UN ITE D STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

MEMORANDUM



### Date: June 6

, 2014 OF F I CE OF
CHEMICAL S A FETY AND
POLLU TION PREVENTION



### SUB J ECT: 

### Imazaquin. Human Health Ri sk Assessment Scoping Document in S upport of Registration R ev i e w.

PC Codes: 128848 (imazaquin), DP Barcode: 418729

128840 (ammonium salt of imazaquin)

Decision No. : 488888 Registration Nos.: NA

Petition No.: NA Regulatory Action: Re gist rati o n R ev iew

Case No.: 72 0 4 Risk Assessment Type Sco ping Do c ument

TXRNo.: NA CAS No. : 81335-37- 7 ; 81335-47-9

MRIDNo.: NA 40 CFR: § I 80.426



### FROM: Danette Drew

, Chemist
Seyed Taday o n
, Chemist**~** 

### , , John Liccion e
, Ph.D.

, Toxico o gist**~** 

### Risk Assessmen t Branches V and I

Health Effects Division (7 509P )



### THRU: MichaelS. Metzger, Branch Chie f 

# t J

# ~ 

# J A

Risk Assessment Branches 

# v and 

# vr D

·'\ v..{;.-

Health Effects Division (7509P)

TO: Wilhelmena Livingston, Chemical Revi ew Manager

Risk Management and Implementation Branch 4

Pesticide Re-evaluation Di v ision (7508 P)

Attached is the Health Effects Division 's (HED) human health risk asses sme nt s coping documen t

for imazaquin in support of the registration review proce ss.

Page 1 

### of22

### Page 2 of 22

E XECUTIVE 

### S U MMARY



### HED has evaluated the available data and the most recent human health risk assessments for imazaquin to determine the scope of work necessary to support the registration review process. HED has considered the currently labeled use patterns

, as well as the available toxicity and exposure information

. The most recent HED human health risk assessment for imazaquin was completed in October 2005 ( S. Stanton, 10/31/2005, D302939

, Imazaquin and its Salts: HED Chapter of the Tolerance Reassessment Eligibility Decision (TRED) Document ) for inclusion in the Report of the Food Quality Protection Act (FQPA) Tolerance Reassessment Progress and Risk Management Decision (TRED) for Imazaquin which was issued in December 2005

.

Imazaquin (i mazaquin [±

- 2

- (4,5

- Dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1H

- imidazol

- 2

- yl)

- 3

- quinolinecarboxylic acid] is an imidazolinone herbicide which controls weeds by inhibiting the synthesis of specific amino acids (valine, leucine and isoleucine) necessary f or plant growth. Imazaquin is formulated as an acid or ammonium salt

. It is registered as a pre

- plant, pre

emergence and early post

- emergenc e herbicide for use on soybeans . It is also registered for pre

and post

- emergence weed control on ornamentals and warm season turfgrass in both residential (lawns) and non

- residential (golf courses) settings

.

The toxicology database for imazaquin is complete. The studies t hat are required in accordance with the 2007 revised 40CFR Part 158 Toxicology Data requiremen ts for subchronic inhalation

, acute neurotoxicity ( ACN ), subchronic neurotoxicity (SCN) and immunotoxicity ha ve not been submitted for imazaquin. However, HED’s Hazard and Science Policy Council (HASPOC ; TXR

0056978 ; 5/22/14 ) has determined that, based on a weight of evidence ( WOE) approach considering all the available hazard and exposure information for imazaquin and other

imidazolinone chemicals

, those studies may be waived for imazaquin.

The toxicology studies with imazaquin indicate that the m ost co mm only observed clinical sign in

the chronic studies (mice and dogs) was decreased body weight

. The toxicity point of departure

selected for chronic dietary oral, short

- term incidental oral, and short

- term and intermediate

- term
dermal and inhalation exposures was based on weight loss, slight ane m ia, evidence of skeletal

m uscle m yopathy and supporting he m atology and clinical che m istry differences seen in the chronic dog study

. There was no endpoint attributable to a single dose

, so an acute point of departure was

not determined

. There was no evidence of neurotoxicity, carcinogenicity, genotoxicity, or mutagenicity. There was no qualitative or quantitative susceptibility of th e developing fetus or offspring

, based on results from the developmental and reproductive toxicity studies. B ased on the completeness of the database, the lack of susceptibility, the lack of neurotoxicity, and the conservative nature of the exposure assessment, HED previously recommended that the required

10x Food Quality Protection Act (FQPA) Safety Factor be reduced to 1x.

The residue chemistry database for imazaquin is complete

, and no additional data are needed. The

residue of concern (in plants and livestock) for tolerance enforcement and risk assessment is parent compound (imazaquin)

. The residue of concern for ground water based drinking water is imazaquin

, and for surface water based drinking water is imazaquin plus its photolytic degradates.

A tolerance has been established under 40 CFR §180.426 for r esidues of i m azaquin in soybean

.

### Page 3 of 22

The current tolerance expression should be updated to comply with HED’s current policy on tolerance expressions. There are currently no international maximum residue limits (MRLs) for imazaquin

, so there are no harmonization issues with Codex, Canada, or Mexico.

The dietary exposure database is adequate. The previous chronic dietary assessment was very conservative (100% crop treated, tolerance level residues, and drinking water concentrations based

on high

- end modeling) and did not result in risk estimates of concern ( dietary risk estimates were

less than 1% of the c PAD). At this time, a revised dietary risk assessment is not anticipated for imazaquin

, provided there are no significant changes to the toxicological points of departure and uncertainty factors and there are no significant changes to EPA’s Environmental Fate and Effect Division’s ( EFED’s ) esti m ated drinking water concentration s (EDWCs)

. EFED has indicated that they will be updating the drinking water assessment under registration review.

There were no residential handler or post

- application risk estimates of concern identified in the

2005 assessments for the home turf use, nor were ther e ris k estimates of concern for the post

application exposures to treated golf courses. A revised residential exposure assessment using the

2012 Residential SOPs will be needed during registration review

. Any revisions to toxicological PODs or uncertainty factors will be incorporated. EPA is now requiring chemical specific TTR

data for imazaquin, s ince the screening estimate for residential turf post

- application exposure using

the 2012 SOPs and default turf transferable residue ( TTR ) values for imazaquin is not minimal in comparison to the level of concern ( i. e.
, MOE is 130 compared to 1000 (ten times the level of concern) for children’s activities on treated turf)

. The required chemical specific TTR will also be

considered for the revised post

- a pplication assessment.

In the 2005 risk assessment, HED provided chronic aggregate risk estimates for combined dietary ( food and drinking water ) exposures and short

- term aggregate risk estimates f rom dietary and residential exposures combined . The aggregate risk s were below HED’s level of concern

. Revised aggregate risk assessments will be performed for imazaquin if there are any significant changes to toxicological PODs or uncertainty factors, if there are significant changes to residential exposu res and risk estimates (using the 2012 updated SOPs and any new TTR data )

, or if there are significant changes to EFED’s EDWCs.

The occupational exposure database is adequate. An occupational exposure assessment was not performed for the 2005 imazaquin TRED. A screening assessment using current SOPs did not

result in risk estimates of concern for handlers and post

- application workers. O ccupational handler and post

- application exposure assessments will be performed under registration review using

current policies . Any changes to the toxicological PODs or uncertainty factors will also be incorporated.

Introduction

Imazaquin [±

- 2

- (4,5

- Dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1H

- imidazol

- 2

- yl)

- 3

- quinolinecarboxylic acid] is a broad spectrum, pre

- plant, preemergence or postemergence herbicide belonging to the imidazolinone class of pesticides. Imazaquin is currently formulated as

an acid or ammonium salt ; there are no current registrations for the sodium salt formulation.

### Page 4 of 22

Imazaquin is registered for food use on soybeans, as well as non

- food use on warm season turfgrass and ornamentals in both residential and non

- residential settings (including golf courses). Applications in residential settings may be made by both commercial applicators and homeowners.

The registered imazaquin formulation types include water dispersible granule (WDG), wettable powder (WP), emulsifiable concentrate (EC) and soluble concentrate (SC).

The nomenclature and physiochemical properties of imazaquin can be found in A ttachment 1.

Hazard Identification/Toxicology

The toxicology database for imazaquin is considered complete and includes the following studies : 21

- day dermal toxicity study in the rabbit, subchronic oral toxicity in the rat, chronic oral toxicity in the dog, chronic t oxicity/carcinogenicity in the rat, carcinogenicity in the mouse, prenatal developmental toxicity in the rat and rabbit, reproductive toxicity in the rat and rabbit , metabolism

in the rat and a special thyroid study in the rat

. In addition, there is a complete battery of genotoxicity studies.

The subchronic inhalation study, acute neurotoxicity study (ACN), sub chronic neurotoxicity study ( SCN), and immunotoxicity study, now required in accordance with new data requirements for conventional pesticide registration (40 CFR Part 158), have not been submitted for imazaquin

. HED’s Hazard and Science Policy Council (HASPOC ; TXR 0056978 ) recently met ( 5/22/14 ) and determined that, based on a weight of evidence ( WOE) approach consideri ng all the available hazard and exposure information for imazaquin and other imidazolinone chemicals

, those studies

are may be waived and that the use of the current oral study POD is protective for assessing

exposures to imazaquin.

Overall, i m azaquin causes subchronic and chronic toxicity at relatively high doses, with few clinical signs identified in rats, m ice, dogs or rabbits. Toxicity was si m ilar in both m ale and fe m ale test
ani m als, with the dog being the m ost sensitive species to i m azaquin exposure. The m ost co mm only

observed clinical sign in the chronic studies was decreased body weight, which was seen in both

m i ce and dogs. In the chronic dog study, additional effects were noted at the LOAEL of 125

m g/kg/day, including slight ane m ia indicated by changes in he m atology para m eters, changes to
clinical che m istry and skeletal m uscle m yopathy at necropsy in both sexes. No effects were observed at the highest dose tested (500 m g/kg/day) in the rat co m bined chronic toxicity/ carcinogenicity study; nor were syste m ic effects seen at the highest dose tested (1000 m g/kg/day) in

the rabbit 21

- day der m al toxicity study.

The imazaquin database is considered adequate to characterize any potential pre

- and/or post

- natal

risk to infants and children. In the developmental study in rats, treatment

- related effects on fetal body weight and reduced ossification were observed, but only at the dose where maternal toxicity

occurred. No treatment

- related effects on fetuses were seen in the rabbit developmental toxicity study; and no toxicity in either the parents or offspring was noted at the highest dose tested in the rat reproductive study . Based on these studies, there is no indication of increased susceptibility of fetuses or offspring to imazaquin. Since there is no increased risk to infants and children and no

### Page 5 of 22

residual uncertainty in either the hazard or exposure assessments , the FQPA Safety Factor has been

reduced to 1X.

No evidence of neurotoxicity was observed in any of the available stud ies.

No evi dence of carcinogenicity was seen in m ice or rats, and i m azaquin was non

- m utagenic in

available m utagenicity tests. Mice were dosed up to 600 m g/kg/day for 18 m onths, and rats were fed up to 500 m g/kg/day for 2 years without any evidence of a treat m ent

- related increased

incidence of tu m ors. I m azaquin was non

- m utagenic in the A m es test and de m onstrated negative responses in the in vitro cell transfor m ation assay, a cytogenetics study with HGPRT in Chinese

ha m ster cells and an unscheduled DNA synthesis assay.

Technical i m azaquin has low (category III/IV) acute toxicity via the oral, der m al and inhalation

routes of exposure. It is non

- irritating to the eye (category IV) and only m ildly irritating to the skin.

I m azaquin did not cause der m al sensitization in the guinea pig.

Based on the use patterns and the submitted toxicology studies, HED previously selected endpoints for assessment of human health risk for chronic dietary exposure, residential incidental oral exposure, and occupational and residential inhalation and dermal exposure s

. For acute dietary exposure, an endpoint resulting from a single ex posure was not identified. As a result, an acute reference dose ( aRfD ) was not determined

. A chronic reference dose (cRfD) of 0.25 m g/kg/day

was established for i m azaquin, based on the NOAEL of 25 m g/kg/day in the dog chronic toxicity study and an uncert ainty factor of 100 (10x for interspecies extrapolation and 10x for intraspecies variation). Effects seen at the LOAEL included body weight loss, clinical che m istry/he m atology differences, slight ane m ia and skeletal m uscle m yopathy. Body weight decreases occurred in the

first 4 weeks of the study; and the he m atology data from the earliest assess m ent at 13 weeks

indicated statistically significant changes in he m atology para m eters, raising concern that the ane m ia

effects of i m azaquin m ay occur within a short or inter m ediate ti m e fra m e. Therefore, the NOAEL

of 25 m g/kg/d a y from this oral study was also selected to assess incidental oral, der m al and inhalation exposures of short

- , inter m ediate

- and long

- term duration

. Although there was no toxic

effect of concern demonstrated in the rabbit 21

- day dermal study at the limit dose (1000 mg/kg/day), and there are no indications of developmental or reproductive toxicity or neurotoxicity, a dermal endpoint has been selected for imazaquin because effects noted in the chronic dog study suggest that the dog may be more sensitive to imazaquin than the rabbit, especially with regard to the induction of anemia. In the last risk assessment, a 50% dermal absorption factor was used based on comparison of the NOAE L of 1000 mg/kg/day from the rabbit

21

- day dermal toxicity study ( n o LOAEL) with the maternal LOAEL of 500 mg/kg/day for body weight effects in the rabbit oral prenatal developmental toxicity study.

See Attachment 2 for Toxicity Profile Tables and Attachm ent 3 for Toxicity Doses and Endpoint s Selection Table.

C onclusions: The toxicology database for imazaquin is complete. HED’s Hazard and Science Policy Council (HASPOC; TXR 0056978 ; 5/22/14) has determined that, based on a weight of

evidence approach considering all the available hazard and exposure information for imazaquin

### Page 6 of 22

and other imidazolinone chemicals

, the requirements for subchronic inhalation , acute neurotoxicity (ACN), subchronic neurotoxicity (SCN) and immunotoxicity studies may be waived

. H ED will re

evaluate the toxicity endpoints, points of departure (PoDs) and uncertainty and other factors during registration review.

Residue Chemistry and Dietary Exposure

Residue Chemistry

The residue of concern for tolerance enforcement and risk assessment (plants and livestock) is the parent compound

, imazaquin. A tolerance has been established under 40 CFR §180.426 for

residues of i m azaquin in or on the raw commodity soybean at 0.05 pp m (method LOQ) . There are

no tolerances for residues of imazaquin on other livestock feed commodities of soybean

, as there

are enforceable grazing restrictions on the labels. Available dat a indicate that a Category 3 situation ( 40 CFR 180.6(a)3 “ no reasonable expectatio n of finite residues ”) exists with respect to

residues of imazaquin in meat, meat by

- products ( mbyp ), fat, and milk of cattle, goats, hogs, horses, and sheep ; and in poultry meat , fat, mbyp, and eggs . T here are currently no tolerances for imazaquin in live stock commodities. Existing analytical methods are considered adequate for both data collection and enforcement purposes.

The residue chemistry database for imazaquin is complete . The 2005 TRED identified t he following two residue data requirements : provide storage durations for the soybean field trials (860. 1380) , and submit multi

- residue testing data for imazaquin (860.1360) . The soybean storage
durations and multi

- residue testing data have since been submitted and reviewed (D. Soderberg,
3/17/08, D 346848, D346852; Imazaquin: BASF response to two data gaps noted in the TRED

- Determination of UV/Vis Absorption Spectra; and storage stability information regarding soybean field trials

, and P.Savoia, 3/17/10, D370270 , Imazaquin. Screening of Imazaquin through Food and Drug Administration (FD A) Multi

- Residue Method Testing). The data requirements identified

in the imazaquin TRED have been adequately fulfilled.

Dietary Exposure

C hronic dietary (food and drinking water) exposure assessments were previously conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database

DEEM

- FCID ( D302943, Susan Stanton, 10/20/05)

. No acute dietary endpoint was identified for

i m azaquin ; therefore, an acute dietary exposure as sessment was not necessary. T he food assumptions included that 100% of the soybean crop is treated and that residues of i m azaquin are present at the tolerance level of 0.05 ppm in all soybean food co mm odities

.

For water, EFED had provided a drinking water assessment ( Drinking Water Assessment for Imazaquin and its Salts ; K. Moore; June 21, 2005, as amended on September 27, 2005). A queous photolysis is the only significant degradation pathway for imazaquin and leads to four majo r degradates greater than 10% of the applied amount of imazaquin ( 3

- quinolinecarboxylic acid; 2,3 quinolinedicarboxylic acid imide; 2,3 dihydro

- 3

- imino

- 1H

- pyrrolo

- [3,4

- b]quinoline

- 1

- one ; and 2,3 quinolinedicarboxylic acid). These degradates are expected t o form in surface water only. They are not expected to form in groundwater, since the parent compound is not exposed to light and aqueous photolysis does not occur.

### Page 7 of 22

HED ha d determined that the surface water degradates of imazaquin have the potential to be toxicologically equivalent to the parent compound; therefore, the residues of concern for risk assessment purposes in surface water include imazaquin and the following photolytic degradates:

3

- quinolinecarboxylic acid; 2,3 quinolinedicarboxylic acid imi de; 2,3 dihydro

- 3

- imino

- 1H

- pyrrolo

- [3,4

- b]quinoline

- 1

- one ; and 2,3 quinoline dicarboxylic acid. The residue of concern in ground

water is parent only.

Drinking water was incorporated directly into the dietary assess m ent using the tier 1 esti m ated drinking water concentration (EDWC) for ground water generated by the SCI

- GROW m odel (turf application scenario). The SCI

- GROW groundwater esti m ate was selected for risk assess m ent purposes, because this esti m ate of i m azaquin only was higher than the PRZM

- EXAMS m odel

esti m ates of i m azaquin and its photolytic degradates in surface water.

All dietary (food and water) risk estimates were less than 1% of the chronic population

- adjusted

dose (cPAD) and were well below HED’s level of concern.

Conclusions: The i m azaquin residue chemistry database is complete a nd no new data are required. The p revious (2005) dietary assessment included all registered food uses and w as very conservative (100% crop treated, tolerance level residues, and drinking water concentrations based

on high

- end modeling) and did not result in risk estimates of concern ( dietary risk estimates were

less than 1% of the c PAD). At this time, a revised dietary risk assessment is not anticipated for imazaquin provided there are no changes to the toxico logical points of departure and uncertainty or other factors, and there are no significant changes to EFED’s esti m ated drinking water
concentration s (EFED has indicated they will be updating the drinking water assessment under registration review)

.

Residential (Non

- Occupational) Exposure

I m azaquin residential uses which may result in handler or post

- application exposures include the

use on lawns and recreational turf , such as golf courses

.

Residential Handler

B ecause imazaquin is not a restricted

- use product (RUP) and a homeowner could potentially apply it in a residential setting

, HED previously conducted a residential handler exposure assessment for

home lawn uses (S.Tadayon

, D302942 , 10/ 6/2005

, Imazaquin: Residential Exposure Assessment

and Recommendations for the Tolerance Reassessment Eligibility Decision (TRED) ). This handler

exposure assessment was conducted using Health Effects Division Science Advisory Committee Policy 12: Recommended Revisions to The Standard Operating Procedures f or R esidential Exposure Assessment ( 2001 )

. T he short

- term dermal and inhalation MOEs for handlers were much greater than the level of concern of 100 ( MOEs ranged from 1,700 to 11,000) and were not of risk

concern. HED’s R esidential SOPs were revised in 2012. A residential handler exposur e assessment using the revised r esidential SOPs will be performed during registration review

. Revising the handler assessment using the updated SOP s is not expected to have a significant impact on the

### Page 8 of 22

previously calculated MOEs but will reflect more accurate exposure assumptions including updated body weights.

Residential Post

-

Application

R esidential post

- application ( dermal and incidental oral exposure) risk assessment s w ere previously conducted for children entering imazaquin

- treated lawns . For adults, dermal exposures were assessed for lawn activities including turf mowing and for golfing (D302942

, 10/6/2005 ). All

of the short

- term MOEs for these exposures were greater than 100 (MOEs ranged from 260 to 1,000,000) , an d were not of risk concern. The se assessments used the 2001 Residential SOPs. A

revised residential post

- application exposur e assessment using the updated 2012 R esidential SOPs

will be needed during registration review

.

Turf Transferable Residue: In accordance with the updated Part 158 data requirements (2007), a TTR study is required for occupational (e.g., sod farms, golf courses, parks, and recreational areas) or residential turf uses. As part of the recent revision to the Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment , HED analyzed all available data and selected new liquid and granular default values for the fraction of the application rate available for transfer after a turf ap plication (F AR 

### ). 1 

### These defaults are 1% for formulations applied as liquids (i.e., emulsifiable concentrates, liquids, wettable powders, dry flowables, etc.) and 0.2% for granular formulations. Of the available TTR studies submitted to the Agency, the

ma ximum F AR 

### value seen using a liquid product was 6.1% or 6.1 times higher than the default

residue transfer value. The maximum F AR 

### value seen in a TTR study using a granular product was 0.69% or 3.5X the default residue transfer value. Therefore, for both liquid and granular formulations, a calculated MOE of approximately 10 times higher than the level of concern (e.g., an MOE > 1,000 if the LOC = 100) using the default residue transfer values would provide an adequate margin of safety for any potentially hig her residues seen in a chemical specific TTR study ( Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies

. 12/12 /2012, Exposure Science Advisory Council). TTR data are not available for i m azaquin

. HED has, for the purposes of this scoping exercise, completed screening level risk estimates based on the default TTR values. For the current uses of imazaquin , a chemical specific TTR study will be required for r egistration r eview since estimated MOEs f or at
least one reside ntial post

- application scenario is less than 1000 (i.e. screening dermal MOEs for activity on treated turf/lawns is 130 for children and 270 for adults ). See Attachment 4.

Spray Drift Residential exposures resulting from off

- site transport (e.g., spray drift or volatilization) might occur as a result of applications of i m azaquin . The Agency is in the process of evaluating these types of exposures and might, as appropriate, develop poli cies and procedures to identify the need for and, subsequently, the way to incorporate these post

- application exposures into the Agency’s

risk assessments.

The residential turf post

- application assessment for imazaquin will provide a worst case estimate of potential exposure from spray drift. As th e turf use rate is equal to or higher than agricultural

1 http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

### Page 9 of 22

application rates for imazaquin , this scenario is protective of any exposure of children via spray drift from agricultural imazaquin applications. The ne ed for volatilization risk assessment for

i m azaquin will be examined during registration review.

Conclusions: There were no residential handler or post

- application risks of concern identified in the 2005 imazaquin TRED. A revised residential exposure assessment using the 2012 Residential

SOPs will be needed during registration review

. Any revisions to toxicological PODs or uncertainty factors will be incorporated. Since the estimated residential turf post

- application

dermal exposure using default turf transferable residue ( TTR ) values for imazaquin is not minimal

in comparison to the level of concern ( i. e.
, MOE is 130 compared to 1000 (ten times the level of concern) for children’s activities on treated turf)

, EPA is now requiring TTR data for imazaquin

. The required chemical specific TTR will also be considered for the post

- application assessment.

Aggregate Risk Assessment

In the 2005 risk assessment, HED provided chronic aggregate risk estimates for combine d food

and drinking water exposures ; and short

- term aggregate risk estimates from food, drinking water and residential (turf use) exposures combined. The short

- term aggregate assessments included combining chronic exposure from drinking water with short

- te rm incidental oral ingestion exposure in infant and children; and chronic exposure from drinking water with short

- term inhalation exposure of adult residential handlers. The aggregate risk estimates were below HED’s

level of concern.

Conclusions: The 2005 aggregate (food, water, and residential exposures ) risk estimates were not

of concern. Revised aggregate risk assessments will be performed for imazaquin if there are any changes to toxicological PODs or uncertainty factors, or if there are significa nt changes to the

revised residential exposures (using the 2012 updated SOPs), or if there are significant changes to

EFED’s EDWCs.

Occupational Exposure

An occu pational exposure risk assessment was not performed for the 2005 imazaquin TRED.

HED has , fo r the purpose of this scoping exercise, conducted a screening level quantitative

o ccupational exposure assessment for the soybean and turf uses (Attachment 5). There are no

i m azaquin specific data available for assessing occupational exposure and risk associated with registered products containing i m azaquin . In the absence of chemical

- specific data, HED has

relied on information in the studies from Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database ; the ARTF database; or the Outdoor Residential Exposure Task Force (ORETF) database and standard assumptions with respect to the area treated and surrogate unit exposure data

.

Occupational Handler All occupational handler scenarios for the soybean use resulted in com bined dermal and inhalation

MOEs that do not exceed HED's level of concern ( MOEs ≥ 100) for short

- term (ST) and

### Page 10 of 22

intermediate

- term (IT) exposure durations at label specified personal protective equipment ( PPE ).

Th e soybean scenario combined MOEs ranged from 110 to 15,000

, and the turf scenario combined MOEs ranged from 370 to 310,000 ( Attachment 5 )

.

Occupational Post

-

Application

Occupational post

- applicat ion dermal exposure to imazaquin is possible for workers entering

treated fields. HED ’s screening level post

- application assessment resulted in dermal MOEs ranging

from 880 to 14,000

, which do not exceed HED's level of concern (MOEs ≥ 100)

.

Based on the occupational screening estimates, t he current label restricted entry interval (REI) of 12 hours is appropriate and in compliance Worker Protection Standard requirements.

Conclusions: The occupational exposure database is adequate to support registration review of imazaquin. An occupational exposure assessment was not performed for the 2005 imazaquin TRED. A screening assessment using current SOPs did not result in risk estimates of concern.

O ccupational handler and post

- application exposure assessments w ill be performed under registration review using current policies . Any changes to the toxicological PODs or uncertainty

factors will also be incorporated.

Public Health and Pesticide Epidemiology Data

HED used OPP’s 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 to determi ne the number and severity of incidents that resulted from imazaquin exposure ( S. Recore, D4 20257, 5/15/14, Imazaquin : Tier I Review of Human Incidents ). For the Main IDS, from January 1, 2009 to March 5, 2014, there were 0 incidents reported involving ima zaquin in the database. In Aggregate IDS, from January 1, 2009 to March 5, 2014, there was 1 incident reported involving imazaquin in the database . This incident was classified as minor severity. The SENSOR

- Pesticides

1998

- 2010 query identified 0 cases inv olving imazaquin. Imazaquin is not included in the Agricultural Health Study ( AHS ) ; therefore

, this study does not provide information for this report.

There does not appear to be a concern at this time that would warrant further investigation, since

t he re was a low frequency of incidents involving imazaquin reported to IDS and SENSOR

Pesticides. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk assessment.

Tolerance Assessment and International Harmonization

Currently, the U.S. tolerance definition for imazaquin is expressed as “ residues of the herbicide 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl]

- 3

- quinoline carboxylic acid.”

The defi nition should be modified to read as follows (as per S. Knizner, 2009

, Interim Guidance on Tolerance Expressions ) :

### Page 11 of 22

Tolerances are established for residues of the herbicide imazaquin, including its metabolites and degradates, in or on the commodities in th e table below. Compliance with the tolerance levels specified below is to be determined by measuring only imazaquin (2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl]

- 3

- quinoline carboxylic acid).

There are currently no international maxim um residue limits (MRLs) for imazaquin ; therefore, there are no harmonization issues with Codex, Canada, or Mexico. See Attachment 6

, International

Maximum Re sidue L imits T able.

International or Intergovernmental Work Sharing

There is no current or forecasted work sharing efforts with other entities (e.g. California, Canada, EU, and OECD) for imazaquin.

Cumulative Risk Assessment

The Food Quality Protection Act (FQPA) requires the Agency to consider the cumulative risks of

ch emicals sharing a common mechanism of toxicity. EPA has not made a determin ation of

whether i m azaquin has a common mechanism of toxicity with other substances

. Therefore, a cumulative risk assessment has not been performed for i m azaquin

.

Data Requirement s

Turf Transferable Residue (TTR) Study: There is a possibility for golfers and golf course maintenance workers to have post

- application dermal exposure to imazaquin on treated turf. Based on the discussion in the residential sections of

this document

, a chemical specific TTR study will be required for imazaquin registration review since the estimated residential turf post

- application dermal exposure using default TTR values is not minimal in comparison to the level of concern (LOC) . E stimated dermal MO Es for turf post

application scenarios are <1000 and the LOC is 100 (i.e. screening dermal MOEs for activity on treated turf/lawns is 130 for children and 270 for adults).

A ttachments

Attachment 1. Chemical Identity Attachment 2. Toxicity Profile Tables

Attachment 3. Toxicity Doses and Endpoint s Selection Table

Attachment 4. Residential Post

- Application Screening Estimates

Attachment 5. Occupational Handler Screening Estimates

Attachment 6 . International Residue Limits Table

### Page 12 of 22

A ttachment 1

Chemical Identity: t he chemical structure and physiochemical properties of i m azaquin are found in

Tables 1.1 and 1 .2 below.

TABLE 1.1. Ima z aquin and Imazaquin, Ammonium Salt Nomenclature

Che m ical Structure

Co mm on na m

e I m azaquin

Molecular For m

ula C 17 H 17 N 3 O 3

Molecular W eight 311.34

IUPAC na m

e (RS)

- 2

- (4

- isopropyl

- 4

- m ethyl

- 5

- oxo

- 2

- i m

idazolin

- 2

- yl)quinoline

- 3

- carboxylic acid

CAS name ±

- 2

- (4,5

- Dihydro

- 4

- m ethyl

- 4

- (1

- m ethylethyl)

- 5

- oxo

- 1H

- i m idazol

- 2

- yl)

- 3- quinolinecarboxylic acid

CAS Registry Nu m

ber 81335

- 37

- 7

PC Code 128848

Che m ical Class I m idazolinone

Che m ical structure

Common name Imazaquin, ammonium salt

IUPAC name ( RS)

- 2

- (4

- isoprop y l

- 4

- meth y l

- 5

- oxo

- 2

- imidazolin

- 2

- y l)quinoline

- 3

- carbox y lic acid,

monoammonium salt

CAS name 2

- [4,5

- dih y dro

- 4

- meth y l

- 4

- (1

- meth y leth y l)

- 5

- oxo

- 1 H

- imidazol

- 2

- y l ]

- 3- quinolinecarbox y lic acid, m onoa mm onium salt

CAS # 81335

- 47

- 9

PC Code 128840

### Page 13 of 22

TABLE 1 . 2 . Physicochemical Properties of Ima z aquin

Para m eter Value Reference

Melting point 219

- 224 °C (decomposes) M RID 00146197; PP#5F3273,

RCB #1265, 1/9/86, A. Smith pH 4.6 at 25 °C

Densit y
, bulk densit y
, or specific gravity 0.39 g/mL untapped; 0.43 g/mL tapped

W a ter solubility at 25 °C 60 ppm

Solvent solubility g/100 m L

Acetone 0.30

DMF 6.80

DMSO 15.9

Ethanol 0.30 Heptane 0.02

Methanol 0.50

Meth y lene chloride 1.36

Toluene 0.04

Vapor pressure <2 x 1 0

- 8 mm Hg at 45 °C

Dissociation constant, p K

a 3.8

Octanol/water partition coefficient 2.2 at 22 °C

UV/visible absorption spectrum Not available

### Page 14 of 22

Attachment 2 Toxicity Profile Tables

Table 2.1

. Imazaquin Acute Toxicity Profile

Guideline

No. Study Type MRID(s) R esults Toxicity Category

870.1100 Acute oral [rat] 00132576 LD 50 = >5000 m g/kg IV

870.1200 Acute der m al [rabbit] 00132576 LD 50 > 2000 m g/kg III

870.1300 Acute inhalation [rat] 00146199 > 5.5 m g/L (4 hours) III

870.2400 Acute eye irritation [rabbit] 00132576 Non

- irritating IV

870.2500 Acute der m al irritation [rabbit] 00132576 Mildly irritating IV

870.2600 Skin sensitization [guinea pig] 00146200 Negative

- not a sensitizer N/A

### Page 15 of 22

Table 2 . 2

. Imazaquin S u bchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3100

90

- Day oral toxicity (rat) 00131553 (1983)

Acceptable/guideline

M&F: 0, 20, 80, 400 or 800

m g/kg/day
0, 250, 1000, 5000 or 10,000

ppm NOAEL: 800 m g/kg/day

LOAEL: not established

870.3150

90

- Day oral toxicity No study. See chronic dog study below.

870.3200

21/28

- Day der m al toxicity (rabbit) 00146204 (1985)

Acceptable/guideline

M&F: 0, 250, 500 or 1000

m g/kg/day Systemic NOAEL = 1000 m g/kg/day

LOAEL = not established

Dermal NOAEL = 1000 m g/kg/day

L OA E L = Not established (no effects at highest dose tested)

870.3250

90

- Day der m al toxicity No study and not required.

870.3465

90

- Day inhalation toxicity (species) No study and not required.

870.3700a

Prenatal develop m ental (rat) 00131552 (1983)

Acceptable/guideline 0, 250, 500 or 2000 m g/kg/day Maternal NOAEL = 500 m g/kg/day

LOAEL = 2000 m g/kg/day, based on salivation, alopecia, lethargy, flaccidity and 2/25 deaths Developmental NOAEL = 500 m g/kg/day

LOAEL = 2000 m

g/kg/day, based on sl ight decrease in fetal weight and

reduced ossification.

870.3700b

Prenatal develop m ental in (rabbit) 00147011 (1984)

Acceptable/guideline 0, 100, 250, or 500 m

g/kg/day Maternal NOAEL = 250 m g/kg/day

LOAEL = 500 m g/kg/day based on decreased weight gain. Developmental NOAEL = 500 m g/kg/day (no effects

seen at highest dose)

LOAEL = not identified

### Page 16 of 22

Table 2.2 Subchronic, Chronic and Other Toxicity Profile

- Imazaquin

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3800 Reproduction and fertility effects (rat) 00147016 (1985)

Acceptable/guideline
0, 92

- 97, 431

- 483 or 870

- 938

m g/kg/day (M)
0, 99

- 108, 498

- 525 or 947

- 1051

m g/kg/day (F) 0, 1000, 5000 or 10,000 ppm (M and F) Parental/Systemic

NOAE L = 870

- 938 m g/kg/day (M)

= 947

- 1051 m g/kg/day (F)

LOAEL = not identified Reproductive NOAEL = 870

- 938 m g/kg/day (M)

= 947

- 1051 m g/kg/day (F)

LOAEL = not identified Offspring NOAEL = 870

- 938 m g/kg/day (M)

= 947

- 1051 m g/kg/day (F)

LOAEL = not identified

870.4100b

Chronic toxicity (dog) 00138972 (1984)

Acceptable/guideline

M&F: 0, 5, 25 or 125 m

g/kg/day
0, 200, 1000 or 5000 ppm NOAEL = 25 m g/kg/day

LOAEL = 125 m g/kg/day, based on decreased body weight gain, skeletal m

uscle m yopathy, elevated clinical

che m istry values (ALT, AST, LDH, CPK) and decreased

he m atology values (RBC, Hgb, Hct, MCV and MCH)

870.4200 Carcinogenicity (rat) See co m bined toxicity/carcinogenicity study in rats below

870.4300 Carcinogenicity ( m ouse) 00146206 (1985)

Acceptable/guideline

M&F: 0, 38, 150 or 600

m g/kg/day (esti m ated by calculation)
0, 250, 1000 or 4000 ppm NOAEL = 150 m g/kg/day (MF)

LOAEL = 600 m g/kg/day, based on decreased body weight gain in fe m ales and m ales

no evidence of carcinogenicity in mice

870.4300

Co m bined chronic toxicity/carcinoge nicity (rat) 00146205 (1985)

Acceptable/guideline

M&F: 0, 50, 250 or 500

m g/kg/day 0, 1000, 5000 or 10,000 ppm NOAEL = 500 m g/kg/day (no effects at highest dose tested).

LOAEL = not identified

no evidence of carcinogenicity in rats

Gene Mutation

870.5100 (Ames test) 00131549

(1982)

Mini m um Non

- m utagenic

Cytogenetics

870.5300 (in

- vitro cell

transfor m ation) 00147018 (1984)

Acceptable Negative

Cytogenetics

870.5375 (HGPRT in

Chinese ha m ster) 00147017 (1985)

Acceptable Negative

### Page 17 of 22

Table 2 . 2 Subchronic, Chronic and Other Toxicity Profile

- Imazaquin

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

Other m echanism

870.5550 (unscheduled

DNA synthesis) 00147019 (1984)

Acceptable/guideline Negative

870.6200a Acute neurotoxicity screening battery No study and not required.

870.6200b

Subchronic neurotoxicity screening battery No study and not required.

870.6300 Develop m

ental neurotoxicity No study and not required.

870.7485

Metabolism and phar m acokinetics (rat) 00131550 (1983)

Acceptable/Nonguideline

0 or 12 m g/kg 94% recovered in urine and 3.94% in the feces with

3.75% recovered in the cage washings. Total recovery

- 102%. Only parent (99.7%) was detected in the

urine.

870.7600

Der m al penetration No study and not required.

Special studies

90

- day thyroid

function (rats) 42054601

- (1991)

Acceptable/Nonguideline
0, 100 and 5000 ppm or 4.98

and 245.4 m g/kg/day. NOAEL = 4.98 m g/kg/day

LOAEL = 245.4 m g/kg/day, based on slight decrease in body weight with a 20% decrease in body weight gain

and increase in TSH (up to 2 fold) acco m panied by a decrease in serum total T4 and a slight decrease in

serum T3.

### Page 18 of 22

Attachment 3 Imazaquin Endpoints and Doses for Risk Assessment

Table 3.1 Summary of Toxicological Doses and Endpoints for Imazaquin for Use in Dietary and Non

Occupational Human Health Risk Assessments

Exposure

Scenario Dose Used in Risk

Assessment, UF Special FQPA SF* and

Level of Concern for

Risk Assessment Study and Toxicological Effects

Acute Dietary (fe m ales 13

- 49) Not Applicable Not Applicable No appropriate acute endpoint

identified for this population (i.e., no toxic effect attributable to a single dose identified). Acute Dietary (general ) population) Not Applicable Not Applicable No appropriate acute endpoint

identified for this population (i.e., no toxic effect attributable to a single dose identified). Chronic Dietary (all populations) NOAEL = 25

m g/kg/day

UF = 100

cRfD = 0.25 FQPA SF = 1 X

cPAD = cRfD FQPA SF

cPAD = 0.25 m

g/kg/day Chronic toxicity

- dog

LOAEL = 125 m g/kg/day, based on weight loss, slight ane m ia, evidence of

skeletal m

uscle m yopathy and supporting he m atology/clinical

che m istry differences

Incidental Oral

- all durations. NOAEL = 25

m g/kg/day FQPA SF = 1 X

MOE of concern = 100 (Residential and Occupational) Sa m e as above.

Der m al

- all durations. NOAEL = 25

m g/kg/day FQPA SF = 1 X

MOE of concern = 100 (Residential and Occupational)

Assu m e 50% der m al absorption. Sa m e as above.

Inhalation

- all durations NOAEL = 25

m g/kg/day FQPA SF = 1X

MOE of concern = 100 (Residential and Occupational)

Assu m e 100% absorption. Sa m e as above.

Cancer (oral,

der m al, inhalation) Classification: No evidence of carcinogenicity in m ice or rats.

UF = uncertainty factor, FQPA SF = FQPA saf e ty factor, NOAEL = no observed adverse effect level,

LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference dose, MOE = m argin of exposure

### Page 19 of 22

Attachment 4

Residential Post

- Application Screening Estimates

Table 4.1 Short

- Term Residential Post

- application Exposure and Risk Estimates for Imazaquin

Lifestage Post

- application Exposure Scenario Dose (mg/kg/day) MOEs

Liquid formulation

Adult

Turf

Liquid

formulation

1.0 lb ai/A Dermal Physical Activities on Turf 0.09 270 Mowing 0.0019 13,000 Golfing 0.0074 3,400

Child 11 < 16 years old Dermal Mowing 0.0022 11,000 Golfing 0.0086 2,900 Child 6 < 11 years

old Dermal Golfing

Child 1 < 2 year

old Dermal Physical Activities on Turf 0.19 130

Hand to Mouth 0.0038 6,600 Object to Mouth 0.00012 220,000

Short

- and Intermediate

- term Incidental Soil

Ingestion 0.0000085 3,000,000

### Page 20 of 22

Attachment 5 Occupational Handler Screening Estimates

Table 5.1 Occupational Handler ST and IT Exposure and Risk Estimates for Imazaquin

Exposure

Scenario Crop or Target Dermal Unit Exposure
(μg/lb ai) 1 Inhalation Unit

Exposure
(μg/lb ai) 1 Maximum

Application

Rate (lb ai/A) 2 Area

Treated (acres) 3 Dermal

(LOC = 100) Inhalation

(LOC = 100) Total

(LOC = 100)

Mitigation Level

= baseline unless

indicated

otherwise Mitigation Level

= baseline unless

indicated

otherwise Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Mixer/Loader (WDG/DF)

Aerial Field crop, high

- acreage

(soybeans)

227 8.96 0.125 1200 0.213 120 0.0168 1500 110

Chemigation Field crop, high

- acreage (soybeans) 350 0.0621 400 0.0049 5,100 370

Groundboom Golf course (tees and greens only) 0.5 5 0.00355 7,000 0.00028 89,000 6,500

Golf course (fairways, tees, greens) 40 0.0284 880 0.00224 11,000 810

Field crop, high

- acreage (soybeans) 0.125 200 0.0355 700 0.0028 8,900 650

Mixer/Loader (L/SC/EC)

Aerial Field crop, high

- acreage (soybeans)

220 0.219 0.125 1200 0.206 120 0.000411 61,000 120

Chemigation Field crop, high

- acreage (soybeans) 350 0.0602 420 0.00012 210,000 420

Groundboom Golf course (tees and greens only) 0.5 5 0.00344 7,300 0.00000685 3,600,000 7,300

Golf course (fairways, tees, greens) 0.5 40 0.0275 910 0.0000548 460,000 910

Field crop, high

- acreage (soybeans) 0.125 200 0.0344 730 0.0000685 360,000 730

Mixer/Loader (WP in soluble packages)

Aerial Field crop, high

- acreage (soybeans)

9.8
(Engineering Control) 0.24

(Engineering Control) 0.125 1200 0.00919 2700 0.00045 56000 2600

Chemigation Field crop, high

- acreage (soybeans) 350 0.00268 9,300 0.000131 190,000 8,900

Groundboom Golf course (tees and greens only) 0.5 5 0.0000769 330,000 0.00000375 6,700,000 310,000

Golf course (fairways, tees, greens) 0.5 40 0.000613 41,000 0.00003 830,000 39,000

Field crop, high

- acreage (soybeans) 0.125 200 0.00153 16,000 0.000075 330,000 15,000

### Page 21 of 22

Table 5.1 Occupational Handler ST and IT Exposure and Risk Estimates for Imazaquin

Exposure

Scenario Crop or Target Dermal Unit Exposure
(μg/lb ai) 1 Inhalation Unit

Exposure
(μg/lb ai) 1 Maximum

Application

Rate (lb ai/A) 2 Area

Treated (acres) 3 Dermal

(LOC = 100) Inhalation

(LOC = 100) Total

(LOC = 100)

Mitigation Level

= baseline unless

indicated

otherwise Mitigation Level

= baseline unless

indicated

otherwise Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Applicator

Aerial Field crop, high

- acreage (soybeans) 5
(Engineering Control) 0.068

(Engineering Control)
0.125 1200 0.00469 5,300 0.000128 200,000 5200

Groundboom Golf course (tees and greens only)

78.6 0.34 5 0.000307 81,000 0.00000266 9,400,000 80,000

Golf course (fairways, tees, greens) 40 0.00246 10,000 0.0000213 1,200,000 9,900

Field crop, high

- acreage (soybeans) 200 0.0123 2,000 0.000106 240,000 2,000
Flagger

Flagger All crops 11 0.35 0.125 350 0.00301 8,300 0.000191 130,000 7,800
Mixer/Loader/Applicator(WDG/DF)
Mechanically

pressurized Handgun Golf course (te e s and greens only) 1960 42 0.25 5 0.0306 820 0.00131 19,000 790

Golf course (fairways, tees, greens) Mixer/Loader/Applicator(LC/SC/EC)
Mechanically

pressurized Handgun Golf course (tees and greens only)

1140 1.9 0.25 5 0.0178 1,400 0.0000594 420,000 1400

Golf course (fairways, tees, greens)

Mixer/Loader/Applicator( WP in soluble packages
Mechanically

pressurized Handgun Golf course (tees and greens only) 1350 18 0.25 5 0.0211 1,200 0.000563 44,000 1200

Golf course (fairways, tees, greens)

Bolded MOEs are below the LOC of 100.

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2013 ); Level of mitigation: Baseline, Eng. Controls.

2 Based on registered and proposed labels

. 3 Exposure Science Advisory Council Policy #9.1 and Registrant information

. 4 Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre) × Area Treated (A/day) ÷ BW ( 80 kg).

5 Dermal MOE = Dermal NOAEL ( 25 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre) × Area Treated (A / day) ÷ BW ( 80 kg).

7 Inhalation MOE = Inhalation NOAEL 25 mg/kg/day) ÷ Inha lation Dose (mg/kg/day).

8 Total MOE = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE)

.

### Page 22 of 22

Attachment 6

International Maximum Residue Limits

Table 6.1

. Summary of US and International Tolerances and Maximum Residue Limits for Imazaquin

Residue Definition :
US Canada Mexico 1 Codex

40 CFR 180. 426

A tolerance is established for residues of the

herbicide 2

- [4,5

- dihydro

- 4

- methyl

- 4

- (1

- methylethyl)

- 5

- oxo

- 1 H

- imidazol

- 2

- yl]

- 3

- quinoline carboxylic acid None None



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

US Canada Mexico 1 

### Codex
Soybean 0.05 Completed by: M. Negussie; 02/19/14

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