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John M. Carley

Kevin Sweeney

Office of Pesticide Programs

EPA Review of Completed 

Carroll-Loye Study LNX-002

A field test of black fly repellency for two 

conditionally registered formulations

containing 20% picaridin
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Organization of Presentation

 Background information

 Science Assessment

 Ethics Assessment
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LNX-002: Basics

 Field test in one habitat of repellency of 2 

picaridin repellents against biting flies

 10 subjects treated with each repellent at 

dose rates established in earlier LNX-001

 2 untreated subjects to confirm pest pressure

 Endpoint is first confirmed landing with intent 

to bite (Libe) for each subject
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LNX-002: Protocol Review

 Protocol of 23 March 2009, was approved by IIRB, Inc. on 24 

March and submitted to EPA by Carroll-Loye Biological Research 

 EPA’s science and ethics review of 18 May 2009 found the 

protocol acceptable with minor changes

 HSRB review on 25 June 2009 concurred with EPA but called for 

testing only with black flies or midges

 Amendment 1, 13 August 2009, addressed EPA and HSRB 

comments and was approved by IIRB, Inc. on 18 August 2009

 Amended protocol was approved by CDPR on 14 September 2009

 HSRB leadership on 16 September 2009 decided scope of 

amendment did not necessitate re-review by HSRB
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LNX-002: Amendment 1

 Provides for collection & analysis of new dosimetry data on the cream 

 As recommended by EPA 

 Corrects drafting error for stopping rules

 Raises minimum landing pressure

 Changes exposure from 5 of every 30 min to 1 of every 15 min

 As recommended by HSRB 

 Focuses test on black flies

 Revises reference to 3rd-party insurance in consent form 

 Revises discussion of how data censorship will be minimized 

 Adds assay of subjects’ attractiveness to target insects 

 Revises protocol and consent form regarding number of subjects and 

details of subject participation 
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Study Execution

26-30 Sep 2009 Dose determination subjects recruited; dose 

determination testing with cream conducted

2 Mar 2010 Progress report submitted to IIRB, Inc.

9 Mar 2010 IIRB, Inc. approves one-year extension

15-19 Mar 2010 Subjects recruited for field test

20 Mar 2010 Field test conducted

1 Apr 2010 Deviation report to IIRB Re: use of superseded 

data collection form

5 Apr 2010 Study completion date 

7 Apr 2010 Final report submitted to EPA

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Study Reporting & Review

7 Apr 2010 Primary report of LNX-002 submitted to EPA

12 Apr 2010 EPA notified CLBR of missing record of IIRB, Inc. 

approval of Amendment 1

19 Apr 2010 CLBR submitted supplement including IIRB, Inc. 

approval of Amendment 1

7 Jun 10 CLBR submitted 2nd supplement reporting discovery 

that second black fly species not named in protocol 

had been present for field test

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Documents Considered in EPA Reviews

 Primary Study Report MRID 48053802

 Supplement 1 Re: IIRB approval MRID 48071301

 Supplement 2 Re: Unnamed fly species MRID 48117601

 EPA Science & Ethics Review of Protocol LNX-002

 HSRB Report of June 2009 review of LNX-002

 CLBR supplemental submission of IIRB, Inc. roster and 

procedures

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Science Assessment: LNX-002

Kevin Sweeney

Registration Division

Office of Pesticide Programs
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Objectives

 To test the black fly repellent efficacy of the 

test materials

 To satisfy a condition of registration imposed 

by EPA

Test Materials

 EPA Reg. No. 39967-50 (cream)

39967-53 (pump spray)

 Both contain 20% Picaridin
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LNX-002 Dose Determination

 Amendment 1 added a dose-determination phase with 

15 additional subjects using the cream, to supplement 

the dosing data collected in study LNX-001 

 The new and old dosing data for the cream were 

pooled to define the standard dose rate for the cream 

used in this study

 The standard dose rate for the spray was based on the 

data collected in LNX-001
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LNX-002 Field Study Design 

 10 subjects treated with each formulation and 2 

untreated control subjects participated in the one-day 

field trial in the Mojave desert

 Untreated subjects monitored black fly pressure; each 

attended by 2 technicians to aspirate landing insects

 Treated and untreated subjects’ forearms were exposed 

to target insects for 1 minute at 15-minute intervals

 Duration of efficacy for each subject was measured as 

the time from treatment to “First Confirmed Landing with 

intent to bite” or “FCLibe”
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Margins of Exposure 

 Based on the mean surface area of treated arms and an 

assumed mean bodyweight of 70 kg, the highest 

picaridin dose administered (cream on arms) delivered a 

mean dose per subject of 2.86 mg/kg

 The limit dose for picaridin dermal toxicity in the rat is 

>2,000 mg/kg

 The margin of exposure (MOE) for dermal toxicity of the 

picaridin cream was at least 699

 Mean dose for pump spray on arms was 1.43 mg/kg; 

MOE ≥ 1399
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Standard Doses and MOEs

Mean 

Repellent 

Applied

Mean 

Picaridin 

applied

Mean 

Dose in 

70-kg adult

MOE

Spray 0.5 g 100 mg 1.43 mg/kg 1399

Cream 1.0 g 200 mg 2.86 mg/kg 699
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Statistical Analysis

 Data analyzed using Kaplan-Meier survival 

analysis 

 Median CPT times were calculable for both 

product tests

 Mean CPT and time to 25% failure were also 

reported
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Field Test Results: LNX-002

Cream Spray

Mean CPT ± sd 

(95% CI)

9.9 ± 2.0 h 

(8.5 - 11.4 h)

9.9 ± 1.5 h 

(8.8 - 11.0 h)

Kaplan-Meier 

Median CPT 10.1 h 9.8 h

Time to 25% 

failure 9.1 h 9.1 h
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Role of Data Censorship

 5 of the 10 subjects treated with the cream 

experienced a FCLIBe

 6 of the 10 subjects treated with the spray 

experienced a FCLIBe

 Censored datapoints led to underestimates of the 

mean and sd, but did not compromise K-M medians

 Only three of the 9 subjects who did not experience 

failure received unconfirmed LIBes 
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Significance of Protocol Deviations

 Use of superseded data collection form

 Presence of unnamed black fly species 

Simulium tescorum

 51⁄2-month lapse between cream dose 

determination and field testing
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Conclusions

 The study design and conduct meet EPA Guideline 

and Good Laboratory Practices standards 

 The study results are sufficiently sound to support 

estimates of the duration of complete protection 

against black flies provided by

 EPA Reg. No. 39967-50 KBR 3023 All-Family Insect Repellent 

Cream (20% picaridin cream) 

 EPA Reg. No. 39967-53 KBR 3023 All-Family Insect Repellent 

Spray (20% picaridin pump-spray)
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Ethics Assessment: LNX-002

John M. Carley

Human Research Ethics Review Officer

Office of Pesticide Programs
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Completeness of Submission

 The primary study report, MRID 48053802, is 

generally complete

 One deficiency noted:

 No record of IIRB, Inc. approval of Amendment 1 

 Corrected by supplemental submission of MRID 48071301

 All requirements of 40 CFR 26.1303 for 

documentation of ethical conduct are satisfied by 

these two documents taken together

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Protocol Deviations

 Three deviations:

 Primary study report documents use of superseded data 

collection form

 Supplemental report of 7 June 2010 documents presence of 

a second species of black fly at field test site

 More than 60 days elapsed between dose determination and 

field testing

 None of these deviations affected the rights or safety 

of the subjects, or compromised informed consent

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Response to Previous Ethics Reviews

 EPA’s single comment in its protocol review of 18 May 09 was 

satisfactorily addressed in Amendment 1

 The HSRB’s request for clarification of “what 3rd-party medical 

coverage means” was addressed in Amendment 1, but not ideally. 

CLBR added the words in red to clarify its promise to pay: 

“costs of such medical treatment that are not covered by your 

own insurance or by a third party that covers you”

EPA now recommends:

“costs of such medical treatment that are not covered by your 

own insurance or by the insurance of a third party under which 

you are covered”

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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” 

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Findings

 The requirements of 40 CFR §26.1303 to document the 

ethical conduct of LNX-002 are satisfied

 LNX-002 did not involve intentional exposure of pregnant 

or nursing women or of children under 18

 Notwithstanding the minor deviations noted, LNX-002 

was conducted in substantial compliance with all 

applicable requirements of 40 CFR part 26, subparts K 

and L

 Subjects were fully informed and participated voluntarily

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Conclusion

 Assuming LNX-002 is determined to be scientifically 

acceptable, I find no barrier in law or regulation to 

EPA’s reliance on it in actions under FIFRA

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LNX-002: Charge Questions

1(a) Is the CLBR study LNX-002 sufficiently sound, 

from a scientific perspective, to be used to 

estimate the duration of complete protection 

against black flies provided by the tested 

repellents? 

1(b) Does available information support a 

determination that study LNX-002 was 

conducted in substantial compliance with 

subparts K and L of 40 CFR Part 26?