Page 3 of 8

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.

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 specific. This system stores incident data for death, major and moderate incidents, and it includes information about the location, date and nat ure of the incident. Main IDS incidents involving only one pesticide 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 M ain IDS, from January 1, 200 7 to September 13, 2012, there was 1 incident reported for involving EPTC in the database

. This incident was classified as major severity (Table 1)

. Overall, there are few incidents involving EPTC reported to IDS.

In A ggregate IDS , from January 1, 200 7 to September 13 , 2012

, there were 5 reported incidents involving EPTC

.

b. NIOSH SENSOR

The NIOSH

- led SENSOR

- Pesticides database covers 11 states from 1998

- 2008, 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, s tate Department of Labor workers’ compensation claims when reported by physicians, reports from Stat e Departments of Agriculture, and physician reports to s tate Departments of Health . Although both occupational and non

- occupational incidents are included i n the database, SENSOR

- Pesticides focuses on occupational pesticide incidents, and is of particular value in providing that information. A state SENSOR contact specialist attempts to follow

- up with cases and obtains medical records to verify symptoms, circ umstances surrounding the exposure, severity, and outcome. Using standardized protocol and case definitions, derived from poison center reporting, SENSOR

- Pesticides coordinators at State Departments of Health enter the incident interview description provi ded by the case , medical report, physician into the data system

. In order to be included in the database, all SENSOR

- Pesticides cases, including low severity cases, must have at least two adverse health effects.

In SENSOR

- Pesticides from 1998 to 2008, ten case reports, stemming from seven events are identified. All ten cases involve a single active ingredient. Eptam is the product implicated in six cases. One case is moderate in severity and 9 cases are low in severity. The moderate severityPage 4 of 8

case experi enced multiple symptoms reported as follows, “ numbness, tingling, muscle weakness, lumps on scalp/hip; immediate: nausea, headache, throat irritation , diarrhea ”.

The most commonly reported health effects among cases were nervous system and gastrointesti nal symptoms. A summary of symptoms is provided in Table 2 below.

Table 2 : Reported Symptoms Respiratory 3 Nervous System 6 GI 6 Eye 4 Dermal 3 Cardiovascular 1

All ten cases are work

- related. In one event that occurred in Louisiana in 2000, four individuals were made ill after an Eptam application, the incident description for all four cases states “A carpentry crew worked in a flowerbed during/after herbicide a pplication ”. These cases experienced a variety of symptoms but all reported gastrointestinal distress.

c. 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 p hase of the process and, if appropriate, fully reviewed in the risk assessment phase of the process

. The AHS includes information on use of 50 different pesticide active ingredients commonly used in agriculture.

Researchers with the AHS have performed seve ral epidemiologic investigations that have included evaluation of occupational exposure to S

- Ethyl

- N,N

- dipropylthiocarbamate (EPTC). Research results mainly relate to the carcinogenic potential of EPTC; however investigators have also evaluated the role of pesticide exposure, including EPTC, and respiratory health (wheeze). A summary of these findings follows:

Cancer:

A number of studies have evaluated EPTC for its carcinogenic potential given its ability to form nitrosamines and its role in inter

- cellu lar oxidative stress. No significant positive associations

were observed with prostate, lung, and breast cancers or with cutaneous melanoma (Alavanja et al., 2004; Alavanja et al., 2003; Dennis, Lynch, Sandler, & Alavanja, 2010; Engel et al., 2005; Lee et al., 2007)

. However, several authors have identified statistically significant associations between EPTC use and leukemia, colon, and pancreatic cancer, as well as prostate cancer among those with a family history of prostate cancer (Alavanja et al., 2003; Andreotti et al., 2009; Barry et al., 2011; van Bemmel et al., 2008) . These findings are discussed in more detail below:Page 5 of 8

Leukemia and Colon cancer Investigators completed a cohort analysis of cancer risk by EPTC exposure status and reported significant, positive assoc iations with both leukemia and colon cancer (van Bemmel et al., 2008)

. Among 48,378 participants in the AHS and controlling for known and suspected risk factors for cancer, researchers observed an approximate 30% increased risk of colon cancer, and two

- fold increased risk of leukemia, comparing the upper

- half of t he exposed group to the non

- exposed group [colon: OR 1.28 (95% CI 1.09, 1.50); leukemia: OR 2.09 (95% CI 1.16, 4.84)]. These study results persisted using alternate exposure metrics, i.e. lifetime exposure days, and referent group. Additional sensitivity analyses did not alter the conclusions from these final models, including simultaneous adjustment for correlated pesticides. Nevertheless, the authors caution that although EPTC was associated with colon cancer in the highest tertile of both lifetime exp osure days and intensity

- weighted lifetime days (RR = 2.09; 95% CI, 1.26

- 3.47 and RR = 2.05; 95% CI, 1.34

- 3.14, respectively) and the trend test was < 0.01 for both, the pattern of RR was not monotonic with increasing use and state that

- given the relati vely small number of cases in the highest exposure tertile (n<5) results should be interpreted with caution and further investigations are needed. A previous study using AHS data investigating the association between pesticide use and colorectal cancers ( Lee et al. (2007)) also explored the relationship between EPTC and colon cancer, but did not find a significantly increased risk using an ever/never exposure metric. In this latter study, the authors estimated odds ratios of 1.1 (95% CI: 0.8, 1.5), 1.2 (9 5% CI: 0.8, 1.8) and 0.9 (95% CI: 0.4, 1.7) for colorectal (n = 305), colon (n=212) and rectal (n=93) cancers, respectively, suggesting no evidence of association between EPTC and colorectal cancers.

Pancreatic cancer: Andreotti et al. (2009) examined pe sticide exposure among pancreatic cancer cases in the AHS cohort in two case

- control studies within the AHS, and observed an increased risk among male applicators who reported use of EPTC. Controlling for the influence of age, smoking, and diabetes, thos e who were most highly exposed to EPTC had 2.5

- times greater odds (risk) (95% CI 1.1

– 5.4, p

- trend, 0.01) than participants who reported never use of EPTC. The use of other pesticides did not alter the risk estimate with pancreatic cancer. Due to limitations of data collection, the authors state that they were not able to control for a family history of pancreatic cancer in the analysis; family history is an established risk factor for pancreatic cancer. In addition, the authors caution in discussing their results that this is the first ever investigation of pancreatic cancer and pesticide exposure and that no a priori hypotheses were offered. The authors hypothesize that since EPTC forms N

- nitroso

- compounds, which are known animal carcinog ens, this may play a role in carcinogenesis; however, they state that the biological mechanisms have not been clearly defined at this time.

Prostate cancer in those with a family history of prostate cancer : Researchers have extended earlier studies with in the cohort in which prostate cancer risk was non

significantly elevated among EPTC users who also reported a family history of prostate cancer (a stratified analysis) (Alavanja et al., 2003) . The more recent study investigated genetic variability in base excision repair genes, pesticide exposure and prostate cance r risk (Barry et al., 2011) . In this study, authors found increased risk of prostate cancer among EPTC users with less than two copies of the dominant alleles at a specific genetic locus known to encode proteins involved in base excision repair mechanisms; althoughPage 6 of 8

the estimated OR was statistically significant, the authors state that the estimate was not statistically significant after adjusting for multiple statistical comparisons.

Overall, authors caution that these are among the first ever investigations of these anatomical

can cer sites with occupational EPTC exposure; that few a priori hypotheses were offered, and that additional biological support is needed to identify mechanisms of action. However, with a large, prospective sample, motivated hypotheses (prostate cancer), and elimination of several of the major non

- causal hypothesis (i.e. biases in the study can explain the positive association), the results are notable and should be considered as part of hazard characterization. Additional studies will help elucidate these pre liminary findings, and possible discount current findings.

Respiratory Health

Farmers generally report having higher rates of respiratory illness such as asthma, chronic bronchitis, and farmers lung than the general population and report higher rates of w heeze, cough, and shortness of breath ( see http://aghealth.nci.nih.gov/pdfs/NCWheeze2005.pdf ). Hoppin et al (2002) investigated self

- reported wheeze among farmers and EPTC was among the pesti cides tested that was associated with wheeze over the previous reporting year in the AHS (Hoppin, Umbach, London, Alavanja, & Sandler, 2002) . The authors hypothesized that that use of OP, carbamates or thiocarbamates may be associated with wheeze based upon previous literature, and studied this question in a cross

- sectional analysis among pesticide applicators in the Agricultural Health Study (AHS). Researchers measured pesticide use with both an ever

never exposure metric and

- for those pesticides positively associated with wheeze using this exposure metric or for which authors proposed a priori hypotheses

- days of use over the past

year were categorized. Authors compared use of certain pesticides between those who did and did not report episodes of wheeze in the previous year. Models were adjusted for age, state, smoking and presence of asthma or atopy. Of the 40 pesticides evaluated in association with wheeze, 34 had odds ratios greater than 1 of which 11 were significantly associated with the outcome. Participants who reported use of EPTC in the last year had a 30% increased risk of wheeze as compared to those who reported no use of EP TC in the previous year using 4

- levels of

exposure

- days [OR 1.32 (95% CI 1.05, 1.65) (p for trend<0.01)]. Neither adjustment for correlated pesticides nor for corn or grain dust exposure changed the observed results. No difference in the association betwe en EPTC use and wheeze was observed between those who did and did not report diagnosis of asthma or allergy. Authors hypothesized that the cholinergic potential of EPTC as a thiocarbamate may lead to bronchoconstriction which may contribute to symptoms of wheeze; however the cholinesterase inhibiting potential of EPTC and thiocarbamates in general is known to be low. While a hypothesized mechanism of action is unclear at this time, several other non

- AHS epidemiological investigations have identified a link between carbamates and respiratory symptoms

While the above AHS findings are only preliminary in nature and the authors caution about the study limitations, further analyses should be conducted. The HED HIT recommends that a more detailed (Tier II) review be conducted at the time of the risk assessment of EPTC which focuses on the epidemiological aspects of exposure to this pesticide.Page 7 of 8

IV. CONCLUSION

Based on the low frequency and severity of incident cases reported for EPTC to both IDS and NIOSH SENSOR

- Pest icides

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

. However, based on current AHS findings we intend to further evaluate follow

- on studies from the AHS . In addition, t he Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be also be included at that time.

Works Cited

Alavanja, M. C., Samanic, C., Dosemeci, M., Lubin, J., Tarone, R., Lynch, C. F., . . . Blair, A. (2003). Use of agricultural pesticides and prostate cancer risk in the Agricultural Health Study cohort. Am J Epidemiol, 157 (9), 800

- 814. Andreotti, G., Freem an, L. E., Hou, L., Coble, J., Rusiecki, J., Hoppin, J. A., . . . Alavanja, M. C. (2009). Agricultural pesticide use and pancreatic cancer risk in the Agricultural Health Study Cohort. Int J Cancer, 124 (10), 2495

- 2500. doi: 10.1002/ijc.24185 Barry, K. H., Koutros, S., Berndt, S. I., Andreotti, G., Hoppin, J. A., Sandler, D. P., . . . Alavanja, M. C. (2011). Genetic variation in base excision repair pathway genes, pesticide exposure, and prostate cancer risk. Environ Health Perspect, 119 (12), 1726

- 1732. doi: 10.1289/ehp.1103454 Hoppin, J. A., Umbach, D. M., London, S. J., Alavanja, M. C. R., & Sandler, D. P. (2002). Chemical predictors of wheeze among farmer pesticide applicators in the agricultural health study. American Journal of Respiratory and Critical C are Medicine, 165 (5), 683

- 689. doi: 10.1164/rccm.2106074 van Bemmel, D. M., Visvanathan, K., Beane Freeman, L. E., Coble, J., Hoppin, J. A., & Alavanja, M. C. (2008). S

- ethyl

- N,N

- dipropylthiocarbamate exposure and cancer incidence among male pesticide appl icators in the agricultural health study: a prospective cohort. Environ Health Perspect, 116 (11), 1541

- 1546. doi: 10.1289/ehp.11371Page 8 of 8

Table 1 : M ain IDS Incident involving EPTC

Human Incidents Chemical: EPTC PC Code: 041401

Incident Package Report Incident

Date Location Registration Number Product Name Exposure Severity* Incident Description

021976

- 00001 4/21/2010 SAGINAW, MI 010163

- 00283 EPTAM 7

- E SELECTIVE

HERBICIDE EMULSIFIABLE LIQUID HB A 59 year old male was applying the product at work on a windy day. He got some of the product on his skin and inhaled some of the blown back product. He went to the hospital and presented SLUDGE symptoms at the time of admission. He was treated as havin g cholinergic manifestation of carbamate poisoning secondary to inhalation and dermal exposure to this product. He was intubated and placed in ICU. He was treated with atropine to control secretions. No cholinesterase testing was performed. Three days la ter he was extubated. At the time of the call and was still hospitalized, he was no longer manifesting the signs of cholinergic crisis, and his prognosis was very good. * Severity Categories
H

- A Human Fatality Death (if the person died)
H

- B Human Major Major (if the person alleged or exhibited symptoms which may have been life

threatening, or resulted in adverse reproductive effects or in residual disability)
H

- C Human Moderate Moderate (if the person alleged or exhibited symptoms more pronounced, more prolonged or of a more systemic nature than minor symptoms; and involved some form of treatment, even though symptoms were not life threatening and the person returned to his/her pre

exposure state of health with no additional residual disability)
H

- D Human Minor Minor (if the person alleged or exhibited some symptoms, but they were minimally traumatic; the symptoms resolved rapidly and usually involve skin, eye or respiratory irritation)
H

- E Human Unspecified Unspecified (if symptoms are unknown, unsp ecified or are alleged to be of a delayed or chronic nature that may appear in the future)
H Human Undetermined ( an undetermined severity) from 40 CFR § 159.184