Ha
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON D.C., 20460

OFFICE OF PREVENTION, PESTICIDES AND
TOXIC SUBSTANCES

March 10, 2008

MEMORANDUM

SUBJECT: Science and Ethics Review of AEAT F Mop Scenario Design and Protocol for Exposure Monitoring

FROM: John M. Carley

Human Research Ethics Review Officer

Timothy Leighton

Antimicrobials Division

Cassi Walls, Ph.D.

Antimicrobials Division

TO: Norm Cook, Chief

Risk Assessment and Scien ce Support Branch (RASSB)

Antimicrobials Division

REF: Selim, S. (2008) A Study For Measurement of Potential Dermal and Inhalation Exposure During Applicat ion of a Liquid Antimicrobial Pesticide Product Using Bucket and Mop Equipment for Cleaning Indoor Surfaces. Unpublished protocol dated January 16, 2008, prepared by

Golden Pacific Laboratories for th e Antimicrobial Exposure Assessment Task Force II under Sponsor ID AEA03 and GPL Study No. 070265. 134 p., plus 335 p. supplement containing IRB correspondence.

We have reviewed the referenced propos al from both scientific and ethics perspectives. Scientific asp ects of the proposed research are assessed in terms of the

recommendations of the EPA Guidelines Se ries 875 and of the EPA Human Studies Review Board. Ethical aspects of the propos ed 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.

Page 1 of 41A. 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 appe nded to this review as Attachment 6. All elements of required documentation are provid ed in the submitted protocol package.

In addition to the final protocol a nd its appendices A through L (pp. 33-166) 1 Volume 1 of the submitted package includes the following supporting documents—all considered in this

review:

• Transmittal Letter (pp. 4-5)

• 40 CFR 26.1125 Checklist (p. 7)

• Mopping Application Scenario: Rationale for Study Design (pp. 8-31)

• IIRB Approval Letter (pp. 168-169)

• IIRB-approved English consent materials (pp. 170, 172-181)

• IIRB-approved Spanish consent materials (pp. 171, 182-193)

• Product Label for test material (p. 88)

• MSDS for test material (pp. 103-104)

• Recruiting materials (pp. 106-111)

Volume 2 of the submitted package in cludes the following additional supporting

documents—also considered in this review:

• Correspondence between the inves tigator and IIRB (pp. 6, 143, 167-190)

• Protocol and appendices as ini tially submitted to IIRB (pp. 7-141)

• Mop scenario design as initially submitted to IIRB (pp. 144-166)

• Protocol as revised 1/16/08 and resubmitted to IIRB, with appendices unchanged from initial submission (pp. 191-325)

• IIRB approval letter of Ja nuary 22, 2008 (pp. 327-328)

• Minutes of 1/22/08 IIRB Meeting and IIRB Membership List (pp. 331-336)

B. Summary Assessment of the Scenario Design

Supporting details are in Attachment 1.

1. Scenario Design: The Antimicrobials Division ( AD) assesses potential occupational and consumer exposure from various antim icrobial products that are applied by a multitude of application techniques including mopping. Mopping can be accomplished with different equipment and techniques. AEATF II defines the mopping application scenario as the mop-ba sed application of a label-specified enduse formulation containing an antimicrobial chemical, including the tasks of mopping

1 Most page images in the submitted volumes bear more than one page number. All page references in this review to Volume 1 are to “page N of 193”, and all page references to Volume 2 are to “page N of 336.”

Page 2 of 41and emptying dirty mop-bucket solution. Th e scope of mop choices includes bucketdipped sponge mops, bucket-dipped string mops, ready-to-use mop systems, and automated “Zamboni-type” floor cleaners. From this array of choices, the regulatory consensus was to monitor bucket-dipped string mops.

EPA intends to use the data developed by the AEATF II for the mopping scenario to describe a typical handler’s daily exposure to the antimicrobial mop solution. The data must be generic enough to be useful for estimating exposures using various types of mops (i.e., sponge, string, RTU), differe nt floor surfaces, room configurations, types of buildings (i.e., homes, schools, medical facilities, commercial office buildings, etc.), handlers (i.e., professiona l and consumer), and antimicrobial active ingredients. AD plans to use the data generated from the proposed mop study generically to estimate dermal and i nhalation exposures and risks for other antimicrobial ingredients where mopping is consistent with product labeling use directions. Antimicrobial products are have been grouped by EPA into the 12 Use Categories listed below. Although mopping of indoor floors may occur in many Use Categories, most mop applicati ons are expected to occur in Use Categories II, III, IV,

and V.

I Agricultural premises and equipment II Food handling/storage establis hments/premises and equipment III Commercial/institutional/industrial premises and equipment IV Residential and public access premises V Medical premises and equipment VI Human drinking water systems VII Material preservatives VIII Industrial processes IX Antifouling coatings X Wood preservatives XI Swimming pools XII Aquatic areas

EPA believes that the AEATF mop scenario is well defined, and we expect that resulting data will meet the needs of EPA and other regulatory agencies. The diversity of daily e xposures under the mopping scenario as defined in this proposal will thus adequately describe a typical handl er’s daily exposure to the antimicrobial

treatment solution.

2. Sampling Design: The AEATF has described in detail their sampling design for the mop scenario and has incorporated random elements were feasible. The AEATF proposes to monitor dermal and inhala tion exposures using passive dosimetry techniques to measure exposure of human subjects mopping indoor floor surfaces. The proposed sample size is the default scheme defined in the AEATF-II Governing Document, involving 3 clusters (sites) with 6 subjects at each. This is believed adequate to provide data to meet EPA’s needs.

Page 3 of 41The mop scenario will consists of prof essional applicators mopping indoor floor surfaces with a string mop and emptying dirty mop solution from the bucket into a sink or drain. The mopping task will o ccur over a range of durations (i.e., 30 – 90 minutes) that represent prof essional applicators’ daily exposures. The focus on professional applicators is a practical nece ssity, given that consumer mopping tasks

are of shorter duration and are likely to result in very lo w exposures, at or below the limit of detection of the analytical methods used. Because of longer task duration and consequent exposure to greater quantit ies of antimicrobial, professional mop applicator exposure is expected to be greater than that of consumers.

The AEATF-II mopping study is further limited to application using string mops and buckets which is typically used by professi onals. String mops are believed to entail higher exposure potential than other kinds of mops based on the observation that string mops have greater surface area than sponge or RTU mop heads, increasing the opportunity for dermal contact. In additi on, application using string mops typically involves a “figure 8” motion that creates greater potential for inadvertent dermal contact compared to the “back and forth” mo tion used with other types of mops. The

scenario does not include the pouring of concentrate into the bucket. Mixer/loader exposure will be monitored in a separate mixing/loading study, which will allow the regulatory agencies to assess either pr ofessional products intended for use with automatic dispensers or RTU mops, or products which require open pouring of the

treatment solution into a bucket.

The amount of DDAC to be handled by each subject will be randomly selected. The subjects will be randomly ordered as they ar e enrolled. At each site tasks are defined

with durations from 30 to 90 minutes at 10 minute intervals. The first subject selected will be assigned to the task with the longest mop duration, although if the subject is unable to complete the assigne d duration, the monitoring event may fit the specification for a shorter mopping task. As additional subjects are assigned to tasks, all defined mopping durations will be reflected in one monitoring event. The amount of DDAC applied will vary among the subj ects on the basis of task duration.

The study location has been purposively se lected to be Fresno County, CA. EPA believes that the application of an anti microbial product in an indoor environment will not vary substantially from one city to another, and therefore that the selection of Fresno County is reasonable. Fresno is close to the laborato ry conducting the study, it is large enough to have a substantial population of professi onal janitors, and it contains many suitable vacant buildings. Conducting all monitoring in a single geographic area will save resources and will not adversely effect the results of the

research.

The mop scenario design calls for three clusters of MEs, each at a different site. It specifies further that each site must be a different type of build ing, that monitoring at different sites must be separated by at leas t one week, and that each selected building must include appropriate surfaces for mopping.

Page 4 of 41Within Fresno County, three sites will be se lected using a stratified random sampling approach. A list of all available vacant bui ldings in Fresno County will be compiled,

and stratified into three cla sses of buildings: office build ing, retail space, or meeting facility. Properties in each of the three categories will be “investigated independently and in random order until a single accepta ble facility is found for each category.” The acceptance criteria ar e that the building:

• Is available for 1-month rental

• Has a functional HVAC system

• Has operating electrical service

• Meets minimum surface area requireme nt with acceptable diversity in available surfaces (e.g., hallways, bathrooms, stairs, empty rooms)

• Does not require cleaning or maintenance before use

The result is a “random sample of one facility from the population of all acceptable facilities of each type in Fresno County.”

The mop scenario calls for monitoring 6 subj ects at each of thr ee sites as they mop floors and dispose of spent mop solution. Therefore, a total of 18 test subjects will be monitored. Two additional test subjects will be enrolled for each site, making a total of 24 subjects in all, in case some subject s withdraw or fail to meet all eligibility criteria. Subjects will be professional janitors, selected randomly from among those who respond to flyers posted in randomly se lected janitorial service companies in the Fresno area, and who meet the eligibility cr iteria for participation. Enrolled subjects will be randomly assigned to mopping tasks of differing durations at one of the three

test sites.

In order to make the most effective use of a limited number of monitoring events, the overall sampling design is purposive. No feasible opportunities to incorporate random elements in the sampling design, however, have been overlooked.

3. Choice of Surrogate Material: The choice of DDAC as th e antimicrobial material for this scenario is appropriate. It is wi dely used, readily available, and there is a reliable and sensitive analyt ical method available for it.

C. Summary Assessment of the Scientific Aspects of the Study Design

Supporting details are in Attachment 2.

1. Statistical design: AEATF-II proposes for the mop s cenario the default design of 3 clusters of 6 monitoring events (MEs) each, as discussed in the Governing Document.

No characteristics of this scenario ha ve been identified which would justify a departure from this norm.

Page 5 of 412. Proposed pattern of human exposure: The AEATF proposes to select professional applicators (i.e., janitors) as subjects for the mopping scenario. The test subjects will use SANI-CARE LEMON QUAT to conduct mopping activities using a string mop and bucket over a range of time durations extending from 30 to 90 minutes in 10 minute increments. The mopping activitie s include actual mopping (without remopping any surface during a given monitori ng event) and emptying the mop bucket at the end of the task. Mopping and dis posal of the remaining solution will be conducted by each subject as they would normally work. The test subjects will not pour the concentrate or mix the mop soluti on – these tasks will be monitored in a separate AEATF study.

SANI-CARE LEMON QUAT which contains the active ingredients didecyl dimethyl ammonium chloride (DDAC) at a concen tration of 2.54% and n-alkyl dimethyl benzyl ammonium chloride (ADBAC) at a concentration of 1.69% will be used as a diluted treatment solution (1: 64) per label directions. Th e concentration of the test material will be constant for all subjects . Variation in exposur es will result from differing exposure durations. Thus, the tota l amount of ai handled will vary by the mopping duration (e.g., 30 – 90 minutes).

The EPA believes that the AEATF mopping study will represent typical worker methods of applying the test substance to i ndoor floors. The sele ction of janitorial subjects, test material , and mopping activities is justified as describe d in the protocol.

3. Endpoints and Measures: The AEATF proposes to measure dermal and inhalation exposures resulting from mopping activities of indoor floors. Dermal and inhalation exposure will be measured using whole-body dosimeters (inner and outer), socks for foot exposure, hand/face washes, and persona l air monitors. The Agencies are most interested in the inner dosimeters to assess potential exposure and/or dose. The outer dosimeters will add to the existing data base on the development of protection factors for single layer of clothing. Foot exposure is generally not measured in pesticide

studies unless there is the potential for foot exposure. However, for mopping there is the potential for foot exposure and therefor e it has been included. The hand/face wash is an appropriate method to dete rmine hand exposure. The personal air samplers will collect residue s from the breathing zone with the sampling cartridge facing downwards (mimicking nostrils). The sampling train will consist of OVS tubes with glass filters backed by XAD sorb ent. Because the air sampling will not size particles, the Agencies will assume all of the residues are inhalable and/or respirable (which tends to overestimate inhalation exposure). The sampling pumps will be calibrated prior to use.

Environmental parameters of the work area such as air temperature, and relative humidity will also be documented. The HVAC system will be described and the air

turnover rates will be measured or estimated.

4. QA/QC Plan: The AEATF QA/QC plan for the mopping study is described in sufficient detail and is adequate to ensure that the measurements are accurate and

Page 6 of 41reliable. The QA/QC plan includes field r ecovery analyses, travel recovery analyses, storage stability studies, and break-through analyses. Method validation results

should be included in th e final study report.

Primary components of the field recovery an alyses include: two fo rtification levels per matrix, triplicate samples per fortific ation level, exposed to ambient conditions for the maximum duration of exposure, and WBD not covered during exposure duration. Field recovery samples will be fo rtified in the field and transported and stored in the same was as the actual study samples, and will be an alyzed concurrently with the actual exposure samples. Correcti on for loss in field recoveries will correct for all phases of potential losses.

Travel fortifications will also be used as insurance if low recoveries are obtained in the field recoveries. However, travel r ecoveries will not be analyzed if acceptable

recoveries are observed in the field recovery samples.

Storage stability samples have been run prio r to the development of the protocol and indicate stability over the six-month period assessed.

5. Statistical Analysis Plan: The results of physical sample analysis will be provided in the final report. The AEATF II will not statistically analyze the monitoring data. However, the mop monitoring data will be imported into the AEATF database (BHED®) where they will be available to regulatory agencies for later statistical analyses. The study documentation will repor t a confidence-interval-based approach to determine the relative accuracy for the arithmetic me an and 95th percentile of exposure normalized by amount of ai handled. The report will further provide the intraclass correlation for clusters (ICC) a nd its confidence interv al, using a variance components model. In addition, the effects of ignoring clusters in the estimation of means and percentiles will be determined by comparing the estimates of a no-cluster

model to those of the random effects model.

D. Compliance with applicable Scientific standards

This protocol adequately a ddresses the following elements according to applicable

scientific standards:

• Scientific objective

• Experimental design for achieving objectives

• Quantification of the test materials

• Data collection, compilation and summary of test results

• Justification for selection of test substance and dilution rate

• Justification for sample size

• Fortification levels and number of sample s for laboratory, field, and storage stability samples

Page 7 of 41Additionally, the AEATF has addr essed the technical aspects provided in the applicable exposure monitoring guidelines (i.e. Series 875 Group A and OECD Applicator Guidelines) as well as Good Laboratory Practices (GLPs).

The following elements in the protocol requir e revision before the research goes forward:

• AEATF did not provide informa tion on how or where the rema ining treatment solution in the mop bucket will be disposed of. More specif icity is needed to ensure that the disposal activity is well documented and represen tative of typical disposal events.

• The efficiency of residue removal through the hand-wash and face/neck wipe methods must be addressed, as well as the possibility of an adjustment to resulting data to compensate for potential incomplete residue removal.

E. Summary Assessment of Ethical Aspects of the Proposed Research

Supporting details are in Attachment 2.

1. Societal Value of Proposed Research: The purpose of the proposed mopping application monitoring study is to devel op more accurate information on worker exposures to antimicrobials while they m op indoor floors. Because many millions of Americans apply antimicrobial products with a mop, the research question is important; it cannot be answered with c onfidence without new monitoring data meeting contemporary standards of quality and reliability.

2. Subject Selection: Twenty-four adult subjects will be recruited from the janitorial/cleaning servic e population of Fresno County. Participants will selfidentify in response to flyers soliciting inte rest, posted in the workplaces of janitorial services companies. Part icipants will be screened in random sequence from among responders, and in that sense will be representative of the population of janitorial

service workers in the Fresno area. There is no reason to think that janitorial service workers in Fresno are not representative of janitorial service workers in any other

area of the United States.

Inclusion/exclusion criteria are complete and appropriate. Pregnant or nursing women and employees or relatives of empl oyees of the investigators are excluded from participation.

No potential subjects are from a vulnera ble population. Recruitment materials and interactions with potential subjects will be conducted in both English and Spanish. To minimize the potential for coercion or undue influence from their employers, subjects will not be recruited directly through contract jani torial service companies. Flyers will encourage interested worker s to contact the investigators directly.

Page 8 of 41Subjects who participate fully will be pa id $100/day. Alternate subjects who are enrolled but are not actually monitore d will be paid $50 for their trouble.

3. Risks to Subjects: The proposed test material is EPA-registered for the use proposed, is of low toxicity to mammals, a nd will be used in fu ll compliance with the approve label. Risks to subjec ts include risks of a reaction to the test material or the solvents used to obtain residues from hands and face/neck; of discomfort and possibly

heat-related illness associated with wear ing two layers of clothing while doing physically demanding work; of a cardiovascular adverse event attributable to physical exertion; of discomfort or inconvenience from wearing the air sampling device; of embarrassment from disrobing in the presen ce of a research technician; of an unexpected result of pregnancy testing. A ll identified risks are characterized as of low probability.

Risks are minimized by exclusion of candida tes known to be sensitive to quaternary ammonium compounds or in poor health or with broken skin on hands, face, or neck; testing in a controlled-temperature e nvironment; alerting subjects to signs and symptoms of heat stress; monitoring heat index with associated stopping rules; limited time of exposure with rest periods at 30-min intervals, or more frequently if requested; close observation of subjects; training of experienced technicians to minimize embarrassment; incorporation of proc edures to keep results of pregnancy testing private and to permit discrete w ithdrawal; provision of appropriate work clothing and PPE.

4. Benefits: This research offers no direct bene fits to the subjects, but subjects may request their individual resu lts, from which they may learn that their work practices produce more or less exposure than average. The principal benefit of this research is likely to be reliable data a bout the dermal and inhalation exposure of workers and the general population mopping floors with antimicrobials, usable by EPA and other regulatory agencies to support exposure assessments for a wide variety of antimicrobial products.

5. Risk/Benefit Balance: Risks to subjects have been thoughtfully and thoroughly minimized in the design of the research. Th e low residual risk is reasonable, in light of the likely benefits to society from ne w data supporting more accurate applicator exposure assessments for a wide range of antimicrobial products used for mopping.

6. Independent Ethics Review: The proposed research has been reviewed and approved by the Independent Investigationa l Review Board, Inc., (IIRB) of Plantation FL. The submitted materials include a full record of correspondence between the investigators and the IIRB.

7. Informed Consent: Informed consent will be obtained from each prospective subject and appropriately documented. Liter acy in English or Spanish is a criterion

for inclusion.

Page 9 of 41Both English and Spanish-language recruiting flyers will be available, and will encourage interested workers to contact either the study Field Coordinator or Spanish-speaking coordinator directly. A Spanish translator will be available at recruitment meetings. Consent forms are available in both languages.

The protocol and consent form indicate that the Principal Inves tigator, who is not fluent in Spanish, will be relied on to in form candidates, who will also be provided product labels and MSDSs, both of which are available only in English. These procedures may not be adequate to en sure comprehension by candidates whose preferred language is Spanish.

8. Respect for Subjects: Subject identifying information will be recorded only once; all subsequent data records and reports w ill refer to individual subjects only by an arbitrary code. Provision is made for disc rete handling of pregnancy testing, required of female subjects on the day of testing. Candidates and subjects will be repeatedly reminded that they are free to decline to par ticipate or to withdraw at any time for any reason, without penalty.

F. Compliance with Applicable Ethical Standards

This is a protocol for third-party resear ch involving intentio nal exposure of human subjects to a pesticide, with the intention of submitting the resulting data to EPA under the pesticide laws. Thus the primary ethical standa rds 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, and because the research will be conducted in California, the provisions of California Code of Regulations Title 3, Section 6710 apply as well. A detailed evaluation of how this proposal addresses applicab le standards of ethica l conduct is included in

Attachment 2.

The following specific deficiencies should be co rrected before the research is initiated:

• Better provision is need for ensuring that Sp anish-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 Califor nia 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.

40 CFR 26 Subpart L, at §26.1703, as amende d effective August 22, 2006, provides in pertinent part:

Page 10 of 41EPA shall not rely on data from any rese arch involving intent ional exposure of any human subject who is a pregnant wo man (and therefore her fetus), a nursing woman, or a child.

The protocol requires that subj ects 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.

Attachments:

1. Summary Review of Mopping S cenario Design dated 14 Jan 08 2. Summary Review of AEATF-II Protocol AEA03 dated 16 Jan 08 3. §26.1111 Criteria for IRB approval of research 4. §26.1116 General requirements for informed consent 5. §26.1117 Documentation of informed consent 6. §26.1125 Criteria for Completeness of Proposals for Human Research

Page 11 of 41Attachment 1

EPA Scenario Review: AEATF-II Mop Application Scenario/Protocol

Title: MOPPING APPLICATION SCEN ARIO: RATIONALE FOR STUDY

DESIGN (Pages 9-31 in AEATF-II Volume I)

Date: 14 January 2008

Sponsor: American Chemistry Council Antimicrobial Exposure Assessment Task Force II c/o Has Shah, Ph.D.

1300 Wilson Blvd Arlington VA 22209

1. Scope of Scenario Design

(a) Is the scenario adequately defined?

Preliminary versions of the mop field st udy protocol have been reviewed by EPA, PMRA, and CDPR to determine the appropria te mopping scenario to assess exposure as accurately as possible, but while ensuring that any error does not underestimate exposure. Many varied antimicrobial products can be applied by mops, from typical consumer applications to kitchen floors to commercial a pplications in hotels, hospitals, schools, or restaurants, to applications in agricultural premises. Mop choices include string mops, sponge mops, and ready-to-use mops. From this array of choices, the regulatory consensus was to select the string mop. The st ring mop is believed to represent the high end of exposure potential because “...string m ops have greater surface area than readyto-use mop heads, increasing the opportunity for dermal contact. In addition, application using string mops involves a ‘figure 8’ motion that creat es greater potential for inadvertent dermal contact compared to the ‘back and forth’ motion used with ready to use mop systems.” (V1:12) 2 The AEATF mop protocol appr opriately proposes to use a string mop and Brite 6185 Mop Bucket with 6127-01 Wringer.

Activities included in the mopping scenario are mopping floors and emptying the mop

bucket. The scenario does not include pouring concentrate into the mop bucket. Mixer/loader exposure will be monitored in a separate study. This separation of tasks will allow regulatory agencies to assess accura tely the exposure associated with either professional products that use automatic dispensers or ot her products requiring open pouring.

2 This pagination convention is used throughout this review. “V1” refers Volume I of the AEATF submission—the “primary documents” volume for the mop scenario design and protocol. “V2” refers to Volume II of the AEATF submission—the “secondary documents” for the mop scenario design and protocol. Entries after the colon are page references; many page images bear more than one page num ber. In volume I the cited page number is always from the expression “p. N of 193”. Volume 2 page refere nces are always from the e xpression “p. N of 336.”

Page 12 of 41Attachment 1

The AEATF study proposes to recruit only prof essional janitors. Ja nitors have been selected to provide longer m opping periods then are typical for consumers, to reduce the likelihood of undetectable residues on sampli ng materials. Alt hough shorter durations typical of consumer mopping are believed to result in detectable residues on the hands, other parts of the body are more likely to pr ovide measurable residues only when longer exposure durations are sampled. Nonethel ess, the upper range of consumer mopping

durations indicated in the Antimicrobial Exposure Joint Venture (AEJV) survey—60 minutes—is within the range of professi onal mopping durations proposed. Thus the scenario design will generate exposure monito ring data directly usable to estimate consumer as well as professional exposures.

(b) Is there a need for the data? Will it fill an important gap in understanding?

The CMA study is the only source of exposure data for the mopping scenario. The CMA data for mopping includes 6 monitoring ev ents and is characterized by low field

recoveries. Based on these data limitati ons, the Antimicrobial Division is requiring dermal and inhalation exposure data in many of its assessments to fill this data gap.

2. Rationale for Scenario Sampling Design

(a) Are the variables in the mopping scenario design likely to capture diverse exposures at the high-end?

The design choices in the string mop scenario to provide diversity in sampling include (1) application equipment; (2) multiple indoor site s in one geographic location; (3) varying the amount of active ingredient handled by th e subjects; and (4) us ing different workers for each monitoring event.

Application equipment. “...The mop technology typically used by professionals, i.e., string mop and bucket systems (source: Johns on Diversey), are expected to have higher exposure potential th an those often used by consumers, e.g., sponge mops, ready-to-use mops. This higher exposure assumption has been discussed with the regulatory agencies (e.g., US EPA, Californi a EPA) and is consid ered likely given the nature of applicator handling with string and bucket mop systems, i.e., sting mops have greater surface area than ready-to-use mop heads, increasing the opportunity for dermal contact. In addition, application using string mops involves a ‘figure 8’ motion that creates greater pot ential for inadvertent dermal contact compared to the

‘back and forth’ motion used with ready-to-use mop systems.” (V1:12)

Sites. Three sites (i.e., buildings) in Fresno C ounty, CA, will be selected for this study. The choice of one geographical location of Fresno County assumes indoor mopping will not differ substantially from one geographic location to another. This assumption is supported by the previous CMA study. Moreover, the available training material for janitorial practices is supported by national organizations (e.g., International Sanitary Supply Association (ISSA)), not regional differences. The choice of sampling vacant buildings allows the researchers “...to be free from

Page 13 of 41Attachment 1

personal interferences with non-subjects... It also allows the focus to be on mopping only as opposed to the broad range of janitorial activities a subject might engage in...” (V1:18). Finally, the geographic area selected in clos e to the laboratory conducting the study and will save resources.

Amount of AI Handled. The amount of active ingredie nt handled will be varied among monitoring events by varying the mopping durations. The AEATF cites existing survey data from ISSA and the Antimicr obial Exposure Joint Venture (AEJV). The ISSA indicates professional applicators m op an average of 83 minutes per day. The AEJV indicates that consumer’s average ~ 10 minutes per event. The mop protocol will monitor mopping for 30 to 90 minutes; task durations will be predefined to vary by approximately ten minutes. (V1:53) Each subject will mop from 2000 to 6000 ft 2
of floor space.

Varying Subjects. The goal of the study is to monito r professional applicators, so the selection of janitors is ap propriate to the goal of the study. Each monitoring event will use a separate individual to maximize diversity. “Each surrogate worker provides his/her unique set of behaviors to the mopping task. Use of the same worker for all monitoring events woul d over-represent a single type of behavior. As a result,

diversification of worker behavior am ong MEs is accomplished by simply requiring

that each ME be based on a different su rrogate worker.” (V1:23) The use of professional applicators is be lieved to be a reasonable surrogate for the range of potential users that may mop with an an timicrobial product such as consumers, building staff/maintenance workers, school ja nitors, for-hire janitorial firms, etc.

(b) How have random elements been incorpor ated into the scenar io sampling design?

“Surrogate worker selection: This proce ss results in a simple random sample of qualifying subjects from the vol unteer pool. Note, however, th at is not the same as a random sample from the existing population of professional janitorial workers. By definition, volunteers are self-selected and c ould have different ch aracteristics than nonvolunteers. Such distinctions have no rele vance in this case, however. There is no particular need to obtain a random sample from the Fresno janitorial population. This existing population is not th e target population for the study. The MEs are synthetic constructs that attempt to predict aspects of a future handler-day population. It is purposive by definition. Thus, a random samp le of just one ME component (e.g. subject) from a subpopulation (e.g. Fresno County) provid es no statistical advantage. In fact, a random sample of subjects from the volunt eer pool is not the only possibility. For example, a more diverse sample of surroga te workers from this pool could also be acceptable if a clear diversifyi ng characteristic were availabl e for all workers. Lacking this, the mop application st udy uses the reasonable defau lt option of a random sample from the volunteer pool.” (V1:23)

“A stratified random sampling approach will be used to locate acceptable facilities.” (V1:19)

Page 14 of 41Attachment 1

“The properties within each of these three categories (office, retail or meeting) will be investigated independently and in random or der until a single acceptable facility is found for each category.”

“Each ME will be randomly assigned to a different task duration interval.” (V1:21)

“Individuals who express a desire to participate in the study w ithin a fixed period of time

will be contacted and screen ed in random order. Surr ogate workers are randomly assigned to MEs.” (V1:23)

”24 subjects are r ecruited randomly from the pool of qualifying volunteers. These 24 subjects are randomly divide d into three groups of eight subjects each.” (V1:53)

”The eight subjects in each site are ordered randomly. The first subject is then assigned to the ME in the longest mopping duration stratu m (i.e., stratum F, 80-90 minutes). No other assignments of subjects to MEs are made un til the subject completes the monitoring task in this stratum. When the ME is complete, the next subject in order is assigned to the next longest stratum (E, 70-80 minutes ). As long as each subject achieves the target mopping duration, the process is continued down to the shortest duration stratum (A, 30-40 minutes) and six MEs have been obtained, one for each of the six strata. If this process proceeds as expected, the last two subj ects are never used for MEs.” (V1:54)

(c) What feasible opportunities to incorp orate random elements in the design—if any—

have been overlooked?

No feasible opportunities to incorporate additional random elements in the sampling design are apparent.

(d) What typical patterns of exposure will likely be included by the sampling design?

“...The mopping application scenario is define d as the mop-based application of a labelspecified end-use formulation containing an an timicrobial chemical. This includes the tasks of mopping and dirty m op bucket solution emptying. It is common in institutional settings today that automated dispensing system s provide the applicator with ready to use mop solutions, and the applicator does not mix and load the end-use mop solution in a bucket. Therefore, the applicator’s exposur e during a single workday in these conditions would arise only from the tasks of applicati on and intermittent disposing or emptying the dirty mop bucket solution.” (V1:11)

“Mopping will be conducted by each particip ant as they would normally work. Past

observation indicates a wide vari ety of application methods (F igure 8, side to side, back and forth motion), wringing preference (thorough agitation vs. dipping prior to wringing) and degree of wringing (single pull vs. mu ltiple). Each subject will not re-mop any surface during a given monito ring event (ME). Disposal of the mopping solution remaining in the buckets will be conducted by each participant as they would normally do.” (V1:50-51)

Page 15 of 41Attachment 1

(e) What typical patterns of exposure will likely be excluded by the sampling design?

The study will monitor professional janitors, so any differences in behavior that a consumer may exhibit while mopping will not be monitored. However, given that mopping is not specialized task, the exclusi on of consumers from the sampling design is

not considered to be a limiting factor.

The mop scenario excludes the task of dilu ting a concentrated pr oduct prior to mopping. The exposures to pouring a liquid concentr ate will be monitored in a separate mixing/loading study as outlined in the AEATF Governing Document. “...a mop applicator could also be ma nually mixing and loading the mop solution, i.e., preparing the end-use dilution by adding a c oncentrate to the water in a buc ket. In these cases, the daily exposure for an antimicrobial handler would arise from two di screte tasks, i.e., mopping (including dirty mop solution dispos al) and mixing/loadi ng of mop solution. These mixing and loading tasks are not in cluded as part of the AEATF II mopping application scenario.” (V1:11)

3. Is the proposed test material an appropriate surrogate?

The test substance, DDAC, is an appropriate choice for the development of surrogate exposure data because it is stable, is characte rized by a low vapor pressure (estimated to

be 2E-11 mmHg) , diluted solutions are not dermally irritating, no systemic toxicity was seen in a 90-day dermal rat study, the pr oduct is registered fo r mopping, and DDAC has

been demonstrated to have a lo w analytical limit of detection.

“The test material, Sani-Care Lemon Quat, an EPA approved product, containing didecyl dimethyl ammonium chloride (DDAC), CAS No. 7173-51-5, and n-alky l dimethyl benzyl ammonium chloride (ADBAC), CAS No. 68424-85- 1 will be applied at a target rate not
to exceed the maximum label-recommended rate. The test material will be used in this study in accordance with the product label.” (V1:40)

“Sani-Care Lemon Quat is a professional use product, and the produc t label specifies the PPE requirements as prot ective eyewear.” (V1:41)

“Based on its safety profile, DDAC and ADBAC have been approved for use in many formulations, and are extensively used in ma ny janitorial products. The test material, Sani-Care Lemon Quat has also been tested for acute effects and has been approved by the EPA. The EPA has recently re-register ed both DDAC and ADBAC and issued REDs for both (EPA, 2006 a,b). Additionally, the safety of the test material has been established through long term professional use of the pr oduct. The product will be used according to its label. The Sani-Care Lemon Quat concentrated formulation will be handled only by researchers and the diluted material (1:64) in a ready-to-use form will be provided to the subjects.” (V1:44)

Page 16 of 41Attachment 1

“The freezer storage stability of DDAC on the di fferent matrices to be used in this study has been completed showing that DDAC is st able on the different matrices when stored in a freezer for 6 months (GPL, 2005).” (V1:48)

4. What is the rationale for the prop osed cluster design and sample size?

AEATF-II proposes for the mop scenario the de fault design of 3 clusters of 6 monitoring events (MEs) each, as discussed in the Govern ing Document. No characteristics of this scenario have been identified which would justify a departure from this norm.

“For the mopping application scenario (as is true for all AEATF II scenarios) only a small number of expensive experimental ly-obtained monitoring events (MEs) are possible.” (V1:15)

“... a practical goal for this study is that th e small sample of mopping application MEs be biased towards increased diversity of handli ng conditions. As a result , the diverse sample of MEs is expected to at least cover the middle portion of the future exposure distribution, cover the upper por tion of the future exposure distribution, and capture the range of exposure variation that is expected to exist.” (V1:16)

“For the mop application study, random nest ed (or cluster) sampling is used as the reference model for the combination of purpos ive and random diversity selection actually used.” (V1:24)

“Benchmark objectives specify accuracy goals th at must be achieved within the reference sampling model when sample size is adequate. In this study, ‘sample size’ means the number of clusters (NC) and the numbe r of MEs per cluste r (NM). For the mop application study, the benchmark objective is that sample es timates of the arithmetic mean and 95th percentile of normalized exposur e are accurate to with in 3-fold 95% of the time.” (V1:5)

Page 17 of 41Attachment 2

EPA Protocol Review: AEATF-II Mop Application Scenario/Protocol

Title: A Study For Measurement of Potential Dermal and Inhalation Exposure During Application of a Liquid Antimicr obial Pesticide Product Using Bucket and Mop Equipment for Cleaning Indoor Surfaces.

Date: 16 January 2008

Principal Investigator and sub-investigators: Sami Selim, Ph.D. Megan T. Boatwright

Tami I. Belcher

Participating Laboratories: Golden Pacific Laboratories, LLC

4720 W. Jennifer Ave. Suite 105 Fresno, CA 93722

Grayson Research, LLC

211 N Main Street

Creedmoor NC 27522

Sponsor: American Chemistry Council Antimicrobial Exposure Assessment Task Force II c/o Has Shah, Ph.D.

1300 Wilson Blvd Arlington VA 22209

Reviewing IRB: Independent Investigational Review Board

6738 West Sunrise Blvd Suite 102

Plantation FL 33313

1. Societal Value of Proposed Research

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

“The primary purpose of the mopping applica tion monitoring study is to develop more accurate information on worker exposures to antimicrobials . . . to support exposure assessments for mopping application.” (V1:15)

“This study is being conducted to determin e potential dermal and inhalation exposures associated with mopping indoor surfaces w ith an antimicrobial pesticide product.” (V1:38)

Page 18 of 41Attachment 2

“A practical goal for this study is that the small sample of mopping application MEs be biased towards increasing diversity of hand ling conditions. . . . The diverse sample of MEs is expected to at least cover the middl e portion of the future exposure distribution, cover the upper portion of th e future exposure distributi on, and capture the range of exposure variation that is e xpected to exist.” (V1:16)

(b) What research question does it addre ss? Why is this question important?

Would the research fill an im portant gap in understanding?

“This study is being conducted to determin e potential dermal and inhalation exposures associated with mopping indoor surfaces w ith an antimicrobial pesticide product.” (V1:38)

“Since 1992 the EPA has conducted professi onal and consumer mixer/loader and applicator exposure and risk assessments relying primarily on the exposure data in PHED. . . . However, PHED does not include any data directly relevant to mopping application methods.” (V1: 12)

“The CMA study represents the only existing data in the case of the mopping scenario. . . Based on EPA’s review, CMA’s study data me t some regulatory agency requirements, but was lacking in other areas.” (V1:13)

“Currently, US EPA relies upon the results of the CMA study conducted more than 15 years ago to characterize exposure from moppi ng using an antimicrobial (Popendorf et al. 1992). That study has a total of 6 measuremen ts of whole body exposure at levels above the Limit of Quantification (LOQ). Analytical methods, exposure dosimetry methods and regulatory needs have changed significan tly since that time. EPA has requested confirmatory exposure monitoring data for a number of antimicrobial use scenarios in Registration Eligibility Decision (RED) documen ts issued over the last 2 years. There appears to be no publicly available data with which to make a credible estimate of exposure for persons using a bucket and stri ng mop. Thus, the rationale for conducting this study is to measure dermal and inha lation exposure in a large enough group of typical users to adequately estimate central tendency and variability for this use of antimicrobial pesticides.” (V1:p41)

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

EPA will consider the data from this study in assessing exposures of occupational or residential applicators using a mop to apply an antimicrobial pestic ide to indoor floors.

(d) Could the research question be answered with existing data? If so, how?

Due to the limitations of existing data, the research question cannot be answered with confidence relying on existing data.

Page 19 of 41Attachment 2

(e) Could the question be answered without newly exposing human subjects? If so how? If not, why not?

“Human subjects are required in this study b ecause they will normally be exposed to the test material when performing their daily ac tivities. There are no acceptable methods or

models that could be used to extr apolate subjects’ exposure.” (V1:42)

2. Study Design

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

is it?

“The primary purpose of the mopping applica tion monitoring study is to develop more accurate information on worker exposures to an timicrobials. These data will consist of dermal and inhalation exposure estimates derived from monitoring subjects under conditions constructed to broadly represent t hose expected for the fu ture application of arbitrary antimicrobial pesticides. AEATF II anticipates the resulting database will contain sufficient data to support exposure assessments for mopping application.” (V1:15)

“This study is being conducted to determin e potential dermal and inhalation exposures associated with mopping indoor surfaces w ith an antimicrobial pesticide product.” (V1:38)”

No hypothesis is stated, nor is the st udy designed to test an hypothesis.

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

The objective cited above can be achieved by the study as proposed.

“...large deviations from the benchmark goals may affect the regulatory usefulness of the data. If large deviations from the benchmark goals are observed the AEATF II will, in consultation with regulatory agencies, determin e the best course of action to take. This may mean the development of guidance for the use of these data that takes the increased imprecision of the estimates into account. It is possible that co llection of additional clusters might be considered.” (V1:78)

2.1 Statistical Design

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

The goal is to use these data to characteri ze some ‘population’ aspect of the future exposure to arbitrary antimicr obial pesticides. Hence, this study is more closely aligned with the random sampling situati on (1).... 1. There is assumed random

Page 20 of 41Attachment 2

sampling from a population and the goal is to estimate some char acteristic of that population.” (V1:24)

“For the mop application study, random nest ed (or cluster) sampling is used as the

reference model for the combination of purposive and random diversity selection.” (V1:24)

“...the benchmark objective is that sample estimates of the arithmetic mean and 95 th
percentile of normalized exposure are accurate to within 3-fold 95% of the time.” (V1:25).

Monte Carlo simulations were used to id entify the most economical number of clusters (3) and subjects pe r cluster (6) consistent with achieving design levels of precision in the results. (V1:28-29)

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

No positive or negative controls are propos ed. This is appropriate for the study design and statistical analysis plan.

(c) How is the study blinded?

The study is not blinded.

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

Candidates selected randomly from among respondents to recruiting flyers will be assigned randomly to one or another ME, pre-defined in terms of its duration and location. (V1:23)

MEs with longer durations will be executed fi rst; a subject who is unable to continue mopping for the designed duration of the ME wi ll be reassigned to a shorter ME, and the next subject in random or der will be assigned to the uncompleted longer ME. (V1:54)

(e) Can the data be statistically analyzed?

The results of the analysis from the sampling will be provided in the final report. (V1:81).

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

“The AEATF II will not statistically analyze the monitoring data in order to characterize exposure or i nvestigate the relationship between exposure and other factors (e.g., room size, level of residual organic matter, environmental conditions

Page 21 of 41Attachment 2

including temperature, humidity, air turnove r rate, etc.) However, regulators and

other users of the constructed database (BHED) may choose to conduct such analyses. The extent of AEATF II’s data analyses will be limited to the statistical characterization of data adequacy for inclusion in BHED scenario monographs. Two specific types of analyses will be performed (these analyses are discussed in more

detail in the AEATF II’s Govern ing Document (AEATF, 2008a):

“1. Evaluation of benchmark adequacy. A confidence interval based approach

will be used to determine the realized relative accuracy for the arithmetic mean and 95th percentile of exposure normalized by amount of ai handled.

“2. Cluster effects. The intr aclass correlation for clusters (ICC) and its confidence interval will be estimated using a variance components model. In addition, the effects, if any, of i gnoring clusters in the estimation of means and percentiles will be determined by comparing the estimates of a no-cluster

model to those of the random effects model.

“We note that the analysis in (1) above may suggest that the realized accuracy bounds differ from the benchmark targets to some extent. This does not invalidate the study

since small deviations would be expected and are of little practical concern. However large deviations from the benchmark goals may affect the regulatory usefulness of the data. If large deviations from benchmark goals are observed the AEATF II will, in consultation with regulatory agencies, determine the best course of action to take. This may mean the development of guidance for the use of these data that takes the increased imprecision of the estimates into account. It is possible that collection of additional clusters might be considered.” (V1:77-78)

(g) Are proposed statisti cal methods appropriate to an swer the research question?

Yes.

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

Because of its Purposive Diversity Sampling Design, the study will support only limited inferences. EPA believes, nonetheless, that it is likely to characterize reliably the exposures of professional janitors in the Fresno area, that those exposures are likely to be similar for other professional jan itors elsewhere, and th at the exposures of professional janitors mopping for extended dur ations can inform assessments of the likely exposure of others mopping for shor ter durations with other classes of equipment. EPA is confident that this design will provide data on mopping exposures

more accurate and reliable than currently available data.

Page 22 of 41Attachment 2

2.2 How and to what will human subjects be exposed?

The test subjects will be exposed to SANI-CARE LEMON QUAT (EPA Reg. No. 47371-131-559) which contains active ingredie nts 2.54% didecyl dimethyl ammonium chloride (DDAC) and 1.69% n-alkyl dimethyl benzyl ammonium chloride (ADBAC). (V1:47).

Test subjects will be exposed during moppi ng activities using a String Mop and Brite 6185 Mop Bucket with 6127-01 Wringer. Mopping activities in clude actual mopping and emptying the mop bucket at the end of the task. Test subjects will not pour the concentrate. (V1:11, 49-50 and 63).

“...represent typical consumer and professi onal worker methods of applying the test substance to indoor floors”. (V1:51)

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

“The test substance for these studies is the formulated product, LEMON QUAT, containing didecyl dimethyl ammonium chloride (DDAC) and n-Alkyl dimethyl benzyl ammonium chlorides (ADBAC). Th e quaternary ammonium antimicrobials are commonly known as “quats”. DDAC is the active ingredie nt selected for measurement, based on its stability, abundan ce in the formulation, and sensitivity of its analytical method.” (V1:47)

“LEMON QUAT is an end use product registered with the EPA for use on smooth surfaces in indoor environments. LEMON QUAT contains didecyl dimethyl ammonium chloride (DDAC) and n-Alkyl dimethyl benzyl ammonium chlorides (ADBAC). DDAC was selected as the analyte based primarily upon its abundance (3x the largest ADBAC homologue), and on its stability, and the sensitivity of its analytical method. The quats ADBAC and DDAC have complete toxicology databases with low mammalian toxicity. Virtually all quat antimicrobial products contain more than a single quat, i.e., a readily available product containing only DDAC was not apparent.

“The analytical method for DDAC on the pr oposed monitoring matrices at very low concentrations has been validated (GPL, 2004). Additionally, DDAC is a single quat (as opposed to ADBAC, the other active in gredient in LEMON QUAT which is an homologous series of quats) and has the requisite degree of stability under field, storage and transit conditions. The freezer storage stability of DDAC on the different

matrices to be used in th is study has been completed showing that DDAC is stable on

the different matrices when stored in a freezer for 6 months (GPL, 2005).

“The very sensitive and selective analytic al method developed for the analysis of DDAC on different study matrices will allow for the detection and quantification of extremely low levels of active ingredient in the collected samples. This will allow for shorter exposure time, thus minimizing the risk to research study subjects.

Page 23 of 41Attachment 2

Additionally, Sani-Care Lemon Quat has been deemed suitable by the Sponsor and EPA as a surrogate compound for generating exposure data for other antimicrobial pesticides.” (V1:48)

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

dose administration?

Concentration of test materials is constant fo r all subjects, as is equipment. Variation in exposure results from monitoring events (MEs) of differing durations. MEs of predefined duration will bracket the range of typical time spent mopping floors per day by professional cleaners, taking into acc ount the limit of quantitation associated with the analytical method. (V1:20-21)

DDAC was selected because of its relatively high concentr ation (2.54%), its stability, and the sensitivity of the analytical method. (V1:48)

The SANI-CARE LEMON QUAT product will be diluted 1:64 with tap water as per label directions. (V1:49)

The same dilute concentration will be used by all MEs. The total amount of ai handled will vary with the duration of mopping.

(c) What duration of exposure is proposed?

Each predefined ME will last from 30 to 90 minutes, with rest breaks at 30-minute intervals in longer-dura tion MEs. (V1:20-21)

Mopping duration will range between 30 and 90 minutes. This interval is partitioned into six mopping duration strata as follows:

A. 30 minutes to less than 40 minutes

B. 40 minutes to less than 50 minutes

C. 50 minutes to less than 60 minutes

D. 60 minutes to less than 70 minutes

E. 70 minutes to less than 80 minutes

F. 80 minutes to 90 minutes

At each site, a single ME is targeted for each stratum. . . . As long as the subject is within the correct stratum, it is unnecessary to control the duration more precisely. However, the subject’s actual mopping dur ation will be recorded to the nearest minute. (V1:53)

Any test subjects not able to mop for the given duration are allowed to stop and as long as the duration was a minimum of 30 mi nutes the dosimeters will be analyzed.

Durations of less then 30 minutes will not be analyzed. (V1:54)

Page 24 of 41Attachment 2

Table 1 Justification for Duration of Ta sk and Area Treated Estimated Cleaning Times for Healthcare – Mop/Wipe Operations (V1:22) includes estimates of exposure

durations from the International Sa nitary Supply Association (ISSA).

2.3 Endpoints and Measures

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

Residues of the surrogate chemical on inne r and outer passive dosimeters, on hands and face/neck, and in personal air samplers. (V1:69-71)

“Light level, air temperature, and relativ e humidity of the work area for the duration of exposure monitoring will be documen ted with automated instrumentation logging...” “HVAC will be described in de tail and the air tur nover rate will be measured or estimated.” (V1:69)

Dermal and inhalation exposures will be m easured using inner and outer dosimeters consisting of 100% cotton long underwear/long j ohns, long pants, long -sleeved shirts, 100% cotton socks, hand wash, face was h, and personal air sampling pumps (OVS tube with glass filter and XAD2 sorbent tubes run at 2 L/min. (V1:65-66). SOP citations for monitoring methods provided V1:70-71.

“....each [personal air monitors] pump will be calibrated to a nominal sample flow rate of approximately 2 L/min... Flow rates will be measured before and after each exposure monitoring period...” (V1:67)

The validated method (GPL-MTH-052) will be tested. “Each an alytical set will include two laboratory fortified samples, a solvent blank and a control” (V1:76)

Storage stability of DDAC fortified matrices were measured (V1:77).

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

The AEATF SOPs provide specific procedures to ensure accurate measurements such as calibration of applicati on solution dispensing (i.e., SOP 10F (V6:70 of 100) and inhalation monitoring devices (i.e., SOPs 10A and 10G (V6:58 and 74 of 100)). “....each [personal air monitors] pump will be calibrated to a nominal sample flow rate of approximately 2 L/min... Flow rates will be measured before and after each exposure monitoring period...” (V1:67) “per SOP AEATF II – 10F and – 10G” (V1:68).

“[air temp, humidity] monitoring equipment will be calibrated or standardized.” (V1:69)

Page 25 of 41Attachment 2

(c) What QA methods are proposed?

Section 10.2.3 Air Sampling for Ambient Pr e-existing DDAC discusses sampling for background air concentrations of DDAC (V1:68)

Field recovery evaluation procedures provide d in SOP 8E. Fortification levels (two levels provided) for each matrix (i.e., dosimet er) listed in table format with the lower fortification levels 4x the LOQ (V1:72). Triplicate samples at each of the two fortification levels (V1:73)

“This study will be conducted according to FIFRA GLP Standards (40 CFR 160).” (V1:80)

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

“...large deviations from the benchmark goa ls may affect the regulatory usefulness of the data. If large deviations from the benchmark goals are observed the AEATF II will, in consultation with regulatory agencies, determine the best course of action to take. This may mean the development of gui dance for the use of these data that takes the increased imprecision of the estimates in to account. It is possible that collection of additional clusters might be considered.” (V1:78)

3. Subject Selection

3.1 Representativeness of Sample

(a) What is the population of co ncern? How was it identified?

The target population is the distribution of future handler /days of applicators applying antimicrobial pesticides in the mopping scenario.

“The community of individuals that use a m op to clean/disinfect surfaces is enormous

and includes millions of workers and at le ast 100 million residents in the U.S. alone” (V1:46)

(b) From what populations will subjects be recruited?

“Adult subjects will be recruited from th e janitorial/cleaning service population of Fresno County. The most-recent US Census i ndicates that 40% of the population in Fresno, CA metropolitan area is Hispanic. The proportion of Hispanics in service industries, e.g., janitorial se rvices, may be even higher than the general population. Therefore, to adequately represent the ethni c diversity in the Fres no area, recruitment

Page 26 of 41Attachment 2

materials and all interactions with potential subjects will be conducted in both English and Spanish.” (V1:55)

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

Expected participants will self-identify in response to flyers so liciting interest, posted in the workplaces of janitorial services companies. They may differ in unknowable ways from other workers who do not step forward. Participants will be screened in random sequence from among responders, and in that sense will be representative of the population of janitorial service workers in the Fresno area. There is no reason to think that janitorial service workers in Fr esno are not representative of janitorial service workers in any other area of the United States.

“The most-recent US Census indicates th at 40% of the population in Fresno, CA metropolitan area is Hispanic. The proportion of Hispanics in service industries, e.g., janitorial services, may be even highe r than the general population.” (V1:55).

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

No discussion is provided on the generalizability of the results.

3.2 Equitable Selection of Subjects

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

Inclusion/exclusion criteria are complete and appropriate. They are listed on V1:58-

59 and below:

“Inclusion Criteria:

• Males or females, 18 to 65 years of age

• In good health

• Willingness to sign the Informed Consen t Form and Subject Self Reporting Demographic Form

• Speak and read English or Spanish

• Reside within Fresno County, California

• Have experience working in janitorial services

Exclusion Criteria

• Skin conditions on the surface of the hands or face/neck (e.g., psoriasis, eczema, cuts or abrasions)

• Pregnancy, as shown by a urine pregnancy test

• Lactation

• Allergies to household chemical-based products, soaps or isopropyl alcohol

Page 27 of 41Attachment 2

• Declines to sign the Informed Consen t Form or the Subject Self Reporting Demographic Form

• Does not read and understand English or Spanish

• Is less than 18 or more than 65 years old

• Is not in good health

• Severe respiratory disorders (e.g., moderate or severe asthma, emphysema)

• Cardiovascular disease (e.g., history of myocardial in farcts, stroke, congestive

heart failure or uncontroll ed high blood pressure)

• Is an employee of Golden Pacific Labor atories or Grayson Research, or is related by blood or marriage to pe rsonnel in either company.”

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

Employees and relatives of employees of the investigators are excluded from participation as subjects. (V1:59)

(c) If any potential subjects are from a vulnerable population, what is the justification for including them?

No potential subjects are from a vulnerable population.

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

The recruiting process is described in V1:55-58

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

“Janitorial services located in Fresno County and providing professional cleaning services for commercial buildings in the Fresno County, CA area will be contacted and asked to post flyers soliciting study subj ects independently from the janitorial service. . . . Those janitori al service managers expre ssing a willingness to post the flyers will be invited to a meeting. . . . At this meeting, the managers will be provided with the flyer and the informed consent fo rm. One purpose of these meetings will be to . . . impress upon the managers the need to remain neutral (un-coercive) in their interactions with employees regarding st udy participation. Also, the meeting may provide an opportunity to hear from organi zed labor, if any of the shops represented are unionized. . . . To avoid the potential for coercion, subjects will not be recruited directly through contract janitorial service companies. Flyers will direct interested workers to contact the study Field Coordi nator or Spanish-speaking coordinator directly.” (V1:55-56)

Page 28 of 41Attachment 2

3.3 Remuneration of Subjects

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

“Individuals that are not te sted including anyone signing the informed consent form but not subsequently being monitored will be compensated for their time and

inconvenience at the rate of $50 per day. . . . Subjects pa rticipating in a monitoring event (ME) will be compensated at $100 for the single day that they are monitored. The values for compensation are based roughly on a day’s wage of $100 and represents potential lost time from secondary sources of employment, travel time and incidental expenses incurred in study participation. Comp ensation will be in the form of cash (U.S. currency) at the completion of participation.” (V1:59)

(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?

“Compensation will be in the form of cas h (U.S. currency) at the completion of participation.” (V1:59)

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 materials?

The proposed test material is EPA-register ed, with an essentially complete supporting

database. The test material is of low toxicity to mammals.

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

Risks are of a reaction to the test material or the solvents used to obtain residues from hands and face/neck; of discomfort and possi bly heat-related illness associated with wearing two layers of clothing; of a cardi ovascular adverse event attributable to physical exertion; of discomfort or in convenience from wearing the air sampling device; of embarrassment from disrobing in th e presence of a rese arch technician; of an unexpected result of pr egnancy testing. (V1:44-45)

Page 29 of 41Attachment 2

Risks discussed in the consent form include ri sk of a reaction to th e test material, risk of over-exertion and stroke or heart attack, risk of discomfort, risk of stinging from alcohol wash and wipes, a small possibility of heat stress, risk of embarrassment, possible surprise at the results of a pr egnancy test, unknown risks to the unborn, and unknown or unforeseeable risks including risks of allergic reaction or interaction with a medication. (V1:177-178)

(c) What is the probability of each risk asso ciated with the research? How was this probability estimated?

All identified risks are characterized as of low probability. No quantitative estimates are reported.

4.2 Risk minimization

(a) What specific steps are proposed to minimize risks to subjects?

Use of test materials shown to be of low toxicity to mammals; use in strict accord with approved labeling; excl usion of candidates known to be sensitive to quaternary ammonium compounds; exclusion of candidates in poor health or with broken skin on hands, face, or neck; testing in a cont rolled-temperature environment; alerting subjects to signs and symptoms of heat stress; monitoring heat index with associated stopping rules; limited time of exposure with rest periods at 30-min intervals, or more frequently if requested; close observati on of subjects; training of experienced technicians to minimize embarrassment; incorp oration of procedures to keep results of pregnancy testing private and to pe rmit discrete withdrawal; provision of appropriate work clothing and PPE. (V1: 44-45, 48-49, 60)

(b) How do proposed dose/exposure levels compare to established NOELs/NOAELs

for the test materials?

The DDAC risk assessment developed to support the Reregist ration Eligibility Decision (RED) document provides for the se lection of the toxicological endpoints for risk assessment purposes. The dermal t oxicological endpoints indicate that low concentrations of DDAC (0.13% ai tested in a 21-day de rmal toxicity study, MRID 45656601) display no dermal irritation eff ects and no systemic effects up to and including the limit dose of 1000 mg/kg/day. The proposed use of DDAC in this protocol by subjects exposed to a dilute d treatment solution of 0.04% ai (i.e., 1/64 product dilution x 2.54% ai in product = 0.04% ai) will not tr igger a risk of concern. The inhalation toxicological endpoint iden tified for DDAC for all exposure durations is based on two oral toxicity studies (prena tal developmental toxicity in rats, MRID 41886701, and a chronic toxicity study in dogs, MRID 41970401). The selected NOAEL from both studies is 10 mg/kg/day. Inhalation exposure from mopping with a low vapor pressure chemical such as DDAC is expected to be minimal.

Page 30 of 41Attachment 2

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

Heat stress index above 95 (V1:61)

Other medical reasons (V1:61)

“If two or more subjects withdraw or are withdrawn from the study for the same medical reasons, the study will be suspended until the cause of the withdrawal is fully investigated and determined.” (V1:61)

(d) How does the protocol provide for medi cal management of potential illness or injury to subjects?

SOP 11.B for Management of Heat Stress (V6:78-92) SOP 11.C for Emergency Procedures (V6:93-95)

(e) How does the protocol provi de for safety monitoring?

“If a subject reports an adverse sk in reaction during the work period, they will be asked to immediately stop wo rking. Research staff will then assist the subject in gently washing exposed skin with clean water and mild soap. After drying the area with a clean towel, the Principal Investigator will be contacted for further

instructions.

“The extra layer of clothing worn by subjects may increase the risk of heat-related illness. To minimize the possibi lity of heat stress, the study will be conducted indoors

in an environment where the heat index (HI) is expected to be less than 85. Research personnel shall monitor the heat index, and stop s ubjects’ work if the heat index exceeds 95. The SOP AEATF 11.B describes the procedure for identification and

control of heat stress. The poster “Controlling Heat Stress Made Simple” will be posted at the field site.

“In brief, researchers will observe subjects for possible signs of early heat illness such as fatigue, dizziness, ir ritability, or decreased concentration, especia lly if the worker has been working for a while. If these symptoms are observed, the subjects will be

asked whether they would like to rest for a moment. If they answer affirmatively, they will stop working, be given their choice of water or a sports drink, and the Principal Investigator will be immediately contacted for further medical management instructions. If they answer negatively, they will be permitted to continue working, and frequently thereafter asked whether they would like to rest for a moment. Any

affirmative answer will be handled as described above.

“If subjects develop visible signs or report symptoms of distress such as pronounced fatigue, headache, cramps, feeling faint, increased pulse, muscle spasms, heavy sweating (or dry skin if previously sweating), extreme thirst, or rapid breathing, the

Page 31 of 41Attachment 2

subjects will be asked to stop working immediately, and given their choice of water or a sports drink. The Principal Investigator wi ll immediately be c ontacted for further medical management instructions. If the worker’s condition app ears to be serious, a member of the study team will call 911 and allow emergency medical personnel to respond and treat the subject.” (V1:60-61)

(f) How does the protocol provide for post-e xposure monitoring or follow-up? Is it of long enough duration to discover adverse events which might occur?

“Subjects will be instructed to inform the Principal Inves tigator or research staff immediately if they feel ill, suffer a skin reaction or experience any other unanticipated adverse effects they feel may be related to the st udy during or following conduct of the study.” (V1:60)

“If two or more subject develop an advers e skin reaction after they leave the study site, all subjects will be cont acted by the Principal Investigator to determine whether further medical management is appropriate.” (V1:61)

(g) How and by whom will medical care for re search-related injuries to subjects be paid for?

“If you are injured as a result of being in this study, medical treatment will be available from a near-by health care facil ity that knows about this study. The people who are paying for this study will pay any cost s of your medical treatment that are not covered by your own insurance or by a thir d party. If necessary, Golden Pacific Laboratories will transport you to receive me dical attention and pay costs associated with reasonable and appropriate treatment of any injuries you get as a result of participating in this study.” (V1:179)

5. Benefits

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

“While there are no direct benefits to the s ubjects participating in this research study,

there are indirect benefits to both the volunteers and society. . . . If individual workers request their results, they may find that their work practice produces more or less exposure than average, and this could be a useful learning tool.” (V1:45-46)

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

“Products containing antimicrobial chemicals are used extensively in hospitals, schools, homes, etc. to control pathogenic bacter ia and viruses known to produce increased morbidity and mortality in humans, domestic animals and pets. Measuring exposure of

workers in this research st udy will produce reliable data about the dermal and inhalation

Page 32 of 41Attachment 2

exposure of workers and the general populati on performing these tasks. The resulting data will improve the completeness and accura cy of the database used by the EPA to assess exposure to these chemicals. The abil ity to accurately predic t risk may allow other

chemical classes of antimicrobials to also be registered based on exposure estimates generated from the data to be pr oduced by this study.” (V1:45-46)

(c) How would societal benefi ts be distributed? Who woul d benefit from the proposed

research?

“Results from the study may benefit EPA and janitorial workers by reducing uncertainty about the range of exposure experien ced by consumers and workers handling antimicrobials. Registrants of antimicrobial s will benefit because they will provide EPA with data on exposure that has been made a condition of re-registration for a number of antimicrobials, and they may be aided in re gistering new antimicrobials using the data generated from this study.” (V1:45-46)

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

The research is very likely to produce more accurate and reliable information concerning exposure in the mop scenario, with resulting societal benefits in the form of more

accurate and confident assessments of applicator exposure and risk.

6. Risk/Benefit Balance: How do the risk s to subjects weigh against the anticipated benefits of the research, to subjects or to society?

“The benefit of maintaining and potentially ad ding new antimicrobials that protect both the subjects involved in this research as well as society (including subjects’ families) in general from microbial diseas es far outweighs any incremen tal risks to subjects. Mortality and morbidity from microbial pat hogens is well-documented. The very slight risks from participation in this study are far lo wer than the risk of not being able to use

effective antimicrobials for lack of inform ation on the exposure to users.” (V1:46)

7. Independent Ethics Review

(a) What IRB reviewed the proposed research?

Independent Investigational Review Board, Inc., Plantation FL (IIRB)

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

Yes

Page 33 of 41Attachment 2

(c) Is this IRB registered with OHRP?

Yes

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

Not reported. IIRB is not listed as an accredited organization on the AAHRPP website ( www.aahrpp.org ). AAHRPP does not identify organiza tions for which accreditation is pending.

(e) Does this IRB hold a Federa l-Wide Assurance from OHRP?

Not reported. IIRB is not listed as holding an FWA on the OHRP website.

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

The transmittal of the protocol and relate d materials to the IIRB (V2:6, 43, 167-190), the IIRB’s approval letter (V1:168-169 and V2:327- 328), minutes of the IIRB meeting at which the proposed research was disc ussed and approved (V2:331-333), and an appropriate membership list (V2:334-336) ar e provided. Acceptable documentation of IIRB procedures has previously been pr ovided directly to EPA under a claim of confidentiality.

(g) What standard(s) of ethical conduct would govern the work?

“The primary ethical standards applicable to this proposal are 40CFR 26, Subparts K and L. In addition, the requirements of FI FRA §12(a)(2)(P) for fully informed, fully voluntary consent of subjects apply, and since the study will be conducted in California, the provisions of the California Code of Regulations, Title 3, §6710 would apply.” (V1:38-39)

8. Informed Consent

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

Yes.

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

Yes. See Attachment 5.

Page 34 of 41Attachment 2

(c) Do the informed consent material s meet the requirements of 40 CFR §26.1116, including adequate characterization of th e risks and discomforts to subjects from participation in the research, the potential be nefits to the subject or others, and the right to withdraw from the research?

Yes. See Attachment 4.

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

Literacy in English or Spanish is a criterion for inclusion (V1:58)

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

“Janitorial services located in Fresno County and providing professional cleaning services for commercial buildings in the Fr esno County, CA area will be contacted and asked to post flyers soliciting study subjects independently from the janitorial service. . . .

The initial contact with serv ice providers will determine language preference (English and/or Spanish) for the flyers.” (V1:55)

“Those janitorial service managers expressi ng a willingness to post the flyers will be invited to a meeting . . . . At this meeting, the managers will be provided with the flyer and the informed consent form. One purpose of these meetings will be to determine if the Spanish translations seems intelligible to the particular dialects that may be represented in the County.” (V1:55-56)

“Flyers will direct interested workers to contact the study Field Coordinator or Spanishspeaking coordinator di rectly.” (V1:56)

“A Spanish translator will be available at recruitment meetings to ensure communication with anyone preferring Spanis h over English.” (V1:57)

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

discomforts?

“A Spanish translator will be available at recruitment meetings to ensure communication with anyone preferring Spanish over Englis h. The Principal Investigator will share information on the study design with interest ed participants, and provide them with copies of the IRB approved Informed Cons ent Form (Appendix B) and answer their questions. The Principal Investigator will desc ribe the study to the individual in great detail and encourage each poten tial subject to ask questions and request clarification at any time during this process as well as in all activities that follow. The Principal Investigator will provide each potential subject with a copy of the product label (Appendix A) and MSDS (Appendix E) and answ er any questions regarding the product to be tested. The Principal Investigator will go over the Inclusion and Exclusion Criteria

Page 35 of 41Attachment 2

(see 9.1.3 below) for the study and answer any qu estions that the poten tial subjects have. They will be provided with copies of the Informed Consent Form (Appendix B), the Subject Self-Reporting Demographic Form (A ppendix D) and the State of California Department of Pesticide Regulation “Experi mental Subject’s Bill of Rights” (Appendix C) and encouraged to take them home with them to discuss with family and friends. The Principal Investigator will explain to potential subjects wishing to remain in consideration that they may w ithdraw from the research study at any time without penalty to their compensation. The Principal Invest igator will then read the “Experimental Subject’s Bill of Rights” to the potential subjects. The amount and form of compensation, the potential risks and discomforts and treatment and compensation for injury will be more fully explained and potenti al subjects encouraged to as k questions. If the potential subjects do not have any questi ons and are interested in participating in this research study, they will then be asked to sign the In formed Consent Form and then fill out the Subject Self-Reporting Dem ographic Form.” (V1:57)

Since the label and MSDS are available only in English, and since the Principal Investigator is not fl uent in Spanish, these procedures may not be adequate to ensure subject comprehension of risks and discomforts.

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

and obtain their consent?

See procedure quoted in 8(f) above.

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

coercion or undue influence?

“Janitorial services located in Fresno County and providing professional cleaning services for commercial buildings in the Fr esno County, CA area will be contacted and asked to post flyers soliciting study subjects independently from the janitorial service.

The initial contact with serv ice providers will determine language preference (English and/or Spanish) for the flyers. . . . Thos e janitorial service managers expressing a willingness to post the flyers will be invi ted to a meeting. . . . One purpose of thesemeetings . . . will be to impress upon the managers the need to remain neutral (uncoercive) in their interactions with employees regarding study participation.

“To avoid the potential for coercion, subjec ts will not be recruited directly through contract janitorial service comp anies. Flyers will direct inte rested workers to contact the study Field Coordinator or Spanish-speaki ng coordinator directly.” (V1:55-56)

9. Respect for Subjects

(a) How will information about prospective and enrolled subjects be managed to ensure their privacy?

Page 36 of 41Page 37 of 41 Attachment 2

“Each volunteer will be assigned an identificat ion number, and all research data will be

recorded under that number. All analysis and reporting will be done using data identified only by the identification number. Your name will appear only in the field raw data, and there only once. The document linking your name to the identific ation number will be stored separately, in a locked cabinet, away from all other study data. You will not be identified by name or any other personal iden tifier in any reports of this study.” (V1:180)

“On the day of the test all female volunteers under 50 will be given a pregnancy test kit like ones you can buy at the drug store. A fema le researcher will be able to explain how to use it and answer questions. After you give yourself the test, we ’ll ask you if you want to continue in the study or withdraw; if you decide to withdraw, you won’t be asked why. . . . If you want to continue in the study, a female research er trained to understand the results of this pregnancy test will check th e results with you privately. No-one but you and she will see the results, and th ey will not be recorded.” (V1:178)

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

See passage quoted in 8(f) above, and th ese passages from the consent document:

“If you decide to participate in this study it wi ll be because you want to. There will be no direct benefit to you if you do decide to par ticipate, and no harm to you if you decide not to. The choice is up to you. Your altern ative is not to part icipate.” (V1:179)

“You are free to withdraw from this study at any time, for any reason. Simply tell Dr.

Selim or another member of the research team if you wish to wit hdraw. Your decision not to participate in this study or to withdraw from this study will not affect your future medical care and will involve no penalty or lo ss of benefits to which you are otherwise entitled.” (V1:180)

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

dealt with?

Those who decline to participate will simply go their way. The consent form states that subjects who withdraw will suffer “no loss of benefits to which you are otherwise entitled”, but is unclear whether and how mu ch they would be paid. Subjects who are withdrawn by the investigators—and all particip ating subjects in the case that the entire study is stopped—are promised payment in full. (V1:180-181)Page 38 of 41 Attachment 3

§ 26.1111 Criteria for IRB approval of research AEATF-II Mop Scenario/Proto col AEA02/070265:Jan 16, 2008)

Criterion Y/N Comment/Page Reference (a)(1)(i) Risks to subjects are minimized by us ing 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 antici pated benefits, if any, to subjects, and the importance of the knowle dge 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 appl ying knowledge gained in the research (for example, the possible effects of the re search 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 in volving 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 prot ect the privacy of subjects and to maintain t he 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. YPage 39 of 41 Attachment 4

§26.1116 General requirements for informed consent AEATF-II Mop Scenario/Proto col AEA02/070265:Jan 16, 2008

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 t he legally effective informed consent of the subject or the subject’s le gally authorized representative OK

An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative suffici ent opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence OK

The information that is given to the subject or the representative shall be in language understandable to the subject or the representative N More attention is needed to ensure bilingual competence among investigators who conduct

recruitment and consent interviews 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 ap pears to release the investigator, the sponsor, the institution or its agents fr om liability for negligence OK

(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 OK

(2) A description of any reasonably fo reseeable risks or discomforts to the subject OK

(3) A description of any benefits to the subject or to others which may reasonably be expected from the research OK

(4) A disclosure of appropriate alternativ e procedures or courses of treatment, if any, that might be advantageous to the subject n/a

(5) A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained OK

(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 OK Although research doesn’t involvemore than minimal risk, compensation and treatment of injuries are provided for (7) An explanation of whom to contact for answers to pertinent questions about the research and research subjec ts’ rights, and whom to contact in the event of a research-related injury to the subject OK Must ensure Spanish capability, and express all time references in
California time(a) In seeking informed consent the following informationshall be provided to each subject

(8) A statement that participation is vol untary, 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 subj ect is otherwise entitled OK

(1) A statement that the particular treatme nt or procedure may involve risks to the subject (or to the embryo or fetu s, if the subject may become pregnant) which are currently unforeseeable OK

(2) Anticipated circumstances under wh ich the subject’s participation may be terminated by the investigator with out regard to the subject’s consent OK

(3) Any additional costs to the subject t hat may result from participation in the

research OK

(4) The consequences of a subject’s decision to withdraw from the research and procedures for orderly termination of participation by the subject OK

(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 n/a(b) When appropriate, one ormore of the following elementsof information shall also beprovided to each subject

(6) The approximate number of subjects involved in the study OK (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. OKPage 40 of 41 Attachment 5

§26.1117 Documentation of informed consent AEATF-II Mop Scenario/Protocol AEA02/070265:Feb xx, 2008

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 gi ven to the person signing the form. OK

(b)(1) The consent form may be a writt en 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 authoriz ed 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 OK

(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 r epresentative. 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 subjec t or the representative. Only the short form itself is to be signed by the subject or t he 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 add ition to a copy of the short form. n/aPage 41 of 41 Attachment 6 40 CFR 26.1125 Prior submission of proposed human research for EPA review AEATF-II Mop Scenario/Protocol AEA02/070265:Jan 16, 2008

Any person or institution who intends to conduct or sponsor hu man 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 addition al information, to the extent not already included: Requirement Y/N Comments/Page Refs (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 V1:8-166; V2:13-172; 194-328

V1:172-192

(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 discus sion of controverted issues and

their resolution. Y V2:340-345

(3) Records of continuing review activities. n/a (4) Copies of all correspondence between the IRB and the investigators. Y V2:4-12; 172-193; 330-335 (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, fu ll-time employee, a member of governing panel or board, stockholder, paid or unpaid consultant. Y

Y V2:333-335

V2:333

(6) Written procedures for the IRB in the same detail as described in §26.1108(a) and §26.1108(b). Y Separately submitted to EPA under confidentiality claimAll information relevant to the proposed research specified by § 26.1115(a)

(7) Statements of significant new findings provided to subjects, as required by §26.1116(b)(5). n/a

(1) The potential risks to human subjects Y V1:43-44 (2) The measures proposed to minimize risks to the human subjects; Y V1:45

(3) The nature and magnitude of all expected benefits of such research, and to whom they would accrue Y Nature V1:45-46. No discussion of magnitude of
benefits (4) Alternative means of obtaining information comparable to what would be collected through the proposed research; and Y V1:42§1125(a)a discussion of:

(5) The balance of risks and benefits of the proposed research. Y V1:46 §1125(b): All information for subjects and written informed consent agreements as originally provided to t he IRB, and as approved by the IRB. Y Orig V2:71-80; 252-261 Approved V1:172-192 §1125(c): Information about how subjects will be recruited, including any advertisements proposed to be used. Y V1:55-59; 106; 109-110

§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 V1:56-57

§1125(e): All correspondence between the IRB and the investigators or

sponsors. Y V2:4-12; 172-193; 330-335The following Information, to theextent not already included:

§1125(f): Official notification to the sponsor or investigator . . . that research involving human subjects has been reviewed and approved by

an IRB. Y V1:168-169