### MEMORANDUM February 26, 20 1 3 OFFICE OF CHEM ICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: Imazapyr: Summary of Hazard and Science Poli cy Council (HASPOC) Meeting of September 13,2012: R ecommendatio ns on the typ e of ri s k assessment (quantitative vs. qualitative) to be conducted. PC Co de: 128821 DP Barcode: N/A Dec isio n No.: N/ A Registration No.: N/ A Petition No.: N/ A Regulatory Actio n : 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: Kri stin Rury , MPH 

## '?-

# 2:-o
Executi ve Secretary, HASPOC Health Effects Division (HED; 7509P) 

### THROUGH: Jes s Rowland, Co-Chair 

# J-..**.,._~** Anna Lowit, Ph.D , Co

- Chair

### ~ ,

### ~ 

### j 1 HA SPOC 

# 6 l.7f HED (7509 P) 

### TO: Mohsen Sa h afeyan Nancy McCarro ll Charles Smith Felicia Fort, Chief Risk Assessment Branch 6 HED (7509 P ) MEETING ATTENDE ES : HASPOC Members: Anna Lowit, Elissa Reaves, E li zabeth Mendez, Jeff Evans, Jess Rowland, John Kough, Jonathan Chen , Michael Metzger, P.V. S hah, Ray Kent Presenters: Other Attendees: Nancy McCarroll/Mosh se n Sahafeyan Felecia Fort , William Irwin , Charles Smith , Yung Yang, Abdallah Khasaw inah, Marquea King , Bridgett Bobo w iec, Thurston Morton, Deborah Smegal, Kri stin R ury, Julie Van Alstine
Page I of5I. PURPOSE OF MEETING: In 2011, the Agency issued a Reregistration E ligibility 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 20 12 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 tes ted of250

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### lOOO mg/kg/day). The following i s a brief description of the use profile; toxicological effects; decisions of the peerreview committees regarding endpoint selection for previous ri sk assessments ; and the exposure assessment that were cons idered and factored into the team's position that a quantitative risk assessment is not justified. The HASPOC met on September 13,2012 to evalua te the hazard and exposure data to determine the type of risk assessment (quantitative vs. quali tative) 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 spe c ies , and ripa rian and emergent aquatic species. Imazapyr is part of the imidazolinone chemical cl ass, and controls plant growth by preventing the synthesis of branched

- chain amino acids. Imazapyr is currently app lied to imidazolinone-resistant field corn and is proposed for application to imported soybeans, grape seeds, sunflower seeds, and lentils. Imazapyr is currently re gistered fo r use on a variety of agricultural , commercial, and residential use sites, including corn , forestry sites, rights

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- way, fence rows, hedge rows, drainage systems , o utdoor 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 support ing th e 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 Assau lt®
. III. HAZARD ASS ESSM ENT: The toxicology database for imazapyr is comp lete according to the 40 CFR Part 1 58 ; it al so includes acute and subchronic neurotoxicity and immuno toxicity studies
. Imazapyr has low tox icity 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 i s negative for dermal sensitization. However , imazapyr causes irreversible eye damage (toxicity category I). Acute and subchronic neuro toxicity studies showed no evidence of neurotoxicity in male or female r ats exposed to the lim it dose (924

- 2000 mg/kg/day). Imazapyr was not im munotoxic in female mice tested up to the li mit dose in an immunotoxicity study . A 21

- day dermal study in

Page 2 of5rabbits showed a no observed adverse effect level (NOAEL) of 400 mg/kg/day (highest dose tested, HOT). There is no repeated dose inhalat ion tox ic ity stu d y or derma l absorption study; however , these stud ie s are not being requested at this time. There were no compound

-related effects on cl inical signs, mortality, body weigh t, food consumption, hematology, clinical chemistry, urinalyses, gross pathology, organ weights, or non-n eop l astic and neoplastic lesions in a one-year dietary toxicity study in beagle dogs up to 10 , 000 ppm (NOAEL equiv alent 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 rat s at I 000 mg/kg/ day , this response was not considered an adverse neurotoxic effect si nc e it occurred at the limit dose and there is no evidence of neurotoxicity in any other studies. Neither the rat nor the r abb i t study sh owed an i ncreased susceptib il ity of the fetus to imazapyr administered pre-natally or post-natally. No increased s usceptibility to offspring was seen in a two- generation reproduc ti on 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 o r 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-dos i ng ; that >90% is recovered within 48 hours ; and that essentially all of i t is recovered by day 7. Imazapyr was classified by the C ancer Peer Review Co mmittee (CPR C) in October 1997 as a " Group E chemica l ," 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 cell s and a mouse dominant lethal assay. V. EXPOSURE ASSESSMENT: Based on th e use patterns of imazapyr, the routes of exposure previously evaluated for imazapyr ant the endpoints selected for the following expo sure 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 o ral point of departure (P OD ) 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.

Pag e 3 of 5With 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 ran ging 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 sw immer's scenario except for dermal which is being driven by a I 00% dermal absorption factor. IV. PREVIOUS RISK ASSESSMENTS In 1997, the H E D 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, th e 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 sens itive 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 variou s fo rms 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 es tablished
. Imazaethapyr: Like Imazapyr, did not induce toxic effects at the HDT (1 0,000 ppm, 250 mg/kg/d ay) in the 1-yea r dog study. Acid, Na, and Nfu Salts of Imazaguin: LO AEL, based on skeletal effects, was 125 mg/kg/day; the NOAEL was 25 mg /kg/day. From this analys i s, 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 lon g- 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 assessme nt s are not needed. This decision was based on the fact that although there is potential

Page 4 of5for exposure to imazapyr and although the existing toxicology studies do not use do ses up the lim it dose , th e avail able data are high quality a nd no haz ard was identified from the toxicity stu dies. No adverse effects we re observed in the s ubmitted toxicological stud ies f or regardle ss of the route of expos ure o r the spec ie s tested. Therefore , a quantitative ri s k assessment is not required.

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