UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: July 17, 2014 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Etoxazole: Summary of the Hazard and Science Policy Council (HASPOC) 

Meeting of May 22, 2014: Waiver for a Subchronic Inhalation Study (870.3465). 

PC Code: 107091 

Decision No.: N/A 

Petition No.: N/ A 

Risk Assessment Type: N/ A 

TXR No.: 0056977 

MRID No.: N/A 

FROM: UmaHabiba 

Executive Secretary, HASPOC 

DP Barcode: N/A 

Registration No.: N/ A 

Regulatory Action: 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 

Jeff Dawson, 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: 

HASPOC Members: Anna Lowit, Christopher Schlosser, Elissa Reaves, John Kough, Jonathan 

Chen, Jonathan Leshin, Michael Metzger, P.V. Shah, Ray Kent, Uma 

Habiba 

Presenter: 

Other Attendees: 

Anwar Dunbar 

Charles HBilly" Smith, Jaclyn Pyne, Jaime D' Agostino, Jennifer Tyler, 

Wade Britton, William Irwin 

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I. PURPOSE OF MEETING: 

Etoxazole is currently going through the registration review process. In accordance with the 

revised CFR part 158, the registrant has submitted the neurotoxicity screening batteries and an 

immunotoxcity study for etoxazole. A waiver for a subchronic inhalation study was previously 

granted by the agency (D388416, A Dunbar et aL, 21·APR-2010). To be consistent with the 

Health Effects Division's current 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 inhalation toxicity study for etoxazole. Thus HED's HASPOC met on May 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 member of the 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 of crops 

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 the use of etoxazole on field com and popcorn (Memo, J. Tyler 

et al., 23-SEP·2011; D439804). 

In previous risk assessments, an endpoint of concern attributable to a single oral dose was not 

identified for either the general U.S. population (including infants and children) or for females 

13-50 years old. 

The chronic dietary endpoint was derived from the chronic toxicity study in the dog. The 

NOAEL of 4.62 mg/kg/day is based upon increased alkaline phosphatase activity, increased liver 

weights, liver enlargement (females), and incidences of centrilobular 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-SEP20 11 ), 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 of etoxazole. Etoxazole is formulated as wettable powders (WPs) packaged 

in water soluble packets (WSP), water dispersible granules (WDGs), emulsifiable concentrates 

(ECs), and pressurized liquids and pressurized gases. Applications can be made using aerial, 

groundboom, airblast, fogger, or handheld equipment, depending on the use site. Occupational 

exposure is expected to occur for short- and intermediate-term durations. The occupational 

handler inhalation MOEs for the registered uses of etoxazole range from 260 (mixing/loading for 

dry flowables (DF)/WDG for aerial applications to high-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 of Pesticide Programs (OPP) used a set of criteria to determine whether or 

not an inhalation study could be waived. These criteria considered the scientific information 

available for the chemical, including its: I) degree of irritation 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 on risk assessment 

approaches for semi-volatile pesticides. As part of that issue paper, an analytical comparison 

was conducted of oral and inhalation experimental toxicology studies. In general, this analysis 

showed that the degree to which oral points of departure (PODs) were protective of potential 

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 of the 

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 extrapolation continue to 

evolve and improve, OPP may incorporate additional considerations into the WOE analysis. 

Inhalation exposure can be to vapors, droplets, and/or particles/dusts. The form of inhalation 

exposure is determined by a number of factors 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 Law constant of8.5 x 10·6 atm-m3

/mol at 25°C. 

However, a low vapor pressure and/or Henry's law constant does not preclude exposure 

to aerosolized droplets or particles/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 of etoxazole, there is the potential for short- and 

intermediate-term occupational handler inhalation exposure through the following 

activities: mixing/loading liquids for aerial, airblast or groundboom applications. 

Mixing/loading liquids for aerial applications to high acreage crops results in the highest 

inhalation exposure for etoxazole. 

3. Margins of Exposure (MOEs): The MOE estimates for inhalation scenarios were 

calculated using the NOAEL from an oral toxicity study and should be considered in the 

WOE analysis for an inhalation toxicology study waiver request. In the past, OPP has 

used MOEs of approximately I 0 times higher than the level of concern 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 of concern will be considered in combination with other factors 

discussed here. All worker exposures are assessed as short- and intermediate-term based 

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on label prescribed uses and expected exposure durations. In the case of etoxazole, the 

lowest inhalation risk estimates of concern (MOE of260 and 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 on the lack of mortality in 5 male and 5 female rats in the 14-day period following 

4·hour inhalation exposure to 1.09 mg/L. No symptoms were noted during exposure. 

Following exposure and on day 1 reqdish adhesive 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 on post-exposure days 7 and 14. 

Etoxazole has low acute toxicity (Toxicity Categories ill and IV) via the oral, and dermal 

routes. It is not an eye or dermal irritant or a dermal sensitizer. 

The liver is the target organ in mice, rats, and dogs through the oral route following 

dietary exposure. In a 90·day toxicity study in dogs, 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, liver enlargement, and 

centrilobular hepatocellular swelling, were observed at high doses. 

Similar effects were observed at the high dose in a mouse carcinogenicity study. 

Subchronic and chronic 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 at terminal stages of the study. 

No quantitative or qualitative evidence of increased 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) at the same dose in ~e rat reproduction study. 

No toxicity was seen at the limit dose in a 28-day dermal toxicity study in rats. There is 

no evidence of immunotoxicity or neurotoxicity 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 of rats following oral 

dosing. Based on the recovery of radioactivity in the urine and bile ofthe bile·duct 

cannulated rats, a substantial portion of the 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 of minor urinary metabolites, the metabolite profile in 

excreta was qualitatively similar between the sexes, and etoxazole was eliminated 

primarily in the feces as parent compound. 

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For considering the need for an inhalation toxicity study, the Agency will evaluate other 

pesticides which share the same Mode of Action (MOA) and/or are in the same class. 

These pesticides can provide important information with respect to potential inhalation 

toxicity. Specifically, if other similar pesticides show inhalation toxicity studies to be 

more sensitive, an inhalation toxicity study may be required regardless of MOE, 

depending on the exposure profile. According to HED's Integrated Structure, 

Toxicology, Endpoints and Properties (I STEP) database, no phenyl pyrazole acaracides 

have subchronic inhalation studies which have been used in risk assessments to date. 

IV. HASPOC RECOMMENDATIONS: 

The HASPOC, based on a WOE approach, concludes that a subchronic inhalation toxicity 

study is required for etoxazole at this time. This approach considered all of the available 

hazard and exposure information for etoxazole, including: (1) etoxazole's MOE's of260 and 660 

which are quantitatively very close HED's LOC of 1 00; (2) suggestive evidence of portal 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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