### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460
OFFI CE 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 .: 4 83346 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, Environmenta l Protection Specialist Ver.Apr

.08

Health Effects Di vision (7509P)**-~-vy---** Toxicology and Epidemiolo gy Branch**~<** 

### L. and Shanna Recore, I ndustrial Hygienist 

### 0 " l?t C\. 

### 0 -"" Toxicology and Epidemiology Branch

### ~**~~** Health Effec ts Division (7509P)**":~** h and 

# r\ ' i 

## , y . I • I I • Carol Christensen, Epidemiologist Toxicology and Epidemiology Branc# 

# I z,o \ 1 1.. 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 Effec ts Division (7509P) and Katherine S tC lair, Chemical Review Manager Risk Management 

### & Implementation Branch 2/4 Pesticide Re-evaluation Di vision (7508P)

Page 1 of8Summary and Conclusions The low frequency and low severi ty 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 E PA concern at this time. The Agency will continue to moni tor the inc ident 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 ofbladder and colon cancers in relation to imazethapyr use. Authors s tate 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 s tructures ofthe carcinogenic aromatic amines and that the toxicological studies submitted to EPA fo r 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 i s 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 ofthe problem formulation phase ofregistration review. Reports of adverse health effects allegedly due to a specific p esticide 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) i s validated or otherwise confirmed by EPA. While it is not always possible to d etermine 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 f eedback to the Agency regarding the veracity and adequacy ofrisk 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 inve stigate a particular chemical or product. Observational epidemiology investigate the role of specific pesticide exposures in the d evelopment of chronic health outcomes such as cancer or neurological effects among the general population or specifi c 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 of8For this evaluation , both the OPP Incident Data System (IDS) and the Centers for Disease Control and Preventi on/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 i s to identify potential patterns in the frequency and severity ofthe 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 imazet hapyr, 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 module s: 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 inc ident. Main IDS incidents involvi ng 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. Thi s incident was classified as moderate severity but due to the nature of the report, i.e., multiple chemical exposure, there i s 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 involv ing imazethapyr reported to ID S.

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### b . SENSOR-Pestic ides The SENSOR-Pes ticides 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 Cont rol Centers, state Department of Labor workers' compensation claims when reported by physicians, reports from State Departments of Agriculture, and phys ici an reports to state Departments of Health. Altho u gh both occupational and non-occupational incidents are included in the database, SENSOR

- Pesticides focuses on occupational pest icide incidents, and is of particular value in providing that information. The state coordinator at each of the 1 1 respective state Departments of Health conducts case followup activities such as obtaining medical records to verify symptoms and severity. Us ing standa rdized protocol and case definitions derived from poison center reporti ng, the state SENSOR-Pesticide coordinator enters the inc ident information into the state-based system which is sent to NIOSH annually t o be aggregated. The information includes an expert judgement as to the verac ity of the claim tha t a specific pesticide active ingredient was a cause of the reported acute poisoning event (likely, unlikely). A query of SENSOR

- Pest icides from 1998-2009 identifies no single ai cases invo lving imazethapyr and one multiple ai case invo lving imazethapyr. This case was low in severity.



### c. Agricultural Health Study (AHS) The AHS is a high quality, prospective epidemio logy study evalua ting the link between pesticide use and various health outcomes including cancer. The AH S includes private and commercial pesticide applicators and their spouses . The AHS includes information on use of 50 different pesticide active ingredients commo nly used in agriculture. Imazethapyr is included in the AHS a

n d the preli minary findings are summarized below. Within the AHS, there has been one specific evaluation of the active ingredient imazethapyr in assoc i ation wi th cancer incidence among pri vate 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 respec t to lifetime use of imazet hapyr. Although largely a hypothesis-generating investigation , specific study hypo theses regarding b ladder and co lon cancer were motivated in part on a prior understandin g by the auth or s tha t imazethapyr is a member of the heterocyclic aromatic amine class of chemicals. Researchers hypothesized 

### a priori that the chemical may be related to e ither bladder or co lon 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 occupationa l studies, and b) dietary studies have noted the link between heterocyclic amine exposure through consumption of well

- cooked meat and co lon cancer. In this st udy, the autho rs 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 initi al enrollment through 2004 used in this analysis. The authors found no stati stical ly-elevated cancers assoc i ated w ith 10 other anatomical cancer sites
Page 4 of8(non-bladder and non-colon cancer sites 1) for which the authors did not hypothesize an a priori relationship. However, the authors reported elevated risk of bladder cancer [relative ri sk 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 T 3 v. 

### To) (95% CI 1.08, 2.93) p for trend 0.02]. Relative risks in the lower exposure categories were not statistically significan tly elevated; however tests for linear trend were statistically significant for both anatomical cancer sites . The authors state tha t 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 s p ecifically examining colorectal cancers and pesticide use, Lee et al. (2007) performed a nes ted case-control study, and reported a non-statistically significantly elevated risk of colon cancer in relation to reporte d 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 sensi tivity 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 intermedia tes often linked to increased incidence of bladder cancer generally contain free amino groups which are requisi te for the hypothesized carcinogenic mechanism of action. With respect to the HCAs and the putative association with colon cancer through the d iet, 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 oft h e 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 inves tigators of non-cancer outcomes such as re spiratory health and neurological effects have not identified exposure to the herbicide imazethapyr as a suspected risk factor (Hoppin et al., 2007; Hopp in , 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 s ite s evaluated were not elevated. Specifically, authors did not observe statistical ev idence that imazethapyr exposure is associated with prostate, lu ng, 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 ima zet hapyr 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 sever ity of incident cases reported fo r imazethapyr in both IDS and SENSOR-Pesticides does not trigger concern at this time. The Agency will continue to moni to r the incident information and if a concern i s triggered, additional analysis will be included in the ri sk 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 informa tion.

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### V. REFERENCES CITED Alavanja, M. C., Dosemeci, M., Samanic, C., Lubin, J., Lynch, C. F. , Knott , C.,

. . . Blair, A. (2004). Pesticides and lung cancer risk in the agricultural health st udy cohort. Am J Epidemiol , 160(9), 876-885. doi: 160 / 9/ 876 [pii] 10.1 093 / aje/kwh290 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), 800-8 1 4. Andreotti, G., Freeman, 

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... Alavanja, M. C. (2009). Agricultural pesticide u se and pancreatic cancer risk in the Agricultural Health Study Cohort. Int J Cancer, 124(1 0) , 2495-2500. doi: 10. 1002/ ijc.24185 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

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### L. S., Hill , D. A. , Hoppin, J. A., Lubin , J. H. , Lynch, C. F. , Pierc e, J.,

... Alavanja, M. C. (2005). Pesticide use and breast cancer risk among farmers' wives in the agricultural health study. Am J Epidemiol, 161(2), 121 -135. doi: 161 / 2/ 121 [pii] 10.1 093 / aje/kwi022 Hoppin, J. A, Umbach, D. M., Kullman, G. J., Henneberger, P. K., London, S

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. Chemical predictors of wheeze among farmer pesticide applicators in the agricultural health study. American Journal of R espiratory and Critical Care Medicine, 165(5), 683- 689. doi : 1 0.1164/rccm.21 06074 Hoppin, J. A., Umbach, D. M., London , S. J., Henneberger, P. K ., Kullman, G. J., Alavanja, M. C. R. , & Sand ler , D.P. (2008). Pesticides and atopic and nonatop ic asthma among farm women in the agricultural health study. American Journal of Respiratory and Critical Care Medicin e, 1 77(1), 11-18. Hoppin, J. A., Umbach, D. M., London, S. J. , Henneberger, P. K. , Kullman , G. J. , Coble, J.,

... Sandler, D.P. (2009). Pesticide use and adult-onset asthma amon g male farmers in the Agricultural Health Study

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. , London, S. J., Lynch , C. F., Alavanja, M. C. R. , & Sandler, D.P. (2006). Pesticides and adult respiratory outcomes in the ag ri cultural health study. 

### In M. A. Mehlman , M. Soffritti, P. Landrigan, E. Bingham & F

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. , Barry, K. H. , .. . Alavanja, M

. C. (2013). Risk of total and aggressive prostate cancer and pesticide use in the Agricultural H ealth Study. AmJEpidemiol, 177(1), 59-74. doi: 10.1093/aje/kws225 Koutros, S., Lynch, C. F., Ma, X., Lee, W. J

. , Hoppin, J. A., Chr i stensen, C

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.. . Alavanja, M. C. (2009). Heterocyclic aromatic amine pesticide use and human cancer risk : results from the U.S. Agricultural H ealth Study. Int JCancer, 124(5), 1206-1212. doi: 10.1 002/ijc.24020 Lee, W. J., Sandler, D.P., Blair, A., Samanic, C., Cross, A. J., & Alavanja, M. C. R. (2007). Pesticide use and colorecta l cancer ri sk in the Agricultural Health Study. International Journal of Cancer, 121 (2), 339-346. doi: 10.1002/ijc

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. . . Hoppin, J. A. (2012). Neurobehavioral function and organophosphate insecticide use among pesticide applicators in the Agricultural H ealth Study

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. , Kame l , F., Lynch, C. F., Jones, M.P., Alavanja, M. C.,

. . . Gerr, F. (2012). Peripheral nervous system functi on and organophosphate pesticide use among licensed pesticide applicators in the Agricultural H ealth Study. E nviron Health Perspect, 120(4), 515-520. doi : 10.1289/ehp.l103944

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