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

MEMORANDUM Date: December 23,2014 OFF I CE OF C H EMICAL SAFETY AND POLLUT I ON PREVENTION

SUBJECT: Etoxazo le; 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 MRIDN o.:NA DP Barcode: 0424313 Registration No .: NA Regulatory Action: NA Case No. : 7616

- 1 CAS No.: 153233-91-1 40 CFR: §180.593
FROM:

# /k~/**· v~**  Anwar Y. Dunbar, Ph.D. {;//' /' '- 1 

# .i/ '1- Pharmaco logist, Risk Assessment Branch 1 Health Effects Divis ion (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, bu t the sc ientific points where the agency and Valent disagree will remain in p l ace, 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. BACKGRO UN D EPA's Human Health Effects D ivision within the Office of Pesticide Programs recently generated a Human-Health Assessment Scoping Document in Support of Regis tration review for Etoxazole. Valent ge nerated comments about ex isting data and reque ste d EPA respond potentially change select stances and d ata interp retation. EPA' s respo n ses are as follow s: Comment #1: (Page 5, Section C) " Page 5 and Table A.2.1., page 14. A waiver ofthe 90-day inhalation t oxicity study was granted mo st recently for the greenhouse use pattern (D ec ision No. 447295: DP Barcode D388416). The date for this waiver document is incorrectl y indicated as 21

-APR-2010. The correct date is 21-APR-2011. The waiver was grante d 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 Respon se: On May 24, 2014 , HED 's Hazard Science and Policy Co uncil (HASPOC) met to re-evaluate th e previous waiver granted to Valent for a subchronic inh a la tion study for etoxazole based upon current practice s (TXR #0056977). Based on a weight of evidence approach, the HASPOC concluded that a subchronic inhalation to xicity study is required for etoxazole at this time. This approach considered all of the available h azard and exposure information for etoxazole, including: (I) etoxazole's MOE ' s of260 and 660 which are quantitatively very c lose HED's LOC of 1 00; (2) sugges tive evidence of portal of entry effects in the acute inhal ation study; and (3) etoxazole' s significant absorption through the oral route suggesting a significant high internal do se via repeated inhalation exposure. The FQPA 1 OX Safety Factor will be retai ned for inhalati on risk assessment until an inha l ation study has been submitted or additional information is submitted to support a waiver. Comment #2: (Page 5, Section C) "Page 5 (i n the f ourt h 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 hi stopathological changes in the adrenal s. HED's Response: HED acknow ledges Valent's position on the female adrenal weights. The original regulatory decision however considered these changes in we ight to be toxicologically s ignificant. This study does not impact th e previously chosen endpoints for risk assessm ent. Should this study be considered for endpoint selection in future actions , these ef fects wi ll be reevaluated. Comment #3: (Page 5, Section C) "Page 15. The acute toxicity category for the Acute Dermal Toxici t y study (MRID 45089921) is incorrectly indicated as II
. The correct Toxicity Category i s I II , and thi s change will be made. HED 's Respon se: HED acknowledges that th e acute dermal study is Category III. Comment #4: (Page 5, Section C) " Page 1 6. Regarding the mouse carcinogenicity study, the description of "No evidence of carc ino gen ic ity" should be written in the 200 1 ye ar 's study not the 1996 year's study.

Page 2 of4HED'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 , Tab le 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), respective ly. 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 gro up. 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 Re sponse: HED acknow ledges Valent 's interpretation of the data. After preliminary review of this s tud y, HED has concluded that there are no treatment-related adverse effects worthy of sett in g systemic or neurotoxicity NOAELs/LOAELs. Comment #6: (Page 5, Section C) "Page 17 , Table A.2.3 870.7800 28-Day I mrnunotoxicity (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 findi n gs were observed in this study; in clinica l s igns, increased inci dences 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 rev iew of this study, HED has conc luded 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 (oxazol e 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 evalua tion 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, rev i se thi s 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 , concentra ti ons of radioactivity over time were generally hi ghest in liver, lymph nodes, thyroids, and fat, and were lowest in brain for both sexes in each dose group. " This state ment is misleading, as the radioactivity found in the lymph nodes was not found to be higher at later time

Page 3 of4points (especially at 168 hrs.) for both sexes in each group . In thyroids, radioactivity was not found at th e hi g he st level in the high dose a nim als , nor in the oxazole-label groups. Finall y, radioactiv ity found in fat is comparable to th at found in other ti ssues and i s generally not higher. The only instanc e where the language "genera lly highest" is correct is fo r the liver. RED 's Response: HED acknowledges Valent's interp retation of the data. After review of the data, whi le HED agrees that there is a time dependence to the amount of radioactivity found in t he various ti ssues , the abov e mentioned interpretation is confirmed. It does not impact the risk assessment and wo n 't be chan ged.

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