UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

MEMORANDUM 

Date: 16-MAY-2013 

WASHINGTON, D.C. 20460 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Imazapic. Human-Health Risk Assessment. Petition for Tolerances for Use on 

Soybeans and Sugarcane without U.S. Registration. 

PC Code: 

Decision Nos.: 

Petition Nos.: 

129041 

440574,464236 

OE7794, 2E8021 

DP Barcodes: 0384054,0401585 

Registration No.: NA 

Regulatory Action: Tolerances without U.S. 

Registration 

Risk Assessment Type: Single Chemical/Aggregate Case No.: 7234 

TXR No.: 

MRID: 

FROM: 

NA CAS No.: 

NA 40CFR: 

Anwar 

William 

Y. 

D. 

Dunbar, 

Wassell, 

Ph.D., 

Chemist 

Pharmacologist 

;W,J/ ~ ~ Risk Assessment Branch 1 (RAB 1) 

Health Effects Division (HED; 7509P) 

I 04098-48-8 

§I 80.490 

THROUGH: George 

Dana 

RAB 1/HE

Vogel, 

F. 

D 

Kramer, 

(7509P) 

Acting 

Ph.D., 

Branch 

Senior 

Chief 

Chemist ~ ~ 

TO: Kable Davis, RM 25 

Registration Division (RD, 7505P) 

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and 

exposure data and conduct dietary, occupational, residential, and aggregate exposure 

assessments, as needed, to estimate the risk to human health that will result from the registered 

and proposed uses of the herbicide imazapic [2-[ 4,5-dihydro-4-methyl-4-( 1-methylethyl)-5-oxolH-imidazol-2-yl]-5-methyl-3-pyridinecarboxylic acid] on sugarcane and genetically-modified 

(GMO) soybeans without U.S. registration. 

A summary of the findings and an assessment of human-health risk resulting from the proposed 

and registered uses of imazapic are provided in this document. The risk assessment, dietary 

exposure assessment and residue chemistry assessment were provided by William Wassell 

(RAB 1 ); the hazard characterization and endpoint selection by Anwar Dunbar (RAB 1 ); and the 

drinking water exposure assessment by J. K. Wolf of the Environmental Fate and Effects 

Division (EFED). Residential and occupational exposure assessments were not required for this 

use. 

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lmazapic Human-Health Risk Assessment DP# 384054 

The most recent human-health risk assessment for imazapic was for a Section 3 registration and 

tolerances to support a proposed use of imazapic on rangeland and pasture grass (Memo, 

08/01/2001, W. Dykstra, et al., D267277). 

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Imazapic Human-Health Risk Assessment DP# 384054

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Table of Contents

1.0 Executive Summary ........................................................................................................... 5

2.0 HED Recommendations .................................................................................................... 7

2.1 Data Deficiencies ............................................................................................................ 7

2.2 Tolerance Considerations.............................................................................................. 8

2.2.1 Enforcement Analytical Method ............................................................................... 8

2.2.2 Recommended Tolerances......................................................................................... 9

2.2.3 Revisions to Petitioned-For Tolerances.................................................................. 10

2.2.4 International Harmonization................................................................................... 10

2.3 Label Recommendations.............................................................................................. 10

3.0 Introduction...................................................................................................................... 11

3.1 Chemical Identity ......................................................................................................... 11

3.2 Physical/Chemical Characteristics ............................................................................. 12

3.3 Pesticide Use Pattern.................................................................................................... 12

3.4 Anticipated Exposure Pathways................................................................................. 13

3.5 Consideration of Environmental Justice.................................................................... 14

4.0 Hazard Characterization and Dose-Response Assessment.......................................... 14

4.1 Toxicology Studies Available for Analysis................................................................. 14

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME) ............................. 14

4.2.1 Dermal Absorption................................................................................................... 15

4.3 Toxicological Effects .................................................................................................... 15

4.3.1 Summary of Toxicological Effects........................................................................... 15

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 16

4.4.1 Completeness of the Toxicology Database.............................................................. 16

4.4.2 Evidence of Neurotoxicity ........................................................................................ 16

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal........ 16

4.4.4 Residual Uncertainty in the Exposure Database ................................................... 16

4.5 Toxicity Endpoint and Point of Departure Selections .............................................. 16

4.5.1 Dose-Response Assessment...................................................................................... 16

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment..... 17

4.5.3 Cancer Classification and Risk Assessment Recommendation............................ 17

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment............................................................................................................................... 17

5.0 Dietary Exposure and Risk Assessment......................................................................... 17

5.1 Residues of Concern Summary and Rationale .......................................................... 18

5.2 Food Residue Profile .................................................................................................... 18

5.3 Water Residue Profile.................................................................................................. 19

5.4 Dietary Risk Assessment.............................................................................................. 20

5.4.1 Description of Residue Data Used in Dietary Assessment.................................... 20

5.4.2 Percent Crop Treated Used in Dietary Assessment .............................................. 21

5.4.3 Acute Dietary Risk Assessment............................................................................... 21

5.4.4 Chronic Dietary Risk Assessment........................................................................... 21

5.4.5 Cancer Dietary Risk Assessment............................................................................. 21

5.4.6 Summary Table......................................................................................................... 21

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 21

6.1 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 21

6.2 Spray Drift........................................................................................................................ 21

7.0 Aggregate Exposure/Risk Characterization.................................................................. 22

7.1 Acute Aggregate Risk................................................................................................... 22

7.2 Chronic Aggregate Risk .............................................................................................. 22
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8.0 Cumulative Exposure/Risk Characterization ............................................................... 23

9.0 Occupational Exposure/Risk Characterization ............................................................ 23

10.0 References......................................................................................................................... 23

Appendix A. Toxicology Profile and Executive Summaries .................................................. 25

Appendix B. Physical/Chemical Properties............................................................................. 26
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1.0 Executive Summary

Background: 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.

Permanent tolerances [40 CFR §180.490(a)(1)] are established for combined residues of the 

herbicide imazapic and its metabolite (±)-2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H -

imidazol-2-yl]-5-hydroxymethyl-3-pyridinecarboxylic acid (also referred to as CL 263,284), both 

free and conjugated, in/on peanuts at 0.1 ppm, and grass forage and hay at 15 and 30 ppm, 

respectively. The conjugated form of CL 263,284 is (±)-2-[4,5-dihydro-4-methyl-4-(1-

methylethyl)-5-oxo-1H-imidazol-2-yl]-5-(β-D-glucopyranosyloxy)methyl-3-pyridinecarboxylic 

acid which is also referred to as CL 189,215. Additionally, permanent tolerances [40 CFR 

§180.490(a)(2)] are established for the combined residues of the herbicide imazapic and its free 

metabolite, CL 263,284, in/on milk and cattle, goats, horse, and sheep commodities, ranging 

from 0.1 ppm (milk and commodities other than kidney) to 1.0 ppm (kidney). 

BASF Corporation has proposed (PP# 0E7794) the use of Cultifix on GMO soybeans grown in 

Brazil destined for the U.S. The GMO soybeans are modified to exhibit tolerance to 

imidazolinone herbicides. There are no U.S. registrations for Cultifix and BASF Corporation has 

not proposed registration of imazapic for use on soybeans in the U.S. Cultifix is a multiple 

active-ingredient (MAI) formulation containing 525 g imazapyr per kg product (52.5%) and 175 

g imazapic per kg product (17.5%). This risk assessment only includes results for imazapic and 

its metabolites; imazapyr results are reported in a separate document. In conjunction with the 

proposed use, BASF has proposed the following tolerance for residues of imazapic:

Soybeans (imidazoline-tolerant)..........................................0.5 ppm.

BASF Corporation has also proposed (PP#2E8021) the use of Plateau® Herbicide on sugarcane 

grown in Brazil, Guatemala, and Costa Rica destined for the U.S. Plateau® Herbicide (EPA Reg. 

No. 241-365) is registered for use on non-crop land, conifer plantations, and pasture and 

rangeland. The U.S. registered product contains 23.6% imazapic; however, the product for use 

on sugarcane contains 70% imazapic. The registrant has not proposed registration of imazapic 

for use on sugarcane in the U.S. BASF has proposed the following tolerance for residues of 

imazapic:

Sugarcane ............................................................................0.01 ppm.

The petitioner has proposed a single foliar application of Cultifix at the rate of 0.013 to 0.016 lb 

ai/A to imidazolinone-tolerant soybeans. The proposed pre-harvest interval (PHI) for soybeans 

is 60 days. 

Additionally, BASF has proposed a single preemergence foliar application of Plateau®to 

sugarcane at the rate of 0.125 to 0.220 lb ai/A. The proposed PHI for this use is 150 to 365 days. 

The use directions also include instructions for an “area preparation” application 30 to 45 days 

prior to planting sugarcane at a rate of 0.312 lb ai/A. The implied PHI for this use would be 180 

to 395 days. 
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Hazard Assessment: Imazapic does not appear to be toxic to rodents via the oral or dermal 

routes of exposure. 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 of 137 mg/kg/day in males and 180 mg/kg/day in 

females. At higher doses, additional effects were seen in the liver (↑absolute weights and 

changes in clinical chemical parameters), kidney (↓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. 

In the developmental toxicity study in rabbits, there was decreased weight gain and food 

consumption in the does at the lowest-observed adverse-effect level (LOAEL) of 500 mg/kg/day, 

with the no-observed adverse-effect level (NOAEL) being 350 mg/kg/day. There were no 

developmental effects in rabbit fetuses in the study up to 500 mg/kg/day. In the two-generation 

reproduction study, no parental or reproductive toxicity was seen at 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 Reference Dose (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.

The imazapic risk assessment team recommends that the Food Quality Protection Act Safety 

Factor (FQPA SF) be retained at 10X for all exposure scenarios. The rationale is described in 

Section 4.4.

Food Residue Profile: The nature of the residue in plants and livestock is adequately 

understood. There is an adequate residue analytical method for the purposes of tolerance 

enforcement. Organization for Economic Co-operation and Development (OECD) tolerancecalculation procedures and the submitted residue data sets were used to calculate the HEDrecommended tolerances for soybeans. Residue data for sugarcane showed residue levels would 

be less than the limit of quantification (<LOQ) for all analytes. The submitted field trial residue 

data are adequate and there are no residue chemistry issues that would preclude establishing 

permanent tolerances for residues of imazapic and its metabolites, as outlined in Table 2.2.2.

Exposure/Risk Assessment Characterization: An acute risk assessment was not required. The 

chronic risk assessments were conducted for dietary exposure based on the existing and proposed 

uses. The chronic assessments directly incorporated drinking water estimates. 

The chronic analyses were unrefined and assumed 100% crop-treated (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 (1.89x). The processing factors for soybean, 
Imazapic Human-Health Risk Assessment DP# 384054

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sugarcane, and peanut (except peanut butter) commodities were reduced to 1x, based upon 

processing data. 

The chronic exposure and risk estimates were not of concern. A cancer dietary assessment was

not conducted because imazapic is classified 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.

There are no registered or proposed residential uses for imazapic; therefore, a residential 

exposure assessment was not conducted.

Since there are no residential uses, the chronic aggregate risks are made up only of dietary 

sources (food and drinking water) and the dietary exposure analyses represent chronic aggregate 

exposure, respectively. Short- and intermediate-term assessments, which are used to evaluate 

aggregate dietary and residential exposures, were not performed because there are no registered 

or proposed residential non-food uses. 

Occupational handler and post-application assessments were not required as the subject petitions 

propose tolerances without U.S. registration. Thus, occupational exposure is not of concern for 

the subject petitions.

This risk assessment does not rely on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. 

2.0 HED Recommendations

2.1 Data Deficiencies

Provided the petitioner submits revised Sections F (see below) and that the petitioner resolves the 

deficiency pertaining to the availability of analytical grade standards at the EPA National 

Pesticide Standards Repository (see below), there are no residue chemistry or toxicological data 

deficiencies that would preclude the establishment of permanent tolerances for residues of 

imazapic and its metabolites as outlined in Table 2.2.2. 

860.1550 Proposed Tolerances

The tolerance expression should be changed to conform to current HED policy. 

Specifically, the tolerance expression for 40 CFR §180.490(a)(1) should be as follows:

Tolerances are established for residues of the herbicide imazapic, including its 

metabolites and degradates, in or on the commodities listed in the following table. 

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 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.
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Additionally, the tolerance expression for 40 CFR §180.490(a)(2) should be as follows:

Tolerances are established for residues of the herbicide imazapic, including its 

metabolites and degradates, in or on the commodities listed in the following table. 

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. 

The petitioner has proposed a tolerance for residues of imazapic in/on soybeans 

(imidazoline-tolerant) at 0.5 ppm. HED concludes the tolerance level for residues in/on 

soybean, seed should be revised to 0.40 ppm. 

The petitioner has proposed a tolerance for residues of imazapic in/on sugarcane at 0.01 

ppm. HED concludes the tolerances level for residues in/on sugarcane, cane should be 

revised to 0.03 ppm. 

860.1650 Submittal of Analytical Reference Standards

An analytical grade reference standard for imazapic metabolite CL 263,284 is currently 

not available at the EPA National Pesticide Standards Repository; however, standards of 

imazapic and metabolite CL 189,215 are available (personal communication with 

Theresa M. Cole of the Standards Repository, 4/16/2013). The registrant must submit 

analytical grade standards for imazapic metabolite CL 263,284 to the Standards 

Repository (see 860.1650 Submittal of Analytical Reference Standards for additional 

information).

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Plant Commodities: 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. The validated LOQ is 0.50 and 0.05 ppm for each analyte in 

grass and peanut commodities, respectively. Residues are confirmed by liquid chromatography 

with a mass spectroscopy detector (LC/MS) analysis. A slightly modified version of CE method 

M 3114 was used for data collection purposes.

Livestock Commodities: 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, LC/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. Identification of residues is confirmed by liquid 

chromatography with tandem mass spectroscopy (LC-MS/MS).

The registrant has submitted validation data both concurrent with the analysis of treated samples 

and prior to sample analysis. Additionally, BASF has submitted data concerning independent 

laboratory validation (ILV) data for imazapic and its metabolites CL 263,284 and CL 189,215 
Imazapic Human-Health Risk Assessment DP# 384054

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from soybean and sugarcane commodities. Samples were analyzed using LC-MS/MS analysis. 

The validated method is SOP-PA.0288 (Rev. 01). A majority of samples were analyzed for 

residues of imazapic and its metabolites using SOP-PA.0288; however, some samples of soybean 

were analyzed for residues of imazapic only using method SOP-PA.0249_E. The two methods 

are nearly identical. Adequate analytical method descriptions and validation data of Method 

SOP-PA.0249 and Method SOP-PA.0288 were submitted. 

The ILVs were successful with soybean commodities in either the first or the second trial. In the 

second ILV trial, the method was performed with minor modifications, including the use of 

matrix-matched standards. The ILV utilizing sugarcane commodities was initially unsuccessful. 

The laboratory determined that the low recoveries were due to peak suppression by the sample 

matrix. In order to overcome the suppression of peaks, matrix-matched standards were prepared 

and used for calibration and quantification; the use of matrix-matched standards is listed as an 

option in the method. Using matrix-matched standards, the ILV was successful for all analytes 

in the first trial (second analysis) of the method.

BASF Corporation has submitted an analytical method description, validation data, and an ILV 

for a method for the determination of residues of imazapic and its metabolites CL 263,284 and 

CL 189,215 in/on soybean (seed), processed fractions of soybean (oil, flaked soybean, meal, and 

toasted meal), sugarcane and sugarcane processed commodities (raw sugar and molasses) using 

LC-MS/MS analysis. The validated method is method SOP-PA.0288 “Determination of 

Imidazoline Residues and Metabolites in Various Matrices and Parts Processed by LC/MS/MS.” 

The method was used for data collection in the soybean and sugarcane crop field trials and the 

soybean and sugarcane processing studies reviewed as a part of the current petitions. All 

samples were quantified by LC-MS/MS. Two characteristic mass transitions were used to 

monitor for imazapic (276 → 231 m/z and 276 → 163 m/z), CL 263,284 (292 → 247 m/z and 

292 → 179 m/z), and CL 189,215 (454 → 292 m/z and 454 → 179 m/z). The reported LOQ 

(determined as the lowest level of method validation, LLMV) is 0.01 ppm; the limit of detection 

(LOD) is 0.002 ppm (20% of the LOQ) for each analyte. 

2.2.2 Recommended Tolerances

Pending submission of revised Sections F (see requirements under Proposed Tolerances) and 

analytical reference standards, there are no residue chemistry or toxicological issues that would 

preclude granting tolerances for residues of imazapic in/on soybeans and sugarcane. In 

accordance with the most recent guidance concerning tolerance expressions, HED recommends 

that the tolerance expression for 40 CFR §180.490(a)(1) be changed as indicated below. A 

revised Section F specifying the new tolerance expression and the HED-recommended tolerances 

should be submitted. 

40 CFR §180.490(a) General (1) should be as follows: Tolerances are established for residues 

of the herbicide imazapic, including its metabolites and degradates, in or on the commodities 

listed in the following table. 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 and (±)-2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1Himidazol-2-yl]-5-(β-D-glucopyranosyloxy)methyl-3-pyridinecarboxylic acid, calculated as the 

stoichiometric equivalent of imazapic.
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40 CFR §180.490(a) General (2) should be as follows: Tolerances are established for residues 

of the herbicide imazapic, including its metabolites and degradates, in or on the commodities 

listed in the following table. 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.

Table 2.2.2. Tolerance Summary for Imazapic.

Commodity Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Correct Commodity 

Definition/Comments

To be established under 40 CFR §180.490 (a) General. (1)

Soybeans (imidazoline-tolerant) 0.5 0.40 Soybean, seed

Sugarcane 0.01 0.03 Sugarcane, cane

2.2.3 Revisions to Petitioned-For Tolerances

The residue data for imazapic and its metabolites in/on GMO soybeans were analyzed using the 

OECD tolerance calculation procedures. The recommended tolerance for residues of imazapic 

and its metabolites is 0.40 ppm in/on soybean, seed. 

The petitioner proposed a tolerance level of 0.01 ppm for residues of imazapic and its 

metabolites in/on sugarcane; however, total residues in sugarcane were 0.03 ppm (sum of LOQs 

for analytes). A revised Section F is required to adjust the tolerance level and to change the 

tolerance expression (see Recommended Tolerances section).

2.2.4 International Harmonization

There are currently no established Codex, Canadian, or Mexican maximum residue limits 

(MRLs) for imazapic on soybeans or sugarcane. Thus, harmonization of tolerances/MRLs is not 

an issue for these petitions.

2.3 Label Recommendations

The proposed use directions for Cultifix on GMO soybeans grown in Brazil are sufficient to 

allow for evaluation of the submitted residue data. The available field trial data support the 

proposed use directions for imazapic on GMO soybeans. Additionally, the proposed use 

directions for Plateau® Herbicide on sugarcane grown in Brazil, Guatemala, and Costa Rica are 

sufficient to allow for evaluation of the submitted residue data. The available field trial data 

support the proposed use directions for imazapic on sugarcane.
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3.0 Introduction

3.1 Chemical Identity

Table 3.1. 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 # 81334-60-3

End-use product/(EP) Cultifix (no U.S. registrations) and Plateau® Herbicide

Table 3.1. Test Compound Nomenclature.

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

CAS registry number 81335-78-6

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
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3.2 Physical/Chemical Characteristics

Imazapic is an imidazolinone herbicide. It controls both pre- and post-emergent annual and 

perennial grasses and broadleaf weeds. The herbicidal activity of imazapic is due to the 

inhibition of AHAS, which is a key plant enzyme in the biosynthesis of the amino acids leucine, 

isoleucine, and valine. Animals lack this biosynthetic pathway and must obtain these amino 

acids from their diet. 

Except for rapid aqueous photolysis, imazapic appears to be extremely persistent, mobile, and 

highly soluble. The major route of dissipation of imazapic appears to be transport with water. 

Therefore, contamination of ground water and surface water by imazapic appears possible. Once 

in ground water or surface water where light cannot penetrate, imazapic will be very persistent. 

A table of the physicochemical properties of imazapic can be found in Appendix B. 

3.3 Pesticide Use Pattern

Soybean: 

BASF Corporation has proposed the use of Cultifix on GMO soybeans grown in Brazil destined 

for the U.S. The GMO soybean is modified to exhibit tolerance to imidazolinone herbicides. 

There are no U.S. registrations for Cultifix and BASF Corporation has not proposed registration 

of imazapic for use on soybeans in the U.S. Cultifix contains 525 g imazapyr per kg product and 

175 g imazapic per kg product. This document addresses the request for the use of imazapic 

only.

The petitioner has proposed a single foliar application of Cultifix at the rate of 0.013 to 0.016 lb 

ai/A to imidazolinone-tolerant soybeans. The application may be made using ground equipment 

(10 to 21 gallons per acre (GPA)) or by air (4.3 to 5.4 GPA). The proposed PHI for soybeans is 

60 days. The petitioner has provided a Portuguese version and an English translation of the 

proposed use directions. 

Sugarcane:

BASF Corporation has proposed the use of Plateau® Herbicide on sugarcane grown in Brazil, 

Guatemala, and Costa Rica destined for the U.S. Plateau® Herbicide (EPA Reg. No. 241-365) is 

registered for use on non-crop land, conifer plantations, and pasture and rangeland. The U.S. 

registered product contains 23.6% imazapic; however, the product proposed for use on sugarcane 

contains 70% imazapic. The registrant has not proposed registration of imazapic for use on 

sugarcane in the U.S. 

BASF has proposed a single preemergence foliar application of Plateau®at the rate of 0.125 to 

0.220 lb ai/A. The application may be made using ground equipment with spray volumes of 21.4 

to 26.7 GPA or by air with spray volumes of 3.5 to 4.3 GPA. The Section B of the petition 

indicates the proposed PHI is 150 to 365 days; however, the PHI is not included on the translated 

label. The petitioner has provided an English translation of the proposed product label. The 

English-translated label also includes directions for an “area preparation” application 30 to 45 

days prior to planting at a rate of 0.312 lb ai/A. The implied PHI for this use would be 180 to 

395 days. The petitioner should note that the “area preparation” use directions should have been 

summarized in Section B of the petition. 
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The proposed use directions are summarized in Table 3.3.

Table 3.3. Summary of Directions for Use of Imazapic.

Applic. Timing, Type, 

and Equip.1

Formulation

[EPA Reg. 

No.]

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. 

Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Soybean (Grown in Brazil)

Broadcast foliar 

application initial postoutgrowth to regular postoutgrowth of infesting 

weeds.

17.5% 

WDG2

[none]

0.013 to 

0.016 1

0.016 

(implied) 60

Apply in a minimum 

of 10 (ground) or 4.3 

(air) GPA.

Sugarcane (Grown in Brazil, Guatemala, and Costa Rica)

Area preparation 

application 30 to 45 days 

before planting

70%

WDG

[none]

0.312 1

0.312

(implied)

180 to 

395

(implied)

Apply in a minimum 

of 21 (ground) or 3.5 

(air) GPA. Addition 

of a non-iconic 

surfactant is 

recommended.

Pre-emergence broadcast 

foliar application to 

infesting weeds.

70%

WDG

[none]

0.125 to 

0.220 1

0.220

(implied)

150 to 

365

Apply in a minimum 

of 21 (ground) or 3.5 

(air) GPA. Addition 

of a non-iconic 

surfactant is 

recommended.

1 May be applied using ground equipment or by air.

2 Cultifix contains 52.5% imazapyr and 17.5% imazapic.

Conclusions: The proposed use directions for Cultifix on GMO soybeans grown in Brazil are 

sufficient to allow for evaluation of the submitted residue data. The available field trial data 

support the proposed use directions for imazapic on GMO soybeans. Additionally, the proposed 

use directions for Plateau® Herbicide on sugarcane grown in Brazil, Guatemala, and Costa Rica 

are sufficient to allow for evaluation of the submitted residue data. The available field trial data 

support the proposed use directions for imazapic on sugarcane.

3.4 Anticipated Exposure Pathways

RD has requested an assessment of human-health risk to support the BASF proposed tolerances 

for residues of imazapic and its metabolites CL 263,284 and CL 189,215 in/on GMO soybeans 

and sugarcane without U.S. registration. Humans may be exposed to imazapic in food and 

drinking water, since imazapic may be applied directly to growing crops and application may 

result in imazapic reaching surface and ground water sources of drinking water. There are no 

residential uses of imazapic, so exposure in residential or non-occupational settings is not likely. 

Since U.S. registration of the uses on soybeans and sugarcane are not requested, exposures in 

occupational settings are not of concern for the subject petitions. 

A risk assessment has been previously conducted for imazapic (Memo, 08/01/2001, W. Dykstra 

et al., D267227). This risk assessment considers all of the aforementioned exposure pathways 

based on the proposed new uses of imazapic, but also considers the existing uses as well for the 

dietary exposure assessment. 
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3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations,” 

(http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). As a part of every 

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to 

well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water 

consumption, and activities in and around the home that involve pesticide use in a residential 

setting. Extensive data on food consumption patterns are compiled by the U.S. Department of 

Agriculture (USDA) under the National Health and Nutrition Examination Survey, What We Eat 

in America, (NHANES/WWEIA; 2003-2008) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary 

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. 

Further considerations are currently in development as OPP has committed resources and 

expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

Imazapic is an imidazolinone herbicide. The herbicidal activity of imazapic, as an 

imidazolinone, is due to the inhibition of AHAS, which is a key plant enzyme in the biosynthesis 

of the amino acids leucine, isoleucine, and valine. Animals lack this biosynthetic pathway and 

must obtain these amino acids from their diet. The fact that the herbicidal mode of action of 

imazapic is through inhibition of a biosynthetic pathway not present in humans and livestock is 

one of the factors contributing to the low toxicity of imazapic in mammalian systems.

4.1 Toxicology Studies Available for Analysis

The existing toxicity database for imazapic is adequate for risk and FQPA assessments. 

Appendix A is a summary of the imazapic toxicological database. There is high confidence in 

the quality of the existing studies and the reliability of the toxicity endpoints identified for use in 

risk assessment. In accordance with the revised 40 CFR §158 Toxicology data requirements, the 

neurotoxicity screening battery tests, and an immunotoxicity study for imazapic have been 

submitted and reviewed. Results from these studies have been incorporated into hazard 

characterization and hazard assessment of imazapic. 

In the previous risk assessment, a 28-day inhalation study was identified as a data gap. 

However, HED’s Hazard Science and Policy Council (HASPOC) using a weight-of-evidence 

approach determined that the 28-day inhalation toxicity study is not required at this time. 
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4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

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

dose-related differences following oral or intravenous administration. 

4.2.1 Dermal Absorption

Since a dermal absorption study is unavailable, a comparison of an oral LOAEL and a dermal 

NOAEL (as an upper bound) from short-term studies in rabbits was made. The oral maternal 

LOAEL of 500 mg/kg/day (rabbit developmental study; MRID 42711423) was divided by the 

dermal NOAEL of 1,000 mg/kg/day in the 21-day dermal toxicity study in rabbits (MRID 

42711420). The upper-bound estimated percent dermal absorption was 50%.

4.3 Toxicological Effects

4.3.1 Summary of Toxicological Effects

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). 

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 of 

137 mg/kg/day in males and 180 mg/kg/day in females. At higher doses, additional effects were 

seen in the liver (↑absolute weights and changes in clinical chemical parameters), kidney 

(↓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. 

In the developmental toxicity study in rabbits, there was decreased weight gain and food 

consumption in the does at the LOAEL of 500 mg/kg/day, with the NOAEL being 350 

mg/kg/day. There were no developmental effects in rabbit fetuses in the study up to 500 

mg/kg/day. In the two-generation reproduction study, no parental or reproductive toxicity was 

seen at 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.
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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.

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

The imazapic risk assessment team recommends that the FQPA SF be retained at 10X for all 

exposure scenarios due to the use of a LOAEL for the point of departure (POD) for the chronic 

dietary endpoint. The rationale is described below. 

4.4.1 Completeness of the Toxicology Database

The toxicology database for imazapic is complete. The following acceptable studies are 

available for FQPA consideration: (1) developmental toxicity studies in rats and rabbits; (2) 

two-generation reproduction study in rats; and (3) acute and subchronic neurotoxicity studies.

4.4.2 Evidence of Neurotoxicity

There is no evidence of neurotoxicity in the imazapic database. In both the acute and subchronic 

neurotoxicity studies, there are no signs of neurotoxicity/neuropathology up to the highest doses 

tested. 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence of increased pre- and/or postnatal susceptibility based on the results of the 

rat and rabbit prenatal developmental toxicity studies, and the rat two-generation reproductive 

toxicity study. 

4.4.4 Residual Uncertainty in the Exposure Database

The exposure databases are sufficient to determine the nature/magnitude of the residue in food 

and water. The dietary exposure analyses are unlikely to underestimate exposure as they 

incorporated tolerance-level residues, 100% CT, and modeled drinking water estimates. 

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

Table 4.5.4.1 summarizes the toxicological doses and endpoints selected for human-health risk 

assessment. Only chronic dietary exposure scenarios were assessed since there are no residential 

uses and U.S. registration is not proposed for imazapic. An acute exposure assessment is not 

required for imazapic as an acute oral endpoint attributed to a single-dose exposure could not be 

identified in any of the studies in the toxicology database. Toxicological doses and endpoints for 

occupational human-health risk assessments are summarized in Appendix A.3.

Acute Dietary Endpoint: An acute dietary RfD for the females 13-50 years of age and the 

general population, including infants and children, was not selected because an acute oral 

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

toxicology database.
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Chronic Dietary (All Populations): The endpoint used for deriving the chronic populationadjusted dose (cPAD) was selected from the chronic toxicity study in dogs. The cPAD, which is 

0.137 mg/kg /day, was derived from a LOAEL of 137 mg/kg/day and a 1000-fold uncertainty 

factor that included a 10X for inter-species extrapolations (UFA), 10X for intra-species variations 

(UFH), and a 10X for FQPA SF. The LOAEL of 137 mg/kg/day is based on the increased 

incidence of minimal degeneration and/or necrosis of skeletal muscle. This POD protects for all 

other effects in the hazard database. It is also appropriate for the duration of exposure and is 

protective of the general population.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Oral and inhalation exposures can be aggregated since an oral NOAEL was selected for 

assessing inhalation risks. Quantification of dermal risk is not required. Dermal exposure 

cannot be combined with inhalation, since a dose/endpoint (hazard) was not identified for shortand intermediate-term dermal exposure risk assessments. 

4.5.3 Cancer Classification and Risk Assessment Recommendation

Imazapic has been classified 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 (TXR #0014560).

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Imazapic for Use in Dietary HumanHealth 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

FQPA SF = 10X

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.

Toxicological doses and endpoints for occupational human-health risk assessments are 

summarized in Appendix A.3.
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5.0 Dietary Exposure and Risk Assessment 

An overview of the metabolism of imazapic can be found in the most recent residue chemistry 

assessment (Memo, pending, W. Wassell, D384710).

5.1 Residues of Concern Summary and Rationale

The nature of the residue in plants, rotational crops, and livestock is adequately understood based 

on acceptable metabolism studies conducted with peanuts, grass, soybeans, sugarcane, lactating 

goats, and laying hens.

Plants (Primary Crops): For the purposes of the proposed uses on GMO soybeans and 

sugarcane, the nature of imazapic in plants is understood based on the adequate metabolism 

studies utilizing GMO soybeans, sugarcane, peanuts, and grass. HED concludes the residues of 

concern in soybeans and sugarcane are imazapic and its hydroxymethyl metabolite, both free and 

conjugated metabolites (metabolites CL 263,284 and CL 189,215). 

Plants (Rotational Crops): As the subject petition is for tolerances for residues on soybeans 

and sugarcane without a U.S. registration, the nature and magnitude of the residue in rotational 

crops are not of concern for the subject petitions.

Livestock: Ruminant feed items are derived from soybean and sugarcane commodities. Data 

concerning the metabolism of imazapic in lactating goats and laying hens were previously 

submitted. In a meeting held May 22, 2001, the HED Metabolism Assessment Review 

Committee (MARC) determined that the residues of concern in livestock commodities include 

imazapic and CL 263,284.

Drinking Water: The HED MARC determined that the residue of concern in water is imazapic 

per se (Memo, 06/07/2001, W. Donovan, et al., D275136). 

Table 5.1. Summary of Metabolites and Degradates to be included in Risk Assessment and Tolerance 

Expression.

Matrix Residues Included in Risk Assessment Residues Included in Tolerance Expression for 

Compliance Monitoring

Plants

Primary 

Crop

Imazapic and its hydroxymethyl metabolite, both 

free and conjugated forms (metabolites CL 

263,284 and CL 189,215). 

Imazapic and its hydroxymethyl metabolite, both 

free and conjugated forms (metabolites CL 263,284 

and CL 189,215). 

Rotational 

Crop Not Applicable1 Not Applicable1

Livestock (Ruminant 

and Poultry) Imazapic and CL 263,284 Imazapic and CL 263,284

Drinking Water Imazapic Not Applicable

1 As the subject petition is for tolerances for residues on soybeans and sugarcane without a U.S. registration, the nature and 

magnitude of the residue in rotational crops are not of concern.

5.2 Food Residue Profile

The submitted magnitude of the residue data for GMO soybeans will support the proposed use 

patterns. BASF Corporation has submitted data for imazapic on GMO soybeans from a total of 

11 crop field trials conducted during 2006-07 (8 trials), 2007-08 (1 trial), and 2010 (2 trials). 

The field trials were conducted in Brazil. The residue data were analyzed using the OECD 
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tolerance calculation procedures. The tolerance worksheet recommended a tolerance for residues

of imazapic and its metabolites at 0.40 ppm in/on soybean seed.

The submitted magnitude of the residue data for sugarcane will support the proposed use 

patterns. BASF Corporation has submitted data for imazapic on sugarcane from five crop field 

trials conducted during 2006-07. The field trials were conducted in Brazil. Residues of 

imazapic and its metabolites were below the LOQ (<0.01 ppm) for each analyte. Total residues 

were <0.03 ppm (sum of LOQs for each analyte).

For soybeans, residue-decline data show that residues of imazapic and its metabolites increased 

from a PHI of 20 days to 60 days, and declined to <LOQ for all subsequent intervals. For 

sugarcane, residues at all PHIs were <LOQ. 

Acceptable soybean processing studies are available. The soybean processing studies shows that 

residues of imazapic and its metabolites do not concentrate into soybean commodities during 

processing. Thus, tolerances for residues in soybean processed commodities are not required for 

the subject petitions. 

HED concludes the sugarcane processing data are adequate for the determination of the need for 

tolerances for residues in/on sugarcane commodities. The data indicate that combined residues 

of imazapic, CL 263,284, and CL 189,215 are not expected to concentrate in sugarcane 

processed commodities. 

Livestock feed items are derived from soybeans and sugarcane. In the U.S., imazapic is 

registered for use on peanuts and grass (pasture and rangeland grass). Ruminant feed items are 

derived from these crops. A livestock feeding study was previously submitted and tolerances for 

secondary residues of imazapic in livestock commodities are established based on this study. In 

determining the need for livestock commodity tolerances, HED previously calculated a 

maximum reasonable dietary burden (MRDB) of 102 ppm. The addition of soybean and 

sugarcane commodities to the livestock diet will not significantly increase the MRDB. HED 

concludes the established tolerances for secondary residues of imazapic in livestock commodities 

are adequate to cover any increased dietary burden due to the addition of soybean or sugarcane 

commodities to the livestock diet.

Poultry feed items are derived from soybean commodities. A poultry metabolism study was 

previously submitted. On the basis of this study and the MRDB, HED concludes that there is no 

reasonable expectation of finite residues of imazapic in poultry commodities based on the use on 

peanuts and/or soybean [Category 3 of 40 CFR §180.6(a)] and therefore, tolerances for 

secondary residues in poultry tissues and eggs are not required. 

As the subject petition is for tolerances for residues on GMO soybeans and sugarcane without 

U.S. registrations, the nature and magnitude of residues in rotational crops are not of concern.

5.3 Water Residue Profile

The information concerning the environmental fate and drinking water assessment of imazapic 

were provided by EFED (Memo, 5/10/2001, J. K. Wolf, D267288; and Memo, 5/23/2001, J. K. 

Wolf, D267288A (Addendum)). Surface and ground water monitoring data are not available for 

imazapic.
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Since water-monitoring data are not available, estimates of imazapic levels in surface and ground 

water were provided by EFED using computer models. Except for rapid aqueous photolysis, 

imazapic appears to be extremely persistent, mobile, and highly soluble. The major route of 

dissipation of imazapic appears to be transport with water. Therefore, contamination of ground 

water and surface water by imazapic appears possible. Once in ground water or surface water, 

where light cannot penetrate, imazapic will be very persistent. 

The FQPA Index Reservoir Screening Tool (FIRST) and Generic Estimated Environmental 

Concentration (version 2, GENEEC2) models were used for Tier 1 assessments. FIRST 

produces both a peak value and an annual average value based on the Index Reservoir scenario. 

It uses a percent cropped area factor (PCA) to adjust the estimated drinking water concentrations 

(EDWCs) for the fraction of the watershed that is planted in the modeled crop. The model 

assumes that all of the area planted is treated with the pesticide. The EDWCs for imazapic in 

ground water were estimated using the Screening Concentration in Ground Water model (SCIGROW). To generate EDWCs, the screening models assumed one application of 0.1875 lb ai/A 

per year. 

The surface water EDWCs from FIRST are 16.8 μg/L for peak day concentration (for acute 

exposure) and 1.46 μg/L annual average concentration (for chronic exposure). The EDWCs for 

imazapic in ground water using the SCI-GROW model was 13.67 μg/L when the half-life was 

assumed to be 1500 days (upper bound used for the model's development) and the median Koc of 

71 was used. Using the half-life of 2010 days, the EDWC is 13.73 μg/L. 

Ground water estimate: 13.73 ppb

Surface water estimate: 16.8 ppb; peak concentration

1.46 ppb; annual average concentration

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

A chronic dietary (food plus drinking water) risk assessment was conducted using the Dietary 

Exposure Evaluation Model - Food Consumption Intake Database (DEEM-FCID), Version 3.16, 

which uses food consumption data from the U.S. Department of Agriculture’s National Health 

and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). This 

dietary survey was conducted from 2003 to 2008. The analyses were conducted in support of a 

human-health risk assessment for the proposed tolerances without U.S. registration for imazapic 

and its metabolites on soybeans and sugarcane. 

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 (1.89x). The processing factors for soybean, sugarcane, and peanut 

(except peanut butter) commodities were reduced to 1x, based upon processing data. Since 

water-monitoring data for imazapic are not available, estimates of levels in surface and ground 

water were made using computer models and were provided by EFED. Except for rapid aqueous 

photolysis, imazapic appears to be extremely persistent, mobile, and highly soluble. The FIRST 

and GENEEC2 models were used for Tier 1 assessments. To generate EDWCs, the screening 

models assumed one application of 0.1875 lb ai/A per year. The EDWC used in the chronic 

analysis is 13.73 μg/L. 
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5.4.2 Percent Crop Treated Used in Dietary Assessment

The chronic dietary analyses assumed 100% CT for all commodities. 

5.4.3 Acute Dietary Risk Assessment

An acute dietary RfD for the general population (including infants and children) and females 13-

50 years of age, was not selected because an acute oral endpoint attributed to a single-dose 

exposure could not be identified in any of the studies in the toxicology database. Thus, an acute 

exposure analysis is not required for imazapic.

5.4.4 Chronic Dietary Risk Assessment

Chronic dietary risk estimates (food and drinking water) are not of concern for the general 

population or any other population subgroup. The chronic exposure estimate is <1.0% of the 

cPAD for the U.S. population. The most highly exposed population subgroup was children 1 to 

2 years old that utilized 4.0% of the cPAD. Thus, chronic dietary exposure to imazapic is not of 

concern. 

5.4.5 Cancer Dietary Risk Assessment

Imazapic has been classified 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. Thus, a cancer exposure analysis is not required for imazapic.

5.4.6 Summary Table

Table 5.4.6. 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.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

6.1 Residential (Non-Occupational) Exposure/Risk Characterization

The proposed uses are not expected to result in residential exposure, and there are no currently 

registered residential uses of imazapic; therefore, a quantitative residential exposure assessment 

was not conducted.
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6.2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for imazapic. The 

Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray-driftmanagement practices (see the Agency’s Spray Drift website for more information1

. The 

Agency has completed its evaluation of the new database submitted by the Spray Drift Task 

Force, a membership of U.S. pesticide registrants, and is developing a policy on how to 

appropriately apply the data and the AgDRIFT®computer model to its risk assessments for 

pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in 

place, the Agency may impose further refinements in spray-drift-management practices to reduce 

off-target drift with specific products with significant risk estimates associated with drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider aggregate pesticide exposures and risks from 

three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure.

For imazapic, aggregate exposure risk assessments were performed for chronic aggregate 

exposure only (food and drinking water). Short- and intermediate-term assessments, which are 

used to evaluate aggregate dietary and residential exposures, were not performed because there 

are no registered or proposed residential non-food uses. Imazapic is classified 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.

7.1 Acute Aggregate Risk

An acute aggregate risk assessment was not performed as a dietary RfD for females 13-50 years 

of age and the general population, including infants and children, was not selected because an 

acute oral endpoint attributed to a single-dose exposure could not be identified in any of the 

studies in the toxicology database.

7.2 Chronic Aggregate Risk

The chronic aggregate risk assessment takes into account average exposure estimates from 

dietary consumption of imazapic (food and drinking water). The chronic dietary exposure 

estimates are not of concern to HED (<100% cPAD) for the general U.S. population and all 

population subgroups (see Table 5.4.6). 

The chronic dietary exposure 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 (1.89x). The processing factors for soybean, 

 

1 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
Imazapic Human-Health Risk Assessment DP# 384054

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sugarcane, and peanut (except peanut butter) commodities were reduced to 1x, based upon 

processing data. 

Since water-monitoring data for imazapic are not available, estimates of levels in surface and 

ground water were made using computer models and were provided by EFED. The EDWC used 

in the chronic analysis was 13.73 μg/L. 

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to imazapic and any other substances and imazapic does not appear to produce a toxic metabolite 

produced by other substances. For the purposes of this tolerance action, therefore, EPA has not 

assumed that imazapic has 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/.

9.0 Occupational Exposure/Risk Characterization

The proposed petitions are for tolerances without U.S. registration; thus, occupational exposure 

is not an issue for these petitions.

10.0 References

Previous Risk Assessment: 

Memo, 08/01/2001, W. Dykstra, et al., D267227

RfD/Peer Review Meeting:

Memo, 5/25/94, G. Ghali, RfD/Peer Review Report of CADRE (AC 263,222).

Memo, 09/27/95, G. Ghali, SECOND RfD/Peer Review Report of CADRE (AC 

263,222).

Residue Chemistry:

Memo, W. Donovan, 06/21/2001, D269038.

Memo, W. Wassell, pending, D384710.

HASPOC Memo: 

Memo, J. Van Alstine, 4/17/2012, TXR # 0052356. 

Drinking Water Memo: 

Memo, 05/10/2001, J.K. Wolf, D267288
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Memo, 05/23/2001, J.K. Wolf, D267288A

Dietary Memo: 

Memo, W. Wassell, pending, D384709.
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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for imazapic are in Table 1. Use of the new guideline numbers 

does not imply that the new (1998) guideline protocols were used.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Acute Eye Irritation .......................................................

870.2500 Acute Dermal Irritation .................................................

870.2600 Skin Sensitization ..........................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 90-Day Oral Toxicity in Rodents ..................................

870.3150 90-Day Oral Toxicity in Non-rodents............................

870.3200 21/28-Day Dermal Toxicity...........................................

870.3250 90-Day Dermal Toxicity................................................

870.3465 90-Day Inhalation Toxicity ...........................................

yes

yes

yes

yes

no

yes

no

yes

no

no

870.3700a Prenatal Developmental Toxicity (rodent).....................

870.3700b Prenatal Developmental Toxicity (non-rodent) .............

870.3800 Reproduction and Fertility Effects.................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent) ..............................................

870.4100b Chronic Toxicity (non-rodent).......................................

870.4200a Carcinogenicity (rat)......................................................

870.4200b Carcinogenicity (mouse)................................................

870.4300 Combined Chronic Toxicity/Carcinogenicity................

yes

yes

no

yes

yes

yes

yes

no

yes

yes

870.5100 Mutagenicity—Bacterial Reverse Mutation Test ..........

870.5300 Mutagenicity—Mammalian Cell Gene Mutation Test ..

870.5xxx Mutagenicity—Structural Chromosomal Aberrations...

870.5xxx Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6200a Acute Neurotoxicity Screening Battery (rat) .................

870.6200b 90-Day Neurotoxicity Screening Battery (rat)...............

870.6300 Developmental Neurotoxicity........................................

yes

yes

no

yes

yes

yes

870.7485 Metabolism and Pharmacokinetics................................

870.7600 Dermal Penetration ........................................................

870.7800 Immunotoxicity .............................................................

yes

no

yes

yes

no

yes
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A.2 Toxicity Profiles

Table A.2.1. 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 A.2.2. 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.

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.
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Table A.2.2. Imazapic Subchronic, Chronic, and Other Toxicity Profile.

Guideline 

No.

Study Type MRID No. (year)/ 

Classification /Doses

Results

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.

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.
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Table A.2.2. Imazapic Subchronic, Chronic, and Other Toxicity Profile.

Guideline 

No.

Study Type MRID No. (year)/ 

Classification /Doses

Results

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).

A.3 Endpoints for Occupational Human-Health Risk Assessments.

Table A.3. 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.
Imazapic Human-Health Risk Assessment DP# 384054

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Appendix B. Physical/Chemical Properties

TABLE B. 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.