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

MEMORANDUM Date: July 17, 2014 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: Etoxazole: Summary ofthe Hazard and Science Policy Council (HASPOC) Meeting ofMay 22, 2014: Waiver for a Subchronic Inhalation Study (870.3465). PC Code: 107091 Decision No.: N/A Petition No.: N/ A RiskAssessment Type: N/ A TXR No.: 0056977 MRID No.: N/A FROM: UmaHabiba Executive Secretary, HASPOC DP Barcode: N/ A Registration No.: N/A RegulatoryAction: N/ A Case No.: N/A CAS No.: N /A 40 CFR: N/A

Health Effects Division (HED; 7509P) THROUGH: Anna Lowit, Ph.D., Co-Chair JeffDawson, Co-Chai HASPOC Health Effects Division (750 P) TO: Anwar Y. 

### Dunbar, Ph.D. Charles Smith, Branch Chief Risk Assessment Branch 1 (RAB 1) HED (7509P) MEETING ATTENDEES:
HASPOCMembers: 

### Anna Lowit, Christopher Schlosser, Elissa Reaves, John Kough, Jonathan Chen, Jonathan Leshin, Michael Metzger, P.V. Shah, Ray Kent, Uma Habiba
Presenter: OtherAttendees: 

### Anwar Dunbar Charles HBilly" Smith, Jaclyn Pyne, Jaime D'Agostino, JenniferTyler, Wade Britton, William Irwin

Page 1of5I. PURPOSE OF MEETING:
Etoxazole is currently going through the registration review process. In accordance with the revised CFRpart 158, the registranthas submitted the neurotoxicity screening batteries and an immunotoxcity study for etoxazole. A waiver for a subchronic inhalation study was previously granted bythe agency (D388416, A Dunbar et aL, 21·APR-2010). Tobeconsistent withthe Health Effects Division'scurrent inhalation risk assessment practices, Risk Assessment Branch 1 requested that the Hazard Science and Policy Council (HASPOC) re-evaluate the need for a repeated dose inhalationtoxicity study for etoxazole. Thus HED'sHASPOC met onMay**22~** 2014 to discuss the need for a repeated dose subchronic inhalation study for etoxazole. II. SUMMARY OF USE PROFILE & PREVIOUS RJSK ASSESSMENT: Etoxazole is a contact acaricide/ovicide and is a memberofthe diphenyloxazoline class of insecticide /miticide. It is formulated as wettable powders (WPs) packaged in water soluble packets (WSPs), water dispersible granules (WDGs), emulsifiable concentrates (ECs), pressurized liquids and pressurized aersols. It is currently registered for use on a variety ofcrops and ornamentals as well as for use in homeowner/residential and commercial greenhouses. The current registrations include SLN registrations on carrots and alfalfa. There are no pending PRJA actions for etoxazole. The most recent quantitative human-health risk assessment was performed in 2011, and was for theuse ofetoxazole on field com and popcorn (Memo, 

### J. Tyler 

### etal., 23-SEP·2011; D439804).
Inprevious risk assessments, anendpoint ofconcern attributable to a single oral dose wasnot identified for either the general U.S. population (including infants and children) orfor females 13-50 years old. The chronic dietary endpoint was derived from the chronic toxicity study inthe dog. The NOAEL of4.62 mg/kg/day is basedupon increased alkaline phosphatase activity, increased liver weights, liver enlargement (females), and incidences ofcentrilobular hepatocellular swelling in the liver at the LOAEL of23.5 mglkg/day.
In the most recent inhalation risk assessment for etoxazole (R-Tyler, J. et al., D385425, 23-SEP2011), the inhalation endpoints were based upon the chronic oral toxicity study in dogs, similar to the chronic dietary endpoint described above. There is the potential for inhalation exposure to occupational handlers from the current and proposed use pattern ofetoxazole. Etoxazole is formulated as wettable powders (WPs) packaged in water soluble packets (WSP), water dispersible granules (WDGs), emulsifiable concentrates (ECs), and pressurized liquids andpressurized gases. Applications can bemade using aerial, groundboom, airblast, fogger, orhandheld equipment, depending onthe use site. Occupational exposure isexpected to occurfor short- and intermedia te-term durations. The occupational handler inhalation MOEs for theregistered uses ofetoxazolerange from 260 (mixing/loading for dry flowables (DF)/WDG for aerial applications tohigh-acreage field crops) to**1~200,000** (applingspray (all formulations) aerially to typical field crops).

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### III. STUDY WAIVER REQUESTS:

a. Inhalation Study Previously, the Office ofPesticide Programs (OPP) used a setofcriteria to determine whether or not an inhalation study couldbe waived. These criteriaconsidered the scientific information available for the chemical, including its: I) 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, OPP developed an issue paper onrisk assessment approaches for semi-volatile pesticides. As part ofthat issue paper, an analytical comparison was conducted oforal and inhalationexperimental toxicology studies. In general, this analysis showed that the degree to which oral points ofdeparture (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, OPP uses a weight ofthe evidence (WOE) approach that builds upon OPP'· s experience 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 WOEanalysis. Inhalationexposure can be to vapors, droplets, and/or particles/dusts. The form ofinhalation exposure is determined by a number offactors including physical-chemical properties, use pattern, and exposure scenarios. OPP's interim WOE approach considers: 1. Physical-chemical properties: Vapor pressure and Henry's law constant are key**co~siderations** 

### with respect to the volatilization after sprays have settled. Etoxazole (MW 

## = 359.42 g/mol) has a low vapor pressure (reported values range from 7 X 

### 10"6 

### tO 5.2 X ]Q· 8 

### mm Hg@

### 25°C) and a low Henris Lawconstant of8.5 x 10·6 

### atm-m3 

### /mol at 25°C. However, a low vapor pressure and/or Henry's lawconstant 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 an inhalation toxicology study waiver request. Airblast and aerial applications are more likely to lead to higher occupational handler inhalation exposure, particularly to droplets; and may also contribute to spray drift. In the case ofetoxazole, there is the potential for short- and intermediate-term occupational handler inhalation exposure through the following activities: mixing/loading liquids for aerial, airblast orgroundboom applications. Mixing/loading liquids for aerial applications to high acreage crops results in the highest inhalation exposure for etoxazole. 3. Margins ofExposure (MOEs): The MOE estimates for inhalation scenarios were calculated using the NOAEL from anoral toxicity study and should beconsidered in the WOE analysis for an inhalation toxicology study waiver request. In the past, OPP has used MOEs ofapproximately I0 times higher than the level ofconcern as a benchmark for granting waiver requests. The 2009 analysis suggests this approach is appropriate for most pesticides but not all. Under the interim WOE approach, MOEs from 10-100 times greater than the level ofconcern will be considered in combination with other factors discussed here. All worker exposures are assessed as short- and intermediate-term based

Page 3 of5on label prescribed uses and expected exposure durations. In the case ofetoxazole, the lowest inhalation risk estimates ofconcern (MOE of260and 660) were associated with mixing/loading a liquid for aerial applications to high acreage field crops. 4. 

### Toxicity: In an acute inhalation study, etoxazole (95.39%) was assigned category III based onthe lack ofmortality in 5 male and 5 female rats in the 14-day period following 4·hourinhalation exposure to 1.09 mg/L. No symptoms were noted during exposure. Following exposure and on day 1 reqdishadhesive materials were noted in the nasal region in most animals; this was gone by post-exposure day 1 in males and day 4 in females. All animals showed an increased body weight onpost-exposure days 7 and 14. Etoxazole has low acute toxicity (Toxicity Categories 

### ill and IV) via the oral, and dermal routes. 

### Itis not aneye ordermal irritant or a dermal sensitizer. The liver is the target organ in mice, rats, and dogs through the oral route following dietary exposure. Ina 90·daytoxicity study indogs, increased liver weights and centrilobular hepatocellular swelling in the liver were observed. Similar effects were observed in a chronic toxicity study In dogs at similar doses, indicating that the systemic effects (mainly liver effects) occur at similar dose levels following short-through longterm exposure without increasing in severity. In a 90-day toxicity study in mice, hepatotoxicity, such as increased relative liver weight, liverenlargement, and centrilobular hepatocellular swelling, were observed at high doses. Similareffects were observed at the high dose in a mouse carcinogenicity study. Subchronic andchronic toxicity studies in rats also produced similar effects (increased liver weights, centrilobular hepatocellular swelling, etc.) as seen in mice and dogs. In addition, slight increases in thyroid weights and incisors were observed in subchronic and chronic toxicity studies in rats at high doses and atterminal stages ofthe study. No quantitative orqualitative evidence ofincreased susceptibility was seen following 

### in utero exposure to rats or rabbits in developmental studies. Offspring toxicity was qualitatively more severe (pup mortality) than parental toxicity (increased liver and adrenal weights) atthe same dose in**~e** rat reproduction study. No toxicity was seen atthe limit dose in a 28-day dermal toxicity study in rats. There is no evidence ofimmunotoxicity orneurotoxicity in any study. HED's Hazard Identification Assessment Review Committee (HIARC) classified etoxazole as "not likely" to be carcinogenic. Etoxazole was not mutagenic. Etoxazole was rapidly absorbed from the gastro intestinal tract ofrats following oral dosing. Based on the recovery ofradioactivity inthe urine and bile ofthe bile·duct cannulatedrats, a substantial portion ofthe dose (48.2-67.5% dose) was absorbed by rats in the low-dose groups. However, absorption (15.2·19.1% dose) was limited in the high· dose groups. With the exception ofminorurinary metabolites, the metabolite profile in excreta was qualitatively similar between the sexes, and etoxazole was eliminated primarily inthe feces as parent compound.

Page4of5For considering the need for an inhalation toxicity study, the Agency will evaluate other pesticides which share the sameMode ofAction (MOA) and/or are in the same class. Thesepesticides can provide important information with respectto potential inhalation toxicity. Specifically, ifother similarpesticides show inhalation toxicity studies to be more sensitive, an inhalation toxicity study may berequired regardless ofMOE, depending onthe exposureprofile. According to HED's Integrated Structure, Toxicology, Endpoints and Properties (ISTEP) database, no phenyl pyrazole acaracides have subchronic inhalation studies which have beenused inrisk assessments to date.
IV. HASPOC RECOMMENDATIONS: 

### TheHASPOC, based on a WOE approach, concludes thata subchronicinhalation toxicity study is 

### required for etoxazole atthis time. This approach considered all ofthe available hazard and exposure information for etoxazole, including: (1) etoxazole's MOE'sof260 and 660 which are quantitatively very close HED's LOC of 1 00; (2) suggestive evidence ofportal of entry effects in the acute inhalation study; and (3) etoxazole's significant absorption through the oral route suggesting a significant high internal dose via repeated inhalation exposure. The FQPA 1

### OX Safety Factor will be retained for inhalation risk assessment until an inhalation study has been submitted or additional information is submitted to support a waiver.

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