MEMORANDUM 

February 26, 2013 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: 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. 

PC Code: 128821 DP Barcode: N/A 

Decision No.: N/A Registration No.: N/A 

Petition No.: N/A Regulatory Action: N/A 

Risk Assessment Type: N/A Case No.: N/A 

TXR No.: 0056464 CAS No.: N/A 

MRID No.: N/A 40 CFR: N/A 

FROM: Kristin Rury, MPH '?-2:-o 

Executive Secretary, HASPOC 

Health Effects Division (HED; 7509P) 

THROUGH: Jess Rowland, Co-Chair J-.. .,._~ 

Anna Lowit, Ph.D, Co-Chair ~ , ~ j 1 

HASPOC 6 l.7f 

HED (7509P) 

TO: Mohsen Sahafeyan 

Nancy McCarroll 

Charles Smith 

Felicia Fort, Chief 

Risk Assessment Branch 6 

HED (7509P) 

MEETING ATTENDEES: 

HASPOC Members: Anna Lowit, Elissa Reaves, Elizabeth Mendez, Jeff Evans, Jess Rowland, 

John Kough, Jonathan Chen, Michael Metzger, P.V. Shah, Ray Kent 

Presenters: 

Other Attendees: 

Nancy McCarroll/Moshsen Sahafeyan 

Felecia Fort, William Irwin, Charles Smith, Yung Yang, Abdallah 

Khasawinah, Marquea King, Bridgett Bobowiec, Thurston Morton, 

Deborah Smegal, Kristin Rury, Julie Van Alstine 

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I. PURPOSE OF MEETING: 

In 2011, the Agency issued a Reregistration Eligibility Document (RED) for Imazapyr. Since 

that time, a new food use has been identified, and this action may result in an increased exposure 

via the dietary route. Accordingly, the toxicology database, the points of departures (PODs) and 

endpoints selected for the previous risk assessment were revisited. In accordance with the 2012 

Updated Residential Standard Operating Procedure, the residential assessment that contributes to 

the aggregate exposure risk assessment was also revisited. The imazapyr risk assessment team 

believes that the selection of endpoints for the risk assessment is not necessary because there is 

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

acceptable guideline studies generally up to the highest dose tested of250 - lOOO mg/kg/day). 

The following is a brief description of the use profile; toxicological effects; decisions of the peerreview committees regarding endpoint selection for previous risk assessments; and the exposure 

assessment that were considered and factored into the team's position that a quantitative risk 

assessment is not justified. The HASPOC met on September 13,2012 to evaluate the hazard and 

exposure data to determine the type of risk assessment (quantitative vs. qualitative) needed for 

imazapyr. 

II. USE PROFILE: 

Imazapyr is a systemic, non-selective, pre- and post-emergent herbicide used for the control of a 

broad range of weeds, including terrestrial annual and perennial grasses, broad-leaved herbs, 

woody species, and riparian and emergent aquatic species. Imazapyr is part of the imidazolinone 

chemical class, and controls plant growth by preventing the synthesis of branched-chain amino 

acids. Imazapyr is currently applied to imidazolinone-resistant field corn and is proposed for 

application to imported soybeans, grape seeds, sunflower seeds, and lentils. 

Imazapyr is currently registered for use on a variety of agricultural, commercial, and residential 

use sites, including corn, 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, and stagnant water), and urban areas. Registrants supporting the use 

of imazapyr include BASF Corporation, Nufarm Americas, Inc., PBVGordon Corporation, 

Rainbow Technology Corporation, and SSI Maxim Company, Inc. Imazapyr is marketed under 

the trade names of Chopper®, Arsenal®, and Assault®. 

III. HAZARD ASSESSMENT: 

The toxicology database for imazapyr is complete according to the 40 CFR Part 158; it also 

includes acute and subchronic neurotoxicity and immunotoxicity studies. Imazapyr has low 

toxicity via the oral (Toxicity Category IV), dermal (Toxicity Category Ill), and inhalation 

(Toxicity Category III) routes of exposure. It is not irritating to the skin and is negative for 

dermal sensitization. However, imazapyr causes irreversible eye damage (toxicity category I). 

Acute and subchronic neurotoxicity studies showed no evidence of neurotoxicity in male or 

female rats exposed to the limit dose (924-2000 mg/kg/day). Imazapyr was not immunotoxic in 

female mice tested up to the limit dose in an immunotoxicity study. A 21 -day dermal study in 

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rabbits showed a no observed adverse effect level (NOAEL) of 400 mg/kg/day (highest dose 

tested, HOT). There is no repeated dose inhalation toxicity study or dermal absorption study; 

however, these studies are not being requested at this time. There were no compound-related 

effects on clinical signs, mortality, body weight, food consumption, hematology, clinical 

chemistry, urinalyses, gross pathology, organ weights, or non-neoplastic and neoplastic lesions 

in a one-year dietary toxicity study in beagle dogs up to 10,000 ppm (NOAEL equivalent to 250 

mg/kg/day). 

No developmental toxicity was observed in rabbits up to 400 mg/kg/day, HOT or in rats up to 

1 ,000 mglkg/day (the limit dose and HDT). While maternal toxicity based on salivation was 

observed in rats at I 000 mg/kg/day, this response was not considered an adverse neurotoxic 

effect since it occurred at the limit dose and there is no evidence of neurotoxicity in any other 

studies. Neither the rat nor the rabbit study showed an increased susceptibility of the fetus to 

imazapyr administered pre-natally or post-natally. No increased susceptibility to offspring was 

seen in a two-generation reproduction rat study up to I 0,000 ppm (HDT) (NOAEL=738 

mg/kg/day males, 933.3 mg/kg/day females). The Food Quality Protection Act (FQPA) factor 

was reduced to 1 X because no increased offspring susceptibility over the parents was seen in the 

rat or rabbit pre-natal developmental studies or in the post-natal rat reproduction study. Data 

from the metabolism studies show that ~70-80% of the applied dose is recovered in the urine 4 

hours post-dosing; that >90% is recovered within 48 hours; and that essentially all of it is 

recovered by day 7. 

Imazapyr was classified by the Cancer Peer Review Committee (CPRC) in October 1997 as a 

"Group E chemical," no evidence of carcinogenicity in at least 2 adequate studies, one in the rat 

and one in the mouse" (TXR # 0012201). This decision was reaffirmed on May 22, 2003 (TXR 

# 0051943). A quantitative cancer risk assessment is not required for imazapyr. Imazapyr was 

also negative for mutagenic potential in the Salmonella reverse gene mutation assay, Chinese 

hamster ovary (CHO) cell HGPRT forward gene mutation assay, in vitro chromosomal 

aberration assay in CHO cells and a mouse dominant lethal assay. 

V. EXPOSURE ASSESSMENT: 

Based on the use patterns of imazapyr, the routes of exposure previously evaluated for imazapyr 

ant the endpoints selected for the following exposure scenarios and durations were: 

chronic dietary 

short- and intermediate-term incidental oral 

short-, intermediate-, and long-term dermal, and 

short-, intermediate-, and long-term inhalation. 

An oral point of departure (POD) of250 mg/kg/day was used for assessing risks via dietary 

(chronic) and non-dietary (dermal and inhalation) routes of exposure. The POD was based on 

the highest dose tested in a chronic study in dogs and a dose that did not produce any toxicity. 

Although no toxicity was seen at this dose, skeletal muscle effects were seen in dogs at 137 

mg/kg/day with imazapic with a structural analog. 

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With regard to risk assessment, the last screening dietary exposure numbers for the highest 

exposed population was 0.005732 mg/kg/day ( <0.0 1% of the cPAD). Since this chemical is also 

an aquatic herbicide, a swimmer's assessment was carried out. Results indicate MOEs ranging 

from 68,000 to over 1,000,000. Similarly, a screen of the turf uses, analyzed as described in the 

new SOPs, shows MOEs in a range comparable to the swimmer's scenario except for dermal 

which is being driven by a I 00% dermal absorption factor. 

IV. PREVIOUS RISK ASSESSMENTS 

In 1997, the HED RID Peer Review Committee considered the 250 mg/kg/day, highest dose 

tested) in the 1-year dog study to be the appropriate endpoint for establishing the chronic RID. 

On February 6, 2003, the HIARC determined. that an appropriate endpoint, attributable to a 

single dose was not available in the database and confirmed the selection of the 1-year dog study 

with a NOAEL of 250 mg/kg/day as the appropriate endpoint for the cRfD of Imazapyr for the 

following reasons: 

1. There were no adverse effects seen at any dose with Imazapyr; consequently, the NOAEL 

was set at 250 mg/kg/day. This value represents the lowest NOAEL in the most sensitive 

species in the Imazapyr database. 

2. A structural analogue of imazapyr, imazapic induced skeletal muscle effects in dogs at 

137 mg/kg/day. 

3. A structural activity relationship (SAR) analysis was also performed by HIARC to search 

for 1-year dog studies conducted with members of the imidazolinone chemical class. As 

shown below, several imidazolinone and various forms of imazaquin (acid and sodium or 

ammonium salts) induced necrosis of the skeletal muscle or skeletal muscle myopathy in 

the dog: 

Imazapic: LOAEL, based on skeletal effects, was 137 mg/kg/day; the 

NOAEL was not established. 

Imazaethapyr: Like Imazapyr, did not induce toxic effects at the HDT (1 0,000 

ppm, 250 mg/kg/day) in the 1-year dog study. 

Acid, Na, and Nfu Salts of Imazaguin: LOAEL, based on skeletal effects, was 

125 mg/kg/day; the NOAEL was 25 mg/kg/day. 

From this analysis, HIARC chose 250 mg/kg/day and skeletal muscle effects, based on the 

imazapyr fmdings and analogy with imazapic, as the POD for assessing risks for chronic dietary, 

short-term and intermediate-term incidental oral exposures as well as the short-term and 

intermediate-term dermal and the short, intermediate, and long-term inhalation exposures. 

VI. HASPOC RECOMMENDATIONS: 

The HASPOC, with reasonable certainty, concludes 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 

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for exposure to imazapyr and although the existing toxicology studies do not use doses up 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 for regardless of 

the route of exposure or the species tested. Therefore, a quantitative risk assessment is not 

required. 

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