Page 1 of 19 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C., 20460

OFFICE OF

CHEMICAL SAFETY AND POLLUTION

PREVENTION

March 17, 2011

MEMORANDUM

SUBJECT: Ethics Review of Completed AEATF II Wipe Scenario Worker Exposure

Monitoring Study

FROM: Kelly Sherman

Human Studies Ethics Review Officer

Immediate Office of the Director

Office of Pesticide Programs

TO: Nader Elkassabany, PhD, Chief

Risk Assessment and Science Support Branch

Antimicrobials Division

REF: Selim, S. (2011) A Study for Measurement of Potential Dermal and

Inhalation Exposure During Application of a Liquid Antimicrobial Pesticide

Product Using Trigger Spray and Wipe or Ready

‐ to

‐ Use Wipes for

Cleaning Indoor Surfaces. Unpublished study prepared by Golden Pacific

Laboratories, LLC, under Project No. AEA02, Report No. 070264. 2000 p.

(MRID 48375601)

I have reviewed all available information concerning the ethical conduct of the

research reported in the referenced document, which describes the execution and

results of a study in which dermal and inhalation exposure of professional janitorial

workers to antimicrobial pesticides was monitored as they wiped indoor surfaces with a

liquid antimicrobial pesticide product containing didecyl dimethyl ammonium chloride

(DDAC). If it is determined to be scientifically acceptable, I find no barrier in regulation

to the Environmental Protection Agency’s (EPA’s) reliance on this study in actions under

the Federal Insecticide, Fungicide, or Rodenticide Act (FIFRA) or the Federal Food, Drug,

and Cosmetic Act (FFDCA).Page 2 of 19 Background and Chronology

The scenario design and protocol for this study, identified by the investigators as

Protocol #070264, was approved by the overseeing investigational review board (IRB),

the Independent Investigational Review Board, Inc. (IIRB), and submitted to EPA for

review in February 2008. The protocol and EPA’s review dated March 10, 2008, were

discussed by the Human Studies Review Board (HSRB) on April 9, 2008. The HSRB

review was generally favorable; their June 25, 2008, final report concluded, with respect

to ethics, that “ if the proposed mop and wipe scenario design, protocol, and supporting

documentation is revised as suggested in EPA’s review, the research would meet the

applicable requirements of 40 CFR part 26, subparts K and L.”

Following the HSRB review, the protocol, consent form, and recruiting materials

were revised to address EPA, HSRB, and California Department of Pesticide Regulation

(CDPR) comments. The revised protocol was submitted to IIRB on February 5, 2009, and

approved, along with certified Spanish translations, on February 11, 2009.

The protocol was subsequently amended eight times, with revised Consent

Forms approved on May 5, 2009 (pp. 1352

‐ 1374, used in monitoring in Cluster 1), and

August 21, 2009 (pp. 1467

‐ 1477, 1499

‐ 1509, used in monitoring at Clusters 2 and 3).

Final approval of the protocol and supporting materials was granted by CDPR on

April 17, 2009. Subject recruitment began the following week on April 24, 2009. Initial

response was slow, and Amendment 3 (pp. 1393

‐ 1401; approved 25 June 2009) revised

the recruiting procedures. Subject enrollment began on July 1, 2009. Recruiting

procedures were revised further to add recruiting by newspaper advertisements in

Amendment 4 (pp. 1402

‐ 1420; approved 13 July 2009.) Initial enrollment of subjects

was completed on July 24, 2009.

After random assignment of enrolled subjects to specific monitoring slots at each

of the three sites, subjects were monitored at Site 1 from August 10

‐ 15, 2009; at Site 2

from August 24

‐ 29, 2009; and at Site 3 from September 28 through October 3, 2009. A

more detailed chronology appears as Attachment 2 to this review.

Completeness of Submission:

The checklist used by EPA to verify satisfaction of the requirements of §26.1303

as they apply to the report of this research appears as Attachment 1 to this review. The

report, together with the materials submitted for the initial protocol review, contains all

required information.Page 3 of 19 Protocol Amendments:

Subsequent to IIRB approval of the revised protocol on February 11, 2009, it was

amended eight times. A summary of the scope of all amendments appears as

Attachment 3 to this review. Amendments 3 and 4 are of primary ethical interest. Both

resulted from the discovery in the field that the planned approach to recruitment—

approaching janitorial service providers and asking to post flyers in their premises—was

unproductive. Revised procedures in Amendment 3 allowed enrollment of individual

qualified candidates before the entire group of potential subjects had been identified,

and Amendment 4 provided for recruiting through newspaper advertising. The choice

of newspapers—three different newspapers, each serving a different community in the

Fresno area—was an appropriate adjustment given the difficulties with the original

recruitment plan. The change to the recruiting process is discussed in more detail on

pages 4

‐ 5 of this review, in the section titled “Recruiting.”

Protocol Deviations:

Reported Deviations

Two reports of protocol deviations were made to the IIRB, Inc. after completion

of the research; they are summarized in Attachment 3. Two points raised in Deviation

Report 1 (pp. 1562

‐ 1567) are of potential ethical interest. Most subjects reportedly

declined to take rest breaks, or took less than the 10 minutes provided for in the

protocol, and at one monitoring site photographs were taken showing subjects’ faces.

No images of subjects’ faces were included in the report. I have concluded that neither

of these deviations affected subject safety or jeopardized the informed consent process.

Unreported Deviations

I noted one unreported deviation. Three enrolled subjects (one who was

monitored and two who were alternates) reported their general health as “fair.” The

protocol specifies that to be included, subjects must be “in good health” (p. 483). The

consent form states that participants “must be healthy adults” (p. 1353, 1468). The

“Subject Self

‐ Reporting Demographic Form,” Appendix D to the protocol (p. 529),

offered candidates a choice in describing their health as ‘Excellent,’ ‘Good,’ ‘Fair,’ or

‘Poor.’ The decision to enroll subjects in only ‘fair’ health is not explained in the report.

The HSRB has considered this issue before, in connection with the AEATF Mop

Study, the partner study to the AEAFT Wipe Study. In the Mop Study (which employed

identical enrollment criteria with respect to participants’ health), the investigators

similarly enrolled 2 subjects who reported “fair” health. (One was monitored, and one

was an alternate.) In its report of the October 2010 HSRB meeting, the Board did not

conclude that this deviation rendered the results unacceptable under EPA’s regulations,Page 4 of 19 but the Board recommended that the AEATF “clarify the criteria used to establish

participants’ health status prior to study enrollment.” I agree with this conclusion.

The AEATF Wipe Study, which is being reviewed here, was conducted during the

summer of 2009, before the October 2010 HSRB meeting. It therefore does not reflect

the lessons learned from the October 2010 HSRB review process. However, before

conducting future studies, the AEATF should develop an SOP that provides procedures

for determining the general health status of potential subjects and whether potential

subjects have any medical condition(s) which could impact their ability to participate in

the research.

Recruiting:

Following approval of the protocol by CDPR, EPA, and IIRB, a randomized list of

janitorial service providers in Fresno County was generated from telephone directories,

the Chamber of Commerce, and information given from janitorial service providers

themselves. Phone calls were placed to the janitorial service providers, and they were

asked if they would be willing to post flyers soliciting study subjects. A letter was then

sent to those managers expressing willingness to post the flyers. The letter instructed

the managers to attend an informational meeting and/or speak with research personnel

before posting the flyers. The purpose of the meeting was to educate the managers

about the monitoring process as well as impress upon them the need to remain neutral

in their interactions with employees regarding study participation. English and Spanish

versions of the flyers were approved by IIRB (Appendix C, D; p. 271, 273).

The recruiting process as initially designed proved unproductive. Very few

service providers were willing to post flyers, and very few candidates responded to the

flyers that were posted. A handful of candidates did respond, but the protocol did not

provide for enrolling them until after the full complement of subjects had been

recruited and randomized. The investigators were concerned that they would lose

contact with the candidates who had been identified, so after discussion with EPA, the

investigators submitted an amendment to IIRB (Amendment 3) to allow them to recruit

and enroll subjects as they came forward, and randomly assign them to monitoring sites

and slots after recruiting was completed. EPA endorsed this revision to the original

plans for recruiting and randomization. IIRB approved the amendment on June 25,

2009.

Response to the recruiting flyers continued to be slow, and after further

discussion with EPA, the AEATF submitted another amendment to IIRB (Amendment 4),

to allow recruiting through newspaper advertisements. This change—and newspaper

advertisements in English and Spanish— was approved by IIRB on July 13, 2009.

Recruiting was completed on July 24, 2009.Page 5 of 19 A total of 72 subjects (primarily identified in response to the newspaper

advertisements) came to Golden Pacific Laboratories (GPL) for the interview, signed the

Informed Consent Forms, and filled out the Subject Demographic forms, enrolling them

in the study. After the enrollment period ended, an attempt was made to contact all

the subjects to verify contact information and confirm that they were still available and

interested in participating. Sixteen of the 72 enrolled subjects were dropped

– two

because they reported taking a medication that, in the study director’s judgment, could

have increased their sensitivity to the test material

– and 14 because they could not be

contacted due to disconnected phone numbers or lack of response after three failed

attempts to reach them via telephone.

An identification number was assigned to each of the remaining 56 subjects and

the numbers were randomized. The first 48 randomized subjects were split into 6

groups of 8 subjects. In each of the 3 clusters, 8 subjects were randomly assigned to use

trigger spray and wipe and the other 8 subjects were assigned to use RTU wipes. The

remaining 8 subjects were held as extras for potential entry into the study in the

sequence determined by the randomization process. Six wiping time durations

(Monitoring Events) were assigned for each cluster ranging from 30 minutes to 210

minutes. In each cluster, six subjects completed the time durations using trigger spray

and wipe and six subjects completed the time durations using ready

‐ to

‐ use wipes. The

last two subjects of the 8 assigned to each cluster and each wiping scenario were

considered alternates. The subjects were contacted and scheduled to come to one of

the sites on a specific day and time. Below is a summary of the demographics of the 72

enrolled subjects (p. 71).

Table 1: AEATF II Wipe Study Subject Characteristics

All Enrolled

Subjects (72) Monitored

Subjects (36) Alternate

Subjects (20) Dropped

Subjects (16)

Male 41 20 12 9

Female 31 16 8 7

English 60 33 15 12

Spanish 12 3 5 4

Range of Experience 6 mos

– 52 yrs 6 mos

– 52 yrs 6 mos

– 36 yrs 1

– 40 yrs

Mean Years Experience 11.9 13.5 9.7 10.9

Age Range 19

‐ 62 20

‐ 62 22

‐ 56 19

– 61

Mean Age 40.6 42.8 38.4 38.8

Health ‘Excellent’ 36 21 8 7

Health ‘Good’ 33 14 10 9*

Health ‘Fair’ 3 1 2 0

Requested Results 53 (74%) 26 (72%) 16 (80%) 11 (69%)

* The two subjects taking medication are included in this number. The protocol (p. 1518) states that subjects will not

be allowed to participate if they are “taking medicines that might react with the test product.”Page 6 of 19 Monitoring

Monitoring was conducted without noteworthy incident. There were four

instances when a subject either spoke to the medical professional observing the study

or reported feeling ill possibly due to inhaling fumes from the test material (details are

provided in Table 2, below), but in all cases the workers continued working and none of

these situations resulted in a report of an adverse event or other incident of concern.

There was one report (RTU, Cluster 3, R4) of a subject leaving early because he was

feeling ill. The observation log does not indicate whether the worker was feeling ill

possibly as a result of his/her participation in the research, or whether his illness was

unrelated to the study.

Table 2: Selected Subject Observations During Monitoring

Scenario/

Cluster Subject Date Time Notes Provided in Observation Log

RTU Wipe

Cluster 1 R5 8/10/09 11:08 am “Worker stops to show his finger tips to medical

personnel. Finger tips he says look white. Worker takes

break and describes finger skin is wrinkling possibly from

being moist so long. EMT will notify Study Director.

Worker says he is fine and wants to continue working.”

(p. 339)

RTU Wipe

Cluster 2 R5 8/26/09 09:48 am

‐

10:10 am “Subject cut left hand on shelf; observed blood on pants

and touched eyewear. Subject wanted to continue study

regardless of cut hand...Subject sat with hands on his

knees...Nurse checked left hand of subject...Subject

wiped surface with right hand while keeping left hand on

pants.” (p. 344)

RTU Wipe

Cluster 3 R4 9/29/09 “Summary” “Subject had to leave before the designated time

because he was feeling ill.” (p. 349) It is not reported

whether the subject was feeling ill possibly as a result of

his participation in the study, or if he was feeling ill for

other reasons.

Trigger

Spray

Cluster 1 T3 8/13/09 09:31 am “Worker ends break and requests to move to another

location. Spray fumes were making worker somewhat

uncomfortable. Worker stated that she had not eaten

this morning. EMT met with worker during break and

asked her condition. Worker wanted to continue

working in another location.” (p. 355)

Trigger

Spray

Cluster 3 T5 10/2/09 “Summary” “Subject reported allergies and asthma during work

period. Study director was notified.” (p. 370)

The observation log reports that many of the workers were sweating from their

faces, a sign that they were feeling hot. But they were given the opportunity to take

breaks and drink their choice of water or a sports drink. It does not appear that any of

the subjects was in danger of suffering heat

‐ related illness. The range of maximum

recorded temperatures during monitoring was relatively low

– 69.9 °F to 76.6 °F.Page 7 of 19 The procedures provided in the protocol and SOPs 10.C.1, 11.B.1, 11.C.1, 11.E.1,

and 11.F.1 related to recording observations, minimizing risks, and protecting the

subjects were followed.

Applicable Ethical Standards

Because this study was initiated after 7 April 2006, prior submission of the

protocol and supporting materials to EPA was required by 40 CFR §26.1125. 40 CFR

§26.1601(c) required EPA to review the protocol and present it to the HSRB for review.

These requirements were satisfied.

EPA Protocol Review Comments

In its Science and Ethics review dated March 10, 2008, EPA noted “the following

specific [ethical] deficiencies should be corrected before the research is initiated:

• Better provision is need for ensuring that Spanish

‐ speaking candidates are fully

informed and fully comprehend what they have been told. It would be better for

candidate interviews to be conducted by a member of the research team fluent

in Spanish than to rely on a translator.

• References in the consent forms to “normal business hours” should be replaced

by references expressed in California local time, and care must be taken to

ensure that a Spanish

‐ speaking responder can be reached at any telephone

number cited as a source for further information.”

In the revisions submitted to the IIRB, Inc. on February 5, 2009 (p. 931), all

references in the protocol and consent form to translators were replaced by references

to researchers fluent in Spanish, to whom the recruiting and consenting responsibilities

of the principal investigator would be delegated when candidates preferred to interact

in Spanish (pp. 956

‐ 7, p. 1107). The Consent Form and California Experimental Subject’s

Bill of Rights were revised to show hours for calling in Pacific (local) time (pp. 1113,

1003).

HSRB Protocol Review Comments

In its June 25, 2008 report of its April 2008 review of the AEATF Mop and Wipe

Scenarios, the HSRB summarized its recommendations as follows:

“The Board concurred with the initial assessment of the Agency that if the proposed

mop and wipe scenario design, protocol, and supporting documentation is revised as

suggested in EPA’s review, the research would meet the applicable requirements of

40 CFR part 26, subparts K and L.”Page 8 of 19 In addition, the HSRB made several specific suggestions for refinements. A

summary of these suggestions, and of how they were addressed by the AEATF, appears

as Attachment 4 to this review.

Regulatory and Statutory Standards

The following provisions of 40 CFR 26 Subpart Q, as amended effective August

22, 2006, define the applicable ethical standards, which read in pertinent part:

§26.1703: Except as provided in §26.1706,

. . . EPA shall 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.

§26.1705: Except as provided in §26.1706,

. . . EPA shall not rely on data from

any research initiated after April 7, 2006, unless EPA has adequate information

to determine that the research was conducted in substantial compliance with

subparts A through L of this part.

. . .

In addition, §12(a)(2)(P) of the Federal Insecticide, Fungicide and Rodenticide Act

(FIFRA) applies. This passage reads:

In general, [i]t shall be unlawful for any person

. . . to use any pesticide in tests

on human beings unless such human beings (i) are fully informed of the nature

and purposes of the test and of any physical and mental health consequences

which are reasonably foreseeable therefrom, and (ii) freely volunteer to

participate in the test.

Findings

Responsiveness to EPA and HSRB reviews

EPA’s comments were satisfactorily addressed, as were most of the HSRB’s

comments, in the revisions approved by the IIRB on February 11, 2009.

Prohibition of research involving intentional exposure of pregnant or nursing

women or of children

All enrolled subjects were at least 18 years old. All female subjects, regardless of

age, self

‐ administered over

‐ the

‐ counter pregnancy tests on the day of monitoring; all

such tests were negative. The prohibition in 40 CFR §26.1703 of research involving

intentional exposure of pregnant or nursing women or of children under 18 was

satisfied.Page 9 of 19 Substantial compliance with 40 CFR 26 subparts A through L

40 CFR §26.1705 requires that EPA have “adequate information to determine

that the research was conducted in substantial compliance with subparts A through L of

this part.” Within this range, only subparts K and L are directly applicable to the conduct

of third

‐ party research.

I identified no noteworthy deficiencies in the ethical conduct of the research.

The protocol was faithfully executed, properly amended when necessary, and all

amendments were approved by the overseeing IRB before they were implemented. The

deviations reported are of the nature to be expected in complicated field research of

this kind, and did not affect the welfare or safety of the subjects, or compromise their

informed and voluntary consent. I conclude that 40 CFR §26.1705 does not prohibit EPA

reliance on this study.

Compliance with 40 CFR §26 subpart M

As documented in Attachment 1 to this review, the central requirements of 40

CFR §26 subpart M, §26.1303 to document the ethical conduct of the research were

addressed.

Compliance with FIFRA §12(a)(2)(P)

The requirement of FIFRA §12(a)(2)(P) that human subjects of research be “fully

informed of the nature and purposes of the test and of any physical and mental health

consequences reasonably foreseeable therefrom,” and “freely volunteer to participate

in the test,” was met for this study.

Conclusions

This study reports research conducted in substantial compliance with the

requirements of 40 CFR 26 subparts A through L. In its conduct, it met all applicable

ethical standards for the protection of human subjects of research. All requirements for

documentation of ethical conduct of the research were also satisfied. If this study is

determined to be scientifically valid and relevant, there is no regulatory barrier to EPA’s

reliance on it in actions under FIFRA or §408 of FFDCA.

Attachment 1: §26.1303 completeness check for AEATF Wipe Scenario Report

Attachment 2: Chronology of AEATF Wipe Study

Attachment 3: Summary of Amendments and Deviations to AEATF Wipe Study

Attachment 4: Responsiveness of AEATF to HSRB Comments on Wipe StudyAttachment 1

§ 26.1303 Check for Completeness of Reports of Human Research Submitted for EPA Review

AEATF II Wipe Scenario Report: MRID 48375601

Page 10 of 19 Any person who submits to EPA data derived from human research covered by this subpart shall provide at the time of submission information

concerning the ethical conduct of such research. To the extent available to the submitter and not previously provided to EPA, such information

should include:

Requirement Y/N Comments/Page References(a)Copiesofalloftherecordsrelevanttotheresearchspecifiedby§26.1115(a)tobepreparedandmaintainedbyanIRB §1115(a)(1): Copies of

• all research proposals reviewed,

• scientific evaluations, if any, that accompany the proposals,

• approved sample consent documents,

• progress reports submitted by investigators, and reports of injuries to subjects. Y

n/a

Y

Y Initially addressed in protocol

p. 1352

‐ 1374; 1467

‐ 1477; 1499

‐ 1509

p. 888

§1115(a)(2): Minutes of IRB meetings which shall be 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. N All post

‐ HSRB IIRB reviews were

under expedited procedures; no

minutes were made.

§1115(a)(3): Records of continuing review activities. Y p. 888

§1115(a)(4): Copies of all correspondence between the IRB and the investigators. Y p. 664

‐ 1574

§1115(a)(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. N Provided separately to EPA

§1115(a)(6): Written procedures for the IRB in the same detail as described in §

26.1108(a) and § 26.1108(b). N Provided separately to EPA

§1115(a)(7): Statements of significant new findings provided to subjects, as required by §

26.1116(b)(5). n/a(b)Copiesofalloftherecordsrelevanttotheinformationidentifiedin§26.1125(a)‐(f)§1125(a)Adiscussionof: (1) The potential risks to human subjects; Y Addressed in protocol

(2) The measures proposed to minimize risks to the human subjects; Y Addressed in protocol

(3): The nature and magnitude of all expected benefits of such research, and to

whom they would accrue; Y Addressed in protocol

(4) Alternative means of obtaining information comparable to what would be

collected through the proposed research; and Y Addressed in protocol

(5) The balance of risks and benefits of the proposed research. Y Addressed in protocol

§1125(b): All information for subjects and written informed consent agreements as

originally provided to the IRB, and as approved by the IRB. Y Original

– in protocol submission

Approved English CF –1352, 1467

Approved Spanish CF 1363, 1499

§1125(c): Information about how subjects will be recruited, including any advertisements

proposed to be used. Y Initially satisfied in protocol.

Flyers & Ads in English & Spanish

§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 Initially satisfied in protocol; see also

amendments 3 and 4

§1125(e): All correspondence between the IRB and the investigators or sponsors. Y p. 664

‐ 1574

§1125(f): Official notification to the sponsor or investigator, in accordance with the

requirements of this subpart, that research involving human subjects has been reviewed

and approved by an IRB.

Y IRB approvals:

Initial p. 674

Renewal p. 898

Post

‐ HSRB approval p. 1117, 1130

Amendment 1, 2 p. 1351

Amendment 3 p. 1400

Amendment 4 p. 1411

Amendment 5 p. 1435Attachment 1

§ 26.1303 Check for Completeness of Reports of Human Research Submitted for EPA Review

AEATF II Wipe Scenario Report: MRID 48375601

Page 11 of 19 Requirement Y/N Comments/Page References

Amend 6 p. 1552

Amendment 7 p. 1466

Amendment 8 p. 1574

(c) Copies of sample records used to document informed consent as specified by §26.1117, but not

identifying any subjects of the research Y pp. 1352, 1467, 1363, 1499

(d) If any of the information listed in paragraphs (a) through (c) of this section is not provided, the

person shall describe the efforts made to obtain the information. n/aAttachment 2

Chronological Listing of Events: AEATF Mop Study

Based on Table 1 from AEATF Submission (pp. 121

‐ 122)

Page 12 of 19 16 Jan 08 GPL submission of undated protocol and supporting materials to IIRB

16 Jan 08 GPL submission of protocol (dated 16 Jan 08) and supporting materials to CDPR

18 Jan 08 GPL re

‐ submission of protocol with version date of 16 Jan 08 and supporting materials

22 Jan 08 IIRB approval of protocol and supporting materials

14 Feb 08 CDPR reviewed ICF submitted on 16 Jan 08 and provided summary of revisions to GPL

25 Feb 08 Submission of IIRB

‐ approved protocol to EPA

10 Mar 08 EPA Science & Ethics Review of Proposal

9 Apr 08 HSRB Discussion of Proposal

11 Apr 08 CDPR submitted summary of revisions needed to be incorporated in protocol submitted on 16

Jan 08 and ICF

25 Jun 08 HSRB Final Report of April public meeting

12 Jan 09 GPL submission of annual progress report to IIRB

21 Jan 09 IIRB extension of approval through 19 Jan 10

23 Jan 09 GPL transmittal of undated protocol with appendices A through L to CDPR

27 Jan 09 GPL submission of responses to CDPR review of 11 Apr 08

02 Feb 09 CDPR provisionary approval of study, prior to final approval

05 Feb 09 GPL submissions of Spanish translated appendices A, B, C, D, F, G, and H and revised protocol

titled “Final 02

‐ 03

‐ 09” with all appendices A through L) to IIRB with extensive changes from

version of Jan 08, not characterized or tracked

10 Feb 09 GPL resubmission of 22 Jan 08 IIRB

‐ approved CF with tracked changes

11 Feb 09 IIRB approval of English ICF (Ver. 11 Feb 09), protocol version 03 Feb 09, California Experimental

Subject‘s Bill of Rights (ESBOR) and Print Ad version “Research Study Volunteers”

23 Feb 09 “Start of search for test site selection”

23 Mar 09 IIRB acceptance of certified Spanish translation of Informed Consent Form (Ver. 11 Feb 09,

Approved 11 Feb 09), ESBOR (Approved) 11 Feb 09 and Print Ad “Research Study Volunteers”

(Approved 11 Feb 09) and other Spanish translated protocol appendices H, A, G and D

7 Apr 09 GPL submission of final IIRB approved protocol (11 Feb 09) and all Spanish translated appendices

to DPR

8 Apr 09 “Study Initiation” [Date on which study director signed protocol]

16 Apr 09 GPL submission of all English IIRB approved appendices to DPR

17 Apr 09 CDPR granted GPL final approval of study

4 May 09 GPL submission of protocol Amendments 1 and 2, English and Spanish appendices B, C, F, G, H to

IIRB

5 May 09 IIRB approval of protocol Amendments 1 and 2, English/Spanish ICF (ver. 5/5/09),

English/Spanish ESBOR (dated 05/05/09), revised Recruiting Flyers (appendices G and H) in

EnglishAttachment 2

Chronological Listing of Events: AEATF Mop Study

Based on Table 1 from AEATF Submission (pp. 121

‐ 122)

Page 13 of 19 6 May 09 IIRB acceptance of certified Spanish translation of appendices G and H

24 Jun 09 GPL submission of Amendment 3 to IIRB. (Amendment text is a paraphrase of what might be

changed in the protocol.)

25 Jun 09 IIRB email reports having faxed approval of Amendment 3

25 Jun 09 IIRB approval of Amendment 3

9 Jul 09 GPL submission of Amendment 4 and English/Spanish recruiting ads to IIRB

10 Jul 09 IIRB approval of Amendment 4

13 Jul 09 IIRB approval of English/Spanish recruiting ads

27 Jul 09 GPL submission of Amendment 5 to IIRB

27 Jul 09 IIRB approval of Amendments 5

10 Aug 09 First subject enrolled/monitored; “Experimental Start”

10

‐ 15 Aug 09 Monitoring at Site 1 (IRS Office Building)

21 Aug 09 GPL submission of Amendment 7 to IIRB

21 Aug 09 IIRB approval of Amendment 7

21 Aug 09 IIRB email reference to approval of revised CFs and supporting materials

24

‐ 29 Aug 09 Monitoring at Site 2

28 Sep

‐ 3 Oct 09 Monitoring at Site 3

3 Oct 09 Last subject monitored

3 Nov 09 Analyses completed for subject and field fortification samples

15 Jan 10 GPL submission of closeout report to IIRB

29 Jan 10 IIRB acceptance of closeout report

20 May 10 GPL submission of Amendment 6 to IIRB

24 May 10 IIRB acceptance of Amendment 6

4 Jun 10 GPL submission of Deviation Report 1 to IIRB

4 Jun 10 IIRB acceptance of Deviation Report 1

14 Nov 10 Analysis of three additional samples

15 Nov 10 “Experimental Termination” (p. 6) “Last day of data collection”

16 Nov 10 GPL submission of Amendment 8, Deviation Report 2 and the revised Closeout Report to IIRB

18 Nov 10 IIRB acceptance of Amendment 8, Deviation Report 2 and the revised Closeout Report

13 Jan 11 “Study Completion”

26 Jan 11 Submission of study to EPAAttachment 3

Summary of Amendments and Deviations

AEATF

‐ II Wipe Study GPL Protocol # 070264

Page 14 of 19 Amendment 1: (Submitted May 4, 2009; Approved May 8, 2009; p. 1249

‐ 1351)

1. Added minimum size of 10,000 square feet in definition of acceptable sites

2. Permitted use of “non

‐ vacant” meeting spaces for hire

3. Added provision to send a copy of the recruitment flyer to employers before

employers make a decision about posting a flyer

Amendment 2: (Submitted May 4, 2009; Approved May 8, 2009; p. 1249

‐ 1351)

1. Clarified that CF would be available in either English or Spanish

2. Added commitment to make MSDS available in both English and Spanish

3. Clarified that at least 7 days would elapse between monitoring at different clusters

4. Clarified that all recruiting materials and communication with subjects would be

available in either English or Spanish

5. Clarified availability of 24

‐ hr toll

‐ free answering service in both English and Spanish

6. Committed to provide each subject with a copy of the label and MSDS

7. Harmonized descriptions of recruiting procedures in sections 9.1.2 and 9.3

8. Reflected name change of Grayson Research in exclusion criteria

9. Changed study procedures to permit discussion with subjects either individually or in a

group

10. Changed study procedures to specify removal of shoes before removal of pants

11. Clarified procedure for weighing spray bottles

12. Clarified collection of sock dosimeters before WBDs

13. Clarified reporting of weights of spray bottles

14. Deleted unnecessary reference to QAU statements

15. Reflected name change of Grayson Research throughout protocol

Amendment 3: (Submitted June 24, 2009; Approved June 25, 2009; pp. 1393

‐ 1401)

1. Clarify the four

‐ week recruiting period begins following completion of the janitorial firm

manager meetings

2. Allow informed consent meetings and enrollment of individuals during the recruiting

period

3. Require three attempts be made to reach and schedule informed consent meetings with

all individuals on the primary call

‐ in list

4. Randomly order all enrolled volunteers at conclusion of the enrollment process, and

select the first (randomly ordered) forty eight volunteers for participation in the study.

Use this same random order to assign participants to the trigger spray and wipe or

ready

‐ to

‐ use scenarios, specific clusters within scenarios, and specific ME slots within

clusters.Attachment 3

Summary of Amendments and Deviations

AEATF

‐ II Wipe Study GPL Protocol # 070264

Page 15 of 19 Amendment 4: (Submitted July 9, 2009; Approved July 13, 2009; pp. 1402

‐ 1420)

1. Added newspaper advertisements (English and Spanish) to recruiting process

Amendment 5: (Submitted and approved July 27, 2009; pp. 1421

‐ 1436)

1. Revised the protocol to provide that the diluted cleaning solution will be prepared at the

study location on the day of use, rather than prepared at the laboratory the day before

the study.

2. Revised method for assigning subjects to ME slots

3. Corrected reference to SOP

4. Revised §10.4 Re: Field Recovery Evaluation to be consistent with revised SOP

Amendment 6: (Submitted August 4, 2009; Approved May 24, 2010; pp. 1549

‐ 1552)

1. Further revised §10.4 Re: Field Recovery Evaluation

2. Revised §12.2 Re: Analytical Method

Amendment 7: (Submitted and approved August 21, 2009; pp. 1437

‐ 1511)

1. Changed Field Study Coordinator and Field Study Associate

Amendment 8: (Submitted November 16, 2009; Approved November 18, 2009; pp. 1569

‐ 1574)

1. Changed the address and management of the Study Director/Principal Investigator (the

study director resigned from Golden Pacific Laboratories, but will continue to serve as

Study Director as an independent contractor. The study director information has

changed to reflect this status change.

Deviation Report 1: (Submitted and acknowledged June 4, 2010; pp. 1553

‐ 1565)

Dates of occurrence:

Cluster 1: August 10

‐ 15, 2009

Cluster 2: August 24

‐ 29, 2009

Cluster 3: September 28

‐ October 3, 2009

1. Subjects washed hands with 50% IPA and water as well as with soap before

monitoring

2. Light readings were not taken at monitoring sites as called for in the protocol

3. Subjects declined to take breaks at 30

‐ minute intervals or took less than 10 minute

breaks

4. The empty weight of each unique trigger spray bottle used by subjects was not

documented as required by Protocol Amendment 2Attachment 3

Summary of Amendments and Deviations

AEATF

‐ II Wipe Study GPL Protocol # 070264

Page 16 of 19 Deviation Report 1 (continued):

5. The final concentration of test substance solution for clusters 2 and 3 was diluted to

1:63 rather than 1:64.

6. Subject face/neck wipe samples at sites 2 and 3 not collected as specified in Protocol

§10.

7. Environmental measurements made less frequently at site 1 than required in Protocol

§8.5 (measurements should have been made at a minimum of 10

‐ minute intervals,

but during cluster 1, some data logger measurements were only recorded every 15 to

30 minutes.

8. During cluster 1, the data logger in the test solution preparation area only recorded

the temperature, not the humidity. During cluster 3, one of the data loggers that

followed the subjects only recorded the temperature, not the humidity.

9. Researchers failed to record the serial number from certain data logger devices in

cluster 1, making it difficult to determine which data loggers accompanied the

concurrently monitored subjects for monitoring events R3 and R4.

10. Study personnel failed to record the RTU canister number in connection with the

ready

‐ to

‐ use wipe sample collected, and as a result, the observational notes from

cluster 1 do not indicate from which RTU canisters the ready

‐ to

‐ use wipe samples

were pulled during monitoring events R5 and R6.

11. Field fortification samples of hand wash at site 1 were not collected at all prescribed

times.

12. The diluted material aliquots were not collected from every trigger spray bottle used

by the subjects during cluster 1, as specified in Protocol Appendix K.

13. Air pump flows were not recorded for subject T6 during cluster 1, and subjects R1 and

R6 during cluster 2.

14. During Cluster 1, the documentation for the air pump calibration on August 11, 2009,

was misplaced. Thus, there are no calibration records or before

‐ pump flow rates from

the T6 pump (contrary to Protocol §10.2.1)

15. During Cluster 1, subject W16 wiped for 165 minutes, 15 minutes short of the allotted

time interval, and subject W10 wiped for 154 minutes, four minutes over the allotted

time interval. In Cluster 2, subject W37 wiped for 61 minutes, one minute over the

allotted time interval, and subject W18 wiped for 121 minutes, one minute over the

allotted time interval.

16. During Cluster 1 monitoring event R5, the field study personnel responsible did not

indicate on the appropriate form whether the subject washed with ivory soap, and

rinsed with 50% IPA:50% water prior to the monitoring event. It is also unknown

whether the hand examination procedure was completed.

17. Air sampling pumps malfunctioned in two instances.

18. On the first day of cluster 2, the subjects were only photographed from the front with

faces included in the photograph. This was contrary to the protocol requirement that

both the front and back should be photographed, and that faces should be excluded.

19. Temperature of walk

‐ in cold locker in which samples were stored was not confirmed

at site 2.Attachment 3

Summary of Amendments and Deviations

AEATF

‐ II Wipe Study GPL Protocol # 070264

Page 17 of 19 Deviation Report 1 (continued):

20. OVS tubes fortified at field site rather than at the laboratory at site 2.

21. Background air samples at site 3 collected at 3 feet instead of 5 feet above the floor.

Deviation Report 2: (Submitted November 16, 2010; acknowledged November 18, 2010; pp.

1568

‐ 1574)

Dates of occurrence:

Cluster 1: August 10

‐ 15, 2009

Cluster 2: August 24

‐ 29, 2009

Cluster 3: September 28

‐ October 3, 2009

1. Some sample fortifications were at incorrect levels

2. Solvent blanks were not injected before all analytical runs as specifiedAttachment 4

Responsiveness to HSRB Ethics

‐ Related Comments on

AEATF

‐ II Wipe Study Protocol

Page 18 of 19 HSRB Comment on Protocol ResponseProtocol Although the risks to subjects from exposure to the test

compound appear very low,

. . . it might be possible to

design scenarios in which instead of an antimicrobicide,

some less toxic tracer substance might be used. It would

be appropriate for protocols to discuss this possibility for

further minimizing risks. EPA believes tracer studies would raise more

new issues, including issues of safety, than

studies with registered antimicrobials used in

approved use patterns.

[T]he requirement for females under the age of 50 to

take a pregnancy test could be refined. It would be

possible to design criteria that created a better fit

between which female subjects might be able to get

pregnant, and which of them are being asked to take

that test. By doing this, the researchers would be

showing greater respect for this group of subjects. Amended to require ALL females, regardless of

age, to take pregnancy test. Investigators

explained to EPA that they thought it would be

less intrusive and more respectful to apply the

requirement to all women than to inquire

about their individual ability to become

pregnant.

[P]rovide a greater justification for why subjects older

than 65 are excluded. “Because this study may require physically

strenuous activities, an upper age limit was

imposed” (p. 958)ConsentForm [M]ake sure that the consent forms are at an

appropriate level of readability.

. . . [T]here appears to

be room for further simplification. Negligible change (from 9.9 to 9.8) in reading

level (Flesch

‐ Kincaid Grade Level for CF.) F

‐ KGL

for some amended material is as high as 16+.

[The consent form does not] describe adequately the

procedures discussed in the protocol relating to (a) still

photography of the subjects, (b) videotaping of the

subjects, and (c) observation of the subjects by members

of the study team. Changed to state that photos and video will be

taken by an assigned observer, and that

subjects’ faces will not be shown in any

reports. “There were always 3 to 4 study

personnel following the subject during a ME.”

(p. 46)

[E]xplain [in CF] that the underlying purpose of the study

will be to collect information that will be provided to the

EPA, and that the EPA would use that information to

determine the appropriate standards for allowable

exposures to products such as the test compound. Not addressed

Replace the confusing term “same

‐ sex person” in

procedure step 4 in CF; replace with the descriptions

used elsewhere in the form, such as “a researcher of

your own sex.” Unchanged in #4 in consent form (p. 1109). In

#11 in consent form, phrase changed to

“researcher of your own gender.” (p. 1110)

Explain any known risks to subjects, such as eye

irritation. “Permanently” changed to “forever” in CF

discussion of risk of eye irritation (p. 1111)

Correct garbled sentence in IIRB

‐ approved CF concerning

risks to the unborn. Corrected (p. 1112)RecruitingFlyer Explain in flyer that research will measure inhalation as

well as dermal exposure Not changed

Correct garbled eligibility criterion in Flyer Corrected

Correct mischaracterization of how EPA will use the

resulting data CorrectedOther Add reference to inhalation monitoring in phone dialogs Already included in phone dialog; no change

required

Provide more detail about how community—including

unions—will be engaged/involved Revised in protocol and in Appendix H.

Intention was to engage unions through pre

‐

recruiting employer meetings, none of which

took place.Attachment 4

Responsiveness to HSRB Ethics

‐ Related Comments on

AEATF

‐ II Wipe Study Protocol

Page 19 of 19 HSRB Comment on Protocol Response

Ensure appropriate dialect is used in translations, and

clarify who is doing translations Translations done by CA translator, who was

part of research team. Protocol states “all

documents

. . . will be translated by an

individual familiar with idioms and common

dialects used in the Fresno area.” (p. 955)