UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: April 15, 2015 

SUBJECT: Mancozeb: Tier I (Scoping) Review of Human Incidents 

PC Code: 0 14504 DP Barcode: 0426276 

Decision No.: 499273 

Petition No.: NA 

Ris k Assessment Type: NA 

TXR No.: NA 

MRID No.: NA 

Registration No.: NA 

Regulatory Action: NA 

Case No.: NA 

CAS No.: 8018-01-7 

40 CFR: NA 

FROM: Elizabeth Evans, Environmental Protection Specialist 

Toxicology and Epidemiology Branch 

Health Effects Division (7509P) 

and 

Ver.Apr.OS 

Shanna Recore, Industrial Hygienist f /J ~ • . _ O. ,.. fl . • 

Toxicology and Epidemiology Branch ~~ 

THROUGH: 

TO: 

Health Effect Division (7509P) 

and . /} Ile 

Carol Christensen, Epidemiologis ~ ""'"'""'""'" 

Toxicology and Epidemiology Branch 

Health Effects Division (7509P) 

,· 1 }~ /'9ofi'/GulS 

David Miller, Acting Branch Chief v'c//11~ 

Toxicology and Epidemiology Branc 

Health Effects Division (7509P) 

Matthew Lloyd, Risk Assessor VII 

Risk Assessment Branch 

Health Effects Division (7509P) 

and 

Steven Snyderman, Chemical Review Manager 

Risk Management & Implementation Branch 3 

Pesticide Re-evaluation Division (7508P) 

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Summary and Conclusions 

With regard to incident data reported to IDS, SENSOR-Pesticides. and NPIC there is a relatively 

low to moderate frequency and severity for mancozeb cases overall. There are, however, a 

number of epidemiological findings regarding mancozeb that will be thoroughly reviewed and 

considered prior to reregistration. These include both the results of the Agricultural Health Study 

(AHS) and a systematic review of the human health effects of mancozeb (reproducti ve toxicity 

specifically) produced by a consortium of science-poli cy investigators under the REACH 

program. For this reason, HED will perform a Tier II assessment of the human health effects of 

mancozcb. including the synthesis of information available in the human population regarding 

mancozeb exposure, to support the integration of this information with the experimental 

toxicological data available. 

Detailed Review 

I. ACTION REQUESTED 

This revie>vv is intended to fulfill our requirement to docket summaries of incident data that were 

reported to the Agency, as well as to ensure human incident data and the Agricultural Health 

Study (AHS) particularly are part of the problem formulation phase of registration review. 

Reports of adverse health effects allegedly due to a specific pestic ide exposure (i.e., an 

.. incident .. ) are largely self-reported and therefore. generally speaking. neither exposure to a 

pesticide or reported symptom (or the connection between the two) is validated or otherwise 

confirmed. Typically. causation cannot be definitively determined based solely on incident data. 

However. incident information can be an important source of feedback to the Agency: incidents 

of severe outcomes -- or a suggested pattern or trend among less severe incidents -- can signal to 

the Agency a need to further investigate a particular chemical or product. Observational 

epidemiology studies relate the risk of disease, e.g.. cancer, and exposure to an agent such as a 

pesticide product in the general population or specific sub-groups I ike pesticide applicators. In 

addition, this memorandum includes a brief review of a voluntarily submission of a systematic 

review to the docket of "'An Updated Look at Mancozeb: Concerns about Farmworker 

Reproductive Health" (D425202).by participants in the "Reach the Decision Makers Program 

(REACH) consortium concerning the reproductive toxicity of mancozeb 

II. BACKGROUND 

Mancozeb is a member of the ethylene bisdithiocarbamate (EBDC) group of fungicides, which 

includes the related active ingredients maneb and metiram. Mancozcb is used in agricultw-e, 

professional turf management. and horticulture and is used on a wide variety of food/feed crops, 

including tree fruits. vegetable crops, field crops. and grapes. ornamental plants, and sod farms. 

Other uses include greenhouse grown flowers and ornamentals. and seed and seed piece 

treatment. Approximately 5.6 million pounds of mancozeb are used annually, with the greatest 

use on potatoes and apples. Mancozeb is also used extensively on grapes, onions, pears, 

tomatoes. squash, and melons. Mancozeb is not a Restricted Use Pesticide . 

Page 2 of 9 
For this evaluation, both the OPP Incident Data System (IDS) and the Centers for Disease 

Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) 

Senti nel Event otification System for Occupational Risk-Pesticides (SENSOR) databases were 

consulted for pesti cide incident data on the acti ve ingredient mancozcb (pc code: 014504). 

Additionally. EPA reviewed for this memo the incident report on mancozeb provided by the 

ational Pesticide Information Center (NPIC). The purpose of the database search is to identify 

potential patterns in the frequency and severity of the heallh effects attributed to mancozeb 

exposure. Mancozeb is included in the AHS and a brief compilation of findings from the 

Agricultural Health Study regarding mancozeb is provided in this document. 

A consortium of advocate-scientist-pol icy professionals prepared a systematic review of the open 

literature regarding the developmental and reproductive toxicity and endocrine effects of 

mancozeb, entitled, An Updated Look at Mancozeh: Concerns about Farmworker Reproductive 

Health''. EPA plans to conduct a more in-depth review the experimental and observational 

studies identified by EPA as well as members of the public (e.g. the REACH systematic review) 

as part of an analysis to be performed at the time of the human health risk assessment for 

mancozeb. 

111. INCIDENTS RESULTS/DISCUSSION 

a. IDS (Incident Data System) 

opp· s ID includes reports of alleged human health incidents from various sources, including 

mandatory Federal Insecticide. Fungicide and Rodenticide Act (FIFRA) Section 6(a)(2) reports 

from registrants, other federal and state health and environmental agencies, and individual 

consumers. Since 1992, OPP has compiled these reports in I OS. IDS contains reports from 

across the U.S. and most incidents have all relevant product information recorded. Rep011s 

submitted to the ID S represent anecdotal reports or allegations only, unless otherwise stated in 

the report. 

IDS records incidents in one of two modules: Main IDS and Aggregate IDS: 

o Main IDS contains incidents resulting in higher severity outcomes and provides 

more detail with regard to case specifics. This system stores incident data for 

death. major and moderate incidents, and it includes infom1ation about the 

location, date and nature of the incident. Ma in ID inc idents involving only one 

active ingredient (as opposed to pesticide products with multiple active 

ingredients) are considered to provide more certain information about the 

potential effects of exposure from the pesticide. 

o Aggregate IDS contains incidents resulting in less severe human incidents (minor. 

unknown. or no effects outcomes). These are reported by registrants only as 

counts in what are aggregate summaries. 

Page 3 of 9 
' For the Main IDS, from January I, 2010 to December 30, 20 14. there were 0 incidents reported 

for the single chemical only in the database. There were 4 incidents reported involving than one 

active ingredient. Three of these incidents were classified as moderate severity and one incident 

was classified as having .. no or unknown symptoms:· rt should be noted there were two 

additiona l incidents that were reported as lawsuits to IDS that are not considered in this report. 

In Aggregate IDS. from January l, 2010 to December 30, 20 14. there were 26 incidents reported 

involving mancozeb. These incidents were classified as minor severity. Overall there are few 

incidents involving mancozeb reported to IDS. 

In addition to the IDS query performed, a study, entitled .. Health and Environmental Assessment 

of Sitio Camocaan, Hago noy, Davao Del Sur," (MRTD 477530-01) was submitted by DuPont to 

comply with 40 CFR § 159 (concerning reporting requirements by registrants on risk/benefit 

information). This study covered incidents occurring prior to 2009. It was recently received by 

EPA and will be added to our IDS and reviewed by HED at a later date for incorporation into 

OPP's Human Tl ealth Risk Assessment (HHRA) for mancozeb. 

b. SENSOR-Pesticides 

The SENSOR-Pestic ides database covers 12 states from 1998-20 11. although reporting varies 

from state to state. Cases of pesticide-related illnesses are ascertained from a variety of sources, 

including: reports from local Poison Control Centers, state Department of Labor workers' 

compensation cla ims when reported by physicians, repo11s from State Departments of 

Agri culture. and physician reports to state Departments of Health. Although both occupational 

and non-occupational incidents are included in the database, SENSOR-Pesticides focuses on 

occupationa l pesticide incident and is of particular value in providing that information. The state 

coordinator at each of the 12 respective state Departments of" Health conducts case follow-up 

activities such as obtaining medical records to verify symptoms and severity. Using standardized 

protocol and case definitions derived from poison center reporting. the state SENSOR-Pesticide 

coordinator enters the incident infom1ation into the state-based system which is sent to NIOSH 

arnrnally to be aggregated. 

A query of SENSOR-Pesticides 1998-20 11 identifies a total o f 84 cases involving mancozeb. Of 

these, 35 in volve the single active ingredient for analysis. The 35 single ai cases stemmed from 

24 events. everal (5) multiple case events were identified. Thirty-one cases (94%) were workrelated. Eleven cases (33%) were directly exposed from an aerial applications in process. 

Seventeen of the 35 cases (49%) involved females. 

With regard to severity of cases: no fatalities were reported. two high severity cases were 

repo11ed, four moderate severity cases were reported and 29 low severity cases were reported. 

Both of the high seve1ity cases (and one moderate case) were exposed to mancozeb from the 

same aerial application overhead while the individuals were conducting routine farm work. One 

high severity case reportedly lost 75 work days fo llowing this exposure event (California, 2004). 

These two high severity cases and the moderate severity case in the same exposure event 

reported multipl e symptoms in volving respiratory, gastrointestinal and cardiovascular effects. 

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All three of these cases experienced a slow heartbeat (bradycardia). Two of them also had chest 

pain and one had palpitations. 

A summary of symptoms reported is provided in Table I. Table 2 provides case details for each 

of the 35 single ai cases involving mancozeb reported to SE SOR-Pesticides from 1998 - 2010. 

The most commonly reported body system effected was nervous system (primarily headache) 

followed by dermal then ocular symptoms. It is notable that a total of eight cases experienced 

cardiovascular symptoms. Specifically, four cases (all cases from event # NY01353 that occurred 

in New York in 20 I 0) had chest tightness and presented '"abnormal electrocardiograms"; three 

cases had slow heattbeat (bradycardia); and two had chest pain. 

Table l. SENSOR-Pesticides 1998-2011 

Reported Health Effects fo r Mancozeb Cases 

(N=35) 

Health Effect # of Times Reported 

Nervous System 16 

Dermal 15 

Ocular 14 

Respiratory 11 

Gastrointestinal 9 

Cardiovascular 8 

Renal 0 

• Cases may report multiple health effects 

Multiple Case Exposure and Illness Events 

I. Event # NYO 1353 in 20 I 0: Five cases became ill a~er the cherry trees outside of their 

office building were sprayed with the product Pentathlon LF (reg # 6769-38). Cases 

were exposed while conducting daily work practices and they inhaled the pesticide fumes 

through the ventilation system. One case was moderate severity and four were low 

severity. These five cases were coded as having '"no label violation identified but person 

still became ill"' 

2. Event # CA 1706 in 2004: Three cases were conducting farm work and were sprayed by 

an aerial application overhead. Two high severity and one moderate severity case. 

3. Event # CA 171 0 in 2004: Three cases were exposed to drift; two fannworkers working 

in a lield and their supervisor who entered the area to evacuate the workers. All three 

cases were low in severity. 

4. Event # TX02016 in 200 I: Three cases were exposed from an aerial application that flew 

over the field they were in: all three were low in severity. 

5. Event # TX02060 in 2001: Two cases were exposed to the pesticide from an aerial 

application that had leaking equipment: both were low in severity. 

Page 5 of 9 
Violation Citations 

A tota l of 17 of the cases involved FIFRA inspections after the event. Twelve of these cases Jed 

to violations cited. Nine cases with violations cited were in Florida where the agricultural 

employer was c ited for failure to provide PPE. incomplete application records, and failure to post 

pesticide information. In the remaining five cases inspected. no violation was found. These five 

.. no violations found .. were the office workers exposed via the ventilation system in ew York in 

20 10. 

Summary of SENSOR Findings 

There are 35 single ai mancozeb cases reported in SEN OR; 82% were low in severity. 

I lowevcr. eight cases experienced cardiovascular symptoms (i ncluding four low-severity cases, 

three that had "abnormal electrocardiograms"). Five multiple case exposure events are recorded 

(involving a total of 16 cases) involving mancozeb. The majority (67%) of these cases occurred 

in agricultural settings, yet 15% happened in an office setting after an appli cation to the trees 

outside around the parameter building. 

c. National Pesticide Information Center (N PIC) 

The National Pesticide Information Center or PIC is a cooperati ve effort between Oregon State 

Uni versity and EPA which is funded by EPA to serve as a source of objective, science-based 

pesticide information and respond to inquiries from the public and to incidents. NPIC functions 

nationally during weekday business hours through a toll-free te lephone number in addition to the 

internet ('-'vww.npic.orst.edu) and email. Similar to Poison Control Centers. PIC's primary 

purpose is not to collect incident data. but rather to provide information to inquirers on a wide 

range of pesti cide topics, and direct callers for pesticide incident investigation and emergency 

treatment. Nevertheless PIC does collect information about incidents (approximately 4000 

incidents per year) from inquirers and records that information in a database. NPIC is a source 

of national inc ident information but generally receives fewer reports than IDS. Regardless, if a 

high frequency is observed in IDS, NPIC provides an additional source of information to see 

whether there is evidence of consistency across national data sets or possibly duplication and 

additional information about the same incident(s). 

From 1/1 / 10 to 12/3 1/ 14, six incidents were reported to NPIC involving mancozeb. Of the six 

reported incidents, 4 were reported as symptomatic and two were asymptomatic exposures. 

NPIC estimates a certainty index as to whether an incident (including reported symptoms) was 

either definitely, probably, possibly. or unlike ly to have been caused by the reported exposure to 

a pesticide, or whether the incident was unrelated to pesticides or if the incident was 

unclassifiable. One incident was classified as probable with minor severity (ocular irritation); 

one case was classified as unlikely with moderate but atypical symptoms; one case was classified 

as possible ' ith moderate severity (dermal irritation); one cases was classified as possible with 

minor severity; and two cases were unclassifiable/asymptomatic. 

The probable case with minor severity involved a caller who got a mancozeb product in her eyes 

from a bottle that was not properly closed. Caller reported it bumcd a little and she immediately 

rinsed as per the label instructions. 

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The possible case with moderate severity involved a caller that reported he was exposed to 

mancozeb while golfing and wanted to report the incident lo NPIC. Caller reported that the 

course where he plays golf sprays mancozeb every Wednesday evening and that during the week 

prior to his call lO PIC he played a game of golf on Thursday morning while the course 

vegetation was still wet. Caller reported that two days later he developed an itchy. blistering. 

poison-ivy like rash on his ankles, legs, hands and face and that this rash was persisting at the 

time of his call to PIC. 

II. Huma n Health Effects in the Human Population (Epidemiology Studies) 

At this time, EPA is aware of several different epidemiological investigations of potential human 

health effects of mancozeb use and exposure in the human population. This includes the 

Agricultural I lcalth Study (AHS) and a voluntarily submission by a consortium of science 

investigators and policy advisors of an analysis of the reproductive toxicity of mancozeb under 

the auspices of the Reach the Decision Makers Fellowship program (the REACH program). 

These data will be comprehensively identified and thoroughly reviewed in the development of 

the human health risk assessment (HHRA) for mancozeb, i.e., EPA will develop a Tier II human 

incident and epidemiology report at the time of the HHRA. 

Briefly. the analysis submitted by REACH, .. An Updated look at Manco::eb: Concerns about 

Farmworker Reproductive Health" was a comprehensive systematic identification, evaluation 

and integration of in vitro. in vivo, and epidemiology studies regarding the potential reproductive 

toxicity of mancozeb, and includes REACH policy recommendations. Regarding the 

epidemiology data. REACH researchers identified 14 studies published between 2001 and 2007 

investigating the potential reproductive toxicity of mancozeb. Most of these epidemiological 

evaluations were case-control studies in design. but there were three cohort studies identified. ,. 

These evaluations of reproductive toxicity included assessment of health outcomes such as fetal 

loss (Arbuckle. Lin, & Mery, 2001; Garry ct al., 2002), bi11h defects (Rull, Ritz, & Shaw, 2006) 

and female reproductive effects (Farr et al., 2006; Farr, Cooper, Cai, Savitz, & Sandler, 2004; 

Lacasana et al., 2006) among other reproductive toxicity endpoints. Although EPA has not yet 

evaluated the REACH report and will do so for the HllRA of mancozeb, the REACH authors 

applied systematic review techniques to identify. evaluate and synthesize information (i.e., 

critically evaluating and rating individual study quality to inform overall synthesis and 

combining information from laboratory-based. animal experimental data, and human 

epidemiology data). EPA will evaluate the REACH report methods and results. including an 

EPA assessment of each study, as well as update the literature review, as needed, at the time of 

the HHRA for mancozeb. 

In addition to information regarding reproductive toxicity. the epidemiological database for this 

chemical includes information as to potential carcinogenic effects and other non-cancer effects of 

mancozeb as studies in the Agricultural Health Study (Al IS). The AHS is a high quality, 

prospective epidemiology study evaluating the link between pesticide use and various health 

outcomes including cancer. The AHS includes private and commercial pesticide applicators and 

their spouses. The AIIS includes information on use of 80 different pesticide active ingredients 

commonly used in agriculture. Mancozeb is included in the AHS. 

Page 7 of 9 
There are several AHS epidemiological investigations which identified a potential role for 

mancozeb, among other compounds, in specific cancer and non-cancer health outcomes. Within 

the AI-IS, Dennis (20 10) compared the incidence of cutaneous me lanoma by pesticide exposure 

in a nested case control study. Controlling for age, sex and other related pesti cides, authors 

reported an elevated odds of melanoma: odds ratio 2.4 (95% confidence interval (95% CI) 1.2, 

4.9) (p=0.006) among 27 1 cases of melanoma and 24, 704 non-cases. Goldner and colleagues 

(20 10) reported an elevated odds of thyroid disease (both hyper- and hypo-thyroidism) among 

female participants in the AHS (N=l 6, 529): in this cross-sectional analysis (exposure and 

disease ascertained simultaneously; temporal occurrence cannot be determined with certainty) 

researchers reported a statistically significant 2-fold elevated odds of thyroid disease (both 

hyper- and hypo-thyroid disease) among female mancozeb users. Investigating further the 

published link between (any) fungicide use and retinal degeneration (RD), Kirrane et al. (2005) 

reported a non-statistically significant 40% increased odds of RD among female participants in 

the AHS (N=3 l ,173) comparing those who reported use of mancozeb to those who reported no 

use of mancozeb. Lastl y, Farr et al. (2004) reported statistically significant evidence of menstrua l 

cycle disruption among female AHS participants who reported exposure to mancozeb or maneb 

(no estimate of mancozeb-only epidemiological risk). Among users of mancozeb OR maneb, the 

authors reported odds of a long- or missed cycle increased 2.5 to 4.5-fold. after controlling for 

age. body mass index, smoking, and physical education. EPA notes that the study by Farr (2004) 

were included in the REACH materials presented to EPA in April 20 14. 

IV. CONCLUSION 

The incident data reported to IDS, SE SOR-Pesticides, and PIC identifies a re lati vely 

low/moderate frequency and severity for mancozeb cases overall. There are. however, a number 

of epidemiological findings regarding mancozeb that will be thoroughly reviewed and 

considered at the time of the development of the HHRA for mancozeb. These include studies of 

the potential reproductive toxicity of mancozeb summarized by participants of the REACH 

program and submitted to EPA voluntarily as well as the findings of a number of studies 

published under the auspices of the AHS, among other information. These data will be 

considered with other information regarding human health effects, and integrated with the 

experimental toxicological data for mancozcb within the HHRA. 

Page 8 of9 
References 

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pesticide exposure on the risk of spontaneous abortion in an Ontario fa1m population. 

Environmental Health Perspectives. 109(8), 851-857. 

Dennis, L. K .. Lynch. C. F., Sandler, D. P., & Alavanja. M. C. (20 I 0). Pesticide use and 

cutaneo us mel anoma in pesticide applicators in the agricultural heath study. Environ 

Ilea/th Perspectives. 118(6). 812-8 17. 

Farr, S., Cai, J., Savitz, D., Sandler, D., Hoppin, J., & Cooper, G. (2006). Pesticide exposure and 

timing of menopause: the Agricultural Health Study. Am . .J. Epidemiol.. 163(8), 731-742. 

Farr, S., Cooper, G .• Cai, J., Savitz, D., & Sandler, D. (2004). Pesticide use and menstrual cycle 

characteristics among premenopausal women in the Agricultura l Health Study. Am . ./. 

Epidemiol.. 160(12), 1194-1204. 

Garry, V. F., Harkins, M. E., Erickson, L. L., Long-Simpson, L. K., Holl and, S. E., & Burroughs, 

B. L. (2002). Birth defects, season of conception, and sex of children born to pesticide 

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Perspectives. 110 Suppl 3, 441-449. 

Goldner, W. S., Sandler, D. P., Yu, F., Hoppin. J. A .. Kamel, F., & Levan, T. D. (2010). 

Pesticide use and thyroid disease among women in the Agri cultural Health Study. Am. J 

Epidemiol. 171(4), 455-464. 

Kirrane, E., Hoppin, L Kamel, F., Umbach. D., Boyes, W .. DeRoos. A., et al. (2005). Retinal 

degeneration and other eye disorders in wives of farmer pesticide applicators enrolled in 

the agricultural health study. Am . .J. Epid.. 161( 11 ). 1020-1 029. 

Lacasana. M., Vazq uez-Grameix. H., Borja-Aburto. V. H., Blanco-Munoz, J .. Romieu, I., 

Aguilar-Ga rduno. C .. et al. (2006). Maternal and paternal occupational exposure to 

agricultural work and the risk of anencephaly. Occupational and Environmental 

Medicine. 63( I 0), 649-656. 

Rull, R. P., Ritz, B., & Shaw, G. M. (2006). Neural tube defects and maternal residential 

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