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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

 WASHINGTON D.C., 20460 

 OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

 September 22, 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 Unpublished document prepared by i2LResearch USA, Inc., 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 OPPTS 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 recommendations 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. All 
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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 attachments. 

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 active ingredients will be tested, along with a variety 

of product types (e.g., lotions, spritz, aerosols, and towelettes). 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 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 consumers 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). Subjects 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. Test 
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subjects will be recruited via advertising, through digital and social media, from the 

Baltimore, Maryland area where the testing will 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 website where interested 

subjects can learn more about the study and, if interested, complete a pre-screening 

qualification form; the form will be automatically uploaded into 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 from the 

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

criteria and will be given 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, and receive answers to 

their questions. The 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 

contact information in case subjects have additional questions in follow-up to their

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 before 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 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. 

4. Benefits: This research offers no direct benefits 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 

Graphic clearly informs consumers about the duration of repellent protection 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, no practical opportunities to further reduce risk to subjects while 
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maintaining the robustness of the scientific design have been overlooked. The residual 

risk to subjects is viewed as low 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 

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

is conditioned on the sponsor obtaining HSRB review, comments and approval. After the 

HSRB review process is complete, the protocol and other documents must be revised by 

the author and sponsor to incorporate comments from EPA and the HSRB, and then resubmitted to SAIRB for final approval before initiating the research. SAIRB is 

independent of the investigators and sponsors. Documentation of SAIRB procedures and 

membership is on file with the Agency. 

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), which 

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. Candidates 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 

compensated for time spent up to the point of withdrawal 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 provided 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 voluntary 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 revised to address EPA’s ethics 

comments in this section, EPA’s science comments, and any forthcoming comments from the 
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EPA Human Studies Review Board. S.C. Johnson and i2LResearch agreed to address all of 

EPA’s comments; Attachment 2 includes the revised language proposed by S.C. Johnson 

(hereafter “Johnson”) and i2LResearch in response to EPA’s comments. HSRB members are 

encouraged to read through Attachment 2 to understand the proposed revisions. After HSRB 

review and comment, the 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, 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.” 

2) Johnson and i2L Research will require a 2 hour training session for study participants 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 questions they may have.” EPA’s 

science and ethics review resulted in the same recommendation regarding the training session; 

the 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 decided to recruit participants instead of relying on a 

“pool of individuals who have expressed interest in testing with i2L.” As a result, please provide 

a revised and detailed description of the recruitment process for inclusion in the revised 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 provided for EPA and HSRB review. 

Following EPA and HSRB review, the advertisement must be reviewed and approved by the

IRB, along with all other changes to the protocol.

4) The last statement in section 2.3.6 (above the chart, on page 17 of the protocol) indicates that, “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) In order to confirm each subject’s understanding of the consent form, Johnson and 

i2LResearch should draft several questions 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 address freedom to withdraw from the study.
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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 participating subjects read 

and sign the consent form more frequently and asks Johnson and i2LResearch to propose an 

approach.

c) EPA recommends 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 number “five” is 

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

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

to “allergies or sensitivities” to tick bites.

f) In the consent form, under “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) Under “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, at the end of the procedures section, please 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 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 adding 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 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.
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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 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. Although 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 the tick repellent study should be 

included in the consent form to avoid unnecessary time being spent by subjects researching 

other material.

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

definition in the revised protocol. 

q) The 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 identification will be 

checked. EPA recommends 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 half) 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 that 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 comparable to other protocols/studies.

8) Regarding the inclusion/exclusion criteria, EPA recommends 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.”

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 preparation work on the day of testing, but 
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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, 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 

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 withdrawn 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 medical 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 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 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 section 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 expand 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 compensation figures agreed to and the 8 

hour timeframe (as opposed to 9 hours), in follow-up to EPA’s comments.
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18) EPA recommends the following changes to the telephone scripts for initial and follow-up contact 

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 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;

• 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 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 they 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 asks about allergies to tick bites, in addition to sensitivity;

• pregnancy test will be performed in private; and

• encouragement 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. 

Throughout the protocol, after it is revised in response to comments, whenever the protocol refers

to other pertinent information as being “above” or “below,” please replace such references with a 

specific section number. 
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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, 2013, provides in 

pertinent part that:

EPA must not rely on data from any research involving 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 §26.1703 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 (Pathogen 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 minute 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 applied 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). “I2LResearch 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 in 
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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 

language. 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 to ticks.

Johnson and i2LResearch propose to revise section 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 act 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 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 (§4.1).”
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 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 test 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 of 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 comments 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 product. 

The standard data analysis method for tick repellency efficacy studies involves the KaplanMeier 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 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).

Kaplan Meier median confidence limits were calculated using SAS, which employs a 

generalization of the Brookmeyer and Crowley (1982) sign test under a log-log transformation.
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► 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 summary 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 Species1

Number of

Human 

Subjects 

per Tick 

Species

(Replicates)

Total 

Replicates 

per 

Product2

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 Species1

Number of 

Human 

Subjects 

per 

Tick 

Species 

(Replicates) 

Total 

Replicates 

per 

Product2

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 Species1

Number of

Human 

Subjects 

per Tick 

Species

(Replicates)

Total 

Replicates 

per 

Product2

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 between 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 cm2 (1.67 mg/cm2) is proposed for 

aerosol and lotion products while 0.5g of product per 600 cm2 (0.835 mg/cm2

) 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/cm2 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 data 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 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 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 on dosimetry data from 

previously EPA/HSRB reviewed repellent studies.” 

To apply the target application rate of 1.67 mg/cm2 for lotions and aerosols the following 

formula will be used: 

[Area of the Limb/600 cm2] * 1 gram = weight (amount) of product to apply 

To apply the target application rate of 0.835 mg/cm2 for spritz/pump sprays the following 

formula will be used: 

[Area of the Limb/600 cm2

] * 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 pipette while observing the 

digital display on the balance and applied to the skin of the subject. A gloved i2L 
Page 16 of 93

Research staff member will spread the substance evenly throughout the treatment 

area. 

• For aerosol sprays the 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 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 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. 

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 LD50

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 EPA’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 sections 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 intervals. 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 material 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 exposure 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 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 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 minutes 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. 

• The tick will be allowed three minutes to move across the boundary line and 3 cm into the 

treated area (to the crossing line).

• 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 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. 

• 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 

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 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.

• 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 within 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 used to 
Page 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 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 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-line 

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 treatments 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 formulation 

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. The 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 to ticks. 

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

confidence interval width when changed 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 Firm
Page 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 Laboratory: 

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 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 
Page 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 society 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 

the 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 

Guideline 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 human 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 several 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 Kaplan-Meier median are positional values in 

the distribution, rather than calculated values as in the case of a confidence interval 
Page 24 of 93

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 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 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.”

(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 positive 

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 pool 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 flipping a coin on the day of treatment. Based on revised 

information submitted to EPA in response to comments, if a subject is used on more than 

one test day, there will be two days between them, and the test arm for the second day
Page 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 estimate 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 nonparametric 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 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 non-parametric data sets. 

The duration of protection for each test substance will 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 compromise between statistical precision and 

cost. 

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 Kaplan-Meier median are positional values in 

the distribution, rather than calculated values as in the case of a confidence interval 
Page 26 of 93

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 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 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.

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 active 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 cm2 (1.67 mg/cm2) 

for aerosol and lotion products, and 0.5 g of product per 600 cm2 (0.835 mg/cm2) 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 

triplicate 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 rates 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. This 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 additional 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/cm2 for lotions and aerosols the 

following formula will be used: 

[Area of the Limb/600 cm2] * 1 gm = weight (amount) of product to apply” 

Johnson proposed: “To apply the target dose of 0.835 mg/cm2 for spritz/pump sprays the 

following formula will be used: 

[Area of the Limb/600 cm2] * 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, the 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 amount 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 exposure 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 tick 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 breakdown (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 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.”
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“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 30 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 median 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 questions being asked and address uncertainty 

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 each 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 monitor 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 proposed? 
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 inspection 

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 

accuracy 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 advantageous 

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 wider. 

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 

duration 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, the recruitment pool to be developed, 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).
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(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 participating 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 group of potential volunteers who will be recruited by the recruiting firm. If the 

recruited pool follows the outlined demographics, the pool should be representative of the 

population of concern. 

(d) Can the findings from the proposed 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 inclusion 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 

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 on the same day as the training session, on a separate 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 

$25.00 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 verified 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 be 
Page 33 of 93

disclosed to anyone other than the test subject, the verifying 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 subject.

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 described 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 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-screening 

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 stratified 

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 be 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 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 enrolling 
Page 34 of 93

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, 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 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 advertisements. 

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 aspects of this training will include 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 included 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 recruiting 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 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 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 alternate is needed will occur within the 

first two hours of the test, before all the treatments have been finished. If an alternate is 
Page 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 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.

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 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 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 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.”

(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 15th 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? 
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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 

requirements 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. 

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

acute dermal LD50 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 

ingredients 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) Fatigue 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 research? 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 testing 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 substances

Participating subjects must be users 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 least 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.

As discussed in the revised language for section 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 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. 

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.

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 any 
Page 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 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 study. 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 verifying 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 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 address 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. The study 

director will provide up to three 15 minute breaks to each test subject per test day and 

opportunities 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, there will 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, 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. Also, 

please see the revised language for sections 9.2.5 – 9.2.6:
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“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 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 

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, 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. 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. 

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 

unanticipated 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 may 
Page 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 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 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 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 

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 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 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 you 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 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 
Page 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? 

The consent form states: “The benefit to society is the knowledge gained regarding the 

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 

additional 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 

efficacy 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 Review 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 govern 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 Federal 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 subjects 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 research? 
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 shared, 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/exclusion 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 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 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. 
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 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 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 session. 

(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 bathroom 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 study. 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 verifying 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 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.

(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 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.

2.5.7 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 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 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.

 
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 this 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, the 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 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 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 day, 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 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 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 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 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 the forearm, 

discussed in step # 8 above, given that their measurements would have already been taken 

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 period that requires the subject to be seated and exposed to ticks. 

Johnson and i2LResearch Response

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 preparation 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 each 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. Breakfast 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 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. 

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 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 material 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. 

7.6.3 Three timers will be pre-set to help aid in the timing of each exposure interval. One 

timer will be set to monitor the 15 minute 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 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.

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 second 3 minute timer will be activated, and 

oriented using the same method as for untreated arm. 

7.6.8 The 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 not 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 ticks 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 crossing. 

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 reasons. 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 changed from 10 to 20 subjects. Submit a simulation 

showing the impact of increasing sample size on the width of 95% confidence interval of 
Page 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) 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 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 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%
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 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 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 

each 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 participate 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-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 will lapse between any given test 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 for 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 i2LResearch Response: 

As proposed, section 2.2.2 will be revised as follows:

2.2.2 Each tick species will be tested separately from the other two tick species. Each 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 study 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 explicit 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 a 
Page 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 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 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 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, 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, 
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discussed in step # 8 above, given that their measurements would have already been taken 

and recorded 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 decided to recruit participants instead of relying on a “pool 

of individuals who have expressed interest in testing with i2L.” As a result, please 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 language 

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. 

Following EPA and HSRB review, the advertisement must be reviewed and approved by the

IRB, along with all other changes to the protocol.

Johnson and i2LResearch Response:

Johnson and i2L Research propose to revise Section 2.3.3 – 2.3.5 as follows:

2.3.3 Potential subjects will be recruited from a pool of individuals who will have expressed

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 group 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 attractiveness 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 to 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 the 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 repellent 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, 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 
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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-screening 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 stratified 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 be 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 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 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 training 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%
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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) The last statement in section 2.3.6 (above the chart, on page 17 of the protocol) indicates that, “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 i2LResearch 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 questions 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 address freedom to withdraw from the study.

Johnson and i2LResearch 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:
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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?

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 participating subjects read 

and sign the consent form more frequently and asks Johnson and i2LResearch to propose an 

approach.

Johnson and i2LResearch 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 participation in each study...”

c) EPA recommends 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 i2LResearch 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 and i2LResearch Response:

The number of studies referenced in the ICD was revised to be consistent with the protocol.

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

to “allergies or sensitivities” to tick bites.

Johnson and i2LResearch Response:

Under suitability, the second paragraph was revised to refer to “allergies or sensitivities” to 

tick bites.

f) In the consent form, under “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. 

Johnson and i2LResearch Response:

There is consistency in the revised materials.

g) Under “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.” 

Johnson and i2LResearch 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 insert the detailed description of the training program in the consent form.

Johnson and i2LResearch 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).
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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 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 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 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 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 by 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 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.” 

i) In the consent form, at the end of the procedures section, please 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 i2LResearch Response:

The proposal is to include the following language in the consent 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 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, 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 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 encourages you to walk around the 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 adding the 

sentence, “There is also the fatigue and discomfort associated with a long testing day.”

Johnson and i2LResearch 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 amounts. (See EPA comment #7.)

Johnson and i2L Research Response:

The 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) EPA 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. Although 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 the tick repellent study should be 

included in the consent form to avoid unnecessary time being spent by subjects researching 

other material.

p) The 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 already 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 subject 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 consenting 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 session.

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. 
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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. However, 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 measurement 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 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 that 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 comparable to other protocols/studies.

Johnson and i2LResearch Response:

Johnson and i2LResearch addressed EPA’s comments. As proposed, section 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 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 alternate is needed will occur within the first two hours 

of the test, before all the treatments have been finished. If an alternate is 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 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.
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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 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 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 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 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 15th and on the last day of each month.”

8) Regarding the inclusion/exclusion criteria, EPA recommends 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 preparation 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:

Johnson 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 session 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 come to i2L on a separate occasion 

to take the pregnancy test, the subject will be paid $25.00 for their time.”
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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 

lunch 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 addition, 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 period. 

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 will 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, 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.” EPA 

recommends that Johnson 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 section 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 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. There are no plans to provide other compensation 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 # 14.

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 i2LResearch 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 preparation 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 each 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. 
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• 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. Breakfast 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 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 being 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 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 provided to help 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:
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16) Regarding medical monitoring and reporting unanticipated problems in section 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 expand 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 continued 
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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 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 

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 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 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 writing 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 the 

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;
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• 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 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 they 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 allergies 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 comments. 

Similarly, throughout the protocol, after it is revised, whenever you refer to other pertinent 

information as being “above” or “below,” please replace such references with a specific section 

number instead.

Johnson and i2LResearch Response: Agreed.
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Attachment 3 - Proposed Revised Consent Form addressing EPA’s Comments

CONSENT INFORMATION FOR PARTICIPATION IN i2LRESEARCH USA, Inc. TICK

REPELLENT LABORATORY STUDIES

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 these research studies, it is important that you read and 

understand the following explanation of the proposed research studies. This consent 

document describes the purpose, procedures, benefits, risks, discomforts and precautions 

associated with the studies. It also describes your right to withdraw from the studies at any 

time. No guarantees or assurances can be made as to the results of the studies.

If you are not completely truthful with the study staff regarding your health history, you may 

harm yourself by participating in these studies.

Timothy Foard and other i2LResearch 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 these studies.

Schulman Associates Institutional Review Board, Inc. (Schulman) has approved the 

information in this consent document and has given approval for the Study Director to run

these studies. 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 participation in the studies. You must think about the information in this consent 

document for yourself. You must then decide if you want to participate in the studies.

PURPOSE OF THE STUDY

i2L wishes to conduct up to eighteen research studies to determine the efficacy of skinapplied 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 minutes for up to 18 hours. Including preparation time, 
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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 species 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. Picaridin 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 asked to participate in these research studies 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 these studies you will 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) at 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 except 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 and 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.
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You will be asked to wear short sleeves on your scheduled test day. All other clothing 

choices will be yours.

Study Duration 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 species 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 testing 

periods. 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. 

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 will be shorter than this.

There will be five test subjects on 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 will 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 completed 

(anticipated to be approximately two hours), you will be allowed to leave i2L.
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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 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 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 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 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 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 by a female member of the study staff in a 

private manner. The results will be kept confidential, will not be recorded, and will 
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not be disclosed to anyone 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 prior to any study procedure 

being done. 

At the beginning of a test day, you 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.

The repellent will be applied to the marked area of your forearm, using either a pipette or 

needle-less syringe, a spatula, or by spraying your forearm directly. A staff member will use 

a gloved finger to evenly spread the repellent on your skin. You must be careful not to touch 

the exposed portion of your forearms to anything for the duration 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 be 
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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, you 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 equivalent or forceps, will place a single tick on the inner 

surface of the release line on the inner surface of your untreated forearm. 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 

your 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 the 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, you 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 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 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 passed, 

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-tip® or 
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equivalent. Unlike 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 repellent

breaks down), you may wash the repellent product off your forearm 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, 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 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 encourages you to walk around the lab 

and or to stretch in between exposure intervals, to minimize any discomfort or fatigue 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 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. 

The ticks which i2L 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, the 
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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 to 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 will 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 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. 

There are non-physical risks associated with taking part in this study, such as the risk of 

accidental 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 still be paid $30.00 for attending 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 needed 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. This 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 if you choose to withdraw from testing early on a test day for a non-health related or nonemergency 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. This will not affect 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 experience during or after the test. 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. 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 your files.

The 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;
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• If it is discovered that you do not meet the study requirements;

• If the study 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 both 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 the 

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 research 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. The reports will be kept as confidential as possible under local, state and 

Federal law. Despite this, i2L 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 of the signed informed consent form. You hereby consent to 

be a participant in these studies.
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Signatures

I have read the above information in a language that I understand well. The content and 

meaning of this information has been explained to me. I hereby voluntarily consent and 

offer to take part in these studies.

____________ ________________________ ________________________

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- The 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 name) 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 

during 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 "Yes") "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

measure 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 end 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 

in one, two or three of these days. You will be notified in advance if you are randomly selected to 

participate in any of the test days, and whether you would be a test subject or an alternate.

"Subjects 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 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 will 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 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 in participating in and would like to learn

more about the study and your potential role in it, I can schedule you for a 15-20 minute phone

discussion with one of the I2L staff. That staff member will go over the inclusion and exclusion

criteria for Test Subjects and answer any further questions you may have about the study.

"Are you interested in learning more about potentially participating in this study?"
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(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 call 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 designated 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") "Thank 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 repellent 

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):

You will attend a training and information 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 consent 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 identification. If after this, you would still like to 

participate in the study, you would sign 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 in 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 each 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 in. All subjects will be randomly selected in 

advance, using assigned code numbers, from those who choose to participate in the study.

"The testing is scheduled to begin (enter time, date month, year) at the I2L laboratory in the 

Catonsville area. You must refrain from 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.

"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 laboratory for about two hours, until it is determined if 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 19 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 stops
Page 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 explained 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 qualify 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 member 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 have 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 health 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 female):

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 will 
Page 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 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.

"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 

interested 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 the 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 (for 

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 

prisoners, 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 safeguards 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 Johnson 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, the 

sponsor, the institution or its agents from liability for negligence 

Y 
Page 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 experimental 

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 obtained 

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. 310-318.

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 

witness 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 Johnson 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 specified 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 intended use 

of data- Section 1.4 - Page 13

See Rationale for human testingSection 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 

Review 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., sufficient 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 

Attachment10.

(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 - Confidentiality 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 System

307 – Approval Letter/Disapproval Letter

308 – Signature Authority for Board Documents

309 - File Maintenance

310 – Site Visits
Page 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.