UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: December 19,2013 

SUBJECT: Imazethapyr: Tier I Review of Human Incidents 

PC Code: 128922, 128923 

Decision No.: 483346 

Petition No.: NA 

Risk Assessment Type: NA 

TXRNo.:NA 

MRIDNo.:NA 

DP Barcode: 0416459 

Registration No.: NA 

Regulatory Action: NA 

Case No.: NA 

CAS No.: 81335-77-5, 101917-66-2 

40CFR:NA 

FROM: Elizabeth Evans, Environmental Protection Specialist 

Ver.Apr.08 

Health Effects Division (7509P) -~-vy---

Toxicology and Epidemiology Branch ~< L. 

and 

Shanna Recore, Industrial Hygienist 0" l?t C\. 0 -"" 

Toxicology and Epidemiology Branch ~ ~~ 

Health Effects Division (7509P) ":~ h 

and r\ ' i ,y . I • I I • 

Carol Christensen, Epidemiologist 

Toxicology and Epidemiology Branc# I z,o \ 11.. 

Health Effects Division (7509P) {1~ l ./ 

;1 .-- J g;t., :;.v,cfu-v5 

THROUGH: David Miller, Acting Branch Chief {/ ~/ ~ Toxicology and Epidemiology Branch 

Health Effects Division (7509P) 

TO: Kelly Lowe, Risk Assessor 

Risk Assessment Branch I 

Health Effects Division (7509P) 

and 

Katherine StClair, Chemical Review Manager 

Risk Management & Implementation Branch 2/4 

Pesticide Re-evaluation Division (7508P) 

Page 1 of8 
Summary and Conclusions 

The low frequency and low severity of acute poisoning cases (also referred to as human incident 

data) reported for imazethapyr in both the Incident Data System (IDS) and SENSOR-Pesticides 

does not trigger an EPA concern at this time. The Agency will continue to monitor the incident 

information and if the magnitude and frequency of reported acute poisoning events increases, 

additional analysis will be performed. 

In one Agricultural Health Study (AHS) study, authors observed an elevated risk of bladder and 

colon cancers in relation to imazethapyr use. Authors state the findings are supported by the 

relatedness of imazethapyr to other heterocyclic amine (HCA) compounds which are putative 

risk factors for these cancers. While this study does show a potential association between bladder 

and colon cancer and imazethapyr use, EPA notes that the HCA structure of imazethapyr is 

unlike the classic structures of the carcinogenic aromatic amines and that the toxicological 

studies submitted to EPA for registration of imazethapyr do not show any evidence of 

carcinogenicity. EPA will continue to monitor the literature for further investigations on this 

topic. 

Detailed Review 

I. ACTION REQUESTED 

This review is intended to fulfill our requirement to provide docket summaries of incident data 

that were reported to the Agency, as well as to ensure human incident data and the 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 by EPA. While it is not always 

possible to determine whether a causal link exists between a specific acute pesticide exposure 

event and a reported acute health outcome, incident information can be an important source of 

feedback to the Agency regarding the veracity and adequacy of risk assessment and risk 

management decisions. For example, 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 investigate the role of specific pesticide exposures in the 

development of chronic health outcomes such as cancer or neurological effects among the 

general population or specific sub-groups like pesticide applicators. 

II. BACKGROUND 

Imazethapyr is an aromatic heterocyclic amine herbicide used in the U.S. on a variety of crops, 

and, in the AHS, is a predominant herbicide used on com and soybean crops in Iowa ( 42% of 

AHS participants reported use of imazethapyr). According to EPA's Screening Level Usage 

Analysis (SLUA; 3/4/13), imazethapyr and its ammonium salt are used predominantly on rice 

and soybeans, with an average of300,000 pounds applied between the years 2004 and 2013. For 

com, an average of 30,000 pounds of imazethapyr was applied to less than 2.5% of the crop. 

Page 2 of8 
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 imazethapyr (pc codes: 128922, 

128923 ). The purpose of the database search is to identify potential patterns in the frequency 

and severity of the health effects attributed or potentially attributed to imazethapyr exposure. 

Imazethapyr is included in the AHS, and preliminary findings of interest are presented in 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. The IDS reports contain 

information from across the U.S., and most incident reports have all relevant product information 

recorded. IDS reports represent anecdotal narratives only, unless otherwise stated in the 

summary. In the review of imazethapyr, the team identified an IDS incident report related to a 

lawsuit and the team excluded that report from this summary. 

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, 2008 to September 11, 2013, there were no incidents reported 

for the single chemical active ingredient imazethapyr in the database. There was 1 incident 

reported involving more than one chemical including imazethapyr. This incident was classified 

as moderate severity but due to the nature of the report, i.e., multiple chemical exposure, there is 

little information to glean for the imazethapyr risk assessment. 

In Aggregate IDS, from January 1, 2008 to September 11, 2013, there were 8 reported incidents 

involving imazethapyr. These incidents were all classified as minor severity. Overall, there are 

few incidents involving imazethapyr reported to IDS. 

Page 3 of8 
b. SENSOR-Pesticides 

The SENSOR-Pesticides database covers 11 states from 1998-2009, 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 11 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. The information includes an expert judgement as to 

the veracity of the claim that a specific pesticide active ingredient was a cause of the reported 

acute poisoning event (likely, unlikely). 

A query of SENSOR-Pesticides from 1998-2009 identifies no single ai cases involving 

imazethapyr and one multiple ai case involving imazethapyr. This case was low in severity. 

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. The AHS includes information on use of 50 different 

pesticide active ingredients commonly used in agriculture. Imazethapyr is included in the AHS 

and the preliminary findings are summarized below. 

Within the AHS, there has been one specific evaluation of the active ingredient imazethapyr in 

association with cancer incidence among private and commercial pesticide applicators (Koutros 

et al., 2009). This study evaluated the risk of all cancers combined, as well as specific 

anatomical cancer sites with respect to lifetime use of imazethapyr. Although largely a 

hypothesis-generating investigation, specific study hypotheses regarding bladder and colon 

cancer were motivated in part on a prior understanding by the authors that imazethapyr is a 

member of the heterocyclic aromatic amine class of chemicals. Researchers hypothesized a 

priori that the chemical may be related to either bladder or colon cancer because a) aromatic 

amines -- a structurally related class of chemicals used in the dye industry -- have long been an 

established risk factor for bladder cancer in occupational studies, and b) dietary studies have 

noted the link between heterocyclic amine exposure through consumption of well-cooked meat 

and colon cancer. 

In this study, the authors examined cancer risk among 49,398 AHS participants, 20,646 (42%) 

who reported using imazethapyr in their lifetime. There were 2,907 imazethapyr-exposed 

incident cancer cases identified from initial enrollment through 2004 used in this analysis. The 

authors found no statistically-elevated cancers associated with 10 other anatomical cancer sites 

Page 4 of8 
(non-bladder and non-colon cancer sites1

) for which the authors did not hypothesize an a priori 

relationship. However, the authors reported elevated risk of bladder cancer [relative risk 2.37 

(category upper T3 v. To) (95% confidence interval1.20, 4.68), p for trend 0.01], as well as colon 

cancer [OR 1.78 (category upper T3 v. To) (95% CI 1.08, 2.93) p for trend 0.02]. Relative risks in 

the lower exposure categories were not statistically significantly elevated; however tests for 

linear trend were statistically significant for both anatomical cancer sites. The authors state that 

chance could have played a role in the observation of these positive associations as multiple 

statistical tests were performed within multiple comparison adjustment; however, researchers 

point to their a priori hypothesis and the structural similarity of imazethapyr with other aromatic 

amines that have associations with bladder cancer (e.g., dye intermediates) and to the 

heterocyclic amines (HCA), which have been shown to have a link to colon cancer through the 

diet (particularly, cooked meat) as biological rationale for the positive findings. 

In a separate AHS analysis specifically examining colorectal cancers and pesticide use, Lee et al. 

(2007) performed a nested case-control study, and reported a non-statistically significantly 

elevated risk of colon cancer in relation to reported use of imazethapyr [OR 1.2 (95% CI 0.8, 

1.7)]. This study, however, reflects a lesser number of cancer cases than Koutros et al. (2009), 

and fewer years of follow-up. In both of these analyses, authors adjusted for established and 

suspected cancer risk factors, including sensitivity analyses as to the best method to model 

smoking in association with both colon and bladder cancers. Smoking is a strong risk factor for 

both bladder and colon cancers. 

Regarding the positive cancer fmdings in relation to lifetime use of imazethapyr, EPA notes that 

the dye intermediates often linked to increased incidence of bladder cancer generally contain free 

amino groups which are requisite for the hypothesized carcinogenic mechanism of action. With 

respect to the HCAs and the putative association with colon cancer through the diet, we note that 

such associations have been directly hypothesized to be as a result of the presence or formation 

aminoimidazoazaarenes (AlAs) and carbolines in cooked meats which -- while indeed members 

of the HCA class-- are not structurally similar to imazethapyr. We further note that OPP 

evaluated the animal bioassays available for this chemical in 2002. In these bioassays, animals 

were dosed at up to 750 mg/kg/day in rats and mice for the lifespan ofthe animals. In both of 

these animal carcinogenicity studies, there was no increase in the incidence of any tumors. OPP 

determined that imazethapyr was "Not Likely to Be Carcinogenic to Humans." 

Studies by AHS investigators of non-cancer outcomes such as respiratory health and 

neurological effects have not identified exposure to the herbicide imazethapyr as a suspected risk 

factor (Hoppin et al., 2007; Hoppin, Umbach, London, Alavanja, & Sandler, 2002; Hoppin et al., 

2008; Hoppin et al., 2009; Hoppin et al., 2006; Kamel et al., 2007; Starks, Gerr, et al., 2012; 

Starks, Hoppin, et al., 2012). 

1 With respect to these non-hypothesized associations, Koutros et al. (2009) reported that estimated risks for all other 

anatomical cancer sites evaluated were not elevated. Specifically, authors did not observe statistical evidence that 

imazethapyr exposure is associated with prostate, lung, rectal, kidney, oral, or pancreatic cancers, or cutaneous 

melanoma, or with alllymphohematopoieteic cancers, NHL, or leukemia. Other AHS cancer evaluations using a 

slightly different study design (nested case control) and different sample sizes similarly reported no evidence of an 

association between imazethapyr use and prostate, breast, lung, pancreatic cancers or cutaneous melanoma 

(Aiavanja et al., 2004; Alavanja et al., 2003; Andreotti et al., 2009; Dermis, Lynch, Sandler, & Alavanja, 2010; 

Engel et al., 2005; Koutros et al., 20 13; Lee et al., 2007). 

Page 5 of8 
IV. CONCLUSION 

The low frequency and low severity of incident cases reported for imazethapyr in both IDS and 

SENSOR-Pesticides does not trigger concern at this time. The Agency will continue to monitor 

the incident information and if a concern is triggered, additional analysis will be included in the 

risk assessment. In epidemiological studies associated with the AHS, no statistically significant 

associations were observed between imazethapyr exposure and prostate, lung, rectal, kidney, 

oral, pancreatic cancers or cutaneous melanoma, or with the lymphohematopoieteic cancers 

(including leukemia and NHL ). The preliminary findings on imazethapyr in relation to bladder 

and colon cancer have been noted, and EPA will continue to monitor the literature for further 

information. 

Page 6 of8 
V. REFERENCES CITED 

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(2004). Pesticides and lung cancer risk in the agricultural health study cohort. Am J 

Epidemiol, 160(9), 876-885. doi: 160/9/876 [pii] 

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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., Freeman, 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 

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Dennis, L. K., Lynch, C. F., Sandler, D.P., & Alavanja, M. C. (2010). Pesticide use and 

cutaneous melanoma in pesticide applicators in the agricultural heath study. Environ 

HealthPerspect, ll8(6), 812-817. doi: 10.1289/ehp.0901518 

Engel, L. S., Hill, D. A., Hoppin, J. A., Lubin, J. H., Lynch, C. F., Pierce, J., ... Alavanja, M. C. 

(2005). Pesticide use and breast cancer risk among farmers' wives in the agricultural 

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Hoppin, J. A, Umbach, D. M., Kullman, G. J., Henneberger, P. K., London, S. J., Alavanja, M. 

C. R., & Sandler, D.P. (2007). Pesticides and other agricultural factors associated with 

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Koutros, S., Beane Freeman, L. E., Lubin, J. H., Heltshe, S. L., Andreotti, G., Barry, K. H., .. . 

Alavanja, M. C. (2013). Risk of total and aggressive prostate cancer and pesticide use in 

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Koutros, S., Lynch, C. F., Ma, X., Lee, W. J., Hoppin, J. A., Christensen, C. H., .. . Alavanja, M. 

C. (2009). Heterocyclic aromatic amine pesticide use and human cancer risk: results from 

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(2012). Neurobehavioral function and organophosphate insecticide use among pesticide 

applicators in the Agricultural Health Study. Neurotoxicol Teratol, 34(1), 168-176. doi: 

10.1 016/j.ntt.2011.08.0 14 

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