thyroid toxicity

Inhalation

(Females 13

- 49 years) NOAEL = 0.079 mg/L [21 mg/kg/day] UF A = 3x

UF H = 10x

UF DB = 10x LOC = 300 Subchronic Inhalation in the rat LOAEL = 0.326 mg/L based on thyroid toxicity

Mancozeb Cancer Cancer (all routes) 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 quantitate risk. Point of Departu re (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse e ffect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to account for the absence of key

dat a (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = a cute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table 4.3.3 Summary of Toxicological Doses and Endpoints for ETU for Use in Dietary and Non

Occupational Human Health Risk Assessments
Exposure PoD Safety Factors RfD, PAD, LoC Study and Tox

ETU Acute Dietary Exposure Acute Dietary (General Pop, including Infants and Children) N/A N/A N/A A study with acute toxicity applicable to the general population was not

identified.

Acute Dietary (Females 13

- 49 years old) NOAEL= 5

mg/kg/day UF A = 10x

UF H = 10x FQPA UF DB = 10x Acute RfD = 0.05

mg/kg/day

aPAD = 0.005 mg/kg/day Developmental Rat Toxicity

MRID No. 45937601 (1973 ) LOAEL = 10 mg/kg/day, based on hydrocephaly and other malformationsMancozeb Human Health Risk Assessment DP No s

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### Page 26 of 77 Table 4.3.3 Summary of Toxicological Doses and Endpoints for ETU for Use in Dietary and Non

Occupational Human Health Risk Assessments
Exposure PoD Safety Factors RfD, PAD, LoC Study and Tox

ETU Chronic Dietary Exposure Chronic Dietary (Females 13

- 49 years of age and

Children < 6 years) NOAEL= 0.18

mg/kg/day UF A = 10 x

UF H = 10x FQPA UF DB = 10x Chronic RfD = 0.0018

mg/kg/day

cPAD = 0.00018 mg/kg/day Dog Chronic Oral Toxicity MRID 42338101 (1992) LOAEL= 1.99 mg/kg/day based on thyroid toxicity

Chronic Dietary (Adult Males,

Females >49 years, Children ≥ 6 years) NOAEL= 0.18

mg/kg/day UF A = 10 x

UF H = 10x FQPA SF = 1x Chronic RfD = 0.0018

mg/kg/day

cPAD = 0.0018 mg/kg/day Dog Chronic Oral Toxicity MRID 42338101 (1992) LOAEL= 1.99 mg/kg/day based on thyroid toxicity

ETU Incidental Oral Exposure

Short

- Term Oral (Children < 6 years of age) NOAEL= 7

mg/kg/day UF A = 10 x

UF H =10x FQPA UF DB = 10x LOC = 10 00 4

- week range

- finding dog study MRID 41863401 (1989) LOAEL= 34 mg/kg/day based on thyroid toxicity

ETU Residential Dermal Exposure

Dermal Short and

Intermediate

Term (Children ` < 6 years of age) NOAEL= 7

mg/kg/day UF A = 10 x

UF H =10x FQPA UF DB = 10x LOC = 10 00 4

- week range

- finding dog study MRID 41863401 (1989) LOAEL= 34 mg/kg/day based on thyroid toxicity

Dermal Short and

Intermediate

Term (Adult Males, Females >49 years, Children ≥ 6 years) NOAEL= 7

mg/kg/day UF A = 10 x

UF H =10x FQPA SF= 1x LOC = 10 0 4

- week range

- finding dog study MRID 41863401 (1989) LOAEL= 34 mg/kg/day based on thyroid toxicity

Dermal Short and

Intermediate

Term (Females

13

- 49 years old) NOAEL= 5

mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973 ) LOAEL = 10 mg/kg/day, based on hydrocephaly and other malformations Dermal Long

Term (Females 13

- 49 years of age and

Children < 6 years) NOAEL=

0.18 mg/kg/day UF A = 10 x

UF H =10x FQPA UF DB = 10x LOC = 10 00 Dog Chronic Oral Toxicity

MRID 42338101 (1992)
LOAEL= 1.99 mg/kg/day based on thyroid toxicity

Dermal Long

Term (Adult Males,

Females >49 years, Children ≥ 6 years) NOAEL=

0.18 mg/kg/day UF A = 10 x

UF H =10x FQPA SF= 1x LOC = 10 0 Dog Chronic Oral Toxicity MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on thyroid toxicity

ETU Residential Inhalation Exposure

Inhalation Short

and Intermediate

Term (Children < 6 years of age) NOAEL= 7

mg/kg/day UF A = 10 x

UF H =10x FQPA UF DB = 10x LOC = 10 00 4

- week range

- finding dog study

MRID 41863401 (1989) LOAEL= 34 mg/kg/day based thyroid toxicity

Inhalation Short

and Intermediate

Term (Adult Males, Females >49 years, Children ≥ 6 years) NOAEL= 7

mg/kg/day UF A = 10 x

UF H =10x FQPA SF= 1x LOC = 10 0 4

- week range

- finding dog study MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based thyroid toxicityMancozeb Human Health Risk Assessment DP No s

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### Page 27 of 77 Table 4.3.3 Summary of Toxicological Doses and Endpoints for ETU for Use in Dietary and Non

Occupational Human Health Risk Assessments
Exposure PoD Safety Factors RfD, PAD, LoC Study and Tox

Inhalation Short

and Intermediate

Term (Females

13

- 49 years old) NOAEL= 5

mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973 ) LOAEL = 10 mg/kg/day, based on hydrocephaly and other malformations Inhalation Long

Term (Females

13

- 49 years of age

and Children < 6 years) NOAEL=

0.18 mg/kg/day UF A = 10 x

UF H =10x FQPA UF DB = 10x LOC = 10 00 Dog Chronic Oral Toxicity MRID 42338101 (1992)
LOAEL= 1.99 mg/kg/day based on thyroid toxicity

Inhalation Long

Term (Adult Males, Females >49 years, Children ≥ 6 years) NOAEL=

0.18mg/kg/da

y UF A = 10 x

UF H =10x FQPA SF= 1x LOC = 10 0 Dog Chronic Oral Toxicity MRID 42338101 (1992) LOAEL= 1.99 mg/kg/day based on thyroid toxicity

ETU Cancer Cancer (all routes) Q 1 * = 6.01 x

10

- 2 (mg/kg/day)

- 1 ETU is classified as a Group B2 carcinogen with a linear low

- dose extrapolation

approach for human risk assessment based on liver tumors in female mice.

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to account for the absence of key data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table 4.3.4 Summary of Toxicological Doses and Endpoints for ETU for Use in Occupational Human Health

Risk Assessments
Exposure PoD Safety

Factors RfD, PAD, LoC Study and Tox

ETU Occupational Dermal Exposure

Dermal Short and

Intermediate

- Term (Adult Males,

Females >49 years) NOAEL= 7

mg/kg/day UF A = 10 x

UF H =10x LOC = 10 0 4

- week range

- finding dog study MRID 41863401 (1989) LOAEL= 34 mg/kg/day based on thyroid toxicity

Dermal Short and

Intermediate

- Term (Females 13

- 49 years old) NOAEL= 5

mg/kg/day UF A = 10x

UF H =10x

UF DB = 10x LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973 ) LOAEL = 10 mg/kg/day, based on hydrocephaly and other malformations Dermal Long

Term (Females 13

- 49 years of age) NOAEL=

0.18 mg/kg/day UF A = 10 x

UF H =10x

UF DB = 10x LOC = 10 00 Dog Chronic Oral Toxicity MRID 42338101 (1992)
LOAEL= 1.99 mg/kg/day based on thyroid toxicity Dermal Long

Term (Adult Males,

Females >49 years) NOAEL=

0.18 mg/kg/day UF A = 10 x

UF H =10x LOC = 10 0 Dog Chronic Oral Toxicity MRID 42338101 (1992)
LOAEL= 1.99 mg/kg/day based on thyroid toxicity

ETU Occupational Inhalation ExposureMancozeb Human Health Risk Assessment DP No s

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### Page 28 of 77 Table 4.3.4 Summary of Toxicological Doses and Endpoints for ETU for Use in Occupational Human Health

Risk Assessments
Exposure PoD Safety

Factors RfD, PAD, LoC Study and Tox

Inhalation Short

and Intermediate

Term (Adult Males, Females >49 years) NOAEL= 7

mg/kg/day UF A = 10 x

UF H =10x LOC = 10 0 4

- week range

- finding dog study MRID 41863401 (1989) LOAEL= 34 mg/kg/day based thyroid toxicity

Inhalation Short

and Intermediate

Term (Females

13

- 49 years old) NOAEL= 5

mg/kg/day UF A = 10x

UF H =10x

UF DB = 10x LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973 ) LOAEL = 10 mg/kg/day, based on hydrocephaly and other malformations Inhalation Long

Term (Females

13

- 49 years of age) NOAEL=

0.18 mg/kg/day UF A = 10 x

UF H =10x

UF DB = 10x LOC = 10 00 Dog Chronic Oral Toxicity MRID 42338101 (1992)
LOAEL= 1.99 mg/kg/day based on thyroid toxicity Inhalation Long

Term (Adult Males, Females >49 years) NOAEL=

0.18mg/kg/da

y UF A = 10 x

UF H =10x LOC = 10 0 Dog Chronic Oral Toxicity MRID 42338101 (1992) LOAEL= 1.99 mg/kg/day based on thyroid toxicity

ETU Cancer Cancer (all routes) Q 1 * = 6.01 x

10

- 2
(mg/kg/day)

- 1 ETU is classified as a Group B2 carcinogen with a linear low

- dose extrapolation

approach for human risk assessment based on liver tumors in female mice.

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a

NOAEL. UFS = use of a short

- term study for long

- term risk assessment. UFDB = to account for the absence of key data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.



### 5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

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. For plants and livestock commodities, the tolerance expression for mancozeb includes parent mancozeb

, measur ed as CS 2

. 

### For risk assessment, however, both parent mancozeb and ETU residues must be considered. Mancozeb, as well as the other EBDC compounds , is short lived in soil and water. The EBDC degradate ETU is highly water soluble, highly vu lnerable to indirect photo lysis, and is

m oderately mobile. ETU has a relatively high vapor pressure, but the high solubility reduces the possibility of losses from surface water due to volatilization. In drinking water, the residue of

concern for risk assessment is the degradate ETU.

Further information on the metabolism and degradation may be found in the risk assessment dated 6/11/07 (D327307 & D327318).Mancozeb Human Health Risk Assessment DP No s

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### Page 29 of 77 Table 5.1 Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Plants Primary Crop Mancozeb & ETU Mancozeb, measured as CS 2

Rotational Crops No data are available. Identified as a data gap in the RED. 1

Livestock Ruminant Mancozeb & ETU Mancozeb, measured as CS 2

Drinking Water ETU only Not Applicable

1 A confined rotational crop study was required in the 2005 mancozeb Reregistration Eligibility Decision and remains outstanding. HED is not requiring the study as a condition of registration to support these new uses because orchard crops a re not rotated after commodity harvest.



### 5 .2 Food Residue Profile

Application of mancozeb to food crops results primarily in surface residues

. For the proposed uses on walnuts and tangerines, adequate 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.

The residue chemistry database fo r mancozeb is adequate to support proposed use on walnuts and imported tangerines. The nature of the residue in plants is adequately understood based on prior metabolism studies made with potato, soybean, sugar beet, tomato, and wheat. The nature

of the residue is also adequately understood in livestock based upon previous metabolism studies made on goats and poultry. HED has concluded that the residue of concern for the tolerance

enforcement of all regulated commodities is mancozeb calculated as CS 2 

### . I n regard to risk assessment, both the EBDC parent mancozeb and its degradate ETU are to be considered for

evaluation. There are adequate methods available for the enforcement of crop tolerances for determining dithiocarbamate residues in/on plant commoditi es. Adequate storage stability data

are available which demonstrate that residues of mancozeb and ETU are stable when stored frozen in almond nutmeats for durations of 10 and 15.7 months, respectively. Stability data

demonstrate that residues of mancozeb a nd ETU are stable in /on tangerines for at least 160 days in frozen storage

.

In the submitted walnut field trials, there were detectable residues of mancozeb, but ETU

residues were non

- detectable or just above the limit of detection. In the tangerine fiel d trials, both mancozeb and ETU were detected, but levels of ETU were significantly lower than those of mancozeb. The results of residue decline studies in tangerines showed that residues of mancozeb

decrease with an increasing PHI

.

No processing data are required to support this proposed use on walnuts. Rotational crop data are also not needed to support this requested use because walnut trees are not rotated following

harvest. There are no animal feed items associated with walnuts

.Mancozeb Human Health Risk Assessment DP No s

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### Page 30 of 77 No processing or rotational crop data are required to support the proposed use of mancozeb on imported tangerines. However, a processing study for tangerine juice demonstrated significant

residue reduction. Because imported tangerines are not expect ed to be processed into dried pulp in the U.S., there are no animal feed items associated with imported tangerines.

5.3 Water Residue Profile

Mancozeb is short lived in soil and water and would therefore not be expected to remain in surface water long en ough 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

drin king water assessment for ETU was conducted to support various EBDC pesticide uses for

the 2005 Reregistration Eligibility Decision ( RED ) ( D286871, 5/15/03 ) . It should be noted that the assessment conducted for the RED combined ETU from all sources of EDBC pesticides, including mancozeb. After consideration of the proposed application rates and use patterns for

walnuts in comparison to the maximum applicat ion rates and use patterns used in the most recent drinking water assessment (for almond use) , as well 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 use on walnuts (the proposed tangerine use is not for use on domestically grown tangerines) (D397306, 7/3/12)

.

ETU surface water estimated drinking water concentrations were based bot h on PRZM

- EXAMS modeling information and available monitoring data. The acute (peak) surface water EDWC ranged from 0.1 ppb from monitoring data to 25.2 ppb as a model output. The chronic/cancer surface water value provided by EFED was 0.1 ppb based on m onitoring 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 monitoring data to be used in the acute, chronic and cancer risk assessments. This value represents the sing le highest concentration found in untreated water sampled 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 where ETU residues

were found in untreated wat er.

A more detailed summary of the ETU drinking water assessment conducted for the RED can be

found in the human health risk assessment develo ped for the RED (D317371, 6/3/ 05, K. Farwell) and additional details on the drinking water assessment are cont ained in the EFED drinking

water assessment memorandum entitled Revision No. 2: Estimated Drinking Water Concentration of Ethylenebisdithocarbamate (EBDC) Degradate Ethylenethiourea (ETU) for the

Use in Human Health Risk Assessment

, D323143 and 323141, 8/ 11/ 06, M. Ruhman.

ETU estimated drinking water concentrations provided by EFED are summarized below.Mancozeb Human Health Risk Assessment DP No s

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### Page 31 of 77 Table 5.3 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 m odels. 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 assessmen t.



### 5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

A cute, chronic, and cancer aggregate dietary food and drinking water exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16 . This software uses 2003

- 2008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We Eat in America, (NHA NES/WWEIA).

Field trial or monitoring data from the EBDC/ETU Market Basket Survey, percent crop treated information, and processing study results were utilized to assess the established uses of

mancozeb. The monitoring data were used for several commod ities (corn, cucumber, onion, pumpkin, potato, squash, starfruit, tomato, meat, and milk). For evaluation of the proposed new uses and tolerances, field trial data, processing factors, percent crop treated data based on Section 18 usage for walnuts, and p ercent imported commodity in domestic consumption data on tangerines for mancozeb were used to refine residue estimates. Modeling estimates (PRZM/EXAMS) for surface water (almond use scenario) were used for ETU EDWCs in the acute assessment and well monitoring data were used for ETU EDWCs for ground water for the

chronic and cancer assessments. The dietary analyses performed for mancozeb were for food only since it is known to degrade quickly i n the environment and is not expected to reach drinking water sources. The dietary analyses performed for ETU were for both food and drinking water.

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

fiel d trials or monitoring data were used to generate residue distribution files (RDFs) for commodities that are considered to be not blended or partially blended. For commodities considered to be blended in this analysis, the average residues incorporating t he likely maximum estimated % CT was used as a point estimate.Mancozeb Human Health Risk Assessment DP No s

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### Page 32 of 77 Chronic anticipated residues were calculated from field trial or monit oring data for mancozeb

and ETU. Averages of the field trials were used for the walnuts and tangerines , while field tr ial and market basket survey data were used for established uses.

5.4.2 Percent Crop Treated Used in Dietary Assessment

For the existing uses of mancozeb, BEAD provided a compilation of percent crop treated (%CT) data (D402049, 6/7/12, J. Alsadek). Additional %CT data for celery, barley, rice and cranberry, as well as percent import data for tangerines and projected crop treated estimate for walnuts

, were provided by BEAD through email correspondence (see D402043, Attachments 6, 7 and 8).

The f ollowing maximum percent crop treated estimates were used in the acute dietary risk assessment for the following crops that are currently registered for mancozeb: almonds: 2.5%; apples: 4 5%; asparagus: 30%; barley: 2.5%; broccoli: 9%; cabbage: 47%; cantalo upes: 15%; carrots: 2.5%; celery: 2.5%; corn: 2.5%; cranberries: 20%; cucumbers: 50%; grapes: 20%; lettuce, head: 66%; lettuce, other: 61%; oats: 1%; onions: 70%; peanuts: 2.5%; pears: 50%; peppers: 48%; potatoes: 65%; pumpkins: 15%; rice: 2.5%; spinach: 2.5%; squash: 30%; sugar beets: 2.5%; sweet corn: 15%; tomatoes: 50%; watermelons: 50%; and wheat: 2.5%. A percent import value of 99% was used for banana.

The following average percent crop treated estimates were used in the chronic and cancer dietary

r isk assessments for the following crops that are currently registered for mancozeb : almonds: 1%; apples: 40 %; asparagus: 15%; barley: 1%; broccoli: 7%; cabbage: 42%; cantaloupes: 5%; carrots: 1%; celery: 1%; cherries: 1 %; corn: 1 %; cranberries: 20%; cucum bers: 25%; grapes: 10%; lettuce, head: 58%; lettuce, other: 59%; oats: 1%; onions: 60%; peanuts: 2.5%; pears: 40%; peppers: 43%; potatoes: 55%; pumpkins: 10%; rice: 1%; spinach: 1%; squash: 20%; sugar beets: 1%; sweet corn: 5%; tomatoes: 25%; watermelons: 40%; and wheat: 1%. A percent import value

of 99% was used for banana.

A maximum percent crop treated projected estimate of 50% for walnuts and a maximum percent import consumption value of 35% for tangerines w ere used in the acute dietary risk assessmen t to support the proposed mancozeb uses. An average percent crop treated estimate of 40% for walnuts as well as an average percent imported commodity in domestic consumption value of 29% for tangerines w ere used in the chronic and cancer dietary risk assessment s. As a further refinement, the commodity having the highest %CT results with livestock feed uses had these values applied to meat and milk (potato; 65% CT maximum for acute and 65% CT average for chronic).

5.4.3 Acute Dietary Risk Assessment

A highly refined probabilistic acute dietary exposure and risk assessment was conducted for both

mancozeb and for mancozeb

- derived ETU to support the proposed new uses of mancozeb

. Ac ute dietary risk estimates are below HED’s level of concern for parent ma ncozeb (food only;

mancozeb is not expected in drinking water ) for all population subgroups. The highest exposure

and risk estimates we re for children 1

- 2 years old at 9.9 % of the aPAD.Mancozeb Human Health Risk Assessment DP No s

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### Page 33 of 77 The mancozeb metabolite and environmental degradate ETU ha s a to xicological endpoint for

acute risk assessment only for the population subgroup of females 13

- 49 years old. Acute risk

estimates for females 13

- 49 years old are below HED’s level of concern for ETU at 58 % of the

aPAD ( food and water )

.

See Table s 5.4.6 .1 and 5.4.6.2 for a summary of the acute dietary exposure and risk estimates.

5.4.4 Chronic Dietary Risk Assessment

A highly refined chronic dietary exposure and risk assessment was conducted for both mancozeb

and for mancozeb

- derived ETU to support the proposed new uses of mancozeb

. The chronic risk

estimates are below HED’s level of concern for mancozeb and ETU for the general U.S. population and all population subgroups. For mancozeb, t he most highly exposed population subgroup is children ages 1

- 2 wi th an estimate of 2.3% of the cPAD (food only; mancozeb is not expected in drinking water ) . For from mancozeb sources, most highly exposed population subgroup is children ages 1

- 2 with an estimate of 51 % of the cPAD (fo o d and water).

See Tables 5.4.6.1 a nd 5.4.6.2 for a summary of the chronic dietary exposure and risk estimates.

5.4.5 Cancer Dietary Risk Assessment

The cancer risk estimate associated with exposure to ETU in food and water, as a result of new and proposed mancozeb uses, is 2 x 10 - 6 

### for the general U.S. population.

See Table 5.4.6.2 for a summary of the cancer dietary exposure and risk estimates.

5.4.6 Summary Table

Table 5.4.6. 1 Summary of Dietary 

### (Food Only) Exposure and Risk for Mancozeb

Population Subgroup Acute Dietary ( 99.9th Percentile) Chronic Dietary Cancer

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

General U.S. Population 0.014388 < 1. 0.000107 < 1. 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 fact or (Q 1 * ) of 6.01 x All Infants (<1 year old) 0.011425 2.3 0.000086 < 1.

Children 1

- 2 years old 0.049471 9.9 0.000374 2.3

Children 3

- 5 years old 0.036223 7.2 0.000260 1.6

Children 6

- 12 years old 0.017499 < 1. 0.000119 < 1.

Youth 13

- 19 years old 0.009590 < 1. 0.000064 < 1.

Adults 20

- 49 years old 0.009912 < 1. 0.000090 < 1.

Adults 50

- 99 years old 0.008187 < 1. 0.000097 < 1.Mancozeb Human Health Risk Assessment DP No s

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### Page 34 of 77 Table 5.4.6. 1 Summary of Dietary 

### (Food Only) Exposure and Risk for Mancozeb

Population Subgroup Acute Dietary ( 99.9th Percentile) Chronic Dietary Cancer

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

Females 13

- 49 years old 0.011634 9.0 0.000101 < 1. 10
- 2 (mg/kg/day)

- 1 to provide a quantitative estimate of

risk.



### . *The values for the highest exposed population for each type of risk assessment is bolded

Table 5.4.6. 2 Summary of Dietary 

### (Food and Water) Exposure and Risk for ETU (derived from mancozeb)

Population Subgroup Acute Dietary ( 99.9th Percentile) Chronic Dietary Cancer

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

General U.S. Population

NA NA 0.000030 1.7 0.0000 30 2 x 10 - 6

All Infants (<1 year old) 0.000045 25

NA NA Children 1

- 2 years old 0.000092 51

Children 3

- 5 years old 0.000062 35

Children 6

- 12 years old 0.000033 1.8

Youth 13

- 19 years old 0.000022 1.2

Adults 20

- 49 years old 0.000027 1.5

Adults 50

- 99 years old 0.000026 1.5

Females 13

- 49 years old 0.002901 58 0.000028 15


### *The values for the highest exposed population for each type of risk assessment is bolded

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no new residential uses being proposed for mancozeb at this time; however, residential uses that could result in mancozeb and ETU exposure ( i.e., home gardeners applying mancozeb to vegetables and golfers contacting mancozeb treated turf after application ) have been

reassessed in this document to reflect up dates to toxicology endpoint selections, updates to the Levels of Concern (LOCs), and updates to HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residentia l

- exposure

- sop.html ), along with policy changes for body weight assumptions. The previous assessment for residential exposures may be

found in D327307 & D327318; D. Davis, et al. , 6/11/07. Reassessed e xposures and risks from

the various residential scenar ios are summarized here since those values are required for the aggregate risk assessment to support the proposed new use that is the subject of this action.Mancozeb Human Health Risk Assessment DP No s

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### Page 35 of 77 6.1 Residential Handler Exposure

The existing residential handler scenario identified for mancozeb is for the application of mancozeb in home gardens ( i.e., vegetables). The anticipated use patterns and current labeling indicate that backpack

, manually pressurized handwand sprayers and hose

- end sprayers could be used by the homeowner to make mancozeb applications. Residential handler risk estimates were assessed for mancozeb (inhalation only ; dermal toxicity is not expected for mancozeb) and it’s degradate ETU (combined dermal and inhalation ). Non

- cance r short

- term assessments were performed for both mancozeb and ETU. A cancer assessment was also performed for ETU.

There are no risk estimates of concern for adults applying mancozeb to home gardens. The details regarding the residential handler assumption s and calculated ri sk estimates are outlined below (for additional details see D 411769

, Mancozeb: Occupational and Residential Risk Assessment to Support Request for Section 3 Registrations on Walnut s).

The quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios:

1. Adults Mixing/Loading/Applying liquids by Manually

- pressurized handwand;

2. Adults Mixing/Loading/Applying liquids by Hose

- End Sprayer; and

3. Adults Mixing/Loading/Applying liquids by Backpack.

Residential Handler Exposure Data and Assumptions

Only inhalation MOEs were calculated for short term mancozeb exposures because no effects

were observed in a mancozeb 28 day dermal toxicity study. Risk calculations were also performed to assess the risk of mancozeb’s degradate ETU

.

The non

- cancer risk calculations for exposures by residential handlers to ETU were calculated in

the same manner as for mancozeb with additional conversions that account for the direct absorption of ETU as well as the metabolic conversion of absorbed mancozeb into ETU. The daily exposure was calculated from environmental sources of ETU (direct exposure via dermal or inhalation absorption) and from metabolic sources of ETU (mancozeb metabolically converted to ETU).

A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments. Each assumption and factor is detailed below.

Application Rate: According to registered labels a mancozeb formulation product ( i.e., Dithane F

- 45; EPA Reg.

62719

- 396) can be applied to home garden vegetables at a maximum single application rate of

2.4 lb ai/acre. Tank mix stability studies submitted to, and reviewed by, the Agency in 1991 indicated that 0.1 percent of the mancozeb paren t converted to ETU during mixing/loading and 0.2 percent converted to ETU during application (D327307 & D327318 ; D. Davis, 6/11/07).Mancozeb Human Health Risk Assessment DP No s

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### Page 36 of 77 Unit Exposures and Area Treated or Amount Handled: Unit exposure values and estimates for

area treated or amount handled were taken from HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ).

Body Weight The standard body weight for the general population (80 kg) was used for assessing

mancozeb inhalation non

- cancer risks and ETU cancer risks since the endpoints selected were not developmental and/or fetal effects. A body weight of 69 kg was used for asse ssing ETU non

- cancer risks since the POD are based on developmental and/or fetal effects

. Risk estimate results for both population sub

- groups (i.e ., females 13 to 49 years old, and males and females>49 years old) are presented since the LOCs for these lifestage population groups are different.

Absorption Factor

s A dermal absorption factor of 1 % was used for mancozeb. A dermal absorption factor of 26 %
was used for ETU. A metabolic conversion factor of 7.5 % 1 

### of the absorbed mancozeb dose is

used to c alculate the ETU dose due to in

- vivo metabolism. Since no inhalation absorption data are available, toxicity by the inhalation route is considered to be equivalent to the estimated toxicity by the oral route of exposure.

Exposure Duration:

Residential h andler exposure is expected to be short

- term in duration. Intermediate

- term exposures are not likely because of the intermittent nature of applications by homeowners.

Residential Handler Non

- Cancer Exposure and Risk Estimate Equations

The non

- cancer risk calculations for exposures to residential handlers were calculated in a similar manner as for occupational handlers. The algorithms used to estimate exposure and dose

for residential handlers can be found in the 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ) and in Appendix A of

D4 11769 ).

Summary of Residential Handler Non

- Cancer Exposure and Risk Estimates for Mancozeb

Residential handler inhalation risk estimates are not of concern ( MOE ≥ 1000 for adult females

13

- 49 years old a nd MOE ≥ 10 0 for other adults (males, females >49 years old))

. Inhalation MOEs for mixing/loading/applying liquid formulation to vegetable gard ens scenarios range from 170,000 for backpack sprayer applications to 20 million for hose

- end sprayer applications. A summary of inhalation risk estimates for residential handlers can be found in Table 6.1.1.

Summary of Residential Handler Non

- Cancer Expo sure and Risk Estimates for ETU from

Mancozeb

Residential handler risk estimates are not of concern (MOE ≥ 1000 for adult females 13

- 49 years

old a nd MOE ≥ 10 0 for other adults (males, females >49 years old)) . MOEs range from 32,700 (mixing/loading/applyi ng liquid formulation to vegetable gardens by backpack) to 130,000

1 A. Kocialski, 09/12/1989. Memo: Establishment of an in

- vivo Metabolic Conversion Factor of 7.5%for all Ethylene Bis(Dithio) Carbamates (EBDCS)when Converting EBDCSs to Ethylene Thiourea (ETU) in

- vivo

.Mancozeb Human Health Risk Assessment DP No s

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### Page 37 of 77 (mixing/loading/applying liquid formulation to vegetable gardens by hose

- end sprayer). A summary of ETU non

- cancer exposure risk estimates for residential handlers can be found in

Table 6.1.2

.

Combining Exposures/Risk Estimates:

The non

- cancer risk calculations for exposures to residential handlers to ETU were calculated in

a similar manner as for occupational handlers. Dermal and inhalation risk estimates were

combined in this assessm ent, since the toxicological effects for these exposure routes were

similar. ETU d ermal and inhalation risk estimates were combined using the following formula:

ETU Total MOE = Point of Departure (mg/kg/day) / Combined dermal + inhalation dose (mg/kg/day)Mancozeb Human Health Risk Assessment DP No s

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### Page 38 of 77 Table 6.1.1 Non

- cancer ( Short

- term ) Residential Handler Exposure and Risk Estimates for Mancozeb.

Exposure Scenario Level of

Concern Inhalation Unit Exposure 2

(mg/lb ai) Maximum Application

Rate 1
(lb ai/ft 2 ) Area Treated or

Amount Handled Daily 2 Inhalation

Dose

MOE 4 (mg/kg/day) 3



### Mixer/Loader/Applicator (Adult Males, Females >49 years)
Home Gardens, liquid concentrate, Manually

pressurized handwand

30 0.018

5.5 x 10
- 5 1200 ft 2 1.35 x 10
- 5 1.6 x 10 6

Home Gardens, liquid concentrate, backpack 0.14 1.05 x 10
- 4 200,000 Home Gardens, liquid concentrate, Hose

- end

sprayer 0.0014 1.05 x 10
- 6 20 x 10 6



### Mixer/Loader/Applicator (Adult Females 13

- 49 years)
Home Gardens, liquid concentrate, Manually

pressurized handwand (Females 13

- 49 years)

300 0.018

5.5 x 10
- 5 1200 ft 2 1.57 x 10
- 5 1.3 x 10 6

Home Gardens, liquid concentrate, backpack 0.14 1.22 x 10
- 4 170,000 Home Gardens, liquid concentrate, Hose

- end

sprayer 0.0014 1.22 x 10
- 6 17 x 10 6

1 

### Based on registered label (EPA Reg. 62719

- 396).

2 Unit exposure values and estimates for area treated or amount handled based on Exposure Science Advisory Council 2012 Residen tial SOPs: http://www.epa.gov/pesticides/science/ residential

- exposure

- sop.html

3 Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal ) x Area Treated or Amount Handled (A or gallons/day) / BW (kg).

4 Inhalation MOE = Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day )Mancozeb Human Health Risk Assessment DP No s

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### Page 39 of 77 Table 6.1.2 Non

- cancer ( Short

- term ) Residential Handler Exposure and Risk Estimates for ETU from Mancozeb.

Exposure Scenario Level of

Concern Dermal

Unit Exposure (mg/lb ai) Inhalation

Unit Exposure 1
(mg/lb ai) Maximum

Application

Rate 2
(lb ai/ft 2 ) Area Treated

or Amount

Handled Daily 1 ETU Dermal Dose

(mg/kg/day) 5 ETU Inhalation Dose
(mg/kg/day) 5

Total ETU

Dose (mg/kg/day) 6 MOE 7 ETU from

Direct Exposure
(Present in
Tank Mix ) 3 ETU

Metabolized

from

Mancozeb 4 ETU from

Direct Exposure (Present in
Tank Mix ) 3 ETU

Metabolized

from

Mancozeb 4



### Mixer/Loader/Applicator (Adult Males, Females >49 years)
Home Gardens, liquid concentrate, Manually

- pressurized handwand

100 63 0.018

5.5 x 10
- 5 1200 ft 2 2.46 x 10
- 5 3.54 x 10
- 5 2.7 x 10
- 8 1.01 x 10
- 6 6.10 x 10
- 5 110,000

Home Gardens, liquid concentrate, backpack 130 0.14 5.07 x 10
- 5 7.31 x 10
- 5 2.10 x 10
- 7 7.88 x 10
- 6 1.32 x 10
- 4 53,000

Home Gardens, liquid concentrate,

Hose

- end sprayer 58 0.0014 2.26 x 10
- 5 3.26 x 10
- 5 2.10 x 10
- 9 7.8 x 10
- 8 5.53 x 10
- 5 130,000



### Mixer/Loader/Applicator (Adult Females 13

- 49 years)
Home Gardens, liquid concentrate, Manually

- pressurized handwand

1 000 63 0.018

5.5 x 10
- 5 1200 ft 2 2.84 x 10
- 5 4.10 x 10
- 5 3.13 x 10
- 8 1.17 x 10
- 6 7.07 x 10
- 5 70,600

Home Gardens, liquid concentrate, backpack 130 0.14 5.87 x 10
- 5 2.12 x 10
- 5 3.43 x 10
- 7 9.13 x 10
- 6 1.53 x 10
- 4 32,700

Home Gardens, liquid concentrate,

Hose

- end sprayer 58 0.0014 2.62 x 10
- 5 3.78 x 10
- 5 2.43 x 10
- 9 9.13 x 10
- 8 6.41 x 10
- 5 78,000

1 Unit exposure values and estimates for area treated or amount handled b ased on ExpoSAC 2012 Residential SOPs: http://www.epa.gov/pesticides/science/residential

- exposure

sop.h tml

2 Based on registered label (EPA Reg. 62719

- 396). Daily Exposure = Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Tre ated or Amount Handled (A or gal/day) x DAF (%)

3 ETU Average Daily Dose from Direct Exposure to ETU (mg/kg/day) = [Daily Exposure (mg ai/day) * Absorption (%)]/ BW (kg) Absorption =0.1 (for mixing and loading) or 0.2 (for application) % of mancozeb.

4 ETU Average Daily Dose From metabolic conversion of mancozeb (mg/kg/day) = [Daily Exposure (mg ai/day) * Absorption (%)*Metabolic ETU Conversion]/ BW (kg) 7.5 percent of the absorbed mancozeb dose is metabolically converted to ETU

5 Dermal or Inhalation Dose= ETU Average Daily Dose from Direct Expo sure to ETU (mg/kg/day) + ETU Average Daily Dose From m etabolic conversion of mancozeb (mg/kg/day)

6 Total ETU Dose = Total Dermal ETU Dose (mg/kg/day) + Total Inhalation ETU Dose (mg/kg/day)

7 Total MOE = NOAEL (mg/kg/day)/Total ETU Dose (mg/kg/day). ETU Short

- Term Dermal and Inhalation NOAEL : 5 mg/kg/day (females 13

- 49); 7 mg/kg/day (males, females >49)Mancozeb Human Health Risk Assessment DP No s

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### Page 40 of 77 Summary of Residential Handler Cancer Exposure and Risk Estimates for ETU from Mancozeb

The cancer risk s to home gardeners were reassessed , as they will be used for the aggregate risk assessment. Further description of the assumptions and data used in the assessment may be

fo und in D4 11769 . As previously noted, mancozeb’s potential for carcinogenicity is due to the

formation of the metabolite ETU. Cancer risks from exposure to ETU as a result of application of mancozeb are calculated by estimating exposure to mancozeb

- derived ETU and using the ETU Q 1 * 

### of 0.0601 (mg/kg/day) - 1 

### to provide a quantitative estimate of risk.

The cancer risk calculations for exposures by residential handlers to ETU were calculated in a similar manner as for occupational handlers with the following assumptions:

Days per year of Exposure To assess cancer risk, it is assumed that residential handlers would be exposed 5 days per year.

Years per Lifetime of Exposure: It is assumed that residential handlers would be exposed for 50 years out of a 78

- year lifespan.

Lifetime Expectancy: Life expectancy values are from the Exposure Factors Handbook 2011 Edition Table 18

- 1 (U.S.

EPA , 2011). The table shows that the overall life expectancy is 78 years based on life expectancy data from 2007. In 2007, the average life expectancy for males was 75 years and 80 years for females. Based on the available data, the recommended value for u se in cancer risk assessments is 78 years.

The cancer risks for all M/L/A scenarios are estimated in the 10 - 8 

### range for residential handlers. Residential handler estimated cancer risks were calculated for applicators using a backpack sprayer, manually pr essurized and hose

- end sprayer. For applicators using backpack sprayers the

estimated cancer risk from mancozeb

- derived ETU was 7 x 10 - 8 

### . Residential handlers using manually pressurized sprayers had an estimated cancer risk of 3 x 10 - 8 

### . Handlers using ho se

- end sprayers had an estimated cancer risk of 3 x 10 - 8



### . A summa ry of ETU cancer exposure risk

estimates for residential handlers can be found in Table 6.1.3

.Mancozeb Human Health Risk Assessment DP No s

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### Page 41 of 77 Table 6.1.3 Residential Handler Cancer Exposure and Risk Estimates for ETU from Mancozeb.

Crop or Target Exposure Scenario Handler

Dermal

ADD 1
(mg/kg/day) Handler

Inhalation

ADD 2
(mg/kg/day) Total Absorbed

Dose

ADD (mg/kg/day) Total LADD 3

(mg/kg/day) 3 Residential

Handler

Cancer

Risk

Estimate 4

Mixer/Loader/Applicator

Home Gardens (Vegetables) Liquid concentrate

- Manually

pressurized handwand 6.00 x 10
- 5 1.04 x 10
- 6 6.10 x 10
- 5 5.36 x 10
- 7 3 x 10
- 8

Liquid concentrate

- Backpack 1.24 x 10
- 4 8.09 x 10
- 6 1.32 x 10
- 4 1.16 x 10
- 6

- 7 x 10
- 8
Liquid concentrate

- Hose

- end

sprayer 5.52 x 10
- 5 8.09 x 10
- 8 5.53 x 10
- 5 4.86 x 10
- 7 3 x 10
- 8

1 Dermal LADD = Dermal dose * Days per year of exposure *Years per lifetime of exposure / (365 days/year x Lifetime expectancy )

. 2 Inhalation LADD = Inhalation Dose * Days per year of exposure *Years per lifetime of exposure / (365 days/year x Lifetime expectancy )

. 3 Total LADD = total absorbed dose [Dermal dose + Inhalation Dose] * Days per year of exposure * Years per

lifetime of exposure / (365 days/year x Lifetime expectancy )

. 4 Cancer risk estimates = LADD * Q 1 * , where Q 1 * = 6.01 x 10 - 2 (mg/kg/day) - 1

.



### 6.2 Post

- Application Exposure

Mancozeb can be used in areas that can be frequented by the general population including residential areas ( vegetable gardens and lawns containing turf from sod farms ) and golf courses. As a result, individu als can be exposed by entering areas that ha ve been previously treated with

mancozeb

. An updated assessment of the most representative s cenarios to be used in the aggregate assessment is presented below.

In addition to the mancozeb uses on home gardens and golf courses there is a registered sod farm use and the treated sod could be subsequently transplanted to a residential setting. HED considers post

- application exposure resulting from this scenario to be negligible for the following reasons: 1) mancozeb has a post

- harvest interval (PHI) of 5 days for sod; 2) it is unlikely that sod treated with mancozeb would be installed more than onc e per year; 3) transplanted sod requires constant and significant watering which will result in decreased mancozeb residues on the transplanted sod; and 4) it is unlikely that adults or children will spend any significant amount of time on recently transpl anted sod until it is rooted which typically occurs around 2 weeks after transplanting. Therefore, dermal and incidental oral post

- application

scenarios were not quantitatively assessed f or the sod farm use of mancozeb. There are no post

application exposu re risks of concern anticipated from the use of mancozeb on sod farms.

The quantitative exposure/risk assessment for residential post

- application exposures is based on: home gardeners (adults and youth) harvesting vegetables from treated gardens and golf ers (adults and youth) contacting mancozeb treated turf after application

. As no dermal hazard was

identified for mancozeb , a quantitative dermal post

- application assessment (non

- cancer /short

-Mancozeb Human Health Risk Assessment DP No s

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### Page 42 of 7 7 term and cancer) was only performed for its metabolite, ETU.

T he lifestages selected for each post

- application scenario are based on an analysis provided as an Appendix in the 2012 Residential SOPs ( http://www.epa.gov/pesticides/science /residential

exposure

- sop.html ). These lifestages are not the only lifestages that could be potentially exposed for these post

- application scenarios; however, the assessment of these lifestages is health protective for the exposures and risk estimates for any other potentially exposed lifestages.

Residential Post

- application Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the residential
post

- application risk assessment. Each assumption and f actor is detailed in the 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html and in Appendix A

of D4 11769

. Assumptions regarding bod y weight

, conversion of mancozeb to ETU, and absorption factors are the same as those outlined in Section 6.1 above.

Home Gardeners

According to registered labels a mancozeb formulation product ( i.e., Dithane F

- 45; EPA Reg.

62719

- 396) can be applied to h ome garden vegetables at a maximum single application rate of

2.4 lb ai/acre. Adults and children may be exposed to mancozeb

- derived ETU while performing high contact activities (e.g., weeding, harvesting) in a residential home garden that has been previou sly treated.

The assumptions for the residential home gardener assessment are:

The lifestages assessed were adults and youth (children 6 to 11 years old). Dermal exposures were assessed for the commodity that might be found in a home garden and led to the highest exposure ( i.e., cucurbit vegetables). Dislodgeable Foliar Residues (DFR) data was derived from a mancozeb study ( MRID
44959306 ) and a n ETU study ( MRID 44959603 ) . While the application rates are the same for west and east cucurbit, the dislodgeable foliar residues for east and west are different. Since west DFR are higher, exposures and risks were estimated for “west” only. Post application non

- cancer risks estim ates from mancozeb

- derived ETU were assessed on Day 0 (the day of application).

Golfers

Adults and children may be exposed to mancozeb

- derived ETU through dermal contact with golf

course turf treated directly with mancozeb. The scenarios, routes of ex posure and lifestages

assessed include:Mancozeb Human Health Risk Assessment DP No s

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### Page 43 of 77 Golfing: adults (females 13

- 49 years old) (dermal); adults ( males, females >49 years old ) (dermal); children 11 < 16 years old, except for females ≥ 13 years old (dermal); and children 6 < 11 years old (dermal).

T he assumptions for the residential golfer assessment are refined as follows:

• Golfer assessment is based on a maximum application rate of 17.4 lb ai/A ( registered

label EPA Reg No. 62719

- 402 ).

• Golfers have been assessed using a transfer coefficient of 5,300 cm 2 

### /hour (derived from a golf course worker exposure study, MRID 46734001). It is assumed golfers wear T

shirt and shorts.

• For golfer non

- cancer and cancer risk assessment it was assumed that the tees, greens and fairways are treated and that the exposure time per day would be four hours.

• Measured Turf Transferable Residues (TTR) values based on a chemical specific (mancozeb) tu rf study (MRID 449585 01 )

.

◦ For golfer non

- cancer risk assessment the highest measured residues from the turf study were u sed: mancozeb initial TTR of 0.20 (ug/cm 2 

### ) ; ETU initial TTR of 0.003 ( ug/cm 2 

### ).

◦ For golfer cancer risk assessment the a verage highest TTR value s (NC, PA, and CA sites) for Mancozeb and ETU residues from the turf study were used:

mancozeb TTR of 0. 15 (ug/cm 2 

### ) ; ETU TTR of 0.003 ( ug/cm 2 

### ).

• For cancer risk assessment, t he exposure days per year for golfers (one day per year) is

assumed to be one based upon the following:

◦ Golfers play an average of 19 rounds per year based upon information from the

National Golf Foundation for the years 1994 through 2003.

◦ According to BEAD, 20% percent of golf c ourses in the U.S. use mancozeb.

◦ According to the Golf Course Superintendent’s Association, fungicides are applied to golf courses an average of 6 times per year.

Residential Post

- application Non

- Cancer Exposure and Risk Equations The algorithms used to estimate residential post

- application exposure and dose can be found in the 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

sop.html ) and in Appendix A of D4 11769

.Mancozeb Human Health Risk Assessment DP No s

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### Page 44 of 77 6.2.1 Home Garden Post

- application Scenarios

Summary of N on

- Cancer Exposure and Risk Estimates for ETU from Mancozeb for Home

Gardeners

Table 6.2.1.1 below summarizes the post

- application non

- cancer risks estimates from mancozeb

derived ETU for adults and youth exposed to treated home gardens on Day 0 (the day of application). Exposures are shown for the commodity that might be found in a home garden and led to the highest exposure ( i.e., cucurbit vegetables). The short

- term dermal MOEs for all subpopulations on Day 0 exceed the LOCs ( i.e., MOE ≥ 1000 for adult females 13

- 49 years old

a nd MOE ≥ 10 0 for youth and other adults (males, females >49 years old) ) and are therefore not
of concern.

Table 6.2.1.1 Mancozeb

- derived ETU Post

- application Short

- Term (Non

- Cancer) Exposure and Risk Estimates for
Adult and Youth Home Gardeners 1

Lifestage LOC Crop

Group Application

Rate (lb ai/a cre) Initial DFR

(ug/cm 2 ) 2
TC

(cm2/ hr) ETU

Foliar

Dose

(mg/kg/day) Mancozeb

Metabolized

Dose to ETU (mg/kg/day) Total

Absorbed

Dermal

Dose (mg/kg/day) MOE

Mancozeb ETU

Adult (Female

13

- 49 years old) 1000

Vegetable

cucurbit

– West 2 2.4 6.77 0.01 8,400 0.0007 0.0012 0.0019 2,700

Adult (males,

females >49 years old) 100 8,400 0.0006 0.0010 0.0016 4,300

6 to 11 yrs old 100 4,600 0.0004 0.0008 0.0012 5,800

11 to <16

years (except

females

13

- 16 years old) 100 8,400 0.000843 0.001419 0.002262 3,100

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

exposure.
2 Note

– while the application rates are the same for west and east cucurbit, the dislodgeable foliar residues for east and west are different. Since west DFR are higher, exposures and risks were estimated for “west” only

. Mancozeb study: MRID 44959306. ETU study: MRID 44959603Mancozeb Human Health Risk Assessment DP No s

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### Page 45 of 77 Summary of Cancer Exposure and Risk Estimates for ETU from Mancozeb for Home Gardeners

Post

- application cancer risks estimates from mancozeb

- derived ETU for adults exposed to treated home gardens on Day 0 (the day of application ) are summarized in Table 6.2.1.2 , below. As in the table above, only the scenario with the highest anticipated exposure was assessed.

Post

- application cancer risks for adult home gardeners are estimat ed at 9 x 10 - 7



### .

Table 6.2.1.2 Mancozeb

- derived ETU Post

- application Cancer Exposure and Risk Estimates for Adult

Gardeners on Day 0 Assuming Five Exposure Days per Year Over a Lifetime

Crop Group Application

Rate (lb ai/acre) 1 Dose

Cancer Risk 5

Total Absorbed

Dermal Dose 3
(mg/kg/day) Lifetime Average Daily Dose (LADD) 4 , (mg/kg/day)

Vegetable,

cucurbit

– (West) 2.4 2 0.0019 1.41 x 10
- 5 9 x 10
- 7

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

exposure.

2 Note

– while the application rates are the same for west and east cucurbit, the dislodgeable foliar residues for east and west are different. Since west DFR are higher, exposures and risks were estimated for “west ” only . Mancozeb study: MRID 44959306. ETU study: MRID 44959603

3 ADD = Absorbed Daily Dose from foliar an metabolized sources of ETU exposure

4 LADD = Lifetime Average Daily Dose = ADD * (5 exposure days per year/365 days per year)*(50 years of exposur e/78 years of life)

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

-



### 6.2. 2 Treated Turf Post

- application Scenario s

Summary of Non

- Cancer Exposure and Risk Estimates for ETU from Mancozeb for Golfers

The MOE s for short

- term dermal risk for young gol fers ( <16 years old ) and adult golfers

, including females 13

- 49 years old, exposed to ETU from contact with mancozeb treated golf

courses are above the LOC s ( 100 for youth and adult s
, other than females 13

- 49 years old

, and

1000 for females 13

- 49 years old) and are therefore, not of concern. A summary of e xposure and

risk estimates for adults and children exposed to ETU from contact with mancozeb treated golf

courses is summarized in Table 6.2. 2.1.

Summary of Cancer Exposure and Risk Estimates for ETU from Mancozeb for Golfers The cancer risk to adult golfers from exposure to mancozeb

- derived ETU is estimated to be 3 x 10 - 8 

### (Table 6.2. 2.2 ).Mancozeb Human Health Risk Assessment DP No s

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### Page 46 of 77 Table 6.2.2.1 Mancozeb

- derived ETU Post

- application Short

- term ( Non

- cancer ) Exposure and Risks Estimates for Golfers

Lifestage LOC Application

Rate 2
(lb ai/acre) Mancozeb

TTR (ug/cm 2 ) ETU

TTR (ug/cm2) Transfer

Coefficient 3
(cm 2 /hr) Hours

per Day Exposure Mancozeb

Dermal Dose 4
(mg/kg/day) Mancozeb

Metabolized

to ETU Dose 5
(mg/kg/day) ETU Foliar

Dose 6
(mg/kg/day) Total ETU

absorbed

Dose 7
(mg/kg/day) ETU

Dermal

MOE 8

Adult (Female

13

- 49 years old ) 1000

17.4 0.20 0. 003 5,300 4. 0. 000614 0.00 0046 0.00 0239 0.00 0286 17,500

11 to <16

years (except

females

13

- 16 years old) 100 4,400 4 0.0 00618 0.00 0046 0.0 00240 0 .000287 24,400

6 to <11

years 100 2,900 4 0. 000725 0.00 0054 0.00 0282 0.00 0337 20,700

Adult ( males,

females

>49 years old) 100 5,300 4 0.0 00529 0.00 0040 0.0 00206 0.0 00246 28,000

1. Based on Mancozeb initial TT R of 0.20 (ug/cm 2 ) and ETU initial TTR of 0.003 ( ug/cm 2 ). Highest residue values from turf study: MRID 449585

- 01. 2. Based on registered label EPA Reg No. 62719

- 402. 3. Transfer Coefficient (TC) values based on ExpoSAC 2012 Residential SOPs: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html 4. Mancozeb Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 4 hrs/day × dermal absorption (%)] BW (kg)

5.Mancozeb Metabolized Dose to ETU= Mancozeb Dermal Dose × 0.075 6. ETU Foliar Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 4 hrs/day × dermal absor ption (%)] BW (kg).

7. Total Dermal Dose = ETU Foliar Dermal Dose + ETU Metabolized Dose to ETU 8.Total MOE = NOAEL (mg/kg/day)/Total ETU Dose (mg/kg/day). ETU Short

- Term Dermal NOAEL: 5 mg/kg/day (females 13

- 49); 7 mg/kg/day (males, females >49, and you th 6 to <16 except females 13

- 49).Mancozeb Human Health Risk Assessment DP No s

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### Page 47 of 77 Table 6.2. 2.2 Summary of ETU Post

- application Cancer Risks for Adults Exposed to Turf

Activity Application

Rate (lb ai/acre) Mancozeb

TTR 1
(ug/cm2) ETU TTR

(ug/cm2) Transfer

Coefficient (cm 2 /hr) Hours per

Day Exposure Days Per

Year Exposure Years of

Exposure

per Lifetime ADD 2

Total ETU

absorbed

Dose (mg/kg/day) LADD 3

(mg/kg/day) Cancer

Risk 4

Golf 17.4 0.15 0.03 5,300 4.0 1 50 0.000237 4.1 x 10
- 7 2.5 x 10
- 8

1 Average highest TTR values (NC, PA, and CA sites) for Mancozeb and ETU residues from turf study: MRID 449585

- 01)

2 ADD = Absorbed Daily Dose from foliar an metabolized sources of ETU exposure

3 LADD = Lifetime Average Daily Dose = ADD * (1 exposure day pe r year/365 days per year)*(50 years of exposure/78 years of life)

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

- 1



### 6. 3 Residential Risk Estimates for Use in Aggregate Assessment

HED combines risk values resulting from separate exposure scenarios when it is likely they can occur simultaneously based on the use pattern and the behavior associa ted with the exposed population. For home garden scenarios a combined (dermal plus inhalation) residential exposure assessment for handlers was condu cted for ETU exposures

. T he residential handler scenario identified for use in performing an aggregate exposure assessment for ETU was for adults treating home gardens with mancozeb formulations (mixing/loading/application) utilizing a backpack sprayer ( ETU combined MOE= 32,700). However, for parent mancozeb exposures, the only route of exposure for handlers was through the inhalation route (no dermal toxicity). T he residential handler scenario identified for use in performing a mancozeb a ggregate exposure assessment was for home gardeners applying mancozeb to vegetables utilizing a backpack sprayer (MOE=170,000). A summary of short

- term residential handler exposure and risk estimates for mancozeb inhalation exposures and ETU combined exposures , for use in the aggregate assessment, is presented i n Tables 6. 3 .1 and 6. 3 .2, respectively.

For residential post

- application , the gardening scenarios represent the most conservative exposure estimates and were used in the
aggregate assessment. The gardening scenario s result in higher estimated exposure than the golfing scenario s and are therefore protective of any golfer risk. The only route of exposure for treated garden post

- application scenarios is through the dermal route ( inhalation exposures are not expected)

. Since mancozeb does not have dermal toxicity, only ETU exposures are assessed for

g ardeners

. The residential post

- application scenarios used in performing an aggregate exposure assessment were adult (females 13

- 49 yrs) and youth gardeners

. A summary of short

- term residential post

- application exposure and risk estimates for ETU from mancozeb

ide ntified for use in performing short

- term post

- application aggregate exposure assessment s is presented in Table 6. 3 .3

.Mancozeb Human Health Risk Assessment DP No s

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### Page 48 of 77 The residen tial handler scenario identified for use in performing an aggregate cancer assessment was for home gardeners applying mancozeb to vegetables utilizing a backpack sprayer

. For applicators using backpack sprayers the estimated cancer risk from mancozeb

- deri ved ETU was

7 x 10 - 8 

### (Table 6. 3.4 ).

The residential post

- application scenario identified for use in performing an aggregate cancer

assessment was for adults exposed to treated home gardens. The cancer risk to adult gardeners from exposure to mancozeb

- derived ETU is estimated in 9 x 10 - 7 

### ( Table 6.3.5 ).

Table 6. 3.1 Residential Exposures and Risks for the Mancozeb Short

- Term Aggregate Assessment (Residential Handler /Garden Use )

Lifestage Handler Exposure Scenario Dose (mg/kg/day) LOC MOEs

Adult (Female 13

- 49 years old) M/L/A

Backpack

sprayer Inhalation Home Garden Activities 0.000122 300 170,000

Adult (Male, female >49 years old) M/L/A

Backpack

sprayer Inhalation Home Garden Activities 0.000105 30 200,000



### Table 6. 3 .2 Residential Exposures and Risks for the ETU ( from Mancozeb ) Short

- Term Aggregate
Assessment (Residential Handler /Garden Use )

Lifestage Handler Exposure Scenario Dose (mg/kg/day) LOC MOEs

Adult (Female 13

- 49 years old) M/L/A

Backpack

sprayer Combined

(Inhalation + Dermal) Home Garden Activities 0.000 153 1000 32,700

Adult (Male, female >49 years old) M/L/A

Backpack

sprayer Combined

(Inhalation + Dermal) Home Garden Activities 0.000 132 100 37,900



### Table 6. 3.3 Residential Exposures and Risks for the ETU (from Mancozeb) Short

- Term Aggregate
Assessment (Post

- Application Exposures/Garden Use) Lifestage Post

- application Exposure Scenario Dose (mg/kg/day) LOC MOEs

Adult

(Female 13

- 49 years old) Liquid

sprays Dermal Home Garden

Activities 0.0019 1000 2,700

Child 6 < 11 years old 0.0012 100 5,800

Child 11 < 1 6 years old 0.00226 100 3,100Mancozeb Human Health Risk Assessment DP No s

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### Page 49 of 77 Table 6. 3.4 Residential Exposures and Risks for the ETU ( from Mancozeb) Aggregate Cancer

Assessment (Residential Handler /Garden Use).

Crop or Target Total Absorbed Dose

ADD (mg/kg/day) Total LADD 3
(mg/kg/day) 3 Residential Handler

Cancer Risk Estimate 4

Mixer/Loader/Applicator ( Liquid concentrate

– Backpack Sprayer)

Home Gardens (Vegetables) 1.32 x 10
- 4 1.16 x 10
- 6

- 7 x 10
- 8



### Table 6. 3.5 Residential Exposures and Risks for the ETU ( from Mancozeb ) Aggregate Cancer

Assessment ( Post

- Application Exposures/Garden Use)

Activity ADD

Total ETU absorbed Dose (mg/kg/day) LADD (mg/kg/day) Cancer Risk

Home Garden Activities 0.0019 1.41 x 10
- 5 9 x 10
- 7



### 6.4 Residential Bystander Post

- application Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for mancozeb or its metabolite ETU at this time. However, volatilization of pesticides may be a potential source of post

- application inhalation exposure to individuals nearby to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, developing policies and procedures, to identifying the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantit ative post

- application inhalation exposure assessment for mancozeb

.

6.5 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the airblast 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 p arties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information 2 

### . The

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmMancozeb Human Health Risk Assessment DP No s

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### Page 50 of 77 Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide re gistrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce

off

- target drift with specific products with significant risk estimates associated with drift.

Furthermore, turf (golfer scenario) and home garden uses were quantitatively assessed a s part of this risk assessment; risk estimates addressed in the golfer turf assessment provide a worst case estimate of potential exposure from spray drift. It is noted that the 17.4 lb ai/acre application rate for turf was modeled to estimate post

- applica tion residential exposure s (i.e., adults and youth 6 to 16 years old) . As this rate is equal to or higher than the agricultural application rates, this scenario is protective of any exposure via spray drift from agricultural mancozeb applications.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate
assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and

durati on of exposure.

Based on the existing and newly proposed uses of mancozeb, exposure to mancozeb and to

mancozeb

- derived ETU can occur both from dietary sources (food and water) and in residential settings. The mancozeb uses in home gardens may result in handler exposure for adults and
post

- application exposure to adults and youth working in the garden. The mancozeb golf course turf use may result in post

- application exposure to adults and youth playing golf.

M ancozeb’s potential for carcinogenicity is due to the formation of the metabolite ETU; therefore, aggregate cancer risks 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 exposur es that are likely to

co

- occur. For the purpose of this risk assessment, HED only aggregated scenarios that are likely

co

- occur. The lifestages selected for the aggregate assessments represent the population subgroups expected to be the most highly expos ed for each scenario. For more information on

the exposure scenarios selected for aggregate assessment, see Section 6. 3 above.

Mancozeb

Residues of mancozeb per se are not expected in drinking water, so aggregate risk assessments

for mancozeb are limited to combined food and residential pathways. Additionally, an endpoint was not selected for dermal risk assessment since there was no systemic toxicity observed at the highest dose tested in the dermal studies; therefore exposure from the dermal route is no t included in the mancozeb aggregate risk assessments.Mancozeb Human Health Risk Assessment DP No s

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### Page 51 of 77 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

- Term Home Garden Aggregate (Adult)

, which considers residential handler exposures (inhalation) to adult applicators combined with average food

exposures

. Mancozeb Long

- Term or Chronic (Non

- Cancer) Aggregate

, which consider s 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 A ggregate

, which considers acute exposure to mancozeb

- derived ETU from

food and water

. ETU S hort

- T erm Home G arden Aggregate (Adult and Youth)

, which considers 1)

handler exposures (inhalation and dermal) plus food and water exposures for adults and 2) post

- applicati on exposures (dermal) plus food and water for adults and youth entering the garden after treatment. ETU Long

- Term or Chronic (Non Can cer) A ggregate

, which considers exposure from food and water only

. ETU Cancer Aggregate

, which co mbines 1) adult handler ho me garden exposures (dermal and inhalation) and chronic food and water and 2) adult post

- application exposures (dermal) plus food and water exposures for g ardening activities

.

Summaries of the aggregate risk assessments can be found below in Sections 7.1 through 7.5.

7.1 Acute Aggregate Risk

HED has calculated the acute dietary risk for females 13

- 49 years of age in Section 5.4 of this risk assessment. Since food is the only source contributing to the acute aggregate risk assessment, the acute aggregate risk assessment s for mancozeb and ETU are equivalent to the acute dietary risk assessment s detailed in Section 5.4. HED has no concern for acute aggregate

risks to females 13

– 49 yrs, the subgroup of concern, resulting from exposure to mancozeb or ETU f rom the existing and new uses of mancozeb.

7.2 Short

- Term Aggregate Risk

The short

- term aggregate assessment for mancozeb and ETU combined adult residential handler exposures and dietary (food only for mancozeb; food and water for ETU ) exposures. There areMancozeb Human Health Risk Assessment DP No s

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### Page 52 of 77 no short

- term aggregate risk estimates of concern for adults applying mancozeb to gardens (Tables 7.2.1 and 7.2.2).

A short

- term aggregate assessment was performed for ETU for adults (using females age 13

- 49

yrs

. old as the most highly exposed population) and children (using youth ages 11

- <16 yr s. old as the most highly exposed population) entering treated gardens. The garden scenarios resulted in higher post

- application exposures than the golfing scenarios; asse ssment of the garden scenario is protective of any post

- application exposures to adult and youth golfers. Post

- application exposures to ETU were combined with dietary (food and water) exposures. There are no short

term aggregate risk estimates of concern for adults or youth entering treated gardens (Table 7.2.3).

Table 7.2 .1 Mancozeb Short

- Term Aggregate Risk Calculations (Residential Handler/ Home Garden Use)

Population Short

- Term Scenario

NOAEL mg/kg/day LOC 1 Max

Allowable Exposure 2
mg/kg/day Average

Food Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Total

Exposure mg/kg/day 4 Aggregate

MOE (food

and residential) 5

Adult Male (and

F emales >49 yrs) 21 30 0.7 0.000107 0.000105 0.000212 99,000

Adult Female (13

- 49 yrs) 21 300 0.07 0.000101 0.000122 0.000223 94,000

1 LOC = 3x inter

- species UF, 10x intra

- species UF, and for females (13

- 49 yrs) the 10x FQPA SF is retained

. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = Inhalation exposure ( S ection 6. 3 ).

4 Total Exposure = Avg Food Exposure + Residential Exposure)

5 Aggregate MOE = [NOAEL / (Avg Food Exposure + Residential Exposure)]

Table 7.2 .2 ETU (derived from mancozeb) Short

- Term Aggregate Risk Calculations (Residential Handler

/ Home Garden Use)

Population Short

- Term Scenario

NOAEL mg/kg/day LOC 1 Max

Allowable Exposure 2
mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Total

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5

Adult Male (and Females >49 yrs) 7 100 0.07 0.000030 0.000132 0.000162 43,000

Adult Female (13

- 49 yrs) 5 1000 0.005 0.000028 0.000153 0.000181 28,000

1 LOC = 10 x inter

- species UF, 10x intra

- species UF ; and for females (13

- 49 yrs) the 10x FQPA SF is retained

. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = [Dermal exposure + Inhalation Exposure]. (Section 6. 3 ).

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure)

5 re + Residential Exposure)]Mancozeb Human Health Risk Assessment DP No s

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### Page 53 of 77 Table 7.2.3 ETU (derived from mancozeb) Short

- Term Aggregate Risk Calculations (Residential Post

- Application/ Home Garden Use)

Population Short

- Term Scenario

NOAEL mg/kg/day LOC 1 Max

Allowable Exposure 2
mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Total

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5

Adult Female (13

- 49 yrs) 5 1000 0.005 0.000028 0.0019 0.001928 2600

Youth (11

- <16 yrs) 7 100 0.07 0.000022 0.0022 0.002222 3200

1 LOC = 10x inter

- species UF, 10x intra

- species UF; and for females (13

- 49 yrs) the 10x FQPA SF is retained.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = [Dermal exposure]. ( Section 6. 3 ).

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure)

5



### 7.3 Intermediate

- Term Aggregate Risk

There are no intermediate

- term residential exposure scenarios for ma ncozeb or ETU, therefore

an intermediate

- term aggregate assessment is not performed.

7.4 Long

- Term or Chronic Aggregate Risk

There are no long

- term residential exposure scenarios 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 includes contribution from dietary (food only) exposure alone. The chronic (non

- cancer) aggregate risk assessment for mancozeb is equivalent to the mancozeb chronic dietary risk assessment conduction in Section 5.4 of this document. HED has no concern for chronic (non

- cancer) aggregate risks to the general population or any regulated subgroup, resulting from exposure to mancozeb per se from the existing and new uses of mancozeb.

The long

- term or chronic (non

- cancer) aggregate risk for mancozeb

- derived ETU includes contribution from dietary (foo d and water) exposure alone. The chronic (non

- cancer) aggregate

risk assessment for mancozeb

- derived ETU is equivalent to the mancozeb

- derived ETU chronic dietary risk assessment conduction in Section 5.4 of this document. HED has no concern for

chronic (non

- cancer) aggregate risks to the general population or any regulated subgroup, resulting from exposure to mancozeb

- derived ETU from the existing and new uses of mancozeb.

7.5 Cancer Aggregate Risk

The cancer aggregate assessment for mancozeb

- derived ETU includes contributions from residential and dietary (food and water) exposures and considers the scenarios resulting in the highest estimated exposures, which are applying mancozeb to gardens and entering treatedMancozeb Human Health Risk Assessment DP No s

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### Page 54 of 77 gardens. The cancer aggregate risk est imate s (handler and post

- application) for the U.S. population are 2 x 10 - 6 

### and 3 x 10 - 6



### , respectively

.

Table 7.5 .1 ETU (derived from mancozeb) Aggregate Cancer Risk Estimates ( Residential Handler/Garden Use)

Population Cancer Slope

Factor (Q 1 

### *) Food and Water

Exposure (mg/kg/day) 1 

### Residential

Exposure (LADD ) ( mg/kg/day ) 2 

### Aggregate

Cancer Risk (food, water, residential) 3



### U

. S

. Population 6.01 x 10 - 2 

### 3 x 10 - 5 

### 1.16 x 10 - 6 

### 2 x 10 - 6

1 Dietary exposure: Table 5.4.6.2.

2 R esidential exposure values used in aggregate assessment : Table 6.4. 4

. 3 Aggregate Cancer Risk = (Q 1 *) (Food & Water Exposure + LADD)



### Table 7.5.2 ETU (derived from mancozeb) Aggregate Cancer Risk Estimates (Post

- Application / G

arden Use )

Population Cancer Slope

Factor (Q 1 

### *) Food and Water

Exposure (mg/kg/day) 1 

### Residential

Exposure (LADD ) ( mg/kg/day ) 2 

### Aggregate

Cancer Risk (food, water, residential) 3



### U

. S

. Population 6.01 x 10 - 2 

### 3 x 10 - 5 

### 1.41 x 10 - 5 

### 3 x 10 - 6

1 Dietary exposure: Table 5.4.6.2.

2 Residential exposure values used in aggregate assessment: Table 6.4. 5

. 3 Aggregate Cancer Risk = (Q 1 *) (Food & Water Exposure + LADD)



### 8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk app roach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to mancozeb and any other substances . Mancozeb does produce a toxic metabolite, ETU, which is produced by other EBDC compounds. Risks from combined exposures to ETU from all EBDC compounds are addressed in a separate ETU aggregate risk assessment. For the purposes

of this tolerance action EPA has not assumed that mancozeb has a common mechanism of toxicity with other substances. For information regar ding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning

common mechanism determination s and procedures for cumulating effects from substances
found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9 .0 Occupational Exposure/Risk Characterization

Mancozeb is a widely used contact fungicide in agriculture, professional turf management, horticulture, and home gardening. Mancozeb formulations include wettable powders, dry flowables, liquid flowables and dusts. The product is current ly registered for foliar application and seed treatment on various agricultural crops. Horticultural uses include ornamental plants inMancozeb Human Health Risk Assessment DP No s

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### Page 55 of 77 nurseries and greenhouses, sod farms, and golf courses. Occupational assessments are performed for the proposed U.S. wal nut use. Occupational assessments are not performed for the proposed use on imported tangerines.

The petitioner has proposed to amend the use pattern for various mancozeb formulations ( i.e.

, Penncozeb Technical [EPA Reg. No.70506

- 188 ] ; Penncozeb 75DF [ EP A Reg. No. 70506

- 185 ] ; P enncozeb 4FL Plowable Fungicide [ EPA Reg. No. 70506

- 194 ] ; Manzate Pro

- Stick F ungicide, [ EPA Reg. No. 70506

- 234 ] ; and Manzate Flowable [ EPA Reg. No. 70506

- 236 ] adding a use on walnuts for the control of walnut blight, a bacterial dis ease caused by Xanthomonas campestris pv. juglandis

.

The proposed use pattern and directions are similar for all mancozeb formulations for applications on walnuts

. Ground and aerial foliar applications are permitted. The maximum single application rate proposed is 1.8 pounds mancozeb per acre. The labels propose a

maximum of ten applications per year ( i.e., maximum total application rate of 18 lb ai/year), and

a Pre

- Harvest Interval (PHI) of 75 days. Applications are to begin at early pre

- bloom prior to or when catkins are partially expanded and additional applications can be made during bloom and early nutlet stage, or as needed if frequent rainfall occurs.

9.1 Short

- and Intermediate

- Term and Cancer Handler Risk

Occupational handler exposure to mancozeb is expected for individuals involved in foliar applications to walnuts ( i.e. , during mixing, loading, and applying). Because ETU is an environmental degradate and metabolite of mancozeb, both mancozeb and ETU exposures have been assessed. Based on application rate and label information, handler exposure is expected to

occur for short

- and intermediate

- term durations. Chronic exposu re is not expected for the proposed use patterns. A cancer assessment is also performed for ETU as ETU has been classified as a Group B2 carcinogen. O nly inhalation exposures were considered for mancozeb

because no effects were observed at the limit dose in a 28

- day dermal rat study. In the case of ETU, however, inhalation and dermal exposures were considered for both the non

- cancer and

cancer risk assessments.

ETU is produced through degradation of mancozeb during spray mix preparation, during spray

app lication and in the environment ( e.g., on treated leaves) after application. Tank mix stability studies submitted to, and reviewed by, the Agency in 1991 indicated that 0.1 percent of the mancozeb parent converted to ETU during mixing/loading and 0.2 perc ent converted to ETU during application (D327307 & D327318 ; D. Davis, 6/11/07). Post

- application assessments were based on empirical measures of ETU in dislodgeable foliar residue dissipation studies. Approximately 7.5% of parent EBDC (mancozeb) is meta bolized to ETU in the body. The ETU

formed from the in vivo metabolism of parent EBDC is added to the ETU to which people are exposed as a degradate (direct exposure) to determine a total ETU absorbed dose.

A series of assumptions and exposure factors se rved as the basis for completing the occupational

risk assessments. See D4 11769, Mancozeb: Occupational and Residential Risk Assessment to Support Request for Section 3 Registrations on Walnuts for complete details regarding bodyMancozeb Human Health Risk Assessment DP No s

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### Page 56 of 77 weight assumptions, absorption, unit exposures, area treated, exposure durations, and the

associated calculations.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is exp ected from the proposed walnut

use . The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios:

1. Mixer/Loader using open pouring of liquids in support of aerial, and airblast operations;

2. Mixer/Loade r using dry flowable and water dispersible granules in support of

aerial and airblast operations;

3. Aerial Applicators (enclosed cockpit);

4. Applicators using airblast equipment; and

5. Mixer/loader/applicator with mechanically pressurized handgun.

Although fla gger scenarios are normally considered for aerial application, they are not considered for mancozeb because the label prohibits the use of human flaggers. As stated on the labels, mixers, loaders and applicators must wear: coveralls, long sleeved shirt, lo ng pants, chemical resistant gloves (waterproof material), socks, and shoes. Mixers and loaders must also wear chemical resistance aprons and protective eyewear. It should be noted that no respiratory protection equipment ( e.g., respirators) is requested o n the labels.

The level of concern (LOC) for mancozeb short

- and intermediate

- term occupational risk

assessments is for MOEs below 30 for adult males and females ( over 49 years of age) , and for

MOEs below 300 for females 13

- 49 years of age . The LOC for m ancozeb

- derived ETU short

and intermediate

- term occupational risk assessments is for MOEs below 100 for adult males and

females ( over 49 years ) , and for MOEs below 1000 for females 13

- 49 years.

Occupational Handlers Non

- Cancer and Cancer Exposure and Ri sk Estimates for Mancozeb and

ETU

HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (long

- sleeve shirt, long pants, shoes, and socks); pilots are not required to wear protective gloves. With this level of protection, there are no risk estimates of concern for applicators.

All mixer/loader non

- cancer risk scenarios do not exceed HED’s level of concern ( i.e. , MOEs ≥ 300 for mancozeb exposures and MOEs ≥1000 for ETU exposures), at some level of ris k mitigation ( e.g., gloves

, respirators, or other engineering control measures). Non

- cancer risk

estimates for M/ L liquids in support of air and airblast applications ranged from MOE=10,500 (females 13

- 49 years old) to MOE=106,600 (males and females >49 years old) at label PPE ( i.e., gloves, no respirator). However, non

- c ancer risks estimates for M/L scenarios using dry flowable (DF) formulations in support of aerial applications to walnuts exceed HED’s level of concern for females age 13

- 49 years ( i.e., MOE=260 for mancozeb inhalation exposures and MOE=750 forMancozeb Human Health Risk Assessment DP No s

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### Page 57 of 77 ETU exposures) at label PPE. It should be noted that no r espiratory protection equipment or other engineering control measures are requested on the DF labels. With the addition of a respirator, MOE=1300 for mancozeb inhalation exposures and MOE=2900 for ETU exposures

for females 13

- 49 mixing and loading the DF f ormulation for aerial application to walnuts.

Likewise, a ll application non

- cancer risk scenarios do not exceed HED’s level of concern at some level of risk mitigation ( e.g
., gloves or other engineering control measures ). Aerial and

airblast applicator r isks do not exceed HED’s level of concern ( i.e. , MOEs ≥ 300 for mancozeb exposures and MOEs ≥1000 for ETU exposures) with engineering control ( i.e., enclosed cockpit

or closed cab). Mixer/loader/ applicator s with mechanically pressurized handgun risks do not
exceed HED’s level of concern at label PPE ( i.e., gloves, no respirator). The handler risks estimates ( i.e., non

- cancer) for mixing/loading (M/L) and application scenarios of the proposed mancozeb formulations on walnuts are presented on Table s 9.1.1 and 9.1.2

.Mancozeb Human Health Risk Assessment DP No s

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### Page 58 of 77 Table 9.1.1 Short

- /Intermediate

- Term Occupational Non

- Cancer Exposure and Risk Estimates for Mancozeb . All estimates are at baseline mitigation ( i.e., without respirator, unless specified).

Exposure Scenario 6 Crop or Target LOC Inhalation Unit Exposure (ug/lb ai) 1 Maximum

Application Rate 2 Area Treated or

Amount Handled Daily 3 Inhalation

Mitigation Level Dose (mg/kg/day) 4 MOE 5


### Mixer/Loader (Adult Males, Females >49 years)

M/L, DF/WDG, Aerial, Broadcast

Walnuts 30 8.96

1.8 lb ai/acre 350 acres 0.070560 300

0.014112
(PF5 Respirator) 7 1,500

M/L, DF/WDG, Airblast, Broadcast 40 acres 0.008064 2,600

M/L, L/SC Aerial, Broadcast 0.219 350 acres 0.001725 12,200

M/L, L/SC Airblast, Broadcast 40 acres 0.000197 106,600



### Mixer/Loader (Females 13

- 49 years)

M/L, DF/WDG, Aerial, Broadcast

Walnuts 300 8.96

1.8 lb ai/acre 350 acres 0.081808 260

0.016361
(PF5 Respirator) 1,300

M/L, DF/WDG, Airblast, Broadcast 40 acres 0.009349 2,200

M/L, L/SC, Aerial, Broadcast 0.219 350 acres 0.002000 10,500

M/L, L/SC; Airblast, Broadcast 40 acres 0.000228 92,000 

### Applicator (Adult Males, Females >49 years)

Applicator, Spray, Aerial, Broadcast

Walnuts 30 0.068

( Engineering Contro l)

1.8 lb ai/acre 350 acres 0.000536 39,200

Applicator, Spray, Airblast, Broadcast

(Open Cab) 4.71 40 acres 0.004239 5,000

Applicator, Spray, Airblast, Broadcast

(Closed Cab) 0.068
( Engineering Contro l) 40 acres 0.000061 343,100



### Applicator (Females 13

- 49 years)

Applicator, Spray, Aerial, Broadcast Walnuts 300 0.068
( Engineering Contro l) 1.8 lb ai/acre 350 acres 0.000621 33,800Mancozeb Human Health Risk Assessment DP No s

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### Page 59 of 77 Table 9.1.1 Short

- /Intermediate

- Term Occupational Non

- Cancer Exposure and Risk Estimates for Mancozeb . All estimates are at baseline mitigation ( i.e., without respirator, unless specified).

Exposure Scenario 6 Crop or Target LOC Inhalation Unit Exposure (ug/lb ai) 1 Maximum

Application Rate 2 Area Treated or

Amount Handled Daily 3 Inhalation

Mitigation Level Dose (mg/kg/day) 4 MOE 5

Applicator, Spray, Airblast, Broadcast

(Open Cab) 4.71 40 acres 0.004914 4,300

Applicator, Spray, Airblast, Broadcast

(Closed Cab) 0.068
( Engineering Contro l) 40 acres 0.000070 297,000



### Mixer/Loader/Applicator (Adult Males, Females >49 years)

M/L/A, DF/ WDG, Mechanically

pressurized Handgun , Broadcast Walnuts 

### 30 3.9 0.018 lb ai/gallon 1000 gallons 0.000878 23,93 0



### Mixer/Loader/Applicator (Females 13

- 49 years)

M/L/A, L/ DF/WDG, Mechanically

pressurized Handgun , Broadcast Walnuts 

### 300 3.9 0.018 lb ai/gallon 1000 gallons 0.001017 20,600

1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( [ March 2012 ] ); includes data from PHED/ORETF/AHETF (level of mitigation: Baseline, PPE, Eng. Controls).

2 Based on registered labels (Reg. No. 70506

- 185
, 70506

- 194
, 70506

- 234
, 70506

- 236).

3 Exposure Science Advisory Council Policy #9.1.

4 Inhalation Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled Daily (A or gal/day) /BW (kg).

5 Inhalation MOE = Inhalation NOAEL (mg/kg/day)/ Inhalation Dose (mg /kg/day).

6 WDG

- Water Dispersible Granules; DF

- Dry Flowable; L/SC

– Liquid/Soluble Concentrate

7 PF5 Respirator is a respirator with a protection factor of 5 ( i.e. , it provides 80 percent inhalation protection ).Mancozeb Human Health Risk Assessment DP No s

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### Page 60 of 77 Table 9.1.2 Short

- /Intermediate

- Term Occupational Non

- Cancer Exposure and Risk Estimates for ETU

. All estimates are at label PPE ( i.e., gloves, no respirator, unless specified.

Exposure Scenario Crop or Target Dermal Unit Exposure (ug/lb ai) 1 Inhalation Unit

Exposure (ug/lb ai) 1

Maximum

Application

Rate 2 Area Treated

or Amount

Handled Daily 3 ETU Dermal Dose

(mg/kg/day) 6 ETU Inhalation Dose
(mg/kg/day) 6

Total ETU

Dose (mg/kg/day) 7 Total

MOE 8 Mitigation

Level Mitigation

Level ETU from

Direct Exposure (Present in
Tank Mix ) 4 ETU

Metabolized

from

Mancozeb 5 ETU from

Direct Exposure (Present in
Tank Mix ) 4 ETU

Metabolized

from

Mancozeb 5



### Mixer/Loader 

### (Females 13

- 49 years)

M/L, DF/WDG, Aerial,

Broadcast

Walnuts 51.6 8.96

1.8 lb ai/acre 350 acres 0.000122 0.000353 0.000081 0.006135 0.006693 7 50

0.0 00122 0.000353 0.000001
(PF5 Respirator) 0.001243

(PF5 Respirator) 0.001719

(PF5 Respirator) 2,900

M/L, DF/W DG, Airblast,

Broadcast 40 acres 0.000 0 14 0.000040 0.000009 0.000701 0.000764 65 00

M/L, L/SC/EC, Aerial,

Broadcast 37.6 0.219 350 acres 0.000089 0.000029 0.000002 0.000049 0.000498 10,0 00

M/L, L/SC/EC, Airblast,

Broadcast 40 acres 0.000010 0.000029 0.000000 0.000017 0.000056 87,7 00



### Applicator (Females 13

- 49 years)

Applicator, Spray, Aerial,

Broadcast

Walnuts 5.0
( Engineering

Contro l) 0.068

( Engineering

Contro l)

1.8 lb ai/acre 350 acres 0.000023 0.000034 0.000001 0.000046 0.000105 47,300

Applicator, Spray, Airblast, Broadcast (Open

Cab) 1,590 4.71 40 acres 0.000863 0.001244 0.000009 0.000369 0.002486 2,000

Applicator, Spray, Airblast, Broadcast (Closed Cab) 14.6 0.068
( Engineering

Contro l) 40 acres 0.000008 0.000011 0.0000001 0.000005 0.000025 202,000



### Mixer/ L oader/Applicator (Females 13

- 49 years)

M/L/A, L/ DF/WDG, Mechanically

- pressurized Handgun, Broadcast Walnuts 390 3.9 0.0180 lb ai/gallon 1000 gallons 0.000053 0.000076 

### 0.000002 0.000076 0.000208 24,100

1 PHED (level of mitigation: Baseline, PPE, Eng. Controls).Mancozeb Human Health Risk Assessment DP No s

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### Page 61 of 77 2 Based on registered labels (Reg. No. 70506

- 185
, 70506

- 194
, 70506

- 234
, 70506

- 236).

3 Exposure Science Advisory Council Policy #9.1. Daily Exposure = Unit Exposure (ug/lb ai ) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day) x DAF (%)

4 .ETU Average Daily Dose from Direct Exposure to ETU (mg/kg/day) = [Daily Exposure (mg ai/day) * Absorption (%)]/ BW (kg) Absorption =0.1 (for mixing and loading) or 0.2 (for application) % of mancozeb.

5 ETU Average Daily Dose From metabolic conversion of mancozeb (mg/kg/day) = [Daily Exposure (mg ai/day) * Absorption (%)*Metab olic ETU Conversion]/ BW (kg) 7.5 percen t of the absorbed mancozeb dose is metabolically converted to ETU

6 Dermal or Inhalation Dose= ETU Average Daily Dose from Direct Exposure to ETU (mg/kg/day) + ETU Average Daily Dose From metabolic conversion of ma ncozeb (mg/kg/day)

7 Total ETU Dose = Total Dermal ETU Dose (mg/kg/day) + Total Inhalation ETU Dose (mg/kg/day)

8 Total MOE = NOAEL (mg/kg/day)/Total ETU Dose ( mg/kg/day)

. ETU Short/ Intermediate

- Term Dermal and Inhalation NOAEL= 5 mg/kg/day. LOC=1000Mancozeb Human Health Risk Assessment DP No s

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### Page 62 of 77 Summary of Occupational Ha ndler Cancer Exposure and Risk Estimates

The cancer risks for all mix ing /loading (M/L) scenarios for private handlers are estimated in the

10 - 6 

### to 10 - 8 

### range at label PPE ( i.e., gloves, no respirator). Cancer risks for both private and

commercial handlers M/L liquids in support of air and airblast applications ranged from 9.5 x 10 - 7



### to 3.6 x10 - 8 

### at label PPE. Cancer risks for commercial handlers M/L scenarios using dry flowable (DF) formulations in support of aerial applications ranged from 1. 3 x10 - 5 

### at label specified PPE,

to 4.9 x 10 - 7 

### with the use of water soluble bags (WSB) as an engineering control measure. Cancer

risks for commercial handlers M/L scenarios using DF formulations in support of airblast applications ranged from 1.5 x10 - 6 

### at label PPE , to 3.8 x 10 - 7 

### with additional PPE ( i.e., PF5 respirator). Cancer risks for private handlers mixing/loading DF formulations in support of aerial applications ranged from 4.3 x10 - 6 

### at label PPE, to 7.0 x 10 - 7 

### with additional PPE ( i.e., PF10 respirator). Canc er risks for private handlers mixing/loading DF formulations in support of airblast applications were estimated at 4.9 x 10 - 7 

### at label PPE.

The cancer risks for all application scenarios are estimated in the 10 - 6 

### (open cab airblast applications) to 10 - 8 

### r ange for both pri vate and commercial handlers (closed cab or cockpit for

airblast and aerial applications

, respectively) The cancer risks for mixing/loading/application (M/L/A) scenarios are estimated in the 10 - 7 

### range for both private and commercial handl ers at
label PPE.

A summary of occupational handler cancer risks for applying mancozeb for the proposed uses is presented on Table 9 .1.3.Mancozeb Human Health Risk Assessment DP No s

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### Page 63 of 77 Table 9 .1.3 Occupational Cancer Exposure and Risk Estimates for ETU from Mancozeb.

All estimates are at label PPE ( i.e. gloves, no respirator) unless specified.

Crop or Target Exposure

Scenario Handler Dermal

ADD 1
(mg/kg/day) Handler

Inhalation ADD 2
(mg/kg/day) Total LADD c Cancer

Private Handler Commercial Handler Private Handler Commercial Handler

LADD 3

(mg/kg/day) LADD (mg/kg/day) 3 Mitigation

Level Risk

Estimate 4 Mitigation

Level 

### Risk

Estimate 4



### Mixer/Loader

Walnuts M/L, DF/WDG,

Aerial, Broadcas t 0.000476 0.006217 7.09 x 10
- 5 2.13 x 10
- 4 Gloves 4.3 x 10
- 6 Gloves 1.3 x 10
- 5

0.000476 0.001243 1.82 x 10
- 5 5.47 x 10
- 5 Gloves,

PF 5 R 5 1.1x 10
- 6 Gloves,

PF 5 R 5 3.3 x 10
- 6

0.000476 0.000622 1.16 x 10
- 5 3.49 x 10
- 5 Gloves,

PF 10 R 7.0 x 10
- 7 Gloves,

PF 10 R 2.1 x 10
- 6

0.000090 0.000167 NA 8.17 x 10
- 6 WSB 6

(Engineering Control) NA WSB 6

(Engineering Control) 4.9 x 10
- 7

M/L, DF/WDG, Airblast,

Broadcast 0.000054 0.000711 8.11 x 10
- 6 2.43 x 10
- 5 Gloves 4.9 x 10
- 7 Gloves 1.5 x 10
- 6

0.000054 0.000142 NA 6.25 x 10
- 6 Gloves,

PF 5 R 5 NA Gloves,

PF 5 R 5 3.8 x 10
- 7

M/L, L/SC/EC, Aerial, Broadcast 0.000347 0.000152 5.28 x 10
- 6 1.59 x 10
- 5 Gloves 3.2 x 10
- 7 Gloves 9.5 x 10
- 7

M/L, L/SC/EC, Airblast,

Broadcast 0.000040 0.000017 1.04 x 10
- 7 1.81 x 10
- 6 Gloves 3.6 x 10
- 8 Gloves 1.1 x 10
- 7



### Applicator

Walnuts Applicator,

Spray, Aerial,

Broadcast 0.000058 0.000048 1,12 x 10
- 6 3.37 x 10
- 6 Closed Cockpit 6.5 x 10
- 8 Closed Cockpit 2.0 x 10
- 7

Applicator, Spray, Airblast, Broadcast (Open Cab) 0.002107 0.000378 2.63 x 10
- 5 7.91 x 10
- 5 Open Cab/No respirator 1.6 x 10
- 6 Open Cab/No respirator 4.8 x 10
- 6

0.000019 0.000076 2.31 x 10
- 5 6.94 x 10
- 5 Open Cab/

PF 5 R 1.4 x 10
- 6 Open Cab/

PF 5 R 4.2 x 10
- 6

Applicator, Spray, Airblast, 0.000019 0.000005 2.63 x 10
- 7 7.89 x 10
- 7 Closed Cab 1.6 x 10
- 8 Closed Cab 4.7 x 10
- 8Mancozeb Human Health Risk Assessment DP No s

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### Page 64 of 77 Table 9 .1.3 Occupational Cancer Exposure and Risk Estimates for ETU from Mancozeb.

All estimates are at label PPE ( i.e. gloves, no respirator) unless specified.

Crop or Target Exposure

Scenario Handler Dermal

ADD 1
(mg/kg/day) Handler

Inhalation ADD 2
(mg/kg/day) Total LADD c Cancer

Private Handler Commercial Handler Private Handler Commercial Handler

LADD 3

(mg/kg/day) LADD (mg/kg/day) 3 Mitigation

Level Risk

Estimate 4 Mitigation

Level 

### Risk

Estimate 4

Broadcast (Closed Cab) 

### Mixer/Loader/Applicator

Walnuts M/L/A,

L/ DF/WDG, Mechanically

pressurized Handgun,

Broadcast 0.000129 0.000078 2.2 x 10
- 6 6.6 x 10
- 6 Gloves 1.3 x 10
- 7 Gloves 4.0 x 10
- 7

1 Dermal ADD = Dermal Absorbed Daily D ose

2 Inhalation ADD = Inhalation Absorbed Daily D ose

3 Total LADD = total absorbed dose [Dermal dose + Inhalation Dose] * Days per year of exposure * Years per lifetime of exposure / (365 days/year x Lifetime expectancy )

. 4 Cancer risk estimates = LADD * Q 1 * , where Q 1 *

= 6.01 x 10

- 2 (mg/kg/day )

- 1

. 5

. PF5 Respirator : is a respirator with a protection factor of 5

6 . WSB Water soluble bags (engineering control)Mancozeb Human Health Risk Assessment DP No s

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### Page 65 of 77 9.2 Short

- and Intermediate

- Term and Cancer Post

- Application Risk

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previously treated area s to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post

- application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

9.2.1 Dermal Po st

- A pplication Risk

Occupational re

- entry workers may experience short

- /intermediate

- term exposure to mancozeb while performing activities after application to walnuts. ETU can also be found as an environmental degradate in post

- application monitoring st udies on agricultural crops and turf so the Agency has also evaluated direct exposures of ETU to post

- application workers as appropriate. Finally, ETU can be formed in the human body via various metabolic pathways after

mancozeb is absorbed. The contribut ions of this metabolic conversion are also considered in the

assessment for ETU

.

E ight dislodgeable foliar residue (DFR) studies were submitted in support of reregistration of

mancozeb and these were reviewed in Mancozeb ORE Assessment for the RED (D317368, T. Dole, 05/31/05). The DFR studies were conducted on apples, grapes

, and tomatoes using airblast and groundboom application of Dithane DF dry flowable fungicide. The DFR study selected for estimating post

- application exposure on walnuts is MRID 449596 02 ( Airblast on WA Apple ). This study monitored for both mancozeb residues and ETU residues.

Since there is no dermal endpoint identified for mancozeb, only dermal post

- application assessment for its degradate ETU has been conducted. Post

- applicat ion non

- cancer (short

- and

intermediate

- term) exposures and cancer exposures are assessed for ETU. The level of concern for the ETU post

- application occupational risk assessment is for MOEs below 1000. The ETU exposure was calculated by adding the ETU dose absorbed from the leaf surface (direct contact) to the ETU that is metabolically converted from absorbed mancozeb.

See D4 11769 Mancozeb: Occupational and Residential Risk Assessment to Support Request for Section 3 Registrations on Walnuts for complete details regarding body weight assumptions, absorption, unit exposures, exposure durations, and the associated calculations. Additional information regarding the residue studies used in this assessment may also be foun d in D4 11769

.

Occupational Post

- application Non

- Cancer Dermal Risk Estimates

All post

- application occupational exposure scenarios assessed resulted in MOEs that do not

exceed HED's level of concern ( i.e.

, ETU MOEs ≥ 1000) at mancozeb current Restricted EntryMancozeb Human Health Risk Assessment DP No s

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### Page 66 of 77 Interval (REI) of 24 ho urs which is also proposed for walnut crops. Post

- application occupational non

- cancer risks estimates are summarized in Table 9.2.1.1

.

Table 9.2.1.1 Summary of Occupational/Commercial ST/IT Post

- application Non

- Cancer

Risk Estimates for ETU from Mancozeb 1

Crop/Site Activities Transfer Coefficient (cm 2 /hr) ETU Foliar

Dose 2

(mg/kg/day) Mancozeb

Metabolized

Dose to ETU 3
(mg/kg/day) Total Dermal

Dose 4
(mg/kg/day) MOE 5

Short

- term /Intermediate

- term

Walnuts Orchard maintenance 100 0.000056 0.000050 0.000106 47,000

Scouting 580 0.000325 0.000290 0.000611 8,100 Weeding, Hand 100 0.000056 0.000050 0.000106 47,000 Transplanting 230 0.000129 0.000115 0.000244 20,500 Harvesting (mechanical shaking) 190 0.000107 0.000095 0.000202 24,800

1. Based on Mancozeb initial DFR of 16.5 (ug/cm 2 ) and ETU initial DFR of 0.053 (ug/cm 2 ). Values from MRID 449596

- 02 (WA Airblast Apple)

2. ETU Foliar Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (%)] BW (kg).

3. Mancozeb Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (%)] BW (kg )

ETU Metabolized Dose to ETU= Mancozeb Der mal Dose × 0.075

4. Total Dermal Dose = ETU Foliar Dermal Dose + ETU Metabolized Dose to ETU 5. MOE = POD (mg/kg/day) / Daily Dermal Dose. LOC= 1000



### Restricted Entry Interval

Mancozeb is classified as Toxicity Category IV via the dermal route and Toxicity Category IV for skin irritation potential. Mancozeb is not a skin sensitizer. Mancozeb’s degradate; ETU is not acutely toxic via the dermal or inhalation routes of exposure. ETU is not a skin or eye

irritant. The interim 24

- hour restricted re

- entry interval (REI) on the proposed label is in compliance with the Worker Protection Standard (WPS) for agricultural pesticides and is consistent with previously approved REIs for reg istered formulations of mancozeb. Short

- and

intermediate

- term post

- application risk estimates were not a concern on day 1 (24 hours following application) for all post

- application activities.

Occupational Post

- application Cancer Dermal Risk Estimates

Th e ETU cancer risk estimates for walnut post

- application worker scenarios assessed are in the

10 - 7 

### to 10 - 8 

### range for private growers and 10 - 6 

### to 10 - 7 

### for commercial growers at Day 1 ( i.e., at the 24 hour REI)

. Post

- application occupational cancer risks est imates are summarized in Table

9.2.1.2

.

Table 9.2.1.2 Occupational Post

- Application Cancer Exposures and Risk Estimates for ETU from Mancozeb

Crop Grouping/Crop Activity Days After

Treatment Dermal LADD

(mg/kg/day) 1 Cancer Risk Estimate 2

Private

Grower Commercial

Grower Private

Grower Commercial

Grower

Trees, Nut, Crop Group 14 (Walnuts) Orchard maintenance 1 0.00000112 0.00000337 6.8 x 10 - 8 2.0 x 10 - 7

Scouting 1 0.00000652 0.00001957 3.9 x 10 - 7 1.2 x 10 - 6

6 0.00000567 0.00001700 3.4 x 10 - 7 1.0 x 10 - 6Mancozeb Human Health Risk Assessment DP No s

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### Page 67 of 77 Table 9.2.1.2 Occupational Post

- Application Cancer Exposures and Risk Estimates for ETU from Mancozeb

Crop Grouping/Crop Activity Days After

Treatment Dermal LADD

(mg/kg/day) 1 Cancer Risk Estimate 2

Private

Grower Commercial

Grower Private

Grower Commercial

Grower Weeding, Hand 1 0.00000112 0.00000337 6.8 x 10 - 8 2.0 x 10 - 7

Transplanting 1 0.00000258 0.00000776 1.6 x 10 - 7 4.7 x 10 - 7

Harvesting (mechanical shaking) 1 0.00000213 0.00000641 1.3 x 10 - 7 3.9 x 10 - 7

1 Dermal LADD = Dermal dose * Day per year of exposure x Years per lifetime of exposure / (365 days/year x Lifetime expectancy).

2 Cancer risk estimates = LADD * Q 1 * , where Q 1 * = 6.01 x 10
- 2 (mg/kg/day)

- 1



### 9.2.2 Inhalation Postapplication Risk

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for mancozeb or for its degradate, ETU, at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV). However , there are mult iple potential sources of post

- application inhalation exposure to individuals performing post

application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates t hat contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009,
and received the SAP’s final report on March 2, 2010 3

. 

### The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the

need for and , subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure

assessment for mancozeb

.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure r esulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. The airblast application handler scenario 4 

### is believed to represent a reasonable worst

- case surrogate estimate of post

- application inha lation exposure during typical post

- application activities on nut crops ( e.g., mechanical harvesting

activities ) . The use of the handler scenario of airblast application for translation to the inhalation exposure of harvesting is a very conservative assum ption. It is assuming harvesting inhalation exposure to be the same as on the last day of treatment. Furthermore, it should be noted that the labels specify a pre

- harvest interval of 75 days. Hence, s ome dissipation of mancozeb residue

3 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

4 See Tables 9.1.1 to 9.2.1.2 for a description of non

- cancer and cancer risk estimates for commercial and private

g rower applications of mancozeb on walnut crops.Mancozeb Human Health Risk Assessment DP No s

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### Page 68 of 77 can be assumed to occur by the harvesting day through chemical degradation or environmental dissipation

. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

10.0 References

P. Savoia, 4/ 8/13, D404217

, Mancozeb . Section 3 Registration for Establishing a Tolerance on Imported Tangerines. Summary of Analytical Chemistry and Residue Data.

P. Savoia, 4/8 /13, D402042, Mancozeb . Section 3 Registration Adding the U se of Mancozeb on Walnuts. Summary of Analytical Chemistry and Residue Data.

P. Savoia, 4/8/13

, D402043 and D405277, Man cozeb. Acute, Chronic, and Cancer Dietary Exposure Assessments of Food and Drinking Water to Support the New Use of Mancozeb on

Walnu ts and the Establishment of a Tolerance on Imported Tangerines for Section 3 Registration.

A. Rivera

- Lupiáñez, 5/14/13 , D 411769 , Mancozeb: Occupational and Residential Risk Assessment to Support Request for Section 3 Registrations on Walnuts.

M. Ruhma n , 7/3/12, D397306, Estimated Drinking Water Concentrations of ETU Degradate (Ethylene

- thio

- urea degradate) of Mancozeb from its Proposed New Use on Walnuts for Use in

Human Health Risk Assessment.

D. Davis, 6/11/07, D327307 & D327318, Mancozeb: Human Health Risk Assessment to Support Proposed New Uses on Broccoli, Cabbage, Lettuce, Peppers and Almonds. PC Code: 014504, Petition No: PP# 4F4333 & PP#4F4324.

M. Ruhman

, 8/11/ 06 , D323143 and 323141 , Revision No. 2: Estimated Drinking Water Concentration of Ethylenebisdithocarbamate (EBDC) Degradate Ethylenethiourea (ETU) for the

Use in Human Health Risk Assessment.

U.S. EPA, 9/20/05, Reregistration Eligibility Decision for MancozebMancozeb Human Health Risk Assessment DP No s

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### Page 69 of 77 A ppendix A

. Toxicology Profile and Executive Summaries

. 

### A.1 .1 Toxicology Data Requirements

- Mancozeb
The requirements (40 CFR 158.340) for food uses for mancozeb are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols w ere used.

Study Technical Required Satisfied 870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ ................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ..................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes 870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes

yes

yes

no

yes yes

yes

yes NA

yes 870.3700a Developmental Toxicity (rodent)

................................ .. 870.3700b Developmental Toxicity (nonrodent)

............................ 870.3800 Reproduction

................................ ................................ . yes

yes

yes yes

yes

yes 870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ ................... yes

no

yes

yes yes

yes

yes

yes a

870.5100 Mutagenicity

— Revers Mutation

- bacterial

.................. 870.5300 Mutagenicity

— in v ivo Mammalian cell Assay

............ 870.5xxx Mutagenicity

— i n v itro Cytogenetics yes

yes

yes yes

yes

yes 870.6100a Acute Delayed Neurotoxicity (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ .......... 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

.............. 870.6300 Develop. Neurotoxicity

................................ ................. no

no

yes

yes

yes NA

NA

yes

yes

yes 870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

yes

yes yes

yes

yes Special Studies : Developmental Thyroid Study yes no b

a This study was unacceptable but does not need to be repeated because carcinogenicity will be assessed by ETU (memo, Doc 013554 ). b The requirement for a developmental thyroid study is being satisfied by a study with ETU as part of an

extended one

- genera tion study. This study is currently underway.Mancozeb Human Health Risk Assessment DP No s

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### Page 70 of 77 A.2 Toxicity Profile s

Table A.2.1 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

Table A.2.2 Toxicity Profile f or Mancozeb Study Type [Guideline #]

, Doses MRID No. Results Subchronic feeding

- rat [870.3100] 0, 30, 60, 125, 250, or 1000 ppm [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 mg/kg/ day in females

LOAEL=17.82 in females based on decreased serum thyroxine.

At HDT in males, females: ↓ BW, changes in thyroid hormones, microscopic changes in liver and thyroids, increased thyroid and liver wt 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.

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. 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. 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.Mancozeb Human Health Risk Assessment DP No s

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### Page 71 of 77 Table A.2.2 Toxicity Profile f or Mancozeb Study Type [Guideline #]

, Doses MRID No. Results 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, o r 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. Acute Neurotoxicity

– rat 0, 500, 1000, 2000 mg/kg/day 47126201 NOAEL=500 mg/kg/day LOAEL=1000 mg/kg/day based on decreased motor activity Subchronic Neuropathology

– rat [870.6100] 0, 20, 125, 750 ppm, or 5000 ppm [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.

339/412 mg: Female mortality, ↓ BW in males ( ↓ 45%); Clinical signs in both sexes

– reluctance to walk, etc Developmental Neurotoxicity

- rat [870.6300] [0, 5, 15, 30 mg/kg/day] 47872902

47872901 maternal NOAEL = 30 mg/kg/day, HDT

offspring NOAEL = 15 mg/kg/day offspring LOAEL = 30 mg/kg/day based on decr eased pup wt (11

- 22%) in range

- finding study

Modified DNT

– rat Tox Sci 120(2). 2011. Axelstad, et al 0, 50, 100, 150/100 mg/kg/day GD 7

– PND 16 Maternal: ↓ BW gain and T4 at 50 mg/kg/day, paralysis and sacrifices at 150 mg/kg/day. No effects on repro
parameters

Offspring: No effects on T4, organ wt, histopath, motor activity, startle response, spatial learning at any dose 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.

At 512 m g/

k g/ d ay : maternal mortality

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 40 433001 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.

2

- Generation Reproduction

- rat [870.3800] 0, 30, 120, or 1200 ppm. [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 mancoze b.Mancozeb Human Health Risk Assessment DP No s

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### Page 72 of 77 Table A.2.2 Toxicity Profile f or Mancozeb Study Type [Guideline #]

, Doses MRID No. Results
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 response 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 response 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 either rat or mouse study.

Dermal Absorption

870.7600 40955401

00250063 Dermal absorption = 1%

Immunotoxicity

- rat [870.7800] 4 8794801 (2012) Acceptable/

Guideline Negative for I mmunotoxicity



### Table A.2.3 Acute Toxicity of ETU

Guideline No. Study Type MRID Nos. Results Toxicity Category

870.1100 Acute Oral

– rat N/A N/A N/A

870.1200 Acute Dermal

- rabbit 458881

- 01 LD 50 > 2000 mg/kg III

870.1300 Acute Inhalation

- rat 458881

- 02 LC 50 > 10.4 mg/L IV

870.2400 Primary Eye Irritation 458881

- 04 No irritation 1 IV

870.2500 Primary Skin Irritation 458881

- 03 No irritation IV

870.2600 Dermal Sensitization N/A N/A N/A

1 The primary eye irritation study was classified unacceptable because a UV light was not observed with fluorescein staining, however, another study is not required (M. Lewis, 4/30/03, D289726).



### Table A.2.4 Toxicity Profile of ETU
Study Type [Guideline No.] MRID No./

Classification Results

Subchronic (13

- week) feeding

- rat [870.3100] 250 ppm (males: 14.28 mg/kg/day; females: 17.81 mg/kg/day) 00 0160704 /1986 Acceptable /non

guideline NOAEL = <14.28 mg/kg/day

LOAEL = 14.28 mg/kg/day, based on reduced body weight, changes in thyroid hormone and TSH levels, increased thyroid and liver weight, microscopic thyroid hyperplasia and liver hypertrophy.

Subchronic (13

- Week) 00 154192 /1985 NOAEL = 1.72 mg/kg/dayMancozeb Human Health Risk Assessment DP No s

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### Page 73 of 77 Table A.2.4 Toxicity Profile of ETU
Study Type [Guideline No.] MRID No./

Classification Results

feeding

- mouse [870.3100] 0, 1, 10, 100, 1,000 ppm (males: 0, 0.16, 1.72, 18.18, 168.2 mg/kg/day; females: 0, 0.22, 2.38, 24.09, 231.1 mg/kg/day) Una cceptable/

G uideline LOAEL = 18.18 mg/kg/day, based on microscopic thyroid

hypertrophy/hyperplasia.

At the high dose, more microscopic thyroid changes and increases in thyroid and liver weight occurred. Unacceptable because ETU concentrations varied w idely.

Subchronic (13

- Week) feeding

- dog [870.3100] 0, 10, 150, 2000 ppm (males: 0, 0.39, 6.02, 66.23 mg/kg/day; females: 0, 0.42, 6.51, 71.62 mg/kg/day) 42174201/1991 Acceptable /

Guideline NOAEL = 0.39 mg/kg/day

LOAEL = 6.02 mg/kg/day, based on elevated cholesterol. (Note: this endpoint was not considered robust enough for use in risk assessment) At 6.02 mg/kg/day, thyroid effects were observed. In high dose group: mortality, anemia, decreased activity, decreased thyroid hormone levels, increased thyroid weight

, microscopic thyroid hyperplasia.

Chronic tox/carcinogenicity

- SD rat [870.4100] 0, 0.5, 2.5, 5.0, or 125 ppm Males: 0, 0.04, 0.17, 0.37,

8.91 mkd Females: 0, 0.05, 0.25, 0.49,

13.57 mkd 42607801/1992 Unacceptable /

Guideline Concentration of ETU in feed varied widely and doses could not

be determined. Microscopic thyroid hyperplasia occurred in the

low

- dose group. At higher doses, changes in thyroid hormone and TSH levels, increased thyroid weight, and grossly enlarged livers

. Increases in thyroid follicular adenomas and pituitary adenomas in high

- dose males.

Chronic (24

- Month) Feeding

– B6C3F1 mouse (NTP) 45924403/1992 Fund. Appl. Tox.

18: 405

- 417

w/ and w/out perinatal

exposure This study was used to determine the Q1* for ETU of 6.01 x 10 - 2

(mg/kg/day) - 1 based upon female mouse liver adenomas and/or

carcinomas. Thyroid follicular cell adenomas and carcinomas, hepatocellular adenomas and carcinomas, and pituitary adenomas

were increased.

Chronic (24

- Month) Feeding

– Fi scher 344 rat (NTP) 45924403/1992 Fund. Appl. Tox.

18: 405

- 417

w/ and w/out perinatal Thyroid follicular cell adenomas and pituitary adenomas were

observed.

Chronic (1

- year) oral toxicity

- dog [870.4100]

0, 5, 50, or 500 ppm (males: 0, 0.18, 1.99, 20.13 mg/kg/day; females: 0, 0.19, 1.79, or 20.15 mg/kg/day) 42338101/1992 Acceptable/

Guideline NOAEL = 0.18 mg/kg/day

LOAEL = 1.99 mg/kg/day, based on increased thyroid weight and microscopic changes in thyroid (hypertrophy, follicular dilatation).

At the high dose, mortality, anemia, and microscopic hepatocellular necrosis.

4

- Week Range

- finding

- Dog 0, 196, 980, 4900 ppm (males: 0, 7.0, 34, or 172 mg/kg/day; females: 0, 8.0, 36, or 197 mg/kg/day) 41863401/1989 Acceptable /non

guideline NOAEL = 7 mg/kg/day

LOAEL = 34 mg/kg/day, based on decreased levels of thyroid hormones, gross thyroid lesions.

Developmental tox icity

SD BR rat [870.3700] 00 093929 /1980 Acceptable/non

guideline Maternal NOAEL = <50 mg/kg/day

Maternal LOAEL = 50 mg/kg/day, based on decreased body weight gain (↓36%)

.Mancozeb Human Health Risk Assessment DP No s

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### Page 74 of 7 7 Table A.2.4 Toxicity Profile of ETU
Study Type [Guideline No.] MRID No./

Classification Results

50 mg/kg/day (distilled water)

GD 6

- 15 Developmental NOAEL = <50 mg/kg/day Developmental LOAEL = 50 mg/kg/day, based on numerous central nervous system defects (hydrocephaly and related malformations); gross development al defects; skeletal defects

, and decreased fetal weight (↓13%)

.

Only one dose group was included in the study. Developmental tox icity

Wistar rat [ non

- guideline ] 0, 5, 10, 20, 40, 80 mg/kg/day 4593760 1 /1973 [Khera, K.S.

1973. Teratology

7:243

- 252] Maternal NOAEL = 40 mg/kg/day

Maternal LOAEL = 80 mg/kg/day, based on mortality (9 of

11after 7

- 8 days).

Developmental NOAEL = 5 mg/kg/day Developmental LOAEL = 10 mg/kg/day based on exencephaly, dilated ventricles, and hypoplastic cerebellum. At 20 mg/kg/day, hydrocephalus, encephalocele, meningocele, micrognathia, abnormal flexion of ankle, kinky or twisted tail; at ≥ 40 mg/kg/day: oligodactyl, domed head, retarded ossification of the skull occurred; a t 80 mg/kg/day: coloboma of the eyelids , hemimelia, syndactyl, cleft palate, ectopic kidney, rudimentary calvarium, short tail, scoliosis and several types of skeletal anomalies occurred. Decreased fetal weight was noted at 40 mg/kg/day in group I (↓10%) and group III (↓21%) and at 80 mg/kg/da y in group II (↓44%). Fetuses at 40 mg/kg/day in group II had weights comparable to controls. Number of live fetuses and corpora lutea were comparable to controls in all groups. Developmental toxicity

SD rat (1) 0, 5, 10, 20, 30, 40, or 80 mg/kg/day f

rom GD 7

- 21. (2) 0, 20, 25, or 30 mg/kg/day from GD 7 to

PND 15 45924404/1979 [Chernoff, et al.,

J. Toxicol. Env.

Health 5: 821

- 834] Maternal NOAEL = 40 mg/kg/day (or lower).

Maternal LOAEL = 80 mg/kg/day, based on reduced body weight

and 25% maternal mortality. Gestational exposure only : Developmental NOAEL = 10 mg/kg/day (↓7% fetal BW) Developmental LOAEL = 20 mg/kg/day, based on hydrocephalus (12 fetuses/5 litters). Decreased ossification was also observed at 30 mg/kg/day and above; at 40 mg/kg/day, encephalocele, kyphosis, and digit defects (oligodactyl, syndactyl) were also observed

. At 80 mg/kg/day, fetal mortality was increased and there were increases in cleft palate, limb defects (micromelia, hemimelia), edema, and micrognathia.

Gestational an d postnatal exposure : Postnatal toxicity at 30 mg/kg/day included hydrocephalus, dome

- shaped heads, and pup mortality. Developmental tox icity

Wistar rat [ non

- guideline ] 0, 15, 30, 45 mg/kg

Dams received a single oral

dose on gestation day 15

. MRID 48985801 [Khera and Tryphonas Tox Appl Pharm

42:85

- 97. 1977 ]

. Maternal NOAEL /LOAEL not reported

Developmental NOAEL = 15 mg/kg Developmental LOAEL = 30 mg/kg based on postnatal mortality, hydrocephal y , microphthalm i a, cerebellar dysplasia, cerebral atrophy, and in survivors, motor defects and dome

- shaped head. Developmental toxicity

Wistar rat 0 or 240 mg/kg No MRID [Ruddick and

Khera. No maternal toxicity observed.

Teratogenic effects in fetuses from GD 10

- 21; greatest frequency

of defects between GD 12

- 15; no defects before GD 10; ETUMancozeb Human Health Risk Assessment DP No s

. 411742 and 411764



### Page 75 of 77 Table A.2.4 Toxicity Profile of ETU
Study Type [Guideline No.] MRID No./

Classification Results

Dams received a single dose on one gestation day between

GD 6

- 21 Teratology

12:277

- 282, 1975] affected development of brain, kidney, eye, and axial and

appendicular systems

Developmental toxicity

SD rat 0, 15, 25, or 35 mg/kg/day

from GD 6

- 20 No MRID [Saillenfait, et al., Fund. Appl.

Toxicol. 17: 300

- 408, 1991] Maternal NOAEL

Maternal LOAEL = 15 mg/kg/day, based on decreased body weight gain Developmental NOAEL = 15 mg/kg/day Developmental LOAEL = 25 mg/kg/day, based on dilated ventricles of the brain, hydroureter, short/kinky tail, and dilated ureters. At 35 mg/kg/day, hydrocephaly, anencephaly, meningocele, meningo r rhea, hyrdronephrosis, dilated renal pelvis,

and vertebral ab normalities were observed. Developmental toxicity

Wistar

- Imamichi rats 0, 10, 20, 30, 40, 50 mg/kg/day

GD 6

- 15. 45924405/1978 [Teramoto, et al., Congenital

Anomalies 18:

11

- 17, 1978] Developmental NOAEL <10 mg/kg/day

Developmental LOAEL = 10 mg/kg/day, based on dilated brain ventricles. At higher doses, fetal death, meningocele, micrognathia, hydronephrosis, renal agenesis, uterine hypoplasia, skeletal anomalies, short/kinky tail, and scoliosis were observed

. Develo pmental

New Zealand White Rabbit [870.3700] 0.5% aqueous methylcellulose 0, 5, 15, 50 mg/kg/day

GD 7

- 29 47976403 /2010 Acceptable /

Guideline Maternal NOAEL = 5 mg/kg/day

Maternal LOAEL = 15 mg/kg/day based on increased postimplantation loss

Developmental NOAEL = 5 mg/kg/day Developmental LOAEL = 15 mg/kg/day based on increased postimplantation loss At 50 mg/kg/day, postimplanation loss, decreased fetal BW (↓10%), hydrocephaly (1), and domed head (2) were observed. Developmental toxicity Syrian Golden hamsters 0, 90, 270, 810 mg/kg/day

from GD 6

- 13. 45924405/1978 [Teramoto, et al., Congenital

Anomalies 18:

11

- 17, 1978] Developmental NOAEL = 90 mg/kg/day

Developmental LOAEL = 270 mg/kg/day, based on skeletal malformations and short/kinky ta il. At 810 mg/kg/day, fetal deaths, dilated brain ventricles, cleft palate, micrognathis, and anal

atresia were observed. Developmental toxicity

JCL

- ICR mouse 0, 200, 400, or 800 mg/kg/day.

GD 7

- 15 45924405/1978 [Teramoto, et al., Congenital

Anomalies 18:

11

- 17, 1978] No maternal or developmental toxicity was observed.

2

- Generation reproduction

– Sprague

Dawley rat [870.3800] 0, 2.5, 25, 125 ppm 42391701/1992 Unacceptable /

Non

- guideline

42391801/1992

ETU content data Doses on mg/kg/day basis could not be determined.

Parental: microscopic thyroid hyperplasia/hypertrophy in mid and/or high

- dose groups.

No reproductive effects attributed to treatment.

Unacceptable because of stability problems (mkd could not be calculated) with test material and poor r ecord keeping. Dermal absorption

– SD

COBS CD rat [870.7600] 403126 01/1987 Acceptable Dermal absorption = 26%

Immunotoxicity

- rat [870.7800] 48794502/2012 Acceptable/

Guideline Negative for ImmunotoxicityMancozeb Human Health Risk Assessment DP No s

. 411742 and 411764



### Page 76 of 77 A ppendix B

. Physical/Chemical Properties

Table B.1 Physicochemical Properties of Mancozeb.

Parameter Value Reference

Melting point/range Decomposes at 150 oC RCB No. 4368, 11/9/88, G. Makhijani pH 6.5 (25% slurry in water)

Density 0.41 g/cc (packed)

Water solubility 1.1 μg/mL at room temperature
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 available
Physicochem ical properties not available for metabolite ETUMancozeb Human Health Risk Assessment DP No s

. 411742 and 411764



### Page 77 of 77 Appendix C

. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from the Pesticide Handlers Exp osure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database; the Agricultural Re

- entry Task Force (ARTF) database; and other registrant

submitted studie s ; (1 ) are subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with a pplicable ethics requirements. For certain studies that review may have included review by t he Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be found at the Agency website. 5

5 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html