OFFICE OFCHEMICAL SAFETYAND POLLUTION PREVENTION



### MEMORANDUM

December 17, 2012 TXR#:0056481

SUBJECT: Quizalofop (quizalofop-ethyl and quizalofop-p-ethyl): Summary ofHazard and Science Policy Council (HASPOC) Meeting ofOctober4, 2012: Recommendations on the Requirement ofthe Neurotoxicity Battery and a Subchronic Inhalation Toxicity Study.

PC Code: 128709, 128711 

### Decision No.: N/ A Petition No.: N/A Risk AssessmentType: N/ A TXR No.: 0056481 MRID No.: N/A DP Barcode: N/A Registration No.: 

### Nl A Regulatory Action: N/ A CaseNo.: N/A CAS No.: NIA 

### 40CFR:N/A
FROM: Kristin Rury, MPH

# ¥-~ Executive Secretary,

# HAS~oW Health Effects Division (7509P)

### ~a-.~ THROUGH: Jess Rowland, Co-Chair

### ~~ I_/ Anna Lowit, Ph.D., Co-Chair**~** 

### HASPOC Health Effects Division (7509P)

TO: William Irwin, PhD, DABT, Toxicologist Danette Drew, Chemist Michael Metzger, Branch Chief Health Effects Division (7509P)

MEETING ATTENDEES:

HASPOC Members: Anna Lowit, Elissa Reaves, JeffEvans, Jess Rowland, John Kough, Julie Van Alstine, Kristin Rury, Michael Metzger, PV Shah, Ray Kent

Presenters: William Irwin, Danette Drew

Page 1of6

### I. PURPOSE OF MEETING: Quizalofop-ethyl is a 50150 racemic mixture ofR- and S-enantiomers, quizalofop-p-ethyl is the purified R-enantiomer, which is the pesticidally active isomer. HED had detennined that the toxicological profile ofthe 50/50 racemic mixture (quizalofop-ethyl) and the R-enantiomer (quizalofop-p-ethyl) are similar, andthat the currently available toxicity andresidue dataon quizalofop-ethyl are adequate to support risk assessments reflecting either quizalofop-ethyl or quizalofop-p-ethyl. The two compounds may be collectively referred to as "quizalofop" in this document. In accordance with the revised 40 CFR Part 158 Toxicology Data Requirements, acute and subchronic neurotoxicity studies arerequired for quizalofop-ethyl and quizalofop-pethyl. A 28-day inhalationtoxicity study in rats is also required due to the potential for repeated inhalation exposure to quizalofop-ethyl and quizalofop-p-ethyL The Hazard and Science Policy Council (HASPOC) met on October4, 2012 to discuss the need for need for the acute and subchronic neurotoxicity studies, and a subchronic inhalation toxicity studyto support registered
uses ofquizalofop.

II. SUMMARY OF USE PROFILE & PREVIOUS RISK ASSESSMENT: Quizalofop-ethyl and quizalofop-p-ethyl are selective herbicides used for the control ofannual andperennial grasses in a variety ofcrops and non-croplands (rights-of-way, fencerows, etc). There are no residential uses. They canbe applied using ground and aerial equipmentas broadcast andbanded applications. All products are formulated as an emulsifiable concentrates (EC). Quizalofop-ethyl is a 50/50 racemic mixture ofR- and S-enantiomers. Quizalofop-p-ethyl is the purified R-enantiomer, which is the pesticidally active isomer. All ofthe currently registered products are formulated asthe R-enantiomer. HED had determined that the toxicological profile ofthe 50/50 racemic mixture (quizalofop-ethyl) and the R-enantiomer (quizalofop-p-ethyl) are similar, and that the currently available toxicity andresidue dataon quizalofop-ethyl are adequate to supportrisk assessments reflecting uses ofeither quizalofopethyl orquizalofop-p-ethyL The two compounds may be collectively referred to as "quizalofop" in this document.

. In the most recent human health risk assessment 

### (I. Negr6n-Encarnaci6n, D384660, 11/17/2011),
an oral point ofdeparture (POD) was used for assessing risk via dietary (food and drinking water) exposure. The POD was based on increased incidence ofcentrilobular enlargement ofthe liver in both sexes ofrats and mild anemiainmale rats seen atthe lowest observed adverse effect level (LOAEL) of3.7 mglkglday (no observed adverse effect level; NOAEL 

## =0.9 mg/kg/day) from the rat chronic toxicity/carcinogenicity study. There were no effects observed in oral toxicity studies that couldbe attributable to a single-dose exposure. Hence, a dose and endpoint have not been selected for assessment ofacute exposure. Similarly, there was no observed toxicity in a dermal sub-chronic study atthe highest dose tested (above the limit dose) so no dermal risk assessment was conducted. A chronic reference dose (cRfD) was established based
on liver effects and decreases inbody weight gain observed in a combined chronic toxicity/carcinogenicity study in rats. Mutagenicity studies conducted onquizalofop-ethyl did not demonstrate evidence ofmutagenic potential. Quizalofop-ethyl is Category D, not classifiable as to human carcinogenicity. As such, a cancer risk assessment was not conducted.

Page 2 of6The chronic dietaryexposure and risk estimate utilized 11% ofthe chronic population adjusted dose (cPAD) for the general U.S. population, and 29% ofthe cPAD for children 1-2 years old, the highest exposed population subgroup. Occupational inhalation exposure assessments were originally not performed for quizalofop. However, as a screening analysis ofoccupational inhalation exposure, HED calculated inhalation riskestimates using the POD from the rat chronic toxicity/carcinogenicity study (NOAEL:::: 0.9 mglkglday) as a conservative exposure estimate. The occupational inhalation margins ofexposure (MOEs) ranged from 2,900 to 211 ,000. The level ofconcern (LOC) for the screening assessment would be anMOE 

### < 100.



### III. STUDY WAIVERREQUESTS

A. Inhalation Study Previously, the Office ofPesticide Programs (OPP) used a set ofcriteria to determine whetheror not an inhalation study could be waived. These criteria considered the scientific information available for the chemical, including its: 1) degree ofirritation and corrosivity; 2) volatility; 3) aerosol particle size; and 4) Acute Toxicity Category and extrapolated MOEs (e.g., MOEs 10 times higher than the target). In 2009, OPPdeveloped an issue paper on risk assessment approaches for semi-volatile pesticides. As partofthat issue paper, an analytical comparison
was conducted oforal and inhalationexperimental toxicology studies. In general, this analysis showed that the degree to which oral point ofdepartures (PODs) were protective ofpotential inhalation toxicity varied. In many cases the oral POD was protective, but in some cases the inhalation PODs were significantly more protective. Currently, OPPuses a weightofthe evidence (WOE) approach

### that builds upon OPP'sexperience using the criteria listed above and conclusions from the 2009 SAP. As approaches for route-to-route extrapolationcontinue to evolve and improve, OPP may incorporate additional considerations into the WOE analysis.

Inhalation exposure can be to vapors, droplets, and/orparticles/dusts. The form ofinhalation exposure is determined by a nwnberoffactors including physical-chemical properties, use pattern, and exposure scenarios. OPP's interim WOE approach considers:
l. 

### Physical-Chemical Properties: Consideration ofvapor pressure and the Henry'slaw constant are essential in**assessin~** volatilization after sprays have settled. The vapor pressure ofquiz.alofop is 8.3x10- 0 nun Hg 20 

### °C, The Henry's law constant is 1.1X10-8 atm-cu m/mol at20 

### °C. However, low vaporpressure and/or Henry's law constant does not preclude exposure to aerosolized droplets orparticles/dusts.

2. 

### Use Pattern & 

### Exposure Scenarios: Any application scenario that leads to inhalation exposure to droplets needs to be considered in the WOE analysis for aninhalation toxicology study waiver request. Airblast and aerial applications are more likely to lead to higheroccupational handler inhalationexposure, particularly to droplets; and may also contribute to spray 

### drift. Quizalofop may be applied with aerial orairblast equipment. In the case ofquizalofop, mixing/loading for aerial application to cotton results in the highest inhalation exposure.

Page 3 of63. 

### Margins of Exposure: TheMOEestimates for inhalation scenarios were calculated using
an oral toxicity study and should be considered inthe WOE analysis for an inhalation toxicology study waiver request. In the past, OPP 

### has used MOEs ofapproximately 10 times higher than the LOC as a benchmark for granting waiver requests. The 2009 analysis suggests this approach is appropriate for most pesticides, butnot all. Under the interim WOE approach, MOEs from 1 0·100 times greater than the level ofconcern will be considered in combination with other factors discussed here. In the case of quizalofop, the inhalation MOEs for occupational handlers range from 2,900 to 211,000 and meetthe waiver criterion ofMOEs ranging from 1 0·100 times the LOC.



### Toxicological Effects: Quizalofop-ethyl and quizalofop-p-ethyl are considered to be toxicologically similar. HED based this determination on a comparison oftoxicity data submitted for the registration ofquizalofop-ethyl and a subsetoftoxicity data for quizalofop-p-ethyl. Specifically, toxicity data available for quizalofop-p-ethyl included:
an acute oral study inthe rat, 90-day subchronic feeding studies inthe rat and mouse. and three mutagenicity studies. Results from these studies were similar to results obtained from the same studies using quizalofop-ethyl. Conclusions regarding the toxicity of quizalofop-ethyl are applicable to quizalofop-p-ethyl. Quizalofop has low acute toxicity viathe oral (Toxicity Category III), dermal (Toxicity Category IV), and inhalation routes (Toxicity Category IV) routes. It is notan eye ordermal irritant nor a skin sensitizer. Following oral administration, quizalofop-ethyl is rapidly absorbed and excreted via urine andfeces. The liver is theprimarytarget organ as evidenced by increased liver weight and histopathological changes. Liver effects and decreases inbody weight gain and food consumption as a result ofrepeat dosing were seen in sub-chronic and chronic/carcinogenicity studies in rats, mice, and dogs. Developmental studies in rats andrabbits and a two-generation reproduction study inrats showedno evidence (qualitative orquantitative) for increased susceptibility following in utero and/or pre/post-natal exposure to quizalofop ethyL

For considering a waiver request for an inhalation toxicity study, the Agency will evaluate otherpesticides which share the same mode ofaction (MOA) and/orare inthe
sameclass. Thesepesticides canprovide important information withrespect to potential inhalation toxicity. Specifically, ifother similarpesticides showinhalation toxicity studies to be more sensitive, an inhalation toxicity study may be required regardless of MOE, depending onthe exposure profile. The ISTEP database did not indicate any inhalation endpoints based on specific inhalation studies for any ofthe related arylphenoxypropionate herbicides which inhibit**acetyl~CoA** carboxylase. There are no multi-day inhalation studies available for the following similarchemicals: fluazifop-Pbutyl, cyhalofop-butyl, diclofop-methyl, haloxyfop-R·methyl, andpropaquizafop.

In a fenoxprop-P·ethyl 28·day inhalation study, the maintarget organ was the liver (organ weightchanges, effects inlipid metabolism), with effects being more pronounced in males than in females. Increased absolute (all dose groups) and relative (0.07 mg/L and above) liver weights wererecorded. Effects onlipid metabolism were evident at 0.3 mg!L. Furthermore, slightchanges were noted inhematology at 0.07 mg/L and greater.

Page4 of6Another target organoffenoxaprop-P-ethyl was the kidney, with increases in absolute and/or relative organ weights observed in both sexes at0.3 mg/L. In conclusion, the NOAEL is considered to be 0.015 mg/L or 2.7 mglkg/day. The hazard componentof chronic risk

### was the NOAEL of0.25 mglkg/day based ondecreased total blood lipids/cholesterol atthe LOAEL of 1.5 mglkg/day in a rat reproductive toxicity study.
Based on a 

### WOE approach**consi~ering** all the availablehazard and exposure information for quizalofop,the HASPOC determined that a 28-day inhalation toxicity study in the ratis not required atthis time. This approach considered all the available hazard and exposure information for quizalofop, including: (I) the lowvapor pressure ofquizalofop (8.3 X w-tO mm Hg); (2) the low acute inhalation toxicity ofquizalofop (Toxicity Category IV); and (3) the use ofan oral POD established for the most sensitive endpoint/target organ system resulting in screening-level MOEsranging from 2,900 to 211,000.

B. Neurotoxicity studies
Acute and sub-chronic neurotoxicity studies are required in the 2007 revised 40 CFRPart 158 Toxicology Data Requirements because they provide important scientific information on potential nervous system effects from pesticide exposure. These studies canprovide dataon a wide range offunctional tests for evaluating neurotoxicity including sensory effects, neuromuscular effects, learning and memory and histopathology ofthe nervous system. Quizalofop did not showclear signs ofneurotoxicity following acute, sub-chronic orchronic dosing in multiple species in the database. However, the existing guideline studies are inadequate in their assessment ofbehavioral effects and do notuse optimal methods to evaluate the potential toxicity to nervous tissue structure and function. With respect to considering whether an acute or sub-chronic neurotoxicity study shouldbe required for quizalofop, the HASPOC used the following weight ofthe evidence (WOE) approach:


### 1. Evidence for neurotoxicity in thequizalofop database oftoxicology studies: Thecurrent toxicology database shows no clearevidence for neurotoxicity. Thetarget organs are the liver and the testis. Other toxicity signs are apical, such

### as decreased body weight, decreased body weight gain ordecreased food consumption.

2. Evidencefor neurotoxicity in the database ofother similar chemicals: Thepesticidal mode ofaction ofquizalofop is by inhibiting acetyl CoAcarboxylase (ACC, a key enzyme inplant fatty acid synthesis and required for maintaining membranes in functioning condition). The ACC inhibitors generally target the liver, kidney, ortestes. A search ofthe !STEP database did not indicate neurotoxicity concerns for similar chemicals, including diclofop-methyl, fenoxaprop-ethyl, and fluazifop acid.

Another ACC inhibitor, cyhalofop-butyl, had a NOAEL of2000 mg/kg in the acute neurotoxicity study, with no LOAEL identified. In the subchronic neurotoxicity study, the NOAELs were 75 mglkg/day in males and 250 mg/kg/day in females, with no LOAELs identified. Incomparison withquizalofop, the risk assessment POD for chronic dietaryexposure to cyhalofop-butyl is at a much lower dose: 0.99 mglkg/day derived from the chronic mouse study.

Page 5 of6AnotherACC inhibitor, fluazifop-P-butyl, showed no evidence ofneurotoxicity but did exhibit liver and the testis asthe target organs, similarto quizalofop

. Based on a WOE approach, the HASPOC concluded that acute and subcbronic neurotoxicity studies are not required at this time. This approach included the following considerations: 1) there was no evidence ofneurotoxicity orneuropathology in the available toxicology studies for quizalofop; 2) liver is the target organ and the oral POD is based on hepatotoxicity providing the most sensitive endpoint; 3) neurotoxicity studies inrats is unlikely to provide a more sensitive endpoint or a lower POD for risk assessment; and 4) the lowconcern for neurotoxicity in other members ofthis class ofchemicals.

IV. HASPOC RECOMMENDATIONS:

Based on a WOE approach and considering all ofthe available quizalofop hazard and exposure information, the HASPOC concludes that a 28-day inhalation toxicity, acute neurotoxicity, and subchronic neurotoxicity studies are notrequired atthis time.

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