Mancozeb Registration Review Human Health Scoping Document D4252 16 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: June 1, 2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Mancozeb: Human Health Risk Assessment Scoping Document in Support of Registration 

Review. 

PC Code: 0 14504; 0 14601 ; 600016 DP Ba r code: 0425216 

Decision No.: 499273 Registration No.: NA 

Petition No.: NA Ree.u latory Action: Rc.e.istration Review 

Risk Assessment Type: NA Case No.: NA 

TXR No.: NA CAS No.: 8018-01-7 

MRID No.: NA 40 CFR: 180. 176 

FROM: Danette Drew, Chemist/Risk Assess-· .]).~-:----A-fifti '--

THROUGH: 

And 

Matt Lloyd, CIH, Expo~ Assessor / _ 

Pete Savoia, Chemist V..-<.---te"-<_.--~~,-c.-c__.., 

Linda Taylor, Ph.D., Toxicologist 

Risk Assessment Branches V and VII 

Hea lth Effects Division (7509P) 

Michael Metzger, Branch Chief ~ ~ /) ) 

Risk Assessment Branches V and VII M tt..f · 

Health Effects Division (7509P) . 

Jess Rowland, Deputy Director 

Dana Vogel, Acting Director 

Health Effects Division (7509P) 

TO: Steven Snyderman, Chemical Review Manager 

Risk Management and Implementation Branch 3 

Pesticide Re-Evaluation Division (7508P) 

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Mancozeb Registration Review Human Health Scoping Document D425216 

Executive Summary 

The Hea lth Effects Division (HED) Mancozeb Registration Review Team has evaluated the 

status of the human health risk assessment for the fungicide mancozeb to determine the scope of 

work necessary to support registration review. This scoping exercise is based primarily on the 

most recently completed human health risk assessment (HHRA) of July 20 13 (0 . Drew et al .. 

7/2/201 3, 041 2677, Mancozeb: Human Heallh Risk Assessment to Support Proposed New 

Section 3 Uses on Walnuts and Tolerances/or Imported Tangerines) and the USEPA September 

2005 Mancozeb Reregistration Eligibility Decision (RED). 

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

ethylcnebisdithiocarbamate) used as a broad-spectrum fungicide. Mancozeb is currentl y 

registered for foliar application and seed treatment on various agricultural crops. Horticultural 

uses include ornamental plants in nurseries and greenhouses, home gardens, sod farms, and golf 

courses. 

In plants and livestock commodities, the residues of concern for risk assessment are the parent 

compound mancozeb and its metabolite/degradate ethylenethiourea (ETU). The residue of 

concern in drinking water is ETU onl y. Tolerances arc currently established for residues of 

mancozeb, including its metabolites and degradates (measured as the degradate CS2), on a 

number of crop and livestock commodities. 

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

includes the fungicides maneb (no registered uses) and metiram; all of these compounds have a 

common metabolite/degradate, ETU. Some of the more notable toxicity in the mancozeb studies 

was due to toxicity from this metabolite. Thyroid toxicity and developmental toxicity in rats 

were attributed to toxicity from ETU. Injury to peripheral nerves occurred in mancozeb toxicity 

studies but not in studies with ETU. For mancozeb, separate risk assessments are performed for 

1) toxicity and exposure to parent compound mancozeb only and 2) toxicity and exposure to ETU 

derivedfrom mancozeb, including combined exposures from both ETU as an environmental 

degradate and ETU as an in vivo metabolite of mancozeb. This document presents the scope of 

work anticipated under registration review for both mancozeb and mancozeb-derived ETU. A 

separate forthcoming HED document (0425218) outlines the scope of work anticipated for 

metiram and metiram-derived ETU. In addition to the individual EBDC pesticide assessments. a 

separate risk assessment is performed addressing the combined (aggregate) risk from ETU 

derived from all registered EBDC pesticides. The conclusions regarding the scope of work 

anticipated under registration review for mancozeb and metiram also apply to the ETU aggregate 

risk assessment. 

For residential, occupational and dietary exposures, including oral, dermal and inhalation routes 

of exposure, a 7.5% in vivo metabolic conversion of absorbed mancozeb to ETU is used, and is 

accounted for in estimating the total exposure (in vivo metabolism combined with direct 

environmental exposure) to ETU. 

The findings in multiple toxicology studies demonstrate that the thyroid is a target organ for 

mancozcb and ETU; these effects are due to inhibition of thyroid peroxidase by the metabolite 

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ETU.

Additional toxic effects following mancozeb exposure include neurotoxicity. In a subchronic 

study in the rat, neuropathology was seen microscopically (injury to peripheral nerves) with 

associated clinical signs. Developmental toxicity was observed in mancozeb studies (but only at 

doses where maternal toxicity was observed). The thyroid toxicity and developmental toxicity 

are attributed to ETU, whereas injury to the peripheral nerves is observed in studies following 

exposure to mancozeb but was not observed in studies following ETU exposure.

Both mancozeb and ETU are classified as probable human carcinogens. There is no indication of 

immunotoxicity potential for mancozeb or ETU.

In the most recent mancozeb HHRA (2013), the FQPA factor of 10X was retained for women of 

childbearing age and for children less than six years old to account for the lack of data on the 

developing thyroid. Since then, an extended one-generation reproductive toxicity (EOGRT) 

study on ETU, which includes an assessment of developmental thyroid toxicity, has been 

submitted and is undergoing review.

The toxicology databases for mancozeb and ETU are sufficient for assessing the toxicity and 

characterizing the hazard of these compounds; no additional data are required to support 

mancozeb registration review. During registration review, the impact of recently submitted ETU 

studies (an EOGRT study and a rabbit developmental toxicity study) on toxicological endpoint 

selection, points of departure (PODs), and uncertainty factors/safety factors (UF/SFs) for the 

dietary/oral, dermal, and inhalation risk assessments will be evaluated.

The mancozeb residue chemistry database is incomplete; outstanding data are required under the 

following guidelines: 860.1200 Directions for Use, 860.1340 Enforcement Analytical Method 

(livestock), 860.1500 Crop Field Trials, 860.1520 Processing Studies, 860.1480 Ruminant 

Feeding Study, and 860.1850 Confined Rotational Crop Study. Additional anticipated 

residue/monitoring data are also needed to support the dietary assessment. The 1990 EBDC 

market basket survey previously used to refine the dietary assessments may be outdated, and any 

changes in application techniques, typical rates, handling, storage, and transportation could result 

in incurring different residue levels today than those reported in the 1990 survey. To allow for 

the continued use of the survey in future dietary assessments, the EBDC registrants must provide 

justification as to whether current good agricultural practices would result in yielding 

comparable residues as those found in the survey. If based on this information HED concludes 

that the market basket data are no longer reflective of current residues, a new market basket 

survey should be conducted. In that event, until adequate updated market basket data are 

submitted, HED will rely on data from available controlled studies (e.g. field trial data, 

processing studies), which will likely result in significantly greater risk estimates that may 

exceed the levels of concern.

No acute or chronic (non-cancer) dietary risks of concern were identified in the 2013 HHRA for 

either mancozeb (food only; mancozeb is not expected in drinking water) or mancozeb-derived 

ETU (food and water) for any populations modeled, including infants and children, and females 
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of child bearing age. The cancer risk estimate associated with exposure to ETU in food and water

was 2 x 10-6for the general U.S. population.

Under registration review of mancozeb, HED may conduct a new dietary assessment if the 

Ecological Fate and Effects Division (EFED) revised Drinking Water Assessment results in ETU 

estimated drinking water concentrations (EDWCs) that are significantly greater than those used 

in the most recent (2013) assessment, which were based on well monitoring data and modeling 

of almond use scenarios. A revised dietary assessment will be performed if there are increases in 

the anticipated residue levels in food. If new toxicological endpoints, PODs or UF/SFs are 

selected as a result of the new toxicological data submissions, these would also be used in any 

revised dietary assessments.

The residential exposure database for mancozeb is complete. There were no residential handler 

or post-application risks of concern identified in the 2013 mancozeb HHRA for either mancozeb 

or its degradate ETU. That assessment was comprehensive of the current residential exposure 

pattern and up to date with the 2012 Residential SOPs. The assessment included chemical 

specific dislodgeable foliar residue (DFR) and turf transferable residue (TTR) data to assess the 

relevant residential exposure scenarios. Any changes in the registered use pattern, exposure 

methodologies, or toxicological endpoints, PODs or UF/SFs, may trigger an update for the 

residential handler or post-application assessments during registration review. 

The most recent (2013) acute and chronic aggregate risk estimates for ETU (food and water 

exposure) were not of concern. The short-term aggregate assessment for mancozeb (residential 

and food) and ETU (residential, food and water) did not result in risk estimates of concern for 

adults or children. The cancer aggregate (residential, food and water) risk estimates ranged up to 

3 x 10-6. Revised aggregate risk assessments will be performed for mancozeb and mancozebderived ETU if there are any changes to toxicological endpoints, PODs or UF/SFs, or if there are 

significant changes to food residues or EFED’s EDWCs.

The occupational exposure database for mancozeb is complete. The previous occupational 

assessments performed (2005, 2011) utilized methodologies that have since been updated. In 

addition, based on toxicological data, there have since been revisions to the levels of concern 

(total uncertainty factors) for the target MOEs. Comprehensive quantitative handler and postapplication occupational risk assessments (cancer and non-cancer) will be performed for all 

currently registered mancozeb uses and will include updated exposure assessment methodology

(e.g. new transfer coefficients, methodology for greenhouse assessments, etc.). The available 

chemical specific turf transferable residue (TTR) and dislodgeable foliar residue (DFR) data will 

also be considered for the post-application assessments. Any revisions to the toxicological 

endpoints, PODs, or UFs will also be incorporated in the occupational assessments.

The HED Tier I incident report for mancozeb concluded low to moderate frequency and severity 

for mancozeb incident cases overall. There are, however, a number of epidemiological findings 

regarding mancozeb that will be reviewed and considered during registration review. These 

include both the results of the Agricultural Health Study (AHS) and the “Reach the Decision 

Makers Program” (REACH) health effects results as presented by a consortium of science-policy 
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investigators. HED will perform a Tier II assessment of the human health effects of mancozeb to 

support the integration of this information with the experimental toxicological data available. 

ETU Aggregate Assessment (All EBDCs)

HED has conducted acute, short-term, chronic, and cancer aggregate assessments for ETU from 

the combined EBDC pesticide uses (metiram and mancozeb) (2013 ETU Aggregate HHRA; 

D412678). The acute and chronic (non-cancer) aggregate assessments included only dietary 

(food and drinking water) exposures. There were no acute or chronic ETU aggregate risk 

estimates of concern for the combined EBDC uses.

The short-term aggregate assessments for ETU combined residential exposures (from mancozeb 

use; there are no residential uses of metiram) and average dietary (food and water; from metiram 

and mancozeb uses) exposures. There were no short-term aggregate risk estimates of concern for 

the combined EBDC uses.

The cancer aggregate assessment for ETU included contributions from residential and dietary 

(food and water) exposures. Cancer aggregate ETU risks for adults were estimated at 2 x 10 -6 

(handler) and 3 x 10-6(post-application).

Under registration review of mancozeb, a revised combined ETU aggregate assessment will be 

performed if there are any significant changes made to the ETU assessments from the individual 

EBDCs (e.g. assessment methodologies, toxicological endpoints, PODs or UF/SFs, EDWCs).

Introduction

HED has evaluated the most recent complete human health risk assessment (HHRA) for 

mancozeb conducted in 2013, as well as older evaluations, to determine any outstanding data 

requirements or additional data required to complete registration review for this fungicide. HED 

has also considered updates to its toxicity, exposure and usage databases, and the latest Agency 

science policy and risk assessment methodologies.

Mancozeb is a broad-spectrum fungicide used in agriculture, professional turf management, and 

horticulture. It is registered for seed treatment and for pre- and post-emergence use on a number 

of agricultural crops (e.g. apples, potatoes, corn, wheat, walnuts), for residential (e.g. home 

vegetable garden) use, and non-residential commercial turf (e.g. golf courses) settings.

Mancozeb formulations include wettable powder, dry flowable, liquid flowable and dust. 

Information on the chemical identity of mancozeb is included in Attachment 1.

Hazard Identification/Toxicology

Mancozeb

The toxicology database for mancozeb is complete. No additional data are required to support 

registration review. 
Mancozeb Registration Review Human Health Scoping Document D425216

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The effects in the mancozeb hazard database are indicative of thyroid toxicity, and these effects 

are due to inhibition of thyroid peroxidase by the metabolite, ethylene thiourea (ETU). The 

thyroid is the target organ for mancozeb and ETU, and thyroid toxicity is manifested as 

alterations in thyroid hormones, increased thyroid weight, and microscopic thyroid lesions 

(mainly thyroid follicular cell hyperplasia). 

Additional toxic effects following mancozeb exposure include neurotoxicity. In the subchronic 

neurotoxicity study in the rat, neuropathology was seen microscopically (injury to peripheral 

nerves) with associated clinical signs (abnormal gait and limited use of rear legs) and loss of 

muscle mass. Decreased motor activity was observed in the acute neurotoxicity study at the limit 

dose. Developmental neurotoxicity was not observed in the rat following mancozeb exposure.

Evidence of sensitivity following mancozeb exposure was observed only in the developmental 

neurotoxicity study (DNT) in rats where decreased fetal body weight occurred in the absence of 

maternal toxicity. Developmental toxicity was observed in the rat (hydrocephaly, gross and 

skeletal developmental defects, cryptorchidism, abortions, increased resorptions, and decreased 

fetal body weight) at dose levels of mancozeb that produced maternal toxicity (mortality and 

abortions). Developmental toxicity was observed in the rabbit (abortions) at the same dose level

of mancozeb where maternal toxicity was observed (mortality and abortions). Reproductive 

toxicity was not observed in the rat at dose levels of mancozeb where thyroid toxicity was 

observed.

The thyroid toxicity and developmental toxicity are attributed to ETU, whereas injury to the 

peripheral nerves is observed in studies following exposure to mancozeb but not to ETU. 

Mancozeb was rapidly absorbed following oral exposure, with the highest levels of radioactivity 

in the thyroid due to ETU residues; no parent compound was detected in the thyroid. The 

majority of mancozeb is metabolized to ETU and excreted in the urine. Peak plasma 

concentrations were reached within 3-6 hours, and the t 1/2 for the rapid phase of elimination was 

4-6 hours. 

Because mancozeb is known to be converted to ETU, a probable human carcinogen (B2) based 

on female mouse liver tumors in the ETU carcinogenicity study, mancozeb is also classified as a

Group B2 carcinogen. Thyroid follicular cell adenomas and carcinomas were increased in both 

male and female rats in the combined chronic oral toxicity/ carcinogenicity study on mancozeb, 

but the mouse carcinogenicity study on mancozeb did not test at an adequate dose level to assess 

carcinogenic potential. 

Mancozeb is not acutely toxic by the oral, dermal, and inhalation routes of exposure, based on 

lethality studies; it is not a skin irritant or an eye irritant and is negative for dermal sensitization. 

There is no indication of immunotoxicity. 

In the previous mancozeb/ETU risk assessment, the default FQPA factor of 10X was retained for 

women of childbearing age (13- 49 years old) and for children less than six years old to account 

for the lack of data on the developing thyroid (database uncertainty factor). The FQPA factor 
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was 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.

New toxicity data (an extended one-generation reproductive toxicity study on ETU, which 

includes an assessment of developmental thyroid toxicity) have been received since the last risk 

assessment. During registration review of mancozeb, the impact of the study results on endpoint 

selection, points of departure (PODs), and uncertainty factors/safety factors (UF/SFs) for the 

dietary, incidental oral, dermal, and inhalation risk assessments will be evaluated.

The toxicity profile tables for mancozeb are included as Attachment 2. The mancozeb endpoints, 

points of departure (PODs), and uncertainty/safety factors (UF/SFs) used in the most recent 

human health risk assessment are summarized in Attachment 3.

Ethylenethiourea (ETU)

Previously, the toxicology database for ETU was limited and HED relied on a combination of 

guideline study data and studies in the open literature to assess hazard for ETU. Since the last 

risk assessment, an extended one-generation reproductive toxicity study (EOGRTS) on ETU was 

submitted, which includes an assessment of reproductive toxicity, developmental neurotoxicity, 

developmental thyroid toxicity, and immunotoxicity (previous ETU datagaps). The toxicology 

database on ETU is sufficient for assessing the toxicity and characterizing the hazard of ETU.

The thyroid is a major target organ for ETU because ETU inhibits the enzyme thyroid 

peroxidase. Thyroid toxicity in subchronic and chronic rat, mouse, and dog studies includes 

decreased levels of the thyroid hormone T4 (thyroxine), changes in T3 (triiodothyronine) levels, 

compensatory increases in levels of thyroid stimulation hormone (TSH), increased thyroid 

weight, and microscopic thyroid changes, chiefly hyperplasia. Overt liver toxicity (necrosis) was 

observed in one chronic dog study. Developmental defects in the rat developmental toxicity 

study included hydrocephaly and related lesions, skeletal system defects, and other gross defects 

in the kidney and stomach. Hydrocephaly and microphthalmia occurred in rats after a single 

dose. Post implantation loss, hydrocephaly, and domed head were observed in the rabbit 

developmental toxicity study. Although there are no neurotoxicity studies on ETU (except as 

assessed in the recently submitted extended one-generation reproductive toxicity study, 

EOGRTS), the toxicity profile of ETU shows that the principal toxic effects are on the thyroid.

The immunotoxicity study on ETU did not show any immunotoxicity potential.

ETU is classified as a probable human carcinogen (B2), based on female mouse liver tumors 

observed in the ETU carcinogenicity study in mice. The ETU cancer potency factor (Q1*) of 

0.0601 (mg/kg/day)-1is used to quantitate risk. 

In the previous mancozeb/ETU risk assessment, the default FQPA factor of 10X was retained for 

women of childbearing age (13- 49 years old) and for children less than six years old to account 

for the lack of data on the developing thyroid (database uncertainty factor). The FQPA factor 

was 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.
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Since the last risk assessment of ETU, an extended one generation reproductive toxicity 

(EOGRT) study on ETU was submitted, which was designed to satisfy the toxicology data gaps 

for ETU (a 2-generation reproduction study in rats, a developmental neurotoxicity study in rats,

and a developmental thyroid toxicity study in rats). This study is currently under. Additionally, a 

rabbit developmental toxicity study on ETU was submitted, which has been reviewed and found 

to satisfy this data requirement. During registration review of mancozeb, the impact of these

study results on endpoint selection, PODs, and UF/SFs for the dietary, incidental oral and dermal 

risk assessments will be evaluated, based on the new data and updated policies and procedures.

The toxicity profile tables for ETU are included as Attachment 2. The ETU endpoints, points of 

departure (PODs), and uncertainty/safety factors (UF/SFs) used in the most recent human health 

risk assessment are summarized in Attachment 3.

Conclusions: The toxicology databases for mancozeb and ETU are sufficient for assessing the

toxicity and characterizing the hazard of these compounds. No additional data are required to 

support registration review. During registration review of mancozeb, the impact of the recently 

submitted ETU studies (an EOGRT study and a rabbit developmental toxicity study) on endpoint 

selection, points of departure (PODs), and uncertainty factors/safety factors (UF/SFs) for the 

dietary, incidental oral, dermal, and inhalation risk assessments will be evaluated.

Residue Chemistry and Dietary Exposure

Residue Chemistry

The nature of the residue in plants is adequately understood based on metabolism studies made

with potato, soybean, sugar beet, tomato, and wheat. The nature of the residue is also adequately 

understood in livestock based on metabolism studies on goats and poultry. HED has concluded 

that the residue of concern for the tolerance enforcement of all regulated commodities is the 

mancozeb parent compound calculated as carbon disulfide (CS2). In plants and livestock 

commodities, the residues of concern for risk assessment are mancozeb and its 

metabolite/degradate ethylenethiourea (ETU). The residue of concern in drinking water is ETU 

only. There are adequate methods available for the enforcement of crop tolerances with PAM 

Vol. II listing Methods I, II, III, IV, and A. Mancozeb is not recovered through any of the FDA 

Multi-Residue Method testing protocols. There remains an outstanding data requirement for the 

enforcement method for livestock commodities (see below).

The residue chemistry database for mancozeb is incomplete. The 2005 residue chemistry chapter 

(D305815, C. L. Olinger, 06/14/2005) supporting the 2005 mancozeb RED identified the 

following residue chemistry data gaps which remain outstanding:

860.1200 Directions for Use

Potato use must specify a 14-day PHI except in the states of CT, DE, FL, MA, ME, MI, 

NH, NY, OH, PA, RI, VT, & WI which follow a 3-day PHI; apple application included 

in orchard crop treatments should be made at a minimum of 10 gal/A using aerial 

equipment on the Rohm and Haas & Griffin labels; field corn use directions on all 

products must be amended to state treatment can only be applied to hybrid seed corn and 
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the 70% DF formulation to specify a maximum seasonal rate of 12 lb ai/A; field and 

sweet corn forage grazing restrictions must be removed from the 75% DF & 80% WP 

labels; and wheat, barley, and oats requires the labels for the small grains to be changed 

from the PHI of 26-days to Feekes Growth Stage 10.5, typically 35-45 days, but no less 

than 26-days. This requirement remains outstanding.

860.1340 Enforcement Analytical Method 

A livestock tolerance enforcement method as required by the 2005 RED was developed 

and supporting independent laboratory validation (ILV) studies were provided for the 

determination of mancozeb and ETU in meat and milk (MRID Nos. 47358701 -

47358703, and 47375201). The ILV data demonstrated that the submitted methods were 

suitable for the tolerance enforcement of livestock commodities but should be revised as 

specified in the studies and submitted to the Agency (DP No. D352531, C. L. Olinger, 

07/16/2009). The revised methods do not appear to have been submitted to date. This 

requirement remains outstanding.

860.1500 Crop Field Trials 

Residue data for tobacco data have not yet been submitted following guidelines to allow

the Agency to conduct an exposure assessment to support this registered use. Safflower 

seed or propagation stock treatment data are required depicting residues of mancozeb and 

ETU in /on safflower seed grown from seed treated with a representative product at 0.11 

lb ai/100 lb of seed. [Reviewer Note: there is no tolerance for mancozeb on safflower in 

the CFR but there is a registered use listed on the most recent Penncozeb 4FL label (EPA 

Reg. No. 70506-194)]. These requirements remain outstanding.

860.1520 Processing Studies 

Wheat (middlings and germ) data depicting residues of mancozeb and ETU processed 

from wheat grain bearing measurable, weathered residues are required; barley (pearled) 

data are required since an acceptable barley processing study is not available; oats 

(rolled) data are required since an acceptable oat processing study is not available; and 

potato processing data are required since the prior study was concluded to be inadequate.

These requirements remain outstanding.

860.1480 Ruminant Feeding Study 

Tolerances on several animal feedstuffs were reassessed in the 2005 RED at higher levels 

which increased the maximum theoretical dietary burden for livestock. Therefore, a new 

ruminant feeding study was required to determine if there is a reasonable expectation of 

finite residues in meat and milk. This requirement remains outstanding.

860.1850 Confined Rotational Crop Study 

There are no rotational crop restrictions currently specified on any mancozeb labels. A 

confined rotational crop study remains outstanding for mancozeb to determine if limited 

field trials for rotational crops are needed. This requirement remains outstanding.

The 2005 residue chemistry chapter supporting the RED also identified the following 

requirement for storage stability data for carrot and onion and crop residue data for wheat hay. 
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As part of this mancozeb scoping exercise, HED has determined that these requirements are now 

considered fulfilled:

860.1380 Storage Stability Data

Carrot, and dry bulb onion; carrot field trial results reported in MRID 44023001 are not 

supported by storage stability data. The carrot samples were stored for up to 153 and 103 

days prior to mancozeb and ETU determination, respectively. To support these results, 

the Agency will allow translation of existing freezer storage stability data for potatoes 

and tomatoes at 12 months, and tangerines at 163 days. In regard to the dry bulb onion 

data, samples in MRID 44725501 were stored frozen without concurrent stability data for 

up to 22 and 19 days prior to determination of mancozeb and ETU residues, respectively. 

To support these results, the Agency will allow translation of existing freezer storage 

stability data for sugar beets which indicate that residues of mancozeb and ETU are 

relatively stable in/on sugar beet roots after 46 days and 68 days, respectively. The 

860.1380 data requirement is considered fulfilled for mancozeb for the currently 

registered uses.

860.1500 Crop Field Trials 

Wheat hay (translated to barley and oat hay) field trial data were requested in the 2005 

residue chemistry chapter along with a proposed tolerance for this RAC. In actuality, that 

requirement had been previously fulfilled as outlined in the May 2, 2001 memorandum 

from Christine L. Olinger to Anne Overstreet, “Reregistration of Mancozeb: Wheat Crop 

Field Trial Data; Chemical No. 14504; DP Barcode D255366, MRID No.: 44802501”, 

which stated: “Wheat hay: The submitted residue data for wheat hay are acceptable. 

They suggest that a tolerance for wheat hay should be established at 50 ppm to support 

the currently maximum registered use pattern.” The cover letter states “No additional 

magnitude of residue data are required to support the reregistration of mancozeb on 

wheat”. The adequacy of those data to fulfill the requirement was reiterated in the 

April, 30, 2008 memo “Mancozeb. Response to Registrant Comments on Mancozeb 

Reregistration Eligibility Decision” (C. Olinger, D344719) along with a recommendation 

to establish the tolerance for mancozeb on wheat hay (and by translation barley hay and 

oat hay) at 30 ppm, based on a MRL calculation procedure. [Note: there are no current 

tolerances for mancozeb on wheat hay, oat hay or barley hay in the 40 CFR. 180.176].

The following new residue chemistry data requirement was identified by HED during this 

registration review scoping exercise for mancozeb:

Anticipated Residue/Monitoring study (non-guideline study): Updated anticipated 

residue/monitoring data are needed to support the dietary assessment of the EBDC 

pesticides, including mancozeb. The 1990 EBDC market basket survey previously used 

to refine the dietary assessments may be outdated, and any changes in application 

techniques, typical rates, handling, storage, and transportation could result in incurring 

different residue levels today than those reported in the 1990 survey. To allow for the 

continued use of the survey in future dietary assessments, the EBDC registrants must 

provide justification as to whether current good agricultural practices would result in 

yielding comparable residues as those found in the survey. If based on this information 
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HED concludes that the market basket data are no longer reflective of current residues, a 

new market basket survey should be conducted. In that event, until adequate updated 

market basket data are submitted, HED will rely on data from available controlled studies 

(e.g. field trial data, processing studies), which will likely result in significantly greater 

risk estimates that may exceed the levels of concern.

Dietary Assessment

Acute, chronic, and cancer dietary risk assessments were most recently performed for mancozeb 

using the Dietary Exposure Evaluation Model software with the Food Commodity Intake 

Database (DEEM-FCID) Version 3.16 (D412565 and D412566, P. Savoia, 07/01/2013). 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, 

(NHANES/WWEIA). These analyses were conducted in support of a human health risk 

assessment for the proposed Section 3 uses of mancozeb on walnuts and the establishment of a 

tolerance on imported tangerines. The acute (probabilistic), chronic, and cancer assessments 

were highly refined determinations which used field trial data, 1990 EBDC market basket survey 

data, percent crop treated/import estimates, and processing and cooking factors.

Modeling estimates (PRZM/EXAMS) for surface water (almond use scenario) were used for 

ETU estimated drinking water concentrations (EDWCs) in the acute assessment. Well 

monitoring data were used for ETU EDWCs for ground water for the chronic and cancer 

assessments. The ETU EDWCs were directly incorporated into the dietary analyses. EDWCs are 

not developed for mancozeb since it degrades quickly in the environment and is not expected to 

reach drinking water sources. Therefore, the dietary analyses for mancozeb are for food only 

and those for ETU (resulting from mancozeb use) are for both food and water. 

No acute or chronic (non-cancer) dietary risks of concern were identified for either mancozeb 

(food) or mancozeb-derived ETU (food and water) for any populations modeled, including 

infants and children, and females of child bearing age. 

For acute exposure to mancozeb in food, the highest exposed population was children 1-2 years 

old at 9.9 % of the aPAD. For acute exposure to ETU in food and water, the risk estimate for 

females 13-49 years old (the only population for which an acute toxicological endpoint was 

identified) was 58% of the aPAD. The majority of the acute ETU exposure was from food 

sources; drinking water was not a large contributor to the ETU dietary exposure.

For chronic (non-cancer) exposure to mancozeb in food, the highest exposed population was 

children ages 1-2 at 2.3% of the cPAD. For exposure to mancozeb-derived ETU in food and 

drinking water, the highest exposed population was children ages 1-2 is at 51% of the cPAD. The 

majority of the chronic ETU exposure was from food sources; drinking water was not a large 

contributor to the ETU dietary exposure.

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

mancozeb uses, was 2 x 10-6for the general U.S. population.
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Conclusions: The mancozeb residue chemistry database is incomplete. Outstanding data (as 

identified in the 2005 residue chemistry chapter) are required under the following guidelines: 

860.1200 Directions for Use, 860.1340 Enforcement Analytical Method (livestock), 860.1500 

Crop Field Trials, 860.1520 Processing Studies, 860.1480 Ruminant Feeding Study, and 

860.1850 Confined Rotational Crop Study. 

In addition, HED has determined, as part of this scoping exercise, that updated anticipated 

residue/monitoring data (non-guideline study) are needed to support the dietary assessments of 

the EBDC pesticides, including mancozeb. The previous dietary analyses for mancozeb/ETU 

were refined through the use of the 1990 EBDC market basket survey provided by the EBDC 

registrants and did not result in risk estimates of concern. The survey measured residues of 

EBDCs in a variety of foods as close to the point of consumption as possible (grocery stores and 

small markets). However, the market basket survey may be outdated and possible changes in 

application techniques, typical rates, handling, storage, and transportation could result in 

incurring different residue levels today than those reported in the 1990 survey. To allow for the 

continued use of the survey in risk assessments, the EBDC registrants must provide justification 

as to whether current good agricultural practices would result in yielding comparable residues. If 

based on this information HED concludes that the market basket data are no longer reflective of 

current residues, a new market basket survey should be conducted. In that event, until adequate 

updated market basket data are submitted, HED will rely on data from available controlled 

studies (e.g. field trial data, processing studies), which will likely result in significantly greater 

risk estimates that may exceed the levels of concern. 

HED may conduct a new dietary assessment if anticipated residues on food or if EFED’s revised 

EDWCs are significantly greater than those used in the most recent assessment. If new 

toxicological endpoints, PODs or UF/SFs are selected as a result of the new toxicological data 

submissions, these would also be used in any revised dietary assessments.

Residential Exposure and Risk

Mancozeb residential uses which may result in handler or post-application exposures include 

home gardens and recreational turf, such as golf courses. The most recent residential exposure 

assessment was performed in 2013 (A. Rivera-Lupiáñez, D411769, 05/14/2013, Mancozeb:

Revised Occupational and Residential Risk Assessment to Support Request for Section 3 

Registrations on Walnuts). Non-cancer risk estimation has been performed as follows:

The residential handler risk assessment considered both mancozeb (inhalation only; no dermal 

hazard identified) and ETU (combined dermal and inhalation) exposure. The residential postapplication assessment included ETU (dermal only exposure). Residential cancer risk estimation 

has been performed for mancozeb-derived ETU.

Residential Handler

Because mancozeb is not a restricted-use product (RUP) and a homeowner could potentially 

apply it in a residential setting, HED previously conducted a residential handler exposure 

assessment for home garden uses. The adult handler exposure assessment was conducted using 

the 2012 Residential SOP. Residential handler inhalation risk estimates from mancozeb 
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exposures were not risk concerns (MOEs > 300 for adult females of childbearing age and MOEs 

> 30 for other adults and youth); inhalation MOEs ranged from 170,000 

(mixing/loading/applying (M/L/A) liquid formulation to vegetable gardens with backpack) to 

millions (for manually pressurized handgun and hose-end sprayer applications). Residential 

handler risk estimates from mancozeb-derived ETU (combined dermal and inhalation) exposures

were also not of concern (i.e., MOEs > 1000 for adult females of childbearing age and MOEs > 

100 for other adults and youth); MOEs ranged from 32,700 to 90,000. The cancer risks for all 

M/L/A residential scenarios were estimated in the 10-8range for residential handlers. 

Residential Post-Application 

The 2013 quantitative exposure/risk assessment for residential post-application exposures was

based on 1) home gardeners entering treated vegetable gardens (for weeding, harvesting, etc.) 

and 2) golfers contacting mancozeb treated turf after application. As no dermal hazard was 

identified for mancozeb, a quantitative dermal post-application assessment (non-cancer and 

cancer) was only performed for mancozeb-derived ETU.

Post application non-cancer risks estimates from mancozeb-derived ETU were calculated for 

home gardening scenarios (day of application) and contact with treated golf course turf, as 

follows:

 Gardening: dermal exposures for adults and youth (children 6 to 11 years old) exposed to 

treated home gardens. 

 Golfing: dermal exposures for adults and youth (children 6 < 11 years old and children 11 

< 16 years old).

No non-cancer risk concerns were identified for any population subgroup assessed for either the 

home gardening or the golf course scenarios. The levels of concern (LOCs) associated with the 

home garden and golf course exposure scenarios vary depending on the population subgroup 

assessed. (i.e., MOE ≥ 1000 for adult females of childbearing age and MOE ≥ 100 for other 

adults and youth). Post-application cancer risks for adult home gardeners are estimated in the 10-

7

range. The cancer risk to adult golfers from exposure to mancozeb-derived ETU is estimated to 

be 2.5 x 10-8(tees, greens and fairways). 

Turf Transferable Residue: In accordance with the updated Part 158 data requirements (2007), a 

TTR study is required for occupational (e.g., golf courses, parks, and recreational areas) or 

residential turf uses. TTR data1are available for mancozeb for use in assessing golfer risk 

estimates. Therefore, no new chemical specific TTR data are required at this time.

Post- Application Volatilization/Spray Drift 

Residential bystander exposures resulting from off-site transport (e.g., spray drift or 

volatilization) may occur as a result of applications of mancozeb. The potential for spray drift 

will be evaluated for each pesticide during the Registration Review process which ensures that 

 

1 Available: MRID 44958501
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all uses for that pesticide will be considered concurrently. The approach is outlined in the 

revised (2012) Standard Operating Procedures for Residential Risk Assessment (SOPs) –

Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of 

Spray Drift. This document outlines the quantification of indirect non-occupational exposure to 

drift. The residential turf post-application assessment for mancozeb is anticipated to provide a 

worst case estimate of potential exposure from spray drift. As the turf use rate is equal to or 

higher than agricultural application rates for mancozeb, this scenario is protective of any 

exposure of children via spray drift from agricultural mancozeb applications.

In terms of volatilization, the agency has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis2. During Registration Review, the agency will 

utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological 

studies) or further analysis is required for mancozeb.

Conclusions: The residential exposure database for mancozeb is complete. There were no 

residential handler or post-application risks of concern identified in the most recent (2013) 

mancozeb HHRA for either mancozeb or its degradate, ETU. That assessment was 

comprehensive of the current residential exposure pattern and up to date with the 2012 

Residential SOPs. The assessment included chemical specific DFR and TTR data to assess the 

relevant residential exposure scenarios. Changes in the registered use pattern, exposure 

methodologies, or toxicological endpoints, PODs, or UF/SFs may trigger an update for the 

residential handler or post-application assessments during registration review. 

Aggregate Risk Assessment (Mancozeb; Mancozeb-derived ETU)

In the 2013 HHRA 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 acute and chronic non-cancer aggregate assessments included 

only dietary (food and drinking water) exposures. There were no acute or chronic aggregate risk 

estimates of concern.

The short-term aggregate assessments combined the residential scenarios that resulted in the 

highest estimated exposures (i.e. adult handler exposure to mancozeb and mancozeb-derived 

ETU when applying to home gardens, and for post-application exposure to ETU, adults and 

youth entering those treated gardens) with average dietary exposures to mancozeb or mancozebderived ETU. There were no short-term aggregate risk estimates of concern for adults applying 

mancozeb to gardens (MOEs were ≥ 28,000). There were no short-term risk estimates of 

concern for adults or youth entering treated gardens (MOEs were ≥ 2600). 

The cancer aggregate assessment for mancozeb-derived ETU included exposures from 

residential and dietary (food and water) sources. The cancer aggregate risk estimates for adults 

applying mancozeb to gardens or entering treated gardens were 2 x 10-6and 3 x 10-6, 

respectively.

 

2 http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219
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Conclusions: The 2013 acute and chronic non-cancer aggregate (dietary: food and drinking 

water) risk estimates for mancozeb and mancozeb-derived ETU were not of concern. The shortterm aggregate (residential and dietary exposures) assessments for mancozeb or ETU did not 

result in risk estimates of concern. The cancer aggregate (residential and dietary exposures) risk 

estimates for ETU ranged up to 3 x 10-6. Revised aggregate risk assessments will be performed 

for mancozeb and mancozeb-derived ETU if there are any changes to toxicological endpoints, 

PODs or UF/SFs, dietary exposures from food, or if there are significant changes to EFED’s 

EDWCs.

Aggregate Risk Assessment (ETU derived from all EBDC Pesticides)

ETU is a common degradate/metabolite of the ethylene bisdithiocarbamate (EBDC) fungicides 

mancozeb and metiram; these are the only currently registered EBDC pesticides. In 2013, HED 

performed ETU aggregate assessments (ETU exposures from food, drinking water, and 

residential) for the combined uses of metiram and mancozeb (7/3/2013, D412678, D. Drew et al, 

Ethylene Thiourea (ETU); Aggregate Human Health Risk Assessment of the Common 

Metabolite/Degradate Ethylene Thiourea (ETU) to Support Proposed New Section 3 Use on 

Walnuts and Tolerance for Imported Tangerines).

HED conducted acute, short-term, chronic, and cancer aggregate assessments for ETU from the 

combined EBDC uses. The aggregate assessments combined the highest estimated residential 

exposures with average food and drinking water exposures. The only EBDC with residential 

uses is mancozeb. The mancozeb garden scenarios resulted in higher post-application exposures 

than the golfing scenarios; aggregate assessments using the garden scenario are protective of any 

post-application exposures to adult and youth golfers. 

The acute and chronic (non-cancer) aggregate assessments include only dietary (food and 

drinking water) exposures. There were no acute or chronic ETU aggregate risk estimates of 

concern.

The short-term aggregate assessments for ETU combined residential exposures (mancozeb use) 

and average dietary (food and water; all EBDC use) exposures. There were no short-term 

aggregate risk estimates of concern (adults applying the EBDC mancozeb to gardens and adults 

or youth entering treated gardens).

The cancer aggregate assessment for ETU includes contributions from residential and dietary 

(food and water) exposures. Cancer aggregate ETU risk estimates for adults applying mancozeb 

to gardens or entering treated gardens were estimated at 2 x 10 -6 and 3 x 10-6, respectively.

Conclusions: Any ETU data gaps identified for each individual EBDC (mancozeb and metiram) 

will apply to the combined ETU aggregate assessment. Under registration review (of mancozeb

and metiram), a revised combined ETU aggregate assessment will be performed if there are any 

significant changes made to the ETU assessments from the individual EBDCs (e.g. assessment 

methodologies, toxicological endpoints, PODs or UF/SFs, EDWCs, or food exposures).
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Occupational Exposure

Mancozeb is currently registered for foliar application and seed treatment on various agricultural 

crops. Horticultural uses include ornamental plants in nurseries and greenhouses, home gardens, 

sod farms, and golf courses. Mancozeb formulations include wettable powders (WP), dry 

flowables (DF), liquid (soluble concentrate) flowables (SC), and dusts. Mancozeb can be applied 

by groundboom, aircraft, airblast sprayer, automated irrigation systems (chemigation), handheld 

equipment, or tractor-drawn spreader. For the registered seed treatment uses, mancozeb can be 

applied by stationary treatment equipment (large commercial units or smaller on-farm units) and 

tractor drawn planters or hopper boxes.

Occupational exposures for parent mancozeb are assessed for short- and intermediate-term 

exposure. For handlers, only inhalation risk estimates are calculated for short- and intermediateterm mancozeb exposures because no toxic effects were observed in mancozeb 28-day dermal 

toxicity study. A quantitative assessment is not required for post-application exposures to parent 

mancozeb as there is no potential for inhalation exposures and there is no dermal toxicity. 

Occupational exposure to mancozeb-derived ETU is also assessed; both via ETU as a degradate 

in the mancozeb product and ETU that is metabolized in the body from absorbed mancozeb. 

Occupational exposure to ETU is assessed for short-, intermediate-term and lifetime exposure 

potential (for the quantitative cancer assessment). Both handler (inhalation and dermal) and postapplication (dermal) exposures are assessed for ETU.

Occupational Handlers

The last comprehensive occupational assessment for mancozeb was conducted in 20053for the 

mancozeb RED. The 2005 RED identified non-cancer risk estimates of concern for some 

occupational handler exposure scenarios (i.e., for seed treatment and commercial turf uses 

particularly with the wettable powder formulation); therefore, mitigation measures were 

implemented such as product use site restrictions, cancelled formulation types (i.e. dust and some 

granular products), reduced application rates, and requirement of additional PPE (e.g., respirator)

for some handler scenarios. Registered mancozeb labels vary in PPE requirements for 

occupational handlers; agricultural applicators are required to wear long-sleeved shirts, long 

pants, shoes, socks, and chemical resistant gloves. Additionally, some labels require the use of 

organic vapor (OV) filtering respirators during mixing and loading scenarios (for turf 

applications based on the SC, DF, and ready to use formulation types and all application sites for 

the wettable powder (WP) and dust formulations). For the occupational handler cancer 

assessment (mancozeb-derived ETU), most of the risks were below 1x10-4 without mitigation 

and all of the cancer risks were below 1x10-4 with the mitigation recommended to address the 

non-cancer risks. 

In the mancozeb RED, handler risk was assessed using data from the Pesticide Handlers 

 

3 Mancozeb: 2nd Revised Occupational and Residential Exposure Assessment and Recommendations for the 

Reregistration Eligibility Decision Document. PC Code 014504; DP Barcode: D317368. T. Dole; 5/31/05.
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Exposure Database (PHED) Version 1.1. Although occupational handler assessments have been 

conducted to estimate risk for all existing uses of mancozeb, the assessments for all use 

sites/formulations have not conducted based on current occupational exposure policies.

Recommended unit exposures for occupational handler assessments had generally been derived 

only from the Pesticide Handlers Exposure Database (PHED) and the Outdoor Residential 

Exposure Task Force (ORETF). More recently, task forces like the Agricultural Handler 

Exposure Task Force (AHETF) have produced pesticide handler exposure monitoring data that 

the Agency is using in place of PHED (http://www.epa.gov/pesticides/science/handler-exposuredata.html). As more reliable data become available, the Agency will continue to replace existing 

data. New exposure monitoring data will be incorporated into revised occupational handler 

assessments, as necessary, during registration review. The previous data requirements (875.1100 

and 875. 1300) outlined in the 2005 RED for occupational handler exposure for seed piece 

treatment is considered fulfilled based on a submission by the AHETF Task Force4.

Subsequent to the 2005 RED, HED conducted a 2011 occupational handler assessment for 

proposed uses of mancozeb on lettuce, peppers, almonds, broccoli, and cabbage (A. RiveraLupiáñez, 11/15/11, D391948). All handler scenarios (M/L/A) resulted in short- and 

intermediate-term MOEs that did not exceed HED's level of concern (LOC) at the time (i.e., 

MOEs ≥ 100 for ETU and mancozeb) at baseline PPE and chemical-resistant gloves as proposed 

on the label. [Note: compared with current MOE levels of concern for females 13-49 yrs old 

(300 for mancozeb and 1000 for ETU), all scenarios at label PPE and gloves are not of concern 

except airblast application to almonds.] The cancer risks for all scenarios were estimated in the 

10-6to 10-7range for both private and commercial handlers.

In 2013 HED performed an occupational handler assessment for the proposed new use on 

walnuts (A. Rivera- Lupiáñez, 5/14/13, D411769, Mancozeb: Occupational and Residential Risk 

Assessment to Support Request for Section 3 Registrations on Walnuts). For walnuts, all 

mixer/loader and applicator non-cancer risk scenarios did not exceed HED’s level of concern

(i.e., MOEs ≥ 300 for mancozeb and MOEs ≥1000 for ETU) at some level of risk mitigation 

(e.g., gloves, respirators, or other engineering control measures). This included the requirement 

to add a respirator to all the current DF labels. All mixer/loader and applicator cancer risk 

estimates for mancozeb-derived ETU were in the 10-8to 10-6range at some level of risk 

mitigation (e.g., water soluble bags, respirators, or other engineering control measures).

Occupational Post-Application

The last comprehensive occupational post-application exposure assessment was performed for 

the 2005 RED (T. Dole, 05/31/05, D317368). There is no quantitative post-application 

assessment (cancer or non-cancer) for parent mancozeb because there is no dermal toxicity 

anticipated and post-application inhalation exposures are not expected. There was a quantitative 

assessment for mancozeb-derived ETU (non-cancer and cancer) post-application dermal 

exposures and no risk estimates of concern were identified with the 24-hour labeled REI. The 

assessment included an extensive number of agricultural crops, commercial applications, and 

seed treatment applications. However, based on a March 2015 review of the registered labels for 

mancozeb, many of the uses assessed in 2005 are anticipated to require reassessment based on 

 

4 HED Review of MRID 45054702 (D412589)
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updated HED policies (i.e., updated transfer coefficients and updated assessment methodology 

for greenhouse grown crops).

In 2011 HED conducted an occupational post-application assessment for proposed uses on 

lettuce, peppers, almonds, broccoli, and cabbage (D391948). Using chemical-specific residue 

data, all post-applications scenarios resulted in short- and intermediate-term MOEs for 

mancozeb-derived ETU that do not exceed HED's current level of concern (i.e., all dermal MOEs 

≥ 1000) on the day of application. The cancer risks for those crop scenarios were in the 1x10-6

range at Day 1 (i.e., at the 24 hour REI). 

In 2013 HED conducted an occupational post-application assessment for proposed new uses on 

walnuts (D411769). Using chemical-specific residue data, no risk estimates of concern were 

identified for mancozeb-derived ETU (i.e., all dermal MOEs ≥ 1000) on the day of application. 

Cancer risk estimates for mancozeb-derived ETU for the walnut scenario were in the 1x10-6

range at Day 1 (i.e., at the 24 hour REI).

Recommended transfer coefficients for the previous occupational post-application assessments 

were derived from Agricultural Reentry Task Force (ARTF) exposure monitoring studies5. 

These transfer coefficients were updated in 2012 based on a reanalysis and submission of new 

monitoring data. HED will incorporate updated transfer coefficients, as necessary, during 

registration review occupational assessments.

There is a possibility for workers to have post-application dermal exposure to mancozeb and 

mancozeb-derived ETU on treated turf (i.e., golf course maintenance workers). As identified in 

the discussion in the non-occupational post-application section, a TTR study will not be required 

for registration review since chemical specific TTR data are already available. However, for sod 

farms, there are post-application activities (e.g., maintenance activities, harvesting of sod, and 

transplanting/planting sod) that have a higher occupational exposure potential than what has been 

assessed previously. An occupational assessment will be performed for dermal post-application 

exposure to ETU (mancozeb-derived) for sod farm activities.

Conclusion: There are no outstanding data requirements for occupational assessment. 

Comprehensive quantitative handler and post-application occupational risk assessments (cancer

and non-cancer) will be performed for all currently registered mancozeb uses and will include 

updated exposure assessment methodology (e.g. new transfer coefficients, methodology for 

greenhouse assessments, etc.). The available chemical specific turf transferable residue (TTR)

and dislodgeable foliar residue (DFR) data will also be considered for the post-application 

assessments. Any revisions to the toxicological endpoints, PODs, or UFs will also be 

incorporated in the occupational assessments.

 

5 Available: http://www.epa.gov/pesticides/science/post-app-exposure-data.html

 
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Public Health and Pesticide Epidemiology Data

HED has provided a Tier I incident report for mancozeb registration review scoping (4/15/15, 

D426276, E. Evans et al, Mancozeb: Tier I (Scoping) Review of Human Incidents) based on 

examination of the OPP Incident Data System (IDS), Sentinel Event Notification System for 

Occupational Risk-Pesticides (SENSOR) and National Pesticide Information Center (NPIC) 

databases for pesticide incident data on the active ingredient mancozeb. That report concluded 

that there is a relatively low to moderate frequency and severity for mancozeb cases overall. 

There are, however, a number of epidemiological findings regarding mancozeb that will be 

thoroughly reviewed and considered during registration review. In addition to the results of the 

Agricultural Health Study (AHS), EPA will evaluate a voluntarily submission of a systematic 

review of the open literature regarding the developmental and reproductive toxicity and 

endocrine effects of mancozeb entitled “An Updated Look at Mancozeb: Concerns about 

Farmworker Reproductive Health” (D425202). This review was prepared by a consortium of 

advocate-scientist-policy professionals as participants in the “Reach the Decision Makers 

Program” (REACH).

Tolerance Assessment and International Harmonization

Permanent tolerances are established under 40 CFR §180.176(a) for mancozeb residues 

(measured as carbon disulfide (CS2)) on a number of crop and livestock commodities There is 

also a tolerance with regional registration for mancozeb established under 40 CFR §180.176(c)

on carrots. The current tolerances for mancozeb on sugar beet tops should be revoked since this 

commodity is no longer a significant livestock feed or a recognized human food item. Also, it 

had been previously recommended (2005 RED) that the mancozeb tolerance for peanut hay 

should be revoked because the Agency does allow the label restrictions against the feeding of 

peanut hay to livestock; this tolerance has not been revoked to date. 

There are no Canadian or Mexican maximum residue limits (MRLs) established for the residues 

of mancozeb or EBDC fungicides in/on raw agricultural or processed commodities. However, 

there are established MRLs for the EBDC fungicides grouped as total dithiocarbamates by 

Codex which have harmonized tolerance definitions with the U.S. (residues measured as CS2). 

All U.S. tolerance levels are harmonized with the Codex MRLs to the greatest extent possible. 

Any tolerances not harmonized with Codex MRLs are due to variation in use patterns as noted in 

the RED (grapes, maize fodder, melons, bulb onion, papaya, pome fruit, pumpkin, summer 

squash, sugar beet, tomato, and winter squash). 

A spreadsheet summarizing the U.S. and international residue limits established for mancozeb is 

presented in Attachment 4.

Cumulative

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to mancozeb and any other substances. Mancozeb does produce a toxic metabolite, ETU, which 

is produced by other EBDC compounds. Risks from combined exposures to ETU from all 
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EBDC compounds are addressed in a separate ETU aggregate risk assessment. For information 

regarding 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 determinations and 

procedures for cumulating effects from substances found to have a common mechanism on 

EPA’s website at http://www.epa.gov/pesticides/cumulative/.

International or Intergovernmental Work Sharing

There are no current or planned international or interagency work sharing efforts for mancozeb.

Data Requirements

Residue Chemistry

The following data requirements were identified in the 2005 residue chemistry chapter 

(D305815) in support of the mancozeb RED and remain outstanding:

Guideline 860.1200 Directions for Use (potato, apple, field corn, wheat, barley, and 

oats). 

Guideline 860.1340 Enforcement Analytical Method (livestock). 

Guideline 860.1500 Crop Field Trials (tobacco, and safflower seed or propagation stock 

treatment).

Guideline 860.1520 Processing Studies (wheat (middlings and germ), barley (pearled), 

oats (rolled), and potato). 

Guideline 860.1480 Ruminant Feeding Study.

Guideline 860.1850 Confined Rotational Crop Study.

The following data requirement was identified by HED during this registration review scoping 

exercise:

Anticipated Residue/Monitoring study (non-guideline study): Updated anticipated

residue/monitoring data are needed to support the dietary assessments of the EBDC 

pesticides, including mancozeb. The 1990 EBDC market basket survey previously used 

to refine the dietary assessments may be outdated, and any changes in application 

techniques, typical rates, handling, storage, and transportation could result in incurring 

different residue levels today than those reported in the 1990 survey. To allow for the 

continued use of the survey in future dietary assessments, the EBDC registrants must 

provide justification as to whether current good agricultural practices would result in 

yielding comparable residues as those found in the survey. If based on this information 

HED concludes that the market basket data are no longer reflective of current residues, a 

new market basket survey should be conducted. In that event, until adequate updated 

market basket data are submitted, HED will rely on data from available controlled studies 

(e.g. field trial data, processing studies), which will likely result in significantly greater 

risk estimates that may exceed the levels of concern.
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References

D317368, Mancozeb: 2nd Revised Occupational and Residential Exposure Assessment and 

Recommendations for the Reregistration Eligibility Decision Document. PC Code 014504, T. 

Dole; 5/31/05.

D305815, Mancozeb. Residue Chemistry Chapter of the Reregistration Eligibility Decision 

Chemical No. 014504, C. L. Olinger, 06/14/2005.

USEPA, September 2005 Mancozeb Reregistration Eligibility Decision (RED).

D391948, Mancozeb: Occupational and Residential Exposure Assessment for a Proposed New 

Foliar Use on Lettuce, Peppers, Almonds, Broccoli, and Cabbage, A. Rivera- Lupiáñez,

11/15/11.

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. M. A. Ruhman, 07/03/2012.

D412678, Ethylene Thiourea (ETU); Aggregate Human Health Risk Assessment of the Common 

Metabolite/Degradate Ethylene Thiourea (ETU) to Support Proposed New Section 3 Use on 

Walnuts and Tolerance for Imported Tangerines). D. Drew, 7/3/2013.

D411769, Mancozeb: Revised Occupational and Residential Risk Assessment to Support Request 

for Section 3 Registrations on Walnuts. A. Rivera- Lupiáñez, 05/14/13.

D412565 and D412566, Mancozeb. Revised Acute, Chronic, Cancer Dietary Risk Assessments 

for Food and Drinking Water, as well as Aggregate Assessment for the Common 

Metabolite/Degradate ETU Resulting from the Combined Uses of the EBDC Fungicides to 

Support the New Use of Mancozeb on Walnuts and the Establishment of a Tolerance on 

Imported Tangerines for Section 3 Registration, P. Savoia, 07/01/2013.

D412677, Mancozeb: Human Health Risk Assessment to Support Proposed New Section 3 Uses 

on Walnuts and Tolerances for Imported Tangerines, D. Drew et al., 7/2/2013.

D425218, Metiram: Human Health Risk Assessment Scoping Document in Support of 

Registration Review, D. Drew, 6/2/2015.

Attachments

Attachment 1. Chemical Identity

Attachment 2. Toxicity Profile Tables

Attachment 3. Endpoint Tables

Attachment 4. International Residue Limits 
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Attachment 1. Chemical Identity

Table A1.1 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) 80% WP (Dithane® M45 Fungicide; EPA Reg. No. 62719-387)

Chemical structure of ETU 

metabolite

Ethylenethiourea

Table A1.2 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, pKa Not applicable; does not dissociate DEB No. 4750, 1/24/89, G. 

Makhijani 

Octanol/water partition coefficient, 

Log(KOW)

3.24 at room temperature RCB No. 4368, 11/9/88, G. 

Makhijani 

UV/visible absorption spectrum Not available

*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 insoluble 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 long enough to reach a location that would 

supply water for human consumption. However, mancozeb’s degradate ETU is highly water soluble, highly 

vulnerable to indirect photolysis, and is moderately 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 volatilization.

N

H

S

S

N

H

S

Mn

S

Zn

x

y

HN NH

S
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Attachment 2. Toxicity Profile Tables

Toxicity Profiles MANCOZEB

Table A2.1 Acute Toxicity Data for Mancozeb

Guideline No. Study Type MRID # Results Tox. Category

870.1100 Acute Oral 00142522 LD50 > 5000 mg/kg IV

870.1200 Acute Dermal 00142522 LD50 > 5000 mg/kg IV

870.1300 Acute Inhalation 00142522 LC50 > 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 A2.2 Subchronic, Chronic and Other Toxicity Profile – Mancozeb

Guideline No. Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral toxicity 

(Crl:CD(SD) rat)

00160704 (1986)

Acceptable/guideline

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

NOAEL=9.24 mg/kg/day (females)

LOAEL=17.82, based on decreased serum 

thyroxine (females).

At HDT (males, females): ↓BW, changes in 

thyroid hormones, microscopic changes in liver 

and thyroids, increased thyroid and liver weight

870.3100 90-Day oral toxicity 

(CD-1 mouse)

00154192 (1985)

Acceptable/guideline

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

NOAEL=18.13/21.68 mg/kg/day 

LOAEL=166.9/233.8 mg/kg/day, based on 

microscopic lesions of thyroid follicular cell 

hypertrophy or hyperplasia in females and 

decreased liver MFO enzyme activity in males.

At HDT, decreased BW (both sexes), increased 

aniline hydroxylase activity (both sexes)

870.3150 90-Day oral toxicity 

(Beagle dog)

00160705 (1986)

Acceptable/guideline

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

NOAEL=2.98/3.35 mg/kg/day (males/females).

LOAEL =28.62/28.91 mg/kg/day 

(males/females), based on dehydration, 

decreased body weights and food consumption, 

anemia, lymphoid depletion of the thymic 

cortex, elevated cholesterol and prostate 

hypogenesis.

870.3200 21/28- Day dermal 

toxicity (Crl:CD (SD) 

BR rat

40588201 (1988)

Acceptable/guideline

0, 10, 100, or 1000 

mg/kg/day

NOAEL ≥ 1000 mg/kg/day [HDT] in males and 

females.
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Table A2.2 Subchronic, Chronic and Other Toxicity Profile – Mancozeb

Guideline No. Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3465 90-Day inhalation 

toxicity 

(Crl:CD(SD)BR rat)

00160782 (1986)

Acceptable/guideline

0, 0.018, 0.079, or 

0.326 mg/L

6 hours/day, 5 

days/week, 13 weeks

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.

870.3700a Prenatal 

developmental in [SD 

BR rat]

00093929 (1980)

Acceptable/guideline

0, 2, 8, 32, 128, or 512 

mg/kg/day

GD 6-15

Maternal NOAEL=32 mg/kg/day.

Maternal LOAEL=128 mg/kg/day, based on 

decreased food consumption, body weight

(11%), and body weight gains.

At 512 mg/kg/day: maternal mortality (1), 2 

abortions, clinical signs (lethargy, scruffy coat, 

diarrhea), decreased BW on GD20 (25%)

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.

abnormalities of the central nervous system: atrophy 

of brain tissue, cranial edema, dilated ventricles of 

the brain, compression and/or hemorrhages of the 

spinal cord, deficiency of tissue in the olfactory 

bulb, meningoencephalocele; abnormalities of the 

skeletal system: incomplete cranial ossification, wide 

cranial sutures, curved clavicle, fused sternebrae, 

absent caudal or sacral vertebrae, fused and/or 

thickened ribs, wavy ribs, misshapen or incomplete 

ossification of hindlimb long bones, kyphosis, 

incomplete ossification or misshapen pelvis; gross 

defects: agnathia, cleft palate, cleft lip, club limb, 

stubby tail, forelimb flexure, and kinked tail; and 

cryptorchidism.

870.3700b Prenatal

developmental in 

[NZW rabbit]

40433001 (1987)

Acceptable/guideline

0, 10, 30, or 80 

mg/kg/day

GD 7-19

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.
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Table A2.2 Subchronic, Chronic and Other Toxicity Profile – Mancozeb

Guideline No. Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3800 Reproduction and 

fertility effects

(Crl:CD BR rat)

41365201 (1988)

Acceptable/guideline

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

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. 

Offspring NOAEL ≥ 69.90/79.37

Reproductive/Offspring LOAEL not identified.

No adverse reproductive or offspring effects 

were attributed to mancozeb.

870.4100a Chronic toxicity

[Crl:CD BD rat]

41903601 (1990)

Acceptable/guideline

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

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.

870.4100b Chronic toxicity 

(Beagle dog)

41810501 (1988)

Acceptable/guideline

males: 0, 1.75, 7.26, 

27.26, 53.52 mg/kg/day

females: 0, 1.84, 7.02,

29.24, or 59.72 

mg/kg/day

NOAEL in males=1.75 mg/kg/day;

LOAEL in males=7.26 mg/kg/day, based on 

decreased body weight gain.

Thyroid effects at 1600 ppm in both sexes 

(thyroid folliculitis, increased # distended 

thyroid follicules, decreased thyroxine levels)

NOAEL in females=7.02 mg/kg/day,

LOAEL in females=29.24 mg/kg/day, based on 

anemia.
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Table A2.2 Subchronic, Chronic and Other Toxicity Profile – Mancozeb

Guideline No. Study Type MRID No. (year)/ 

Classification /Doses

Results

870.4300 Chronic toxicity/ 

carcinogenicity

Crl:CD BR rat

41903601 (1990)

Acceptable/guideline

0, 10, 30, 65, or 375 

ppm; ↑ gradually to 0, 

20, 60, 125, or 750 ppm

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

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.

Thyroxine levels were decreased beginning at 3 

months;remained decreased until 18 months (males)/

study termination (females). Triiodothyronine was 

decreased at 3 months (both sexes) but rebounded at 

3 months;remained elevated throughout the study. 

TSH was elevated beginning at 6 months until study 

termination. Absolute and relative thyroid/

parathyroid weights were increased at 24 months but 

not at 12 months. Microscopically, the incidence of 

thyroid follicular cell hypertrophy/hyperplasia was 

increased at 2 years, but not at 1 year, in 750 ppm 

males and females. The incidence of thyroid nodular 

follicular cell hyperplasia was also increased in 750 

ppm males and females at 2 years. Thyroid 

follicular cell adenomas were increased in high-dose 

males (0/60, 1/62, 1/60, 0/58, and 20/61) and 

females (1/62, 1/60, 1/62, 1/61, and 6/61). Thyroid 

follicular cell carcinomas were increased in highdose males (0/60, 0/62, 2/60, 2/58, 14/61) and 

females (0/62, 0/60, 0/62, 1/61, 4/61).

870.4200 Carcinogenicity

(CD-1 mouse)

41981801 (1991)

Guideline/unacceptable

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.

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. 

Gene Mutation

870.5100

Salmonella 

typhimurium

TA98, TA100, 

TA1535, Ta1537, 

Ta1538

00259044 ()

40388805 (1987)

40388806

Negative with and without activation

Mammalian 

cell forward 

gene mutation 

assay

870.5300

CHO/HGPRT

Mouse host-mediated

00259044 ()

00148237 (1985)

40810203 (1987)

00259044 ()

Negative with and without activation

Negative 
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Table A2.2 Subchronic, Chronic and Other Toxicity Profile – Mancozeb

Guideline No. Study Type MRID No. (year)/ 

Classification /Doses

Results

In vitro

chromosomal 

aberration 

assay

870.5375

Chinese hamster 

ovary (CHO) cells 

(+/-S9)

00259004 () Negative 

In vivo mouse 

micronucleus 

assay

870.5395

CD-1 mouse 40778901 (1987) Negative

Other Effects 

870.5550

Unscheduled DNA 

Synthesis

- hepatocytes

- HeLa cells

- SCE in CHO cells

- in vitro

transformation 

10T1/2 cell

- in vitro

transformation/promo

tion10T1/2 cell

- DNA damage in E. 

coli pol A

40611701 (1988)

40810205 (1986)

00259044

00259044

00259044

40810201 (1986)

Negative

Pos with/without activation, not concentration 

dependent

Positive without activation, negative with 

activation

Negative

Negative

Positive (stronger response without activation)

Other Effects 

870.5900

sister 

chromatid 

exchange assay

Chinese hamster 

ovary cells

40810202 (1986) Positive (stronger response without activation)

870.6200a Acute neurotoxicity 

screening battery 

(Fisher 344 rat)

47126201 (2005)

Acceptable/guideline

0, 500, 1000, 2000 

mg/kg/day

NOAEL=500 mg/kg/day

LOAEL=1000 mg/kg/day based on decreased

motor activity

870.6200b Subchronic 

neurotoxicity 

screening battery

Crl:CD BR rat

42034101 (1991)

Acceptable/guideline

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

NOAEL=8.21/10.5 mg/kg/day (males/females).

LOAEL=49.7/63.3 mg/kg/day, based on 

microscopic evidence of peripheral nerve 

damage and decreased body weight gain in 

females.

At HDT (339/412 mkd): Female mortality, ↓

BW in males (↓45%); lcinical signs in both

sexes – reluctance to walk, etc

870.6300 Developmental 

neurotoxicity 

(Crl:CD (SD) rat)

47872902 (2008)

47872901 (2008)

Acceptable/guideline

0, 5, 15, 30 mg/kg/day

GD 6-LD 21-28

maternal NOAEL = 30 mg/kg/day, HDT

offspring NOAEL = 15 mg/kg/day

offspring LOAEL = 30 mg/kg/day, based on 

decreased pup body weight (11-22%) in rangefinding study
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Table A2.2 Subchronic, Chronic and Other Toxicity Profile – Mancozeb

Guideline No. Study Type MRID No. (year)/ 

Classification /Doses

Results

870.6300 Developmental 

neurotoxicity (rat)

Axelstad, et al., Tox Sci 

120(2). 2011. 

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

870.7485 Metabolism and 

pharmacokinetics

(CD rat, CD-1 

mouse)

00159611 (1986)

00159612 (1986)

41656301 (1990)

Rapidly absorbed after oral administration, 

highest accumulations in thyroid. No 

significant overall accumulation in the body in 

either rat or mouse study.

870.7600 Dermal penetration 

(Crl:CD BR rat)

40955401 (1988)

00127950 (1980)

Acceptable/guideline 

(combined)

Dermal absorption = 1%

870.7800 Immunotoxicity

[Crl:CD(SD) rat]

48794801 (2012)

Acceptable/Guideline

Negative for Immunotoxicity

Special Studies

OECD 443

Extended onegeneration 

reproductive toxicity

[Crl:CD(SD) rat]

Comparative thyroid 

assessment on ETU

49140301/2013 Under Review

Toxicity Profiles ETU

Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity 

(Crl:CD(SD) rat)

000160704/1986

Acceptable/non-guideline

250 ppm 

males: 14.28 mg/kg/day

females: 17.81 mg/kg/day

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.
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Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (CD-1 

mouse)

00154192/1985

Unacceptable/Guideline

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

NOAEL = 1.72 mg/kg/day

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 widely.

870.3150 90-Day oral 

toxicity (Beagle 

dog)

42174201/1991

Acceptable/Guideline

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

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, no thyroid effects were 

observed.

In high dose group: mortality, anemia, 

decreased activity, decreased thyroid hormone 

levels, increased thyroid weight, microscopic 

thyroid hyperplasia.

870.3150 4-Week Rangefinding 

(Beagle dog)

41863401/1989

Acceptable/non-guideline

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

NOAEL = 7 mg/kg/day

LOAEL = 34 mg/kg/day, based on decreased 

levels of thyroid hormones, gross thyroid 

lesions.

At HDT, decreased body weight and food 

consumption in addition to thyroid effects.

Histopathology and organ weights were not 

assessed.

870.3200 21/28- Day dermal 

toxicity (species)

Not presented to HASPOC since ETU is metabolite/degradate

Data requirement not applicable

870.3465 90-Day inhalation 

toxicity (species)

Not presented to HASPOC since ETU is metabolite/degradate

Data requirement not applicable

870.3700a Prenatal 

developmental in 

[SD BR rat]

00093929/1980

Acceptable/non-guideline

Maternal NOAEL = <50 mg/kg/day

Maternal LOAEL = 50 mg/kg/day, based on 

decreased body weight gain (↓36%).

Developmental NOAEL = <50 mg/kg/day

Developmental LOAEL = 50 mg/kg/day, based 

on numerous central nervous system defects 

(hydrocephaly and related malformations); 

gross developmental defects; skeletal defects;

and decreased fetal weight (↓13%).

Only one dose group was included in the study.
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Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3700a Prenatal 

developmental in 

[Wistar rat]

45937601/1973

Acceptable/Non-guideline

[Khera, K.S. 1973. 

Teratology 7:243-252]

0, 5, 10, 20, 40, 80 

mg/kg/day

Dosing: 21-42 days before 

conception to pregnancy 

day 15, and on days 6-15 

or 7-20 of pregnancy

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; at 

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/day 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. 

870.3700a Prenatal 

developmental in 

[Sprague-Dawley 

rats]

45924404/1979

[Chernoff, et al., J. 

Toxicol. Env. Health 5: 

821-834]

0, 5, 10, 20, 30, 40, or 80 

mg/kg/day (GD 7-21)

0, 20, 25, or 30 mg/kg/day 

(GD 7 to PND 15)

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 and postnatal exposure:

Postnatal toxicity at

30 mg/kg/day included hydrocephalus, domeshaped heads, and pup mortality. 
Mancozeb Registration Review Human Health Scoping Document D425216

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Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3700a Prenatal 

developmental in 

[Wistar rat]

MRID 48985801

[Khera and Tryphonas 

Tox Appl Pharm 42:85-

97. 1977]. 

Acceptable/non-guideline

0, 15, 30, 45 mg/kg

Dams received a single 

oral dose on gestation 

day 15.

Maternal NOAEL/LOAEL not reported

Developmental NOAEL = 15 mg/kg

Developmental LOAEL = 30 mg/kg based on 

postnatal mortality, hydrocephaly, 

microphthalmia, cerebellar dysplasia, cerebral 

atrophy, and in survivors, motor defects and 

dome-shaped head.

870.3700a Prenatal 

developmental in 

[Wistar rat]

No MRID 

[Ruddick and Khera. 

Teratology 12:277-282, 

1975]

Acceptable/non-guideline

0 or 240 mg/kg

Dams received a single 

dose on one gestation day 

between GD 6-21

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; ETU affected 

development of brain, kidney, eye, and axial 

and appendicular systems

870.3700a Prenatal 

developmental in 

[SD rat]

No MRID 

Saillenfait, et al., Fund. 

Appl. Toxicol. 17: 300-

408, 1991

Acceptable/non-guideline

0, 15, 25, or 35 mg/kg/day 

from GD 6-20

Maternal NOAEL not attained.

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, meningorrhea, hyrdronephrosis, 

dilated renal pelvis, and vertebral abnormalities

were observed.

870.3700a Prenatal 

developmental in 

[Wisrar Imamichi 

rat]

45924405/1978

[Teramoto, et al., 

Congenital Anomalies 18: 

11-17, 1978]

Acceptable/non-guideline

0, 10, 20, 30, 40, 50 

mg/kg/day 

GD 6-15.

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. 

870.3700b Prenatal 

developmental in 

[New Zealand 

White rabbit]

47976403/2010

Acceptable/Guideline

0.5% aqueous 

methylcellulose

0, 5, 15, 50 mg/kg/day

GD 7-29

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.
Mancozeb Registration Review Human Health Scoping Document D425216

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Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3700b Prenatal 

developmental in 

[Syrian Golden 

hamsters

45924405/1978

Acceptable/non-guideline

[Teramoto, et al., 

Congenital Anomalies 18: 

11-17, 1978]

0, 90, 270, 810 mg/kg/day 

from GD 6-13.

Developmental NOAEL = 90 mg/kg/day

Developmental LOAEL = 270 mg/kg/day, 

based on skeletal malformations and 

short/kinky tail. At 810 mg/kg/day, fetal deaths, 

dilated brain ventricles, cleft palate, 

micrognathis, and anal atresia were observed.

870.3700b Prenatal 

developmental in 

[JCL-ICR mouse]

45924405/1978

Acceptable/non-guideline

[Teramoto, et al., 

Congenital Anomalies 18: 

11-17, 1978]

0, 200, 400, or 800 

mg/kg/day.

GD 7-15

No maternal or developmental toxicity was 

observed.

870.3800 Reproduction and 

fertility effects

(Sprague-Dawley 

rat)

42391701/1992

Unacceptable/Nonguideline

42391801/1992

ETU content data 

0, 2.5, 25, 125 ppm

Doses on mg/kg/day basis could not be 

determined.

Parental: microscopic thyroid 

hyperplasia/hypertrophy in mid and/or highdose groups.

No reproductive effects attributed to treatment.

Unacceptable because of stability problems 

(mkd could not be calculated) with test material 

and poor record keeping.

870.3800 Reproduction and 

fertility effects

(Crl:CD(SD) rat)

49140301/2013

Acceptable/OECD 

guideline

0, 2.8, 28, 140 ppm 

0, 0.2, 2, 10 mg/kg/day

4 weeks prior to mating; 

14-day mating period), 

through gestation, 

lactation to weaning; 

Parental males from day 

44 for 7 weeks until 

sacrifice

Parental females through 

gestation/lactation (LD 0-

22)

NOAEL = 140 ppm (10 mg/kg/day).

LOAEL = not attained.

No effects on reproductive indices, precoital 

intervals, gestation length, gonadal function, 

estrous cycle, sperm maturation, parturition, 

lactation, or tissues and organs of the 

reproduction system. 

870.4100a Chronic toxicity

Fischer 344 rat 

45924403/1992

Fund. Appl. Tox. 18: 405-

417 (feeding NTP)

w/ and w/out perinatal

Thyroid follicular cell adenomas and pituitary 

adenomas were observed.
Mancozeb Registration Review Human Health Scoping Document D425216

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Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.4100b Chronic toxicity 

(Beagle dog)

42338101/1992

Acceptable/Guideline

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

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.

870.4200 Combined 

Chronic/

Carcinogenicity

(SD rat)

42607801/1992

Unacceptable/Guideline

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

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. 

870.4300 Carcinogenicity

(B6C3F1 mouse)

45924403/1992

Fund. Appl. Tox. 18: 405-

417 (feeding NTP)

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. 

870.6200a Acute 

neurotoxicity 

screening battery

Not required for metabolite; the thyroid is the target organ for ETU; injury to 

the peripheral nerves is observed in studies following exposure to mancozeb 

and metiram but not to ETU. 

870.6200b Subchronic 

neurotoxicity 

screening battery

Not required for metabolite; the thyroid is the target organ for ETU; injury to 

the peripheral nerves is observed in studies following exposure to mancozeb 

and metiram but not to ETU.

870.6300 Developmental 

neurotoxicity

[Crl:CD(SD) rat]

49140301/2013

Acceptable/OECD 

guideline

0, 2.8, 28, 140 ppm 

0, 0.2, 2, 10 mg/kg/day

4 weeks prior to mating; 

14-day mating period), 

through gestation, 

lactation to weaning; 

Parental males from day 

44 for 7 weeks until 

sacrifice

Parental females through 

gestation/lactation (LD 0-

22)

NOAEL = 28 ppm (2 mg/kg/day).

LOAEL = 140 ppm (10 mg/kg/day), based on 

decreased brain size.

870.7485 Metabolism and 

pharmacokinetics

(species)

Not required for metabolite

870.7600 Dermal penetration 

(SD COBS CD rat)

40312601/1987

Acceptable

Dermal absorption = 26%
Mancozeb Registration Review Human Health Scoping Document D425216

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Table A2.3 ETU Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.7800 Immunotoxicity

[Wistar rat]

48794502/2012

Acceptable/Guideline

0, 10, 50, 250 mg/kg/day

Males: 0, 1, 4, 19 

mg/kg/day

Negative for Immunotoxicity

Thyroid toxicity observed at all dose levels.

OECD 443 Extended onegeneration 

reproductive 

toxicity

[Crl:CD(SD) rat]

49140301/2013 Under Review
Mancozeb Registration Review Human Health Scoping Document D425216

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Attachment 3. Endpoint Tables

Table A.3.1 Summary of Toxicological Doses and Endpoints for MANCOZEB Used in Previous

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

UFA= 10x

UFH = 10x

FQPA SF = 1x 

Acute RfD = 5 

mg/kg/day

Acute PAD = 5 

mg/kg/day

Acute 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

UFA= 10x

UFH = 10x

FQPA UFDB = 

10x 

Acute RfD = 

5 mg/kg/day

Acute PAD = 0.5 

mg/kg/day

Acute 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

UFA= 10x

UFH = 10x

FQPA UFDB = 

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 Exposure

Chronic Dietary 

(Adult Males, 

Females >49, and 

Children ≥ 6 

years)

NOAEL = 

4.83 

mg/kg/day

UFA= 3x

UFH = 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

UFA= 3x

UFH = 10x

FQPA UFDB = 

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

UFA= 3x

UFH = 10x

FQPA UFDB = 

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 IntermediateTerm, 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 (LongTerm) (Adult 

Males, Females 

>49 years, 

Children ≥ 6 

years)

NOAEL = 

4.83 

mg/kg/day

DA = 1%

UFA= 3x

UFH = 10x

FQPA SF = 1x

LOC = 30 Toxicity/Carcinogenicity in the rat. 

LOAEL = 30.9 mg/kg/day based on 

thyroid toxicity

Dermal (LongTerm) (Females 

13-49 years and 

Children < 6 

years)

NOAEL = 

4.83 

mg/kg/day

DA = 1%

UFA= 3x

UFH = 10x

FQPA UFDB = 

10x

LOC = 300 Toxicity/Carcinogenicity in the rat. 

LOAEL = 30.9 mg/kg/day based on 

thyroid toxicity
Mancozeb Registration Review Human Health Scoping Document D425216

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Table A.3.1 Summary of Toxicological Doses and Endpoints for MANCOZEB Used in Previous

Dietary and Non-Occupational Human Health Risk Assessments

Exposure POD Safety Factors RfD, PAD, LOC Study and 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)

UFA= 3x

UFH = 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)

UFA= 3x

UFH = 10x

FQPA UFDB = 

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 (Q1

*

) of 6.01 x 10 -2

(mg/kg/day)-1to quantitate risk.

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 observed 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. 

DA = dermal absorption. N/A = not applicable. 

Table A3.2 Summary of Toxicological Doses and Endpoints for MANCOZEB Used in Previous 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%

UFA= 3x

UFH = 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%

UFA= 3x

UFH = 10x

UFDB = 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]

UFA= 3x

UFH = 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]

UFA= 3x

UFH = 10x

UFDB = 10x

LOC = 300 Subchronic Inhalation in the rat

LOAEL = 0.326 mg/L based on 

thyroid toxicity

Mancozeb Cancer
Mancozeb Registration Review Human Health Scoping Document D425216

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Table A3.2 Summary of Toxicological Doses and Endpoints for MANCOZEB Used in Previous Occupational 

Human Health Risk Assessments 

Exposure POD Safety Factors RfD, PAD, LOC Study and Toxicity

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 (Q1

*

) of 6.01 x 10 -2

(mg/kg/day)-1to quantitate risk.

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 observed 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. DA = dermal absorption. 

N/A = not applicable.

Table A3.3 Summary of Toxicological Doses and Endpoints for ETU for 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

UFA= 10x

UFH = 10x

FQPA UFDB = 

10x

Acute RfD = 0.005

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 malformations

ETU Chronic Dietary Exposure

Chronic Dietary 

(Females 13-49 

years of age and 

Children < 6 

years)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH = 10x

FQPA UFDB = 

10x

Chronic RfD = 

0.00018 

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

UFA= 10x

UFH = 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

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 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

IntermediateTerm (Children` 

< 6 years of age)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based on 

thyroid toxicity
Mancozeb Registration Review Human Health Scoping Document D425216

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Table A3.3 Summary of Toxicological Doses and Endpoints for ETU for Dietary and Non-Occupational Human 

Health Risk Assessments 

Exposure PoD Safety Factors RfD, PAD, LOC Study and Tox

Dermal Short and

IntermediateTerm (Adult 

Males, Females 

>49 years, 

Children ≥ 6 

years)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

LOC = 100 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based on 

thyroid toxicity

Dermal Short and 

IntermediateTerm (Females 

13-49 years old)

NOAEL= 5 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973)

LOAEL = 10 mg/kg/day, based on 

hydrocephaly and other malformations

Dermal LongTerm 

(Females 13-49 

years of age and 

Children < 6 

years)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

Dermal LongTerm 

(Adult Males, 

Females >49 

years, Children ≥ 

6 years)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

LOC = 100 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

ETU Residential Inhalation Exposure

Inhalation Short 

and IntermediateTerm (Children < 

6 years of age)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based thyroid 

toxicity

Inhalation Short 

and IntermediateTerm (Adult 

Males, Females 

>49 years, 

Children ≥ 6 

years)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

LOC = 100 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based thyroid 

toxicity

Inhalation Short 

and IntermediateTerm (Females 

13-49 years old)

NOAEL= 5 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973)

LOAEL = 10 mg/kg/day, based on 

hydrocephaly and other malformations

Inhalation LongTerm (Females 

13-49 years of 

age and Children 

< 6 years)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH=10x

FQPA UFDB = 10x

LOC = 1000 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

Inhalation LongTerm (Adult 

Males, Females 

>49 years, 

Children ≥ 6 

years)

NOAEL=

0.18mg/kg/d

ay

UFA= 10x

UFH=10x

FQPA SF= 1x

LOC = 100 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

ETU Cancer

Cancer (all 

routes)

Q1

* = 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 
Mancozeb Registration Review Human Health Scoping Document D425216

Page 39 of 43

exposures. NOAEL = no observed 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.

Table A3.4 Summary of Toxicological Doses and Endpoints for ETU for Occupational Human Health Risk 

Assessments 

Exposure PoD Safety 

Factors RfD, PAD, LoC Study and Tox

ETU Occupational Dermal Exposure

Dermal Short and

IntermediateTerm 

(Adult Males, 

Females >49 

years)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

LOC = 100 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based on 

thyroid toxicity

Dermal Short and 

IntermediateTerm (Females 

13-49 years old)

NOAEL= 5 

mg/kg/day

UFA= 10x

UFH=10x

UFDB = 10x

LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973)

LOAEL = 10 mg/kg/day, based on 

hydrocephaly and other malformations

Dermal LongTerm 

(Females 13-49 

years of age)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH=10x

UFDB = 10x

LOC = 1000 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

Dermal LongTerm 

(Adult Males, 

Females >49 

years)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH=10x

LOC = 100 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

ETU Occupational Inhalation Exposure

Inhalation Short 

and IntermediateTerm (Adult 

Males, Females 

>49 years)

NOAEL= 7 

mg/kg/day

UFA= 10x

UFH=10x

LOC = 100 4-week range-finding dog study

MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based thyroid 

toxicity

Inhalation Short 

and IntermediateTerm (Females 

13-49 years old)

NOAEL= 5 

mg/kg/day

UFA= 10x

UFH=10x

UFDB = 10x

LOC = 1000 Developmental Rat Toxicity

MRID No. 45937601 (1973)

LOAEL = 10 mg/kg/day, based on 

hydrocephaly and other malformations

Inhalation LongTerm (Females 

13-49 years of 

age)

NOAEL= 

0.18 

mg/kg/day

UFA= 10x

UFH=10x

UFDB = 10x

LOC = 1000 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

Inhalation LongTerm (Adult 

Males, Females 

>49 years)

NOAEL=

0.18mg/kg/da

y

UFA= 10x

UFH=10x

LOC = 100 Dog Chronic Oral Toxicity

MRID 42338101 (1992)

LOAEL= 1.99 mg/kg/day based on 

thyroid toxicity

ETU Cancer

Cancer (all 

routes)

Q1

* = 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 observed 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 
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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.
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Attachment 4. International Residue Limits Table 

Mancozeb (014504; 03/10/2015)

Table A4.1 Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

U.S. Canada Mexico2 Codex

40 CFR 180.176:

Plant/Livestock: mancozeb (a coordination 

product of zinc ion and maneb (manganese 

ethylenebisdithiocarbamate)), including its 

metabolites and degradates, in or on the 

commodities in the following table. 

Compliance with the tolerance levels 

specified in this paragraph is to be 

determined by measuring only those 

mancozeb residues convertible to and 

expressed in terms of the degradate carbon 

disulfide.

None Total dithiocarbamates, determined as 

CS2,

evolved during acid digestion and 

expressed as mg CS2/kg

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Almond 0.1 0.1 (*)3

Almond, hulls 4 205

Apple 0.6 5 pome fruits3

Asparagus 0.1 0.13

Atemoya 3.0

Banana 2 2

3

Barley, bran 20

Barley, flour 20

Barley, grain 5 1

3

Barley, pearled barley 20

Barley, straw 25 25 barley straw and fodder, dry3(MRL 

mainly based on mancozeb)

Beet, sugar, dried pulp 3.0

Beet, sugar, roots 1.2 0.5 sugar beet3

Beet, sugar, tops 60

Broccoli 7

Cabbage 9 5 cabbages, head3

Canistel 15.0

Cattle, kidney 0.5 0.1 edible offal (mammalian) 3(MRL 

Cattle, liver 0.5 mainly based on mancozeb)

Cherimoya 3.0

Corn, field, forage 40

Corn, field, grain 0.1

Corn, field, stover 15 2 maize fodder (dry) 3

Corn, pop, grain 0.1

Corn, pop, stover 40

Corn, sweet, forage 70

Corn, sweet, kernel plus cob 

with husks removed

0.1 0.1 (*) sweet corn (corn-on-the cob) 3

Corn, sweet, stover 40

Cotton, undelinted seed 0.5

Crabapple 0.6 5 pome fruits3
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Table A4.1 Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

U.S. Canada Mexico2 Codex

Cranberry 5 5

3

Custard apple 3.0

Fennel 2.5

Flax, seed 0.15

Ginseng 1.2

Goat, kidney 0.5 0.1 edible offal (mammalian) 3(MRL 

Goat, liver 0.5 mainly based on mancozeb)

Grape 1.5 5

3

(MRL mainly based on mancozeb)

Hog, kidney 0.5 0.1 edible offal (mammalian) 3(MRL 

Hog, liver 0.5 mainly based on mancozeb)

Horse, kidney 0.5 0.1 edible offal (mammalian) 3(MRL 

mainly based on mancozeb)) 3 Horse, liver 0.5

Lettuce, head 3.5 0.53(MRL mainly based on mancozeb 

and maneb)

Lettuce, leaf 18 10 cos lettuce3

Mango 15.0 2

3

Oat, flour 20

Oat, grain 5

Oat, groats/rolled oats 20

Oat, straw 25

Onion, bulb 1.5 0.5 onion bulb, garlic, leek3(MRL mainly 

based on mancozeb)

Papaya 10 5

3

Peanut 0.1 0.1 (*)3

Peanut, hay 65 5 peanut fodder3

Pear 0.6 5 pome fruits3

Pepper 12 1 peppers, sweet (including pimento or 

pimiento)3

10 peppers Chili, dried3

Potato 0.2 0.23

Poultry, kidney 0.5 0.1 poultry edible offal of3

Poultry, liver 0.5

Quince 0.6 5 pome fruits3

Rice, grain 0.06

Rye, bran 20

Rye, grain 5

Rye, straw 25

Sapodilla 15.0

Sapote, mamey 15.0

Sapote, white 15.0

Sheep, kidney 0.5 0.1 edible offal (mammalian) 3(MRL 

Sheep, liver 0.5 mainly based on mancozeb)

Sorghum, grain, forage 0.15

Sorghum, grain, grain 0.25

Sorghum, grain, stover 0.15

Star apple 15.0

Sugar apple 3.0

Tangerine1 10 10 mandarins3

Tomato 2.5 2

5
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Table A4.1 Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

U.S. Canada Mexico2 Codex

Vegetable, cucurbit, group 9 2.0 2 cucumber3

0.5 melons, except watermelon3(MRL 

mainly based on mancozeb)

0.2 pumpkins3

1 squash summer3 watermelon3

0.1 winter squash3

Walnut 0.70

Wheat, bran 20

Wheat, flour 20

Wheat, germ 20

Wheat, grain 5 1

3

(MRL mainly based on mancozeb)

Wheat, middlings 20

Wheat, shorts 20

Wheat, straw 25 25 wheat straw and fodder, dry3(MRL 

mainly based on mancozeb)

Completed: M. Negussie; 03/10/2015

1There are no U.S. registrations for use of mancozeb on tangerine.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 The MRL is based primarily on residue data for mancozeb but does include data for the other dithiocarbamate 

active ingredients.

c) Tolerances with regional registrations. A tolerance with regional registrations, as defined in §180.1(l), 

is established for residues of the fungicide mancozeb, (a coordination product of zinc ion and maneb 

(manganese ethylenebisdithiocarbamate)), including its metabolites and degradates, in or on the 

commodity in the following table in this paragraph. Compliance with the tolerance levels specified in this 

paragraph is to be determined by measuring only those mancozeb residues convertible to and expressed in 

terms of the degradate carbon disulfide.

Commodity Parts per million Codex

Carrot, roots 1 1

3