### M a ncoz e b Regi s tration Rev i ew Huma n H ealth Scop i ng D ocument 

### D4252 1 6

UNITED STATES ENV IRONMENTAL PRO TECTION AGENCY

WASHINGTON, D .C. 20460



### MEM ORA N D UM

Dat e: Jun e 1

, 2015 OFFICE OF
CHEMICAL SAFETY AND
PO L LUTIO N PREVENTION



### SUBJECT: Mancozeb: Human H ea lth Ri sk Assessment Sco pin g Docum e nt in Support of R eg i stra ti on Review.

P C Co d e: 0 1 4504 ; 0 1 4601 ; 600016 DP B a r code: 0425216

D ec i s i o n No.: 4992 7 3 Re gist r at i on No.: NA

Petition No.: NA Ree.u l atory Action: R c.e. i stra ti o n Revi ew
Ri s k Asses s m e nt T y pe : NA Ca s e No.: NA

TXR No.: NA C AS No.: 8018-01-7

MRID No.: NA 40 CFR : 180

. 176



### FROM: D a nett e Dr ew
, Chemist/Risk Assess-·**.]).~-:----A-f if** **ti '--** 



### THROUGH:

And Ma tt Lloyd

, CIH

,**Expo~** 

### As se ssor /

_ P e t e Savoia, C h e mist 

### V..-<.---te"-<_ .--**~~,-c.-c__..,** 

### Linda T ay l or
, P h.D., T ox ic o l og i s t

Ri s k Asse s s m e nt Branches V and V II

H ea lth Eff ec ts Di v i s i o n 

### (75 09P )

Michael Metzger

, Branch Chief

# ~**~** /) )

Risk Assessme nt Branches V an d V II 

# M tt..f ·

H ea lth Effec t s Divi s ion 

### (7509 P )

.

J ess Ro w l a nd

, D e puty Direct o r
Dana Vogel, Acting Dir ecto r
Health Effec t s D i v i s i o n 

### (7509P)

TO: S t eve n Snyderma n
, Ch em ical R ev i ew M a n ager
Ri sk Management and Im plementation Bran ch 3

P estic i de R e-Eva l uation Di v i sion 

### (7508 P )

Page 1 of 43

### Mancozeb Re g i s trati o n Review Human H ea lth Sco pin g D ocu ment D425216

E xecutive S u mmary



### T h e H ea lth Effec t s Division ( H E D ) Manco ze b Re g i s tration Revi ew T ea m h as eva lu ated the

status of the human health ri sk assessment fo r the fun g icid e manc ozeb t o d ete rmine the scope of

work n ecessa r y to suppo rt r eg i s trati o n r ev i ew

. T hi s sco pin g exerc i se i s bas e d p ri maril y on th e

mo st rec e ntl y co mpleted human health ri sk assessment ( HH RA) of Jul y 20 1 3 ( 0

. Dr ew 

### e t al

.. 7 / 2 /2 01 3, 041 2677

, 

### Man coze b : Human H e allh Ri sk Assessmen t to Support Proposed New

Sect ion 3 Uses on Walnuts and Tolerances/or Import ed Tangerin es) and th e USEPA Sep temb e r
2005 M a ncoz e b R e r eg i s tr at i o n E li g i bil it y Dec i s i o n (RED).

Manco zeb i s a coordi nati o n product of z in c ion and maneb ( manganes e ethy lc nebisdithiocarbamate) u se d as a broad-spectrum fungicide. Man cozeb i s curre ntl y

re g i s t ered for fo liar a pplicat i on a n d see d tr ea tm e nt on va riou s agricultural crops. Horti c ultu ra l

u ses include o rnamental plants in nur ser ie s and gree nhou ses, home ga rden s, sod far m s, a nd go lf

cour ses.

I n plants an d li ves tock commoditie s, the r es idu es of co n cern for ri s k assessme nt are the parent

compou n d m a ncoz eb and its m eta b o li te / d eg rad ate ethy l enethiourea (ETU)

. The residue of

concern in drinki n g water i s ETU o nl y

. Tolerances arc curr e nt l y es tabli s hed fo r r es idu es of

m a ncoz eb, in c ludin g its m e t abo li tes an d degradates ( m easure d as the degradate CS 2), on a
number of crop and li vestoc k com m odi ti es.

M a nco ze b i s a fun g i c id e in th e clas s of e th y l e n eb i s dithioc arba mat es (EB D Cs), wh ich also

in c lud es the fung i cides m aneb ( no r egis ter ed u ses) and me ti ram; a ll of the se co mp ou nd s ha ve a

common met abo li t e/ d eg r a date

, E TU. So m e of th e m o r e not ab l e toxic it y in th e m a n cozeb s tudi es

was du e t o t ox icit y from this metabolite. Th yro id toxic i t y a n d developmental toxi c it y in rat s

were attributed to t ox icit y from ETU. In jury t o periphera l nerve s occ urr ed in mancozeb toxi c ity

studies but n o t in s tudi es with ETU. Fo r mancozeb, separa t e ri sk assess m en t s are performed for

1 ) t ox icit y and e xpo s ure to par e nt compou nd 

### mancoz eb onl y and 2) toxicity and ex po s ur e to 

### ETU derivedfrom man cozeb, includin g combined exposures from bot h ET U as an environ m ental

d egra d a te and E TU as an 

### in vivo m e t a bo li t e of manco ze b. This document present s the sco pe o f

work antic i pated under r eg istr a tion review for both m a nco zeb and m ancozeb -deri ved ETU. A

separa t e fort h co min g H ED document (04252 1 8) o utlin es th e scope of work a nticip ated fo r

m et iram and metiram

- d e rived ETU. I n addition t o th e indi vid ual E BD C p estic ide assess m ents

. a
separate ri s k assess ment i s performed a ddr essi n g th e comb in e d (agg r ega te ) r i sk from ETU

d e riv e d from a ll r eg i s t e r ed EBDC pe s ticid es. The co n clusions r ega r di n g th e sc ope of wo rk anticipated un der r eg istr a ti on r ev i ew for manco ze b a nd metiram a l so app l y t o th e E TU agg r egate

ri sk assessment.

F o r residen t ial

, occupational and d i e tar y ex po s ur es, inc l udin g oral

, dermal and inhalation routes

of ex po s ure
, a 7.5% 

### in v i vo m e t abo li c conversion of abso rb e d m a nco zeb to ET U i s u sed

, a nd i s

accoun t ed for in estimat in g th e total exposure 

### (in vivo met abo li s m combined w ith direct

environmenta l expos ure ) t o ETU.

The findin gs in multiple toxico l ogy s tudi es dem o nstrat e th at the th y roid i s a t arget o r ga n for

man cozcb and ETU; the se effec t s ar e due t o inhibiti on of th yro id peroxidase by th e metabolite

P age 2 of 

### 43

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 3 of 43 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 w as observed in mancozeb studies (but only at doses where maternal toxicity was observed)

. The thyroid toxicity and developmental toxicity

are attrib uted 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 classifi ed 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 fo r children less than six years old to account for the lack of data on the

deve loping thyroid. Since then, an extended one

- generation reproductive toxicity (EOGRT) study on ETU, which includes an assessment of developmental thyroid toxicity, has been

submitt ed and is undergoing review.

The toxicology database s for mancozeb and ETU are sufficient for assessing the toxicity and characterizing the hazard of these compounds; n o additional data are required to support

mancozeb registration review. D uring registration review, the impact of recently submitted ETU studies (an EOGRT study an d a rabbit developmental toxicity study ) on toxicological endpoint selection, points of departure (PODs), and uncertainty factors/safety fa ctors (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, 8 60.1480 Rumin ant 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 m ay be ou tdated, 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 b asket 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; manco zeb is not expected in drinking water ) or mancozeb

- derived ETU (food and water) for any populations modeled, including infants and children, and females

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 4 of 43 of child bearing age. The cancer risk estimate associated with exposure to ETU in food and water

was 2 x 10

- 6 

### for 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 concentrat ions ( 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 an ticipated 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 mancoze b is complete. There were no residential handler

or post

- application risks of concern identified in the 2013 mancozeb HHRA for ei ther 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 c hanges 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 ris k estimates for ETU (food and water exposure) were not of co ncern. 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 ( residen tial, food and water) risk estimates 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 toxicologic al endpoints, PODs or UF/SFs, or if there are significant changes to food residues or EFED’s EDWC s

.

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 post

application occupational risk assessments (cancer and non

- cancer) will be performed for all currently re gistered 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 regis tration 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

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 5 of 43 investigators. HED will perform a Tier II assess ment 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 asses sments for ETU from the combined EBDC pesticide uses (metiram and mancozeb ) (2013 ETU Aggregate HHRA ; D412678 ). The acute and chronic (non

- cancer) aggregate assessments include d only dietary (food and drinking water) exposures. There were no acute or chron ic 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 a ggregate ETU risk s 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, toxicologic al 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 c o nsidered updates to its toxicity, exposure and usag e 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

- emer gence 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 formu lations include wettable powder, dr y flowable, liquid flowable and dust

.

Information on the chemical identity of m ancozeb 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

Page 6 of 43 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 thiour ea (ETU). T he thyroid is the target organ for mancozeb and ETU, and t hyroid toxicity is manifested as alterations in thyroid hormones, increased thyroid weight, and microscopic thyroid lesions (mainly thyroid follicular cell hyperplasia).

Additional tox ic 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 l evels 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 , m ancozeb is also classified as a Group B2 carcinogen. T hyroid 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 a ssess 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 thyr oid (database uncertainty factor) . The FQPA factor

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 7 of 43 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 ( a n e xtended one

- generation reproductive toxicity study on ETU, which

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

assessment

. D uring registration review of mancozeb, the impact of the study results on endpoi nt selection, points of departure (PODs), and uncertainty factors/safety factors (UF/SFs) for the dietary, incidental oral, dermal, and inhalation risk assessments will be evaluate d

.

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.

Ethylenet hiourea (ETU)

Previously, the toxicology database for ETU wa s 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 include s 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 T 4 

### (thyroxine), changes in T 3 

### (triio dothyronine) 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. Developmenta l 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

- generati on 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

observ ed in the ETU carcinogenicity study in mice. The ETU cancer potency factor (Q 1 

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

### is 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 facto r 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.

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 8 of 43 Since the last risk assessment of ETU, an extended one generation reprodu ctive toxicity (EOGRT) study on ETU was submitted, which was designed to satisfy the toxicology d ata 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 review ed and found to satisfy this data requirement. D uring registration review of mancozeb

, the impact of the se study results on endpo int 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 database s 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. D uring 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

Residu e 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 ( CS 2 

### )

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

Multi

- Residue Method testing protocols. There remains a n 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

P otato 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

equ ipment 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

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 9 of 43 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 t he 2005 RED was developed

and supporting independent laboratory validation (ILV) studies were provided for th e 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 specifie d 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

R esidue data for t obacco data h ave not yet been submitted following guidelines to allow the Agency to conduct an exposure assessment to support this registered use. S afflower seed or propagation stock treatment data are required depicting residues of mancozeb and

ETU in /on safflower se ed grown from seed treated with a representative produ ct 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. 7050 6

- 194)]. These requirements remain outstanding.

860.1 520 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

T olerances 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

rumin ant 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

The re are no rotational crop restrictions currently spe cified on any mancozeb labels. A confined rotational crop study remains outstanding for mancozeb to determine i f limited field trials for rotational crops are needed. This requirement remains outstanding.

The 2005 residue chemistry chapter supporting th e RED also identified the following requirement for storage stability data for carrot and onion and crop residue data for wheat hay

.

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 10 of 43 As part of this mancozeb scoping exercise, HED has determined that the se requirement s are now considered fulfilled:

860.1380 Storage Stability Data

C arrot, 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 determinatio n, 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 we re 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 Cr op 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 mem orandum 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 m ay 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

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 11 of 43 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 estima tes 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, p ercent crop treated/import estimates

, and processing and cooking factors.

Modeling estimates (PRZM/EXAMS) for surface water (almond use scena rio) were used for ETU estimated drinking water concentrations (EDWCs) in the acute assessment . W ell 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 ch ild bearing age.

For acute exposure to mancozeb in food, t he 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 w hich 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, t he 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

, t he highest exposed population was c hildren 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

- 6 

### for the general U.S. population

.

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 12 of 43 Conclusions: The mancozeb residue chemistry database is incomplete . O utstanding 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, 8 60.1480 Ruminant Feeding Study, and 860.1850 Confined Rotational Crop Study

.

In addition, HED has determined

, as part of this scoping exercise

, that updated an ticipated residue/monitoring data (non

- guideline study) are needed to support the dietary assessment s of the EBDC pesticides, including mancozeb . Th e previous dietary analyses for mancozeb /ETU were refined through the use of the 1990 EBDC market basket sur vey 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 bask et 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 stud ies), 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 i n the most recent assessment. If new toxicological endpoints, PODs or UF /SF s 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 residen tial 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; n o dermal hazard identified) and ETU (combined dermal and inhalation) exposure. The residential post

application assessment included ETU (dermal only exposure). Residential c ancer risk estimation has been performed for mancozeb

- derived ETU.

Residential Han dler

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. Th e adult handler exposure assessment was conducted using

the 2012 Residential SOP. Residential handler inhalation risk estimates from mancozeb

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 13 of 43 exposures were not risk concern s (MOEs > 300 for adult females of childbearing age and MOEs > 30 for other adults and youth ) ; i nhalation MOEs range d 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 d ermal 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 rang ed from 32,700 to 90,000. The cancer risks for all

M/L/A residential scenarios were estim ated in the 10

- 8 

### range 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.)

a nd 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.

P ost 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

hom e 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 ≥ 10 0 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).

Tur f 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 data 1 

### are available for mancozeb for use i n assessing golfer risk estimates. Therefore, no new chemical specific TTR data are required at this time.

Post

- A pplication Volatilization/Spray Drift

Residential bystander exposures resulting from off

- site transport (e.g., spray drift or

volatilizati on) 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

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 14 of 43 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 resid ential 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 prot ective 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 Analysis 2 

### . 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 fo r 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 exposu re 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. C hanges in the registered use pattern , exposure methodologies, or toxicological endp oints, 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) expos ures. 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

- deriv ed 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 mancoze b

derived ETU. There were no short

- term aggregate risk estimates of concer n for adul ts 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 exposu res 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

- 6 

### and 3 x 10

- 6



### , respectively.

2 http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 15 of 43 Conclusions: The 2013 acute and chronic non

- cancer aggregate ( dietary: food and drinking water) ris k estimates for mancozeb and mancozeb

- derived ETU were not of concern

. The short

term aggregate ( residential and dietary exposures) assessment s for mancozeb or ETU did not

result in risk estimates of concern. The c ancer 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 a re any changes to toxicologic al endpoints,

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

EDWC s

.

Aggregate Risk Assessment (ETU derived from all EBDC Pesticides)

ETU is a common degradate/ metabolite of the ethy lene 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 m etiram 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. T he 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 adul t 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 applyi ng the EBDC mancozeb to gardens and adults or youth entering treated gar dens).

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, toxicologic al endpoints, PODs or UF/SFs, EDWCs , or food exposures ).

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 16 of 43 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. Mancoze b 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 exposure s for parent manco zeb are assessed for short

- and intermediate

- term

exposure. For handlers, o nly inhalation risk estimates are calculated for short

- and intermediate

term 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 handl er (inhalation and dermal) and post

application (dermal) exposures are assessed for ETU.

Occupational Handlers

The last comprehensive occupational assessment for mancozeb was conducted in 2005 3 

### for the

mancozeb RED. The 2005 RED identified non

- cancer ri sk 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 occupation al 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 scenar ios (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 Reregi stration Eligibility Decision Document. PC Code 014504; DP Barcode: D317368. T. Dole; 5/31/05.

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 17 of 43 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 Expos ure 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

- exposu re

data.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. T he previ ous data requirement s (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 Force 4



### .

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. Rivera

Lupiáñez , 11/15/11, D391948). All h andler 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: c ompared 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 can cer risks for all scenarios were estimated in the

10

- 6 

### to 10

- 7 

### range 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 ris k mitigation ( e.g., gloves

, respirators, or other engineering control measures ). This included the requirement to add a respirator to all the current DF labels. A ll mixer/loa der and applicator cancer risk

estimates for mancozeb

- derived ETU were in the 10

- 8 

### to 10

- 6 

### range at some level of ris k mitigation ( e.g., water soluble bags, res pirators, 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, b ased 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)

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 18 of 43 updated HED policies (i.e., updated transfer coefficients and updated assessment methodology for greenhous e grown crops).

In 2011 HED conducted a n occupational post

- application assessment for proposed uses on lettuce, peppers, almonds, broccoli, and cabbage ( D391948 )

. Using chemical

- specific residue

data , a ll 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 der mal 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 studies 5



### . These transfer coefficients were updated in 2012 based on a reanalysis and submission of new monitoring data. HED will incorp orate 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 mai ntenance 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

- ap plication activities (e.g., maintenance activities, harvesting of sod, and transplanting/planting sod) that have a higher occupational exposure potential than what has been

a ssessed previously. An occupational assessment will be performed for dermal post

- a pplication exposure to ETU ( mancozeb

- derived ) for sod farm activities.

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

C omprehensive 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 tran sferable 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/pestici des/science/post

- app

- exposure

- data.html

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 19 of 43 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 wil l be thoroughly reviewed and considered during registration review

. In addition to the resul ts 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 Mancoze b: 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 Har monization

Permanent tolerances are established under 40 CFR §180.176(a) for mancozeb residues (measured as carbon disulfide (CS 2 

### )) 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 C anadian or Mexican maximum residue limits (MRLs) established for the residues

of mancozeb or EBDC fungicides i n/on raw agricultu ral 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 CS 2 ). 

### All U.S. tolerance levels are harmo nized 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 base d 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

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 20 of 43 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, se e 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 inter agency 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 safflo wer seed or propagation stock treatment).

Guideline 860.1520 Processing Studies (wheat (middlings and germ), barley (pearled), oats (rolled), a nd 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 assessment s of the EBDC pesticides, including mancozeb . The 1990 EBDC market basket survey previously used to refine the dietary assessments m ay be outdate d, 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 diet ary 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, pro cessing studies), which will likely result in significantly greater risk estimates that may exceed the levels of concern.

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 21 of 43 References

D317368, Mancozeb: 2nd Revised Occupational and Residential Exposure Assessment and Recommendations for the Reregistrati on 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).

D 391948, 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.

D397 306, Estimated Drinking Water Concentrations of ETU Degradate (Ethylene

- thio

- urea
D egradate) of Mancozeb from its Proposed New Use on Walnuts for Use in Human Health Risk

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

.

D412678, Ethylene Thiourea (ETU); Aggregate Hu man 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

.

D 412565 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, 0 7 / 0 1/20 13.

D4 12677 , 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 , M etiram : Human Health Risk Assessment Scoping Document in Support of Registration R eview, D. Drew, 6 /2/2015.

Attachments

Attachment 1. Chemical Identity

Attach ment 2. Toxicity Profile Tables Attachment 3. Endpoint Tables

Attachment 4. International Residue Limits

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 22 of 43 Attachment 1. Chemical Identity

Table A 1. 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

E thylenethiourea

Table A1.2 Physico chemical Properties of Mancozeb*

Parameter Value Reference

Melting point/range Decomposes at 150 oC RCB No. 4368, 11/9/88, G. Makhijani pH 6.5 (25% slurry in water)

Density 0.41 g/cc (packed)

Water solubility 1.1 μg/mL at room temperature

Solvent solubility Insoluble in most organic solvents DEB No. 4689, 12/16/88, G. Makhijani

Vapor pressure Not applicable; negligible RCB No. 4368, 11/9/88, G. Makhijani

Dissociation constant, pK

a Not applicable; does not dissociate DEB No. 4750, 1/24/89, G. Makhijani

Octanol/water partition coefficient, Log(K OW ) 3.24 at room temperature RCB No. 4368, 11/9/88, G. Makhijani

UV/visible absorption spectrum Not available

* 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 deco mposes 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 da ys. 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.

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 23 of 43 Attachment 2. Toxicity Profile Tables

Toxicity Profiles MANCOZEB

Table A 2.1 Acute Toxicity Data for Mancozeb

Guideline No. Study Type MRID # Results Tox. Category

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

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

870.1300 Acute Inhalation 00142522 LC 50 > 5.14 mg/L IV

870.2400 Eye Irritation 00142522 corneal involvement clearing in < 7 days III

870.2500 Skin Irritation 00142522 Negative IV

870.2600 Dermal Sensitization 40469501 Negative N/A



### Table 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) 00 160704 (1986)

Acceptable /guideline

0, 30, 60, 125, 250, or 1000 ppm males: 1.78, 3.4 9, 7.42, 14.98, 57.34 mg/kg/day females: 0, 2.20, 4.3 8, 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, mic roscopic changes in liver and thyroids, increased thyroid and liver w eigh t

870.3100 90

- Day oral toxicity

(CD

- 1 mouse) 00 154192 (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), increase d aniline hydroxylase activity (both sexes)

870.3150 90

- Day oral toxicity

(Beagle dog) 00 160705 (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.

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 24 of 43 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) 001 60782 (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 m g/

k g/ d ay : maternal mortal ity (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. Developme ntal LOAEL=80 mg/kg/day, based

on abortions.

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 25 of 43 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 hy perplasia.

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, o r 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 lev els) NOAEL in females=7.02 mg/kg/day, LOAEL in females=29.24 mg/kg/day, based on

anemia.

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 26 of 43 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 high

dose males (0/60, 0/62, 2/60, 2/58, 14/61) and females (0/62, 0/60, 0/62, 1/61, 4/61).

870.4 2 00 Carcinogenicity

(CD

- 1 mouse) 41981801 (1991)

Guideline/unacceptable

ma les: 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

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 27 of 43 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 407 7 8901 (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, 1.3 5, 8.21, 49.7, or 339 mg/kg/day females: 0, 1.6 7, 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 m kd) : Female mortality, ↓ BW in males ( ↓ 45%); l c inical 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

decr eased pup body w eight (11

- 22%) in range

finding study

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 28 of 43 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) 00 159611 (1986)

00 159612 (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)

00 127950 (1980) Acceptable/guideline (combined) Dermal absorption = 1%

870.7800 Immunotoxicity

[Crl:CD(SD) rat] 4 8794801 (2012)

Acceptable/Guideline Negative for Immunotoxicity

Special Studies

OECD 443 Extended one

generation 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) 00 0160704 /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.

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 29 of 43 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) 00 154192 /1985

Una cceptable/ G uideline 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 thy roid 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 Range

finding (Beagle d og ) 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 th yroid 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] 00 093929 /1980

Acceptable/non

- guideline Maternal NOAEL = <50 mg/kg/day Maternal LOAEL = 50 mg/kg/day, based on decreased body weight gain (↓36%)

.

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 decrea sed fetal weight (↓13%)

.

Only one dose group was included in the study.

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 30 of 43 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] 4593760 1 /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: oligod actyl, domed head, retarded ossification of the skull occurred; a t 80 mg/kg/day: coloboma of the eyelids, hemimelia, syndactyl, cleft palate, ectopic kidney, rudimentary calvarium, short tail, scoliosis and several types of skeletal

anomalies occurred. Decreased fetal weight was noted at 40 mg/kg/day in group I (↓10%) and group III (↓21%) and at 80 mg/kg/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 comparab le 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 increase d 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, dome

shaped heads, and pup mortality.

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 31 of 43 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, hydrocephal y
, microphthalm i a, 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;

gr eatest 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, meningo r rhea, 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/da y 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

Page 32 of 43 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 / Non

guideline

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 high

dose 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 at tained.

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

Page 33 of 43 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, m ortality, 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 live rs. 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 ) 403126 01/1987

Acceptable Dermal absorption = 26%

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 34 of 43 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 one

generation reproductive toxicity

[Crl:CD(SD) rat] 49140301/2013 Under Review

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 35 of 43 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 P O D Safety Factors RfD, PAD, L O C Study and Toxicity

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

500 mg/kg/day UF A = 10x

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

mg/kg/day

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

Acute Dietary

(Children < 6 years) NOAEL =

500 mg/kg/day UF A = 10x

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

5 mg/kg/day

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

Acute Dietary

(Females 13

– 49 years) NOAEL =

128 mg/kg/day UF A = 10x

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

mg/kg/day

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

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

malformations Mancozeb Chronic Dietary Exposure Chronic Dietary

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

4.83 mg/kg/day UF A = 3x

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

mg/kg/day

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

Chronic Dietary

(Females 13

- 49 years and

Children < 6 years) NOAEL =

4.83 mg/kg/day UF A = 3x

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

mg/kg/day

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

Mancozeb Incidental Oral Exposure

Short

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

9.24 mg/kg/day UF A = 3x

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

Mancozeb Residential Dermal Exposure Dermal (Short

- , and Intermediate

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

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

Dermal (Long

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

4.83 mg/kg/day

DA = 1% UF A = 3x

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

Dermal (Long

Term) (Females

13

- 49 years and

Children < 6 years) NOAEL =

4.83 mg/kg/day

DA = 1% UF A = 3x

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

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 36 of 43 Table A.3.1 Summary of Toxicological Doses and Endpoints for MANCOZEB Used in Previous Dietary and Non

- Occupational Human Health Risk Assessments
Exposure P O D Safety Factors RfD, PAD, L O C 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 ) UF A = 3x

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

Inhalation (Females 13

- 49 years and

Children < 6 years) NOAEL =

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

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

Mancozeb Cancer Cancer (all routes) Mancozeb’s potential for carcinogenicity is due to the formation of the metabolite

, ETU

, which is

classified as a probable human carcinogen (B2). Mancozeb’s cancer risk is calculated by estimating exposure to mancozeb

- derived ETU and using the ETU cancer potency factor (Q 1 * ) of 6.01 x 10

- 2 (mg/kg/day)

- 1 to quantitate risk. Point of Departu re (POD) = A data point or an estimated point that is derived from observed dose

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

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

- term study for long

- term risk

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

Table A 3.2 Summary of Toxicological Doses and Endpoints for MANCOZEB Used in Previous Occupational

Human Health Risk Assessments
Exposure PO D Safety Factors RfD, PAD, LO C Study and Toxicity

Mancozeb Occupational Dermal Exposure Dermal (Short

- , and

Intermediate

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

- Term)

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

DA = 1% UF A = 3x

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

based on thyroid toxicity

Dermal (Long

- Term)

(Females 13

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

DA = 1% UF A = 3x

UF H = 10x

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

based on thyroid toxicity

Mancozeb Occupational Inhalation Exposure (all durations)

Inhalation

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

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

Inhalation

(Females 13

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

UF H = 10x

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

Mancozeb Cancer

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 37 of 43 Table A 3.2 Summary of Toxicological Doses and Endpoints for MANCOZEB Used in Previous Occupational

Human Health Risk Assessments
Exposure PO D Safety Factors RfD, PAD, LO C 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 (Q 1 * ) of 6.01 x 10

- 2 (mg/kg/day)

- 1 to 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

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

Table A 3 .3 Summary of Toxicological Doses and Endpoints for ETU for Dietary and Non

- Occupational Human

Healt h Risk Assessments Exposure PoD Safety Factors RfD, PAD, LO C Study and Tox

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

identified.

Acute Dietary (Females 13

- 49 years old) NOAEL= 5

mg/kg/day UF A = 10x

UF H = 10x FQPA UF DB = 10x Acute RfD = 0.005

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 UF A = 10x

UF H = 10x FQPA UF DB = 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 UF A = 10x

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

mg/kg/day

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

ETU Incidental Oral Exposure

Short

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

mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 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

Intermediate

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

mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 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

Page 38 of 43 Table A 3 .3 Summary of Toxicological Doses and Endpoints for ETU for Dietary and Non

- Occupational Human

Healt h Risk Assessments Exposure PoD Safety Factors RfD, PAD, LO C Study and Tox

Dermal Short and

Intermediate

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

mg/kg/day UF A = 10x

UF H =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

Intermediate

Term (Females

13

- 49 years old) NOAEL= 5

mg/kg/day UF A = 10x

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

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

Term (Females 13

- 49 years of age and

Children < 6 years) NOAEL=

0.18 mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 Dog Chronic Oral Toxicity MRID 42338101 (1992) LOAEL= 1.99 mg/kg/day based on thyroid toxicity

Dermal Long

Term (Adult Males,

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

0.18 mg/kg/day UF A = 10x

UF H =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 Intermediate

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

mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 4

- week range

- finding dog study

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

Inhalation Short

and Intermediate

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

mg/kg/day UF A = 10x

UF H =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 Intermediate

Term (Females

13

- 49 years old) NOAEL= 5

mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 Developmental Rat Toxicity MRID No. 45937601 (1973)

LOAEL = 10 mg/kg/day, based on hydrocephaly and other malformations Inhalation Long

Term (Females

13

- 49 years of age and Children < 6 years) NOAEL=

0.18 mg/kg/day UF A = 10x

UF H =10x FQPA UF DB = 10x LOC = 1000 Dog Chronic Oral Toxicity MRID 42338101 (1992)

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

Inhalation Long

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

0.18mg/kg/d

ay UF A = 10x

UF H =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) Q 1 * = 6.01 x

10

- 2 (mg/kg/day)

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

- dose extrapolation

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

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

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

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 39 of 43 exposures. NOAEL = no ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

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

Table 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

Intermediate

Term (Adult Males,

Females >49 years) NOAEL= 7

mg/kg/day UF A = 10 x

UF H =10x LOC = 10 0 4

- week range

- finding dog study MRID 41863401 (1989)

LOAEL= 34 mg/kg/day based on thyroid toxicity

Dermal Short and

Intermediate

Term (Females

13

- 49 years old) NOAEL= 5

mg/kg/day UF A = 10x

UF H =10x

UF DB = 10x LOC = 1000 Developmental Rat Toxicity

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

Term (Females 13

- 49 years of age) NOAEL=

0.18 mg/kg/day UF A = 10 x

UF H =10x

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

Term (Adult Males,

Females >49 years) NOAEL=

0.18 mg/kg/day UF A = 10 x

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

ETU Occupational Inhalation Exposure

Inhalation Short

and Intermediate

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

mg/kg/day UF A = 10 x

UF H =10x LOC = 10 0 4

- week range

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

Inhalation Short

and Intermediate

Term (Females

13

- 49 years old) NOAEL= 5

mg/kg/day UF A = 10x

UF H =10x

UF DB = 10x LOC = 1000 Developmental Rat Toxicity

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

Term (Females

13

- 49 years of age) NOAEL=

0.18 mg/kg/day UF A = 10 x

UF H =10x

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

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

0.18mg/kg/da

y UF A = 10 x

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

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

10

- 2 (mg/kg/day)

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

- dose extrapolation

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

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

- response data and

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

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 40 of 43 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.

### Mancozeb Registration Review Human Health Scoping Document D425216

Page 41 of 43 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 Mexico 2 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

det ermined by measuring only those

mancozeb residues convertible to and expressed in terms of the degradate carbon

disulfide. None Total dithiocarbamates, determined as

CS 2 , evolved during acid digestion and expressed as mg CS 2 /kg

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

US Canada Mexico 2 Codex

Almond 0.1 0.1 (*) 3

Almond, hulls 4 20 5
Apple 0.6 5 pome fruits 3
Asparagus 0.1 0.1 3
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, dry 3 (MRL mainly based on mancozeb) Beet, sugar, dried pulp 3.0 Beet, sugar, roots 1.2 0.5 sugar beet 3
Beet, sugar, tops 60

Broccoli 7 Cabbage 9 5 cabbages, head 3

Canistel 15.0 Cattle, kidney 0.5 0.1 edible offal (mammalian) 3 (MRL mainly based on mancozeb) Cattle, liver 0.5 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 fruits 3

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Page 42 of 43 Table A4.1 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
U.S. Canada Mexico 2 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 mainly based on mancozeb) Goat, liver 0.5 Grape 1.5 5 3 (MRL mainly based on mancozeb) Hog, kidney 0.5 0.1 edible offal (mammalian) 3 (MRL mainly based on mancozeb) Hog, liver 0.5 Horse, kidney 0.5 0.1 edible offal (mammalian) 3 (MRL mainly based on mancozeb)) 3 Horse, liver 0.5
Lettuce, head 3.5 0.5 3 (MRL mainly based on mancozeb and maneb)
Lettuce, leaf 18 10 cos lettuce 3
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, leek 3 (MRL mainly based on mancozeb) Papaya 10 5 3

Peanut 0.1 0.1 (*) 3
Peanut, hay 65 5 peanut fodder 3

Pear 0.6 5 pome fruits 3
Pepper 12 1 peppers, sweet (including pimento or pimiento) 3 10 peppers Chili, dried 3

Potato 0.2 0.2 3
Poultry, kidney 0.5 0.1 poultry edible offal of 3
Poultry, liver 0.5 Quince 0.6 5 pome fruits 3
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 mainly based on mancozeb) Sheep, liver 0.5 Sorghum, grain, forage 0.15 Sorghum, grain, grain 0.25 Sorghum, grain, stover 0.15 Star apple 15.0 Sugar apple 3.0 Tangerine 1 10 10 mandarins 3

Tomato 2.5 2 5

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Page 43 of 43 Table A4.1 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
U.S. Canada Mexico 2 Codex Vegetable, cucurbit, group 9 2.0 2 cucumber 3 0.5 melons, except watermelon 3 (MRL mainly based on mancozeb) 0.2 pumpkins 3 1 squash summer 3 watermelon 3 0.1 winter squash 3

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, dry 3 (MRL mainly based on mancozeb) Completed: M. Negussie; 03/10/2015

1 There 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 §1 80.1(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