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

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

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55 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

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

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

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

99 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

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

11 Elements in Science Review Dose determination Margin of Exposure Study Design Efficacy Conclusion

12 Dose Determination 13 subjects self-dosed each test material to 250 cm 2 area of forearm Dose measurement  Weight change of container for lotion  Weight change of 50 cm 2 tape dosimeter on arm for spray Repeated three times for each test material Grand mean of subjects means used for efficacy trial

13 Dose Determination Results

14 Calculation of Margin of Exposure

15 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

16 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

17 Repellency Results

18 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.

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

20 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. G A382 and Project No p. MRID 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. G A382 and Project No p. MRID EPA Science & Ethics Review of Protocol (3/7/08) HSRB Report of April 2008 meeting (6/25/08) 20

21 Completeness of Submission MRID inadequately documents ethical conduct of the research Most deficiencies were satisfactorily addressed in supplemental submission MRID 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

22 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

23 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.

24 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

25 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

26 Applicable Standards 40 CFR § , requiring documentation of the ethical conduct of the research 40 CFR § , forbidding EPA to rely on data from research involving intentional exposure of pregnant or nursing women or of children 40 CFR § , 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

27 Findings With the supplemental submission of 27 Apr 08, the requirements of 40 CFR § 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

28 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

29 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?