1. 11 AEATF II Aerosol Application Scenario: Rationale for Study Design and A Study for Measurement of Potential Dermal and Inhalation Exposure During Application of a Liquid Antimicrobial Pesticide Product Using a Pressurized Aerosol Can for Indoor Surface Disinfecting

2. 22 Status Summary AEATF II submitted an IRB-approved scenario design and study protocol dated August 4, 2009, for an aerosol spray exposure study The EPA Science and Ethics Review of September 21 reflects review of the August 4 proposal, and was informed by the Governing Document and SOPs of the AEATF II

3. 33 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

4. 44 Completeness for Review The August 4 submission contains all elements required by 40 CFR §26.1125 EPA believes this proposal is ready for HSRB review

5. 55 Organization of Presentations Background and Context John Carley Science Assessment Tim Leighton Ethics Assessment Kelly Sherman

6. 66 Background and Context for AEATF II Aerosol Scenario John M. Carley Human Research Ethics Review Officer Office of Pesticide Programs

7. 77 Background for Exposure Monitoring In early 1990’s individual pesticide handler exposure studies were combined in a shared database—the Pesticide Handlers Exposure Database, or PHED PHED has supported meta-analyses across studies, and demonstrates the value of approaching exposure generically PHED has been the basis for most subsequent OPP exposure assessments Additional exposure monitoring for antimicrobials was conducted in the CMA study

8. 88 Limitations of PHED/CMA Data PHED/CMA remain the best data available, but have clear limitations— especially for antimicrobials:  Spotty coverage of antimicrobial use patterns  Studies had been conducted for different purposes; inconsistent methods increase uncertainty of inferences

9. 99 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

10. 10 Formation of AEATF II EPA imposed requirements for new exposure studies in re-registration of antimicrobials In response to EPA requirements, members of the antimicrobials industry joined together beginning in 2004 to share technical and financial resources in the design and execution of a new antimicrobial exposure monitoring program

11. 11 Primary Objective of AEATF II “To generate handler exposure monitoring studies to estimate and characterize exposures distributions for a multitude of occupational/industrial and consumer exposure scenarios involving antimicrobial products”

12. 12 Scope of AEATF II Program Defined through extensive consultation with EPA, Health Canada, and CDPR (California) Focuses on handler exposure first, with monitoring of post-application exposures to residues on hard and soft surfaces to follow Covers the most common categories of antimicrobial pesticide use sites and the most common antimicrobial handler tasks

13. 13

14. 14 Antimicrobial Handler Tasks

15. 15

16. 16 Additional Simplifications Some scenarios are defined to include common combinations of tasks In some scenarios only higher-exposure variants are tested Subjects wear minimum required Personal Protective Equipment (PPE)

17. 17 The Generic Principle Exposure depends more on the characteristics of the use pattern than on the specific chemical  Physical form and properties of the pesticide  Method of application  Amount of pesticide used  User behaviors Data obtained by monitoring exposure from use of one chemical can be used, with appropriate adjustments, to estimate likely exposure from similar uses of other chemicals

18. 18 AEATF II Exposure Scenarios A set of similar uses of physically similar chemicals is an “exposure scenario”  The unit in a scenario is a handler-day  A “Monitoring Event” (ME) is a dataset fully describing a monitored handler-day The target population is the universe of future handler-days  EPA wants to be able to characterize future exposures likely to result from use of a specific amount of an antimicrobial product in a well-defined exposure scenario

19. 19 Each Monitored Handler-Day is a Monitoring Event (ME) Each ME characterizes dermal and inhalation exposure for a single subject over at least half a day The set of MEs for a scenario should characterize the range of expected exposures Measured exposures from each set of MEs will be used to represent future handler-day exposures to antimicrobial pesticides used in a particular scenario

20. 20 AEATF II Sampling Design Overall purposive sampling to characterize a broad range of exposures with a small sample size  In guestrooms at 3 hotels/motels in Fresno area, differing in kitchen facilities  At different times  With a wide range in quantity of pesticide handled  With different subjects (each subject monitored only once) Incorporating these random elements  Sequence of screening hotels/motels  Sequence of contacting janitorial services providers  Assignment of enrolled subjects to sites and ME slots

21. 21 EPA Provisos EPA decided in November 2007, after considering the recommendations of the HSRB and others, to accept an overall purposive sampling design for the AEATF II monitoring program, with these provisos: The AEATF II must:  Describe in detail their sampling design for each scenario  Incorporate random elements whenever it is feasible  Document their rationale for using a particular approach, including all decisions regarding the feasibility of randomization of specific elements in the design

22. 22 Diversity Sampling Maximizes Regulatory Utility Maximizes—with a small sample—diversity in conditions expected to influence exposure Ensures that different MEs differ with respect to factors likely to affect exposure Increases the chance that the range of conditions expected to affect exposure in future handler-days is reflected in the set of MEs collected

23. 23 Consequence of Diversity Sampling As noted by the HSRB in earlier reports, the resulting distribution is not statistically representative of exposures to the target population, and statistical inferences cannot be drawn from results of AEATF II monitoring Distribution is deemed by EPA to adequately characterize for regulatory purposes the “middle” and “larger” exposure values for the target population of future handler-days

24. 24 AEATF II Study Participants Experienced professional handlers of antimicrobial pesticides Recruited through flyers and newspaper ads—not through employers Qualified volunteers are enrolled in the order of their response to recruiting efforts Enrolled subjects are assigned randomly to monitoring sites and specific ME slots

25. 25 AEATF II Study Results Study results will be reported to EPA in a monograph of each completed scenario Scenario monographs will be reviewed by EPA and, for scenarios involving scripted exposure, by the HSRB Upon acceptance, data for each scenario will be posted to the Biocide Handlers Exposure Database (BHED™)

26. 26

27. 27 EPA Science Assessment of AEATF II Aerosol Scenario and Protocol Tim Leighton Antimicrobials Division Office of Pesticide Programs

28. 28

29. 29 Overview: Aerosol Scenario/Protocol Scenario Definition Study Objectives Selection of Surrogate Material for Testing Toxicity of Selected Surrogate Test Material Study Design  Site location & selection  Sample characteristics  Amount to be handled  Allocation of subjects  Spraying procedures Measurements Compliance with Scientific Standards

30. 30 Aerosol Application Scenario Definition Hand-held pressurized aerosol-based application of an end-use formulation containing an antimicrobial chemical  Includes spraying a ready-to-use aerosol product until the treated surface is wet  Excludes wiping treated surfaces

31. 31 Objectives To develop more accurate information on worker exposures to antimicrobials to support exposure assessments for aerosol spray applications 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 aerosol products and uses

32. 32 Criteria for a Surrogate Aerosol Product Stable Appropriate vapor pressure Robust and sensitive analytical method Exposure at the high end of the range for different aerosol product types  Hard surface disinfectant spray  Soft surface disinfectant spray  Foaming aerosol spray  Air fresheners/sanitizers

33. 33 Variables Affecting Exposure from Aerosols Amount of material used Release rate Particle size distribution Nozzle technology Pressure in the can Temperature/humidity at time of use Surface on which product is used Orientation of the can during use

34. 34 Surrogate Selection Followed long and complex discussion with regulatory agencies Analysis of the variables affecting exposure showed hard-surface aerosols are likely to provide highest exposures and are appropriate surrogates for other aerosol types and uses Details are reported in Volume 1, Appendix A

35. 35 Selected Surrogate Test Material Commercial Solutions ® Clorox ® Disinfecting Spray EPA Reg. No. 67619-03 Active Ingredients 0.252% ADBAC: n-Alkyl dimethyl benzyl ammonium chloride 0.0945% DDAC: Didecyl dimethyl ammonium chloride 0.189% ODAC: Octyl decyl dimethyl ammonium chloride 0.0945% DODAC: Dioctyl dimethyl ammonium chloride

36. 36 Toxicity of Test Materials: ADBAC ADBAC dermal NOAEL reported in EPA RED is 20 mg/kg/day (333 ug/cm 2 ) for dermal irritation  No dermal toxicity data available for low concentrations  No systemic effects observed, only irritation 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 MOEs will not be of concern

37. 37 Toxicity of Test Materials: DDAC EPA relies on toxicity data on DDAC for all AIs in the DDAC cluster, including ODAC and DODAC 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 (0.38% ai) 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 MOEs will not be of concern.

38. 38 Study Design: Cluster Location Fresno County  Indoor aerosol spraying tasks do not vary geographically  Efficient: analytical lab is in Fresno Hotel/Motel Facilities  Sufficient appropriate surfaces to be sprayed  Readily available with varying configurations Full kitchen Kitchenette No kitchen

39. 39 Method for Site Selection List all hotels/motels in Fresno County yellow pages Screen properties in random sequence against criteria:  20 or more units  Management willing to cooperate with research  Room configuration provides diversity of surfaces  Functioning HVAC and electric systems  Does not require cleaning or maintenance before use Select first qualifying property with each:  Full kitchen  Kitchenette  No kitchen

40. 40 Sample Characteristics Professional janitors—to ensure exposures are long enough to obtain usable data with exposure >LOD 24 subjects will be enrolled; 18 will be monitored  3 clusters/sites  6 subjects plus 2 alternates at each site EPA finds this sample size acceptable  Rationale is consistent with all available aerosol data  Size exceeds requirements of EPA and OECD Guidelines  No existing data can substitute for any proposed new MEs

41. 41 ME Stratification by Amount Handled Constant concentration of test material; exposure varies with amount handled and subject-specific behaviors Minimum amount sprayed is 1 can to ensure detectable residues Maximum amount sprayed is consistent with amount sprayed per room (AEJV, 113 g/room) and upper bound of 20 rooms cleaned/day One ME at each site at each pre-defined range of amount sprayed:

42. 42 Allocation of Subjects to MEs Eight enrolled subjects at each site are ordered randomly; the last two are alternates The first subject in order is assigned to the ME with highest number of cans—i.e., Tier 6 Each subsequent subject is assigned to the available ME with the highest remaining number of cans

43. 43 Spraying Procedure Subjects will follow label directions  Spray 6-10 inches above surface until surface is thoroughly wet (3-4 seconds) Each subject will spray as they normally would on the job Subjects will not wipe surfaces after spraying

44. 44 Field Measurements Air temperature & relative humidity Hotel/motel design and materials Characteristics of HVAC system Amount of material applied Observations/Video/Photographs

45. 45 Measurement of Dermal ADBAC 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 before breaks and at end of task Face/neck wipe at end of task

46. 46 Measurement of Inhalation Exposure Personal Air Samplers include both OVS tubes and RespiCon filters  OVS tube will be run at 2 L/min  RespiCon filter will be run at 3.1 L/min and will size particles: <2.5 microns <10 microns <100 microns

47. 47 Analytical Phase Collected samples—dosimeters, hand/face washes, and air samplers—are shipped on dry ice to the lab and frozen within 4 hours Method validation QA/QC plan  Field recovery analysis  Travel recovery analysis  Storage stability studies  Break-through analysis

48. 48 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 No scientific deficiencies requiring correction have been identified by EPA

49. 49 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  The study design should produce data adequate to achieve the objective

50. 50 EPA Ethics Assessment of AEATF II Aerosol Scenario and Protocol AEA-04 Kelly Sherman Human Research Ethics Reviewer Office of Pesticide Programs

51. 51 Value to Society Reliable exposure data for aerosol antimicrobial products are needed to support EPA exposure assessments Existing data are inadequate Knowledge likely to be gained will be usable in exposure assessments for  Both professional users and consumers  Wide variety of aerosol products and use patterns

52. 52 Recruiting Process Subjects will be recruited from professional janitorial workers of Fresno County  Workplace flyers in English and Spanish  Advertisements in three Fresno newspapers Calls from individuals responding to flyers or ads will be received by a field researcher  One field researcher is identified on the flyers and in ads as bilingual in English and Spanish

53. 53 Recruiting Process 2 Callers are informed about the study using an IRB-approved script Callers are screened for janitorial experience and other eligibility factors, and then scheduled for informed consent meetings “at the caller’s convenience”

54. 54 Consent Process Essentially the same for English and Spanish Investigator meets with interested candidate  Provides information about study design in candidate’s preferred language  Applies eligibility criteria  Reviews Informed Consent Document and “Experimental Subject’s Bill of Rights”  Provides label and MSDS  Answers questions Principal Investigator confirms understanding and solicits consent to participate

55. 55 Change in Consent Process Unlike earlier AEATF II Mop and Wipe studies, the list of candidates responding to flyers or ads will not be randomized before scheduling consent interviews AEATF II has learned from Mop and Wipe studies that delaying informed consent meetings to allow randomization of lists leads to significant attrition EPA has agreed to this change, and considers this proposal still to comply with direction to incorporate random elements whenever feasible

56. 56 Recruiting and Consent  Equitable subject selection  Fully informed choice  Fully voluntary choice

57. 57 Respect for Participants Participant privacy will be maintained Photographs and videos will be altered to protect subjects’ identities Proposed remuneration is reasonable Participants will be free to withdraw at any time, for any reason

58. 58 Risks and Risk Minimization Irritant response to test material or to solvents used to obtain residues from hands and face/neck Discomfort or heat-related illness due to extra layer of clothing and air pump Embarrassment while changing Surprise at results of pregnancy test

59. 59 Benefits No direct benefits to subjects Potential indirect benefit to subjects who learn individual results and how their exposure compares to that of others Sponsors will benefit by maintaining regulatory compliance Likely societal benefit is higher quality exposure and risk assessments for aerosol antimicrobial products

60. 60 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

61. 61 Independent Ethics Review Independent Investigational Review Board, Inc., of Plantation FL (IIRB, Inc.) reviewed and unanimously approved the protocol and supporting documents in English and Spanish IIRB-approved protocol was re-dated prior to submission to EPA  AEATF II has confirmed that the version submitted to EPA is identical to the version approved by IIRB, notwithstanding that it was re-dated after IIRB approval  In future submissions, the AEATF must maintain a version date as a permanent attribute of the file, to maintain the integrity of the record

62. 62 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

63. 63 Corrections Called For by EPA Clarify compensation for research-related injuries:  Change: “We will pay for needed medical treatment that is not paid for by your own insurance or by someone else.”  To: “…by your own insurance or by the insurance of a third party under which you are covered.” Institute version control in all study documents

64. 64 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 requested corrections are made, the AEATF II Aerosol Scenario and Protocol will likely meet the applicable requirements of 40 CFR part 26, subparts K and L

65. 65 Charge Questions If the proposed AEATF II aerosol application scenario and field study protocol AEA04 is revised as suggested in EPA’s review and if the research is performed as described:  Is the research likely to generate scientifically reliable data, useful for assessing the exposure of handlers who apply antimicrobial pesticides formulated as aerosol sprays?  Is the research likely to meet the applicable requirements of 40 CFR part 26, subparts K and L?