EPA Science Assessment 

of AEATF II Liquid Pour 

Scenario and Protocol 

1

Tim Leighton

Antimicrobials Division

Office of Pesticide Programs
Organization of Presentations

Background and Science Assessment

• Tim Leighton

Ethics Assessment

2



• Kelly Sherman
Overview: Liquid Pour Scenario/Protocol

 Regulatory Context

 Scenario Definition

 Study Objectives

3

 Surrogate Material for Testing

 Study Design

 Measurements

 Compliance with Scientific Standards
Regulatory Context

 This is a proposal for research involving scripted 

exposure, and thus intentional exposure of 

human subjects, with the intent to submit the 

resulting data to EPA under FIFRA

4

 The following regulatory requirements apply:

 40 CFR §26.1125 requires prior submission of the 

protocol and supporting documentation

 40 CFR §26.1601 requires review of the protocol by 

EPA and the HSRB 
New Exposure Studies are Needed

 A new generation of exposure monitoring is 

needed

 To address the limitations of PHED/CMA data

 To maximize the utility of generic data

5

 To standardize study design and methods 

 FIFRA SAP (Jan 2007) concurred in 

 Need for new studies

 Soundness of the “generic principle”

 General methods and study designs
Use Categories

MopWipeAerosolPour LiquidPour SolidSprayImmerse/DipPump LiquidPlace SolidFogPressure TreatMetalwork FluidBrush/RollerAirless Spray

Ag. Premises & Equipt XXXXXXXX

Food Handling P&E XXXXXXXX

Comm. & Indus. P&E XXXXXXXX

Residential & Public Access XXXXXXX

6

Residential & Public Access XXXXXXX

Medical P&E XXXXXXXX

Drinking Water Systems X

Indus. Process Water Sys XX

Material Preservatives XXXXXXXXX

Antifoulant Coatings XX

Wood Preservatives XXXXX

Swimming Pools XXXX

Aquatic AreasXXXX
Liquid Pour Scenario Definition

 Manual pouring of a liquid formulation 

containing an antimicrobial chemical into 

receiving containers 

7

 Includes manual pouring of a liquid product 

 Excludes applying the antimicrobial
Objectives

 To develop more accurate information on exposures 

to antimicrobials to support exposure assessments 

for liquid formulations that are manually poured

 To satisfy a requirement for new data imposed by 

8

EPA’s Reregistration Eligibility Decision (RED) 

documents

 To support Registration Review as well as pending 

and future registrations for various antimicrobial 

liquid products and uses
Quick View of Study Design

Scenario Group MEs Number of Source 

Containers to be Poured

Total Volume 

Potentially 

Poured

Receiving 

Container

Conventional

(DDAC)

1

(Small)

6 Each ME to pour 10 small 

containers 

Up to 5 gallons 2 sizes

2 6 Each ME to pour 10 medium Up to 14 gallons 3 sizes

9

2

(Medium)

6 Each ME to pour 10 medium

containers 

Up to 14 gallons 3 sizes

3

(Large)

6 Each ME to pour 4 large 

containers

20 gallons 1 size

Reduced 

Splash

(ADBAC)

1

(Small)

6 Each ME to pour 15 small 

containers 

Up to 7.5 gallons 2 sizes

2

(Medium)

6 Each ME to pour 15 medium

containers 

Up to 21 gallons 3 sizes

3

(Large)

6 Each ME to pour 6 large 

containers

30 gallons 1 size
Reduced-splash Container

10
Criteria for a Surrogate Liquid Product

 Stable 

 Appropriate low vapor pressure

 Robust and sensitive analytical method

11

 Exposure at the high end of the range for different 

liquid product types

 Small to large source containers

 Various receiving container sizes and configurations

 Use of (or not) measuring cup

 Appropriate volume poured
Variables Affecting Exposure from Liquid Pouring

 Source container design (2 exposure scenarios)

 Conventional

 Reduced-splash

 Amount of material poured

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 Source container size

 Height of pouring

 Receiving container type, size, and contents

 Volume and number of pours

 Use or non-use of measuring cup

 Inter variability of subjects
Selected Surrogate Test Material

 Two chemicals proposed

 DDAC for conventional source containers

 ADBAC for reduced-splash containers

13

 Maquat WP and Maquat DS 1412 

 EPA Reg. Nos. 10324-91 and 10324-25

 Active Ingredients to be used in source containers

0.2% ADBAC: n-Alkyl dimethyl benzyl ammonium chloride

0.2% DDAC: Didecyl dimethyl ammonium chloride 
Toxicity of Test Materials: ADBAC

 ADBAC dermal NOAEL reported in EPA RED is 

20 mg/kg/day (333 ug/cm2) for dermal irritation

 No dermal toxicity data available for low concentrations

 No systemic effects observed, only irritation

14

 ADBAC inhalation NOAEL reported in EPA RED is 

3 mg/kg/day, based on an oral study

 Based on the ADBAC RED, predicted dermal and 

inhalation risks will not be of concern
Toxicity of Test Materials: DDAC

 DDAC dermal NOAEL reported in EPA RED is 

1000 mg/kg/day at 0.13% ai (the highest dose tested) 

 No systemic effects; no irritation observed

 Proposed concentration of DDAC in the test product is low (0.2% ai)

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 DDAC inhalation NOAEL reported in EPA RED is 

10 mg/kg/day, based on an oral study

 Based on the DDAC RED, predicted dermal and 

inhalation risks will not be of concern
Study Design: Single Location

 Concord, Ohio

 Pouring of a liquid product does not vary 

geographically

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 Study to be conducted in laboratory

• 2 rooms with laboratory

• Room dimension 12 ft x 24 ft (ceiling?)
Sample Characteristics

 Professional janitors and/or maintenance workers—to 

ensure sufficient volume of product is poured to 

obtain usable data with exposure >LOD

 Same study subjects will be used for both 

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conventional and reduce-splash container scenarios

 Within 1 monitoring event (ME) the subject will pour both a 

series of conventional source containers containing DDAC 

and a series of reduced-splash containers containing ADBAC

 Dosimeters analyzed for both DDAC and ADBAC which will 

make the distinction between the 2 scenarios
Sample Characteristics (continued)

 Characteristics to capture the high end of 

potential exposure

 Source container type and size

18

 Receiving container type, size, and contents

 Height of pouring

 Pouring volume and number of pours

 Use or non-use of a measuring cup
Summary of Study Design

Scenario Group MEs Source Container Size 

and Number to be 

Poured

Total Volume 

Potentially 

Poured

Receiving 

Container

Conventional

(DDAC)

1

(Small)

6 Each ME to pour 10 containers 

randomly selected from 24, 32, 

and 64 fluid ounce sizes

40 oz to 5 gallons 32 oz spray 

bottles and 2 

gal bucket

2 6 Each ME to pour 10 containers 7.5 to 14 gallons 2 and 4 gallon 

19

2

(Medium)

6 Each ME to pour 10 containers 

randomly selected from 96, 128, 

and 180 fluid ounce sizes

7.5 to 14 gallons 2 and 4 gallon 

buckets and 

10+ gal basin

3

(Large)

6 Each ME to pour four 5 gallon 

buckets

20 gallons 10+ gallon 

basin

Reduced 

Splash

(ADBAC)

1

(Small)

6 Each ME to pour 15 containers 

randomly selected from 60 and 

64 fluid ounce sizes

60 oz to 7.5 

gallons

32 oz spray 

bottles and 2 

gal bucket

2

(Medium)

6 Each ME to pour 15 containers 

randomly selected from 96, 128, 

and 180 fluid ounce sizes

11.25 to 21 

gallons

2 and 4 gallon 

buckets and 

10+ gal basin

3

(Large)

6 Each ME to pour six 5 gallon 

buckets

30 gallons 10+ gallon 

basin
ME Stratification by Amount Handled

 Constant concentration of test material; exposure varies with amount 

handled, subject-specific behaviors, and characteristics of sample 

design

 Minimum amount poured 40 fluid ounces

 Maximum amount poured using the 5 gallon buckets is 30 gallons

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 Amount (volume) to be poured will be randomly selected

 10 source containers to be poured

 The exact sizes of source containers to be poured will depend on the random 

selection from the fixed container sizes within each size group 

 Anticipated exposure duration is 10 to 60 minutes
Random Design Elements 

 The following is a list of random design 

elements incorporated in protocol:

 Selection of study participants

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 Source containers assigned to ME 

 Receiving container height

 Scenario order (conventional vs reduced-splash)

 Study participant assignment by size group
Pouring Procedures

 Each subject will pour from 10 source containers 

into empty receiving containers

 Conventional source containers

22

 Reduced-splash source containers 

 Measuring cup

 Single measure cup into spray bottle (Group 1), fill 

spray bottle with water

 Two measuring cups into bucket, then pour entire 

source container into bucket (Groups 1 & 2)
Field Measurements

 Air temperature & relative humidity

 Characteristics of HVAC system

23

 Measurements of room dimensions

 Amount of material applied

 Observations/Video/Photographs
Measurement of Dermal Residues

 Whole body dosimeters 

 Inner dosimeters 

• Long-johns

• provide estimate of dermal exposure

24

 Outer dosimeters 

• Normal work clothing consistent with label PPE

• provide estimate of protection provided by a single layer of 

clothing

 Hand wash at end of task

 Face/neck wipe at end of task 
Measurement of Inhalation Exposure

 Personal Air Samplers 

 OSHA Versatile Sampler (OVS) tubes

 Run at 2 L/min 

25
Analytical Phase

 Collected samples—dosimeters, hand/face washes, 

and air samplers

 Method validation

QA/QC plan 

26



 Samples simultaneously fortified with ADBAC and DDAC

 Field recovery analysis

 Storage stability studies

 Break-through analysis 
Compliance with Scientific Standards

 This protocol has addressed the technical aspects of 

applicable exposure monitoring guidelines

 EPA Series 875 Group A - Applicator Monitoring Test 

Guidelines

27

 OECD Applicator Guidelines

 Good Laboratory Practices (GLPs) (40 CFR Part 160)

 Previous comments by EPA and JRC have all been 

satisfactorily addressed

 EPA has provided several new recommendations
Recommendations 

 Additional random elements

 Randomize the order in which source container will be poured 

and describe selection process

 Randomize use of measuring cup (Group 2)

 Allow workers to fill spray bottles as they normally would do

 Describe how airflow in room will be measured

 Monitor activities associated with “spills/cleanup” 

 Specify allocation of receiving containers in each Group

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Summary Conclusion

• This protocol is likely to yield scientifically reliable 

information, satisfying the following criteria:

 It would produce important information to fill an identified 

regulatory need

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 This need cannot be addressed except by research with 

human subjects

 It has a clear scientific objective

 The study design should produce data adequate to achieve 

the objective
EPA Ethics Assessment 

of AEATF II Liquid Pour 

Scenario and Protocol

30

Kelly Sherman

Human Research Ethics Reviewer

Office of Pesticide Programs
Value to Society

 Many consumers and workers pour antimicrobial 

products, so reliable data on potential dermal and 

inhalation exposure are needed to support EPA 

exposure assessments

31

 Existing data have limitations

 Knowledge likely to be gained will be usable in 

exposure assessments for

 Both professional users and consumers

 Wide variety of antimicrobial products and use 

patterns
Subject Selection

 Subjects will be professional janitorial 

workers recruited through newspaper 

advertisements

 Callers will be informed about the study 

32

using an IRB-approved script

 Callers will be screened for janitorial 

experience and other eligibility factors, and 

then scheduled for informed consent 

meetings
Subject Selection 2

 Inclusion/Exclusion Criteria are complete and 

appropriate

 No potential subjects are from a vulnerable 

population

33

 Subjects will be recruited through newspaper 

advertisements, not through employers

 Recruitment materials and interactions with 

potential subjects will be conducted in English 

or Spanish, depending on subject preference
Consent Process

 Principal investigator (or bilingual researcher) meets 

individually with interested candidate

 Provides information about study design in candidate’s 

preferred language

 Applies eligibility criteria

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 Reviews Informed Consent Document

 Provides label and MSDS

 Answers questions

 Principal Investigator confirms understanding and 

solicits consent to participate
Risks and Risk Minimization

Four categories of risk; protocol provides 

appropriate measures to minimize each

1. Irritant response to test materials or to solvents

35

2. Heat-related illness

3. Embarrassment while changing

4. Unwanted disclosure of pregnancy test results
Benefits

• No direct benefits to subjects

• Sponsors will benefit from improved 

exposure and risk assessments

36

• Likely societal benefit is higher quality 

exposure and risk assessments for 

antimicrobial products
Risk-Benefit Balance

 Risks have been effectively minimized

 Residual risks to subjects will be low

37

 Risks to subjects are reasonable in 

light of potential societal benefits
Respect for Participants

 Observations will be as unobtrusive as 

possible

 Participant privacy will be maintained

38

 Proposed payments to subjects are 

reasonable

 Participants will be free to withdraw at any 

time, for any reason
Independent Ethics Review

 Independent Investigational Review 

Board, Inc. (IIRB) was the reviewing 

institutional review board

39

 IIRB reviewed and approved the protocol 

and supporting documents in English and 

Spanish 
Applicable Ethical Standards

 This is a proposal for third-party research 

involving intentional exposure of human 

subjects to a pesticide, with the intention of 

submitting the resulting data to EPA under 

40

the pesticide laws

 The primary ethical standards applicable to 

this research are 40 CFR 26, subparts K and L
Revisions Requested by EPA

Before Research Proceeds

 Identify the newspapers in which the 

recruiting advertisements will be placed



41

Advertisements should be placed in multiple 

newspapers targeting different demographic 

groups

 Replace generic references to “second 

alternate language” with “Spanish”
Revisions Requested by EPA

Before Research Proceeds—2

 Add a statement to consent form stating 

that subjects should contact the study 

director if, within 24 hours of participation in 

the study, they experience a reaction or 

other symptom that they believe is related to 

the study

 Develop procedures for handling such a call 

and document them in an SOP

42
Revisions Requested by EPA

in Future Protocols

 Develop and implement a process for 

improving and verifying the accuracy of the 

Spanish translations

 Incorporate the HSRB’s forthcoming 

guidance about how to provide personal 

exposure results to subjects

43
Compliance with Ethical Standards

 All requirements of §26.1111, §26.1116, and 

§26.1117 are met

 All requirements of §26.1125 are met

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 Requirements of §26.1203 are met

 If EPA’s and HSRB’s requested corrections are 

made, research conducted according to this 

scenario and protocol will likely meet the 

applicable requirements of 40 CFR part 26, 

subparts K and L
Charge Questions

If the proposed AEATF II liquid pour study 

proposal is revised as suggested in EPA’s review 

and if the research is performed as described:

45

1) Is the research likely to generate scientifically 

reliable data, useful for assessing the exposure of 

individuals who manually pour liquid antimicrobial 

products? 

2) Is the research likely to meet the applicable 

requirements of 40 CFR part 26, subparts K and L?