### 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: 038405 4 ,0 401585 Registration No.: NA Regulatory Ac ti o n: Tolerances without U.S. Reg i strat i on Risk Assessment Type : Single Chemical / Aggregate Case No.: 7234 TXR No.: MRID:

FROM: NA CAS No.: NA 40CFR:

William D. Wassell, Chemist 

# ;W,J/**~ ~**  Anwar Y. Dunbar, Ph.D., Pharmacologist Risk Assessment Branch 1 (RAB 1) Heal t h Effects Division (HED; 7509P) I 04098-48-8 §I 80.490

THROUGH: George F. Kramer, Ph.D., Senior

# Chemist**~ ~**  Dana Vogel, Acting Branch Chief RAB 1/HE D (7509P)

TO: Kable Davis, RM 25 Registration Di vision ( RD

, 7505P)

The HED of th e 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 o f th e herbicide imazap ic [2-[ 4,5-dihydro-4-methyl-4-( 1-methylethyl)-5-oxolH

- imidazol-2-yl]-5-methyl-3-pyridinecarboxylic acid] on sugarca ne 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 res idue chemistry assessment were provided by William Wassell (RAB 1 ); the hazard characte ri zation and endpoint select ion by Anwar Dunbar (RAB 1 ); and the drinking water exposure assessment by 

### J. K. Wolf of the Environmental Fa t e and Effects Division (EFED). Residential and occupational expos ure assessments were not required for this

use.

Page 1 of29lma zap ic Human-Health Risk Assessment DP # 384054
The most recent human-health risk assessment for imazapic was for a Section 3 regi stration and tolerances to support a proposed us e of imazapic on rangeland and pasture grass (Memo, 08 / 01 / 2001, W. Dykstra, et al., D267277).

Page 2 of29Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 3 of 29 

### Table of Contents 1.0 Executive Summary

................................ ................................ ................................ ........... 5 2.0 HED Recommendations

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

................................ ................................ ................................ ............ 7 2.2 Toleranc e 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 Physic al/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

................................ ................................ ................................ ........................ 2 1 7.0 Aggregate Exposure/Risk Characterization

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

................................ ................................ ................................ ... 22 7.2 Chronic Aggregate Risk

................................ ................................ .............................. 22Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 4 of 29 

### 8.0 Cu mulative 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

................................ ................................ ............. 26Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 5 of 29 

### 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 m etabolite (±)

- 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- 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,
resp ectively. The conjugated form of CL 263,284 is (±)

- 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- 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 p pm (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 Culti fix 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 lan d, 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 directi ons 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.Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 6 of 29 

### 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 necros is 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 cli nical 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 decrea sed 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 stud y 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 neur otoxicity 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 as says. Based on these results, it is concluded that the overall mutagenic potential of imazapic is negative.

Imazapic has been classified by the R eference 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. Organiza tion for Economic Co

- operation and Development (OECD) tolerance

calculation procedures and the submitted residue data sets were used to calculate the HED

recommended tolerances for soybeans. Residue data for sugarcane showed residue levels would be less t han 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 o utlined 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 inc orporated 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 # 3840 54

Page 7 of 29 

### 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 be low) 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 p reclude 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 tol erance 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 tol erance levels specified is to be determined by measuring the sum of imazapic (2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl]

- 5

- methyl

- 3

- pyridinecarboxylic acid) and its metabolite (±)

- 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- im idazol

- 2

- yl]

- 5

- hydroxymethyl

- 3

- pyridinecarboxylic acid and (±)

- 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl]

- 5

- (β

- D

glucopyranosyloxy)methyl

- 3

- pyridinecarboxylic acid , calculated as the stoichiometric equivalent of imazapic.Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 8 of 29 

### Additional ly, 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

- 1 H

- imidazol

- 2

- yl]

- 5

- methyl

- 3

- pyridinecarboxylic acid) and its metabolite (±)

- 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl]

- 5

- hydroxymethyl

- 3

- pyridinecarboxylic acid, calculated as the stoichiometric equivalent of imazapic.

The petitioner has proposed a tolerance for residues of im azapic 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. HE D 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 The resa 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
pea nut 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 li quid 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 lab oratory validation (ILV) data for imazapic and its metabolites CL 263,284 and CL 189,215Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 9 of 29 

### 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 ana lyzed 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 a nd 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, inclu ding 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 pe aks, 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
t oasted 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 I midazoline 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 cu rrent 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 expressio n 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

- 1 H

- imidazol

- 2

- yl]

- 5

- methyl

- 3

- pyridinecarboxylic acid) and its metabolite (±)

- 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl]

- 5

- hydroxymethyl

- 3

- pyridinecarboxylic acid and (±)

- 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

imidazol

- 2

- yl]

- 5

- (β

- D

- glucopyranosyloxy)methyl

- 3

- pyridinecarboxylic acid , calculated as the stoichiometric equivalent of imazapic.Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 10 of 29 

### 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 followi ng 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

- 1 H

- imidazol

- 2

- yl]

- 5

- methyl

- 3

- pyridinecarboxylic acid) and its metabolite (±)

- 2

- [4,5

- dihydro

- 4

- me thyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- 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 toleranc e 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 expr ession (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
propose d 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 fi eld trial data support the proposed use directions for imazapic on sugarcane.Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 11 of 29 

### 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

- 1 H

- imidazol

- 2

- yl]

- 5

- methyl

- 3

- pyridinecarboxylic acid CAS # 81334

- 60

- 3 End

- use product/(EP) Cultifix (no U.S. registration s) 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

- 1 H

- imidazol

- 2

- yl]

- 5

- hydroxymethyl

- 3

- pyridinecarboxylic acid
IUPAC name 5

- (hydroxymethyl)

- 2

- (4

- isopropyl

- 4

- methyl

- 5

- oxo

- 2

- imidazolin

- 2

- yl)nicotinic 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

- 1 H

- imidazol

- 2

- yl]

- 5

- (β

- D

glucopyranosyloxy)methyl

- 3

- pyridinecarboxylic acid
IUPAC name 5

- [( β

- D

- glucopyranosyloxy)methyl]

- 2

- (4

- isopropyl

- 4

- methyl

- 5

- oxo

- 2

- imidazolin

- 2

- yl)nicotinic acidImazapic Human

- Health Risk Assessment DP # 3840 54

Page 12 of 29 

### 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 m ajor 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 p ersistent.

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 soybe an 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 a nd 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 applica tion 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, an d 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 o f 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 direction s 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 i n Section B of the petition.Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 13 of 29 

### 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 post

outgrowth to regular post

outgrowth of infesting weeds. 17.5% WDG 2 [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 Exposur e 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 expose d 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 previo usly 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.Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 14 of 29 

### 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 consum er 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/WW EIA; 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 a ble 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 s oftware 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 s tudies 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 b een 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.Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 15 of 29 

### 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 ir ritating 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 appl ications 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 male s 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, an d 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 neuropathol ogy) 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 n egative 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 Human

- Health Risk Assessment DP # 3840 54

Page 16 of 29 

### 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 reco mmends 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 neuro toxicity 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

- ge neration 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 underesti mate 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 end points 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 a n 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 Di etary 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.Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 17 of 29 

### Chronic Dietary (All Populations ) : The endpoint used for deriving the chronic population

adjusted 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 (UF A 

### ), 10X for intra

- species variations (UF H 

### ), and a 10X for FQPA SF. The LOAEL of 137 mg/kg/day is based on the increased incidence of minim al degeneration and/or necrosis of skeletal muscle. This POD protects for all other effects in the haza rd database. It is also appropriate for the duration of exposure and is protective of the general population.

4.5.2 Recommendation for Combining Route s 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 short

and 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 Human

Health Risk Assessments.

Exposure Scenario Point of Departure Uncertainty/

FQPA SFs RfD, PAD, LOC

for Risk Assessment Study and Relevant Toxicological Effects

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

Acute Dietary (Females 13

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

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

UF H = 10X 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 h uman carcinogen by any relevant route of administration based on the absence of carcinogenicity in acceptable studies in mice and rats. Abbreviations: UF = uncertainty factor; UF A = extrapolation from animal to human (interspecies); UF H = potential variation in sensitivity among members of the human population (intraspecies); UF FQPA = FQPA Safety Factor; NOAEL = no

- observed adverse

- effect level; LOAEL = lowest

observed adverse

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

- adjusted dose; LOC = level of concern.


### Toxicological doses and endpoints for occupational human

- health risk assessments are summarized in Appendix A.3.Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 18 of 29 

### 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 livestoc k 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 natur e 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 d erived 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 M etabolites 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 Applicable 1 Not Applicable 1

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 tr ials were conducted in Brazil. The residue data were analyzed using the OECDImazapic Human

- Health Risk Assessment DP # 3840 54

Page 19 of 29 

### 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 mag nitude 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 i mazapic 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 da ys 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 th e 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 subm itted 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 p pm. 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 con cludes 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 ar e 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 no t available for imazapic.Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 20 of 29 

### 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 persiste nt, 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 ca nnot penetrate, imazapic will be very persistent.

The FQPA Index Reservoir Screening Tool (FIRST) and Generic Estimated Environmental Concentration (version 2, GEN EEC2) models were used for Tier 1 assessments. FIRST produces both a peak value and an ann ual 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 th at 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 (SCI

GROW). 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 K oc 

### 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 estimat e: 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 Dietar y 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.Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 21 of 29 

### 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. Thu s, 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 exposu re 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 Imazapic 1

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

- 2 years old NA NA 0.005510 4.0 Children 3

- 5 years old NA NA 0.003411 2.5 Children 6

- 12 years old NA NA 0.001986 1.4 Youth 13

- 19 years old NA NA 0.001033 <1.0 Adults 20

- 49 years old NA NA 0.000889 <1.0 Adults 50

- 99 years old NA NA 0.000839 <1.0 Females 13

- 49 years old NA NA 0.000895 <1.0
1 The values for the highest exposed population for each type of risk assessment are bolded.



### 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 residenti al uses of imazapic; therefore, a quantitative residential exposure assessment was not conducted.Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 22 of 29 

### 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 pes ticide regulation and other parties to develop the best spray

- drift

management practices (see the Agency’s Spray Drift website for more information 1 

### . The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a me mbership 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 polic y 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 w ith 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 wer e 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 res idential 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. populati on 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.htmImazapic Human

- Health Risk Assessment DP # 3840 54

Page 23 of 29 

### 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 lev els in surface and ground water were made using computer models and were provided by EFED. The EDWC used in the chronic analysis wa s 13.73 μg/L.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative r isk 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 websit e 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, D267288Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 24 of 29 

### Memo, 05/23/2001, J.K. Wolf, D267288A

Dietary Memo:

Memo, W. Wassell, pending, D384709.Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 25 of 29 

### Appendix A. Toxicology Profile and Executive Summ aries

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 yesImazapic Human

- Health Risk Assessment DP # 3840 54

Page 26 of 29 

### 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 LD 50 >5,000 mg/kg IV

870.1200 Acute dermal [new Zealand white

rabbit] 42711408 LD 50 >2000 mg/kg III

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

white rabbit] 42711410 minimal irritation III

870.2500 Acute dermal irritation [new

Zealand white rabbit] 42711411 non

- irritating IV

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

Table 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/guidelin e 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.Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 27 of 29 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 ma crophage 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/gui deline 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 Mutagenic

Forward Muta tion 42711425 (1992)

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

Unscheduled DNA Synthesis 42711428 (1992)

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

neurotoxicity screening battery (rat) 48468902 (2011)

Acceptable/guideline 0, 200, 6 00, 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.Imazapic Human

- Health Risk Assessment DP # 3840 54

Page 28 of 29 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/g uideline

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

- rela ted 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 Intermediate

Term (1

- 30 days and 1

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

- week period. Since no hazard was identified, quantification is not required. Inhalation Short

- and Intermediate

Term (1

- 30 days and 1

- 6 months) NOAEL =

350 mg/kg/day

100% Absorption Factor UF A = 10X

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

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

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

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

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

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

- observed adverse

- effect level, LOAEL = lowest

observed adverse

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

- Health Risk Assessment DP # 3840 54

Page 29 of 29 

### 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 al. , 8/01/01 pH NA Density 0.38 g/mL Water solubility (25 ± 1°C) 0.215 g/100 mL in deionized water Solvent solubility NA Vapor pressure at 25 ± 1°C <1 x 10 - 7 mmHg Dissociation constant (pK a ) 2.0, 3.6, 11.1 Octanol/water partition coefficient Log(K OW ) 4.83 between n

- octanol and pH 4

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