United States Environmental Protection Agency Washington, D.C

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

MEMORANDUM

Date: 26-SEP-2018

SUBJECT: Imidazolinone Herbicides: Imazamox, Imazapic, and Imazethapyr. Draft Human Health Risk Assessment for Registration Review

PC Codes: 129171, 129041, 128943, 128922, 128923 DP Barcodes: D446950, D446951, D447462 Decision Nos.: 540766, 540767, 541775 Registration No.: NA Petition No.: NA Regulatory Action: Registration Review Risk Assessment Type: Multiple Chemical/Aggregate Case Nos.: 7238, 7234, 7208 TXR No.: NA CAS Nos.: 114311-32-9, 104098-48-8, 104098-49-9, 81335-77-5; 101917-66-2 MRID No.: NA 40 CFR: §180.1223, §180.490, §180.447

FROM: Cassi L. Walls, Ph.D., Senior Biologist Monique M. Perron, Sc.D., Toxicologist Sarah J. Levy, Chemist Risk Assessment Branch 1 (RAB1) Health Effects Division (HED, 7509P)

THROUGH: Christine L. Olinger, Branch Chief George F. Kramer, Ph.D., Senior Chemist RAB1/HED (7509P)

TO: Patricia Biggio, Chemical Review Manager Eric Fox, Chemical Review Manager Ricardo Jones, Team Leader Risk Management and Implementation Branch 1 Pesticide Re-Evaluation Division (PRD) (7508P)

Matthew Manupella, Chemical Review Manager Katherine St. Clair, Chemical Review Manager Nicole Zinn, Team Leader Risk Management and Implementation Branch 2 Pesticide Re-Evaluation Division (PRD) (7508P)

As part of Registration Review, PRD of the Office of Pesticide Programs (OPP) has requested that HED evaluate the hazard and exposure data and conduct occupational and residential exposure assessments, as needed, to estimate the risk to human health that will result from the

Page 1 of 19 Imazamox, Imazapic, Imazethapyr Human Health Risk Assessment DP Nos. 446950, 446951, 447462 currently registered uses of pesticides. This memorandum serves as HED’s draft human health qualitative risk assessment of the dietary, occupational and residential exposure, and aggregate risk from the registered uses of the imidazolinone herbicides imazamox, imazapic, and imazethapyr. A quantitative human health risk assessment of imazapyr, also an imidazolinone herbicide, is not required for registration review because the details are presented in a separate document (M. Sahafeyan, D417328, 03/05/2014). A quantitative human health risk assessment for another imidazolinone herbicide, imazaquin, is required and will be presented in a separate document.

The most recent human health risk assessments were performed as follows:  Imazamox (L. Venkateshwara, D416556, 05/28/2014),  Imazapic (W. Wassell, D384054 and D401585, 05/16/2013), and  Imazethapyr (H. Johnson, D321723, 11/07/2005).

The following risk assessment updates have been made for imazapic:  The chronic oral toxicity study in dogs was updated to reflect current practices in hazard evaluation. As a result, effects in the database were only noted in two studies at doses that are not considered relevant for human health risk assessment (>500 mg/kg/day). Therefore, no endpoints were selected for imazapic and a quantitative assessment is not needed.

The following risk assessment updates have been made for imazethapyr:  The toxicological database and endpoints were reevaluated. No effects were seen at doses relevant for human health risk assessment; therefore, a quantitative assessment is not needed for imazethapyr.

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Table of Contents 1.0 Executive Summary ...... 4 2.0 Risk Assessment Conclusions ...... 5 2.1 Data Deficiencies ...... 5 2.2 Tolerance Considerations ...... 6 2.2.1 International Harmonization ...... 6 2.3 Label Recommendations ...... 7 3.0 Introduction ...... 7 3.1 Chemical Identity and Physical/Chemical Characteristics ...... 7 3.2 Pesticide Use Pattern ...... 7 3.3 Anticipated Exposure Pathways ...... 8 3.4 Consideration of Environmental Justice ...... 8 4.0 Hazard Characterization and Dose-Response Assessment ...... 9 4.1 Endocrine Disruptor Screening Program ...... 10 5.0 Dietary Exposure, Residential and Aggregate Exposure, Non-Occupational Bystander Exposure, Non-Occupational Spray Drift Exposure and Occupational Exposure 11 6.0 Cumulative Exposure/Risk Characterization ...... 11 7.0 Incident and Epidemiological Data Review ...... 12 8.0 References ...... 15 Appendix A. Literature Search Details ...... 16 Appendix B. Toxicity Profile for Imazapic ...... 17

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1.0 Executive Summary

The HED has conducted a human health draft risk assessment (DRA) to evaluate all existing registrations of the active ingredients (ai) imazamox, imazapic and its ammonium salt, and imazethapyr and its ammonium salt. These herbicides are members of the imidazolinone class of chemicals that kills weeds by inhibiting the acetolactate synthase (ALS) enzyme, which is also known as acetohydroxyacid synthase (AHAS). This enzyme is involved in the synthesis of three branched-chain aliphatic amino acids. The inhibition causes a disruption in protein synthesis that leads to an interference in DNA synthesis and cell growth. These broad-spectrum contact herbicides target broadleaf weeds, annual or perennial grasses, and vine species in agricultural crops, aquatic areas, and on commercial and residential turf. This assessment was conducted as part of Registration Review.

Use Profile Imazamox, imazapic, and imazethapyr are currently registered for use on a variety of agricultural crops, non-crop areas, pasture and rangeland grasses, aquatic areas, and commercial and residential turf. The agricultural crops include alfalfa, beans (dry), canola, chicory, clover grown for seed, corn (field), edamame, legumes, lentil, lima bean (succulent), nongrass animal feeds, peas (dry), pea (English), peanuts, snap bean, soybean, sugarcane, rice, sunflower and wheat. The non-crop areas include railroad, highway, utility, and pipeline rights-of-way, and Conservation Reserve Program land. The commercial and residential turf areas include athletic fields, parks, residential lawns, sod farms, golf courses, and areas around schools/universities, libraries, and hospitals.

In addition, there are three Special Local Needs (SLN) registrations for imazamox which provide control of weeds in edamame and Ladino clover grown for seed, and provide for increased residues in irrigation water from the aquatic area use. There is one SLN registration for imazethapyr, which provides additional environmental precautions and soil-type restrictions for the soybean use, and one SLN for imazethapyr, ammonium salt for use on edamame.

Exposure Profile Humans may be exposed to imazamox, imazapic, and imazethapyr in food and drinking water since they may be applied directly to growing crops, and applications may result in them reaching surface and ground sources of drinking water. In an occupational setting, applicators may be exposed while handling the pesticides prior to application as well as during applications. There is also potential for post-application exposure for workers re-entering treated fields. In a residential setting, residential adult handlers may be exposed while handling imazamox, imazapic, and imazethapyr and adults and children may be exposed following outdoor applications. Non-occupational exposure resulting from spray drift from agricultural applications onto residential areas may also occur.

Hazard Characterization & Dose Response Assessment In the available guideline studies, imazamox, imazapic, and imazethapyr exhibited very low toxicity in mammalian systems, and no effects were seen at doses relevant for human health risk assessment. No additional toxicological studies are currently required, and additional safety factors to protect children are needed.

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Since no effects were seen in any guideline toxicity studies at doses relevant for human health risk assessment, no toxicological points of departure (PODs) were selected for imazamox, imazapic, and imazethapyr and, as a result, quantitative risk assessments are not required to support the currently registered uses.

Dietary, Residential and Aggregate, Non-Occupational Spray Drift, and Occupational Exposures and Risk Assessments The residue chemistry and dietary, residential, and occupational exposure databases are adequate to support current registration requirements of imazamox, imazapic, and imazethapyr. Due to the low toxicity of these active ingredients, quantitative exposure assessments are not required. Thus, HED concludes with reasonable certainty that dietary, residential, non-occupational and occupational exposures to imazamox, imazapic, and imazethapyr do not pose a significant human health risk.

Environmental Justice Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations.1” Furthermore, due to the low toxicity of these active ingredients, there are no environmental justice concerns.

Human Studies This risk assessment does not rely on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their exposure.

2.0 Risk Assessment Conclusions

HED determined that qualitative dietary, residential, non-occupational and occupational assessments are sufficient based on the low toxicities of imazamox, imazapic and imazethapyr. Therefore, HED concludes with reasonable certainty that exposures to imazamox, imazapic and imazethapyr do not pose a significant human health risk.

Tolerances are currently established in 180.447 for imazethapyr and 180.490 for imazapic. EPA has re-evaluated the toxicity databases for these chemicals and determined that these chemicals exhibit minimal toxicity. Therefore, EPA recommends establishing exemptions from the requirement of a tolerance for imazapic and imazethapyr concomitant with revoking the existing tolerances. Establishment of these exemptions would provide consistency among the three chemicals

2.1 Data Deficiencies

There are no data deficiencies for imazamox, imazapic, and imazethapyr.

1 https://www.epa.gov/laws-regulations/summary-executive-order-12898-federal-actions-address-environmental-justice

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Turf Transferable Residue (TTR) and Dislodgeable Foliar Residue (DFR): In accordance with the updated Part 158 data requirements (2007), one or more DFR studies are required when a pesticide has occupational uses that could result in post-application dermal exposure. Furthermore, TTR studies are required when a pesticide has turf uses that could result in residential post-application dermal or incidental oral exposures. However, since no quantitative exposure assessments are necessary for imazamox, imazapic, and imazethapyr, DFR or TTR studies are not required at this time.

2.2 Tolerance Considerations

A tolerance exemption has been established for imazamox in 180.1223; no changes to this exemption are recommended.

Tolerances are established in 180.447 for imazethapyr, and 180.490 for imazapic. EPA has reevaluated the toxicity databases for these chemicals and determined that these chemicals exhibit minimal toxicity. Therefore, EPA is recommending establishing exemptions from the requirement of a tolerance for imazapic and imazethapyr concomitant with revoking the existing tolerances. Establishment of these exemptions would provide consistency among the three chemicals.

2.2.1 International Harmonization

Tolerances are not established for residues of imazamox on food or feed commodities in the U.S. as imazamox is exempt from the requirement of a tolerance on all food commodities when applied as an herbicide in accordance with good agricultural practices. Furthermore, EPA is recommending establishing exemptions from the requirement of a tolerance for imazapic and imazethapyr.

Canadian Maximum Residue Limits (MRLs) are established for residues of imazamox in/on borage seeds, dry beans and peas, dry lentils, dry soybeans, sunflower seed, wheat, and poultry and ruminant commodities. The Canadian MRL expression includes residues of imazamox only. Mexico and Codex have not established MRLs for residues imazamox. HED concludes international harmonization is not an issue for imazamox.

There are currently no established Canadian or Mexican MRLs for imazapic. Codex MRLs exist for residues in/on grass hay or fodder at 3 ppm, peanut at 0.05 ppm, sugarcane at 0.01 ppm and livestock commodities. The Codex MRL expression for both plant and livestock commodities is for residues of imazapic only.

Canadian MRLs are established for residues of imazethapyr expressed as its ammonium salt in/on canola seed, dry soybean, dry legume, field corn grain, borage seeds, fenugreek seeds, and sunflower seeds. Mexico and Codex have not established MRLs for residues of imazethapyr.

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2.3 Label Recommendations

There are no label recommendations based on reviews of the dietary, residential, occupational, and non-occupational assessments and databases for imazamox, imazapic, and imazethapyr.

3.0 Introduction

3.1 Chemical Identity and Physical/Chemical Characteristics

The chemical structures and physical/chemical properties of imazamox, imazapic, and imazethapyr can be found in the following documents:

 Imazamox. Human-Health Assessment Scoping Document in Support of Registration Review; L. Venkateshwara; D417140; 06/05/2014.  Imazapic (129041) and the Ammonium Salt of Imazapic (128943); Human Health Assessment Scoping Document in Support of Registration Review; W. Wassell; D421209; 09/04/2014.  Imazethapyr. Human Health Assessment Scoping Document in Support of Registration Review; K. Lowe; D415244; 03/12/2014.

3.2 Pesticide Use Pattern

Imazamox is registered for use on alfalfa, beans (dry), chicory, clover grown for seed, edamame, lima bean (succulent) peas (dry), pea (English), snap bean, soybean, canola, lentil, rice, sunflower and wheat. It is also registered for control of vegetation in and around aquatic and noncropland sites including areas that may be grazed or cut for hay. In addition, there are three SLN Registrations for imazamox which provide control of weeds in edamame and Ladino clover grown for seed, and provide for increased residues in irrigation water. Imazamox is formulated as a liquid, granules, water-dispersible granules (WDG) in water-soluble packaging (WSP). Applications can be made using ground and aerial equipment at maximum application rates ranging from 0.047 – 0.91 lb ai/A. The restricted entry intervals (REIs) range from 4 – 12 hours.

Imazapic and its ammonium salt are registered for use on grass (pastures and rangeland), peanut, and non-crop areas including railroad, highway, utility, and pipeline rights-of-way, and Conservation Reserve Program land. Tolerances without a U.S. registration are established for imazapic in/on soybean and sugarcane. It is also used for residential spot-treatment for weed control on/in walkways, driveways, gravel pathways etc. It can be applied as a spot treatment (residential uses) or broadcast foliar application during the dormant or growing seasons. Imazapic and its ammonium salt are formulated as WDG, WDG in WSP, granules, emulsifiable concentrates (EC), soluble concentrates (SC), and ready-to-use liquids (RTU). Applications can be made using ground, aerial and handheld equipment at maximum application rates ranging from 0.063 – 0.98 lb ai/A and the REI is 12 hours.

Imazethapyr, as its acid or ammonium salt, is registered for use on legume vegetables (Group 6), nongrass animal feeds (Group 18), soybean, peanut, rice, and field corn. In addition, there is a tolerance without a U.S. registration on canola. It is also registered for use on turf, including

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highway rights of way, athletic fields, parks, residential lawns, sod farms, golf courses, and areas around schools/universities, libraries, hospitals, and commercial/industrial areas. In addition, there is one SLN Registration for imazethapyr, which provides additional environmental precautions and soil type restriction, and one SLN for imazethapyr, ammonium salt for use on edamame. Imazethapyr, as its acid or ammonium salt, is formulated as a liquid, dry flowable (DF), and wettable powder in WSP. Applications can be made using ground, aerial and handheld equipment at maximum application rates ranging from 0.003 – 0.95 lb ai/A. The REIs range from 4 – 48 hours.

3.3 Anticipated Exposure Pathways

Humans may be exposed to imazamox, imazapic, and imazethapyr in food and drinking water since they may be applied directly to growing crops and applications may result in them reaching surface and ground sources of drinking water. In an occupational setting, applicators may be exposed while handling the pesticides prior to application as well as during applications. There is also potential for post-application exposure for workers re-entering treated fields. In a residential setting, residential adult handlers may be exposed while handling imazamox, imazapic, and imazethapyr and adults and children may be exposed following outdoor applications. Non-occupational exposure resulting from spray drift from agricultural applications onto residential areas may also occur.

3.4 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (https://www.archives.gov/files/federal-register/executive-orders/pdf/12898.pdf). As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated. Spray drift can also potentially result in post-application exposure and it was considered in this analysis. Further considerations are also currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to other types of possible bystander exposures and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. Furthermore, due to the low toxicity of these active ingredients, there are no environmental justice concerns.

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4.0 Hazard Characterization and Dose-Response Assessment

The pesticidal mode of action of imazamox, imazapic, and imazethapyr involves inhibition of the ALS (or AHAS) enzyme. This plant enzyme plays a key role in the biosynthesis of the three branched-chain amino acids, leucine, isoleucine, and valine. While humans do have an ALS enzyme, its function is unknown. Valine, leucine, and isoleucine are essential amino acids, meaning they cannot be synthesized by mammals and must be ingested, indicating that the role of ALS in humans, if any, is likely different than in plants. Imazamox, imazapic, and imazethapyr demonstrate low toxicity in mammalian studies.

Imazamox Based on a weight-of-evidence approach, the Hazard and Science Policy Council (HASPOC) concluded that subchronic inhalation, immunotoxicity, and neurotoxicity (acute and subchronic) studies were not required for imazamox at this time (M. Perron; TXR# 0056929; 04/02/2014). A broad survey of the literature identified 3 studies, of which none were identified as containing information that would impact the draft human health risk assessment for imazamox (Appendix A). For imazamox, there were no effects seen in guideline studies up to doses approaching or exceeding the limit 1000 mg/kg/day. As stated in the human health scoping document in support of Registration Review (L. Venkateshwara; D417140; 06/05/2014), a qualitative assessment was determined to be sufficient based on the low toxicity of imazamox; therefore, endpoints were not selected. Available toxicology studies for imazamox are presented in Attachment 2 of the scoping document.

Imazapic Based on a weight-of-evidence approach, the HASPOC concluded that subchronic inhalation study was not required for imazapic at this time (J. Van Alstine; TXR# 0052356; 04/17/2012). A broad survey of the literature identified 2 studies, of which none were identified as containing information that would impact the draft human health risk assessment for imazapic (Appendix A). Endpoints were previously selected for imazapic; however, the toxicological database was reevaluated as part of Registration Review. The no-observed adverse-effect level (NOAEL) and lowest-observed adverse-effect level (LOAEL) for the chronic oral toxicity study in dogs was updated to reflect current practices in hazard evaluation. The NOAEL is 501 and 534 mg/kg/day in males and females, respectively. The LOAEL is 1,141 and 1,092 in males and females, respectively, based on decreased body weight, increased incidence of salivation and emesis, changes in hematological parameters, red blood cell morphology findings, changes in clinical chemistry parameters, gross pathology in the bone marrow, and histopathological findings. As a result, effects in the database were only noted in two studies at doses that are not considered relevant for human health risk assessment (>500 mg/kg/day). Therefore, no endpoints were selected for imazapic and a quantitative assessment is not needed. The available toxicology studies with the updated NOAEL/LOAEL for the chronic dog study is presented in Appendix A of this document.

Imazethapyr Based on a weight-of-evidence approach, the HASPOC concluded that subchronic inhalation, immunotoxicity, and neurotoxicity (acute and subchronic) studies were not required for

Page 9 of 19 Imazamox, Imazapic, Imazethapyr Human Health Risk Assessment DP Nos. 446950, 446951, 447462 imazethapyr (M. Perron; TXR# 0056841; 12/17/2013). A broad survey of the literature identified 8 studies (Appendix A), of which 2 have been considered as part of the epidemiology/incident report. The remaining 6 did not contain information that would impact the draft human health risk assessment for imazethapyr. Endpoints were previously selected for imazethapyr; however, the toxicological database and endpoints were reevaluated as part of Registration Review. No adverse effects were seen in subchronic and chronic oral toxicity studies in rats, mice, and dogs up to the highest doses tested (≥250 mg/kg/day), as well as a dermal toxicity study in rabbits up to 1096 mg/kg/day. The only effects were observed via gavage in maternal animals in the rat and rabbit developmental studies at or exceeding the limit. Therefore, no effects were seen at doses relevant for human health risk assessment and a quantitative assessment is not needed for imazethapyr. Available toxicology studies for imazethapyr are presented in Attachment 2 of the human health scoping document in support of Registration Review (K. Lowe; D415244; 03/12/2014).

4.1 Endocrine Disruptor Screening Program

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its most recent registration decision or reregistration decision for imazamox, imazapic, and imazethapyr, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), imazamox, imazapic, and imazethapyr are subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine-related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67

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chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list 2 of chemicals identified for EDSP screening was published on June 14, 2013 and includes some pesticides scheduled for registration review and chemicals found in water. Neither of these lists should be construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website3.

5.0 Dietary Exposure, Residential and Aggregate Exposure, Non-Occupational Bystander Exposure, Non-Occupational Spray Drift Exposure and Occupational Exposure

The residue chemistry and dietary, residential, and occupational exposure databases are adequate to support current registration requirements of imazamox, imazapic, and imazethapyr. Due to the low toxicity of these active ingredients, quantitative exposure assessments are not needed. HED concludes with reasonable certainty that dietary, residential, non-occupational and occupational exposures to imazamox, imazapic, and imazethapyr do not pose a significant human health risk.

Imazamox, imazapic, and imazethapyr have low acute toxicity via the oral, dermal and inhalation routes (Toxicity Categories III and IV). They are not eye (Toxicity Category III) or skin irritants (Toxicity Category IV) or shown to be skin sensitizers. Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute Toxicity III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12-hour REI. Therefore, the [156 subpart K] Worker Protection Statement (WPS) interim REI of 12 hours is adequate to protect agricultural workers from post-application exposures to imazamox, imazapic, and imazethapyr as required on the current labels.

The REIs on the registered labels for imazamox and imazethapyr range from 4 to 12 hours. While the Worker Protection Standard (WPS)-recommended REI for imazamox and imazethapyr based on their acute toxicity categories is 12 hours, REIs may be further reduced if certain criteria are met for both the technical material and the different end-use products in accordance with the Pesticide Registration (PR) Notice 95-3 [WPS Interim REIs for Certain Low Risk Pesticides]4. Imazamox and imazethapyr technical material meet the criteria for a reduction to a 4-hour REI.

6.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to imazamox, imazapic, and imazethapyr and any other substances and imazamox, imazapic, and

2 See https://www.regulations.gov/document?D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of chemicals. 3 http://www.epa.gov/endo 4 Available: http://www.epa.gov/PR_Notices/pr95-3.html

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imazethapyr do not appear to produce a toxic metabolite produced by other substances. For the purposes of this action, therefore, EPA has not assumed that imazamox, imazapic, and imazethapyr have a common mechanism of toxicity with other substances. In 2016, EPA’s Office of Pesticide Programs released a guidance document entitled, Pesticide Cumulative Risk Assessment: Framework for Screening Analysis5. This document provides guidance on how to screen groups of pesticides for cumulative evaluation using a two-step approach beginning with the evaluation of available toxicological information and if necessary, followed by a risk-based screening approach. This framework supplements the existing guidance documents for establishing common mechanism groups (CMGs)6 and conducting cumulative risk assessments (CRA)7. During Registration Review, the agency will utilize this framework to determine if the available toxicological data for imazamox, imazapic, and imazethapyr suggests a candidate CMG may be established with other pesticides. If a CMG is established, then a screening-level toxicology and exposure analysis may be conducted to provide an initial screen for multiple pesticide exposure.

7.0 Incident and Epidemiological Data Review

Based on the low frequency and severity of incident cases reported for imazamox and imazapic in both IDS and SENSOR-Pesticides, there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the registration review interim decision (E. Evans, D417802, 02/06/2014 and E. Evans, D421531, 07/31/2014).

Imazethapyr incidents were previously reviewed in 2013 (E. Evans et al, D416459, 12/19/2013). At that time, the following was concluded:

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 lymphohematopoietic 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.

In the current five-year IDS analysis from January 1, 2013 to June 25, 2018, one incident involving a single active ingredient and three incidents involving multiple active ingredients were reported to Main IDS; there were three cases reported to Aggregate IDS. A query of SENSOR-Pesticides 1998-2014 identified one incident involving imazethapyr.

5 https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/pesticide-cumulative-risk-assessment- framework 6 Guidance For Identifying Pesticide Chemicals and Other Substances that have a Common Mechanism of Toxicity (USEPA, 1999) 7 Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity (USEPA, 2002)

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The Agricultural Health Study (AHS) is a federally-funded study that evaluates associations between pesticide exposures and cancer and other health outcomes and represents a collaborative effort between the US National Cancer Institute (NCI), National Institute of Environmental Health Sciences (NIEHS), CDC’s National Institute of Occupational Safety and Health (NIOSH), and the US EPA. Imazethapyr is included in the AHS and these epidemiological findings are summarized are included. Overall, we considered the epidemiological evidence to be inadequate at this time to conclude that a clear associative or causal association between imazethapyr exposure and the carcinogenic and non-carcinogenic health outcomes assessed in the studies reported here. The Agency will continue to monitor the epidemiological literature relative to imazethapyr exposure.

Imazethapyr Epidemiology Conclusion

Published AHS studies investigating the potential association between imazethapyr and various health effects were reviewed. There were few studies per health outcome (generally, 1 – 4 studies per outcome) that investigated imazethapyr exposure. Overall, we conclude that there is inadequate evidence to suggest a clear associative or causal relationship between exposure to imazethapyr and any of the carcinogenic and non-carcinogenic health outcomes investigated in the studies reported here.[1] Specifically:

 With respect to carcinogenic effects, studies reported no evidence of a significant positive association between imazethapyr exposure and rectal cancer, colorectal cancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer, melanoma, oral cavity cancer, kidney cancer, lymphohematopoietic cancers (considered jointly), leukemia, multiple myeloma as well as all cancers (considered jointly).

For bladder cancer, two studies were reviewed, Koutros et al. (2009) and a later study, Koutros (2016) which updated the former study. Koutros (2009) reported evidence of a moderately strong association for intensity-weighted lifetime days of exposure to imazethapyr in the highest tertile only along with a significant p- trend. Nevertheless, there were only a small number of cases reported and no evidence of a significant positive association in any other exposure tertile. The Koutros et al. (2016) update on bladder cancer extended this earlier study with 6-7 years of additional follow-up and an additional 100 exposed cases. In this later follow-up study, an ever/never analysis showed no evidence of a significant positive association between imazethapyr exposure and risk of bladder cancer; when the data were subsequently categorized by exposure levels, a moderately strong statistically significant relationship was evident only in the bottom half of the top quartile, with all other quartiles (including the top half of Q4) showing non-statistically significant odds ratios that were all less than 1 and for which the p-for-trend was not significant. When the data was further stratified by smoking status, evidence of a positive association was seen only in the upper half of the highest imazethapyr

[1] Causality as defined by the Bradford-Hill considerations: strength of association, consistency of evidence, specificity of the association, temporality, dose-response, biological plausibility, and coherence with established knowledge. Via Hill, Austin Bradford. "The environment and disease: association or causation?" Proceedings of the Royal society of Medicine 58.5 (1965): 295.

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exposure quartile in the never smoking group and a significant p-trend was observed; there were no statistically significant results in the remaining quartiles or in any of the former- or current- smoking groups. Based on these results, we are unable to conclude that a clear associative or causal relationship exists relative to imazethapyr exposure at this time due to the small number of cases reported, the multiple comparisons made, and the negative results (OR= 1.03; 95% CI: 0.76, 1.4) observed for the larger ever/never analysis that was performed.

For colon cancer, one study (Lee et al., 2007) reported no evidence of a significant positive association between colon cancer and exposure to imazethapyr, based on ever-use. A second study (Koutros et al., 2009) reported evidence of a positive association relative to intensity-weighted lifetime days of exposure to imazethapyr in the highest tertile only, and with a significant p-trend. A further analysis was conducted by the authors relative to two sites of origin of colon cancer - the proximal colon[2] and the distal colon[3] – and evidence of a moderately strong association was observed only for proximal colon cancer and only in two exposure tertiles for imazethapyr. No evidence of a significant positive association was observed for distal colon cancer in any imazethapyr exposure tertile. Given the small number of cases involved, there is insufficient evidence at this time to conclude that there is a clear associative or causal relationship between exposure to imazethapyr and colon cancer.

 For non-carcinogenic effects, the studies reviewed reported no evidence of a significant positive association between imazethapyr exposure and thyroid disease, eye disorders, depression, sleep apnea, myocardial infarction, amyotrophic lateral sclerosis (ALS), suicide, birth weight, diabetes, asthma, chronic bronchitis, rhinitis, fatal injury, and Parkinson’s disease.

One study, Lebov et al. (2016), reported evidence of a positive association between imazethapyr exposure and ESRD among male pesticide applicators based on ever/never use. For intensity-weighted lifetime-days of exposure, evidence of a moderately strong association was observed between ESRD among male pesticide applicators and imazethapyr exposure in the mid-exposure tertile only. Given that a statistically significant, positive association was only observed in the mid-exposure tertile and there was no significant p-trend, there is insufficient evidence at this time to conclude that there is a clear associative or causal relationship between exposure to imazethapyr and ESRD.

Three studies (De Roos et al. 2005, Parks et al. 2016, Meyer et al. 2017) investigated the association between imazethapyr exposure and rheumatoid arthritis (RA) among male pesticide applicators and female spouses of pesticide applicators. For male pesticide applicators, evidence of a positive association was observed relative to imazethapyr exposure in the lowest tertile of exposure group only. No evidence of a

[2] The proximal colon included the following sites: cecum, appendix, ascending colon, hepatic flexure, and the transverse colon. [3] The distal colon included the following sites: splenic flexure, descending colon, and the sigmoid colon.

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significant positive association was observed between imazethapyr exposure and RA in female spouses of pesticide applicators in either study (De Roos et al. 2005, Parks et al. 2016). In total, we consider the evidence inadequate to conclude that there is a clear associative or causal relationship between exposure to imazethapyr and RA.

For wheeze, four studies (Hoppin et al. 2002, Hoppin et al. 2006a, Hoppin et al. 2006b, Hoppin et al. 2017) evaluated the association for imazethapyr exposure among pesticide applicators and two of these studies reported evidence of a slight positive association (Hoppin et al. 2006b, Hoppin et al. 2017). We consider these studies inadequate to conclude that there is a clear associative or causal relationship between exposure to imazethapyr and wheeze.

8.0 References

E. Evans; Imazamox: Tier I Review of Human Incidents; D417802; 02/06/2014

E. Evans; Imazapic & Imazapic Ammonium: Tier I Review of Human Incidents; D421531; 07/31/2014

E. Evans; Imazethapyr: Tier I Review of Human Incidents and Epidemiology for Draft Risk Assessment; D447493; 09/25/2018

H. Johnson; Imazethapyr: Human Health Risk Assessment for Tolerance Increase on Rice and Crayfish; D321723; 11/07/2005

K. Lowe; Imazethapyr. Human Health Assessment Scoping Document in Support of Registration Review; D415244; 03/12/2014

L. Venkateshwara; Imazamox: Human-Health Risk Assessment for Proposed Section 3 Uses to Increase the Maximum Use Rate for Sunflower. D416556, 05/28/2014

L. Venkateshwara; Imazamox. Human-Health Assessment Scoping Document in Support of Registration Review; D417140; 06/05/2014

W. Wassell; Imazapic. Human-Health Risk Assessment. Petition for Tolerances for Use on Soybeans and Sugarcane without U.S. Registration. D384054 and D401585, 05/16/2013

W. Wassell; Imazapic (129041) and the Ammonium Salt of Imazapic (128943); Human Health Assessment Scoping Document in Support of Registration Review; D421209; 09/04/2014

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Appendix A. Literature Search Details

Imazamox Search:

Date and Time of Search: 07/27/2018; 10:05 am Search Details: ((Imazamox)) AND (rat OR mouse OR dog OR rabbit OR monkey OR mammal) PubMed hits: 3

Imazapic Search:

Date and Time of Search: 07/27/2018; 1:14 pm Search Details: ((Imazapic)) AND (rat OR mouse OR dog OR rabbit OR monkey OR mammal) PubMed hits: 2

Imazethapyr Search:

Date and Time of Search: 07/27/2018; 10:32 am Search Details: ((Imazethapyr)) AND (rat OR mouse OR dog OR rabbit OR monkey OR mammal) PubMed hits: 8

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Appendix B. Toxicity Profile for Imazapic

Table B.1. Acute Toxicity Profile – Imazapic. Guideline No. Study Type MRID(s) Results Toxicity Category 870.1100 Acute oral [rat] 42711407 LD50 >5,000 IV mg/kg 870.1200 Acute dermal [New Zealand white 42711408 LD50 >2000 III rabbit] mg/kg 870.1300 Acute inhalation [rat] 42711409 LC50 >5.52 mg/L IV 870.2400 Acute eye irritation [New Zealand 42711410 minimal irritation III white rabbit] 870.2500 Acute dermal irritation [New 42711411 non-irritating IV Zealand white rabbit] 870.2600 Skin sensitization [guinea pig] 42711412 not a dermal sensitizer

Table B.2. Imazapic Subchronic, Chronic, and Other Toxicity Profile. Guideline Study Type MRID No. (year)/ Results No. Classification /Doses 870.3100 90-Day oral 42711419 (1992) NOAEL = 1522 mg/kg/day in males, 1728 toxicity (rat) Acceptable/guideline mg/kg/day in females (HDT). 0, 5000, 10000, 20000 LOAEL = not established. ppm M: 0, 386, 760, 1522 mg/kg/d F: 0, 429, 848, 1728 mg/kg/day 870.3200 21/28-Day dermal 42711420 (1992) NOAEL = 1000 mg/kg/day (males and toxicity (rabbit) Acceptable/guideline females). 0, 250, 500, 1000 LOAEL = not established. mg/kg/day 870.3700a Prenatal 42711422 (1992) Maternal NOAEL = 1000 mg/kg/day (HDT). developmental in Acceptable/guideline LOAEL = not established. (rat) 0, 250, 500, 1000 Developmental NOAEL = 1000 mg/kg/day. mg/kg/day LOAEL = not established. 870.3700b Prenatal 42711423 (1992) Maternal NOAEL = 350 mg/kg/day. developmental in Acceptable/guideline LOAEL = 500 mg/kg/day based on decreased (rabbit) 0, 175, 350, 500, 700 body-weight gain and food consumption. mg/kg/day Developmental NOAEL = 500 mg/kg/day. LOAEL = not established.

High mortality among animals at the 700 mg/kg/day precluded results from this dose level to be included in the determination of the NOAELs and LOAELs for maternal and developmental toxicity.

Note: This study was not updated to reflect current practices in hazard evaluation and may be considered conservative since updating would results in higher NOAEL/LOAEL values.

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Table B.2. Imazapic Subchronic, Chronic, and Other Toxicity Profile. Guideline Study Type MRID No. (year)/ Results No. Classification /Doses 870.3800 Reproduction and 43320305 (1994) Parental/Systemic NOAEL = 1205 mg/kg/day fertility effects Acceptable/guideline in males, 1,484 mg/kg/day in females (HDT). (rat) 0, 5000, 10000, 20000 LOAEL = not established. ppm Reproductive NOAEL = 1205 mg/kg/day in M: 0, 301, 605, 1205 males, 1,484 mg/kg/day in females. mg/kg/day LOAEL = not established. F: 0, 378, 737, 1484 Offspring NOAEL = 1,205 mg/kg/day in males, mg/kg/day 1,484 mg/kg/day in females. LOAEL = not established. 870.4100b Chronic toxicity 42711421 (1993) NOAEL = 501-534 mg/kg/day (M/F). (dog) Acceptable/guideline LOAEL = 1141/1092 mg/kg/day (M/F) based 0, 5000, 10000, 20000 on decreased body weight, increased incidence ppm of salivation and emesis, changes in M: 0, 137, 501, 1141 hematological parameters, RBC morphology mg/kg/day findings, decreased creatinine, increased F: 0, 180, 534, 1092 creatine kinase, increased ALT, increased AST, mg/kg/day gross pathology in the bone marrow, and histopathological findings (degeneration/necrosis and infiltrates in the diaphragm, skeletal muscle and esophagus; increased erythropoiesis in the spleen, bone marrow, and bone). 870.4300 Chronic/ 43320307 (1994) NOAEL = 1029 mg/kg/day in males, 1237 Carcinogenicity Acceptable/guideline mg/kg/day in females (HDT). (rat) 0, 5000, 10000, 20000 LOAEL = not established. ppm M: 0, 253, 505, 1029 No evidence of carcinogenicity. mg/kg/day F: 0, 308, 609, 1237 mg/kg/day 870.4300 Carcinogenicity 43320306 (1994) NOAEL = 1134 mg/kg/day in males, 1422 (mouse) Acceptable/guideline mg/kg/day in females (HDT). 0, 5000, 10000, 20000 LOAEL = not established. ppm M: 0, 271, 551, 1134 No evidence of carcinogenicity. mg/kg/day F: 0, 369, 733, 1422 mg/kg/day 870.5265 Ames Assay 42711424 (1992) Negative for reverse gene mutation in S. Acceptable/guideline typhimurium TA strains and E. coli WP2 at doses up to 5000 µg/plate. 870.5300 Chromosome 42711427 (1992) Negative for chromosome aberrations in CHO Aberration assay Acceptable/guideline cells exposed up to 3000 µg/mL, with/ without (in vitro) activation. 870.5375 Chromosome 42711426 (1992) Negative for aberrations in bone marrow cells Aberration assay Acceptable/guideline of rats treated orally up to 5000 mg/kg. (in vivo) 870.5385 Mutagenic- 42711425 (1992) Negative for forward mutation in CHO cells Forward Mutation Acceptable/guideline treated up to soluble levels (5000 µg/mL; 4000 µg/mL/+S9.

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Table B.2. Imazapic Subchronic, Chronic, and Other Toxicity Profile. Guideline Study Type MRID No. (year)/ Results No. Classification /Doses 870.5550 Mutagenic- 42711428 (1992) Reportedly negative for inducing UDS in rat Unscheduled Unacceptable/ guideline hepatocytes at doses greater than 1000 µg/ mL DNA Synthesis (excess precipitation), but lower (soluble) doses not evaluated. 870.6200a Acute 48468902 (2011) NOAEL = 2000 mg/kg bw. neurotoxicity Acceptable/guideline LOAEL = not established. screening battery 0, 200, 600, or 2000 (rat) mg/kg bw 870.6200b Subchronic 48490201 (2011) NOAEL = 1038/927 mg/kg/day [M/F]. neurotoxicity Acceptable/guideline LOAEL = not established. screening battery 0, 98/97, 292/287, and (rat) 1038/927 mg/kg bw/day [M/F] 870.7485 Metabolism and 42711429 (1993) Total recovery of the administered dose was pharmacokinetics Acceptable/guideline 98-106% at 7 days. Urinary excretion was the (rat) 10 or 1000 mg/kg major route of elimination (94-102% of the dose), with only unchanged parent detected. There was no evidence of bioaccumulation in the tissues. There were no sex- or dose-related differences following oral or intravenous administration. 870.7800 Immunotoxicity 48468901 (2011) Systemic NOAEL = 1364 mg/kg/day. (mice) Acceptable/guideline Systemic LOAEL = not established. Immunotoxicity NOAEL = 1364 mg/kg/day. 0, 500, 1500, 5000 ppm Immunotoxicity LOAEL = not established. (equivalent to 0, 130, 450, (There were no treatment-related effects on 1364 mg/kg/day [F]) spleen or thymus weights, or the sheep red blood cell assay).

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