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EPA Review of Completed ICR Study A-382

EPA Review of Completed ICR Study A-382. A laboratory test of stable fly repellency for two conditionally registered formulations containing 20% picaridin. John M. Carley Kevin Sweeney Office of Pesticide Programs. 1. A-382 Characteristics.

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EPA Review of Completed ICR Study A-382

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  1. EPA Review of Completed ICR Study A-382 A laboratory test of stable fly repellency for two conditionally registered formulations containing 20% picaridin John M. Carley Kevin Sweeney Office of Pesticide Programs 1

  2. A-382 Characteristics • General design similar to earlier ICR cage study with mosquitoes, but with these differences • Test species is stable flies • Endpoint is first bite, without confirmation • Standard for aggressiveness/attractiveness differs • Includes preliminary dose-determination phase • Test repellents are same 20% lotion and pump spray picaridin products tested in LNX-001

  3. Protocol Review • Protocol A-382 was reviewed favorably by the HSRB in April, 2008 • ICR revised the protocol to reflect EPA comments • ICR further revised the protocol to reflect HSRB comments • Revised protocol was approved by EIRB on September 2, 2008 • Still further revised protocol was approved by EIRB on November 24, 2008 5

  4. Study Execution 18 Sep 08 Dose determination began under 9/2/08 protocol 2 Oct 08 Dose determination completed 7 Oct 08 Repellency testing attempted unsuccessfully 24 Nov 08 Revised protocol approved by EIRB 9 Dec 08 Repellency testing executed successfully 6

  5. Study Reporting & Review 3 Apr 09 Informal study submission to EPA 9 Apr 09 ICR notified of gaps in ethics documentation 23 Apr 09 Formal study submission to EPA by Lanxess 27 Apr 09 Formal submission of supplemental ethics documentation by Lanxess 7

  6. Science Assessment: ICR A-382 Kevin Sweeney Senior Entomologist Registration Division Office of Pesticide Programs 8

  7. Objectives • To test the repellent efficacy of the test materials against caged stable flies in the laboratory • To determine a typical consumer dose of the lotion and pump spray products • To satisfy a condition of registration 9

  8. Test Materials • EPA Reg. No. 39967-50 (lotion) 39967-53 (pump spray) • Both contain 20% Picaridin • Oral LD-50 > 5,000 mg/kg • Dermal LD-50 > 2,000 mg/kg

  9. Elements in Science Review • Dose determination • Margin of Exposure • Study Design • Efficacy • Conclusion

  10. Dose Determination • 13 subjects self-dosed each test material to 250 cm2 area of forearm • Dose measurement • Weight change of container for lotion • Weight change of 50 cm2 tape dosimeter on arm for spray • Repeated three times for each test material • Grand mean of subjects means used for efficacy trial

  11. Dose Determination Results

  12. Calculation of Margin of Exposure

  13. Repellent Study Design 12 treated subjects (7 males, 5 females) 1 negative control used to establish the aggressiveness of stable flies Spray applied to one arm and lotion to the other; treatments were randomized Staff who recorded results were blinded to treatments 15

  14. Stable flies • Stomoxys calcitrans L. • 50 adult flies per cage • Six cages – two subjects used each cage • Arms of each subject exposed for 5 minutes every 30 minutes for up to 10 hours or until failure • Endpoint was Time to First Bite

  15. Repellency Results

  16. Conclusions • The study was scientifically sound and the data from this study can be used to assess the repellency of the tested formulations against stable flies in the laboratory.

  17. Ethics Assessment: ICR A-382 John M. Carley Human Research Ethics Review Officer Office of Pesticide Programs 19

  18. Documents Considered • Primary Study Report: Gaynor, W. (2009) Evaluation of the Efficacy of KBR 3023 (Picaridin; Icaridin)-Based Personal Insect Repellents (20% Cream and 20% Spray Against Stable Flies in the Laboratory. Unpublished report prepared by ICR, Inc., under Protocol No. G4330108001A382 and Project No. 0108-433-0161. 268 p. MRID 47732701. • ICR supplemental submission: Gaynor, W. (2009) Chronology of Lanxess Stable Fly Repellent Protocol Approvals by the Essex Institutional Review Board: Supplement to the Study “Evaluation of the Efficacy of KBR 3023 (Picaridin; Icaridin)-Based Personal Insect Repellents (20% Cream and 20% Spray Against Stable Flies in the Laboratory.” Unpublished report prepared by ICR, Inc., under Protocol No. G4330108001A382 and Project No. 0108-433-0161. 132 p. MRID 47734901. • EPA Science & Ethics Review of Protocol (3/7/08) • HSRB Report of April 2008 meeting (6/25/08) 20

  19. Completeness of Submission • MRID 47732701 inadequately documents ethical conduct of the research • Most deficiencies were satisfactorily addressed in supplemental submission MRID 47734901 • Remaining deficiencies: • Documentation of EIRB member experience and expected contributions • Documentation of fulfillment of promises of signature pages to EIRB • Evidence of substantive discussion of the proposal and amendments by EIRB 21

  20. Response to EPA Ethics Reviews • EPA’s protocol review of 7 Mar 08 called for addition to the protocol of a discussion of the relation of risks and benefits; this new section headed “Balance of Risks and Benefits” was added: Since the potential risks of product safety, disease transmission, and bite irritation are minimal, the benefit of potentially providing two effective stable fly repellent products, more than offsets these minor risks 22

  21. HSRB Comments: Justice • Exclusion of subjects over 70 inadequately justified • New protocol text cites expected 10-h duration that ‘could get very tiring for older people’ • No explanation of how ability of subjects to read, speak and understand English will be assessed, or of why reading English is required • New protocol text explains that reading is needed for informed consent process; does not address methods for assessing abilities • No plans for ensuring a racially diverse sample • New protocol text adds repeated promises to recruit and select minorities, and provides for advertising if word-of-mouth isn’t adequate to solve the problem. Actual sample included minorities.

  22. HSRB Comments: Respect for Persons • HSRB expressed concern for blanket requirement for pregnancy testing, even of post-menopausal or surgically sterile women • Protocol revision of 10 Nov 08 provides for a signed statement in lieu of pregnancy testing

  23. HSRB Comments: Beneficence • Clarify whether flies would be fed bovine blood before use • Amended protocols assured no blood meal • ICR staff assessing outcomes should be blinded to protect scientific integrity of study • Different staff applied treatments and assessed outcomes • Randomize treatments to L or R arms • Treatments were randomized to L or R arms

  24. Applicable Standards • 40 CFR §26.1303, requiring documentation of the ethical conduct of the research • 40 CFR §26.1703, forbidding EPA to rely on data from research involving intentional exposure of pregnant or nursing women or of children • 40 CFR §26.1705, forbidding EPA to rely on data from research initiated after April 6, 2006 “unless EPA has adequate information to determine that the research was conducted in substantial compliance with subparts A through L of this part” • FIFRA §12(a)(2)(P), which defines as unlawful “for any person . . . to use any pesticide in tests on human beings unless such human beings (i) are fully informed . . . and (ii) freely volunteer to participate in the test” 26

  25. Findings • With the supplemental submission of 27 Apr 08, the requirements of 40 CFR §26.1303 to document the ethical conduct of A-382 were addressed well enough to support a thorough review • A-382 did not involve intentional exposure of pregnant or nursing women or of children under 18 • No deviations from the protocol were reported • Investigators made at least an effort to address EPA and HSRB comments, although efforts were not uniformly effective 27

  26. Conclusions • Conduct of this research was substantially consistent with the protocol as amended and approved by the responsible IRB • None of the shortcomings in ICR responses to EPA and HSRB comments affected the rights or safety of the subjects, or compromised the informed consent process • The overall record shows that the investigators prepared for and conducted A-382 in substantial compliance with 40 CFR part 26, subparts A-L • I find no barriers in law or regulation to EPA’s reliance on A-382 in its actions under FIFRA or §408 of FFDCA 28

  27. ICR A-382: Charge Questions 3.1 Is the ICR study A-382 sufficiently sound, from a scientific perspective, to be used to assess the repellent efficacy of the tested formulations against stable flies in the laboratory? 3.2 Does available information support a determination that study A382 was conducted in substantial compliance with subparts K and L 40 CFR Part 26? 29

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