tsca workplan chemical risk assessment of nmp

DRAFT DO NOT CITE OR QUOTE

United States Office of Chemical Environmental Protection Safety and Pollution Agency Prevention

TSCA Workplan Chemical Risk Assessment

N-Methylpyrrolidone: Paint Stripping Use

CASRN: 872-50-4

December 2012

NOTICE

This document is an External Review Draft. This information is distributed solely for the purpose of pre-dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by EPA. It does not represent and should not be construed to represent any Agency determination or policy. It is being circulated for review of its technical accuracy and science policy implications.

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Table of Contents

AUTHORS / CONTRIBUTORS / ACKNOWLEDGEMENTS / REVIEWERS ...................................... 8

GLOSSARY OF TERMS AND ABBREVIATIONS ........................................................................... 9

EXECUTIVE SUMMARY ......................................................................................................... 12

CHAPTER 1: BACKGROUND AND SCOPE............................................................................... 14

INTRODUCTION ............................................................................................................................................................. 14 SCOPE OF THE ASSESSMENT ............................................................................................................................................ 15

CHAPTER 2: SOURCES AND ENVIRONMENTAL FATE ............................................................. 17

INTRODUCTION ............................................................................................................................................................. 17 2.1. CHEMICAL AND PHYSICAL PROPERTIES ....................................................................................................................... 17 2.2. PRODUCTION VOLUME AND USES ............................................................................................................................. 18

2.2.1. Consumer Uses .......................................................................................................................................... 19 2.2.2. Paint Stripping Applications ...................................................................................................................... 19

2.3. CONCLUSIONS ON PRODUCTION VOLUME AND USES ..................................................................................................... 20 2.4. ENVIRONMENTAL FATE ........................................................................................................................................... 20

2.4.1. Fate in Air .................................................................................................................................................. 20 2.4.2. Fate in Water ............................................................................................................................................ 20 2.4.3. Fate in Soil and Sediment .......................................................................................................................... 21 2.4.4. Bioconcentration and Persistence ............................................................................................................. 21

2.5. CONCLUSIONS OF ENVIRONMENTAL FATE ................................................................................................................... 22

CHAPTER 3: HUMAN HEALTH RISK ASSESSMENT ................................................................. 23

INTRODUCTION ............................................................................................................................................................. 23 3.1. HUMAN EXPOSURE ASSESSMENT .............................................................................................................................. 23

3.1.1. Occupational Exposures ............................................................................................................................ 23 3.1.2. Background and Context of Paint-Stripping Industry ................................................................................ 24 3.1.3. Occupational Dermal Exposure Assessment ............................................................................................. 26 3.1.4. Occupational Inhalation Exposure Assessment ......................................................................................... 27 3.1.5. Residential Exposure Assessment ............................................................................................................. 28 3.1.6. Residential Dermal Exposure Assessment ................................................................................................. 28 3.1.7. Residential Inhalation Exposure Assessment ............................................................................................ 30

3.2. HUMAN HEALTH ASSESSMENT ................................................................................................................................. 44 3.2.1. TOXICOKINETICS ........................................................................................................................................... 45 3.2.2. Hazard Identification................................................................................................................................. 46 3.2.3. Dose-Response Assessment ...................................................................................................................... 47 3.2.4. Key Studies, PODs, and Levels of Concern for the Dermal Pathway.......................................................... 48 3.2.5. Key Studies, PODs, and Levels of Concern for the Inhalation Pathway ..................................................... 49

3.3. HUMAN HEALTH RISK CHARACTERIZATION ................................................................................................................. 51 3.3.1. Risk Estimation Approach for Acute and Chronic Exposures ..................................................................... 52 3.3.2. Risk Estimates for Non-Cancer Acute Dermal Exposures in a Residential Setting ..................................... 54 3.3.3. Risk Estimates for Non-Cancer Acute Inhalation Exposures in a Residential Setting ................................ 54 3.3.4. Risk Estimates for Non-Cancer Chronic Dermal Exposures to Workers ..................................................... 57 3.3.5. Risk Estimates for Non-Cancer Chronic Inhalation Exposures to Workers ................................................ 57

3.4. DISCUSSION OF KEY SOURCES OF UNCERTAINTY AND DATA LIMITATIONS ......................................................................... 58 3.4.1. Key Uncertainties and Data Limitations for Occupational Exposure Estimates ........................................ 58 3.4.2. Uncertainties in the Residential Exposure Assessment ............................................................................. 59 3.4.3. Uncertainties in the Hazard- and Dose-Response Assessments ................................................................ 61


3.5. RISK ASSESSMENT CONCLUSIONS .............................................................................................................................. 64

REFERENCES ........................................................................................................................ 65

APPENDIX A. ENVIRONMENTAL EFFECTS SUMMARY ........................................................... 78

APPENDIX B. BIOMONITORING DATA ................................................................................. 80

APPENDIX C. OCCUPATIONAL EXPOSURE ASSESSMENT SUPPORT INFORMATION ................ 81

DERIVATION OF NMP CONCENTRATION CONVERSION FACTOR FOR OCCUPATIONAL EXPOSURE CALCULATIONS .............................. 81 DESCRIPTIONS OF OCCUPATIONAL PROCESSES AND ACTIVITIES ............................................................................................... 82 FACILITY AND POPULATION DATA .................................................................................................................................... 86 OCCUPATIONAL INHALATION EXPOSURE LITERATURE DATA ................................................................................................... 90 DERMAL EXPOSURE MODELING ....................................................................................................................................... 93

APPENDIX D. CONSUMER EXPOSURE ASSESSMENT ............................................................. 95

ESTIMATION OF EMISSION PROFILES FOR PAINT REMOVERS/STRIPPERS ................................................................................... 95 SENSITIVITY ANALYSIS FOR INHALATION SCENARIOS ........................................................................................................... 103 INHALATION EXPOSURE SCENARIO INPUTS ....................................................................................................................... 103 INHALATION MODEL OUTPUTS AND EXPOSURE CALCULATIONS ............................................................................................ 111 MCCEM INHALATION MODELING CASE SUMMARIES ........................................................................................................ 118 DERMAL ASSESSMENT INPUTS ....................................................................................................................................... 142

APPENDIX E. TOXICOLOGY STUDIES .................................................................................. 145

INHALATION TOXICITY STUDIES ...................................................................................................................................... 145 DERMAL TOXICITY STUDIES ........................................................................................................................................... 148 IRRITATION, SENSITIZATION, AND CANCER ....................................................................................................................... 149

APPENDIX F. BMD ANALYSIS OF SAILLENFAIT ET AL. (2003) DATA ...................................... 150

APPENDIX G. EPA’S EVALUATION OF THE POET ET AL. (2012) PBPK MODEL FOR NMP ....... 154


List of Tables

Table 2-1. Physical-Chemical Properties of NMP. ........................................................................ 17

Table 2-2. NMP Production Volume Information. ..................................................................... 18

Table 2-3. Consumer Uses of NMP. ............................................................................................. 19

Table 2-4. Environmental Fate Characteristics of NMPa.............................................................. 22

Table 3-1. 2007 NAICS Codes Identified that Include Paint Stripping Activities. ......................... 24

Table 3-2. Summary of Worker Dermal Model Parameters and Resultsa. ................................... 26

Table 3-3. Summary of Ranges of NMP Inhalation Exposures and Calculated ADCs for Workers. ................................................................................................................................... 28

Table 3-4. Estimated Consumer Dermal Exposure Results. ......................................................... 30

Table 3-5. NMP Exposure Scenarios for the Characterizing Consumer Inhalation Exposure. .... 37

Table 3-6. NMP Consumer Paint Stripping Scenario Descriptions and Parameters. .................... 39

Table 3-7. Summary of Modeled NMP Concentrations to Which Consumer Users and Non-Users are Exposed, by Scenario. .......................................................................................... 42

Table 3-8. Summary of Exposure Pathways, Toxic Endpoints and Risk Approach. ...................... 44

Table 3-9. Time Scaling of Chronic POD Values. ........................................................................... 51

Table 3-10. Dose-Response Values and Risk Approaches for NMP’s Human Health Risk Assessment. ............................................................................................................... 53

Table 3-11. Acute MOEs for Residential Users and Non-Users of NMP-Based Paint Strippers Dermal Exposures. ..................................................................................................... 54

Table 3-12. Acute MOEs for Residential Users and Non-Users of NMP-Based Paint Strippers Inhalation Exposures. ................................................................................................ 56

Table 3-13. Chronic MOEs for Worker Dermal Exposures. ........................................................... 57

Table 3-14. Chronic MOEs for Worker Inhalation Exposures. ...................................................... 58

Table A-1. Summary Table for Aquatic Toxicity Data of NMP ...................................................... 78

Table C-1. 2007 US Economic Census Data for Painting and Wall Covering and Flooring Contractors. ............................................................................................................... 86


Table C-2. 2007 US Economic Census Data for Automotive Body, Paint, and Interior Repair and Maintenance. ............................................................................................................. 87

Table C-3. 2007 US Economic Census Data for Reupholstery and Furniture Repair. ................... 87

Table C-4. 2007 US Economic Census Data for Industry Sectors that May Engage in Art Restoration and Conservation Activities. .................................................................. 88

Table C-5. 2007 US Economic Census Data for Aircraft Manufacturing. ..................................... 88

Table C-6. 2007 US Economic Census Data for Ship Building and Repairing. ............................... 89

Table D-1. MRI Studies: Products Emissions Fit to Exponential Profile. ...................................... 95

Table D-2. Fitted Parameters to the US EPA (1994b) Study Results for the Two DCM-Containing Paint Strippers. .......................................................................................................... 98

Table D-3. Fitted Parameters to the US EPA (1994b) Study Results for Wood Finisher’s Pride. ................................................................................................................................. 101

Table D-4. Time Schedule for Paint Stripping with Repeat Application. ................................... 105

Table D-5. NMP Mass Released, by Application Target and Method. ....................................... 106

Table D-6. Literature-Reported Vapor Pressure Values for NMP. ............................................. 109

Table D-7. Dermal Modeling Scenarios. ..................................................................................... 142

Table D-8. Summary of Dermal Input Parameters. ................................................................... 142

Table F-1. Fetal body weight data from pregnant Sprague-Dawley rats exposed to NMP from GD 6-20.a ................................................................................................................. 150

Table F-2. Summary of dose-response analysis and point of departure estimation for fetal body weight from pregnant Sprague-Dawley rats exposed to NMP from GD 6-20. ....... 150

Table G-1. Comparison of average daily plasma NMP AUCs from Poet et al. 2012 (Tables 3 and 4) and present (10/16/12) simulations of rat inhalation repro/developmental bioassays, using study-specific body weights. ......................................................... 158

Table G-2. Comparison of rat internal dose BMC values and HECs from Poet et al. (2012) and present simulations ................................................................................................. 164


List of Figures

Figure 2-1. Chemical Structure of NMP. ....................................................................................... 17

Figure 3-1. Time-varying Consumer User Personal Concentration and Maximum TWA Values for Selected Averaging Times. ......................................................................................... 34

Figure 3-2. Time-varying Consumer Non-user Personal Concentration and Maximum TWA Values for Selected Averaging Times......................................................................... 34

Figure 3-3. Model Sensitivity Results (Percent Change from Base-case Response) for Peak One-hr TWA for Consumer User and Non-user................................................................. 36

Figure 3-4. Model Sensitivity Results (Percent Change from Base-case Response) for 24-hr TWA for Consumer User and Non-user. ............................................................................. 36

Figure C-1. Typical Flow Tray for Applying Stripper to Furniture (IRTA, 2006). ........................... 84

Figure C-2. Typical Water Wash Booth Used to Wash Stripper and Coating Residue from Furniture (IRTA, 2006). .............................................................................................. 84

Figure C-3. Example Diagram of a Dipping Tank for Furniture Stripping (HSE, 2001). ................. 85

Figure D-1. Model Fit to MRI (US EPA, 1994b) Data for BIX Spray-On (Spray Application). ....... 97

Figure D-2. Model Fit to MRI (US EPA, 1994b) Data for Strypeeze (Brush Application). ............ 98

Figure D-3. Theoretical Cumulative Mass of DCM Released for BIX Spray-On Stripper.............. 99

Figure D-4. Theoretical Cumulative Mass of DCM Released for Strypeeze Stripper. .................. 99

Figure D-5. Model Fit to MRI (US EPA, 1994b) Data for Wood Finisher’s Pride (Brush Application). ............................................................................................................. 101

Figure D-6. Theoretical Cumulative Mass of NMP Released from Wood Finisher’s Pride. ....... 102

Figure D-7. Zone Volumes and Airflow Rates for Workshop Scenarios. .................................... 108

Figure D-8. Zone Volumes and Airflow Rates for Bathroom Scenario. ...................................... 108

Figure D-9. Example of the Personal Concentration Calculation as Defined in Equation C-13. 112

Figure D-10. Modeled NMP Concentrations for Scenarios 1 and 4, Stripper Application in Workshop using Parameter Values selected for Central Tendency Exposure. ....... 114

Figure D-11. Modeled NMP Concentrations for Scenarios 2 and 5, Stripper Application in Workshop using Parameter Values selected for Upper-end User Exposure. ......... 115


Figure D-12. Modeled NMP Concentrations for Scenarios 3 and 6 Stripper Application in Workshop using Parameter Values selected for Upper-end Non-User Exposure. . 116

Figure D-13. Modeled NMP Concentrations for Scenarios 7 and 8, Brush Application in Bathroom using Parameter Values selected for Upper-end to Bounding User and Non-User Exposures. ............................................................................................... 117

Figure F-1. Plot of mean response by dose (mg/m3) for fetal body weight with fitted curve for Exponential model 2. ............................................................................................... 152

Figure F-2. Plot of mean response by dose (mg/m3) for fetal body weight with fitted curve for Exponential model 3. ............................................................................................... 153


Authors / Contributors / Acknowledgements / Reviewers

This report was developed by the Office of Pollution Prevention and Toxics (OPPT), Office of Chemical Safety and Pollution Prevention (OCSPP). The 2012 workplan risk assessments were prepared based on existing data and any additional information received up to June 15, 2012. EPA Assessment Team Lead: Scott Prothero, OPPT/EETD Team: Kent Anapolle, OPPT/EETD Judith Brown, OPPT/EETD

Iris Camacho, OPPT/RAD Mary Dominiak, OPPT/CCD Ernest Falke, OPPT/RAD Conrad Flessner, OPPT/EETD

Amuel Kennedy, OPPT/RAD Andy Mamantov, OPPT/EETD Justin Roberts, OPPT/EETD Contributors Chester E. Rodriguez, OPP/HED Paul Schlosser, ORD/NCEA Kan Shao, ORD/NCEA Acknowledgements Portions of this document were developed with support from:

Contractor name (contract number): Abt Associates (EP-W-08-010) Production and Uses Eastern Research Group (EP-W-10-014) Releases Versar (EP-W-10-005) Fate, Modeling, Monitoring SRC, Inc. (EP-W-09-027) Technical Editing

Internal Peer Reviewers

H. Kay Austin, OPPT/EETD Stan Barone Jr, OPPT/RAD Todd Stedeford, OPPT/RAD

External Peer Review - A peer review panel is being arranged for this influential workplan assessment product based upon need and following Agency peer review guidance. The format will be a teleconference of an ad hoc panel meeting consisting of independent experts.


Glossary of Terms and Abbreviations °C Degrees Celsius 2HMSI 2-Hydroxy-N-methylsuccinimide 5HNMP 5-Hydroxy-N-methyl-2-pyrrolidone ACH Air changes per hour ADC Average daily concentration ADR Acute dose rate AIC Akaike’s Information Criterion AIHA American Industrial Hygiene Association AUC Area under the curve BAF Bioaccumulation factor BCF Bioconcentration factor BMC Benchmark concentration BMCL 95 Percent lower confidence limit of the benchmark concentration BMCL1SD 95 Percent lower confidence limit of one standard deviation of the benchmark

concentration BMD Benchmark dose BMDS Benchmark Dose Software BMR Benchmark response BOD Biochemical oxygen demand BW Body weight CASRN Chemical Abstracts Service Registry Number CDC Center for Disease Control and Prevention cm Centimeter(s) cm2 Square centimeter(s) CO2 Carbon dioxide DAF Dosimetry adjustment factor DCM Dichloromethane (or methylene chloride) DIY Do-it-yourself DOC Dissolved organic carbon dw dry weight EC European Commission EFH Exposures Factors Handbook EPA Environmental Protection Agency EU European Union ft Foot/feet ft2 or sq ft Square foot/feet FTIR Fourier transform infrared g Gram(s) g/cm2 Gram(s) per square meter g/cm3 Gram(s) per cubic centimeter


g/ft2 Gram(s) per square feet g/L Gram(s) per liter g/cm2-hour Gram(s) per square meter per hour g/minute Gram(s) per minute GD Gestation day H2S Hydrogen sulfide HEC Human equivalent concentration HED Human equivalent dose HHE Health hazard evaluation HPV High production volume hr Hour(s) IRIS Integrated Risk Information System IURR Inventory Update Reporting Rule kg kilogram(s) L Liter(s) Lb(s) Pound(s) LC50 Lethal concentration 50 percent LD50 Lethal dose 50 percent LOAEL Lowest-observed-adverse-effect level m2 Square meter(s) m3 Cubic meter(s) m/hour Meter(s) per hour m3/hr Cubic meter(s) per hour MCCEM Multi-Chamber Concentration and Exposure Model mg Milligram(s) mg/cm2 Milligram(s) per square centimeter mg/cm2-hour Milligram(s) per square centimeter per hour mg/cm3 Milligram(s) per cubic centimeter mg/g Milligram(s) per gram mg/kg Milligram(s) per kilogram mg/L Milligram(s) per liter mg/m3 Milligram(s) per cubic meter min Minute(s) MITI Ministry of International Trade and Industry MMAD Mass median aerodynamic diameter mmHg millimeter of mercury mmol Millimole(s) mmol/mol Millimole(s) per mole MOE Margin of exposure mol Mole(s) MRI Midwest Research Institute MSDS Material Safety Data Sheet MSI N-Methylsuccinimide NAICS North American Industry Classification System


NHANES National Health and Nutrition Examination Survey NIH National Institutes of Health NIOSH National Institute for Occupational Safety and Health NMP N-Methylpyrrolidone NOAEC No-observed-adverse-effect concentration NOAEL No-observed-adverse-effect level NOES National Occupational Exposure Survey OCSPP Office of Chemical Safety and Pollution Prevention OECD Organisation for Economic Cooperation and Development OPPT Office of Pollution Prevention and Toxics OSHA Occupational Safety and Health Administration PBPK Physiologically based pharmacokinetic PMN Premanufacture Notification POD Point of departure PPE Personal protection equipment ppm Parts per million PVC Polyvinyl chloride ROH Rest of the house SCBA Self-contained breathing apparatus SIC Standard Industry Classification SIDS Screening Information Data Set STEL Short-term exposure limit TRI Toxic Release Inventory TSCA Toxic Substances Control Act TWA Time-weighted average UF Uncertainty factor UFA Interspecies uncertainty factor UFH Intraspecies uncertainty factor US United States VOC Volatile organic compound WEEL Workplace Environmental Exposure Level WHO World Health Organization


Executive Summary N-Methylpyrrolidone (NMP) was assessed as part of the United States (US) Environmental Protection Agency (EPA) Existing Chemicals Management Program. EPA reviewed readily available information on NMP including uses, physical and chemistry properties, fate, exposure potential, and associated hazards to humans and the environment. NMP was identified for assessment based on high concern for hazard due to its reproductive toxicity, although the inclusion of more recent studies in this assessment indicates that NMP is of low concern for this endpoint. This substance also ranked high for potential exposure because it is widely used in consumer products, is present in drinking water and indoor environments, and has high reported releases to the environment (US EPA, 2012c). NMP is expected to have low persistence and low bioaccumulation potential in the environment. NMP is produced or imported to the US in large quantities (i.e., over a range of 100 to 500 million pounds)/per year). It has a variety of uses including, petrochemical processing, engineering plastics, coatings (i.e., resins, paints, finishes, inks, and enamels), paint stripping, agricultural chemicals, electronic cleaning, and industrial/domestic cleaning. Though NMP is reportedly used in a variety of consumer products, EPA found only a limited number of personal care products (i.e., mascaras and nail polish) that were reported to contain NMP. NMP is a colorless liquid that is a mildly volatile organic compound; therefore, inhalation exposures may occur during its use. The Organization for Economic Cooperation and Development (OECD) Screening Information Data Set (SIDS) program recently reviewed the human health hazard profile for NMP. The OECD determined that dermal penetration through human skin is very rapid and that prolonged exposures to neat (i.e., pure) NMP increased the permeability of skin. For these reasons, both inhalation and dermal exposures to residential and occupational use of NMP-containing paint stripping products were assessed by the Agency. Paint stripping accounts for about nine percent of the total use of NMP. EPA assumed that direct contact or close proximity to the use (i.e., for a consumer or commercial application with substantial frequency or duration of exposure) would likely provide the highest exposures to NMP paint strippers. Many of the other identified uses of NMP involve closed processes that generally limit exposures and are of low concern. EPA reviewed and summarized available published studies on aquatic toxicity to better understand the potential ecological effects of NMP releases to the environment on aquatic organisms including acute and chronic toxicity to invertebrates, fish, and plants, and toxicity to birds. The ecological hazard of NMP is considered low, based on aquatic and terrestrial studies; thus potential risks to ecological organisms based on releases of NMP from paint stripping activities were not evaluated further in this assessment. Occupational exposures were focused on workers employed by “small commercial shops” or those that employ less than 10 workers. The remaining facilities (with >10 workers) were


viewed by EPA as large-scale or unassigned operations and were not included in this assessment. Large-scale manufacturing exposures are not addressed in this assessment because EPA understands that such industrial operations are generally better controlled and monitored than those exposures that may occur in the consumer/small-shop commercial settings. Occupational exposures by the dermal and inhalation routes of exposure were evaluated. Chronic dermal exposure concentrations were estimated, whereas chronic inhalation exposure concentrations were derived from published studies. Inhalation exposure data were only found for paint stripping applications in the professional contracting and graffiti removal workplace settings. As a result of limited data on consumer exposures, EPA used modeling approaches to estimate acute dermal and inhalation exposures to residential users of NMP-based paint stripping products. Dermal exposures were estimated with the thin film modeling approach, and variations in dermal dose were calculated for NMP paint strippers for brush- and spray-applied formulations. Inhalation exposures to users and non-users (i.e., bystanders) were estimated with the EPA’s Multi-Chamber Concentration and Exposure Model (MCCEM). EPA evaluated the sensitivity (i.e., by a sensitivity analysis) of the MCCEM input parameters (e.g., amount of chemical applied, room air volume, rate of exchange between rooms, etc.). Margins of exposure were calculated for occupational and consumer uses. Significant uncertainties exist in EPA’s dermal and chronic inhalation exposure estimates. For dermal exposures, NMP is corrosive and the exposure scenarios assumed prolonged direct contact with skin representing a “worst case” assumption, which may not represent real world conditions. The available inhalation exposure data for workers and consumers are limited. This was reflected in the wide range of MOEs, which spanned nearly four orders of magnitude. Thus, the findings below should be viewed as uncertain. The following findings are limited to women of child-bearing age, because the only observed toxicological endpoint is developmental toxicity.

• Workers may have potential risks of concern from dermal exposure when no gloves are worn.

• Consumers may have potential risks of concern from dermal exposure assuming

appropriate gloves are not worn. • Consumers may have potential risks of concern from inhalation exposure (although of

lower concern than from dermal exposure) if exposed for more than 4 hours at lower ventilation rates.


Chapter 1: Background and Scope INTRODUCTION The chemical, N-methylpyrrolidone or 1-methyl-2-pyrrolidinone (NMP; Chemical Abstracts Service Registry Number [CASRN] 872-50-4), was identified for assessment as part of the United States (US) Environmental Protection Agency’s (EPA)’s Existing Chemicals Management Program (http://www.epa.gov/oppt/existingchemicals/pubs/workplans.html). NMP is a mildly volatile organic compound with moderate atmospheric photooxidation. It was identified for further assessment by EPA initially based on concerns for reproductive toxicity; however, more recent studies reviewed during EPA’s initial scoping and evaluation indicate that NMP is of low concern for this endpoint. This substance has high potential exposures because it is widely used in consumer products, is present in drinking water and indoor environments, and has high reported releases to the environment. NMP is expected to have low persistence and low bioaccumulation potential in the environment. NMP is currently on the candidate list of substances of very high concern for authorization in the European Union (ECHA, 2011) and has been the subject of regulation by the EPA, including listing on the Toxics Release Inventory (US EPA, 1994c). According to the 2010 TRI dataset, 370 facilities reported a total of 5.99 million pounds (lbs) of on- and off-site disposal and other releases of NMP (US EPA, 2011b). The substance is not listed for an Occupational Safety and Health Administration permissible exposure limit (PEL). NMP is currently approved for use by EPA as a solvent and co-solvent pesticide inert in both food and non-food uses, and is exempt from the requirement of a tolerance (40 CFR 180.920).

The human health hazard profile for the toxicity of NMP has been reviewed recently as part of the Organization for Economic Cooperation and Development (OECD) Screening Information Data Set (SIDS) program. The OECD showed that dermal penetration through human skin is very rapid and that prolonged exposures to neat (i.e., pure) NMP increased the permeability of the skin. NMP may cause skin swelling, blistering, and burns after prolonged direct contact with skin (CPSC, 1995). The ecological hazard of NMP is considered low, based on aquatic and terrestrial studies. This substance has a low estimated bioaccumulation and bioconcentration such that the potential bioconcentration in aquatic organisms has been determined to be low (OECD, 2007; US EPA, 2012a, 1999). Thus, the potential risks to ecological organisms based on releases of NMP from paint stripping activities were not evaluated further in this assessment. NMP is produced or imported into the US in large quantities (i.e., over a range of 100 to 500 million pounds (lbs)/yr). It has a variety of uses including petrochemical processing, engineering plastics, coatings (resins, paints, finishes, inks, and enamels), paint stripping, agricultural chemicals, electronic cleaning, and industrial/ domestic cleaning. EPA determined

http://www.epa.gov/oppt/existingchemicals/pubs/workplans.html


that NMP has a variety of household consumer uses, but is used in only a very few consumer personal products (not regulated by TSCA) including mascaras and a nail polish remover (EWG, 2012). Though paint stripping accounts for only about nine percent of the total use of NMP, EPA had specific concerns about this end-use, because paint stripping offers the greatest potential for exposure. Many of the other identified uses of NMP involve closed processes that generally limit exposures and are of low concern. In the following section, the focus and scope of EPA’s risk assessment of NMP is described.

SCOPE OF THE ASSESSMENT This assessment focused on the use of NMP in paint strippers. EPA assumed that direct contact or close proximity to the use (i.e., for a consumer or commercial application with substantial frequency or duration of exposure) would likely provide the highest exposures to NMP-based paint strippers. In either consumer or occupational settings, there may be dermal and/or inhalation exposures during the use of these products. There also may be oral ingestion of these products, but EPA determined this exposure route was less likely and of less concern, thus it was not evaluated further. In addition to product users, there also may be non-users or bystanders who may not come in direct contact with the product, but may be exposed indirectly via inhalation while in a nearby area during product application. NMP is a colorless liquid that is a mildly volatile organic compound; therefore, inhalation exposures may occur during its use. The Organization for Economic Cooperation and Development (OECD) Screening Information Data Set (SIDS) program recently reviewed the human health hazard profile for NMP. The OECD determined that dermal penetration through human skin is very rapid and that prolonged exposures to neat (i.e., pure) NMP increased the permeability of skin. For these reasons, both dermal and inhalation exposures to residential and occupational use of NMP-containing paint stripping products were assessed by the Agency. While paint stripping accounts for only about nine percent of the total use of NMP, EPA assumed that direct contact or close proximity to the use (i.e., for a consumer or commercial application with substantial frequency or duration of exposure) would likely provide the highest exposures to NMP paint strippers. Many of the other identified uses of NMP involve closed processes that generally limit exposures and are of low concern. EPA understands that exposures that result from large-scale industrial operations are generally monitored and well controlled. Exposures in small commercial or consumer settings may not adhere to the same types of controls. Thus, large-scale manufacturing occupational exposure scenarios were not addressed in this assessment. Rather, EPA focused this assessment on exposures to workers employed by “small commercial shops.” For the purpose of this assessment, EPA considered a small shop as one that employs less than 10 workers (i.e., the remaining facilities were considered large facilities and were not considered in this assessment). Other uses beyond paint stripping were not evaluated in this assessment.


EPA reviewed and summarized available published studies on aquatic toxicity to better understand the potential ecological effects of NMP releases to the environment on aquatic organisms including acute and chronic toxicity to invertebrates, fish, and plants, and toxicity to birds (Appendix A). The ecological hazard of NMP is considered low, based on aquatic and terrestrial studies (OECD, 2007; US EPA, 2012a, 1999); thus, potential risks to ecological organisms based on releases of NMP from paint stripping activities were not evaluated further n this assessment.


Chapter 2: Sources and Environmental Fate

INTRODUCTION To assess the human health risk concerns of N-methylpyrrolidone or 1-methyl-2-pyrrolidinone (NMP), a firm understanding of the physical and chemical properties, sources related to production and uses, and fate in the environment is important. These topics are introduced in Chapter 2 and discussed in relation to the risk characterization in Chapter 3. 2.1. CHEMICAL AND PHYSICAL PROPERTIES The chemical structure for NMP is shown in Figure 2-1.

Figure 2-1. Chemical Structure of NMP. NMP is a colorless to slightly yellow liquid with a slight amine odor that is typically used as a solvent. A summary of the most relevant physical and chemical properties of NMP are provided in Table 2-1. NMP is in a class of dipolar aprotic solvents that are miscible in water (water solubility = 1,000 g/L at 25 °C; log Kow = -0.727 at 25 °C); aprotic solvents do not contain acidic hydrogen. NMP exhibits mild volatility (i.e., vapor pressure = 0.190 Torr at 25 °C), high boiling point (202 °C), low flammability, no explosivity, and relatively low toxicity. However, variations in humidity can cause a range of saturation concentrations. Also, NMP is not readily oxidizable (Lide, 2001; EC, 2000; O'Neil et al., 2001). Table 2-1. Physical-Chemical Properties of NMP.

Molecular formula C5H9ON

Molecular weight 99.13

Physical form Colorless to slightly yellow liquid; slight amine odor

Melting point -24.4 °C

Boiling point 202 °C

Vapor pressure 0.190 mmHg at 25 °C

Log Kow -0.727 at 25 °C

Water solubility 1,000 g/L at 25 °C

Flash point 95 °C (open cup); 91 °C (closed cup) Source: EC (2000).

N O


2.2. PRODUCTION VOLUME AND USES

NMP’s chemical name, CASRN, and 2006 TSCA Inventory Update Reporting Rule (IURR) production volume are provided in Table 2-2. The 2006 public IURR indicates that 100 million to 500 million lbs of NMP were produced or imported into the US that year, making NMP a high production volume (HPV) chemical (US EPA, 2010a). BASF Corporation, International Specialty Products, Inc., and Lyondell Chemical Company currently manufacture NMP in the US. Table 2-2. NMP Production Volume Information.

CASRN CA Index Name Acronym IURR Production Volume

872-50-4 1-Methyl-2-pyrrolidinone NMP 100-500 million lbs Source: US EPA (2010a).

NMP is an effective solvent used in a variety of industrial, commercial, and consumer use applications, including: as listed below (Harreus et al., 2011):

• Petrochemical processing, acetylene recovery from cracked gas, extraction of aromatics and butadiene, gas purification (removal of carbon dioxide [CO2] and hydrogen sulfide [H2S]), lube oil extraction

• Engineering plastics: reaction medium for the production of high-temperature polymers such as polyethersulfones, polyamideimides, and polyaramids

• Coatings: solvent for acrylic and epoxy resins, polyurethane paints, waterborne paints or finishes, printing inks, synthesis/diluent of wire enamels, coalescing agent

• Agricultural chemicals: solvent and/or cosolvent for liquid formulations • Electronics: cleaning agent for silicon wafers, photoresist stripper, auxiliary in

printed circuit board technology • Industrial and domestic cleaning: component in paint strippers and degreasers (e.g.,

removal of oil, fat, and soot from metal surfaces, and carbon deposits and other tarry polymeric residues in combustion engines)

Other use applications also have been reported inducting: microelectronics industry plastic solvent; extraction of acetylene and butadiene; metal finishing; printed circuit board manufacturing; dehydration of natural gas; spinning agent for polyvinyl chloride (PVC); lube oil processing; petrochemical processing; pigment dispersant; and adjuvant for slimicides in food-contact paper (Ash and Ash, 2009). Though paint stripping accounts for only about nine percent of the total use of NMP, EPA is specifically concerned about this use, because the potential for exposure is high; many of the other uses of NMP involve closed processes (TURI, 1996). While the cited paint stripping use percentage is from reports dated in the 1980s and 1990s, proprietary information (i.e., known but not cited here) as recent as 2011 confirmed that paint stripping is still a low percentage use for NMP in terms of market consumption.


2.2.1. Consumer Uses

The 2006 IURR data indicate that NMP is used in the following commercial and consumer use categories: “electrical and electronic products” and “paints and coatings” (US EPA, 2010a). The National Institutes of Health (NIH) Household Products Database currently lists 47 products containing NMP, in concentrations ranging from one to 100 percent. The product forms include liquid, aerosol, kit, paste, and pump spray (NIH, 2012). Furthermore, according to the Environmental Working Group’s Skin Deep Cosmetics Database, six cosmetic products contain NMP: five mascara products and one nail polish remover (EWG, 2012). Table 2-3 presents the major consumer uses of NMP, which represent <30 percent of the total domestic NMP market. Table 2-3. Consumer Uses of NMP.

Consumer Uses

Auto products Leather cleaner/conditionera Rubbing compounda Paint protectanta Cleaner for fuel injection/carburetora

Arts and crafts products Stripper/paint removera

Home maintenance products Adhesive removera Paint, varnish, wood stain, etc.a Wood sealanta Paint strippera Graffiti removera Brush cleanera Floor finisha Floor cleanera

Pesticides Fungicidea Herbicidea Insecticidea

Cosmetics Polish removerb Mascarab

aNIH (2012). bEWG (2012).

2.2.2. Paint Stripping Applications

Some states have done extensive research about the paint stripping market which is of interest to the EPA’s assessment of NMP. In the State of California, there are approximately 80 facilities that have stripping equipment and use relatively large quantities of stripper that they typically purchase in quantities ranging in size from five- to 55-gallon drums. Other companies provide on-site services to consumers for stripping kitchen or office cabinets for which they purchase product from paint supply or hardware stores. There are approximately 500 additional facilities


in the state that do some stripping as part of their business, which would include small shop facilities like antique shops; these facilities purchase small quantities of stripper from hardware or paint supply stores. Residential/consumers also purchase stripper from paint supply and hardware stores (Cal EPA, 2006).

2.3. CONCLUSIONS ON PRODUCTION VOLUME AND USES NMP is a high production volume chemical (US EPA, 2010a). Though paint stripping accounts for only about nine percent of the total use of NMP, EPA is specifically concerned about this use, because the potential for exposure is high; many of the other uses of NMP involve closed processes which typically have little exposure and are of less concern. NMP is used as an alternative for DCM in paint stripping applications and both paint strippers were identified for assessment as part of the EPA’s Existing Chemicals Management Program (http://www.epa.gov/oppt/existingchemicals/pubs/workplans.html).

2.4. ENVIRONMENTAL FATE The environmental fate of a compound is important to understanding its potential impact on specific environmental media (e.g., water, sediment, soil, and plants) and exposures to target organisms of concern. Due to its mild volatility, it is possible for NMP to enter the atmosphere where moderate photooxidation may occur by reaction with photochemically produced hydroxyl radicals. Releases of NMP to soil may volatilize from soil surfaces or migrate through soil and contaminate groundwater. NMP has been shown to biodegrade readily. This section summarizes current knowledge of the transport, persistence, bioaccumulation, and bioconcentration of NMP in the environment including biological and abiotic reactions and environmental distribution. 2.4.1. Fate in Air

If released to the atmosphere, NMP is expected to exist solely in the vapor-phase based on its vapor pressure. Vapor-phase NMP is degraded in air by reaction with photochemically produced hydroxyl radicals. The half-life of this reaction is approximately 5.8 hours, assuming a hydroxyl radical concentration of 1.5 × 106 hydroxyl radicals/cm3 air over a 12-hour day. 2.4.2. Fate in Water

When released to water, NMP is not expected to adsorb to suspended solids or sediment in the water column based upon its Koc value. The rate of volatilization from water is expected to be low based on a Henry’s Law constant of 3.2 × 10-9 atm-m3/mole. Biodegradation is expected to occur rapidly in aerobic waters. NMP, present at 100 mg/L, achieved 73 percent of its theoretical biochemical oxygen demand (BOD) in four weeks using an activated sludge inoculum and the Japanese Ministry of International Trade and Industry (MITI) test (OECD 301C). It was not readily biodegradable in a standard closed bottle (OECD 301C) test; however,

http://www.epa.gov/oppt/existingchemicals/pubs/workplans.html


it achieved 88 percent of its theoretical BOD using a modified procedure in which the mineral nutrient solution was fortified with the essential vitamin and trace metal solutions and a pre-acclimation procedure was applied to the inoculum. NMP was degraded 91 percent as measured by CO2 evolution and 91 percent as measured by dissolved organic carbon (DOC) removal using the AFNOR (OECD 301A) test. NMP passed an inherent biodegradation test, degrading 98 percent after four days using the Zahn-Wellens (OECD 302B) method. These data suggest that NMP will not be persistent in aerobic surface waters. NMP is not expected to hydrolyze in water since it does not contain functional groups that are typically susceptible to hydrolysis under environmental conditions. 2.4.3. Fate in Soil and Sediment

Based on its low soil organic carbon partitioning coefficient (log Koc = 0.9), NMP is likely to possess high mobility in soils and may leach from soils into groundwater. Volatilization is expected to be low given the Henry’s Law constant of this compound. It is not expected to be persistent in the environment. It was shown to be both readily biodegradable and inherently biodegradable in several OECD screening tests. NMP was incubated for up to three months in soils at an initial concentration of 1.7 mg/kg dw. The half-lives were 4, 8.7, and 11.5 days in clay, loam, and sandy soil, respectively. After 21 days, the extractable level of NMP had dropped below 0.1 mg/kg dw for all soils tested. 2.4.4. Bioconcentration and Persistence

Bioconcentration and persistence are qualitatively characterized according to the criteria set forth in the Premanufacture Notification (PMN) program (US EPA, 1999). Measured bioconcentration studies for NMP were not located; however, the estimated bioaccumulation factor (BAF) and bioconcentration factor (BCF) of 0.9 and 3.16, respectively, suggest that bioaccumulation and bioconcentration in aquatic organisms is low. Biodegradation studies have consistently shown this substance to be readily biodegradable. Based upon the experimental evidence and environmental fate data available, NMP is expected to have low bioaccumulation potential and low persistence. Table 2-4 provides a summary of the environmental fate information for NMP1.


Table 2-4. Environmental Fate Characteristics of NMPa.

Property Value

CASRN 872-50-4

Photodegradation half-life 5.8 hours (estimated)

Hydrolysis half-life Stable

Biodegradation Half-life of 4 days in a clay soil Half-life of 8.7 days in a loam soil Half-life of 11.5 days in a sandy soil 73% after 28 days (readily biodegradable, OECD 301C) 91-97% after 28 days (readily biodegradable, OECD 301A) 88% after 30 days (readily biodegradable, OECD 301D) 98% after 4 days (inherently, biodegradable, OECD 302B) 99% after 8 days (inherently biodegradable, OECD 303A)

Bioconcentration BAF = 0.9 (estimated)b BCF = 3.16

Log Koc 0.9 (estimated)b

Fugacity (Level III Model)b

Air (%) Water (%)

Soil (%) Sediment (%)

0.1 32.5 67.3

0.1

Persistencec low

Bioaccumulationc low aOECD (2008). bUS EPA (2012a). cUS EPA (1999).

2.5. CONCLUSIONS OF ENVIRONMENTAL FATE

NMP is expected to possess high mobility in soil. Numerous studies indicate that NMP is both readily and inherently biodegradable, and is not expected to be persistent in the environment. The rate of hydrolysis is negligible. Volatilization is considered low given its Henry’s Law constant of 3.2 × 10-9 atm-m3/mole. The rate of atmospheric photooxidation is moderate. No measured bioconcentration data were located; however, the low estimated bioaccumulation and bioconcentration factors, 0.9 and 3.16, respectively, suggest that bioconcentration in aquatic organisms is low (OECD, 2007; US EPA, 2012a, 1999).


Chapter 3: Human Health Risk Assessment INTRODUCTION EPA reviewed readily available information on the chemistry, uses, sources, fate, exposure, and hazard of NMP to humans and the environment. The review of this information helped focus the scope of this risk assessment. Biomonitoring data were reviewed, but were not used for the risk analyses. A summary of these data is provided in Appendix E. This chapter has five major sections: (1) Exposure Assessment; (2) Hazard Summary and Dose Response Information; (3) Risk Characterization; (4) Discussion of Uncertainties and Data Gaps; and (5) Conclusions.

3.1. HUMAN EXPOSURE ASSESSMENT This assessment focused on the use of NMP in paint strippers. EPA assumed that direct contact or close proximity to the use (i.e., for a consumer or commercial application with substantial frequency or duration of exposure) would likely provide the highest exposures to NMP-based paint strippers. In either consumer or occupational settings, there may be dermal and/or inhalation exposures during the use of these products. There may also be oral ingestion of these products, but EPA determined this exposure route was less likely and of less concern, thus it was not assessed. In addition to product users, there also may be non-users or bystanders who may not come in direct contact with the product, but may be exposed indirectly while in a nearby area during product application. EPA focused the exposure assessment on the dermal route. NMP has a low vapor pressure (i.e., 0.190 mmHg at 25 °C) and mild volatility, so that inhalation exposures are of less concern. Taking this approach is consistent with the recent OECD determination that dermal penetration through human skin is very rapid and prolonged exposures to neat (i.e., pure) NMP increases the permeability of the skin. To quantify potential risks of concern, EPA focused on assessing acute dermal exposures to residential users and acute inhalation exposures to residential users/non-users. Dermal exposures likely would be negligible for residential non-users located at a distance from the product use area; therefore, this route of exposure was not assessed for residential non-users. For workers, chronic dermal and inhalation exposures were assessed. The exposure assessment has two main sections covering non-occupational/residential and occupational exposures. 3.1.1. Occupational Exposures

This section addresses dermal and inhalation exposures in workplace settings. According to the 1983 National Occupational Exposure Survey (NOES), over 25,000 US employees were exposed to NMP at 2,450 facilities. Thirteen percent of these exposures occurred during manufacture,


whereas 87 percent of the exposures occurred from NMP-based product use (US EPA, 1990). To estimate occupational dermal and inhalation exposures to NMP during paint stripping activities in workplace settings, EPA conducted a literature search to identify published exposure studies and existing data on exposure concentrations and activity patterns (i.e., duration of exposure, etc.). No studies for dermal occupational exposures were found, and only a limited number of inhalation exposure studies were identified. Chronic occupational dermal exposures were estimated by modeling dermal exposures to NMP in liquid products. To estimate chronic inhalation exposures to workers using NMP paint stripping products, EPA used existing exposure data from a limited number of observational studies. Appendix C contains a summary of relevant data and a description of the modeling information and approach. 3.1.2. Background and Context of Paint-Stripping Industry

Background. To better understand the potential extent and impact of occupational exposures to NMP, this section presents information on industry sectors that employ potentially exposed worker populations and exposure levels to workers using NMP-based paint stripping products. Also included is a summary of non-regulatory exposure limits that can affect exposures. Occupational Exposure Limits. The Occupational Safety and Health Administration (OSHA) has not established regulatory exposure limits for NMP. The only recommended exposure limit identified for NMP is a non-regulatory limit established by the American Industrial Hygiene Association (AIHA) workplace environmental exposure level (WEEL) of 10 ppm for an eight-hr Time Weighted Average (TWA), with the addition of a cautionary note addressing concerns for skin contact (AIHA, 2011). EPA believes that some workplaces may consider this WEEL when instituting respiratory protections. Industries that Employ Paint Stripping Activities. A number of industries include paint stripping among their business activities. EPA used the 2007 North American Industry Classification System (NAICS) codes to identify industries likely to include paint stripping activities. Table 3-1 provides the NAICS codes for industries with paint stripping activities. Appendix C provides additional information on: the approach for identifying industries likely to use NMP-based paint strippers, paint stripping processes and associated worker activities, facility and worker population data, and respiratory and dermal protection.

Table 3-1. 2007 NAICS Codes Identified that Include Paint Stripping Activities.

2007 NAICS 2007 NAICS Title Rationale for Inclusion of NAICS with Paint Stripping Activities

238320 Painting and wall covering contractors

US Census reports an index entry of “Paint and wallpaper stripping” (US Census, 2007b).

238330 Flooring contractors US Census reports index entries of “Floor laying, scraping, finishing, and refinishing” and “Resurfacing hardwood flooring”(US Census, 2007b). The National Institute for


Occupational Safety and Health (NIOSH) cites the paint stripping of flooring by a wood flooring and restoration company (NIOSH, 1993).

811121 Automotive body, paint, and interior repair and maintenance

NAICS code 811121 is identified for automobile refinishing per the OECD Coating Application via Spray-Painting in the Automotive Refinishing Industry ESD (OECD, 2010).

811420 Reupholstery and furniture repair US Census reports index entries of “Furniture refinishing shops” and “Restoration and repair of antique furniture” (US Census, 2007b).

711510 Independent artists, writers, and performers

US Census reports index entries of “Painting restorers, independent” and “Conservators (i.e., art, artifact restorers), independent” (US Census, 2007b). Research has shown art conservation to use paint strippers based on DCM or, preferably, NMP (Wollbrinck, 1993).

712110 Museums Research has shown art conservation to use paint strippers based on DCM or, preferably, NMP (Wollbrinck, 1993).

336411 Aircraft manufacturing US Census reports an index entry of “Aircraft rebuilding (i.e., restoration to original design specifications)” (US Census, 2007b). Paint removal during the restoration process may use DCM- or NMP-based paint strippers.

336611 Ship building and repairing US Census 2007 NAICS definition includes shipyards involved in the construction of ships as well as “their repair and conversion and alteration” (US Census, 2007b). Any paint removal activities during repair, conversion, and alteration may use DCM- or NMP-based paint strippers.

Size of Paint Stripping Facilities. Because EPA expects that small commercial shops may not strictly adhere to monitoring and control measures to limit worker exposures to NMP in paint stripping applications, EPA focused this assessment on exposures to workers employed by “small commercial shops” (i.e., less than 10 workers). EPA identified published information to characterize these industries for potential occupational exposures; however, the data and background information were not sufficient to estimate the total number of employees per facility in each of the potentially exposed populations. The Agency made some generalizations about the relative sizes of small commercial facilities or shops that employ paint-stripping workers. Using the facility and population data from Appendix D, the industries included in this assessment were categorized using an average number of employees per facility into the size classifications as follows:

• Small shops could generally be expected to include facilities with <10 workers (e.g., professional contractors, automotive refinishers, furniture refinishers, and independent art restorers, etc.):


• Larger facilities could generally be expected to include facilities with >10 workers (e.g., aircraft and ship paint stripping, etc.);

• The exposures labeled Graffiti Removers or Unspecified Workplace Setting cannot be classified into either small shop or larger facilities.

These simple size distinctions may not be entirely applicable to the exposure data in the industry categories identified. 3.1.3. Occupational Dermal Exposure Assessment

Background. Because EPA found no published data to assess dermal exposures to small commercial shop workers, dermal exposures were estimated using a standard generic thin film modeling approach (i.e., the EPA’s 2-Hand Dermal Contact with Liquid Model). EPA assumed that small commercial shop workers did not wear protective gloves while working with NMP-based paint stripping products. This approach uses a more conservative or “worst case” assumption that confers a more protective approach to assessing the potential risks of concern. EPA did not assess exposures to workers wearing gloves. Model Assumptions. EPA utilizes a series of standard models to quantitatively estimate dermal exposures to liquid and solid chemicals in workplace settings. To estimate occupational dermal exposure, all of the models assume the following default values: a specific skin surface area contacted by a material containing the chemical of interest; a specific surface density of the material on the skin (i.e., quantity of the liquid or solid material containing the chemical that remains on the skin after contact); and no use of personal protective equipment (e.g., gloves) to reduce the exposure. These assumptions and default parameters were defined based on the nature of the exposure (e.g., one hand or two hand, immersion in material, and contact with surfaces, etc.). Details on EPA’s dermal exposure model are outlined in Appendix D. Table 3-2 shows EPA’s assumptions for the modeling parameters (e.g., number events per day, skin area exposed, and body weight, etc.) used to estimate dermal exposures to workers using NMP paint strippers. In addition to these assumptions, EPA also assumed 100 weight percent NMP and maximal absorption through the skin (i.e., 100 percent; (SCCS, 2011)).

Table 3-2. Summary of Worker Dermal Model Parameters and Resultsa.

Result Description

Weight Fraction

Surface Density of

Film

Skin Surface

Area

Frequency of Events

Body Weight

Normalized Dermal

Exposure

Fchem Qremain_skin AREAsurface Nevent BWworker EXPdermal_bw

(Unitless) (mg/cm2) (cm2) (Events/day) (kg) (mg/kg-day)

Low end of range 100 0.7 840 1 80 7.4

High end of range 100 2.1 840 1 80 22 a Appendix C contains the model equations and explanation.


Model Results for Occupational Dermal Exposures. The following results were estimated using the model equations:

• Dermal exposure to liquid (EXPdermal) of 590 to 1,800 mg NMP/day; and, • Dermal exposure normalized by body weight (EXPdermal_bw) of 7.4 to 22 mg NMP/kg-

day as potential dose rates. • Absorbed dose rates may be assumed to be equal to potential dose rates.

Limitations of the Occupational Dermal Exposure Analysis. There were no published data available to develop statistical distributions of exposure for worker populations, so a modeling approach was used to estimate occupational dermal exposures. There are limitations to the analysis that include: 1) the resulting dermal potential dose rates show a wide range of variability; 2) most of the model input parameters were default values which may not reflect the conditions in workplace settings; and, 3) the representativeness of the model results to the broader worker populations that are exposed to NMP during its use in various paint stripping products and applications cannot be determined. 3.1.4. Occupational Inhalation Exposure Assessment

This section provides estimates of inhalation exposure for occupational use of paint-stripper products containing NMP for users and non-user/bystanders. To estimate inhalation exposures, EPA conducted a literature search for industries using NMP products. EPA used existing exposure data from a limited number of observational studies to establish a reasonable range of exposure concentrations. Occupational Inhalation Exposure. Table 3-3 summarizes the available published data that EPA located for ranges of NMP inhalation exposures for two exposed populations (i.e., “Professional Contractors” and “Graffiti Removal”). However, information for other industries utilizing NMP paint stripping applications was identified, but there was insufficient data to include them in the assessment (i.e., see Appendix C for more information on these industries). EPA used available data on ranges of inhalation exposures to workers and Average Daily Concentration (ADC) values were calculated from available eight-hr TWA exposures (i.e., using Equation 3-1). ADC Calculations. ADCs is calculated from Equation 3-1 (US EPA, 2009). It is equivalent to EC in the equation below, with the substitution of the appropriate averaging time (AT) value.

(Eq. 3-1) where: EC = exposure concentration (mg/m3); C = contaminant concentration in air (mg/m3); ED = exposure duration (hours/day; default: 8); EF = exposure frequency (days/yr; default: 250); WY = working years per lifetime (yrs; ADC : 40 yrs); and AT = averaging time (lifetime in yrs × 365 days/yr × 24 hours/day; ADC: 40 yrs).


Table 3-3. Summary of Ranges of NMP Inhalation Exposures and Calculated ADCs for Workers.

Industry Number of Studies

Time Range of Studies

Range of Task-Based, Short-Term, or Peak Exposures

(mg/m3)a

Range of 8-hr TWA Exposures (mg/m3)b

ADC (mg/m3)c

Professional contractors

2 1993–1994 13-39 (3.3-10 ppm)

– –

Graffiti removal 3 1993-2004 0.01-30 (0.002-7.4 ppm)

– –

1 2000 – 0.03-4.5 (0.007-1.1 ppm)

0.007-1.0

aThese exposures include task-based exposures averaged over a time period of <8 hrs, short-term (i.e., short-term exposure limit [STEL]) exposures, and peak exposures. Exposures are provided in units of mg/m3, except values in parentheses are in units of ppm (by volume). bThese exposures include 8-hr TWA exposures that were either directly measured or calculated from shorter time frame exposures by the study authors. cADCs are only calculated from 8-hr TWA exposures. Note: Airborne concentration conversion factor for NMP is 4.06 mg/m3 per ppm (see Appendix C).

Limitations of the Occupational Inhalation Exposure Analysis. Limitations were identified with the observational studies that EPA used to estimate worker exposures to NMP paint strippers. These limitations included the following: 1) there were few studies available that provided enough useful data or background information to develop statistical distributions of exposure for the populations; 2) the available exposure concentration data were extremely variable; and 3) the representativeness of the available data to the broader worker populations exposed to NMP during its use in various paint stripping applications cannot be determined. The variability in the derived exposure concentrations (Table 3-3) was significant and precluded EPA from deriving relevant margins of exposure (MOEs) for occupational inhalation exposures. 3.1.5. Residential Exposure Assessment

This section provides estimates of dermal and inhalation exposures for residential/consumer use of paint-stripper products containing NMP. These exposures were assessed using a modeling-based approach; acute dermal exposures were calculated for product users only, while acute inhalation exposures were calculated for both users and non-users. A thin-film modeling approach, similar to that used for the occupational dermal exposure assessment, was used to predict consumer dermal exposures. EPA’s Multi-Chamber Concentration and Exposure Model (MCCEM) was utilized to predict concentrations in air to estimate consumer inhalation exposures to an NMP- based paint stripper in various hypothetical consumer-use scenarios. 3.1.6. Residential Dermal Exposure Assessment

To better understand potential risks of concern to consumers from the use of NMP-containing paint stripping products, EPA conducted a dermal exposure assessment. Estimates were made


of central-tendency (i.e., near average or median) exposures and upper-end (i.e., plausible exposures from the upper half of expected exposure amounts); these exposure estimates are generally required for risk assessments. Dermal Exposure Assessment Methodology. Dermal exposures for consumer use of NMP paint strippers were calculated using a similar approach to that for occupational dermal exposures, the thin-film modeling approach described in US EPA (1996) and US EPA (2007). However, unlike with the occupational assessment, default values were not used for all of the input parameters. The following values were derived : 1) the weight fraction values for consumer products are well enough understood to derive central tendency (median) and high end (90th percentile) values for both the brush-on and spray-on products (Cf. the occupational model assumed a value of 1, i.e., 100 percent NMP); 2) the film thickness value in the consumer modeling was based on a professional judgment estimate based on information from a chemist employed by a paint stripper manufacturer (Cf. the occupational model used surrogate values based on measured film thickness from several non-paint-stripper surrogate liquids); 3) the surface area for the exposed skin in the consumer modeling assumed that half of each average adult hand would be exposed (Cf. the occupational model assumed a 70 percent greater surface area); and, 4) because there were limited data available for the dermal model input parameters, central and high-end scenarios for each application type (i.e., brush or spray) were constructed by varying the weight fraction of the applied product. More discussion of these values can be found in the Discussion of Key Sources of Uncertainty and Data Limitations of this chapter, and the dermal exposure modeling sections for occupational exposures in Appendix C. The model equation, expressed in the form of the acute dose rate (ADR), is provided below in Equation 3-2.

ADRdermal = (Eq. 3-2)

Where: ADRdermal (mg/kg-day) = acute dose rate WF (unitless) = weight fraction (used in place of concentration) PD (mg/cm3) = product density FT (cm) = film thickness SA (cm2) = surface area ED (days) = exposure duration FQ (events/day) = frequency of use BW (kg) = body weight AT (days) = averaging time Dermal Exposure Scenarios. Four different dermal exposure scenarios were evaluated as shown in Table 3-4 (i.e., see Dermal Assessment Inputs in Appendix D for more detail). Dermal exposures were calculated for the adult user not wearing protective gloves. EPA assumed that dermal exposure to other residential occupants, i.e., non-users, was unlikely and therefore was


not assessed. Dermal exposure scenarios were completed for both brush-on and spray-on paint stripping applications. Table 3-4. Estimated Consumer Dermal Exposure Results.

Case ID

Scenario Description

Weight Fraction

Product Density

Film Thickness

Surface Area

Exposure Duration

Frequency of Use

Body Weight

Averaging Time

Acute Dermal

Exposure

WF PD FT SA ED FQ BW AT ADRdermal

(Unitless) (mg/cm3) (cm) (cm2) (Days) (Events/

day) (kg) (Days)

(mg/kg-day)

1 Brush-on, central

0.25 1,100 0.03 490 1 1 80 1 50

2 Brush-on, high-end

0.50 1,100 0.03 490 1 1 80 1 100

3 Spray-on, central

0.44 1,100 0.03 490 1 1 80 1 89

4 Spray-on, high-end

0.53 1,100 0.03 490 1 1 80 1 110

Dermal Exposure Modeling Results. Results from the dermal exposure calculations are described in Table 3-4. Estimates of acute dermal exposures for consumer users of NMP paint stripping products ranged from 50 to 100 mg/kg-day for the brush-on scenarios and from 89 to 110 mg/kg-day for the spray-on scenarios. Limitations of Dermal Assessment. The exposure estimates for consumer NMP paint stripping product users are considered hypothetical as a result of uncertainties with the model input parameters, especially with the assumptions for film thickness and surface area of skin that would be exposed to the paint stripping product. One important uncertainty in the dermal model is with the assumption that with each exposure event, only one thin film contacts the skin. This uncertainty was addressed in US EPA (1996) which stated that the number of times that a person contacts the paint remover product per exposure event is unknown. In the consumer dermal exposure scenarios, all parameters have equal sensitivity; thus, a change in a parameter value will provide direct proportional changes in the acute dermal exposures. 3.1.7. Residential Inhalation Exposure Assessment

Background. In the absence of representative air monitoring data, MCCEM was used to estimate consumer inhalation exposure concentrations. The parameters needed to support the modeling effort, i.e., model input values and the rationale for their use in different exposure scenarios, are described in this section.


Model Input Parameters and Rationale. MCCEM requires inputs of several chemical-specific parameters including values for: current product characteristics, use patterns, exposure factors, and air concentrations to develop appropriate exposure scenarios. The majority of the source documents EPA used for these input values were over a decade old. All sources were compared to EPA quality criteria (i.e., currency, scope, accuracy/reliability, transparency, clarity, and completeness of the information provided). EPA used published values for NMP-containing products currently available for consumer purchase to determine reasonable percentages of NMP in products and product densities (Brown, 2012). Other resources that provided information on product characteristics included: (1) the NIH’s Household Products Database; (2) Material Safety Data Sheets; and (3) Product Labels and Technical Data Sheets (i.e., TDS). The information collected from available product labels or TDSs included approximately half of the products listed in Brown (2012). In the absence of actual air monitoring data for consumer use of an NMP paint stripper, EPA reviewed several air monitoring studies for consumer paint strippers that used DCM-containing products, including US EPA (1994b), EC (2004), a Consumer Product Safety Commission study (as cited in US EPA, 1996; and Riley et al., 2000), and a study conducted in the Netherlands by van Veen et al. (2002). EPA determined, however, that data from these studies could not be used for this assessment because of differences in the chemical properties between NMP and DCM. Most importantly, NMP has a much lower volatility and emission rate than DCM. Additionally, these studies generally did not reflect current use patterns in the US, did not provide sufficient raw data to support necessary calculations, and/or were conducted using test chambers that did not provide air concentrations for areas other than the application room. To estimate air concentrations for consumer inhalation exposures, EPA identified published air monitoring data from one occupational study. This experimental study was conducted for EPA (US EPA, 1994b). Despite its age, the study and the data were considered accurate, transparent, and complete. In that study, chamber experiments were conducted for five paint stripping products including one product containing 65 to 70 percent NMP (i.e., fairly high concentration). However, the experimental data could not be used directly to model residential inhalation exposures because the values for the required exposure factors (e.g., room/house volume, airflow rates, and surface area of object) were not entirely representative of the range of residential values. Additionally, the experiments (US EPA, 1994b) were conducted in a one-room chamber which did not provide concentrations for areas of the house other than the treatment room. An advantage of this study was that it used a US product and provided sufficient descriptions of the study design and results. The study was useful in determining product application rates (i.e., in g/ft2 and g/minute) and in estimating the fraction of applied chemical mass released to indoor air (i.e., details described in Appendix D). Information on exposure-factors was identified from a variety of sources, including the EPA’s Exposure Factors Handbook (EFH) (US EPA, 2011c). The EFH provides information on generic exposure factors such as body weights, body part surface areas, house volumes, and house


ventilation rates. Information on specific uses of paint strippers (i.e., use amounts, frequencies, and durations) was obtained from WESTAT (1987) and Abt (1992). EPA utilized some additional information on use patterns of paint strippers as reported by Riley et al. (2001). This study had some limitations, including: a single-site survey was used in the study; it was not specific to NMP paint strippers; it was based on a small sample size (n = 20); and it was based on respondent recall of product-use behavior. Other information, not specific to paint strippers but used to identify input parameters for the inhalation modeling, such as interzonal air flows and air exchange rates, was obtained from peer-reviewed publications, including US EPA (1995) and Matthews et al. (1989). Finally, in the case where no data were available for fitting model-specific parameters, professional judgment was used and confirmed with other sources of information where possible. This information has been identified in the report along with the rationale for the chosen values. Methodology. EPA estimated consumer inhalation exposures for both users and non-users to NMP emitted during paint stripper application and associated scraping using MCCEM (US EPA, 2010b). MCCEM is ideally suited to this application, as it provides for modeling of “incremental source” emissions, whereby a product is applied at a constant rate and the emission rate of the chemical in each instantaneously applied segment is assumed to decline exponentially over time. Depending on the type of applied product, either one or two exponential expressions may be needed to characterize the declining emission rate. In this case, it was determined that a double-exponential expression was appropriate (for more details, see Estimation of Emission Profiles for Paint Removers/Strippers in Appendix D). To select exposure scenarios for characterizing the consumer inhalation exposures, EPA conducted a sensitivity analysis for optimizing the parameters used in the model for those that had the most influence over the results of the assessment. Changing those values (i.e., by varying combinations of parameters) enabled the generation of a wide range of plausible exposure scenarios and increased the level of confidence in the model results. The methods for, and results of, this sensitivity analysis are described immediately below. Sensitivity Analysis Background. The types of factors that can be varied in the MCCEM model include the following:

• The configuration of the structure (residence in this case) being modeled, including the number of zones, volume of each zone, airflow rates between each zone and outdoors, and airflow rates between zones (i.e., interzonal airflow rates).

• The quantity of NMP emitted from the applied product and the time-varying emission rate, which are related to: (1) the type and area of surface being stripped; (2) the type of application (e.g., brush-on vs. spray-on); and (3) the rate at which the product is applied to the surface.

• Locations during and after stripping of: (1) the user(s)—the individual(s) applying the product and (2) the non-user(s)—other individual(s) present in the house who are not involved in the paint-stripping activity and, by assumption, are located in a house zone other than the one in which the paint-stripping activity is taking place.


The sensitivity analysis was conducted using an approach that has been termed “nominal range sensitivity analysis” (Frey and Patil, 2002). With this approach, an initial “base case” set of model parameters is first defined, typically consisting of central tendency values (i.e., approximating average or median values) for each model parameter (input). Next, the inputs are varied—one at a time—and the model result (estimated average or peak concentrations to which individuals are exposed) is noted. The index of sensitivity is the magnitude of change in the model results, typically expressed as a percent change from that for the base case. Details on this approach are in the Sensitivity Analysis for Inhalation Scenarios in Appendix D. The time required to apply and scrape the paint stripper, including the wait time between applying and scraping, is typically on the order of an hour, as determined by Abt (1992). The model was run for a 24-hr period for the sensitivity analysis and the formal model runs to capture all or most of the declining indoor-air concentrations following the product use event. For this assessment, the relevant exposure measures include the maximum or peak TWA concentrations for certain averaging periods (i.e., one minute, 10 minutes, 30 minutes, one hour, four hours, and eight hours) in addition to the 24-hr TWA value. Illustrative time-varying concentrations, to which the user and non-user could be exposed, based on a preliminary model run, are shown in Figure 3-1 and Figure 3-2 ,along with the maximum TWA values and the corresponding time periods for selected averaging times. For the sensitivity analysis, only the maximum one-hr TWA along with the 24-hr TWA were used.


Figure 3-1. Time-varying Consumer User Personal Concentration and Maximum TWA Values for Selected Averaging Times.

Figure 3-2. Time-varying Consumer Non-user Personal Concentration and Maximum TWA Values for Selected Averaging Times.


The base case for the sensitivity analysis was formed using central (i.e., roughly equivalent to “average” or mean) values for the various inputs, as follows:

• House volume of 492 m3 (corresponds to 36 × 30 ft2, two-story house with an eight-foot ceiling)Workshop (area of product use) volume of 54 m3 (corresponds to 20 × 12 ft2 with an eight-foot ceiling) and an indoor-outdoor airflow rate of 68 m3/hr (expected value for a room with multiple open windows)

• Airflow rate of 197 m3/hr for the rest of the house (ROH), assuming windows closed, corresponding to an air exchange rate of 0.45 air changes per hr (ACH)

• Brush-on application with a target surface area of 10 ft2Applied product mass of 1,080 g (108 g/ft2) and emitted (released to indoor air)

• NMP mass of 70.2 g, assuming an NMP weight fraction of 0.25 in the product and a release fraction of 0.26

• User located in workshop during application and scraping periods, but in ROH during wait periods between applying/scraping and after completion of all applying/scraping.

Sensitivity Analyses Results. The results of the sensitivity analyses for two exposure measures, peak one- and 24-hr TWAs, are displayed in Figure 3-3 and Figure 3-4, respectively. For both measures, and for both the user and the non-user, the change in model output for changing chemical mass was 75 percent. This outcome is indicative of a linear and proportional response. For the user, the model response was highly sensitive to location during the wait period between applying and scraping (i.e., consumer stays in workshop versus moving to the ROH), so that if the consumer stayed in the workshop during the wait period, inhalation exposures likely would be higher. The model response was somewhat less sensitive to the ROH air exchange rate with outdoor air (ROH ACH) for the non-user, but not for the user. This outcome could be explained for the non-user as the rate of air exchange in the ROH is less of a factor in inhalation exposure because initial exposures to the non-user were likely low. For the user, initial exposures were higher and if the user moves to the ROH, the rate of air flow in the ROH could reduce inhalation exposures under some conditions (i.e., high exchange rates).


Figure 3-3. Model Sensitivity Results (Percent Change from Base-case Response) for Peak One-hr TWA for Consumer User and Non-user.

Figure 3-4. Model Sensitivity Results (Percent Change from Base-case Response) for 24-hr TWA for Consumer User and Non-user. Results and Implications of Model Sensitivity Analyses. As a result of the model sensitivity analyses, EPA concluded that the chosen modeling scenarios should include some variations in each of the three factors (i.e., chemical mass, location, and ROH ACH); with greater model sensitivity, it is more likely a wide range of plausible exposures can be estimated. The more plausible the exposure scenarios, the more representative they are to “real world” conditions, which aids with reducing the degree of uncertainty. Description of Exposure Scenarios. Inhalation exposures to residential users and non-users were determined. EPA developed eight exposure scenarios for the assessment, as summarized in Table 3-5. The following factors were considered in developing the exposure scenarios:

• The type of application (i.e., brush-on or spray-on), weight fraction of applied product, application rate, surface area of object to be stripped, and emission rate of


the chemical concern, which can affect the amount of NMP that ultimately is released to the indoor environment;

• The location where the product is applied, which relates to exposure factors such as the room volume and its air exchange rate with outdoors;

• The house volume and air exchange rate, for reasons similar to those for the product use location; and

• Precautionary behaviors such as opening windows in the application room and the user leaving the application room during the use period, and related changes to the air exchange rates and the proximity of the user to the source of NMP emissions.

Table 3-5. NMP Exposure Scenarios for the Characterizing Consumer Inhalation Exposure.

Case ID Case Description

Type of Application

Location of Product Use

Concentration Characterizationa

1 Brush-on Workshop Central tendency

2 Brush-on Workshop User upper-end

3 Brush-on Workshop Non-user upper-end

4 Spray-on Workshop Central tendency

5 Spray-on Workshop User upper-end

6 Spray-on Workshop Non-user upper-end

7 Brush-on Bathroom Upper-end to bounding for user and non-user, constrained by Csat = 1,300 mg/m3

8 Brush-on Bathroom Upper-end to bounding for user and non-user, constrained by Csat = 640 mg/m3

aConditions obtained by varying the most sensitive parameters: NMP mass emitted; user location during the effect or wait period; and the ROH air exchange rate with outdoors.

The primary distinctions among the eight cases, are in terms of type of application (i.e., brush versus spray), location of product application (i.e., workshop versus bathroom), and values used for other inputs including the NMP mass emitted, the user’s location during the use or wait period, and the ROH air exchange rate with outdoors (i.e., central tendency1 versus upper-end2). Of the eight scenarios listed in Table 3-5, two were considered central tendency for both

1 As noted in Section 2.3.1 (Individual Risk) of the US EPA (1992a) exposure assessment guidelines, “Individual risk descriptors will generally require the assessor to make estimates of high-end exposure, and sometimes additional estimates (e.g., estimates of central tendency such as average or median exposure).” For this assessment, scenarios with central parameter values refer to a set of inputs that are expected to result in a central (i.e., near the median) estimate of individual exposure. 2 As noted in US EPA (1992a), “a high end exposure estimate is a plausible estimate of the individual exposure for those persons at the upper end of an exposure distribution. The intent of this designation is to convey an estimate of exposures in the upper range of the distribution, but to avoid estimates that are beyond the true distribution. Conceptually, the high end of the distribution means above the 90th percentile of the population distribution, but


the user and the non-user; two were developed to estimate upper-end concentrations for the user; and two were developed to estimate upper-end concentrations primarily for the non-user. Central-tendency values are exposure values expected to be near the average or median for the range of exposure values; upper-end values are plausible exposure values from the upper half of the range of expected exposure amounts. These descriptive exposure estimates are generally required for risk assessments. The final two Scenarios, 7 and 8, were developed to estimate NMP concentrations for the user and non-user from use conditions similar to those reported by the Centers for Disease Control and Prevention (CDC)/National Institute of Occupational Safety and Health (NIOSH) occupational exposure case to a DCM paint stripper used on a bathtub (CDC, 2012). The bathtub scenarios represent high product use in a confined (i.e., closed, poorly ventilated) space. Selected parameter values for these scenarios (e.g., large surface area, small room size, minimal ventilation, upper-end weight fraction, and low ROH ventilation) would increase concentrations and exposures so that the combinations of parameter values would be expected to result in upper-end to bounding3 concentrations for the user and non-user and, as a result, the concentrations could approach or exceed the vapor saturation concentration for NMP. The only difference between Scenarios 7 and 8 is the assumed saturation concentration. Further details of the exposure scenario inputs, including the parameter values for the NMP saturation concentration and the procedures for representing the NMP emission behavior at the saturation concentration, are discussed in the Inhalation Exposure Scenario Inputs section in Appendix D. Summary of Exposure Scenarios and Model Inputs. The exposure scenario inputs are as follows: the amount of NMP released, stripping method, room of use volume and ventilation characteristics, house volume and ventilation characteristics, the user location during the wait period, and the non-user location. The inputs for all eight scenarios are summarized in Table 3-6, from which the major and subtle differences among the eight scenarios are shown. For example, Scenarios 2 and 3, and their spray-application counterparts, Scenarios 5 and 6, are targeted toward estimation of upper-end exposures for the user and non-user, respectively, by changing the application amount, location of the user, and airflows.

not higher than the individual in the population who has the highest exposure.” For this assessment, scenarios labeled “upper-end” were modeled by selecting low- and high-end values for sensitive parameters. An “upper-end” exposure estimate is above central tendency and may include the high end of the exposure distribution. 3 As noted in US EPA (1992a), an exposure above the distribution of actual exposures is termed 'bounding.'


Table 3-6. NMP Consumer Paint Stripping Scenario Descriptions and Parameters.

Case ID

Scenario

NMP Released

Stripping Method

Room of Use House User Location During Wait

Periodb

Non-User Location Weight

Fraction Surface Area Treateda ft2

Application Rate, g/ft2

Release Fraction

Volume, m3

Ventilation/ ACH, 1/hr

Volume, m3

ROH ACH, hr-1

Brush-on Exposure Scenarios in Workshop

1 Central 0.25 (central)

10 Coffee table (central)

108 0.26 1. Coffee table: 5-minute application, 30-minute wait, and 10-minute scrape per application; process repeated after completion of first scraping 2. Scrapings removed from house after last scraping

54 (central)

Open windows / 1.26 (Professional judgment, 90th

percentile)

492 (central)

0.45 (central)

ROH ROH (entire time) 2 Upper-end

for user 0.5 (upper-end)

Workshop

3 Upper-end for non-user

25 Chest of drawers (upper-end)

3. Chest: 12.5/ 30/25 minutes per application; process repeated after completion of first scraping 4. Scrapings removed after last scraping

0.18 (low-end)

ROH

Spray-on Exposure Scenarios in Workshop

4 Central 0.44 (central)

10 Coffee table (central)

81 0.52 5. Coffee table: 2.5-minute application, 30-minute wait, and 10-minute scrape per application; process repeated after completion of first scraping 6. Scrapings removed from house after last scraping

54 (central)

Open windows / 1.26 (Professional judgment, 90th

percentile)

492 (central)

0.45 (central)

ROH ROH (entire time) 5 Upper-end

for user 0.53 (upper-end)

Workshop

6 Upper-end for non-user

25 Chest of drawers (upper-end)

7. Chest: 6.25/ 30/25 minutes per application; process repeated after completion of first scraping 8. Scrapings removed after last scraping

0.18 (low-end)

ROH


Table 3-6. NMP Consumer Paint Stripping Scenario Descriptions and Parameters.

Case ID

Scenario

NMP Released

Stripping Method

Room of Use House User Location During Wait

Periodb

Non-User Location Weight

Fraction Surface Area Treateda ft2

Application Rate, g/ft2

Release Fraction

Volume, m3

Ventilation/ ACH, 1/hr

Volume, m3

ROH ACH, hr-1

Brush-on Exposure Scenario in Bathroom

7 and 8

Upper-end to bounding for user and non-user

0.5 (upper-end)

36 Bathtub (maximum)

108 0.26 9. Bathtub: 18-minute application, 30-minute wait, and 36-minute scrape per application; process repeated after completion of first scraping 10. Scrapings removed from house after last scraping

9c (low-end)

Window closed, no exhaust fan/ 0.18d (low-end)

492 (central)

0.18 (low-end)

ROH ROH (entire time)

aThe surface area values were selected so that the calculated amount of product applied (g) corresponds approximately to the Abt (1992) survey results for amount of paint stripper used (50th percentile value of 32 ounces or 1,000 g for the central surface area of 10 ft2 and ~80th percentile value of 80 ounces or 2,500 g for the upper-end surface area of 25 ft2). bFor all scenarios, the user is in the treatment room during the application and scraping times and in the ROH after the last scraping.

c1 m3 for the vicinity of the tub (source cloud) and 8 m3 for the rest of the bathroom. dBecause the user is working in close proximity to the target (bathtub) for an extended period, a third zone (“source cloud”) was created within the bathroom to represent the NMP concentrations in the vicinity of the tub; this is a virtual zone, with no physical boundaries. The airflow rate between the cloud and the rest of the bathroom was based on work by Matthews et al. (1989). (For more information, see discussion in Appendix C under Inhalation Exposure Scenario Inputs (Airflow Rates and Volumes.)


Model Outputs and Exposure Calculations. To account for an individual’s location at specific times, MCCEM provides a detailed time series of zone-specific (i.e., house, workshop, and bathroom) and personal concentrations. This model output is in the form of instantaneous values at the end of consecutive one-minute time intervals for the entire duration of the model run (i.e., 24 hrs). The model is responsive to changes in location of the user during the 24-hr model run, Consequently, average concentrations to which the user and non-user were exposed were calculated for successive one-minute time intervals by taking the average of the instantaneous values at the beginning and end of each interval. A more detailed, mathematical description of the calculations is provided in Appendix D in the Inhalation Model Outputs and Exposure Calculations section). Appendix D provides a summary of NMP exposure concentrations for the consumer user and non-user of NMP-containing paint strippers. These concentrations were calculated by first computing running averages and then taking the maximum of these averages. For example, for the one-hour averaging period, the one-hour average concentration was calculated for each one-minute start time during the 24-hr period (e.g., 0-60 minutes, 1-61 minutes, etc.), for which the maximum of these averages is reported in Table 3-7. As the exposure averaging time increases, the user to non-user exposure ratio decreases. For the one-minute averaging time, the ratios of user to non-user highest concentrations are fairly consistent for central parameter values and upper-end parameter values, ranging from 4:1 to 6:1 and approximately 16:1 for the bathroom case. For longer averaging times, the maximum concentrations were quite similar for the user and the non-user, with the single exception of the bathroom scenario. The MCCEM Inhalation Modeling Case Summaries can be found in Appendix D summarizing each of the eight scenarios modeled with MCCEM, including both model inputs and results.


Table 3-7. Summary of Modeled NMP Concentrations to Which Consumer Users and Non-Users are Exposed, by Scenario.

Scenario Individual Maximum Values for Averaging Period, mg/m3 (ppm)

1 Minute 10 Minutes 30 Minutes 1 Hr 4 Hrs 8 Hrs 24 Hrs

1. Brush application in workshop, central tendency scenario

User 33 (8.1) 30 (7.5) 15 (3.7) 13 (3.3) 6.6 (1.6) 3.8 (0.9) 1.3 (0.3)

Non-user 7.3 (1.8) 7.3 (1.8) 7.2 (1.8) 6.9 (1.7) 4.6 (1.1) 2.7 (0.7) 0.9 (0.2)

2. Brush application in workshop, upper-end scenario for user

User 94 (23) 92 (23) 82 (20) 65 (16) 29 (7.1) 15 (3.8) 5.2 (1.3)

Non-user 15 (3.6) 14 (3.6) 14 (3.5) 14 (3.4) 9.1 (2.3) 5.5 (1.4) 1.9 (0.5)

3. Brush application in workshop, upper-end scenario for non-user

User 200 (50) 180 (45) 150 (36) 98 (24) 59 (15) 38 (9.5) 15 (3.6)

Non-user 39 (9.7) 39 (9.7) 39 (9.6) 38 (9.4) 31 (7.7) 23 (5.7) 9.4 (2.3)

4. Spray application in workshop, central tendency scenario

User 89 (22) 83 (20) 40 (9.9) 34 (8.3) 17 (4.2) 9.6 (2.4) 3.3 (0.8)

Non-user 19 (4.7) 19 (4.7) 19 (4.6) 18 (4.4) 12 (2.9) 7.1 (1.8) 2.4 (0.6)

5. Spray application in workshop, upper-end scenario for user

User 150 (37) 148 (36) 130 (32) 100 (26) 45 (11) 24 (5.9) 8.1 (2.0)

Non-user 23 (5.7) 23 (5.7) 23 (5.6) 22 (5.3) 14 (3.5) 8.6 (2.1) 2.9 (0.7)

6. Spray application in workshop, upper-end scenario for non-user

User 320 (78) 300 (74) 240 (60) 150 (38) 90 (22) 57 (14) 22 (5.4)

Non-user 62 (15) 61 (15) 61 (15) 60 (15) 49 (12) 36 (8.8) 14 (3.6)

7. Brush application in bathroom, upper-end to bounding for user and non-user; Csat = 1,300 mg/m3

User 1,300 (320) 1,300 (320) 1,300 (320) 830 (200) 520 (130) 290 (72) 110 (27)

Non-user 110 (27) 110 (27) 110 (27) 110 (26) 91 (22) 72 (18) 33 (8.2)

8. Brush application in bathroom, upper-end to bounding for user and non-user; Csat = 640 mg/m3

User 640 (160) 640 (160) 640 (160) 580 (140) 310 (76) 170 (43) 64 (16)

Non-user 65 (16) 65 (16) 64 (16) 63 (16) 54 (13) 43 (11) 20 (4.9)


Limitations of the Consumer Inhalation Exposure Analysis. EPA conducted a literature search to identify published studies and data to assess consumer inhalation exposures to NMP paint stripping products. There was no relevant air monitoring data from consumer settings for evaluating inhalation exposures from the use of NMP-containing paint strippers; to estimate air concentrations for consumers, EPA identified published air monitoring data from one occupational study conducted for EPA (US EPA, 1994b). Given the lack of measured data to calculate inhalation exposures, consumer inhalation exposures were determined using a modeling-based approach. EPA’s MCCEM was used to predict concentrations in air to estimate consumer inhalation exposures in various hypothetical consumer-use scenarios. MCCEM requires input parameters including values for: product characteristics, use patterns, exposure factors, and air concentrations to develop appropriate exposure scenarios. Published data was used to determine product characteristics and use patterns, while other default information was obtained from EPA’s EFH for other model inputs (i.e., body weight, body part surface areas, house volumes, and house ventilation rates). EPA’s consumer inhalation exposure assessment utilized a complex modeling approach which had a number of limitations: 1) Air concentration data for NMP was obtained from an occupational study which may or may not closely resemble residential workshop or consumer use settings and introduces uncertainty in the model results and the overall risk assessment; 2) Data inputs also were derived from older studies introducing uncertainty as to their relevance for current consumer settings where NMP paint strippers may be used; and, 3) The assumptions used for the model exposure scenarios were hypothetical, which may or may not reflect actual use conditions in consumer settings. Thus, the limited data and variable results when used to extrapolate to consumer acute inhalation risk characterization are uncertain.


3.2. HUMAN HEALTH ASSESSMENT This section discusses the hazard, dose-response, and risk analyses for NMP, and includes an evaluation of the uncertainty and variability in the non-cancer risk estimates. As identified in the problem formulation and scoping phase, the assessment calculated dermal and/or inhalation risk estimates for three categories of individuals: (1) occupational users dermal and inhalation; (2) ) occupational non-users who are being indirectly (inhalation only) exposed, (3) residential users dermal and inhalation; and (4) residential non-users who are being indirectly (inhalation only) exposed to NMP. The information is presented in the context of the exposure pathways and exposure durations that are relevant to this human health risk assessment, which are summarized in Table 3-8.

Table 3-8. Summary of Exposure Pathways, Toxic Endpoints and Risk Approach.

Exposure Receptors

Exposure Pathwaya

Acute Dermal

Acute Inhalation

Chronic Dermal

Chronic Inhalation

Analytical Approach

Workers Workers are likely to be exposed repeatedly to NMP. It was assumed that a single exposure is unlikely to occur in workers. Thus, acute risks were not evaluated.

Workers are likely to be exposed repeatedly to NMP. It was assumed that a single exposure is unlikely to occur in workers. Thus, acute risks were not evaluated.

Toxic endpoint: Developmental toxicity Risk approach: MOE

Toxic endpoints: Maternal and developmental toxicity Risk approach: MOE

Consumer Users and Non-Users

Toxic endpoint: Developmental toxicityb Risk approach: MOE

Toxic endpoint: Developmental toxicityb Risk approach: Margin of Exposure (MOE)

This exposure pathway is not expected to occur in residents. Chronic risks were not evaluated.

This exposure pathway is not expected to occur in residents. Chronic risks were not evaluated.

aResidential exposures typically occur infrequently and over a period of a day (acute inhalation/dermal exposure), while worker exposures are exposed daily on the job (chronic inhalation/dermal exposure). bAcute dermal and inhalation toxicity studies were not used because they typically measure lethality at high doses and do not provide the level of analysis to assess non-effect levels from single exposures.

Note that the EPA’s Integrated Risk Information System (IRIS) program has not developed a toxicological review for NMP. In the absence of an IRIS assessment, the toxicological information primarily was obtained from the OECD’s SIDS assessment report for NMP (OECD, 2007).


3.2.1. TOXICOKINETICS

NMP is well absorbed following inhalation (40 to 60 percent) and dermal (≤100 percent depending on conditions) exposures. In rats, NMP is distributed throughout the organism and eliminated mainly by hydroxylation to polar compounds, which are excreted via urine. About 80 percent of the administered dose is excreted as NMP and NMP metabolites within 24 hours. The major metabolite is 5-hydroxy-N-methyl-2-pyrrolidone (5HNMP). Studies in humans show that NMP is rapidly biotransformed by hydroxylation to 5HNMP, which is further oxidized to N-methylsuccinimide (MSI); this intermediate is further hydroxylated to 2-hydroxy-N-methyl-succinimide (2HMSI). The excreted amounts of NMP metabolites in the urine after inhalation or oral intake represented about 100 and 65 percent of the administered doses, respectively (OECD, 2007). Dermal absorption has been extensively studied as it typically poses the greatest potential for human exposure. Due to its irritant properties, neat NMP is unlikely to remain in voluntary contact with the skin for more than several hours. Dermal penetration through human skin has been shown to be very rapid and the absorption rate is in the range of one to two mg/cm2-hr. These values are two- to three-fold lower than those observed in the rat during the same period. Prolonged exposures to neat NMP was shown to increase the permeability of the skin. Skin penetration can also be affected by solvents and to a lesser extent by the state of occlusion. Water inhibits dermal absorption while other organic solvents (e.g., d-limonene) can increase it. The dermal penetration of 10 percent NMP in water is 100-fold lower than that of neat NMP, while dilution of NMP with d-limonene can increase the absorption of NMP by as much as 10-fold. The dermal absorption of neat NMP under different conditions indicated that dermal absorption one hour post-exposure was greatest under unoccluded conditions (69 percent), followed by semi-occluded (57 percent) and occluded (50 percent) conditions (OECD, 2007). Dermal uptake of airborne NMP has been reported in toxicokinetic studies in humans. Bader et al. (2008) exposed volunteers for eight hours to 80 mg/m3 of NMP. Exposure was whole body or dermal-only. Excretion of NMP and metabolites was used to estimate absorption under different conditions. The authors found that dermal-only exposures resulted in the excretion of 71 mg NMP equivalents whereas whole-body exposures in resting individuals resulted in the excretion of 169 mg NMP equivalents. Under a moderate workload, the excretion increased to 238 mg NMP equivalents. Thus, the dermal absorption component of exposure from the air will be in the range of 30 to 42 percent under whole-body exposure conditions to vapor. It is interesting to note that there is evidence to support that absorption and effect are very similar by oral and dermal routes. Oral LD50 values were 4,150, 3,914 and 3,605 mg/kg in rats (Ansell and Fowler, 1988; Bartsch et al., 1976; BASF AG, 1963; as cited in OECD, 2007, respectively) and 7,725 and 4,050 mg/kg in mice (Bartsch et al., 1976; Weisbrod and Seyring, 1980; Weisbrod, 1981; as cited in OECD, 2007) to dermal dose levels.


3.2.2. Hazard Identification

Oral exposures to NMP-containing products are expected to be negligible and were not evaluated in this assessment. However, EPA has concerns for exposures to NMP when it is used as a paint stripper because it is rapidly absorbed through skin and may be inhaled as a vapor in confined spaces. Below is a summary of the toxicological information that supported the decision to analyze dermal and inhalation exposures as the most relevant pathways. Detailed summarizes of the available toxicology studies are provided in Appendix E. NMP is well absorbed following dermal (< 100 percent) and inhalation (40 to 60 percent) exposures. The hazards associated with exposure by each of these routes have been evaluated in a number of different repeated-dose studies. A brief description of the studies relevant to chronic and acute dermal and inhalation exposure scenarios is provided below. Dermal. Dermal repeated dose toxicity studies in rats and rabbits have shown that developmental toxicity is the endpoint of concern; rats are more sensitive than rabbits. In a developmental toxicity study in rats administered NMP at dose levels of 75, 237, and 750 mg/kg, a NOAEL for maternal and developmental toxicity of 237 mg/kg was identified (Becci et al., 1981; Becci et al., 1982; FDRL, 1979; E.I. Dupont de Nemours & Co., 1992; as cited in OECD, 2007). At the limit dose, dams (i.e. mothers) experienced a 17 percent decrease in body weight; developmental toxicity was expressed as fewer live fetuses, increased resorption rate, reduced fetal body weight, and skeletal abnormalities. In a subchronic dermal toxicity study in rabbits administered NMP at dose levels of 413, 826, and 1,653 mg/kg, a NOAEL for systemic toxicity of 826 mg/kg was identified (GAF Corp., 1986; Industrial Biology Research and Testing Laboratories., 1963; as cited in OECD, 2007). One rabbit died in the limit dose group; no systemic toxicity to clinical, hematological, or histopathological measures was seen in the remaining rabbits in this dose group. No dermal subchronic studies in rats were identified. Inhalation. Whole-body inhalation studies with NMP as a vapor have shown marginal developmental toxicity in rats and rabbits, as the only endpoint of toxicological concern. As with dermal exposures, rats were the more sensitive species. In a developmental toxicity study, the no-observed-adverse-effect level (NOAEL) for decreased maternal and fetal body weight was 60 ppm (122 mg/m3) and 120 ppm (243 mg/m3), respectively (Saillenfait et al., 2001; Saillenfait et al., 2003; as cited in OECD, 2007). No chronic toxicity was observed in a two-year study in rats exposed to vapor concentrations up to 100 ppm (405 mg/m3) (E.I. Dupont de Nemours & Co., 1990; Lee et al., 1987; WHO, 1986; Kennedy, 2008; as cited in OECD, 2007). No effects were observed in additional rat studies that evaluated reproductive toxicity, neurotoxicity, etc., when NMP was administered up to saturation. In contrast, NMP as an aerosol has been shown to cause overt acute and subchronic toxicity in rats. A four-hour exposure to aerosolized NMP at concentrations of 4,800 mg/m3 and 8,800 mg/m3, was lethal to four of six rats and six of six rats, respectfully (E.I. du Pont de Nemours., 1988; as cited in OECD, 2007). In a 28-day study, eight of thirty rats exposed to aerosolized NMP at 740 mg/m3 died within nine days after the cessation of exposures and five rats were sacrificed in extremis (US EPA, 1989; E.I. Dupont de Nemours & Co., 1991).


The differences between the effects observed with NMP as a vapor versus an aerosol may be explained from the higher internal dose that animals receive with aerosolized NMP. In the inhalation chamber, the amount of vapors and aerosols is dependent on the airborne NMP concentration, temperature, and humidity in the inhalation chamber. When NMP ambient concentrations become saturated, it is expected that the exposure has an inhalation component to NMP vapors and a dermal component to NMP aerosols. This notion was discussed by the OECD (2007), which stated:

“The maximum vapor phase at room temperature is 1,286 mg/m3 (315 ppm) in dry air (0% relative humidity), 525 mg/m3 (128 ppm) at normal animal room humidity (50% relative humidity) and 0 mg/m3 (0 ppm) in humidity saturated air (100% relative humidity BASF AG, 1995c, b, a, 1989, 1992). Thus, the vapor saturation of NMP under normal conditions is considered to be in the range of 480-640 mg/m3 (120-160 ppm) depending on humidity and temperature (BASF AG, 1995b).”

To summarize, the available studies on NMP have shown five primary points about the hazard of this compound: 1) NMP is well absorbed following dermal and inhalation exposures; 2) rats are more sensitive to NMP than rabbits; 3) dermal exposures lead to the greatest hazard; 4) inhalation exposures result in marginal toxicological effects up to saturation (i.e., aerosol formation); and 5) developmental toxicity is the endpoint of concern for dermal and inhalation exposures. 3.2.3. Dose-Response Assessment

This section presents the dose-response assessment conducted by EPA for the non-cancer health effects associated with dermal and inhalation exposures to NMP. Data from the hazard/toxicological studies summarized in Appendix E were evaluated to determine NMP’s dose-response relationships, which were used to inform the estimation of risks for specific exposure scenarios. When NMP is used in paint stripping applications, exposures are expected to occur predominantly by the dermal route when proper personal protective equipment (e.g., gloves) are not used. Inhalation exposures to NMP also may occur, primarily to NMP as a vapor, when used in confined spaces. Therefore, EPA developed dose-response assessments from dermal toxicity studies and from inhalation toxicity studies where NMP was administered primarily as a vapor. In order to select the most appropriate key studies for this analysis, the relative merits of the animal studies were evaluated with respect to: (1) their adequacy to the exposure pathways (i.e., dermal and inhalation) and exposure durations (i.e., acute and chronic) under consideration; (2) the exposure levels at which adverse effects were observed; and (3) the species susceptibility to NMP exposure. Also, EPA focused on the most sensitive effects (e.g.,


developmental effects) reported in the toxicological literature that are relevant to exposure scenarios for paint stripping. The selected key studies provided the dose-response information for the selection of points of departure (PODs). EPA defines a POD as the dose-response point that marks the beginning of a low-dose extrapolation. This point can be the lower bound on the dose for an estimated incidence or a change in response level from a dose-response model (e.g., benchmark dose or BMD), a NOAEL, or a lowest-observed-adverse-effect level (LOAEL) for an observed incidence, or a change in level of response. PODs were adjusted as appropriate to conform to the exposure scenarios derived in Chapter 2. 3.2.4. Key Studies, PODs, and Levels of Concern for the Dermal Pathway

Acute Dermal Exposures. The adult acute dermal toxicity studies were not used for the acute dermal POD because no acute toxic effects or lethality were observed at dose levels up to 5,000 mg/kg (Clark et al., 1984; Weisbrod, 1981; Weisbrod and Seyring, 1980; as cited in OECD, 2007). This toxicological finding is relevant to women of childbearing age, including pregnant woman, who may be directly or indirectly exposed to NMP from single-event paint stripping uses. Subchronic Dermal Exposures. In a four week subchronic repeated dose study, mild irritation was noted in rabbits in all treatment groups; a NOAEL of 826 mg/kg was reported for systemic toxicity (GAF Corp., 1986; Industrial Biology Research and Testing Laboratories., 1963; as cited in OECD, 2007). The rabbit subchronic study reported a NOAEL of 826 mg/kg for systemic toxicity. This value was several times higher than the reported NOAELs of 237 mg/kg and 300 mg/kg for developmental toxicity in the rat and rabbit, respectively (Becci et al., 1981; Becci et al., 1982; FDRL, 1979; E.I. Dupont de Nemours & Co., 1992; as cited in OECD, 2007). Rationale for Study and Endpoint Selection for Acute and Chronic PODs. Developmental studies involve multiple exposures on the order of 10-15 days; however, they are relevant to single exposures because developmental effects may result from a single exposure at a developmentally critical period (Van Raaij et al., 2003; US EPA, 1991b; Davis et al., 2009). Therefore, the dermal developmental studies represented the most relevant endpoint for estimating the acute risks for residential scenarios. This approach is supported by Van Raaij et al. (2003). These authors evaluated several developmental toxicity studies that reported NOAELs and LOAELs for single day exposures or repeated exposures over the developmental period. An examination of the fetal body weight loss parameter (n = 12 studies) showed that the ratio of the single-dose to repeated-dose NOAELs was less than four-fold for nine of the 12 studies. The dermal developmental studies of NMP exposure reported NOAELs that were several times lower than the NOAEL reported in the rabbit subchronic study. Therefore, because these were more sensitive indicators of effect, the developmental studies were also used for developing the chronic POD.


NOAELHED approach for Acute Dermal POD. The rat NOAEL of 237 mg/kg was converted to a human equivalent dose (HED) of 56 mg/kg using the BW¾ correction assuming a rat body weight of 0.25 kg and a human body weight of 80 kg (i.e., NOAELHED = 237 mg/kg ÷ [0.25 kg-0.25 ÷ 80 kg-0.25]) (US EPA, 2011d). Note that the correction also was made to the rabbit NOAEL, but the adjusted rabbit value (i.e., NOAELHED = 70 mg/kg) was higher than the one obtained for the rat NOAEL. NOAELHED approach for Chronic Dermal POD. Developmental effects may occur in response to single or repeated exposures to NMP, particularly during specific windows of susceptibility during pregnancy and affect the developing fetus. Thus, EPA used the acute dermal POD (56 mg/kg) to evaluate the risks of chronic dermal exposures to NMP. The POD for this toxicological finding is relevant to women of childbearing age, including pregnant woman, who may be directly or indirectly exposed to NMP from repeated paint stripping uses. 3.2.5. Key Studies, PODs, and Levels of Concern for the Inhalation Pathway

Acute Inhalation Exposures. NMP has a comprehensive set of inhalation toxicity studies that comprise acute, developmental, reproductive, and subchronic studies as well as a two-year carcinogenicity study (Appendix E). In this spectrum of tests, the acute four-hour and developmental inhalation studies were the most relevant to assess single exposure (acute) PODs. The acute exposure studies demonstrated lethal toxicity at doses much higher than seen in the developmental toxicity studies and involved exposures to aerosolized NMP. For example, no animals died when exposed to NMP for four hrs at 5,100 mg/m3 (head-nose exposure) (BASF AG, 1988a; as cited in OECD, 2007). Rats exposed to a range of NMP concentrations (3,100 to 4,800 or 5,000 to 8,800 mg/m3; head-nose exposure) only died when exposed to 4,800 or 8,800 mg/m3 (i.e., four of six and six of six animals, respectively) (E.I. du Pont de Nemours., 1988; as cited in OECD, 2007). The lowest exposure tested in these studies was 3,100 mg/m3 for four hrs. Because effects were seen in developmental toxicity studies at much lower exposures to NMP as a vapor, the four-hr acute studies were not used for the acute inhalation POD for residential users and non-users. Rational for Study and Endpoint Selection for Acute PODs. Developmental inhalation studies have been performed with rats and rabbits. Due to the greater susceptibility of rats, the NOAEL for developmental toxicity reported by Saillenfait et al. (2001); Saillenfait et al. (2003) (as cited in OECD, 2007) was used in this assessment. Using these data, acute PODs were derived using two approaches. In the first approach, benchmark dose modeling (BMD) was performed to derive a benchmark concentration level (BMCL). This value was converted to a human equivalent concentration (HEC) (i.e., BMCLHEC approach). In the second approach, a NOAEL was used as the POD (i.e., NOAEL or “default” approach). A physiologically based pharmacokinetic (PBPK) approach also was considered, but not carried forward in the assessment because of model limitations, as discussed below. Currently, the BMD approach is the preferred approach


for representing the PODs since its makes estimates based upon the entire dose–response curve with its variability and not based on a single nominal dose group in a given study as is the case in the NOAEL/LOAEL approach. A summary of these approaches is described below. BMCLHEC approach for Inhalation Acute POD. EPA performed benchmark dose (BMD) modeling on the fetal body weight data from the Saillenfait et al. (2001) and Saillenfait et al. (2003) studies (as cited in OECD, 2007). A benchmark concentration level (BMCL) with a benchmark response of five percent for this endpoint was used to derive a six-hour BMCL05 of 302 mg/m3 (Appendix F; Table F-2). The six-hr BMCL05 was adjusted to account for dosimetric extrapolation from animals to humans according to EPA’s guidance (US EPA, 2011a, 2009, 1994a). The adjustments consisted of using blood:air partition coefficients in animals and humans to estimate a dosimetry adjustment factor (DAF), which was used to calculate a human equivalent concentration (HEC). A default value of one was used for the DAF because the blood:air partition coefficients were unknown. Therefore, the six-hr BMCLHEC of 302 mg/m3 was used as the acute POD for informing risk determinations for inhalation scenarios in residential settings. NOAEL Approach for Inhalation Acute POD. EPA selected the NOAEL of 243 mg/m3 for decreased fetal body weight from the (Saillenfait et al., 2001; Saillenfait et al., 2003) studies (as cited in OECD, 2007) as an acute POD. Other rat developmental studies, while not used for development of the POD, were supportive (Hass et al., 1994; Solomon et al., 1995). This approach was presented for comparison with the BMCLHEC approach, but it was not used for informing risk determinations.

PBPK Model for Extrapolation. Poet et al. (2010) developed a PBPK model to reduce uncertainty associated with extrapolating findings from animal toxicity studies to humans. These authors initially developed the model for adult non-pregnant rats and then extrapolated it to pregnancy. EPA evaluated this model4 and determined that it contained limitations that precluded its utility for quantitative use in deriving a POD for this risk assessment (Appendix G). Chronic Inhalation Exposures. A comprehensive set of inhalation studies were available for NMP, which included: reproductive toxicity studies, developmental toxicity studies, subchronic toxicity studies, and a chronic toxicity study. Each of these studies was considered for deriving the chronic exposure PODs. Chronic PODs were developed for various toxicological endpoints and the rationale for their selection is discussed below. Rational for Study and Endpoint Selection for Chronic PODs. Based on the toxicological studies performed on NMP, developmental toxicity has been shown to be the endpoint of concern. Because of this, EPA has concerns about chronic exposures of female workers of child bearing age, including pregnant females, to NMP-containing paint strippers. Therefore, the Saillenfait et al. studies (Saillenfait et al., 2001; Saillenfait et al., 2003; as cited in OECD, 2007) were used

4 The model titled “NMP PBPK Model.zip” is available at http://www.epa.gov/oppt/existingchemicals/pubs/workplans.html


for deriving chronic PODs using a BMCLHEC approach for fetal toxicity and a NOAEL approach for maternal and fetal toxicity. BMCLHEC Approach for Inhalation Chronic POD. The six-hr BMCLHEC of 302 mg/m3 (BMCLHEC approach) that was derived from the Saillenfait et al. studies (Saillenfait et al., 2001; Saillenfait et al., 2003; as cited in OECD, 2007) was used as the chronic POD for informing risk determinations. NOAEL Approach for Inhalation Chronic POD. The maternal and fetal chronic PODs were based on the NOAELs of 122 mg/m3 and 243 mg/m3, respectively, for decreased body weight (Saillenfait et al., 2001; Saillenfait et al., 2003; as cited in OECD, 2007). These values derived from the NOAEL/LOAEL approach were used for comparison purposes only and are not the preferred risk determinations.

3.3. HUMAN HEALTH RISK CHARACTERIZATION

Time Scaling of Chronic PODs. Haber’s rule (C x t = k) was used to time scale all of the chronic inhalation PODs (see Table 3-9). Chronic PODs correspond to six- hr/day exposures, but the human exposure estimates (exposure section) were expressed as ADCs, which are continuous 24-hr/day exposures for a working lifetime (40 yrs).

This section provides an evaluation of the different occupational and consumer exposure scenarios and develops margins of exposure (MOEs) using the PODs derived in the previous section. The resulting MOEs were used for informing risk determinations, as discussed below.

Table 3-9. Time Scaling of Chronic POD Values.

Toxicological Effect

POD and Exposure Duration

Scaled POD values for 24 Hrs/day, 7 Days/Weeka

Fetal toxicity (BMCLHEC) 302 mg/m3 6 hrs/day, 7 days/week

76b mg/m3

Maternal toxicity (NOAEL) 122 mg/m3 6 hrs/day, 7 days/week

31c mg/m3

Fetal toxicity (NOAEL) 243 mg/m3 6 hrs/day, 7 days/week

61c mg/m3

a Scaled value = concentration (mg/m3) × days (6 hrs/24 hrs) bPOD used in risk characterization. cPODs shown for comparison with the BMCLHEC approach.


3.3.1. Risk Estimation Approach for Acute and Chronic Exposures

To estimate non-cancer acute and chronic risks, EPA calculated MOEs. These values represent the ratio of the scaled POD to the exposure. This approach allows the reader to better understand the toxicological basis for the risks and the uncertainties that went into the risk determinations. MOEs were compared to benchmark MOE levels to determine whether potential risks of concern were present for the different exposure scenarios. Benchmark MOE s were established based on the composite value of uncertainty factors (UFs) that addressed intraspecies uncertainty (UFH; i.e., human to human) and interspecies uncertainty (UFA; i.e., animal to human). A default value of 10 is typically used for each UF (i.e., UFH = 10; UFA = 10). The default value of 10 is derived from the composite value of 3.16 for toxicokinetics (TK) and 3.16 for toxicodynamics (TD) according to the equation: 3.16 [TK] × 3.16 [TD] = 10. For the NOAELHED and BMCLHEC PODs, the TK component of the UFA was reduced to 1, based on Agency guidance (US EPA, 2011a,d) applying allometric scaling of BW3/4. The resulting UFA of ~3 accounts for TD uncertainty. Therefore, if an MOE was less than a benchmark of 30 (i.e., 10 [UFH] × 3 [UFA]), a potential risk of concern was identified. As a comparison, a default benchmark of 100 (i.e., 10 [UFH] × 10 [UFA]) was presented for PODs based on the NOAEL approach. Table 3-10 depicts a summary of the dose-response data (e.g., POD, toxicological effects, levels of concern) and risk approaches EPA used in NMP’s risk assessment. MOEs greater than the benchmark levels were viewed as negligible risks of concern.


Table 3-10. Dose-Response Values and Risk Approaches for NMP’s Human Health Risk Assessment.

Exposure Scenario Concentration(s) and Time

Duration(s) Used in Risk Assessment

Total UFs Toxicological Endpoint Risk

Estimation Approach

Non-Cancer Acute Dermal Risks

Residential usersa POD of 56c mg/kg (NOAELHED approach)

UFH=10, UFA=3 Total UF=30

Increased resorption, fewer live fetuses, reduced body weight, skeletal abnormalities

MOE

Non-Cancer Acute Inhalation Risks – POD Scaled to 4 Hours Exposure

Residential usersa and non-usersb

Scaled POD of 453c mg/m3 for 4 hours exposure from Saillenfait et al. (2003) (BMCLHEC approach)


Fetal body weight decrease MOE Scaled POD of 65d mg/m3 for 4 hours exposure from the Saillenfait et al. (2003) (NOAEL or Default approach)


Non-Cancer Chronic Dermal Risks

Occupational workers POD of 56c mg/kg (NOAELHED

approach) UFH=10, UFA=3

Total UF=30

Increased resorption, fewer live fetuses, reduced body weight, skeletal abnormalities

MOE

Non-Cancer Chronic Inhalation Risks – POD Scaled to 24 Hours/Day, 7 Days/Week to Correspond to ADC

Occupational workers

Scaled POD of 76c mg/m3 (BMCLHEC approach)


BMCL of 5% reduction in fetal body weight MOE

Scaled POD of 31d mg/m3 (Default approach)

UFH=10, UFA=3 Total UF=30 Decrease in maternal body weight gain

MOE aResidential users are those who would be working directly with the NMP-containing paint stripper in a home workshop or a bathroom.

bResidential non-users would be individuals who would be in the ROH at the time of the paint stripper application. cPOD used for informing risk determinations. dPODs shown for comparison with the BMCLHEC approach.


3.3.2. Risk Estimates for Non-Cancer Acute Dermal Exposures in a Residential Setting

Table 3-11 shows the acute dermal MOEs for consumers using NMP-based paint strippers without personal protective equipment (i.e., gloves) in the home. The analysis does not evaluate risks to other residential occupants because the skin of non-users is not expected to be in contact with the product. The exposure analysis assumed that a defined surface area of the residential/consumer user’s skin was exposed to a thin film of the product. The thin-film modeling approach also assumed exposure to an adult individual of 80-kg for one time only (i.e., one event in a single day). Central and high-end exposure scenarios were estimated for brush-on or spray-on applications. Acute dermal MOEs ranged from 0.5 to 1.0. For all of the modeled scenarios, the MOEs were below the benchmark of 30, indicating potential risks of concern for consumers using NMP-based paint strippers without personal protective equipment.

Table 3-11. Acute MOEs for Residential Users and Non-Users of NMP-Based Paint Strippers Dermal Exposures.

Case ID Scenario Description Acute Dermal Exposure,

ADRdermal (mg/kg-day)

Acute Dermal MOEs POD = 56 mg/kg-day;

Level of Concern MOE <30

1 Brush-on, central estimate 50 1.1a

2 Brush-on, high-end estimate 100 0.56

3 Spray-on, central estimate 89 0.63

4 Spray-on, high-end estimate 110 0.51 a Bolded values are below the MOE and indicate potential risks of concern. 3.3.3. Risk Estimates for Non-Cancer Acute Inhalation Exposures in a Residential Setting

Table 3-12 shows the acute four-hour inhalation MOEs for various do-it-yourself (DIY) exposure scenarios. These hypothetical (i.e., “what if”) scenarios assumed brush or spray applications in either a workshop or a bathroom. The user location during application was varied in the exposure scenarios. Scenarios 2 and 5 assumed that the user remained in the workshop after applying NMP. Scenarios 1, 3, 4, 6, 7, and 8 assumed that the user went to the ROH after applying NMP. MOEs for inhalation exposures were estimated for both residential users and non-users. The MOEs calculated by the BMCLHEC approach ranged from 0.87 to 69 and from five to 98 for users and non-users, respectively. For scenario 1, the MOEs for users and non-users were above the benchmark of 30, indicating negligible risks of concern. For scenarios 2, 4, and 5, the MOEs for users that were below the benchmark of 30, indicating potential risks of concern for users.


Scenarios 3, 6, 7, and 8 resulted in MOEs for users and non-users that were below the benchmark of 30, indicating risks of concern for both users and non-users. For Scenarios 1 to 6 (workshop), MOEs calculated by the NOAEL approach ranged from 0.1 to 9.8 and from 0.7 to 14 for users and non-users, respectively. MOEs for users and non-users of the bathroom scenarios (7 and 8) ranged from 0.7 to 1.2 and 0.1 to 0.2, respectively. These MOEs were below the benchmark of 30, indicating potential risks of concern for both users and non-users.


Table 3-12. Acute MOEs for Residential Users and Non-Users of NMP-Based Paint Strippers Inhalation Exposures.

Scenario Individual

Maximum Values for 4-hr

Averaging Period, (mg/m3)

MOEs BMCLHEC

APPROACH Scaled POD= 453 mg/m3


MOEs Default

APPROACH Scaled POD=

65 mg/m3 Level of Concern

MOE <30


User 6.6 69 9.8a

Non-User 4.6 98 14


User 29 16 2.2

Non-User 9.1 50 7.1


User 59 7.7 1.1

Non-User 31 15 2.1


User 17 27 3.8

Non-User 12 38 5.4


User 45 10 1.4

Non-User 14 32 4.6


User 90 5 0.7

Non-User 49 9.2 1.3


User 520 0.87 0.1

Non-User 91 5 0.7


User 310 1.5 0.2

Non-User 54 8.4 1.2

a Bolded values are below the MOE and indicate potential risks of concern.


3.3.4. Risk Estimates for Non-Cancer Chronic Dermal Exposures to Workers

Table 3-13 shows the chronic dermal MOEs for workers when applying NMP-based paint strippers. Note, these values were calculated with the assumption that appropriate gloves were not worn.

Dermal exposures were estimated using a conservative modeling approach that assumed exposure to liquid NMP, maximum skin absorption (100 percent), and a stripper content of 100 weight percent of NMP. The potential dose rates ranged from 590 to 1,800 mg and corresponded to exposure to liquid NMP per day. Body weight-normalized potential dose rates ranged from 7.4 to 22 mg NMP/kg/day. Chronic dermal MOEs ranged from 2.5 to 7.6 and were below the benchmark MOE of 30, indicating potential risks of concern to workers when applying NMP-based paint strippers. Table 3-13. Chronic MOEs for Worker Dermal Exposures.

Industry

Chronic Dermal Exposure, mg/kg-day

MOE POD = 56 mg/kg-day


Any workplace setting (no gloves) 7.4-22 7.6-2.5a a Bolded values are below the MOE and indicate potential risks of concern. 3.3.5. Risk Estimates for Non-Cancer Chronic Inhalation Exposures to Workers

The exposure assessment examined the occupational literature and looked for air monitoring data in small shop operations expected to use NMP-based paint strippers. Air concentrations reported as eight-hr TWAs were used to estimate ADCs used in the MOE calculations. The availability of eight-hr TWA exposures was limited and only available for industries using NMP-based paint strippers in graffiti removal. Table 3-14 presents the calculated MOEs for workers in the graffiti removal industry. The MOEs were as high as 10,857 if the lower end of the air concentrations were used, and as low as 72 when the high end of the air concentration was used with the BMCLHEC approach. These values exceed the benchmark MOE of 30, indicating negligible risks of concern for workers. In comparison, the NOAEL approaches resulted in MOEs below the respective benchmark levels for high concentrations of NMP, indicating potential risks of concern. It should be noted that EPA does not consider the MOEs based on the BMCLHEC approach reliable due to the limited amount of exposure data from which these values were derived.


Table 3-14. Chronic MOEs for Worker Inhalation Exposures.

Industry

Exposure Ranges of MOEs

ADC (mg/m3)

Systemic Toxicity (Default approach)

POD = 72 mg/m3 Level of Concern

MOE <30

Maternal Toxicity (Default approach)


MOE <30

Fetal Toxicity (BMCLHEC approach)


MOE <30

Fetal Toxicity (Default

approach) POD = 61

mg/m3 Level of Concern MOE <30

Graffiti removal

0.007-1.0 10,286-72a 4,286-30 10,857-76 8,714-61

a Bolded values are below the MOE and indicate potential risks of concern.

3.4. DISCUSSION OF KEY SOURCES OF UNCERTAINTY AND DATA LIMITATIONS 3.4.1. Key Uncertainties and Data Limitations for Occupational Exposure Estimates

Dermal Exposures. The EPA dermal exposure model used in this assessment presents a hypothetical estimate of dermal exposure to a liquid by assuming that appropriate gloves were not worn to reduce exposure. It is important to note that the EPA dermal exposure model uses a default value of one exposure event per worker per day. Chemicals with high skin absorption can cause variations of surface densities, which can also be impacted by the number of exposure events per worker per day. However, since NMP is corrosive, the default assumption of one exposure event per day was considered appropriate because it may address accidental exposures that may occur in the workplace. Inhalation Exposures. Limitations of the inhalation exposure data also introduce uncertainties into the exposure summary (Table 3-3). The principal limitation of the exposure data is the uncertainty in the representativeness of the data. EPA identified a limited number of exposure studies that provided with data on the number of facilities, job sites, or residences where NMP was used. These studies primarily focused on single sites. This small sampling pool introduces uncertainty into the observed data because it is unclear how representative the data are to all sites and for all workers within the particular end-use application across the US. Differences in work practices and engineering controls across sites can introduce variability and limit the representativeness of any one site with regard to all sites. The impact of these uncertainties precluded EPA from describing actual exposure distributions. Central tendency and high-end exposures may or may not lie within the range of exposures estimated for this assessment. The age of the identified exposure studies also adds some uncertainty. Most of the exposure studies were conducted in the 1990s. Some references have suggested a trend to reduce the use of DCM in paint stripping products; NMP has been suggested as an alternative paint


stripping component to DCM. If accurate, this change could have a direct impact on the frequency of exposure and the number of workers exposed to NMP. In the absence of actual exposure distributions, the reliability of the calculated MOEs for workers is unclear. The assumed values for several parameters for use in the equation to estimate ADCs introduce some additional uncertainties. Exposure frequencies were assumed to be 250 days/yr (i.e., every work day), and working years per lifetime was assumed as 40 years, which seems likely to be a high-end estimate. The impact of these uncertainties is that some exposures in this assessment will be overestimated for workers who are not exposed each work day or for a full shift for their full working career. 3.4.2. Uncertainties in the Residential Exposure Assessment

The consumer dermal exposure scenarios developed for this assessment were hypothetical based on uncertainties in the modeling methods and input parameters. As described in US EPA (1992a), this approach answered questions about individual exposures, but did not provide information about how likely the combination of values that were used might be in the actual population. According to US EPA (1996), hypothetical estimates answer the question, “What is the exposure if the assumptions are valid?” The consumer inhalation exposure assessment is composed of modeled exposure scenarios whose inputs were based on experimental data, survey information, and a number of assumptions with varying degrees of uncertainty. The results were characterized as either plausible estimates of individual exposure (e.g., central tendency) or possibly greater than the distribution of actual exposures (e.g., bounding). The biases of the uncertainties identified below are not known, so differences in the parameters that were discussed could result in either larger or smaller exposure estimates. Further discussion of uncertainties as they relate specifically to the dermal and inhalation assessments is provided in the subsections that follow. Dermal Exposure. One of the major uncertainties in the dermal model is the assumption that one thin film per exposure event gets on the skin. As stated in US EPA (1996), the number of times per exposure event that a person contacts the paint remover product is unknown. It also is assumed that protective gloves are not worn. This assumption was considered relevant because consumers, unlike workers, may not have the experience with taking the necessary precautions (i.e., wearing appropriate gloves) to avoid dermal exposures to corrosive compounds like NMP. Additionally, there is uncertainty in the film thickness value used, and there are questions about the uniformity of films associated with product usage. The only film thickness value available that is specific to paint strippers (0.03 cm) is based on professional judgment from a Klean Strip chemist (US EPA, 1996). No details are available regarding the derivation of this


value. Limited film thickness values are available in the EFH for a variety of liquids (e.g., mineral oil, cooking oil, bath oil, bath oil/water, water, and water/ethanol), but they were not relevant to paint stripper products and were based on a limited number of observations. For comparison purposes only, the film thickness for water (50 percent)/ethanol (50 percent) on skin was estimated to be 0.0065 cm after full immersion of the hand into the liquid with no wiping. Another case of parameter uncertainty is the surface area of the skin that is exposed to the product. No studies have been conducted on this value; thus, the assumed surface area of 50 percent of both hands (central estimate) is based on professional judgment. The US EPA (1996) report assumed that the palms and fingers of both hands would be exposed. As noted above for the inhalation assessment, there is a high degree of confidence in the weight fractions and product density for the paint stripper products. There also is a high degree of confidence in the chosen surface area and body weight values, which are recommended values in the EFH. An input value of one was used for exposure duration (day), frequency (events/day), and averaging time (days). Though these estimates were based on professional judgment, they are typical for the calculation of acute dermal doses. Inhalation Exposure. There is a high degree of confidence in the weight fractions and product density for the paint stripper products. These values are based on currently available consumer products, as identified in Brown (2012). However, the products were not weighted for percent of market share. Similarly, there is a high degree of confidence in the values chosen to represent the house volume and air exchange rate, as they are based on scientifically defensible data cited in the EFH. The confidence level is similarly high for amount of product applied and application rates, with data ties to surveys cited in the EFH as well as experiments conducted in US EPA (1994b). For the stripping sequence, the wait time per segment has a high level of confidence because the time is based on what is shown on current product labels. The application and scraping times have a slightly lower confidence level because they are based on the US EPA (1994b) study, which is considered to be of high quality but only included a limited number of experiments. High-quality US EPA (1994b) data were available as a quantitative basis for development of the estimates for the fraction of applied chemical mass that is released to the indoor air (see the Estimation of Emission Profiles for Paint Removers/Strippers in Appendix D), but the number of cases on which the estimates were based was very limited. The MCCEM inputs for the interzonal airflow rates assumed in the model represent another area of uncertainty. The chosen rates are tied to an empirical algorithm, by authors whose report was cited in the EFH. This algorithm is expected to provide a rough approximation of the “average case,” but there are numerous consumer choices that can significantly affect the extent of residential air flow, such as whether to operate a central heating and air conditioning


system, if available, and whether to close or open doors to certain rooms or areas in the house. However, the sensitivity analysis indicated that the modeling results are relatively insensitive to the value assumed for the interzonal airflow rate. Given such potential variability across paint stripping exposure scenarios not only for airflow rates, but also for factors such as amount of product used, application rates, and locations in the house, uncertainties exist in the percentiles of the distribution that are represented by the modeled scenarios. A final/last set of uncertainties is associated with the fit of the exponentially declining emission rates to the US EPA (1994b) chamber tests, and the extrapolation of the fitted exponentials to the spray application using the DCM results. Though there are no data for the spray application of NMP-containing stripper and this is an expedient and reasonable means of filling this data gap, there is uncertainty in this approach. DCM and NMP have significantly different chemical properties (e.g., vapor pressure, solubility, melting point, boiling point, etc.). These differences may result in uncertainties in the extrapolation. For both the brush and spray application, there are potential chemical equilibrium and rate effects associated with the differences in vapor pressure and diffusivities. The US EPA (1994b) data were for one specific product on a specific substrate, and differences between products, additives, and substrates also introduce uncertainty. Because of the uncertainties discussed above, the general term “upper-end,” instead of more definitive descriptors (e.g., high-end), was used to characterize plausible exposure values greater than central tendency; more definitive descriptors would imply an inappropriate level of accuracy. Regarding the bathtub stripping scenario, it is uncertain whether a DIY consumer would use practices, based on an occupational scenario, that violate label warnings for ventilation; for this reason, the user characterization is upper-end to bounding. Given the sensitivity of concentrations in the ROH to room-of-use ACH and interzonal air flow, there is also uncertainty about the likelihood that a non-user would be exposed to this scenario’s ROH concentrations, and thus the non-user was characterized as upper-end to bounding. However, under conditions where the user had protective gear (e.g., independent air supply), it appears more plausible that the high exposure concentrations could occur in the bathroom, and thus in the ROH. 3.4.3. Uncertainties in the Hazard- and Dose-Response Assessments

Varying degrees of uncertainty are associated with the evaluation of adverse health effects in potentially exposed populations to NMP-based paint strippers. Some of the identified sources of uncertainty in the toxicity assessment follow. Selection of Developmental Toxicity for the Evaluation of Single Exposure. Developmental toxicity was used as an endpoint to evaluate risks associated acute and chronic inhalation and


dermal exposures to NMP. Though the developmental toxicity studies were to multiple exposures, they were used to evaluate acute exposure because of the possibility that developmental effects could manifest after a single exposure to NMP. EPA chose to use a conservative approach to protect susceptible populations (i.e., women of childbearing age and pregnant women). Extrapolation of Dermal PODs Based on Developmental Toxicity to Chronic Occupational Exposures. The chronic dermal POD was based on a developmental toxicity study that exposed rats for 10 days (GDs 6 to 15). During pregnancy, women may be exposed to NMP on a repeated basis, but the exposure does not qualify as a “chronic exposure,” which is defined in this analysis as an assumed working lifetime of 40 years. Nevertheless, the repeated nature of the exposure during pregnancy, specifically if it targets developmental windows of susceptibility, warranted using developmental toxicity as the most sensitive and conservative endpoint for the dermal chronic exposures to NMP. EPA also is interested in the impact of NMP on other subpopulations, such as male workers. This would require using an alternative dermal POD based on systemic toxicity to assess potential risks of concern to male workers, instead of using the POD based on developmental toxicity. Additional chronic dermal toxicity studies might assist the Agency in elucidating other adverse effects that would not be captured in the developmental toxicity studies. EPA recognizes that there are uncertainties with current approach which might overestimate the risks to some worker subpopulations. Dermal Uptake Duration Inhalation Exposures. Acute or chronic inhalation risks were evaluated with developmental toxicity studies. The Saillenfait et al. studies (Saillenfait et al., 2001; Saillenfait et al., 2003; as cited in OECD, 2007) used to select the acute and chronic inhalation PODs, did not detect NMP aerosols in the inhalation chambers. Extrapolation of Data Due to Intraspecies Variability. Heterogeneity among humans is another uncertainty associated with extrapolating the derived PODs to a diverse human population. The intraspecies UF of 10 was used for all of the derived PODs. In general, EPA did not have the sufficient data/information on susceptible human populations or on the distribution of susceptibility in the general population to reduce the default intraspecies UF of 10 to a lower value (e.g., 1 or 3). As such, EPA used an intraspecies UF of 10 for the risk assessment. Extrapolation of Data from Animals to Humans. EPA used an interspecies extrapolation UF to account for uncertainties related to interspecies differences for specific NMP-related toxicological effects. The standard value for the interspecies UF is 10, which can be broken down into a factor of ~3 for the adjustment of toxicokinetic differences and a factor of ~3 for the uncertainty of toxicodynamics.


Allometric scaling (BW¾) was used for the dermal PODs to obtain toxicologically-equivalent doses across species. The BW¾ correction accounts for toxicokinetic differences supporting an interspecies UF of 3 for toxicodynamics in the dermal PODs. This type of scaling is most appropriate for toxicity resulting from the internal dose of the parent compound integrated over time (i.e., area under the curve or AUC) (US EPA, 2011d), which EPA assumed for this analysis. Another alternative is that effects are from peak blood levels. The toxicology experiments on NMP do not provide enough information to distinguish between a mode of action and which internal dose metric would be most appropriate for these two modes of action. Narcosis effects are probably due to peak blood levels, and other effects such as body weight change are more likely from AUC considerations or somewhere between AUC and peak blood concentration mode(s) of action. The standard EPA approach is to assume AUC when the mode(s) of action is unknown. The BW¾ scaling approach has a number of potential limitations that are pertinent to this analysis and have been described by US EPA (2011d).

“Differing allometric patterns among various sized individuals of the same species (Rhomberg and Lewandowski, 2004, 2006) may pose an uncertainty to intraspecies scaling, while differences across species in patterns of development (Finlay and Darlington, 1995; Renwick and Lazarus, 1998; Clancy et al., 2001) can complicate interspecies extrapolation from immature animals to humans. With regard to variation in toxicokinetic processes, recent analyses suggest that a BW3/4 relationship is descriptive of some TK differences observed with pharmaceuticals among ages including early lifestages, down to about 6 months (Ginsberg et al., 2004; Ginsberg et al., 2002; Hattis et al., 2004)”.

Time Scaling for Acute and Chronic PODs. A time extrapolation of acute or chronic PODs was conducted to obtain PODs that could be used with human exposure estimates calculated in the exposure assessment. Time scaling assumed that the effects are related to concentration × time, independent of the daily (or weekly) exposure regimen (i.e., a daily exposure of six hours to four mg/m3 is considered equivalent to 24 hours of exposure to one mg/m3). However, the validity of this assumption is unknown.


3.5. RISK ASSESSMENT CONCLUSIONS

NMP is used in the home and commercially as a paint stripper. Exposures may occur by the dermal and inhalation routes. Consumer acute dermal and inhalation exposures were modeled to develop TWAs for a number of durations up to 24 hours for a number of scenarios. For worker exposures, acute and chronic dermal exposures were modeled. Chronic inhalation exposures were developed from a limited number of published monitoring studies. Developmental toxicity studies were used to develop the acute and chronic dermal and inhalation PODs. These values were converted to human equivalent doses or concentrations. The MOEs were compared to a benchmark level of 30. This value accounted for intra- and interspecies uncertainty. MOEs below 30 were interpreted as potential risks of concern. Occupational MOEs for dermal chronic exposures ranged from 2.5 to 7.6. These values were below the benchmark level of 30 and indicated potential risks of concern. Occupational MOEs for inhalation chronic exposures ranged from 75 to 10,857 with the BMCLHEC approach. These values exceeded the benchmark level of 30 and indicated negligible risks of concern. However, the EPA considers these MOEs unreliable because of the limited amount of inhalation exposure data. Consumer MOEs ranged from 0.51 to 1.1 for acute dermal exposures. Consumer MOEs for acute inhalation exposures ranged from 0.87 to 98 using the BMCLHEC approach. Based on these MOEs and the previously stated uncertainties, EPA has made the following conclusions, which are limited to women of child-bearing age: • Workers may have potential risks of concern from dermal exposure when no gloves are

worn.

• Consumers may have potential risks of concern from dermal exposure assuming appropriate gloves are not worn.

• Consumers may have potential risks of concern from inhalation exposure (although of lower concern than from dermal exposure) if exposed for more than 4 hours at lower ventilation rates.


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Appendices


Appendix A. Environmental Effects Summary EPA evaluated available published studies to better understand the potential environmental effects of NMP releases to the environment on aquatic organisms including (i.e., acute and chronic toxicity) invertebrates, fish, and plants, as well as to birds. A summary of these data is provided in Table A-1. Table A-1. Summary Table for Aquatic Toxicity Data of NMP

Endpoint Value

Fish 96-hour LC50 (mg/L) >500-4,030

Aquatic invertebrate 48-hour EC50 (mg/L) >1,000-4,897

Aquatic plant 72-hour EC50 (mg/L) >500

Aquatic invertebrate chronic toxicity 21-day (mg/L) 12.5

Avian toxicity LD50 (mg/kg body weight) 2,500-5,000

Avian toxicity LC50 (ppm) >5,000

Environmental Effects – Aquatic Toxicity The aquatic toxicity of NMP fish, aquatic invertebrates, and aquatic plants is low. The toxicity of NMP for avians is low (US EPA, 1992b, 2012c). The acute 96-hour LC50 for fish ranges from >500 to 4,030 mg/L. The acute 48- and 96-hour EC50 for aquatic invertebrates ranges from >1,000 to 4,897 mg/L. The toxicity for aquatic plants is >500 mg/L. The chronic toxicity for aquatic invertebrates is 12.5 mg/L. A brief summary of the environmental toxicity is described below. Acute Toxicity to Fish Fathead minnows (Pimephales promelas) were exposed to unspecified measured concentrations of NMP under flow-through conditions for 96 hours. A 96-hour LC50 of 1,072 mg/L was reported (SRC, 1979; as cited in Verschuren, 2009). Orfe (Leuciscus idus) were exposed to unspecified concentrations of NMP for 96 hours. No other details about the study was provided. A 96-hour LC50 of 4,000 mg/L was reported (BASF AG, 1986; as cited in Verschuren, 2009). Guppies (Poecilia reticulata) were exposed to unspecified nominal concentrations of NMP under static conditions for 96 hours. A 96-hour LC50 of 2,673 mg/L was reported (Weisbrod and Seyring, 1980; as cited in OECD, 2007; and Verschuren, 2009). Bluegill sunfish (Lepomis macrochirus 10/replicate) were exposed to nominal concentrations of 0, 360, 600, 1,00, 1,667, 2,775, and 4,629 mg/L of NMP under unspecified conditions for 96 hours. A 96-hour LC50 of 832 mg/L was reported (GAF Corp., 1979; as cited in OECD, 2007; and Verschuren, 2009).


Rainbow trout (Oncorhynchus mykiss, formerly known as Salmo gairdneri, 10/replicate) were exposed to a single concentration of NMP of 500 mg/L under static conditions for 96 hours. A 96-hour LC50 of >500 mg/L was reported (SRC, 1979; BASF AG, 1983; as cited in OECD, 2007). Acute Toxicity to Aquatic Invertebrates Water fleas (Daphnia magna) were exposed to unspecified nominal concentrations of NMP under static conditions for 48 hours. A 48-hour EC50 of 4,897 mg/L was reported (GAF Corp., 1979; as cited in OECD, 2007; and Verschuren, 2009). Water fleas (D. magna) were exposed to unspecified concentrations of NMP under unspecified conditions for 48 hours. A 48-hour EC50 of 1,230 mg/L was reported (Lan et al., 2004). Grass shrimp (Palaemonetes vulgaris) were exposed to unspecified nominal concentrations of NMP under static conditions for 48 hours. A 96-hour EC50 of 1,107 mg/L was reported (GAF Corp., 1979; as cited in OECD, 2007; and Verschuren, 2009). Chronic Toxicity to Aquatic Invertebrates Water fleas (D. magna) were exposed to unspecified concentrations of NMP under unspecified conditions for 21 days. A two-day NOEC of 12.5 mg/L was reported (BASF AG, 2001; as cited in OECD, 2007). Toxicity to Aquatic Plants Green algae (Scenedesmus subspicatus) were exposed to unspecified nominal concentrations of NMP under static conditions for 96 hours. A 72-hour EC50 of >500 mg/L was reported (BASF AG, 1988b; as cited in Verschuren, 2009). Toxicity to Avians Bobwhite quails (Colinus virginianus) (five male and five female) were orally dosed at concentrations of 0, 312.5, 625, 1,250, 2,500, and 5,000 mg/kg body weight of NMP for 14 days. The LD50 values ranged between 2,500 and 5,000 mg/kg body weight (Hazelton Laboratories America, 1980; as cited in OECD, 2007). Mallard ducks (Anas platyrhynchus) were exposed (through basal feed) to concentrations of 0, 156.3, 312.5, 625, 1,250, 2,500, and 5,000 ppm of NMP for eight days. No mortalities were observed and an LC50 of >5,000 ppm was derived from this study (Hazelton Laboratories America, 1979; as cited in OECD, 2007).


Appendix B. Biomonitoring Data The following paragraphs were extracted from the OECD document (OECD, 2007).

“Exposure to NMP can be evaluated by combining standard toxicokinetic methodologies with measurements of the level of 5HNMP, the principal metabolite of NMP, in plasma or urine. There is also a very good correlation between NMP exposure and the metabolites MSI and 2HMSI (Akesson and Paulsson, 1997; Jonsson and Akesson, 2003; Akesson and Jonsson, 2000; Jonsson and Akesson, 2001; Anundi et al., 2000). Within the frame work of an occupational field study, individual exposures to NMP were investigated in 7 workers and 3 scientific co-workers, who used a cleaner containing NMP to remove resin from mixing drums and tools. The average NMP concentration in the ambient air was about 3 mg/m³ in the mixing area with short-term peak concentrations of up to 19 mg/m³ in the vicinity of the cleaning activity. The parent compound NMP and metabolite 5HNMP were found in the post shift urine samples. None of the exposed workers reported symptoms such as respiratory irritation or headache. Air measurements and biomonitoring results were comparable to those reported by other working groups (Akesson and Jonsson, 2000; Anundi et al., 2000). Furthermore, it was demonstrated that dermal absorption accounts for the majority of the internal NMP burden (Bader et al., 2003; Wrbitzky and Bader, 2003). A representative end user exposure to NMP was investigated in 4 male volunteers during paint stripping of furniture using a commercial product containing NMP (19 percent), limonene (<1 percent), and dibasic ester (75 percent). The air concentrations of NMP during the 2 to 3 hour exposure period averaged 0.4 to 3.8 mg/m³. As an indication of dermal and inhalation uptake, the maximum urinary levels of NMP and 5HNMP were 0.11 mg NMP/l and 7.4 mg 5HNMP/l, respectively. Valid values for 2HMSI could not be obtained (Will et al., 2004).”


Appendix C. Occupational Exposure Assessment Support Information This appendix contains the following information:

• Derivation of NMP Concentration Conversion Factor for Occupational Exposure Calculations

• Paint Stripping Processes and Associated Worker Activities • Facility and Population Data and Information • Occupational Exposure Literature Data • Dermal Exposure Modeling

DERIVATION OF NMP CONCENTRATION CONVERSION FACTOR FOR OCCUPATIONAL

EXPOSURE CALCULATIONS A factor to convert between airborne concentrations measured in volume- or mole-based ppm and airborne concentrations measured in mg/m3 was not identified in the literature search. Therefore, a conversion factor was derived and the methodology of this derivation is presented here. To convert the units of concentration between a volume- or mole-based ppm to mg/m3 at ambient room conditions, it is assumed that the ideal gas law applies to a mixture of NMP and air at ambient conditions. The mass-based concentration of NMP in air from the ideal gas law is solved for as follows:

(C-1) where:

C = NMP concentration (mg/m3); m = total mass of NMP (mg); V = total volume of gas (m3); y = mole fraction of NMP (mol/mol); P = total pressure (atm); M = molecular weight of NMP (g/mol); R = universal gas constant (m3-atm/kmol-K); and T = temperature (K).

Here, the mole fraction of NMP, y, is equal to the NMP concentration in ppm divided by one million. At ambient conditions (one atm and 298 K), with an NMP molecular weight of 99.13


g/mol and a gas constant of 0.082 m3-atm/kmol-K, the unit conversion is 4.06 mg/m3 per ppm of NMP.

DESCRIPTIONS OF OCCUPATIONAL PROCESSES AND ACTIVITIES Techniques for paint stripping typically include manual coating, tank dipping, and spray application (TNO, 1999). Pouring, wiping, and rolling are also possible application techniques, and application can be manual or automated (ECHA, 2011). An individual’s exposure to paint stripping chemicals greatly depends on control measures taken and work practices adopted (TNO, 1999). The following sections summarize processes and activities for the industries found to employ paint stripping. Paint Stripping By Professional Contractors Paint strippers can be used by professional contractors to strip paint and varnish from walls, wood flooring, and kitchen and wood cabinets. Professional contractors are expected to purchase strippers in commercially available container sizes that commonly range from one liter up to five gallons, although they may also purchase consumer paint stripper products from hardware stores. Stripper is typically applied to wall or floor surfaces using a hand-held brush. Strippers used in these applications often have a high viscosity since they can be applied to vertical surfaces. After application, the stripper is allowed to set and soften the old coating. Once the stripper has finished setting, the old coating is removed from the surface by scraping and brushing. During wood floor stripping, old coating and stripper may also be removed using an electric floor buffer. After the old coating is removed, the surface is wiped clean before moving to the next stages of the job. The stripping process is often completed on an incremental basis with treatment for one section of wall or flooring being completed before moving to the next section (EU, 2007; IRTA, 2006; NIOSH, 1993; TNO, 1999). Paint Stripping at Automotive Body Repair and Maintenance Shops Automotive refinishing shops apply coatings to motor vehicles subsequent to the original manufacturing process. The overall refinishing process typically involves the following steps:

• Structural repair; • Surface preparation (cleaning and sanding); • Primer coat mixing; • Spray application of primer coat; • Curing; • Sanding; • Solvent wipe-down; • Topcoat (basecoat color and clearcoat) mixing; • Spray application of topcoat; and • Curing.


The surface preparation step of the refinishing process involves “removing residual wax, grease, or other contaminants from the surface to be painted, to ensure adhesion of the new coating. The new coating may be applied over an existing coating if it is free of chips or cracks after it has been roughened through sanding. Alternatively, the previous coating may be removed using a mechanical method (e.g., sanding) or a paint-removing solvent. After the coating is roughened or removed, the surface is typically wiped down with a solvent- or water-based surface preparation product” (OECD, 2010). More detailed information on the methods used to apply paint stripper to motor vehicles was not identified. Wood Furniture Stripping During furniture stripping, paint stripper may be applied to the furniture by either dipping the furniture in an open tank containing the stripper, brushing or spraying the stripper onto the furniture surface, or manually applying the stripper. Larger facilities may pump the stripper through a brush. The application method depends on the size and structure of the furniture as well as the capabilities of the facility. The application area typically has a sloped surface to allow for collection and recycling of unused stripper. Larger facilities use a flow tray to apply the stripper to parts. The flow tray is a sloped, shallow tank with a drain at the lower end. After application, the stripper is left to soak on the furniture surface to soften the surface coating. Once soaking is complete, the unwanted coating is scraped and brushed from the furniture surface. The furniture is then transferred to a washing area where residuals are washed from the furniture. Washing can be performed using low-pressure washing operations or high-pressure water jets or high-pressure wands. Wash water may contain oxalic acid to brighten the wood surface. Wash water is collected and either recycled or disposed of as waste. After washing, the furniture is transferred to a drying area where it is allowed to dry before being transferred to other refinishing processes (e.g., sanding, painting, reupholstery) (IRTA, 2006; HSE, 2001; NIOSH, 1990, 1992). Larger facilities likely purchase stripper in drum quantities from suppliers. Smaller facilities that use hand stripping instead of stripping equipment likely purchase their stripper from hardware and home improvement stores. Stripper applied using application equipment has low viscosity so it can be pumped through the pumps in the flow tray. Stripper applied using hand stripping are typically more viscous so they will remain on the part long enough to strip the coating (IRTA, 2006). Figure C-1 shows a typical flow tray used by larger furniture strippers to apply stripper to furniture parts, obtained from IRTA (2006). Figure C-2 shows a typical water wash booth used to wash stripper and coating residue from stripped furniture, obtained from IRTA (2006). Figure C-3 shows an example diagram of a dipping tank for furniture stripping complete with local exhaust ventilation, obtained from HSE (2001).


Figure C-1. Typical Flow Tray for Applying Stripper to Furniture (IRTA, 2006).

Figure C-2. Typical Water Wash Booth Used to Wash Stripper and Coating Residue from Furniture (IRTA, 2006).


Figure C-3. Example Diagram of a Dipping Tank for Furniture Stripping (HSE, 2001). Art Restoration and Conservation Art restoration and conservation can include the care and maintenance of paintings to reverse negative effects of aging and dirt accumulation. It can also include repairing paintings that have suffered paint loss, weakened canvas, tears, water damage, fire damage, and insect damage (Smithsonian, 2012a). Art restoration and conservation can include paint cleaning, which can entail removing dirt and other obscuring material, removing varnish, or removing overpaint while maintaining the original layer of paint (Smithsonian, 2012b). These activities can involve the use of paint strippers. Although paint strippers used in this field can contain DCM, the use of DCM is not always favored as DCM can penetrate through the overpaint layer that is being removed and into the original paint layer that is being conserved. NMP may serve as a suitable alternate for DCM in strippers used in this field (Wollbrinck, 1993). More detailed information on the use of paint strippers in art restoration and conservation was not identified. It is anticipated that paint strippers are applied manually in this field. Aircraft Paint Stripping During aircraft paint stripping, paint stripper is pumped from bulk storage containers and applied to the body of the aircraft using hoses. Once the paint stripper has been applied, it is allowed to set for a certain period of time (usually about 30 minutes) to allow the paint to soften. Once setting is complete, the stripper and loose paint are scraped down into a collection area. Any remaining stripper and paint residue are then brushed away with water


and brushes. Once the surface of the aircraft has dried, a new layer of primer, paint, and top coat are applied (NIOSH, 1977). Ship Paint Stripping Process description information for paint stripping of ships has not been identified. It is anticipated that paint stripping of ships may involve similar processes as the paint stripping of aircraft.

FACILITY AND POPULATION DATA This section summarizes data on the number of establishments, number of paid employees and workers, and production hours and work day estimates (for manufacturing industries). It may be noted that population demographics were not examined for this assessment, but may be worthy of consideration in a more detailed assessment. For example, some segment of the worker population could include children (e.g., teenagers). Paint Stripping By Professional Contractors Table C-1 summarizes the number of establishments and average number of construction workers for painting and wall covering contractors and flooring contractors according to the 2007 US Economic Census. The Census data do not include hours worked for construction industry sectors. Note that these Census data do not include bathtub refinishers/reglazers. Census data that include bathtub refinishers/reglazers were not identified. Table C-1. 2007 US Economic Census Data for Painting and Wall Covering and Flooring Contractors.

2007 NAICS 2007 NAICS Title 2007 Number of Establishments

2007 Average Number of Construction Workers

238320 Painting and Wall Covering Contractors

35,619 174,276

238330 Flooring Contractors 14,575 49,085 Source: US Census (2007a). The number of painting and wall covering contractors and flooring contractors who use NMP-based paint strippers, or the number of jobs per yr a contractor uses NMP-based paint strippers, and the exact number of construction workers within a job site exposed to NMP-based paint strippers are unknown. Therefore, the number of establishments and construction workers from the US Census are possibly overestimates of the number of establishments and construction workers potentially exposed to NMP during paint stripping. Paint Stripping at Automotive Body Repair and Maintenance Shops Table C-2 summarizes the number of establishments and average number of paid employees for automotive body, paint, and interior repair and maintenance according to the 2007 US Economic Census. The Census data do not include hours worked for this industry sector.


Table C-2. 2007 US Economic Census Data for Automotive Body, Paint, and Interior Repair and Maintenance.


2007 Number of Paid Employees

811121 Automotive Body, Paint, and Interior Repair and Maintenance

35,581 223,942

Source: US Census (2007a). The present day number of automotive body repair and maintenance shops within the US that use NMP-based paint strippers, and the number of employees within an establishment exposed to NMP-based paint strippers are unknown. Therefore, the number of establishments and employees from the US Census are possibly overestimates of the number of establishments and employees potentially exposed to NMP during paint stripping. Wood Furniture Stripping Table C-3 summarizes the number of establishments and average number of paid employees for reupholstery and furniture repair according to the 2007 US Economic Census. The Census data do not include hours worked for this industry sector. Table C-3. 2007 US Economic Census Data for Reupholstery and Furniture Repair.



811420 Reupholstery and Furniture Repair

4,693 16,142

Source: US Census (2007a). The present-day number of reupholstery and furniture repair establishments that use NMP-based paint strippers and the number of employees within an establishment exposed to NMP-based paint strippers are unknown. Therefore, the number of establishments and employees from the US Census are possibly overestimates of the number of establishments and employees potentially exposed to NMP during paint stripping. Art Restoration and Conservation Table C-4 summarizes the number of establishments and average number of paid employees for independent artists, writers, and performers and museums according to the 2007 US Economic Census. The Census data do not include hours worked for these industry sectors.


Table C-4. 2007 US Economic Census Data for Industry Sectors that May Engage in Art Restoration and Conservation Activities.



711510 Independent Artists, Writers, and Performers

20,612 48,321

712110 Museums 4,664 83,899 Source: US Census (2007a). NAICS code 711510 includes a wide variety of professions, including independent art restorers and independent conservators. The majority of the professions listed within this NAICS code according to the US Census Bureau are not expected to engage in paint stripping. Furthermore, the extent that art restorers and conservators engage in paint stripping, particularly using NMP-based paint strippers, is unknown. Similarly, the number of museums within NAICS code 712110 that engage in paint stripping, and use NMP-based paint strippers, is unknown. Therefore, the number of establishments and employees from the US Census are likely overestimates of the number of establishments and employees potentially exposed to NMP during paint stripping. Aircraft Paint Stripping Table C-5 summarizes the number of establishments, average number of production workers, and production workers hours for aircraft manufacturing according to the 2007 US Economic Census. The table also estimates the average worker days per yr and average worker hours per day. These parameters are estimated from the production workers hours and the average number of production workers. The average worker days per yr are estimated assuming eight worker hrs/day, and the average worker hours per day are estimated assuming 250 worker days/yr. The estimates of worker days per yr and worker hours per day are within 10 percent of the EPA New Chemicals Program default values of 250 days/yr and eight hrs/day, respectively. Table C-5. 2007 US Economic Census Data for Aircraft Manufacturing.

2007 Economic Census Data Parameters Calculated from the Corresponding 2007 Economic

Census Data

2007 NAICS Code

2007 NAICS Title

Number of Establishments

Average Number of Production

Workers

Production Workers

Hours (1,000 Hrs)

Average Worker Days per Yr (Assuming 8 hrs/day)

Average Worker Hours

per Day (Assuming 250

Days/yr)

336411 Aircraft Manufacturing

254 81,456 157,589 242 7.74

Source: US Census (2007a).


The present-day number of aircraft manufacturing establishments that use NMP-based paint strippers and the number of employees within an establishment exposed to NMP-based paint strippers are unknown. Therefore, the number of establishments and employees from the US Census are possibly overestimates of the number of establishments and employees potentially exposed to NMP during paint stripping. Ship Paint Stripping Table C-6 summarizes the number of establishments, average number of production workers, and production workers hours for ship building and repairing according to the 2007 US Economic Census. The table also estimates the average worker days per yr and average worker hours per day. These parameters are estimated from the production workers hours and the average number of production workers. The average worker days per year are estimated assuming eight worker hrs/day, and the average worker hours per day are estimated assuming 250 worker days/yr. The estimates of worker days per yr and worker hours per day are within 10 percent of the EPA New Chemicals Program default values of 250 days/yr and eight hrs/day, respectively. Table C-6. 2007 US Economic Census Data for Ship Building and Repairing.

2007 Economic Census Data Parameters Calculated from

the Corresponding 2007 Economic Census Data

2007 NAICS Code

2007 NAICS Title

Number of Establishments

Average Number of Production

Workers

Production Workers

Hours (1,000 Hs)

Average Worker Days

per Yr (Assuming

8 Hours/day)

Average Worker Hours

per Day (Assuming

250 Days/yr)

336611 Ship building and repairing

656 65,737 136,929 260 8.33

Source: US Census (2007a). The number of ship building and repair establishments that use NMP-based paint strippers and the number of employees within an establishment exposed to NMP-based paint strippers are unknown. Therefore, the number of establishments and employees from the US Census are possibly overestimates of the number of establishments and employees potentially exposed to NMP during paint stripping. Respiratory Protection The 13 MSDSs for paint strippers obtained through the literature search were reviewed for recommended respiratory protection information. Of these 13 MSDSs, only three contained NMP, one of which also contained DCM. One of the NMP-only MSDSs recommends a NIOSH-approved respirator for organic solvent vapors without further specification of the respirator type (WM Barr, 2011). The second NMP-only MSDS recommends that a “NIOSH/MSHA-


approved air-purifying respirator with an organic vapor cartridge or canister may be permissible under certain circumstances where airborne concentrations are expected to exceed exposure limits” (WM Barr, 2009a). It further states that protection provided by air-purifying respirators may be limited, in which case, a positive pressure, air-supplied respirator is recommended (such as for uncontrolled releases or unknown exposure levels) (WM Barr, 2009a). The MSDS for the paint stripper that contained both DCM and NMP recommends a NIOSH-approved self-contained breathing apparatus (SCBA) (WM Barr, 2009b). However, the recommendation for SCBA is likely heavily influenced by the presence of DCM in addition to NMP. Dermal Protection The 13 MSDSs for paint strippers obtained through the literature search were reviewed for recommended dermal protection information. Of these 13 MSDSs, only three contained NMP, one of which also contained DCM. All of the three MSDSs recommend either chemical-resistant or impermeable gloves. One MSDS recommended nitrile gloves and another recommended nitrile or neoprene gloves. All of the three MSDSs recommend safety glasses, chemical goggles, or face shields for eye protection or where eye or face contact is likely (WM Barr, 2009b, a, 2011).

OCCUPATIONAL INHALATION EXPOSURE LITERATURE DATA This assessment uses existing exposure data to estimate occupational exposures to NMP by inhalation. Several exposure studies were identified through a literature search. Paint Stripping by Professional Contractors In 1993, NIOSH was requested to conduct a health hazard evaluation (HHE) during the renovation of an antique residence in Atlanta, Georgia. NIOSH was requested to conduct the HHE by the owner of a wood flooring and restoration company for the purpose of assessing exposures during the use of an experimental solvent to remove paint from the wood floor of the building. The solvent was highly viscous, had a pH of two to three and a vapor pressure of five to six mmHg at 20 oC, and its primary component was NMP (at 65 to 79 percent). The renovation work was conducted entirely by the company owner. NIOSH conducted air sampling on November 27 and December 14, 1993 and obtained personal breathing zone and area air samples (NIOSH, 1993). The worker paint stripped the floor using a passive refinishing method. In this method, the worker brush-applies the solvent to the floor, allows it to set for 30 to 60 minutes, then uses a powered electric buffer with bristles to agitate and dislodge the loosened paint. The worker then uses a rubber squeegee to remove the spent solvent-paint mixture and mixes it with sawdust for disposal. Sawdust is applied to the floor, scrubbed with a wire brush, and scraped with a putty knife. The worker applies a water-alcohol mixture and additional sawdust to the floor, performs additional buffing with an abrasive disc, and repeats the process if needed (NIOSH, 1993).


On the November 22nd sampling day, the average concentration of the personal, breathing zone samples was 3.3 ppm (13.4 mg/m3) (sampling times ranged from 46 to 93 minutes). Area samples taken at two feet and five feet above the floor had average concentrations of 3.9 ppm (15.8 mg/m3) and 3.6 ppm (14.6 mg/m3), respectively (sampling times ranged from 40 to 127 minutes). The door to the room was kept closed for the duration of the work, but the window was both closed and opened during the work day. The lowest concentrations were observed while the window was open and while solvent was not being applied to the floor (NIOSH, 1993). On the December 14th sampling day, the average concentration of the personal, breathing zone samples was 4.0 ppm (16.2 mg/m3) (sampling times ranged from 43 to 52 minutes). Area samples taken two feet above the floor had an average concentration of 7.7 ppm (31.2 mg/m3) (sampling times ranged from 42 to 46 minutes). The door to the room was again kept closed for the duration of the work, but the window was also kept closed the entire work day due to inclement weather. The higher concentrations were expected due to the closed window as compared to the first sampling day (NIOSH, 1993). NIOSH noted that the worker wore a half-mask air-purifying respirator with organic vapor cartridges during the paint stripping process. NIOSH further noted that protective gloves were used intermittently and no mechanical ventilation was used during the renovation (NIOSH, 1993). An EU report states that there is “probably…no fundamental difference between the application of paint removers by professional painters and consumers” and goes on to further state that, in regard to the cited consumer exposure studies, “the test situations and data described…are assumed valid for occupational exposure during professional use as well” (TNO, 1999). However, professional contractors are expected to have a higher frequency of exposure as compared to consumers. It is also not clear whether overall activity patterns and practices of contractors match those of consumers or whether the overall distributions of exposures of contractors and consumers have any semblance to one another. Despite these uncertainties, some of the literature data for consumers may be considered. Midwest Research Institute (MRI) prepared a report for EPA in 1994 that resulted from an experimental investigation of consumer exposures to solvents contained in paint stripping products with eliminated or reduced DCM content. MRI investigated five paint strippers, two of which contained DCM (along with other solvents, but the concentrations were not specified). The paint stripping was conducted in a laboratory-based, environment-controlled, room-sized test chamber. The paint strippers were used on a plywood panel coated with a primer coat and two finish coats. The air exchange rate for the experiments ranged from 0.54 to 0.76 ACH, with an average of 0.58 ACH. The air exchange rate of approximately 0.5 ACH was intended to replicate the ventilation rate of an enclosed room in a typical residence as a worst-case scenario. During each experiment, the following samples were taken: a personal breathing zone sample of the test subject using the paint stripper; two stationary air samples for the


duration of the paint stripping task; and one stationary air sample beginning at the start of the paint stripping and lasting for eight hours (US EPA, 1994b). In the MRI investigation, the only NMP-based paint stripper was brush applied. The breathing zone concentrations of NMP ranged from 37 to 39 mg/m3 (9.1 to 9.6 ppm). The stationary length-of-task concentrations ranged from 38 to 45 mg/m3 (9.4 to 11.1 ppm). The eight-hour TWA concentrations ranged from 46 to 74 mg/m3 (11.3 to 18.2 ppm) (US EPA, 1994b). Paint Stripping at Automotive Body Repair and Maintenance Shops NMP exposure data from paint stripping during automotive body repair and maintenance were not identified. Wood Furniture Stripping NMP exposure data from paint stripping of wood furniture were not identified. Art Restoration and Conservation NMP exposure data associated with art restoration and conservation were not identified. Aircraft Paint Stripping NMP exposure data from paint stripping of aircraft were not identified. Ship Paint Stripping NMP exposure data from paint stripping of ships were not identified. Paint Stripping in Graffiti Removal and other Non-specific Workplace Settings Some NMP exposure data were identified for which work place settings were not specified and more specific information on the industries (such as applicable NAICS or Standard Industrial Classification [SIC] codes, primary industrial functions or products, or number of sites or workers) were not provided in the identified reference. A 2001 report by the World Health Organization (WHO) identified NMP exposures from graffiti removers in the literature. Personal breathing zone concentrations were as high as 10 mg/m3 (2.5 ppm) for both peak exposure and eight-hour TWA exposure (WHO, 2001). A literature search conducted by the NMP Producer’s Group identified four studies of graffiti removing (ranging from 1993 to 2004), which resulted in short-term exposures ranging from 0.01 to 30 mg/m3 (0.002 to 7.4 ppm), and eight-hour TWA exposures ranging from 0.03 to 4.52 mg/m3 (0.007 to 1.1 ppm) (NMP Producer's Group, 2012). The same WHO report also identified NMP exposures in a non-specified paint stripping industry in the literature. Personal breathing zone samples had eight-hour TWA exposures as high as 64 mg/m3 (16 ppm) and one-hour peak exposures as high as 280 mg/m3 (69 ppm) (WHO, 2001). The NMP Producer’s Group literature search results were in general agreement with the WHO report. The NMP Producer Group identified four studies of non-specified paint stripping activities with peak exposure as high as 280 mg/m3 (69 ppm) (the same study cited in the WHO


report). Additional exposures from additional studies were identified as low as 0.01 mg/m3 (0.002 ppm), but the sampling time was not specified (NMP Producer's Group, 2012).

DERMAL EXPOSURE MODELING Dermal exposure modeling was employed to estimate dermal exposures to NMP in liquid products. A summary of relevant data from the literature search and the modeling information follows. Direct exposures to children (e.g., teenagers) who may use these products in work, training, or other situations are not expected to differ significantly from that of adults; therefore, their exposures would likewise not be expected to differ significantly. Dermal exposure data of NMP specifically as related to paint stripping were not identified during the literature search. Some permeability information was found. A 1995 experimental investigation measured the permeability of various solvents through living human skin. The permeability rate of NMP was measured to be 171 g/m2-hour (Ursin et al., 1995). Also, a European report on NMP calculated dermal exposure dose to NMP assuming a maximum absorption through the skin of 100 percent (SCCS, 2011). This assessment estimates dermal exposures to liquid products containing NMP using EPA models. EPA has developed a series of standard models for quantitatively estimating worker dermal exposures to liquid and solid chemicals during various types of activities; this series of models cannot be used for dermal exposures to vapors. To estimate dermal exposure, all of these dermal exposure models assume that a specific surface area of the skin is contacted by a material containing the chemical of interest, as well as a specific surface density of the material on the skin (quantity of the liquid or solid material containing the chemical that remains on the skin after contact, in mg/cm2-event). The models also assume no use of controls or gloves to reduce the exposure. These assumptions and default parameters are defined based on the nature of the exposure (e.g., one hand or two hand, immersion in material, contact with surfaces). The standard EPA dermal model equation is shown in Equation C-2 (US EPA, 1991a, 2000).

(C-2) where:

EXPdermal = dermal exposure, as a potential dose rate, to the liquid or solid chemical per day (mg chemical/worker-day);

AREAsurface = surface area of the skin that is in contact with liquid or solid material containing the chemical (840 cm2; EPA/OPPT 2-Hand Dermal Contact with Liquid Model);

Qremain_skin = quantity of the liquid or solid material containing the chemical that remains on the skin after contact (0.7 to 2.1 mg/cm2-event; EPA/OPPT 2-Hand Dermal Contact with Liquid Model);


Fchem = weight fraction of the chemical of interest in the material being handled in the activity (assume 1; i.e., up to 100 percent NMP); and

Nevent = frequency of events for the activity (EPA default = one event/worker-day). Dermal dose rates in this report are estimated in units further normalized by worker body weight, as indicated in Equation C-3:

(C-3) where:

EXPdermal_bw = dermal exposure, as a potential dose rate, to the liquid or solid chemical per day normalized by worker body weight (mg chemical/kg-day);

EXPdermal = dermal exposure to the liquid or solid chemical per day (mg chemical/worker-day); and

BWworker = body weight of an average worker (kg; EPA default value = 80 kg (US EPA, 2011c).

It is important to note that this EPA dermal exposure model uses a default value of one exposure event per worker per day. However, highly volatile or high skin absorption chemicals can cause variations of surface densities, which can also be impacted by the number of exposure events per worker per day. If a chemical with high skin absorption, such as NMP, absorbs into the worker’s skin during the worker’s shift, the worker’s additional exposure events of NMP during the shift can serve to replenish the surface density. Therefore, the EPA default value of one exposure event per worker per day may not be appropriate for NMP; however, a more appropriate value has not been determined. Dermal exposures to NMP liquid are estimated using the EPA/OPPT 2-Hand Dermal Contact with Liquid Model and the default values provided above. Assuming a stripper content of 100 weight percent NMP, the following values are estimated: dermal exposure to liquid (EXPdermal) of 590 to 1,800 mg NMP/day as potential dose rates, and dermal exposure normalized by body weight (EXPdermal_bw) of 7.4 to 22 mg NMP/kg-day as acute potential dose rates. Also, assuming a maximum absorption through the skin of 100 percent (SCCS, 2011), absorbed dose rates may be assumed to be equal to potential dose rates.


Appendix D. Consumer Exposure Assessment

ESTIMATION OF EMISSION PROFILES FOR PAINT REMOVERS/STRIPPERS In 1993, MRI conducted a series of chamber studies for EPA on five paint stripping products, including two containing DCM and one containing NMP, as shown in Table D-1 (US EPA, 1994b). For each study, continuous air concentrations were measured using a Fourier transform infrared (FTIR) spectrometer. In addition, three stationary samplers and a personal sampler were used to collect an integrated sample on activated charcoal. These data were analyzed and a process was undertaken to fit the data to exponential equations to represent the time-varying emission profile that led to the air concentrations. Table D-1. MRI Studies: Products Emissions Fit to Exponential Profile.

Product Application Type Chemical

BIX Spray-On Stripper Spray DCM

Strypeeze Brush DCM

Wood Finisher’s Pride Brush NMP

In evaluating the experimental data, an exponential emission was chosen because of the general shape of the concentration profile and similarity to other emission behavior (e.g., chemicals from paint). The emission equation has the following form:

(D-1) where: E0 = initial emission rate (the emission rate at t = 0), mg/hour k = first-order rate constant, hour-1 t = time since application, hour Integrating Equation C-1 to time of infinity gives the mass released represented by the exponential, as follows:

Mass Released (D-2) or: E0 = (Mass Released) * k (D-3)


Integration of the single compartment, mass-balance equation for the air concentration equation for a single and double exponential representation of the emissions is given in Equations D-4 and D-5 (US EPA, 1997), respectively.

(D-4) where: V = chamber volume, m3

Q = air flow rate in and out of the chamber, m3/hour

(D-5) where: E01 = initial emission rate for the first exponential, mg/hour E02 = initial emission rate for the second exponential, mg/hour k1 = first-order rate constant for the first exponential, hour-1 k2 = first-order rate constant for the second exponential, hour-1 The two DCM products were applied in eight, approximately one-minute applications, with each one-minute application followed by an approximately 10-minute wait time prior to the start of the subsequent application, resulting in about 11 minutes between applications. In each case, the emissions from each application are represented by a single or double exponential, with each exponential identical to the other seven, but with a different start time set at the midpoint of the application period. Based on this approach, the start times of the eight DCM exponentials are 0.5, 11.5, 22.5, 33.5, 44.5, 55.5, 66.5, and 77.5 minutes from the start of the stripping activity, respectively. For the two DCM products, a single exponential was found to provide a good fit to the data. The fitting process involves:

(1) Extracting measured concentration values from the US EPA (1994b) data and co-plotting the points with Equation D-4. The concentration values were extracted for runs 4, 5, and 6 for BIX Spray-On and runs 7, 8, and 9 at each 0.5-hour time point as well as peaks and significant changes in slope. This resulted in eight or nine data points per run.

(2) Calculating the mass of DCM applied during the test and assigning 1/8th of the applied mass to each of the eight exponentials.

(3) Iterating to obtain the best fit to the experimental data by varying the “Fraction Released” and the first-order rate constant (k) using Equation D-4 and the following relationship:


E0 = (Mass Applied) * (Fraction Released) * k (C-6)

This analysis was conducted using Excel to solve the equations and plot the results. The best fit was arrived at by visual comparison of the results of Equation D-4 with the extracted US EPA (1994b) data, attempting to fit the Equation D-4 curve midway between the maximum and minimum values of the data. In general, the height of the concentration curve is related primarily to the DCM mass released, and the length and shape of the decay portion of the curve is closely related to the first-order rate constant, k. The resulting fit for the BIX Spray-On Stripper product is shown in Figure D-1 and the fit for the Strypeeze product (brush application) is shown in Figure D-2. In each figure, the underlying eight exponentials are shown in the lower part of the figure, with the sum shown as the fitted, dashed line. The parameters for these two DCM cases are shown in Table D-2.

Figure D-1. Model Fit to MRI (US EPA, 1994b) Data for BIX Spray-On (Spray Application).


Figure D-2. Model Fit to MRI (US EPA, 1994b) Data for Strypeeze (Brush Application). Table D-2. Fitted Parameters to the US EPA (1994b) Study Results for the Two DCM-Containing Paint Strippers.

Product Mass of Product Applied, g

DCM Mass Applied, g

DCM Fraction Released

First-Order Rate Constant, Hour-1

BIX Spray-On Stripper 540 495 0.66 10

Strypeeze 722 121 0.33 10

A numerical integration of the fitted “sum of 8 exponentials” shown in Figures D-1 and D-2 was performed by using the average concentration for each one-minute interval and conducting a mass-balance calculation for the test chamber, accounting for the mass in the chamber and the mass that has been removed through ventilation. The resulting mass released from the product as a function of time is shown in Figures D-3 and D-4 for BIX Spray-On and Strypeeze stripper, respectively.


Figure D-3. Theoretical Cumulative Mass of DCM Released for BIX Spray-On Stripper.

Figure D-4. Theoretical Cumulative Mass of DCM Released for Strypeeze Stripper.

111 minutes

111 minutes


The NMP-containing product, Wood Finisher’s Pride, was fit in a similar manner as the two DCM-containing products. A double exponential was needed to provide an acceptable fit to the data, due to the lower volatility of NMP and the resulting longer tail to the emission profile shown in the US EPA (1994b) study, runs 10, 11, and 12. The first exponential is used to represent the rapid rise during application and the second exponential is used to capture the extended “slower” release of chemicals from the surface after application. The study applied the product in eight, approximately 30-second applications, followed by an approximately 10.5-minute wait time prior to the start of the subsequent application, resulting in about 11 minutes between applications. The emissions from each application are represented by a double exponential, with each pair of exponential identical to the other seven pairs, but with a different start time set at the midpoint of the application period. Based on this approach, the start times of the eight NMP double exponentials are 0.25, 11.25, 22.25, 33.25, 44.25, 55.25, 66.25, and 77.25 minutes from the start of the stripping activity, respectively. For Wood Finisher’s Pride, the fitting process involved:

1. Extracting measured concentration values from the US EPA (1994b) data and co-plotting the points with Equation D-5. The concentration values were extracted for runs 10, 11, and 12 at each 0.5-hour time point as well as the peak value. This resulted in 11 data points per run.

2. Calculating the mass of NMP applied during the test and assigning 1/8th of the applied mass to each of the eight double exponentials.

3. Iterating to obtain the best fit to the experimental data by varying the “Fraction Released” and the first-order rate constant (k) using Equation D-5 for the first and the second exponential and the following relationships:

E01 = (Mass Applied) * (Fraction Released in the 1st Exponential) * k1 (D-7) E02 = (Mass Applied) * (Fraction Released in the 2nd Exponential) * k1 (D-8)

Excel was used to solve Equation D-5 and plot the results. The best fit was arrived at by visual comparison of the results of Equation D-5 with the extracted US EPA (1994b) data, attempting to fit the Equation D-5 curve midway between the maximum and minimum values of the data. The resulting fit for is shown in Figure D-5, with the underlying eight exponentials shown in the lower part of the figure, with the sum shown as the fitted, dashed line. The parameters for the Wood Finisher’s Pride case are shown in Table D-3.


Figure D-5. Model Fit to MRI (US EPA, 1994b) Data for Wood Finisher’s Pride (Brush Application). Table D-3. Fitted Parameters to the US EPA (1994b) Study Results for Wood Finisher’s Pride.

Product Mass of Product

Applied, g

NMP Mass Applied, g

1st Exponential 2nd Exponential

NMP Fraction Released

First-Order Rate Constant,

Hour-1

NMP Fraction Released

First-Order Rate Constant,

Hour-1

Wood Finisher’s Pride

866 390 0.02 10 0.24 0.05

In a similar manner to the numerical integration described above, a numerical integration of the fitted “sum of 8 exponentials” shown in Figure D-5 yielded the mass released relationship shown in Figure D-6 for Wood Finisher’s Pride.


Figure D-6. Theoretical Cumulative Mass of NMP Released from Wood Finisher’s Pride. Discussion and Conclusions From the exponential fits to the US EPA (1994b) data, we estimate that 66 percent of the applied DCM in the spray product (Figure D-1) was released to air, versus 33 percent of the applied DCM in the brush product (Figure D-2). We estimate that virtually all of the 66 and 33 percent of the DCM mass will be released by two hours after application for the spray and brush product, respectively, very shortly after the last scraping is finished, due to the higher volatility. Thus, the concentration-decline part of Figures D-1 and D-2, after the peak, is due almost exclusively to ventilation rather than to declining emissions, and therefore, these exposures could be virtually eliminated through ventilation. On the other hand, for the NMP brush-on product, only about two percent of the applied mass is accounted for by the first exponential. For the second exponential, the percent accounted for depends on the duration of the activity and resulting exposure, as the off-gassing after application is very slow. Three hours after the start of the run, about 4.7 percent of the applied NMP mass is accounted for by the two exponentials (two percent by the first exponential and 2.7 percent by the second exponential). At 24 hours, about 18 percent of the applied NMP mass was accounted for (two percent by the first exponential and 16 percent by the second exponential). Integrating the two exponentials to time of infinity yields a prediction of a total potential release of 26 percent of the applied NMP. US EPA (1994b) had no NMP spray-on stripper products, so a release fraction from a spray could not be derived from measured data. Instead, the ratio of DCM spray to brush-on release fractions, 0.66/0.33, was applied to the brush-on NMP release fraction of 0.26 to estimate a release fraction of 0.52 for NMP in a spray-on product. Factors that should be considered in applying these findings to a model-based approach using MCCEM include the effect of varying the product use behavior and the effect of the quantity of the chemical applied. It appears that the off-gassing rate is a function of the mass applied and


the duration of application; based on the limited data available, the emission rate does not exhibit significant inhibition of volatilization due to increased concentrations in the range of air concentrations observed in the US EPA (1994b) study. If this holds true, then the results of this analysis can be applied to a variety of product use behavior by modifying MCCEM to represent this behavior. MCCEM’s capability of representing the application as an incremental exponential may further improve the representativeness of the predicted concentrations.

SENSITIVITY ANALYSIS FOR INHALATION SCENARIOS For this analysis, each input that could be measured on a continuum (e.g., emission rate, airflow rate) was first halved and then doubled while holding all others at their base-case values. For an input to which the model output is directly and linearly proportional, and for which the exposure measure for the base case is denoted as X, the result for the halved case would be ½X and the result for the doubled case would be 2X. Computing and averaging the two differences from the base case gives the following result: ([X-1/2X] + [2X-X]) / 2) / X = ¾ or 75% (D-9) For an input that cannot be varied over a continuum, or that can be dealt with only discretely or perhaps dichotomously (e.g., in the use zone or not at certain key times), the above procedure can still be used but the sensitivity measure reduces to: |Y-X| / X (expressed as a percent) (D-10) Where Y is the output associated with the change in location pattern from the base case.

INHALATION EXPOSURE SCENARIO INPUTS Model Inputs Method of Application. A review of product labels and technical data sheets indicates that paint stripping products can be applied using either brush-on or spray-on (i.e., aerosol or trigger-pump) application methods. Exposures were assessed for both brush-on and spray-on products due to differences in chemical release characteristics, NMP weight fraction of products, application rates, and time required for application, as discussed below. Application Amount (Product Mass). The product application mass (grams of product) was determined using application rates (g/ft2) calculated from the chamber tests in US EPA (1994b) and the surface area of objects to be stripped (ft2). Surface areas were selected so that the resulting product mass corresponded approximately to central (near the median) and upper-end (near the 90th percentile) estimates for the amount of paint stripper product used per event from the large nationwide Abt (1992) survey, as reported in EFH Table 17-20. EFH reports a median value of 32 fluid ounces or ¼ gallon. Conversion to metric units (3.75 L/gallon) and consideration of the nominal product density (~1.1 g/cm3) (calculated from


Brown, 2012) yields a product mass on the order of 1,000 g as a central estimate. An upper-end application amount (~80th percentile) from the same survey is 80 ounces or 2,500 g. Similarly, the small Riley et al. (2001) survey reported 32 ounces as the median amount of paint stripper product used. Specific product masses used in this assessment for the brush-on scenarios were 1,080 g for Scenarios 1 and 2, 2,700 g for Scenario 3, and 3,888 g for Scenarios 7 and 8. Product masses for the spray-on scenarios were 810 g for Scenarios 4 and 5 and 2,025 g for Scenario 6. As previously mentioned, the application amounts assumed in this assessment for Scenarios 1 through 6 are a product of application rates calculated from the US EPA (1994b) experiments and the surface area of objects to be treated. The calculated application rate was ~108 g/ft2 for the brush-on application (866 g of product applied to eight ft2). There were no US EPA (1994b) applications involving NMP-containing spray-on strippers. Consequently, the DCM brush/spray ratio (540 g/722 g) was applied to the NMP brush amount of 108 g/ft2 to estimate the NMP spray application, resulting in an estimated NMP spray product application rate of 81 g/ft2 (648 g of product applied to eight ft2). These application rates are similar to those recommended on the Savogran Company website for paint strippers in general, one gallon per 50 to 100 ft2 (~42 to 83 g/ft2 based on a nominal density of 1.1 g/cm3) (Savogran, 2012). The applied surface areas selected for central and upper-end values were 10 and 25 ft2, respectively. The upper-end surface area is 2.5 times higher than the central surface area and provides sufficient distinction from the central case. Application targets with surface areas close to the two specified surface areas (10 and 25 ft2) were used in the exposure scenarios to reflect real-world situations. A coffee table with nominal dimensions of 4 feet × 2.5 feet for the top surface was selected for the central case (10 ft2) (Abbas, 2012) and a chest of drawers with nominal dimensions of 4 feet high by 2.5 feet wide by 1.5 feet deep (American Unfinished Furniture, 2012 shows an illustrative chest of drawers with nearly the same dimensions) was selected for the upper-end case (4 × 2.5 ft2 for front + 2.5 × 1.5 ft2 for top + 2 × 4.5 × 1.5 ft2 for sides ≈ 25 ft2). For the bathroom scenario, a bathtub surface area of 36 ft2 was calculated assuming nominal dimensions of five feet wide by 2.5 feet deep by 1.5 feet high. Stripping Sequence. The sequence chosen to characterize product application was intended to be consistent with labeling instructions. The stripping event consisted of an initial stripping sequence (apply-wait-scrape) followed by a second stripping sequence. The NMP product labels advise that the stripper be applied to the object followed by a wait period of at least 30 minutes (up to 24 hours). The labels generally do not indicate that the product needs to be applied in small sections. The application sequence is also supported by Internet discussion forums suggesting that an advantage to NMP formulations is that they allow the user more flexibility because the product will not evaporate (OldHouseOnline, 2012). The application time was derived from the US EPA (1994b). From the protocol description in that report, it was deduced that the NMP stripper was brush-applied at a rate of two ft2/minute and spray applied at a rate of four ft2/minute. It was further assumed that the scrape time was double the application time, meaning that the surface was scraped at a rate of one ft2/minute.


For the bathtub case (Scenarios 7 and 8), because of the larger surface area, the application and scrape times were scaled up proportionally to 18 and 36 minutes, respectively. The scaled initial and secondary application times, wait times, and scrape times are summarized in Table D-4. Table D-4. Time Schedule for Paint Stripping with Repeat Application.

Scenario Elapsed Time From Time Zero, Minutes (Product User Location)

Apply 1 Wait 1 Scrape 1 Apply 2 Wait 2 Scrape 2


0-5 (workshop)

5-35 (ROH) 35-45 (workshop)

45-50 (workshop)

50-80 (ROH)

80-90 (workshop)


0-5 (workshop)

5-35 (workshop)

35-45 (workshop)

45-50 (workshop)

50-80 (Workshop)

80-90 (workshop)


0-12.5 (workshop)

12.5-42.5 (ROH)

42.5-67.5 (workshop)

67.5-80 (workshop)

80-110 (ROH)

110-135 (workshop)


0-2.5 (workshop)

2.5-32.5 (ROH)


42.5-45 (workshop)

45-75 (ROH)

75-85 (workshop)


0-2.5 (workshop)

2.5-32.5 (workshop)


42.5-45 (workshop)

45-75 (workshop)

75-85 (workshop)


0-6.25 (workshop)

6.25-36.25 (ROH)

36.25-61.25 (workshop)

61.25-67.5 (workshop)

67.5-97.5 (ROH)

97.5-122.5 (workshop)


0-18 (bathroom)

18-48 (ROH)

48-84 (bathroom)

84-102 (bathroom)

102-132 (ROH)

132-168 (bathroom)


0-18 (bathroom)

18-48 (ROH)

48-84 (bathroom)

84-102 (bathroom)

102-132 (ROH)

132-168 (bathroom)

Amount of Chemical Released. The amount of chemical released during and after the stripping event is the product of three parameters: amount applied (discussed above), weight fraction of chemical in the applied product, and fraction of the chemical that is released to indoor air. From the product list developed by Brown (2012), the median NMP weight fraction was determined to be 0.25 for the brush-on application (range of 0.03 to 0.53) and 0.44 for the spray-on application (range of 0.28 to 0.53). The weight fractions were determined from the Brown (2012) spreadsheet by using only products intended for consumer use (i.e., adhesive removers, paint brush cleaners, deglossers, and industrial/commercial use products were


removed). The application method (brush-on or spray-on) for a product was determined by examining the product labels/technical data sheets and product names, and through Internet research. If an application method could not be determined through the above methods, then the product was assigned to the brush category, as most paint stripping products are applied by the brush method, and formulations such as semi-paste would be difficult to apply using a sprayer. If a weight fraction range was provided in the product list, then the average of the minimum and maximum weight fractions was used in calculations. The weight fractions were not weighted to reflect the market share of products. Analysis of the US EPA (1994b) data (see Estimation of Emission Profiles for Paint Removers/Strippers) indicates NMP release fractions of 0.26 for brush-on and 0.52 for spray-on. The resultant mass applied for different application targets is summarized in Table D-5. Table D-5. NMP Mass Released, by Application Target and Method.

Target (Surface Area) and Method

Application Rate, g/ft2 a

Weight Fractionb Release Fraction NMP Mass

Released, g

Coffee table (10 ft2) Brush-on Spray-on

108 81

0.25 | 0.50 0.44 | 0.53

0.26 0.52

70.2 | 140.4 185.3 | 223.2

Chest of drawers (25 ft2) Brush-on Spray-on

108 81

0.50 0.53

0.26 0.52

351.0 558.1

Bathroom tub (36 ft2) Brush-on 108 0.5 0.26 505.4 aReflects repeat application for each segment. bFor the coffee-table case, two weight fractions are given, one for central and one for upper-end. Airflow Rates and Volumes. The model run requires conceptualization of a residence in terms of the number of zones and their respective volumes. The airflow rates needed to model the central and upper-end cases described above are: (1) rates between indoors and outdoors for each zone; and (2) rates between the zones. Airflow for tub stripping in the bathroom, which is somewhat more complex to conceptualize, is described below, after the central and upper-end cases. For the central and upper-end cases, the house in which the modeled stripper application occurs is conceptualized as having two zones: (1) the workshop where application occurs; and (2) the ROH. The house volume chosen for the model runs, 492 m3, was the central value listed in the EFH. The volume assigned to the in-house workshop area was 54 m3, corresponding to 12 feet × 20 feet with an eight-foot ceiling (20 × 12 × 8 = 1,920 ft3 or ~54 m3). This room volume is similar to the value reported in Riley et al. (2001) for the mean volume of the room used for paint stripping (51 m3). The volume for the ROH, 438 m3, is determined by subtraction (492 to 54 m3). For the bathroom scenario, the bathroom volume was set at nine m3 for consistency with that reported in a CDC/NIOSH case (CDC, 2012).


The indoor-outdoor airflow for any zone of the house is governed by the choice of air exchange rate, in ACH. The central and low-end values for the air exchange rate, 0.45/hour and 0.18/hour that were used in assigning the indoor-outdoor airflow rate for the ROH are the mean and 10th percentile values, respectively, from the EFH. (Note that a low-end ACH would be expected to contribute to upper-end concentration estimates.) For the workshop, it was assumed that multiple windows were opened. The indoor-outdoor airflow rate assigned to this zone, 68 m3/hour, was obtained by multiplying the room volume of 54 m3 by the 90th percentile (1.26/hour) of the air-exchange-rate distribution from the EFH, thought to be a reasonable representation of the open-window case. The use of open windows in the room of use is supported by both label instructions and survey data. Even though NMP is not highly volatile, the majority of the labels indicate that adequate ventilation must be used and that to prevent build-up of vapors, windows and doors should be opened to achieve cross ventilation. Additionally, Pollack-Nelson (1995) reported that an average of 70.7 percent of paint stripper users (all products) kept a window or door open during use based on data from the WESTAT (1987) survey and that 88.8 percent of paint stripper users (all products) kept a window or door open during use based on data from the Abt (1992) survey. The increase was significant between the survey years. The more recent, small Riley et al. (2001) survey also indicates that the majority of paint stripper users (55 percent) opened a window. Both Pollack-Nelson (1995) and Riley et al. (2001) also reported that some users used an exhaust fan during the stripping process, which would affect the air exchange rate. The percentage of fan users was not reported in Pollack-Nelson (1995). The Riley et al. (2001) data suggest that only ~27 percent of the users who worked indoors used an open window and fan. Due to the small percentage of people who used a fan, coupled with the fact that a couple of labels indicate that the product should be kept away from heat, sparks, flame, and all other sources of ignition, none of the scenarios were assumed to involve use of a fan in the room of product use. The interzonal airflow rate was estimated using the following algorithm, presented in US EPA (1995):

Q = (0.078 + 0.31*ACH) * house volume (D-11) where Q is the interzonal airflow rate, in m3/hour, and ACH is the air exchange rate, in 1/hour. Substitution of the central air exchange rate of 0.45/hour and the house volume of 492 m3 yields an estimated interzonal airflow rate of 107 m3/hour. The corresponding number for the upper-end case, with an air exchange rate of 0.18/hour, was 65.8 m3/hour. Figure D-7 depicts the volumes and airflows that were used for the workshop scenarios.


Figure D-7. Zone Volumes and Airflow Rates for Workshop Scenarios. As previously noted, the bathroom case (Figure D-8) is more complex. Because the user is working in close proximity to the target (bathtub) for an extended period, a third zone (“source cloud”) was created within the bathroom to represent the NMP concentrations in the vicinity of the tub; this is a virtual zone, with no physical boundaries. The airflow rate between the cloud and the rest of the bathroom was based on work by Matthews et al. (1989), who determined experimentally that such an airflow could be estimated as the product of the room air velocity (in m/hour) and the entry/exit surface area (in m2). Using their suggested value of 65 m/hour for air velocity together with an assumed entry/exit surface area of five ft by two ft (10 ft2 or 0.93 m2) yields an estimated airflow rate of 60 m3/hour between the source cloud and the rest of the bathroom. Based on professional judgment, the interzonal airflow rate between the bathroom and ROH of the house was assumed to be ~2/3 lower than that for the workshop central case, given the small bathroom volume. The indoor-outdoor airflows were based on an assumed air exchange rate of 0.18 ACH.

Figure D-8. Zone Volumes and Airflow Rates for Bathroom Scenario. Locations of Exposed Individuals. Two location patterns were specified, one for a product user and one for a non-user. The user was assumed to be in the work area for stripper application and scraping for all scenarios. For the waiting phase of the stripping process, the user was assumed to be in the ROH as a central-tendency assumption for the user (Scenarios 1 and 4), in

denotes air flow

1.6m3/hr

Rest of Bathroom

(8 m3)35

m3/hr

Rest of House

(483 m3)

“Source Cloud”(1 m3)

86.9m3/hr

60m3/hr

Room of Use

(54 m 3 ) 68

m 3 /hr 107

m 3 /hr

Rest of House

(438 m 3 ) 197

m 3 /hr

Central Values

Room of Use

(54 m 3 ) 68

m 3 /hr 65.8

m 3 /hr

Rest of House

(438 m 3 ) 78.8

m 3 /hr

Values for Upper - end Concentration Scenarios

d enotes air flow


the workshop as an upper-end assumption for the user (Scenarios 2 and 5), and in the ROH of the house for Scenarios 3, 6, 7, and 8, which were developed to model upper-end concentrations primarily for the non-user. The user was placed in the ROH during the waiting phase for the central assumption because the user is assumed to be aware of potential inhalation health concerns from using paint strippers based on label warnings (“Vapor Harmful”) on some labels (which are often for products containing multiple active ingredients, not solely NMP), and because the Riley survey (Riley et al., 2001) reported that 65 percent of users reported taking breaks outside the work area. Breaks typically involved a specific break activity and location, such as going to the kitchen and making a sandwich, or going outside to do yard work. For the upper-end Scenarios 2 and 5, it was assumed that the user would stay in the workshop, based on the fact that some people do not read/skim labels (~28% in 1990; Pollack-Nelson, 1995) and that the Riley survey (Riley et al., 2001) indicated that 20 percent of participants reported taking breaks inside the work area. For all scenarios, the user was assumed to leave the workroom immediately after the stripping process, based on the WESTAT (1987) and Abt (1992) surveys with a median value of zero minutes spent in the room after using the product (US EPA, 2011c). The non-user was assumed to be in the ROH throughout the model run, as was the user for the portion of the run after all applying/scraping was completed. For the bathroom scenario, the user was assumed to be in the ROH during the wait times. It was further assumed that the scrapings were removed from the house as soon as scraping was completed for the last segment. The implication for modeling purposes is that any remaining NMP emissions would be truncated at that time. Saturation Concentration Constraint. As discussed above, Scenarios 7 and 8 were used to estimate NMP concentrations for conditions similar to those reported in a CDC/NIOSH occupational exposure case to a DCM paint stripper (CDC, 2012); as a result, the modeled NMP concentrations for these scenarios may approach the saturation concentration. For the purposes of this assessment, the saturation concentration was calculated based on reported vapor pressures for NMP, using the ideal gas law to convert the reported vapor pressure into airborne concentrations. The literature-reported vapor pressures for NMP vary widely. A sampling of the reported vapor pressures is provided in Table D-6, along with the calculated saturation concentrations. As apparent in the table, there is a fairly broad range of reported values: from 1,287 to 1,871. A saturation concentration of 1,300 mg/m3 (vapor pressure = 0.24), within the range of reported values, was selected and used in Scenario 7. Table D-6. Literature-Reported Vapor Pressure Values for NMP.

Vapor Pressure at 20 °C (Torr)

Saturation Concentration at 20 °C (mg/m3) Source

0.237 1,286.7 BASF Product Information(BASF, 2007)

0.29 1,572.5 Cisco Chemicals MSDS (CISCO, 2011)

0.3 1,626.7 Lyondell MSDS (Lyondell, 2004)


0.24 1,301.4 Taminco MSDS (Taminco, 2011)

0.345 1,870.7 EPA NMP Assessment Memo (US EPA, 2006)

0.293 1,586.2 WHO Report (WHO, 2001)

MCCEM prevents the airborne concentrations of NMP from exceeding NMP’s saturation concentration through the input of a saturation constraint value. The model normally will apply the emission rates specified by the user without regard to the chemical’s saturation concentration in air; in other words, the saturation concentration could be exceeded. If the user selects the saturation constraint, then the model will check to ensure that the saturation concentration is not exceeded, adjusting the emission rate as needed to meet this constraint. In such cases, the same chemical mass ultimately will be released, but at a slower rate than implied by the user's source model. The following equation is used to estimate the value for the saturation concentration:

Csat = (VP/760 mm Hg/atm × MW × 1,000 mg/g × 1,000 L/m³) / (R × T) (D-12)

where: Csat = saturation concentration (mg/m³) VP = vapor pressure (mm Hg) MW = molecular weight (g/mole) R = gas constant = 0.0821 liter atm/mole °K T = temperature of the air (°K)

At each time step, MCCEM checks whether the current value for the emission rate results in an indoor concentration that exceeds Csat. If so, then the emission rate is reduced to a value that results in the indoor concentration equaling Csat. In such a case, MCCEM keeps track of the cumulative mass that has been "subtracted" to meet the Csat constraint; release of this accumulated "excess" mass is initiated at a later point in time, when the modeled concentration otherwise would be below the Csat value. This procedure is continued until all excess mass has been released, unless the end of the time period for the model run is encountered first. NMP’s saturation concentration is affected by the level of relative humidity. An NMP Initial Assessment Report (OECD, 2007) by the OECD5 reported that several studies measured the relationship between vapor pressure for NMP and relative humidity and reported the following:

It is noteworthy that NMP exists in various proportions of vapor and aerosol depending on the concentration, temperature and humidity. The maximum vapor phase at room temperature is 1.286 mg/l (315 ppm) in dry air (0% relative humidity), 0.525 mg/l (128 ppm) at normal animal room humidity (50% relative

5 OECD, 2, rue André Pascal, 75775 PARIS Cedex 16, France. www.oecd.org.

http://www.oecd.org/


humidity) and 0 mg/l (0 ppm) in humidity saturated air (100% relative humidity BASF AG, 1995c, b, a, 1989, 1992).

Based on the cited findings, the OECD report concludes:

Thus, the vapor saturation of NMP under normal conditions is considered to be in the range of 0.48 - 0.64 mg/l (120 - 160 ppm) depending on humidity and temperature.

The studies and associated data cited by OECD were conducted by BASF AG; however, the studies are unpublished and are not readily available. To examine this potential relative humidity impact, Scenario 8 imposes a saturation concentration constraint of 640 mg/m3, representing the upper-end saturation concentrations associated with "normal humidity conditions." This concentration corresponds to an estimated RH, calculated by interpolation, of approximately 42 percent.

INHALATION MODEL OUTPUTS AND EXPOSURE CALCULATIONS Personal Concentrations Peak TWA concentrations for different averaging periods, described below, were calculated from the one-minute averages for both the user and non-user based on their respective personal concentration time series. The calculations took into account the possibility that the user can change zones within a one-minute interval (e.g., at an elapsed time of 6.25 minutes). The personal concentration was calculated for each one-minute interval in the modeling period (24 hours or 1,440 one-minute intervals) as follows: For each time interval, i to i +1, for i = 0 to 1,440:

(D-13) Where:

PCi,i+1 = the personal concentration over the time interval i to i +1 C1,i and C1,i+1 = the concentrations in the use zone at times i and i+1, respectively CROH,i and CROH,i+1 = the concentrations in the ROH zone at times i and i+1, respectively Fi,i+1 = the fraction of time spent in the use zone during the time interval i to i +1

These calculations, illustrated in Figure D-9, were implemented for each of the eight scenarios.


Figure D-9. Example of the Personal Concentration Calculation as Defined in Equation C-13. TWA Concentrations In addition to the maximum one-minute concentration and the 24-hour average concentration to which the user and non-user were exposed, a peak TWA personal concentration also was calculated for each of the following averaging periods: 10 minutes, 30 minutes, one hour, four hours, and eight hours. The peak TWA concentration for any averaging period was defined as the highest value of the consecutive running averages for that averaging period. For any averaging period, there are (1,440-length of the averaging period) TWA concentration values within the 24-hour (1,440-minute) time series. For example, there are 1,430 10-minute averaging periods (1,440-10), the first of which is for time 0 to 10 minutes, the second of which is for time one to 11 minutes, and so on, with the last for time 1,430 to 1,440 minutes. The running averages for each averaging period were computed in an Excel spreadsheet, from which the maximum value was determined. Modeling Results The zone and personal concentrations predicted by MCCEM are presented in Figures D-10 through D-13 at the end of this section. Figure D-10 shows the zone and user personal concentration results for Scenario 1 (brush application in the workshop with central parameter values; top two figures) and Scenario 4 (spray application in the workshop using central parameter values). The non-user personal concentrations are assumed to be those in the ROH. As indicated in Figure D-10, the peak concentrations are higher for the spray application case than those for the brush application case, even though the mass of product applied is higher for the brush application case (1,080 g stripper applied for the brush application case as compared to 810 g for the spray application). This difference is explained primarily by two factors: (1) the weight fraction of NMP in the stripper product (0.44 for the spray product vs. 0.25 for the brush product); and (2) the potential release fraction of the mass emitted (assumed to be the 52 percent for spray and 26 percent for brush applications). This release is termed the

Time Interval

= (D5 + D4) / 2

Fraction of Time Spent in Use Zone

= H5*J5 + I5*(1-J5)


"potential release" because NMP emissions take place over an extended period (>24 hours) and, consequently, much of the release is truncated due to earlier completion of the stripping activity and removal of the scrapings. As a result, the ratio of NMP mass emitted for spray/brush application is ~2.4 (1,080 g × 0.25 × 0.26 = 70 g for the brush activity vs. 810 g × 0.44 × 0.52 = 190 g for the spray activity). As described in Section 2.1.2, the release fraction is based on analysis of chamber data from US EPA (1994b) (see the section on Estimation of Emission Profiles for Paint Removers/Strippers in Appendix C) for NMP for the brush application and extrapolation to the spray application using a relationship for DCM derived from US EPA (1994b), because no chamber data are available for the NMP spray application. Figure D-11 shows the zone and user personal concentration results for Scenarios 2 and 5 (brush and spray application, respectively) for the workshop with parameter values selected to estimate upper-end concentrations for the user. For these scenarios, the ratio of peak concentrations between the spray and brush application cases is 1.6. Figure D-12 shows the zone and user personal concentration results for Scenarios 3 and 6 (brush and spray application, respectively) for the workshop with parameter values selected to estimate upper-end concentrations for the non-user; the results also indicate a pronounced increase in exposure for the user. Figure D-13 shows the air concentrations for the bathroom case, bathroom bathtub stripping activity. Scenario 7, which imposes a saturation concentration constraint of 1,300 mg/m3, has modeled peak concentrations of 1,300 mg/m3 (320 ppm) and 920 mg/m3 (230 ppm) for the source cloud and bathroom, respectively. Scenario 8, which imposes a saturation concentration constraint of 640 mg/m3, has modeled peak concentrations of 640 mg/m3 (160 ppm) and 560 mg/m3 (140 ppm) for the source cloud and bathroom, respectively. For both scenarios, the predicted airborne concentrations reach the saturation concentration in the source cloud, but remain lower than the saturation concentration in the bathroom.


a) Scenario 1, Brush Applied

b) Scenario 4, Spray Applied Figure D-10. Modeled NMP Concentrations for Scenarios 1 and 4, Stripper Application in Workshop using Parameter Values selected for Central Tendency Exposure.

(Non-user assumed to be in ROH)




b) Scenario 5, Spray Applied Figure D-11. Modeled NMP Concentrations for Scenarios 2 and 5, Stripper Application in Workshop using Parameter Values selected for Upper-end User Exposure.





b) Scenario 6, Spray Applied Figure D-12. Modeled NMP Concentrations for Scenarios 3 and 6 Stripper Application in Workshop using Parameter Values selected for Upper-end Non-User Exposure.




a) Scenario 7, Saturation Concentration Constraint at 1,300 mg/m3

b) Scenario 8, Saturation Concentration Constraint at 640 mg/m3 Figure D-13. Modeled NMP Concentrations for Scenarios 7 and 8, Brush Application in Bathroom using Parameter Values selected for Upper-end to Bounding User and Non-User Exposures.

Csat = 1300 mg/m3 Csat = 1300 mg/m3


Csat = 640 mg/m3 Csat = 640 mg/m3


MCCEM INHALATION MODELING CASE SUMMARIES NMP Summaries Formula: C5H9NO CASRN: 872-50-4 Molecular Weight: 99.13 g/mol Density: 1.028 g/cm2 (liquid) Appearance: clear liquid Melting Point: -24 °C = -11 °F = 249 K Boiling Point: 203 °C = 397 °F = 476 K Vapor Pressure (at 20 °C): ~32.4 Pa = 0.243 Torr = 0.00032 atm = 0.0047 psi Conversion units: 1 ppm = 4.054397 mg/m3 Saturation Concentration: ~1,300 mg/m3 NMP Scenario 1. Coffee Table, Brush-On, Workshop, User in ROH during wait time, 0.45 ACH, 0.25 Weight Fraction MCCEM Input Summary Application Method: Brush-on Volumes: Workshop volume = 54 m3 ROH volume = 492 – 54 = 438 m3 Airflows: Workshop-outdoors 68 m3/h ROH-outdoors 197.1 m3/h (0.45 ACH) Workshop-ROH 107 m3/h NMP Mass Released: Coffee table = 10 sq ft surface area Applied product mass = 108 g/sq ft = 1,080 g Applied NMP = 1,080 g × 0.25 (wt fraction) = 270 g Total NMP mass released (both exponentials) = 1,080 g × 0.25 (wt fraction) × 0.26 (release fraction, theoretical) = 70.2 g For each of the 2 applications: k1 = 10/hr % Mass for Exponential 1 = 2% = 0.02*1,080*0.25 (wt fraction) * 0.5 (half per application)

= 2.7 g or 7.7% of released NMP E01 = Mass * k1 = 2.7*10 = 27 g/hr (NOTE: only k and Mass are needed as MCCEM inputs)


k2 = 0.05/hr % Mass for Exponential 2 = 24% = 0.24*1,080*0.25 (wt fraction) * 0.5 (half per application)

= 32.4 g E02 = Mass * k2 = 32.4*0.05 = 1.624 g/hr (NOTE: only k and Mass are needed as MCCEM inputs) Application Times and Activity Patterns:

Episode

Elapsed Time from Time Zero, Minutes (Product User Location)


1) Coffee Table, Brush-On, Workshop, User ROH during wait time, 0.45 ACH, 0.25 Weight Fraction

0-5 (Use) 5-35 (ROH)

35-45 (Use)

45-50 (Use)

50-80 (ROH)

80-90 (Use)

User in ROH at the end of Scraping 2 User in ROH for the remainder of the run (22 hours, 30 minutes) Model Run Time: 0-24 hours User takes out scrapings after 90 minutes, emissions truncated MCCEM Results Summary Personal Exposures (maximum values over first 24 hours):

In mg/m3 Individual 1 min 10 min 30 min 1 hour 4 hour 8 hour 24 hour User 32.7 30.5 15.0 13.3 6.6 3.8 1.3 Other 7.3 7.3 7.2 6.9 4.6 2.7 0.9

In ppm Individual 1 min 10 min 30 min 1 hour 4 hour 8 hour 24 hour User 8.1 7.5 3.7 3.3 1.6 0.9 0.3 Other 1.8 1.8 1.8 1.7 1.1 0.7 0.2 Plots:


NMP Scenario 2. Coffee Table, Brush-On, Workshop, User in Workshop during wait time, 0.45 ACH, 0.5 Weight Fraction MCCEM Input Summary Application Method: Brush-on Volumes: Workshop volume = 54 m3 ROH volume = 492 – 54 = 438 m3 Airflows: Workshop-outdoors 68 m3/h ROH-outdoors 197.1 m3/h (0.45 ACH) Workshop-ROH 107 m3/h NMP Mass Released: Coffee Table = 10 sq ft surface area Applied product mass = 1,080 g Applied NMP = 1,080 g × 0.5 (wt fraction) = 540 g Total NMP mass released (both exponentials) = 1,080 g × 0.5 (wt fraction) × 0.26 (release fraction, theoretical) =140.4 g For each of the 2 applications: k1 = 10/hr % Mass for Exponential 1 = 2% = 0.02*1,080*0.5 (wt fraction) * 0.5 (half per application) = 5.41 g or 7.7% of released NMP E01 = Mass * k1 = 5.41*10 = 54.1 g/hr (NOTE: only k and Mass are needed as MCCEM inputs) k2 = 0.05/hr % Mass for Exponential 2 = 24% = 0.24*1,800*0.5 (wt fraction) * 0.5 (half per application) = 64.8 g E02 = Mass * k2 = 64.8*0.05 = 3.2 g/hr (NOTE: only k and Mass are needed as MCCEM inputs) Application Times and Activity Patterns:

Episode



2) Coffee Table, Brush-On, Workshop, User in Workshop during wait time, 0.45 ACH, 0.5 Weight Fraction

0-5 (Use) 5-35 (Use) 35-45 (Use)

45-50 (Use)

50-80 (Use)

80-90 (Use)

User in ROH at the end of Scraping 2 User in ROH for the remainder of the run (22 hours, 30 minutes)


Model Run Time: 0-24 hours User takes out scrapings after 90 minutes, emissions truncated MCCEM Results Summary Personal Exposures (maximum values over first 24 hours):




NMP Scenario 3. Chest, Brush-On, Workshop, User in ROH during wait time, 0.18 ACH, 0.5 Weight Fraction MCCEM Input Summary Application Method: Brush-on Volumes: Workshop volume = 54 m3 ROH volume = 492 – 54 = 438 m3 Airflows: Workshop-outdoors 68 m3/h ROH-outdoors 78.8 m3/h (0.18 ACH) Workshop-ROH 65.8 m3/h NMP Mass Released: Chest = 25 sq ft surface area Applied product mass = 2,700 g Applied NMP = 2,700 g × 0.5 (wt fraction) = 1,350 g Total NMP mass released (both exponentials) = 2,700 g × 0.5 (wt fraction) × 0.26 (release fraction, theoretical) =351 g For each of the 2 applications: k1 = 10/hr % Mass for Exponential 1 = 2% = 0.02*2,700*0.5 (wt fraction) * 0.5 (half per application)

= 13.51 g or 7.7% of released NMP E01 = Mass * k1 = 13.51*10 =135.1 g/hr (NOTE: only k and Mass are needed as MCCEM inputs) k2 = 0.05/hr % Mass for Exponential 2 = 24% = 0.24*2,700*0.5 (wt fraction) * 0.5 (half per application)

= 162 g E02 = Mass * k2 = 162*0.05 = 8.1 g/hr (NOTE: only k and Mass are needed as MCCEM inputs) Application Times and Activity Patterns:

Episode



3) Chest, Brush-On, Workshop, User in ROH during wait time, 0.18 ACH, 0.5 Weight Fraction

0-12.5 (Use)

12.5-42.5 (ROH)

42.5-67.5 (Use)

67.5-80 (Use)

80-110 (ROH)

110-135 (Use)



NMP Scenario 4. Coffee Table, Spray-On, Workshop, User in ROH during wait time, 0.45 ACH, 0.44 Weight Fraction MCCEM Input Summary Application Method: Spray-on Volumes: Workshop volume = 54 m3 ROH volume = 492 – 54 = 438 m3 Airflows: Workshop-outdoors 68 m3/h ROH-outdoors 197.1 m3/h (0.45 ACH) Workshop-ROH 107 m3/h NMP Mass Released: Coffee Table = 10 sq ft surface area Applied product mass = 810 g Applied NMP = 810 g × 0.44 (wt fraction) = 356.4 g Total NMP mass released (both exponentials) = 810 g × 0.44 (wt fraction) × 0.52 (release fraction, theoretical) =185.3 g For each of the 2 applications: k1 = 10/hr % Mass for Exponential 1 = 4% = 0.04*810 *0.44 (wt fraction) * 0.5 (half per application)

= 7.14 g or 7.7% of released NMP E01 = Mass * k1 = 7.14*10 =71.4 g/hr (NOTE: only k and Mass are needed as MCCEM inputs) k2 = 0.05/hr % Mass for Exponential 2 = 48% = 0.48*810 *0.44 (wt fraction) * 0.5 (half per application)


Episode



4) Coffee Table, Spray-On, Workshop, User in ROH during wait time, 0.45 ACH, 0.44 Weight Fraction

0-2.5 (Use)

2.5 -32.5 (ROH)

32.5-42.5 (Use)

42.5-45 (Use)

45-75 (ROH)

75-85 (Use)



NMP Scenario 5. Coffee Table, Spray-On, Workshop, User in workshop during wait time, 0.45 ACH, 0.53 Weight Fraction MCCEM Input Summary Application Method: Spray-on Volumes: Workshop volume = 54 m3 ROH volume = 492 – 54 = 438 m3 Airflows: Workshop-outdoors 68 m3/h ROH-outdoors 197.1 m3/h (0.45 ACH) Workshop-ROH 107 m3/h NMP Mass Released: Coffee Table = 10 sq ft surface area Applied product mass = 810 g Applied NMP = 810 g × 0.53 (wt fraction) = 429.3 g Total NMP mass released (both exponentials) = 810 g × 0.53 (wt fraction) × 0.52 (release fraction, theoretical) =223.2 g For each of the 2 applications: k1 = 10/hr % Mass for Exponential 1 = 4% = 0.04*810 *0.53 (wt fraction) * 0.5 (half per application)

= 8.6 g or 7.7% of released NMP E01 = Mass * k1 = 8.59*10 =85.9 g/hr (NOTE: only k and Mass are needed as MCCEM inputs) k2 = 0.05/hr % Mass for Exponential 2 = 48% = 0.48*810 *0.53 (wt fraction) * 0.5 (half per application)

= 103 g E02 = Mass * k2 = 103*0.05 = 5.2 g/hr (NOTE: only k and Mass are needed as MCCEM inputs) Application Times and Activity Patterns:

Episode



5) Coffee Table, Spray-On, Workshop, User in workshop during wait time, 0.45 ACH, 0.53 Weight Fraction

0-2.5 (Use)

2.5 -32.5 (Use)

32.5-42.5 (Use)

42.5-45 (Use)

45-75 (Use)

75-85 (Use)



NMP Scenario 6. Chest, Spray-On, Workshop, User in ROH during wait time, 0.18 ACH, 0.53 Weight Fraction MCCEM Input Summary Application Method: Spray -on Volumes: Workshop volume = 54 m3 ROH volume = 492 – 54 = 438 m3 Airflows: Workshop-outdoors 68 m3/h ROH-outdoors 78.8 m3/h (0.18 ACH) Workshop-ROH 65.8 m3/h NMP Mass Released: Chest = 25 sq ft surface area Applied product mass = 2,025 g Applied NMP = 2,025 g × 0.53 (wt fraction) = 1,073.25 g Total NMP mass released (both exponentials) = 2,025 g × 0.53 (wt fraction) × 0.52 (release fraction, theoretical) =558.09 g For each of the 2 applications: k1 = 10/hr % Mass for Exponential 1 = 4% = 0.04*2,025 *0.53 (wt fraction) * 0.5 (half per application)

= 21.5 g or 7.7% of released NMP E01 = Mass * k1 = 21.5*10 =214.9 g/hr (NOTE: only k and Mass are needed as MCCEM inputs) k2 = 0.05/hr % Mass for Exponential 2 = 48% = 0.48*2,025 *0.53 (wt fraction) * 0.5 (half per application)


Episode



6) Coffee Table, Spray-On, Workshop, User in ROH during wait time, 0.18 ACH, 0.53 Weight Fraction

0-6.25 (Use)

6.25-36.25 (ROH)

36.25-61.25 (Use)

61.25-67.5 (Use)

67.5-97.5 (ROH)

97.5-122.5 (Use)

User in ROH at the end of Scraping 2 User in ROH for the remainder of the run (21 hours, 57.5 minutes)


Model Run Time: 0-24 hours User takes out scrapings after 122.5 minutes, emissions truncated MCCEM Results Summary Personal Exposures (maximum values over first 24 hours):




NMP Scenario 7. Bathtub, Brush-On, Bathroom + Source Cloud, User in ROH during wait time, 0.18 ACH, 0.5 Weight Fraction MCCEM Input Summary Application Method: Brush-on Volumes: Bathroom Volume = 9 m3 (8 m3 after removing source cloud zone) Source Cloud Volume = 1 m3 ROH volume = 492 – 9 = 483 m3 Airflows: Bathroom-outdoors 1.6 m3/h Source cloud - bathroom 60 m3/h Source cloud - outdoors 0 ROH-outdoors 86.9 m3/h (0.18 ACH) Bathroom-ROH 35 m3/h NMP Mass Released: Bathtub Chest = 36 sq ft surface area Applied product mass = 3,888 g Applied NMP = 3,888 g × 0.5 (wt fraction) = 1,944 g Total NMP mass released (both exponentials) = 3,888 g × 0.5 (wt fraction) × 0.26 (release fraction, theoretical) = 505.4 g For each of the 2 applications: k1 = 10/hr % Mass for Exponential 1 = 2% = 0.02*3,888*0.5 (wt fraction) * 0.5 (half per application)

= 19.5 g or 7.7% of released NMP E01 = Mass * k1 = 19.5*10 = 195 g/hr (NOTE: only k and Mass are needed as MCCEM inputs) k2 = 0.05/hr % Mass for Exponential 2 = 24% = 0.24*3,888*0.5 (wt fraction) * 0.5 (half per application)

= 233.3 g E02 = Mass * k2 = 233.3*0.05 = 11.7 g/hr (NOTE: only k and Mass are needed as MCCEM inputs)


Application Times and Activity Patterns:

Episode



7) Bathtub, Brush-On, Bathroom + Source Cloud, User in ROH during wait time, 0.18 ACH, 0.50 Weight Fraction

0-18 (Use) 18-48 (ROH)

48-84 (Use)

84-102 (Use)

102-132 (ROH)

132-168 (Use)

User in ROH at the end of Scraping 2 User in ROH for the remainder of the run (21 hours 12 minutes) Model Run Time: 0-24 hours User takes out scrapings after 168 minutes, emissions truncated MCCEM Results Summary Personal Exposures (maximum values over first 24 hours):

In mg/m3 Individual 1 min 10 min 30 min 1 hour 4 hour 8 hour 24 hour User 1,300 1,300 1,300 830.8 515.1 292.0 107.7 Other 109.7 109.6 108.9 106.9 90.8 72.1 33.4

In ppm Individual 1 min 10 min 30 min 1 hour 4 hour 8 hour 24 hour User 320.6 320.6 320.6 204.9 127.0 72.0 26.6 Other 27.1 27.0 26.9 26.4 22.4 17.8 8.2


Plots:


NMP Scenario 7. Bathtub, Brush-On, Bathroom + Source Cloud, User in ROH during wait time, 0.18 ACH, 0.5 Weight Fraction MCCEM Input Summary MCCEM saturation concentration constraint invoked at 640 mg/m3 Application Method: Brush-on Volumes: Bathroom Volume = 9 m3 (8 m3 after removing source cloud zone) Source Cloud Volume = 1 m3 ROH volume = 492 – 9 = 483 m3 Airflows: Bathroom-outdoors 1.6 m3/h Source cloud - bathroom 60 m3/h Source cloud - outdoors 0 ROH-outdoors 86.9 m3/h (0.18 ACH) Bathroom-ROH 35 m3/h NMP Mass Released: Bathtub Chest = 36 sq ft surface area Applied product mass = 3,888 g Applied NMP = 3,888 g × 0.5 (wt fraction) = 1,944 g Total NMP mass released (both exponentials) = 3,888 g × 0.5 (wt fraction) × 0.26 (release fraction, theoretical) = 505.4 g For each of the 2 applications: k1 = 10/hr % Mass for Exponential 1 = 2% = 0.02*3,888*0.5 (wt fraction) * 0.5 (half per application)

= 19.5 g or 7.7% of released NMP E01 = Mass * k1 = 19.5*10 = 195 g/hr (NOTE: only k and Mass are needed as MCCEM inputs) k2 = 0.05/hr % Mass for Exponential 2 = 24% = 0.24*3,888*0.5 (wt fraction) * 0.5 (half per application)

= 233.3 g E02 = Mass * k2 = 233.3*0.05 = 11.7 g/hr (NOTE: only k and Mass are needed as MCCEM inputs)


Application Times and Activity Patterns:

Episode



7) Bathtub, Brush-On, Bathroom + Source Cloud, User in ROH during wait time, 0.18 ACH, 0.50 Weight Fraction

0-18 (Use) 18-48 (ROH)

48-84 (Use)

84-102 (Use)

102-132 (ROH)

132-168 (Use)

User in ROH at the end of Scraping 2 User in ROH for the remainder of the run (21 hours 12 minutes) Model Run Time: 0-24 hours User takes out scrapings after 168 minutes, emissions truncated MCCEM Results Summary Personal Exposures (maximum values over first 24 hours):


In ppm Individual 1 min 10 min 30 min 1 hour 4 hour 8 hour 24 hour User 157.9 157.9 157.9 143.1 75.7 42.8 15.8 Other 16.0 16.0 15.9 15.6 13.3 10.6 4.9


Plots:


DERMAL ASSESSMENT INPUTS Because of limited data for the dermal exposure inputs, differences in the dermal exposure were only estimated by varying the application method and weight fraction, as shown in Table D-7. Table D-7. Dermal Modeling Scenarios.

Case ID Application Method Weight Fraction

1 Brush

Central

2 High-end

3 Spray

Central

4 High-end

Model Inputs Table D-8 provides a summary of the parameter inputs for the dermal exposure calculations. Further discussion of each input follows below. Table D-8. Summary of Dermal Input Parameters.

Parameter Units

Parameter Value

Source Scenario 1: Brush-on,

Central

Scenario 2: Brush-on, High-end

Scenario 3: Spray-on,

Central

Scenario 4: Spray-on, High-end

Weight fraction (WF)

– 0.25 (median)

0.50 (90th percentile)

0.44 (median)

0.53 (90th percentile)

Brown (2012)

Product density (PD)

g/cm3 1.10 (median) Brown (2012)

Film thickness (FT) cm 0.03 (professional judgment) US EPA (1996)

Surface area (SA)

cm2 490 (average); based on 50% of both hands (professional judgment)

US EPA (2011c)

Exposure duration (ED)

days 1 (instantaneous) Professional judgment

Frequency of use (FQ)

event/ day 1 Professional judgment

Body weight (BW) kg 80 (average) US EPA (2011c)

Averaging time (AT)

days 1 Professional judgment


Weight Fraction The brush-on and spray-on application methods were assessed using both median weight fractions (central estimate) and 90th percentile weight fractions (high-end estimate) of paint stripping products currently available to consumers. The weight fractions used were 0.25 and 0.50 for the brush-on scenarios and 0.44 and 0.53 for the spray-on scenarios, as determined from Brown (2012). The calculation of these values is discussed above in Inhalation Exposure Scenario Inputs. There is a high degree of confidence in the weight fractions used for the paint stripper products because the values are based on currently available consumer products, as identified in Brown (2012). However, the weight fractions were not weighted for market share of products. Product Density As the range of product densities in NMP-containing paint strippers currently available to consumers is narrow (0.09 to 1.31 g/cm3), a median product density of 1.10 g/cm3 for all formulation types was used, as calculated from data in the Brown (2012) spreadsheet. Similar to the weight fraction parameter, there is a high degree of confidence in the weight fractions used for the paint stripper products because the values are based on currently available consumer products, as identified in Brown (2012). Film Thickness The film thickness is the amount of material that remains on the skin after contact with the paint stripper. The data on film thickness are limited, and no data are available specifically for NMP-based paint strippers. The EFH (US EPA, 2011c) provides film thickness values for a variety of liquids (mineral oil, cooking oil, bath oil, bath oil/water, water, and water/ethanol), but not for paint stripper products. Therefore, a generic film thickness value for paint strippers (0.03 cm) was used based on information provided by Mr. Jordon, a chemist at Klean Strip. There is a high degree of uncertainty in the film thickness value used because it is based on professional judgment and there are no details available regarding the derivation of the value. Additionally, there are questions about the uniformity of films associated with product usage. Surface Area There are currently no data on the area of skin exposed to paint stripper products during paint stripping activities, assuming that protective gloves are not worn. Based on professional judgment, it is assumed that 50 percent of both hands are exposed to the paint stripper. This assumption is similar to the previous assumption used in the US EPA (1996) document, “Consumer Exposure Assessment for the Paint Removal Use Cluster,” in which it was assumed that that the palms and fingers of both hands would be exposed to paint strippers (professional judgment).


A value of 490 cm2 was calculated, which is 50 percent of the average surface area of adult male and female hands, based on average surface areas provided in EFH (1,070 cm2 for males and 890 cm2 for females). Combined male and female values were not provided in EFH. There is a high degree of uncertainty with respect to the assumption that 50 percent of both hands are exposed to the paint stripping product, as no studies have been conducted on this value. There is a low degree of uncertainty, however, with respect to the surface area values used for this assumption, as they are recommended values from EFH (US EPA, 2011c), based on EPA analysis of National Health and Nutrition Examination Survey (NHANES) 2005-2006 data. Body Weight A mean body weight of 80 kg was used, as recommended in EFH (US EPA, 2011c) for male and female adults combined. Both mean body weights and surface areas were used, as combining surface area distributions with unrelated body weight data may lead to biases in estimating exposures (Phillips et al., 1993). There is a low degree of uncertainty with respect to the body weight value used, as it a recommended value from EFH (US EPA, 2011c), based on EPA analysis of NHANES 1999-2006 data. Exposure Duration For acute exposures, an exposure duration of one day was assumed (professional judgment). This value is typical for the calculation of acute dermal doses. The model assumes that exposure is instantaneous. Frequency of Use For acute exposures, a single exposure event was expected to occur per day (professional judgment). This value is typical for the calculation of acute dermal doses. Averaging Time For acute exposures, an averaging time of one day was assumed (professional judgment). This value is typical for the calculation of acute dermal doses.


Appendix E. Toxicology Studies

INHALATION TOXICITY STUDIES

There were no human health effects studies after exposure to NMP. A summary of the inhalation animal studies that EPA considered in the analysis follows. Acute Inhalation Studies. Male and female Wistar rats were exposed head-nose for four hours to 5,100 mg/m3 of NMP (BASF AG, 1988a; as cited in OECD, 2007). The vapor/aerosol mixture had a mass median aerodynamic diameter (MMAD) of 4.6 µm, and 87 percent of the particles were in the respirable range. No animals died in the 14-day observation period, and all animals gained weight. Male Crl:CD BR rats were head-nose exposed for four hours to 3,100 to 4,800 and 5,000 to 8,800 mg/m3 (E.I. du Pont de Nemours., 1988; as cited in OECD, 2007). At 4,800 mg/m3, four of six rats died and at 8,800 mg/m3, six of six rats died. Developmental Toxicity Inhalation Studies. Rats were exposed whole-body to 0, 30, 60, and 120 ppm (122, 243, and 486 mg/m3) for six hrs/day during gestation days (GDs) 6 through 20 (Saillenfait et al., 2001; Saillenfait et al., 2003; as cited in OECD, 2007). There was no difference in the number of particles in the exposure chamber between control and exposure doses, so the exposures were to vapor. Slight maternal toxicity was evidenced by significantly decreased body weight gain in the dams on GDs 6 though 13 at 243 and 486 mg/m3 as well as decreased food consumption at 486 mg/m3 on GDs 13 through 21. There were no effects on embryo/fetal viability or teratogenic effects at any dose. There was a slight body weight decrease in the fetus at 486 mg/m3. The no-observed-adverse-effect level (NOAEL) for maternal toxicity was 122 mg/m3 and the observed fetal NOAEL was 243 mg/m3. EPA performed BMD modeling on the fetal body weight data (Appendix F; Table F-2). A benchmark concentration level (BMCL) with a benchmark response of five percent for decreased fetal body weight was used to derive a BMCL05 of 302 mg/m3 (US EPA, 2012b). Rats were exposed to 100 and 360 mg/m3 (analytical) of NMP for six hrs/day from GD 6 through 15 (Lee et al., 1987). Exposures were to aerosol, and the particle size distribution was not analyzed. However, in a 28-day study in the same laboratory, 95 percent of the particles were <10 µm in diameter. In the dams, sporadic lethargy and irregular respiration were observed during the first three days of exposure in both dose groups. These signs were not seen during the remainder of the exposure period or during the 10-day recovery period. These minor signs of neurotoxicity were reversible and were not considered adverse enough to be used in the derivation of a point of departure (POD). At 100 mg/m3, there was an increased number of females with less than 10 corpora lutea compared with controls; this was not treatment related because NMP exposure began on GD 6. The number of resorptions per litter was lower in this dose group and the fetal body weight was increased, which could be related to the decreased


corpora lutea. There were no treatment-related increases in variations or defects in organs or skeletal anomalies. The maternal and fetal NOAEL for six hours of exposure was 360 mg/m3. Hass et al. (1994) investigated the effects of NMP on postnatal development and behavior in rats. Dams were exposed by whole-body inhalation to analytically determined levels of 151 ppm (612 mg/m3) for six hrs/day from GD 7 to 20. Offspring were weighed through day 22 and males were examined with a series of different behavioral tests from day 1 to 7.5 months. There were no signs of maternal toxicity, but the mean body weight in litters from exposed dams was significantly lower than control. The difference in weights was no longer statistically significant after five weeks of age. Some developmental milestones and reflexes (i.e., surface righting reflex, incisor eruption, etc.) were delayed in exposed animals. In neurobehavioral measures (i.e., motor and balance function assessed on rotorod), as well as in activity level (i.e., open field) and performance in learning tasks that had a low grade of complexity, there were no differences between control and exposed animals. However, performance was impaired in more difficult tasks (i.e., reversal procedure in Morris water maze and operant delayed spatial alternation). It is interesting to note that the offspring with the lowest score in the Morris water maze test were those with the lowest body weight at weaning. Himalayan rabbits were exposed to 0, 200, 500, and 1,000 mg/m3 of NMP for six hrs/day from GD 7 through 19 (BASF AG, 1991, 1993b; as cited in OECD, 2007). In this study, there was no maternal toxicity observed. However, a range finding study that assessed a wider range of parameters showed increased liver weights and impaired clinical chemistry at 1,000 and 2,000 mg/m3. Slight fetal toxicity was observed at 1,000 mg/m3 in the form of increased incidence of supernumerary rib 13. The NOAEL for maternal toxicity was 1,000 mg/m3 and the NOAEL for developmental toxicity was 500 mg/m3. OECD (2007) stated that the exposure was to vapor and vapor-aerosol mixture. Reproductive Effects Inhalation Studies. Solomon et al. (1995) and E.I. du Pont de Nemours and Company (1990) exposed rats whole body to 10, 51, and 116 ppm (41, 210, and 470 mg/m3 analytical) for six hrs/day, seven days/week in a 14-week, two-generation reproductive effects study (as cited in OECD, 2007). There were no effects on reproductive performance. Ovaries and testes were examined macroscopically, and were weighed and fixed, but no histology was done. No difference between control and exposed animals in ovary or testis weights was seen. The only effect seen in the parents was a slight reduced responsiveness to sound at 470 mg/m3. This effect was minor and the technician performing the test knew which group was the high dose group. This effect was poorly described in the study. It is unclear how long the effect persisted. While this will be used to set a NOAEL for the parents, no other signs of narcosis were observed and this effect was relatively minor (this was considered a mild narcotic effect). No macroscopic effects or weight changes were seen in testes. However, the testes were not examined microscopically. The NOAEL for the parents was 210 mg/m3. The only stated effect for offspring was a slight decrement in fetal and postpartum body weights. In the fetal phase of the study, there were only control and 470 mg/m3 groups exposed, so only a LOAEL can be established. However, the Saillenfait et al. (2003) study demonstrated reduced fetal weights at 486 mg/m3, but not at 243 mg/m3. It is likely that 210 mg/m3 would be a NOAEL for fetal body


weight change in the Solomon et al. (1995) study. The postpartum data from exposed male and female animals are difficult to interpret. The low and high doses at days 1, 4, 14, and 21 post partum showed a statistical difference from the control but the mid-dose did not. The differences were slight and at the p ≤ 0.05 level. Given the lack of a dose response and the NOAEL for body weight change in the Saillenfait et al. (2003) study, the postpartum weight differences were not considered significant. Subchronic Inhalation Studies. Lee et al. (1987) (US EPA, 1989; E.I. Dupont de Nemours & Co., 1991) exposed rats whole body to design concentrations of 100, 500, and 1,000 mg/m3 of NMP for six hrs/day, five days/week for 28 days. Some animals were examined after a 14-day recovery period. Exposure was to a respirable aerosol, with 95 percent of the particles <10 µm in diameter. The measured average calculated NMP concentrations in the test chambers over the test period were 88, 423, and 740 mg/m3. All rats at all doses exhibited signs of lethargy and irregular respiration about three to four hours into the exposure through the end of exposure. Rats recovered within 45 minutes post exposure in the 88 and 423 mg/m3 exposures, but few recovered by 18 hours after exposure in the 740 mg/m3 group. At 740 mg/m3, there were effects on the bone marrow, spleen, lymph tissue in thymus and lymph nodes, and severe testicular atrophy. However, this was also a lethal level, with eight of 30 rats dying within nine days and five rats sacrificed in extremis. Dead animals exhibited marked pulmonary edema and congestion as well as severe systemic effects (bone marrow-hemorrhage, hypoplasia, necrosis in hemopoietic cells; lymphoid tissue atrophy and necrosis; thymus necrosis). These effects were reversible in surviving animals. The only systemic effects seen at 88 and 423 mg/m3 were slight reversible testicular atrophy in one of 10 male animals in each dose group (E.I. Dupont de Nemours & Co., 1991) (note Lee et al., 1987 did not mention the testicular effects ). E.I. Dupont de Nemours & Co. (1991) stated that the testicular results were tentatively compound related and that this diagnosis would be resolved with the two-year study. The Lee et al. (1987) report on the two-year study did not indicate any testicular toxicity at 41 or 405 mg/m3. Since the testicular effects were not repeated, the NOAEL for systemic effects in the subchronic study is 423 mg/m3. It is interesting to note that the exposures were vapor in the chronic study and aerosol in the 28-day study to aerosol. The question remains about the reversible signs of lethargy and irregular respiration at all doses. There was no mention of such signs in the two-year study (Lee et al., 1987) at doses up to 405 mg/m3. In the Lee et al. (1987) teratogenicity study at levels of 100 and 360 mg/m3, these signs were seen the first 3 days of exposure but not after. Since the signs of lethargy and irregular respiration are reversible and their occurrence differs between experiments, they were not considered adverse when identifying a NOAEL. BASF AG (1993a) (as cited in OECD, 2007) conducted a head-nose inhalation study with Wistar rats. The animals were exposed to 10, 30, and 100 mg/m3 NMP for six hrs/day, five days/week for 28 days. No treatment-related effects were observed. BASF AG (1994) exposed Wistar rats head-nose to 500 and 1,000 mg/m3 for six hrs/day, five days/week for 3 months. A satellite group was exposed to 3,000 mg/m3 for 3 months with a four-week recovery period. The MMAD was 1.6 to 3.5 µm. Nasal irritation was observed at


≥1,000 mg/m3 concentrations. Male rats at 1,000 and 3,000 mg/m3 exhibited a decreased body weight gain. Male rats at 3,000 mg/m3 exhibited cellular depletion in the testis. Changes in blood parameters were noted as well as clinical chemistry changes that indicated liver damage, but the concentration was not specified in the reference. After recovery, the males still exhibited lower body weight gain and cellular depletion in the testes at 3,000 mg/m3. The NOAEL for systemic toxicity was 500 mg/m3. BASF conducted a unique set of experiments on NMP toxicity and the character of the inhalation experience (BASF AG, 1995c, 1989, 1995b, a, 1992; as cited in OECD, 2007). Sprague-Dawley or Wistar rats were exposed whole body or head-nose to 1,000 mg/m3 for six hrs/day, five days/week for two or four weeks. Exposure to NMP was to coarse and fine particles of NMP in a vapor aerosol mixture. Regardless of particle size, the head-nose exposure caused only slight nasal irritation. However, rats exposed whole body to coarse droplets and high humidity experienced massive mortality and severe effects on organs and tissues, as well as other effects. Whole-body exposures to fine droplets under high or low humidity conditions did not result in mortality, and effects seen were less severe than with the coarse droplets. Chronic Inhalation Studies. DuPont conducted a two-year cancer bioassay in rats (E.I. Dupont de Nemours & Co., 1990; Lee et al., 1987; WHO, 1986; Kennedy, 2008; as cited in OECD, 2007). Rats were exposed whole body to 10 and 100 ppm (41 and 405 mg/m3) for six hrs/day, five days/week for two years. Exposure was to vapor; only a trace amount of aerosol was detected. The design concentrations were 10 and 100 ppm, and the “means of the high- and low-exposure weekly time-weighted average concentrations were 99.3% and 97.4% of design, respectively, over the duration of the study” (E.I. Dupont de Nemours & Co., 1990). The duration of the study was 24 months with interim sacrifices at 3, 12, and 18 months. There were no signs of intoxication. Males at 405 mg/m3 exhibited a six percent body weight loss. At the 405 mg/m3 exposure, male rats exhibited higher-than-normal hematocrit, alkaline phosphatase, and urine volumes. Exposed rat urine was darker than control. No treatment-related tumors were found, and the hematology, clinical chemistry, urinalysis, gross pathology, and histopathology did not exhibit treatment-related changes other than noted above. The effects seen at 405 mg/m3 are minimal and not biologically significant. The NOAEL for this study was 405 mg/m3.

DERMAL TOXICITY STUDIES

There were no human health effects studies identified for dermal exposure to NMP. A summary of the available dermal animal studies that EPA considered is provided below. Acute Dermal Toxicity Studies. Male and female Sprague-Dawley rats (two per sex) were exposed dermally for 24 hours to 5,000 mg/kg of NMP (Clark et al., 1984; as cited in OECD, 2007). No rats died, and there was no mention of any gross pathology changes.


Female Wistar rats (number not specified) were exposed dermally to 5,000 and 10,000 mg/kg for 24 hours (Weisbrod, 1981; Weisbrod and Seyring, 1980; as cited in OECD, 2007). No rats died at 5,000 mg/kg, and all rats died at 10,000 mg/kg. Developmental Toxicity of Dermal Exposures. Rats were exposed dermally for eight hours to 75, 237, and 750 mg/kg from GD 6 through 15. Dams had collars to prevent oral ingestion (Becci et al., 1981; Becci et al., 1982; FDRL, 1979; E.I. Dupont de Nemours & Co., 1992; as cited in OECD, 2007). Patches of dry skin were noted in a dose-dependent manner at the application site at all doses in the dams. The dams experienced a 17 percent (incorrectly cited as 28 percent in OECD, 2007) reduction in body weight gain at 750 mg/kg, but not at the lower doses. Developmental toxicity expressed as fewer live fetuses, increased resorption rate, reduced fetal body weight, and several skeletal abnormalities only at the high dose. It was not determined whether the fetal toxicity was due to maternal toxicity or directly to the compound. The NOAEL for maternal and developmental toxicity was 237 mg/kg. An important note comes from the results of a range-finding study conducted by the same authors. In this study, all dams from a 2,500 mg/kg exposure group died before GD 20. In the 1,100 mg/kg exposure group, 65 of 66 fetuses were resorbed. The NOAEL of 237 mg/kg is essentially within a factor of 4+ of a totally lethal outcome for the fetus. Rabbits were exposed dermaly for six hrs/day to 100, 300, and 1,000 mg/kg from days seven through 19 of pregnancy (BASF AG, 1993b). There were no toxic effects expressed in the dams. The only sign of fetal toxicity was a small increase in supernumerary 13th ribs at the high dose, a common variation in Himalayan rabbits. The NOAEL for maternal toxicity in this experiment was 1,000 mg/kg, and the NOAEL for fetal toxicity was 300 mg/kg. Subchronic Dermal Toxicity Studies. Albino rabbits were exposed to 413, 826, and 1,653 mg/kg on intact or abraded skin for five days/week over four weeks (GAF Corp., 1986; Industrial Biology Research and Testing Laboratories., 1963; as cited in OECD, 2007). Mild irritation was noted at all doses. Other than one death in a 1,653 mg/kg treated rabbit in the abraded skin group, no systemic toxicity to clinical, hematological, or histopathological measures were seen. The NOAEL for systemic toxicity was 826 mg/kg.

IRRITATION, SENSITIZATION, AND CANCER

NMP is a mild skin and eye irritant in rabbits. In animal studies, exposure to aerosols leads to upper respiratory irritation. In humans, NMP is not irritating to the eyes or upper respiratory tract, but is a skin irritant. Information from secondary literature sources suggests that NMP is not a skin sensitizer in animals or humans (OECD, 2007). NMP is considered non-carcinogenic, and most mutagenicity studies have been negative.


Appendix F. BMD Analysis of Saillenfait et al. (2003) Data BMD Analysis Dose-response modeling was performed using the EPA’s Benchmark Dose Software (BMDS, v.2.1.1.) in accordance with the Benchmark Dose Technical Guidance Document (U.S. EPA, 2012). All standard continuous-variable models were fit to the selected continuous dataset shown in Table F-1. Since developmental studies with nested study designs often have greater sensitivity, and the effect being modeled is a developmental effect a BMR of 5% relative deviation was used (US EPA, 2012b). Inhalation Data The mean fetal body weight data shown in Table F-1 were assessed against the maternal NMP levels. Table F-1. Fetal body weight data from pregnant Sprague-Dawley rats exposed to NMP from GD 6-20.a

Dose mg/m3 (ppm)

Number (all fetuses)

Fetal body weight (g) Mean ± Standard Deviation

0 (0) 24 5.671 ± 0.370

122 (30) 20 5.623 ± 0.358

243 (60) 19 5.469 ± 0.252

487 (120) 25 5.393 ± 0.446 a Raw data obtained directly from the study authors; summary data were provided in Table 2 of Saillenfait et al. (2003)

BMD Modeling Results BMD modeling resulted in the estimation of the POD for fetal/pup body weight changes observed in rats without accounting for litter effects. The BMCL05 is defined as the lower 95 percent confidence limit of the five percent decrement in fetal body weight. A list of the resulting BMCs and BMCL05s are shown in Table F-2. Adequate model fits were achieved for the dataset with Exponential Model 2 (Figure F-1) and Exponential Model 3 (Figure F-2).

Table F-2. Summary of dose-response analysis and point of departure estimation for fetal body weight from pregnant Sprague-Dawley rats exposed to NMP from GD 6-20.

Modela,b AIC

BMC

mg/m3 (ppm) (BMR = 5% Relative

Deviation)

BMCL mg/m3 (ppm)

(BMR = 5% Relative Deviation)

Hill -81.07 612.42 (151.05) 130.19 (32.11)

Linear -84.49 476.96 (117.64) 307.53 (75.85)


Table F-2. Summary of dose-response analysis and point of departure estimation for fetal body weight from pregnant Sprague-Dawley rats exposed to NMP from GD 6-20.

Modela,b AIC

BMC

mg/m3 (ppm) (BMR = 5% Relative

Deviation)

BMCL mg/m3 (ppm)

(BMR = 5% Relative Deviation)

Polynomial (second order) -84.49 476.96 (117.64) 307.53 (75.85) Power -84.49 476.96 (117.64) 307.53 (75.85) Exponential Model 2 -84.51 475.34 (117.24) 301.97 (74.48) Exponential Model 3 -84.51 475.34 (117.24) 301.97 (74.48) Exponential Model 4 -82.63 460.58 (113.60) 173.41 (42.77) a BMD model runs were performed on the data from Table D-1 using EPA’s Benchmark Dose Software (BMDS) Version 2.1. bThe models with the lowest AIC values are shown in bold; the plots of these values are shown in Figures F-1 and F-2.


Figure F-1. Plot of mean response by dose (mg/m3) for fetal body weight with fitted curve for Exponential model 2.

5.2

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5.4

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5.8

0 20 40 60 80 100 120 140

Mea

n R

espo

nse

dose

Exponential Model 2 with 0.95 Confidence Level

17:14 09/06 2012

BMDBMDL

Exponential


Figure F-2. Plot of mean response by dose (mg/m3) for fetal body weight with fitted curve for Exponential model 3.

5.2

5.3

5.4

5.5

5.6

5.7

5.8

0 20 40 60 80 100 120 140

Mea

n R

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Exponential Model 3 with 0.95 Confidence Level

17:14 09/06 2012

BMDBMDL

Exponential


Appendix G. EPA’s Evaluation of the Poet et al. (2012) PBPK Model for NMP Summary EPA's review of the PBPK model (Poet et al., 2010) found that a number of the results shown in the published model and its figures are not reproducible using (preferentially) the model parameters listed in that publication (model parameters not listed in the publication were taken from model files supplied by the authors). While the model structure, including its description of physiological changes during pregnancy, appears to be mostly appropriate, there is significant unresolved uncertainty as to which fitted (chemical-specific) parameters were actually used to obtain the fits shown by Poet et al. (2010). Therefore, if there is a single, consistent set of parameters that adequately describes the pharmacokinetic data for rats and humans, it is not transparent. Resolution of these issues may simply require replacing parameter values listed in the publication with those found in model code files. Alternately, re-calibration of the rat and human models may be necessary. EPA’s Evaluation of the Poet el al. (2010) PBPK Model This appendix describes the EPA’s attempt to reproduce and thereby partially test the PBPK model of Poet et al. (2012) for NMP disposition in rats and humans. The model was implemented in acslX v. 3.0.2.1 (The AEgis Technologies Group, Inc., Huntsville, AL). The containing acslX workspace has two “projects”, one for the rat PBPK model and one for the human PBPK model. Both are based upon model files received from the authors, with relatively minor substantial modification, though a number of comments have been added. For both rats and humans the “pregnancy” versions of the model were used, and a “switch” was added, where when the parameter “PREG” is set to zero, the time-dependent changes that occur during pregnancy are turned off, hence the model represents a non-pregnant adult female as being identical to the physiological state at the immediate inception of pregnancy. This was done to simplify the model evaluation process, and with the assumption that the physiological differences between an adult male and an adult non-pregnant female will have a negligible effect on model predictions. The non-pregnant versions of the model code received do not have any gender-specific tissues, such as a uterus or mammary gland. The volume of the uterus is relatively small in non-pregnant females and mammary tissue would otherwise be lumped into the slowly perfused or fat compartments of both males and females, and neither of these are metabolizing tissues. Therefore, pregnancy-day-zero model predictions are reasonably expected to be essentially identical to male/gender-non-specific model simulations, provided that the chemical-specific parameters are otherwise identical and appropriate values for the physiological parameters are used. Below, results of simulations with the models in this workspace are shown and described.


“Rat NMP” workspace / model results Besides the specific “Runtime” (.m) files listed below, the workspace contains “rat_params.m”, which sets the parameters (called by other files), two “half vmax” files used to test the sensitivity to that parameter, and “ghantinhaldata.m” which defines the data set for Figure 4. The first figure below attempts to reproduce Figure 2A of Poet et al. (2012), and is created using “Poet 2012 Fig 2a.m” in the workspace. The curves are simulations obtained by EPA with the model. The points were obtained from the published figure using digitization software. While most of the published curves were reproduced well, the changes in fetal weight are a bit off and the total body weight (BW) diverges considerably after day 10. Neither the paper nor the code files received specified the number of fetuses used, but a value of 11 was found to provide an exact match for the fetal volume (weight) and the best possible match for the (total) fetus volume (weight).

The next plot, produced by “Poet 2012 Figure 3A.m” compares current simulations with published results in Figure 3A. The large points are the data shown in the figure, while the small points were digitally extracted from the published figure. The current simulation (solid line) matches almost exactly the published results.


The next two figures, produced by “Poet Fig4 2012.m”, compare current simulations with published results in Figure 4. Figure 4A (first plot) only showed the upper set of male-rat data, and the heavy dark line as a prediction. The current simulations for “males” and “females” were obtained by setting gender-specific body weights to those set correspondingly in the model code files received, for these specific data sets. Both sets of current simulations fail to match the published result to a degree that is numerically significant (more than should be expected from using a newer software platform) and the female data (not shown in the published figure) are over-predicted almost two-fold.


The following table compares results obtained with files “Saillenfait 2003 rat.m” and “Solomon 1995 rat.m” to those in Tables 3 and 4, respectively, of Poet et al. (2012).


Table G-1. Comparison of average daily plasma NMP AUCs from Poet et al. 2012 (Tables 3 and 4) and present (10/16/12) simulations of rat inhalation repro/developmental bioassays, using study-specific body weights.

Saillenfait et al. (2003) / Poet et al. Table 3 Solomon et al. (1995) / Poet et al. Table 4

External Concentration (ppm)

Published Average Daily Plasma NMP AUC (mg*hr/L)

Present Average Daily Plasma NMP AUC (mg*hr/L)

% difference

External Conc. (ppm)

Published Average Daily Plasma NMP AUC (mg*hr/L)

Present Average Daily Plasma NMP AUC (mg*hr/L)

% difference

30 94.6 95.9 1.0 10.3 31.8 32.2 1.3 60 193 195.8 1.0 50.8 162 163 0.6 120 403 407.5 1.0 116 387 387 0.0

“Human NMP” workspace / model results Besides the results shown below, the workspace includes “Preg vs nonpreg AUCs.m” which shows how the AUC metric changes during pregnancy and “Table 7 HECs with half Vmax.m” that allows for a comparison with that change in the Vmax. “Poet 2012 Fig 2B human.m” and “Poet 2012 Fig 2C human.m” show an effectively identical match between the current simulations and published results (next 3 plots).


The next set of plots are attempts to reproduce the panels of Figure 6, produced by “Poet 2012 Fig 6 human.m”. As the model files received included the data for individual subjects from the study conducted by Poet et al., those data are shown rather than the single points (assumed to be averages) shown in the published figure. In the first four plots below (panels A-D) the thin, dotted lines are digitized from the published figure, and the heavy solid lines are current model predictions. It is seen that the current simulations differ significantly from those shown in the publication. While the results for NMP, Figure 6A and 6C, are within the range of variability shown by the data, the results for the metabolite 5-HNMP significantly under-predict the data (and published simulations).


The next plot, Figure 6E, shows current model simulations vs. the data. In this case the model reproduces the published simulations (not shown) quite well.


However, in Figure 6F the simulated results (curves shown) under-predict the published simulations at short times (results not shown) and over-predicts those results at later times.

The next two figures, produced by “Poet 2012 Fig 7 human.m”, attempt to reproduce the panels for subject A and Observers. The simulated results (curves shown) substantially under-predict the data (points) and simulations shown in the published figure (results not shown).


The next table compares results from Poet et al. Table 7 to those produced by “Poet 2012 Table 7 HECs.m”. The current simulations yield HECs that are 11-21% higher than published.


Table G-2. Comparison of rat internal dose BMC values and HECs from Poet et al. (2012) and present simulations

Simulations Rat Data Set

Internal Dose (avg daily NMP AUC,

mg*hr/L)

HEC in ppm (8hrs/day, 5 days/week,

9 months) BMC1SD BMCL1SD BMC1SD BMCL1SD

Poet et al. (2012) Table 7

Saillenfait et al. 2003 470 340 650 470 Solomon et al. 2003 540 360 750 500

Present Saillenfait et al. 2003 470 340 745 569

Solomon et al. 2003 540 360 832 597

PBPK model uncertainty, BMD and PBPK extrapolation for inhalation POD. The rat PBPK model established the relationship between NMP concentrations in maternal blood and reductions in fetal/pup BWs following exposure to NMP vapor. This relationship is based on the assumption that maternal dose is proportional to fetal dose (Poet et al., 2010). Direct evidence is not available for this assumption, which is a key uncertainty of this modeling study. One of the most sensitive toxicological endpoint associated with exposure (oral, dermal, and inhalation) to NMP is fetal/pup body weight deficits resulting from maternal exposures. In an effort to reduce uncertainty associated with extrapolating findings from animal toxicity studies to humans, a PBPK model was developed by Poet et al. (2010) initially for adult non-pregnant rats and then extrapolated to pregnancy. Although the model represents a good effort towards reducing uncertainty due to extrapolation, it falls short at this time for quantitative use in deriving a point of departure for risk assessment. EPA's initial review of the PBPK model (Poet et al., 2010) has found that a number of the results shown in the published model figures are not reproducible using (preferentially) the model parameters listed in that publication (Model parameters not listed in the publication were taken from model files supplied by the authors). The model structure, including its description of physiological changes during pregnancy, appears to be mostly appropriate. However, there is uncertainty as to which fitted (chemical-specific) parameters were actually used to obtain the fits shown by Poet et al. (2010), and hence if there is a single, consistent set of parameters which adequately describe the pharmacokinetic (PK) data for rats and humans. Resolution of these issues may simply require replacing parameter values listed in the publication with those found in model code files. Alternately, re-calibration of the rat and human models may be necessary. Another issue of significant concern is that the rat PBPK model was calibrated using nose-only inhalation exposure (pharmacokinetic) data, and hence with skin absorption set to a near-zero value. However the bioassays from which dose-response data are available used whole-body exposures, for which skin absorption is expected to be significant. Therefore skin absorption


should be enabled when simulating bioassay conditions, and this component of the rat model has not been calibrated or tested against any PK data. Another uncertainty is that the metabolic parameters obtained by calibration against PK data from non-pregnant adults are assumed to remain unchanged during pregnancy. There are no PK data for NMP during pregnancy to test this assumption, but rates of metabolism of some other substances are known to change substantially during pregnancy. It should be noted, though, that such an assumption is effectively implicit in default risk-extrapolation methods which do not make use of PBPK models. Identification of the specific enzymes involved in NMP metabolism and any data on their changes during pregnancy could address this uncertainty. An acute POD can be derived from the PBPK modeling of the Saillenfait et al. data (Poet et al., 2010). The modeled HEC was 1,905 mg/m3 for an 8-hour exposure. Poet et al. (2010) used rat and human PBPK models in combination with Benchmark Dose (BMD) analysis to predict the HEC from rat exposure data to better inform dose-response calculations. The model estimated adult blood concentrations of NMP in the rat and used BMD analysis on the modeled results to determine a HEC. The toxicity of NMP is greatest from exposure to the parent compound. NMP had the most embryotoxic effect in whole-embryo culture (Flick et al., 2009 as cited in Poet et al., 2010) and in in vivo developmental toxicity studies (Saillenfait et al., 2007 as cited in Poet et al., 2010). NMP’s major metabolite is 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) which can be further metabolized into N-methylsuccinimide (MSI) and 2-hydrooxy-N-methyl succinimide (2-HMSI). In the PBPK modeling, blood AUC levels of both NMP and 5-HNMP were modeled but the NMP concentrations were used to estimate the HEC. Maternal blood concentrations of NMP were well predicted in rats and humans. NMP levels were proportionally higher than 5-HNMP in rats because humans metabolize NMP at a higher rate. Maternal blood concentrations of NMP were used as the metric because the lack of fetal validation data made the fetal internal dose measures too uncertain. This was considered to be a conservative approach because the modeled human fetal concentrations are relatively lower than the rat (Poet et al., 2010). Two inhalation studies were modeled: Saillenfait et al. (2003) and Solomon et al. (1995) with Staples (1990; as cited in Poet et al., 2010). These studies are described in the Hazard Identification section. The Haskell’s inhalation rat reproductive and developmental studies were reported in Solomon et al. (1995) and E.I. du Pont de Nemours and Company (1990) (the latter also called Staples 1990 in Poet et al., 2010 and in the PBPK descriptions below). Saillenfait et al. (2003) reported a reduced fetal body weight (BW) NOAEL and LOAEL of 243 mg/m3 (60 ppm) and 486 mg/m3 (120 ppm), respectively. A NOAEL of 210 mg/m3 was reported for pup body weight decrease in Solomon et al. 1995 and E.I. du Pont de Nemours and Company, 1990/Staples, 1990. Mean fetal BWs were assessed against the modeled maternal NMP levels using the US EPA Benchmark Dose Software (BMDS, version 2.1). BMD modeling resulted in the estimation of the POD for fetal/pub BW changes observed in rats without accounting for litter effects. A nested model for continuous datasets was not available to the authors when conducting the


PBPK modeling. They also argued that the mild and reversible maternal effects rendered support to not using the nested model in the analysis (Poet et al., 2010). The fetal/pub POD and the human PBPK model are used to estimate the HEC corresponding to the lower 95% confidence limit of the 8-hr benchmark concentration for 1 standard deviation (or 8-hr BMCL1SD). This estimate is considered a NOAEL for the human health risk assessment. From Saillenfait et al. (2003), the HEC corresponding to the 8-hr BMCL1SD was 1,905 mg/m3 (470 ppm). For the Solomon et al. (1995)/Staples (1990) data (as cited in Poet et al., 2010), the HEC corresponding to the BMCL1SD was 2,027 mg/m3 (500 ppm). Because the HEC BMCL1SD values are very similar (i.e., 1,905 versus 2,027 mg/m3), this analysis uses the 8-hr HEC BMCL1SD value (1,905 mg/m3) from Saillenfait et al. (2003) to alternatively assess the acute inhalation risks for residential users and non-users. Time scaling is required for both acute PODs [i.e., 6-hr HEC of 302 mg/m3 (BMD analysis) and 8-hr HEC BMCL1SD of 1,905 mg/m3 (PBPK modeling)]. This is because the acute PODs correspond to 6- or 8-hr exposures, but the human exposure estimates are presented as peak TWAs for 1, 10, and 30 minutes and 1, 4, 8 and 24 hours. Most users would be applying NMP-containing paint strippers for about a period of 4-hrs. We chose to time scale the acute PODs to 4 hrs. Assuming Haber’s Rule (C x t=k), the scaled acute PODs (4-hr) are the following: (1) 453 mg/m3 (based on the BMD analysis) and (2) 3,810 mg/m3 (based on the PBPK modeling). The PBPK modeling is increasing the acute POD by approximately 10-fold when compared to the default approach (i.e., BMD analysis with no modeling). On the other hand, the alternative acute POD (3,810 mg/m3) was derived with PBPK modeling, which reduced the pharmacokinetic uncertainties of extrapolating from animals to humans. In this case, the interspecies component is reduced from 10 to 3. The default intraspecies UF of 10 is retained because of insufficient data to support a reduction. The total uncertainty (or level of concern) captured in the MOE approach for the PBPK-derived POD is 30.

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