Page 2 of 43

technical registrants in response to data requirements. This document provides an overview of 

what is currently known regarding the environmental fate and ecological effects associated with 

imazapic acid, its ammonium salt and its degradates and outlines uncertainties regarding 

attributes of the parent compound and its transformation products. It describes the preliminary 

ecological risk hypothesis and the processes that will be used during the completion of drinking 

water and ecological risk assessments in support of Registration Review. This document also 

recommends studies that should be included in a data call-in (DCI) to address uncertainties 

surrounding the environmental fate and potential ecological effects of imazapic.

At least two uses of imazapic (rangeland and Conservation Reserve program) are subject to prior 

ESA consultation by other Federal agencies (Bureau of Land Management and USDA). EPA 

will review any existing biological opinions (BiOps) at the time of risk assessment to determine 

whether any aspects of the consultation can inform the draft risk assessment for listed species. 
Page 3 of 43

Problem Formulation 

for the 

Environmental Fate and Ecological Risk, Endangered 

Species, and Drinking Water Assessments 

in Support of the 

Registration Review of Imazapic and its Ammonium Salt

 

PC Code: 129041, 128943

CAS #: 104098-48-8, 104098-49-9

Environmental Fate and Effects Division:

Environmental Risk Branch VI

Michael Wagman, Biologist

Iwona L. Maher, Chemist

Reviewed by:

William Eckel, Ph.D., Senior Science Advisor

Amy Blankinship, Chemist

Monica Wait, Risk Assessment Process Leader

Mark Corbin, Branch Chief

U. S. Environmental Protection Agency

Office of Pesticide Programs

1200 Pennsylvania Ave., NW

Mail Code 7507P

Washington, DC 20460
Page 4 of 43

Table of Contents

1. Executive Summary................................................................................................................. 5

2. Introduction ............................................................................................................................. 6

3. Use Characterization................................................................................................................ 7

4. Conclusions from Previous Risk Assessments........................................................................ 9

4.1 Ecological Risk and Drinking Water Assessments.......................................................... 9

4.2 Clean Water Act Programs............................................................................................. 11

5. Environmental Fate and Transport ........................................................................................ 11

6. Receptors............................................................................................................................... 16

7. Exposure Pathways of Concern............................................................................................. 22

8. Analysis Plan ......................................................................................................................... 23

8.1 Stressors of Concern....................................................................................................... 23

8.2 Measures of Exposure .................................................................................................... 23

8.3 Measures of Effect ......................................................................................................... 24

9. Endangered Species Assessment........................................................................................... 24

10. Endocrine Disruptor Screening Program............................................................................... 24

11. Preliminary Identification of Data Gaps................................................................................ 25

11.1 Environmental Fate..................................................................................................... 25

11.2 Effects......................................................................................................................... 27

12. References.............................................................................................................................. 33

Appendix A. Screening Level Models to Evaluate Potential Importance of Drinking Water 

and Inhalation Exposure Pathways........................................................................................... 35

Appendix B. Predictive Data for Parent Imazapic and its Degradates from QSAR Modeling 

using Ecosar v1.11.................................................................................................................... 37

Appendix C. Data Justification Tables for Non-guideline Studies.......................................... 41
Page 5 of 43

1. Executive Summary

The Environmental Fate and Effects Division (EFED) has completed the preliminary problem 

formulation for the ecological risk, environmental fate, endangered species, and drinking water 

assessments to be conducted as part of the registration review of imazapic (PC code 129041) and 

its ammonium salt (PC code 128943). The problem formulation describes the methods to be 

used for the drinking water and ecological risk assessments in support of registration review and 

provides an overview of the environmental fate, ecological effects, and potential risks associated 

with the use of imazapic as well as uncertainties unique to risk assessment of imazapic. This 

document also identifies additional studies that would be beneficial to the conduct of an 

ecological risk assessment. 

Data needs for ecological effects are:

 Avian Acute Oral Toxicity (850.2100)—study conducted with a passerine species using 

TGAI

 Adult Honey Bee Acute Oral Toxicity (non-guideline) using TGAI

 Adult Honey Bee Chronic Oral Toxicity (non-guideline) using TGAI

 Larval Honey Bee Acute and Chronic Oral Toxicity (non-guideline) using TGAI

 Field Testing for Pollinators (850.3040)—may be waived pending the results of the lower 

tier larval and adult honey bee acute and chronic oral toxicity studies

 Seedling Emergence and Seedling Growth (850.4100) – Tier II study conducted with a 

technical end-use product (TEP) on tomato, ryegrass and oat

 Vegetative Vigor (850.4150) – Tier II study conducted with a representative end-use 

product on 10 plant species

The lack of ecological effects data on the toxicity of imazapic’s degradates (through aquatic 

photolysis) to vascular aquatic plants is considered a data gap, but no data is requested at this 

time. For example, if imazapic degradates approach the toxicity of parent imazapic with respect 

to aquatic vascular plants, than there may be implications on the risk picture for listed and nonlisted species of this taxa. In the absence of any additional data, EFED will make conservative 

assumptions including using a Total Toxic Residues (TTR) approach to model exposure for 

vascular aquatic plants in the risk assessment and assume that all imazapic degradates have equal 

toxicity to vascular aquatic plants. 

Data needs for fate and exposure assessment are:

 Aerobic Soil Metabolism (835.4100) - need three additional soils as per guidelines 

requirement using TGAI

 Aerobic Aquatic Metabolism (835.4300) using TGAI

 Anaerobic Soil Metabolism (835.4200) using TGAI

 Soil Storage Stability Study - to support submitted PGW studies (MRIDs: 47001701 and 

47002001)

 Environmental Chemistry Methods and independent laboratory validations for parent

imazapic and its major degradates in Soil and Water (850.6100)
Page 6 of 43

2. Introduction

Imazapic (Figure 1) is an herbicide which belongs to the imidazolinone class of pesticides which 

also includes imazamox, imazapyr, imazethapyr, imazamethabenz, and imazaquin. All of the 

imidazolinone herbicides share a common mechanism of herbicidal action that involves the 

inhibition of the acetolactate synthase (ALS) enzyme (also referred to as acetohydroxyacid 

synthesis (AHAS) inhibitor). ALS is an enzyme found in plants and is required for the synthesis 

of essential branched chain amino acids (i.e., valine, leucine, and isoleucine), all of which are 

important for plant growth (Tan et al. 2005). Animals do not synthesize these amino acids via 

this pathway; therefore, imidazolinone herbicides generally exhibit very little toxicity to 

mammals, birds, fish, or insects.

Imazapic is the common name for (±)-2-[4,5-Dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1Himidazol-2-yl]-5-methyl-3-pyridinecarboxylic acid and is identical to imazapyr with the addition 

of a methyl group on the pyridine ring:

Figure 1: Chemical structure of imazapic (PC Code 129041)

Ammonium salt of imazapic (Figure 2) is the common name for (±)-2-[4,5-Dihydro-4-methyl-4-

(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-5-methyl-3-pyridinecarboxylic acid monoammonium 

salt.

Figure 2: Chemical Structure ammonium salt of imazapic (PC Code 129043)

The risk assessment will be conducted assuming imazapic refers to the free acid of imazapic (as 

drawn in Figure 1). All end-use products of imazapic contain the imazapic acid or the

ammonium salt of imazapic as indicated in the use Table 1. Fate and ecotoxicity studies 
Page 7 of 43

generally did not specify whether they were conducted with the acid or ammonium salt, but the 

assessment will assume that all fate and ecotoxicity studies were conducted using the free acid 

(TGAI) of imazapic unless other information is provided.

Imazapic was first granted a registration for peanuts in the United States in 1994. Additional uses 

have been granted since the initial registration. The uses in the profile to be evaluated by EFED 

include terrestrial non-crop areas including rights-of-way, non-residential turf, and wildlife 

habitat management. Details of treated crops and areas as well as application rates and methods 

are provided in Section 3 of this document.

EFED evaluated the most recent ecological risk assessments for imazapic in association with the 

updated toxicity, exposure, and usage information to determine if sufficient data are available or

if further updates are needed to support registration review. In addition, EFED considered the 

latest Agency science policies and risk assessment methodologies. 

3. Use Characterization

The chemical profile produced by Biological and Economic Analysis Division (BEAD), located 

in the registration review docket, lists the use patterns of maximum exposures for the current 

uses of imazapic and its ammonium salt. BEAD’s chemical profile includes both a summary of 

labeled uses and application rates as well as a summary of available reported usage data. The 

Screening Level Usage Analysis (SLUA) and chemical profile reports conducted by BEAD 

showed that the main use (>98% of total pounds applied) for imazapic is on peanuts with 

approximately 55% of the crop treated, based on available data from 2004—2012 (USEPA, 

2014a). This use is primarily in the states of Georgia, Alabama and Florida. Pastureland 

constitutes most of the remainder of imazapic use (1.4% of total pounds applied). The Bureau of 

Land Management (BLM) has reported increasing imazapic use from 2002 to 2011, with ~2100 

pounds of active ingredient (a.i.) applied on ~21,200 acres in 2011 (BLM Proprietary Data, 

2012). EFED will use application scenarios that result in maximum exposure scenarios for a 

given use for the risk assessment. Any absence of information on the labels that specifies the 

maximum single application rate, the application interval, the annual maximum rate allowed 

(expressed as pounds of acid equivalent per acre per year) (lbs a/acre/year), or application 

method, may result in overly conservative assumptions.

The use profile to be utilized for EFED’s risk assessment includes the terrestrial uses described 

in Table 1. The highest use rate of 0.9171 lbs ae/A (nonagricultural uncultivated areas/soils) is 

substantially higher than any other use site. This application rate is associated with two labels 

(EPA Registration Numbers 71995-49 and 71995-51; both labels with imazapic ammonium salt 

co-formulated with glyphosate and diquat dibromide) for use on small areas such as cracks and 

crevices on sidewalks, walkways, gravel pathways, along fences and in driveways and parking 

areas. This application rate is typically applied only as a spot treatment and will be modeled 

accordingly in the risk assessment. Information on a typical percentage of an area that is spot 

treated for this use site would be useful for the risk assessment.
Page 8 of 43

Table 1. Profile of currently registered uses of Imazapic Acid and its Ammonium Salt

Crop

Maximum

Single 

Application

Rate 

(lb ae/acre)

Annual 

Maximum

Number of 

Applications or 

Annual 

Maximum 

Application 

Rate 

Geographic 

Restrictions

Application 

Method(s)

End-use 

Product 

Labels

Agricultural 

Fallow/Idleland/

Conservation Reserve

0.1994A ae 0.1994 Aerial or 

ground

241-393

241-409

241-417

71368-99

SD090005

Conifers 0.1859A ae 0.1859 Aerial or 

ground 2935-557

Nonagricultural 

Uncultivated Areas/Soils 0.9171Bae

NSD, E AerialD or 

ground

241-365

241-393

241-409

241-417

241-425

241-444

2935-557

7969-320

66222-141

71368-99

71995-38

71995-40

71995-47

71995-49

71995-51

71995-54

81927-19

SD090005

Pastures 0.1994B ae 0.1994 Aerial or 

ground

241-365

241-417

241-444

66222-141

71368-99

81927-19

SD090005

Peanuts 0.0638

B

ae 0.0638 ae

Registered only for 

use in Alabama, 

Arizona, Arkansas, 

Florida, Georgia, 

Louisiana 

Mississippi,

Missouri,

New Mexico, 

North Carolina, 

Oklahoma, 

Ground

241-364

241-381

241-444

66222-141
Page 9 of 43

Table 1. Profile of currently registered uses of Imazapic Acid and its Ammonium Salt

Crop

Maximum

Single 

Application

Rate 

(lb ae/acre)

Annual 

Maximum

Number of 

Applications or 

Annual 

Maximum 

Application 

Rate 

Geographic 

Restrictions

Application 

Method(s)

End-use 

Product 

Labels

South Carolina,

Tennessee, Texas, 

Virginia

Rangeland 0.1994Bae 0.1994 Aerial or 

ground

241-365

241-417

241-444

66222-141

71368-99

81927-19

SD090005

Mulch 0.2339Cae NS Ground

241-425

71995-38

71995-47

71995-54

Ornamental 0.2339Cae NS Ground

241-425

71995-38

71995-47

71995-54

A- formulated as imazapic acid

B

- Both imazapic acid and imazapic ammonium salt are registered for this use site

C

- Formulated as ammonium salt.

D- Aerial applications on nonagricultural uncultivated areas/soils are only allowed with imazapic acid formulations and 

the maximum single and annual application rate for aerial applications is 0.1994 lbs ae/A

E

- NS = not specified

4. Conclusions from Previous Risk Assessments

The Agency has conducted previous ecological risk assessments and drinking water assessments 

for imazapic that serve as a basis for this problem formulation. Results of the most recent 

assessment are briefly summarized below. Neither an endangered species assessment nor a Reregistration Eligibility Decision (RED) have been conducted by EPA for imazapic. Several other 

federal agencies including the BLM and the Forest Service have previously conducted ecological 

risk assessments on imazapic (ENSR, 2005; SERA, 2004)

4.1 Ecological Risk and Drinking Water Assessments

The most recent EFED risk assessment for imazapic was completed in 2001 (DP Barcode:

D277341). EFED conducted a Drinking Water Assessment (DWA, D267228 and D267228A) 

and an Ecological Risk Assessment (ERA) for imazapic and its end-product Plateau DG
Page 10 of 43

herbicide for the control of weeds in pasture, rangeland, and the Conservation Reserve Program. 

The acute (peak value) and chronic (yearly average) estimated drinking water concentrations 

(EDWCs) for the herbicide as predicted by the FIRST model were 16.8 μg ae/L and 1.46 μg 

ae/L, respectively. Levels of Concern were exceeded for listed and non-listed species of nontarget terrestrial plants and vascular aquatic plants. The SCI-GROW model provided estimated 

ground water concentrations at 13.73 μg/L. The Health Effects Division’s (HED) Metabolism 

Assessment Review Committee (MARC) determined that the residue of concern in drinking 

water is imazapic per se (USEPA, 2001a; D275136).

A summary of conclusions for ecological risk concerns identified in the previous ecological risk 

assessment are provided in Table 2.

Table 2. Summary of Risk Concerns Identified for Imazapic in Previous Assessments

Birds Mammals Terr.

Plants

Terr.

Inverts Fish BCF Aquatic Inverts

Aquatic 

Plants

Groundwater 

Contamination Persistence Degradates of Concern

No No Yes NA No No No Yes Potential Yesa None

Yes = at least one LOC was exceeded in previous assessments

No = LOCs were not exceeded in previous assessments

NA = RQs were not calculated previously.

a Stable to hydrolysis, soil photolysis, aerobic soil metabolism, anaerobic aquatic metabolism

4.1.1 Bureau of Land Management Assessment

In 2005, the Bureau of Land Management (BLM) completed an ecological risk assessment for 

the use of imazapic and nine other herbicides to control invasive plants and weeds on 

approximately one million acres (ENSR, 2005). The assessment modeled both typical (0.0313 

lbs a.i./A) and maximum (0.1875 lbs a.i./A) application rates. This assessment concluded that 

risk to terrestrial wildlife and fish was not predicted. Acute risk was not predicted for aquatic 

invertebrates, but chronic risk was predicted under a single direct spray scenario at the maximum 

application rate. Risk to terrestrial and aquatic non-target plants was considered likely when 

plants or water bodies are accidentally sprayed. Risk to non-target aquatic plants was considered 

likely at the maximum application rate from surface runoff in sandy soils with at least 25 inches 

of precipitation per year, in clay/loam watersheds with at least 50 inches of precipitation per 

year, and in loam watersheds with at least 100 inches of precipitation per year. For risk from 

spray drift, at the maximum application rate risk was predicted for listed and non-listed terrestrial 

plant species for aerial applications with less than 300 feet (if conducted by forested plane) or 

100 feet (for helicopters and non-forested planes) buffers. Spray drift resulted in risk to aquatic 

plants under maximum application rates in forested areas with less than 100 foot buffers. 

4.1.2 Forest Service Assessment

In 2004, the Forest Service completed a human health and ecological risk assessment for the use 

of two formulations (PlateauTM and Plateau DGTM, both containing the ammonium salt of 
Page 11 of 43

imazapic) in its vegetation management programs (SERA, 2004). The ecological risk 

assessment concluded that risk to terrestrial and aquatic animals was unlikely. Sensitive plant 

species were determined to be potentially at risk by off-site spray drift of imazapic at distances of 

50 feet for ground applications or over 100 feet for aerial applications. Damage to terrestrial 

plants from runoff was considered possible in some areas but unlikely to be substantial. 

Vascular aquatic plants were considered to be at risk under conditions in which runoff is favored, 

such as in areas with clay soils and relatively high rainfall rates. 

4.2 Clean Water Act Programs 

Imazapic is not identified as a cause of impairment for any water bodies listed as impaired under 

section 303(d) of the Clean Water Act. No Total Maximum Daily Load (TMDL) criteria have 

been developed for imazapic. Based on its chemical structure, this compound falls under the 50 

microgram per liter New York State drinking water standard for “unspecified organic 

contaminants” (10 NYCRR Part 5, Public Water Systems). Aquatic benchmarks have been 

established for imazapic acid and are available at 

http://www.epa.gov/oppefed1/ecorisk_ders/aquatic_life_benchmark.htm. The lowest benchmark 

was set at 6.1 μg/L for vascular aquatic plants and was >50,000 μg/L and 96,000 μg/L for acute 

and chronic concerns to aquatic animals. Any data submitted or otherwise located as part of the 

registration review process may be used to update aquatic life benchmarks if applicable. 

5. Environmental Fate and Transport 

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

highly soluble. Imazapic is expected to occur in an ionized form in the natural environment. The 

major route of dissipation of imazapic appears to be aqueous photolysis and transport with water 

(D256432). Therefore, contamination of ground water and surface water by imazapic appears 

possible via leaching, runoff and spray drift. Once in ground water or surface water where light 

cannot penetrate, imazapic will be very persistent. This assessment is consistent with other 

imidazolinone herbicides.

In laboratory studies, except for rapid aqueous photolysis (t1/2 =< 8 hours), imazapic is stable 

(≥94.3% parent remained after 30 days) to hydrolysis at pH 5, 7, and 9, soil photolysis (t1/2 = 106 

days), aerobic soil metabolism (extrapolated t1/2 = 2010 days), and anaerobic aquatic metabolism 

(extrapolated t1/2 = 2400 days). Based on batch equilibrium data conducted on six soils, imazapic 

appears to be very mobile to mobile in soil (Kd = 0.17 - 2.99). The Koc model does not appear to 

be valid for imazapic as its mobility is not correlated with the organic carbon content of soil. 

Volatility does not appear to be a major route of dissipation since very little (≤1%) volatile 

compounds were isolated in the laboratory studies and the vapor pressure of < 10-7 mm Hg 

indicates that the compound would not be volatile. Imazapic has a very low bioconcentration 

factor (maximum of 0.12 in inedible parts) demonstrating a lack of accumulation in fish; further,

the compound was rapidly excreted within three days of exposure to less than the detection 

limits. The low Kow value of < 1 supports the conclusion of low bioaccumulation of imazapic.

In the field, imazapic proved to be mobile and persistent. Imazapic terrestrial field dissipation 

half-lives ranged from 31 to 223 days in six sites of AR, FL, GA (2 sites), NC, and TX, with the 
Page 12 of 43

average of 122 days, and median 102 days, for the currently registered liquid formulations.

Imazapic photodegradates were not monitored in the field studies. In a prospective ground water 

study conducted in NC, after application of Plateau® (an aqueous solution formulation; 22.2% 

a.e.) residues of imazapic were detected at levels ≤ 0.08 ppb in 3 (shallow) of the 9 wells. 

Imazapic degradate CL 354825 was not detected in shallow or deep wells. In another study 

conducted in GA after application of Cadre® DG (a dispersible granule formulation; 70% a.i.)

residues of imazapic were not detected above the LOD in any shallow or deep monitoring wells.

This GA site, however, did not represent conditions that maximize imazapic persistence and 

mobility as determined during a review of the study protocol (USEPA 1999, D256957).

Registrant-submitted data characterizing the physical, chemical, fate and transport characteristics 

associated with imazapic are summarized below in Table 3.

Table 3: Physiochemical Properties and Environmental Fate Characteristics of Imazapic Acid

Parameter Value1 Description Source

(MRID)

Selected Physical/Chemical Parameters

CAS No.: 104098-48-8

IUPAC name 2-[(RS)-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

Smiles O=C(O)c1c(ncc(c1)C)/C2=N/C(C(=O)N2)(C(C)C)C

Molecular Mass of Imazapic 

(Molecular Formula)

and its ammonium salt

275.3 g/mol

(C14 H17 N3 O3)

292.3 g/mol

Imazapic acid

Ammonium Salt

IUPAC Site

Vapor pressure 

(25°C) <1.0 x 10-7mm Hg Non-volatile under normal field conditions 42711403

Aqueous solubility 

(25C) ppm

2,150; 36,000; 479,000; and 

518,000

In de-ionized water, pH5, 

pH7, and pH9, respectively 42711403

Apparent (the sum of the ionized 

and non-ionized forms) Log 

octanol-to-water partition 

coefficient (KOW) 

pH 4: 0.462

pH 5: 0.158

pH 6: 0.0318

pH 7: 0.0101

pH 8: 0.0053

pH 9: 0.0024

Not likely to bioaccumulate 42711403

Persistence

Hydrolysis: Half-life

(25±1C)

pH 5: Stable

pH 7: Stable

pH 9: Stable

Not a major degradation 

pathway 42711444

Aqueous Photolysis: Half-life 

(25±1C)

pH 5: 7.2 hrs.

pH 7: 6.0 hrs.

pH 9: 6.2 hrs.

Most rapid degradation 

process

43320311
Page 13 of 43

Table 3: Physiochemical Properties and Environmental Fate Characteristics of Imazapic Acid

Parameter Value1 Description Source

(MRID)

Soil Photolysis: Half life

(25±1C; pH: 5.4)

106 d

(Sassafras sandy loam)

Not a major degradation 

pathway 43320312

Aerobic Soil Metabolism: 

Extrapolated Half-life 

(25±1°C)

2010 d Sassafras sandy loam soil

pH of 5.2 and 1.3% OM 42711445

Anaerobic Aquatic Metabolism: 

Extrapolated Half-life (25±1°C) 2400 d -- 43320313

Mobility

Soil-water partition coefficients 

(Kd-ads) 

Organic carbon-normalized 

partition coefficients (KOC)

0.19, 058, 0.82, 2.8, and 4.1 

l/kg

7 to 267

Very mobile to mobile 42711446

Field Dissipation

Terrestrial Field Dissipation: Halflife and DT75

Leaching depth

31 d (0-6 in. depth);

DT75: 90 d

Leached to 6 in. depth1

Near Jamesville, NC

Sandy loam soil 43320314

223 d (0-6 in. depth);

DT75: >120 d

Leached to 6 in. depth

Shoffner, AR

Loam soil

43320314

184 d (0-6 in. depth);

DT75: >120 d

Leaching to 6 in. depth1

Pinehurst, GA 

Sandy loam soil

43320314

93 d (0-18 in. depth);

DT75: 240 d

Leached to 18 in. depth

Snook, TX

Silty loam soil

43320314

104 d (0-18 in. depth);

DT75: 299 d

Leached to 18 in. depth

Montezuma, GA

Loamy sand soil

43320314

99 d (0-18 in. depth);

DT75: 450 d

Leached to 18 in. depth

Malone, FL

Loamy sand soil

43320314

Small-Scale Prospective GroundWater Monitoring Study

Parent detected in 3 of 9 

wells, CL 354825 was not 

detected in any wells.

Neither parent nor CL 

354825 were detected above 

LOD in any wells.

Lucy loamy sand, 

Richmond County, NC

(Plateau®; an aqueous 

solution formulation)

Eustis sandy loam,

Dooly County, GA

(Cadre® DG, dispersible 

granule formulation)

47001701

47002001

Fish Bioconcentration
Page 14 of 43

Table 3: Physiochemical Properties and Environmental Fate Characteristics of Imazapic Acid

Parameter Value1 Description Source

(MRID)

Fish Bioaccumulation Factors

(28 d BCFs for bluegill sunfish)

Edible: < LOQ

Inedible: 0.12X

Whole Body: 0.10X

Depuration: 50% and > 99%

by day 3 and 14.

Does not bioaccumulate in 

fish 43320315

Abbreviations: C - degrees Celsius; d = day; DT - disappearance time; hrs. = hours; in. = inch; l = liters; kg = 

kilograms; LOQ = level of quantitation; < = less than; 

Notes:

1 Except for one replicate that showed the parent leached below 6in. depth.

The laboratory data indicate the only identifiable degradation process of imazapic that is rapid 

enough to yield detectable degradates is photolysis. In the aqueous photolysis study, six 

degradates, including CO2, were identified at concentrations >l0% of the applied (Table 4). In

the soil photolysis study, one major product was formed which accounted for greater than 10% 

of the applied dose (11%). This product was identified as the diacid, AC 312,622, and it is a 

common degradate for imazamox, another imidazolinone pesticide, and imazapic. In addition, 

there were three unidentified radiolabeled components, each of which represented between 3 to 

8% of the applied dose.

In an anaerobic aquatic metabolism study, there were no metabolites detected which accounted 

for greater than 10% of the applied dose, or were present at levels greater than 0.01 ppm. There 

were no metabolites detected in the aerobic soil metabolism study, and imazapic degradates were 

not monitored in the field dissipation studies. The transformation product CL 354825 was 

analyzed for in a small-scale PGW study in North Carolina on sandy soil and it leached into all 

soil depths. It was not detected, however, above the LOQ in soil pore-water samples with the 

exception of three samples, concentrations of 0.06 ppb, and was not detected in shallow or deep 

wells. Below Table 3 presents identified major degradates and their maximum percent of applied 

radioactivity.

Table 4. Degradates identified and maximum percent of applied radioactivity in the 

aqueous and soil photolysis studies.

Degradates Structure

Study Type 

(Reference)

Percent of 

applied 

radioactivity 

(%) at

pH5 pH7 pH9

Carbon dioxide (C02) 45.5 21.0 10.3
Page 15 of 43

5-methyl-3-pyridinecarboxylic acid

CAS: 3222-49-9

5-Methylnicotinic acid 

Smiles String:

C1=C(C=NC=C1C(O)=O)C

MF: C7H7NO2

MW: 137.14

CL 263,407

Aqueous 

Photolysis

MRID 

43320311

29.9 17.2 15.7

2-[(1-carbamoyl-1,2-demethypropyl)

carbamoyl]-5-methyl-nicotinic acid

Smiles String:

C1=C(C=NC(=C1C(O)=O)C(=O)NC(C(

C)C)(C(=O)N)C)C

MF: C14H19N3O4

CL 290,610

Aqueous 

Photolysis

MRID

43320311

30.8 29.0 41.3

5-methyl-2-3-pyridine dicarboxylic acid

Smiles String:

C1=C(C=NC(=C1C(O)=O)C(=O)O)C

MF: C8H7NO4

CL 290,811

Aqueous 

Photolysis

MRID 

43320311

13.0 10.3 5.3

2-carbamoyl-5-methyl-nicotinic acid

Smiles String:

C1=C(C=NC(=C1C(O)=O)C(=O)N)C

MF: C8H7NO3

Aqueous 

Photolysis

MRID 

43320311

10.5 12.9 9.7
Page 16 of 43

2-carbamoyl-5-methyl-3-nicotinic acid

Smiles String (2-ring structure):

C1=C(C=NC2=C1C(=O)OC2O)C

Smiles String (1-ring structure):

C1=C(C=NC(=C1C(=O)O)C=O)C

Aqueous 

Photolysis

MRID 

43320311

18.4 43.3 44.3

Name:

3,5-Pyridinedicarboxylic acid, 2-(4-

isopropyl-4-ethyl-5-oxo-2-imidazolin-2-

yl)-

Smiles String:

C1=C(C=NC(=C1C(O)=O)C2=NC(C(N

2)=O)(C(C)C)C)C(O)=O

MF: C14 H15 N3 O5

MW: 305.29

CL 312.622

Soil Photolysis

MRID

43320312

 11 (30 d)

Abbreviations: MF - Molecular Formula; MW- Molecular Waight; d – days.

6. Receptors

Tables 5 and 6 provide a summary of the taxonomic groups tested to characterize the potential 

acute and chronic ecological effects of imazapic. In addition, the tables provide a preliminary 

overview of the potential acute toxicity of imazapic by providing the acute toxicity 

classifications. No toxicity data for any imazapic degradates is available. It was unclear from 

some of the submitted toxicological studies whether they were conducted with imazapic acid or 

imazapic ammonium salt, however for the risk assessment, EFED will assume that all studies 

were conducted with the acid, unless information is provided to contradict this assumption.

Although this is an uncertainty, if any ecotoxicological studies were conducted with the 

ammonium salt instead of the acid, than by using the acid equivalency EFED would only be 

underestimating actual toxicity by approximately 6%.
Page 17 of 43

Technical grade imazapic is classified as practically non-toxic to freshwater and saltwater fish 

and aquatic invertebrates on an acute exposure basis (Table 5). No effects were seen in chronic 

aquatic studies conducted with freshwater fish and invertebrates. Chronic exposure effect data 

for saltwater fish and invertebrates have not been submitted to the Agency. Duckweed (Lemna 

gibba) was the most sensitive aquatic plant species to imazapic with an IC50 of 6.22 ppb ae/L and 

a NOAEC of 2.58 ppb ae/L; however, growth inhibition was generally not observed in 

freshwater or estuarine/marine non-vascular aquatic plants based on toxicity testing with 

maximum concentrations of 44.1—67.4 ppb ae/L. However, in a limit test with freshwater 

diatoms (Navicula pelliculosa), inhibition was 11% at the limit dose of 46.4 ppb, which did not 

include one presumed outlier that would have resulted in inhibition of 32.9% at the limit dose. 

EPA does not currently classify toxicity to aquatic plants.

Previous assessments (USEPA, 2001) indicated potential for risk to listed and non-listed species 

of aquatic vascular plants. No data is available for the toxicity of imazapic degradates to aquatic 

plants or other aquatic taxa. Other chemicals in the imidazolinone class (i.e. imazapethyr) have 

some degradates that are analogous to imazapic’s degradates and for which empirical data is 

available. For example, two degradates of imazapethyr (CL 290084 and CL 271197) are 

analogous to imazapic’s degradates, CL 263,407 and CL 290,811, respectively, except that 

imazapethyr’s degradates have attached ethyl groups while imazapic’s degradates only contain 

attached methyl groups. Those imazapethyr degradates were more toxic to several aquatic taxa 

including daphnids and green algae and although less toxic than parent imazapethyr to duckweed 

were still reasonably sensitive (NOECs ranged from 23.54 μg a.i./L to 49.8 μg a.i./L). 

Aquatic invertebrates and nonvascular plants would likely have to be > 5 orders of magnitude 

more sensitive to imazapic degradates than parent imazapic in order to approach levels of 

concern. However, for aquatic vascular plants, if imazapic degradates approach the toxicity of 

parent imazapic than there may be implications on the risk picture for listed and non-listed 

species of aquatic vascular plants. The lack of data on imazapic degradates’ toxicity to aquatic 

vascular plants is considered a data gap, but no additional data is requested at this time. EFED 

attempted to see if quantitative structural activity relationships (QSAR) could be used to estimate 

the toxicity of imazapic degradates (Appendix B). However, this analysis (conducted using 

ECOSAR v1.11) found that QSAR relationships poorly predicted the actual toxicity of parent 

imazapic to green algae (though had better predictive capacity for aquatic invertebrates and fish) 

and lacked predictive capability for toxicity to duckweed and would therefore be inappropriate to 

use to characterize the toxicity of the degradates to aquatic vascular plants. For the risk 

assessment, in the absence of any additional aquatic vascular plant toxicity data on the 

degradates, EFED will conservatively characterize this risk by utilizing a TTR approach. In this 

approach, a single exposure concentration is estimated for total residues (i.e. parent imazapic + 

the five degradates identified in the aqueous photolysis study) and compared to a representative 

toxicity endpoint for the parent (i.e. assumes equal toxicity of each degradate to parent 

imazapic). This approach may not be sufficiently conservative if degradates are actually more 

toxic than parent imazapic, however available data for other chemicals in the imidazolinone class 

(i.e. imazapethyr) indicate that for the aquatic taxa most likely to be at risk (aquatic vascular 

plants), the degradates are not as toxic as the parent compound (USEPA, 2014b). 
Page 18 of 43

Table 5. Summary of the Most Sensitive Endpoints from Aquatic Toxicity Studies for Imazapic Acid

Taxonomic 

Group

Study 

Type Tested Species Toxicity Value

Acute 

Toxicity 

Classification

Source

(Study Classification)

Comments

Freshwater 

fish1

Acute

Bluegill sunfish

(Lepomis 

macrochirus)

Rainbow trout 

(Oncorhynchus 

mykiss)

96-Hr LC50 > 

100 ppm ae

Practically 

non-toxic

42711434 & 42711435

(Acceptable)

Max mortality was 10% at 

the limit concentration

Chronic 

Fathead minnow

Pimephales 

promelas

28-D NOAEC 

= 96 ppm ae

LOAEC > 96 

ppm ae

N/A

44728202 (Acceptable)

No mortality or sublethal

effects

Freshwater 

invertebrates

Acute Water Flea 

(Daphnia magna)

48-Hr EC50 > 

100 ppm ae

Practically 

non-toxic

42711437 (Acceptable

No mortality or sublethal 

effects

Chronic Water Flea 

(Daphnia magna)

21-D NOAEC 

= 96 ppm ae

LOAEC > 96 

ppm ae

N/A

44728201 (Acceptable) 

No mortality or sublethal 

effects

Estuarine/ 

marine fish

Acute

Sheepshead 

Minnow 

(Cyprinodon 

variegatus)

96-Hr LC50 > 

98.7 ppm ae

Practically 

non-toxic

44817702 (Supplemental)

Chronic No data

Estuarine/

marine 

invertebrates

Acute

Mysid shrimp 

(Americamysis 

bahia)

96-Hr LC50 > 

97.7 ppm ae

Practically 

non-toxic

44817704 (Acceptable)

No mortality of sublethal 

effects

Chronic No data

Aquatic 

plants and 

algae

Vascular Duckweed 

(Lemna gibba)

14-D IC50 = 

6.22 ppb ae 

(95% CI: 

5.75—6.75)

NOAEC = 2.58 

ppb ae

N/A

43320310 (Acceptable)

Tier II study with 

technical grade material, 

number of fronds at 14 

days was most sensitive. 

Nonvascular

Marine Diatom

Skeletonema 

costatum

120-Hr IC50 > 

44.1 ppb ae

NOAEC = 

44.1 ppb ae

N/A

43320310 (Acceptable)

Tier 1 study with technical

grade material, Day 0 

Concentrations (Day 5 

concentrations had 

decreased by over 40%)

1 Freshwater fish may be surrogates for aquatic-phase amphibians.

Imazapic is practically non-toxic to birds on an acute oral basis and a dietary basis, and it is 

practically non-toxic to mammals on an acute oral exposure basis (Table 6). No acute passerine 

bird toxicological data is available. No mammalian inhalation toxicity data is available for this 
Page 19 of 43

chemical, however due to its low vapor pressure, inhalation exposure is not expected. Hatchling 

body weight was reduced in the mallard reproduction study at 994 mg a.e./kg-diet while in the 

bobwhite reproduction study, effects were seen on hatchling body weight, number of live 

embryos/number of viable embryos and number of hatchlings/number of live embryos at 1907 mg 

a.e./kg-diet. No reproductive effects were observed in the chronic mammal study at concentrations 

up to 20,000 ppm. 

Although no mortality was observed in the acute oral and dietary studies with bobwhite and 

mallard, sublethal effects of reduced food consumption were observed in the mallard acute oral 

study and both the mallard and bobwhite subacute dietary studies. Chronic effects were also seen 

on hatchling body weight for both mallards and bobwhite quail and additional reproductive effects 

(reduced survival of live embryos and hatchlings) were seen in the bobwhite quail reproduction 

study. Additionally the maximum application rate of 0.9171 lbs ae/A (for the spot treatment on 

nonagricultural uncultivated areas/soils use site) results in upper bound Kenaga residue estimates 

on short grass that are greater than 1/10 the highest dose tested in the acute oral studies. In the 

absence of additional data, risk to listed avian species may be uncertain. Therefore, a new avian 

acute oral study using a passerine species is needed for the risk assessment to evaluate acute risk 

to listed avian species. Maximum use rates for all other imazapic use sites are significantly lower 

and would not result in the need for a passerine study to reduce potential uncertainties regarding 

acute oral-based exposure for listed avian species. If the maximum application rate from the spot 

treatment was reduced by approximately 45% to 0.50 lbs ae/A, than the upper bound residue 

estimates would be sufficiently low on all dietary items such that additional avian data would not 

be needed. 

Acute contact toxicity to bees was low, with observed mortality being 25% at the highest treatment 

level of 100 μg ae/bee. Acute oral toxicity data is not available for adult bees nor is chronic toxicity 

data available for adult bees or acute or chronic data available for larval bees. Data on pollinator 

toxicity is required to sufficiently evaluate risk to pollinators.

Terrestrial plant seedling emergence and vegetative vigor data was originally considered 

acceptable, but are now being downgraded to supplemental as they were conducted with TGAI

and not an end-use product. Additionally, in the available Tier 2 terrestrial plant studies,

continuation tests were performed as a result of the fact that the initial tests did not include low 

enough concentrations to allow determination of the NOAEC and/or IC25. EFED does not support 

combining the results of multiple tests for statistical analysis of assessment endpoints. Therefore, 

for those species/tests where the NOAEC/IC05 and the IC25 both cannot be determined from only 

the base test or the continuation test alone, the study has been further downgraded to invalid for 

the vegetative vigor test (supplemental—qualitative for the seedling emergence test). Due to these 

factors a new vegetative vigor study is requested on the full standard suite of species using a typical 

end-use product (TEP). Additionally, new seedling emergence data is requested for tomato, oat, 

and ryegrass using a TEP.

In the case of the seedling emergence test with ryegrass, EFED believes that a NOAEC and IC25

can be determined from the continuation test data alone. However, raw test data (other than 

phytotoxicity data) for ryegrass were not included in the test report (MRID 43320308). Therefore 
Page 20 of 43

if raw test data for ryegrass dry weight and plant height are provided for the continuation test, new 

seedling emergence test data for ryegrass would not be needed. 

No toxicity data is available for imazapic’s degradates.

Table 6. Summary of the Most Sensitive Endpoints from Terrestrial Toxicity Studies for Imazapic

Taxonomic 

Group

Study 

Type

Tested Species Toxicity 

Value

Acute Toxicity 

Classification 

Source

(Study Classification)

Comments

Birds1

Acute

Bobwhite quail

(Colinus 

virginianus) & 

Mallard Duck

(Anas 

platyrhynchos)

21-D 

LD50 > 

2150 mg

ae/kg-bw

Practically nontoxic

42711430 & 

42711431(Acceptable)

No mortality or 

sublethal effects in the 

bobwhite study. Food 

consumption was 

reduced 25% in the 2150 

mg/kg test group in the 

mallard study for days 1-

3.

Sub-acute 

dietary

Bobwhite quail 

(C. virginianus) 

&

Mallard duck (A. 

platyrhynchos)

8-D LC50 

> 4685 mg 

ae/kg-diet 

Practically nontoxic

42711432 & 42711433 

(Supplemental)

No treatment-related 

mortality. Food 

consumption was 

reduced in both the 

mallard and bobwhite 

studies.

Chronic

Bobwhite quail 

(C. virginianus)

NOAEC = 

1187 mg 

ae/kg-diet

LOAEC = 

1907 mg 

a.e./kg-diet

N/A

44638102 (Acceptable)

Endpoints affected: 14-d 

hatchling weight, live 

embryos/viable 

embryos, hatchlings/live 

embryos

Mallard duck (A. 

platyrhynchos)

NOAEC = 

538 mg 

ae/kg-diet

LOAEC = 

994 

a.e./kg-diet 

N/A

44638101 (Acceptable)

Endpoints affected: 14-

D hatchling weight

Mammals

Acute Oral

Laboratory rat 

(Rattus 

norvegicus)

LD50

>5000 mg 

ae/kg-bw 

Practically nontoxic

42711407 (Acceptable)

No mortality.

Acute 

Inhalation No Data -- N/A N/A
Page 21 of 43

Table 6. Summary of the Most Sensitive Endpoints from Terrestrial Toxicity Studies for Imazapic

Taxonomic 

Group

Study 

Type

Tested Species Toxicity 

Value

Acute Toxicity 

Classification 

Source

(Study Classification)

Comments

Chronic Laboratory rat 

14-Week 

NOAEC > 

20,000 mg 

ae/kg-diet

LOAEC =

20,000 mg 

ae/kg-diet

N/A

43320305 (Acceptable)

(1205 mg ae/kgbw/day M; 1484 mg 

ae/kg-bw /day F). No 

effects observed.

Insects

Acute 

contact

Honey bee 

(Apis mellifera L.)

48-Hr 

LD50 > 100 

μg a.e./bee 

NOEC = 

36 μg

a.e./bee

Practically nontoxic

42711438 (Acceptable)

Study mortality = 25% 

at limit dose. 

Acute Oral Honey bee 

(Apis mellifera L.)

No Data N/A N/A

Chronic 

10-Day

Honey bee 

(Apis mellifera L.)

No Data N/A N/A

Larval 

Emergence

Honey bee 

(Apis mellifera L.)

No Data N/A N/A

Terrestrial 

plants

Seedling 

Emergence

Dicot – cabbage

Brassica oleracea

IC25 = 

0.00042

lbs ae/acre

IC05 = 

0.00014

lbs ae/acre 

N/A

43320308 

(Supplemental—

Quantitative for 5 

species, Qualitative for 

tomato) TGAI was 

tested. Dry weight most 

sensitive parameter. For 

cabbage, IC25 and IC05 

were based on 

continuation data only.

Monocot – onion

(Allium cepa)

21-D IC25

= 0.0018

lbs ae/acre

NOAEC = 

0.0010 lbs 

ae/acre N/A

43320308 

(Supplemental—

Quantitative for 2 

species, Qualitative for 

oat and ryegrass). 

Technical was tested. 

Dry weight most 

sensitive parameter. For 

onion, NOAEC and IC25 

were based on 

continuation data only.

Vegetative 

vigor Dicot—No Data

N/A

--

43320309

(Supplemental—

Qualitative for 5 species, 

invalid for tomato). Test 

material was TGAI.
Page 22 of 43

Table 6. Summary of the Most Sensitive Endpoints from Terrestrial Toxicity Studies for Imazapic

Taxonomic 

Group

Study 

Type

Tested Species Toxicity 

Value

Acute Toxicity 

Classification 

Source

(Study Classification)

Comments

Monocot--No 

Data

N/A

--

43320309

(Supplemental—

Qualitative for ryegrass, 

invalid for corn, onion 

and oat). Test material 

was TGAI

1 Birds represent surrogates for terrestrial-phase amphibians and reptiles.

A review of the Ecological Incident Information System (EIIS, version 2.1) and the Avian 

Monitoring Information System (AIMS) was completed on July 2, 2014. There is only one 

reported incident in EIIS for imazapic acid (described below) and no reported incidents for 

imazapic’s ammonium salt. The single reported incident in EIIS indicated effects on non-target 

terrestrial plants (crop damage) and the likelihood of the effects being caused by imazapic was 

considered possible. No ecological incidents involving imazapic were identified in AIMS. In 

addition to the incident recorded in EIIS, additional incidents have been reported to the Agency 

in aggregated incident reports. Pesticide registrants report certain types of incidents to the 

Agency as aggregate counts of incidents occurring per product per quarter. Ecological incidents 

reported in aggregate reports include those categorized as ‘minor fish and wildlife’ (W-B), 

‘minor plant’ (P-B), and ‘other non-target’ (ONT) incidents. ‘Other non-target’ incidents include 

reports of adverse effects to insects and other terrestrial invertebrates. For imazapic acid, 

registrants have reported 0 minor fish and wildlife, 1 minor plant, and 0 other non-target 

incidents. For imazapic’s ammonium salt, registrants have reported 1 minor fish and wildlife, 11 

minor plant and 0 other non-target incidents. Incident databases will be reviewed again at the 

time of the risk assessment. 

Incident I011838-012 in June, 2001 in Mitchell County, GA found 70 acres of peanuts had 

phytotoxic symptoms and stand reduction after application with imazapic. Glyphosate, 

bentazon, fluazifop-butyl, and flumioxazin were also applied, but application rates were not 

provided in the report for any of the herbicides except for flumioxazin which was applied at 3 

oz/Acre. The certainty of injury being attributed to the non-target plants was categorized as 

probable for flumioxazin and possible for imazapic and the other herbicides. It was 

undetermined whether this use was in accordance with the registered use for imazapic and the 

other herbicides, except for flumioxazin for which it was considered a registered use. 

7. Exposure Pathways of Concern

The environmental fate properties and use patterns of imazapic indicate runoff, drift, and leaching

from imazapic applications represent potential transport mechanisms of imazapic to aquatic and 

terrestrial organisms. 

The drinking water exposure pathway for birds and mammals was screened using the SIP 

(Screening Imbibition Program) screening method. The inhalation exposure pathway is typically 
Page 23 of 43

evaluated using the STIR (Screening Tool for Inhalation Risk) screening method. SIP and STIR 

are described in detail at: http://www.epa.gov/oppefed1/models/terrestrial/index.htm. Because of 

the high water solubility of imazapic under certain conditions (e.g. neutral to basic conditions), 

the drinking water pathway was found to be an exposure pathway of potential concern. SIP 

results are presented in Appendix A. The inhalation exposure pathway could not be evaluated 

using STIR as a result of the lack of mammalian inhalation data. However, due to the low vapor 

pressure (< 1 x 10-7 mmHg), the inhalation exposure pathway is not considered likely to be an 

exposure pathway of potential concern.

8. Analysis Plan 

8.1 Stressors of Concern

8.1.1 Ecological Risk 

The stressor of ecological concern for terrestrial and aquatic organisms is the parent compound, 

imazapic. 

8.1.2 Drinking Water 

HED MARC determined that the residue of concern in drinking water is imazapic per se (Memo, 

06/07/2001, W. Donovan, et al., D275136). Therefore, the chemical that will be assessed in 

drinking water from surface and ground water is the parent compound only.

8.2 Measures of Exposure 

8.2.1 Modeling of Ecological Exposure 

EFED will use standard available models to evaluate potential exposures to aquatic and 

terrestrial organisms as described at http://www.epa.gov/pesticides/science/models_db.htm. 

Screening level calculations suggested that drinking water pathway may be significant for 

terrestrial organisms. This exposure pathway may be further considered at the time of the risk 

assessment (Appendix A). 

8.2.2 Modeling of Drinking Water in Human Dietary Risk Assessment

The drinking water assessments conducted to support future human health risk assessments of 

imazapic will incorporate modeling of imazapic in surface and ground water. Since the last 

drinking water assessment was conducted, EFED has updated its surface and ground water 

models, the drinking water modeling input parameters, and the percent cropped area (PCA) 

guidelines. Through the course of the imazapic registration review, the Agency will determine 

whether a revised drinking water assessment will need to be conducted. For all modeling, input 

parameters are selected according to the current input guidelines, and where in question a 
Page 24 of 43

conservative approach is taken in the selection of half-lives. Descriptions of all executable 

versions of current models for drinking water exposure can be obtained from the following URL 

link: http://www.epa.gov/oppefed1/models/water/

8.2.3 Available Water Quality Monitoring Data 

EFED will consider all ground and surface water monitoring data available to us, and will 

conduct a comprehensive evaluation of the data for the risk assessment. The data that may be 

considered include the United States Geological Survey (USGS) National Water-Quality 

Assessment (NAWQA) Program monitoring data, and any State data available at the time of risk 

assessment.

8.3 Measures of Effect 

Toxicity data presented in Section 6 of this problem formulation will be used to calculate risk 

quotients. Any additional information submitted by the registrant or found in the open literature 

prior to conduct of the risk assessment will be considered. The open literature studies are 

identified using EPA’s ECOTOXicology database (ECOTOX) (USEPA, 2007c), which employs 

a literature search engine for locating chemical toxicity data for aquatic life, terrestrial plants, 

and wildlife. The evaluation of both sources of data can also provide insight into the direct and 

indirect effects of pesticides on biotic communities from loss of species that are sensitive to the 

chemicals and from changes in structure and functional characteristics of the affected 

communities.

9. Endangered Species Assessment

Consistent with the Agency’s responsibility under the Endangered Species Act (ESA), the 

Agency will evaluate risks to federally threatened and/or endangered (listed) species from 

registered uses of pesticides in registration review. The process for evaluating potential risks to 

listed species is further described at 

http://www.epa.gov/oppfead1/endanger/litstatus/riskasses.htm. Other agencies (USDA, Forest 

Service) may have previously conducted endangered species risk assessments for various use 

sites (e.g. rangeland, conservation reserve program land), which will be examined at the time of 

risk assessment.

10. Endocrine Disruptor Screening Program

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 
Page 25 of 43

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of the Problem Formulation for Registration Review for imazapic,

EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment 

scenarios from the existing hazard database. However, as required by FFDCA section 408(p), 

imazapic is subject to the endocrine screening part of the Endocrine Disruptor Screening 

Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list 

of chemicals identified for EDSP screening was published on June 14, 20131and includes some 

pesticides scheduled for registration review and chemicals found in water. Neither of these lists 

should be construed as a list of known or likely endocrine disruptors. 

For further information on the status of the EDSP, the policies and procedures, the lists of 

chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website.2

11. Preliminary Identification of Data Gaps 

11.1 Environmental Fate 

Table 7 identifies environmental fate studies by MRID that offer data for each guideline 

requirement, as well as study classifications and whether or not further data for imazapic acid are 

needed to support the risk assessment. A guideline-compliant aerobic soil metabolism study

(835.4100) containing at least three different soil types is required to better characterize rates of 

transformation of imazapic, and a guideline aerobic aquatic metabolism study (835.4300) and 

anaerobic soil metabolism are requested. In addition, soil storage stability data are requested and 

the analytical method validation report needs to be provided to support the PGW studies

(MRIDs: 47001701 and 47002001). 

 

1 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of 

chemicals.

2 http://www.epa.gov/endo/
Page 26 of 43

All studies should be conducted on imazapic acid, its end use product or its TGAI, and its 

degradate where appropriate (e.g. ECMs and storage stability).

 

Table 7. Available environmental fate data for imazapic and remaining data gaps. 

158

Guideline

(OPPTS)

Description MRID Classification Data 

Gap? Comments

835.1240

(163-1)

Adsorption/ 

Desorption 42711446 Acceptable No --

835.2120

(161-1) Hydrolysis 42711444 Acceptable No --

835.2240

(161-2)

Photodegradation

in Water 43320311 Acceptable No --

835.2410 

(161-3)

Photodegradation

on Soil 43320312 Supplemental No --

835.4100

(162-1)

Aerobic Soil 

Metabolism 42711445 Acceptable Yes Need three additional 

soils using TGAI.

835.4200

(162-2)

Anaerobic Soil 

Metabolism None Yes Need guideline study for TGAI.

835.4300

(162-4)

Aerobic Aquatic 

metabolism None Yes Need guideline study for TGAI.

835.4400

(162-3)

Anaerobic 

Aquatic 

Metabolism

43320313 Acceptable No --

835.6100

(164-1)

Terrestrial Field 

Dissipation 43320314 Supplemental No --

850.6100

Environmental 

Chemistry 

Method: Soil

43320314 Acceptable Yes

The available method 

supports terrestrial field 

dissipation study. 

However, any updates to 

the analytical methods 

are requested to be 

submitted.
Page 27 of 43

Table 7. Available environmental fate data for imazapic and remaining data gaps. 

158

Guideline

(OPPTS)

Description MRID Classification Data 

Gap? Comments

Freezer Storage 

Stability:

(in soil)

43320314

47001701

47002001

Yes

In NC PGW study soil 

samples were stored for a 

maximum of 32 months.

Available storage 

stability data indicate that 

residues of imazapic are 

stable in frozen soil for at 

least 24 months and 

residues of CL 354,825 

are stable in frozen soil 

matrices for at least 24 

months. Adequate storage 

data are required to 

support the PGW study.

835.7100

(166-1)

Prospective 

Ground-Water 

Monitoring Study

47001701

47002001 Supplemental No1

The independent 

laboratory validation 

(ILV) of analytical 

methods (soil and water) 

were conducted but data 

were not provided in the

study report. The ILV of 

ECMs are required to be 

submitted. Clarifications 

on length of sample 

storage (GA) and storage 

length for field water 

spikes (NC) are required.

850.1730

(165-4)

Fish 

Bioconcentration 

Factor

43320315 Acceptable No --

1

- Additional information is requested. 

11.2 Effects

Tables 8 and 9 identify ecological effects studies by MRID that offer data for each guideline 

requirement, as well as study classifications and whether or not further data are needed in order 

to support risk assessment. 
Page 28 of 43

Table 8. Available ecological effects data for aquatic organisms exposed to imazapic and remaining 

data gaps. 

OCSPP

Guideline

Data 

Requirement

Submitted 

Studies 

(MRID)

Study 

Classification

Are data 

needed to 

conduct 

risk 

assessment?

Justification and Assumptions 

EPA will Make in Absence of Data

850.1010 Freshwater 

invertebrate 

acute toxicity

42711437 Acceptable No

850.1025

850.1035

850.1045

850.1055 

Saltwater 

invertebrate 

acute toxicity 

44817704

44817703

Supplemental

Supplemental

No

850.1075 Freshwater 

fish acute 

toxicity 

42711434 Acceptable No

42711435 Acceptable

850.1075 Saltwater fish 

acute toxicity 

44817702 Supplemental No

850.1300 Freshwater 

invertebrate 

life cycle 

44728201 Acceptable No

850.1350 Saltwater 

invertebrates 

life cycle 

No data N/A No No studies have been submitted. 

Exposure is estimated to be low, no 

acute toxicity was observed in the 

acute saltwater invertebrate studies 

and no chronic toxicity was 

observed in the chronic freshwater 

invertebrate study. Therefore, 

EFED will use the NOAEC from the 

freshwater invertebrate life cycle 

study (96 ppm) as the chronic 

saltwater invertebrate endpoint 

unless additional data is available. 

850.1400 Freshwater 

fish 

early-life 

stage

44728202 Acceptable No

850.1400 Saltwater fish 

early-life 

stage 

No data No No studies have been submitted. 

Exposure is estimated to be low, no 

acute toxicity was observed in the 

acute saltwater fish study and no 

chronic toxicity was observed in the 
Page 29 of 43

Table 8. Available ecological effects data for aquatic organisms exposed to imazapic and remaining 

data gaps. 

OCSPP

Guideline

Data 

Requirement

Submitted 

Studies 

(MRID)

Study 

Classification

Are data 

needed to 

conduct 

risk 

assessment?

Justification and Assumptions 

EPA will Make in Absence of Data

chronic freshwater fish study. 

Therefore, EFED will use the 

NOAEC from the freshwater fish 

early life stage study (96 ppm) as the 

chronic saltwater fish endpoint 

unless additional data is available. 

850.1500 Fish life cycle No data No Data have not been submitted to 

fulfill this guideline. A data gap was 

not identified as these data are not 

necessary for risk assessment at this 

time.

850.4400 Aquatic plant 

Toxicity Test 

using Lemna

spp.

43320310 Acceptable No

850.4500 Algal toxicity 43320310 Acceptable No

850.4550 Cyanobacteria 43320310 Acceptable No
Page 30 of 43

Table 9. Available ecological effects data for terrestrial organisms exposed to imazapic and remaining data 

gaps. 

OCSPP 

Guideline

Data 

Requirement

Submitted 

Studies 

(MRID)

Study 

Classifications

Are data 

needed for 

risk 

assessment?

Justification and Assumptions EPA 

will Make in Absence of Data

850.2100 Avian oral 

toxicity

42711431 Acceptable Yes An acute oral study with a passerine 

species has not been submitted to the 

agency. A data gap is identified at this 

time due to sublethal effects in the 

avian acute oral and dietary studies, 

chronic effects in the avian 

reproduction studies and the maximum 

application rate of 0.9171 lbs ae/A

(nonagricultural uncultivated 

areas/soils) which results in expected 

maximum EECs that are greater than 

1/10 the highest application rate tested 

in the avian acute oral studies where 

sublethal effects were observed. Risk 

to listed avian species from the 

maximum application rate would not be 

able to be precluded without this data. 

Other use patterns for imazapic have 

greatly reduced application rates that 

would not trigger this data gap. Study 

should be conducted on imazapic acid.

42711430 Acceptable

850.2200 Avian dietary 

toxicity 

42711433 Acceptable No

42711432 Acceptable

850.2300 Avian 

reproduction

44638101 Acceptable No

44638102 Acceptable

NonguidelineAvian 

inhalation

No Data N/A No Data have not been submitted to fulfill 

this guideline. A data gap was not 

identified as these data are not 

necessary for risk assessment at this 

time.

850.3020 Honey bee 

acute contact 

toxicity

42711438 Acceptable No
Page 31 of 43

Table 9. Available ecological effects data for terrestrial organisms exposed to imazapic and remaining data 

gaps. 

OCSPP 

Guideline

Data 

Requirement

Submitted 

Studies 

(MRID)

Study 

Classifications

Are data 

needed for 

risk 

assessment?

Justification and Assumptions EPA 

will Make in Absence of Data

850.3030 Honey bee 

residue on 

foliage

No Data N/A No Data have not been submitted to fulfill 

this guideline. A data gap was not 

identified as these data are not 

necessary for risk assessment at this 

time.

NonguidelineHoney bee 

acute oral 

toxicity

No Data N/A Yes Although acute contact data are 

available for honey bees, a study is 

needed to evaluate the ingestion route 

of exposure to complete the risk 

assessment for pollinators. Although 

EPA has not developed a guideline for 

this study, OECD TG213 may be used 

to assess the acute oral exposure 

pathway for adult bees. Study should be 

conducted with imazapic acid.

NonguidelineHoney bee 

chronic oral 

toxicity

No Data N/A Yes Chronic (repeated dose) data is needed 

on adult honey bees to evaluate chronic 

risk to pollinators for the risk 

assessment. Although EPA has not 

developed a guideline for this study, 

guidance for a 10-day oral toxicity 

study is currently in development by 

OECD. A protocol should be 

submitted prior to study initiation. 

Study should be conducted with 

imazapic acid. 
Page 32 of 43

Table 9. Available ecological effects data for terrestrial organisms exposed to imazapic and remaining data 

gaps. 

OCSPP 

Guideline

Data 

Requirement

Submitted 

Studies 

(MRID)

Study 

Classifications

Are data 

needed for 

risk 

assessment?

Justification and Assumptions EPA 

will Make in Absence of Data

NonguidelineHoney bee 

larval acute 

and chronic 

oral toxicity

No Data N/A Yes In addition to the adult honey bee data 

gaps identified above, data is needed 

for the additional honey bee life stage 

of larvae to complete the risk 

assessment for pollinators. Although 

EPA has not developed a guideline for 

these studies, OECD TG237 may be 

used to assess acute oral effects on 

larvae. Chronic (repeat dose) study 

guidance for assessing chronic oral 

toxicity to honey bee larvae is currently 

in development by OECD. A protocol 

should be submitted prior to study 

initiation. Study should be conducted 

using imazapic acid. 

850.3040 Field testing 

for 

pollinators

No Data N/A Yes Data have not been submitted to fulfill 

this guideline. Results from lower tier 

studies should inform the conduct of 

the field test to address remaining 

uncertainties. Pending the results of 

lower tier studies (adult honey bee 

acute oral, chronic adult honey bee, 

acute and chronic larval), a field testing 

study may not be needed to complete 

the risk assessment for pollinators. A 

protocol should be submitted prior to 

test initiation.

850.3100 Earthworm 

Subchronic 

Toxicity Test 

None N/A No Data have not been submitted to fulfill 

this guideline. A data gap was not 

identified as these data are not 

necessary for risk assessment at this 

time.
Page 33 of 43

Table 9. Available ecological effects data for terrestrial organisms exposed to imazapic and remaining data 

gaps. 

OCSPP 

Guideline

Data 

Requirement

Submitted 

Studies 

(MRID)

Study 

Classifications

Are data 

needed for 

risk 

assessment?

Justification and Assumptions EPA 

will Make in Absence of Data

850.4100 Seedling 

Emergence 

and Seedling 

Growth

43320308 Supplemental

(Quantitative

for 7 species, 

Qualitative for 

tomato, oats 

and ryegrass)

Yes The current study is being downgraded 

due to the use of TGAI and the use of 

continuation tests in concert with a base 

test to determine NOAEC/IC05 and IC25

endpoints. EFED does not support 

combining the results of multiple 

studies for statistical analysis of 

assessment endpoints. Therefore, new 

seedling emergence data is requested 

for tomato, oat and ryegrass using a 

representative TEP. 

850.4150 Vegetative 

Vigor

43320309 Supplemental

Qualitative for 

6 species, 

Invalid for 

corn, oats, 

onion and 

tomato).

Yes The current study is being downgraded 

due to the use of TGAI and the use of 

continuation tests in concert with a base 

test to determine NOAEC/IC05 and IC25

endpoints. EFED does not support 

combining the results of multiple 

studies for statistical analysis of 

assessment endpoints. Therefore, new 

vegetative vigor data is requested on 

the entire suite of 10 species using a 

representative TEP.

12. References 

ENSR, 2005. Imazapic Ecological Risk Assessment Final Report. Prepared for the USDI BLM, 

Nevada State Office, Reno, Nevada. November, 2005. ENSR Document Number 09090-020-

650.

SERA (Syracuse Research Corporation), 2004. Imazapic—Human Health and Ecological Risk 

Assessment—Final Report. Prepared for the USDA Forest Service, Forest Health Protection. 

Syracuse, New York. December 23, 2004. SERA TR 04-43-17-04b

USEPA, 2014a. BEAD Chemical Profile for Registration Review: Imazapic (129041) and 

Imazapic-ammonium (128943). Office of Pesticides Program, Biological and Economic 

Analysis Division. Arlington, VA. July 10, 2014
Page 34 of 43

USEPA, 2014b. Registration Review Problem Formulation for Imazethapyr and Imazethapyr 

Ammonium Salt. D415245. Office of Pesticide Program, Environmental Fate and Effects 

Division. Arlington, VA. 

USEPA, 2014c. Guidance for Assessing Pesticide Risks to Bees. Office of Pesticide Programs, 

USEPA, Washington D.C. Health Canada Pest Management Regulatory Agency, Ottawa, ON, 

Canada. California Department of Pesticide Regulation, Sacramento, CA. June 23, 2014.

USEPA, 2001a. Imazapic. Results of the Health Effects Division (HED) Metabolism Assessment

Review Committee (MARC) Meeting Held on 22-MAY-2001. Chemical#s 128943 & 129041. 

Barcode D275136. Case 291904. Submission 8581930. Office of Pesticides Program, Health

Effects Division, Arlington, VA. June 7, 2001.

USEPA, 2001b. Imazapic (Chemical 129041): American Cyanamide Company; Section 3 review 

for use of imazapic herbicide (Plateau DG) to control weeds in pasture, rangeland, and the 

Conservation Reserve Program; D277341. Office of Pesticides Program, Environmental Fate and 

Effects Division, Arlington, VA. Oct. 15, 2001

USEPA, 2001. Correction of estimated & water concentration from FIRST (DP Barcode 

D267288, dated May 10, 2001). D267228A. Office of Pesticides Program, Environmental Fate 

and Effects Division, Arlington, VA. May 28, 2001

USEPA, 2001. Imazapic Section 3 - Pasture and Rangeland Use Tier 1 Water Assessment.

D267228. Office of Pesticides Program, Environmental Fate and Effects Division, Arlington, 

VA. May 10, 2001. 

USEPA, 1999. Imazapic: Rate of Dissipation of CL 263222 Residues in Soil after Treatment 

with CADRE@ DG Peanut Herbicide Applied Postemergence to Peanuts in Georgia (MRID: 

4483 1801). D256957. Office of Pesticides Program, Environmental Fate and Effects Division, 

Arlington, VA. June 28, 1999.

USEPA, 1995. The Ecological Effects Branch's (EEB) environmental risk assessment for the use 

of the imidazolinone type herbicide CADRE on peanuts--- (Chemical Code 128943): DP 

Barcode D209889 and D209896. Office of Pesticides Program, Environmental Fate and Effects 

Division, Arlington, VA. Aug 25, 1995. 
Page 35 of 43

Appendix A. Screening Level Models to Evaluate Potential 

Importance of Drinking Water and Inhalation Exposure Pathways

SIP (Screening Imbibition Program, v1.0) Inputs and Conclusions

Table 1. Inputs

Parameter Value

Chemical name Imazapic

Solubility (in water at 25oC; mg/L) 518000

Mammalian LD50 (mg/kg-bw) 5000

Mammalian test species laboratory rat

Body weight (g) of "other" mammalian 

species

Mammalian NOAEL (mg/kg-bw) 20000

Mammalian test species laboratory rat

Body weight (g) of "other" mammalian 

species

Avian LD50 (mg/kg-bw) 2150

Avian test species northern bobwhite quail

Body weight (g) of "other" avian species

Mineau scaling factor 1.15

Mallard NOAEC (mg/kg-diet) 538

Bobwhite quail NOAEC (mg/kg-diet) 1187

NOAEC (mg/kg-diet) for other bird species

Body weight (g) of other avian species

NOAEC (mg/kg-diet) for 2nd other bird 

species

Body weight (g) of 2nd other avian species

Table 2. Mammalian Results

Parameter Acute Chronic

Upper bound exposure (mg/kg-bw) 89096.0000 89096.0000

Adjusted toxicity value (mg/kg-bw) 3845.8028 15383.2113

Ratio of exposure to toxicity 23.1671 5.7918
Page 36 of 43

Conclusion*

Exposure through 

drinking water alone is 

a potential concern for 

mammals

Exposure through drinking water 

alone is a potential concern for 

mammals

Table 3. Avian Results

Parameter Acute Chronic

Upper bound exposure (mg/kg-bw) 419580.0000 419580.0000

Adjusted toxicity value (mg/kg-bw) 1548.9235 26.6916

Ratio of exposure to acute toxicity 270.8849 15719.5765

Conclusion*

Exposure through 

drinking water alone is 

a potential concern for 

birds

Exposure through drinking water 

alone is a potential concern for 

birds

*Conclusion is for drinking water exposure alone. This does not combine all routes of exposure. Therefore, when 

aggregated with other routes (i.e., diet, inhalation, dermal), pesticide exposure through drinking water may 

contribute to a total exposure that has potential for effects to non-target animals.
Page 37 of 43

Appendix B. Predictive Data for Parent Imazapic and its Degradates 

from QSAR Modeling using Ecosar v1.11

All values are in ppm

ND = No empirical Data

NP = No prediction made for this class. 

Red highlighted cells indicate poor agreement (i.e. > 10x difference) between empirical data and 

predicted values.

Yellow highlighted cells indicate reasonable agreement (i.e. between 5x and 10x difference) 

between empirical data and predicted values.

Green highlighted cells indicate good agreement (i.e. <5x difference) between empirical data and 

predicted values.

The empirical EC50 for green algae was nondefinitive with no effects found at the limit dose of 

0.0523 ppm. However, since the level of predicted toxicity is 6 orders of magnitude higher than 

the tested doses, it is unclear how well the model predicts the actual toxicity of parent imazapic 

and therefore the QSAR approach should not be used in risk assessment to evaluate the toxicity 

of imazapic metabolites to green algae.

Green Algae EC50 Empirical 

EC50

Amides--

acid

Neutral 

Organic

Parent >0.0523 23147 1110

268,407 ND NP 1617

290,610 ND 226 1062

290,811 ND NP 769

2-carbamoyl-5-

methyl-nicotinic acid

ND 199 973

2-carbamoyl-5-

methyl-3-nicotinic 

acid (2-ring structure)

ND NP 2122

2-carbamoyl-5-

methyl-3-nicotinic 

acid (1-ring structure)

ND NP 528

The empirical NOAEC for green algae is 5 orders of magnitude below the predicted toxicity 

using the amides and neutral organic chemical classes. Therefore, it is unclear how well the 

model predicts the actual toxicity of parent imazapic and therefore the QSAR approach should 

not be used in the risk assessment to evaluate the toxicity of imazapic metabolites to green algae.

Green Algae NOAEC Empirical 

NOAEC

Amides--

acid

Neutral 

Organic

Parent 0.0523 115 212

268,407 ND NP 362

290,610 ND 114 206
Page 38 of 43

290,811 ND NP 145.8

2-carbamoyl-5-

methyl-nicotinic acid

ND 90.3 179

2-carbamoyl-5-

methyl-3-nicotinic 

acid (2-ring structure)

ND NP 349

2-carbamoyl-5-

methyl-3-nicotinic 

acid (1-ring structure)

ND NP 104

The empirical EC50 for daphnids was nondefinitive with no effects found at the limit dose of 100 

ppm. Since, the level of predicted toxicity was 1-2 orders of magnitude higher than the tested 

doses, it is unclear how well the model predicts the actual toxicity of parent imazapic and 

therefore the QSAR approach should not be used in the risk assessment to evaluate the toxicity 

of imazapic metabolites to freshwater invertebrates on an acute basis.

Daphnid EC50 Empirical 

EC50

Amides--

acid

Neutral 

Organic

Parent > 100 23,147 2681

268,407 ND NP 2910

290,610 ND 21387 2500

290,811 ND NP 1880

2-carbamoyl-5-

methyl-nicotinic acid

ND 22300 2520

2-carbamoyl-5-

methyl-3-nicotinic 

acid (2-ring structure)

ND NP 6800

2-carbamoyl-5-

methyl-3-nicotinic 

acid (1-ring structure)

ND NP 1205

The empirical NOAEC for daphnids is less than 5x more sensitive than the predicted toxicity 

from the Amides-acid and Neutral Organic Chemical Structure Classes. This indicates that there 

is relatively good agreement between the modeled values and the empirical data. Imazapic 

degradates were predicted to have similar toxicity as parent imazapic. 2-carbamoyl-5-methyl-3-

nicotinic acid (1-ring structure) was predicted to be twice as toxic as parent imazapic, but 

considering these predicted values are approximately 4-5 orders of magnitude greater than the 

maximum EECs from previous assessments, it is considered unlikely that empirical data for this 

degradate would have much value for the risk assessment to evaluate chronic effects of imazapic 
Page 39 of 43

to freshwater invertebrates or that this degradate would contribute greatly to risk conclusions for 

imazapic.

Daphnid NOAEC Empirical 

NOAEC

Amides--

acid

Neutral 

Organic

Parent 96 470 176

268,407 ND NP 233

290,610 ND 454 167

290,811 ND 122

2-carbamoyl-5-

methyl-nicotinic acid

ND 401 158

2-carbamoyl-5-

methyl-3-nicotinic 

acid (2-ring structure)

ND NP 370

2-carbamoyl-5-

methyl-3-nicotinic 

acid (1-ring structure)

ND NP 82

There was 10% mortality at the limit concentration of 100 ppm for the acute fish study. Since, 

the level of predicted toxicity was 1-2 orders of magnitude higher than the tested doses, it is 

unclear how well the model predicts the actual toxicity of parent imazapic and therefore the 

QSAR approach should not be used in the risk assessment to evaluate the toxicity of imazapic 

metabolites to freshwater fish on an acute basis.

Fish LC50 Empirical 

EC50

Amides--

acid

Neutral 

Organic

Parent > 100 10350 5441

268,407 ND NP 5500

290,610 ND 9866 5041

290,811 ND NP 3828

2-carbamoyl-5-

methyl-nicotinic acid

ND 9160 5200

2-carbamoyl-5-

methyl-3-nicotinic 

acid (2-ring structure)

ND NP 14700

2-carbamoyl-5-

methyl-3-nicotinic 

acid (1-ring structure)

ND NP 2415

The empirical NOAEC is less than 5x more sensitive than the predicted toxicity from the Neutral 

Organic Chemical Structure Class but >10x less sensitive than the predicted toxicity from the 

Amides-acid Chemical Structure Class. This indicates that there is relatively good agreement 

between the modeled values for the Neutral Organic Chemical class and the empirical data.
Page 40 of 43

Imazapic degradates were predicted to have similar toxicity as parent imazapic. 2-carbamoyl-5-

methyl-3-nicotinic acid (1-ring structure) was predicted to be >2x more toxic than parent 

imazapic, but considering these predicted values are approximately 5 orders of magnitude greater 

than the maximum EECs from previous assessments, it is considered unlikely that empirical data 

for this degradate would have much value for the risk assessment to evaluate chronic effects of 

imazapic to freshwater invertebrates or that this degradate would contribute greatly to risk 

conclusions for imazapic.

Fish NOAEC Empirical 

NOAEC

Amides--

acid

Neutral 

Organic

Parent 96 7.11 450

268,407 ND NP 495

290,610 ND 7.06 420

290,811 ND NP 315

2-carbamoyl-5-

methyl-nicotinic 

acid

ND 5.64 422

2-carbamoyl-5-

methyl-3-nicotinic 

acid (2-ring 

structure)

ND NP 1120

2-carbamoyl-5-

methyl-3-nicotinic 

acid (1-ring 

structure)

ND NP 203
Page 41 of 43

Appendix C. Data Justification Tables for Non-guideline Studies

Guideline Number: Non-Guideline

Study Title: Adult Honey Bee Acute Oral Toxicity

Rationale for Requiring the Data

This study is needed for the assessment to evaluate risks to honey bees if the registered uses will result in 

bee exposure. Imazapic uses include aerial applications to pastures, rangeland, agricultural 

fallow/idleland/conservation reserve, conifer plantations, forest trees, and nonagricultural uncultivated 

areas/soils where spray drift may land on blooming non-target plants and result in residues in pollen and 

nectar which could then be transported to colonies where in-hive bees including young adult and 

developing brood (i.e., eggs, larvae and pupae) may be exposed. Therefore, exposure at all bee life stages 

would be expected. 

The Agency has recently finalized its framework to assess risk to pollinators (USEPA, 2014c). EPA now 

requires this study for all use sites where potential exposure to pollinators may occur. Registrants may 

request a waiver of the study if use practices significantly restrict exposure of the pesticide to bees.

Although EPA has not developed a guideline for this study, the Organization for Economic Cooperation 

and Development (OECD) has developed a formal test guideline for an acute oral toxicity study with adult 

honey bees (OECD TG213) that may be used to assess the acute oral exposure pathway for adult bees.

Practical Utility of the Data

How will the data be used and how could the data impact the Agency’s future decision-making? 

The acute oral toxicity study with adult bees provides median lethal dose (LD50) value for honey bees (A. 

mellifera) based on acute oral exposure. These data are used in conjunction with acute contact LD50 data 

obtained through OCSPP 850.3020 to estimate the acute toxicity of technical grade active ingredient (TGAI) 

to individual young adult honey bees. The studies also provide slopes for the dose-response curves that can 

in turn be used for estimating the likelihood of individual effects and sublethal effects observed in the study 

will be used to further characterize effects observed following a single exposure to the technical grade 

material. Data obtained from this study will be used in estimating acute risk to individual adult bees. Risk 

estimates based on these data will be considered along with other lines of evidence to determine whether 

higher-tier studies are needed at the whole colony level.

These data are needed for the registration review risk assessment and for future endangered species 

assessments. The data would allow the Agency better characterize the potential for risk to insects (including 

beneficial pollinators) from the use of imidazolinone-class chemicals. This data may help the Agency 

determine whether any mitigations are needed. If the registration review and any future endangered species 

risk assessments are performed without these data, the Agency would have to assume that imidazolinoneclass chemicals "may affect" insects, including bees and beneficial pollinators, directly (and endangered 

species from other taxa indirectly), and uses of imazapic might need to be restricted in areas where 

pollinators could be exposed. 
Page 42 of 43

Guideline Number: Non-Guideline

Study Title: Adult Honey Bee Chronic Oral Toxicity

Rationale for Requiring the Data

This study is needed for the assessment to evaluate risks to honey bees if the registered uses will result in 

bee exposure. Imazapic uses include aerial applications to pastures, rangeland, agricultural 

fallow/idleland/conservation reserve, conifer plantations, forest trees, and nonagricultural uncultivated 

areas/soils where spray drift may land on blooming non-target plants and result in residues in pollen and 

nectar which could then be transported to the colony where in-hive bees including young adult and 

developing brood (i.e., eggs, larvae and pupae) may be exposed. Therefore, exposure at all bee life stages 

would be expected and may extend for chronic exposures since imazapic is relatively persistent except 

from degradation through aqueous photolysis. 

The Agency has recently finalized its framework to assess risk to pollinators (USEPA, 2014c). EPA now 

requires this study for all use sites where potential exposure to pollinators may occur. Registrants may 

request a waiver of the study if use practices significantly restrict exposure of the pesticide to bees.

Although EPA has not developed a guideline for this study and OECD has yet to finalize test guidance for 

chronic studies, efforts are currently underway to develop standardized guidelines for assessing effects 

from chronic (10-day) exposures to adult bees in the laboratory. 

Practical Utility of the Data

How will the data be used and how could the data impact the Agency’s future decision-making? 

The 10-day toxicity study with young adult bees provides no-observed adverse effect level (NOAEL) and 

lowest-observed adverse effect level (LOAEL) for assessing chronic effects. Data obtained from this study 

will be used in estimating chronic risk to individual adult bees. Risk estimates based on these data will be 

considered along with other lines of evidence to determine whether higher-tier studies are needed at the 

whole colony level.

These data are needed for the registration review risk assessment and for future endangered species 

assessments. The data would allow the Agency better characterize the potential for risk to insects (including 

beneficial pollinators) from the use of imidazolinone-class chemicals. This data may help the Agency 

determine whether any mitigations are needed. If the registration review and any future endangered species 

risk assessments are performed without these data, the Agency would have to assume that imidazolinone -

class chemicals "may affect" insects, including bees and beneficial pollinators, directly (and endangered 

species from other taxa indirectly), and uses of imazapic might need to be restricted in areas where 

pollinators could be exposed.

Guideline Number: Non-Guideline

Study Title: Larval Honey Bee Acute and Chronic Oral Toxicity

Rationale for Requiring the Data

These studies are needed for the assessment to evaluate risks to honey bees if the registered uses will 

result in bee exposure. Imazapic uses include aerial applications to pastures, rangeland, agricultural 

fallow/idleland/conservation reserve, conifer plantations, forest trees, and nonagricultural uncultivated 

areas/soils where spray drift may land on blooming non-target plants and result in residues in pollen and 

nectar that can in turn be brought back to bee colonies where in-hive bees including young adult and 

developing brood (i.e., eggs, larvae and pupae) may be exposed. Therefore, exposure at all bee life stages 
Page 43 of 43

Guideline Number: Non-Guideline

Study Title: Larval Honey Bee Acute and Chronic Oral Toxicity

Rationale for Requiring the Data

would be expected and may extend for chronic exposures since imazapic is relatively persistent except 

from degradation through aqueous photolysis. 

The Agency has recently finalized its framework to assess risk to pollinators (USEPA, 2014c). EPA now 

requires these studies for all use sites where potential exposure to pollinators may occur. Registrants may 

request a waiver of the studies if use practices significantly restrict exposure of the pesticide to bees.

Although EPA has not developed a guideline for this study, the 21-day larval toxicity study currently 

under development by OECD potentially provides acute as well as chronic oral toxicity endpoints on 

developing bee brood and (when this guidance is finalized) may be used to satisfy the requirement for 

both acute and chronic oral toxicity to honey bee larvae. Registrants are at liberty though to submit a 

separate acute (single dose) larval toxicity study following OECD TG 237 as well as the 21-day repeat 

dose chronic toxicity study. 

Practical Utility of the Data

How will the data be used and how could the data impact the Agency’s future decision-making? 

The 21-day larval toxicity study under development by OECD provides both acute and chronic toxicity data 

on developing bee brood and will yield a median lethal dose (LD50) for assessing acute toxicity during the 

early part of the study as well as a 21-day no-observed adverse effect level (NOAEL) and lowest-observed 

adverse effect level (LOAEL) for assessing chronic effects. Effects on survival and development (adult bee 

emergence) from repeat exposures to the active ingredient will be used in estimating chronic risk to 

individual brood. Risk estimates based on these data will be considered along with other lines of evidence 

to determine whether higher-tier studies are needed at the whole colony level.

These data are needed for the registration review risk assessment and for future endangered species 

assessments. The data would allow the Agency better characterize the potential for risk to insects (including 

beneficial pollinators) from the use of imidazolinone-class chemicals. This data may help the Agency 

determine whether any mitigations are needed. If the registration review and any future endangered species 

risk assessments are performed without these data, the Agency would have to assume that imidazolinoneclass chemicals "may affect" insects, including bees and beneficial pollinators, directly (and endangered 

species from other taxa indirectly), and uses of imazapic might need to be restricted in areas where 

pollinators could be exposed.