UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: December 23,2014 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Etoxazole; Response to comments from Valent regarding HED's most recent 

Human Health Registration Review Seeping Document for Etoxazole. 

PC Code: 107091 

Decision No.: 497892 

Petition No.: NA 

Risk Assessment Type: NA 

TXRNo.: NA 

MRIDNo.:NA 

DP Barcode: 0424313 

Registration No.: NA 

Regulatory Action: NA 

Case No.: 7616-1 

CAS No.: 153233-91-1 

40 CFR: §180.593 

FROM: Anwar Y. Dunbar, Ph.D. {;//' /k~/ /''- 1 

· .i/v~ '1-

Pharmacologist, Risk Assessment Branch 1 

Health Effects Division (HED) (7509P) 

THROUGH: Charles W. Smith III, 

Chief, Risk Assessment Branc 

Health Effects Division (HED) (7509P) 

TO: Julia Stokes, Risk Review Manager 

Registration Division (7505P) 

I. CONCLUSIONS 

HED has read and acknowledged Valent's comments noted in its correspondence. The errors 

noted will be changed, but the scientific points where the agency and Valent disagree will remain 

in place, specifically those regarding the characterization of the rat excretion and tissue 

accumulation data. 

II. ACTION REQUESTED 

Please address Valent's comments regarding EPA's most recent Human-Health Assessment 

Seeping Document in Support ofRegistration review (EPA Docket ID: EPA-HQ-OPP-2014-

0133). 

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III. BACKGROUND 

EPA's Human Health Effects Division within the Office of Pesticide Programs recently 

generated a Human-Health Assessment Scoping Document in Support of Registration review for 

Etoxazole. Valent generated comments about existing data and requested EPA respond 

potentially change select stances and data interpretation. EPA's responses are as follows: 

Comment #1: (Page 5, Section C) "Page 5 and Table A.2.1., page 14. A waiver ofthe 90-day 

inhalation toxicity study was granted most recently for the greenhouse use pattern (Decision No. 

447295: DP Barcode D388416). The date for this waiver document is incorrectly indicated as 

21 -APR-2010. The correct date is 21-APR-2011. The waiver was granted on the basis of large 

MOE's for product packaged in water soluble packets (all exceeding 1 000), low exposures and 

low acute toxicity of the Valent formulated and TGAI material." 

HED's Response: On May 24, 2014, HED's Hazard Science and Policy Council (HASPOC) met 

to re-evaluate the previous waiver granted to Valent for a subchronic inhalation study for 

etoxazole based upon current practices (TXR#0056977). Based on a weight of evidence 

approach, the HASPOC concluded 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: (I) 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 FQP A 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. 

Comment #2: (Page 5, Section C) "Page 5 (in the fourth paragraph) and Table A.2.3 page 15. In 

the reproduction and fertility study, increases in the adrenal weight of the P parental females was 

not considered to be toxicologically significant because there were no treatment related 

histopathological changes in the adrenals. 

HED's Response: HED acknowledges Valent's position on the female adrenal weights. The 

original regulatory decision however considered these changes in weight to be toxicologically 

significant. This study does not impact the previously chosen endpoints for risk assessment. 

Should this study be considered for endpoint selection in future actions, these effects will be reevaluated. 

Comment #3: (Page 5, Section C) "Page 15. The acute toxicity category for the Acute Dermal 

Toxicity study (MRID 45089921) is incorrectly indicated as II. The correct Toxicity Category is 

III, and this change will be made. 

HED's Response: HED acknowledges that the acute dermal study is Category III. 

Comment #4: (Page 5, Section C) "Page 16. Regarding the mouse carcinogenicity study, the 

description of "No evidence of carcinogenicity" should be written in the 2001 year's study not 

the 1996 year's study. 

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HED's Response: HED acknowledges the change in this descriptor for carcinogenicity was 

assigned to the wrong study, and this change will be made. 

Comment #5: (Page 5, Section C) "Page 17, Table A.2.3: 870.6200b Subchronic Neurotoxicity 

(Rat): According to the results of the above-mentioned study, the systemic NOAEL and LOAEL 

are considered to be 5000/1500 and 15000 ppm (MIF), respectively. The following findings 

were observed in this study; Abnormalities of incisor, elongation, whitening, and partial loss of 

upper and/or lower incisor, were detected in females of the 5000 ppm group and/or both sexes of 

the 15000 ppm group. Significant decreases in body weights were observed in females of the 

15000 ppm group at weeks 8 to 13. In addition, enlargement of the liver was observed in both 

sexes of the 15000 ppm group at necropsy after 1 3 weeks of treatment. No evidence of 

neurotoxicity was observed. 

HED's Response: HED acknowledges Valent's interpretation of the data. After preliminary 

review of this study, HED has concluded that there are no treatment-related adverse effects 

worthy of setting systemic or neurotoxicity NOAELs/LOAELs. 

Comment #6: (Page 5, Section C) "Page 17, Table A.2.3 870.7800 28-Day Imrnunotoxicity 

(Rat): According to the results of the above mentioned study, the systemic NOAEL and LOAEL 

are considered to be 1000 and 5000 ppm [F), respectively. The following findings were 

observed in this study; in clinical signs, increased incidences of whitening of incisors was 

observed in the 15000 ppm group. The food consumption of the 15000 ppm group was lower 

than the control at 1 week of treatment. At necropsy, macroscopic findings included increased 

incidences of whitening of incisors in the oral cavity and enlargement in the liver in the 15000 

ppm group, as well as increased incidences of whitening of incisor in the 5000 ppm group. No 

evidence of lmmunotoxicity was observed. 

HED's Response: HED acknowledges Valent's interpretation of the data. After preliminary 

review of this study, HED has concluded that there are no treatment-related adverse effects 

worthy of setting systemic or imrnunotoxicity NOAELs/LOAELs. 

Comment #7: (Page 6, Section C) Page 4. The half-life of only one label (oxazole label for low 

and t-butylphenyllabel for the high dose) is shown and the values are not significantly different 

between sexes. The sentences indicating sex-related differences should be deleted. 

HED's Response: HED acknowledges Valent's interpretation of the data. After re-examining 

the metabolism data evaluation record for etoxazole, the data do support sex related differences 

for the low and high doses, and the patterns for the half-lives are similar for both labels ('4

Cbutylphenyl and 14C-oxazole). For future actions, revise this language to be clearer. 

Comment #8: (Page 6, Section C) On page 5, and in Table A.2.3 on page 17 ofthe HumanHealth Assessment Seeping Document, the following statement is found "Excluding the 0.1. 

tract, concentrations of radioactivity over time were generally highest in liver, lymph nodes, 

thyroids, and fat, and were lowest in brain for both sexes in each dose group." This statement is 

misleading, as the radioactivity found in the lymph nodes was not found to be higher at later time 

Page 3 of4 
points (especially at 168 hrs.) for both sexes in each group. In thyroids, radioactivity was not 

found at the highest level in the high dose animals, nor in the oxazole-label groups. Finally, 

radioactivity found in fat is comparable to that found in other tissues and is generally not higher. 

The only instance where the language "generally highest" is correct is for the liver. 

RED's Response: HED acknowledges Valent's interpretation of the data. After review of the 

data, while HED agrees that there is a time dependence to the amount of radioactivity found in 

the various tissues, the above mentioned interpretation is confirmed. It does not impact the risk 

assessment and won't be changed. 

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