.\,)~,~tosr.qr<>.r. UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

[ ~ ~ WASHINGTON,D.C. 20460 0 'f 

~ .l' 

"''~-r c."'.p 'I( O~~ OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: 

Subject: 

04-SEP-20 14 

Imazapic (129041) and the Ammonium Salt oflmazapic (128943); Human Health 

Assessment Scoping Document in Support of Registration Review. 

PC Code: 129041 (imazapic) 

128943 (imazapicammonium salt) 

DP Barcode: 0421209 

Decision No.: 492629 Registration 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 'l ,__ h _ ~ _ 

Lata V enkateshwara, Environmental Scientist L r. -h V c.."" f· lRisk Assessment Branch 1 (RAB 1) 

Health Effects Division (HED, 7509P) 

Charles 

George F. 

W. 

Kramer, 

Smith lll, 

Ph.D., 

Branch 

Senior 

Chief 

Chemi

,---

~'-!:::V"illiiiiiJ!II!~~::::=:~~~ 

.. 0~ ... <-':<':::-' ___ _ 

RAB1/HED (7509P) · . 

Thomas Moriarty!Ricardo Jones, RM-51 

Risk Management & Implementation Branch I 

Pesticide Re-Evaluation Division (PRD, 7508P) 

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

ammonium salt of imazapic to support Registration Review. 

Executive Summary 

Imazapic (2-[ 4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-irnidazol-2-yl]-5-methyl-3-

pyridinecarboxylic acid] and the ammonium salt of imazapic [2-( 4;5-dihydro-4-methyl-4-( lmethylethyl)-5-oxo-1H-imidazol-2-yl)-5-methyl-3-pyridinecarboxylic acid monoammonium 

salt] are imidazolinone herbicides that target broadleafweeds, 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), peanut 
Imazapic 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. Tolerances without U.S. 

registration are established for residues inion soybeans and sugarcane. Additionally, tolerances 

for residues of imazapic in livestock commodities are established. Imazapic may be applied as a 

spot-treatment or broadcast foliar application during the dormant 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 the human health assessments for imazapic to determine 

whether sufficient data are available and whether any updates are needed to support Registration 

Review. The most recent human health risk assessments for imazapic were considered with 

respect to its toxicity, exposure, usage databases, and the most updated Agency science policy 

and risk assessment methodologies to determine the scope of work necessary to support 

Registration Review. 

The toxicity database is adequate and complete to support Registration Review. No new 

toxicological data are required. HED does not anticipate the need to revise the toxicological 

endpoints, points of departure, or safety factors for imazapic during Registration Review. 

The imazapic residue chemistry database is sufficient to assess dietary exposure for Registration . 

Review. The 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 endpoint attributed to a single-dose exposure could not be identified in any of the 

studies in the toxicology database. The chronic exposure estimate is <1.0% of the chronic 

population-adjusted dose (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. 

There are currently no established Canadian, or Mexican maximum residue 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 residues inion grass, peanut, and sugarcane are significantly lower than 

established U.S. tolerances. The U.S. tolerance expression for plant commodities includes the 

parent and two metabolites, while the U.S. tolerance expression for livestock commodities 

consists of parent plus a metabolite and the Codex MRL expression is for imazapic only. 

Despite the differences in the tolerance/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 information 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 toxicological endpoints. The need for spray drift and volatilization risk assessment 

for imazapic will also be examined during Registration Review. 

There is sufficient information available to assess occupational handler exposure associated with 

agricultural uses of imazapic for Registration Review. Currently, there are no short- and 

intermediate-tenn dermal points of departure (PODs) for imazapic; thus, a dermal 

Page 2 of25 
Imazapic Registration Review Human health Assessment Scoping Document

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

occupational 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 imazapic during 

Registration Review. 

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 noncrop 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. 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 

following 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 required 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 maximum 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

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2.0 Hazard Identification/Toxicology

The toxicity 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 evidence of 

bioaccumulation of imazapic in tissues. Additionally, there were no sex- or dose-related 

differences following oral or intravenous administration. 

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 clinical 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 the 

esophagus 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 rabbit 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, imazapic 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 classified by the RfD/Peer Review Committee as 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.

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) Considerations

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 conventional 
Imazapic Registration Review Human health Assessment Scoping Document

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100X uncertainty factor, an additional 10X uncertainty factor is applied for the use of a lowestobserved adverse-effect level (LOAEL; UFL) to derive the chronic reference dose (cRfD). 

Conclusions

The toxicity database for imazapic is complete. No new data are expected 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 imazapic residues in plants is adequately understood based on adequate 

metabolism studies utilizing peanuts, grass, sugarcane, and genetically modified (GMO)

soybeans. The 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 263,284 and its glucose conjugate (CL 189,215) 

were 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 and 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. The 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 and the dietary burden for poultry, 

HED concludes that there is no reasonable expectation of finite residues of imazapic in poultry 

commodities based on the uses 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. Residues 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 fat. The method LOQs were 

reported as 0.010 ppm for milk and 0.050 ppm for tissues. 

An adequate confined rotational crop study has been submitted. In this study, winter wheat, 

spring wheat, carrots, and lettuce were planted at intervals of 181, 318, and 363 days, 

respectively in a field treated with [14C]imazapic at 0.195 lb ai/A (the maximum proposed 

seasonal use). Total radioactive residues (TRRs) 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 of 
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imazapic, CL 263,284, CL 189,215, and CL 312,622 were identified in all rotational crop 

matrices at 0.001 ppm. 

Established PBIs are as follows:

Minimum plantback 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 Bean

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 Months1 18 to 24 Months1 26 to 36 Months1 40 to 48 Months1

Bahiagrass

Clearfield corn 

hybrids

Peanut

Rye

Wheat

Snap Beans

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 the 4-month PBI for rye and wheat and 9-month PBI for legume 

vegetables are not currently supported by rotational crop data and requested data to support these 

intervals. HED has reconsidered these requirements and has concluded the established PBIs are 

adequate. This conclusion is based on the following: 

 All samples in the confined rotation crop study exhibited TRRs 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 the 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 

residues 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. Adequate 

confined rotational crop data are available and support the label-specified PBIs. 

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. An 
Imazapic Registration Review Human health Assessment Scoping Document

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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 Evaluation 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 1994-1996, 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, sugarcane, and peanut (except 

peanut butter) commodities were reduced to 1X, 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 assessments. 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 potential 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 

cracks 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, along 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 summary 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 

risk 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 12
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(Attachment 3) for a summary 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 residential 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 exposures 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: Consideration 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 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 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 and 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 risk 
Imazapic Registration Review Human health Assessment Scoping Document

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estimates did not exceed HED's LOC. Short- and intermediate-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 dietary exposure 

analyses and/or residential exposure assessments.

7.0 Occupational Exposure

Imazapic containing herbicides are used for weed control in peanuts, pastures, rangeland, and 

other non-crop areas. Based on these uses, there is a potential for 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 postapplication worker exposure from entering into 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. Therefore, 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 occupational 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 water dispersible granule in watersoluble 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. Therefore, 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 multiple 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 that 
Imazapic 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 occupational 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, occupational 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 

imazapic 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 the 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 frequency 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 recorded. 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 imazapicammonium 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 gastrointestinal 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 severity. An incident classified as minor 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 summarized in more detail in the 2014 HED imazapic and imazapicammonium 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 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 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 metabolite. The 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. Executive 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 statements 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

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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 pesticides, 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 them 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 requirements 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 analysis 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 residential 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 required 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

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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 

Screening. 

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 09/15/1995

PP#4F4390: Ammonium Salt of CL 263,222 

(Cadre®) in/on Peanut RAC's. Evaluation of 

Analytical Methods and Residue Data. 

J. Garbus D222184 02/06/1996

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-1H-imidazol-2-yl]-5-methyl3-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-1H-imidazol-2-yl]-5-methyl3-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 and 
Imazapic Registration Review Human health Assessment Scoping Document

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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 Sugarcane 

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 Adults and Children.

Attachment 5: Imazapic International Residue Limit Status.
Imazapic Registration Review Human health Assessment Scoping Document

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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-1H-imidazol-2-yl]-5-methyl-3-

pyridinecarboxylic acid 

CAS # 104098-48-8 

End-use product/(EP) Journey® Herbicide

Compound Chemical Structure

Common name Ammonium salt of imazapic

CAS name 2-(4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-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-1H -imidazol-2-yl]-5-

hydroxymethyl-3-pyridinecarboxylic acid

IUPAC name 5-(hydroxymethyl)-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid
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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-1H-imidazol-2-yl]-5-(β-Dglucopyranosyloxy)methyl-3-pyridinecarboxylic acid

IUPAC name 5-[(β-D-glucopyranosyloxy)methyl]-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-

yl)nicotinic acid

Table 4. Physicochemical Properties of the Technical Grade of Imazapic.

Parameter Value Reference

Melting point/range 207-208°C DP# 267227, W. Dykstra et 

pH NA al., 8/01/01

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 (pKa) 2.0, 3.6, 11.1

Octanol/water partition coefficient Log(KOW) 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

UFA = 10X

UFH = 10X

UFL = 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 carcinogen by any relevant route of 

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

Abbreviations: UF = uncertainty factor; UFA = extrapolation from animal to human (interspecies); UFH = potential variation in sensitivity among 

members of the human population (intraspecies); UFFQPA = FQPA Safety Factor; NOAEL = no-observed adverse-effect level; LOAEL = lowestobserved adverse-effect level; RfD = reference dose (a = acute, c = chronic); PAD = population-adjusted dose; LOC = level of concern.
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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 

IntermediateTerm (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 

IntermediateTerm (1-30 days 

and 1-6 months)

NOAEL =

350 mg/kg/day

100% 

Absorption 

Factor

UFA = 10X

UFH = 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, UFA = extrapolation from animal to human (interspecies), UFH = potential variation in sensitivity among 

members of the human population (intraspecies), UFFQPA = FQPA Safety Factor, NOAEL = no-observed adverse-effect level, LOAEL = lowestobserved 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 LD50 >5,000 

mg/kg

IV

870.1200 Acute dermal [new Zealand white 

rabbit]

42711408 LD50 >2000 

mg/kg

III

870.1300 Acute inhalation [rat] 42711409 LC50 >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.
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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 

developmental 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 vivo)

42711426 (1992)

Acceptable/guideline

Negative for aberrations in bone marrow cells 

of rats treated orally up to 5000 mg/kg.
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Table 8. Imazapic Subchronic, Chronic, and Other Toxicity Profile.

Guideline 

No.

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5385 MutagenicForward Mutation42711425 (1992)

Acceptable/guideline

Negative for forward mutation in CHO cells 

treated up to soluble levels (5000 μg/mL; 4000 

μg/mL/+S9.

870.5550 MutagenicUnscheduled 

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).
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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 ImazapicAmmonium 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 

Ratea

(lb ai/gallon)

Amt

Handled Daily 

(gallons)

Inhalation 

Unit 

Exposureb

(μg/lb ai)

Inhalation 

Dosec

(mg/kg/day)

Inhalation MOEd

(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 inhalation NOAEL (350 mg/kg/day) / inhalation daily dose (mg/kg/day). Level of concern = 100.
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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

WaterDispersible 

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

EmulsifiableConcentrate 

(EC)

19.4%

Aerial, low 

volume ground 

sprayer, 

backpack 

sprayer

Not specified

241-417

Journey 

Herbicide

SolubleConcentrate 

8.13%

Aerial, ground, 

backpack 

sprayer

0.1875 lb 

ai/A 12 hour

2935-557

Open RangeTM

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

KIFIXTM 70 DG 

Herbicide

Nonagricultural Uncultivated 

areas/soils EC 17.5%

Aerial, boom 

sprayer, 

backpack 

sprayer, 

handgun

0.175 lb ai / 

A Not specified
Imazapic Registration Review Human health Assessment Scoping Document

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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-toUse 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

ImposeTM

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-toUse 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-toUse 0.017 %Ready to Use 

Spray Container

Not 

specified Not specified

71995-49

RD 1686 

Herbicide

Nonagricultural Uncultivated 

areas/soils

FlowableConcentrate 

1.6%

Tank Type 

Sprayer

0.94648708 

lb ai/A Not specified

71995-51

RD 1687 

Herbicide

Nonagricultural Uncultivated 

areas/soils

Ready-toUse 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-toUse 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 hours
Imazapic Registration Review Human health Assessment Scoping Document

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Table 14. Summary of Representative Occupational Exposure Scenarios and Risks for Conventional Uses of 

Imazapic and Imazapic-Ammonium Salt1.

Exposure Scenario Assessed DP# Formulation App. Rate

Daily 

Amount 

Treated

Unit 

Exposure MOE1

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

DispersibleGranule 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

DispersibleGranule in 

WSP

20.8 lb 

ai/day

1,000 

gallons 0.12 mg ai/lb >8,000

Liquid/Open Pour - Backpack 275220, 

267227

DispersibleGranule 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 Imazapic1.

Population Subgroup

Acute Dietary (95th 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

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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 Mexico2 Codex3,4

40 CFR 180.490

Plants: the sum of imazapic (2-[4,5-

dihydro-4-methyl-4-(1-methylethyl)-5-

oxo-1H-imidazol-2-yl]-5-methyl-3-

pyridinecarboxylic acid) and its 

metabolites (±)-2-[4,5-dihydro-4-

methyl-4-(1-methylethyl)-5-oxo-1Himidazol-2-yl]-5-hydroxymethyl-3-

pyridinecarboxylic acid and (±)-2-[4,5-

dihydro-4-methyl-4-(1-methylethyl)-5-

oxo-1H-imidazol-2-yl]-5-(β-Dglucopyranosyloxy)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 Mexico2 Codex3,4

Grass, forage 15 

Grass, hay 30 3 hay or fodder (dry) of grasses

Peanut 0.1 0.05 (*)

Soybean, seed1 0.40

Sugarcane, cane 0.03 0.01 (*) 

40 CFR 180.490 Canada Mexico2 Codex3,4

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-1H-imidazol-2-

yl]-5-methyl-3-pyridinecarboxylic 

acid) and its metabolite (±)-2-[4,5-

dihydro-4-methyl-4-(1-methylethyl)-5-

oxo-1H-imidazol-2-yl]-5-

hydroxymethyl-3-pyridinecarboxylic 

acid, calculated as the stoichiometric 

equivalent of imazapic.

None Livestock: Imazapic

The residue is not fat-soluble

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex3,4

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

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Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3,4

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

1There 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 be measured on the 

fat portion of the sample. 

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