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 ofHuman Incidents

PC Code : 071003 , 071004 Decision No.: 503984 Petition No.: NA DP Barcode: 0427127 Registration No.: NA Regulatory Action: NA Case No.: NA Risk Assessment Type: 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) 

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### 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 ofcases 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.

Page 1of5With respect to PD given the several a priori hypotheses regarding the role ofrotenone in the etiology ofPD 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 ofthe problem formulation phase ofregistration 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 offeedback 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 ofdisease, 

### 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 ofproduct 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 ofthe database search is to identify potential patterns in the frequency and severity ofthe 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.
Page 2of5IDS records incidents in one oftwo 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 ofthe 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 ofexposure 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 ofpesticide-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 ofHealth. Although both occupational and non-occupational incidents are included in the database, SENSOR-Pesticides focuses on occupational pesticide incidents , and is ofparticular value in providing that information. The state coordinator at each ofthe 12 respective state Departments ofHealth conducts case followup activities such as obtaining medical records to verif y 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). Ofthese, six cases involve a single active ingredient. All six cases were low in severity. None ofthese six were work-related. Four ofthe 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

.

Page 3 of 5One case is described as follows , " A 44-year-old malefell into water whileprotesting the application of pesticides to a lake by a government agenc y. He changed his clothes and rinsed his e y es 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. Ifthere 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 ofthe process and, if appropriate, fully reviewed in the risk assessment phase ofthe 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 ofPD 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 ofnigral dopaminergic neurons in the substantia nigra, a key pathological feature ofPD 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 ofrotenone 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 ofPD by pesticide use status among 110 PD cases and 358 frequency matched non-cases . Adjusting for age, state and sex, authors reported elevated rates ofPD 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 ofthe disease did not thus substantially influence pesticide use.

Page 4of5Furlong and colleagues (2014) as part ofthe AHS investigated whether use ofprotective 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 compare d the pesticide-PD associations by 

### PPE use. Among ever vs. 

## never u gerg o fr otenon e and contr olling 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 ofrotenone in the etiology ofPD , 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 ofcases 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 ofrotenone in the etiology ofPD 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 ofEpidemiology, 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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