### .\,)~,~tosr.qr<>.r. 

### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY [

# ~**~** WASHINGTON,D.C. 20460

0 'f**~** .l'**"''~-r** c."'.p

'I (**O~ ~**  O F FIC E O F C HEMI C AL SAFETY AND PO LL UTION PR E VEN T ION 

### MEMORANDUM

Date:

Subject: 04-SEP-20 14

Imazapic (129041) and the Ammonium Salt oflmazapic (128943); Human Hea l th Assessment Scoping Document in Support of Registration Review.

PC Code: 129041 (imazapic) 128943 (imazap i cammonium salt) DP Barcode: 0421209

Decision No.: 492629 Regist ration Nos.: 241-381, 241-393

, 241-409, 241-417,2935-557,71368-99, 7969 -320 Petition No.: None Regulatory Registration Review Scoping Actions: Document Risk Assessment Type: Not Applicable Case No.: TXRNo.: NA CAS No.: · 104098-48-8 (imazapic) I 04098-49-9

MRID No.:



### From:

Through:

To: (imazapic-ammonium salt) None 40 CFR: § 180.490



### William D. Wassell, Chemist 

# /WI}**~-lf'/~ 0/)**  Anwar Y. 

### Dunbar, Ph.D., Pharmacologist 

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### Lata V enkateshwara, Environmen ta l Scientist 

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### Risk Assessment Branch 1 (RAB 1) Health Effects Division (HED, 7509P)

Charles W. Smith lll, Branch Chief ,--- . .

# 0~ George F. Kramer, Ph.D., Senior**Chemi ~'-!:::V"illiiiiiJ!II!~~::::=:~~~**  

### ... 

### <-':<':::-'

___ _ RAB1/HED (7509P)**·** 

### .

Thomas Moriarty!Ricardo Jone s, RM-51 Risk Management & Im p lem en tation Branch I Pesticide Re-Evaluation Di vis ion (PRD, 7508P)

Attached is RED's human health risk assessment scoping document for imazapic and the

ammo nium salt of imazapic to suppo rt Registration Review.

Executive Summary

Imazapic (2-[ 4,5-d ih ydro-4-methyl-4-(1-me thy lethy l)-5-oxo-1 H -irnidazol- 2 -yl ] -5-meth yl-3- pyridinecarboxylic acid] and the ammonium sa lt of imazapic [2-( 4 ; 5-dihydro-4-methyl-4-( lmethylethyl)-5-oxo-1H-imidazol-2-yl)-5

- methyl-3-pyridinecarboxylic acid monoammonium salt] are im idazo lin one herbicides that target broadle afweeds, annual or perennial grasses, and vine species. Throughout this document the active ingredient 

### (ai) is primarily referred to as imazapic. Imazapic is registered for agricultural uses on grass (pastures and rangeland), peanutImazapic Registration Review Human health Assessment Scoping Document 

### and for use in residential settings, non-crop areas including railroad, highway

, utility, and pipeline rights-of-way, and Conservation Reserve Program land. Toleranc es without U .S. registration are established for residues inion soybeans and s ugarcan e. Additionally, tole rances for re sidues of imazapic in li vestock commodities are established. Ima zapic may be applied as a spot-treatment or broadcast foliar application during the dorma n t or growing seasons.

The most recent risk assessment for a Section 3 registration of agricultural uses for imazapic was completed in 2013 (Memo, W. Wassell, 

### et al., 05/16/2013; 0384709).

HED has evaluated the status of th e human health assessments for imazapic to determine whether sufficien t data are available and whether any updates are needed to s upport Registration Review. The most recent h uma n health risk assessments for imazap ic were considered with respect to its toxicity, exposure, usage databases, and the most updated Agency science policy and r is k assessment methodologies to determine the scope of work n ecessary to suppo rt Registration Review.

The toxicity database is adequate and complete to sup port Registration Review. No new toxicological data are required. HED does not an ticipa te the need to revise the tox icolo gical endpo int s, points of departure

, or safety factors for imazapic during Regis tra tion Review.

The imazapic residue chemistry database is sufficient to assess dietary expos u re for Registration

. Review. T h e most recent dietary exposure assessment was completed on 05/19/2013 (Memo, W. Wassell, D384709). An acute dietary exposure assessment was not required for imazapic since

an acute oral endpoin t attributed to a si n gle-dose exposure could not be identified in any of the studies in the tox icology database. The chronic exposure estimate is < 1.0% of the chronic
pop ulation -adjusted do se (cPAD) for th e U.S. popula t ion

. The most highly exposed popu la t ion

s ubgroup was children 1 to 2 years old, which utilized 4.0% of the cPAD. Thus, chronic dietary
exposure to imazapic is not of concern.

There are currently no established Canadian, or Mexican maximum re sidue limits (MRLs) for imazapic (see Attachment 5). Codex MRLs exist for residues of imazapic in or on grass hay or fodder at 3 ppm, peanut at 0.05 ppm, sugarcane at 0.01 ppm and livestock commodities. The established MRLs for re sidues inion grass, peanut, and sugarcane are significantly lower tha n established U.S. tol era nces. The U.S. tolerance expression for plant commodities includ es the parent and two metabolites, while the U .S. tolerance expression for livestock commodities consists of parent plus a metabolite and th e Codex MRL express ion is for imazapic only

. Despite the differences in the tole rance / MRL expressions and the magnitude in the differences between U.S

. tolerances and Codex MRLs, harmonization oftolerances/MRLs will be considered during Registration Review.

There is sufficient informa tio n available to assess residential exposure resulting from residential spot-treatment for weed control for Registration Review. During Registration Review, all · residential handler inhalation exposure scenarios need to be assessed using HED's 2012 Residential Standard Operating Procedures (SOPs) along with policy changes for body weights and current to xicological endpoints. The need for spray drift and volatilizat ion risk assessment for imazapic will also be examined during Regis tra tion Review.

T h ere is sufficient i nformation available to assess occupational handler exposure associated with agricultural uses of imazapic for Registration Re view. Currently, the re are no short

- and intermediate-tenn dermal points of departure (PODs) for imazapic; th us , a derma l
Page 2 of25Imazapic Registration Review Human health Assessment Scoping Document

Page 3 of 25 

### postapplication exposure assessment is not necessary for imazapic. During Registration Review

, occupational handler inhalation ex posure assessments need to be performed for the scenarios that have not been previously assessed. In addition, the need for a quantitative occupational postapplication inhalation exposure assessment will be considered for imazapic during Registration Revi ew

.

1.0 Introduction

Imazapic is an imidazolinone herbicide that targets broadleaf weeds and annual or perennial grasses. It can be used as both a pre

- emergent or post

- emergent herbicide. The herbicidal activity of imazapic, as an imidazolinone, is due to the inhibition of acetohydroxyacid synthetase (AHAS), which is a key plant enzyme in the biosynthesis of the amino acids leucine, isoleucine, and valine. Imazapic is registered for use on grass (pastures and rangeland), peanut, and non

crop areas i ncluding 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 we ed control. This includes 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. There are no pending PRIA actions for imazapic . The most recent risk assessment for a Section 3 registration of agricultural uses of imazapic was completed in 2013 (Memo, 5/16/2013, W. Wassell, et al ., D384054).

No data deficiencies were identified for imazapic however EPA anticipates conducting the followin g risk assessment updates during Registration Review :
Toxicology:

o None.

Residue Chemistry/Dietary and Aggregate Exposure:

o A revised dietary exposure analysis may be required to reflect the most recent dietary exposure models , policies, and potential revised estimated drinking water concentrations (EDWCs)

. Aggregate Exposure:

o A revised aggregate risk assessment may be r equired during Registration Review to incorporate revised dietary exposure analyses and/or residential exposure assessments.

Occupational and Residential Exposure:

o Revised occupational and residential exposure assessments to cover all registered uses and formulations, accounting for maxi mum application rates, and/or policy changes may be required during Registration Review

. o The need for spray drift and volatilization risk assessments for imazapic will be examined during Registration Review

.Imazapic Registration Review Human health Assessment Scoping Document

Page 4 of 25 

### 2.0 Hazard Identification/Toxicology

The t oxicity database for imazapic is adequate to support Registration Review

. Imazapic was well absorbed into the body following oral exposure and urinary excretion was the major route of elimination, with only unchanged parent detected. There was no eviden ce of bioaccumulation of imazapic in tissues. Additionally, there were no sex

- or dose

- related differences following oral or intravenous administ ration.

Imazapic does not appear to be toxic to rodents via the oral or dermal routes. Following repeated oral administration for 90 days to rats and dermal applications for 21 days to rabbits, no toxicity was observed. In the one

- year dog feeding study, minimal degeneration, and/or necrosis of the skeletal muscle of the thigh and/or abdomen in both sexes was seen at the lowest dose tested for both sexes. At higher doses, additional effects were seen in the liver ( increased ( ↑ ) absolute weights and changes in cl inical chemical parameters), kidney ( decreased ( ↓ ) urinary pH in females), and erythropoietic system (changes in hematological parameters and microscopic changes in the bone marrow and spleen). At the high dose, there was also inflammation in th e esophagu s similar to that in skeletal muscle as well as discoloration of the lung in both sexes. In the developmental toxicity study with rats, no maternal or developmental toxicity was seen at the limit dose.

There were no developmental effects in rats or rabb it fetuses up to the highest doses tested. In the two

- generation reproduction study, no parental, offspring or reproductive toxicity was seen up to the limit dose.

There was no evidence of neurotoxicity (clinical signs or neuropathology) at the limit dose in the acute and subchronic neurotoxicity studies. There is no evidence of immunotoxicity for imazapic.

In an acceptable battery of mutagenicity studies, imazapi c was negative in forward and reverse gene mutation assays, and was negative in both the in vitro and in vivo cytogenetic assays. Based on these results, it is concluded that the overall mutagenic potential of imazapic is negative.

Imazapic has been clas sified by the RfD/Peer Review Committee as a “Group E” c hemical

- not likely to be a human carcinogen by any relevant route of administration based on the absence of carcinogenicity in acceptable studies in mice and rats.

Imazapic was categorized as having low acute toxicity by the oral, inhalation, and dermal routes of exposure (Toxicity Category IV). It is minimally irritating to the eye (Toxicity Category III) and non

- irritating to the skin (Toxicity Category IV ).

Food Quality Protection Act (FQPA) Con siderations

The toxicology database is complete for imazapic

. Using a weight of evidence approach considering all available hazard and exposure data, HED’s Hazard Science and Policy Council (HASPOC) determined that a repeated exposure subchronic inhalation toxicity study is not required at this time (Memo, 04/17/2012 , J. Van Alstine, TXR# 0052356)

. The FQPA Safety Factor is reduced (i.e., 1X) since the toxicology and exposure databases are complete and there are no residual uncertainties for pre and or post natal toxicity

. In addition to the conventionalImazapic Registration Review Human health Assessment Scoping Document

Page 5 of 25 

### 100X uncert ainty factor , an additional 10X uncertainty factor is applied for the use of a lowest

observed adverse

- effect level (LOAEL ; UF L 

### ) to derive the chronic r eference d ose (cRfD).

Conclusion s The toxicity database for imazapic is complete. No new data are exp ected and for the next action, the endpoints, doses, and safety factors used in the most recent human health risk assessments should be used for the next assessment.

3.0 Residue Chemistry

The nature of the imazap ic residues in plants is adequately understood based on adequate metabolism studies utilizing peanuts, grass, sugarcane, and genetically modified ( GMO ) soybeans. T he HED Metabolism Assessment Review Committee ( MARC ) determined that the residues of concern in grass (and peanuts) include imazapic and its hydroxymethyl metabolite, both free and conjugated ( metabolites CL 263,284 and CL 189,215 ) . In soybean and sugarcane

, imazapic , the hydroxymethyl metabolite CL 263,28 4 and its glucose conjugate (CL 189,215)

w ere also identified. Based upon the soybean and sugarcane data and the previous MARC decision, HED concludes the residues of concern in plant commodities are imazapic and its hydroxymethyl metabolite, both free an d conjugated (metabolites CL 263,284 and CL 189,215).

Ruminant feed items are derived from soybean, peanut, grass, and sugarcane commodities. Data concerning the metabolism of imazapic in lactating goats and laying hens were previously submitted. T he MARC determined that the residues of concern in livestock commodities include imazapic and CL 263

, 284.

Poultry feed items are derived from soybean and peanut commodities. A poultry metabolism study was previously submitted. On the basis of this study an d the dietary burden for poultry, HED concludes that there is no reasonable expectation of finite residues of imazapic in poultry commodities based on the use s on peanuts and/or soybean [Category 3 of 40 CFR §180.6(a)], and therefore , there is no need for secondary tolerances in poultry tissues and eggs.

Adequate capillary electrophoresis (CE) methods (CE method M 3114 and CE method M 2379) are available for the enforcement of tolerances for residues in grass and peanut commodities, respectively. Residu es are quantified by analysis using CE. The validated method limit of quantification (LOQ) is 0.50 and 0.05 ppm for each analyte in grass and peanut commodities

, respectively

.

CE methods M 3188 and M 3222 are available for enforcement of tolerances for imazapic and its metabolite CL 263,284 in milk (method M 3188) and livestock tissues (method M 3222). Additionally, high

- performance liquid chromatography (HPLC)/MS method M 3233 is available for enforcement of tolerances for imazapic and CL 263,284 in f at. The method LOQs were reported as 0.010 ppm for milk and 0.050 ppm for tissues.

An a dequate confined rotational crop study has been submitted. In this study, winter wheat, spring wheat, carrots, and lettuce were planted at intervals of 181, 318, a nd 363 days, respectively in a field treated with [ 14 

### C]imazapic at 0.195 lb ai/A (the maximum proposed seasonal use)

. Total radioactive residues (TRR s ) were <0.01 ppm in all crops. Although the TRRs in all rotational crops at the various PBIs were < 0.01 ppm, the petitioner subjected crop commodities with TRR >0.003 ppm to characterization/identification procedures. Residues ofImazapic Registration Review Human health Assessment Scoping Document

Page 6 of 25 

### imazapic, CL 263

, 284, CL 189

, 215, and CL 312

, 622 were identified in all rotational crop matrices at  0.001 ppm.

Establish ed PBIs are as follows:

Minimum p lantback intervals for Plateau ® DG Herbicide (EPA Reg. No. 241

- 393) 4 Months 9 Months 18 Months 26 Months 40 Months Bahiagrass Rye Wheat Field Corn

Snap B ean Southern Pea Soybean Tobacco Barley

Cotton Grain Sorghum Oats Sweet Corn All crops not

otherwise listed Canola

Potato Red Table Beet Sugar Beet

Minimum Plantback intervals for Plateau ® Herbicide (EPA Reg. No. 241

- 365) 12 Months 12 to 18 Months 1 18 to 24 Months 1 26 to 36 Months 1 40 to 48 Months 1 Bahiagrass Clearfield corn hybrids Peanut Rye Wheat Snap B eans

Southern Peas Soybeans Tobacco Barley

Cotton Grain Sorghum Oats Field Corn

All crops not otherwise listed Canola

Potato Red Table Beet Sugar Beet

1 Minimum interval based on application rate of ≤4 oz/A and maximum rate based on application rate of 9 to 12 oz/A.



### HED previously concluded t he 4

- month PBI for rye and wheat and 9

- month PBI for legume vegetables are not currently supported by rotational c rop data and requested data to support these intervals. HED has reconsidered these requirements and has conclude d the establish ed PBI s are adequate. This conclusion is based on the following:

 All samples in the confined rotation crop study exhibited T RRs of <0.01 ppm

 All samples were extracted and the extracts were analyzed for the residues of concern.

 Residues levels in all commodities were ≤ 

### 0.001 ppm for all residues of concern.

Imazapic is registered for use on grass (pastures and rangeland) and peanut . Tolerances without U.S. registration are established for soybean and sugarcane

. Adequate field trial data are available and support th e established uses.

Conclusions The residue chemistry database is adequate to support Registration Review of imazapic. The qualitative nature of imazapic residues in plants and livestock is adequately understood. The residue s of regulatory concern for tolerance setting and risk assessment purposes for plant commodities (primary and secondary crops) are imazapic and its hydroxymethyl metabolite, both free and conjugated ( metabolites CL 263,284 and CL 189,215 )

. The residues of regulatory concern for tolerance setting and risk assessment purposes for livestock commodities are imazapic and its hydroxymethyl metabolite (CL 263,284). Tolerances are established for secondary residues of imazapic in ruminant meat, meat byproduct, fat, and milk. A dequate confined rotational crop data are available and support the label

- specified PBI s

.

4.0 Dietary Exposure

The most recent dietary

- exposure assessment for imazapic was performed in conjunction with petitions for the use of imazapic on sugarcane and GMO soybeans without U.S. registration. AnImazapic Registration Review Human health Assessment Scoping Document

Page 7 of 25 

### acute dietary exposure assessment was not performed for imazapic since an acute oral endpoint attributed to a single

- dose exposure could not be identified in any of the studies in the toxicology database. Imazapic chronic dietary (food plus drinking water) exposure assessments were conducted using the Dietary Exposure Evalu ation Model software with the Food Commodity Intake Database (DEEM

- FCID)

, Version 3.16, which uses food consumption data from the U.S. Department of Agriculture’s (USDA’s) Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994

- 19 96, and 1998.

The chronic analyses were unrefined and assumed 100% CT and tolerance

- level residues for all commodities included in the assessment. The DEEM (ver. 7.81) default processing factor for peanut butter was assumed. The processing factors for soybean, suga rcane, and peanut (except peanut butter) commodities were reduced to 1 X , based upon processing data. The FQPA Index Reservoir Screening Tool (FIRST) and Generic Estimated Environmental Concentration (GENEEC2) models were used for Tier 1 drinking water ass essments. The EDWCs used in the chronic analysis was 13.73 μg/L (Memo, 5/10/2001, J. Wolf, D267288; and Memo, 5/23/2001, J. Wolf, D267288A (Addendum)).

. The chronic dietary exposure was estimated to be <1.0% of the cPAD for the U.S. population. The most highly exposed population subgroup was children 1 to 2 years old

, which utilized 4.0% of the cPAD. Thus, chronic dietary exposure to imazapic is not of concern.

Conclusions The dietary

- exposure database is adequate to support Registration Review of imazapic. In the most recent risk assessment, chronic dietary exposures were not of concern to HED. However, as part of Registration Review , a revised dietary exposure analysis may be required to reflect the most recent dietary exposure models and po tential revised EDWCs.

5.0 Residential Exposure

Imazapic is registered for use as a residential spot treatment for weed control. There are four imazapic

- ammonium salt (128943) products currently registered for use by homeowners. The four products are MON 78868 Herbicide (71995

- 38), RD 1653 Herbicide (71995

- 47), RD 1687 Herbicide (71995

- 51) and M1739 Herbicide (71995

- 54). The use sites include walkways, driveways, gravel pathways, parking areas, brick patios, along fences, foundations and curbs, on

cr acks and crevices in concrete sidewalks, driveways, patios and tennis courts, areas around the base of well

- established ornamental plants, shrubs or trees, decorative rock, mulch or bark landscapes, alo ng the edge of lawns, tree rings, and retaining walls. It is not intended for broadcast use or use on residential lawns or for lawn renovation. A s ummary of residential uses is listed in Attachment 3 (Tables 9 and 10 ).

Residential Handlers

HED has previously assessed the use of imazapic for residential spot treatment of weed control (Memo, 10/16/03, M. Dow, D294111). The products registered for residential spot treatment can be applied by homeowners; therefore, short

- term residential handler dermal and inhalation exposure is expected. However, since no short

- term dermal PODs were selected, only residential handler inhalation exposures were assessed. Residential handler exposure was assessed at a rate of 0.00077 lb ai/gallon for spray applications. The results of the residential handler exposure and ri sk assessment indicate that inhalation risks do not exceed HED’s level of concern ( LOC; i.e., margins of exposure (MOEs) greater than 100) for any of the use scenarios. See Table 12Imazapic Registration Review Human health Assessment Scoping Document

Page 8 of 25 

### (Attachment 3) for a sum mary of assessed residential handler use patterns and corresponding MOEs.

A review of the currently registered labels indicates that one of the labels (71995

- 47) does not have an explicit application rate. The residential handler assessment for this scenario may need to be revised based on the new re sidential SOPs. In addition, all residential exposure scenarios need to be assessed using HED’s 2012 Residential SOPs along with policy changes for body weights and current toxicological endpoints.

Residential Post

- Application

Imazapic can be applied as a residential spot

- treatment for weed control; therefore, there is the potential for residential postapplication exposure. However, per HED’s 2012 Residential SOPs, residential post

- application assessments do not need to be performed if label directions indicate the turf use is a specific spot treatment

. These types of uses can result in residues on turf but residential exposure is expected to be negligible.

Application Volatilization/Spray Drift

Volatilization/Spray Drift

Residential bystander expos ures resulting from off

- site transport (e.g., spray drift or volatilization) may occur as a result of applications of imazapic. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process that ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) SOPs for Residential Risk Assessment

– Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consider ation of Spray Drift (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2013

- 0676). This document outlines the quantification of indirect non

- occupational exposure to drift.

In terms of volatilization, the agency has developed a Volatilization Scree ning Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219 ). During Registration Review , the agency w ill utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for specific chemicals.

Conclusions There is sufficient information available to assess residential exposure. During Registration Review , all residential handler inhalation exposure scenarios need to be assessed using HED’s 2012 Residential SOPs along with policy changes for body weights an d current toxicological endpoints

. The need for spray drift and volatilization risk assessment for imazapic will also be examined during Registration Review

.

6.0 Aggregate Risk Assessment

The most recent aggregate

- risk assessment was performed in conjunction with the 2013 HED human

- health risk assessment. An acute aggregate risk assessment was not performed because an endpoint of concern attributable to a single oral dose was not selected for any population subgroup (including infants and children). A chronic aggregate (food + drinking water) risk assessment was conducted and the chronic aggregate (food + drinking water) exposure and riskImazapic Registration Review Human health Assessment Scoping Document

Page 9 of 25 

### estimates did not exceed HED's LOC. Short

- and int ermediate

- term aggregate risk assessments have not previously been performed and will need to be conducted during Registration Review

. A cancer aggregate risk assessment is not required because imazapic is not carcinogenic. The chronic aggregate (food + drinking water) exposure and risk estimates did not exceed HED's LOC.

Conclusions There is sufficient information available to assess aggregate exposure. A new aggregate risk assessment may be required during Registration Review to incorporate revised di etary exposure analyses and/or residential exposure assessments.

7.0 Occupational Exposure

Imazapic containing herbicides are used for weed control in peanuts, p astures, rangeland, and other non

- crop areas. Based on these uses, there is a potential fo r exposure to imazapic in occupational scenarios from handling imazapic products during the application process (i.e., mixer/loaders, applicators, flaggers, and mixer/loader/applicators) and a potential for post

application worker exposure from entering in to areas previously treated with imazapic. A summary of occupational uses is listed in Attachment 3 as Tables 12 and 13

. Occupational Handlers

No chemical

- specific data were available with which to assess potential exposure to pesticide handlers. The refore, occupational handler assessments were based primarily on surrogate unit exposures from the Pesticide Handlers Exposure Database (PHED) as presented in the PHED Surrogate Exposure Guide and from the Outdoor Residential Exposure Task Force (ORETF). The risk calculations were based on maximum application rates and assuming maximum area treated per day. The currently registered occupationa l use patterns, maximum application rates, and formulations are provided in Tables 12 and 13

. Occupational handler assessments have not been performed for the following use scenarios:

 All granular formulation scenarios (aerial and ground).

 All emulsifiable concentrate and soluble concentrate scenarios (aerial, ground and backpack sprayer).

 All ready

- to

- use spray container scenarios.

 All wettable

- powder/water

- soluble bag formulation scenarios.

 All backpack mixer/loader/applicator scenarios for wat er dispersible granule in water

soluble bag at rates higher than 0.83 lb ai/day.

Occupational Post

- application

An appropriate POD attributable to short

- and intermediate

- term exposure through the dermal route for imazapic was not identified. Therefor e, dermal postapplication exposure assessments are not required for imazapic. Based on the Agency's current practices, a quantitative occupational postapplication inhalation exposure assessment has not been performed for imazapic. However, there are mult iple potential sources of postapplication inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates th atImazapic Registration Review Human health Assessment Scoping Document

Page 10 of 25 

### contain pesticides. In terms of volatilization, the agency has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219). During Registration Review

, the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for specific chemicals.

Conclusions There is sufficient information available to assess occup ational postapplication exposure for Registration Review . Currently, there are no short

- and intermediate

- term dermal PODs for imazapic; thus, a dermal postapplication exposure assessment is not necessary for imazapic. During Registration Review , occupat ional handler inhalation exposure assessments need to be performed for the scenarios that have not been previously assessed. In addition, the need for a quantitative occupational postapplication inhalation exposure assessment will be considered for imazap ic during Registration Review

.

8.0 Public Health and Pesticide Epidemiology Data

An updated review of imazapic incident reports was recently prepared by HED (Memo, 07/16/2014, E. Evans, D421531). For this evaluation, the OPP Incident Data System (IDS) was consulted for pesticide incident data on the active ingredient imazapic and imazapic

- ammonium salt. Imazapic and imazapic

- ammonium salt data from the Agricultural Health Study (AHS) were also considered. The report represents incidents occurring in t he U.S. from 2009 to the present.

For this evaluation, the OPP IDS was utilized for pesticide incident data on the active ingredient imazapic and imazapic

- ammonium salt. The purpose of the database search is to identify potential patterns on the frequenc y and severity of the health effects attributed to imazapic exposure. The 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 compiles these reports in IDS. IDS contains reports from across the U.S. and most incidents have all relevant product information recor ded. Reports submitted to the IDS represent anecdotal reports or allegations only, unless otherwise stated in the report. There were zero incidents reported for imazapic and single chemical imazapic

ammonium salt in the database. However, there were 22 incidents reported for products that contained more than one active ingredient for imazapic

- ammonium salt. All cases involved products that contained multiple active ingredients. Twelve cases involved Glyphosate Residual Concentrate (EPA Reg. No. 7199

- 40 ); and six cases were Round

- Up ready

- to

- use products). Three cases were work

- related and 17 cases were non

- occupational. All 20 cases were low severity. The most commonly reported case symptoms were ocular such as eye irritation followed by gastrointest inal symptoms such as nausea.

For IDS aggregate summaries, from January 1, 2009 to March 5, 2014, there are no incidents reported for imazapic and 442 incidents reported involving imazapic

- ammonium salt. These incidents were classified as minor severit y. An incident classified as m inor severity is one in which a person alleged or exhibited some symptoms, but the symptoms were minimally traumatic and the symptoms resolved rapidly and usually involved skin, eye, or respiratory irritation. These are summ arized in more detail in the 2014 HED imazapic and imazapic

ammonium salt incident report.Imazapic Registration Review Human health Assessment Scoping Document

Page 11 of 25 

### Conclusions No incidents were identified for imazapic. A moderate frequency of incidents involving imazapic

- ammonium salt were identified in IDS, all of which involved multiple active ingredients, primarily glyphosate. Further, the imazapic

- ammonium salt incidents identified were all low in severity. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk assessment.

9.0 Tolerance Assessment and International Harmonization

U.S. permanent tolerances (listed in 40 CFR §180.490) and Mexican, Canadian, and Codex MRLs are summarized in Attachment 5.

There are currently no esta blished 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 established MRLs for residues in/on grass, peanut, and sugarcane

are significantly lower than established U.S. tolerances. The tolerance expression for U.S. tolerances on plant commodities includes the parent and two metabolites, while the U.S. tolerance expression for livestock commodities consists of parent plus a metab olite . T he Codex MRL expression for both plant and livestock commodities is for residues of imazapic only. Despite the differences in the tolerance/MRL expressions and the magnitude in the differences between U.S. tolerances and Codex MRLs, harmonization of tolerances/MRLs will be considered during Registration Review.

10.0 Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the human health risk assessment, in accordance with U.S. Executi ve Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations,” (http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). The OPP typically considers the highest potential exposures from the legal use of a pesticide when conducting human health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., and people who may be exposed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best available information.

11.0 Cumulative

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 for imazapic and any other substances; and imazapic does not appear to produce a toxic metabolite produced by other substances. Therefore, EPA has assumed that imazapic does not have a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statemen ts released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.Imazapic Registration Review Human health Assessment Scoping Document

Page 12 of 25 

### 12.0 Human Studies

Past imazapic risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pe sticides, comprise generic pesticide exposure databases such as PHED and the Agricultural Reentry Task Force (ARTF) Database. EPA has reviewed all the studies in these multi

- pesticide generic exposure databases, and based

on available evidence has found t hem to have been neither fundamentally unethical nor significantly deficient relative to standards of ethical research conduct prevailing when they were conducted. There is no regulatory barrier to continued reliance on these studies, and all applicable r equirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR § 26) have been satisfied.

13.0 Data Requirements and Risk Assessment Updates Required Under Registration Review :
No data deficiencies were identified for imazapic however EPA anticipates conducting the following risk assessment updates during Registration Review :
Toxicology:

o None.

Residue Chemistry/Dietary and Aggregate Exposure:

o A revised dietary exposure analys is may be required to reflect the most recent dietary exposure models and potential revised EDWCs.

Aggregate Exposure:

o A revised aggregate risk assessment may be required during Registration Review to incorporate revised dietary exposure analyses and/or r esidential exposure assessments.

Occupational and Residential Exposure:

o Revised occupational and residential exposure assessments to cover all registered uses and formulations, accounting for maximum application rates, and/or policy changes may be requir ed during Registration Review

. o The need for spray drift and volatilization risk assessments for imazapic will be examined during Registration Review

.

14.0 References

Table 2. Memoranda Relevant to Registration Review. Author Barcode Date Title

F. Griffith, Jr. D195919 02/01/1994 PP# #3G4203/3H5669

- CL 263,222, Ammonium Salt (Cadre®) in Peanut Nutmeats and Peanut Hulls. Review of Product Chemistry Data.

F. Griffith, Jr. D191715 03/24/1994 PP# 3G4203/3H5669

- CL 263,222, Ammonium Salt (Cadre®) in Peanut Nutmeats and Peanut Hulls. Review of EUP Application, Residue Data, and Analytical Method.Imazapic Registration Review Human health Assessment Scoping Document

Page 13 of 25 Table 2. Memoranda Relevant to Registration Review. Author Barcode Date Title

G. Kramer D207046 09/13/1994 PP# 4F04390. ID#s 000241

- GAU & 000241

- GAG. Cadre® in or on peanuts. New Chemical Scre ening.
F. Griffith, Jr. D211849 02/06/1995 Multiresidue Method (MRM) Validation Data for CL 263,222 (Cadre®)

F. Griffith, Jr. D211443 03/03/1995 PP# 4F4390

- CL 263,222, Ammonium Salt (Cadre®) In Peanut Nutmeats and Peanut Hulls

. Tolerance Method Validation Requests.

J. Garbus D219117 09/13/1995 PP# 4F4390: New Chemical:Ammonium Salt of CL 263,222 ( Cadre® ) in/on Peanut RAC's. Issues to be Presented to HED's Metabolism Committee.

J. Garbus D207019 0 9/15/1995 PP#4F4390: Ammonium Salt of CL 263,222 ( Cadre® ) in/on Peanut RAC's. Evaluation of Analytical Methods and Residue Data.

J. Garbus D222184 0 2/06/1996 PP#4F4390: Ammonium Salt of CL 263,222 ( Cadre® ) in/on Peanut RAC's. Amendments Proposing Revised Sections B and F and Responses to Deficiencies Noted in CBTS's Review of 9/18/95.

B. Madden None 02/15/1996 Ammonium Salt of (±) 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl]

- 5

- methyl

3

- pyridinecarboxylic acid

- 128943 and 129041 : Health Effects Division Risk Characterization for Ammonium Salt of (±) 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl]

- 5

- methyl

3

- pyridine carboxylic acid for Use as a Herbicide in/on Peanuts.

W. Donovan D256953 06/24/1999 ID# 99NE0009. Section 18 Exemption for the Use of Imazapic on Rangeland/Pastureland to Control Leafy Spurge in Nebraska: Acute and Chronic Dietary Exposure Analysis

. W. Dykstra, et al. D256433 07/08/1999 ID# 99NE0009. Section 18 Exemption for the Use of Imazapic

- Ammonium on Pasture/Rangeland In Nebraska.

W. Donovan D265325 05/11/2000 ID#KS000001. Section 24(c) Special Local Needs (SLN) Registration. Imazapic Use for the Control of Johnsongrass on Conservation Reserve Program (CRP) Lands.

W. Donovan D271474 01/17/2001 PP# 9F05092. Imazapic in/on Pasture and Rangeland Grasses. Request for Petition Method Validation (PMV).

M. Dow D275220 05/29/2001 Exposure/Risk Assessment of the Proposed New Uses of Imazapic Used on Pasture and Rangeland.

W. Donovan, et al. D275136 06/07/2001 Imazapic. Results of the Health Effects Division (HED) Metabolism Assessment Review Committee (MARC) Meeting Held on 22

- MAY

- 2001.

W. Donovan D269038 06/12/2001 PP# 9F05092. Imazapic use on Pasture and Rangeland Grasses. Evaluation of Residue Data and Analytical Methods

.

W. Donovan D275580 06/19/2001 PP# 9F05092. Imazapic in/on Grass Pastures and Rangeland: Chronic Dietary Exposure Analysis. W. Dykstra, et al. D267227 08/01/2001 PP# 9F05092. Imazapic In/On Pastures And Rangeland. HED Risk Assessment

.

W. Donovan D278411 10/25/2001 PP# 9F05092. Imazapic. Additional Data to Amend HED's Residue Data and Analytical Methods Memorandum Concerning Pasture andImazapic Registration Review Human health Assessment Scoping Document

Page 14 of 25 Table 2. Memoranda Relevant to Registration Review. Author Barcode Date Title Rangeland Grasses.

W. Donovan D283477 06/21/2002 PP# 9F05092. Imazapic in Pasture and Rangeland Grasses. Results of Petition Method Validation (PMV).

M. Dow D294111 10/16/2003 Imazapic Ammonium Salt

– Exposure/Risk Assessment of the Imazapic Ammonium Salt for Residential “Spot

- Treatment” Weed Control

J. Van Alstine TXR#

0052356 04/17/2012 Imazapic: Summary of Hazard and Science Policy Council (HASPOC) Meeting of March 15, 2012: Recommendations on the requirement of a 28

- day inhalation study.

W. Wassell D394347 04/24/2012 Imazapic (PC Code: 129041). Registration of New Formulation.

W. Wassell D384709 05/16/2013 Imazapic (PC Code: 129041). Petition for Tolerances for Use on Soybeans and Sugarcane without U.S. Registration. Dietary Exposure Analysis.

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

W. Wassell D384710 07/08/2013 Imazapic (PC Code: 129041). Petition for Tolerances for Use on Soybeans and Sugarca ne without U.S. Registration. Summary of Analytical Chemistry and Residue Data.

E. Evans D421531 07/16/2014 Imazapic & Imazapic Ammonium Tier I Review of Human Incidents



### Attachments :
Attachment 1: Chemical Identity Tables

. Attachment 2: Imazapic Endpoint Selection Table

. Attachment 3: Residential and Occupational Exposure Tables

. Attachment 4: Dietary Exposure and Aggregate Risk Potential for Adult s and Child ren

. Attachment 5 : Imazapic International Residue Limit Status

.Imazapic Registration Review Human health Assessment Scoping Document

Page 15 of 25 

### Attachment 1: Chemical Identity Tables

Table 3. Test Compound Nomenclature. Compound Chemical Structure

Common name Imazapic IUPAC name ( RS )

- 2

- (4

- isopropyl

- 4

- methyl

- 5

- oxo

- 2

- imidazolin

- 2

- yl)

- 5

- methylnicotinic acid CAS name 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl]

- 5

- methyl

- 3

- pyridinecarboxylic acid CAS # 104098

- 48

- 8 End

- use product/(EP) Journey ® Herbicide

Compound Chemical Structure

Common name Am m onium salt of imazapic
CAS name 2

- (4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl)

- 5

- methyl

- 3

- pyridinecarboxylic acid monoammonium salt
CAS # 104098

- 49

- 9
End

- use product/(EP) Cadre ® and Plateau ® Herbicide

Compound (Metabolite)

Common name CL 263,284 Company experimental name CL 263,284
CAS name (±)

- 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl]

- 5

- hydroxymethyl

- 3

- pyridinecarboxylic acid
IUPAC name 5

- (hydroxymethyl)

- 2

- (4

- isopropyl

- 4

- methyl

- 5

- oxo

- 2

- imidazolin

- 2

- yl)nicotinic acidImazapic Registration Review Human health Assessment Scoping Document

Page 16 of 25 Table 3. Test Compound Nomenclature. Compound (Metabolite)

Common name CL 189,215 Company experimental name CL 189,215
CAS name (±)

- 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl]

- 5

- (β

- D

glucopyranosyloxy)methyl

- 3

- pyridinecarboxylic acid
IUPAC name 5

- [( β

- D

- glucopyranosyloxy)methyl]

- 2

- (4

- isopropyl

- 4

- methyl

- 5

- oxo

- 2

- imidazolin

- 2

- yl)nicotinic acid

T able 4 . Physicochemical Properties of the Technical Grade of Imazapic

. Parameter Value Reference Melting point/range 207

- 208°C DP# 267227, W. Dykstra et al. , 8/01/01 pH NA Density 0.38 g/mL Water solubility (25 ± 1°C) 0.215 g/100 mL in deionized water Solvent solubility NA Vapor pressure at 25 ± 1°C <1 x 10

- 7 mmHg Dissociation constant (pK a ) 2.0, 3.6, 11.1 Octanol/water partition coefficient Log(K OW ) 4.83 between n

- octanol and pH 4

- 6 buffers UV/visible absorption spectrum NA NA = not available.



### Attachment 2: Endpoint Selection Table for Imazapic

Table 5. Summary of Toxicological Doses and Endpoints for Imazapic for Use in Dietary Human Health Risk Assessments.

Exposure Scenario Point of Departure Uncertainty/

FQPA SFs RfD, PAD, LOC

for Risk Assessment Study and Relevant Toxicological Effects

Acute Dietary (General Population, including Infants and Children) NA NA NA An acute dietary endpoint was not selected based on the absence of an appropriate endpoint attributed to a single dose.

Acute Dietary (Females 13

- 49 Years) NA NA NA An acute dietary endpoint was not selected based on the absence of an appropriate endpoint attributed to a single dose.

Chronic Dietary (All Populations) LOAEL = 137 mg/kg/day UF A = 10X

UF H = 10X UF L = 10X FQPA SF = 1X Chronic RfD =

0.137 mg/kg/day cPAD = 0.137 mg/kg/day One Year Dog Feeding Study

LOAEL = 137 mg/kg/day based on increased incidence of minimal degeneration and/or necrosis of skeletal muscle. Cancer (Oral, Dermal, Inhalation) Classification: a “Group E” Chemical

- not likely to be a human carcinog en by any relevant route of administration based on the absence of carcinogenicity in acceptable studies in mice and rats. Abbreviations: UF = uncertainty factor; UF A = extrapolation from animal to human (interspecies); UF H = potential variation in sensitivity among members of the human population (intraspecies); UF FQPA = FQPA Safety Factor; NOAEL = no

- observed adverse

- effect level; LOAEL = lowest

observed adverse

- effect level; RfD = reference dose (a = acute, c = chronic); PAD = population

- adjusted dose; LOC = level of concern.Imazapic Registration Review Human health Assessment Scoping Document

Page 17 of 25 Table 6 . Summary of Toxicological Doses and Endpoints for Imazapic Use in Occupational Human Health Risk Assessments. Exposure Scenario Point of

Departure Uncertainty Factors LOC for Risk Assessment Study and Toxicological Effects

Dermal Short

- and Intermediate

Term (1

- 30 days and 1

- 6 months) NA NA NA No systemic toxicity was seen following repeated dermal application at 1,000 mg/kg/day over a 3

- week period. Since no hazard

was identified, quantification is not required. Inhalation Short

- and Intermediate

Term (1

- 30 days and 1

- 6 months) NOAEL =

350 mg/kg/day

100% Absorption Factor UF A = 10X

UF H = 10X Occupational LOC MOE ≤100 Rabbit Developmental Study

LOAEL = 500 mg/kg/day based on decreased body weight and food consumption during dosing.

Cancer (oral, dermal, inhalation) Classification: a “Group E” Chemical

- not likely to be a human carcinogen by any relevant route of

administration based on the absence of carcinogenicity in acceptable studies in mice and rats.

Abbreviations: UF = uncertainty factor, UF A = extrapolation from animal to human (interspecies), UF H = potential variation in sensitivity among members of the human population (intraspecies), UF FQPA = FQPA Safety Factor, NOAEL = no

- observed adverse

- effect level, LOAEL = lowest

observed adverse

- effect level, RfD = reference dose (a = acute, c = chronic), MOE = margin of exposure, LOC = level of concern.

Table 7 . Acute Toxicity Profile

– Imazapic. Guideline No. Study Type MRID(s) Results Toxicity Category 870.1100 Acute oral [rat] 42711407 LD 50 >5,000 mg/kg IV

870.1200 Acute dermal [new Zealand white

rabbit] 42711408 LD 50 >2000 mg/kg III

870.1300 Acute inhalation [rat] 42711409 LC 50 >5.52 mg/L IV 870.2400 Acute eye irritation [new Zealand

white rabbit] 42711410 minimal irritation III

870.2500 Acute dermal irritation [new

Zealand white rabbit] 42711411 non

- irritating IV

870.2600 Skin sensitization [guinea pig] 42711412 not a dermal sensitizer -

Table 8 . Imazapic Subchronic, Chronic, and Other Toxicity Profile. Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3100 90

- Day oral

toxicity (rat) 42711419 (1992)

Acceptable/guideline 0, 5000, 10000, 20000
ppm M: 0, 386, 760, 1522 mg/kg/d F: 0, 429, 848, 1728 mg/kg/day NOAEL = 1522 mg/kg/day in males, 1728 mg/kg/day in females (HDT). LOAEL = not established.

870.3200 21/28

- Day dermal

toxicity (rabbit) 42711420 (1992)

Acceptable/guideline 0, 250, 500, 1000 mg/kg/day NOAEL = 1000 mg/kg/day (males and females). LOAEL = not established.

870.3700a Prenatal

developmental in (rat) 42711422 (1992)

Acceptable/guideline 0, 250, 500, 1000 mg/kg/day Maternal NOAEL = 1000 mg/kg/day (HDT). LOAEL = not established. Developmental NOAEL = 1000 mg/kg/day. LOAEL = not established.Imazapic Registration Review Human health Assessment Scoping Document

Page 18 of 25 Table 8 . Imazapic Subchronic, Chronic, and Other Toxicity Profile. Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3700b Prenatal

developmental in (rabbit) 42711423 (1992)

Acceptable/guideline 0, 175, 350, 500, 700 mg/kg/day Maternal NOAEL = 350 mg/kg/day. LOAEL = 500 mg/kg/day based on decreased body

- weight gain and food consumption.

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 dev elopmental toxicity. 870.3800 Reproduction and

fertility effects (rat) 43320305 (1994)

Acceptable/guideline 0, 5000, 10000, 20000
ppm M: 0, 301, 605, 1205 mg/kg/day F: 0, 378, 737, 1484 mg/kg/day Parental/Systemic NOAEL = 1205 mg/kg/day in males, 1,484 mg/kg/day in females (HDT). LOAEL = not established. Reproductive NOAEL = 1205 mg/kg/day in males, 1,484 mg/kg/day in females. LOAEL = not established

. Offspring NOAEL = 1,205 mg/kg/day in males, 1,484 mg/kg/day in females. LOAEL = not established. 870.4100b Chronic toxicity

(dog) 42711421 (1993)

Acceptable/guideline 0, 5000, 10000, 20000
ppm M: 0, 137, 501, 1141 mg/kg/day F: 0, 180, 534, 1092 mg/kg/day NOAEL = not established. LOAEL = 137 mg/kg/day in males, 180 mg/kg/day in females based on increased incidence of minimal degeneration and/or necrosis and lymphocyte and/or macrophage infiltration in skeletal muscle in both males and females and slightly decreased blood creatinine levels in females (LDT). 870.4300 Chronic/

Carcinogenicity (rat) 43320307 (1994)

Acceptable/guideline 0, 5000, 10000, 20000
ppm M: 0, 253, 505, 1029 mg/kg/day F: 0, 308, 609, 1237 mg/kg/day NOAEL = 1029 mg/kg/day in males, 1237 mg/kg/day in females (HDT). LOAEL = not established.

No evidence of carcinogenicity.

870.4300 Carcinogenicity

(mouse) 43320306 (1994)

Acceptable/guideline 0, 5000, 10000, 20000
ppm M: 0, 271, 551, 1134 mg/kg/day F: 0, 369, 733, 1422 mg/kg/day NOAEL = 1134 mg/kg/day in males, 1422 mg/kg/day in females (HDT). LOAEL = not established.

No evidence of carcinogenicity.

870.5265 Ames Assay 42711424 (1992) Acceptable/guideline Negative for reverse gene mutation in S. typhimurium TA strains and E. coli WP2 at doses up to 5000 μg/plate. 870.5300 Chromosome

Aberration assay ( in vitro ) 42711427 (1992)

Acceptable/guideline Negative for chromosome aberrations in CHO cells exposed up to 3000 μg/mL, with/without activation. 870.5375 Chromosome

Aberration assay ( in v ivo ) 42711426 (1992)

Acceptable/guideline Negative for aberrations in bone marrow cells of rats treated orally up to 5000 mg/kg.Imazapic Registration Review Human health Assessment Scoping Document

Page 19 of 25 Table 8 . Imazapic Subchronic, Chronic, and Other Toxicity Profile. Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.5385 Mutagenic

Forward Mutation 42711425 (1992)

Acceptable/guideline Negative for forward mutation in CHO cells treated up to soluble levels (5000 μg/mL; 4000 μg/mL/+S9. 870.5550 Mutagenic

Unscheduled DNA Synthesis 42711428 (1992)

Unacceptable/ guideline Reportedly negative for inducing UDS in rat hepatocytes at doses greater than 1000 μg/mL (excess precipitation), but lower (soluble) doses not evaluated. 870.6200a Acute

neurotoxicity screening battery (rat) 48468902 (2011)

Acceptable/guideline 0, 200, 600, or 2000 mg/kg bw NOAEL = 2000 mg/kg bw. LOAEL = not established.

870.6200b Subchronic

neurotoxicity screening battery (rat) 48490201 (2011)

Acceptable/guideline 0, 98/97, 292/287, and 1038/927 mg/kg bw/day [M/F] NOAEL = 1038/927 mg/kg/day [M/F]. LOAEL = not established.

870.7485 Metabolism and

pharmacokinetics (rat) 42711429 (1993)

Acceptable/guideline 10 or 1000 mg/kg Total recovery of the administered dose was 98

- 106% at 7 days. Urinary excretion was the 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

(mice) 48468901 (2011)

Acceptable/guideline

0, 500, 1500, 5000 ppm (equivalent to 0, 130, 450, 1364 mg/kg/day [F]) Systemic NOAEL = 1364 mg/kg/day. Systemic LOAEL = not established. Immunotoxicity NOAEL = 1364 mg/kg/day. Immunotoxicity LOAEL = not established. (There were no treatment

- related effects on spleen or thymus weights, or the sheep red blood cell assay).Imazapic Registration Review Human health Assessment Scoping Document

Page 20 of 25 

### Attachment 3: Residential and Occupational Exposure Tables

Table 9 . Summary of Residential Use Patterns, Formulations, and Application Rates for Uses of Imazapic

. Registration Number and Product Name Crop/Use Site Formulation and Percent Active Ingredient Application

method Maximum

App Rate (lb ai/A) REI

None

Table 10 . Summary of Residential Use Patterns, Formulations, and Application Rates for Uses of Imazapic

Ammonium Salt. Registration Number and Product Name Crop/Use Site Formulation and Percent Active Ingredient Application

method Maximum

App Rate (lb ai/A) REI

71995

- 38 MON 78868 Herbicide Terrestrial Non

- Food and

Outdoor Residential Ready to Use 0.017 % Ready

- to

- Use

Spray Container 0.20731707

lb ai/A Not specified

71995

- 47 RD 1653 Herbicide Terrestrial Non

- Food and

Outdoor Residential Ready to Use 0.017 % Ready

- to

- Use

Spray Container Not

specified Not specified

71995

- 51 RD 1687 Herbicide Nonagricultural Uncultivated areas/soils Ready to Use 0.08 % Ready

- to

- Use

Spray Container 0.97560976

lb ai / A Not specified

71995

- 54 M1739 Herbicide Terrestrial Non

- Food and

Outdoor Residential Ready to Use 0.02 % Ready

- to

- Use

Spray Container 0.24883856

lb ai /A Not specified

Table 11 . Uses of Imazapic

– Summary of Residential Handler Exposures and Risks.

Exposure Scenario DP# Application Directed At Application

Rate a (lb ai/gallon) Amt

Handled Daily (gallons) Inhalation

Unit Exposure b (μg/lb ai) Inhalation

Dose c (mg/kg/day) Inhalation MOE d

(Target MOE = 100) Mixer/Loader/Applicator

– Liquid/Open Pour

– Low Pressure

- Handwand D 294111 Ground 0.0077 lb ai/gal 5 gallons 0.03 0.0000193 18,000,000

a . Application rates based on proposed ornamental uses on label for Roundup Weed & Grass1 Ready

- To

- Use (EPA Reg. No. 71995

- 23). b. Unit exposures from PHED.

c

. Inhalation dose (mg/kg/day) = daily unit exposure (μg/lb ai) x application rate ( lb ai/gallon ) x amount handled /day ( gallons/day ) x

conversion factor (1 mg/1,000 μg) x absorption factor (100%) / body weight (60

- kg adult). d . Inhalation MOE = short

- term i nhalation NOAEL (350 mg/kg/day) / inhalation daily dose (mg/kg/day). Level of concern = 100.Imazapic Registration Review Human health Assessment Scoping Document

Page 21 of 25 Table 12 . Occupational Exposure Scenarios for Conventional Uses of Imazapic (129041).
Registration Number and Product Name Crop/Use Site Formulation and Percent Active Ingredient Application

method Maximum

App Rate (lb ai/A) REI

241

- 381 CADRE ® DG Peanut Herbicide Peanuts

Water

Dispersible Granule 70% Ground 0.063 lb ai/A 12 hours

241

- 393 PLATEAU ® DG Herbicide

Agricultural

Fallow/Idleland/Conservation

Reserve Aerial, ground, backpack
sprayer, handheld sprayer, truck mounted
sprayer 0.063 lb

ai/A 12 hours

241

- 409 Oasis ® Herbicide Emulsifiable

Concentrate (EC) 19.4% Aerial, low

volume ground
sprayer, backpack
sprayer Not specified

241

- 417 Journey Herbicide Soluble

Concentrate 8.13% Aerial, ground,

backpack
sprayer 0.1875 lb

ai/A 12 hour

2935

- 557 Open Range TM G Conifers

(Plantations/Nurseries), Nonagricultural Uncultivated areas/soils Granular 0.885% Aerial, ground 0.1875 lb ai/A 12 hour

71368

- 99 NUFARM Imazapic 2SL Agricultural

Fallow/Idleland/Conservation

Reserve Ready

- to

- Use

Solution 23.3% Aerial, ground,

backpack
sprayer 0.19943344

lb ai/A 12 hour

7969

- 320 KIFIX TM 70 DG Herbicide Nonagricultural Uncultivated areas/soils EC 17.5% Aerial, boom
sprayer, backpack
sprayer, handgun 0.175 lb ai /

A Not specifiedImazapic Registration Review Human health Assessment Scoping Document

Page 22 of 25 Table 13 . Occupational Exposure Scenarios for Uses of Imazapic

- ammonium Salt (128943).
Registration Number and Product Name Crop/Use Site Formulation and Percent Active Ingredient Application

method Maximum

App Rate (lb ai/A) REI

241

- 364 CADRE ® Herbicide Peanuts SC 23.6% Ground 0.06785 lb ai /A 12 hours

241

- 365 Plateau ® Herbicide Agricultural Fallow/Idle

land/Conservation Reserve SC 23.6 % Aerial, ground, backpack
sprayer 0.199125 lb

ai/A 12 hours

241

- 425 Glyphosate Residual RTU Terrestrial Non

- Food and

Outdoor Residential Ready

- to

Use 0.017 % Ready to Use

Spray Container 0.20731707

lb ai /A Not specified

241

- 444 ETI 115 OI H Agricultural Fallow/Idle

land/Conservation Reserve, Nonagricultural Uncultivated areas/soils, Pastures, Peanuts, Rangeland EC 23.3 % Aerial, ground, backpack
sprayer 0. 19440938

lb/A 12 hour

66222

- 141 Impose TM Herbicide Aerial, ground, backpack sprayer, boom
sprayer 0.19965188

lb ai/A 12 hour

71995

- 38 MON 78868 Herbicide Terrestrial Non

- Food and

Outdoor Residential Ready

- to

Use 0.017 % Ready to Use

Spray Container 0.20731707

lb ai/A Not specified

71995

- 40 Glyphosate Residual Concentrate Nonagricultural Uncultivated areas/soils SC 0.3% Tank Type Sprayer 0.175 lb ai /

A Not specified

71995

- 47 RD 1653 Herbicide Terrestrial Non

- Food and

Outdoor Residential Ready

- to

Use 0.017 % Ready to Use

Spray Container Not

specified Not specified

71995

- 49 RD 1686 Herbicide Nonagricultural Uncultivated areas/soils Flowable

Concentrate 1.6% Tank Type

Sprayer 0.94648708

lb ai/A Not specified

71995

- 51 RD 1687 Herbicide Nonagricultural Uncultivated areas/soils Ready

- to

Use 0.08 % Ready to Use

Spray Container 0.97560976

lb ai / A Not specified

71995

- 54 M1739 Herbicide Terrestrial Non

- Food and

Outdoor Residential Ready

- to

Use 0.02 % Ready to Use

Spray Container 0.24883856

lb ai /A Not specified

81927

- 19 ALLIGARE PANORAMIC 2SL Herbicide Agricultural Fallow/Idle

land/Conservation Reserve, Nonagricultural Uncultivated areas/soils, Pastures, Rangeland EC 23.3 % Aerial, ground, backpack
sprayer 0.18414281

lb ai /A 12 hoursImazapic Registration Review Human health Assessment Scoping Document

Page 23 of 25 Table 14 . Summary of Representative Occupational Exposure Scenarios and Risks for Conventional Uses of Imazapic and Imazapic

- Ammonium Salt 1

.

Exposure Scenario Assessed DP# Formulation App. Rate Daily Amount Treated Unit

Exposure MOE 1

Inhalation ST/IT

Mixer/Loader Groundboom applications 218884 Water

- Soluble Packet (WSP) 0.0625 lb

ai/A 103 acres 44 μg/lb ai Not calculated

Aerial applications 275220, 267227 Dispersible

Granule in WSP 0.19 lb ai/A 1200 acres/day 0.0012 mg

ai/lb ai >76,000

Mixer/ Loader/ Applicator Liquid/Open Pour High

Pressure Handwand 275220, 267227 Dispersible

Granule in WSP 20.8 lb

ai/day 1,000

gallons 0.12 mg ai/lb >8,000

Liquid/Open Pour

- Backpack 275220, 267227 Dispersible

Granule in WSP 0.83 lb

ai/day 40 gallons 0.03mg ai/lb > 800,000

Applicator Groundboom

– open cab 218884 WSP 0.0625 lb ai/A 103 acres 15 μg/lb ai μg/lb ai Not calculated

1 ST = Short

- term, IT = Intermediate

- term.



### Attachment 4: Dietary Exposure and Aggregate Risk Potential for Adults and Children

Dietary Risk Estimates

Table 15. Summary of Dietary (Food and Drinking Water) Exposure Risk for Imazapic 1

.
Population Subgroup Acute Dietary (95 th Percentile) Chronic Dietary Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD General U.S. Population NA NA 0.001249 <1.0 All Infants (<1 year old) NA NA 0.000892 1.8 Children 1

- 2 years old NA NA 0.005510 4.0 Children 3

- 5 years old NA NA 0.003411 2.5 Children 6

- 12 years old NA NA 0.001986 1.4 Youth 13

- 19 years old NA NA 0.001033 <1.0 Adults 20

- 49 years old NA NA 0.000889 <1.0 Adults 50

- 99 years old NA NA 0.000839 <1.0 Females 13

- 49 years old NA NA 0.000895 <1.0

1 The values for the highest exposed population for each type of risk assessment are bolded.Imazapic Registration Review Human health Assessment Scoping Document

Page 24 of 25 

### Attachment 5 : Imazapic International Residue Limit Status

Imazapic (129041; 05/20/2014) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex 3,4 40 CFR 180.490 Plants: the sum of imazapic (2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

-
oxo

- 1 H

- imidazol

- 2

- yl]

- 5

- methyl

- 3

- pyridinecarboxylic acid) and its metabolites (±)

- 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

imidazol

- 2

- yl]

- 5

- hydroxymethyl

- 3

- pyridinecarboxylic acid and (±)

- 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

-
oxo

- 1 H

- imidazol

- 2

- yl ]

- 5

- (β

- D

glucopyranosyloxy)methyl

- 3

- pyridinecarboxylic acid, calculated as the stoichiometric equivalent of imazapic. None Plants: Imazapic The residue is not fat

- soluble

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex 3,4 Grass, forage 15 Grass, hay 30 3 hay or fodder (dry) of grasses

Peanut 0.1 0.05 (*) Soybean, seed 1 0.40 Sugarcane, cane 0.03 0.01 (*)

40 CFR 180.490 Canada Mexico 2 Codex 3,4 Livestock: Compliance with the tolerance levels specified is to be determined by measuring the sum of imazapic (2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl]

- 5

- methyl

- 3

- pyridinecarboxylic acid) and its metabolite (±)

- 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

-
oxo

- 1 H

- imidazol

- 2

- yl]

- 5

- hydroxymethyl

- 3

- pyridinecarboxylic acid, calculated as the stoichiometric equivalent o f imazapic. None Livestock: Imazapic The residue is not fat

- soluble

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex 3,4 Cattle, fat 0.10 0.1 Mammalian fats (except milk fats) Cattle, kidney 1.0 1 edible offal (mammalian) Cattle, meat byproducts, except kidney 0.1

Cattle, meat 0.1 0.1 Meat (from mammals other than marine mammals) Goat, fat 0.1 0.1 Mammalian fats (except milk fats) Goat, kidney 1.0 1 edible offal (mammalian) Goat, meat byproducts, except kidney 0.1

Goat, meat 0.1 0.1 Meat (from mammals other than marine mammals)Imazapic Registration Review Human health Assessment Scoping Document

Page 25 of 25 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex 3,4 Horse, fat 0.1 0.1 Mammalian fats (except milk fats) Horse, kidney 1.0 1 edible offal (mammalian) Horse, meat byproducts, except kidney 0.1

Horse, meat 0.1 0.1 Meat (from mammals other than marine mammals) Milk 0.1 0.1 Sheep, fat 0.1 0.1 Mammalian fats (except milk fats) Sheep, kidney 1.0 1 edible offal (mammalian) Sheep, meat byproducts, except kidney 0.1

Sheep, meat 0.1 0.1 Meat (from mammals other than marine mammals) MRLs with NO US Equivalent Eggs 0.01 (*) Maize 0.01 (*) Poultry fats 0.01 (*) Poultry meat Poultry edible offal of Rapeseed 0.05 (*) Rice 0.05 (*) Wheat 0.05 (*) Wheat straw and fodder, dry 0.05 (*) Completed: M. Negussie; 05/22/14

1 There are no US registrations as of April 4, 2014.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to b e measured on the fat portion of the sample.

4 All MRLs are proposed and have not been finalized by the CCPR and the CAC.