### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460



### MEMORANDUM

Date: 5-JUNE-20 14 OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION



### SUBJECT: Imazamox

. Human -Heal th Assessment Seeping Document in Support of Registration Review.

PC Code: 129171 Decision No.: 486514 Petition No.: N/A DP Barcode: D417140 Registration No.: RegRev-7238-1 Regulatory Action: Registration Review Scoping Document Case No .: 7238 R isk Assessment Type: N/ A TXRNo.: N/A CAS No. : 114311-32-9 40 CFR: § 180.1223 MRID No.: N/A



### FROM: Lata Venkateshwara, Environmental Scientist William D. Wassell, Chemis t Risk Assessment Branch 1 (RAB 1) Health Effects Division (HED, 7509P)



### THROUGH : Charles W. Smi t h 

### III, Branch Chief 

# e__:

_ George F. Kramer, Ph.D., Senior**Chemi ~** **~** 

### RABIIHED (7509P)



### TO: Kelly Ballard, Chemical Review Manager Pesticide Re-Evaluation Division (PRD) (7508P)

Attached is HED's scopingdocument for imazamox to support Registration Review.

Page 1 of 14lmazamox Registration R eview Human-Health Assessment Scoping Document



### Executive Summary



### HED has prepared a scoping document to support Registration Review of the herbicide imazamox. Imazamox is the common name of the active ingredient ammonium sa l t ofimazamox (2-[ 4,5

- dihydro-4-m e thyl-4-(1-methylethyl)-5-oxo-1 H -imidazol

- 2-yl]

- 5-(methoxymethl)- 3- pyridinecarboxylic acid). lmazamox is registered for use on alfalfa, beans (dry), chicory, clover grown for seed, edamame, lima bean (succulent) peas (dry), pea (English), snap bean, soybean
, canola, lenti l
, rice, sunflower and wheat. It is also registered for control of vegetation in 

### and around aquatic and noncropland s i tes includin g areas that may be grazed or cut for hay

. In 

### addition, there are three Special Local Needs (SLN) Registrations for imazamox: AR130001 provides control of weeds in edamame, CA070005 provides suppression in La dino clover grown for seed, and FL090007 provides for increas ed re sidues of imazamox in irri gat ion water resulting from applicat i on to irrigation canals. Im azamox is applied by ground or aerial applicat i on and
may be app li ed postemergence. 1 

### lmazamox is exempt from the requirem ent of a tolerance on all food commodities when applied as a herbicide in accordance with good agricultural practices. The most recent human-health risk assessment was performed in 2001, and was for new uses on alfalfa, canola, legume vegetables and w heat (Memo
, W. Donavan 

### et al.

, 13

- AUG-2001; D276570). There is currently one pending PRIA action for imazamox. This action is for an increased maximum rate for Clearfield® Plus on sunflowe rs. The PRIA due date is September 11
, 2014.

HED has eval uat ed the status of the human-health assess ment s for imazamox to determine whether sufficient data are availab le and whether any updates are needed to support Registration Review. HED has considered all available data and human-health risk assessments fo r imazamox with respect to its toxicity, exposure, and usage databa ses, and the most updated Agency sc ience policy and risk assessment methodologies to support Registration Review.

The toxicity database is adequate for hazard characterization and Food Quality Protection Act (FQ P A) Safety Factor (SF) evaluation. lmazamox exhi bits low toxicity in mammalian systems. No additional toxicolo g ical

· studies are currently required

. Since no effects were seen in any guideline toxicity s tudie s, no toxicological points of departure (PODs) were selected for imazamox and, as a result, a quantitative risk assessment is not required for imazamox for Registration Review to support the currently registered uses.

The residue chemistry and dietary-exposure databases for imazamox are adequate to support current registration requirements. As 

### per 40 CFR §180.1223, imazarnox i s exempt from the requirement of a tolerance on all food commodities when applied as a herbicide in accordance with good agricultural practices. Thus, residue chemistry data for imazamox are not required. Currently, a quantitative dietary exposure assessment is not required as toxicological PODs have
not been identi fied for imazamox. 'Since it has been determined that a qualitative assessment is

s ufficient based on the low toxicity of imazamox, a quantitative dietary exposure assessment is
not needed for Re gistration Review for HED to conclude with reasonable certainty that dietary
exposures to imazamox do not pose a significant human-health risk.

There is sufficient information available to assess occupational and residentia l exposure and ri sk from the regist ered uses. In the August 2001 human-health risk assessment , occupational

1 EPA factsheet found on lin e at: http: / / www.epa.gov/opp00001/chem

_ search/reg_actions/registrationlfs

_ PC129171_22-May-97.pdf Page 2 of 14Imazamox Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 3 of 14 

### exposures were qualitatively assessed since no toxicological PODs we re identified for imazamox

. Residential exposure scenarios have not previously been assessed ; h owever , since it has been determined that a qualitative assessment is sufficient based on the low toxicity of imaz amox , neither quantitative occupational nor re sidential exposure assessments are needed for Registration Review for HED to conclude with reasonable certainty that non

- dietary and occupational exposures to imaz amox do not pose a significant human

- health risk.

With regard to p ublic h ealth and p esticide e pidemiology d ata , b ased on the low frequency and low severity of incident cases reported for imaz amox in both the OPP Incident Data System ( IDS ) and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notif

ication System for Occupational Risk

- Pesticides ( SENSOR )

- Pesticides, there does not appear to be a concern at this time that would warrant further investigation. HED will continue to monitor the incident information and if a concern is triggered then addi tional analysis will be conducted during Registration Review

.

There are no data deficiencies for imaz amox

. Since it has been determined that no toxicological PODs will be selected for imaz amox for Registration Review and future actions; HED does not

an ticipate the need for conducting any quantitative exposure or risk assessments during Registration Review

.

1 .0 Introduction

Imaz amox is a member of the imidazolinone class of chemicals that kills weeds by inhibiting the enzyme acetohydroxyacid synthetase ( A HAS ) . This enzyme is involved in the synthesis of three branched

- chain aliphatic amino acids. The inhibition causes a disruption in protein synthesis that leads to an interference in DNA synthesis and cell growth. Imaz amox is registered for use on al falfa, beans (dry), chicory, clover grown for seed, edamame, lima bean (succulent) peas (dry), p ea (English), snap bean
, soybean
, canola, l entil, rice, sunflower and wheat . It is also registered for control of vegetation in and around aquatic and noncropl and sites including areas that may be grazed or cut for hay. In addition, there are three SLN Registrations for imazamox : AR130001 provides control of weeds in edamame, CA070005 provides suppression in Ladino clover grown for seed
, and FL090007 provides for increased residues of imazamox in irrigation water. The most recent human

- health risk assessment was performed in 2001
, and was for new uses on alfalfa, canola, legume vegetables and wheat ( Memo, W. Donavan et al. , 13

- AUG

- 2001; D276570 ). There is cur

rently one pending PRIA action for imazamox. This action is for an increase d maximum rate for Clearfield® Plus sunflowers. The PRIA due date is September 11, 2014. The structure, chemical names, and other identifiers as well as the physical/chemical pro perties of imaz amox can be found in Attachment 1

.

2 .0 Hazard Characterization/Assessment

The pesticidal mode of action of imazamox involves inhibition of AHAS , which is a key plant enzyme in the biosynthesis of the amino acids leucine, isoleucine, and valine. Mammals lack this biosynthetic pathway and must obtain these amino acids from their diet. The low toxicity exhibited by imazamox is consistent with the proposed pesticidal mode of action and the lack thereof in mammalian systems.

Toxicological S tudies Available for Analysis The Hazard Identification Assessment Review Committee (HIARC) met in July 2001 (HED Doc. No. 014611, P.V. Shah, 11

- JUL

- 2001) to discuss the appropriate endpoints and PODs forImazamox Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 4 of 14 

### imazamox. At that time, no additional toxicity dat a were deemed required because of the low toxicity exhibited by imazamox. As part of the revised 40 CFR Toxicology Data Requirements, inhalation, neurotoxicity (acute and subchronic), and immunotoxicity studies are necessary for registration; however t he Hazard and Science Policy Council (HASPOC) concluded using a weight

- of

- evidence approach that these studies are not required at this time. (M.Perron; 18

- MAR

- 2014, TXR#0056929). Therefore, the current toxicity database is adequate for hazard characteriza tion, toxicity endpoint selection, and FQPA SF evaluation.

Absorption, Distribution, Metabolism, and Excretion Following oral administration in rats, imazamox was extensively absorbed following in t ravenous or oral dosing as reflected by the high percentag e excreted in the urine (75%) within 24 hours of dosing. Within 168 hours of dosing, 88

- 99% of the administered dose was recovered (74

- 91% in urine). Metabolism of the parent chemical was minimal as the major residue excreted in both urine and feces was the parent chemical.

Toxicological Effects Imazamox exhibited very low toxicity in mammalian systems. In subchronic and chronic toxicity studies in rats and dogs, there were no toxic effects identified. There is no evidence of increased prenatal suscept ibility following in utero exposures to rats and rabbits. In both studies, there were no developmental or maternal effects reported at any dose (highest dose tested was 1,000 mg/kg/day in rats and 900 mg/kg/day in rabbits). Similarly, in a rat two

- generation reproductive toxicity study, there were no parental or offspring effects reported up to 1,705 mg/kg/day in females and 1,469 mg/kg/day in males. No toxicity was seen at doses exceeding the l imit

- d ose in long

- term studies in mice (1,053 mg/kg/day), rats (1,068 mg/kg/day), and dogs (1,156 mg/kg/day). In a rat dermal toxicity study, there were no effects (local or systemic) up to the highest dose tested (1,000 mg/kg/day). Although there are no neurotoxicity studies available for imazamox, there is no indication of neurotoxici ty in any of the available studies. There is no evidence that imazamox is genotoxic or carcinogenic based on the results of studies in mice and rats.

The HIARC met in July 2001 (HED Doc. No. 014611, P.V. Shah, 11

- JUL

- 2001) to discuss the appropriate endpo ints and PODs for imazamox. At this meeting, it was determined that no effects were seen in any of the guideline toxicity studies and thus no PODs or additional SF to protect children were needed for imazamox. As a result, quantitative risk assessment is not required for imazamox. In addition, it was determined that the toxicological profile of imazamox supports a tolerance exemption for this chemical.

Conclusions : The toxicology database is adequate to supp ort existing registrations and R egistration R eview (Attachment 2). No additional toxicological studies are currently required. Since no effects were seen in any guideline toxicity studies, n o toxicological PODs will be selected for imazamox and as a result, a quantitative risk assessment is not required for imazamox for Registration Review to support the currently registered uses.

3 .0 Residue Chemistry

As per 40 CFR §180.1223, imazamox is exempt from the requirement of a tolerance on all food commodities when applied as a herbicide in accordan ce with good agricultural practices. Thus, residue chemistry data for imazamox are not required.Imazamox Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 5 of 14 

### 4.0 Dietary Exposure and Risk Assessment

Currently, a quantitative dietary exposure assessment is not required as toxicological endpoints of concern have not been identified for imazamox. Since it has been determined that a qualitative assessment is sufficient based on the low toxicity of imazamox , a quantitative dietary exposure assessment is not needed for Registration Review f or HED to conclude with reasonable certainty that dietary exposures to imazamox do not pose a significant human

- health risk.

Conclusions : The dietary

- exposure database is adequate to support current registration requirements. Since it has been determined that a qualitative assessment is sufficient based on the low toxicity of imazamox , a quantitative dietary exposure assessment is not needed for Registration Review for HED to conclude with reasonable certainty that dietary expo sures to imazamox do not pose a significant human

- health risk.

5 .0 Residential Exposure /Risk Assessment

Imaz amox is currently registered for control of vegetation in aquatic sites. Aquatic sites that may be treated include estuarine and marine sites, p onds, lakes, reservoirs, wet l ands, marshes, swamps, bayous, arroyos, ditches, canals, streams, rivers, creeks and other slow

- moving or quiescent bodies of water. Residential exposures from these uses have not previously been quantitatively assessed . Howe ver, since it has been determined that a qualitative assessment is sufficient based on the low toxicity of imaz amox , a quantitative residential exposure assessment is not needed for Registration Review for HED to conclude with reasonable certainty that residential non

- dietary exposures to imaz amox do not pose a significant human

- health risk.

Spray Drift Residential exposures resulting from off

- site transport (e.g., spray drift or volatilization) may occur as a result of applications of imaz amox ; however , due to the low toxicity of imaz amox , quantitative spray drift and/or bystander assessments are not necessary for Registration Review

.

Conclusions : The residential

- exposure database is adequate to support current registration requirements. Since it h as been determined that a qualitative assessment is sufficient based on the low toxi city of imazamox , a quantitative res i dential exposure assessment is not needed for Registration Review for HED to conclude with reasonable certainty that residential non

- di etary exposures to imaz amox do not pose a significant human

- health risk.

6 .0 Aggregate Exposure/ Risk Assessment

In the November 200 1 human

- health r isk assessment ( Memo, W. Donavan et al. , 1 3

- AUG

- 200 1 ; D 276570 ) , a quantitative aggregate assessment was deemed unnecessary since no toxicological PODs were selected for imazamox

. S ince it has been determined that a qualitative assessment is sufficient based on the low toxicity of imazamox, a quantitative aggregate exposure assessment is not needed for Regis tration Review for HED to conclude with reasonable certainty that aggregate exposures to imaz amox do not pose a significant human

- health risk.

7 .0 Occupational Exposure /Risk Assessment

Occupational handler and post

- application exposures are expected b ased on the registered agricultural uses of imaz amox

. Imazamox is also currently registered for control of vegetation inImazamox Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 6 of 14 

### aquatic sites. Attachment 4 provides a summary of the occupational use pattern. The current registrations include three active SLN r egistrations. The commercial formulations include Raptor ®



### , Raptor ® 

### DG, Clearcast ®



### , Beyond ® 

### and Clearmax ®



### . Occupational exposures were qualitatively assessed in the 2001 human

- health risk assessment since no toxicological PODs were selected. Since it has been determined that a qualitative assessment is sufficient ba sed on the low toxicity of imazamox , a quantitative occupational exposure assessment is not needed for Registration Review for HED to conclude with reasonable certainty that occupational non

di etary exposures to imazamox do not pose a significant human

- health risk.

In accordance with the updated Part 158 data requirements (2007), one or more dislodgeable foliar residue (DFR) studies are required when a pesticide has occupational uses that could result in post

- application dermal exposure. However, s ince no quantitative dermal exposure assessment is necessary for imaz amox , a DFR study is not required at this time.

Imaz amox has low acute toxicity via the oral, dermal and inhalation routes (Toxicity Categories III and IV). It is not an eye (Toxicity Category III) or skin irritan t (Toxicity Category IV). Imazamox was not shown to be a skin sensitizer. Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute Toxicity III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12

- hour restricted entry interval ( REI ) . Therefore, the [156 subpart K] Worker Protection Statement (WPS) interim REI of 12 hours is adequate to protect agricultural workers from post

- appl ication exposures to imaz amox

. The REIs on the r egistered labels for imazamox range from 4 to 12 hours

. W hile the WPS

- recommended REI for imaz amox based on its acute toxicity categories is 12 hours, REIs may be further reduced if certain criteria are met for both the technical material and the different end

- use products in accordance with the Pesticide Registration (PR) Notice 95

- 3 [Reduction of Worker Protection Standard (WPS) Interim Restricted Entry Intervals (REIs) for Certain Low Risk Pesticides] 2



### . I maz amox meets one of the criteria for a reduction to a 4

- h ou r REI b ased only on its acute toxicity categories, however, during Registration Review, the additional criteria listed in PR Notice 95

- 3 will be checked to ensure they are met for both the ai and the end

- use product for those products listing a 4

- h ou r REI.

Conclusions : The occupational exposure database is adequate to support the Registration Review process for imazamox

. Since it has been determined that a qualitative assessment is sufficien t based on the low toxicity of imaz amox , a quantitative occupational exposure assessment is not needed for Registration Review for HED to conclude with reasonable certainty that occupational exposures to imazamox do not pose a significant human

- health ri sk. During Registration Review, the products listing a 4

- hour REI will be checked against the criteria listed in PR Notice 95

- 3 to ensure they are met for both the active ingredient and the end

- use product for those products listing a 4

- hr REI.

8 .0 Public Health and Pesticide Epidemiology Data Memo, E. Evans, S. Recore, D41 7802
, 6

- FEB

- 201 4

.


### The OPP IDS and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) SENSOR databases were consulted for pesticide incident data on the active ingredient imaz amox ( PC codes: 12 9171 ). The purpose of the database search was to identify potential patterns in the frequency and severity of the health effects attributed or potentially attributed to imaz amox ex posure.

2 Available: http://www.epa.gov/PR_Notices/pr95

- 3.htmlImazamox Registration Review Human

- Health Assessment Scoping Document

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Page 7 of 14 

### For the Main IDS (which contains incidents resulting in higher severity outcomes and provides more detail with regard to case specifics), there were no incidents reported for the single chemical ai ima zamox in the database from January 1, 200 9 t o January 15, 2014

. In Aggregate IDS (which contains incidents resulting in less severe human incidents (minor, unknown, or no effects outcomes)), there were no reported incidents involving imaz amox from January 1, 2009
to January 15, 201 4 . Overall, there are no incidents involving imaz amox reported to IDS. A query of SENSOR

- Pesticides from 1998

- 20 10 identifie d one single ai case involving imaz amox and no multiple ai case s involving imaz amox

. This case was low in severity. The low frequency and low severity of acute poisoning cases (also referred to as human inciden t data) reported for imazamox in both the IDS and SENSOR

- Pesticides does not trigger an EPA concern at this time. HED will continue to monitor the incid ent inf ormation
, and if the magnitude and frequency of reported acute poisoning events increases, then additional analysis will be performed.

Imazamox is not included in the A gricultural Heath Study (AHS)

. EPA will continue to monitor the literature for furthe r investigations on this topic.

Conclusions : Based on the low frequency and generally low severity of incident cases reported for imaz amox in both IDS and SENSOR

- Pesticides, there does not appear to be a concern at this time that would warrant further investigation. HED will continue to monitor the incident information and if a concern is triggered additional analysis will be conducted during Registration Review

.

9.0 Tolerance Assessment and International Harmonization

Tolerances are not established for residues of imazamox on food or feed commodities in the U.S. as imazamox is exempt from the requirement of a tolerance on all food commodities when applied as a herbicide in accordance with good agricultural practices. Canadian Maximum Res idue Limits (MRLs) are established for residues of imazamox in/on borage seeds, dry beans and peas, dry lentils, dry soybeans, sunflower seed, wheat, and poultry and ruminant commodities (see Attachment 4). The Canadian MRL expression includes residues of imaz a mox only. Mexico and Codex have not established MRLs for residues imazamox. HED concludes international harmonization is not an issue for imazamox.

10.0 Environmental Justice

Potential areas of environmental justice concerns, to the extent possi ble, were con sidered in the most recent imazamox human

- health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

Income Populations,” ( http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf ). The OPP typically considers the highest potential exposures from the legal use of a pesticide when conducting human

- health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., and people who may be exposed when harvesting crops. S hould these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best available information.

11.0 CumulativeImazamox Registration Review Human

- Health Assessment Scoping Document

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Page 8 of 14 

### 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 for imaz amox and any other substances; and imaz amox does not appear to produce a toxic metabolite produced by other substances. Fo r the purposes of this tolerance action, therefore, EPA has assumed that imaz amox does not have 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 mecha nism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

1 2 .0 Risk Assessment Updates and Data Deficiencies

There are no data deficiencies for imaz amox . Since it has been determined that no toxicological PODs will be selected for imaz amox for Registration Review and future actions; HED does not anticipate the need for conducting any quantitative exposure or risk assessments during Registration Review

.

13.0 References

Memoranda Relevant to Registration Review. Author Barcode Date Title

R. Cook D203639 12/09/94 PP4G4350. AC 299263 [2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl]

- 5

- methoxymethyl

- 3

- pyridine carboxylic acid, formulated as ammonium salt] for use on soybeans. EUP and temporary tolerance: Evaluation of Product Chemistry Data.

R. Cook D205708 3/28/95 PP4G4350. AC 299263 [2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1H

- imidazol

- 2

- yl]

- 5

- methoxymethyl

- 3

- pyridinecarboxylic acid, formulated as ammonium salt] for use on soybeans. EUP and temporary tolerance: Evaluation of Residue Chemistry Data.
R. Co ok D212351 02/27/95 Multiresidue Method (MRM) Validation Data For AC 299,263)

.
R. Cook D212349 03/02/95 PP4G4350

- AC 299,263 [(±)

- 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1H

- imidazol

- 2

- yl]

- 5

- methoxymethyl

- 3

- pyridinecarboxylic acid]

. D. McCall D222198 03/26/96 New Chemical Screen for AC 299.263 Toxicology and Chemistry Data Requirements.

R. Cook D224405 5/20/96 PP4G3350. AC 299,263 in soybeans. Review of Petition Method Validation (Confirmation) Report.

R. Cook D227228 0 7/ 0 3/96 PP4G4350. AC 299,263 in Soybeans. Review of Petition Method Validation Report

. R. Cook None 07/10/96 AC 299,263 . Issues to be presented to the HED Metabolism Committee.

R. Cook D225340 8/6/96 PP#6F4649. AC 299263 [2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1H

- imidazol

- 2

- yl]

- 5

- methoxymethyl

- 3

- pyridinecarboxylic acid, formulated as ammonium salt] for use on soybeans. Permanent Tolerance and Registration: Evaluation of Residue Chemistry Dat a. G. Tompkins D233731 03/12/97 Perform Occupational and Residential Exposure Assessment for New Herbicide

– AC299,263.

B. Madden D222186 05/09/97 Imazamox

– 129171: Health Effects Division Risk Characterization for Use of the New Chemical Imazamox in/o n Soybeans (6F4649).
W. Donovan D253305 02/19/99 Imazamox

- Chronic Dietary Exposure Analysis.

O. Odiott et al

. D252590,

D252608, D252613, D252631 02/26/99 ID#99CA0010. Section 18 Exemption for the Use of Imazamox on IMITM (Imidazolinone Tolerant) Canola to Control Wild Mustard in North Dakota and Minnesota ; and In Dry Beans to Control Nightshade Species in Wyoming and Montana.

W. Donovan D252590 02/26/99 ID# 99CA0010. Section 18 Exemption For The Use Of Imazamox On ImiTM (Imidazolinone Tolerant) Canola To Control Wild Mustard In North Dakota And Minnesota; And In Dry Beans To Control Nightshade Species In Wyoming And Montana.Imazamox Registration Review Human

- Health Assessment Scoping Document

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Page 9 of 14 Memoranda Relevant to Registration Review. Author Barcode Date Title

W. Donovan D253418 04/05/99 ID#UT990001. Section 24(c) Special Local Needs Registration. Imazamox in/on Alfalfa Grown for Seed. Determination of Food/Non

Food Use.

W. Donovan D274996 05/23/01 PP# 0F06088. Imazamox in/on Alfalfa, Canola, Legume Vegetables, and Wheat. Request f

or Petition Method Validation (PMV).

P.V. Shah HED Doc.

No. 014611 0 7/11/01 Imazamox

- Report of the Hazard Identification Assessment Review Commitee

W. Donovan D263875 07/26/01 PP# 0F06088. Imazamox use on Alfalfa, Canola, Legume Vegetables, and Wheat. Evaluation of Residue Data and Analytical Methods.

W. Donovan D276570 08/13/01 PP#0F06088. Imazamox in/on Alfalfa, Canola, Legume Vegetables, and Wheat. HED Risk Assessment.

W. Donovan D278055 09/27/01 PP# 0F06088. Addendum To “Imazamox In/On Alfalfa, Canola, Legume Vegetables, And Wheat. HED Risk Assessment, D276570, 13

- AUG

2001.”

W. Wassell D371544 03/05/10 Imazamox (129171); Registration No.: 241

- 437. Label Amendmen t For An Increase in Application Rate to Aquatic and Terrestrial Non

- crop Sites.
E. Evans et al. D417802 0 2/ 0 6/14 Imazamox : Tier I Review of Human Incidents

M. Perron TXR

0056929 3/ 18 /14 Imazamox: Summary of Hazard and Science Policy Council (HASPOC) Meeting of March 13, 2014: Recommendations on the requirement of a 28

- day inhalation study, neurotoxicity (acute and subchronic), and immunotoxicity studies

.


### Attachments:

Attachment 1: Imaz amox Id entity and Physicochemical Properties

. Attachment 2 : Imaz amox Acute, Subchronic, and Chronic Toxicity Profile

. Attachment 3 : Summary of Occupational and Residential Registered Uses

. Attachment 4 : Imaz amox International Residue Limit Status Sheet.

cc: L. Venkateshwara (RAB1 ), W. Wassell (RAB1), RDI: RAB1 ( 6 / 5 /14 ) , C. Smith ( 6 / 5 /1 4 ) L. Venkateshwara : S10956: PY

- S :( 703 ) 308

- 2722 :7509P:RAB1Imazamox Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ __________________________

Page 10 of 14 

### Attachment 1: Imaz amox Identity and Physicochemical Properties

.

C hemical Identity of Imazamox.

Nomenclature. Imaz amox Chemical structure

Common name Imaz amox IUPAC nomenclature 2

- [( RS )

- 4

- isopropyl

- 4

- methyl

- 5

- oxo

- 2

- imidazolin

- 2

- yl]

- 5

- methoxymethylnicotinic acid CAS nomenclature 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1H

- imidazol

- 2

- yl]

- 5

- (methoxymethyl)

- 3

- pyridinecarboxylic acid CAS registry number 114311

- 32

- 9



### Physical/Chemical Characteristics of Imazamox.

Physicochemical Properties of Imazamox. Parameter Value Reference Melting range 166.0

- 166.7 o C Memo, 12/09/94, R. Cook, D203639 pH 2.35; 1% aqueous suspension (w:v) at 24.5 ° C Density (g/mL) 0.423 g/mL tapped bulk density at 24.5 ° C 0.304 g/mL untapped bulk density at 24.5 ° C Water solubility (ppm) 4413 ppm ( deionized water at 20°C) 114,000 ppm ( pH 5 buffer ) >643,000 ppm ( pH 7 buffer ) >652,000 ppm ( pH 9 buffer ) Solvent solubility (g/100mL) h exane : 0.0006

m ethanol : 6.68

a cetonitrile : 1.85
t oluene : 0.21

a cetone : 2.93 dichloromethane : 14.3 ethyl acetate : 1.02 Vapor pressure <1.0 x 10

- 7 torr at 25 ° C Dissociation constant, pK a 2.3 and 3.3 at low to medium pH (0.5

- 6) and 10.8 at high pH (9

- 13) Octanol/water partition coefficient K ow = 5.36 at pH 5 and 6 and 25 C UV/visible absorption spectrum Not AvailableImazamox Registration Review Human

- Health Assessment Scoping Document

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Page 11 of 14 

### Attachment 2 : Imaz amox Acute, Subchronic, and Chronic Toxicity Profile

Acute Toxicity Profile

- Imaz amox Technical

. Guideline No. Study Type MRID # Results Toxicity Category

870.1100 Acute Oral 43193207 LD 50  5,000 mg/kg ( limit dose ) IV

870.1200 Acute Dermal 43193208 LD 50  4 ,000 mg/kg ( twice the limit dose ) III

870.1300 Acute Inhalation 43193209 LD 50  6.3 mg/L I V 870.2400 Primary Eye Irritation 43193210 Moderately irritating III 870.2500 Primary Skin Irritation 43193211 Not an irritant IV 870.2600 Dermal Sensitization 43193212 Not a skin sensitizer N/A

Subchronic, Chronic, or Other Toxicity Profile of Imaz amox . Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day oral toxicity rodents

- rat 43193219 ( 1992 )

Acceptable/guideline 0; 1,000 ; 10,000 ; or 20,000 ppm 0; 81 ; 833 ; or 1,661 mg/kg/day NOAEL = > 1,661 mg/kg/day (HDT). LOAEL = not observed.

870.3150 90

- Day oral toxicity nonrodents

- dog 43193220 ( 1994 )

Acceptable/guideline 0; 1,000 ; 10 ,000 ; or 40 ,000 ppm 0; 34 ; 329 ; or 1333 mg/kg/day NOAEL = > 1,333 mg/kg/day (HDT). LOAEL = not observed.

870.3200 2 8

- Day dermal toxicity

- ra t 43876213 ( 199 5 )

Acceptable/guideline 0; 2 50 ; 5 00 ; or 1000 mg/kg/day NOAEL = > 1
, 0 00 mg/kg/day (HDT). LOAEL = not observed.

870.3700a Prenatal developmental in rodents

- rat 43193221 ( 1994 )

Acceptable/guideline 0 ; 100 ; 500 ; or 1000 mg/kg/day Maternal : NOAEL= >1,000 mg/kg/day (HDT)

. LOAEL = not observed.

Developmental : NOAEL = >1,000 mg/kg/day (HDT). LOAEL = not observed.

870.3700b Prenatal developmental in nonrodents

- rabbit 43876216 ( 199 5 )

Acceptable/guideline 0 ; 300 ; 600 ; or 900 mg/kg/day Maternal : NOAEL = >9 00 mg/kg/day (HDT)

. LOAEL = not observed.

Developmental : NOAEL = >900 mg/kg/day (HDT). LOAEL = not observed.

870.3800 Reproduction and fertility effects

- rat 43876217 ( 199 5 )

Acceptable/guideline 0 ; 1,000 ; 10 ,000 ; or 2 0,000 ppm 73 ; 748 ; or 1469 mg/kg/day for males and 88 ; 892 ; or 1705 mg/kg/day for females Parental/Systemic NOAEL = >1
, 705 mg/kg/day (HDT). LOAEL = not observed.

Reproductive NOAEL = >1
, 705 mg/kg/day (HDT). LOAEL = not observed.

Offspring NOAEL = >1
, 705 mg/kg/day (HDT). LOAEL = not observed.

870.4100b Chronic toxicity

- dog 43876214 ( 199 5 )

Ac ceptable/guideline 0 ; 1,000; 10,000 ; or 4 0,000 ppm 0 ; 9.5 ; 282.5 ; or 1165 mg/kg/day NOAEL = 1, 165 mg/kg/day (HDT). LOAEL = not observed.

870.4300 Chronic/ Carcinogenicity

- rat 43891001 ( 199 5 )

Acceptable/guideline 0 ; 1,000 ; 10,000 ; or 20,000 ppm 0; 52 ; 528 ; or 1,068 mg/kg/day NOAEL = 1,068 mg/kg/day (HDT). LOAEL = not observed. No evidence of carcinogenicity at doses tested.Imazamox Registration Review Human

- Health Assessment Scoping Document

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Page 12 of 14 Subchronic, Chronic, or Other Toxicity Profile of Imaz amox . Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.4300 Carcinogenicity

mouse 43876215 ( 19 9 5 )

Acceptable/guideline 0 ; 500 ; 3,500 ; or 7,000 ppm 73 ; 535 ; or 1,053 mg/kg/day for males and 96 ; 664 ; or 1,348 mg/kg/day for females NOAEL = 1,348 mg/kg/day (HDT, females). No evidence of carcinogenicity at doses tested.

870.5100 Gene Mutation 43193222 ( 1994 )

Acceptable/guideline 0 ; 100 ; 500 ; 1
, 000 ; 2
, 500 ; or 5,0 00 μg/plate Non

- mutagenic when tested up to 5
, 000 ug/plate, in presence and absence of metabolic activation, in S. typhimurium strains A1535 , TA1538, TA98
, TA100 and E.coli strain WP2uvra.

870.5300 Gene Mutation 43193223 ( 1993 )

Acceptable/guideline 50 ; 100 ; 500 ; 1
, 000 ; 2
, 000 ; or 4
, 000 μg/mL There was no indication that imazamox, tested up to insoluble levels, induced a mutagenic response in the presence or absence of S9 activation.

870.5375 Chromosome aberration 43193224 ( 1993 )

Acceptable/guideline 1
, 250 ; 2
, 500 ; or 5000 mg/kg Non mutagenic; no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow cells were seen

.

870.5375 Chromosome aberration 4319322 5 ( 1994 )

Acceptable/guideline 833 ; 1
, 667 ; or 3
, 333 μg/mL both in the presence of Aroclor 1254

- induced rat liver activation No indication that imazamox, tested up to insoluble levels, induced a clastogenic response in the presence or absence of S9 activation.

870.7485 Metabolism and pharmacokinetics

– rat 438 76218 ( 199 5 )

single intravenous dose at 10 mg/kg body weight or orally by gavage as a single dose at 10 or 1,000 mg/kg or as a single oral dose at 10 mg/kg following a 14

- day pretreatment with unlabeled imazamox at 10 mg/kg [ 14 C]AC 299,263 was readily absorbed by male and female rats following intravenous or oral dosing; >73% of the administered dose was excreted in the urine within 24 hours of dosing. Pretreatment and dose level had little effect on the proportion of dose eliminated in urine from the oral dose groups. The rate of urinary excretion for the low and high oral dose groups was lower (74.0

- 82.0%) than the intravenous groups (84.5

- 91.2%), suggesting a lack of complete absorption of the test substance. Within 168 hours of dosing at 10 mg/kg (with or without pretreatment) or 1,000 mg/kg, 88.0

- 99.3% of the administered dose was recovered from both sexes, of which 74.0

- 91.2% was in the urine. Fecal excretion comprised 1.9

- 2.7% of the administered dose in the intravenous groups, compared to 12.2

- 24.2% in all oral dose groups. Organic volatiles were not expected to form (not measured). Total [ 14 C]AC 299,263 equivalents in tissues accounted for < 0.007% of the actual administered dose for all treatment groups.Imazamox Registration Review Human

- Health Assessment Scoping Document

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Page 13 of 14 

### Attachment 3 : Summary of Occupational and Residential Registered Uses

Registration Number and Product Name Crop/Use Site Formulation and Percent Active Ingredient Application

method Maximum

App Rate (lb ai/A) REI

241

- 378 Imazamox Herbicide Technical Alfalfa, chicory,

CLEARFIELD ® canola, CLEARFIELD ® rice, CLEARFIELD ®

, sunflowers, CLAERFIELD ® wheat, clover grown for seed, edible legumes and soybeans 97.4 % N/A N/A N/A

241

- 379 Raptor ® Herbicide Alfalfa, beans (dry), chicory, clover grown for seed, edamame, lima bean (succulent), Peas (dry), pea (English), snap bean and soybean Liquid
,

12.1% aerial,

ground, (no chemigation) 0.047 lb ae/A 4 hours

241

- 380 RAPTOR ® TM DG Herbicide Soybeans WSP 70% aerial,

ground, (no chemigation) 0.91 lb ai/A 4 hours

241

- 437 CLEARCAST ® Herbicide Control of

vegetation in and around aquatic and noncropland sites including areas that may be grazed or cut for hay Liquid

12.1% aerial,

ground, (no chemigation) Not specified Not specified

241

- 439 CLEARCAST ® 2.7G Herbicide Control of

vegetation in aquatic sites Granular

2.7% aerial and

drawdown application Not specified Not specified

241

- 441 Beyond ® Clearfield ® Production System Herbicide For use only on

Clearfield ® canola, Clearfield lentil, Clearfield rice, Clearfield and Clearfield ® Plus sunflower, and Clearfield and Clearfield ® Plus Wheat Liquid

12.1% aerial,

ground, (no chemigation) 0.062 lb ae/A 4 hours

7969

- 238 CLEARMAX ® Clearfield ® wheat Liquid 12.1% aerial,

ground, (no chemigation) Not Specified 12 hoursImazamox Registration Review Human

- Health Assessment Scoping Document

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Page 14 of 14 

### Attachment 4 : Imaz amox International Residue Limit Status Sheet

.



## International Residue Limits Imazamox (PC Code; 02/26/14 ) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 

### Codex 

### 40 CFR 180.1223 exemption from the requirement of a tolerance.

The herbicide imazamox, (±) 2,

- [4,5

- dihydro

4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1H

imidazol

- 2

- yl]

- 5

- (methoxymethyl)

- 3

- pyridinecarboxylic acid, is exempt from the requirement of a tolerance on all food commoditie s when applied as a herbicide in accordance with good agricultural practices. 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl]

- 5

- (methoxymethyl)

- 3

- pyridinecarboxylic acid None



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

US Canada Mexico 1 

### Codex 0.05 Borage seeds, cuphea seeds, echium seeds, flaxseeds, gold of pleasure seeds, hare's ear mustard seeds, milkweed seeds, mustard seeds (oil seed type), oil radish seeds, poppy seeds, rapeseeds (canola), sesame seeds, sweet rocket seeds 0.05 Dry (adzuki beans, beans, blackeyed peas, broad beans, catjang seeds, chickpeas, cowpea seed, guar seeds, kidney beans, lablab beans, lentils, lima beans, moth beans, mu ng beans, navy beans, pink beans, pinto beans, rice beans, southern peas, tepary beans, urd bea ns); grain lupin

0.25 dry lentils

0.1 Dry soybeans 0.01 Eggs 0.05 fenugreek seeds 0.01 Meat byproducts of (cattle, goats, horses, poultry, sheep) 0.01 Meat of (cattle, goats, horses, poultry, sheep) 0.01 Milk 0.05 Peas 0 .3 sunflower seeds 0.05 wheat Completed: M. Negussie; 02/2 7 /14

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