Page 1 of 93 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON D.C., 20460

OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

September 2 2 , 2015

MEMORANDUM

SUBJECT: Science and Ethics Review of a Protocol for Laboratory Testing of S.C. Johnson Skin Applied Tick Repellent Products

FROM: Kevin J. Sweeney, Senior Entomologist Registration Division

Eric Bohnenblust, Ph.D., Entomologist Registration Division

Maureen Lydon , Human Research Ethics Review Officer

Office of the Director (On Detail )

TO: Marietta Echeverria, Chief, Invertebrate

- Vertebrate Branch 1 Registration Division Office of Pesticide Programs

REF: Styer, K. (2015) Protocol Submission Package for Testing of S.C. Johnson

Personal Tick Repellent Products to Support their Use of the EPA Repellency Awareness Graphic. Unpublished document prepared by i2LResearch USA, Inc., Baltimore, Maryland. July 28, 2015. 353 p. (MRID 49686701) (D428880)

We have reviewed the referenced protocol for a laboratory test of skin applied tick repellent products from both scientific and ethics perspectives. This review assesses the scientific aspects of the proposed research for an efficacy study to assess skin applied insect repellent products in terms

of the recommendations of the EPA OP PTS 810.3700 Guideline, the EPA Repellency Awareness Graphic Guidance, and the EPA Human Studies Review Board (HSRB). Ethical aspects of the proposed research are assessed in terms of the standards defined by 40 CFR 26 subparts K and L and

the recommendat ions of the EPA Human Studies Review Board.

A. Completeness of Protocol Submission

The submitted protocol was reviewed for completeness against the required elements listed in 40 CFR §26.1125. EPA’s checklist is appended to this review as Attachment 8

. AllPage 2 of 93 elements of required documentation are provided in the submitted protocol package and separate materials provided by the Schulman Associates Institutional Review Board (SAIRB) directly to the U.S. Environmental Protection Agency (EPA)

.

B. Summary Assessment of Ethical Aspects of the Proposed Research

Here is a summary of our observations about the ethical aspects of the proposed protocol. Supporting details are in the attachment s

.

1. Societal Value of Proposed Research: This study will determine the complete protection time (CPT) of up to eighteen EPA

- registered skin applied repellent products from S.C. Johnson & Son, Inc. on volunteer human subjects in a laboratory against three tick species

. Up to three different act ive ingredients will be tested , along with a variety of product types (e.g., lotions, spr itz, aerosols

, and towelettes). Direct testing of the duration of efficacy is important because consumers, who rely on repellents to avoid tick bites, cannot readily a ssess the efficacy of a product independent of EPA’s approval. EPA requires efficacy testing of these specific formulations to support their use of the EPA Repellency Awareness Graphic for ticks on their product labels. This graphic is intended to help co nsumers easily identify the repellency time (based on the Median CPT)

. Labeling repellent products with the graphic that identifies the type of pest the product is expected to repel, and the amount of time the repellent will be effective, benefits society by informing consumers about the efficacy of various products when they are choosing a repellent product to purchase. The sample diagram below describes the graphic (and includes a fictional example of repellency hours which are not intended

to apply to the study products)

.

2. Subject Selection: Ten subjects (5 males and 5 females) will be treated with a test

substance. Each test subject will serve as their own untreated control. There will be two alternate test subjects (one male and one female). Su bjects will be between 18 and 55 years of age . As described in the protocol language revised to address EPA’ s comments, subjects will be recruited for each study to best represent the demographics of U

. S

. repellent users, based on Neilson data identified in the protocol. Revised §2.3.6 of the protocol describes the targets for each sub

- population of U.S. repellent users. TestPage 3 of 93 subjects will be recruited via advertising

, through digital and social media, from the Baltimore, Maryland area where the testing w ill be conducted. A Spanish language advertisement will also be posted on line using the same digital and social media, along

with an online Spanish language newspaper that advertises within the recruitment area. The advertisements will contain a link to a study

- specific secure websi te where interested subjects can learn more about the study and , if interested, complete a pre

- screeni ng qualification form ; the form will be automatically uploaded int o a secure and encrypted portal to which i2LResearch employees will have access. Every effort will be made to achieve the demographic composition described in revised §2.3.6

. Individuals fro m the

recruitment pool will be contacted to determine whether they meet the basic inclusion

criteria and will be gi ven a brief outline of the study. If they are interested in enrolling in the study, they will meet with i2L staff for a training session to learn more about the

details of the study and their potential role in it, review the inclusion/exclusion criteria

, confirm their understanding of the informed consent document, a nd receive answers t o their ques tions

. T he training program is outlined in detail in §2.2.5 of the revised protocol language. All subjects who meet the requirements for participation and agree to participate in the study will signed the informed consent document, which will include

c onta ct information in case subject s have additional questions in follow

- up to the ir training

.

3. Risks to Subjects: Risks to subjects include the risk of adverse reaction , either irritation or allergic reaction, to the test substances; exposure to ticks ; the risk of exposure to tick vectored diseases; unanticipated loss of confidentiality or privacy ; and fatigue and/or physical discomfort from the length of the test day . Risks are minimized in the protocol by excluding candidates known to be sensitive to the test material; excluding candidates

known to be sensitive or allergic to ticks bites; conducting the research with disease free

ticks ; technician removal of ticks be fore they bite; using subject identification codes to help ensure privacy ; and incorporating procedures to keep the results of pregnancy testing private and permit discrete withdrawal. To try to address fatigue and physical discomfort, the study sponsor wi ll provide breakfast, lunch and dinner to participating subjects as described in the revised protocol , breaks and opp ortunities to stretch during the test day

, and support for the subject’s arm as it’s held at an angle during the exposure period. Also,

t he re will be a two

- day break between test days. P ractical steps to minimize subject risks have been taken, and the remaining risks have a low probability of occurrence.

4. Benefits: This research offers no direct benefit s to subjects, but may provide indirect

benefits to subjects and society by providing data that can be used by EPA to allow the

addition of the Repellency Awareness Graphic to skin applied tick repellent labels

. The

G raphic clearly informs consumers about the duration of repellent pro tection so that they can make informed choices about the repellent products they purchase and use , thereby allowing for better protection of consumers from nuisance bites and bites that lead to arthropod

- borne diseases

.

5. Risk/Benefit Balance: Based on the revised protocol language submitted in response to EPA comments, n o practical opportunities to further reduce risk to subjects whilePage 4 of 93 maintaining the robustness of the scientifi c design have been overlooked. The r esidual risk to subjects is viewed as lo w and reasonable in light of the potential benefits of the data to society.

6. Independent Ethics Review: The Schulman Associates IRB (SAIRB) has reviewed and

condi tionally approved the protocol and informed consent form. SAIRB’s final approval

is condi tioned on the sponsor obtaining HSRB review

, comments and approval. After the HSRB review process is complete, the pro tocol and other documents must be revised by the author and sponsor to incorporate comments from EPA and the HSRB, and then re

submitted to SAIRB for final approval before initiating the research. SAIRB is independent of the investigators and sponsors. D ocumentation of SAIRB procedures and membership is on file with the A gency.

7. Informed Consent: The protocol contains a description of the process by which potential subjects will be recruited and informed, and the process for seeking their consent to participate. The draft of the consent document (conditionally approved by the

SAIRB pending HSRB review/approval ) and the revised draft (in Attachment 3 ), w hich was prepared by the author in response to EPA comments

, meet the requirements of 40 CFR §§26.1116 and 26.1117.

8. Respect for Subjects : Study documents will refer to individual subjects using a code number and subjects will not be identified in any published reports or presentations about this research. The protocol specifies procedures for discrete handling of the pregnancy testing. Ca ndidates and subjects will be repeatedly informed that they are free to decline to participate or to withdraw at any time for any reason. Multiple opportunities exist to ask questions and receive information in response. Subjects who withdraw will be

compe nsated for time spent up to the point of withdr awal as described in the protocol

. Medical care for research related injuries will be provided through the sponsor at no cost to the subjects. As described in the revised protocol language, meals will be provi ded to participating subjects at the test site consistent with the length of each test day.

C. Compliance with Applicable Ethical Standards

This is a protocol for third

- party research involving intentional exposure of human subjects to a pesticide, with the intention of submitting the resulting data to EPA under FIFRA

. Thus the primary ethical standards applicable to this proposal are 40 CFR 26, Subparts K and L. In addition, the requirements of FIFRA §12(a)(2)(P) for fully informed, fully volunta ry consent of subjects apply. Attachment 1 provides a point

- by

- point evaluation of how this protocol addresses the requirements of 40 CFR 26 Subparts K and L and the criteria recommended by the

HSRB

.

EPA Ethics Comments

Before the research is initiated, the documents should be revise d to address EPA ’s ethics

comments in this section

, EPA’s science comments, and any forthcoming comments from thePage 5 of 93 EPA Human Studies Review Board. S.C. Johnson and i2LResearch agreed to address all of

EPA’s comments ; A ttachment 2 includes the revised language proposed by S.C. Johnson (hereafter “Johnson”) and i2LResearch in resp onse to EPA’s comments. HSRB members are encouraged to read through Attachment 2 to understand the proposed revisions

. After HSRB

review and comment, t he revised materials must be submitted to the SAIRB for final approval

.

EPA’s ethics comments are listed below (in order of the pertinent sections of the draft July 28, 2015 protocol to which they apply) :

1) For purposes of clarity, pleas e expand upon the following statement in Section 2.2.2 : “ Each tick species will be tested separately from the other two tick species over the course of two test days

, each lasting up to 18 hours (test period) for a total of 6 test days (3 testing period s) per study.”

2) Johnson and i2L Research will require a 2 hour training session for study p articipa nts prior to the test day in order for subjects to “learn more about the study and their potential role in it, go over the inclusion/exclusion criteria, and receive answers to any q uestions they may have.” EPA’s

science and ethics review resulted in the same recommendation regarding the t raining session ; th e protocol should be explicit with regard to the training outline and specific topics to be

addressed

.

3) Regarding the recruitment process described in sections 2.3.3

– 2.3.6 (on pages 15

– 16 of the

draft protocol ), Johnson and i2LResearch d ecide d to recruit participants instead of relying on a “pool of individuals who have expresse d interest in testing with i2L. ” As a result, p lease provide a revised and detailed description of the recruitment process for inclusion in the revise d protocol. The recruitment process should include advertisements in one or more local Spanish language newspapers. 40 CFR Section 26.1125(c) requires that the sponsor submit any advertisements proposed to be used; the advertisement language must be provi de d for EPA and HSRB review.

F ollowing EPA and HSRB review, the advertisement must be reviewed and approved by the IRB, along with all other changes to the protocol.

4) T he last statement in section 2.3.6 (above the chart, on page 17 of the protocol ) indicates tha t, “If

the individual desires

, this discussion may also take place by telephone or email.” OPP recommends deleting or revising this statement because it conflicts with the statement in section 2.4.1 (on page 19) that prior to participating in any study

- related procedure, each potential subject will meet in person with the Study Director or another designated staff member.

5) In order to strengthen the consent process and Informed Consent Document , EPA recommends the changes noted below. The revised consent form which Johnson and i2LResearch proposed in response to EPA comments is in Attachment 3.

a) I n order to confirm each subject’s understanding of the consent form, Johnson and

i2LResearch should draft several questions to be asked of e ac h potential subject prior to the subjects signing the consent form ; those questions should be included in the revised materials that are reviewed by the HSRB and SAIRB before the study is initiated. One of the questions

should address freedom to withdraw f rom the study.Page 6 of 93 b) The draft protocol indicates that participants sign the consent form once, r egardless of the

number of studi es in which they participate. EPA recommends that participating subjects read and sign the consent form more frequent ly and asks Johnson and i2LResearch to p ropose an

appro ach.

c) EPA r ecommend s that a section on “Test Material” and the identity of the pesticide and the

nature of its pesticidal function be included in the consent form

. As a result of this, please delete the language in protocol section 7.4 on blinding of subjects as to identity of test

substance.

d) In the consent form, under “purpose of study,” it says the Johnson and i2LResearch wish to conduct “five to eighteen research studies.” This is the first place where the num ber “five” is

used. EPA recommends consistency between the protocol and the consent form.

e) In the draft consent form, u nder “suitability,” second paragraph, EPA recommends referring

to “allergies or sensitivities ” to tick bites.

f) In the consent form, u nder “study duration and number of subjects,” when referencing the number of days of the study and number of testing periods, please be consistent with the proposed revisions to the protocol , specifically section 2.2.9.

g) U nder “study duration and number of subjects,” at the end of the first paragraph, please add the following language: “Each test subject can only take part once in any two

- day testing period. Subjects who become test subjects in two studies within one week will have different

arms treated for each study to avoid the risk of carry

- over of the first treatment to the second study.”

h) Please insert the detailed description of the training program in the consent form.

i) In the consent form, a t the end of the procedures section, p lease insert language about a

fifteen minute lunch break and fifteen minute dinner break

. Please reference that breakfast, lunch and dinner will be provided. T he breaks and providing breakfast during the preparation

time

, and lunch and dinner during the test day

, are necessary due to the length of the test day.

j) At the end of the “discomfort and hazards/risks” section, EPA recommends add ing the sentence, “There is also the fatigue and discomfort associated with a long testing day.”

k) Please update the compensation figures in the consent form consistent with EPA’s comments on compensation amounts. (See EPA comment # 7 .)

l) In the introduction to the consent form, please remove the reference to “alternative procedures” described in the cons ent form because suc h procedures are not discussed.

m) Please reference the updated preparation time, in addition to the potential length of the testing period, in the consent form.Page 7 of 93 n) In the consent form’s section on study duration and number of subjects, there is a reference to “zero to five female subjects plus five to zero male subjects.” EPA recommends that you replace this with a statement that both male and female subjects will participate.

o) EPA recommends deleting the section in the original draft c onsent form entitled, “Research Participation Information.” This section lists 5 different websites that subjects can check for information about participation in human research studies in general. Although EPA appreciates the intent of Johnson and i2LRese arch, given that these websites do not focus on the tick repellent study for which subjects are being recruited, EPA believes this section is unnecessary. Only the information directly relevant to the tick repellent study should be

included in the consent form to avoid unnecessary time be ing spent by subjects researchi ng other material.

p) The definition of the repellant breakdown/failure in the consent form needs to match the definition in the revised protocol.

q) T he consent form and phone scripts must be updated consistent with any other revisions to the protocol approved by EPA and the HSRB

.

6) EPA recommends that the training session require that each subject provide proof of age with a driver’s license, passport or other valid identification; Johnson already identified this inclusion factor in the protocol, but the protocol needs to specify at what point the ide ntification will be

checked. EPA recommend s that occur during the training session and at the beginning of each study, on the first day that a subject arrives for participation.

7) Section 2.5 of the protocol states that, for each test day, test subjects will be paid $99.00 for any length of participation up to 9 hours and if a test day exceeds 9 hours, subjects will be paid $16.50 (time and a ha lf) for each additional hour, rounded up to the nearest hour. The compensation of $11 per hour is not comparable to similar recent human studies. OPP recommends that S.C. Johnson increase compensation to $13 per hour up to 8 hours and if a test day exceeds 8 hours, subjects will be paid $19.50 (time and a half) for each additional hour, rounded up to the nearest hour. The protocol currently states that subjects will be paid $25 for taking part in the training session. Section 2.2.5 (page 14) indicates tha t the training session will

be about two hours. Given that the training session will be two hours in length, $30 seems like reasonable compensation and would be comparab le to other protocols/studies.

8) Regarding the inclusion/exclusion criteria, EPA recommend s the following changes:

“ 2.6.7. The subject must have no known allergies or sensitivities to tick bites. 2.6.9. The subjects must not be hypersensitive to repellent or latex or other skin care products. The subjects must be free from skin disea se, skin problems such as eczema, psoriasis or atopic

dermatitis. ”

9) EPA recommends that the pregnancy test be conducted within 48 hours prior to the test day. We understand that it’s necessary to conduct other prep aration work on the day of testing, butPage 8 of 93 Johnson can take steps to reduce the length of the day by having the pregnancy test completed in

advance.

10) Please update section 2.7.3 under “restrictions,” to indicate that there must be at least 48 hours, not 24, between each test day. Similarly update section 4.2 to indicate that there will be two days (not one) between test days.

11) The section on hazards to human subjects, section 2.10, page 24, currently discusses four types of potential hazards

. To be comprehensive in the protocol and consent form, J ohnson and

i2LResearch should add the hazard of, “Fatigue and/or physical discomfort from length of test day” and actions being taken to reduce this discomfort , including the provision of breaks for
lunch and dinner, subjects being encouraged to stretch as needed , and a 2 day break between test days.

12) The “hazards to human subjects” section 2.10 .10 , page 26 also states, “Subjects will be told that if anyone experiences any skin reaction, experiences an injury, or simply feels unwell, he or she should inform i2L staff right away. Such subjects will immediately be given appropriate care, may be withd rawn from testing, and may be transported to a local hospital if necessary.” EPA

recommends that Johnson and i2LResearch add language that the closest hospital and directions

will be identified prior to the test date

, and discussing reimbursement for medi cal care costs as applicable

.

13) Johnson and i2LResearch should try to reduce the length of the 2 hour preparation time which

occurs prior to the exposure period and limit it to essential activities which must occur during

that timeframe

. (If the preparation time is reduced in length, please reflect the new length in the

consent form

. )

14) Given the potential length of the test day, Johnson and i2LResearch should provide breaks and breakfast, lunch and dinner to the subjects.

15) Section 7.6 on repelle ncy observations explains that subjects will hold their forearm at approximately a 45 degree angle from the horizontal. EPA recommends that support material be provided to help bolster the subject’s arm and for comfort while it’s being held at a 45 degree angle. Please provide a photograph illustrating this support for EPA and the HSRB.

16) Regarding medical monitoring and reporting unanticipated problems in s ection 9.2, please add that subjects will be informed “in a timely manner”, both “orally” and in writing, of any significant new findings or new information. Please ex pand the title for section 9.2. to include “Stop Rule” given the proposed expanded content for that section.

17) In section 9.3 on study termination, individual participation, and withdrawal, in 9.3.2, after the

reference to medical management, please add: “This is discussed in detail in section 2.10.10.” Please update sections 9.3.6

– 9.3.9 to reflect the new compe nsation figures agreed to and the 8 hour timeframe (as opposed to 9 hours), in follow

- up to EPA’s comments.Page 9 of 93 18) EPA recommends the following changes to the telephone script s for initial and follow

- up contac t with potential subjects who respond to recruitment advertisements; the original scripts are included on pages 319

- 325 of the draft protocol

.

Initial contact script

Please add:

• the length of the test day will depend on the length of time that the repellent effectively repels ticks;

• training session will be about 2 hours;

• for privacy reasons, names of subjects will not appear anywhere on the data sheets or in the study reports;

• subjects will be paid according to the updated compensation figures; please use the updated figures in the script; and

• subjects ar e free to quit or withdraw from the study at any point of time and they will be paid for hours worked.

Follow

- up contact script

Please add :

• the length of the test day will depend on the length of time that the repellent effectively repels ticks;

• training session will take place prior to participating in each study and will be about 2 hours;

• subjects will be asked for identification/proof of age during the training session;

• for privacy reasons, names of subjects will not appear anywhere on the data sheets o r in the study reports;

• subjects will be paid according to the updated compensation figures; please use the updated figures in the script;

• subjects are free to quit or withdraw from the study at any point of time and the y will be paid for hours worked;

• su bjects will be provided breakfast, lunch and dinner if they are still participating in the study during these meal times;

• breaks will be provided at specified times;

• an expanded question that ask s about allergies to tick bites, in addition to sensitivity;

• pregnancy test will be performed in private; and

• encourage ment to read the consent form in advance of the training.

Johnson and i2LResearch submitted revised scripts , in Attachment 4, in response to EPA’s

comments.

19) Please update Appendix A, checklist of elements, with regard to page numbers and other pertinent information, after the protocol is revised in response to EPA and HSRB comments.

T hroughout the protocol, after it is revised in response to comments , whenever the protocol refer s to other pertinent information as being “above” or “below,” please replace such references with a specific section number

.Page 10 of 93 Attachment 2 includes responses and revised language proposed by Johnson and

i2LResearch in reaction to EPA’s comments.

40 CFR 26 Subpart Q, at §26.1703, as amended effective April 15, 2 013, provides in pertinent part that: EPA must not rely on data from any research involvin g intentional exposure of any human subject who is a pregnant woman (and therefore her fetus), a nursing woman, or a

child.

This protocol requires that subjects be at least 18 years old and excludes female subjects who are pregnant or lactating. Thus §2 6.1703 would not forbid EPA to rely on a study executed according to this protocol.

D. Summary Assessment of Scientific Aspects of the Proposed Research

“The objective of this study is to establish the complete protection time of up to eighteen

EPA

- registered repellent products (‘test substances’) from S.C. Johnson & Son, Inc. on human subjects in a laboratory setting against three species of ticks (Pathog en free Amblyomma
americanum, Dermacentor variabilis, and Ixodes scapularis). Testing will take place in a series of up to 18 individual studies (one study per test substance), possibly over several weeks, months, over a year, with each study individually conducted according to this protocol. This data will be used to allow these products to use EPA’s new Repellency Awareness Graphic for the labels.” (p. 12 of 353, §1.1).

The Repellency Awareness Graphic system assigns duration of protection (in hours) on the EPA label, coupled with a graphic symbol for the target pest(s), which in this case is for ticks. The First Confirmed Crossing (FCC), defined as a tick crossing into the treated area followed by another crossing (confirming the first) within two 15 min ute test periods (or within 30 minutes), will determine repellent failure for each tick species (p. 37 of 353, § 7.6.14). A CPT will be calculated for each tick species. The CPT for “ticks” to be used on the insect repellency graphic will be from the tick species with the lowest CPT value (p. 40 of 353, §10.2.5). In this experiment the product dose will be standardized for product comparisons, so the study as proposed has no dosimetry phase to determine the typical consumer dose of these products when app lied by human subjects participating in the study.

This study will be conducted in accordance with EPA, FIFRA (Federal Insecticide, Fungicide and Rodenticide Act), and Good Laboratory Practice Standards (GLP); 40 CFR, Part 160 (October 1989). “I2LRe search USA, Inc.’s independent Quality Assurance Unit (QAU) in the person of Jennifer Hostetler will perform all QA duties.” (p. 12 of 353 §1.2.1)

Johnson and i2LResearch agreed to incorporate all of EPA’s comments on their draft protocol dated July 28, 2015; their responses to comments and proposed revisions are inPage 11 of 93 Attachment 2 . This section of EPA’s review takes into account their revised procedures and design.

1. Study procedures and design:

Study site location and testing facility: i2LResearch USA, Inc., Baltimore, Maryland, USA.

Study Director: Timothy Foard

Study Sponsor: S.C. Johnson & Son, Inc., Racine, Wisconsin, USA

Subject selection: §2.1.

- §2.7 on pages 14

- 23 of 353 describe the process of subject recruitment, qualification, compensation, training, and selection

. §2.1.3

- 4, §2.2, §2.3.3

-- 10, §2.6, and §2.7 on pages 14

- 18 and 21

- 23 of 353, respectively, are most relevant to the science review because they discuss the number of test subjects and alternates, test subject withdrawal from the study and study conduct thereafter, subject inclusion/exclusion criteria, and restrictions. Twelve subjects (ten test subjects and two alternates) will be selected from a pool of subjects to be recruited in the Baltimore Metro area. As described in revisions to §2.3.4 and §2.3. 6, it’s intended that the pool of subjects to be recruited will generally

represent the demographics of U.S. repellent users. The approach to be used to determine the subject pool from which test subjects and alternates will be selected is explained in §2.3.6

, revised to address EPA’s comments, and includes target % demographic levels of U.S. insect repellent users categorized by sex, age, race, ethnic background, and ability to speak a second lang uage. An individual must be an insect repellent user to be included in the study (§2.6.8). From a science perspective this approach is acceptable because of the absence of data showing that any of these factors make an individual more or less attractive t o ticks.

Johnson and i2LResearch propose to revise s ection 2.3.8 to include the following;

“ For each testing period, twelve test subjects (six female and six male) will be selected from the pool of subjects that fulfill the inclusion/exclusion criteria and have signed the ICD for the study, by a subject allocation table via appropriate software ( such as Excel or Minitab) . This selection will be achieved by randomly selecting the test subjects’ assigned code number. The first five females and five males will be assigned as the test subjects. The sixth female and the sixth male will be assigned to a ct as alternates.

Using a number generating statistical software (such as Excel or Minitab), a second random selection will be made from the ten test subjects to determine the testing day on which each subject will participate. The first five selected wi ll participate in the first test day, and the remaining five subjects will participate in the second test day. Alternates will be asked to be available for both days.

For logistical ease for each test day, SC Johnson and i2L prefer to keep the decision a s to which limb (left or right) will be treated based on a coin toss ( § 4.1). ”Page 12 of 93 Five subjects will participate on Day 1 while the other five will participate on Day 2. Alternates are to be available on both days of testing ( §2.3.8 and §2.3.9) . If a subject withdraws from a study once it has started, the study will continue with the remaining subjects. The study director may also exclude a subject from a study in the rare event that they are not attractive to ticks, that is, none of the ticks placed on the skin of an untreated subject’s arm crawl a minimum qualifying distance up the subject’s arm ( §2.6.13). Any subjects wishing to participate in more than one day of testing will not be allowed to participate on two consecutive days. Based on comments from EPA, a minimum of 48 hours (two calendar days) is needed between test days to avoid the possibility of any repellent carrying over from an earlier test day to the following one ( Revised §2 .7.3).

Treatments and replication : Ten subjects will be treated with the test substance for each tick species repellency evaluation. Each subject will serve as their own treatment and untreated control (using opposite arms) to allow for comparison of tick behavior in the presence and absence of the tes t substance. The decision as to which arm to treat will be based on a coin toss on the day of the treatment. A positive control substance will not be used (§4.0, pp. 30

- 31 of 353).

Justification for sample size is discussed in §10.2 on pp. 41

- 43 of 353 o f the protocol, specifically in §10.2.2 and §10.2.3 where literature is referenced to support the need for more than five subjects per test but retaining ten subjects. These sections will be revised to include Johnson’s and i2L’s response to EPA co mments as follows (see Attachment 2 of this review):

“ The number of test subjects for a tick repellency efficacy study should strike a balance among three critical and competing criteria:

a) Minimization of potential hazard to test subjects, where fewer subjects is better.

b) Statistical robustness, where more subjects results in greater precision of numeric

estimates.

c) Consistency with previous repellent efficacy studies. Current and recent practice is to
utilize ten subjects for each test site/test p roduct.

The standard data analysis method for tick repellency efficacy studies involves the Kaplan

Meier estimator, and the measure of interest is the Kaplan

- Meier median. The confidence limits associated with the Kaplan

- Meier median are positional values in the distribution, rather than calculated values as in the case of a confidence interval around the mean. The table below indicates which positions in the distribution of values constitute the lower confidence limit (LCL) and upper confidence lim it (UCL) of the median for various sample
sizes. The assumption is that the values are sorted in increasing order, so value “1” in the distribution refers to the smallest value (i.e., the minimum).

Kaplan Meier median confidence limits were calculated us ing SAS, which employs a generalization of the Brookmeyer and Crowley (1982) sign test under a log

- log transformation.Page 13 of 93 ► Table 1: Kaplan

- Meier Median Confidence Limits for a Range of Sample Sizes.

Sample

size Distributional position for

95% LCL Distributional position for

95% UCL Percent of

values above

LCL

10 1 8 90%

12 2 10 83%

15 3 11 80%

20 5 15 75%

As evidenced by the table, sample sizes larger than ten would provide only marginal increases in precision relative to the increase in the number of exposed test subjects. Given that a sample size of ten meets criteria a) and c), and a sample size greater than ten has limited impact in criterion b), I recommend the continued use of ten as the sample size for tick repellency efficacy studies. ”

Doubling the number of subjects would also increase the cost of the study significantly. The test as designed uses the lowest CPT from the three tick species tested to avoid an overestimate of CPT for the Insect Repellency Graphic.

Tables 1, 2, and 3 list the eighteen product treatments to be tested and a summ ary of the test design. Product names are listed in §3.1.1

- 3.1.18 on pages 26

- 29 of 353 of the protocol. The footnotes are listed once but apply to all three tables.

Table 1. Study Design

– DEET Products

Repellent Product

EPA Reg. No. Product Type Number of Tick Species 1 Number of

Human Subjects per Tick Species
(Replicates ) Total Replicates

per Product 2 Maximum
Number of Tick Exposures per Species /Product

Test (18 hours) 3

4822

- 415 5% DEET Spritz 3 10 30 72/206

4822

- 552 5.6% DEET Towelette 3 10 30 72/206

4822

- 395 7% DEET Spritz 3 10 30 72/206

4822

- 380 15% DEET Aerosol 3 10 30 72/206

4822

- 543 15% DEET Aerosol 3 10 30 72/206

4822

- 167 25% DEET Aerosol 3 10 30 72/206

4822

- 258 25% DEET Towelette 3 10 30 72/206

4822

- 399 25% DEET Spritz 3 10 30 72/206

4822

- 572 25% DEET Aerosol 3 10 30 72/206

4822

- 397 30% DEET Aerosol 3 10 30 72/206

4822

- 276 98.25% DEET Spritz 3 10 30 72/206

1 Adult American dog tick, adult Lone Star tick, and adult or nymphal blacklegged (deer) tick.Page 14 of 93 2 Ten replicates per tick species for a total of 30 replicates. A CPT will be calculated for each species
based on ten treatment replicates. The lowest CPT will be used for the Insect Repellency Graphic.

3 Based on four tick exposures to the treatment per hour (One every 15 minutes.). This value
doubles to 412 when untreated control exposures are included.

Table 3 . Study Design

– Picaridin Products

Repellent Product

EPA Reg. No. Product Type Number of Tick Species 1 Number of

Human Subjects

per Tick Species (Replicates) Total Replicates

per Product 2 Maximum
Number of Tick Exposures

per Species

/Product Test

(18 hours) 3

4822

- 536 5% Picaridin Spritz 3 10 30 72/206

4822

- 535 5% Picaridin Lotion 3 10 30 72/206

4822

- 556 20% Picaridin Spritz 3 10 30 72/206

4822

- 564 20% Picaridin Aerosol 3 10 30 72/206

Table 4 . Study Design

– p
- Methane

- 3, 8

- Diol (PMD) Products

Repellent Product

EPA Reg. No. Product Type Number of Tick Species 1 Number of

Human Subjects per Tick Species (Replicates) Total Replicates

per Product 2 Maximum
Number of Tick Exposures

Per
Species/Product

Test (18 hours) 3

4822

- 526 8% PMD Towelette 3 10 30 72/206

4822

- 515 10% PMD Lotion 3 10 30 72/206

4822

- 528 10% PMD Spritz 3 10 30 72/206

Product application : Each subject will have one forearm treated with the repellent product to be tested. The choice of forearm treatment will be made by the study director or designated staff on the day of the test based on a coin toss. As a result, the surface area of

both forearms will be measured for every subject. Surface area calculation is described in §5.2 on page 31 of 353 of the protocol and will be calculated as follows:

Area = C * D

For the forearm, ‘C’ equals the circumference of the forearm (based on the mean of four equidistant measurements made from 6 cm above the wrist bone to 12 cm above that point towards the elbow (18 cm above the wrist bone) and ‘D’ equals the distance betwe en the wrist and the elbow measurements. An example is provided in Appendix I of the protocol.Page 15 of 93 A set (fixed) application rate of 1 gram of product per 600 cm 2 (1.67 mg/cm 2 ) is proposed for aerosol and lotion products while 0.5g of product per 600 cm 2 (0.8 35 mg/cm 2 ) will be applied for spritz/pump spray products. Test substances will be applied by i2L Research staff. A dosimetry phase to determine a ‘typical consumer application rate’ by dose titration, which would be based on the grand mean of triplicate applications made/cm 2 by the test subjects will not be performed. Five reasons for using a set (fixed) application rate rather than a titrated application rate are stated (p. 32 of 353, §6.1.2

– §6.1.2.5):

“(1) Influence of outliers: A single outlier da ta point can unduly influence the mean of 10 application rates applied by subjects. A set application rate avoids this risk;

(2) Inter

- test variability: Choice of dosing from dosimetry often results in selecting different application rates for different tests since the groups of subjects will apply varying application rates. This can obscure the cause of any different outcomes from two otherwise identical tests. This risk is avoided by using a set application rate;

(3) Product (test substance) effect: Varying a pplication rates between studies make it impossible to determine if performance difference is driven by the application rate or the test products;

(4) Time and cost: Subject

- derived application rates introduce additional time and cost to a study compared to a set rate; and

(5) Relation to actual consumer use: A set application rate can be related to known consumer behavior. Subject

- derived application rates allow the possibility of an atypical result. The application rates proposed in this protocol are based o n dosimetry data from previously EPA/HSRB reviewed repellent studies. ”

To apply the target application rate of 1.67 mg/cm 2 for lotions and aerosols the following

formula will be used:

[Area of the Limb/600 cm 2 ] * 1 gram = weight (amount) of product to apply

To apply the target application rate of 0.835 mg/cm 2 for spritz/pump sprays the following

formula will be used:

[Area of the Limb/600 cm 2 ] * 0.5 gram = weight (amount) of product to apply

The application of repellent product to the skin of each subject will depend on the product type (§6.7 on pages 33

- 34 of 353):

• For pump sprays the test substance container is placed on a balance, weighed, and the balance is tared. The required weight is drawn up by pipe tte while observing the digital display on the balance and applied to the skin of the subject. A gloved i2LPage 16 of 93 Research staff member will spread the substance evenly throughout the treatment

area.

• For aerosol sprays the test substance container is placed o n a balance and the balance is tared. The test substance is then sprayed from the container directly onto the skin. After the spray, the sample is returned to the balance and the amount applied is determined. If the amount is below the required weight, more test substance is sprayed onto the limb targeting the required weight as closely as possible. The acceptable range will be within 10% of the target weight.

• For lotions the test substance container is placed on a balance and the balance is tared.

The required weight of the test substance is then removed by spatula or similar implement

- carefully observing the balance read out.

• For towelettes a 250 ml beaker is placed on a top loader balance. The balance is tared. A single towelette is placed in the b eaker and the balance is re

- tared to determine the weight. The towelette is removed from the beaker and squeezed gently over the treatment area. The procedure is repeated until the target quantity of product

has been delivered.

Product treatments will be made by the i2LResearch’s staff. The target dose weight and actual weight applied will be recorded on a data sheet (p. 47 of 353, Appendix II). Margin of Exposure (MOE) estimates are based on an assumed 80 kg subject and the acute dermal LD 50 value for each product at the limit dose of greater than 2,000 mg/kg. Based on the dose/application rates presented by S.C. Johnson in Appendix VIII (pp. 63

- 68 of 353), the MOE values for the products and their associated active ingredients will exceed E PA’s level of concern of MOE = 100. Specific MOE values will be provided for each product when the study is conducted.

Test area demarcation and product treatment: “ Four lines will be drawn on both of the subjects forearm as follows (§7.5 on pp. 35

- 36 of 353) :

• ‘Release line’ 3 cm above the wrist bone towards the elbow;

• ‘Boundary line’ 3 cm above the release line towards the elbow (this will be the edge of the treated area);

• ‘Crossing line’ 3 cm above the boundary line;

• An upper boundary line 12 cm above the boundary line; this will not be used during testing and serves only to denote the boundary of the treated area.

The treatment will be applied as previously described.”

Subject training : Subject training is adequately explained in Johnson’s and i2LResearch’s revised training description in Attachment 2 , in the response to EPA’s comment # 1.

Conducting the test and repellency observations ( §7.3 and §7.6 on pages 35

- 38 of 353).

In response to EPA comments, as proposed, the section s on experimental design and repellency observations will be revised to include the following information :Page 17 of 93 • Each species evaluation will be conducted separately on different days.

• Ticks will be tested one at a time on each test subject, at 15 minute interva ls. The test day could last up to 19 hours: 1 hour for preparation time, and up to 18 hours for exposure period, depending on the repellent tested.

• Test subjects will wash their forearms with soap and water and dry them thoroughly with a paper towel.

• Test substances will be applied to the test subject’s forearm as described in § 7.5 “ Test

area demarcation and treatment”.

• Section 7.6 includes revised language reflecting the following steps :

• Thirty minutes after the treatment is applied, the first tick exposure will begin.

• For each exposure, the subject will sit in a chair and hold their control (untreated) forearm at an approximately 45 degree angle from the horizontal, fingers pointing down. The subject will hold their forearm so that the inner surface faces away from the body and upwards. Support m aterial will be provided to help bolster the subject’s arm and for comfort while it’s being held at a 45 degree angle from the horizontal.

• Three timers will be pre

- set to help aid in the timing of each exp osure interval. One timer will be set to monitor the 15 minute exposure interval, and two timers will be set for three minutes each for the ticks’ response on the control and treated arms, respectively.

• The 15 minute timer will be activated . An i2L Resea rch staff member will gently pick

up a single tick from the holding vial, using fine forceps or a cotton

- tipped applicator stick or equivalent, and place it on the release line on the inner surface of the subject’s control forearm, and activate the first three minute timer

.

• The tick will be oriented gently towards the elbow using forceps or a cotton

- tipped applicator stick or equivalent. A normally active tick will begin to crawl up the forearm

towards the elbow. The tick will be allowed three m inutes to move across the boundary

line.

• If the tick crosses the boundary line within three minutes, it will be considered to be actively questing, and will be immediately removed from the control arm. The tick will be accepted as attracted to the subject’ s skin and behaving normally and thus acceptable for use in the repellency test. If the tick is not attracted, it will be removed and discarded by immersing it in isopropyl alcohol , and the process will be repeated until a control tick is

verified. The 3 minute timer will be stopped and reset accordingly.

• Once an acceptable tick is selected, the subject may relax their control arm. They will then lower their treated forearm to 45 degrees from the horizontal. The confirmed tick will be placed at the release line on the treated arm , and the second 3 minute timer will be activated, and oriented using the same method as for untreated arm.

• T he tick will be allowed three minutes to move across the boundary line and 3 cm into the treated area (to the crossing lin e).

• If the tick does not cross the boundary line to the treated area within three minutes, it will be recorded as being repelled.

• If the tick crosses the boundary line into the treated area, but then does not reach the crossing line within three minutes of being released, it will be also reported as being repelled.

• If the tick crawls to the crossing line within three minutes of being released, it will be reported as not repelled.Page 18 of 93 • The tick will subsequently be killed by immersion in isopropyl alcohol. No ticks will be

re

- used.

• The above procedures will be repeated for each exposure period, every 15 minutes. The start time for each will be recorded as the time that the first tick is placed on the subject’s

untreated forearm.

• The exposure of a single tick e very 15 minutes will continue for 18 hours or until the test substance ‘breaks down’ (i.e. fails to repel, see below). Each exposure may last anywhere from 6 to 15 minutes, depending on control tick behavior.

• Test substance breakdown occurs when one tic k is recorded as not being repelled (i.e. crossing or repellent failure) and one of the two following events occur: (i) the first subsequent tick to be exposed is also recorded as not being repelled or (ii) the first subsequent tick is repelled, but the se cond subsequent tick is recorded as not being repelled. Either (i) or (ii) will be counted as confirming crossings within 30 minutes of the first crossing. The time of breakdown will be recorded as the time of the first confirmed crossing.

• Subjects will be instructed to wash their arms with mild soap and water once the product on their arm has broken down, or at the conclusion of the test day

.

• The ticks will not be allowed to bite the subjects for health and safety reasons. Any tick

that ceases movement f or more than a few seconds will be gently prodded with forceps or

a cotton

- tipped applicator stick or equivalent. It should be noted that, unlike mosquitoes, most ticks will not bite immediately but will often crawl about on the host for hours

before bitin g.

• Repeat the above procedure every 15 minutes for up to 18 hours or repellent failure.

2. Endpoints and Measures

“Test substance breakdown” occurs when one tick is recorded as not being repelled and one of the following events occur:

(i) The first subsequent tick to be exposed is also recorded as not being repelled or (ii) The first subsequent tick is repelled, but the second subsequent tick is recorded as not being repelled.

Either one of the above events will be counted as confirming crossings w ithin 30 minutes of the first crossing. The time of breakdown will be recorded as the time of the First Confirmed Crossing (FCC), which defines repellent failure for that replicate. The time of the first crossing is recorded as the CPT for that replicate.

Calculation of Complete Protection Time (CPTs) and Duration of Protection

CPTs will be calculated as the time from test substance application to the time of breakdown (i.e., First Confirmed Crossing). The breakdown times of each test subject will be calculated as the number of hours from treatment time to first confirmed crossing. The time in hours for each individual test subject will be used to calculate the median protection time for each species separately. The breakdown times will be u sed toPage 19 of 93 calculate the median CPT (within a 95% confidence interval) for each substance for each species ( § 10.3.1 and § 10.3.2 on pages 43

- 44 of 353).

The duration of protection for each test substance will be defined as the lowest median CPT from the three tick species tested. This value will be rounded down to the closet full hour and used for the Repellency Awareness Graphic ( §10.3.3 on page 44 of 353).

. 3. Data Analysis:

The objective of the data analysis is to estimate the Median Complete Protection Time. The Median CPT of all test subjects will be calculated using the Kaplan

- Meier estimator, which is advantageous since CPTs may not be normally distributed. Kaplan

- Meier has an advantage as a non

- parametric method for surviv al analysis; this method does not require or assume the data to follow a particular parametric distribution. This method can also

account for censored observation. Kaplan Meier estimator has been accepted by EPA and

the HSRB for the Median CPT calculation in past repellent efficacy studies and is also recommended by the World Health Organization for CPT calculation from these nonparametric data sets (§10.3.6 on page 44 of 353).

The statistical software may consist of widely used software packages or on

- li ne resources for the Kaplan

- Meier Estimator.

Alternate subjects: § 10.2.9 states: “There will be two alternate subjects, one of each gender, in case any of the test subjects withdraw from the study before treatment applications are completed. Once treatmen ts have been applied, subjects cannot be replaced. Therefore, if a subject withdraws after a test has begun, testing will continue with only the remaining subjects.”

E

. Compliance with Applicable Scientific Standards

This protocol adequately addresses the following elements according to applicable

scientific standards assuming that EPA’s comments, outlined below, are addressed :

• Prerequisite acute toxicity research to characterize toxicological profile of the formul ation and calculate margin of exposure (MOE) ;

• Experimental design ; and

• Training.

EPA Science Comments

The five elements listed below require revision/amendment before the research goes

forward . Johnson and i2LResearch agreed to address all of EPA’s comments. Attachment 2 includes their proposed revisions in response to the following comments:Page 20 of 93 1) Pre

- training of subjects is barely described. More information is required. Th e protocol should be explicit with regard to the training outline and specific topics to be addressed

.

2) Please provide more details on the exact timing of the testing. The protocol needs to explicitly describe the amount of time the technician has to do testing and the amount of time in a 15 minute period that requires the subject to be seated and exposed t o ticks.

3) Repellent sample size selection: The protocol cites one example of the effect of sample size on

confidence interval width when c hanged from 10 to 20 subjects. Submit a simulation showing the impact of increasing sample size on the width of 95% confidence interval of median CPT where median CPT will be estimated using Kaplan Meier method. This can be presented in table form.

4) A randomization mechanism needs to be inserted into sections 2.3.8 and 2.3.9.

5) Amend the protocol to require subjects to wait at least two calendar days (48 hours) between experiments if they participate in multiple experiments.

Attachments :

1. EPA Protocol Review

2. Revised Language from S.C. Johnson and i2LResearch in Response to EPA’s Science

and Ethics Comments

3. Proposed Revised Consent Form Addressing EPA’s Comments

4. Revised Scripts for Initial and Follow

- up Telephone Contact with Potential Subjects who Respond during Recruitment

5. §26.1111 Criteria for IRB approval of research

6. §26.1116 General requirements for informed consent

7. §26.1117 Documentation of informed consent

8. §26.1125 Criteria for Completeness of Proposals for Human Research

9. Additional information submitted by SAIRB directly to EPA

10. SAIB Board Roster

11. Proposed Recruitment Materials submitted by Recruitment FirmPage 21 of 93 Attachment 1

EPA Protocol Review

Title: Testing of S.C. Johnson Personal Tick Repellent Products to Support their Use of the EPA Repellency Awareness Graphic.

Date on Draft Protocol : July 28, 2015

Principal Investigator and any sub

- investigators: Timothy Foard

Participating Laborato ry: I2LResearch USA, Inc. 1330 Dillon Heights Avenue Baltimore, MD 21228

Sponsor:
S.C. Johnson & Son, Inc.

1525 Howe Street Racine, WI 53403

IRB:

Schulman Associates IRB Sawgrass Plaza, Suite 120 1530 Sawgrass Corporate Parkway
Fort Lauderdale, FL 33323

1. Societal Value of Proposed Research

(a) What is the stated purpose of the proposed research?

“ This data will be used to support these products’ use EPA’s new Repellency Awareness Graphic for labels. This system assigns duration of protection (in hours) by the repellent on the EPA label, coupled with a graphic symbol for the target pest(s), in this case Ticks ” (pp. 13, §1.4.2).

This study is designed to determine the complete protection time (CPT) against adults of three species of ticks (pathogen free Amblyomma americanum

, Dermacentor variabilis

, and Ixodes scapularis ) on human subjects in a laboratory setting for up to eighteen EPA registered repellent products from S.C. Johnson & Son, Inc. Direct testing of the duration of efficacy is important because consumers, who rely on repellents to avoid tick bites, cannot readily assess the efficacy of a product independent of EPA’s app roval. EPA requires efficacy testing of these specific formulations to support their use of the EPA Repellency Awareness Graphic for ticks on their product labels. This graphic is intendedPage 22 of 93 to help consumers easily identify the repellency time (based on the tick species with the lowest CPT) for ticks (and mosquitoes when requested). Labeling repellent products with the graphic that identifies the type of pest the product is expected to repel, and the amount of time the repellent will be effective, benefits s ociety by informing consumers about the efficacy of various products when they are choosing a repellent product to purchase. The diagram below describes the graphic.

(b) What research question does it address? Why is this question important? Would

th e research fill an important gap in understanding?

To determine the Complete Protection Times of eighteen S.C. Johnson & Son, Inc. personal tick repellent products. This information does not currently exist.

(c) How would the study be used by EPA?

EPA will consider the study to satisfy product specific efficacy data requirements for use of the EPA Repellency Awareness Graphic on the eighteen S.C. Johnson & Son, Inc. personal repellent labels.

(d) Could the research question be answered with existing data? If so, how? If not, why not?

EPA requires product

- specific efficacy data conducted to assess skin applied insect repellent products in terms of the recommendations of the EPA OPPTS 810.3700

G uideline and EPA Repellency Awareness Graphic Guidance. Previous tests of these products against ticks under the proposed use pattern do not meet these recommendations for repellent efficacy.

(e) Could the question be answered without newly exposing hu man subjects? If so, how? If not, why not?Page 23 of 93 Human subjects are required because they represent the target system for the test material, and reliable non

- human models for repellency testing have not been developed.

2. Study Design

(a) What is the scientific objective of the study? If there is an explicit hypothesis, what

is it?

“To establish the duration of protection of up to eighteen EPA

- registered repellent products (‘test substances’) from S.C. Johnson & Son, Inc. (‘Johnson’) on human subjects, in a laboratory setting, against three species of tick (Amblyomma americanum, Dermacentor variabilis, and Ixodes scapularis). Testing will take place in a series of up to 18 individual studies (one study per test substance), possibly over s everal weeks, months, or a year with each study conducted individually according to this protocol” to be revised based on comments from EPA and the HSRB. (pp. 12, §1.1)

. “The rationale is to provide data on the duration of protection from ticks crossing onto human skin that has been treated with one of Johnson’s eighteen EPA

- registered test substances (personal tick repellent products

. )” (p.13 , §1.4.2).

(b) Can the study as proposed achieve that objective or test this hypothesis?

The objective may be achieved by the study as proposed if the protocol is revised and amended to explain, in more detail, the items noted in the EPA science comments of this

review

.

2.1 Statistical Design

(a) What is the rationale for the choice of sample size?

The rationale for the sample size appears on pp. 41

- 43 of 353 (§10.2). The researcher’s justification for sample size is based on EPA accepted repellent protocols recommended by the HSRB including: Carroll

- Loye Biological Research SPC

- 002, HSRB review of February 2009; and LNX

- 003, HSRB review September 2010.

In addition, the registrant provided the following rationale regarding sample size: “ The number of test subjects for a tick repellency efficacy study should strike a balance among three critical and competing criteria:

a) Minimization of potential hazard to test subjects, where fewer subjects is better.

b) Statistical robustness, where more subjects results in greater precision of numeric estimates.

c) Consistency with previous repellent efficacy studies. Current and recent practice is to
utilize ten subjects for each test site/test product.

The confidence limits associated with the Ka plan

- Meier median are positional values in the distribution, rather than calculated values as in the case of a confidence intervalPage 24 of 93 around the mean. The table below indicates which positions in the distribution of values constitute the lower confidence lim it (LCL) and upper confidence limit (UCL) of the median for various sample sizes. The assumption is that the values are sorted in increasing order, so value “1” in the distribution refers to the smallest value (i.e., the minimum).

► Table 1: Kaplan

- Meier Median Confidence Limits for a Range of Sample Sizes.

Sample

size Distributional position for

95% LCL Distributional position for

95% UCL Percent of

values above

LCL

10 1 8 90%

12 2 10 83%

15 3 11 80%

20 5 15 75%

As evidenced by the table, sample sizes larger than ten would provide only marginal increases in precision relative to the increase in the number of exposed test subjects. Given that a sample size of ten meets criteria a) and c), and a sample size gr eater than ten has limited impact in criterion b), I recommend the continued use of ten as the sample size for tick repellency efficacy studies.”

(b) What negative and positive controls are proposed? Are proposed controls appropriate for the study design and statistical analysis plan?

Ten subjects (5 males and 5 females) will be treated with the test substance. One arm from each subject will remain untreated and serve as the untreated control, and the other arm will be treated with the test product and serve as the treatment group. A p ositive control will not be used (pp. 30

- 31 § 4.0).

(c) How is the study blinded? Based on revised material submitted in response to EPA comments, the study is not

blinded.

(d) What is the plan for allocating individuals to treatment or control groups?

The test subjects (5 male and 5 female) will be randomly selected from a poo l of potential subjects (pp. 17

- 18 of 353, §2.3) to be developed, based on revised information submitted to EPA in response to comments . One arm from each subject will remain untreated and serve as the untreated control, and the other arm will be treated with the test product and serve as the treatment group. The arm serving as part of the treatment group will be selected randomly by fl ipping a coin on the day of treatment. Based on revised information submitted to EPA in response to comments, i f a subject is used on more than one test day, there will be two days between them, and the test arm for the second dayPage 25 of 93 will be opposite of the one used in the earlier test day to minimize any risk of repellent carryover (pp. 30

- 31 § 4.0).

(e) Can the data be statistically analyzed?

Yes.

(f) What is the plan for statistical analysis of the data?

The objective of the data analysis is to esti mate the Complete Protection Time. Complete Protection Time (CPT) will be calculated as time from application of each test substance to a subject and the first confirmed tick crossing on that subject. The median CPT of all test subjects will be calculated using the Kaplan

- Meier estimator, which is advantageous since CPTs may not be normally distributed. Kaplan

- Meier has an advantage as a non

parametric method for survival analysis; this method does not require or assume the data to follow a particular parametric distribution. This method can also account for censored

observation. Kaplan Meier estimator has been accept ed by EPA and the HSRB for (Median) CPT calculation in past repellent efficacy studies and is also recommended by the World Health Organization for CPT calculation from these non

- parametric data sets. The duration of protection for each test substance wil l be the median CPT from the tick species with the shortest median CPT. This value will be rounded down to the closest full hour (pp. 43

- 44 of 353, §10.3).

(g) Are proposed statistical methods appropriate to answer the research question?

The analysis will provide the lowest Median Complete Protection Time. As proposed, the analysis addresses CPT values and associated uncertainties.

(h) Does the proposed design have adequate statistical power to definitively answer the research question?

The sample size of 10 subjects per treatment is consistent with past studies reviewed by EPA and the HSRB since 2006 and is a comp romise between statistical precision and

cost.

The number of test subjects for a tick repellency efficacy study should str ike a balance among three critical and competing criteria:

a) Minimization of potential hazard to test subjects, where fewer subjects is better.

b) Statistical robustness, where more subjects results in greater precision of numeric estimates.

c) Consi stency with previous repellent efficacy studies. Current and recent practice is to utilize ten subjects for each test site/test product.

The confidence limits associated with the Kaplan

- Meier median are positional values in the distribution, rather than calculated values as in the case of a confidence intervalPage 26 of 93 around the mean. The table below indicates which positions in the distribution o f values constitute the lower confidence limit (LCL) and upper confidence limit (UCL) of the median for various sample sizes. The assumption is that the values are sorted in increasing order, so value “1” in the distribution refers to the smallest value ( i.e., the minimum).

► Table 1: Kaplan

- Meier Median Confidence Limits for a Range of Sample Sizes.

Sample

size Distributional position for

95% LCL Distributional position for

95% UCL Percent of

values above

LCL

10 1 8 90%

12 2 10 83%

15 3 11 80%

20 5 15 75%

As evidenced by the table, sample sizes larger than ten would provide only marginal increases in precision relative to the increase in the number of exposed test subjects. Given that a sample size of ten meets criteria a) and c), and a sample size gr eater than ten has limited impact in criterion b), I recommend the continued use of ten as the sample size for tick repellency efficacy studies.

2.2 How and to what will human subjects be exposed?

Subjects will be exposed to tick repellent products that are registered by the US EPA. The application of these products to the skin of subjects in this study will be consistent with the directions for use on these products, and therefore the use has been determined to be

safe. The acti ve and inert ingredients have undergone EPA review and the requirements are fulfilled for EPA registration of repellent products for contact skin use (pp. 27

- 29 of 353, §3.3). Additional information on each product is provided in Appendix VI and VII

of the protocol on pages 56

- 62 of 353 and in Tables 1, 2, and 3 in this review.

(a) What is the rationale for the choice of test material and formulation?

Johnson must submit efficacy data to EPA to satisfy product performance requirements and support label claims for these products. EPA requires submission of product performance data for all products claiming efficacy against public health pests. EPA recommendations in EPA OPPTS Guideline 810.3700 and the EPA Repellency Awareness Graphic must be met to add the Repellency Awareness Graphic to a product

label.

(b) What is the rationale for the choice of dose/exposure levels and the staging of

dose administration?Page 27 of 93 Johnson is proposing a set dosage rate of 1 gram of product per 600 cm 2 (1.67 mg/cm 2 )

for aerosol and lotion products, and 0.5 g of product per 600 cm 2 (0.835 mg/cm 2 ) for spritz/pump spray products. The study will not have a dosimetry phase to determine a ‘typical consumer dose’ by dose titration, which would be based on the grand mean of tripl icate applications made by the test subjects. Johnson stated five reasons for using a set dose rather than a titrated dose (pp. 32

- 33 of 353, §6.1.2):

(1) “Influence of outliers: A single outlier data point can unduly influence the mean of 10 application rat es applied by subjects. A set application rate avoids this
risk;

(2) Inter

- test variability: Choice of dosing from dosimetry often results in selecting application rates for different tests since the groups of subjects will apply varying application rates. Th is can obscure the cause of any different outcomes from two otherwise identical tests. This risk is avoided by using a set dose;

(3) Product (test substance) effect: Varying application rates between studies make it impossible to determine if performance difference is driven by the application rate or the test products;

(4) Time and cost: Subject

- derived application rates introduce addit ional time and cost to a study compared to a set dose; and

(5) Relation to actual consumer use: A set application rate can be related to known consumer behavior. Subject

- derived application rates allow the possibility of an atypical result. The application rates proposed in this protocol are based on dosimetry data from previously EPA/HSRB reviewed repellent studies.”

Johnson proposed: “To apply the target dose of 1.67 mg/cm 2 for lotions and aerosols the following formula will be used:

[Area of the Limb/6 00 cm 2 ] * 1 gm = weight (amount) of product to apply”

Johnson proposed: “To apply the target dose of 0.835 mg/cm 2 for spritz/pump sprays the following formula will be used:

[Area of the Limb/600 cm 2 ] * 0.5 gm = weight (amount) of product to apply”

The application of repellent product to the skin of each subject will depend on the product type (pp. 33

- 34, § 6.7.1

– 6.7.4)

• For pump sprays, the test substance container is placed on a balance and the balance is tared. The required weight is drawn up by pipette while observing the digital display on the balance and applied to the skin of the subject.Page 28 of 93 • For aerosol sprays, th e test substance container is placed on a balance and the balance is tared. The test substance is then sprayed from the container directly onto the skin. After the spray, the sample is returned to the balance and the amount applied is

determined. If the a mount applied is below the required weight, the limb will be sprayed with more test substance targeting the required weight as closely as possible. The acceptable range will be within 10% of the target weight.

• For lotions, the test substance container is placed on a balance and the balance is tared. The required weight of the test substance is then removed by spatula or similar implement while carefully observing the balance read out.

• For towelettes, a 250 ml beaker is placed on a top loader balance. The balance is tared. A single towelette is placed in the beaker and the balance is re

- tared to determine the weight. The towelette is removed from the beaker and squeezed gently over the treatment area. The procedure is repeated until the target quantity of product has been

delivered.

• Treatments will be made by study staff. §6.4

- 6.6 on pages 33 of 353 describe preparations before treatments are made. The target dose weight and actual weight applied will be recorded on a data sheet (p. 47 of 353, Appendix II).

(c) What duration of expo sure is proposed?

The exposure is a 3

- minute period starting 30 minutes after application where the tick is placed on the untreated arm to determine if it is attracted to the subject’s skin. After a tick is deemed to be attracted to the subject, the ti ck is then placed on the treated arm for 3 minutes. This exposure process is repeated every 15 minutes thereafter for 18 hours or until the test substance fails to repel the tick. (pp. 36

- 37
, § 7.6.4

– 7.6.13)

2.3 Endpoints and Measures

(a) What endpoints will be measured? Are they appropriate to the question(s) being

asked?

Endpoints/Measures for efficacy evaluation: “Complete Protection Times (CPT) will be calculated as time from test substance application to the time of br eakdown (i.e., the first confirmed crossing).

To assess crossing, four lines will be drawn on the treated and untreated forearms as

follows:

i. “A ‘release’ line 3 cm above the wrist bone. ii. A ‘boundary’ line 3 cm above the release line and is at th e edge of the treated area.

iii. A ‘crossing’ line 3 cm above the boundary line, and iv. An upper boundary line 12 cm above the boundary line which will denote the upper boundary of the treated area.”Page 29 of 93 “A ‘crossing’ occurs when a tick crosses the ‘crossing’ line on the treated skin of a subject. Test substance breakdown occurs when one tick is recorded as being repelled (i.e., crossing or repellent failure) and one of the following events occur: (i) the first subsequent tick to be exposed is also recorded as not being repelled or (ii) the first subsequent tick is repelled, but the second subsequent tick is recorded as not being repelled. Either (i) or (ii) will be counted as confirming crossings within 3 0 minutes of the first crossing. The time of breakdown will be recorded as the time of the first confirmed crossing.”

Using the Kaplan

- Meier estimator, the Median CPT will be calculated for all test subjects exposed to each tick species. The lowest media n CPT of the three tick species will be

used on the label.

Subjects with repellent failures will be removed from the test. The test will be terminated no later than 18 hours after the first tick exposure.

The endpoints are appropriate to the questi ons being asked and address uncerta inty associated with the sample size, values, and the lowest Median Complete Protection Time

value.

The data form for each tick exposure is presented in Appendix III on page 48 of 353.

(b) What steps are proposed to ensure measurements are accurate and reliable?

• Good Laboratory Practices, as defined by 40 CFR part 160 will be followed throughout all studies.

• Study staff will conduct a training session with the subjects on a day prior to

the test date.

• Study staff will treat the skin of the exposed limb with the test substance and

the limb will be measured in advance

.

• Study staff will place ticks on the untreated and treated arms.

• Study staff will monitor and record tick movement and the start and stop times

for ea ch exposure period.

• Study staff and the study director will track test substance samples, closely monitor the testing, and data recording.

• Alternate subjects will be enrolled to ensure adequate sample size.

• A Quality Assurance Unit will be in place to m onitor all study activities and

data collection.

• Test subjects can only take part once in any two

- day testing period. If scheduled to participate in two studies within one week, there will be two calendar days in between test days.

(c) What QA methods are p roposed?Page 30 of 93 “A representative of i2LResearch USA, Inc.’s (i2L) independent quality assurance unit (QAU) in the person of Jennifer Hostetler will perform all QA duties. The QA representative will conduct critical phase inspections at intervals adequate to ensure study integrity, and maintain written and signed records of each inspection. Records

shall identify the study and include the date of the inspection, positive and negative findings, actions recommended and taken to resolve negative findings, the scheduled date for re

- inspection (if any), and the dates(s) the findings are reported. All inspectio n findings will be reported to management and the study director. Any problems, amendments or deviations discovered shall be brought to the attention of the sponsor, Study Director and management immediately. The QA will review the final reports for

accura cy and compliance with GLPs and the protocol. A signed QA statement will be included in each final report that lists the phase inspections that were conducted, their dates, and the dates their findings were reported to management and the study director.” (pp. 12 of 353, §1.2)

(d) How will uncertainty be addressed? Will point estimates be accompanied by measures of uncertainty?

Complete Protection Time (CPT) will calculated as time from test substance application to the time of breakdown (i.e., the first confirmed crossing). The Median CPT of all test subjects will be calculated using the Kaplan

- Meier estimator, which is advanta geous since CPTs may not be normally distributed. Kaplan

- Meier is more conservative than competing parametric methods (Weibull and Normal) in that the Median CPT is likely to be lower and the 95% confidence interval around the median CPT is likely to be wi der. Kaplan

- Meier estimator has been accepted by EPA and the HSRB for (Median) CPT calculation in past repellent efficacy studies and is also recommended by the World Health Organization for CPT calculation from these nonparametric data sets. The

duratio n of protection for each test substance will the median CPT for the tick species

with the lowest median CPT. This value will be rounded down to the closest full hour (pp. 43

- 44 of 353, §10.3).

3.1 Representativeness of Sample

(a) What is the population of concern?

The population of concern consists of people who would purchase and use tick repellents and who best represent U.S. repellent users . Information to characterize this population is

available from Neilson information, including the 2015 Neilson survey, which shows that the majority of repellent users are caucasians between the ages of 35

- 55. Additionally, about 13% of repellent buyers are Hispanic. Based on revised information submitted to
EPA, t he recruitment pool to be develope d, from which subjects will be recruited , is expected to be in line with the indices above and described in revised section 2.3.6. (pp.

16

- 17 of 353, §2.3.6).Page 31 of 93 (b) From what populations will subjects be recruited?

Subjects will be recruited by a recruiting firm. Using advertisements in digital, and social media mediums in both English and Spanish languages, the firm will recruit a pool of people from the Baltimore, MD area who are generally interested in participati ng in

research studies. Test subjects will be recruited for each study following demographics included in section 2.3.6 in order to best represent U.S. repellent users

. The firm will

contact individuals

, in the recruitment pool to be developed, by email or telephone to compile a list of potentially interested and eligible subjects.

(c) Are expected participants representative of the population of concern? If not, why not?

The table in section (p. 17 of 353, §2.3.6) outlines the intended demographics of the initial gr oup of potential volunteers who will be recruited by the recruiting firm. If the recruited pool follows the outlined demographic s , the pool should be representative of the population of concern.

(d) Can the findings from the pr oposed study be generalized beyond the study sample?

Yes. Each test substance tested will be evaluated with three species of ticks which are the most common species that occur throughout the United States.

3.2 Equitable Selection of Subjects

( a) What are the inclusion/exclusion criteria? Are they complete and appropriate?

The inclusion/exclusion criteria

, with EPA’s comments highlighted below

, are complete and appropriate. The sponsor agreed to address EPA’s comments.

“ 2.6.1 The subject must be between 18

- 55 years old and provide proof of age with a driver's license, passport or other valid identification.

2.6.2 The subject must be able to read and speak English fluently.

2.6.3 The subject must not be an immediate employee of Johnson or of i2L, or be immediately related to employees or owners of either company.

2.6.4 The subjects must have a reliable form of transportation to get to and from the i2L laboratory.

2.6.5 Subjects must feel they are healthy enough to participate in the study and do not have any heath conditions that may affect the study or be worsened by the application of repellent products.Page 32 of 93 2.6.6 The subjects must be willing to be exposed to crawling ticks with the understanding all measures possible will be taken to prevent bites.

2.6.7 The subjects must have no known allergies or sensitivities to tick bites.

2.6.8 Subject must be a user of insect repellent products.

2.6.9 The subjects must not be hypersensitive to repellent or latex or other skin care products. The subject must be free from skin disease, skin problems such as eczema, psoriasis, or atopic dermatitis

.

2.6.10 The subjects must be willing to wear short sleeves on their scheduled test day(s) (other clothing choices will be optional).

2.6.11 The subjects must agree to inform the Study Director or other staff if they have violated any study

- related restrictions in the previous 12 hours (see 'Restrictions', below) as soon as possible, so a decision can be made whether to continue inclus ion of the subject in that day's testing.

2.6.12 The subjects must be able to sit in a chair for long periods (with breaks for limb stretching and movement given at reasonable intervals).

2.6.13 Confirmation will be needed that the ticks in the study are attracted to the subjects' untreated skin (this confirmation will occur during the test, when each subject acts as their own negative control

— see 'Methodology for Testing Tick Repellency' below). If a subject is

found to be unattractive to ticks at the first exposure, they will be replaced with an alternate subject. In the unlikely event that a subject is determined not be attractive to the ticks, when the study is underway, they will not be allowed to continue to participate in the study. The study will continue with the remaining subjects.

2.6.14 The subjects must be willing to follow the study procedures as explained and be willing to sign an ICD.

2.6.15 The subjects must not be pregnant or be breast

- feeding. To confirm that participating

tes t subjects are not pregnant, within 48 hours prior to their scheduled test day, female subjects will be required to perform an over

- the

- counter pregnancy test that will be supplied by i2L. This can be done on the same day as the training session, on a sepa rate visit to i2L at

a later day or on the day of the test. If the test is done on separate day, the subject will be paid $25.0 0 for their time.

The test will be performed by each test subject alone, in a private bathroom, at the i2L facility. The results will be initially seen by the test subject only. After completion of the pregnancy test, a female i2L employee will ask, in a private setting, if the potential subject

still wants to participate in the study. If they do, the negative test result will be v erified by that i2L employee and relayed to the Study Director (if the Study Director is not the verifying employee). The results will be kept confidential, will not be recorded, and will not bePage 33 of 93 disclosed to anyone other than the test subject, the verifyin g employee, and/or the Study Director. Test subjects will not be required to disclose the results of the test, with the understanding that if they do not, they will not be allowed to participate in the test. Test results will be disposed by the test subjec t.

2.6.16 This procedure will be repeated for each test day that any female subject participates in, that will take place more than 48 hours after the most recent negative, pregnancy test. ”

(b) What, if any, is the relationship between the investigator and the subjects?

The protocol excludes people who are employees of S.C. Johnson or i2LResearch or immediately related to employees or owners of either company.

(c) Will subjects be recruited from a vulnerable population?

No.

(d) What process is proposed for recruiting and informing potential subjects?

Recruitment

Based on updated information submitted to EPA, the recruitment process will use the approach descri bed below:

Test subjects will be recruited for each study following the demographics table in section

2.3.6 to best represent US repellent users . Subjects will be recruited from the Baltimore, Maryland area, via advertising through digital and social media

. Advertisements will be posted in digital and social media mediums, such as Facebook, Yahoo/Bing, Google and Craigslist. A Spanish language advertisement will also be posted on line using the same media, plus an online Spanish language newspaper tha t advertises within the recruitment area. The advertisements will contain a link to a study

- specific secure website where interested respondents can learn more about the study as well as complete a pre

- screening qualification form. The forms that are fille d out on the website will be automatically uploaded into a secure and encrypted portal, to which i2L employees will have access. Every effort will be made to achieve the demographic composition, via a stratified random sample of the pool of recruited subje cts. The qualifying subjects will be stratified into smaller subgroups according to their race/ethnicity, age, and gender to help ensure that the sample demographic composition of the test subjects will be approximately

similar to that of the table below f or each test day. The final report will specify the demographic composition goals, and the demographics of test subjects who participated in the study, due to availability of test subjects on each test day.

Individuals from the pool will be contacted by telephone or e

- mail (in which case a follow up telephone call will be made) to determine whether they meet the basic inclusion

criteria. They will be given a brief outline of the study. If they are interested in enrollingPage 34 of 93 in the study, they will be giv en a time, date and location to meet with i2L staff for a training session to learn more about the study and their potential role in it, go over t he inclusion/exclusion criteria, and receive answers to any questions they may have. Contact

information is i ncluded on the consent form for any individual who has additional questions or if further clarification is desired after they have attended the training session.

Informing Potential Subjects and Informed Consent

Several mechanisms will be used to inform potential subjects. The revised phone scripts

included in Attachment 4 describe the information to be shared

, in initial and follow

- up phone conversations

, with potential subjects who respond to recruitment adverti sements

. All interested and eligible participants must attend a 2 hour training session prior to participating in each study. The details of the training program are explained in

Attachment 2 in response to EPA comment # 1 and will be inserted in section 2 .2.5 of the protocol . One of several aspect s of this training will inclu de review of the Informed

Consent Document (ICD)

. The trainer will also provide test subjects with the study director’s contact information (name, email, and phone number) to answer any follow up questions. This information will be on the first page of the provided ICD. Prior to each study, all subjects must provide informed consent by signing the proposed revised

Informed Consent Document in cluded in Attachment 3

.

(e) If any subjects are potentially subject to coercion or undue influence, what specific safeguards are proposed to protect their rights and welfare?

Subjects will be recruited by a professional r ecruiting firm. There will be no

communication between the researchers and the potential subjects’ employers, which minimizes the potential for coercion or undue influence. In addition, employees of

S.C. Johnson and i2LResearch and their families , are excluded from participation.

3.3 Remuneration of Subjects

(a) What remuneration, if any, is proposed for the subjects?

In response to EPA comments, SC Johnson and i2LResearch propose the following compensation in revised Section 2.5 :

2.5.1 Each subject will be paid $ 30 for taking part in each training session.

2.5.2 For each test day, test subjects will be paid $ 104 .00 ($13 per hour) for any length of participation up to 8 hours (see ‘Study termination, individual participation, and withdrawal’ in Section 9 for exceptions). If a test day exceeds 8 hou rs, subjects will be paid $ 19 .50 (time and a half) for each additional hour, rounded up to the nearest hour.

2.5.3 An alternate who is not needed to replace a test subject will be able to leave and will be paid $50. The decision as to whether an alternat e is needed will occur within the first two hours of the test, before all the treatments have been finished. If an alternate isPage 35 of 93 asked to replace a subject, he or she will be paid at the same rate as other test subjects, as

described above.

2.5.4 Subjects who have participated in the training session, but then choose to withdraw or are asked to withdraw from or during the training session, will still be paid $ 30 .00 for attending all or part of this session.

2.5.5 Any female subject who has to visit i2L s olely for the purpose of taking a pregnancy test ( which will occur within 48 hours prior to the test day ), will be paid $25.00.

2.5.6 Subjects may decline to participate at any time during the training session or test day without penalty.

2.5.7 If the Study Director or other i2L USA staff ask a subject to withdraw from the test and they have complied with all of their requests, or if a test subject needs to withdraw early because of a health or emergency reason, full payment will still be made even if the test subject has participated for less than eight hours. This will not affect payment for any previous tes t days that had been completed.

2.5.8 The Study Director or other designated i2L USA staff may end a particular subject’s participation in a tr aining session or on a test day, at any time, for any reason. If a test subject is asked to withdraw from the test because they have not followed all their directions or if they choose to withdraw from testing early on a test day for a non

- health

related o r non

- emergency reason, full payment will not be made if the test subject participates in less than eight hours. Instead, they will be paid for the number of hours worked (rounded to the nearest hour) at a rate of $13.00 per hour. This will not affect

pa yment for any previous test days that had been completed

. ”

(b) Is proposed remuneration so high as to be an undue inducement?

No.

(c) Is proposed remuneration so low that it will only be attractive to economically disadvantaged subjects?

No.

(d) How and when would subjects be paid?

“Subjects will be paid by checks sent in the mail, or hand delivered while they are on site at the i2L facility. I2L issues checks on the 15 th and on the last day of the month.”

4. Risks to Subjects

4.1 Risk characterization

(a) Have all appropriate prerequisite studies been performed? What do they show

about the hazards of the test material?Page 36 of 93 Subjects will be exposed to tick repellent products that are registered by the US EPA. The application of these products to the skin of subjects in this study will be consistent with the directions for use on these products, and therefore the use has been determined to be safe. The active and inert ingredients have undergone EPA review and fulfilled the requirement s needed for EPA registration as repellent products for contact skin use (pp.

27

- 29 of 353, §3.1). Additional information on each product is provided in Appendix VI and VII of the protocol on pages 56

- 62 of 353 and in Tables 1, 2, and 3 in this review.

Ma rgin of Exposure (MOE) estimates are based on an assumed 80 kg subject and the

acute dermal LD 50 value for each product at the limit dose of greater than 2,000 mg/kg. Based on the dose rates presented by Johnson, the MOE values for the tested active ingre dients will exceed EPA’s level of concern of MOE = 100 (Appendix VIII pp. 63

- 68 of 353). Specific MOE values will be provided for each product when the study is

conducted.

(b) What is the nature of the risks to subjects of the proposed research?

There are five types of hazard associated with this type of study: 1) Adverse reaction to the test substances 2) Exposure to ticks 3) Exposure to tick

- vectored diseases 4) Unanticipated loss of confidential information. 5) F atigue and/or physical discomfort from length of test day

(c) How do proposed dose/exposure levels compare to the established NOAELs for

the test material?

The test materials are EPA

- registered tick repellent products and they will be used consistent with the Directions for Use on the product labels. Therefore, EPA considers the exposure of the subjects to the tested levels of the test substance to be safe

.

(d) What is the probability of each risk associated with the re search? How was this probability estimated?

No numerical probability is estimated, but risks have a low probability of occurrence.

Risks are minimized by excluding candidates known to be sensitive to the test material; excluding candidates known to be sensitive or allergic to ticks bites; conducting the research with disease free ticks; technician removal of ticks before they bite; using subject identification codes to help ensure privacy; and incorporating procedures to keep the results of pregnancy te sting private and permit discrete withdrawal. To try to address fatigue and physical discomfort, the study sponsor will provide breakfast, lunch and dinner to participating subjects as described in the revised protocol, breaks and opportunities to stretch during the test day, and support for the subject’s arm as it’s held at an angle during the exposure period. Also, there

will be a two

- day break between test days. Practical steps to minimize subject risks have been taken, and the remaining risks have a low probability of occurrence.Page 37 of 93 4.2 Risk minimization

(a) What specific steps are proposed to minimize risks to subjects? 1) Adverse reaction to the test substances 2) Exposure to ticks 3) Exposure to tick

- vectored diseases 4) Unanticipated loss of confidential information. 5) Fatigue and/or physical discomfort from length of test day

Risk of adverse reaction to test substance s Participating s ubject s must be user s of insect repellent products. The subjects must not be hypersensitive to repellent or latex or skin care products. The subject must be free from skin disease, skin problems such as eczema, psoriasis, or atopic dermatitis

.

As discussed in section 2.8 of the protocol, i2L will have at l east two First

- Aid qualified staff members and supplies on site to monitor subjects for medical problems. In the case of medical emergency, i2L staff will call 911, ask for emergency assistance, and follow instructions given by the emergency dispatcher.

A s discussed in the revised language for section 2.10. 2. 10, s ubjects will be told that if anyone experiences any skin reaction, experiences an injury, or simply feels unwell, he or she should inform i2L staff right away. Such subjects will immediately be g iven appropriate care, may be withdrawn from testing, and may be transported to a local hospital if necessary. The closest hospital to the laboratory test site and directions will be identified prior to the test date. At least one study staff member will remain with the other subjects if other staff members have to depart with an injured or ill subject. The study sponsor will reimburse test subjects for the costs of medical care. All adverse effects will

be followed until resolution is reached.

Subject s may also ask for standard first aid items, such as bandages, antiseptics, and mild topical antihistamines as any point during the study, though they will not be able to apply topical antihistamines to the treated areas of their skin while still taking pa rt in the test. They may also request first aid assistance at any time.

Risk of exposure to ticks

The participating subjects must have no known allergies or sensitivities to tick bites. Staff members will be trained to move or remove ticks from subjects before they have the opportunity to bite. Tick exposure will be limited to one tick at a time, and only on the

area of the forearm.

Risk of exposure to tick

- vectored diseases To greatly reduce, if not eliminate, the risk of contracting any tick

- borne diseases, the study will be conducted with laboratory

- reared ticks, which are not known to harbor anyPage 38 of 93 pathogens. This will be documented with confirmation from the supplier lab. Staff members will be trained to move or remove ticks from subjects before they have the opportunity to bite. Tick exposure will be limited to one tick at a time, and only on the

area of the forearm.

Risk of Unanticipated loss of confidentiality All efforts will be taken to maintain the confidentiality of the pregnancy tests results. The test will be performed by the potential subject in a private bathroom at the i2L facility. The results will be verified by the subject only. After completion of t he pregnancy test, a female member of the study staff will ask in a private setting if the potential subject is still interested in participating in the study. If they are no longer interested they do not need to explain why. If the test subject is interes ted in participating, the results will be verified by that female i2LResearch employee and relayed to the Study Director (if the Study Director is not the verifying employee.) The results will be kept confidential, will not be recorded, and will not be di sclosed to

anyone other than the test subject, the verifying employee, and/or the Study Director

.

All efforts will be taken to maintain the confidentiality by protecting the subjects’ personal information in the following ways. Each subject will be assi gned a code number. Only subjects’ code numbers will appear on data sheets. The subjects’ names will not appear in the report. The study records will be maintained at the testing facility in locked cabinets and electronic files kept on a password

- protected computer
server. No one outside the recruitment firm, i2L, Johnson, the IRB, or certain governmental agencies (such as USEPA) will have access to subjects’ personal

information.

Fatigue and/or physical discomfort from length of test day To try to addre ss fatigue and physical discomfort, the study sponsor will provide breakfast, lunch and dinner to participating subjects assuming the test day extends to
those meal times, as described in section 7.3.6 of the revised protocol

. T he study director will provide up to three 15 minute breaks to each test subject per test day and

opp ortunities to stretch throughout the test day

, as well as support for the subject’s

arm as it’s held at an angle during the exposure period. Also, t here wi ll be a two

- day break between test days.

(b) What stopping rules are proposed in the protocol?

As described in section 2.10. 2. 10, s ubjects will be told that if anyone experiences any skin reaction, experiences an injury, or simply feels unwell, he or she should inform i2L staff right away. Such subjects will immediately be given appropriate care, may be withdrawn from testing, and may be transported to a local hospital if necessary. Also, please see the revised language for sections 9.2.5

– 9.2.6:Page 39 of 93 “ 9.2.5 The nearest local hospital to i2L's laboratory will be located and directions

identified prior to any study

- related procedures taking place.

9.2.6 Should a Type 1 allergic reaction (i.e. anaphylaxis) occur on the test day or if any other serious in jury or medical issue occurs, the i2L staff will call 911and follow the instructions given by the emergency dispatchers. If instructed to transport the subject to a hospital, one study staff member and one other i2L staff member (one to

drive and one to o bserve and take care of subject) will perform this task. If there are not sufficient Study staff present to both carry on the study and transport the affected subject(s), the Study Director or Principle Investigator will abort the test day. ”

(c) How does the protocol provide for medical management of potential illness or injury to subjects?

As discussed in section 2.8 of the protocol, i2L will have at least two First

- Aid qualified staff members and supplies on site to monitor subjects for medical problems.

Based on the revised language for section 2.10. 2. 10, s ubjects will be told that if anyone experiences any skin reaction, experiences an injury, or simply feels unwell, he or she should inform i2L staff right away. Such subjects will immediately be given appropriate care, may be withdrawn from testing, and may be transported to a local hospital if necessary. The closest hospital to the laboratory test site and directions will be identified prior to the test date. At least one study staff member will remai n with the other subjects if other staff members have to depart with an injured or ill subject. The study sponsor will reimburse test subjects for the costs of medical care. All adverse effects will be

followed until resolution is reached.

Subjects may also ask for standard first aid items, such as bandages, antiseptics, and mild topical antihistamines as any point during the study, though they will not be able to apply topical antihistamines to the treated areas of their skin while still taking part in the test. They may also request first aid assistance at any time.

Also, as proposed, section 9.2, on Medical monitoring and reporting

u nanticipated problems
, will be revised as follows (as per EPA’s

recommendations ):

“ 9.2.1 The i2L staff will watch for unanticipated problems or adverse effects to the subjects. Subjects will be told that if anyone experiences any skin reaction, experiences an injury, or simply feels unwell, he or she should inform i2L staff right away. Such subjects will immediately be given appropriate care, may be withdrawn from testing, and may be transported to a local hospital if necessary. 9.2.2 Any problems or adverse effects will be promptly reported to Johnson, and the

IRB. 9.2.3 Subjects will be informed in a timely manner both orally and in writing of any significant new findings discovered during the course of this study which mayPage 40 of 93 influence their continued participation. The Study Director and recruitment firm will keep on file the phone numbers and addresses for each study pa rticipant as a means

to contact them if needed. 9.2.4 New findings will also be reported, in writing, to Johnson and the IRB in a timely manner. 9.2.5 The nearest local hospital to i2L's laboratory will be located and directions

identified prior to any stu dy

- related procedures taking place. 9.2.6 Should a Type 1 allergic reaction (i.e. anaphylaxis) occur on the test day or if any other serious injury or medical issue occurs, the i2L staff will call 911and follow the instructions given by the emergency disp atchers. If instructed to transport the subject to a hospital, one study staff member and one other i2L staff member (one to drive and one to observe and take care of subject) will perform this task. If there are not sufficient Study staff present to both carry on the study and transport the affected subject(s), the Study Director or Principle Investigator will abort the test day. 9.2.7 Subjects will be instructed that if they develop a rash or other irritation on their

treated forearm within 48 hours of t he end of the most recent test day, they should inform i2L staff and seek medical advice. All adverse effects will be reported to

Johnson and the IRB within five business day of their being noted, or within the same day in the case of serious adverse effec ts.
9.2.8 If i2L or Johnson learns of new findings or new information relating to the safety or hazard of any of the test substances, i2L will contact the subjects and advise them accordingly both orally and in writing in a timely manner . The IRB will also be

advised. ”

(d) How does the protocol provide for post

- exposure monitoring or follow

- up? Is it of long enough duration to discover adverse events which might occur?

The consent form states: “If yo u have any questions about these studies or suffer a

research

- related reaction, call the Study Director listed on the front page of this consent form at 410

- 747

- 4500 , or Safety Call at (866) 344

- 3932 available 24

- hours.”

There is no time limit given.

(g) How and by whom will medical care for research

- related injuries to subjects be paid for?

The revised consent form , in Attachment 3

, states:

“ Compensation for Injury In the unlikely event that you are injured as a result of your participation in this study, medical care will be made immediately available. The sponsor will reimburse you for the costs of this care that is not paid for by any insurance policy that covers you in case of

illness. All adve rse effects will be followed until resolution is reached. Th ere are no plans to provide other compensation beyond that which is listed in this informed consent document. You will not lose any of your legal rights or release the Sponsor, the StudyPage 41 of 93 Director, the study staff, or study site from liability for mistakes or intentional misconduct by signing this consent document. ”

5. Benefits

(a) What benefits of the proposed research, if any, would accrue to individual subjects?

There are no direct benefits to subjects. The consent form states: “You will not personally benefit from these studies. The benefit to society is the knowledge gained regarding the efficacy of personal tick repellents.”

(b) What benefits to society are anticipated from the information likely to be gained through the research?

Th e consent form states: “The benefit to society is the knowledge gained regarding t he efficacy of personal tick repellents.”

(c) How would societal benefits be distributed? Who would benefit from the proposed

research?

One beneficiary of the research is the sponsor, S.C. Johnson, which is seeking the Repellency Graphic across the company’s line of topically

- applied repellent products. Indirect beneficiaries would include users of these products who may benefit from

addi tional information about the period of effectiveness of these products.

(d) What is the likelihood that each identified societal benefits would be realized?

The testing is likely to demonstrate the complete protection time for each of the tested products.

6. Risk/Benefit Balance

(a) How do the risks to subjects weigh against the anticipated benefits of the research, to subjects or to society?

The protocol

, revised to address EPA’s comments, reduces risks to subjects without reducing the robustness of the scientific design. The resulting residual risk to subjects is very low. The potential benefits from availability of additional information about the

efficac y of skin

- applied repellent products are likely to be realized, and make the residual risks to subjects in this proposed research reasonable.

7. Independent Ethics Review

(a) What IRB reviewed the proposed research?Page 42 of 93 Schulman Associates Institutional Revi ew Board, Inc. (SAIRB)

(b) Is this IRB independent of the investigators and sponsors of the research? Yes

(c) Is this IRB registered with OHRP? Yes

(d) Is this IRB accredited? If so, by whom?

SAIRB has full AAHRPP accreditation.

(e) Does this IRB hold a Federal

- Wide Assurance from OHRP?

Yes.

(f) Are complete records of the IRB review as required by 40 CFR 26.1125 provided?

Yes, the IRB provided records of their review to EPA.

(e) What standard(s) of ethical conduct would gov ern the work?

This is a protocol for third

- party research involving what EPA has interpreted to be intentional exposure of human subjects to a pesticide. The study is being conducted with the intention of submitting the resulting data to EPA under the F ederal Insecticide Fungicide and Rodenticide Act (FIFRA). Thus, the primary ethical standards applicable to this proposal are 40 CFR 26, Subparts K and L. In addition, the requirements of FIFRA §12(a)(2)(P) for fully informed, fully voluntary consent of su bjects apply.

8. Informed Consent

(a) Will informed consent be obtained from each prospective subject?

Yes.

(b) Will informed consent be appropriately documented, consistent with the requirements of 40 CFR 26.1117?

Yes.

(c) Do the informed consent materials meet the requirements of 40 CFR 26.1116, including adequate characterization of the risks and discomforts to subjects from participation in the research, the potential benefits to the subject or others, and the right to withdraw from the researc h?Page 43 of 93 Yes , based on the revised language submitted in response to EPA’s comments

.

(d) What is the literacy rate in English or other languages among the intended research subjects?

Ability to speak and read English is a requirement for participation.

(e) What measures are proposed to overcome language differences, if any, between investigators and subjects?

N/A

(f) What measures are proposed to ensure subject comprehension of risks and

discomforts?

Frequent opportunities to ask questions during the consent process.

(g) What specific procedure will be followed to inform prospective subjects and to seek

and obtain their consent?

Initial information on the study will be s hared, via telephone, with prospective subjects who respond during the recruitment process. Prior to participating in any aspect of the study

, each potential subject who has expressed interest in participating in the study and

has met the inclusion/exclusi on criteria will be required to complete a 2 hour training

program.

If a subject chooses to participate in multiple studies, as discussed in revised section 2.2.7, the subject will be required to attend a training session prior to their participation in each study.

During the training session, the following aspects of the study will be discussed and the following activities completed:

1. Upon arrival, subjects will be asked to provide proof of age with a driver’s license, passport,

or other valid identification.

2. Test subjects will be given the Informed Consent Document (ICD), time to read the ICD, and the opportunity to ask questions abou t it. The trainer will provide a brief outline of the study, the test subjects’ potential role in the study, the potential length of the study on any given test day, and discuss the

inclusion/exclusion criteria.

3. Any questions or concerns about the study will be discussed and answered.

4. The employee conducting the training session with test subjects will let all training attendees know that if a test subject needs to speak to the study director in private about an y aspect of the study, time will be made for this discussion once the general training session is over.Page 44 of 93 5. To confirm understanding of the consent form, the following questions will be asked:

a. Do you understand that you will be exposed to live ticks and that individual ticks will be placed on your arm, monitored, taken off, and discarded in order to collect study

data?

b. Do you understand that a repellent product will be applied to your arm and left remain on your arm for a potential exposure period of 18 hours maximum?

c. Do you understand that one test day has the potential to last up to 19 hours, including up to 18 hours of testing and 1 hour of preparation?

d. Do you understand that you have the freedom to quit or withdraw from the study at any time, and that you will be paid for the hours worked?

e. Do you understand that your participation in this study is voluntary and that you may leave the study at any time?

6. All subjects who meet the requirements for participation and agree to participate in the study will sign t he ICD and will receive a copy of the signed ICD. They will also receive a copy of the testing schedule.

7. The trainer will provide test subjects with the study director’s contact information (name, email, and phone number) to field any follow up questions. This information will be on the first page of the provided ICD.

8. The subjects will then have their forearms measured for the future testing as per section 5 of the protocol, and will be shown how to position their arm for testing. The procedures of each 15 minute exposure interval will be briefly explained.

9. Female subjects will take the pregnancy test within 48 hours prior to the first testing day. If the time until this day is more than 48 hours, these subjects will be asked to come to i2L on a
separate occasion to take this test.

10. If the subject is eligible to participate in a subsequent study and chooses to do so within 3 months of having completed full training, they will have the option of completing a shorter training session prior to the next study ; the shorter training session would be the same as that described above but would exclude the measurement of the forearm, discussed in step # 8 above, given that their measurements would have already been taken and recorded during the first training sessi on.

(h) What measures are proposed to ensure fully voluntary participation and to avoid

coercion or undue influence?

Candidates are offered repeated opportunities to decide not to participate; participants are offered repeated opportunities to withdraw. Exclusion factors rule out participation by employees of the sponsor or their family members . Recruitment of alternate subjects reduces the likelihood that subjects might be reluctant to withdraw.

9. Respect for Subjects

(a) How will information about prospective and enrolled subjects be managed to ensure their privacy?Page 45 of 93 All efforts will be taken to maintain the confidentiality of the pregnancy tests results. The test will be performed by the potential subject in a private ba throom at the i2L facility. The results will be verified by the subject only. After completion of the pregnancy test, a female member of the study staff will ask in a private setting if the potential subject is still interested in participating in the stud y. If they are no longer interested they do not need to explain why. If the test subject is interested in participating, the results will be verified by that female i2LResearch employee and relayed to the Study Director (if the Study Director is not the ve rifying employee.) The results will be kept confidential, will not be recorded, and will not be disclosed to anyone other than the test subject, the verifying employee, and/or the Study Director.

All efforts will be taken to maintain the confidentiality by protecting the subjects’ personal information in the following ways. Each subject will be assigned a code number. Only subjects’ code numbers will appear on data sheets. The subjects’ names will not appear in the report. The study records will be maint ained at the testing facility in locked cabinets and electronic files kept on a password

- protected computer server. No one outside the recruitment firm, i2L, Johnson, the IRB, or certain governmental agencies (such as USEPA) will have access to subjects’ p ersonal information.

(b) How will subjects be informed of their freedom to withdraw from the research at any time without penalty?

The revised informed consent form states: “Participation in any of these studies is voluntary. You may refuse to take part or quit at any time without penalty or loss of benefits to which you may be otherwise entitled. ”

Subjects are informed about their right to withdraw during both the initial and follow

- up telephone conversations which occur after potential subjects apply for participation in the study during the recruitment process. Subjects are again informed of their right to withdraw during the training program and when questions are asked during the training program to confirm their understanding of the consent form.

(c) How will subjects who decline to participate or who withdraw from the research be

dealt with?

Please see the revised language proposed for the sections cited below.

2.5.4 Subjects who h ave participated in the training session, but then choose to withdraw or are asked to withdraw from or during the training session, will still be paid $ 30 .00 for attending all or part of this session.

2.5.7 If the Study Director or other i2L USA staff ask a subject to withdraw from the test and they have complied with all of their requests, or if a test subject needs to withdraw early because of a health or emergency reason, full payment will still be made even if the test subject has participated for less than eight hours. This will not affect payment fo r any previous test days that had been completed.Page 46 of 93 2.5.8 The Study Director or other designated i2L USA staff may end a particular subject’s participation in a training session or on a test day, at any time, for any reason. If a test subject is asked to withdraw from the test because they have not followed all their directions or if they choose to withdraw from testing early on a test day for a non

- health

related or non

- emergency reason, full payment will not be made if the test subject participates in le ss than eight hours. Instead, they will be paid for the number of hours worked (rounded to the nearest hour) at a rate of $13.00 per hour. This will not affect payment for any previous test days that had been completed

.Page 47 of 93 Attachment 2

Revised Language from S.C. Johnson and i2LResearch in Response to EPA’s Science and

Ethics Comments

Before the research is initiated, the documents should be revised to address the EPA

science and ethics comments in t his attachment and any forthcoming comments from the EPA Human Studies Review Board. (EPA’s comments are listed in order of the pertinent sections of the draft July 28, 2015 protocol to which they apply.) Johnson and i2LResearch agreed to

address all of EPA’s comments. This attachment includes the revised language proposed by Johnson and i2LResearch in response to each of EPA’s comments. After HSRB review and

comment, t he revised materials must be submitted to the SAIRB for final approval

.

EPA Comments and Responses from SC Johnson and i2LResearch

Science Comments

The following elements in the protocol require revision/amendment before the research goes

forward.

1) Pre

- training of subjects is barely described. More information is required. The protocol should be explicit with regard to the training outline and specific topics to be addressed.

Johnson and i2LResearch Response :

As proposed, section 2.2.5 of the protocol will revised to read as follows and outlines each

element of the tra ining program:

“2.2.5 Within 4 weeks prior to the first test day for any given subject, the subject will attend a training session that will last approximately two hours. Any test subject who has not previously participated in the study must attend a training session prior to their participation. If a subject chooses to participate in multiple studies, as discussed in section 2.2.7, the subject will be required to attend a training session prior to their participation in each study.

During the training session, the following aspects of the study will be discussed and the following activities completed:

1. Upon arrival, subjects will be asked to provide proof of age with a driver’s license, passport, or other valid identification.

2. Test subjects will be given the Informed Consent Document (ICD), time to read the ICD, and the opportunity to ask questions about it. The trainer will provide a brief outline of the study, the test subjects’ potential role in the study, the potential length of the study on any given test da y, and discuss the

inclusion/exclusion criteria.

3. Any questions or concerns about the study will be discussed and answered.Page 48 of 93 4. The employee conducting the training session with test subjects will let all training attendees know that if a test subject needs to speak to the study director in private about any aspect of the study, time will be made for this discussion once the general training

session is over.

5. To confirm understanding of the consent form, the following questions will be asked:

a. Do you understa nd that you will be exposed to live ticks and that individual ticks will be placed on your arm, monitored, taken off, and discarded in order to collect study data?

b. Do you understand that a repellent product will be applied to your arm

and left remain on yo ur arm for a potential exposure period of 18 hours

maximum?

c. Do you understand that one test day has the potential to last up to 19 hours, including up to 18 hours of testing and 1 hour of preparation?

d. Do you understand that you have the freedom to quit or withdraw from the study at any time, and that you will be paid for the hours worked?

e. Do you understand that your participation in this study is voluntary and that you may leave the study at any time?

6. All subjects who meet the requirements for participation and agree to participate in the study will sign the ICD and will receive a copy of the signed ICD. They will also receive a copy of the testing schedule.

7. The trainer will provide test subjects with the study director’s contact information (name, email, a nd phone number) to field any follow up questions. This information will be on the first page of the provided ICD.

8. The subjects will then have their forearms measured for the future testing as per section 5 of the protocol, and will be shown how to positi on their arm for testing. The procedures of each 15 minute exposure interval will be briefly explained.

9. Female subjects will take the pregnancy test within 48 hours prior to the first testing day. If the time until this day is more than 48 hours, these s ubjects will be asked to come to i2L on a separate occasion to take this test.

10. If the subject is eligible to participate in a subsequent study and choose to do so within 3 months of having completed full training, they will have the option of completing a shorter training session prior to the next study; the shorter training session would be the

same as that described above but would exclude the measurement of th e forearm, discussed in step # 8 above, given that their measurements would have already been t aken and recorded during the first training session.”

2) Please provide more details on the exact timing of the testing. The protocol needs to explicitly describe the amount of time the technician has to do testing and the amount of time in a 15 minute per iod that requires the subject to be seated and exposed to ticks.

Johnson and i2LResearch R espon se

Johnson and i2LResearch propose to revise sections 7.3 and 7.6 as noted below.

Section 7.3 Experimental Design will have the following added:Page 49 of 93 7.3.3 Each species evaluation will be conducted separately on different days.

7.3.4 Ticks will be tested one at a time on each test subject, at 15 minute intervals. The test day could last up to 19 hours: 1 hour for prep aration time, and up to 18 hours for exposure period, depending on the repellent tested.

7.3.5 Prior to the start of the exposure period , approximately one hour for prep time will be needed. During this hour the following will occur:

• Valid identification from e ach test subject will be verified upon arrival.

• The study director will briefly review the basic procedures for testing (e.g. how to position the arm, breaks, etc.).

• Test subjects will wash their forearms with soap and water and dry them thoroughly with

a paper towel.

• Test substances will be applied to the test subject’s forearm, per section 7.5 Test area

demarcation and treatment.

• Subjects will be made aware that meals will be provided as appropriate for the testing day

as described below in section 7.3 .6 . Subjects will have an opportunity to eat breakfast during this prep time.

7.3. 6 Up to three 15 minute breaks will be provided to each test subject per test day to give subjects a lunch, dinner, and one additional break. Breaks will be given at approximately 5 hours, 10 hours, and 15 hours after the start of test day, when the test day extends to these time frames. Breaks will be synced with each individual’s exposure interval schedule to be determined at time of test substance application. Bre akfast will be provided to test subjects prior to the exposure period. Lunch and dinner will be provided to test subjects each test day if testing is still being conducted at the scheduled break time.

7.3. 7 In the event that a tick is not repelled just prior to a test subject’s scheduled break, the subject will be asked to participate in the following 15 minute exposure to see if the subsequent tick confirms product breakdown. The test subject will then be either excused for their break

until the next e xposure (if breakdown did not occur at this time), or will be excused from the remainder of the test day, as breakdown has occurred. However, if the test subject wishes to break at the scheduled time, then their request will be honored and they will conti nue participation after their break is over.

Section 7.6 Repellency Observations will be revised as follows:

7.6.1 Thirty minutes after the treatment is applied, the first tick exposure will begin.

7.6.2 For each exposure, the subject will sit in a chai r and hold their control (untreated) forearm at an approximately 45 degree angle from the horizontal, fingers pointing down. The subject will hold their forearm so that the inner surface faces away from the body and upwards. Support material will be provi ded to help bolster the subject’s arm and for comfort while it’s being held at a 45 degree angle from the horizontal.

7.6.3 Three timers will be pre

- set to help aid in the timing of each exposure inter val. One

timer will be set to monitor the 15 minut e exposure interval, and two timers will be set for 3 minutes each for the ticks’ response on the control and treated arms, respectively.

7.6. 4 The 15 minute timer will be activated . An i2L Research staff member will gently pick up a single tick from the holding vial, using fine forceps or a cotton

- tipped applicator stick or equivalent, and place it on the release line on the inner surface of the subject’s control forearm,

and activate the first 3 minute timer

.Page 50 of 93 7.6. 5 The tick will be oriented gently towards the elbow using forceps or a cotton

- tipped applicator stick or equivalent. A normally active tick will begin to crawl up the forearm towards the elbow. The tick will be allowed three minutes to move across the boundary line.

7.6. 6 If the tick crosses the boundary line within three minutes, it will be considered to be actively questing, and will be immediately removed from the control arm. The tick will be accepted as attracted to the subject’s skin and behaving normally and thus acc eptable for use in the repellency test. If the tick is not attracted, it will be removed and discarded by immersing it in isopropyl alcohol , and t he process will be repeated until a control tick is verified. The 3 minute timer will be stopped and reset ac cordingly.

7.6. 7 Once an acceptable tick is selected, the subject may relax their control arm. They will then lower their treated forearm to 45 degrees from the horizontal. The confirmed tick will be placed at the release line on the treated arm , and the s econd 3 minute timer will be activated, and oriented using the same method as for untreated arm.

7.6. 8 T he tick will be allowed three minutes to move across the boundary line and 3 cm into the treated area (to the crossing line).

7.6. 9 If the tick does no t cross the boundary line to the treated area within three minutes, it will be recorded as being repelled.

7.6. 10 If the tick crosses the boundary line into the treated area, but then does not reach the crossing line within three minutes of being released , it will be also reported as being repelled.

7.6. 11 If the tick crawls to the crossing line within three minutes of being released, it will be reported as not repelled.

7.6. 12 The tick will subsequently be killed by immersion in isopropyl alcohol. No tic ks will

be re

- used.

7.6. 13 The above procedures will be repeated for each exposure period, every 15 minutes. The start time for each will be recorded as the time that the first tick is placed on the subject’s

untreated forearm.

7.6. 14 The exposure of a single tick every 15 minutes will continue for 18 hours or until the test substance ‘breaks down’ (i.e. fails to repel, see below). Each exposure may last anywhere from 6 to 15 minutes, depending on control tick behavior.

7.6. 15 Test substance breakdown occurs when one tick is recorded as not being repelled (i.e. crossing or repellent failure) and one of the two following events occur: (i) the first subsequent tick to be exposed is also recorded as not being repelled or (ii) the first subsequent tick is repelled, but the second subsequent tick is recorded as not being repelled. Either (i) or (ii) will be counted as confirming crossings within 30 minutes of the first crossing. The time of breakdown

will be recorded as the time of the first confirmed cross ing.

7.6. 16 Subjects will be instructed to wash their arms with mild soap and water once the product on their arm has broken down, or at the conclusion of the test day

. 7.6. 17 The ticks will not be allowed to bite the subjects for health and safety reason s. Any tick that ceases movement for more than a few seconds will be gently prodded with forceps or a

cotton

- tipped applicator stick or equivalent. It should be noted that, unlike mosquitoes, most ticks will not bite immediately but will often crawl about on the host for hours before biting.

3) Repellent sample size selection: The protocol cites one example of the effect of sample size

on confidence interval width when c hanged from 10 to 20 subjects. Submit a simulation showing the impact of increasing sample size on the width of 95% confidence interval ofPage 51 of 93 median CPT where median CPT will be estimated using Kaplan Meier method. This can be presented in table form.

Johnson and i2LResearch Response

Kaplan Meier median confidence limits are calculated using SAS, which employs a generalization of the Brookmeyer and Crowley (1982) sign test under a log

- log transformation.

Please see the memo below which was generated by Thomas Rosholt of Morspace as justification for our chosen sample size:

Memorandum

To Julie Palm, Associate Manager

– Entomology, SC Johnson & Son, Inc

. From Tom Rosholt, Vice President

– Analytics & Modeling at Morpace Inc.

Date September 8, 2015

Subject Sample size recommendation for tick repellency efficacy studies

The number of test subjects for a tick repellency efficacy study should strike a balance among three critical and competing criteria :
a) M inimization of potential hazard to test subjects , where fewer subjects is better.

b) S tatistical robustness , where more subjects results in greater precision of numeric estimates.

c) C onsistency with previ ous repellent efficacy studies. Current and recent practice is to utilize ten subjects for each test site/test product.

The standard data analysis method for tick repellency efficacy studies involves the Kaplan

- Meier estimator, and the measure of interest is the Kaplan

- Meier median. The confidence limits associated with the Kaplan

- Meier median are positional values in the distribution, rather than calculated

value s as in the case of a confidence interval around the mean. The table below indicates which positions in the distribution of values constitute the lower confidence limit (LCL) and upper confidence limit (UCL) of the median for various sample sizes. The as sumption is that the values are sorted in increasing order, so value “1” in the distribution refers to the smallest value (i.e., the minimum).

► Table 1: Kaplan

- Meier Median Confidence Limits for a Range of Sample Sizes.

Sample

size Distributional positio n for
95% LCL Distributional position for
95% UCL Percent of

values above

LCL

10 1 8 90%

12 2 10 83%

15 3 11 80%

20 5 15 75%Page 52 of 93 As evidenced by the table, sample sizes larger than ten would provide only marginal increases in precision relative to the increase in the number of exposed test subjects. Given that a sample size of ten meets criteria a) and c), and a sample size greater than ten has limited impact in criterion b), I recommend the continued use of ten as the sample size for tick repellency efficacy studies.

4) Randomization mechanism needs to be inserted into sections 2.3.8 and 2.3.9.

Johnson and i2LResearch Response

Section 2.3.8 will be revised as follows:

2.3.8 For each testing period, twelve test subjects (six female and six male) will be selected from the pool of subjects that fulfill the inclusion/exclusion criteria and have signed the ICD for the study, by a su bject allocation table via appropriate software (such as Excel or Minitab) . This selection will be achieved by randomly selecting the test subjects’ assigned code number. The first five females and five males will be assigned as the test subjects. The sixt h female and the sixth male will be assigned to act as alternates.

2.3.9 Using a number generating statistical software (such as Excel or Minitab), a second random selection will be made from the ten test subjects to determine the testing day on which

eac h subject will participate. The first five selected will participate in the first test day, and the remaining five subjects will participate in the second test day. Alternates will be asked to be available for both days.

For logistical ease for each test day, SC Johnson and i2L prefer to keep the decision as to which limb (left or right) will be treated based on a coin toss (section 4.1).

5) Amend the protocol to require subjects to wait at least two calendar days (48 hours) between experiments if they part icipate in multiple experiments.

Johnson and i2LResearch Response

Johnson and i2LResearch agreed to the changes, as shown below, in proposed revisions to sections 2.28, 2.73 and 4.2 and the addition of section 2.10.2.15.

Section 2.2.8 will be revised as follows:

2.2.8 Subjects who become test subjects in two studies within one week will wait 2 calendar days in between test days to avoid the risk of carry

- over of the first treatment to the second study.

Section 2.7.3 will be revised as follows:

2.7.3 Any subjects wishing to participate in more than one day of testing will not be allowed to do on two consecutive days. There must be at least 2 calendar days between each test day. This is to avoid the possibility of any repellent carrying over from an earlier test day to the following one. This includes alternates who had repellents applied to their arms.Page 53 of 93 Section 2.10.2.15 will be added to the protocol as follows:

2.10.2.15 Each study has been designed to take place over the course of non

- consec utive testing days . No test day , regardless of species tested or a new study testing a different product will ever be tested consecutively. At least 2 calendar days will lapse between any given te st day and the following test day to allow both subjects and staff to rest.

Section 4.2 will be revised as follows:

4.2 If a subject participates in more than one test day, care will be taken to ensure that there will be at least 2 calendar days in between each test day. The reason f or this is to minimize any risk of carry

- over of repellent from one test day to the next.

Ethics Comments

EPA’s comments are listed in order of the pertinent sections of the draft July 28, 2015 protocol to which they apply.

1) For purposes of clarity, please expand upon the following statement in Section 2.2.2: “ Each tick species will be tested separately from the other two tick species over the course of two test days, each lasting up to 18 hours (test period) for a total of 6 test days (3 testing periods) per study.”

Johnson and i2L Research Response : As proposed, s ection 2.2.2 will be revised as follows:

2.2.2 Each tick species will be tested separately from the other two tick species

. E ach species of

tick will be tested on 2 separate test days (5 test subjects on each day), each potentially lasting up

to 19 hours (including one hour of preparation time). The two test days per species total one testing period. Each study will consist of 3 testing periods (one for each species of tick), totaling 6 test days of study conduct.

2) Johnson and i2L Research intend to require a 2 hour training session for study participants prior to the test day in order for subjects to “learn more about the stu dy and their potential role in it, go over the inclusion/exclusion criteria, and receive answers to any questions they may have.” EPA’s science and ethics review resulted in the same recommendation regarding the training session; the protocol should be ex plicit with regard to the training outline and specific topics to

be addressed.

Johnson and i2L Research Response : As proposed, section 2.2.5 of the protocol will revised to read as follows and outlines each element of the training program:

“ 2.2.5 Within 4 weeks prior to the first test day for any given subject, the subject will attend a training session that will last approximately two hours. Any test subject who has not previously participated in the study must attend a training session prior to their participation. If aPage 54 of 93 subject chooses to participate in multiple studies, as discussed in section 2.2.7, the subject will be required to attend a training session prior to their participation in each study.

During the training session, the following aspects of the study will be discussed and the following activities completed:

1. Upon arrival, subjects will be asked to provide proof of age with a driver’s license, passport, or other valid identification.

2. Test subjects will be given the Informed Consent Document (ICD), time to read the ICD, and the opportunity to ask questions about it. The trainer will provide a brief outline of the study, the test subjects’ potential role in the study, the potential length of the study on any given test day, and discuss the

inclusion/exclusion criteria.

3. Any questions or concerns about the study will be discussed and answered.

4. The employee conducting the training session with test subjects will let all training attendees know that if a test subject needs to spea k to the study director in private about any aspect of the study, time will be made for this discussion once the general training

session is over.

5. To confirm understanding of the consent form, the following questions will be asked:

a. Do you understand that you will be exposed to live ticks and that individual ticks will be placed on your arm, monitored, taken off, and discarded in order to collect study data?

b. Do you understand that a repellent product will be applied to your arm and remain on your arm for a potential exposure period of 18 hours maximum?

c. Do you understand that one test day has the potential to last up to 19 hours, including up to 18 hours of testing and 1 hour of preparation?

d. Do you understand that you have the freedom to quit or withdraw fro m the study at any time, and that you will be paid for the hours worked?

e. Do you understand that your participation in this study is voluntary and that you may leave the study at any time?

6. All subjects who meet the requirements for participation and agree t o participate in the study will sign the ICD and will receive a copy of the signed ICD. They will also receive a copy of the testing schedule.

7. The trainer will provide test subjects with the study director’s contact information (name, email, and phone num ber) to field any follow up questions. This information will be on the first page of the provided ICD.

8. The subjects will then have their forearms measured for the future testing as per section 5 of the protocol, and will be shown how to position their arm for testing. The procedures of each 15 minute exposure interval will be briefly explained.

9. Female subjects will take the pregnancy test within 48 hours prior to the first testing day. If the time until this day is more than 48 hours, these subjects will be asked to come to i2L on a separate occasion to take this test.

10. If the subject is eligible to participate in a subsequent study and chooses to do so within 3 months of having completed full training, they will have the option of completing a

shorter tr aining session prior to the next study; the shorter training session would be the same as that described above but would exclude the measurement of the forearm,Page 55 of 93 discussed in step # 8 above, given that their measurements would have already been taken

and re corded during the first training session. ”

3) Regarding the recruitment process described in sections 2.3.3

– 2.3.6 (on pages 15

– 16 of the protocol ), Johnson and i2LResearch d ecide d to recruit participants instead of relying on a “pool

of individuals who have expresse d interest in testing with i2L.” As a result, p lease provide a revised and detailed description of the recruitment process for inclusion in the protocol. The recruitment process should include advertisements in one or more local Spanish lang uage newspapers. 40 CFR Section 26.1125(c) requires that the sponsor submit any advertisements proposed to be used; the advertisement language must be provided for EPA and HSRB review.

F ollowing EPA and HSRB review, the advertisement must be reviewed and approved by the IRB, along with all other changes to the protocol.

Johnson and i2L Research Response : Johnson and i2L Research propose to revise Section 2.3.3

– 2.3.5 as foll ows:

2.3.3 Potential subjects will be recruited from a pool of individuals who will have express ed interest in testing with i2L. This pool will generally represent the demographics and ethnicities of US repellent users

. This process is described in more detail in the following sections.

2.3.4 Subjects will be recruited from a gr oup from the general public at least three times greater than the number required for any one study. A recruitment firm will initially advertise to potential subjects and compile a pool of potentially interested subjects who respond to a secure study website and fill out a form with their contact information . This pool will generally represent the demographics of US repellent users.

2.3.5 Current repellent product labels are in English and the language that someone speaks does not directly affect at tractiveness to ticks

. To target users familiar with and that understand the product labels, we will be recruiting English

- speaking subjects , with a minimum of 10% bilingual

. This research does not offer benefits to the subjects ; so limiting recruitment t o English speakers

, with 10% of subjects being bilingual

, will not result in equity

- of

- access issues. To recruit a minimum of 10% bilingual subjects, i2L will also have the advertisements translated to Spanish.

2.3.6 2015 Neilson data2 shows that for US repellent users, Caucasian households show a stronger household penetration as buyers than non

- Caucasian, and people ages 35

- 55 purchase more repellents products than consumers under 35 years old. Approximately 13% of t he share dollars for repellents comes from the Hispanic population in the US. I2L will target recruiting a minimum of 10% bilingual (English and one other language) so as not to restrict recruitment to English

- only speakers.

Penetration among US repellen t buyers fits within the indices for sex, age and race used in recruitment for this study. Test subjects will be recruited for each study following the table below to best represent US repellent users

. Subjects will be recruited from the Baltimore, Maryla nd

area , v ia advertising through digital and social media

. Advertisements will be posted in digital and social media mediums, such as Facebook, Yahoo/Bing, Google and Craigslist. A SpanishPage 56 of 93 language advertisement will also be posted on line using the same media, plus an online Spanish language newspaper that advertises within the recruitment area. The advertisements will contain a link to a study

- specific secure website where interested respondents can learn more about the study as well as complete a pre

- sc reening qualification form. The forms that are filled out on the website will be automatically uploaded into a secure and encrypted portal, to which i2L employees will have access. Every effort will be made to achieve the demographic composition,

via a str atified random sample of the pool of recruited subjects. The qualifying subjects will be stratified into smaller subgroups according to their race/ethnicity, age, and gender to help ensure that the sample demographic composition of the test subjects will b e approximately similar to that of the table below for each test day. The final report will specify the demographic composition goals, and the demographics of test subjects who participated in the study, due to availability of test subjects on each test d ay.

Individuals from the pool will be contacted by telephone or e

- mail (in which case a follow up telephone call will be made) to determine whether they meet the basic inclusion criteria

. They will be given a brief outline of the study. If they are int erested in enrolling in the study, they will be given a time, date and location to meet with i2L staff for a training session to learn more about the study and their potential role in it, go over the inclusion/exclusion criteria (see ‘Individual

inclusion/ exclusion criteria’, below), and receive answers to any questions they may have. Contact information is included on the consent form for any individual who has additional questions or if further clarification is desired after they have attended the traini ng session.

Demographic Quota

Male 50%

Female 50%

Age 18

- 30 20

- 30%

Age 31

– 44 30

- 40%

Age 45

- 54 30

- 40%

Caucasian 50

- 85%

African

American

,

Asian

, or other 5

– 25%Page 57 of 93 Hispanic 10

– 25%

Speaks another

language at

home Minimum

10%

References:

1. Nielsen Total US Homescan Household Panel Database, Calendar Year data.

2. Nielsen Homescan Hispanic Panel; 52 Weeks Ending 12/27/2014.

3. http://factfinder.census.gov/faces/tableservices/jsf/pages/productview.xhtml?pid=ACS_13_3Y R_CP02& prodType=table ”

– End of excerpt

-

The draft recruitment language which Johnson and i2LResearch propose to use is provided for

HSRB review in Attachment 11

.

4) T he last statement in section 2.3.6 (above the chart, on page 17 of the protocol) indicates tha t, “If

the individual desires

, this discussion may also take place by telephone or email.” OPP recommends deleting or revising this statement because it conflicts with the statement in section 2.4.1 (on page 19) that prior to participating in any study

- related procedure, each potential subject will meet in person with the Study Director or another designated staff member.

Johnson and i2L Research Response : The proposal is to revise the last sentence in Section 2.3.6 to state that “Contact information is included on the consent form for any individual who has additional questions or further clarification is desired, after they have attended the training session.”

5) In order to strengthen the consent process and Informed Consent Document , EPA recommends the changes noted below. The proposed revised consent form addressing EPA

comments is in Attachment 3.

a) If Johnson and i2LResearch wish to confirm each subject’s understanding of the consent form, they should draft several quest ions to be asked of each potential subject prior to the subjects signing the consent form; those questions should be included in the revised materials that are reviewed by the HSRB and SAIRB before the study is initiated. One of the questions

should addres s freedom to withdraw from the study.

Johnson and i2L Research Response : The Informed Consent Document or ICD was updated to inform participants that they will be asked several questions to confirm their understanding of the study and their role in it. The proposed questions are also included in the revised language for section 2.2.5 on the training program and listed below:Page 58 of 93 a. Do you understand that you will be exposed to live ticks and that individual ticks will be placed on your arm, monitored, taken of f, and discarded in order to collect study data?

b. Do you understand that a repellent product will be applied to your arm

and left remain on your arm for a potential exposure period of 18 hours

maximum?

c. Do you understand that one test day has the potential to last up to 19 hours, including up to 18 hours of testing and 1 hour of preparation?

d. Do you understand that you have the freedom to quit or withdraw from the study at any time, and that you will be paid for the hours worked?

e. Do you understand that your p articipation in this study is voluntary and that you may leave the study at any time?

b) The draft protocol indicates that participants sign the consent form once, regardless of the number of studies in which they participate. EPA recommends that participat ing subjects read and sign the consent form more frequently and asks Johnson and i2LResearch to propose an approach.

Johnson and i2L Research Response : As proposed, the consent form will be signed prior to participating in each study during the required training program which precedes each study. The revised consent form states, ”All test subjects will attend a training session prior to their participation in each study, and will be required to sign a new ICD prior to their par ticipation in each study...”

c) EPA r ecommend s that a section on “Test Material” and the identity of the pesticide and the

nature of its pesticidal function be included in the consent form

. As a result of this, please delete the language in protocol section 7. 4 on blinding of subjects as to identity of test

substance.

Johnson and i2L Research Response : Agreed. The following section was added to the consent form:

Test Material The test substances for these tests have all been registered by the U.S. Environmental Protection Agency under the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA). These test substances are typical insect repellant products marketed to consumers.

Up to 18 different insect repellent products may be tested in these studies. The products vary between three different registered active ingredients (A.I.’s):

1. DEET ranging from 5% to 98.25% A.I.

2. Picaridan ranging from 5% to 20% A.I.

3. p

- Menthane

- 3, 8 diol ranging from 8% to 10% A.I.Page 59 of 93 d) In the consent form, under “purpose of study,” it says the Johnson and i2LResearch wish to conduct “five to eighteen research studies.” This is the first place where the number “five” is

used. EPA recommends consistency between the protocol and the consent form.

Johnson a nd i2L Research Response : The number of studies referenced in the ICD was revised to be consistent with the protocol.

e) In the draft consent form, u nder “suitability,” second paragraph, EPA recommends referring

to “allergies or sensitivities ” to tick bites.

Johnson and i2L Research Response : Under suitability, the second paragraph was revised to refer to “allergies or sensitivities ” to

tick bites.

f) In the consent form, u nder “study duration and number of subjects,” when referencing the number of days of the s tudy and number of testing periods, please be consistent with the proposed revisions to the protocol , specifically section 2.2.9.

Johnson and i2L Research Response : There is consistency in the revised materials.

g) U nder “study duration and number of subjects,” at the end of the first paragraph, please add the following language: “Each test subject can only take part once in any two

- day testing period. Subjects who become test subjects in two studies within one week w ill have different arms treated for each study to avoid the risk of carry

- over of the first treatment to the second study.”

Johnson and i2L Research Response : The proposal is to revise the consent form to include the following statement:

“ You can only take part once in any two

- day testing period. If you are scheduled to participate in two studies within one week, there will be 2 calendar days in between test days to avoid the risk of carry

- over of the first treatment to the second study. ”

h) Please i nsert the detailed description of the training program in the consent form.

Johnson and i2L Research Response : The proposal is to include the following training section in the revised consent form:

“Training Session I2L Research will host a training session to help potential study participants understand what will occur during the study. All interested potential subjects will need to take part in a training session prior to their first test day. The training session will take about 2 hours and will occur within 4 weeks prior to the first test day in which a subject participates. During this session the following will occur:

1. Upon arrival, you will be asked to provide proof of age with a driver’s license, passport, or other validation. You will be given time to read the Informed Consent Document (ICD).Page 60 of 93 2. The trainer will provide a brief outline of the study, your potential role in the study, the potential length of the study on any given test day, and discuss the inclusi on/exclusion

criteria.

3. Any questions or concerns about the study will be discussed and answered.

4. The employee conducting the training session will let all training attendees know that if anyone needs to speak to the study director in private about any a spect of the study, time will be made for this discussion once the general training session is over.

5. To confirm understanding of the consent form, the trainer will ask you a few questions to ensure that you are aware of the parameters of the study and your role in it.

6. If you meet the requirements for participation and agree to participate in the study, you will be asked to willingly sign the ICD and will receive a copy of the signed ICD. You will also receive a copy of the testing schedule.

7. The trainer will provide you with the study director’s contact information (name, email, and phone number) to field any follow up questions. This information is on the first page of this

ICD.

8. You will then have your forearms measured for the future testing to calcul ate their surface area. To do this, the circumference of each forearm will be measured at a point 6 cm above your wrist bone, 12 cm above this point, and at two p oints midway between the first two measurements. The mean (average) of these four circumfere nces will be used to calculate the mean circumference. This latter measurement will be multiplied by 12 cm to give the surface area to be treated with a repellant for each of your forearms. You will also be shown how to position your arm for testing. The procedures of each 15 minute exposure interval will be briefly explained.

9. If you are a female subject, you will need to take an over the counter pregnancy test within 48 hours before each of your scheduled testing days (if the training session is within 48 hours prior to your first scheduled testing day, you may take a test on your training session day). The pregnancy test kit will be provided by i2L. Each female who takes the pregnancy test will verify the result of their own test. After completion of the pregnancy test, a female member of the study staff will ask in a private setting if you are still interested in participating. You only need to give a yes or no answer. If you choose to participate, the results of the pregnancy test

will then be verified b y a female member of the study staff in a private manner. The results will be kept confidential, will not be recorded, and will not be disclosed to anyone other than the test subject and the female staff member. Your decision to or not to participate in th e study will be shared with the Study Director or Principal Investigator.

If you choose to participate in multiple studies, you will be required to attend a training session prior to your participation in each study. However, if after any study you par ticipate in a subsequent study within the next 3 months, you have the option of attending a shorter training session which excludes the measurement of your fo rearm described in step number 8 above. You may opt to participate in the full training session i f you would like.”

i) In the consent form, a t the end of the procedures section, p lease insert language about a

fifteen minute lunch break and fifteen minute dinner break

. Please reference that breakfast, lunch and dinner will be provided. The breaks and the provision of breakfast during the preparation time, and lunch and dinner during the test day are necessary due to the length of the test day.

Johnson and i2L Research Response : The proposal is to include the following language in the c onsent form:Page 61 of 93 “ Breaks and Meals Provided Due to the potential of a long test day of up to 19 hours, food and beverages (breakfast, plus lunch and dinner, when the test day extends to these time points) will be provided to participants. Breakfast will

be a vailable during the one hour preparation period on each test day in which you participate. A 15 minute lunch break will be provided approximately 5 hours after arrival to the lab, and a 15 minute dinner break will be provided approximately 10 hours after arrival to the lab. When appropriate, a third 15 minute break will be provided approximately 15 hours after arrival to the lab.

If, just prior to a participant’s scheduled break, a tick is not repelled, we will ask you to participate in the following 1 5 minute exposure to see if the subsequent tick confirms product breakdown. You will then be either excused for the break until the next exposure (if product breakdown did not occur), or will be excused from the remainder of the test day, as breakdown did occur. However, if you would rather take the break at the originally scheduled time, we will respect your request and will resume testing after the 15 minute break.

In addition to the scheduled breaks, testing staff will encourage s you to walk around th e lab and or to stretch in between exposure intervals, to minimize any discomfort or fatigue given the potential length

of the test day.”

j) At the end of the “discomfort and hazards/risks” section, EPA recommends add ing the sentence, “There is also the fatigue and discomfort associated with a long testing day.”

Johnson and i2L Research Response : Additional language is proposed below:

“ Discomfort and Hazard/Risks The main risks associated with the proposed study are the potential for allergic or irritation responses to the test product, exposure to ticks , and fatigue and/or physical discomfort from the length of the test day

....

To try and minimize the fatigue and/or physical discomfort due to the length of the test day, you will be provided breakfast, lunch and dinner and up to 3 fifteen minute breaks. Each break is expected to occur 5, 10, and 15 hours after you first arrive at the lab. Also, in between exposure intervals, testing staff will encourage you to walk around the lab and stretch as needed.”

The entire discomfort and hazard/risks section is in the revised consent form in Attachment 3

to this memo.

k) Please update the compensation figures in the consent form consistent with EPA’s comments on compensation a mounts. (See EPA comment #7.)

Johnson and i2L Research Response:

T he compensation figures in the consent form were updated in response to EPA’s comments.

The revised consent form in Attachment 3.Page 62 of 93 l) In the introduction to the consent form, please remove the reference to “alternative procedures” described in the consent form because such procedures are not discussed.

m) Please reference the updated preparation time, in addition to the potential length of the testing period, in the consent form.

n) In the consent form’s section on study duration and number of subjects, there is a reference to “zero to five female subjects plus five to zero male subjects.” EPA recommends that you replace this with a statement that both male and female subjects will participate.

o) EP A recommends deleting the section in the original draft consent form entitled, “Research Participation Information.” This section lists 5 different websites that subjects can check for information about participation in human research studies in general. A lthough EPA appreciates the intent of Johnson and i2LResearch, given that these websites do not focus on the tick repellent study for which subjects are being recruited, EPA believes this section is unnecessary. Only the information directly relevant to t he tick repellent study should be included in the consent form to avoid unnecessary time being spent by subjects researching

other material.

p) T he consent form and phone scripts must be updated consistent with any other revisions to the protocol approved by EPA and the HSRB

.

Johnson and i2LResearch Response : Johnson and i2LResearch revised the consent form and phone scripts to address all of EPA’s

comments on the draft. The revised consent form is in Attachment 3 to this memo. The revised phone scripts with EPA’s comments included are in Attachment 4

.

6) EPA recommends that the training session require that each subject provide proof of age with a driver’s license, passport or other valid identification; Johnson al ready identified this inclusion factor in the protocol, but the protocol needs to specify at what point the identification will be checked. We recommend that occur during the training session and at the beginning of each study, on the first day that a subj ect arrives for participation.

Johnson and i2LResearch Response : Section 7.3.5 has been revised to read that subjects will provide ID upon arrival to the lab each test day.

In addition , as proposed, Section 2.4 on Consenting will be updated as follows:

“2.4.1 Prior to participating in any study

- related procedure, each potential subject will meet in person with the Study Director, or another designated i2L staff member who is fully familiar with the protocol and the consenti ng procedure , for a training session. Logistics for the training

session are listed in section 2.2.5

. Test subjects will be asked to provide proof of age with a driver’s license, passport, or other valid identification upon arrival to the training sessio n. 2.4.2 The potential subjects will be provided with copies of the Informed Consent Document

and will then be asked to read the entire document.Page 63 of 93 2.4.3 After the potential subjects have completed reading this document, the staff member leading the discussion will ask the subjects if they have any questions regarding the information in the consent form, the study and their role in the study. Any questions will be answered. The

trainer will let subjects know that if a private matter needs to be discussed regarding their role in the study, then time will be made for this discussion once the general training session is over.

2.4.4 The potential subject will be given ample time to ask and have all questions answered.

2.4.5 If an individual still wishes to enroll in the study, he or she will be asked to sign the ICD, which will be witnessed by the staff member who led the consent discussion. The subject will then be given a photocopy of the signed ICD and testing schedule

. 2.4.6 All test subjects will attend a training session prior to participation in each study, and will be required to sign a new ICD prior to their participation in each study. Howeve r, if the subject participates in test days within 3 months of the next study’s start, then they will not be required to attend the full training session. Instead they may opt to come to the training session to only

fulfill all steps except for measuremen t of their forearm described in step #9 in section 2.2.5. If they would like to attend the full training session, they may opt to do so. Payment will be the

same for each training session participation. ”

7) Section 2.5 of the protocol states that, for each test day, test subjects will be paid $99.00 for any length of participation up to 9 hours and if a test day exceeds 9 hours, subjects will be paid $16.50 (time and a half) for each additional hour, rounded up to the nearest hour. The compensation of $11 p er hour is not comparable to similar recent human studies. OPP recommends that S.C. Johnson increase compensation to $13 per hour up to 8 hours and if a test day exceeds 8 hours, subjects will be paid $19.50 (time and a half) for each additional hour,

roun ded up to the nearest hour. The protocol currently states that subjects will be paid $25 for taking part in the training session. Section 2.2.5 (page 14) indicates that the training session will

be about two hours. Given that the training session will b e two hours in length, $30 seems like reasonable compensation and would be comparable to other protocols/studies.

Johnson and i2LResearch Response : Johnson and i2LResearch addressed EPA’s comments. As proposed, s ection 2.5 on Subject compensation will be revised as follows:

“2.5.1 Each subject will be paid $ 30 for taking part in each training session.

2.5.2 For each test day, test subjects will be paid $ 104 .00 ($13 per hour) for any length of participation up to 8 hours (see ‘Study termination, individual participation, and withdrawal’ in Section 9 for exceptions). If a test day exceeds 8 hours, subjects will be paid $ 19 .50 (time and a half) for each additional hour, rounded up to the nearest hour.

2.5.3 An altern ate who is not needed to replace a test subject will be able to leave and will be paid $50. The decision as to whether an alternate is needed will occur within the first two hours of the test, before all the treatments have been finished. If an alternate i s asked to replace a subject, he or she will be paid at the same rate as other test subjects, as described above.

2.5.4 Subjects who have participated in the training session, but then choose to withdraw or are asked to withdraw from or during the traini ng session, will still be paid $ 30 .00 for attending all or part of this session.

2.5.5 Any female subject who has to visit i2L solely for the purpose of taking a pregnancy test ( which will occur within 48 hours prior to the test day ), will be paid $25.00

.Page 64 of 93 2.5.6 Subjects may decline to participate at any time during the training session or test day without penalty.

2.5.7 If the Study Director or other i2L USA staff ask a subject to withdraw from the test and they have complied with all of their requests, or if a test subject needs to withdraw early because of a health or emergency reason, full payment will still be made even if the test subject has participated for less than eight hours. This will no t affect payment for any previous test days that had been completed.

2.5.8 The Study Director or other designated i2L USA staff may end a particular subject’s participation in a training session or on a test day, at any time, for any reason. If a test sub ject is asked to withdraw from the test because they have not followed all their directions or if they choose to withdraw from testing early on a test day for a non

- health related or non

- emergency reason, full payment will not be made if the test subject p articipates in less than eight hours. Instead, they will be paid for the number of hours worked (rounded to the nearest hour) at a rate of $13.00 per hour. This will not affect payment for any previous test days that had been completed

. 2.5.9 Subjects wi ll be paid by checks sent in the mail, or hand delivered while they are on site at the i2L facility. I2L issues checks on the 15th and on the last day of each month. ”

8) Regarding the inclusion/exclusion criteria, EPA recommend s the following changes:

“ 2.6. 7. The subject must have no known allergies or sensitivities to tick bites. 2.6.9. The subjects must not be hypersensitive to repellent or latex or other skin care products. The subjects must be free from skin disease, skin problems such as eczema, psoriasis or atopic

dermatitis. ”

Johnson and i2LResearch Response : Johnson and i2LResearch propose to revise sections 2.6.7 and 2.6.9 as recommended above.

9) EPA recommends that the pregnancy test be conducted within 48 hours prior to the test day. We understand that it’s necessary to conduct other prep aration work on the day of testing, but Johnson can take steps to reduce the length of the day by having the pregnancy test completed in

advance.

Johnson and i2LResearch Response : Joh nson and i2LResearch propose to revise the first five sentences in sections 2.6.15 to read as

follows:

“2.6.15 The subjects must not be pregnant or be breast

- feeding. To confirm that participating test subjects are not pregnant, within 48 hours prior to their scheduled test day, female subjects will be required to perform an over

– the

- counter pregnancy test that will be supplied by i2L. This can be done at the training session, if it’s within 48 hours prior to the start of the test day. If the training ses sion is conducted more than 48 hours prior to the start of the test day, the test subject will be required to come to i2L on a separate occasion, within 48 hours prior to the start of the test day, to take the pregnancy test. If a subject is required to co me to i2L on a separate occasion to take the pregnancy test, the subject will be paid $25.00 for their time. ”Page 65 of 93 10) Please update section 2.7.3 under “restrictions,” to indicate that there must be at least 48 hours, not 24, between each test day. Similarly update section 4.2 to indicate that there will be two days (not one) between test days.

Johnson and i2LResearch Response : Agreed.

11) The section on hazards to human subjects, section 2.10, page 24, currently discusses four types of potential hazards

. To be comprehensive in the protocol and consent form, Johnson and

i2LResearch should add the hazard of, “Fatigue and/or physical discomfort from length of test day” and actions being taken to reduce this discomfort, including the provision of breaks for

lu nch and dinner, subjects being encouraged to stretch as needed, and a 2 day break between test days.

Johnson and i2LResearch Response : Johnson and i2LResearch propose to revise section 2.10.1 as follows:

2.10.1 There are five types of potential hazards associated with these studies: A) adverse reaction to the test substances, B) exposure to ticks, C) exposure to tick

- vectored diseases (see below for more information), D) unanticipated loss of confidential information. E) fatigue and/or physical discomfort from length of test day

In addition, the following sections are proposed to be added in response to EPA’s comments:

2.10.2.14 Subjects will be provided with up to three 15

- minute breaks throughout the potential up to 19 hour test day when appropriate, specifically a lunch (approximately 5 hours from when the test subject arrived), dinner (approximately 10 hours after the test subject arrived), and one other break period at approximately 15 hours from when the subject arrived.

In addi tion, any time remaining immediately following an exposure period and before the start of the following exposure period, subjects will be encouraged to stretch and walk around as needed to try to minimize the discomfort from the length of the testing perio d.

2.10.2.15 Each study has been designed to take place over the course of non

- consecutive testing days. No test day, regardless of species tested or a new study testing a different product will ever be tested consecutively. At least 2 calendar days wi ll lapse between any given test day and the following test day to allow both subjects and staff to rest.

12) The “hazards to human subjects” section 2.10 .10 , page 26 also states, “Subjects will be told that if anyone experiences any skin reaction, experienc es an injury, or simply feels unwell, he or she should inform i2L staff right away. Such subjects will immediately be given appropriate care, may be withdrawn from testing, and may be transported to a local hospital if necessary.” EPA

recommends that Joh nson and i2LResearch add language identifying the closest hospital and directions, prior to the test date, and discussing reimbursement for medical care costs as applicable.Page 66 of 93 Johnson and i2LResearch Response : The proposal is to update s ection 2.10.2.10 as follows:

2.10.2.10 Subjects will be told that if anyone experiences any skin reaction, experiences an injury, or simply feels unwell, he or she should inform i2L staff right away. Such subjects will immediately be given appropriate care, may be with drawn from testing, and may be transported to a local hospital if necessary. The closest hospital to the laboratory test site and directions will be identified prior to the test date. At least one study staff member will remain with the other subjects if other staff members have to depart with an injured or ill subject. The study sponsor will reimburse test subjects for the costs of medical care. All adverse effects will be followed until resolution is reached. There are no plans to provide other compens ation beyond what is listed in this protocol and informed consent document.

13) Johnson and i2LResearch should try to reduce the length of the 2 hour preparation time which

occurs prior to the exposure period and limit it to essential activities which must occur during that timeframe. (If the preparation time is reduced in length, please reflect this in the consent form as well.)

Johnson and i2LResearch Response : Johnson and i2LResearch reduced the length of the preparation time to one hour and identified the preparation activities under comment # 1 4

.

14) Given the potential length of the test day, Johnson and i2LResearch should provide breaks and breakfast, lunch and dinner to the subjects.

Johnson and i2LRes earch Response : In response to comments #13 and #14

, Johnson and i2LResearch propose to expand section 7.3 to include the following :

7.3.3 Each species evaluation will be conducted separately on different days.

7.3.4 Ticks will be tested one at a time on each test subject, at 15 minute intervals. The test day could last up to 19 hours: 1 hour for prep aration time, and up to 18 hours for exposure period, depending on the repellent tested.

7.3.5 Prior to the sta rt of the exposure period , approximately one hour for prep time will be needed. During this hour the following will occur:

• Valid identification from each test subject will be verified upon arrival.

• The study director will briefly review the basic procedur es for testing (e.g. how to position the arm, breaks, etc.).

• Test subjects will wash their forearms with soap and water and dry them thoroughly with a paper towel.

• Test substances will be applied to the test subject’s forearm, per section 7.5 Test area

demarcation and treatment.Page 67 of 93 • Subjects will be made aware that meals will be provided as appropriate for the testing day

as described below in section 7.3.6 . Subjects will have an opportunity to eat breakfast during this prep time.

7.3. 6 Up to three 15 minute breaks will be provided to each test subject per test day to give subjects a lunch, dinner, and one additional break. Breaks will be given at approximately 5 hours, 10 hours, and 15 hours after the start of test day, when the test day exte nds to these time frames. Breaks will be synced with each individual’s exposure interval schedule to be determined at time of test substance application. Breakfast will be provided to test subjects prior to the exposure period. Lunch and dinner will be p rovided to test subjects each test day if testing is still being conducted at the scheduled break time.

7.3. 7 In the event that a tick is not repelled just prior to a test subject’s scheduled break, the subject will be asked to participate in the follo wing 15 minute exposure to see if the subsequent tick confirms product breakdown. The test subject will then be either excused for their break until the next exposure (if breakdown did not occur at this time), or will be excused from the

remainder of the test day, as breakdown has occurred. However, if the test subject wishes to break at the scheduled time, then their request will be honored and they will continue participation after their break is over.

15) Section 7.6 on repellency observations explains that subjects will hold their forearm at approximately a 45 degree angle from the horizontal. EPA recommends that support material be provided to help bolster the subject’s arm and for comfort while it’s bei ng held at a 45 degree angle. Please provide a photograph illustrating this support for EPA and the HSRB.

Johnson and i2LResearch Response : Please see proposed revised language for 7.6.2:

7.6.2 For each exposure, the subject will sit in a chair and ho ld their control (untreated) forearm at an approximately 45 degree angle from the horizontal, fingers pointing down. The subject will hold their forearm so that the inner surface faces away from the body and upwards. Support material will be provided to h elp bolster the subject’s arm and for comfort while it’s being held at a 45 degree angle from the horizontal.

I2LResearch and SC Johnson supplied the following photograph:Page 68 of 93 16) Regarding medical monitoring and reporting unanticipated problems in s ection 9.2, please add that subjects will be informed “in a timely manner”, both “orally” and in writing, of any significant new findings or new information. Please ex pand the title for section 9.2. to include “Stop Rule” given the proposed expanded content for that section.

Johnson and i2LResearch Response : Please see proposed revised language for section 9.2:

Section 9.2 Stop Rule, Medical monitoring and reporting unanticipated problems will be revised as follows (as per EPA’s recommendations in Attachment 1):

9.2.1 The i2L staff will watch for unanticipated problems or adverse effects to the subjects. Subjects will be told that if anyone experiences any skin reaction, experiences an injury, or simply feels unwell, he or she should inform i2L staff right away. Such subjects will immediately be given appropriate care, may be withdrawn from testing, and may be transported to a local hospital if

necessary. 9.2.2 Any problems or adverse effects will be promptly reported to Johnson, and the IRB. 9.2.3 Subjects will be informed in a timely manner both orally and in writing of any significant new findings discovered during the course of this study which may influence their continuedPage 69 of 93 participation. The Study Director and recruitment firm will keep on file the phone numbers and addresses for each study participant as a means to contact them if needed. 9.2.4 New findings will also be reported, in writing, to Johnson and the IRB in a timely manner. 9.2.5 The nearest local hospital to i2L's laboratory will be located an d directions identified prior to any study

- related procedures taking place. 9.2.6 Should a Type 1 allergic reaction (i.e. anaphylaxis) occur on the test day or if any other serious injury or medical issue occurs, the i2L staff will call 911and follow the instructions given by the emergency dispatchers. If instructed to transport the subject to a hospital, one study staff member and one other i2L staff member (one to drive and one to observe and take care of subject) will perform

this task. If there are no t sufficient Study staff present to both carry on the study and transport the affected subject(s), the Study Director or Principle Investigator will abort the test day. 9.2.7 Subjects will be instructed that if they develop a rash or other irritation on th eir treated forearm within 48 hours of the end of the most recent test day, they should inform i2L staff and seek medical advice. All adverse effects will be reported to Johnson and the IRB within five business day of their being noted, or within the same day in the case of serious adverse effects.

9.2.8 If i2L or Johnson learns of new findings or new information relating to the safety or hazard of any of the test substances, i2L will contact the subjects and advise them accordingly both orally and

in writi ng in a timely manner . The IRB will also be advised.

17) In section 9.3 on study termination, individual participation, and withdrawal, in 9.3.2, after the

reference to medical management, please add: “This is discussed in detail in section 2.10.10.”

Please update sections 9.3.6

– 9.3.9 to reflect the new compensation figures agreed to and the 8 hour timeframe (as opposed to 9 hours), in follow

- up to EPA’s comments.

Johnson and i2LResearch Response : Agreed.

18) EPA recommends the following changes to the telephone scripts for initial and follow

- up contact with potential subjects, included on pages 319

- 325 of the submittal to EPA and the HSRB:

Initial contact script

Please add:

• the length of the test day will depend on the length of time that the repellent effectively repels ticks;

• training session will be about 2 hours;

• for privacy reasons, names of subjects will not appear anywhere on the data sheets or in the study reports;

• subjects will be paid according to the updated compensation figures; please use t he updated figures in the script; and

• subjects are free to quit or withdraw from the study at any point of time and they will be paid for hours worked.

Follow

- up contact script

Please add:

• the length of the test day will depend on the length of time that the repellent effectively repels ticks;Page 70 of 93 • training session will take place prior to participating in each study and will be about 2 hours;

• subjects will be asked for identification/proof of age during the training session;

• for privacy reasons, names of subje cts will not appear anywhere on the data sheets or in the study reports;

• subjects will be paid according to the updated compensation figures; please use the updated figures in the script;

• subjects are free to quit or withdraw from the study at any point of time and the y will be paid for hours worked;

• subjects will be provided breakfast, lunch and dinner if they are still participating in the study during these meal times;

• breaks will be provided at specified times;

• an expanded question that ask about alle rgies to tick bites, in addition to sensitivity;

• pregnancy test will be performed in private; and

• subjects are encouraged to read the consent form in advance of the training.

Johnson and i2LResearch Response : Johnson and i2LResearch agreed and submitted revised scripts in response to EPA comments

which are included in Attachment 4.

19) Please update Appendix A, checklist of elements, with regard to page numbers and other pertinent information, after the protocol is revised in response to EPA and HSRB commen ts. Similarly, throughout the protocol, after it is revised, whenever you refer to other pertinent information as being “above” or “below,” please replace such reference s with a specific section

number instead.

Johnson and i2LResearch Response : Agreed.Page 71 of 93 

### Attachment 3

- Proposed Revised Consent F orm addressing EPA’s Comments

CONSENT INFORMATION FOR PARTICIP ATION IN i2LRESEARCH USA, Inc. TICK

REPELLENT LABORATORY STUD IES

Title: TESTING OF S. C. JOHNSON PERSONAL TICK REPELLENT PRODUCTS TO SUPPORT THEIR USE

OF THE EPA REPELLENCY AWARENESS GRAPHIC

Protocol No: 15/222

SCJ WR#: 90017620 Principal Investigator / Study Director : Timothy Foard , M.S. Timothy@i2LResearch.com Site of Investigation: i2LResearch USA, Inc. 1330 Dillon Heights Avenue Baltimore, Maryland 21228 Site Telephone #: 410

- 747

- 4500 24 Hour Telephone #: 866

- 344

- 3932

INTRODUCTION Before agreeing to participate in th ese research stud ies , it is important that you read and

understand the following explanation of the proposed research stud ies . This consent document describes the purpose, procedures, benefits, risks, discomforts and precautions

associated with the stud ies . It also describes your right to withdraw from the stud ies at any time. No guarantees or assurances can be made as to the results of the stud ies

.

If you are not completely truthful with the study staff regarding your health history, you may harm yourself by participating in th ese stud ies

.

Timothy Foard and other i2LRes earch USA, Inc. (‘i2L’) staff are paid to test pest control products, but they do not have a financial interest in the outcome of any of th ese stud ies

. Schulman Associates Institutional Review Board, Inc. (Schulman) has approved the

information in this con sent document and has given approval for the Study Director to run the se stud ies . An institutional review board (IRB) is an independent committee established to help protect the rights of research subjects. This does not mean the IRB has approved
your part icipation in the stud ies . You must think about the information in this consent document for yourself. You must then decide if you want to participate in the stud ies

.

PURPOSE OF THE STUDY

i2L wishes to conduct up to eighteen research stud ies to determine the efficacy of skin

applied repellents for protection against ticks. Human subjects will serve as the source of attraction by exposing one untreated forearm and one repellent

- treated forearm to single ticks, for brief intervals , every 15 min utes for up to 18 hours. Including preparation time,Page 72 of 93 each test day has the potential to last up to 19 hours. The ticks will not be allowed to bite the subjects. The purpose of this study is to determine how long these products will repel ticks of the speci es Amblyomma americanum (the lone star tick), Dermacentor variabilis (the American dog tick) and Ixodes scapularis (the deer or black

- legged tick).

Test Material The test substances for these tests have all been registered by the U.S. Environmental Protection Agency under the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA). These test substances are typical insect repellant products marketed to consumers.

Up to 18 different insect repellent products may be tested in these studies . The products vary between three different registered active ingredients (A.I.’s):

1. DEET ranging from 5% to 98.25% A.I.

2. Picaridi n ranging from 5% to 20% A.I.

3. p

- Menthane

- 3, 8 diol ranging from 8% to 10% A.I.

Your Suitability for the Study You are being as ked to participate in th ese research stud ies because you are a healthy

female or male, age between 18 and 55 , with no significant skin conditions that may be worsened by the application of repellent products

.

Before participating in the se stud ies you wil l be questioned about any allergies or sensitivities to tick bites, insect repellents or other topically

- applied skin products, and about any skin conditions that you may have. In addition, female test subjects may not participate if they are pregnant or breastfeeding.

If you are a female, within 48 hours prior to any of your scheduled test days, you must take a pregnancy test using an over

- the

- counter test (provided by i2L) a t the i2L facility. This will be done at the training session, or on a separate visit to the i2L test facilities. You will be allowed to do this alone in a private bathroom. Once you know the test results, a female employee of i2L will ask you, again in a private area, if you still want to take part in the test. If you say that you do, this employee will ask to see your result to make sure it is negative. The result will be kept confidential and will not be recorded and will not be disclosed to

anyone exc ept the Study Director. You may choose not to disclose the results of the pregnancy test to anybody at i2L, in which case you will not be allowed to participate in the study for health and safety reasons.

You must not be an employee of i2L or SC Johnson a nd Son Inc. or an immediate family member of any employee of i2L or SC Johnson and Son Inc.

If i2L decides that you should not take part in this test because of any of your answers to these questions , you will not take part in it. If this happens

, it is no reflection upon you.Page 73 of 93 You will be asked to wear short sleeves on your scheduled test day. All other clothing choices will be yours.

Study D uration and Number of Subjects These studies may take up to 108 test days (54 two

- day testing periods) , depending on the number of repellents tested. You may choose to participate in one, some, or all of the testing periods for which you are selected, and you may participate in more than one study

. You may be exposed to one test substance and one tick spe cies on each day of participation. Therefore, with participation in 1

- 54 test days, you can expect exposure to 1

- 18 test substances and 1

- 3 tick species. There may be long intervals between test ing periods. You can only take part once in any two

- day test ing period. If you are scheduled to participate in two studies within one week , there will be 2 calendar days in between test days to avoid the risk of carry

- over of the first treatment to the second study.

Testing on each test day will last up to 18 hours after the repellent is applied to your

forearm. The maximum total time that you may have to be present at i2L on a test day will

be 19 hours. If the repellent on your arm is not effective or loses its effectiveness, the time of your participation wi ll be shorter than this.

There will be five test subjects o n each day of testing

. Both male and female subjects will participate in the studies. There will also be two alternate subjects, one female and one

male

, present on each day of testing. Each repellent will be tested on ten subjects per tick species ; therefore two days will be needed to test each repellent /tick species combination

. The same five test subjects from the first testing day will not participate on the second day.

Test Subjects and Alternate Subjects If you agree to participate in testing, and satisfy all the requirements noted in this consent form, you may be randomly chosen (via a treatment allocation table) to take part in one or more testing periods for these studies. If you agree to this, for each testing period you will be randomly chosen by the Study Director to be either a test subject or an alternate subject.

This choice will be made via statistical software that will formulate a subject allocation table of all participants, assigned by code. The first five males and first five females chosen will be designated as test subjects; the sixth of each will be designated as alternates. Each subject will be assigned a code number in the study. If you are selected as a test subject, your code number wi ll be placed in a second allocation table which will determine whether you participate in the first or second test day for each testing period.

The two alternate subjects will act as replacements if any test subjects withdraw from or do not appear for a test day. If you are chosen as an alternate, you will need to arrive at i2L’s laboratory at the same time as the test subjects on both scheduled test days. If all the test subjects of your gender are present and none withdraw before treatments are complet ed (anticipated to be approximately two hours), you will be allowed to leave i2L.Page 74 of 93 Training Session I2L Research will host a training session to help potential study participants understand what will occur during the study . All interested potential subjects will need to take part in a training session prior to their first test day. The training session will take about 2 hours and will occur within 4 weeks prior to the first test day in which a subject participates. During this session the following will occur:

1. Upon arrival, you will be asked to provide proof of age with a driver’s license, passport, or other validation. You will be given time to read the Informed Consent Document (ICD).

2. The trainer will provide a brief outline of the study, your po tential role in the study, the potential length of the study on any given test day, and discuss the
inclusion/exclusion criteria.

3. Any questions or concerns about the study will be discussed and answered.

4. The employee conducting the training session will let all training attendees know
that if anyone needs to speak to the study director in private about any aspect of
the study , time will be made for this discussion once the general training session
is over.

5. To confirm understanding of the consent form, the trainer will ask you a few questions to ensure that you are aware of the parameters of the study and your
role in it.
6. If you meet the requirements for participation and ag ree to participate in the study, you will be asked to wil lingl y sign the ICD and will receive a copy of the signed ICD. You will also receive a copy of the testing schedule.

7. The trainer will provide you with the study director’s contact information (name, email, and phone number) to field any follow up questions. This information is on the first page of this ICD.

8. You will then have your forearms measured for the future testing to calculate their surface area. To do this, the circumference of each forearm will be measured at a point 6 cm above your wrist bone, 12 cm above this point, and at two points midway between the first two measurements. The mean (average) of these four
circumferences will be used to calculate the mean circumference. This latter measurement will be multiplied by 12 cm to give the surface area to be treated
with a repellant for each of your forearms. You will also be shown how to position your arm for testing. The procedures of each 15 minute exposure interval will be briefly explained.

9. If you are a female subject, you will need to take an over the counter pregna ncy test within 48 hours before each of your scheduled testing days (if the training
session is within 48 hours prior to your first scheduled testing day, you may take a test on your training session day). The pregnancy test kit will be provided by

i2L. Ea ch female who takes the pregnancy test will verify the result of their own test. After completion of the pregnancy test, a female member of the study staff will ask in a private setting if you are still interested in participating. You only need to give a yes or no answer. If you choose to participate, the results of the pregnancy test will then be verified by a female member of the study staff in a private manner. The results will be kept confidential, will not be recorded, and willPage 75 of 93 not be disclosed to any one other than the test subject and the female staff member. Your decision to or not to participate in the study will be shared with the Study Director or Principal Investigator.

If you choose to participate in multiple studies, you will be required to attend a training session prior to your participation in each study

. However, if after any study you participate in a subsequent study within the next 3 months, you have the option of attending a shorter training session which excludes the measurement of your forearm described in step

number 8 above. You may opt to participate in the full training session if you would like.

Study Design

Each test subject will have one repellent applied to their forearm skin. Their other forearm

will not be treated and will act as an untreated control

.

Procedures to be followed on each test day Upon arrival to the lab on each test day, you will be asked to provide a valid form of

identification.

I2L staff will verify that you have signed this consent form p rior to any study procedure being do ne.

At the beginning of a test day, y ou will wash your arm using a gentle soap and dry it thoroughly with a paper towel before any treatment is applied.

On any one test day, only one randomly

- chosen forearm will be treated. Four lines will be drawn on your forearm which is to be treated as follows ; i) a ‘release’ line 3 cm above the wrist bone; ii) a ‘boundary’ line 3 cm above the release line and is at the edge of the treated

area ; iii) a ‘crossing’ line 3 cm above the boundary line

, and iv) an upper boundary line 12 cm above the boundary line, which will denote the upper boundary of the treated area. Equivalent lines will be drawn on your other forearm.

T he repellent will be applied to the marked area of your forearm, using either a pipe tte or

needle

- less syringe , a spatula, or by spraying your forearm directly . A staff member will use a gloved finger to evenly sp read the repellent on your skin . You must be careful not to touch the exposed portion of your fore arms to anything for the dur ation of the test, in order to avoid removing any of the repellent or adding any contaminants to the arms that may

influence tick behavior.

Thirty minutes after your arm is treated, you will start exposing your forearms to ticks at 15 minute exposure intervals

. Each exposure interval may last up to 15 minutes, which will bePage 76 of 93 dependent on control tick behavior for verification of a healthy tick. All handling of ticks will be done by i2L employees.

For each exposure period, y ou will sit in a chair and hold your untreated (control) arm at an approximately 45 degree angle from the horizontal, with your fingers pointing down. You will need to hold your forearm so that the inner surface faces away from you and upwards.

An i2L employee, using a Q

- tip ® or e quivalent or forceps , will place a single tick on the inner

surface of the release line on the inner surface of your untreated fore arm . The i2L employee will gently move the tick until it is facing towards your elbow. A normally active tick will begin to crawl up your forearm towards your elbow. The tick will be allowed three minutes to move across the boundary line. If the tick does not crawl beyond the boundary

line within three minutes , it will not be acceptable for testing and it will be removed from

y our arm and killed by dropping it into a beaker of isopropyl alcohol. This procedure will then be repeated until an acceptable tick is found. If the tick does cross the boundary line within three minutes, it will be considered acceptable for testing, and t he i2L employee will promptly remove it from your arm

, and you can relax this arm for the remainder of the exposure interval

.

Once an acceptable tick is found, y ou will lower your treated forearm to 45 degrees from the horizontal, with fingers pointing down. The confirmed tick will be placed at the release

line and oriented the same as was done on your untreated arm. The tick will be allowed three minutes to move across the boundary line and into the treated area (to the crossing line).

If the tick d oes not cross the boundary line to the treated area within three minutes, it will be recorded as being repelled. If the tick crosses the boundary line into the treated area, but then does not reach the crossing line within three minutes of being released, it will also be reported as being repelled.

If the tick crawls over the crossing line within three minutes of being released, it will be reported as not repelled.

Regardless of whether it was repelled or not, the tick will now be killed by immersing it in isopropyl alcohol. Ticks will not be re

- used at any point during the study

.

The above procedures will be repeated for each exposure period. Exposure periods will

occur every 15 minutes until the repellent ‘breaks down’ or until 19 hours have passe d, whichever occurs first. Breakdown occurs when two ticks are not repelled in a 30

- minute period

.

The ticks will not be allowed to bite you at any time during the study . Any tick that stops moving for more than a few seconds will be gently prodded with forceps

, a Q

- t ip ® orPage 77 of 93 equivalent

. U nlike mosquitoes, most ticks will not bite immediately, but will often crawl about on the person for hours before they bite.

Once testing is complete (either after 19 hours of being at the lab , or sooner if the repellen t breaks down) , you may wash the repellent product off your fore arm and leave i2L

.

Breaks and Meals Provided Due to the potential of a long test day of up to 19 hours, food and beverages (breakfast, plus lunch and dinner, when the test day extends to these time points) will be provided to participants . Breakfast will be available during the one hour preparation period on each test day in which you participate. A 15 minute lunch break will be provided approximately 5 hours after arrival to the lab, an d a 15 minute dinner break will be provided approximately 10 hours after arrival to the lab. When appropriate, a third 15 minute break will be provided approximately 15 hours after arrival to the lab.

If, just prior to a participant’s scheduled break, a tick is not repelled, we will ask you to participate in the following 15 minute exposure to see if the subsequent tick confirms product breakdown. You will then be either excused for the break until the next exposure (if product breakdown did not occur) , or will be excused from the remainder of the test day, as breakdown did occur. However, if you would rather take the break at the originally scheduled time, we will respect your request and will resume testing after the 15 minute

break.

In addition to the scheduled breaks, testing staff will encourage s you to walk around the lab and or to stretch in between exposure intervals, to minimize any discomfort or f atigue given the potential length of the test day.

Restrictions You must refrain from using alcohol during the 12 hours before and during the test. You must also refrain from using nicotine and fragranced products (e.g. scented soap, perfume, cologne, hair spray, scented lotion, antiperspirant/deodorant, etc.) during the test.

Discomfort and Ha zard/Risks The main risks associated with the proposed study are the potential for allergic or irritation responses to the test product, exposure to ticks , and fatigue and/or physical discomfort from the length of the test day

.

The ticks which i 2L will use have been reared in a laboratory and are not known to carry any diseases, and also will not be allowed to bite subjects at any time.

If you become allergic to the test product or experience other reactions during the test, medical care will be made immediately available. Should a Type 1 allergic reaction (i.e. anaphylaxis) occur on the test day or if any other serious injury or medical issues occur, thePage 78 of 93 i2L staff will call 911 and follow the instructions given by the emergency dispatchers. If you do become allergic to the test product or experience other reactions during the test , it does not necessarily mean that your skin would react t o it under normal use conditions. If it appears that you should avoid contact with a certain material or type of material in the future, you will be told this in a timely manner . If you have a serious reaction to the product, the product’s ingredients wil l be identified for you

.

To try and minimize the fatigue and/or physical discomfort due to the length of the test day, you will be provided breakfast, lunch and dinner and up to 3 fifteen minute breaks. Each break is expected to occur 5, 10, and 15 hour s after you first arrive at the lab. Also, in between exposure intervals, testing staff will encourage you to walk around the lab and

stretch as needed.

There are non

- physical risks associated with taking part in this study, such as the risk of

accident al disclosure of your personal information , but all reasonable measures will be taken to protect personal information and maintain confidentiality.

Unknown /Unforeseeable Risks There may be other risks of study participation that are unknown or we can’t predict. If we learn of anything new that might affect your decision to be in the study, we will share it with you right away.

Compensation for Participation Training session: All potential subjects who take part in a training session will be paid $ 30 for each training session , regardless of whether or not they are selected to participate in the study afterward. Potential test subjects that choose to withdraw or are asked to withdraw from the training session will s till be paid $ 30 .00 for att ending all or part of each training

session.

Test subjects: For each test day you participate in, you will be paid $ 104 (equal to $13 per hour) for any length of participation up to eight hours (see exceptions, below). If a test day goes beyond eight hours, you will be paid at a rate of time and one half ($ 19 .50/hour

, rounded up to the nearest hour ) for the overtime hours up to an expected maximum of

nineteen hours.

Alternates: You will be paid $50 for each day of participation that you are not neede d to replace a test subject. If you need to replace a test subject, you will be paid at the rate specified for test subjects above.

If you have to visit i2L solely for the purpose of taking a pregnancy test for a testing day which is within the following 48 hours, you will be paid $25.00.Page 79 of 93 Payment is provided by check on the 15th or on the last day of the month. Checks will be

mailed or hand

- delivered to all subjects at the lab.

Exceptions: If i2L asks you to withdraw from the test and you have complied with all of their requests, or if you need to withdraw early because of a health or emergency reason, full payment will

still be made even if you have participated for less than eight hours

. T his will not affect payment for any previous test days you have completed.

If i2L asks you to withdraw from the test because you have not followed all their directions

or i f you choose to withdraw from testing early on a test day for a non

- health related or non

emergency reason, full payment will not be made if you participate for less than eight hours. Instead, you will be paid for the number of hours you participated (rounded to the nearest hour) at a rate of $ 13 .00 per hour. T his will not a ffect payment for any previous test days you have completed.

Costs There will be no charge to you for your participation in these studies . The study

- related procedures and study visits will be provided at no charge to you or your insurance

company.

Benefits You will not personally benefit from these studies . The benefit to society is the knowledge gained regarding the efficacy of personal tick repellents.

Alternative to Participation

These studies are for research purposes only. The only alternative is to not participate.

Your Rights You have been given an opportunity to discuss with i2L personnel any aspects of this document which are not clear to you. You have been informed that your consent must be freely given after you are certain that you understand the nature of the test, its purpose, and the procedure to be used together with the potential discomforts, risks or other adverse effects you may experi ence during or after the test. Participation in any of these studies is voluntary. You may refuse to t ake part or quit at any time without penalty or loss of benefits to which you may be otherwise entitled. After you read, and sign the consent form to signify agreement to participate as described , you will receive a copy of the signed consent form for you r files.

T he Study Director can stop your participation at any time without your consent for the following reasons:

• If you fail to follow directions for participating in the study;Page 80 of 93 • If it is discovered that you do not meet the study requirements;

• If the s tudy is cancelled.

Compensation for Injury In the unlikely event that you are injured as a result of your participation in this study, medical care will be made immediately available. The sponsor will reimburse you for the

costs of this care that is not paid for by any insurance policy that covers you in case of

illness. All adverse effects will be followed until resolution is reached. There are no plans to provide other compensation beyond that which is listed in this informed consent document.

You will not lose any of your legal rights or release the Sponsor, the Study Director , the study staff, or study site from liability for mistakes or intentional misconduct by signing this

consent document.

New Information

You will be informed in a timely manner bo th orally and in writing of any significant new findings discovered during the course of these studies which may influence your continued participation.

Questions If you have any questions about these studies or suffer a research

- related reaction, call th e Study Director listed on the front page of this consent form at 410

- 747

- 4500, or call Safety Call at (866)

- 344

- 3932 available 24

- hours.

If you have any questions about your rights as a research subject, and/or concerns or complaints regarding these res earch studies , you should write to Schulman Associates Institutional Review Board, Inc. 4445 Lake Forest Drive

– Suite 300, Cincinnati, Ohio 45242, or call toll

- free 1

- 888

- 557

- 2472 during business hours Monday

– Friday 8:00 a.m. to 6:00 p.m. EST.

Confidentiality The information obtained from your taking part in these studies will be used by i2L and its sponsor and will become part of the study reports . Only a code number will identify you on

the data sheets. Th e report s will be kept as confidenti al as possible under local, state and

Federal law. Despite this, i 2L cannot guarantee absolute confidentiality. Schulman Associates IRB, Inc. has the right to review your records. If the results of these studies are published or presented at meetings, you will not be identified.

Closing Statement You have read the information which has been stated above and have received satisfactory answers to all of the questions which you have asked and you willingly sign this consent form. You will receive a copy o f the signed informed consent form. You hereby consent to be a participant in th ese stud ies

.Page 81 of 93 Signatures I have read the above information in a language that I understand well

. The content and meaning of this inform ation has been explained to me. I hereby voluntarily consent and offer to take part in th ese stud ies

.

____________ ________________________ ________________________ Date/Time Print research participant name Research participant signature

____________ ________________________ _________________ _______ Date/Time Print name of person Signature of person conducting the Informed conducting the Informed

Consent discussion Consent discussion

Copy of consent form given to subject on (date) _________Page 82 of 93 Attachment 4

Revised scripts for initial and follow

- up telephone contact with potential subjects who respond during recruitment period

The study sponsor and author propose to revise the telephone scripts as noted below in response to

EPA’s comments on the draft.

[Procedure for Initial Contact in Recruiting Test Subjects over the telephone for Insect Repellent Bio

- Efficacy Studies.] (Words in parenthesis will not be spoken) (Initial Contact Script

- Read to recruits to determine if recruit is interested in participating). (Phone Call

- Th e initial phone call will be placed by employee of i2LResearch USA, Inc. or by a recruitment firm).

"Hello (Potential Test Subject's name), this is (enter nam e) from i2LResearch USA, Inc. ( i2L).

I am calling to ask if you might be interested in participating in an upcoming insect repellent study.

"This study will be conducted at the i2LResearch USA, Inc. laboratory in Catonsville, MD. The study

will evaluate skin

- applied repellents to see if they work against ticks. The test will be conducted

du ring the month of (enter month). The purpose of this study is to determine how long these products will repel ticks.

"Are you interested in learning more about this study?"

(If they respond "No") "Ok, thank you for your time today."

(If they respond "Ye s") "May I ask if you are between the ages of 18 and 55?"

(If "No") "Unfortunately we do require subjects to be between the ages of 18 and 55, but I do thank you for your time today."

(If "Yes"):

"If chosen to be a Test Subject, you would participate in one or more days of testing, each of which would last between approximately two to nineteen hours. The length of each test day will depend on the length of time that the repellent effectively repels ticks.

"More than the 12 subjects that will be needed for the study will be recruited. Subjects will attend a training and information session at i2L. The training session will be about 2 hours. If at the end of the session, more than 12 people are qualified and still interested in participating in the study, they will be assigned code numbers. For privacy reasons, names of subjects will not appear anywhere on the data sheets or in the study reports; instead, we’ll use code numbers

. i2L will then randomly select six females and six males to participate in the each of the test days of the study. You will be notified at that time if you have been randomly selected to participate in one or more of the test days.Page 83 of 93 "If you have been selected, a member of the study staff will measure your forearms using a tape

measu re in preparation for the study. This is because the amount of repellent applied to the skin during the study is based on the surface area of your forearm.

"The following will occur during a testing day:

• Subjects will be required to wear short sleeves, with all other clothing choices up to the subjects.

• A member of the study staff will apply Insect repellent to the skin of the Test Subject's forearms. The study staff will wear a glove when applying the Insect Repellent.

• During each the testing day , Test Subjects will have a single tick at a time placed on one of their forearms and then on their other forearm. Each tick will be watched closely and will not be allowed to leave the area of the forearm or to bite the test subjects at any time. At

the e nd of this time, the tick will be removed and killed. This procedure will be repeated with a new tick every 15 minutes until the repellent stops working or until 19 hours have passed, whichever occurs first.

• The study will be conducted over six test days with one Insect Repellent. Each subject may take part

i n one, two or three of these days. You will be notified in advance if you are randomly selected to participate i n any of the test days, and whether you would be a test subject or an alternate.

"S ubjects will be paid for their participation as follows:

• Test subjects will be paid $30 for participating in a training session which will last about two

hours.

• Assigned Test Subjects will be paid $104 (which is equal to $13 per hour) for any length of participation up to 8 hours on a test day, and $19.50 for each additional hour after the first 8 hours, rounded up to the nearest hour.

• Assigned Alternates who are not needed to replace an absent or withdrawn test subject will be paid $50 for th eir time and i nconvenience. It is expected they would be at the laboratory for about two

hours i n this case. If an alternate is needed to replace a test subject, they will be paid $ 104 for any length of participation up to 8 hours, and $1 9 .50 for each additional hour after the first 8 hours, rounded up to the nearest hour.

"Payment is provided by check on the 15th or on the last day of the month. Checks will be mailed or

hand

- delivered to all subjects at the lab.

"If this sounds like something you might be interested i n participating in and would like to learn

more about the study and your potential role in i t, I can schedule you for a 15

- 20 minute phone discussion with one of the I2L staff. That staff member will go over the i nclusion and exclusion criteria for Test Subjects and answer any further questions you may have about the study.

"Are you interested i n learning more a bout potentially participating i n this study?"Page 84 of 93 (If they respond "No") "Ok, thank you for your time today."

(If they respond "Yes") " I want to state upfront that you have the freedom to quit or withdraw from the study at any point in time. You will be paid for the hours worked.

What would be the best time to have a member of the I2L staff cal l you back to further discuss the study with you? Please remember that this phone conversation could take up to 20 minutes."(Schedule Time)

"Great and what would be the best number to reach you?"

Proposed Revised Script for Follow

- up Contact

The follow

- up contact script will be revised as follows:

[Procedure for Follow

- Up Contact in Recruiting Test Subjects over the telephone for

Insect Repellent Bio

- Efficacy Studies ] (Words in parenthesis will not be spoken) (Follow

- Up Contact Script

- Read to individuals who have indicated, based on the initial telephone contact, that they are interested in learning more about the study to determine if the recruit is still interested in participating).

(These individuals will be contacted by phone by a designa ted member of the i2L staff, at the time scheduled in the initial contact.]

(The i2L staff member will go over in more detail the study and the potential subject's role).

"My name is (enter name) and I am with i2LResearch USA, Inc. You indicated that you may be interested in participating in a tick repellent study with us and I am calling to follow up and let you know more information.

"Are you still interested in learning more about the study?"

(If "No") Thank you for your time today.'

(If "Yes") "Tha nk you for talking to me today and expressing interest in potentially participating in this study.

"The purpose of this research study is to determine how well skin

- applied tick repellents repel three different species of ticks in the laboratory. Human Test Subjects will serve as a source of attraction by exposing their forearms to ticks for brief intervals throughout the test day, which will last between

two to nineteen hours. The length of each test day will depend on the length of time that the repel lent effectively repels ticks.

"Let me go over in more detail what this study entails. Please ask any questions at any time.Page 85 of 93 "If you choose to potentially participate in and qualify for the study...

(Read for all):

Y

ou will attend a training and i nformation session at I2L prior to participating in each study. During this training, which will be approximately 2 hours, study staff will describe the study in detail, review the Inclusion and exclusion criteria, and thoroughly go through an Informed con sent document with you. They will also answer any questions you have. You will be asked to provide proof of age with a driver’s license, passport, or other valid identificatio n. If after this, you would still like to participate in the study, you would si gn the Informed consent document.

"If you do, you will then be assigned a code number, which would be subject to a random drawing with the other subjects to determine if you will be chosen to participate i n the study. For privacy reasons, names of subjects will not appear anywhere on the data sheets or in the study reports; instead, we’ll use code numbers. If you are selected, the study staff will measure your arms with a tape measure, would review the restrictions you must adhere to during your participation, and you would be informed of your scheduled test day.

"Ten test subjects and two alternates will be needed to test over a period of two days

. That means five test subjects and two alternates will be needed for e ach test day. The five test subjects will be different on the two test days, but the same alternates will be used on both days. There would be a maximum of three test days you could participate i n. All subj ects will be randomly selected i n advance, using a ssigned code numbers, from those who choose to participate in the study.

"The testing is scheduled to begin (enter time, date mont h, year) at the I2L laboratory i n the Catonsville area. You must refrain from alcohol for 12 hours before the test, and refra in from using nicotine and fragranced products (e.g. scented soap, perfume, cologne, hair spray, scented lotion,

a ntiperspirant/deodorant, etc.) during the test.

"On your scheduled test days, you would need to wear short sleeves. By advance random selection, five subjects will be assigned to have a repellent applied to one of their forearms, and the other two subjects will be assigned as alternates. If you are assigned as an alternate, you will be asked to

remain at the laborat ory for about two hour s, until i t i s determined i f you are needed to replace a test subject who Is absent or has chosen to withdraw from the study. If this doesn't happen, you will

be allowed to leave the laboratory.

"If you are selected to be treated with an insect repellent, the study staff will draw some lines on your arms in ink pen, and then apply the repellent to one of your forearms. You will have a single tick placed on one of your forearms at a time, for a period of up to 15 minutes. Staff will watch it closely

and it will not be allowed to crawl anywhere else on your body but your forearm, and it will not be allowed to bite you. This will be repeated every 15 minutes, either until the Insect repellent stops working or until 1 9 hours have elapsed , whichever occurs first . Once this happens, you will be able to wash the repellent off your arm and leave the laboratory.

"Since it is important for i2L staff to observe the repellent results all the way until it stopsPage 86 of 93 working or until 19 hours have elapsed during the test day

, you will remain at the laboratory for the entire time the repellent is on your arm, unless you have an emergency or choose to officially withdraw from testing. You have the freedom to quit or withdraw from the study at any point in time. You will be paid for the hours worked. Once you leave, you will not be able to rejoin the test at a

later time. Breakfast, lunch, and dinner will be provided to you each test day, if you are still in the study during these meal times. Up to three fifteen minute breaks will be provided at approximately 5, 10, and 15 hours after your arrival to the lab. The 15 minute breaks that occur 5 and 10 hours after you arrive are intended to be your lunch and dinner breaks. "Now that I have further ex plained the training session and test days, are you still interested in potentially volunteering as a test subject for this study?"

(If the potential test subject is still interested the staff member will proceed with the following):

"To see if you quali fy to participate in the study, I need to go over the criteria for test subjects. Some of the questions may be sensitive, such as questions about medical conditions. You only have to answer YES or NO to the questions, or you do not have to answer any of the questions you do not want to answer. I will not be documenting any of the answers you give me during this conversation. Do I have your permission to proceed?"

(If they give permission to proceed, the following yes/no questions will be asked:)

1. Are you within the ages of 18

- 55 and can provide proof of age by a driver's license, passport, or other valid identification? (MUST SAY YES)

2. Can you read and speak English fluently? (MUST SAY YES)

3. Are you an employee of i2L or of SC Johnson and Son Inc. or an immediate family membe r of an employee of i2L or of SC Johnson and Son Inc. ? (MUST SAY NO TO BOTH)

4. Do you have a reliable form of transportation to get to and from the test location? (MUST SAY YES)

5. Are you willing to ha ve crawling ticks placed on your forearms? (MUST SAY YES)

6. Are you hypersensitive or allergic to tick bites? (MUST SAY NO)

7. Are you highly sensitive or allergic to latex, Insect repellents , or skin care products? (MUST SAY NO)

8. Do you have any known skin conditions such as eczema, psoriasis, or atopic dermatitis? (MUST SAY NO)

9. Do you feel you are healthy enough and do not have any hea l th conditions that would make you unable to sit in a chair for up to 15 minutes every 15 minutes at a time, with breaks for limb stretching and movement at reasonable intervals, for up to 19 hours? (MUST SAY YES)Page 87 of 93 10. Are you willing to refrain from using alcohol for 12 hours before the test, and refrain from using nicotine and fragranced products (e.g. scented soap, perfume, cologne, hair spray, scented lotion, antiperspirant/deodorant, etc.) during the test? (MUST SAY YES)

11. Are you willing to follow the study procedures as explained? (MUST SAY YES)

12. Are you male or female?

(If fe male):

13. Do you know if you are currently pregnant? (MUST NOT BE PREGNANT )

14. Are you currently breastfeeding? (MUST SAY NO)

15. Are you willing to perform an over the counter pregnancy test in private that will be supplied by the lab, either on the day of the training session, or within 48 hours before your scheduled testing days? You will only need to disclose the results if they are negative and you still wish to participate in the testing, in which case you would share them with a female member of study staff. The results themselves will not be recorded. (MUST SAY YES)

(If the person does not qualify for the study):

"Unfortunately, you do not meet all of the test subject criteria for this study. You will not be able to volunteer as a test subject for this study, but thank you for your interest and for taking the time to answer these questions."

(If the person qualifies for the study based on this initial discussion):

"You meet the criteria to participate. Are you still interested in potentially participating in this study?"

(If the person is not interested): "Thank you for your time today."

(If the person is still interested):

Great thank you. The compensation for the study will be as follows:

• You will be paid $30 for participating in each training session

• (if female) If you are required to come to i2L on a separate occasion to take a pregnancy test, you will be paid $25 for your time.

• Assigned Test Subjects will be paid $104 for any length of participation up to 8 hours on a

test day, and $ 19.50 for each additional hour after the first 8 hours, rounded up to the

nearest hour.

• Assigned Alternates who are not needed to replace an absent or withdrawn test subject will be paid $50 for their time and inconvenience. It is expected they would be at the laboratory for about two hours in this case. If an alternate is needed to replace a test subject, they willPage 88 of 93 be paid $104 for any length of participation up to 8 hours, and $19.50 for each additional hour after the first 8 hours, rounded up to the near est hour.

• Payment is provided by check on the 15th or on the last day of the month. Checks will be

mailed or hand

- delivered to all subjects at the lab.

"The training and information session will be held on (enter date and time) at the following location: 1330 Dillon Heights Avenue, Baltimore, MD 21228. If you have any questions or need to contact the study staff the phone number is (410

- 747

- 4500). At the session we will completely review the informed consent document, give you time to ask any questions and determine if you are still

i nterested in participating in the study

.

"If you have an email or mailing address you are willing to provide, I can send you the informed consent document to review prior to the testing day. Although we encourage you to read t he consent form in advance, it is not required that you read the document ahead of the training session. We will completely review it with you at that session, so if you don't get a chance to read it ahead of time, that is okay.

"Thank you for your time today.'

- END of ATTACHMENT 4

-Page 89 of 93 Attachment 5 § 26.1111 Criteria for IRB approval of research Field Testing of SC Johnson Tick Repellent Products to Support their Use of the EPA Repellency Awareness Graphic

Criterion Y/N Comment/Page Reference

(a)(1)(i) Risks to subjects are minimized by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk. Y

(a)(1)(ii) Risks to subjects are minimized, whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes. N/A

(a)(2) Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits subjects would receive even if not participating in the research). The IRB should not consider possible long

- range effects of applying knowledge gained in the research (f or example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility. Y

(a)(3) Selection of subjects is equitable, taking into account the purposes of the research and the setting in which it will be conducted, and being particularly cognizant of the special problems of research involving vulnerable populations, such as prison ers, mentally disabled persons, or economically or educationally disadvantaged

persons. Y

(a)(4) Informed consent will be sought from each prospective subject or the subject’s legally authorized representative, in accordance with, and to the extent required by §26.1116. Y

(a)(5) Informed consent will be appropriately documented, in accordance with, and to the extent required by §26.1117. Y

(a)(6) When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects. Y

(a)(7) When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data. Y

(b) When some or all of the subjects are likely to be vulnerable to coercion or undue influence, additional safegu ards have been included in the study to protect the rights and welfare of these subjects. N/A

Attachment 6

§26.1116 General requirements for informed consent Field Testing of SC Johns on Tick Repellent Products to Support their Use of the EPA Repellency Awareness Graphic

Criterion Y/N Comment/Page Reference

No investigator may involve a human being as a subject in research covered by this subpart unless the investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative Y

An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence Y

The information that is given to the subject or the representative shall be in language understandable to the subject or the representative Y

No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject’s legal rights, or releases or appears to release the investigator, t he sponsor, the institution or its agents from liability for negligence YPage 90 of 93 (1) A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject’s participation, a description of the procedures to be followed, and identification of any procedures which are experi mental Y

(2) A description of any reasonably foreseeable risks or discomforts to the subject Y

(3) A description of any benefits to the subject or to others which may reasonably be expected from the research Y No benefits to subject. Benefits to society. (4) A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject N/A Alternative is not to participate.

(5) A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained Y

(6) For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be ob tained Y

(7) An explanation of whom to contact for answers to pertinent questions about the research and research subjects’ rights, and whom to contact in
the event of a research

- related injury to the subject Y

(8) A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled Y

(1) A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject may become pregnant) which are currently unforeseeable Y

(2) Anticipated circumstances under which the subject’s participation may be terminated by the investigator without regard to the subject’s consent Y

(3) Any additional costs to the subject that may result from participation in
the research N/A No additional cost to subject.

(4) The consequences of a subject’s decision to withdraw from the research and procedures for orderly termination of participation by the subject Y

(5) A statement that significant new findings developed during the course of the research which may relate to the subject’s willingness to continue participation will be provided to the subject Y

(6) The approximate number of subjects involved in the study Y

(e) If the research involves intentional exposure of subjects to a pesticide, the subjects of the research must be informed of the identity of the pesticide and the nature of its pesticidal function. Y

Attachment 7

§26.1117 Documentation of informed consent Field Testing of SC Johnson Tick Repellent Products to Support their Use of the EPA Repellency Awareness Graphic

Criterion Y/N Comment/Page Reference

(a) Informed consent shall be documented by the use of a written consent form approved by the IRB and signed by the subject or the subject’s legally authorized representative. A copy shall be given to the person signing the form. Y Consent form pp. 310

- 3 18. Revised consent form addressing EPA
comments is in Attachment 3 to EPA’s
review memo.Page 91 of 93 (b)(1) The consent form may be a written consent document that embodies the elements of informed consent required by §26.1116. This form may be read to the subject or the subject’s legally authorized representative, but in any event, the investigator shall give either the subject or the representative adequate opportunity to read it before it is signed; or Y

(b)(2) The consent form may be a short form written consent document stating that the elements of informed consent required by §26.1116 have been presented orally to the subject or the subject’s legally authorized representative. When this method is used, there shall be a witness to the oral presentation. Also, the IRB shall approve a written summary of what is to be said to the subject or the representative. Only the short form itself is to be signed by the subject or the representative. However, the
witn ess shall sign both the short form and a copy of the summary, and the person actually obtaining consent shall sign a copy of the summary. A copy of the summary shall be given to the subject or the representative, in addition to a copy of the short
form. Not applicable.

Attachment 8 40 CFR 26.1125 Submission of proposed human research for EPA review Field Testing of SC Johns on Tick Repellent Products to Support their Use of the EPA Repellency Awareness Graphic

Any person or institution who intends to conduct or sponsor human research covered by §26.1101(a) shall, after receiving approval from all appropriate IRBs, submit to EPA prior to initiating such research all information relevant to the proposed
research s pecified by §26.1115(a), and the following additional information, to the extent not already included:

Requirement Y/N Comments/Page Refs

(1) The potential risks to human subjects Y Section 2.10. pp. 24

- 26. EPA
comments in Attachment 2.
(2) The measures proposed to minimize risks to the human subjects; Y Section 2.10, to be revised in response
to EPA comments. (3) The nature and magnitude of all expected benefits of such research, and to whom they would accrue Y Section 2.11, p. 26.

(4) Alternative means of obtaining information comparable to what would be collected through the proposed research; and Y See Rationale and int ended use
of data

- Section 1.4

- Page 13 See Rationale for human testing

Section 2.1

– pp. 13

- 14. (5) The balance of risks and benefits of the proposed research. Y §1125(b): All information for subjects and written informed consent agreements as originally provided to the IRB, and as approved by the IRB. Y See IRB’s conditional approval statement on page 352.

§1125(c): Information about how subjects will be recruited, including any advertisements proposed to be used. Y See revised language for sections

2.3.3

– 2.3.6.

§1125(d): A description of the circumstances and methods proposed for presenting information to potential human subjects for the purpose of obtaining their informed consent. Y pp. 310

- 318 of draft. See revised language for section 2.4. Revised ICD
is in attachment 3 to review memo. §1125(e): All correspondence between the IRB and the investigators or

sponsors. Y pp. 343

- 353. Additional information
sent to EPA is in Attachment 9.

§1125(f): Official notification to the sponsor or investigator. . . that research involving human subjects has been reviewed and approved by an IRB. Y The research has been conditionally approved, pending HSRB

R eview and approval . p. 352.Page 92 of 93 (1) Copies of

• all research proposals reviewed by the IRB,

• scientific evaluations, if any, that accompanied the proposals reviewed by the IRB,

• approved sample consent documents,

• progress reports submitted by investigators, and reports of injuries to subjects. Y
n/a

Y
n/a

(2) Minutes of IRB meetings . . . in sufficient detail to show

• attendance at the meetings;

• actions taken by the IRB;

• the vote on these actions including the number of members voting for, against, and abstaining;

• the basis for requiring changes in or disapproving research;

• a written summary of the discussion of controverted issues and
their resolution. Y

pp. 343

- 353. IRB also provided information directly to EPA. See
Attachment 9 for the HSRB.

(3) Records of continuing review activities. n/a

(4) Copies of all correspondence between the IRB and the investigators. Y pp. 343

- 353
(5) A list of IRB members identified by name; earned degrees; representative capacity; indications of experience such as board certifications, licenses, etc., suffic ient to describe each member’s chief anticipated contributions to IRB deliberations; any employment or other relationship between each member and the institution, for example, full

- time employee, a member of governing panel or board, stockholder, paid or unpaid consultant. Y p. 353 and list of members in
Attachment 10

.

(6) Written procedures for the IRB in the same detail as described in §26.1108(a) and §26.1108(b). N On file with EPA . SAIRB provided the
SOPs listed below to EPA. (7) Statements of significant new findings provided to subjects, as required by §26.1116(b)(5). n/a n/a for protocols

Attachment 8 ( a )

Schulman Associates Institutional Review Board (IRB) SOPs Submitted to EPA

Schulman Associates IRB submitted directly to the EPA, the following SOPs, with a watermark indicating that their

content is “Confidential Business Information.”

101

– Review Board SOPs: Development, Implementation and Revision

102

– Review Board Purpose and Responsibility

103

- Confidenti ality of Records

201

– Role of Review Board Members

202

– Role of Review Board Chair and Vice Chair

204

– Composition

205

– Review Board Conflict of Interest

206

– Orientation and Continuing Education

207

– Granting Review Board Authority

208

– Management of Undue Influence

300

– Initial and Continuing Review of a Research Study

301

– Expedited Review of Investigator and Research Sites

302

– Review Board Meetings

303

– Voting

304

– Minutes of Review Board Meetings

305

– Consultants

306

- Primary Review Syst em
307

– Approval Letter/Disapproval Letter

308

– Signature Authority for Board Documents

309

- File Maintenance

310

– Site VisitsPage 93 of 93 311

– Expedited Review of Protocols

312

– Recruitment Materials/Study

- Related Materials

313

– Emergency Use of a Test Article

314

– Chair Designate Review

315

– Safety Information

316

– Device Studies

317

– Appeal of Board Decisions

318

– Privacy Rule (HIPAA)

319

– Subject Compensation

320

– Vulnerable Research Subjects

321

– Management of External Reporting of Regulatory Issues

322

– Amendments

323

– Management of Unanticipated Problems Involving Risks of Human Subjects or Others

324

– Application of Laws and Regulations

325

– Suspension and Termination

326

– Additional Ethical Considerations

327

– Site Modifications

401

– Informed Consent

402

– Consent via Legally Authorized Representatives

403

– Consent Process for Subjects who Lack Decision Making Capacity

501

– Principal Investigator’s Responsibilities

502

– Management of Investigator Noncompliance

503

– Investigator Conflict of Interest

601

– Electronic Signature

602

– Internal Client Support for Schulman Electronic Systems

603

– System Use and Operation of Schulman Enterprise System

Note: Attachments 9

– 11 are provided in separate files.