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John M. CarleyJohn M. CarleyKevin SweeneyKevin Sweeney

Office of Pesticide ProgramsOffice of Pesticide Programs

EPA Review of EPA Review of Completed ICR Study A-Completed ICR Study A-

382382

A laboratory test of stable fly repellencyfor two conditionally registered

formulationscontaining 20% picaridin

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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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Protocol ReviewProtocol 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

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Study ExecutionStudy 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

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Study Reporting & ReviewStudy 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

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Science Assessment: ICR A-382Science Assessment: ICR A-382

Kevin Sweeney

Senior EntomologistRegistration Division

Office of Pesticide Programs

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ObjectivesObjectives

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

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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

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Elements in Science Review

Dose determination

Margin of Exposure

Study Design

Efficacy

Conclusion

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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

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Dose Determination Results

Test Material Grand Mean Dose Volumetric Dose

Lotion 20% 0.87 g/250 cm2 3.551 μl/cm2

Spray 20% 0.99 g/250 cm2 4.125 μl/cm2

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Calculation of Margin of Exposure

Lotion dose (mg) 870

Picaridin from lotion (mg) 174

Spray dose (mg) 990

Picaridin from spray (mg) 198

Total picaridin (mg) 372

mg picaridin/70 kg bw 5.3

Margin of Exposure 376

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Repellent Study DesignRepellent 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

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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

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Repellency Results

Lotion 20% Spray 20%

Mean CPT + SD (Range)

4.5 h + 2.0 (2.5 -- 6.5)

6.3 h + 2.0 (4.3 – 8.3)

Median CPT 5.5 h 6.5 h

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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.

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Ethics Assessment: ICR A-382Ethics Assessment: ICR A-382

John M. Carley

Human Research Ethics Review OfficerOffice of Pesticide Programs

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Documents ConsideredDocuments 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

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Completeness of SubmissionCompleteness 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

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Response to EPA Ethics ReviewsResponse 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

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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.

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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

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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

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Applicable StandardsApplicable 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

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FindingsFindings 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

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ConclusionsConclusions

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

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ICR A-382: Charge QuestionsICR 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?