UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

DATE: 5-MAR-2014 

SUBJECT: Imazapyr, Isopropylamine Salt: Registration Review Seeping 

Document for Human Health Assessment. 

PC Code: 128821 and 128829 

Decision No.: 486732 

DP Barcode: D417328 

Registration No.: 172267 

Petition No.: NA Regulatory Action: Registration Review 

Risk Assessment Type: Single Case No.: 3078 

Chemical/ Aggregate 

TXRNo.: NA 

MRIDNo.: NA 

CAS No.: 81334-34-1, 81510-83-0 

40 CFR: §180.500 

FROM: Mohsen Sahafeyan, Chemist and Risk&s.sessok:! J LJ4y-' Nancy McCarroll, Toxicologist /tl ~ ltc ":::"vu---~ 

Bridgett Bobowiec, Biologist ~ ~ ~ 

Risk Assessment Branch VI (RAB VI) 

Health Effects Division (HED, 7509P) 

Office of Pesticide Programs 

THROUGH: 

He

Registration 

Donna 

alth Effects 

Davis, 

Action 

Acting 

Division 

Branch 

Branch 

(HE

6 

D, 

Chief 

(RAB6) 

7509P) 

~ 

TO: Joel Wolf, Chemical Review Manager 

Tom Myers, Team Leader 

Risk Management and Implementation Branch 4 

Pesticide Re-Evaluation Division (7508P) 

Executive Summary 

The Health Effects Division (HED) imazapyr Registration Review Team has evaluated 

the status of the human health risk assessment for imazapyr (PC code: 128821), including 

its isopropylamine salt (PC code: 128829) to determine the scope of work necessary to 

support Registration Review. In this document when referred to imazapyr, 

isoporpylamin salt is also included. Imazapyr is a systemic, non-selective herbicide used 

Page 1 of 15 
for the pre- and post-emergence control of a broad range of terrestrial and aquatic weeds. 

The most recent risk assessment for imazapyr was completed in 2013 (M. Sahafeyan, et. 

al., D384035, July 2, 2013) to support import tolerances without U.S. registration for 

residues of imazapyr on imidazolinone-tolerant soybean of Cultivance® Production 

System, rapeseed subgroup 20A, sunflower subgroup 20B and lentil. 

The irnazapyr toxicology database is considered to be adequate and no additional studies 

are required for registration review. The BASF tolerance request for imported 

genetically-modified soybean and crop group 20A, 20B and lentil triggered a review of 

the imazapyr toxicity database and endpoints for risk assessment. In September of2012, 

the HED imazapyr review team called for a meeting of Hazard and Science Policy 

Council (HASPOC) to revisit the toxicity of imazapyr and determine whether a 

quantitative risk assessment was needed. After reviewing the available toxicology 

database for imazapyr, HASPOC concluded, with reasonable certainty that dietary, 

occupational and residential exposures to imazapyr do not pose a significant human 

health risk and therefore, risk assessments are not needed. This decision was based on 

the fact that although there is potential for exposure to irnazapyr and although the existing 

toxicology studies do not use doses up to the limit dose, the available data are high 

quality and no hazard was identified from the toxicity studies. No adverse effects were 

observed in the submitted toxicological studies regardless of the route of exposure or the 

species tested. Therefore, a quantitative risk assessment is not required. Further, a draft 

risk assessment will not be required for registration review. 

Because there is no hazard identified for imazapyr from toxicity studies and there are no 

risk concerns from exposure to imazapyr, an exemption from the requirement of a 

tolerance would be appropriate for imazapyr; however, the regulatory divisions may 

chose to leave the tolerances as they are, remove all tolerances, or remove tolerances for 

crops without any other international harmonization issues at their discretion. 

Introduction 

Imazapyr, [2-[ 4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-lH-imidazol-2-yl]-3-

pyridinecarboxylic acid] is a systemic, non-selective imidazolinone herbicide for pre- and 

post-emergence control of a broad range of weeds, including terrestrial annual and 

perennial grasses, broad-leaved herbs, woody species, and riparian and emergent aquatic 

species. The structure, chemical names, and other identifiers for imazapyr may be found 

in Table lA and lB. 

The imazapyr Reregistration Eligibility Decision Document (RED) was issued on June 

14, 2006. The addendum to the 2006 RED which contained the Agency's revisions to the 

imazapyr RED label language was issued on October 23, 2008. The most recent risk 

assessment for imazapyr was completed in 2013 (M. Sahafeyan, et. al., 0384035, July 2, 

2013) to support import tolerances without U. S. registration for residues of imazapyr on 

imidazolinone-tolerant soybean of Cultivance® Production System, rapeseed subgroup 

20A, sunflower subgroup 20B and lentil. 

Page 2 of 15 
Page 3 of 15

Imazapyr is formulated as a liquid, a wettable powder (in water soluble bags only), and as 

a granular. Terrestrial applications of imazapyr consist of ground and aerial sprays, as 

well as granular broadcast applications. Aquatic applications of imazapyr can be made 

using the liquid formulated products. The herbicide, imazapyr, is an anionic, organic 

acid that is non-volatile and is both persistent and mobile in soil. Commercial 

formulations contain either imazapyr acid or the imazapyr isopropylamine salt, both of 

which are dissolved in a water solution. 

The mechanism of action of imidazolinone herbicides on weeds and non-tolerant plants is 

by inhibition of the AHAS enzyme which is the key control enzyme for biosynthesis of 

branched-chain amino acids within plants. For genetically-modified soybean (CV127), 

because the binding site for imidazolinone on AHAS enzyme is altered, there is a 

tolerance to imidazolinone herbicide while AHAS enzyme maintains its biosynthesis 

function of branched-chain amino acids. 

There are currently twenty-seven tolerances established in 40 CFR §180.500 for residues 

of the herbicide imazapyr, applied as the acid or ammonium salt. Tolerances are 

established for imazapyr residues in field corn and its forage and stover, and in grass 

forage and hay. Import tolerances are established for rapeseed subgroup 20A, sunflower 

subgroup 20B and lentil. An import tolerance on the imidazolinone-tolerant soybean 

from the Cultivance®Production System has also been recommended by HED

(Sahafeyan, M., DP# D384035 and D403741; 7/2/2013). Tolerances are also established 

for secondary residues of imazapyr in milk, meat, fish, and shellfish. Imazapyr is also 

registered for use on a variety of commercial and residential use sites, including forestry 

sites, rights-of-way, fence rows, hedge rows, drainage systems, outdoor industrial areas, 

outdoor buildings and structures, domestic dwellings, paved areas, driveways, patios, 

parking areas, walkways, various water bodies (including ponds, lakes, streams, swamps, 

wetlands, stagnant water, and urban areas). Imazapyr may also be used as a spot 

treatment in recreation areas, athletic fields, and golf course roughs. There are 11 Special 

Local Needs (SLNs) for imazapyr (including its isopropylamine salt) in states of AL, FL, 

HI, ME, ND, NM, SD, and TX. 

Hazard Identification/Toxicology

The toxicological database for imazapyr is complete. Imazapyr is not irritating to the

skin, and is negative for dermal sensitization; however, the technical grade (99.3% a.i.) of 

the active ingredient was tested for eye irritation and results indicated irreversible eye

damage (toxicity category I). The toxicity data show that there is no evidence of 

neurotoxicity, immunotoxicity, genotoxicity, or carcinogenicity for imazapyr. Further, 

no adverse developmental effects or adverse reproductive effects were detected in wellconducted guideline studies. 

The latest assessment of the toxicity database for imazapyr was conducted in September 

2012 (Imazapyr: Summary of Hazard and Science Policy Council (HASPOC) Meeting of 

September 13, 2012: Recommendations on the type of risk assessment (quantitative vs. 

qualitative) to be conducted. TXR# 0056464, 2/26/13). HASPOC considered whether a 

quantitative risk assessment was necessary for imazapyr. Because there is no hazard 
Page 4 of 15

identified for imazapyr in the available database (i.e., no toxicity demonstrated in 

acceptable guideline studies generally up to the highest doses tested of 250 – 1000 

mg/kg/day), the HASPOC concluded that a quantitative risk assessment was not required 

for imazapyr. Since July 2005, when the most recent Reregistration Eligibility Document 

(RED) for Imazapyr was prepared (Jarvis et al., 2005), no new data have been received 

that would warrant a change in the acute or chronic reference doses (RfDs), the 

occupational/residential toxicological endpoint selections, the uncertainty factors, or the 

FQPA Safety Factor. 

Dietary Exposure 

The current residue chemistry database is sufficient to support the registration review of 

imazapyr. No additional residue chemistry studies are needed. However, if in the future

imazapyr use on additional GM crops or the same crops with different types of genetic 

modifications are sought, adequate rational and information should be provided to show 

that the metabolic pathways in non-tolerant and tolerant plants are comparable. 

No dietary hazard was identified in the imazapyr toxicity database. Because imazapyr 

does not pose a dietary (food and drinking water) risk, a quantitative dietary risk 

assessment is not required. Consequently, an updated or revised dietary risk assessment 

will not be required for registration review.

Residential (Non-Occupational) Exposure

The current occupational and residential database is sufficient to support the registration 

review of imazapyr. No additional studies are needed.

No hazard was identified in the imazapyr toxicity database; eye irritation issue is 

addressed in the occupational section below. Because imazapyr does not pose a 

residential risk, a quantitative dietary risk assessment is not required. Consequently, an 

updated or revised occupational and residential risk assessment will not be required for 

registration review. 

Aggregate Exposure and Risk

HASPOC in September 2012 determined that there is no hazard identified in the toxic 

studies for imazapyr and concluded with reasonable certainty that dietary, occupational 

and residential exposures to imazapyr do not pose a significant human health risk and, 

therefore, quantitative risk assessments, including aggregate risk assessments are not 

needed.

Occupational Exposure

The current occupational and residential database is sufficient to support the registration 
Page 5 of 15

review of imazapyr. No additional studies are needed.

No hazard was identified in the imazapyr toxicity database. Because imazapyr does not 

pose an occupational risk, a quantitative dietary risk assessment is not required. 

Consequently, an updated or revised occupational and residential risk assessment will not 

be required for registration review. However, because of toxicity category for primary 

eye irritation for technical grade imazapyr, HED recommends that the requirements for 

personal protective equipment (PPE) on end-use products for occupational handler and 

post-application exposure be re-reviewed. Requirement for protective eyewear should 

appear on all labels of end-use products that are toxic category I for eye irritation. 

Application to non-crop areas such as rights-of-way is not bound by worker protection 

standards (WPS). Imazapyr end-use products that are currently registered for corn should 

retain a restricted entry interval (REI) of 48 hours for post-application workers. 

Public Health and Pesticide Epidemiology Data

OPP Incident Data System (IDS) and the Centers for Disease Control and 

Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel 

Event Notification System for Occupational Risk-Pesticides (SENSOR) databases were 

consulted for pesticide incident data on the active ingredient Imazapyr (PC codes: 128821 

and 128829). The purpose of the database search is to identify potential patterns in the 

frequency and severity of the health effects attributed to Imazapyr exposure. Agricultural 

Health Study (AHS) was not consulted as imazapyr is not included in that study.

Based on the low severity and relatively low frequency of incident cases reported for 

imazapyr in both IDS and SENSOR-Pesticides, there does not appear to be a concern at 

this time that would warrant further investigation. Ortho® GroundClear® Vegetation 

Killer Concentrate (Reg No 239-2657) does appear to be implicated in a disproportionate 

amount of incidents which may be attributable to high use of this product by consumers. 

Ortho® GroundClear® Vegetation Killer Concentrate is a co-formulated product, which 

in addition to imazapyr (0.8%), also contains the active ingredient glyphosate (5%). This 

may be potentially attributable to the high use of this product by consumers. (Recore, 

Shanna, D417421, 1/25/2014)

Tolerance Assessment and International Harmonization

U.S. permanent tolerances for imazapyr are listed in 40 CFR 180.500 and are 

summarized in Table 2. 

Canadian Maximum Residue Limits (MRLs) are established for a variety of agricultural 

crops, as well as in livestock commodities. There are no Codex or Mexican MRLs 

established for imazapyr.

Because there is no hazard identified for imazapyr from toxicity studies and there are no 

risk concerns from exposure to imazapyr, an exemption from the requirement of a 

tolerance would be appropriate for imazapyr; however, the regulatory divisions may 
Page 6 of 15

chose to leave the tolerances as they are, remove all tolerances, or remove tolerances for 

crops without any other international harmonization issues at their discretion. Should the 

regulatory division choose to harmonize with Canada, the following section details HED 

recommendations.

The Canadian residue definition is the same as that of U. S. The current U.S. tolerances 

are harmonized with Canadian MRLs with respect to the level of regulation except for the 

kidney of ruminants. Canada does not have a separate tolerance for residues on imazapyr 

in kidney of ruminants, instead it is covered under meat byproducts MRLs at 0.05 ppm. 

However, there are separate US tolerances for kidney (at 0.2 ppm) and meat byproducts, 

except kidney (0.05 ppm). HED recommends that separate US tolerance for kidney be 

revoked and “meat byproduct, except kidney” be changed to “meat byproducts” (at 0.05 

ppm) to harmonize with Canadian MRLs according to the following table.

Commodity US Tolerance 

(ppm)

Canada Proposed US 

Tolerance

Cattle, kidney 0.2 0.05 meat 

byproducts of 

cattle

revoke

Cattle, meat 

byproducts, 

except kidney

0.05 0.05 meat 

byproducts of 

cattle

change the 

commodity 

definition to: 

Cattle, meat 

byproducts

Goat, kidney 0.20 0.05 meat 

byproducts of 

goat

revoke

Goat, meat 

byproducts, 

except kidney

0.05 0.05 meat 

byproducts of 

goat

change the 

commodity 

definition to: 

Goat, meat 

byproducts

Horse, kidney 0.20 0.05 meat 

byproducts of 

horse

Revoke

Horse, meat 

byproducts, 

except kidney

0.05 0.05 meat 

byproducts of 

horse

change the 

commodity 

definition to: 

Horse, meat 

byproducts

Sheep, kidney 0.20 0.05 meat 

byproducts of 

sheep

Revoke

Sheep, meat 

byproducts, 

except kidney

0.05 0.05 meat 

byproducts of 

sheep

change the 

commodity 

definition to: 

Sheep, meat 

byproducts
Page 7 of 15

There are also commodities with US tolerances for which there are no Canadian MRLs. 

The regulatory division may, as the registration review for imazapyr progresses, revoke

all those tolerances to harmonize with Canadian MRLs.

International or Intergovernmental Work Sharing

HED is not currently involved in any joint international review projects that involve the 

active ingredient, imazapyr. Additionally, HED is unaware of any ongoing international 

assessments for imazapyr. Given the lack of toxicity for this chemical and the lack of 

any identified new work, HED has not identified any potential work sharing opportunities 

for imazapyr.

Cumulative Risk Assessment

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

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

finding as to imazapyr and any other substances and imazapyr 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 imazapyr has a common mechanism of 

toxicity with other substances. For information regarding EPA’s efforts to determine 

which chemicals have a common mechanism of toxicity and to evaluate the cumulative 

effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide 

Programs concerning common mechanism determinations and procedures for cumulating 

effects from substances found to have a common mechanism on EPA’s website at 

http://www.epa.gov/pesticides/cumulative/.

Data Requirements

None

References

Author Barcode Date Title

P. Yvonne 

Barnes

D320579 08/29/2005 Imazapyr: Summary of Product Chemistry 

Data for Reregistration Eligibility Decision 

(RED) Document.

William 

Donovan

D288806 3/26/2003 Imazapyr. Chronic Dietary Exposure 

Assessment for the Section 3 Registration 

Action on Grasses and Aquatic Sites.

Christina 

Jarvis, 

et.al.

D324106 8/12/2005 Imazapyr: Revised HED Chapter of the 

Reregistration Eligibility Document

(RED). 

Kristin 

Rury

TXR# 

0056464

2/26/13 Imazapyr: Summary of Hazard and Science 

Policy Council (HASPOC) Meeting of 
Page 8 of 15

September 13, 2012: Recommendations on 

the type of risk assessment (quantitative vs. 

qualitative) to be conducted.

Mohsen 

Sahafeyan, 

et.al.

D384035, 

D403741

7/2/2013 Imazapyr: Petition for the Establishment of 

Import Tolerances on Genetically-Modified 

(GM) Soybean, Rapeseed subgroup 20A, 

Sunflower Subgroup 20B and Lentils

Charles 

Smith

D320582 08/31/2005 Imazapyr: Occupational and Residential 

Exposure Assessment for the Reregistration 

Eligibility Decision Document

Shanna 

Recore D417421 1/25/2014 Imazapyr: Tier I Review of Human Incidents

Table 1A - Chemical Identity of Imazapyr 

Chemical structure

Common name Imazapyr

Company experimental name BAS 693 H

IUPAC name 2-[(RS)-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl]nicotinic acid

CAS name 2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-3-

pyridinecarboxylic acid

CAS registry number 81334-34-1

End-use product (EP) Not Specified

Table 1B - Physicochemical Properties of Imazapyr

Parameter Value Reference

Melting point 169-173°C DP# 324106, C. Jarvis et al., 

12/08/05 pH 2.5 at 25°C

Density 0.35 g/mL

Water solubility 1.11 g/100 mL

Solvent solubility NA

Vapor pressure <2 x 10-7 mm Hg at 25°C

Dissociation constant, pKa pk1 = 1.9, pk2 = 3.6

Octanol/water partition coefficient, Log(KOW) 1.3 at 22°C

UV/visible absorption spectrum NA

N

N

H

N

O

CH(CH3)

2

CH3

COOH
Page 9 of 15

Table 2 - Summary of US and International Tolerances and Maximum Residue 

Limits

Residue Definition:

US Canada Mexico2 Codex

40 CFR 180.500

imazapyr [2-[4,5-dihydro-4-methyl-4-(1-

methylethyl)-5-oxo-1H-imidazol-2-yl]-3-

pyridinecarboxylic acid]

2-[4,5-dihydro-4-methyl-4-

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

pyridinecarboxylic acid

None

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

US Canada Mexico2 Codex

Cattle, fat 0.05 0.05

Cattle, kidney 0.20 0.05 meat byproducts of cattle

Cattle, meat 0.05 0.05

Cattle, meat byproducts, except 

kidney

0.05 0.05 meat byproducts of cattle

Corn, field, forage 0.05

Corn, field, grain 0.05

Corn, field, stover 0.05

Fish 1.0

Goat, fat 0.05 0.05

Goat, kidney 0.20 0.05 meat byproducts of goat

Goat, meat 0.05 0.05

Goats, meat byproducts, except 

kidney

0.05 0.05 meat byproducts of goat

Grass, forage 100

Grass, hay 30

Horse, fat 0.05 0.05

Horse, kidney 0.20 0.05 meat byproducts of horse

Horse, meat 0.05 0.05

Horse, meat byproducts, except 

kidney

0.05 0.05 meat byproducts of horse

Lentil10.2 0.2 dry lentils

Milk 0.01 0.01

Rapeseed subgroup 20A10.05 0.05 seeds (borage, cuphea, 

echium, flax, gold of pleasure, 

hare's ear mustard, milkweed, 

mustard seed (oilseed type), 

oil radish, poppy, rapeseed 

(canola), sesame, sweet rocket

Sheep, fat 0.05 0.05

Sheep, kidney 0.20 0.05 meat byproducts of sheep

Sheep, meat 0.05 0.05

Sheep, meat byproducts, except 

kidney

0.05 0.05 meat byproducts of sheep

Shellfish 0.10

Sunflower subgroup 20B10.05

MRLs with NO US Equivalent

Eggs 0.05

Fat of hogs 0.05

Fat of poultry 0.05

Meat byproducts of hogs 0.05
Page 10 of 15

Meat byproducts of poultry 0.05

Meat of hogs 0.05

Meat of poultry 0.05

Completed: M. Negussie; 1/08/2014

1There are no U.S. Registrations

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

Table 3 - Summary of Maximum Application Rates for Registered Imazapyr Commercial Uses

Crop Type/Use Site

Target of 

Application Application Equipment

Maximum Application 

Rate

non-crop areas (including highway 

rights-of-way, turfgrass (recreation 

areas, athletic fields, golf course roughs, 

commercial/ industrial areas)

grasses, weeds, 

paved surfaces

aerial, groundboom, low-pressure handwand, highpressure handwand, handgun, rights-of-way sprayer, 

backpack 1.5 lb ai/A (liquid)

non-crop areas (including highway 

rights-of-way, turfgrass (recreation 

areas, athletic fields, golf course roughs, 

commercial/ industrial areas) grasses, weeds

aerial, tractor drawn spreader, push-type spreader, 

backpack spreader 1.5 lb ai/A (granular)

broadcast application to aquatic areas or 

draw down area

aquatic 

vegetation aerial, boat, handgun, low-pressure handwand 1.5 lb ai/A

trees brush, trees aerial, groundboom, handgun, rights-of-way sprayer 1.25 lb ai/A

areas grazed or cut for hay saltcedar aerial, groundboom, low-pressure handwand 1.0 lb ai/A

trees brush, trees EXJECT capsule injection equipment - -

Table 4 - Summary of Maximum Application Rates for Registered Imazapyr Residential Uses

Crop Type/Use Site

Target of 

Application Application Equipment

Maximum Application 

Rate 

driveways, parking areas, brick walls, gravel 

pathways, patios, along sidewalks and bare 

ground grasses, weeds low-pressure handwand, sprinkling can 0.19 lb ai/1,000 sq ft

Table 5 - Status of Required Toxicological Studies for Imazapyr 

Guideline Numbers

(Note: Use of the new guideline numbers does not imply that the new 

(1998) guideline protocols were used)

Technical

Required Satisfied1 

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

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

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

870.2400 Primary Eye Irritation ..............................................................

870.2500 Primary Dermal Irritation.........................................................

870.2600 Dermal Sensitization................................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes
Page 11 of 15

Table 5 - Status of Required Toxicological Studies for Imazapyr 

Guideline Numbers

(Note: Use of the new guideline numbers does not imply that the new 

(1998) guideline protocols were used)

Technical

Required Satisfied1 

870.3100 Oral Subchronic (rat and mouse) .............................................

870.3150 Oral Subchronic (dog)..............................................................

870.3200 21/28-Day Dermal (rat)............................................................

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

870.3465 28-Day Inhalation ....................................................................

yes

yes

yes

no

no

yes

yes

yes

---

---

870.3700a Developmental Toxicity (rat)...................................................

870.3700b Developmental Toxicity (rabbit)..............................................

870.3800 Reproduction (rat)....................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rat) ..............................................................

870.4100b Chronic Toxicity (dog).............................................................

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

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

870.4300 Chronic/Carcinogenicity (rat) ..................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial................................

870.5300 Mutagenicity—Gene Mutation - mammalian...........................

870.5375 Mutagenicity—Structural Chromosomal Aberrations..............

870.5395 Mutagenicity—Mammalian Erythrocyte Micronucleus...........

870.5450 Mutagenicity—Rodent dominant lethal assay 

870.5500 Mutagenicity— Bacterial DNA Damage or Repair Test

870.5550 Mutagenicity—Unscheduled DNA Synthesis.............................

yes

yes

yes

yes

no

no

no

yes

yes

yes

see footnote 1

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity. (hen) ........................................

870.6100b 90-Day Neurotoxicity (hen) .....................................................

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

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

870.6300 Developmental Neurotoxicity (rat) ..........................................

no

no

yes

yes

no

---

---

yes

yes

see footnote 1

870.7485 General Metabolism (rat).........................................................

870.7600 Dermal Penetration, in vivo (male rat) .....................................

yes

no 

yes

yes

870.7800 Immunotoxicity (rat and mouse)........................... yes

see footnote 1

Non-Guideline: Comparative dermal absorption, in vitro (rat 

 and human skin)

no --

1

According to the present HED policies, the toxicology database is considered to be adequate and no additional studies are required. 

This is because, HASPOC confirmed that the available data do not suggest that there is a concern for neurotoxicity, immunotoxicity, 

genotoxicity, or carcinogenicity (Imazapyr: Summary of Hazard and Science Policy Council (HASPOC) Meeting of September 13, 

2012: Recommendations on the type of risk assessment (quantitative vs. qualitative) to be conducted. TXR# 0056464, 2/26/13). 
Page 12 of 15

Table 6 - Acute Toxicity of Imazapyr Technical Grade Active Ingredient (TGAI)

Guideline No/Study Type MRIDs Results Toxicity Category

870.1100 Acute Oral 41551002 (1990)

93048016 (1990) LD50 = > 5000 mg/kg IV

870.1200 Acute Dermal 41551003 (1990)

93048017 (1990) LD50 = >2000 mg/kg III

870.1300 Acute Inhalation

TXR# 0006998

00132032 (1983)

93048018 (1990)

LC50 = >1.3 mg/L (gravimetric)

> 5.1 mg/L (nominal)

III

870.2400 Primary Eye Irritation/NZW rabbit 41551001 (1990)

93048019 (1990)

2/6 rabbits with corneal opacity at 

21 days; discharge in 1/6 rabbits at 

21 days; vascularization of cornea 

in 1/6 rabbits at 21 days;

Irreversible Eye Damage

I

Tested with 99.3% 

technical fine powder

870.2400 Primary Eye Irritation/NZW rabbit Accession# 252004

Corneal opacity cleared within 72 

hours; conjunctivitis reversible by 

day 7

III

Tested with 93% 

technical

870.2500 Primary Skin Irritation 41551004 (1990)

93048020 (1990)

non-irritating to slight erythema 

and edema IV

870.2600 Dermal Sensitization 00131607 (1983)

93048021 (1990) Negative -

Table 7 - Toxicity Profile of Imazapyr Technical.

Guideline No./

Study Type

MRID No. (year)/ 

Classification/Doses

Results

870.3100

90-Day oral toxicity

rodents (rat)

42774401 (1992)

Acceptable/guideline

0, 15,000, or 20,000 ppm 

(equivalent to 0, 1248, or 

1695 mg/kg bw/day in males 

and 0, 1423 or 1784 mg/kg 

bw/day in females).

NOAEL =1,695 mg/kg/day for males and =1,784 

mg/kg/day for females (HDT).

LOAEL = None.

870.3200

21/28-Day dermal toxicity

(rabbit)

00131609 (1983)

93048022 (1990)

Acceptable/guideline

0, 100, 200 or 400 

mg/kg/day, 6 hrs/day for 5 

d/week during a 21-day 

period.

NOAEL =400 mg/kg/day (HDT).

LOAEL = None.

870.3700a

Prenatal developmental toxicity 

in rodents

(rat)

00131611 (1983)

93048023 (1990)

Acceptable/guideline

0, 0, 100, 300 or 1,000 

mg/kg/day from days 6 

through 15 of gestation.

Maternal NOAEL = 300 mg/kg bw/day. LOAEL 

=1,000 mg/kg bw/day, based on salivation.

Developmental NOAEL =1,000 mg/kg/day. This was 

the HDT; therefore, there is no LOAEL.
Page 13 of 15

Table 7 - Toxicity Profile of Imazapyr Technical.

Guideline No./

Study Type

MRID No. (year)/ 

Classification/Doses

Results

870.3700b

Prenatal developmental toxicity 

in non rodents

(rabbit)

00131613 (1983)

93048024 (1990)

Acceptable/guideline

0, 25, 100, or 400 mg/kg/day 

from days 6 through 18 of 

gestation.

Maternal NOAEL =400 mg/kg bw/day This was the 

HDT; therefore, there is no LOAEL.

Developmental NOAEL =400 mg/kg bw/day. This was 

the HDT; therefore, there is no LOAEL.

870.3800

Reproduction and fertility 

effects

(rat)

41039505 (1987)

Acceptable/guideline

0, 1,000, 5,000 and 10,000 

ppm in the diet (equivalent to 

0, 74.2, 380.5, or 738 mg/kg 

bw/day for males and 0, 94.3, 

471.2, or 933.3 mg/kg 

bw/day for females).

Parental systemic, reproductive and offspring

NOAEL =10,000 ppm (738 mg/kg bw/day in males 

933.3 mg/kg bw/day in females). This was the HDT; 

therefore, there is no LOAEL.

870.4100a

Chronic toxicity

(rodent)

NA; see 870.4300 NA

870.4100b

Chronic toxicity

(dog)

41039502 (1987)

Acceptable/guideline

0, 1,000, 5,000 or 10,000 

ppm (equivalent to 0, 25, 125 

or 250 mg/kg/day) for 1 year.

NOAEL is =10,000 ppm (250 mg/kg/day)(HDT). 

LOAEL. = None.

870.4200a

Carcinogenicity

(rat)

NA; see 870.4300

870.4200b

Carcinogenicity

(mouse)

41038505 (1988)

42774401 (1992)

Acceptable/guideline

0, 1,000, 5,000 or 10,000 

ppm (equivalent to 0, 126, 

674 or 1,301 mg/kg /day in 

males and 0, 151,776 or 

1,639 mg/kg /day in females) 

for 18 months.

NOAEL =10,000 ppm (1,301 mg/kg/day in males and 

1,639 mg/kg/day in females). This was the HDT; 

therefore, there is no LOAEL.

870.4300 Combined 

Chronic/Carcinogenicity 

(Sprague Dawley rat)

41039503 (1988)

Acceptable/guideline 1

0, 100, 5000, 10000 ppm 

(M/F: 0/0, 49.9/64.2, 

252.6/317.6, 503/638.6 

mg/kg/day)

NOAEL = 10000 ppm (M/F: 503/638.6 mg/kg/day.

LOAEL = None was shown, however a statistically 

significant (but within normal range) increase in BUN 

and a nominal decrease in body weight gain in males 

(2%)(may have approached a toxic dose) and a nominal 

increase (not statistically significant, pair wise) in brain 

astrocytomas was seen in females, which the CARC 

classified as a “group E chemical”, no evidence of 

carcinogenicity in mice or rats. A 90-day study in rats 
Page 14 of 15

Table 7 - Toxicity Profile of Imazapyr Technical.

Guideline No./

Study Type

MRID No. (year)/ 

Classification/Doses

Results

showed no adverse effects at levels including the limit 

dose of 20,000 ppm (1000 mg/kg/day).

870.5100

Bacterial reverse mutation 

(Ames Assay)

00131615 (1983)

93048025 (1990) 

Acceptable/guideline

Negative up to 5,000 μg/plate.

870.5300

In vitro mammalian cell gene 

mutation

00151641 (1984)

93048028 (1990)

Acceptable/guideline

Negative up to cytotoxic doses (5,000 μg/mL) with and 

without activation.

870.5375

In vitro mammalian 

chromosome aberration (CHO)

00151640 (1984)

93048026 (1990)

Acceptable/guideline

Negative up to cytotoxic doses (5,000 μg/mL) with and 

without activation.

870.5550

Unscheduled DNA synthesis 

(RPH)

00151639 (1984)

93048027 (1990) 

Acceptable/guideline

Reported as negative (unacceptable, 1989), but 

considered acceptable in 1997. 2

870.5450

Rodent Dominant Lethal

00151638 (1985)

Acceptable/guideline

Reported as negative (unacceptable, 1989), but 

considered acceptable in 1997. 2

870.6200a

Acute neurotoxicity screening 

battery (rat)

48469001 (2011)

Acceptable/guideline

0, 200, 600 mg/kg

NOAEL =≥2000 MG/KG (HDT); THEREFORE, 

THERE IS NO LOAEL

870.6200b

90 Day neurotoxicity screening 

battery (rat)

48469001 (2011)

Acceptable/guideline

0, 300, 1000 mg/kg/d

(0, 89, 272, 924 mg/kg/d ♂; 

0 92, 283, 933 mg/kg/d ♀)

NOAEL ≥924 mg/kg/d (♂); ≥933 mg/kg/d (♀) (HDT); 

therefore, there is no LOAEL
Page 15 of 15

Table 7 - Toxicity Profile of Imazapyr Technical.

Guideline No./

Study Type

MRID No. (year)/ 

Classification/Doses

Results

870.7485

Metabolism and 

pharmacokinetics

(rat)

43861501 (1994)

Acceptable

M&F: unlabeled or labeled 

imazapyr ~ 9.5 mg/kg or 924 

mg/kg single gavage dose or 

as 14-daily doses of 

unlabeled imazapyr followed 

by single labeled dose of 

9.26 mg/kg.

M&F: 10 mg/kg labeled 

imazapyr single gavage dose 

to measure excretion via 

expired air (pilot study).

M&F: 9.94 mg/kg labeled 

imazapyr by intravenous 

injection.

No sex-related differences in absorption were apparent. 

Within 48 hours of treatment, >90% of the administered 

dose was recovered in the excreta suggesting that 

elimination of the labeled test material was rapid. No 

specific sequestering tissues or organs were identified. 

Seven days after treatment, essentially all the test 

material had been eliminated. Rats that received the test 

material by intravenous injection excreted 87-95% of the 

administered dose in the urine and approximately 6% 

into the feces. This suggests that 15-28% if the oral 

administered dose recovered in the feces represents 

unabsorbed material.

Metabolite characterization studies show that essentially 

all of the test material was excreted unchanged. Two 

minor metabolites CL 252,974 and CL 60,032 were 

detected in the urine or feces of treated rats; however, 

their contribution combined was <0.5% of the 

administered dose. Up to 12 additional unidentified 

metabolites were isolated, but they constituted <3% of 

the administered dose. Based on the results, the study 

author suggests that what limited metabolism of CL 

243,997 occurs, proceeds through hydrolysis to form the 

2-carbonyl derivatives: CL 252,974 and CL 60,032.

870.7600

Dermal penetration NA NA

870.7800

Immunotoxicity

48490102 (2011)

Acceptable/guideline

0, 500, 1500, 5,000 ppm 

(equivalent to 0, 155, 525 or 

1,668 mg/kg /day in female 

mice)

NOAEL = ≥1,668 mg/kg/day; LOAEL was not 

established.

1 The study is acceptable for regulatory purposes according to documentation in TXR# 0011692 (1995), TXR# 

0051943 (2003), and TXR# 0011213 (1994). 

2 Memorandum, dated 3/10/97, from Steve Robbins et al. of HED to Phillip Errico RD.