UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: June 4, 2015 

SUBJECT: Rotenone: Tier I Review of Human Incidents 

PC Code: 071003, 071004 

Decision No.: 503984 

Petition No.: NA 

DP Barcode: 0427127 

Registration No.: NA 

Regulatory Action: NA 

Risk Assessment Type: NA Case No.: NA 

TXRNo.: NA 

MRIDNo.:NA 

CAS No.: 83-79-4 

40CFR: NA 

FROM: Elizabeth Evans, Environmental Protection Specialist 

Toxicology and Epidemiology Branch 

Health Effects Division (7509P) .A}1A/1 

/J Shanna ~~core, Industrial Hygienist {/)J! V l 

/" Toxicology and Epidemiology Branch 

Health Effect Division (7509P) /} / ~ 

THROUGH: David Miller, Acting Branch Chief t/Jtfv;} ~ Toxicology and Epidemiology Branch 

TO: 

Health Effects Division (7509P) 

Bridgette Bobowiec, Risk Assessor 

Risk Assessment Branch VI 

Health Effects Division (7509P) 

and 

Kelly Ballard, Chemical Review Manager 

Risk Management & Implementation Branch 1 

Pesticide Re-evaluation Division (7508P) 

Summary and Conclusions 

Ver.Apr.08 

Based on the low frequency and severity of cases reported for rotenone in both IDS and 

SENSOR-Pesticides, there does not appear to be a concern at this time that would warrant further 

investigation for incidents. The Agency will continue to monitor the incident information and if a 

concern is triggered, additional analysis will be included in the risk assessment. 

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With respect to PD given the several a priori hypotheses regarding the role of rotenone in the 

etiology of PD and the continued, on-going work within the AHS and other long-term studies on 

this issue, a follow up epidemiology report is warranted for this pesticide. 

Detailed Review 

I. ACTION REQUESTED 

This review 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) are part of the problem formulation phase of registration review. Reports of 

adverse health effects allegedly due to a specific pesticide 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 determined based on incident data. However, incident 

information can be an important source of feedback to the Agency: incidents of severe outcome, 

or a suggested pattern or trend among less severe incidents, can signal the Agency 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 like pesticide applicators. 

II. BACKGROUND 

Rotenone is registered as a Restricted Use Pesticide (RUP) botanical pesticide registered for fish 

kill uses. In 2011 EPA issued a cancellation order for several rotenone product registrations 

including many pet products. The list of product cancellations can be accessed in the docket at: 

http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2005-0494-0068 

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) 

Sentinel Event Notification System for Occupational Risk-Pesticides (SENSOR) databases were 

consulted for pesticide incident data on the active ingredient rotenone (pc codes: 071003, 

071004). The purpose of the database search is to identify potential patterns in the frequency 

and severity of the health effects attributed to rotenone exposure. Rotenone is included in the 

AHS which is summarized for this report. 

III. RESULTS/DISCUSSION 

a. IDS (Incident Data System) 

OPP's IDS 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 IDS. IDS contains reports from 

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

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

the report. 

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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 information about the 

location, date and nature of the incident. Main IDS incidents 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. 

For the Main IDS, from January 1, 2010 to February 4, 2015, there were no incidents reported 

involving rotenone. 

In Aggregate IDS, from January 1, 2010 to February 4, 2015, there were 3 incidents reported 

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

incidents reported to IDS involving rotenone. 

b. SENSOR-Pesticides 

The SENSOR-Pesticides database covers 12 states from 1998-2011 , 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 claims when reported by physicians, reports from State Departments of 

Agriculture, and physician reports to state Departments of Health. Although both occupational 

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

occupational pesticide incidents, and is of particular value in providing that information. The 

state coordinator at each of the 12 respective state Departments of Health conducts case followup 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 information into the state-based system which 

is sent to NIOSH annually to be aggregated. 

A review of SENSOR-Pesticides 1998-2011 identifies a total of28 cases, stemming from 25 

events, involving rotenone (pc codes 071004 and 071003). Of these, six cases involve a single 

active ingredient. All six cases were low in severity. None of these six were work-related. Four 

of the six cases involved some type of splash or spill while handling the product. 

Five cases reported ocular irritation, two cases reported cardiovascular symptoms (rapid 

heartbeat, high blood pressure, and chest pain). One case reported ocular, respiratory, 

gastrointestinal, neurological and cardiovascular symptoms after falling into a lake during an 

application to the lake, case details in italics below. 

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One case is described as follows, "A 44-year-old male fell into water while protesting the 

application of pesticides to a lake by a government agency. He changed his clothes and rinsed 

his eyes but 30 minutes later developed burning in eyes and throat. He sought medical attention 

and was discharged the same day. Three agencies, WSDA, Fish & Wildlife and Ecology were 

involved in the incident." 

Two cases were applying ear mite drops to cats and got the product in their eyes. One case was 

applying the dust to her dog to treat fleas. The wind blew the dust into her face and she inhaled 

some. These rotenone pet products were cancelled in 2011. The two remaining cases provided 

no descriptive detail. 

c. Agricultural Health Study (AHS) 

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. If there are AHS findings relevant to a particular 

pesticide going through registration review, the Agency will ensure they are considered in the 

problem formulation/scoping phase of the process and, if appropriate, fully reviewed in the risk 

assessment phase of the process. The AHS includes information on use of 80 different pesticide 

active ingredients commonly used in agriculture. 

In a nested case control study within the AHS, scientists with the FAME (Farming and 

Movement Evaluation) study (Tanner et al, 2011) evaluated the role ofrotenone exposure in 

relation to Parkinson's disease (PD) using data from the U.S. Agricultural Health Study. The 

authors report that mitochondrial dysfunction has been implicated as a possible 

pathophysiological mechanism underlying PD and genetic forms of PD associated with various 

mutations in certain genes may involve these mechanisms. They further state that other studies 

had found that rotenone, in experimental (animal) models, causes selective injury of nigral 

dopaminergic neurons in the substantia nigra, a key pathological feature of PD and induces 

behavioral changes associated with human PD. The authors had previously investigated this 

potential association between rotenone use and self-reported PD using AHS study data and 

reported that PD was associated with increasing lifetime days of any pesticide use (Kamel et al. 

2007) but that they were not able to identify specific pesticides as being statistically associated 

with PD (use of rotenone was associated with a non-statistically significant elevation in the OR 

for PD (OR = 1.7 95% Cl: 0.6, 4.7)): they acknowledged that self-reported PD can be unreliable, 

with 15-25% of such diagnosis being reported as being incorrect. In the follow-up study, the 

authors sought to more accurately diagnose the PD condition by requiring mutual agreement 

among two physician neurologists and using verified PD assessment tools with a high degree of 

accuracy and reliability (Tanner et al., 2011). Ascertaining Parkinson's disease through use of 

neurological specialists and using self-reported information concerning pesticide use, authors 

compared the rates of PD by pesticide use status among 110 PD cases and 358 frequency 

matched non-cases. Adjusting for age, state and sex, authors reported elevated rates of PD 

among users ofrotenone (2.5 (95% CI 1.3, 4.7). The authors were also able to look separately at 

pesticide exposure reported at 5-, 10-, and 15 year lag periods to verify that PD symptoms did 

not influence pesticide use and reported that OR did not differ significantly by lag period and 

thus early onset of the disease did not thus substantially influence pesticide use. 

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Furlong and colleagues (2014) as part of the AHS investigated whether use of protective gloves, 

use of other PPE or hygiene practices modified the observed relationship between rotenone, and 

other pesticide compounds, and PD. Using self-reported information concerning both pesticide 

use and PPE use, authors compared the pesticide-PD associations by PPE use. Among ever vs. 

never ugerg of rotenone and controlling only for state, smoking, sex, and age, authors found an 

adjusted OR of 3.7 (95% CI: 1.7, 8.1). 

Given the several a priori hypotheses regarding the role of rotenone in the etiology of PD, and 

the continued, on-going work within the AHS and other long-term studies on this issue, a follow 

up report is warranted for this compound. 

IV. CONCLUSION 

Based on the low frequency and severity of cases reported for rotenone in both IDS and 

SENSOR-Pesticides, there does not appear to be a concern at this time that would warrant further 

investigation for incidents. The Agency will continue to monitor the incident information and if a 

concern is triggered, additional analysis will be included in the risk assessment. 

With respect to PD given the several a priori hypotheses regarding the role of rotenone in the 

etiology of PD and the continued, on-going work within the AHS and other long-term studies on 

this issue, a follow up epidemiology report is warranted for this pesticide. 

Citations: 

Tanner C. M., Kamel, F., Ross, G. W., Hoppin, J. A., Goldman, S. M., Korell, M., .. . Langston, 

J. W. (2011). Rotenone, paraquat, and Parkinson's disease. Environ Health Perspect, 119(6), 866-

872. doi: 10.1289/ehp.1002839 

Kamel F., Tanner C., Umbach D., Hoppin J., Alavanja M., Blair A., Comyns K., Goldman S., 

Korell M., Langston J., Ross G., Sandler D. (2007). Pesticide exposure and self-reported 

Parkinson's disease in the agricultural health study. American Journal of Epidemiology, 165 (4), 

364-374. 

Furlong M., Tanner C.M., Goldman S.M., Bhudhikanok G.S., Blair A., Chade A., Comyns 

K., Hoppin J.A., Kasten M., Korell M·, Langston J.W., Marras C., Meng C., Richards M., Ross 

G.W., Umbach D.M., Sandler D.P., Kamel F. (2014). Protective glove use and hygiene habits 

modify the associations of specific pesticides with Parkinson's disease. Environment 

International, 75 :144-50. doi: 10.1016/j.envint.2014.11.002 

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