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EPA Science Assessment of 

AEATF II Solid Pour Scenario 

and Protocol 

Tim Leighton

Kelly Sherman

USEPA

Office of Pesticide Programs

Jonathan Cohen, PhD

ICF International

April 8, 2014
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Organization of Presentations

Background and Science Assessment

• Tim Leighton (USEPA)

• Jonathan Cohen, PhD (ICF International)

Ethics Assessment

• Kelly Sherman (USEPA)

Note: Joint Regulatory Committee (JRC) comprised of CDPR and 

HC/PMRA participated in initial protocol design reviews.
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Overview: Solid Pour Scenario/Protocol

 Regulatory Context

 Scenario Definition

 Study Objectives

 Surrogate Material for Testing 

 Study Design

 Measurements

 Compliance with Scientific Standards

 Recommendations/Conclusions
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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

 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 
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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

 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
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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

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
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Solid Pour Scenario Definition

 Manual pouring of solid formulations to 

represent an antimicrobial chemical into 

receiving containers 

 Includes manual pouring of solid products

• Powders

• Granules 

 Excludes applying the product
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Objectives

 To develop more accurate information on exposures 

to antimicrobials to support exposure assessments 

for solid formulations that are manually poured

 To satisfy a requirement for new data imposed by 

EPA’s Reregistration Eligibility Decision (RED) 

documents

 To support Registration Review as well as pending 

and future registrations for various antimicrobial solid 

products and uses
Quick View of Study Design

Use Pattern Scenarios

Grouping of 

AaiH

Occupational

Granules

Occupational

Powders

Consumers

Granules

Consumers

Powders

Group 1 5 to 25 lbs

(n=6)

5 to 25 lbs

(n=6)

1 to 12 lbs

(n=6)

1 to 12 lbs

(n=6)

Group 2 25 to 50 lbs

(n=6)

25 to 50 lbs

(n=6)

12 to 30 lbs

(n=6)

12 to 30 lbs

(n=6)

Group 3 50 to 100 lbs

(n=6)

50 to 100 lbs

(n=6)

30 to 50 lbs

(n=6)

30 to 50 lbs

(n=6)

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Criteria for a Surrogate Solid Product

 Stable 

 Appropriate low vapor pressure

 Robust and sensitive analytical method

 Exposure at the high end of the range for both 

powder and granule product types

 Small to large source containers

 Various receiving container sizes and configurations

 Use of (or not) scoop

 Appropriate amount poured
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Selected Surrogate Test Material

 Cyanuric Acid (CYA) proposed

 Pool chemical used as a stabilizer

 Not an EPA registered antimicrobial

 CAS Number 108-80-5

 100 percent active ingredient

 Can be formulated as both granule and powder

 Can be used without chemical resistant gloves
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Toxicity of Test Material

 The rat developmental oral NOAEL for monosodium 

isocyanurate is used to represent CYA

 NOAEL is 200 mg/kg/day based increased 

hydrocephaly in offspring at the next highest dose 

tested (LOAEL = 500 mg/kg/day)

 No route-specific, repeat dose toxicity testing, for 

dermal or inhalation routes available

 Acute dermal and inhalation testing in rabbits and 

rats (respectively) indicate minimal acute toxicity
Subject’s Potential Dose Estimates to Powders 

 Exposure (Dose) Estimate Approaches

 Two approaches to evaluate absorbed 

dermal dose

• Unit Exposure & Dermal absorption (1 percent)

• Max skin flux (Jmax in units of mg/cm2/hr)

 Inhalation

• Inhalation dose

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Potential Dose/Risk Estimates (continued)

 Unit exposure (UE) approach

 Dermal (consumer, powder) = 3.7 mg/lb ai * 50 lb ai * 

0.01 DA * (1/70 kg)= 0.0264 mg ai/kg

 Inhalation (worker, powder) = 0.0434 mg/lb ai * 100 lb 

ai * (1/70 kg)= 0.062 mg ai/kg

 Margin of Exposure (MOE) = NOAEL/Dose 

 Dermal = 200 mg/kg / 0.0264 mg/kg = 7,600

 Inhalation = 200 mg/kg / 0.062 mg/kg = 3,200

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Potential Exposure/Risk Estimates (continued)

 Maximum skin flux (Jmax in units of mg/cm2/hr)

= Permeability coefficient, Kp (cm/hr) * Solubility saturation, Csat (g/cm3)

= 7.54E-3 cm/hr * 2.7 g/cm3

= 2.04E-2 mg/cm2/hr

 Theoretical maximum absorbed dose (mg/kg)

= Jmax (mg/cm2/hr)* Body SA (cm2)*(1 hr/24 hr)*(1/70 kg)

=2.04E-2 mg/cm2/hr*20,450 cm2*0.0417 hrs*(1/70kg)

=0.249 mg/kg

 MOE (1hr) = NOAEL (200 mg/kg) / Max Abs Dose (0.249 mg/kg) = 800

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Study Design: Single Location

 Concord, Ohio

 Pouring of a solid product does not vary 

geographically

 Indoor portion of the study for the occupational 

scenarios to be conducted in the Ricerca 

Biosciences laboratory (warehouse)

 Outdoor portion of the study for the consumer 

scenarios is outside at same warehouse 

(simulated pool)
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Variables Affecting Exposure from Solid Pouring

 Amount of material poured

 Source container size

 Height of pouring

 Receiving container type, size, and contents

 Number of pours

 Use or non-use of scoop

 Pre-dissolving product 

 Inter variability of subjects
Proposed Scoops

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Sample Characteristics

 Occupational Scenarios – Test subjects will be 

professional applicators who pour solids as part of 

their job; no restriction to a specific industry or years 

of experience

 Consumer Scenarios – Test subjects will be from the 

general public, lived within last 5 yrs in a home with 

a swimming pool, and experienced using pool 

chemicals (no restriction on years of experience)

 Same subjects will be tasked to participate in both 

the granule and powder scenarios

 18 different subjects to be used for 2 occupational scenarios

 18 different subjects to be used for 2 consumer scenarios 
Summary of Study Design

Group

Number

Occupational (Gloves)

25, 50, and 90 lb containers

Consumer (No Gloves)

1, 2, 6, and 25 lb containers

Method Scenarios Method Scenarios

Granules Powders Granules Powders

1 Scoop

(n=6)

5 - 25 lbs 5 - 25 lbs Pour

(n=6)

1-12 lbs 1-12 lbs

2 Scoop 

(n=3) 

Pour&Scoop

(n=3)

25 - 50 lb 25 - 50 lb Pour (n=3)

Pour&Scoop

(n=3)

12-30 lbs 12-30 lbs

3 Scoop 

(n=3) 

Pour&Scoop

(n=3)

50 to 100 

lbs

50 - 100 

lb

Pour (n=3)

Pour&Scoop

(n=3)

30-50 lbs 30-50 lbs

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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 5 lbs for occupational and 1 lb for consumer

 Maximum amount poured 100 lbs occupational and 50 lbs for 

consumer

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

 The number of source containers to be poured by each ME not assigned yet

 The sizes of source containers to be poured during each ME will depend on the 

random selection from the fixed container sizes 

 Anticipated exposure duration is 6 to 40 minutes
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Random Design Elements 

 The following is a list of random design 

elements incorporated in protocol:

 Selection of study participants

 Source containers assigned to ME 

 Assigning consumers to pre-dissolve solid product

 Order in which MEs pour granule vs powder

 Study participant assignment by size group
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Pouring Procedures

 Each subject will open source containers and then pour 

into receiving containers

 Source containers: bags, cans, pails, drums

 Receiving containers will simulate industrial tanks and pools

 Pre-dissolving powder formulation (4 of 18 consumer MEs)

 Scoop

 New EPA recommendation: Where scoops are applicable, scoop 

until you can’t scoop no more, then pour remainder

 Size of scoop to be determined by researchers; subjects will be 

offered multiple scoops to choose from
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Field Measurements

 Air temperature & relative humidity

 Characteristics of HVAC system

 Amount of material applied

 Observations/Video/Photographs
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Measurement of Dermal Residues

 Whole body dosimeters 

 Inner dosimeters 

• Long-johns

• Provide estimate of dermal exposure

 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 
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Measurement of Inhalation Exposure

 Personal Air Samplers 

 OSHA Versatile Sampler (OVS) tubes

 IOM Sampler

• Inhalable particles up to 100 μm

• Respirable particles ≤4 μm

 Flow rate 2 L/min 
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Analytical Phase

 Matrices – WBD dosimeters, hand washes, 

face/neck wipes, and air samples

 Method validation

 QA/QC plan 

 Field recovery analysis

 Storage stability studies

 Break-through analysis 
Fold Relative Accuracy

Parameter Fold Relative Accuracy

Arithmetic Mean 2.6

95th Percentile 2.8

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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

 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 

 Describe the orientation of the airflow in relationship of the “pouring” 

and the test subject for both indoors and outdoors (e.g., is powder 

being blown in direction of or away from the subject?).

 The test subjects representing the consumer population should also 

wear the same respiratory protection as the occupational test 

subjects (prudent).

 Make final individual ME assignments of scoop sizes, AaiH, and 

containers.

 Empty source containers (where applicable) with scoop and then 

pour out the remainder.

 Add a wind speed stop criteria for conducting study outdoors.

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Recommendations (continued)

 Need to account for hand wash removal efficiency in 

the final study (e.g., default correction factors, 

literature, hand wash removal efficiency study, etc.)

 Default correction factors, if no other information, 

and if hands and neck/face are:

 ≤20% of total dermal, then no correction;

 20 to 60% of total dermal, then 50% correction;

 ≥60% of total dermal, then removal efficiency 

study

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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;

 This need cannot be addressed except by research with 

human subjects;

 It has a clear scientific objective; and

 The study design should produce data adequate to achieve 

the objective.
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EPA Ethics Assessment 

of AEATF II Solid Pour 

Scenario and Protocol

Kelly Sherman

Human Research Ethics Reviewer

Office of Pesticide Programs
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Value to Society

 Many consumers and workers pour solid 

antimicrobial products, so reliable data on potential 

dermal and inhalation exposure are needed to 

support EPA exposure assessments

 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
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Subject Selection

 Subjects will be recruited through 

newspaper advertisements

 Callers will be informed about the study 

using an IRB-approved script

 Callers will be screened for eligibility, and 

then scheduled for informed consent 

meetings

 Inclusion/Exclusion Criteria are complete 

and appropriate except that “skin conditions 

of the face/neck” should be added
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Subject Selection 2

 No potential subjects are from a vulnerable 

population

 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
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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

 Reviews Informed Consent Document

 Provides label and MSDS

 Answers questions

 Principal Investigator confirms understanding and 

solicits consent to participate
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Risks and Risk Minimization

Four categories of risk; protocol provides 

appropriate measures to minimize each

1. Irritant response to test material or to the soapy 

mixture used to wash the hands and face/neck

2. Heat-related illness

3. Embarrassment while changing

4. Unwanted disclosure of pregnancy test results
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Benefits

• No direct benefits to subjects

• Sponsors will benefit from improved 

exposure and risk assessments

• Likely societal benefit is higher quality 

exposure and risk assessments for 

antimicrobial products
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Risk-Benefit Balance

 Risks have been effectively minimized

 Residual risks to subjects will be low

 Risks to subjects are reasonable in 

light of potential societal benefits
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Respect for Participants

 Participant privacy will be maintained

 Proposed payments to subjects are 

reasonable

 Participants will be free to withdraw at any 

time, for any reason
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Independent Ethics Review

 Schulman Associates IRB was the 

reviewing institutional review board

 Schulman Associates reviewed and 

approved the protocol and supporting 

documents in English and Spanish 
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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 

the pesticide laws

 The primary ethical standards applicable to 

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

Before Research Proceeds

 Add “skin conditions of the face/neck” to the 

exclusion criteria

 Revise section 9D of the protocol to specify 

that eye irritation or respiratory irritation 

experienced by two or more subjects (in 

addition to adverse skin reaction) will trigger 

the Study Director to contact all subjects to 

determine if further medical management is 

needed
Revisions Requested by EPA

Before Research Proceeds—2

 Revise residential monitoring consent form 

to explain that subjects will need to wear a 

particulate dust mask

 Add “skin reaction and respiratory irritation” 

to the research-related injuries section of the 

consent form

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Revisions Requested by EPA

Before Research Proceeds—3

 Revise the newspaper advertisement for 

the Occupational Scenario to specify the 

requirement for job experience pouring 

solid antimicrobials

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Revisions Requested by EPA

in Future Protocols

 Incorporate the HSRB’s forthcoming 

guidance about how to provide personal 

exposure results to subjects

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Compliance with Ethical Standards

 All requirements of §26.1111, §26.1116, and 

§26.1117 are met

 All requirements of §26.1125 are met

 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
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Charge Questions

If the proposed AEATF II solid pour study 

proposal is revised as suggested in EPA’s review 

and if the research is performed as described:

1) Is the research likely to generate scientifically 

reliable data, useful for assessing the exposure of 

individuals who manually pour solid antimicrobial 

products? 

2) Is the research likely to meet the applicable 

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