v/EPA
United States EPA DocumentW 740-R1-5002
Environmental Protection Agency March 2015
Office of Chemical Safety and
Pollution Prevention
TSCA Work Plan Chemical Risk Assessment
N-Methylpyrrolidone:
Paint Stripper Use
CASRN: 872-50-4
N
March 2015
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TABLE OF CONTENTS
TABLE OF CONTENTS 2
AUTHORS / CONTRIBUTORS / ACKNOWLEDGEMENTS / REVIEWERS 9
ABBREVIATIONS 11
EXECUTIVE SUMMARY 14
1 BACKGROUND AND SCOPE 20
1.1 INTRODUCTION 20
1.2 USES AND PRODUCTION VOLUMES 21
1.2.1 Assessment and Regulatory History 21
1.2.2 Scope of the Assessment 23
1.3 PROBLEM FORMULATION 23
1.3.1 Physical and Chemical Properties 24
1.3.2 Environmental Fate 25
1.3.3 Conceptual Model 26
1.3.3.1 Exposure Pathways 26
1.3.3.2 Health Effects and Human Receptors 27
1.3.4 Analysis Plan 28
2 EXPOSURE ASSESSMENT 30
2.1 OCCUPATIONAL EXPOSURES 30
2.1.1 Approach and Methodology 30
2.1.1.1 Identification of Relevant Industries 31
2.1.1.2 Approach for Determining Occupational Exposure Data and Input Parameters for PBPK Modeling
31
2.1.1.3 Estimates of Occupational Exposure Parameters and Number of Exposed Workers 32
2.1.2 Use of Occupational Exposure Estimates in PBPK Modeling 35
2.2 CONSUMER EXPOSURES 37
2.2.1 Approach and Methodology 37
2.2.1.1 Consumer Dermal Exposure Assessment 38
2.2.1.2 Consumer Users and Residential Non-Users Inhalation Exposure Assessment 38
2.2.2 Model Outputs and Exposure Calculations 46
2.2.3 Use of Consumer Exposure Estimates in PBPK Modeling 46
3 HAZARD IDENTIFICATION AND DOSE-RESPONSE 48
3.1 APPROACH AND METHODOLOGY 48
3.1.1 Selection of Peer-Reviewed Assessments for Hazard Identification and Dose-Response Analysis..48
3.1.2 Hazard Summary and Hazard Identification 49
3.1.3 Selection of Developmental Toxicity Studies and Endpoints 60
3.1.3.1 Decreased Fetal and Postnatal Body Weights 63
3.1.3.2 Resorptions and Fetal Mortality 65
3.1.3.3 Other Fetal Effects 66
3.1.3.4 Conclusions and Selection of Key Endpoints 67
3.2 DOSE-RESPONSE ASSESSMENT AND STUDY SELECTION 68
3.2.1 Identification of Studies for BMD Modeling 68
3.2.2 Derivation of Internal Doses 69
3.2.3 PODs for Acute Exposure 73
3.2.4 PODs for Chronic Exposure 76
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3.2.5 Considerations for Sensitive Subpopulations and Lifestages 78
4 HUMAN HEALTH RISK CHARACTERIZATION 80
4.1 RISK ESTIMATION APPROACH FOR ACUTE AND CHRONIC EXPOSURES 80
4.1.1 Risk Estimates for Acute Occupational Exposure to NMP 82
4.1.2 Risk Estimates for Acute Consumer Exposure to NMP 87
4.1.1 Risk Estimates for Chronic Occupational Exposures to NMP 90
4.2 HUMAN HEALTH RISK CHARACTERIZATION SUMMARY 94
4.3 KEY SOURCES OF UNCERTAINTY AND DATA LIMITATIONS 95
4.3.1 Key Uncertainties in the Occupational Exposure Assessment 95
4.3.2 Key Uncertainties in the Consumer Exposure Assessment 96
4.3.3 Key Uncertainties in the Hazard and Dose-Response Assessments 99
4.3.4 Key Uncertainties in the Risk Assessment 101
4.4 RISK ASSESSMENT CONCLUSIONS 103
REFERENCES 106
APPENDICES 120
Appendix A ENVIRONMENTAL EFFECTS SUMMARY 121
A-l ACUTE TOXICITY TO AQUATIC ORGANISMS 121
A-2 CHRONIC TOXICITY TO AQUATIC ORGANISMS 123
A-3 TOXICITY TO SEDIMENT AND SOIL ORGANISMS 123
A-4 TOXICITY TO WILDLIFE 123
A-5 SUMMARY OF ENVIRONMENTAL HAZARD ASSESSMENT 124
Appendix B CHEMICAL REPORTING DATA 125
B-l CONSUMER USES 127
B-2 PAINT STRIPPING APPLICATIONS 128
Appendix C STATE NMP REGULATIONS 129
Appendix D OCCUPATIONAL EXPOSURE ASSESSMENT SUPPORT INFORMATION 130
D-l SUMMARY OF DERMAL EXPOSURE PARAMETERS, INHALATION CONCENTRATIONS AND EXPOSURE REDUCTION FACTORS 130
D-2 DATA NEEDS AND DATA COLLECTION 130
D-3 INDUSTRIES THAT EMPLOY PAINT STRIPPING ACTIVITIES 133
D-4 OCCUPATIONAL PAINT STRIPPING PROCESSES AND ASSOCIATED WORKER ACTIVITIES 134
D-5 FACILITY AND POPULATION DATA AND INFORMATION 139
D-6 DERMAL EXPOSURE PARAMETERS 144
D-7 OCCUPATIONAL INHALATION EXPOSURE LITERATURE DATA 146
Appendix E CONSUMER EXPOSURE ASSESSMENT 153
E-l ESTIMATION OF EMISSION PROFILES FOR PAINT REMOVERS/STRIPPERS 153
E-2 SENSITIVITY ANALYSIS FOR INHALATION SCENARIOS 165
E-3 INHALATION EXPOSURE SCENARIO INPUTS 166
E-4 INHALATION MODEL OUTPUTS AND EXPOSURE CALCULATIONS 177
E-5 MCCEM INHALATION MODELING CASE SUMMARIES 185
E-5-1 NMP Scenario 1. Coffee Table, Brush-On, Workshop, User in ROM during wait time, 0.45 ACH, 0.25
Weight Fraction 185
£-5-2 NMP Scenario 2. Coffee Table, Brush-On, Workshop, User in Workshop during wait time, 0.45
ACH, 0.5 Weight Fraction 188
£-5-3 NMP Scnario 3. Chest, Brush-On, Workshop, User in ROH during wait time, 0.18 ACH, 0.5 Weight
Fraction 191
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£-5-4 NMP Scenario 4. Bathtub, Brush-On, Bathroom + Source Cloud, User in ROM during wait time,
0.18 ACH, 0.5 Weight Fraction 194
£-5-5 NMP Scenario 5. Bathtub, Brush-On, Bathroom + Source Cloud, User in ROH during wait time,
0.18 ACH, 0.5 Weight Fraction 197
£-5-6 NMP Scenario 6a. Coffee Table, Spray-On, Workshop, User in workshop during wait time, 0.45
ACH, 0.53 Weight Fraction 200
£-5-7 New Scenario 6b. Coffee Table, Spray-On, Workshop, User in workshop during wait time, 0.45
ACH, 0.53 Weight Fraction 203
£-5-S NMP Scenario 7a Chest, Spray-On, Workshop, User in ROH during wait time, 0.18 ACH, 0.53
Weight Fraction 206
£-5-9 NMP Scenario 7b Chest, Spray-On, Workshop, User in ROH during wait time, 0.18 ACH, 0.53
Weight Fraction 209
Appendix F TOXICOLOGY STUDIES 212
F-l LITERATURE COLLECTION 212
F-2 STUDY QUALITY AND SELECTION CONSIDERATIONS 212
F-3 DEVELOPMENTAL TOXICITY STUDIES CONSIDERED FOR USE IN RISK ASSESSMENT 214
F-3-1 Oral Toxicity Studies 214
F-3-2 Inhalation Toxicity Studies 218
F-3-3 Dermal Toxicity Studies 221
F-4 HUMAN CASE REPORT 221
Appendix G HUMAN EXPOSURE STUDIES 223
G-l REVIEW OF AKKESON ETAL, 2004 224
G-2 REVIEW OF AKKESON AND JONSSON, 2000 225
G-3 REVIEW OF AKESSON AND PAULSSON, 1997 226
G-4 REVIEW OF BADER ETAL, 2005 227
G-5 REVIEW OF BADER AND VAN THRIEL, 2006 228
G-6 REVIEW OF BADER ETAL, 2007 229
G-7 REVIEW OF BADER ETAL, 2008 230
G-8 REVIEW OF XIAOFEI ETAL, 2000 231
Appendix H BENCHMARK DOSE ANALYSIS 232
H-l BENCHMARK DOSE MODELING OF FETAL/PUP BODY WEIGHT CHANGES FOR CHRONIC EXPOSURES 232
H-l-1 Results for Saillenfaitetal., 2003 234
H-l-2 Results for Saillenfaitetal.,2002 237
H-l-3 Results for Saillenfaitetal., 2002 and 2003 combined 240
H-l-4 Results for Du Pont, 1990 243
H-l-5 Results for Becci et al., 1982 246
H-2 BENCHMARK DOSE MODELING OF EFFECTS FOR ACUTE EXPOSURES 248
H-2-1 Results for Saillenfaitetal., 2002 and 2003 combined using Cmax 249
H-2-2 Results for Saillenfaitetal., 2002 and 2003 combined using AUC 252
H-2-3 Results for Sitareket al., 2012 255
Appendix! PBPK MODELING 256
1-1 RAT MODEL 256
1-2 HUMAN MODEL 263
1-2-1 Corrections to Human Model Structure 264
LI STOP TABLES
Table 1-1 Physical and Chemical Properties of NMP 24
Table 1-2 Environmental Fate Characteristics of NMP 26
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Table 2-1 Summary of Parameters for Worker Dermal Exposure to Liquids3 33
Table 2-2 Summary of Parameters for Worker Inhalation Exposure Concentrations3 34
Table 2-3 Workplace Exposure Scenario Characteristics 36
Table 2-4 NMP Exposure Scenarios for Characterizing Consumer Inhalation Exposures 44
Table 2-5 NMP Consumer Paint Stripping Scenario Descriptions and Parameters 47
Table 3-1 Summary of Studies with Reproductive or Developmental Effects 52
Table 3-2 Summary of Exposure Pathways, Toxicity Endpoints and Risk Estimation Approach 60
Table 3-3 NMP Studies with Evidence for Developmental Toxicity 62
Table 3-4 Summary of Derivation of the PODs for Fetal Resorptions and Fetal Mortality Following Acute Exposure
to NMP 75
Table 3-5 Summary of Derivation of the PODs for Decreased Body Weight Following Chronic Exposure to NMP....77
Table 4-1 Margin of Exposure (MOE) Equation to Estimate Non-Cancer Risks Following Acute or Chronic Exposures
to NMP 80
Table 4-2 Use Scenarios, Populations of Interest and Toxicological Endpoints for Assessing Risks to NMP-containing
Paint Strippers 81
Table 4-3 Acute Risk Estimates for Occupational Exposures to NMP-Based Paint Strippers - Miscellaneous Stripping
Activities 84
Table 4-4 Acute Risk Estimates for Occupational Exposures to NMP-Based Paint Strippers - Graffiti Removal 85
Table 4-5 Acute Risk Estimates for Consumer Exposures to NMP-Based Paint Strippers 88
Table 4-6 Chronic Risk Estimates for Occupational Exposures to NMP-Based Paint Strippers - Miscellaneous
Stripping Activities 91
Table 4-7 Chronic Risk Estimates for Occupational Exposures to NMP-Based Paint Strippers - Graffiti Removal 92
Table 4-8 Spectrum of Exposure and Risks Based on Scenarios Evaluated in This Risk Assessment 105
LIST OF APPENDIX TABLES
Table_Apx A-l Aquatic Toxicity Data for NMP-Acute Toxicity 122
Table_Apx A-2 Aquatic Toxicity Data for NMP - Chronic Toxicity 123
Table_ApxA-3 Aquatic Toxicity Data for NMP-Wildlife 124
Table_Apx B-l National Chemical Information for NMP from 2012 CDR 125
Table_Apx B-2 Summary of Industrial NMP Uses from 2012 CDR 125
Table_Apx B-3 NMP Commercial/Consumer Use Category Summary 127
Table_Apx B-4 Consumer Uses of NMP 128
Table_ApxC-l State NMP Regulations 129
Table_Apx D-l Study Quality Criteria and Acceptance Specifications 132
Table_Apx D-2 2007 North American Industry Classification System (NAICS) Codes 133
Table_Apx D-3 2007 US Economic Census Data for Painting and Wall Covering and Flooring Contractors 140
Table_Apx D-4 2007 US Economic Census Data for Automotive Body, Paint and Interior Repair and Maintenance
141
Table_Apx D-5 2007 US Economic Census Data for Reupholstery and Furniture Repair 142
Table_Apx D-6 2007 US Economic Census Data for Industry Sectors that May Engage in Art Restoration and
Conservation Activities 142
Table_Apx D-7 2007 US Economic Census Data for Aircraft Manufacturing 143
Table_Apx D-8 2007 US Economic Census Data for Ship Building and Repairing 144
Table_Apx D-9 Summary of NMP Inhalation Exposure Data Identified in the Literature 147
Table_Apx D-10 NMP Personal Air Measurements Obtained during Graffiti Removal (Anundi et al., 2000) 151
Table_Apx E-l Sequence of Stripping Activities for MRI study 156
Table_Apx E-2 Results from GC-FID Samples (EPA, 1994a) 157
Table_Apx E-3 Table 1 from the MRI Report to EPA (EPA, 1994a) 158
Table_Apx E-4 Fitted Parameters to the Rescaled MRI (EPA, 1994) Results for Wood Finisher's Pride 161
Table_Apx E-5 Assumed Model Parameters for Estimates of User and Non-user Exposures for a Spray-applied
Product Containing NMP 164
Table_Apx E-6 Time Schedule for Paint Stripping with Repeat Application 168
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Table_Apx E-7 NMP Mass Released for Brush-on Application, by Application Target 169
Table_Apx E-8 NMP Mass Released for Spray-on Application, by Application Target 169
Table_Apx F-l Study Quality Considerations 213
Table_Apx F-2 Reproductive Performance of Females, Summarized from Sitarek et a I, 2012 215
Table_Apx H-l Fetal Body Weight Data Selected for Dose-Response Modeling for NMP 232
Table_Apx H-2 Model Predictions for Fetal Body Weights in Rats Exposed to NMP by Inhalation Using Daily Average
AUCasthe Dose Metric (Saillenfait et al., 2003) 234
Table_Apx H-3 Model Predictions for Fetal Body Weights in Rats Exposed to NMP by Gavage Using Daily Average
AUCasthe Dose Metric (Saillenfait et al., 2002) 237
Table_Apx H-4 Model Predictions for Fetal Body Weights in Rats Exposed to NMP by Gavage or Inhalation using
Daily Average AUC as the Dose Metric (Saillenfait et al., 2002 and 2003) 240
Table_Apx H-5 Model Predictions for Fetal Body Weights in Rats Exposed to NMP by Inhalation using Daily Average
AUCasthe Dose Metric (DuPont 1990) 243
Table_Apx H-6 Model Predictions for Fetal Body Weights in Rats Exposed to NMP Dermally Using Daily Average
AUCasthe Dose Metric (Becci et al., 1982) 246
Table_Apx H-7 Skeletal Malformations, Resorptions and Fetal Mortality Data Selected for Dose-Response Modeling
for NMP 248
Table_Apx H-8 Model Predictions for Resorptions in Rats Exposed to NMP via Gavage or Inhalation Using Cmax as
the Dose Metric (Saillenfait et al., 2002 and 2003) 249
Table_Apx H-9 Model Predictions for Resorptions in Rats Exposed to NMP via Gavage or Inhalation Using AUC as
the Dose Metric (Saillenfait et al., 2002 and 2003) 252
Table_Apx H-10 Model Predictions for Fetal Mortality in Rats Exposed to NMP by Gavage Using Cmaxas the Dose
Metric (Sitarek etal., 2012) 255
Table_Apx 1-1 Estimated PBPK Parameters for Each Subject of the Baderand van Thriel (2006) Experiments 273
LIST OF FIGURES
Figure 1-1 Chemical Structure of N-Methylpyrrolidone 24
Figure 1-2 Schematic of Human Exposure Pathways for NMP 27
Figure 1-3 Schematic of Analysis Plan for Quantifying Risks of NMP 29
Figure 2-1 Example of Time-varying User Exposure Concentration and Maximum TWA Values for Selected
Averaging Times 41
Figure 2-2 Example of Time-varying Non-user Exposure Concentration and Maximum TWA Values for Selected
Averaging Times 42
Figure 2-3 Model Sensitivity Results (Percent Change from Base-case Response) for Peak 1-hr TWA for Consumer
User and Non-user 43
Figure 2-4 Model Sensitivity Results (Percent Change from Base-case Response) 43
Figure 3-1 Hazard Identification and Dose-Response Process 48
Figure 3-2 Studies that Measured Fetal/Pup Body Weight after Oral Exposure of the Dams to NMP with NOAELand
LOAELs Identified 64
Figure 3-3 Studies that Measured Fetal/Pup Body Weight after Inhalation and Dermal Exposure of the Dams to
NMP with NOAELand LOAELs Identified 65
Figure 3-4 Analysis of Fit: Average Daily AUC vs Fetal or Postnatal Body Weight 73
LIST OF APPENDIX FIGURES
Figure_Apx D-l Typical Flow Tray for Applying Stripper to Furniture (IRTA, 2006) 136
Figure_Apx D-2 Typical Water Wash Booth Used to Wash Stripper and Coating Residue from Furniture (IRTA, 2006)
137
Figure_Apx D-3 Example Diagram of a Dipping Tank for Furniture Stripping (HSE, 2001) 137
Figure_Apx E-l Results from FTIRSamples (EPA, 1994a) 157
Figure_Apx E-2 Uncorrected (Run 12) and Corrected (All Runs) FTIR Results for NMP-Wood Finisher's Pride 158
Figure_Apx E-3 Corrected and Rescaled FTIR Results for NMP - Wood Finisher's Pride (Brush Application) 159
Figure_Apx E-4 NLS Fit of Exponential-emissions Model to Rescaled FTIR Results for Wood Finisher's Pride 160
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Figure_Apx E-5 Theoretical Cumulative Mass of NMP Released from Wood Finisher's Pride 161
Figure_Apx E-6 Zone Volumes and Airflow Rates for Workshop Scenarios 171
Figure_Apx E-7 Zone Volumes and Airflow Rates for Bathroom Scenario 171
Figure_Apx E-8 Modeling Representation of the Bathtub and Virtual Compartment (aka "Source Cloud") 173
Figure_Apx E-9 Air Velocity Distributions from Matthews et al. (1989) 174
Figure_Apx E-10 Example of the Personal Concentration Calculation as Defined in Equation C-13 178
Figure_Apx E-ll Scenario 1, Brush Applied: Modeled NMP Concentrations and User Exposure for Stripper
Application in Workshop Using Parameter Values Selected for Central Tendency Exposure 180
Figure_Apx E-12 Scenario 2, Brush Applied: Modeled NMP Concentrations and User Exposure for Stripper
Application in Workshop Using Parameter Values Selected for Upper-end User Exposure 180
Figure_Apx E-13 Scenario 3, Brush Applied: Modeled NMP Concentrations for Stripper Application in Workshop
using Parameter Values Selected for Upper-end User and Non-User Exposures 181
Figure_Apx E-14 Modeled NMP Concentrations for Scenarios 4 and 5, Brush Application in Bathroom using
Parameter Values selected for Upper-end to Bounding User and Non-User Exposures 182
Figure_Apx E-15 Modeled NMP Concentrations for Scenarios 6a and 6b, Spray Application to Coffee Table in
Workshop using Lower and Upper Estimates for Emission Parameter Values selected for Upper-end User
Exposures 183
Figure_Apx E-16 Modeled NMP Concentrations for Scenarios 7a and 7b, Spray Application to Chest in Workshop
using Lower and Upper Estimates fir Parameter Values selected for Upper-end User and Non-user
Exposures 184
Figure_Apx H-l Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body Weight in Rats
Exposed to NMP via Inhalation (Saillenfait et al., 2003) 235
Figure_Apx H-2 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body Weight in Rats
Exposed to NMP via Gavage (Saillenfait et al., 2002) 238
Figure_Apx H-3 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body Weight in Rats
Exposed to NMP via Gavage or Inhalation (Saillenfait et al., 2002 and 2003) 241
Figure_Apx H-4 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body Weight in Rats
Exposed to NMP via Inhalation (DuPont 1990) 244
Figure_Apx H-5 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body Weight in Rats
Exposed to NMP Dermally (Becci etal., 1982) 246
Figure_Apx H-6 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Resorptions in Rat
Exposed to NMP via Gavage or Inhalation (Saillenfait et al., 2002 and 2003) 250
Figure_Apx H-7 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Resorptions in Rat
Exposed to NMP via Gavage or Inhalation (Saillenfait et al., 2002 and 2003) 253
Figure_Apx 1-1 Model Fits to IV Injection Data in Rats 258
Figure_Apx 1-2 Model Fits to Rat Oral PK Data 260
Figure_Apx 1-3 Model Fits to Dermal PK Data from Payan etal. (2003) in Rats 261
Figure_Apx 1-4 Model Simulations vs. Inhalation PK Data from Ghantous (1995) for NMP Inhalation in Rats 262
Figure_Apx 1-5 NMP Blood Concentration Data from Bader and van Thriel (2006) 270
Figure_Apx 1-6 Alternate Fits to Collective Data from Bader and van Thriel (2006) 271
Figure_Apx 1-7 Model Fits to Subjects 1 and 4 of Bader and van Thriel (2006) 274
Figure_Apx 1-8 Model Fits to Subjects 10 and 12 of Bader and van Thriel (2006) 275
Figure_Apx 1-9 Model Fits to Subjects 14 and 16 of Bader and van Thriel (2006) 276
Figure_Apx 1-10 Model Fits to Subjects 17 and 25 of Bader and van Thriel (2006) 277
Figure_Apx 1-11 Model Fits to Human Inhalation Data of Akesson and Paulsson (1997), With and Without Dermal
Absorption of Vapors 278
Figure_Apx 1-12 Model Fits to Human Dermal Exposure Data of Akesson et al. (2004) 280
Figure_Apx 1-13 Workplace Observer Simulations Representing Subjects of Xioafei et al. (2000) 281
LIST OF EQUATIONS
Equation D-l Mass Balanced Concentration of NMP 153
Equation E-l Exponential Decay of Emissions 154
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Equation E-2 Total Mass Released 154
Equation E-3 Initial Emission Rate 154
Equation E-4 Air Concentration fora Single Exponential as a Function of Time 155
Equation E-5 Air Concentration for a Double Exponential as a Function of Time 155
Equation E-6 Sensitivity Analysis of Linear Variables 165
Equation E-7 Sensitivity Analysis for Discrete Variables 165
Equation E-8 Interzonal Airflow Rate 170
Equation E-9 Saturation Concentration 176
Equation E-10 Maximum Time Weighted Concentrations 177
Equation H-l Linear Model. (Version: 2.19; Date: 06/25/2014) 235
Equation H-2 Exponential Model. (Version: 1.9; Date: 01/29/2013) 238
Equation H-3 Exponential Model. (Version: 1.9; Date: 01/29/2013) 241
Equation H-4 Exponential Model. (Version: 1.9; Date: 01/29/2013) 244
Equation H-5 Polynomial Model. (Version: 2.19; Date: 06/25/2014) 246
Equation H-6 Hill Model. (Version: 2.17; Date: 01/28/2013) 250
Equation H-7 Power Model. (Version: 2.18; Date: 05/19/2014) 253
Equation 1-1 Cardiac Output 257
Equation 1-2 Rat Skin Model Equations 260
Equation 1-3 Rat Skin Partition Coefficients 261
Equation 1-4 Dermal Dosing Equations 262
Equation 1-5 NMP Dermal Transport 263
Equation 1-6 NMP Vapor Exposure Control 263
Equation 1-7 5-HNMP Metabolism and Elimination 264
Equation 1-8 Vapor Exposure Scheduling 265
Equation 1-9 NMP Liquid Rate of Delivery to Skin 266
Equation 1-10 NMP Vapor Rate of Delivery to Skin 266
Equation 1-11 NMP Unabsorbed Fraction Remaining on Skin 266
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AUTHORS / CONTRIBUTORS / ACKNOWLEDGEMENTS /
REVIEWERS
This report was developed by the United States Environmental Protection Agency (EPA), Office
of Pollution Prevention and Toxics (OPPT), Office of Chemical Safety and Pollution Prevention
(OCSPP). The 2012 Work Plan Risk Assessment for N-Methylpyrrolidone (also called N-Methyl-
2-Pyrrolidinone, or NMP) was prepared based on existing data and any additional information
received during the public comment period and peer review process. Mention of trade names
does not constitute endorsement by EPA.
EPA Assessment Team
Leads:
Cal Baier-Anderson, OPPT/Risk Assessment Division (RAD)
Iris Camacho, OPPT/RAD
Team Members:
Kent Anapolle, OPPT/ Chemistry, Economics and Sustainable Strategies Division (CESSD)
Chris Brinkerhoff, OPPT/RAD
Judith Brown, OPPT/CESSD
Ernest Falke, OPPT/RAD
Amuel Kennedy, OPPT/RAD
Andy Mamantov, OPPT/RAD
Scott Prothero, OPPT/RAD
Justin Roberts, OPPT/CESSD
Paul Schlosser, Office of Research and Development (ORD)/National Center for
Environmental Assessment (NCEA)
David Tobias, OPPT/RAD
Management Lead:
Stan Barone Jr., OPPT/RAD
Contributors
Chester E. Rodriguez, formerly with Office of Pesticide Programs (OPP)/Health Effects
Division (HED), currently, The Coca Cola Company
Kan Shao, formerly with ORD/NCEA, currently, Indiana University, School of Public
Health, Department of Environmental Health
Acknowledgements
We acknowledge the contributions of Mary Dominiak (OPPT/Chemical Control Division; retired)
and Conrad Flessner (OPPT/RAD; retired) in the development of the draft work plan risk
assessment for NMP. In addition, we appreciate the assistance from members of OPPT's
Environmental Assistance Division (John Shoaff, Ana Corado and Pamela Buster) for providing
updates to the regulatory history of NMP. Portions of this document were prepared for
EPA/OPPT by Abt Associates, the Eastern Research Group (ERG), Inc., SRC and Versar.
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EPA Internal Peer Reviewers
Office of Chemical Safety and Pollution Prevention
Anjali Lamba, OPPT/RAD
Office of Children's Health Protection
Brenda Foos and Greg Miller
Federal Peer Reviewers
Occupational Safety and Health Administration
Val Schaeffer and Joe Coble
National Institute of Occupational Safety and Health
David Dankovic and Christine Whittaker
Consumer Product Safety Commission
Mike Babich
External Peer Reviewers
EPA/OPPT released the peer review plan in August of 2012 and draft risk assessment and
charge questions for peer review for public comment in January 2013. EPA/OPPT contracted
with The Scientific Consulting Group, Inc. (SCG) to convene a panel of ad hoc reviewers to
conduct an independent external peer review for the EPA/OPPT's draft work plan risk
assessment for NMP. As an influential scientific product, the draft risk assessment was peer
reviewed in accordance with EPA's peer review guidance. The peer review panel performed its
functions by web conference and teleconference between September 26 and December 13,
2013. The panel consisted of the following individuals:
Gary Ginsberg (Chair), Ph.D.
Connecticut Department of Public Health
Thomas W. Armstrong, Ph.D.
Occupational Hygiene Consulting, LLC
Frank A. Barile, Ph.D.
St. John's University College of Pharmacy
and Health Sciences
Anneclaire J. De Roos, PhD.
Drexel University School of Public Health
Ronald D. Hood, Ph.D.
Ronald D. Hood and Associates, Toxicology
Consultants
Dale Hattis, Ph.D.
George Perkins Marsh Institute,
Clark University
John C. Kissel, Ph.D.
University of Washington
Stephen B. Pruett, Ph.D.
College of Veterinary Medicine, Mississippi
State University
Please visit the EPA/OPPT's Work Plan Chemicals web page for additional information on the
NMP's peer review process (http://www.epa.gov/oppt/existingchemicals/pubs/riskassess.html)
and the public docket (Docket: EPA-HQ-OPPT-2012-0725) for the independent external peer
review report and the response to comments document.
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ABBREVIATIONS
°C Degrees Celsius
2-HMSI 2-Hydroxy-N-methylsuccinimide
5-HNMP 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
APF Assigned protection factor
Atm atmosphere(s)
AUC Area under the curve
BAF Bioaccumulation factor
BCF Bioconcentration factor
BMC Benchmark concentration
BMCL 95 Percent lower confidence limit of the benchmark concentration
BMCLiso 95 Percent lower confidence limit of one standard deviation of the benchmark
concentration
BMD Benchmark dose
BMDS Benchmark Dose Software
BMR Benchmark response
BW Body weight
CASRN Chemical Abstracts Service Registry Number
CDC Center for Disease Control and Prevention
cm Centimeter(s)
cm2 Square centimeter(s)
cm3 Cubic centimeter(s)
Cmax Peak concentration
CCh Carbon dioxide
CYP Cytochrome P450
CYP2E1 Cytochrome P450, family 2, subfamily E, polypeptide 1
DCM Dichloromethane (or methylene chloride)
DIY Do-it-yourself
DNEL Derived no effect level
dw Dry weight
E Emission Rate
EC European Commission
EFH Exposure Factors Handbook
EPA Environmental Protection Agency
ESD Emission Scenario Document
EU European Union
ft Foot/feet
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ft2or sq ft Square foot/feet
FTIR Fourier transform infrared
g Gram(s)
GC-FID Gas chromatography with flame ionization detection
GD Gestation day
hhS Hydrogen sulfide
HHE Health hazard evaluation
HPV High production volume
hr(s) Hour(s)
IMIS Integrated Management Information System
IRIS Integrated Risk Information System
IUR Inventory Update Reporting
K Kelvin
Kp rate constant of permeability coefficient
kg kilogram(s)
kmol Kilomole(s)
L Liter(s)
Lb(s) Pound(s)
LCso Lethal concentration 50 percent
LDso Lethal dose 50 percent
LOAEL Lowest-observed-adverse-effect level
m Meter
m2 Square meter(s)
m3 Cubic meter(s)
MCCEM Multi-Chamber Concentration and Exposure Model
mg Milligram(s)
min Minute(s)
MITI Ministry of International Trade and Industry
mmHg millimeter of mercury
mmol Millimole(s)
MOE Margin of exposure
mol Mole(s)
MRI Midwest Research Institute
MSDS Material Safety Data Sheet
MSHA Mining Safety and Health Administration
MSI N-Methylsuccinimide
NAICS North American Industry Classification System
NESHAP National Emission Standards for Hazardous Air Pollutants
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
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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
PC Partition coefficient
pH Measure of acidity or basicity of an aqueous solution
PMN Premanufacture Notification
POD Point of departure
PPE Personal protection equipment
ppm Parts per million
PSKA skin:airPC
PSKL skin:saline PC
PV Dermal permeability or penetration constant for vapor exposure
PVC Polyvinyl chloride
PVL Dermal permeability constant for liquid exposure
RAC Risk Assessment Committee
RIVM Dutch National Institute for Public Health and the Environment
ROH Rest of the house
SA Surface area
SAVC Fraction of total skin area exposed to NMP vapors
SCBA Self-contained breathing apparatus
SIC Standard Industry Classification
SIDS Screening Information Data Set
STEL Short-term exposure limit
TD Toxicodynamics
IDS Technical Data Sheets
TK Toxicokinetics
TRI Toxic Release Inventory
TSCA Toxic Substances Control Act
TWA Time-weighted average
UF Uncertainty factor
UFA Interspecies uncertainty factor
UFn Intraspecies uncertainty factor
UK United Kingdom
US United States
VOC Volatile organic compound
WEEL Workplace Environmental Exposure Level
WHO World Health Organization
Yr Year(s)
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EXECUTIVE SUMMARY
As a part of EPA's comprehensive approach to enhance the Agency's existing chemicals
management program, in March 2012 EPA identified a work plan of chemicals for further
assessment under the Toxic Substances Control Act (TSCA)1. The Agency is performing risk
assessments on chemicals in this work plan. If an assessment identifies unacceptable risks to
humans or the environment, EPA will pursue risk reduction. EPA/OPPT assessed N-
methylpyrrolidone, also referred to as l-methyl-2-pyrrolidinone (TSCA inventory name) or
NMP, as part of this work plan.
NMP is a solvent that exhibits low volatility, low flammability and no explosivity. It has low
persistence and low bioaccumulation potential in the environment. NMP is produced or
imported to the US in large quantities (i.e., 184.7 million Ibs in 2012). It has a variety of TSCA
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.
In the work plan, EPA/OPPT identified NMP for further evaluation based on high concern for
hazard due to its reproductive toxicity and high concern for potential exposure due to use in
consumer products. During scoping and problem formulation, EPA/OPPT considered all TSCA
uses and chose to focus on occupational and consumer paint stripping uses because of high
content in products and high potential exposure to workers and consumers. In addition,
EPA/OPPT reviewed available toxicological data and existing risk assessments and concluded
that the data on developmental toxicity was more relevant, consistent and sensitive than the
reproductive toxicity data. Therefore the NMP hazard identification focused on developmental
toxicity.
Focus of this Risk Assessment
This assessment characterized human health effects associated with NMP-based paint stripping
uses. Based on the physical-chemical properties of NMP and the paint stripping use scenarios
described in this assessment, EPA/OPPT expects the predominant route of exposure for NMP to
be dermal, including absorption of vapor-through-skin.
EPA/OPPT did not include a quantitative assessment of environmental effects in this risk
assessment. Because NMP has a low hazard profile for ecological receptors and low persistence
and bioaccumulation if released into aquatic or terrestrial environments, EPA/OPPT did not
evaluate potential risks to the environment associated with releases of NMP from paint
stripping activities as part of this assessment.
http://www.epa.gov/oppt/existingchemicals/pubs/workplans.html
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Main Conclusions of this Risk Assessment
This assessment evaluated risks of adverse developmental toxicity associated with acute and
chronic exposures to NMP-based paint strippers. Acute exposures were defined as occurring
within a single day. Chronic exposures were defined as exposures comprising 10% or more of a
lifetime (EPA, 2011a). Repeated exposures, e.g., 5 consecutive days or more, are anticipated
during chronic exposure. Adverse developmental outcomes can arise from acute or repeated
exposures during critical windows of development at any time during pregnancy, pregnancy can
occur any time during women's reproductive years and exposures can result in persistent
chronic adverse effects. Therefore the risk assessment was based on developmental toxicity
associated with consideration of acute and repeated exposures.
The risk assessment evaluated a number of exposure scenarios that cover consumer and
worker uses. The outcome of the risk assessment demonstrates that duration of use and
product concentration are both important drivers of risk. Short term (e.g., 1-2 hour) exposures
to products with low concentrations of NMP (e.g., 25% or less) result in no risks. However, the
use of higher concentration products that can readily be purchased by both consumers and
workers may result in risks. Specifically:
The assessment identified risks from acute exposures of:
• Four hours per day, when gloves were not used.
• Greater than 4 hours per day, and risks were not mitigated by personal protective
equipment such as respirators or gloves.
The assessment identified risks from chronic (repeated) exposures of:
• Four hours per day, when gloves were not used.
• Greater than 4 hours per day, and risks were not mitigated by personal protective
equipment such as respirators or gloves.
Based on the use scenarios evaluated, there are no expected risks to people not directly
engaged in using NMP, regardless of duration of exposure.
Other hazards, in particular adverse reproductive and other systemic effects, could be a
concern at higher exposures levels, but exposures that are protective of pregnant women and
women who may become pregnant are expected to also be protective of other lifestages and
subpopulations.
The use of gloves was determined to be effective in reducing modeled estimates of exposure,
as demonstrated by the higher MOEs. For chronic exposure, gloves may not provide sufficient
protection in all scenarios. More importantly, not all glove types are effective in protecting
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against NMP exposure. EPA/OPPT did not evaluate glove efficacy, however California DOH
recommends the use of gloves made of butyl rubber or laminated polyethylene/EVOH2.
Human Populations Considered in This Assessment
EPA/OPPT assumed that people using NMP-based paint strippers would be persons of both
sexes (>16 years old), including pregnant women. EPA assessed if there would be risks to
individuals of any age group (e.g., children, adults, elderly) who may be exposed if they are in a
nearby area during product application.
The quantification of exposures focused on pregnant women and women of childbearing age
who may become pregnant, because the most sensitive health effects selected for use in the
risk assessment affect the fetus. EPA/OPPT assumed that exposures that do not result in
unacceptable risks for these specific lifestages would also be protective of others, including
children, for other adverse outcomes. Support for this assumption includes:
• Toxicological effects that may be relevant to children and adults (i.e., reproductive
effects and other systemic toxicity) are expected to occur at higher exposure
concentrations (e.g., an order of magnitude higher) relative to the fetal effects, based
on rodent studies.
• EPA/OPPT does not expect exposures of adult males to reach levels that would be
associated with reproductive effects or other systemic toxicity.
• Similarly, EPA/OPPT estimated exposures to children who may be nearby the user and
found that exposures were below levels of concern for developmental endpoints, and
would thus be below levels of concern for other endpoints associated with higher
exposure levels.
Acute Exposures Using NMP-Based Paint Stripper
EPA/OPPT evaluated acute exposures by the dermal and inhalation routes, including vapor-
through-skin exposure. Exposures to people who may be nearby those using NMP-based paint
stripping products (i.e., nearby non-users) were also estimated, based on inhalation, vapor-
through-skin and incidental dermal contact exposure routes. For the exposure assessment
EPA/OPPT used data from literature sources where available; in the absence of data, EPA/OPPT
relied on generalized use patterns and the physical and chemical properties of NMP as inputs to
modeling approaches.
EPA/OPPT used two different approaches to quantify acute exposures to workers and
consumers. The first approach incorporated assumptions based on occupational exposures of 1,
4, or 8 hours duration, whereas the second approach incorporated assumptions considering
consumer use on a single project (table, chest of drawers or bathtub). The use of personal
2 See California Health Hazard Advisory, available at:
http://www.cdph.ca.gov/programs/hesis/Documents/nmp.pdf (accessed December 18, 2014)
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protective equipment was varied to determine how this might affect exposure in both
approaches.
EPA/OPPT did not quantify risks to consumers who may use NMP-based paint strippers on
multiple products for 4 hours or more. Based on a qualitative analysis of the outcomes it is
possible that exposures of 4 or more hours could present risks comparable to those associated
with acute worker exposure scenarios.
Chronic Exposures to NMP-Based Paint Strippers
EPA/OPPT evaluated chronic exposures by the dermal and inhalation routes, including vapor-
through-skin exposure. Exposures to people who may be nearby those using NMP-based paint
stripping products (i.e., nearby non-users) were also estimated, based on inhalation, vapor-
through-skin and incidental dermal contact exposure routes. For the exposure assessment
EPA/OPPT used data from literature sources where available; in the absence of data, EPA/OPPT
relied on generalized use patterns and the physical and chemical properties of NMP as inputs to
modeling approaches.
EPA/OPPT developed exposure scenarios that simulated repeated exposures to NMP from
miscellaneous stripping, and graffiti removal, activities that are generally, but not exclusively,
associated with workers. For each basic scenario EPA/OPPT considered low, moderate and
high-end exposure parameters and the impact of different combinations of personal protective
equipment (PPE) on exposure:
• Respirator and gloves
• Respirator only
• Gloves only
• Neither respirator nor gloves
EPA/OPPT assumed that these variations cover most of the spectrum of repeated paint stripper
uses. Since the hazard endpoint of interest was based on developmental effects, EPA/OPPT
considered repeated exposures of 5 or more consecutive days to be potentially significant.
Use of PBPK Model
EPA/OPPT used a physiologically-based pharmacokinetic (PBPK) model to calculate internal
doses of NMP, which are expected to better represent exposures related to potential adverse
effects (McLanahan et al., 2012). The PBPK model also allowed EPA/OPPT to estimate aggregate
exposures across multiple exposure routes, specifically dermal, vapor-through-skin and
inhalation exposures. The PBPK model was based on a published, peer-reviewed model that
was adapted and validated for use by EPA/OPPT.
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NMP Hazard Identification and Dose-Response Analysis
A number of adverse effects were observed in different studies, including effects on body
weight, liver, kidney, spleen, thymus, testes and brain. EPA/OPPT reviewed the evidence for
NMP toxicity and selected developmental toxicity endpoints as the most robust, sensitive and
consistent adverse effects for dose-response analysis.
EPA/OPPT specifically selected increased fetal resorptions (fetal death) to assess risks from
acute exposures and decreased fetal body weight to evaluate risks from chronic exposures. The
exposure concentrations used in the rat studies were converted to internal doses using the
PBPK model. EPA/OPPT applied benchmark dose (BMD) modeling to the internal doses to
generate the appropriate point of departure (POD) for chronic and acute exposure scenarios.
The POD is the dose used to estimate risk and is generally based on the No Observable Adverse
Effect Level (NOAEL) or a surrogate metric, such as the BMDL (lower confidence limit on the
BMD).
Risk Assessment Approach
EPA/OPPT calculated Margins of Exposure (MOEs) and compared them to a benchmark MOE to
determine if unacceptable risks were present. EPA/OPPT calculated acute or chronic MOEs
(MOEacute or MOEchronic) separately based on the appropriate POD and estimated exposure. A
benchmark MOE of 30 was selected; MOEs below 30 indicated the presence of risks.
Uncertainties of this Risk Assessment
There are a number of uncertainties associated with this risk assessment. Uncertainties
pertaining to the lack of measured data on dermal exposure resulted in several parameter
values being based on assumptions. There are also uncertainties associated with the efficacy of
glove use, durations of contact, and surface areas exposed.
There are also uncertainties associated with the inhalation exposure assessment; the small
number of exposure studies means that the data may not be representative of all scenarios.
Differences in use practices and engineering controls could introduce unknown variability that
EPA/OPPT could not account for in this assessment.
The actual number of people exposed to NMP in paint strippers is not known. There are no data
for the number of people using NMP-based paint stripper that would allow for a reliable
estimate of the size of the affected population. However, it is expected that NMP-based paint
strippers are less common than DCM-based strippers, so the number of potentially exposed
people should be less than the number of people exposed to DCM-based strippers. The number
of workers using DCM-based strippers was estimated to be 230,000 (EPA, 2014b); the number
of consumers using DCM-based strippers is unknown.
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There are a number of uncertainties associated with the consumer exposure assessment.
Limited data were available on consumer uses and the duration of exposure. EPA/OPPT did not
quantify risks to consumers who may use NMP-based paint strippers on multiple projects for
greater than 4 hours.
For all exposure scenarios, inter-individual variability was assumed, but not quantified. This
variability was reflected in the selection of uncertainty factors used in the calculation of risk
estimates, specifically 10X for intra-human variability and 3X for interspecies (extrapolation of
rat to human) uncertainty.
There is also uncertainty associated with assessing risks of developmental toxicity based on
decreased fetal body weight in rodents. In particular, there is uncertainty regarding the timing
and duration of the exposures in humans, relative to the controlled rodent exposure studies.
EPA/OPPT selected fetal resorptions/fetal mortality to evaluate risks associated with acute
exposures because they were consistent, relevant and sensitive. There is uncertainty in
interspecies extrapolation of concentration-response for resorptions and fetal mortality
observed in rodents to spontaneous abortions and fetal mortality in humans.
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1 BACKGROUND AND SCOPE
1.1 INTRODUCTION
As a part of EPA's comprehensive approach to enhance the Agency's existing chemicals
management, in March 2012 EPA/OPPT identified a work plan of chemicals for further
assessment under the Toxic Substances Control Act (TSCA)3. EPA/OPPT is assessing chemicals in
this work plan; if an assessment identifies unacceptable risks to humans or the environment,
EPA/OPPT will pursue risk reduction options. After gathering input from stakeholders,
EPA/OPPT developed criteria used for identifying chemicals for further assessment4. The
criteria focused on chemicals that meet one or more of the following factors: (1) potentially of
concern to children's health (for example, because of reproductive or developmental effects);
(2) neurotoxic effects; (3) persistent, bioaccumulative and toxic (PBT); (3) probable or known
carcinogens; (4) used in children's products; or (5) detected in biomonitoring programs. Using
this methodology, EPA/OPPT developed a TSCA Work Plan of chemicals as candidates for risk
assessment in the next several years. In the prioritization process, N-methylpyrrolidone or
l-methyl-2-pyrrolidinone (NMP; Chemical Abstracts Service Registry Number [CASRN] 872-50-
4) was identified for assessment based on high human health hazards and exposure potential.
The target audience for this risk assessment is primarily EPA/OPPT risk managers; however, it
may also be of interest to the broader risk assessment community as well as US stakeholders
that are interested in issues related to NMP, especially when used as a paint stripper. The
information presented in the risk assessment may be of assistance to other Federal, State and
Local agencies as well as to members of the general public who are interested in the risks
associated with the use of NMP-based paint strippers.
The initial step in EPA/OPPT's risk assessment development process includes scoping and
problem formulation and is distinct from the exercise to put a chemical on the work plan.
During scoping and problem formulation EPA/OPPT reviews currently available data and
information, including but not limited to, assessments conducted by others (e.g., authorities in
other countries), published or readily available reports and published scientific literature.
During scoping and problem formulation, a robust review may result in refinement - either
addition/expansion or removal/contraction - of specific hazard or exposure concerns previously
identified in the work plan methodology.
3 http://www.epa.gov/oppt/existingchemicals/
4 http://www.epa.gov/oppt/existingchemicals/pubs/wpmethods.pdf
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1.2 USES AND PRODUCTION VOLUMES
According to the 2012 Chemical Data Reporting (CDR), 184.7 million pounds (Ibs) of NMP were
produced or imported into the US that year, making NMP a high production volume (HPV)
chemical (EPA, 2013a). BASF Corporation, NOVA Molecular Technologies, Inc., Ashland, Inc, OM
Group, Inc., Toray Holding (USA), Inc. and Lyondell Chemical Company currently manufacture
NMP in the US (Appendix A-l).
NMP is an effective solvent used in a variety of industrial, commercial and consumer use
applications, including (Harreus et al., 2011):
• Petrochemical processing, acetylene recovery from cracked gas, extraction of
aromatics and butadiene, gas purification (removal of carbon dioxide [CCh] and
hydrogen sulfide [HhS]), 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 co-solvent for liquid formulations;
• Electronics: cleaning agent for silicon wafers, photoresist stripper, auxiliary in
printed circuit board technology; and
• 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).
Although paint stripping accounts for only about nine percent of the total use of NMP,
EPA/OPPT is specifically concerned about this use because the potential for exposure is high;
some of the other uses of NMP involve closed processes or lower concentrations that generally
reduce exposures and are of less concern. While the cited paint stripping use percentage is
from reports dated in the 1980s and 1990s, confidential business information (i.e., known to
EPA/OPPT but cannot be cited here) as recent as 2011 confirmed that paint stripping is still a
low percentage use for NMP in terms of market consumption.
1.2.1 Assessment and Regulatory History
NMP is subject to a number of EPA regulations. NMP is listed on the Toxics Release Inventory
(TRI) and is therefore subject to reporting pursuant to Section 313 of the Emergency Planning
and Community Right-to-Know Act (EPCRA)5. According to the 2013 TRI dataset, 386 facilities
reported releases or transfers and the top 100 facilities disposed of or released a total of
5 List of Toxics Release Inventory Chemicals, Section 313, Emergency Planning and Community Right to Know Act
(EPCRA), Toxics Release Inventory (TRI) Program, US Environmental Protection Agency, 40 CFR 372.65, July 1, 2002.
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7.747 million Ibs of NMP (EPA, 2013a). NMP is on The Clean Air Act (CAA) Section 111,
Standards of Performance for New Stationary Sources of Air Pollutants - Equipment Leaks
Chemical List6. NMP is currently approved for use by EPA as a solvent and co-solvent inert
ingredient in pesticide formulations for both food and non-food uses and is exempt from the
requirements of a tolerance limit.7
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): a workplace
environmental exposure level (WEEL) of 10 ppm as an 8-hr time weighted average (TWA), with
the addition of a cautionary note addressing concerns for skin contact (AIHA, 2013). EPA/OPPT
expects that some workplaces may consider this WEEL when instituting respiratory and dermal
protections.
A number of states have taken action to address NMP hazard and risk concerns; this
information is available in Appendix B.
NMP is currently on the candidate list of substances of very high concern for authorization in
the European Union. In August 2013, the Dutch National Institute for Public Health and the
Environment (RIVM) submitted a proposal for the restriction of NMP to the European
Chemicals Agency (ECHA) under the Registration, Evaluation, Authorisation and Restriction
(REACH) regulation (RIVM, 2013). The restriction proposal was modified by the Risk Assessment
Committee (RAC) (ECHA, 2014) and the combined opinion will be sent to the European
Commission for final decision. The RAC recommended using long-term exposure DNELs for
pregnant workers (the most sensitive population) for both inhalation and dermal exposure. The
proposal would require that "Manufacturers, importers and downstream users of the
substance on its own or in mixtures in a concentration equal or greater than 0.3% shall use in
their chemical safety assessment and safety data sheets by a long term Derived No Effect Level
(DNEL) value for workers inhalation exposure of 10 mg/m3 and a long term DNEL for workers
dermal exposure of 4.8 mg/kg/day"(ECHA, 2014).
When Canada conducted a categorization of the Domestic Substances List for its Chemicals
Management Plan in 2006, NMP met Canada's human health categorization criteria. NMP has
been the subject of a Tier II health risk assessment in Australia under the Inventory Multi-tiered
Assessment and Prioritisation (IMAP) (NICNAS, 2013). It is currently subject to labeling and
related requirements based on concern for skin, eye and respiratory irritation and for
reproductive toxicity. These government assessments consider NMP to be of low
environmental concern. Australia concluded that further risk management is required and
6 List of Regulated Toxic Substances and Threshold Quantities for Accidental Release Prevention (Table 1) and List
of Regulated Flammable Substances and Threshold Quantities for Accidental Release Prevention (Table 3), Section
112(r), Federal Clean Air Act Amendments, US Environmental Protection Agency, 40 CFR 68.130, Tables 1 and 3,
July 1, 2008.
7 EPA Action Memorandum: Inert Reassessment: N-methylpyrrolidone (CAS Reg. No. 872-50-4), June 2006.
http://www.epa.gov/opprd001/inerts/methvl.pdf (accessed October 28, 2014)
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additional assessment (Tier III) is needed to determine if current exposure controls are
adequate to protect workers and the public when NMP is used in domestic products.
1.2.2 Scope of the Assessment
Based on a review of available data, EPA/OPPT focused on NMP in paint stripping applications,
because of high content in products and high potential exposure to workers and consumers.
EPA/OPPT determined that general population and agricultural exposures were outside the
scope of this assessment. Narrowing of the scope was based on a comparison of potential
exposures among the primary uses identified relative to paint stripping. These comparative
judgments considered potential exposure among the primary uses identified. In addition, NMP
is a potential substitute for dichloromethane (DCM) in paint stripping applications, which
EPA/OPPT recently assessed under the TSCA Work Plan and found to present significant cancer
and non-cancer risks; hence, EPA/OPPT considered it prudent to evaluate NMP because
manufacturers may consider it to be a replacement for DCM as a paint stripper.
EPA/OPPT's assessment of paint stripping activity quantitatively evaluated the risks for workers
using NMP-based paint strippers considering both acute and chronic exposures. Acute exposure
was defined as exposure over the course of a single day, and chronic exposure was defined as
exposure of 10% or more of a lifetime (EPA, 2011a). Repeated exposures over the course of a
work week are anticipated during chronic worker exposure. Occupational exposures include
possible direct exposures to workers who may use these products at work, in training or other
situations. Data sources did not often indicate whether exposure concentrations were for
occupational users or workers who may be nearby those using NMP-based paint stripping
products (i.e., nearby worker non-users). Therefore, EPA/OPPT assessed both populations of
occupational workers.
This assessment also examined consumer exposures to NMP-based paint strippers in consumer
use scenarios. EPA/OPPT also evaluated exposures to other residents who did not use the
product, but may be indirectly exposed in the home while located nearby while the product is
being used (i.e., nearby residents). The consumer exposures were assumed to be of short
duration (acute), based on a single project (e.g., strip paint off of a coffee table, chest of
drawers or bathtub) and that NMP is readily eliminated from the body, mainly by extensive
metabolism and rapid excretion in the urine (Akesson and Paulsson, 1997; Jonsson and
Akesson, 2003; Payan, 2002).
1.3 PROBLEM FORMULATION
During problem formulation, EPA/OPPT defined which exposure pathways, receptors and
health endpoints would be included in this risk assessment. To make this determination,
physical chemical properties and environmental fate were evaluated within the context of the
selected use scenarios: occupational and consumer paint stripping.
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Problem formulation also led to EPA/OPPT's conclusion not to evaluate environmental risks
related to the use of NMP in paint stripping products. EPA/OPPT reviewed and summarized
available published studies on ecotoxicity (EPA, 1999b, 2012b; OECD, 2007) to understand the
potential environmental effects of NMP releases to the environment on ecological receptors
including toxicity to fish, invertebrates, plants and birds. Based on this review, EPA/OPPT
concluded that the ecotoxicological hazard of NMP is low. Thus, the potential risks to the
environment based on releases of NMP from paint stripping activities were not evaluated
further in this assessment. Appendix A contains a summary of the aquatic toxicity studies
considered in the evaluation of environmental hazards of NMP.
1.3.1 Physical and Chemical Properties
Figure 1-1 presents the chemical structure of NMP. Table 1-1 summarizes NMP's physical
chemical properties.
N
0
Figure 1-1 Chemical Structure of N-Methylpyrrolidone
NMP is a colorless to slightly yellow liquid with a slight amine odor. NMP is in a class of dipolar
aprotic solvents that are miscible in water and do not contain acidic hydrogen. Neat NMP
exhibits low volatility, high boiling point, low flammability and no explosivity. Variations in
humidity can cause a range of saturation concentrations. NMP is not readily oxidizable (EC,
2000; Lide, 2001; O'Neil et al., 2001).
Table 1-1 Physical and Chemical Properties of NMP
Molecular formula
Molecular weight
Physical form
Melting point
Boiling point
Vapor pressure
Log Kow
Water solubility
Flash point
C5H9ON
99.13
Colorless to slightly yellow liquid; slight amine odor
-24.4 °C
202 °C
0.190mmHgat25°C
-0.727 at 25 °C
1,000 g/L at 25 °C
95 °C (open cup); 91 °C (closed cup)
Source: EC (2000)
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1.3.2 Environmental Fate
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. Fate characteristics are summarized in Table 1-2.
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 hrs, assuming a
hydroxyl radical concentration of 1.5 x 106 hydroxyl radicals/cm3 air over a 12-hr day. NMP in
the atmosphere can be expected to dissolve into water droplets, where it will be removed by
condensation or further reactions with hydroxyl radicals.
When released to water, NMP is not expected to adsorb to suspended solids or sediment in the
water column based upon its Koc value. Although neat NMP is slightly volatile, the rate of
volatilization from water is expected to be low based on a Henry's Law constant of
3.2 x 10~9 atm-m3/mole. Based on its low soil organic carbon partitioning coefficient (log Koc =
0.9), NMP is expected to possess high mobility in soil; releases of NMP to soil may volatilize
from soil surfaces or migrate through soil and contaminate groundwater.
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 (EPA, 1999b, 2012b;
OECD, 2007). Based on the available environmental fate data, NMP is expected to have low
bioaccumulation potential and low persistence.
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Table 1-2 Environmental Fate Characteristics of NMP
Property
CASRN
Photodegradation
half-life
Hydrolysis half-
life
Biodegradation
Bioaccumulation
Bioconcentration
Log Koc
Fugacity
(Level III Model)b
Air (%)
Water (%)
Soil (%)
Sediment (%)
Persistence0
Bioaccumulation0
Value
872-50-4
5.8 hrs (estimated)
Stable
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, MITI (1))
91-97% after 28 days (readily biodegradable, OECD 301B)
88% after 30 days (readily biodegradable, OECD 301D)
98% after 4 days (inherently, biodegradable, OECD 302B)
99% after 19 days (inherently biodegradable, OECD 301E)
BAF = 0.9 (estimated)13
BCF = 3.16
0.9 (estimated)13
<0.1
32.5
67.3
<0.1
low
low
Notes:
aOECD(2008)
bEPA(2012b)
cEPA(1999b)
1.3.3 Conceptual Model
1.3.3.1 Exposure Pathways
The following conceptual model (Figure 1-2) illustrates NMP uses and pathways that may result
in occupational, consumer and general population exposures. The shaded components indicate
the exposure pathways considered in this risk assessment, as summarized above in section
1.2.2.
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Worker exposure assessment: Risks to workers using NMP-based paint strippers and nearby
worker non-users, based on acute and chronic dermal and inhalation exposure.
Consumer exposure assessment: Risks to consumers using NMP-based paint strippers and
nearby consumer non-users, based on acute dermal and inhalation exposure.
SOURCES
EXPOSURE PATHWAYS
HUMAN RECEPTORS
EFFECTS
Occupational:
Paint Strippers
Occupational:
Coatings, Electronics,
Petrochemical,
Process Solvents
I
>
/
JAir/Vapor, 1
"*[ Direct Contact J"
Body Weight
Reductions
Developmental
Toxicity
Reproductive
Toxicity
Liver/ Kidney
Effects
Neurotoxicity
dinical
Chemistry
Food Crops
>-
LEGEND
• Solid lines = Pathway can be quantified
• Dashed lines - Pathway out of scope, not quantified
• Shaded boxes/ovals - Elements proposed for inclusion in risk
assessment; exposure and toxicity can be quantified
Figure 1-2 Schematic of Human Exposure Pathways for NMP
Pathways Excluded from the Risk Assessment
EPA/OPPT excluded the following exposure pathways from this assessment:
• Use of NMP in coatings, electronics and petrochemical processing, were excluded
because EPA/OPPT assumed the NMP content and exposure potential are relatively low.
• Use of NMP in consumer cleaning products were excluded because EPA/OPPT assumed
the products contain a low percentage of NMP and that exposure potential is low due to
infrequent use.
• General population exposure from use in agricultural products was excluded as this use
is covered under the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA).
J.^,3.,;^^
Although there are a number of hazards associated with NMP exposure (section 3.1.2),
EPA/OPPT identified developmental toxicity as the focus of this risk assessment (section 3.1.3).
NMP was initially prioritized for assessment based on high concern for reproductive toxicity.
Consideration of the body of evidence, including more recent studies, indicated that the data
Page 27 of 281
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on developmental toxicity were more relevant, consistent and sensitive than the reproductive
toxicity data. Reproductive and developmental toxicity endpoints can occur on a continuum
and in some cases it can be difficult to distinguish whether an endpoint is due to reproductive
or developmental toxicity. EPA/OPPT determined that using developmental toxicity endpoints
for dose-response calculation would be protective of the most sensitive lifestages, including the
fetus.
Since developmental toxicity and fetal effects were more sensitive and of greatest concern, the
risk assessment focused on pregnant women and women of child-bearing age who may
become pregnant. EPA/OPPT recognizes that other effects, including reproductive effects and
other organ toxicity, might be associated with higher exposures and may affect other lifestages
and subpopulations. By basing the risk calculation on the most sensitive endpoint for the most
sensitive receptors, EPA/OPPT assumed that scenarios that show no risks for developmental
effects should also be protective of other receptors, including children. This issue is discussed in
more detail in section 3.2.5 with specific examples in section 4.1
1.3.4 Analysis Plan
Figure 1-3 describes the approach taken to quantify risks associated with use of NMP-based
paint strippers. EPA/OPPT quantified occupational exposure based on a combination of
monitoring data and generic assumptions (2.1.1.2) to derive dermal and inhalation exposure
parameters and concentrations (2.1.1.3).
EPA/OPPT estimated consumer dermal exposure based on modeled consumer behavior
patterns (2.2.1.1), while inhalation exposure was informed by emissions data from a chamber
study and mathematical modeling (2.2.1.2).
EPA/OPPT used a physiologically-based pharmacokinetic (PBPK) model to calculate internal
doses because, in general, internal doses are expected to correlate more closely with effects
(McLanahan et al., 2012) and it allows for aggregating exposures across multiple exposure
routes. The PBPK model was used to calculate internal doses for workers (2.1.2) and consumers
(2.2.3), from dermal, vapor-through-skin and inhalation exposure routes for different scenarios.
The PBPK model was based on a published model that was adapted for use by EPA/OPPT
(Appendix I).
For hazard identification and dose-response, EPA/OPPT reviewed available data and selected a
subset of rat studies that, taken as a whole, demonstrated the most robust, sensitive and
consistent fetal effects compared to other studies, for use in the risk assessment (3.1.3).
EPA/OPPT converted the exposure concentrations in the selected studies to internal doses
using a rat PBPK model (3.2.2). EPA/OPPT used benchmark dose (BMD) modeling to generate
the appropriate point of departure (POD) for chronic (3.2.3) and acute (3.2.3) exposure
scenarios. The POD is the dose used to estimate risk and is generally based on the No
Observable Adverse Effect Level (NOAEL) or a surrogate metric, such as the BMDL (lower
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confidence limit on the BMD). EPA/OPPT quantified risk based on the Margin of Exposure
(MoE), which is the ratio of exposure (i.e., internal doses) with the POD (4.1).
Exposure
Assessment
Dose-Response
Assessment
Occupational
Monitoring Studies
(chronic exposure)
Chamber
Study
Consumer Inhalation
Exposure Model
(acute exposure)
Developmental Toxicity Endpoints:
• Fetal body weight (chronic exposures)
• Skeletal malformations, resorptions, fetal
mortality (acute exposures)
NMP
Exposure
Concentrations
(8-hr TWA for
low-, mid- and
hfgh-end ranges)
NMP
Exposure
Time-Courses
up to 24 hrs
Dermal &
Inhalation
Inputs
Human Internal
Doses
Occupational and
Consumer Exposures
Rat PBPK
Model
Rat Internal Doses
{NMP concentration,
AUC or Cm ax)
BMD Models
Rat Internal Dose
PODs
BMDLsorNOAELs
Human Equivalent
Internal Dose (HED)
PODs
Margins of Exposure =
POPHED
Human Internal Dose
Figure 1-3 Schematic of Analysis Plan for Quantifying Risks of NMP
See text in section 1.3.4 for details.
Page 29 of 281
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2 EXPOSURE ASSESSMENT
The exposure pathways of interest included dermal, vapor-through-skin and inhalation. NMP is
well absorbed following dermal exposures and dermal absorption including NMP from the
vapor phase typically contributes significantly to human exposure (Bader et al., 2008; Keener et
al., 2007). NMP diluted in water has reduced dermal absorption (Keener et al., 2007; Payan,
2003) while NMP diluted in other solvents, such as d-limonene, can increase the absorption of
NMP (HLS, 1998) and prolonged exposures to neat (i.e., pure) NMP increases the permeability
of the skin (RIVM, 2013). NMP is also absorbed via inhalation (Akesson and Paulsson, 1997) but
the low vapor pressure and mild volatility can limit the amount of NMP available for inhalation.
For nearby non-users, exposures were limited to inhalation and vapor-through-skin exposure
routes. In all cases, internal doses integrating the different exposure routes were derived using
a PBPK model.
The previously published PBPK model for NMP in humans (Poet et al., 2010) was adapted for
use by EPA (see Appendix I). The model predicted absorption of liquid or vapor from the NMP
concentration, duration of contact and physiological descriptions such as body weight. The
physiological parameters of body weight and skin surface area used were specific to pregnant
women and women of childbearing age. Absorption of NMP via inhalation depended on the
NMP concentrations in air. Dermal absorption of NMP depended on the NMP weight fraction in
liquid, NMP vapor concentration and skin surface area exposed to liquid and vapor. The
thickness of the liquid film did not factor directly into the estimate of liquid NMP absorption. As
a conservative estimate for user scenarios it was assumed that fresh material would be
constantly deposited over the time of use such that the concentration on the skin would remain
essentially constant at the formulation concentration. The exposure parameters used to
estimate internal NMP doses for the occupational and consumer exposure scenarios are
described below.
2.1 OCCUPATIONAL EXPOSURES
2.1.1 Approach and Methodology
This section identifies relevant industries and worker population estimates and summarizes the
occupational dermal and inhalation exposure parameters and concentrations for NMP-based
strippers. These parameters were used as PBPK model inputs. Appendix D provides background
details on industries that may use NMP-based strippers, worker activities, processes, numbers
of sites and number of potentially exposed workers. Appendix D also provides detailed
discussion on the values of the dermal exposure parameters and air concentrations and
associated worker inhalation parameters presented in this section.
Page 30 of 281
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2.1.1.1 Identification of Relevant Industries
Because a variety of industries include paint stripping among their business activities,
EPA/OPPT made an effort to determine and characterize these industries. EPA/OPPT reviewed
the published literature and evaluated the 2007 North American Industry Classification System
(NAICS) codes to determine industries that likely include paint stripping activities (see Appendix
D, Table_Apx D-2). The identified industries are:
• Professional contractors;
• Bathtub refinishing;
• Automotive refinishing;
• Furniture refinishing;
• Art restoration and conservation;
• Aircraft paint stripping;
• Ship paint stripping; and
• Graffiti removal.
Identifying these industries is useful to identify workers who may be exposed to NMP due to
the use of the NMP-based strippers. However, EPA/OPPT was not able to determine the extent
of use of NMP-based strippers in these industries. Appendix D details the industries identified
and processes and worker activities that may contribute to worker exposures.
2.1.1.2 Approach for Determining Occupational Exposure Data and Input
Parameters for PBPK Modeling
To derive internal dose estimates for acute and chronic occupational exposures, the PBPK
model required as input parameters to describe NMP concentration, duration and physiological
descriptors such as surface area and body weight. EPA/OPPT used literature sources for
estimating many of these occupational exposure parameters and generic assumptions were
used when data were not available.
EPA/OPPT used air concentration data and estimates found in literature sources to serve as
inhalation exposure concentration inputs to the PBPK modeling for occupational exposures to
NMP. EPA/OPPT searched the OSHA's Integrated Management Information System (IMIS)
database for inspection data from OSHA and its State Plan States for NMP inhalation exposures.
However, NMP exposure data in the IMIS database are limited, did not include any industries
that matched the NAICS codes identified in Appendix D and did not appear relevant for paint
stripping.
For most dermal exposure parameters and inhalation concentrations, EPA/OPPT did not find
enough data to determine statistical distributions of the actual exposure parameters and
concentrations. Ideally, EPA/OPPT would like to know 50th and 95th percentiles for each
parameter. The means and mid-ranges (means are preferable to mid-ranges) served as
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substitutes for 50th percentiles, and high ends of ranges served as substitutes for 95th
percentiles. However, these substitutes were highly uncertain and not ideal substitutes for the
percentiles. EPA/OPPT could not determine whether these concentrations were suitable to
represent statistical distributions of real world scenarios. Parameters were selected for the
most sensitive lifestages: pregnant women and women of childbearing age who may become
pregnant.
2.1.1.3 Estimates of Occupational Exposure Parameters and Number of
Exposed Workers
Exposure Data and Input Parameters for PBPK Modeling
Table 2-1 and Table 2-2 show the occupational dermal and inhalation exposure parameters,
respectively, used in the PBPK modeling for this assessment. The skin surface area and body
weight dermal parameters were specific to the lifestages of interest: pregnant women and
women of childbearing age who may become pregnant. Two scenarios were included for the
inhalation pathway: one for miscellaneous NMP-based stripping (assumed mostly indoor and
includes paint stripping by professional contractors, wood furniture stripping and other settings
for which the literature source did not specify the industry) and one for NMP-based graffiti
removal (assumed mostly outdoor but may include semi-confined spaces, such as outdoor
escalators and elevators).
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Table 2-1 Summary of Parameters for Worker Dermal Exposure to Liquids3
Parameter
Characterization
Low end of range
Mid-range
High end of
range
NMP Weight
Fraction in Liquid
Paint Stripper
(Unitless)
0.25
0.625
1
Skin Surface Area
Contacting Liquid
Paint Stripperb
(cm2)
445
668
890
Duration of
Contact with
Liquid
(hrs/day)
1
4
8
DM *J. .
oodv
i A i _ :—|»j.
vvGi&nt
(kg)
74
(50th
percentile)
Notes:
a Physiological parameters are specific to the most sensitive population: women of childbearing age
who are or may become pregnant. Appendix D contains the detailed explanations for the
parameters and associated assumptions. Dermal exposure to vapor is discussed in 1-2.
b These areas are for workers who do not wear gloves. For workers who wear gloves, the glove
effectiveness was assumed to be up to 90% for the gloves with the most effective protection against
NMP. The effectiveness value is used in the PBPK modeling to reduce the values of skin surface area
contacting the liquid stripper shown in this table using the following equation: Skin Surface Area
Contacting the Liquid Stripper (no glove use
x (1 - % glove effectiveness / 100) = Skin Surface Area
Contacting the Liquid Stripper (using the most effective gloves). For dermal exposure to vapor, the
PBPK model assumed up to 25% of the total skin surface area, corresponding to the face, neck, arms
and hands, was exposed to and capable of absorbing vapors, minus any area covered by personal
protection equipment (PPE).
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Table 2-2 Summary of Parameters for Worker Inhalation Exposure Concentrations3
Scenario
Miscellaneous stripping
(assumed mostly indoor)
Graffiti removal
(assumed mostly
outdoor but may include
semi-confined spaces)
Parameter
Characterization
Low end of range
Mid-range
High end of range
Low end of range
Mean
High end of range
NMP Exposure Concentration
(mg/m3, 8-hr TWA)b
1.0
32.5
64
0.03
1.01
4.52
Notes:
a Appendix D contains detailed explanations including data sources and selection of values in the
ranges.
b These exposure concentrations are for workers who do not wear respirators. For workers who wear
respirators, it was assumed that respirators used have an assigned protection factor (APF) of 10 and
that this APF was achieved during use. This APF was used in the PBPK modeling to reduce the NMP
exposure concentrations shown in this table using the following equation: exposure concentration
(using no respirator) / APF = exposure concentration (using respirators with APF of 10).
Inhalation data sources did not often indicate whether NMP exposure concentrations were for
occupational users or nearby worker non-users. Therefore, EPA/OPPT assumed that inhalation
exposure data were applicable for a combination of users and nearby non-users. Some nearby
worker non-users may have lower inhalation exposures than users, especially when they are
further away from the source of exposure. EPA/OPPT assumed that non-users that might be
close by workers handling NMP usually do not directly contact the liquid strippers.
Numbers of Exposed Workers and Shop Sizes
Knowing the sizes of exposed populations provides perspective on the prevalence of the
potential health effects. For this assessment, the exposed populations were workers exposed to
NMP from NMP-based paint strippers. However, EPA/OPPT was unable to estimate the current
total number of workers in the potentially exposed populations for this assessment.
Estimates of the number of workers exposed to DCM during paint stripping provide perspective
on the number of workers potentially exposed to NMP during paint stripping. EPA/OPPT
estimated that over 230,000 workers at 13,500 facilities nationwide were directly exposed to
DCM from DCM-based strippers, including 23,400 workers at 3,000 facilities classified as area
sources (EPA, 2014b).
EPA/ OPPT assumed that DCM is more widely used as a paint stripper than NMP and that fewer
workers are exposed to NMP than to DCM during paint stripping. Therefore, EPA/ OPPT
assumed that fewer than 230,000 workers nationwide are directly exposed to NMP during paint
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stripping. These estimates do not account for workers within the facilities who are indirectly
exposed due to proximity to the paint stripping operations.
EPA/OPPT estimated the average number of employees per facility which can be a factor in
determining shop sizes. These estimates were derived by combining the facility and population
data obtained from the US Census data, as described in Appendix D. The average number of
employees for the identified industries based on Census data were the following:
• Professional contractors (likely to include bathtub refinishing): 5 workers/facility;
• Automotive refinishing: 6 workers/facility;
• Furniture refinishing: 3 workers/facility;
• Art restoration and conservation (not estimated);
• Aircraft paint stripping: 320 workers/facility (for aircraft manufacturing only);
• Ship paint stripping: 100 workers/facility; and
• Graffiti removal: 8 workers/facility.
These averages give some perspective on shop size but are simple generalizations.
2.1.2 Use of Occupational Exposure Estimates in PBPK Modeling
EPA/OPPT used air concentrations and dermal contact patterns as described above as inputs for
the PBPK model to calculate internal dose. The skin area exposed to liquid NMP preparations
(25% of the total skin surface area, corresponding to the face, neck, arms and hands) was
assumed to be exposed to and capable of absorbing vapors, minus any area covered by
personal protection equipment (PPE). It was assumed that respirators had an assigned
protection factor (APF) of 10. In addition, it was assumed that protective gloves reduced the
skin surface area exposed to 10% of the area exposed without gloves (but with the liquid
concentration being the same). However, it was assumed that PPE completely eliminated vapor
absorption for the covered areas: 3% of the total skin surface (599 cm2) for the face mask and
4.5% (890 cm2, both sides of both hands) for gloves. The latter is a generic assumption; since
vapor absorption through these limited skin areas is predicted to be fairly small, the difference
between assuming complete elimination and 90% is negligible.
Workplace Exposure Scenarios
EPA/OPPT evaluated six use scenarios representing combinations of the uses and exposure
parameters listed in Table 2-1 and Table 2-2 (low, mid, high end of the range). For each scenario
in Table 2-3 EPA/OPPT assumed that the skin was exposed dermally to NMP at the specified
liquid weight fraction and skin surface area and that there was simultaneous exposure by
inhalation and vapor-through-skin absorption for unobstructed skin areas. At the end of each
work period, air concentrations were assumed to drop immediately to zero and any liquid on
the skin was assumed to be removed by cleaning. For scenarios 3 and 6 exposure was simulated
as occurring for two 4-hr work periods, with a 30 min break in between and cleaning of the skin
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assumed to occur after each 4-hr shift. Acute scenarios assumed 1 day of exposure and chronic
scenarios assumed 5 days of exposure per week.
Table 2-3 Workplace Exposure Scenario Characteristics
Scenario
#
1
2
3
4
5
6
Scenario
description
Miscellaneous
stripping low
end of range
Miscellaneous
stripping
mid-range
Miscellaneous
stripping high
end of range
Graffiti
removal low
end of range
Graffiti
removal
mean
Graffiti
removal high
end of range
Liquid
weight
fraction
25%
62.5%
100%
25%
62.5%
100%
Skin area
exposed3
(cm2)
445
668
890
445
668
890
8-hr
TWA
(mg/m3)b
1
32.5
64
0.03
1.01
4.52
Duration0
1 hr/day
4 hr/day
8 hr/day with
30-min break
1 hr/day
4 hr/day
8 hr/day with
30-min break
Air
concentration11
(mg/m3)
8
65
64
0.24
2.02
4.52
Notes:
a Total area potentially exposed to liquid NMP, in the absence of protective gloves.
bTWA taken from Table 2-2.
c Duration taken from Table 2-1.
d Air concentration = TWA x 8hr/duration, with PBPK simulations run at concentration listed. Acute
scenarios assumed 1 exposure day and chronic scenarios assumed 5 exposure days/wk. For 8-hr
exposures a 30-min mid-day break was assumed.
EPA/OPPT evaluated 5 sub-cases for each workplace scenario. Each workplace scenario was
evaluated including the following PPE:
• Respirator and gloves
• Respirator only
• Gloves only
• Neither respirator nor gloves.
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The 5th case was for a nearby worker, not directly working with NMP (non-user) and assumed to
not be wearing a respirator and to have incidental dermal contact equal to 1% of the skin area
listed in Table 2-3.
With regard to respirator use, only one of the NMP studies containing worker inhalation data
used in this assessment specified a particular type of respirator in use by the workers in the
study. This respirator, a half mask air-purifying respirator with organic vapor cartridges (NIOSH,
1993), is classified as having an assigned protection factor (APF) of 10. While respirators with
other APFs may have been used, EPA/ OPPT only included the APF of the respirator type
specified in the 1993 NIOSH study. Therefore, EPA/OPPT assumed a "what-if" type assumption
that the use of respirators providing an APF of 10 will reduce inhalation concentrations by a
factor of 10 when this type of respirator is used in accordance with OSHA's Respiratory
Protection standard (29 CFR 1910.134).
The efficacy of gloves was not evaluated in this assessment, however California recommends
the use of gloves made of butyl rubber or laminated polyethylene/EVOH. See California Health
Hazard Advisory, available at: http://www.cdph.ca.gov/programs/hesis/Documents/nmp.pdf
(accessed 12/18/14).
2.2 CONSUMER EXPOSURES
2.2.1 Approach and Methodology
This section summarizes the consumer exposure parameters and concentrations for NMP
estimated for use of NMP-based paint strippers. The exposure scenario presumed that the
consumer would work on a single project (table, chest of drawers or tub), with inputs reflecting
that consumers do not reliably use personal protective equipment (e.g., no ventilation fan, not
wearing effective gloves8). The consumer would be exposed via inhalation, dermal contact and
vapor-through-skin, while non-users who may be nearby would only be exposed via inhalation
and vapor-through-skin. In the absence of representative air monitoring data, EPA/OPPT used
the Multi-Chamber Concentration and Exposure Model (MCCEM) 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.
8 California recommends the use of gloves made of butyl rubber or laminated polyethylene/EVOH. See California
Health Hazard Advisory, available at: http://www.cdph.ca.gov/programs/hesis/Documents/nmp.pdf. EPA/OPPT
does not assume consumers will always use gloves, or select the proper gloves. Risks were assessed with and
without gloves.
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2.2.1.1 Consumer Dermal Exposure Assessment
To better understand potential risks to consumers from the use of NMP-containing paint
stripping products, EPA/OPPT included dermal exposure in calculating internal doses. Dermal
absorption of NMP depended on the liquid and vapor concentrations, dermal contact patterns
and exposed skin surface area. Estimates for the amount of surface area exposed to the
chemical during brush or spray application were designed to be protective or upper end9.
EPA/OPPT assumed that the skin surface area exposed to liquid NMP during brush application
was 490 cm2 to represent the palm side of both hands and for spray application, that 1 cm2 was
wetted by liquid to approximate the tip of one finger. For brush application scenarios where
gloves were worn, a glove effectiveness factor of 90% was applied and the exposed surface
area was reduced to 49 cm2. EPA/OPPT assumed that the surface area exposed to NMP vapor
was up to 25% of the total body surface area or 4989 cm2, to account for the face, neck, arms
and hands minus the area covered by gloves when used. It was also assumed that a thin film of
NMP could remain on the user's hands for the period of product application. For further details
please see the PBPK Appendix 1-2.
2.2.1.2 Consumer Users and Residential Non-Users Inhalation Exposure
Assessment
Background
In the absence of representative air monitoring data, EPA/OPPT used MCCEM 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.
9 As noted in Section 2.3.1 (Individual Risk) of the EPA (1992) 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.
As noted in EPA (1992), "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
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.
As noted in EPA (1992), an exposure above the distribution of actual exposures is termed 'bounding.'
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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 emissions data to develop
appropriate exposure scenarios. The majority of the source documents EPA/OPPT used for
these input values were over a decade old. All sources were compared to EPA/OPPT quality
criteria (i.e., currency, scope, accuracy/reliability, transparency, clarity and completeness of the
information provided).
EPA/OPPT 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., IDS). The information collected from available product
labels orTDSs included approximately half of the products listed in Brown (2012).
To estimate air concentrations for consumer inhalation exposures, EPA/OPPT identified
published air monitoring data from one chamber study of NMP previously conducted for
EPA/OPPT (EPA, 1994a). Despite its age, EPA/OPPT considered the study to be reliable and that
the associated data to be transparent and complete. In this 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 consumer 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 consumer values. Additionally, the experiments 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 for the purposes of this risk assessment.
The chamber study was useful in determining product application rates (i.e., in g/ft2and g/min)
and in estimating the fraction of applied chemical emission mass emitted to indoor air. As also
described in Appendix E, chamber data were available for brush-on products but not for spray-
on products. EPA/OPPT obtained the raw data associated with the study and conducted a
thorough evaluation of the data and reported results. Through this evaluation, EPA/OPPT
identified analytical method calibration issues for the near real-time sampling data that were
collected for brush-on products, as well as incomplete adjustments made to some of data with
respect to relative humidity and temperature conditions. After EPA /OPPT made adjustments to
account for these issues, as discussed in Appendix E, the data were considered reliable for use
as model inputs.
Information on exposure factors was identified from a variety of sources, including the EPA's
Exposure Factors Handbook (EFH) (EPA, 2011a). The EFH provides information on generic
exposure factors such as body weights, body part surface areas, house volumes and house
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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/OPPT incorporated additional information on use patterns of paint strippers as reported by
Riley et al. (2001). This study had 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 EPA (1995) and (Matthews et al., 1989). Finally, in cases where no data were available
for fitting model-specific parameters, EPA/OPPT applied professional judgment 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/OPPT estimated consumer inhalation exposures for both users and non-users to NMP
emitted during paint stripper application and associated scraping using MCCEM (EPA, 2010).
Non-user residents or occupants may be individuals of any age indirectly exposed to NMP while
being in the rest of the house during product use. 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 E-l, Estimation of Emission Profiles for Paint Removers/Strippers in Appendix E).
Sensitivity Analysis Background
To select exposure scenarios for characterizing the consumer inhalation exposures, EPA/OPPT
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.
The types of factors that can be varied in the MCCEM model include:
• 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: the type and area of surface being stripped, the
type of application (i.e., brush-on vs. spray-on), and the rate at which the product is
applied to the surface; and
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• Locations during and after stripping of: the user(s)—the individual(s) applying the
product and 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 was first defined, consisting of central tendency values (i.e., approximating
average or median values) for each model parameter (input). Next, the inputs were varied-
one at a time—and the model result (estimated average or peak concentrations to which
individuals are exposed) was noted. The index of sensitivity was 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 section E-2 Sensitivity Analysis for Inhalation Scenarios in Appendix E.
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.
Illustrative time-varying concentrations, to which the user and non-user could be exposed,
based on a preliminary model run, are shown in Figure 2-1 and Figure 2-2 along with the
maximum TWA values and the corresponding time periods for selected averaging times. For the
sensitivity analysis, only the maximum 1-hr TWA along with the 24-hr TWA were used.
•User Exposure Concentration
•10-min max
-30-min max
•1-hr max
•4-hr max
Time, hours
Figure 2-1 Example of Time-varying User Exposure Concentration and Maximum TWA Values for
Selected Averaging Times
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200
ISO
160
"g 140 -
E120
i
5100 •
e
g so
I
5 60
40 -
20
Non-user Exposure Concentration
10-min max
30-min max
1-hr max
4-hr max
2
6
Time, hours
Figure 2-2 Example of Time-varying Non-user Exposure 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 x 30 ft2, two-story house with an 8-foot
ceiling), workshop (area of product use) volume of 54 m3 (corresponds to 20 x 12 ft2
with an 8-foot ceiling) and an indoor-outdoor airflow rate of 68 m3/hr (approximate
value for a room with multiple open windows).
• Airflow rate of 197 m3/hr for the rest of the house (ROM), assuming windows are 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 ft2, applied 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 ROM during
wait periods between applying/scraping and after completion of all applying/scraping.
Sensitivity Analyses Results
Figure 2-3 and Figure 2-4 display the results of the sensitivity analyses for two exposure
measures, peak 1- and 24-hr TWAs, 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 was 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.,
Page 42 of 281
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consumer stays in workshop versus moving to the ROM), 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 ROM air exchange rate with outdoor air (ROM 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 ROM 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 ROM, the rate of air flow in the ROM could reduce inhalation exposures under some
conditions (i.e., high exchange rates).
160.0%
140.0%
120.0%
100.0%
so.0%
60.0%
40,0%
20.0%
0.0%
11-hour Peak User
11-hour Peak Non-User
ChemMa« ROM ACH Workshop Interzonal Workshop User Slavs in
ACH Flow Volume Workshop
Figure 2-3 Model Sensitivity Results (Percent Change from Base-case Response) for Peak 1-hr TWA for
Consumer User and Non-user
100.0%
90.0%
80.0%
70.0%
60.0%
50.0%
40,0%
30,0%
20.0%
10.0%
0.0%
24-hour Average User
124-hour Average Non-User
ChemMass ROHACH
Workshop Interzonal Workshop User M ,1 •. in
ACH Flow Volume Workshop
Figure 2-4 Model Sensitivity Results (Percent Change from Base-case Response)
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/OPPT concluded that the chosen modeling
scenarios should include some variations in each of the three factors (i.e., chemical mass,
Page 43 of 281
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location and ROM ACH); with greater model sensitivity, it is more likely a wide range of plausible
exposures can be estimated.
Description of Exposure Scenarios
Inhalation exposures for consumer users and non-users were determined. EPA/OPPT developed
seven exposure scenarios for the assessment, as summarized in Table 2-4. 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,
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, the user
leaving the application room during the wait period and related changes to the air
exchange rates and the proximity of the user to the source of NMP emissions.
Table 2-4 NMP Exposure Scenarios for Characterizing Consumer Inhalation Exposures
Case ID
1
2
3
4
5
6
7
Case Description
Type of Application
Brush-on
Brush-on
Brush-on
Brush-on
Brush-on
Spray-on
Spray-on
Location of
Product Use
Workshop
Workshop
Workshop
Bathroom
Bathroom
Workshop
Workshop
Concentration Characterization3
Central tendency
User upper-end
Non-user upper-end
Upper-end to bounding for user and non-user,
constrained by Csat = 1,013 mg/m3
Upper-end to bounding for user and non-user,
constrained by Csat = 640 mg/m3
User upper-end b
Non-user upper-end b
Notes:
3 Conditions obtained by varying the most sensitive parameters: NMP mass emitted; user location during the
effect or wait period; and the ROM air exchange rate with outdoors.
bScenarios 6 and 7 provide lower (6a & 7a) and upper (6b & 7b) estimates with different NMP volatility parameters;
See Estimation Procedures for Spray Application in section E-l of Appendix E for a detailed description.
The primary distinctions among the seven cases above are the application method (i.e., brush
or spray), location of product application (i.e., workshop versus bathroom), the user's location
during the use or wait period and values used for certain inputs, including the NMP mass
emitted and the ROM air exchange rate with outdoors (i.e., central tendency versus upper-end).
Page 44 of 281
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Of the five brush-on scenarios listed in Table 2-4, one was considered central tendency for both
the user and the non-user, one was developed to estimate upper-end concentrations for the
user and one was 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 end
of the range of expected exposure amounts.
Scenarios 4 and 5 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) for an
occupational-exposure case involving brush application of a DCM-containing paint stripper used
on a bathtub in a small bathroom (CDC, 2012b). The brush application in a small bathroom
scenario represents high product use in a confined (i.e., closed, poorly ventilated) space, and
the shape of the bathtub produces a "cloud" of NMP above it ("source cloud"), which
contributes to elevated exposures, particularly, the absorption of vapor through the skin and
inhalation. Selected parameter values for these scenarios (i.e., large surface area, small room
size, minimal ventilation, upper-end weight fraction and low ROM ventilation) would increase
concentrations and exposures so that the combinations of parameter values would be expected
to result in upper-end to bounding concentrations for the user and non-user; as a result, the
concentrations could approach or exceed the vapor saturation concentration for NMP. The only
difference between Scenarios 4 and 5 is the assumed saturation concentration.
EPA/OPPT developed the two spray-on scenarios listed in Table 2-4 to estimate upper-end
concentrations for the user (Scenario 6) and for the non-user (Scenario 7) by setting the
consumer behavior pattern inputs (mass of product used, time in room of use, etc.) to high end
values. After running the scenarios, the calculated concentrations from scenario 7 were found
to be higher than scenario 6 for both the user and non-user. No chamber study data are
available for a spray applied NMP product, so a lower emission simulation for the evaporation
of the NMP to the room air from a spray applied product used the coefficients from the brush
product. However it is likely that a spray product would result in more NMP entering the room
air quickly due to the greater surface area of the droplets moving through the air to the
application surface. To reflect this effect, the brush-on coefficients were altered to create a
simulation of upper emission parameters which assumed more of the NMP mass would
volatilize rapidly.
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 Appendix E, section E-3 (Inhalation Exposure
Scenario Inputs).
Summary of Exposure Scenarios and Model Inputs
The exposure scenario inputs are as follows: the stripping method, the amount of NMP
released, room of use volume and ventilation characteristics, house volume and ventilation
Page 45 of 281
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characteristics, the user location during the wait period and the non-user location. Table 2-5
summarizes the inputs used for all seven scenarios, in which the major and minor differences
among the scenarios are shown. For example, Scenarios 2 and 3 (for brush-on products)
estimated upper-end exposures for the user and non-user, respectively, by changing the
application amount, location of the user during the wait period and airflows between the
workshop and the ROM. Similarly, Scenarios 6 and 7 (for spray-on products) estimated upper-
end exposures for the user and non-user, respectively.
2.2.2 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 exposure concentrations. This model
output is in the form of instantaneous values at the end of consecutive 1-min time intervals for
the entire duration of the model run (i.e., 24 hrs). The model is responsive to changes in the
location of the user during the 24-hr model run. Appendix E provides a more detailed,
mathematical description of the calculations.
The MCCEM Inhalation Modeling Case Summaries in section E-5 of Appendix E list both model
inputs and results for each of the seven scenarios modeled with MCCEM.
2.2.3 Use of Consumer Exposure Estimates in PBPK Modeling
Air concentrations and dermal contact patterns were used as inputs for the PBPK model to
calculate measures of internal dose, specifically the peak blood concentration of NMP and the
24-hr area-under-the-concentration-curve (AUC). EPA/OPPT assumed that for consumer
exposures, use occurred on a single day and the AUC calculated for the 24 hrs starting with the
initiation of use.
Consumer Exposure Scenarios
For consumer scenarios the predicted air concentrations from the exposure modeling for users
and non-users, such as depicted in Figure 2-1 and Figure 2-2 respectively, were inputs to the
PBPK modeling software, acsIX and used to define the moment-by-moment air concentration
inhaled and in contact with unobstructed skin. The liquid weight fractions for dermal contact
were as defined in Table 2-5 and dermal contact assumed to occur only during the periods of
application, with removal by washing at the end of each application. EPA/OPPT assumed that
consumer users did not to wear respirators, but evaluated exposure both with and without
gloves, which reduced the exposed area by 90%. The concentration in the liquid on the exposed
skin was assumed to be constant for the period of application. The non-user was assumed to be
in another room and to have negligible dermal contact.
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Table 2-5 NMP Consumer Paint Stripping Scenario Descriptions and Parameters
Case
ID
Scenario
NMP Released
Weight
Fraction
Surface Area
Treated3 ft2
Application
Rate, g/ft2
Release
Fraction
Stripping Method
Room of Use
Volume,
m3
Ventilation/
ACH, hr -1
House
Volume,
m3
ROM
ACH, hr -1
User Location
During Wait
Period"
Non-
User
Location
Brush-on Exposure Scenarios in Workshop
1
2
3
Central
Upper-end for user
Upper-end for
non-user
0.25
(central)
0.5
(upper-
end)
10
Coffee table
(central)
25
Chest of drawers
(upper-end)
108
0.8695
Coffee table: 5-min. application, 30-min. wait
and 10-min. scrape per application; process
repeated after completion of first scraping.
Scrapings removed from house after last
scraping.
Chest: 12.5/ 30/25 min. per application;
process repeated after completion of first
scraping. Scrapings removed from house
after last scraping.
54
(central)
Open windows
/1.26
(Professional
judgment,
90th
percentile)
492
(central)
0.45
(central)
0.18
(low-end)
ROM
Workshop
ROM
ROM
(entire
time)
Brush-on Exposure Scenario in Bathroom
4 and
5
Upper-end to bounding
for user and non-user
0.5
(upper-
end)
36
Bathtub
(maximum)
108
0.8695
Bathtub: 18-min. application, 30-min. wait
and 36-min. scrape per application; process
repeated after completion of first scraping.
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)
ROM
ROM
(entire
time)
Spray-on Exposure Scenarios in Workshop
6a
6b
7a
7b
Upper-end for user
(Lower spray volatility) e
Upper-end for user
(Upper spray volatility) e
Upper-end for non-user
(Lower spray volatility) e
Upper-end for
non-user
(Upper spray volatility) e
0.53
(upper-
end)
0.53
(upper-
end)
10
Coffee table
(central)
25
Chest of drawers
(upper-end)
81
0.8695
Coffee table: 2.5-min. application, 30-min.
wait and 10-min. scrape per application;
process repeated after completion of first
scraping. Scrapings removed from house
after last scraping.
Chest: 6.25/ 30/25 min. per application;
process repeated after completion of first
scraping. Scrapings removed from house
after last scraping.
54
(central)
Open windows
/1.26
(Professional
judgment,
90th
percentile)
492
(central)
0.45
(central)
0.18
(low-end)
Workshop
ROM
ROM
(entire
time)
Notes:
aSurface 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 percent ile value
of 32 ounces or 1,000 g for the central surface area of 10ft2 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 ROM after the last scraping.
cl 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 E under Inhalation Exposure Scenario Inputs (Airflow Rates and Volumes.)
eFor the first exponential, the Upper spray case assigns 10 times the mass of the Lower spray case. The theoretical total mass released is the same for the two cases. See Estimation Procedures for Spray
Application in section E-l of Appendix Efora detailed description.
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3 HAZARD IDENTIFICATION AND DOSE-RESPONSE
3.1 APPROACH AND METHODOLOGY
Figure 3-1 depicts the process EPA/OPPT used for review and selection of studies for use in the
risk assessment. EPA/OPPT reviewed existing assessments for the purpose of hazard
identification (3.1.1). Brief summaries for each hazard endpoint are presented in section 3.1.2
with more detailed information about study quality review for study selection provided in
Appendix F. Developmental and reproductive toxicity endpoints were evaluated for
consistency, sensitivity and relevance (section 3.1.3). Based on this review, EPA/OPPT narrowed
the focus to increased fetal resorptions and fetal mortality (section 3.1.3.4). EPA/OPPT then
conducted the dose-response assessment for these endpoints (section 3.2), including
benchmark dose analysis (section 3.2.1) using rat PBPK model-derived internal doses (section
3.2.2), to select the points of departure (PODs) (sections 3.2.3 and 3.2.4) for use in the risk
characterization (section 4).
Reproductive
& Develop-
mental
Toxicity
Increased
Resorptions
Fetal
Mortality
Figure 3-1 Hazard Identification and Dose-Response Process
3.1.1 Selection of Peer-Reviewed Assessments for Hazard Identification and
Dose-Response Analysis
EPA reviewed a number of reports and peer reviewed studies on NMP. EPA/OPPT notes that an
Integrated Risk Information System (IRIS) toxicological review is not available for NMP.
Toxicological information was obtained from the following peer-reviewed assessments:
• RIVM Proposal for a Restriction of NMP (RIVM, 2013);
• OECD SIDS Initial Assessment Report (OECD, 2007);
• WHO Concise International Chemical Assessment Document (CICAD) for NMP (WHO,
2001); and
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• California Office of Environmental Health Hazard Assessment (OEHHA) Maximum
Allowable Dose Levels (MADL) for NMP (OEHHA, 2003).
EPA/OPPT considered these assessments to be reasonably robust, as they were peer reviewed
and generally consistent in their conclusions. EPA/OPPT began by reviewing these assessments
to identify key endpoints, meaning those endpoints that are relevant, sensitive and found in
multiple studies. Once key endpoints were identified, EPA/OPPT collected all publicly available
data to refine the hazard identification and complete the dose-response analysis. Additional
studies were identified based on public comments and peer review. Appendix F contains
information on literature collection, study quality evaluation and summaries of toxicology
studies considered in the risk assessment.
3.1.2 Hazard Summary and Hazard Identification
A number of adverse effects were observed in different studies, including effects on body
weight, liver, kidney, splenic, thymic, and testicular effects and neurotoxicity.
Irritation and Sensitization
NMP is a skin, eye and possible respiratory irritant (OSHA, 2012; RIVM, 2013; WHO, 2001).
Human volunteer chamber studies revealed some discomfort during exposure but are
otherwise suggestive of humans being less sensitive to NMP irritation than rodents (RIVM,
2013). NMP is not corrosive. There are limited data to draw conclusions on sensitization; the
available studies have significant limitations (RIVM, 2013), but there have been multiple
intentional human exposure studies (0) and no reports of sensitization following those
exposures.
Acute Toxicity
The acute toxicity of NMP is considered to be low based on a number of studies including oral,
dermal, inhalation, intraperitoneal and intravenous routes of exposure in rats and mice (OSHA,
2012; RIVM, 2013; WHO, 2001). Oral LD50 values ranged from 3605 to 7725 mg/kg bw, dermal
LD5o values ranged from 5000 to 7000 mg/kg bw and the 4 hr LC5o was > 5100 mg/m3 (RIVM,
2013).
Systemic Effects
Systemic effects identified via oral repeat dose testing include body weight reductions, foot
splay, alterations in clinical chemistry and blood cell counts, liver and kidney toxicity,
neurotoxicity and thymic atrophy, with highly variable NOAELs (OSHA, 2012; RIVM, 2013; WHO,
2001). The RIVM report highlights a 90-day oral repeat dose study in rats with a neurotoxicity
screening panel that identified a NOAEL of 169/217 mg/kg bw/day for males and females,
respectively, based on decreased body weight, foot splay (males only) and reversible neurotoxic
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effects (RIVM, 2013). The results of rabbit 28-day dermal exposure study yielded a NOAEL of
826 mg/kg bw/day, although local irritation was observed at lower doses (OECD, 2007; RIVM,
2013). More severe effects were noted in a whole body inhalation study, compared to two
head-nose exposure studies. The whole body study, which likely included dermal contact and
oral contact through grooming, identified bone marrow hypoplasia, testicular effects, necrosis
of lymphoid tissue in the thymus, spleen and lymph nodes, as well as mortality at the highest
dose (RIVM, 2013). The NOAEC was considered to be 500 mg/m3 (OECD, 2007; RIVM, 2013).
Mutagenicity and Carcinogenicity
NMP is not mutagenic, based on results from multiple bacterial and mammalian in vitro test
and in vivo systems and is not considered carcinogenic (OECD, 2007; OEHHA, 2011; RIVM, 2013;
WHO, 2001).
Neurotoxicity
A small number of studies noted effects related to neurotoxicity. Mass et al. (1994) investigated
the effects of NMP on postnatal development and behavior in rats. Dams were exposed by
whole-body inhalation to measured levels of 151 ppm (612 mg/m3) for six hrs/day from GD 7 to
20. Performance was impaired in certain difficult tasks (i.e., reversal procedure in Morris water
maze and operant delayed spatial alternation). Performance appeared to be associated with
body weight at weaning. Since only one dose was used, a NOAEL could not be established.
In a study by Lee et al. (1987) rats were exposed to 100 and 360 mg/m3 (analytical) of NMP for
six hrs/day from GD 6 through 15. In the dams, sporadic lethargy and irregular respiration were
observed during the first three days of exposure in both dose groups. These effects were not
seen during the remainder of the exposure period or during the 10-day recovery period and
thus considered reversible.
Reproductive and Developmental Toxicity
When observed, reproductive effects were variable in occurrence and dose ranges. Several
studies identified some type of testicular effect. Four oral repeat dose studies detected
testicular lesions, atrophy or smaller testes with NOAELs ranging from 207 mg/kg bw/day to
1,057 mg/kg bw/day (BASF AG, 1978; Malek et al., 1997; Malley et al., 2001; Sitarek and
Stetkiewicz, 2008). Two different 28-day repeat dose studies found testicular lesions and/or
degeneration at oral doses > 2000 mg/kg/ bw/day (BASF AG, 1978; Malek et al., 1997). In a
study involving pre-mating and mating oral exposures of male rats, cellular depletion of the
seminiferous tubule epithelium were recorded at the highest dose, 1000 mg/kg/bw/day
(Sitarek and Stetkiewicz, 2008). Two inhalation studies, one a 28-day and the other a 90-day,
also identified testicular atrophy (BASF AG, 1994; Lee et al., 1987). The 90-day BASF study had a
LOAEC of 1000 mg/m3 bw/day. Whereas the 28-day Lee et al. study identified slight atrophy at
88 mg/m3, the lowest dose tested, and very low incidence of severe atrophy at 1000 mg/m3. As
described in Table 3-1 a larger number of studies did not identify testicular effects.
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The occurrence of reproductive effects was significantly less frequent or consistent than the
occurrence of developmental effects. For example, two oral reproductive studies found
reduced fertility or reproductive success; Exxon Biomedical Sciences (1991) reported a NOAEL
of 50 mg/kg bw/day based on decreased male fertility and female fecundity and Sitarek et al.
(2012) reported a NOAEL of 150 mg/kg bw/day based on decreased percent of pregnant
females. A number of studies yielded no effects at the highest dose tested (DuPont, 1990;
Exxon Biomedical Sciences, 1992; Lee et al., 1987; NMP Producers Group, 1999a, 1999b;
Saillenfait et al., 2002; Saillenfait et al., 2003).
The reproductive toxicity findings are more difficult to interpret due to the wide-ranging effect
levels and lack of consistency in findings, when looking at the complete database. In contrast,
as described below, developmental effects occurred with greater consistence at similar or
lower exposures.
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Table 3-1 Summary of Studies with Reproductive or Developmental Effects
Species
and
Strain
Study Type
Doses or exposure
concentrations
NOAEL or LOAEL for
Reproductive Effects and
Maternal Body Weight
NOAEL or LOAEL for
Developmental Effects
Reference
Oral Studies
Rat, SD
2-generation
reproductive
0, 50, 160, 500 mg/kg
bw/day
Diet, premating through
weaning
LOAEL=50 mg/kg bw/day
NOAEL= not determined
4/ Male fertility3, female
fecundity3
LOAEL= 500 mg/kg bw/day
NOAEL= 160 mg/kg bw/day
4/ Maternal body weights
Insufficient data presented to
make a determination
Exxon
Biomedical
Sciences,
1991b
Rat,
Wistar
2-generation
reproductive
0, 50, 160, 350 mg/kg
bw/day in diet. Highest
dose was reduced from
500 to 350 mg/kg bw/day
due to severe pup
mortality
Premating, mating,
gestation and lactation
exposure, with rest period
between pregnancies.
NOAEL=350 mg/kg bw/day
Highest dose tested
Reproductive effects
LOAEL=350 mg/kg bw/day
NOAEL=160 mg/kg bw/day
4/ Maternal body weight
LOAEL=350 mg/kg bw/day
NOAEL=160 mg/kg bw/day
4/ Pup body weights
1" Pup mortality
NMP
Producer's
Group 1999b
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Species
and
Strain
Study Type
Doses or exposure
concentrations
NOAEL or LOAEL for
Reproductive Effects and
Maternal Body Weight
NOAEL or LOAEL for
Developmental Effects
Reference
Rat, SD
2-generation
reproductive
0, 50, 160, 350 mg/kg
bw/day in diet. Highest
dose was reduced from
500 to 350 mg/kg bw/day
due to severe pup
mortality
Premating, mating,
gestation and lactation,
exposure with rest period
between pregnancies
NOAEL=350 mg/kg bw/day
Highest dose tested
Reproductive effects
Maternal body weights
LOAEL=350 mg/kg bw/day
NOAEL=160 mg/kg bw/day
4/ Mean litter size
4/ Pup body weights
^ Pup mortality
NMP
Producer's
Group 1999b
Rat, SD
Developmental
0, 40, 125, 400 mg/kg
bw/day by oral gavage,
gestation day 6-15
NOAEL=400 mg/kg bw/day
Highest dose tested
Reproductive effects
LOAEL=400 mg/kg bw/day
NOAEL=125 mg/kg bw/day
4/ Maternal body weight
LOAEL= 400 mg/kg bw/day
NOAEL=125 mg/kg bw/day
4, Fetal BW
Exxon
Biomedical
Sciences,
1992b
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Species
and
Strain
Study Type
Doses or exposure
concentrations
NOAEL or LOAEL for
Reproductive Effects and
Maternal Body Weight
NOAEL or LOAEL for
Developmental Effects
Reference
Rat, SD
Developmental
0, 125, 250, 500, 750
mg/kg bw/day by oral
gavage, gestation day 6-
20
NOAEL=750 mg/kg bw/day
Highest dose tested
Reproductive effects
LOAEL=250 mg/kg bw/day
NOAEL=125 mg/kg bw/day
4/ Maternal body weight
LOAEL=250 mg/kg bw/day
NOAEL=125 mg/kg bw/day
4, fetal BW
Saillenfait et
al., 2002
LOAEL=500 mg/kg bw/day
NOAEL=250 mg/kg bw/day
^ Resorptions/post-implantation
loss
^ Skeletal malformations
Rabbit,
New
Zealand
White
Developmental
0, 55, 175, 540 mg/kg
bw/day in aqueous NMP
solution, gestation day 6-
18
NOAEL= 540 mg/kg bw/day
Highest dose tested
Reproductive toxicity
LOAEL=175 mg/kg bw/day
NOAEL=55 mg/kg bw/day
4/ Maternal body weight
LOAEL=540 mg/kg bw/day
NOAEL=175 mg/kg bw/day for
Developmental toxicity and
malformations
IRDC, 1991'
Rat,
Wistar
Male
reproduction
0, 100, 300, 1,000 mg/kg
bw/day by gavage
Males: prematingand
mating exposures
LOAEL= 1,000 mg/kg bw/day
NOAEL=300 mg/kg bw/day
Cellular depletion of the
seminiferous tubule
epithelium
LOAEL=300 mg/kgc bw/day
NOAEL=100 mg/kg bw/day
4, Pup survival PNDO-4
Sitarek and
Stetkiewicz,
2008
Page 54 of 281
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Species
and
Strain
Rat,
Wistar
Rat, SD
Rat, SD
Rat, SD
Rat, SD
Study Type
Female
reproduction
28-day
subchronic
28-day
subchronic
study
3-month
subchronic
neurotoxicity
2-year chronic
bioassay
Doses or exposure
concentrations
0, 150, 450, 1,000 mg/kg
bw/day by gavage
Premating, mating and
gestation days 1-20,
lactation exposures
0, 258, 516.5, 1,033,
2,066 mg/kg bw/day by
gavage
0, 149/161, 429/493,
1,234/1,548,
2,019/2,269 mg/kg
bw/day by diet
males/females
0,169/217,433/565,
1,057/1,344 mg/kg
bw/day by diet
males/females
0, 66/88, 207/283,
678/939 mg/kg bw/day by
diet males/females
NOAEL or LOAEL for
Reproductive Effects and
Maternal Body Weight
LOAEL=450 mg/kg bw/day
NOAEL=150 mg/kg bw/day
4/ Percent of pregnant
females
LOAEL=150 mg/kg bw/day
NOAEL=not determined
4/ Maternal body weight -
through gestation only, no
difference during lactation
LOAEL=2,066 mg/kg bw/day
NOAEL=1,033 mg/kg bw/day
4/ Testes size
^ Testicular lesions
(degeneration of
seminiferous tubules)d
LOAEL= 1,234 mg/kg bw/day
NOAEL=429 mg/kg bw/day
^ Testes degeneration/
atrophy
NOAEL= 1,057/1,344 mg/kg
bw/daye
Highest dose tested
LOAEL=678 mg/kg bw/day
NOAEL=207 mg/kg bw/day
4/ Testes size
NOAEL or LOAEL for
Developmental Effects
LOAEL=150 mg/kg bw/day
No NOAEL
1^ Pup mortality PND 0-4 & 0-21
4> Pup BW PND 0-4
LOAEL=450 mg/kg bw/day
NOAEL=150 mg/kg bw/day
^ Pup BW PND 4-21
LOAEL=1000 mg/kg bw/day
NOAEL=450 mg/kg bw/day
^ Dead pups/litter
N/A
N/A
N/A
N/A
Reference
Sitarek et al.,
2012
BASF AG
1978bb
Malek et al
1997b
Malley et al.,
1999b
Malley et al.,
2001b
Page 55 of 281
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Species
and
Strain
Study Type
Doses or exposure
concentrations
NOAEL or LOAEL for
Reproductive Effects and
Maternal Body Weight
NOAEL or LOAEL for
Developmental Effects
Reference
Mouse,
B6C3F1
28-day
subchronic
0, 160, 820, 2500,
3370 mg/kg bw/day by
diet
NOAEL = 3370 mg/kg
bw/dayf
N/A
Malek et al.,
1997b
Mouse,
B6C3F1
28-day
subchronic
0, 229/324, 561/676,
1704/2158 mg/kg bw/day
by diet males/females
NOAEL =2158 mg/kg
bw/dayg
N/A
Malley et al.,
1999 b
Inhalation Studies
Rat,
Charles
River
CD
Developmental
0, 100, 360 mg/m3
(0, 25, 89 ppm) aerosol for
6 hrs/day on days 6-15 of
gestation
NOAEC=360 mg/m3
Highest dose tested
Reproductive effects
Maternal body weight
NOAEC=360 mg/m3
Highest dose tested
Lee et al.,
1987
Rat, SD
Reproductive 2-
generation
0, 42, 206, 470 mg/m3
(0, 10, 52, 116 ppm)
6 hrs/day, 7 days/week
Premating, mating,
gestation day 1-20 and
postpartum day 21
exposures
NOAEC=470 mg/m3
Highest dose tested
Reproductive effects
Maternal body weight
LOAEC= 470 mg/m3
Highest dose tested
•^ Pup BW
Developmental
toxicity
0, 470 mg/m3
(0, 116 ppm) 6 hrs/day, 7
days/week
Premating, mating and
Gestation day 1-20
exposures
N/A
LOAEC=470 mg/m3
Only dose tested
•^ Fetal BW
^ Incomplete ossification3
^ Skeletal malformations3
^ Fetal resorptions3
DuPont1990
Rat,
Wistar
Developmental
toxicity
0, 669 mg/m3
(0, 165 ppm) g hrs/day,
Gestation days 4-20
NOAEC=669 mg/m3
4/Maternal body weight
LOAEC=669 mg/m3
Only dose tested
^ Preimplantation loss
4, Fetal BW
^ Delayed ossification
Hass et al.,
1995
Page 56 of 281
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Species
and
Strain
Rat,
Wistar
Rat, SD
Rat,
Charles
River
CD
Rat,
Wistar
Rat,
Wistar
Study Type
Developmental
neurotoxicity
Developmental
28-day
subchronic
28-day
subchronic
90-day
subchronic
Doses or exposure
concentrations
0, 612 mg/m3
(0, 151 ppm) 6 hrs/day,
Gestation days 6-20
0,122,243,487 mg/m3
(0, 30, 60, 120 ppm)
6 hrs/day on gestation
day 6-20
0, 88, 423, 740 mg/m3
(0, 22, 104, 182 ppm)
0, 10, 30, 101 mg/m3
(0, 2.5, 7.4, 25 ppm)
0, 500, 1,000,
3,000 mg/m3 (123, 247,
740 ppm)
NOAEL or LOAEL for
Reproductive Effects and
Maternal Body Weight
NOAEC=612 mg/m3
Only dose tested
Reproductive effects
Maternal body weight
NOAEC=487 mg/m3
Highest dose tested
Reproductive effects
LOAEC=243 mg/m3
NOAEC=122 mg/m3
4/Maternal body weight
LOAEC=88 mg/m3
Lowest dose tested
slight testicular atrophy3
NOAEC=101 mg/m3
Highest dose tested
LOAEC=3,000 mg/m3
NOAEC= 1,000 mg/m3
^testes germinal
epithelium cellular
depletion, testicular atrophy
NOAEL or LOAEL for
Developmental Effects
LOAEC=612 mg/m3
Highest dose tested
4/ Fetal, pup BW, delayed
developmental milestones and
difficult tasks
LOAEC=487 mg/m3
NOAEC=243 mg/m3
•^ Fetal BW
N/A
N/A
N/A
Reference
Hass et al.,
1994
Saillenfait et
al., 2003
Lee et al.,
1987
BASF AG,
1993b
BASF AG,
1994b
Page 57 of 281
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Species
and
Strain
Study Type
Doses or exposure
concentrations
NOAEL or LOAEL for
Reproductive Effects and
Maternal Body Weight
NOAEL or LOAEL for
Developmental Effects
Reference
Dermal Studies
Rat, SD
Developmental
0, 75, 237, 750 mg/kg
bw/day
Gestation day 6-15
NOAEL=750 mg/kg bw/day
Highest dose tested
Reproductive effects
LOAEL=750 mg/kg bw/day
NOAEL=237 mg/kg bw/day
4/ Maternal body weight
LOAEL=750 mg/kg bw/day
NOAEL=237 mg/kg bw/day
^ Incomplete ossification
4/ Fetal and pup BW
^ Resorptions
4/ Viable offspring
Becci et al.,
1982
Notes:
a Considered biologically, but not statistically significant.
b As cited in OECD (2007)
c Due to internal conflicts in data, this study is considered unreliable.
d NOAEL= 258 mg/kg bw/day, LOAEL=516.5 mg/kg bw/day for 4, BW in males
e NOAEL= 169 mg/kg bw/day, LOAEL= 433 mg/kg bw/day for 4, BW in males
f NOAEL= 820 mg/kg bw/day, LOAEL= 2500 mg/kg bw/day for epithelial swelling of distal kidney tubuli
8 NOAEL= 2500 mg/kg bw/day, LOAEL= 7500 mg/kg bw/dayfor 4, ALP and centrilobular liver cell hypertrophy (at 3 months after end of dosing)
SD = Sprague Dawley
PND = postnatal day
Page 58 of 281
-------
Nearly every study that evaluated developmental toxicity identified some type of adverse
effect. Moreover, a review of effect levels reveals that the effects are observed within a
comparable dose range, with NOAELs typically 100-200 mg/kg bw/day for oral exposure studies
and effect levels ranging 479-612 mg/m3 in the inhalation exposure studies. Specifically,
EPA/OPPT identified a number of biologically relevant, consistent and sensitive effects that
represent a continuum of reproductive and developmental effects, including decreased fetal
and pup body weight, delayed ossification, skeletal malformations and increased fetal and pup
mortality, for consideration in assessing human health risks. These endpoints are discussed in
more detail below in the section 3.1.3.
In addition to the laboratory animal studies, there is one case report that is consistent with a
hypothesis of NMP fetotoxicity but no cause and effect was established. In this report the fetus
of a pregnant woman died in utero at week 31 of pregnancy (Solomon et al., 1996). The worker
was exposed throughout pregnancy to NMP by inhalation and dermal exposure but the
exposure levels were unknown. The worker's tasks involved other chemicals, including acetone
and methanol, among others. During week 16 of the pregnancy the worker cleaned up a spill of
NMP using latex gloves that dissolved in the NMP. She was ill for the next 4 days and
experienced malaise, headache, nausea and vomiting. This study provides some evidence that
NMP may be fetotoxic. The lack of quantitative exposure data precludes its use in the risk
assessment.
While NMP was initially prioritized based on reproductive toxicity EPA/OPPT's subsequent in-
depth analysis determined that developmental toxicity was a more appropriate sensitive
endpoint for risk assessment purposes. EPA/OPPT assessed developmental toxicity within the
context of the exposure pathways and exposure durations identified in the exposure
assessment, as summarized in Table 3-2.
Page 59 of 281
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Table 3-2 Summary of Exposure Pathways, Toxicity Endpoints and Risk Estimation Approach
Receptors
Worker
Users and
Nearby
Worker
Non-Users
Consumer
Users and
Nearby
Residential
Non-Users
Exposure Pathway and Analytical Approach
Acute Dermal and Inhalation
Exposures
Toxic endpoint: Developmental toxicity3
Risk approach: Margin of Exposure
(MOE)
Chronic Dermal and Inhalation
Exposures
Toxic Endpoint: Developmental toxicity
Risk approach: Margin of Exposure
(MOE)
Chronic risks were not evaluated. This
pathway was not expected to occur in
consumer users or nearby occupants.
Notes:
a Acute 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.
3.1.3 Selection of Developmental Toxicity Studies and Endpoints
This section identifies the developmental toxicity studies that EPA/OPPT selected for use in the
risk assessment. Available data were reviewed to determine test species, test conditions,
toxicity endpoints, statistical significance and strengths/limitations of the study, which were
summarized and evaluated for study quality (see Appendix F). Guideline studies as well as
studies using other protocols were included if they met study quality criteria. The selected
studies were then evaluated in the dose-response assessment.
The endpoints that were observed in multiple studies, sensitive and biologically relevant, were
considered for selecting point of departures (PODs) for dose-response in the risk assessment.
These endpoints included:
• Decreased fetal/pup weight, PND 0, 4, 21
• Increased fetal/pup mortality, PND 0, 4, 21
• Skeletal malformations
• Incomplete skeletal ossification.
It is not clear if the fetus is the target or if fetal effects are secondary to maternal effects,
although there is evidence that NMP can cross the placenta (RIVM, 2013). While maternal body
weights or weight gain were decreased in a number of studies, the effect level was similar to
that of the fetal effects. Therefore EPA/OPPT considered the fetal effects to be more direct and
biologically relevant.
Page 60 of 281
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There are a number of rat studies available to assess these endpoints (Table 3-3). Most studies
are based on the oral exposure route, although several studies relied on inhalation exposure. A
single study was conducted based on dermal exposure. The availability of the PBPK model
allows for the conversion of data from different dosing route studies to a single, internal dose
metric. Table 3-3 summarizes the endpoints observed in the developmental studies reviewed
and illustrates which endpoints are consistent and which are not. Different outcomes may be
due to differences in exposure duration, the exposure window, route of exposure or other as
yet uncharacterized factors, e.g., dose rate and frequency. EPA/OPPT interpreted the presence
of concurrent outcomes across exposure routes, exposure windows and durations as
supportive of the robustness of the continuum of developmental toxicity endpoints.
Page 61 of 281
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Table 3-3 NMP Studies with Evidence for Developmental Toxicity
ORAL
STUDIES
INHALATION
STUDIES
DERMAL
STUDIES
Study
Sitareket al.,
2012
Sitareket al.,
2008
NMP
Producers
Group, 1999a
NMP
Producers
Group, 1999b
Saillenfait et
al., 2002
Exxon, 1992
Saillenfait et
al., 2003
H asset
al.,1995
Hasset al.,
1994
DuPont, 1990
Leeetal.,
1987
Becci et al.,
1982
Fetal Weight
GD20-PND1
~
NA
^
^
^
^
^
^
—
*
Pup Weight
PND4
t
NA
t
t
NA
NA
NA
t
*
NA
NA
Pup Weight
PND21
t
NA
t
t
NA
NA
NA
t
±
NA
Fetal Mortality
(multiple
metrics3)
t
~
t
t
t
~
t
~
*tvb
~
t
Pup
Mortality
PND4
t
t
t
t
NA
NA
NA
~
~
NA
NA
Pup
Mortality
PND21
t
~
t
t
NA
NA
NA
~
~
NA
Incomplete
Ossification
NA
NA
t
~
t
NA
±
—
t
Skeletal
Malformations
NA
NA
t
~
~
NA
±
—
t
Notes:
\|/ indicates decrease, T" indicates increase, - indicates no change
a May be based on resorptions, post-implantation loss, dead pups at birth or decreased live pups at birth
b Statistically significant increase for p = 0.1
NA = Not Assessed
Blank = Data not publicly available
Page 62 of 281
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3.1.3.1 Decreased Fetal and Postnatal Body Weights
Decreased fetal and/or postnatal body weights were consistently observed across studies
despite variations in dosing time and exposure routes. The fetal and postnatal body weight
effects noted in Table 3-3 were plotted graphically in exposure-response arrays (Figure 3-2).
Exposure-response arrays are a graphical representation of available dose-response data for
significant effects. Included in the exposure-response arrays are LOAELs and NOAELs, based on
applied doses. The graphical display allows the reader to quickly compare the outcomes of a
number of studies, based on the same or groups of related endpoints for growth and
development. In this case, the exposure -response arrays illustrate that there is a coherence
and consistency of these effects - meaning that the effects were present in multiple studies
and the NOAELs and LOAELs occurred within a narrow range.
As illustrated in Figure 3-2, fetal body weights were decreased with oral (gavage) exposures of
250 mg/kg bw/day (Exxon Biomedical Sciences, 1992) and at 400 mg/kg bw/day (Saillenfait et
al., 2002). Sitarek et al. (2012) observed decrements in PND 4 pup body weight at 450 mg/kg
bw/day and at PND 4-21 pup body weight at 1000 mg/kg bw/day (Sitarek et al., 2012). In the
Sitarek study exposures to dams continued through the post-natal period, therefore the
decreased pup body weights may indicate that NMP was transferred to the pup via lactation.
Figure 3-3 presents the exposure-response array for the inhalation studies. At inhalation
exposure concentrations of 479 to 612 mg/m3, statistically significant decreased body weights
at CDs 20 or 21 and PNDs 0 or 1 were observed in multiple studies (DuPont, 1990; Mass et al.,
1995; Mass et al., 1994; Saillenfait et al., 2003). Both Saillenfait et al. (2003) and DuPont (1990)
observed decrements in fetal body weights at 486 mg/m3 and 479 mg/m3, respectively. Two
studies by Mass et al. (1995; 1994) also indicated that fetal body weights were decreased in
both Wistar and Sprague- Dawley rats, however only one dose (612 mg/m3) was used in each
study. In contrast, no changes in fetal body weight were observed in a study by (Lee et al.,
1987).
The study by DuPont and the studies by Mass et al. also noted decreased pup body weights
(DuPont, 1990; Mass et al., 1995; Mass et al., 1994). In the DuPont study, exposures to dams was
suspended from GD 20 through PND 4, yet decreased body weight was not a transient effect,
lending support to the consideration that decreased body weight is a persistent, adverse effect.
Based on the observations of decreased fetal and postnatal body weights, EPA/OPPT selected
decreased fetal body weights as a key endpoint for use in the risk calculation for chronic
exposure. These effects were consistent among multiple studies with different dosing regimens
and across exposure routes. Reduced fetal body weight is a sensitive endpoint that is
considered a marker for fetal growth restriction which is often assumed to be representative of
chronic rather than acute exposures (Van Raaij et al., 2003). Decreases in fetal and postnatal
body weights occur at similar dose levels. Fetal body weights were assumed to be the
proximate event.
Page 63 of 281
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decreased fetal/pup BW in rats
A LOAEL
ANOAEL
I Doses > LOAEL D Doses < NOAEL
J.LAJU
Sr
n
TJ
"So
01
8
0
2
01 nn
1 n
exposure
duration
species, strain
day of
nhcprvatfnn
It
A
I 8
CN tH
— i r c"
CD O
S S
1
'S
GD6-20
Rat, SD Rat, SD
GD21
A
III
kO
£ Srtareket al., 2012
^~ *
L/l
Rat, Wistar
PND 1
•
1
ID
S. Sitareketal., 2012
L/l
Rat, Wistar
PND 4
A
A
ID
S. Sitareketal., 2012
in
Rat, Wistar
PND 21
Figure 3-2 Studies that Measured Fetal/Pup Body Weight after Oral Exposure of the Dams to NMP
with NOAEL and LOAELs Identified
Page 64 of 281
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decreased fetal/pup A LOAEL A NOAEL
BW in rats • Doses > LOAEL D Doses < NOAEL
1 nnn
1UUU
1 nn
1UU
00
c
_g
2
c
0
O
£
x 1
UJ
exposure
duration
species, strain
day of
observation
i
L
C
A
E
L
L
3 r
L
i
CD
O
L
Ol
•I-*
c
o
Q.
Q
2 gen
Rat, CD
H
"ro
o>
In
ro
X
GD 7-20
Rat,
Wistar
PND21
Dermal Exposure Concentration (mg/kg) M o
1-1 O O O
re
H
o
ca
GD6-15
Rat, Charles
River CD
GD21
Figure 3-3 Studies that Measured Fetal/Pup Body Weight after Inhalation and Dermal Exposure of the
Dams to NMP with NOAEL and LOAELs Identified
3.1.3.2 Resorptions and Fetal Mortality
Fetal resoptions have been observed in oral, inhalation and dermal studies (Becci et al., 1982;
DuPont, 1990; Saillenfait et al., 2002). Fetal and postnatal mortality have also been observed in
oral and dermal studies (Becci et al., 1982; NMP Producers Group, 1999a, 1999b; Sitarek et al.,
2012). Statistically significant increases in resorptions or mortality were seen consistently at
administered doses of 500 - 1000 mg/kg bw/day in all studies at the tested doses.
Page 65 of 281
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In the single dermal study fetal/pup mortality was increased at 750 mg/kg bw/day (Becci et al.,
1982). In inhalation studies with exposures up to the air saturating concentration statistically
significantly increased resorptions or fetal and postnatal pup mortality were not observed,
possibly due to the limited NMP exposure concentration (see TK/PBPK section). Resorptions
and mortality can occur as a consequence of single exposures during a sensitive developmental
stage and as such, resorptions and fetal and postnatal mortality are a relevant endpoint for
acute effects (Van Raaij et al., 2003).
EPA/OPPT also considered the relevance of increased postnatal mortality observed in the
Sitarek et al. (2012) and NMP Producers Group (NMP Producers Group, 1999a, 1999b) studies.
This outcome was not consistently observed in other studies: Sitarek et al. (2012) observed
increased pup mortality at 150 mg/kg bw/day, the NMP producers group studies did not see
increased pup mortality until 350 mg/kg bw/day and no increase in pup mortality was observed
in DuPont (1990). When increased post-natal mortality was observed, the NOAELs were within
the same range as other sensitive endpoints, such as reduced fetal body weight (e.g., see Table
3-5).
EPA/OPPT selected increased fetal resorptions/fetal mortality as a key endpoint for the
calculation of risks associated with acute exposures. Fetal resorptions and mortality, may result
from a single exposure at a developmentally critical period (Davis et al., 2009; EPA, 1991b; Van
Raaij et al., 2003). In the studies reviewed, increased fetal mortality occurred at relatively low
exposures, suggesting that this was a sensitive and relevant endpoint, suitable for use in the
risk assessment.
3.1.3.3 Other Fetal Effects
Incomplete ossification was observed following exposures to NMP via oral, inhalation and
dermal routes. Incomplete ossification is a decrease in the amount of mineralized bone
expected for developmental age and is one of the most common findings in developmental
toxicity studies (Carney and Kimmel, 2007). Saillenfait et al. (2002) reported statistically
significant increases in incidences of incomplete ossification of sternebrae, skull and thoracic
vertebral centra at GD 20 for oral doses of 500 and 750 mg/kg bw/day. Mass et al. (1995)
reported statistically significant increases in delayed ossification of cervical vertebrae 4 through
7 and digital bones following an inhalation exposure at a concentration of 669 mg/m3. Becci et
al. (1982) reported a statistically significant increase in incidences of incomplete ossification of
vertebrae at 750 mg/kg bw/day dermal application. On the other hand, increased incidences of
incomplete ossification were not observed in inhalation studies (DuPont, 1990; Lee et al., 1987;
Saillenfait etal., 2003)
The areas of increased incomplete ossification that were observed in fetuses at GD 20 or 21
were in bones that are undergoing rapid ossification during the period of observation, but there
are a number of hormones considered to be important for regulating skeletal development
(Carney and Kimmel, 2007). There are several clues that may be indicative of effects due to
Page 66 of 281
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something other than generalized delay, including: delays in the presence of specific skeletal
malformations, teratogenesis or unusual patterns of delayed ossification (Carney and Kimmel,
2007; Van Raaij et al., 2003). Based on these observations EPA/OPPT considered NMP-
associated delayed ossification to represent a continuum of effects related to delays in fetal
growth and development, associated with decreased fetal and/or pup body weight.
Skeletal malformations are considered to be permanent structural changes that are likely to
adversely affect the survival or health of the species (Daston and Seed, 2007) and were
observed in some NMP studies via oral exposure. The Saillenfait et al. (2002) study reported
aggregated skeletal malformations (including ribs, vertebrae and others) at GD 20 for oral doses
of 500 and 750 mg/kg bw/day. In contrast, skeletal malformations were not observed in one
dermal study and inhalation studies conducted up to the air saturating concentration. Increased
skeletal malformations may not have been observed in the inhalation studies because the
vapor pressure of NMP limited the attainment of toxic concentration in air.
3.1.3.4 Conclusions and Selection of Key Endpoints
Collectively, decreased fetal and postnatal body weight, incomplete ossification, skeletal
malformations and fetal and postnatal mortality are biologically relevant endpoints that
provide important insight into NMP toxicity and may represent a coherent continuum of
possibly related effects. The observed effects, even those from different studies, occur within a
narrow range of doses of 100 to 1000 mg/kg bw/day (for oral exposures) or 470 to 669 mg/m3
(for inhalation exposures). In addition, these body weight and mortality effects appeared to
persist, based on those studies that carried out the observations to PND 21.
EPA/OPPT has selected reduced fetal body weight as the basis of the dose-response analysis for
chronic exposures. As documented above, reduced fetal body weight was consistent among
multiple studies with different dosing regimens and across exposure routes. Reduced fetal body
weight is a sensitive endpoint that is considered a marker for fetal growth restriction which is
often assumed to be representative of chronic rather than acute exposures (Van Raaij et al.,
2003). A comparison of the NOAEL and LOAELs for repeated and single dose studies across a
range of chemicals showed that for fetal body weight the repeat dose NOAELs and LOAELs are
2-4 fold lower than single-dose values (Van Raaij et al., 2003), showing these endpoints are
more sensitive to repeated exposures. As such fetal body weight reduction is most applicable to
estimating risks for chronic exposures.
EPA/OPPT has selected fetal resorptions and fetal mortality as the basis of the dose-response
analysis for acute exposures. Acute toxicity studies were not used for the acute POD because
the doses at which acute toxic effects or lethality were observed are higher than those that
caused toxic effects in developmental studies. Developmental studies involve multiple
exposures given on the order of 10-15 days; however, they are relevant to single exposures
because some developmental effects, such as fetal resorptions and mortality, may result from a
single exposure at a developmentally critical period (Davis et al., 2009; EPA, 1991b; Van Raaij et
Page 67 of 281
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al., 2003). In an analysis of the utility of developmental toxicity repeat dose studies for use in
the assessment of risks following acute exposures, Van Raaij found that there is a relatively
small difference between the NOAEL and LOAELs for resorptions and related mortality events in
repeated and single dose studies (Van Raaij et al., 2003). Consequently, EPA/OPPT concluded
that these endpoints are most applicable to assessing risks from acute exposures, where the
risk of their occurrence is assumed to depend on exceedance of a threshold value for even a
single day (i.e., peak concentration) rather than a time weighted average value and the
magnitude of the exposure is considered to be more important for these effects under these
study conditions.
3.2 DOSE-RESPONSE ASSESSMENT AND STUDY SELECTION
EPA/OPPT evaluated data from studies described above (3.1.2) to characterize NMP's dose-
response relationships and select studies to quantify risks for specific exposure scenarios.
In order to select the most appropriate key studies for this analysis, EPA/OPPT considered the
relative merits of the oral, inhalation and dermal animal studies, with respect to: (1) the
availability of primary data for statistical analysis; (2) the robustness of the dose-response
analysis; and (3) the exposure levels at which adverse effects were observed.
The selected key studies provided the dose-response information for the selection of points of
departure (PODs). EPA/OPPT 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 (i.e., benchmark
dose or BMD), a NOAEL or a lowest-observed-adverse-effect level (LOAEL) for an observed
incidence or change in level of response. PODs were adjusted as appropriate to conform to the
exposure scenarios derived in section 1.3.
3.2.1 Identification of Studies for BMD Modeling
Studies with only one exposure group (Mass et al., 1995; Mass et al., 1994) provide limited
information about the shape of the dose-response curve and could not be used for BMD
modeling. Given their concordance with other studies that had multiple exposure groups they
were still seen as supportive of the dose-response relationship. Studies that did not report a
statistically significant effect for the endpoint being considered (Lee et al., 1987) may help with
dose metric selection, but provide only limited information about the shape of the dose-
response curve and were not included in the dose-response assessment of that endpoint.
For reduced fetal body weights EPA/OPPT selected the following studies for dose-response
analysis:
• Becci et al., 1982;
• DuPont, 1990;
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• Saillenfaitetal., 2002 and
• Saillenfaitetal., 2003.
For fetal resorptions and increased fetal mortality EPA/OPPT selected the following studies for
dose-response analysis:
• Becci et al., 1982;
• Saillenfaitetal., 2002;
• Saillenfaitetal., 2003 and
• Sitareketal, 2012.
The Saillenfait et al. (2002) and Saillenfait et al. (2003) studies administered NMP via different
routes but were otherwise similar using the same exposure duration (GD 6-20) and the same
strain of rat (Sprague-Dawley), so these studies were combined based on PBPK-derived internal
dose metrics to provide additional statistical power for informing the dose-response curve.
EPA guidance recommends a hierarchy of approaches for deriving PODs from data in laboratory
animals, with the preferred approach being physiologically-based pharmacokinetic modeling
(EPA, 2012a). When data were amenable, benchmark dose (BMD) modeling was used in
conjunction with the PBPK models to estimate PODs. For the studies for which BMD modeling
was not possible (Becci et al., 1982; Sitarek et al., 2012), the NOAEL was used for the POD.
Details regarding BMD modeling can be found in Appendix H. Details regarding the PBPK model
can be found in Appendix I.
3.2.2 Derivation of Internal Doses
This section summarizes the toxicokinetics of NMP, the PBPK model and dose metrics used to
estimate internal doses.
Toxicokinetic Parameters used in PBPK Modeling
NMP is well absorbed following inhalation, oral and dermal exposures (NMP Producers Group,
1995). 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 hrs. The major
metabolite is 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP). Studies in humans show that NMP
is rapidly biotransformed by hydroxylation to 5-HNMP, which is further oxidized to N-methyl-
succinimide (MSI); this intermediate is further hydroxylated to 2-hydroxy-N-methylsuccinimide
(2-HMSI). 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 (Akesson and
Jonsson, 1997).
Dermal absorption of NMP has been extensively studied as it typically poses the greatest
potential for human exposure. Dermal penetration through human skin has been shown to be
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very rapid and the absorption rate is in the range of 1-2 mg/cm2-hr. These values are 2- to
3-fold lower than those observed in the rat. Prolonged exposures to neat NMP were shown to
increase the permeability of the skin. Water reduces the amount of dermal absorption (Payan,
2003) while other organic solvents (e.g., d-limonene) can increase it (HLS, 1998). 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 occulsion conditions indicated that dermal absorption
1 hr post-exposure was greatest under un-occluded conditions (69 percent), followed by semi-
occluded (57 percent) and occluded (50 percent) conditions (OECD, 2007).
Dermal uptake of vapor NMP has been reported in toxicokinetic studies in humans. Bader et al.
(2008) exposed volunteers for 8 hrs to 80 mg/m3 of NMP. Exposure was whole body or dermal-
only (i.e., with a respirator). 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 authors estimated that 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.
Previously published PBPK models for NMP in rats and humans (Poet et al., 2010) were adapted
for use by EPA. (See Appendix I for details on changes made by EPA and Dr. Torka Poet). The rat
version of the model allows for estimation of NMP time-courses in rat blood from inhalation,
oral and dermal exposures. The human version of the model, based on non-pregnant and
pregnant women, also includes skin compartments for portions of the skin in contact with NMP
vapor and liquid and we describe here some of those details because it is an important
component of human risk.
Analyzing the experimental studies of Akesson et al. (2004), the model yielded an average
uptake of 2.1 mg/cm2-hr of neat NMP, but only 0.24 mg/cm2-hr of 50% NMP diluted in water.
Therefore distinct values of the liquid permeability constant (PVL), 2.05xlO~3 cm/h and
4.78xlO"4 cm/h, were identified from the experimental data. The appropriate value of PVL for
neat vs. diluted NMP was used in the respective exposure scenarios in this assessment.
Absorption also depends on the partition coefficient (PC) skin:liquid equilibrium, PSKL, which
was taken to be the skin:saline PC reported by Poet et al. (2010), PSKL = 0.42 [no units] and
assumed not to vary with dilution.
Predicted dermal uptake from liquid exposure is then a function of the liquid concentration,
skin surface exposed and duration of contact. The thickness of the liquid film does not factor
directly into the estimate. As a conservative estimate for user scenarios it is assumed that fresh
material is constantly depositing over the time of use such that the concentration on the skin
remains essentially constant at the formulation concentration. This is in contrast to simulations
of experimental studies where the volume placed on the skin at the start of the experiment is
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not replenished (Akesson et al., 2004), in which case the model tracks the amount of NMP
remaining in the film and hence the changing concentration for absorption from diluted NMP.
Penetration from vapor was estimated as part of model calibration using the Bader and van
Thriel (2006) inhalation data set. This report does not state how the subjects were dressed but
the exposures were conducted between late May and mid-June in Germany, so EPA/OPPT
assumed they wore short-sleeved shirts and long pants. While there is no reason to expect that
NMP vapors do not penetrate clothing, clothing likely reduces uptake compared to open areas
of skin. Since the fitted penetration constant (PV) is multiplied by the skin surface area assumed
to be exposed when calculating the penetration rate, these cannot be uniquely determined
from the toxicokinetic data. For the purpose of calibration and subsequent modeling, it is
assumed that the head, arms and hands are entirely exposed unless personal protection
equipment (PPE) is worn. Together the fractional skin area exposed to vapor (SAVC) is 25% of
the total skin surface area in the absence of PPE or liquid dermal contact.
The skin:air PC, PSKA, was calculated from the measured skin:saline and blood:saline PCs
reported by Poet et al. (2010) and the blood:air PC specified in their model code: PSKA = 44.5.
With these values of SAVC and PSKA, the average permeation constant for vapor-skin transport
was estimated as PV = 16.4 cm/h. These assumptions and the value of PV resulted in a
prediction of 20% of a total uptake from air (vapor) exposure via the dermal route. In contrast,
Bader et al. (2008) measured 42% of total urinary excretion occurring after only dermal
exposure to vapors compared to combined inhalation and dermal exposure under resting
conditions. The discrepancy between the Bader et al. (2008) data and the current model
predictions could be because the subjects in Bader and van Thriel (2006), on which this model is
based, wore long-sleeved shirts, thereby reducing dermal absorption or due to the use of an
idealized model of inhalation uptake which could over-predict uptake by that route.
For use scenarios in this assessment the air concentration in contact with the skin is assumed to
be the same as that available for inhalation with SAVC kept at 25% for consistency, except as
specified in the sections below when PPE is worn.
Rat Internal Doses for BMD
EPA/OPPT modified and validated PBPK models for extrapolating NMP doses across routes of
exposure and from animals to humans based on NMP-specific data (See PBPK section, Appendix
I). An internal dose metric such as a measure of toxicant concentration in the blood is expected
to be a better predictor of response than the applied dose (e.g., concentration in air) since it is
closer to the site of the toxic effect (McLanahan et al., 2012). Further, a good internal dose
metric should correlate with or be predictive of toxicity irrespective of the route of exposure by
which it occurs. However this is only true if the metric is in fact a measure of the likelihood of a
toxic response or intensity of a toxic effect.
For NMP the existing toxicity data identified the parent (NMP) rather than the metabolites 5-
hydroxy-N-methyl-2-pyrrolidone (5-HNMP), N-methylsuccinimide (MSI) or 2-hydroxy-N-methyl-
Page71of281
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succinimide (2-HMSI) as the proximate toxicant (Saillenfait et al., 2007). Therefore, PBPK
model-derived blood concentrations of NMP were considered a better basis than applied dose
for the dose-metric used in extrapolation of health effects.
Dose Metrics Selected
The selection of the internal dose metric, used to establish "equivalent" exposures, is an
important decision in the use of the PBPK model for extrapolation of doses across routes and
from rats to humans. Internal dose metric selection is endpoint specific (EPA, 2006). For
example, the dose metric area-under-the curve (AUC) of the average blood concentration, is
generally considered appropriate for endpoints associated with repeat dose, assuming that a
sustained internal dose of NMP is needed to induce the effects. Endpoints that are associated
with a single or short term acute exposure, assuming that a single dose effect is needed to
induce these effects, are generally best evaluated by a metric that captures peak exposure,
SUCh as Cmax.
As described above in section 3.1.3.4, the endpoint of decreased fetal body weight was
presumed to be a marker of reduced fetal growth resulting from chronic exposure. Therefore
decreased fetal body weight is expected to be better represented by the AUC of average blood
concentration during the vulnerable period of fetal development.
EPA/OPPT evaluated average AUC (total AUC divided by the number of days, starting from the
first day of exposure until the day of measurement), e.g., GD6-20 for Becci et al. (1982) or GD5-
21 for Saillenfait et al. (2003) with decreased fetal body weights for oral, inhalation and dermal
routes of exposure to confirm the metric is consistent in its estimation of a toxic response
across routes. Seven studies that measured fetal body weights were used for evaluating
consistency between the internal dose and the response expressed as percent change from
control in body weight. The data points were fit to a line and the correlation coefficient (R2) was
used to evaluate linearity, shown in Figure 3-4. The Average Daily AUC metric had a reasonable
correlation with fetal body weight changes. Varying the period of averaging for the daily AUC
metric may provide higher correlations with fetal body weights.
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oral
inhalation
dermal
op
>• c
T3 O
O <->
m c
"ro o
S -
C (U
t! ^P
o |
Saillenfait et al., 2002 • Sitarek et al., 2012
Dupont, 1990
Lee et al., 1987
Saillenfait etal., 2003
• Mass etal., 1995
Beccietal., 1982
03
-I— '
CU
10%
0%
-10%
-20%
-30%
-40%
-50%
-60%
y = -4E-05x
R2 = 0.787
0 2000 4000 6000 8000 10000
Average Daily AUC (hr mg/L)
Figure 3-4 Analysis of Fit: Average Daily AUC vs Fetal or Postnatal Body Weight
As described in section 3.1.3.4, fetal resorptions and fetal mortality are assumed to be
associated with acute exposures during fetal development, but lacking a clear understanding of
the possible mode of action, the best dose metric for the evaluation of fetal resorptions and
mortality is unclear. Per EPA guidance (EPA, 2006), both AUC and peak blood dose (Cmax) were
used to evaluate this endpoint.
3.2.3 POPs for Acute Exposure
Acute exposure was defined for workers as a 1, 4, or 8 hour exposure over the course of a
single day. For consumer uses, acute exposure was based a single project on a given day for a
specified duration, less than 4 hours. EPA/OPPT selected increased resorptions and fetal
mortality as the most relevant endpoint for calculating risks associated with acute worker and
consumer scenarios. Since the studies used to evaluate resorptions and fetal mortality were
repeat dose studies and the mode of action was uncertain, EPA/OPPT assessed dose-response
with both the internal dose metric of Cmax and AUC.
The Saillenfait et al. (2002); Saillenfait et al. (2003); Becci et al. (1982); and Sitarek et al. (2012)
studies were selected for dose-response analysis. The Saillenfait et al. studies measured fetal
resorptions and were pooled across exposure routes. The Saillenfait et al. studies also used the
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same exposure duration (GD 6-20) and the same strain of rat (Sprague-Dawley). Combining the
data sets should provide additional statistical power for identifying the BMDL and provide a
more robust dose-response (low to high). Moreover the results for this endpoint were similar,
via inhalation and oral exposure routes. Therefore, the combined analysis was retained. A BMR
of 1% for increased resorptions/fetal mortality was used to address the relative severity of this
endpoint (EPA, 2012a). Table 3-4 summarizes the calculations leading to the determinations of
a POD for each of the studies selected for dose-response analysis.
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Table 3-4 Summary of Derivation of the PODs for Fetal Resorptions and Fetal Mortality Following
Acute Exposure to NMP
Endpoint and
reference
(exposure
duration/route)
Dose
Metric
Model3
BMR
BMD
Internal
dose
BMDL
Internal
dose
POD
Internal
dose
Equivalent
administered
dose (route)3
Resorptions
Saillenfait et al.
2002 and 2003
(GD 6-20, oral
and inhalation)
Becci et al., 1982
(GD 6-15,
dermal)
max
(mg/L)
AUC(hr
mg/L)
Hill
Power
1%
RD
1%
RD
429
3343
216
2128
NOAEL = 237 mg/kg bw/day
216
2128
662
218 mg/kg
bw/day
(oral)
217 mg/kg
bw/day
(oral)
237 mg/kg
bw/day
(dermal)
612 mg/kg
bw/day
(oral)b
Fetal Mortality
Sitarek et al.,
2012
(GD1-PND1 oral)
C-max
(mg/L)
No
model
selected0
1%
RD
N/A
N/A
NOAEL = 450 mg/kg bw/day
N/A
265
264 mg/kg
bw/day
(oral)
Notes:
RD = relative deviation
ER = extra risk
a Assuming daily oral gavage and initial BW 0.259 kg (i.e. the same experimental conditions as the Saillentfait et
al., 2002 study) for the purposes of comparison across the studies.
b An oral dose of 612 mg/kg bw/day, given on GD 6-20, is predicted to yield the same peak concentration
(662 mg/L).
c BMD modeling failed to calculate an adequate BMD or BMDL value by either dose metric (see 0).
EPA/OPPT selected the combined analysis of the Saillenfait et al. (2002) oral study and the
Saillenfait et al. (2003) inhalation study for the derivation of the POD, 216 mg/L, to be used in
the calculation of risk estimates associated with acute exposure. The combination of the two
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Saillenfait et al. studies provides a larger number of dose levels, hence further characterization
of the dose-response curve. Moreover, similar results for this endpoint were obtained in these
studies which supports combining them. Additionally the Saillenfait et al. studies were
amenable to BMD modeling which also accounts for the variability in the observed response.
Neither the Becci study nor the Sitarek study were suitable for BMD modeling, hence the
NOAEL was used to derive a POD. Accordingly EPA/OPPT selected fetal resorptions from the
combined Saillenfait et al. studies for use as the basis for calculating risk for acute NMP
exposures.
The PODs based on internal dose (AUC and Cmax) were converted to an equivalent applied dose
using the PBPK model. The calculated equivalent administered doses are nearly the same as the
NOAELs identified in each study demonstrating consistency between the two methods for
deriving PODs.
3.2.4 PODs for Chronic Exposure
Chronic worker exposure was defined as exposure of 10% or more of a lifetime (EPA, 2011a).
Repeated exposures over the course of a work week are anticipated during chronic worker
exposure. The most sensitive endpoint was selected based on developmental studies on NMP.
These adverse outcomes can arise from exposure during critical windows of development
during pregnancy and pregnancy can occur any time during the defined chronic worker
exposure period. The derivation of the point of departure based on developmental toxicity
considered repeated exposures, and is expected to be protective of pregnant women and
women who may become pregnant.
Decreased fetal body weight was selected as the endpoint of concern and the Becci et al.
(1982), DuPont (1990), Saillenfait et al. (2002), and Saillenfait et al. (2003) studies were selected
for dose-response analysis. The PBPK model and BMD modeling were applied to these studies
to calculate the BMDLs and PODs. A benchmark response (BMR) of 5% relative deviation for
decreased fetal body weight was used because in the absence of knowledge as to what level of
response to consider adverse, it has been suggested to consider a 5% change relative to the
control mean for developmental endpoints (Kavlock et al., 1995). The results are summarized in
Table 3-5. It should be noted that the Saillenfait et al. studies were analyzed separately and
combined. Also, the PBPK model was used to present the POD as the equivalent applied oral
dose, to allow for comparison.
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Table 3-5 Summary of Derivation of the PODs for Decreased Body Weight Following Chronic Exposure
toNMP
^1 • . 1
Endpomt and
reference
(exposure
duration/route)
Model3
BMR
BMD
• . 1
Internal
dose
AUC (hr
mg/L)
BMDL
• . 1
Internal
dose
AUC (hr
mg/L)
POD
Internal
dose AUC
(hr mg/L)
Equivalent applied
oral dose3
Fetal Body Weight
Saillenfait et al.
2002 and 2003
(GD 6-20, oral
and inhalation)
Saillenfait et al.
2002
(GD 6-20 oral)
Saillenfait et al.
2003
(GD 6-20
inhalation)
DuPont 1990
(pre-conception
exposure, GD
1-20,
inhalation)
Becci et al.,
1982
(GD 6-15,
dermal)
Exponential
(M5)b
Exponential
(M5)
Linear
Exponential
(M2)
Polynomial
/ -}O\
(3 )
5%
RD
5%
RD
5%
•J /U
n r\
RD
5%
RD
5% RD
1937
1637
652
315
5341
1424
1184
411
223
4018
1424
1184
411
223
4018
152 mg/kg bw/day
129 mg/kg bw/day
48 mg/kg bw/day
27 mg/kg bw/day
375 mg/kg bw/day
Notes:
RD = relative deviation
The POD selected for calculating risk of chronic NMP exposures is highlighted in bold.
a Assuming daily oral gavage GDs 6-20 and initial BW 0.259 kg (i.e. the same experimental conditions as the
Saillentfait et al., 2002 study) for the purposes of comparison across the studies.
b The Saillenfait et al. 2002 and 2003 studies do not meet the assumption of homogeneity of variance as
recommended for Benchmark Dose Modeling (EPA, 2012a), however the means are well-modeled. EPA/OPPT
evaluated the impact on the BMDLof the smallest observed standard deviation for all dose levels, the largest
standard deviation and the pooled standard deviation. The BMDLs differed by less than 25% which provides
assurance that the impact of the variances on the BMDL was minimal.
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EPA/OPPT selected the Saillenfait et al. (2003) inhalation study for the derivation of the POD,
(411 hr mg/L) to be used in the calculation of risk estimates associated with chronic exposure.
This study yielded results similar to the DuPont (1990) study, had a strong, significant dose-
response relationship and was adequately modeled by the BMD model.
The combination of the Saillenfait et al. (2002) and Saillenfait et al. (2003) studies routes
provided a more extensive characterization of the dose-response curve. However the Saillenfait
et al. (2003) study observed a statistically significant decrease in fetal body weights at an
internal dose that corresponds to an oral dose lower than the NOAEL in the Saillenfait et al.
(2002) oral study. This implies that the rats were more sensitive to inhalation exposures and
this was not fully accounted for in the PBPK model. Therefore the combined analysis was not
retained.
The two inhalation studies, DuPont (1990) and Saillenfait et al. (2003), had similar BMD and
BMDLs that are more conservative PODs than exposures via other routes. In addition, both
were whole body exposures where dermal absorption of NMP vapors likely contributed to the
toxicity, which is similar to human exposure scenarios; however the unknown differences
between human and rat dermal absorption of NMP vapor adds uncertainty to values derived
from either of these studies alone. While the POD for the DuPont study was lower than the
Saillenfait study, the dose-response relationship in the DuPont study was not as robust as the
Saillenfait study, which had lower variability in body weights than in the DuPont study, where
statistically significant differences only occurred in the lowest and highest dose groups, not the
middle dose group. Therefore, EPA/OPPT selected the Saillenfait et al. inhalation study as the
basis for the POD.
There are limitations to the Becci study: the duration of dosing was shorter than for the
Saillenfait studies and it resulted in a higher POD. The uncertainty regarding exposure duration
and sampling time leads to uncertainty about recovery and compensation. Therefore, this study
was not selected for the POD.
The PODs based on internal dose (AUC) were converted to an equivalent applied dose using the
PBPK model. The calculated equivalent administered doses are nearly the same as the NOAELs
identified in each study demonstrating consistency between the two methods for deriving
PODs.
3.2.5 Considerations for Sensitive Subpopulations and Lifestages
Certain human subpopulations may be more susceptible to exposure to NMP than others. One
basis for this concern is that the enzyme CYP2E1 is partially involved in metabolism of NMP in
humans and there are large variations in CYP2E1 expression and functionality in humans
(Ligocka et al., 2003). The variability in CYP2E1 in pregnant women could affect how NMP
reaches the fetus, which typically does not express CYP2E1 (Mines, 2007). Therefore, the
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variability in CYP2E1 was identified as an important uncertainty that was reflected in the
calculation of the benchmark MOE (described below in section 4.1.1).
Based on a review of studies during hazard identification, the most sensitive endpoint is
associated with fetal effects. Therefore the lifestages that are of greatest concern would be
pregnant women and women of childbearing age who may become pregnant. In addition there
is some evidence that exposures to male rats prior to mating could be a contributing factor to
developmental toxicity (DuPont, 1990; Sitarek and Stetkiewicz, 2008). However, neither study
was particularly robust; in the DuPont (1990) study, significant decreases in fetal body weight
were not observed at every dose level and the Sitarek and Stetkiewicz (2008) study had errors
in reporting that decreased confidence in the study.
Based on the end points and range of doses considered in this risk assessment, consideration
that other endpoints like male reproductive endpoints may be less sensitive, EPA/OPPT
assumed that exposures that are protective of women of childbearing age and pregnant
women will also be protective of other lifestages and subpopulations.
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4 HUMAN HEALTH RISK CHARACTERIZATION
This assessment determined risk estimates for four categories of individuals: (1) occupational
users via dermal contact, vapor-through-skin and inhalation; (2) occupational non-users who
are being indirectly exposed (inhalation and vapor-through-skin) through proximity to use, (3)
consumer users via dermal contact, vapor-through-skin and inhalation; and (4) consumer non-
users who are being indirectly exposed (inhalation and vapor-through-skin) to NMP in paint
strippers through proximity to use.
4.1 RISK ESTIMATION APPROACH FOR ACUTE AND CHRONIC
EXPOSURES
EPA/OPPT calculated MOEs and compared them to a benchmark MOE to determine if
unacceptable risks were present. EPA/OPPT calculated acute or chronic MOEs (MOEaCute or
MOEchronic) separately based on the POD and estimated exposure (Table 4-1).
Table 4-1 Margin of Exposure (MOE) Equation to Estimate Non-Cancer Risks Following Acute or
Chronic Exposures to NMP
MOE acute or chronic = Non-cancer Hazard value (POD)
Human Exposure
MOE =
Hazard value (POD) =
Human Exposure =
Margin of Exposure (unitless)
PBPK derived from toxicological studies (see Table 3-4 and Table
3-5)
Internal dose exposure estimate from occupational or consumer
exposure assessment.
The benchmark MOE was used as a threshold to determine the presence or absence of risk and
was obtained by multiplying the total uncertainty factors (UFs) associated with each POD. These
UFs accounted for (1) the variation in susceptibility among the members of the human
population (i.e., inter-individual or intraspecies variability) and (2) the uncertainty in
extrapolating animal pharmacodynamic data to humans (i.e., interspecies uncertainty).
Table 4-2 explains the selection of UFs and derivation of the benchmark MOE, based on the use
scenarios, populations of interest and toxicological endpoints that were used for estimating
acute or chronic risks, respectively.
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Table 4-2 Use Scenarios, Populations of Interest and Toxicological Endpoints for Assessing Risks to
NMP-containing Paint Strippers
Use& Exposure
^Scenarios
Populations
And Toxicological
Approach
CONSUMER USE
ACUTE EXPOSURE
OCCUPATIONAL USE
ACUTE AND CHRONIC EXPOSURE
Population of Interest and
Exposure Scenario:
Users
Women of childbearing age and
pregnant women (>16 years old)
exposed to NMP, single project.
Women of childbearing age and
pregnant women (>16 years old)
exposed to NMP during an 8-hr workday
a,b
Population of Interest and
Exposure Scenario:
Nearby Non-User
Women of childbearing age and
pregnant women (>16 years old)
exposed to NMP while being in the rest
of house (ROM) during product use.
Women of childbearing age and
pregnant women (>16 years old)
indirectly exposed to NMP while being
in the same building during product use.
Health Effects of Concern,
Concentration and Time
Duration
Decreased fetal body weight, Internal dose, chronic exposure
Increased fetal resorptions, Internal dose, acute exposure
Uncertainty Factors (UF)
used in Benchmark Margin
of Exposure (MOE)
calculations
UFA accounts for the uncertainties in extrapolating from rodents to humans,
comprised of toxicodynamics (TD), toxicokinetic (TK) differences and differences in
sensitivity. 3X was used for TD differences between laboratory animals and humans
and the differences in sensitivity. Use of the PBPK model accounted for TK
differences between laboratory animals and humans.
UFn accounts for the variation in sensitivity within the human population. 10X was
used to account for human variability. The PBPK model did not account for human
pharmacokinetic variability. The majority of the data used for calibrating and
evaluating the PBPK model were from healthy males. These data are assumed to
represent an average person i.e., the 50th percentile. However there are no data
pertaining to differential NMP metabolism based on lifestage. In addition, CYP2E1 is
partly involved in the metabolism of NMP in humans. There are large variations in
CYP2E1 activity in humans (Ligocka et al., 2003) which supported the retention of
the 10X uncertainty factor for human toxicokinetic variability.
Benchmark MOE = 30
Notes:
a It is assumed that there is no substantial buildup of NMP in the body between exposure events due to NMP's
short biological half-life (~2.5 hrs).
b EPA/OPPT expects that the users of these products are generally adults, but younger individuals may be users of
NMP-based paint strippers.
Because fetal effects were selected as key endpoints, risks were calculated for pregnant women
and women of childbearing age who may become pregnant. It was assumed that exposures
that do not result in unacceptable risks for these particular lifestages would also be protective
of other receptors, including children and adult males. The basis of this is:
• Toxicological effects that may be relevant to children and other adult receptors (i.e.,
reproductive effects and other systemic toxicity) are expected to occur at higher
Page 81 of 281
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exposure concentrations, relative to the fetal effects, based on rodent studies, e.g., an
order of magnitude higher.
• EPA/OPPT does not expect exposures of other adult workers (e.g., males) to reach levels
that would be associated with reproductive effects or other systemic toxicity.
• Similarly, EPA/OPPT estimated exposures to children who may be nearby the consumer
user and found that exposures were below levels of concern for developmental
endpoints, and would thus be below levels of concern for other endpoints associated
with higher exposure levels.
For example, simulations with the physiological parameters representative of a 1 year old girl in
the "rest of house" residential scenarios estimated internal exposures similar to adults.
Simulations were run for a 9-kg, 75 cm tall person, approximately the average weight/height for
a 1-year-old girl. Air concentrations for the "rest of house" residential scenarios were used as
inputs. While children have faster respiration/body weight and higher skin surface area/body
weight, once they are metabolically competent that metabolism is also expected to be
relatively faster based on allometric scaling. The resulting simulations predict that while peak
concentrations in the child would be 22-34% higher than a 74 kg woman, the blood AUC would
actually be 0.6 to 2.4% lower than the adult. In addition this estimation of small differences in
internal exposures between a child and an adult also suggests that lifestages in the women of
child bearing ages (from young women to adults) would have similar internal exposures.
In addition, the exposure of residents nearby the consumer users are via inhalation, (with
limited dermal contact for nearby workers) whereas dermal exposure is the more important
pathway. EPA/OPPT does not expect that exposures of children near to the consumer user to
be significantly greater than the exposure of adults near to the consumer user.
To assess risks, the MOE estimate was interpreted as a risk of concern if the MOE estimate was
less than the benchmark MOE (i.e. the total UF). On the other hand, the MOE estimate
indicated negligible concerns for adverse human health effects if the MOE estimate exceeded
the benchmark MOE. Typically, the larger the MOE, the more unlikely it is that an adverse
effect would occur.
4.1.1 Risk Estimates for Acute Occupational Exposure to NMP
Increased fetal resorptions was used as the toxicological endpoint to evaluate the occupational
acute exposure scenario. Given that fetal effects are considered most sensitive, the focus for
the risk calculations was on women of childbearing age and pregnant women. As described in
Table 2-1 and Table 2-2, the selected exposure scenarios represent combined inhalation,
dermal and vapor-through-skin exposures with a range of conservative assumptions. The
assumptions are then varied, such as use of PPE (respirator and gloves), time spent in contact
with NMP and concentration of NMP in the product, to obtain a range of plausible scenarios.
The acute exposure scenario was based on a single day's work.
Page 82 of 281
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Table 4-3 and Table 4-4 show the MOE estimates calculated for workers handling NMP-based
paint strippers on an acute basis. Table 4-3 summarizes the MOE estimates calculated for acute
exposures to NMP-based paint strippers, miscellaneous stripping activities, while Table 4-4
summarizes the results of the risk estimates for graffiti removal. The Margin of Exposure was
derived based on the ratio of the PODaCute of 216 mg/L (the BMDL for 1% increased fetal
resorptions, based on Saillenfait et al. 2002 and Saillenfait et al. 2003, as described in Table 3-4)
to the estimated peak exposure (Cmax, mg/L) for the sensitive lifestages. As described in section
4.1, the presence of risk was defined as MOEs below the benchmark MOE of 30. Calculations of
risks for the full set of scenarios are provided in the supplemental Excel spreadsheet,
Occupational PBPK Results and Risk Estimates.xlsx, located in the public docket (Docket: EPA-
HQ-OPPT-2012-0725).
There were very small differences in the risk estimates for women of childbearing age and
pregnant women. As with the chronic exposure scenarios, since risks were highly influenced by
dermal exposure, the small difference in risk estimates is likely due to the relatively small
differences in exposed surface area between women of childbearing age and pregnant women
on which estimates were calculated. Risks were identified in a number of exposure scenarios.
For miscellaneous stripping scenarios (Table 4-3), unacceptable risks were identified for
workers in contact with NMP for a total of 8 hrs/day (two 4 hr segments), regardless of whether
PPE (gloves or respirator) were used. For workers in contact with NMP for 4 hrs/day, risks could
be mitigated with the use of gloves. Further mitigation occurs with use of a respirator, but use
of a respirator alone is not sufficient to mitigate the risk. Workers in contact with NMP for
1 hr/day should not experience excess risk. There were no risks to nearby worker non-users.
A similar situation is observed for the graffiti removal scenarios (Table 4-4). Unacceptable risks
were identified for workers in contact with NMP for a total of 8 hrs/day (two 4 hr segments),
regardless of whether PPE (gloves or respirator) were used. For workers in contact with NMP
for 4 hrs/day, risks could be mitigated with the use of gloves. Unlike the miscellaneous paint
stripping scenarios, respirator use did not appear to provide any significant mitigation because
the air concentrations are lower. Workers in contact with NMP for 1 hr/day should not
experience excess risk. There were no risks to nearby workers not directly engaged in using
NMP.
Page 83 of 281
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Table 4-3 Acute Risk Estimates for Occupational Exposures to NMP-Based Paint Strippers - Miscellaneous Stripping Activities
Exposure Scenario
1) Miscellaneous stripping (assumed
mostly indoor)
- low end of parameter range
1 hr/day contact
1) Nearby worker non-user
2) Miscellaneous stripping (assumed
mostly indoor)
characterization
4 hr/day contact
2) Nearby worker non-user
3) Miscellaneous stripping (assumed
mostly indoor)
- high end of parameter range
two 4 hr/day contacts
PPE Used
No respirator, No gloves
With respirator, No gloves
No respirator, With gloves
With respirator and gloves
NA
No respirator, No gloves
With respirator, No gloves
No respirator, With gloves
With respirator and gloves
NA
No respirator, No gloves
With respirator, No gloves
No respirator, With gloves
Air
Concentration
mg/m3a
8
65
64
Exposure, Internal Dose
Blood Cmax, mg-hr/L
Women of
Childbearing
Age
1.81
1.75
0.25
0.20
0.08
16.99
15.75
2.97
1.89
1.53
320.55
317.44
21.56
Pregnant
Women
1.60
1.55
0.23
0.18
0.07
16.03
14.84
2.87
1.80
1.49
294.92
292.00
20.79
Margin of Exposure (MOE)
Women of
Childbearing
Age
119.5
123.4
849.0
1092.8
2619.9
12.7
13.7
72.6
114.2
141.4
0.7
0.68
10.0
Pregnant
Women
135.0
139.6
951.6
1233.6
2886.5
13.5
14.6
75.3
119.7
144.8
0.7
0.74
10.4
Page 84 of 281
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Exposure Scenario
3) Nearby worker non-user
PPE Used
With respirator and gloves
NA
Air
Concentration
mg/m3a
Exposure, Internal Dose
Blood Cmax, mg-hr/L
Women of
Childbearing
Age
19.76
1.95
Pregnant
Women
19.03
1.95
Margin of Exposure (MOE)
Women of
Childbearing
Age
10.93
111.0
Pregnant
Women
11.35
111.0
NOTES:
a For parameters influencing air concentrations, see Tables 2-1, 2-2 and 2-3
MOEs that are < 30, denoting unacceptable risks are highlighted in bold.
NA= Not applicable
PPE = Personal protective equipment
APF = Assigned Protection Factor; and APF of 10 means that the respirator will reduce the personal breathing concentration by 10-fold (0.1)
AUC = Area Under Curve
Table 4-4 Acute Risk Estimates for Occupational Exposures to NMP-Based Paint Strippers - Graffiti Removal
Exposure Scenario
4) Graffiti removal (assumed mostly
outdoor but may include semi-confined
spaces)
- low end of parameter range
~ 0.25 weight fraction, 445 cm2 skin
surface area, 1 hr/day contact
4) Nearby worker non-user
PPE Used
No respirator, No gloves
With respirator, No gloves
No respirator, With gloves
With respirator and gloves
NA
Air Concentration
mg/m3
0.24
Exposure, Internal Dose
Blood Cmax, mg/L
Women of
Childbearing
Age
1.73
1.73
0.17
0.17
0.003
Pregnant
Women
1.53
1.53
0.15
0.15
0.002
Margin of Exposure (MOE)
Women of
Childbearing
Age
124.9
125.1
1238.8
1251.0
86051.5
Pregnant
Women
141.3
141.5
1399.3
1413.6
94837.9
Page 85 of 281
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Exposure Scenario
5) Graffiti removal (assumed mostly
outdoor but may include semi-confined
spaces)
characterization
— 0 625 weight fraction 668 cm2 skin
surface area, 4 hr/day contact
5) Nearby worker non-user
6) Graffiti removal (assumed mostly
outdoor but may include semi-confined
spaces)
- high end of parameter range
-- 1.0 weight fraction, 890 cm2 skin
surface area, two 4 hr/day contacts
6) Nearby worker non-user
PPE Used
No respirator, No gloves
With respirator, No gloves
No respirator, With gloves
With respirator and gloves
NA
No respirator, No gloves
With respirator, No gloves
No respirator, With gloves
With respirator and gloves
NA
Air Concentration
mg/m3
2.02
4.52
Exposure, Internal Dose
Blood Cmax, mg/L
Women of
Childbearing
Age
15.32
15.28
1.47
1.43
0.05
316.59
316.37
19.17
19.05
0.14
Pregnant
Women
14.44
14.40
1.40
1.37
0.05
291.22
291.01
18.47
18.34
0.14
Margin of Exposure (MOE)
Women of
Childbearing
Age
14.1
14.1
147.2
150.6
4574.2
0.7
0.68
11.3
11.34
1579.2
Pregnant
Women
15.0
15.0
154.4
158.1
4678.4
0.7
0.74
11.7
11.78
1579.0
NOTES:
MOEs that are < 30, denoting unacceptable risks are highlighted in bold.
NA= Not applicable
PPE = Personal protective equipment
APF = Assigned Protection Factor; and APF of 10 means that the respirator will reduce the personal breathing concentration by 10-fold (0.1)
AUC = Area Under Curve
Page 86 of 281
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4.1.2 Risk Estimates for Acute Consumer Exposure to NMP
Increased fetal resorptions was used as the toxicological endpoint to evaluate the consumer
acute exposure scenario. Given that fetal effects are considered most sensitive, the focus for
the risk calculations was on women of childbearing age and pregnant women. Conservative
assumptions were used to evaluate a variety of possible exposure scenarios based on combined
inhalation, dermal and vapor-through-skin exposures. The assumptions are then varied, with
and without the use of gloves, to obtain a range of plausible exposure scenarios.
Table 4-5 summarizes the MOE estimates calculated for acute exposure. The Margin of
Exposure was derived based on the ratio of the PODaCute of 216 mg/L (the BMDL for 1%
increased fetal resorptions, based on Saillenfait et al. 2002 and Saillenfait et al. 2003, as
described in Table 3-4) to the estimated peak exposure (Cmax, mg/L) for the sensitive lifestages.
As described in section 4.1, the presence of risk was defined as MOEs below the benchmark
MOE of 30. Calculations of risks for the full set of scenarios are provided in the supplemental
Excel spreadsheet, Consumer PBPK Results and Risk Estimates.xlsx, located in the public docket
(Docket: EPA-HQ-OPPT-2012-0725).
The results of the risk calculations for all exposure scenarios indicates that one scenario in
particular, brush application on a bathtub, in a bathroom, upper-end parameters, with higher
air saturation and in the absence of gloves, yields an MOE of 29.5 for woman of childbearing
age. EPA/OPPT considers this value to be equivalent to the benchmark MOE of 30, indicating
low risk. EPA/OPPT designed this scenario to represent an upper bound exposure scenario
based on assumptions from a reported fatality using a DCM-based paint stripper and is thus
considered an upper bounding estimate of exposure for surface area treated (and hence mass
of product used), volume of room of use and ventilation rate for both the room of use and the
entire house. The shape of the bathtub contributed to the production of a "source cloud",
consisting of higher NMP concentrations above the tub. These factors combined to result in the
highest airborne concentrations of NMP in the room of use. The only difference between the
two scenarios, 4 and 5, is the choice of saturation concentration for the NMP, with the higher
saturation concentration leading to larger exposures. The brush on product was used in the
bathroom scenario because it was the only product that had measured emission rates (there
are no measured emission data for NMP spray products), it is also possible that dermal
exposure would be more likely from a brush on product.
In general, the proper use of gloves significantly reduces exposures across scenarios, based on
higher MOEs. It should be noted that not all gloves provide effective protection against NMP
exposure; EPA/OPPT has not independently evaluated glove efficacy, but California
recommends the use of gloves made of butyl rubber or laminated polyethylene/EVOH (See
California Health Hazard Advisory, available at:
http://www.cdph.ca.gov/programs/hesis/Documents/nmp.pdf, accessed 12/18/14.)
Page 87 of 281
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Table 4-5 Acute Risk Estimates for Consumer Exposures to NMP-Based Paint Strippers
Exposure Scenario
Scenario #1
Brush application in
workshop,
central parameter
values
Scenario #2
Brush application in
workshop,
upper-end values for
user
Scenario #3
Brush application in
workshop, upper-end
values for nearby
residents
Scenario #4
Brush application in
bathroom, upper-end
for user and nearby
residents, constrained
by Csat = 1,013 mg/m3a
Scenario #5
Brush application in
bathroom, upper-end
for user and nearby
residents, constrained
by Csat = 640 mg/m3a
Scenario #6a
Individual
User
without
gloves
User with
gloves
Nearby
resident
User
without
gloves
User with
gloves
Nearby
resident
User
without
gloves
User with
gloves
Nearby
resident
User
without
gloves
User with
gloves
Nearby
resident
User
without
gloves
User with
gloves
Nearby
resident
User
without
gloves
Peak Blood Exposure
Cmax, mg/L
Women of
Childbearing
Age
0.65
0.10
0.03
1.36
0.26
0.06
2.55
0.56
0.19
7.32
4.76
0.62
6.98
4.42
0.62
0.18
Pregnant
Women
0.56
0.08
0.03
1.17
0.24
0.06
2.15
0.48
0.19
6.28
4.12
0.61
5.99
3.84
0.61
0.17
Margin of Exposure (MOE)
Women of
Childbearing
Age
333
2244
7725
159
836
3862
85
385
1134
29.5b
45.4
350
30.9
48.9
350
1203.8
Pregnant
Women
388
2613
7855
184
912
3927
101
447
1141
34.4
52.4
352
36.1
56.3
352
1295.1
Page 88 of 281
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Exposure Scenario
Spray application in
workshop, upper-end
values for user
Scenario #6b
Spray application in
workshop, upper-end
values for user
Scenario #7a
Spray application in
workshop, upper-end
values for nearby
residents
Scenario #7b
Spray application in
workshop, upper-end
values for nearby
residents
Individual
User with
gloves
Nearby
resident
User
without
gloves
User with
gloves
Nearby
resident
User
without
gloves
User with
gloves
Nearby
resident
User
without
gloves
User with
gloves
Nearby
resident
Peak Blood Exposure
Cmax, mg/L
Women of
Childbearing
Age
0.17
0.04
1.55
1.47
0.35
0.23
0.24
0.12
1.45
1.38
0.88
Pregnant
Women
0.16
0.04
1.36
1.30
0.34
0.21
0.22
0.12
1.36
1.30
0.86
Margin of Exposure (MOE)
Women of
Childbearing
Age
1268.4
4882
139.8
147.1
619
944.6
897.6
1802
149.2
156.4
246
Pregnant
Women
1354.8
4965
158.5
166.0
630
1029.0
980.8
1832
159.4
166.5
251
NOTES:
MOEs that are < 30, denoting unacceptable risks are highlighted in bold.
a For scenarios 4 and 5, unrestrained exposure modeling predicts concentrations above the level of saturation,
hence the exposure concentration for these scenarios had to be capped at saturation. For other scenarios
predicted concentrations remained below saturation.
b EPA/OPPT considers 29.5 to be equivalent to 30.
Page 89 of 281
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4.1.1 Risk Estimates for Chronic Occupational Exposures to NMP
The assessment of risks to workers, based on chronic exposures, used decreased fetal body
weight as the critical endpoint for the derivation of the POD. As described in Table 2-1 and
Table 2-2, the selected exposure scenarios represent combined inhalation, dermal and vapor-
through-skin exposures with a range of conservative assumptions. The assumptions are then
varied, such as use of PPE (respirator and gloves), time spent in contact with NMP and
concentration of NMP in the product, to obtain a range of plausible scenarios.
Table 4-6 and Table 4-7 show the MOE estimates calculated for workers handling NMP-based
paint strippers on a repeated basis. Table 4-6 summarizes the results of the risk estimates for
miscellaneous stripping activities, while Table 4-7 summarizes the results of the risk estimates
for graffiti removal. The MOE was derived based on the ratio of the PODchronic of 415 mg-h/L
(the BMDL for 5% reduction in fetal body weight, based on Saillenfait et al. (2003), as described
in Table 3-5) to the estimated average exposures (AUC ) for the sensitive lifestages. As
described in section 4.1, the presence of risk was defined as MOEs below the benchmark MOE
of 30. Calculations of risks for the full set of industries and scenarios are provided in the
supplemental Excel spreadsheet, Occupational PBPK Results and Risk Estimates.xlsx, located in
the public docket (Docket: EPA-HQ-OPPT-2012-0725).
There were very small differences in the risk estimates for women of childbearing age and
pregnant women. Since risks were highly influenced by dermal exposure, the small difference in
risk estimates is likely due to the relatively small differences in exposed surface area between
women of childbearing age and pregnant women on which estimates were calculated. Risks
were identified in a number of exposure scenarios. For miscellaneous stripping scenarios (Table
4-6), unacceptable risks were identified for workers in contact with NMP for a total of 8 hrs/day
(two 4 hr segments), regardless of whether PPE (gloves or respirator) were used. For workers in
contact with NMP for 4 hrs/day, risks could be mitigated with the use of gloves. Further
mitigation occurs with use of a respirator, but use of a respirator alone is not sufficient to
mitigate the risk. Workers in contact with NMP for 1 hr/day should not experience excess risk.
There were no risks to nearby worker non-users.
A similar situation is observed for the graffiti removal scenarios (Table 4-7). Unacceptable risks
were identified for workers in contact with NMP for a total of 8 hrs/day (two 4 hr segments),
regardless of whether PPE (gloves or respirator) were used. For workers in contact with NMP
for 4 hrs/day, risks could be mitigated with the use of gloves. Unlike the miscellaneous paint
stripping scenarios, respirator use did not appear to provide any significant mitigation because
the air concentrations are rather low. Workers in contact with NMP for 1 hr/day should not
experience excess risk. There were no risks to nearby workers not directly engaged in using
NMP.
Page 90 of 281
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Table 4-6 Chronic Risk Estimates for Occupational Exposures to NMP-Based Paint Strippers - Miscellaneous Stripping Activities
Exposure Scenario
1) Miscellaneous stripping (assumed
mostly indoor)
- low end of parameter range
1 hr/day contact
1) Nearby worker non-user
2) Miscellaneous stripping (assumed
mostly indoor)
characterization
4 hr/day contact
2) Nearby worker non-user
3) Miscellaneous stripping (assumed
mostly indoor)
- high end of parameter range
two 4 hr/day contacts
PPE Used
No respirator, No gloves
With respirator, No gloves
No respirator, With gloves
With respirator and gloves
NA
No respirator, No gloves
With respirator, No gloves
No respirator, With gloves
With respirator and gloves
NA
No respirator, No gloves
With respirator, No gloves
No respirator, With gloves
Air
Concentration
mg/m3a
8
65
64
Exposure, Internal Dose
Blood AUC, mg-hr/L
Women of
Childbearing
Age
4.24
4.09
0.60
0.46
0.20
75.55
69.63
12.95
8.10
6.73
4085.28
4021.20
146.65
Pregnant
Women
4.23
4.08
0.61
0.46
0.21
75.09
69.08
13.07
8.10
6.87
3969.28
3905.60
145.84
Margin of Exposure (MOE)
Women of
Childbearing
Age
97.0
100.4
680.1
892.4
2008.6
5.4
5.9
31.7
50.7
61.1
0.1
0.1
2.8
Pregnant
Women
97.1
100.7
676.4
893.2
1968.6
5.5
5.9
31.5
50.8
59.9
0.1
0.1
2.8
Page 91 of 281
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Exposure Scenario
3) Nearby worker non-user
PPE Used
With respirator and gloves
NA
Air
Concentration
mg/m3a
Exposure, Internal Dose
Blood AUC, mg-hr/L
Women of
Childbearing
Age
133.88
13.35
Pregnant
Women
133.87
13.62
Margin of Exposure (MOE)
Women of
Childbearing
Age
3.1
30.8
Pregnant
Women
3.1
30.2
NOTES:
a For parameters influencing air concentrations, see Tables 2-1, 2-2 and 2-3
MOEs that are < 30, denoting unacceptable risks are highlighted in bold.
NA= Not applicable
PPE = Personal protective equipment
APF = Assigned Protection Factor; and APF of 10 means that the respirator will reduce the personal breathing concentration by 10-fold (0.1)
AUC = Area Under Curve
Table 4-7 Chronic Risk Estimates for Occupational Exposures to NMP-Based Paint Strippers - Graffiti Removal
Exposure Scenario
4) Graffiti removal (assumed mostly
outdoor but may include semi-confined
spaces)
- low end of parameter range
~ 0.25 weight fraction, 445 cm2 skin
surface area, 1 hr/day contact
4) Nearby worker non-user
PPE Used
No respirator, No gloves
With respirator, No gloves
No respirator, With gloves
With respirator and gloves
NA
Air Concentration
mg/m3
0.24
Exposure, Internal Dose
Blood AUC, mg-hr/L
Women of
Childbearing
Age
4.04
4.04
0.41
0.40
0.006
Pregnant
Women
4.03
4.02
0.40
0.40
0.006
Margin of Exposure (MOE)
Women of
Childbearing
Age
101.7
101.8
1013.6
1024.5
66048.7
Pregnant
Women
102.0
102.1
1015.1
1026.4
64746.5
Page 92 of 281
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Exposure Scenario
5) Graffiti removal (assumed mostly
outdoor but may include semi-confined
spaces)
characterization
— 0 625 weight fraction 668 cm2 skin
surface area, 4 hr/day contact
5) Nearby worker non-user
6) Graffiti removal (assumed mostly
outdoor but may include semi-confined
spaces)
- high end of parameter range
-- 1.0 weight fraction, 890 cm2 skin
surface area, two 4 hr/day contacts
6) Nearby worker non-user
PPE Used
No respirator, No gloves
With respirator, No gloves
No respirator, With gloves
With respirator and gloves
NA
No respirator, No gloves
With respirator, No gloves
No respirator, With gloves
With respirator and gloves
NA
Air Concentration
mg/m3
2.02
4.52
Exposure, Internal Dose
Blood AUC, mg-hr/L
Women of
Childbearing
Age
67.64
67.46
6.27
6.13
0.21
4003.88
3999.38
129.79
128.91
0.94
Pregnant
Women
67.11
66.92
6.26
6.11
0.21
3888.80
3884.33
128.82
127.93
0.96
Margin of Exposure (MOE)
Women of
Childbearing
Age
6.1
6.1
65.5
67.1
1981.3
0.1
0.1
3.2
3.2
438.4
Pregnant
Women
6.1
6.1
65.6
67.3
1941.8
0.1
0.1
3.2
3.2
429.7
NOTES:
MOEs that are < 30, denoting unacceptable risks are highlighted in bold.
NA= Not applicable
PPE = Personal protective equipment
APF = Assigned Protection Factor; and APF of 10 means that the respirator will reduce the personal breathing concentration by 10-fold (0.1)
AUC = Area Under Curve
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This risk assessment focused on the occupational and consumer uses of NMP-containing paint
strippers. The population of interest consisted of people using NMP-based paint strippers, and
those who may be nearby. Dermal and inhalation routes of exposure, including vapor-through-
skin, were considered in this risk assessment.
As discussed in section 4.1, because the fetal effects are the most sensitive, EPA/OPPT
calculated risks for pregnant women and women of childbearing age who may become
pregnant. It was assumed that exposures that do not result in unacceptable risks for these
particular lifestages would also be protective of other receptors, including children and adult
males against other adverse outcomes.
EPA/OPPT identified acute and chronic risks for a number of exposure scenarios. The variables
that were associated with elevated risks included longer duration of contact time (e.g., 4 or
more hours), the NMP content of the product (e.g., > 25%) and not using gloves.
EPA/OPPT identified low concern for acute exposures to products formulated with low
concentrations of NMP. For example, consumer use of 25% NMP-based paint for 30 minutes
does not result in significant risk, nor does worker use of 25% NMP-based paint stripper for one
hour. Users of NMP-based paint stripper formulated with 62.5% NMP or higher for 4 hours or
more may be at risk, particularly when gloves are not used. Risks to consumers who may use
NMP-based paint strippers on multiple projects for 4 hours or more, were not quantified. Based
on a qualitative analysis of the outcomes it is possible that exposures of 4 or more hours could
present risks comparable to those associated with acute worker exposure scenarios.
The use of appropriate gloves can reduce exposures, as demonstrated by higher MOEs achieved
when gloves were used. Not all glove types are effective in protecting against NMP exposure.
EPA/OPPT did not evaluate glove efficacy, however California recommends the use of gloves
made of butyl rubber or laminated polyethylene/EVOH10.
The risk assessment found low concern for non-users nearby to either the worker user or
consumer user scenarios. EPA/OPPT expects that this risk assessment will be protective of other
lifestages and subpopulations for the occupational and consumer scenarios evaluated because
it was based on the most sensitive endpoints.
10 See California Health Hazard Advisory, available at:
http://www.cdph.ca.gov/programs/hesis/Documents/nmp.pdf (accessed December 18, 2014)
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4.3 KEY SOURCES OF UNCERTAINTY AND DATA LIMITATIONS
The characterization of variability and uncertainty is fundamental to the risk assessment.
Variability refers to "the true heterogeneity or diversity in characteristics among members of a
population (i.e., inter-individual variability) or for one individual over time (infra-individual
variability)'''(EPA, 2001). This risk assessment was designed to reflect critical sources of
variability to the extent allowed by available methods and data and given the resources and
time available.
On the other hand, uncertainty is "the lack of knowledge about specific variables, parameters,
models, or other factors" (EPA, 2001) and can be described qualitatively or quantitatively.
Uncertainties in the risk assessment can raise or lower the confidence of the risk estimates. In
this assessment, the uncertainty analysis also included a discussion of data gaps/limitations.
Below is a discussion of the uncertainties and data gaps in the exposure, hazard/dose-response
and risk characterization.
4.3.1 Key Uncertainties in the Occupational Exposure Assessment
Uncertainties in the occupational exposure assessment arise from the following sources:
Dermal Exposure Parameters
The dermal exposure parameters (Table 2-1) used in this assessment have uncertainties
because no data were found for these parameters and all of their values were based on
assumptions. The assumed parameter values with the greater uncertainties are glove
effectiveness, durations of contact and skin surface areas for contact with liquids. The assumed
values for effectiveness, durations and surface areas may or may not be representative of
actual values. The assumed values for human body weight and NMP concentrations in strippers
have relatively lower uncertainties. The midpoints of the ranges serve as substitutes for 50th
percentiles of the actual distributions and high ends of ranges serve as substitutes for 95th
percentiles of the actual distributions. However, these substitutes are uncertain and are weak
substitutes for the ideal percentiles.
Inhalation Exposure Parameters
Limitations of the inhalation exposure data also introduce uncertainties into the exposure
summary (Table 2-2). The principal limitation of the exposure data is the uncertainty in the
representativeness of the data. EPA/OPPT identified a limited number of exposure studies that
provided data on the number of facilities, job sites or residences where NMP was used. These
studies primarily focused on single sites. This small sample 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
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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/OPPTfrom describing actual exposure
distributions. The midpoint of the range serves as a substitute for 50th percentile of the actual
distributions and high ends of ranges serve as substitutes for 95th percentiles of the actual
distributions. However, these substitutes are uncertain and are weak substitutes for the ideal
percentiles. Central tendency and high-end exposures may or may not lie within the range of
values estimated for this assessment.
Number of Exposed Workers
EPA/OPPT could not estimate the number of workers exposed to NMP-based stripper as there
are no data available. Literature data are available on the use of DCM-based paint strippers and
since NMP-based paint strippers are expected to be less common than DCM-based paint
strippers, the DCM data provides an upper-limit estimate of possible worker exposures. The
comparison of the estimated worker population exposed to DCM-based strippers and the
NIOSH National Occupational Exposure Study (NOES) data for NMP give only a rough estimate
of this population.
4.3.2 Key Uncertainties in the Consumer Exposure Assessment
EPA/OPPT based the consumer dermal exposure scenarios for this assessment on survey data
for hand sizes and activity patterns involved in consumer use of paint strippers. The resulting
assessments were intended to be upper end to bounding assessments of potential dermal
exposures.
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 central tendency exposures or upper end bounding exposures. Further
discussion of uncertainties as they relate specifically to the dermal and inhalation assessments
is provided in the subsections that follow.
Dermal Exposure
It was assumed that protective gloves were not worn as upper bound of exposures. This
assumption was considered relevant because consumers, unlike workers, may not take the
necessary precautions (i.e., wearing appropriate gloves) to avoid dermal exposures to irritating
compounds like NMP. It is known that consumer do not reliably utilize appropriate personal
protective approaches, whether exhaust fans to reduce exposure, only using certain products
outside or reading MSDS to look for product warnings (Abt, 1992).
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Another case of parameter uncertainty is the surface area of the skin exposed to the product.
No studies have been conducted on this value for paint stripping with NMP; thus, the assumed
surface area of 50 percent of both hands (central estimate) was based on professional
judgment. The EPA (1996) report assumed that the palms and fingers of both hands would be
exposed. This was not based on information specific to NMP product use and there is no
information on how long a consumer would allow the chemical to remain on the hands.
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 (EPA, 2011a).
Limitations of the Consumer Inhalation Exposure Analysis
Due to the absence of indoor air monitoring data from consumer use of NMP, the EPA used
modeling based on chamber emissions data to estimate indoor air concentrations resulting
from the use of paint strippers. This complex modeling approach of indoor air concentration
has a number of limitations. The primary limitation is that the model input for the emissions
profile was derived from an older chamber study, introducing uncertainty as to the relevance
for current consumer settings where NMP paint strippers may be used. In addition, EPA/OPPT
considers the assumptions used for the model exposure scenarios are believed to be
reasonable, but may not reflect actual usage patterns or use conditions in consumer settings.
Consequently, the limited data and variable results associated with different exposure
scenarios, when used to extrapolate to consumer acute inhalation risk characterization, have
associated uncertainty.
As noted in Appendix E (see Discussion and Conclusions at the end of section E-l), there also is
uncertainty in the NMP near real-time sampling results from the chamber tests that provided a
basis for estimating an emission profile as one of the MCCEM inputs. 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. This data was collected with two measurement techniques, infrared
spectroscopy which collected time series data and by gas chromatography using activated
charcoal which collected an integrated measure of total mass released over the experiment.
Unfortunately information in the study shows that the IR data was miscalibrated and the
assessment used the integrated data to post-calibrate the IR data. This assumes that
miscalibration resulted in only a scaling error and that the relative magnitude of the
measurement was still correct.
As discussed in Appendix E another uncertainty is the lack of chamber data for the spray
applied product. The emissions profile for the brush applied product was used as a baseline
with the assumption that spray application would result in a larger fraction of the applied
product aerosolizing during its use. During the use of a spray product a large number of
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droplets are propelled toward the use site, as these droplets move through the air, a large
amount of surface area is available for an initial burst of evaporation of the solvent to the room
air. To capture this effect the brush applied product emission constants were modified to result
in a larger initial burst of NMP into the room air, based on professional judgment. The spray
application has the same limitations as the brush application, as well as an additional limitation
- the NMP volatility estimates may not have accounted for all relevant factors governing NMP
emissions and, thus, may have underestimated the magnitude of the maximum emission rates
for a spray NMP product.
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 were based on scientifically defensible data cited
in the EFH. The confidence level is similarly high for the amount of product applied and
application rates, with data from surveys cited in the EFH as well as experiments conducted in
EPA (1994b). For the paint stripping sequence, the wait time per segment has a high level of
confidence because the time was based on what is shown on current product labels. The
application and scraping times have a slightly lower confidence level because they were based
on the EPA (1994b) study, which is considered to be of high quality but only included a limited
number of experiments with limited formulations.
The MCCEM inputs for the interzonal airflow rates assumed in the model represent another
area of uncertainty. The chosen rates were based on 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 were 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.
Regarding the brush application on a bathtub in a bathroom 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.
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4.3.3 Key Uncertainties in the Hazard and Dose-Response Assessments
Varying degrees of uncertainty are associated with the evaluation of adverse health effects in
potentially exposed consumer populations to NMP-based paint strippers. Some of the
identified sources of uncertainty in the toxicity assessment follow.
Uncertainty Regarding Neurotoxicity
A small number of studies noted effects related to neurotoxicity; additional studies would be
needed to clarify concern for this endpoint. Both Mass et al. (1994) and Lee et al. (1987)
identified effects that could be linked to neurotoxicity. Mass investigated the effects of NMP on
postnatal development and behavior in rats and found that performance was impaired in
certain difficult tasks (i.e., reversal procedure in Morris water maze and operant delayed spatial
alternation). Since only one dose was used, a NOAEL could not be established (Mass et al.,
1994). Lee exposed rats to 100 and 360 mg/m3 NMP for six hrs/day from GD 6 through 15. The
dams initially exhibited sporadic lethargy and irregular respiration, which the study authors
considered reversible. A review of intentional human studies (0) did not yield evidence of
reportable neurotoxicity, such as headaches or indicators of irritation. It is possible that the
concentrations used in the intentional human studies were not sufficiently high to initiate
irritation or other neurotoxic effects.
Extrapolation ofPODs Based on Developmental Toxicity to Chronic Exposures
The chronic POD was based on decreased fetal body weight in a developmental toxicity study
that exposed rats for 15 days (CDs 5-20), with the assumption that fetal effects are the most
sensitive. During pregnancy, working women may be exposed to NMP on a regular basis,
continuing over a period of human pregnancy (fetal development) comparable to that of the rat
developmental study. To distinguish them from single-day exposures that are more likely for
someone using NMP at home (consumers), the cases for work-place NMP use occurring every
work-day for weeks or months of time are herein considered "chronic" and the associated risks
predicted from the rat developmental studies.
Selection of Developmental Toxicity for the Evaluation of Acute Exposure
Increased fetal resorptions was selected as an endpoint to evaluate risks associated with acute
exposures to NMP. Although the developmental toxicity studies included repeated exposures,
EPA/OPPT considered evidence that a single exposure to a toxic substance can result in adverse
developmental effects, described by Van Raaij et al. (2003), as relevant to NMP.
Although there is clear evidence of biological effects in both the fetus and neonate, there are
uncertainties in extrapolating doses for these lifestages. It is not known if NMP or its
metabolites are transferred to the pups via lactation. It is possible that the doses reaching the
fetus and the neonate are similar and that these lifestages are equally sensitive. But it is also
possible that one lifestage is more sensitive than the other or that doses are different.
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Additional data would be needed to refine dose estimates for the fetus and pups and to
determine if there are specific windows of sensitivity.
Protection of Different Lifestages and Subpopulations
EPA also is interested in the impact of NMP on other lifestages and subpopulations.
Consideration of other lifestages, such as male and non-pregnant female workers in the
occupational environment, children in the home environment would require using an
alternative POD based on systemic toxicity, instead of using the POD based on developmental
toxicity. Other endpoints associated with systemic toxicity generally had higher human
equivalent doses than those associated with developmental toxicity. Therefore EPA assumed
that margins of exposure for pregnant women would also be protective of other lifestages.
While it is anticipated that there may be differential NMP metabolism based on lifestage;
currently there are no data available so the impact of this cannot be quantified. Similarly, while
it is known that there may be genetic differences that influence CYP2E1 metabolic capacity,
there may also be other metabolizing enzymes that are functional. There is insufficient data to
quantify these differences for risk assessment purposes.
Dermal Absorption Rate of Liquid NMP
There is uncertainty in the rate of dermal absorption of liquid NMP. NMP diluted in water has
reduced dermal absorption (Keener et al., 2007; Payan, 2003) while NMP diluted in other
solvents, such as d-limonene, can increase the absorption of NMP (HLS, 1998) and prolonged
exposures to neat (i.e., pure) NMP increases the permeability of the skin (RIVM, 2013). The
PBPK model simulates dermal absorption of liquid NMP as a first order process with the rate
constant of permeability coefficient (Kp) and the value of Kp was optimized to human data
separately for neat NMP and for NMP diluted in water (Akesson et al., 2004). For exposure
scenarios with neat NMP the value for Kp was fit to neat NMP was used. For exposure scenarios
with diluted NMP the NMP was assumed diluted in water and Kp fit to diluted NMP was used.
The effects of prolonged exposures to NMP on permeability were not accounted for in the
model because there are not sufficient data to quantify this effect. It is possible that chronic
exposures to NMP could be more quickly absorbed and increase the risk.
Dermal Uptake Duration Inhalation Exposures
The use of a PBPK model made it possible to assess the uptake of vapor through the skin for
both the acute or chronic exposure scenarios. The key developmental toxicity study based on
the inhalation route, Saillenfait et al. (2003) used whole-body exposures, which would allow the
rats to also absorb NMP vapors through their skin. Hence, actual internal doses may have been
higher than those predicted by the PBPK model, which was calibrated using nose-only
inhalation data. However this uncertainty is health-protective in that higher internal doses in
the rat bioassay would lead to higher PODs and hence higher benchmark MOEs.
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On the other hand, there is uncertainty as to the extent of exposed skin and hence dermal
uptake among various human study populations and scenarios. It is possible that NMP readily
penetrates normal clothing, hence that vapor uptake through the skin occurs over most of the
body. The modeling assumes that the net uptake by vapor-through-skin penetration in worker
and consumer users is the same as in the Bader and van Thriel (2006) study used to calibrate
the human model. Specifically it was assumed that the extent to which clothing other than
protective gloves or face-masks might reduce vapor uptake did not differ between the Bader
and van Thriel (2006) subjects and the workers and consumers for whom risks were assessed. It
was assumed that 25% of the total skin surface, corresponding to face, neck, arms and hands,
was available for uptake and the effective uptake (penetration) constant (PV) for vapor-through
skin was then fitted to the data of Bader and van Thriel (2006). Roughly, net uptake is given by
the product of the exposed surface area (SA) and PV: uptake ~ SA x PV. Therefore, if the actual
SA was twice as much as assumed, then the fitted PV would have come out to one half of the
value obtained here such that SA x PV, hence predicted net uptake, remained the same.
To the extent that workers' and users' clothing occludes more of the skin surface than the
subjects of Bader and van Thriel (2006), their absorption and risk would be reduced, but the
contribution of this route is fairly small, so the error is not expected to be large. However the
use of protective gloves or face-mask and liquid-dermal contact, were assumed to completely
block vapor uptake by the skin areas they occlude. While this correction only had a small impact
on the predictions, they were easy to implement and the skin area affected was known.
It is possible that a worker or consumer user might wear less clothing; e.g., shorts and a tank-
top vs. long pants and a short-sleeved shirt. But given the small contribution of this route and
the fact that some clothing penetration probably occurred in the PK study (Bader and van
Thriel, 2006), the increased risk from such a difference should be negligible.
4.3.4 Key Uncertainties in the Risk Assessment
Extrapolation of Data Due to Intraspecies Variability
Heterogeneity among humans is an uncertainty associated with extrapolating the derived PODs
to a diverse human population. One component of human variability is toxicokinetic such as
variations in CYP2E1 activity in humans (Ligocka et al., 2003) which is partly involved in the
metabolism of NMP in humans. EPA evaluated the impact of CYP2E1 and physiological
parameters across lifestages for a related chemical, DCM and found the ratio between the 1st
percentile and the mean was approximately 2 for the RfD and 3 for the RfC (EPA, 2011b). Given
the significant differences between DCM and NMP (e.g. the use of different dose metrics
because DCM toxicity is mediated by its metabolite while NMP developmental toxicity is due to
NMP) this result is not directly applicable, however it suggests that the default UF for intra-
human toxicokinetic variability of 3 may be protective across the human population. Therefore
to account for the variation in toxicokinetic variability within the human population the default
factor of 3 was used.
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EPA did not have the chemical specific data/information on susceptible human populations or
on the distribution of susceptibility in the general population to decrease or increase the
default intraspecies UFn for toxicodynamic variability of 3. As such, EPA used an intraspecies
of 10 for the risk assessment.
Extrapolation of Data from Animals to Humans
In the derivation of the benchmark MOE, EPA/OPPT applied an uncertainty factor to account
for the uncertainties in extrapolating from rodents to humans. In the absence of data, the
default UFA of 10 is adopted which breaks down to a factor of 3 for toxicokinetic variability and
a factor of 3 for toxicodynamic variability. In this assessment the PBPK model accounted for the
interspecies extrapolation using rodent toxicokinetic data to estimate internal doses for a
particular dose metric, thus reducing the interspecies toxicokinetic uncertainty to 1. Since the
PBPK model did not address interspecies toxicodynamic differences, the total UFA of 3 was
retained (EPA, 2011b)
Time Scaling for Acute and Chronic PODs
The risk associated with NMP exposures was calculated using internal doses from PODs
relevant acute or chronic exposures based on studies in rats compared with internal doses from
human exposure scenarios. The chronic PODs were the AUC calculated for exposures of
6 hrs/day (Saillenfait et al., 2003). The occupational exposure scenarios calculated internal
doses for exposures of varying duration from 1 to 8 hrs/day. Comparing the chronic PODs to
occupational exposure scenarios implicitly assumes that the effects are related to
concentration x time, independent of the exposure regimen. The differences in exposure
durations between the chronic POD and exposure scenarios adds uncertainty to the estimation
of risk.
For acute occupational and consumer exposures the Cmax was calculated over the single day in
which the use occurs; the risk is then estimated by comparing the Cmax to the POD associated
with increased fetal resorptions evaluated from the combined data of Saillenfait et al. (2002;
2003). However, the validity of these time extrapolation assumptions is unknown.
Repeated Use by Consumers
The consumer use scenario considered a single paint stripping project period on a single day
with a duration of less than four hrs. It is possible that a subset of consumers may be more
frequent users of paint strippers (e.g., hobbyists). Since NMP is rapidly metabolized and
excreted, it is considered unlikely that more frequent use (e.g., a repeated project lasting less
than four hrs each weekend) will result in risks, given that the single-use scenarios had an
adequate MOE, particularly if exposures are limited to less than four hrs per day. In fact, given
the half-life (ti/2) is approximately 2 1/z hrs, exposures are effectively independent events unless
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multiple projects are undertaken over a very short time. However there is a lack of information
regarding frequent use patterns to inform a quantitative assessment.
4.4 RISK ASSESSMEN^ CONCLUSIONS
NMP is used by workers and consumers as a paint stripper. Exposures may occur by the dermal
and inhalation routes. For all scenarios, EPA/OPPT based the exposure estimates on combined
dermal, inhalation and vapor-through-skin absorption. Exposure values were converted to
internal doses using PBPK modeling.
EPA/OPPT selected the developmental toxicity endpoints of decreased fetal body weight and
increased fetal resorptions/fetal mortality for quantifying dose-response and calculating the
PODs, because they were consistent, relevant and sensitive across studies. EPA/OPPT has high
confidence in these endpoints, as they were identified in multiple studies, with different
exposure routes.
EPA/OPPT calculated MOEs by dividing the POD by internal dose exposure estimates. The MOEs
were compared to a benchmark MOE of 30. The benchmark MOE value accounted for intra-
(10X for humans) and interspecies (3X for rat to human TD) uncertainty. Hence, EPA/OPPT
interpreted exposures with MOEs below 30 to present potential risks.
Acute exposure was defined as exposure over the course of a single day. EPA/OPPT used two
different approaches to evaluate acute exposures. The first approach incorporated assumptions
based on occupational exposures of 1, 4, or 8 hours duration, whereas the second approach
incorporated assumptions considering consumer use on a single project lasting less than
4 hours.
Chronic exposures were defined as exposures comprising 10% or more of a lifetime (EPA,
2011a). Chronic exposures are mostly, but not exclusively, associated with occupational uses.
Repeated exposures over the course of a work week, e.g., 5 consecutive days, are anticipated
during chronic exposures. Since the most sensitive endpoints were adverse developmental
effects, EPA/OPPT recognized that these outcomes can arise from exposure during critical
windows of development during pregnancy, that pregnancy can occur any time during a
woman's reproductive years and the exposure can result in persistent chronic adverse effects.
Therefore, the derivation of the POD was based on developmental toxicity associated with
repeated exposures. This is expected to be protective of pregnant women and women who may
become pregnant.
EPA/OPPT has moderate confidence in the exposure assessments, which aggregated inhalation,
dermal and vapor-through-skin exposure routes. It was not possible to quantify variability
among humans.
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The actual number of people exposed to NMP in paint strippers is not known. There are no data
for the number of people using NMP-based paint stripper that would allow for a reliable
estimate of the size of the affected population. However, it is expected that NMP-based paint
strippers are less common than DCM-based strippers, so the number of potentially exposed
people should be less than the number of people exposed to DCM-based strippers. The number
of workers using DCM-based strippers was estimated to be 230,000 (EPA, 2014b); the number
of consumers using DCM-based strippers is unknown.
Outcome of Risk Assessment
The assessment identified risks from acute exposures of:
• Four hours per day, when gloves were not used.
• Greater than 4 hours per day, and risks were not mitigated by personal protective
equipment such as respirators or gloves.
The assessment identified risks from chronic (repeated) exposures of:
• Four hours per day, when gloves were not used.
• Greater than 4 hours per day, and risks were not mitigated by personal protective
equipment such as respirators or gloves.
Based on the use scenarios evaluated, there are no expected risks to people not directly
engaged in using NMP, regardless of duration of exposure
Other hazards, in particular reproductive and other systemic effects, could present risks at
higher exposures levels, but exposures that are protective of pregnant women and women who
may become pregnant are expected to also be protective of other lifestages and
subpopulations.
The use of gloves was determined to be effective in reducing modeled estimates of exposure,
as demonstrated by the higher MOEs. For chronic exposure, gloves may not provide sufficient
protection in all scenarios. More importantly, not all glove types are effective in protecting
against NMP exposure. EPA/OPPT did not evaluate glove efficacy, however California
recommends the use of gloves made of butyl rubber or laminated polyethylene/EVOH11.
Risk Conclusions
Although EPA/OPPT did not quantify risks to consumers who may use NMP-based paint
strippers on multiple projects with exposure duration equal to or greater than 4 hours, based
on analysis of other acute exposure scenarios in this risk assessment it is possible that
consumer exposures greater than 4 hours could present risks. An EU report states that there is
"probably...no fundamental difference between the application of paint removers by
11 See California Health Hazard Advisory, available at:
http://www.cdph.ca.gov/programs/hesis/Documents/nmp.pdf (accessed December 18, 2014)
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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). EPA/OPPT used different
methods to quantify occupational and consumer risks in this assessment, so a direct
quantitative comparison is not feasible. Table 4-8 presents a qualitative comparison of a subset
of different exposure scenarios evaluated in this assessment, illustrating general trends.
Duration of use and product concentration are both important drivers of risk. Short term (e.g.,
1-2 hours) exposures to products with low concentrations of NMP (e.g., 25% or less) result in no
risks. However, the use of higher concentration products that can be readily purchased by both
consumers and workers may result in risks.
Table 4-8 Spectrum of Exposure and Risks Based on Scenarios Evaluated in This Risk Assessment
Based on Women of Childbearing Age, With no PPE in Use.
Exposure Duration
Product Concentration
Use Scenario #
User Population
Acute
Exposure
Risks MOE
to:
User
Nearby
Non-user
30 Minutes
25%
Consumer 1
Consumer
333
7752
IHour
25%
Worker 1
Worker
119.5
2619.9
2 Hours
50%
Consumer 4
Consumer
29.5
350
4 Hours
62.5%
Worker 2
Worker
2.7
141.4
8 Hours
100%
Worker 3
Worker
0.7
111.0
Based on this qualitative analysis, it appears that consumers could engage in a pattern of use
that is comparable to worker exposures that present risk. Therefore, EPA/OPPT considers there
to be risks to both workers and consumers associated with acute exposures to NMP-based
paint strippers of four hours or more.
The scenarios examined included both spray on and brush on application methods, with and
without glove use. The use of gloves was determined to be effective in reducing modeled
estimates of exposure, as demonstrated by the higher MOEs. Not all glove types are effective in
protecting against NMP exposure. EPA/OPPT did not evaluate glove efficacy, however California
recommends the use of gloves made of butyl rubber or laminated polyethylene/EVOH12.
For both occupational and consumer exposure scenarios, EPA/OPPT focused this risk
assessment on developmental toxicity endpoints. As discussed in section 3.1.2, there are a
number of hazard concerns other than developmental toxicity associated with NMP exposures;
in particular, testicular toxicity stood out, with a number of studies, but not all, indicating an
association with NMP exposure. The evidence indicates that these effects were associated with
higher doses than those associated with decreased fetal body weight. EPA/OPPT assumed that
exposures below those that present risks to workers and consumer would also be protective
against other hazard endpoints for all subpopulations and lifestages.
12 See California Health Hazard Advisory, available at:
http://www.cdph.ca.gov/programs/hesis/Documents/nmp.pdf (accessed 12/18/14)
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Page 119 of 281
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APPENDICES
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Appendix A ENVIRONMENTAL EFFECTS SUMMARY
EPA/OPPT conducted a literature search to identify ecotoxicity data for NMP. In addition to
NMP synonyms, the search terms included freshwater and saltwater fish, aquatic invertebrates
and aquatic plants; pelagic and benthic organisms; acute and chronic sediment toxicity in
freshwater and saltwater and terrestrial toxicity to soil organisms, birds and mammals. For each
study identified, EPA/OPPT evaluated the test species, test conditions, toxicity endpoints,
statistical significance and strengths/limitations and study quality.
NMP has been tested for acute and chronic aquatic toxicity and toxicity to birds. EPA/OPPT
found no ecotoxicity studies for sediment or soil dwelling organisms. For aquatic toxicity studies
that met EPA's study quality criteria, a hazard characterization (i.e., high, medium or low
toxicity) was assigned based on EPA's methodology for existing chemical classification (EPA,
2009).
EPA/OPPT summarized the available NMP ecotoxicity data that met the acceptability criteria for
ecotoxicity studies (EPA, 1999a) below and in Table_Apx A-l, Table_Apx A-2 and Table_Apx A-3.
A-l Acute Toxicity to Aquatic Organisms
Table_Apx A-l summarizes the available toxicity studies of NMP to aquatic organisms.
Acute Toxicity to Fish
Six species of fish were tested, five were freshwater and one was saltwater. All species, test
conditions and protocols were acceptable for evaluating the acute toxicity of NMP to fish. The
most sensitive species for freshwater fish is the Bluegill sunfish (96-hr LC50 of 832 mg/L) (EPA,
2013b). Overall, the acute toxicity of NMP to fish is low based on EPA's aquatic hazard
characterization criteria (EPA, 2009).
Acute Toxicity to Aquatic Invertebrates
EPA/OPPT identified three acute toxicity studies with aquatic invertebrates (Table_Apx A-l);
two used the water flea and one used grass shrimp. All exposures were conducted at nominal
concentrations under static conditions for 48-hrs. The 48-hr ECso for the water fleas ranged
from 1,230 - 4,897 mg/L and the reported 48-hr EC5o for the grass shrimp was 1,107 mg/L. (GAF
Corp., 1979; Lan et al., 2004; as cited in OECD, 2007; and Verschuren, 2009). The acute toxicity
of NMP to aquatic invertebrates is low based on EPA's aquatic hazard characterization criteria
(EPA, 2009).
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Toxicity to Aquatic Plants
Only one study was identified testing the toxicity of NMP to aquatic plants (Table_Apx A-l).
Green algae (Scenedesmus subspicatus) were exposed to nominal concentrations of NMP under
static conditions for 96 hrs. A 72-hr EC5o of >500 mg/L was reported (BASF AG, 1988; as cited in
Verschuren, 2009). The toxicity of NMP to aquatic plants is low based on EPA's aquatic hazard
characterization criteria (EPA, 2009).
Table_Apx A-l Aquatic Toxicity Data for NMP - Acute Toxicity
rest Species
Fresh/
Salt
Water
Duration
End-
point
Cone.
(mg/L)
Test
Analysis
Effect
References
Fish
Fathead minnow
(Pimphales promelas)
Bluegill sunfish (Lepomis
macrochirus)
Orfe
(Leuciscus ictus)
Guppies
(Poecilia reticulata)
Rainbow trout
(Oncorhynchus mykiss)
Fresh
Fresh
Fresh
Fresh
Fresh
96-hr
96-hr
96-hr
96-hr
96-hr
LCso
LCso
LCso
LCso
LCso
1,072
832
4,000
2,673
>500
Measured
Nominal
Nominal
Nominal
Nominal
Mortality
Mortality
Mortality
Mortality
Mortality
SRC (1979);
Verschuren (2009)
Dawsonetal. (1977)
BASF (1986)
Verschuren (2009)
OECD, (2007a);
Verschuren (2009);
Weisbrod and Seyring
(1980)
BASF AAG (1983 as
cited in OECD 2007a);
SRC (1979)
Aquatic Invertebrates
Water flea
(Daphnia magna)
Water flea
(Daphnia magna)
Grass shrimp
(Palaemonetes vulgaris)
Fresh
Fresh
Fresh
48-hr
48-hr
48-hr
ECso
ECso
ECso
4,897
1,230
>299
Nominal
Nominal
Nominal
Immobiliza
tion
Immobiliza
tion
Mortality
GAF Corp (1979 as
cited in OECD, 2007a);
Verschuren (2009)
Lan et al., (2004)
GAF Corp (1979 as
cited in OECD, 2007a);
Verschuren (2009)
Aquatic Plants
Green algae
(Scenedesmus
subspicatus)
Fresh
72-hr
ECso
>500
Nominal
Not
reported
BASF AG(1988a as
cited in Verschuren,
2009)
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A-2 Chronic Toxicity to Aquatic Organisms
Chronic Toxicity to Aquatic Invertebrates
EPA/OPPT identified only one study reporting the chronic toxicity of NMP to aquatic organisms
was identified (Table_Apx A-2). Water fleas (D. magna) were exposed to unspecified
concentrations of NMP for 21 days. A 21-day NOEC of 12.5 mg/L was reported (BASF AG, 2001;
as cited in OECD, 2007). The chronic toxicity of NMP to aquatic invertebrates is low based on
EPA's aquatic hazard characterization criteria (EPA, 2009).
Table_Apx A-2 Aquatic Toxicity Data for NMP - Chronic Toxicity
Test Species
Fresh/
Salt
Water
Duration
End-
point
Cone.
(mg/L)
Test
Analysis
Effect
References
Aquatic Invertebrates
Water flea
(Daphnia magna)
Fresh
21-day
NOEC
12.5
Nominal
Biomass/
Growth rate
BASF AG (2001
as cited in
OECD, 2007a)
A-3 Toxicity to Sediment and Soil Organisms
There were no available acute or chronic toxicity studies that characterize the hazard of NMP to
sediment- or soil-dwelling organisms.
A-4 Toxicity to Wildlife
Toxicity to Birds
There were two studies identified that reported the toxicity of NMP in birds as summarized in
Table_Apx A-3. In one study, Bobwhite quail (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 LDso values ranged between 2,500 and 5,000 mg/kg body weight
(Hazelton Laboratories America, 1980; as cited in OECD, 2007). In another study, 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 8 days. No mortalities were observed and an LC5o
of >5,000 ppm was derived from this study (Hazelton Laboratories America, 1979; as cited in
OECD, 2007). Both of these studies show that the hazard of NMP to birds is low based on EPA's
aquatic hazard characterization criteria (EPA, 2009).
Page 123 of 281
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Table_Apx A-3 Aquatic Toxicity Data for NMP - Wildlife
Test Species
Duration
End-
point
Cone.
(mg/kg/bw)
Test
Analysis
Effect
References
Avian
Bobwhite quail
(Colinus virginianus)
Mallard duck
(Anas platyrhynchus)
14-day
8-Day
LDso
LCso
2,500 - 5,000
>5,000
Nominal
Mortality
Mortality
Hazelton Laboratories
America (1980 as cited in
OECD, 2007a)
Hazelton Laboratories
America (1980 as cited in
OECD, 2007a)
A-5 Summary of Environmental Hazard Assessment
Ecotoxicity studies for NMP have been conducted in fish, aquatic invertebrates, aquatic plants
and birds. There were no acceptable studies identified for sediment or soil dwelling organisms.
Based on available data, EPA/OPPT concluded that NMP has low acute and chronic toxicity to
aquatic organisms and birds.
Page 124 of 281
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Appendix B CHEMICAL REPORTING DATA
Industry reported to the EPA under the TSCA Chemical Data Reporting (CDR) program that NMP
production volume was 184.7 million pounds in the 2012. Six companies reported domestic
manufacturing DCM: BASF Corporation; NOVA Molecular Technologies, Inc.; Ashland, Inc.; OM
Group, Inc.; Toray Holding (USA), Inc.; and Lyondell Chemical Company (EPA, 2013a). There
were also some companies that claimed confidential business information (CBI) and that
information cannot be made public. Data in Table_Apx B-l, Table_Apx B-2 and Table_Apx B-3
were extracted from the 2012 CDR records (EPA, 2013).
Table_Apx B-l National Chemical Information for NMP from 2012 CDR
Production Volume (aggregate)
Maximum Concentration (at manufacture or import site)
Physical form(s)
Number of reasonably likely to be exposed industrial manufacturing, processing and use
workers (aggregated)
Was industrial processing or use information reported?
Was commercial or consumer use information reported?
184.7 million
pounds
>90%
Liquid
>1,000
Yes
Yes
Table_Apx B-2 Summary of Industrial NMP Uses from 2012 CDR
Industrial Sector [Based on
North American Industry
Classification System (NAICS)]
Adhesives and sealant
chemicals
Not Known or Reasonably
Ascertainable
Solvents (for cleaning or
degreasing)
Solvents (for cleaning or
degreasing)
Solvents (which become part
of product formulation or
mixture)
Plating agents and surface
treating agents
Processing aids, not otherwise
listed
Other (specify)
Industrial Function
Processing-incorporation into
formulation, mixture or reaction
product
Not Known or Reasonably Ascertainable
Use-non-incorporative activities
Processing-incorporation into
formulation, mixture or reaction
product
Processing-incorporation into
formulation, mixture or reaction
product
Processing-incorporation into
formulation, mixture or reaction
product
Use-non-incorporative activities
Processing-incorporation into article
Type of Processing
Adhesives and sealant chemicals
Not Known or Reasonably
Ascertainable
Solvents (for cleaning or
degreasing)
Solvents (for cleaning or
degreasing)
Solvents (which become part of
product formulation or mixture)
Plating agents and surface treating
agents
Processing aids, not otherwise
listed
Other (specify)
Page 125 of 281
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Industrial Sector [Based on
North American Industry
Classification System (NAICS)]
Solvents (for cleaning or
degreasing)
Solvents (which become part
of product formulation or
mixture)
Processing aids, specific to
petroleum production
Processing aids, specific to
petroleum production
Paint additives and coating
additives not described by
other categories
Paint and Coating
Manufacturing
Processing aids, not otherwise
listed
Solvents (which become part
of product formulation or
mixture)
Processing aids, specific to
petroleum production
Intermediates
Other (specify)
Intermediates
Other (specify)
Other (specify)
Printing Ink Manufacturing
Paint additives and coating
additives not described by
other categories
Solvents (for cleaning or
degreasing)
Not Known or Reasonably
Ascertainable
Industrial Function
Use-non-incorporative activities
Processing-incorporation into article
Use-non-incorporative activities
Use-non-incorporative activities
Processing-incorporation into
formulation, mixture or reaction
product
Solvents (which become part of product
formulation or mixture)
Use-non-incorporative activities
Processing-incorporation into
formulation, mixture or reaction
product
Use-non-incorporative activities
Processing as a reactant
Processing as a reactant
Processing as a reactant
Processing-incorporation into
formulation, mixture or reaction
product
Processing-incorporation into article
Paint additives and coating additives not
described by other categories
Processing-incorporation into article
Use-non-incorporative activities
Not Known or Reasonably Ascertainable
Type of Processing
Solvents (for cleaning or
degreasing)
Solvents (which become part of
product formulation or mixture)
Processing aids, specific to
petroleum production
Processing aids, specific to
petroleum production
Paint additives and coating
additives not described by other
categories
Processing-incorporation into
formulation, mixture or reaction
product
Processing aids, not otherwise
listed
Solvents (which become part of
product formulation or mixture)
Processing aids, specific to
petroleum production
Intermediates
Other (specify)
Intermediates
Other (specify)
Other (specify)
Processing-incorporation into
formulation, mixture or reaction
product
Paint additives and coating
additives not described by other
categories
Solvents (for cleaning or
degreasing)
Not Known or Reasonably
Ascertainable
Page 126 of 281
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Table_Apx B-3 NMP Commercial/Consumer Use Category Summary
Commercial/Consumer Product
Category
Electrical and Electronic Products
Batteries
Paints and Coatings
Metal Products not covered elsewhere
Adhesives and Sealants
Fabric, Textile and Leather Products not
covered elsewhere
Intended for Commercial
and/or Consumer Uses or Both
Commercial
Both
Both
Commercial
Commercial
Commercial
Intended for Use in Children's
Products in Related Product
Category
Not Known or Reasonably
Ascertainable
No
No
No
No
No
Other use applications also have been reported including: 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/OPPT
is specifically concerned about this use, because the potential for exposure is high; some of the
other uses of NMP involve closed processes or lower concentrations that generally reduce
exposures and are of less concern. 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.
B-l Consumer Uses
The 2012 CDR data indicate that NMP is used in the following commercial and consumer use
categories: "electrical and electronic products", "paints and coatings", "batteries", "metal
products not covered elsewhere", "adhesives and sealants" and "fabric, textile and leather
products not covered elsewhere" (EPA, 2013a). The National Institutes of Health (NIH)
Household Products Database currently lists 47 products containing NMP, in concentrations
ranging from 1-100 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).
Page 127 of 281
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Table_Apx B-4 presents the major consumer uses of NMP, which represent <30 percent of the
total domestic NMP market.
Table_Apx B-4 Consumer Uses of NMP
Auto products
Arts and crafts products
Home maintenance products
Pesticides
Cosmetics
Leather cleaner/conditioner3
Rubbing compound3
Paint protectant3
Cleaner for fuel injection/carburetor3
Stripper/paint remover3
Adhesive remover3
Paint, varnish, wood stain, etc.3
Wood sealant3
Paint stripper3
Graffiti remover3
Brush cleaner3
Floor finish3
Floor cleaner3
Fungicide3
Herbicide3
Insecticide3
Polish removerb
Mascarab
Notes:
aNIH (2012)
bEWG (2012)
B-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 facilities
like antique shops; these facilities purchase small quantities of stripper from hardware or paint
supply stores. Consumers also purchase stripper from paint supply and hardware stores (Cal
EPA, 2006).
Page 128 of 281
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Appendix C STATE NMP REGULATIONS
Table_Apx C-l State NMP Regulations
State
California
California
California
California
Washington
Minnesota
New Hampshire
New Jersey
Pennsylvania
Vermont
Regulation
California's Proposition 65 list
because it is known to cause birth
defects or other reproductive harm
Proposed a permissible exposure limit
(PEL) at 1 ppm as an 8-hr time-
weighted average (TWA) to reduce
the risk of developmental effects
Regulations that require employees
that handle NMP to wear appropriate
protective gloves
California lists NMP as an
informational candidate chemical
under California's Safer Consumer
Products regulations
Listed as chemical of high concern
under the Children's Safe Product Act
Listed chemical of high concern
(development)
Listed toxic air pollutant
Listed hazardous substance
Listed hazardous substance
Listed air pollutant
Link or Reference
State of California Environmental Protection Agency Office of Environmental Health Hazard
Assessment (CA EPA OEHHA). (2007). OEHHA Proposition 65 in Plain
Language!. http://oehha.ca.gov/prop65/background/p65plain. html
(accessed September 11, 2014)
Occupational Safety and Health Standards Board, STATE OF CALIFORNIA - DEPARTMENT OF
INDUSTRIAL RELATIONS Edmund G. Brown Jr., Governor Title 8: Division 1, Chapter 4, Subchapter
7, Article 107, Section 5155 of the General Industry Safety Orders
http://www.dir.ca.gov/title8/sb7g2alO.html
(accessed October 28, 2014)
http://www.dtsc.ca.gov/SCP/ChemList.cfm
(accessed October 28, 2014)
http://www.ecy.wa.gov/programs/swfa/cspa/chcc.html
(accessed October 28, 2014)
http://www.health.state.mn.us/divs/eh/hazardous/topics/toxfreekids/chclist/mdhchc2013.pdf
(accessed September 10, 2014)
Regulated Toxic Air Pollutants, New Hampshire Code of Administrative Rules, Chapter CHAPTER
Env-A 1400, Table- 1450-1 2009
Environmental Hazardous Substance List," New Jersey Department of Environmental Protection,
N.J.A.C. 7:lG-2, as printed in the Community Right to Know Survey Instruction Book, 2005.
http://web.doh.state.ni.us/rtkhsfs/rtkhsl.aspx
(accessed December 5, 2014)
Regulated Substances List, Pennsylvania Department of Environmental Protection, Bureau of
Environmental Cleanup and Brownfields: Division of Storage Tanks. Revised: 3/2014
http://www.portal.state.pa. us/portal/server.pt?open=514&obilD=552962&mode=2
(accessed December 5, 2014)
Air Pollution Control Regulations, State of Vermont Agency of Natural Resources, A-l: Hazardous
Air Contaminants. 2014
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Appendix D OCCUPATIONAL EXPOSURE ASSESSMENT SUPPORT
INFORMATION
D-l Summary of Dermal Exposure Parameters, Inhalation
Concentrations and Exposure Reduction Factors
Data sources did not often indicate whether NMP exposure concentrations were for
occupational users or nearby workers. Therefore, EPA/OPPT assumes that exposures are for a
combination of users and nearby workers. Some nearby workers may have lower exposures
than users, especially when they are further away from the source of exposure.
D-2 Data Needs and Data Collection
Before data collection began, EPA/OPPT defined the data needs for the completion of the
occupational exposure assessment of NMP during paint stripping. These data needs include
both quantitative data (e.g., exposure measurements) and qualitative information (e.g.,
descriptions of worker activities). The following data needs were required for the occupational
exposure portion of this risk assessment:
• Inhalation exposure monitoring data of NMP during paint stripping.
o Only breathing zone or personal samples were considered for use. Area samples
were not considered for use.
o Modeling results were not considered for use.
o Biological measurements (e.g., blood or urine samples) were not considered for
use.
o Data from non-paint stripping industries were not considered for use.
• Dermal exposure data of NMP during paint stripping.
• Description of processes and worker activities used to perform paint stripping.
• Description of engineering controls and personal protective equipment used during
paint stripping.
• Estimates of number of workers exposed to NMP during paint stripping in the US.
• Estimates of the number of facilities that perform NMP-based paint stripping in the US.
The inhalation exposure data presented in Table_Apx D-9 below met the first bulleted data
need above (breathing zone monitoring data of NMP during paint stripping).
EPA/OPPT obtained inhalation exposure data from a literature search and the OSHA IMIS
database. EPA/OPPT also obtained some additional studies identified during the public and
peer reviews of the 2012 draft of this document. EPA/OPPT's literature search comprised a
general Internet search and a targeted search of specific Internet resources. To begin the
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literature search, EPA/OPPT defined primary keywords to use in the search queries. The defined
primary keywords were:
• N-methylpyrrolidone
• l-Methyl-2-pyrrolidinone
• paint stripp*
EPA/OPPT included both chemical synonyms "N-methylpyrrolidone" and "l-methyl-2-
pyrrolidinone." The wildcard (*) allows for variations of the word "strip", including "stripper"
and "stripping." To sort through extensive search results, EPA/OPPT used secondary keywords
including, but not limited to, the following:
• expos*
• inhal*
• breathing zone
• dermal
Here, the wildcard (*) allows for the variations: "exposure", "exposures", "exposed", "inhale"
and "inhalation."
EPA/OPPT used these keywords in queries performed in an Internet search engine (e.g.,
Google) for the general Internet search and in the following targeted NIOSH online resources.
• NIOSH Workplace Survey Reports: http://www.cdc.gov/niosh/surveyreports/
• NIOSH Health Hazard Evaluations (HHEs): http://www2a.cdc.gov/hhe/search.asp
Before data collection began, EPA/OPPT defined criteria to evaluate the quality of collected
data. EPA/OPPT then determined acceptance specifications for each study quality criterion to
determine if the collected data are of acceptable quality for use in this risk assessment.
Table_Apx D-l summarizes the study quality criteria, the definition or description of each
criterion and the corresponding acceptance specifications used to determine if the data are
acceptable for use.
EPA/OPPT accepted surrogate data for furniture paint stripping for use in the occupational
exposure portion of this risk assessment. The accepted surrogate data are personal monitoring
data collected during a chamber test study designed to replicate consumer paint stripping of
wood products. The uncertainties associated with these surrogate data are described in the
Occupational Inhalation Exposure Literature Data section of this appendix. Inclusion of the
surrogate data do not impact the inhalation data input to the PBPK model.
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Table_Apx D-l Study Quality Criteria and Acceptance Specifications
Quality Criterion
Currency (up to
date)
Geographic Scope
Reliability
Unbiased
Comparability
Representativeness
Applicability
Description/Definition
The information reflects present conditions.
The information reported reflects an area
relevant to the assessment.
The information reported is reliable. For
example, this criterion may include the
following acceptance specifications:
• The information or data are from a peer-
reviewed, government or industry-specific
source.
• The source is published.
• The author is engaged in a relevant field
such that competent knowledge is expected
(i.e., the author writes for an industry trade
association publication versus a general
newspaper).
• The information was presented in a
technical conference where it is subject to
review by other industry experts.
The information is not biased towards a
particular product or outcome.
The data are comparable to other sources
that have been identified.
The data reflect the typical industry
practices. The data are based on a large
industry survey or study, as opposed to a
case study or sample from a limited number
of sites.
For surrogate data, the data are expected to
be similar for the industry or property of
interest.
Acceptance Specification
Data from all years are acceptable.
Exposure and process description data
from the United States and the rest of
world are acceptable.
Only US estimates of number of workers
and number of facilities that perform
paint stripping are acceptable.
Data are reliable if they are from one of
the following sources:
US or other government publication.
Sources by an academic researcher
where:
• Publication is in peer-reviewed
journal; or
• Presented at a technical conference;
or
• Source has documented qualifications
or credentials to discuss particular
topic.
Sources by an industry expert or trade
group where:
• Presented at a technical conference
where the information is subject to
review by other industry experts; or
• Source has documented qualifications
or credentials to discuss particular
topic; or
• Source represents a large portion of
the industry of interest.
• Objective of the information is clear.
• Methodology is designed to answer a
specific question.
Data sources will not be accepted or
rejected based on their comparison to
data from other sources.
Literature sources are not rejected based
on the sample size of sites. Large industry
surveys as well as case studies and limited
sample sizes are acceptable.
Surrogate data deemed applicable if they
are inhalation exposure or airborne
concentration data of NMP measured
during paint stripping.
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D-3 Industries that Employ Paint Stripping Activities
Because a variety of industries include paint stripping among their business activities, an effort
was made to determine and characterize these industries. EPA/OPPT reviewed the published
literature and evaluated the 2007 North American Industry Classification System (NAICS) codes
to determine industries that likely included paint stripping activities presented in Table_Apx
D-2.
Table_Apx D-2 2007 North American Industry Classification System (NAICS) Codes
Paint Stripping Activities
2007
NAICS
238320
238330
811121
811420
711510
712110
336411
336611
2007 NAICS Title
Painting and wall covering contractors
Flooring contractors
Automotive body, paint and interior
repair and maintenance
Reupholstery and furniture repair
Independent artists, writers and
performers
Museums
Aircraft manufacturing
Ship building and repairing
Rationale for Inclusion of NAICS with Paint
Stripping Activities
US Census reports an index entry of "Paint and wallpaper
stripping" (USDOC, 2007a).
US Census reports index entries of "Floor laying, scraping,
finishing and refinishing" and "Resurfacing hardwood
flooring"(USDOC, 2007a). The National Institute for
Occupational Safety and Health (NIOSH) cites the paint
stripping of flooring by a wood flooring and restoration
company (NIOSH, 1993).
NAICS code 811121 is identified for automobile refinishing per
the OECD Coating Application via Spray-Painting in the
Automotive Refinishing Industry ESD (OECD, 2010).
US Census reports index entries of "Furniture refinishing shops"
and "Restoration and repair of antique furniture" (USDOC,
2007a).
US Census reports index entries of "Painting restorers,
independent" and "Conservators (i.e., art, artifact restorers),
independent" (USDOC, 2007a). Research has shown art
conservation to use paint strippers based on DCM or,
preferably, NMP (Wollbrinck, 1993).
Research has shown art conservation to use paint strippers
based on DCM or, preferably, NMP (Wollbrinck, 1993).
US Census reports an index entry of "Aircraft rebuilding (i.e.,
restoration to original design specifications)" (USDOC, 2007a).
Paint removal during the restoration process may use DCM- or
NMP-based paint strippers.
US Census 2007 NAICS definition includes shipyards involved in
the construction of ships as well as "their repair and conversion
and alteration" (USDOC, 2007a). Any paint removal activities
during repair, conversion and alteration may use DCM- or
NMP-based paint strippers.
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D-4 Occupational Paint Stripping Processes and Associated
Worker 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 1 liter
up to 5 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 (EC, 2007; IRTA, 2006; NIOSH, 1993; TNO, 1999). Professional
contractors can use portable local exhaust ventilation machines to increase ventilation in the
vicinity of the paint stripping (EC, 2007).
Graffiti Removal
Graffiti removal is expected to employ similar job-site characteristics as professional
contractors as opposed to the fixed facility operations performed in the other studied
industries. Swedish studies of graffiti removal companies (using both DCM- and NMP-based
solvents) identified that solvents are either spray or brush applied. Sprayed solvents can be
swabbed or wiped with a cloth or tissue. After spraying and wiping or brushing the solvent on
the surface, the surface is then washed with heated (70°C) wash water using a high-pressure
spray. The observed work was performed in train depots and underground stations and
included semi-confined spaces, such as elevators and train cars. The study authors noted poor
ventilation in the semi-confined spaces. The authors also noted the potential for members of
the general public to be indirectly exposed as work was conducted during the day while
travelers were occupying the train depots and stations (Anundi et al., 2000; Anundi et al.,
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1993). The prevalence of graffiti removal companies in the US is uncertain. Graffiti removal in
the US may be performed by public works municipal workers or contractors.
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
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transferred to other refinishing processes (e.g., sanding, painting, re upholstery) (HSE, 2001;
IRTA, 2006; 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_Apx D-l shows a typical flow tray used by larger furniture strippers to apply stripper to
furniture parts, obtained from IRTA (2006).
Figure_Apx D-2 shows a typical water wash booth used to wash stripper and coating residue
from stripped furniture, obtained from IRTA (2006).
Figure_Apx D-3 shows an example diagram of a dipping tank for furniture stripping complete
with local exhaust ventilation, obtained from HSE (2001).
Figure_Apx D-l Typical Flow Tray for Applying Stripper to Furniture (IRTA, 2006)
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Figure_Apx D-2 Typical Water Wash Booth Used to Wash Stripper and Coating Residue from Furniture
(IRTA, 2006)
Drying enclosure
45" min slope
1000fpm maximum
plenum vefocity
ip tank
Figure_Apx D-3 Example Diagram of a Dipping Tank for Furniture Stripping (HSE, 2001)
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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, 2012b). 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, 2012a). 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 or tanks
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 or washed 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.
Respiratory Protection
The 13 MSDS for paint strippers obtained through the literature search were reviewed for
recommended respiratory protection information. Of these 13 MSDS, only three contained
NMP, one of which also contained DCM. One of the NMP-only MSDS recommends a NIOSH-
approved respirator for organic solvent vapors without further specification of the respirator
type (W. M. 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" (W. M. 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) (W. M. Barr,
2009a). The MSDS for the paint stripper that contained both DCM and NMP recommends a
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NIOSH-approved self-contained breathing apparatus (SCBA) (W. M. Barr, 2009b). However, the
recommendation for SCBA is likely heavily influenced by the presence of DCM in addition to
NMP.
Dermal Protection
The 13 MSDS for paint strippers obtained through the literature search were reviewed for
recommended dermal protection information. Of these 13 MSDS, only three contained NMP,
one of which also contained DCM. All of the three MSDS mentioning NMP recommended either
chemical-resistant or impermeable gloves. One MSDS recommended nitrile gloves and another
recommended nitrile or neoprene gloves. All of the three MSDS recommend safety glasses,
chemical goggles or face shields for eye protection or where eye or face contact is likely (W. M.
Barr, 2009a, 2009b, 2011).
D-5 Facility and Population Data and Information
EPA/OPPT attempted to estimate the current total number of workers in the potentially
exposed populations. Knowing the sizes of exposed populations provides perspective on the
potential prevalence of the health effects. 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 (EPA, 1990). However, it is unknown what
fraction of the NMP-based product use exposures were due to paint stripping.
Estimates of the number of workers exposed to DCM during paint stripping provide perspective
on the number of workers potentially exposed to NMP during paint stripping. EPA/OPPT
estimated that over 230,000 workers nationwide are directly exposed to DCM from DCM-based
strippers. EPA/OPPT assumes that DCM is more widely used as a paint stripper than NMP;
therefore, it is likely that fewer workers are exposed to NMP than to DCM during paint
stripping. Therefore, it is likely that less than 230,000 workers nationwide are directly exposed
to NMP during paint stripping. These estimates do not account for workers within the facility
who are indirectly exposed. EPA/OPPT's "TSCA Work Plan Chemical Risk Assessment for
Dichloromethane: Paint Stripping Use" discussed how the estimate of number of workers
exposed to DCM was derived (EPA, 2014b).
EPA's 2007 National Emission Standards for Hazardous Air Pollutants (NESHAP) Paint Stripping
Operations at Area Sources proposed rule cited a previous estimate from 1999 that
approximately 27,000 facilities perform paint stripping nationwide (EPA, 2007). This estimate
includes facilities that perform chemical paint stripping as well as physical paint stripping (such
as mechanical and thermal paint stripping). The fraction of these 27,000 facilities that used
NMP-based paint stripping is not known.
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This section summarizes data on the number of establishments, number of paid employees and
workers and production hrs and work day estimates (for manufacturing industries) for each
paint stripping industry. These industry population estimates are for the industries as a whole
and do not estimate the fractions of facilities and workers that use NMP-based paint stripping.
Some of these data are useful for determining the average number of workers per
establishment, which can indicate relative sizes of the businesses. 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).
Numbers of Workers per Facility by Industry
Paint Stripping By Professional Contractors, Bathtub Refinishing and Graffiti Removal
Table_Apx D-3 summarizes the number of establishments and average number of workers for
painting and wall covering contractors and flooring contractors according to the 2007 US
Economic Census (USDOC, 2007b). The Census data do not include hours worked for
construction industry sectors. Note that these Census data do not include bathtub
refinishers/reglazers or graffiti removal. Census data that include bathtub refinishers/reglazers
or graffiti removal were not identified.
Table_Apx D-3 2007 US Economic Census Data for Painting and Wall Covering and Flooring
Contractors
2007 NAICS
238320
238330
2007 NAICS Title
Painting and Wall
Covering
Contractors
Flooring
Contractors
2007 Number of
Establishments
35,619
14,575
2007 Average Number of
Construction Workers
174,276
49,085
Source: USDOC (2007a)
The number of painting and wall covering contractors and flooring contractors who use
NMP-based paint strippers or the number of jobs per year a contractor uses NMP-based paint
strippers and the number of workers within a job site exposed to NMP-based paint strippers is
unknown. The number of establishments and workers from the US Census provide some
context for potential numbers of establishments and workers potentially exposed to NMP
during paint stripping. While some fraction of these workers may be exposed to NMP, the
Census data do not include self-employed, single person businesses and some of these workers
may also be exposed to NMP. The Census data indicate an average of approximately four to five
workers per establishment.
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Many bathtub refinishers are self-employed or a small business (CDC, 2012b). Past
investigations of fatalities that occurred during bathtub refinishing indicate it is likely that only
one contractor refinishes a bathtub at a time (CDC, 2012a, 2012b; MSU/MIFACE, 2011).
Swedish studies of graffiti removal companies identified one company with 12 workers (Anundi
et al., 1993) and a separate study monitored a total of 38 workers over five companies (an
average of seven to eight workers monitored per company) (Anundi et al., 2000). As previously
discussed, the prevalence of graffiti removal companies in the US is uncertain and graffiti
removal may also be performed by public works municipal workers or contractors.
Paint Stripping at Automotive Body Repair and Maintenance Shoos
Table_Apx D-4 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 hrs worked for this industry sector.
The Census data indicate an average of approximately six employees per facility. A 2003 Rhode
Island study observed two comparably-sized vehicle repainting shops. One of the two shops
had a total of 14 employees (Enander et al., 2004).
Table_Apx D-4 2007 US Economic Census Data for Automotive Body, Paint and Interior Repair and
Maintenance
2007 NAICS
811121
2007 NAICS Title
Automotive Body,
Paint and Interior
Repair and
Maintenance
2007 Number of
Establishments
35,581
2007 Number of Paid
Employees
223,942
Source: USDOC (2007b).
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_Apx D-5 summarizes the number of establishments and average number of paid
employees for reupholstery and furniture repair according to the 2007 US Economic Census.
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The Census data do not include hrs worked for this industry sector. The Census data indicate an
average of approximately three employees per facility.
Table_Apx D-5 2007 US Economic Census Data for Reupholstery and Furniture Repair
2007 NAICS
811420
2007 NAICS Title
Reupholstery and
Furniture Repair
2007 Number of
Establishments
4,693
2007 Number of Paid
Employees
16,142
Source: USDOC (2007b).
The present-day population 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 population of establishments and
employees potentially exposed to NMP during paint stripping.
Art Restoration and Conservation
Table_Apx D-6 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 hrs worked for these industry sectors.
Table_Apx D-6 2007 US Economic Census Data for Industry Sectors that May Engage in Art Restoration
and Conservation Activities
2007 NAICS
711510
712110
2007 NAICS Title
Independent Artists,
Writers and
Performers
Museums
2007 Number of
Establishments
20,612
4,664
2007 Number of Paid
Employees
48,321
83,899
Source: USDOC (2007b)
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
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overestimates of the number of establishments and employees potentially exposed to NMP
during paint stripping.
Aircraft Paint Stripping
Table_Apx D-7 summarizes the number of establishments, average number of production
workers and production workers hrs for aircraft manufacturing according to the 2007 US
Economic Census. The table also estimates the average worker days/year and average worker
hrs/day. These parameters are estimated from the production workers hrs and the average
number of production workers. The average worker days/year are estimated assuming 8
worker hrs/day and the average worker hrs/day are estimated assuming 250 worker days/yr.
The estimates of worker days/year and worker hrs/day are within 10 percent of the EPA/OPPT
New Chemicals Program default values of 250 days/yr and 8 hr/day, respectively.
The Census data indicate an average of approximately 320 production workers per facility. This
observation is consistent with two dichloromethane exposure studies identified in the
literature. A 1977 NIOSH study of an aircraft refinishing facility observed approximately 1,400
employees working in the dock area, which constituted seven refinishing docks but appeared to
exclude workers and employees associated with security checkpoints, the front lobby,
cafeterias, the credit union, the turbine shop, the medical bay and maintenance activities
(NIOSH, 1977). Similarly, a 1994 French study of an aeronautical workshop monitored 30
painters, although the total number of employees was not identified (Vincent et al., 1994).
Table_Apx D-7 2007 US Economic Census Data for Aircraft Manufacturing
2007 Economic Census Data
2007
NAICS
Code
33641
1
2007 NAICS
Title
Aircraft
Manufacturi
ng
Number of
Establishments
254
Average
Number of
Production
Workers
81,456
Production
Workers
Hrs (1,000
hr)
157,589
Parameters Calculated from
the Corresponding 2007
Economic Census Data
Average
Worker Days
per Year
(Assuming
8 hr/day)
242
Average
Worker Hrs
per Day
(Assuming 250
Days/yr)
7.74
Source: USDOC (2007b).
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
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Census are possibly overestimates of the number of establishments and employees potentially
exposed to NMP during paint stripping.
Ship Paint Stripping
Table_Apx D-8 summarizes the number of establishments, average number of production
workers and production workers hrs for ship building and repairing according to the 2007 US
Economic Census. The table also estimates the average worker days/year and average worker
hrs/day. These parameters are estimated from the production workers hrs and the average
number of production workers. The average worker days/year are estimated assuming 8
worker hrs/day and the average worker hrs/day are estimated assuming 250 worker days/yr.
The estimates of worker days/year and worker hrs/day are within 10 percent of the EPA/OPPT
New Chemicals Program default values of 250 days/yr and 8 hr/day, respectively. The Census
data indicate an average of approximately 100 production workers per facility.
Table_Apx D-8 2007 US Economic Census Data for Ship Building and Repairing
2007 Economic Census Data
2007
NAICS
Code
336611
2007 NAICS
Title
Ship building
and repairing
Number of
Establishment
s
656
Average
Number of
Production
Workers
65,737
Production
Workers
Hrs (1,000
hr)
136,929
Parameters Calculated
from the Corresponding
2007 Economic Census
Data
Average
Worker Days
per Year
(Assuming
8 Hrs/day)
260
Average
Worker Hrs
per Day
(Assuming
250 Days/yr)
8.33
Source: USDOC (2007b).
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.
D-6 Dermal Exposure Parameters
EPA/OPPT identified dermal exposure parameter values from the literature for use in the PBPK
modeling, dermal exposure assessment. Table 2-1 summarizes the parameter values used for
the occupational dermal exposure assessment and this section provides a detailed discussion of
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the selected values. The dermal exposure parameters needed for the PBPK modeling are the
following:
• NMP weight fraction in the liquid paint stripping product;
• Skin surface area in contact with the liquid paint stripping product;
• Body weight of the individual handling the liquid paint stripping product; and
• Duration of dermal contact with the liquid paint stripping product.
EPA/OPPT performed the dermal exposure assessment for the sub-population most sensitive to
NMP: pregnant women. Therefore, several of the dermal exposure parameters, as described
below in this section, are specific to pregnant women.
The occupational dermal exposure assessment modeled a low-end, high-end and mid-range
value for several of the parameters described below. In each case, the mid-range value is the
mid-point between the low-end and high-end values. EPA/OPPT provided this mid-range value
to provide perspective on the variability of the parameter values since EPA/OPPT was not able
to determine statistical distributions of values for the parameters.
NMP Weight Fraction in Liquid Paint Stripping Product
Both the occupational and consumer dermal exposure assessments require the weight fraction
of NMP in the paint stripping product. Paint stripping products marketed for professional
applications may contain higher concentrations of the active ingredients than those marketed
for consumer applications. For the consumer dermal exposure assessment, EPA/OPPT surveyed
several material safety data sheets (MSDS) for NMP-containing paint strippers. The lowest NMP
weight fraction identified in this sample of MSDS was 0.25. EPA/OPPT used this value of 0.25 as
a low-end value for the PBPK modeling for both the consumer and occupational dermal
exposure assessments. However, to account for uncertainties in the formulations of paint
strippers that workers may actually use, EPA/OPPT used a high-end value of one for the PBPK
modeling for the occupational dermal exposure assessment as opposed to the value of 0.53
used in the consumer dermal exposure assessment.
Skin Surface Area in Contact with Liquid Paint Stripping Product
Both the consumer and occupational dermal exposure assessments used skin surface area
values for the hands of women, obtained from the 2011 edition of EPA's Exposure Factors
Handbook (Table 7-13) (EPA, 2011a). The Exposure Factors Handbook does not differentiate
skin surface area values between pregnant and non-pregnant women.
For the occupational dermal exposure assessment, EPA/OPPT used a high-end value of 890 cm2,
which is representative of two, full hands exposed to a liquid. EPA/OPPT used a low-end value
of 445 cm2, which is half of two, full hands exposed to a liquid and represents only the palm-
side of both hands exposed to a liquid.
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Body Weight
Both the consumer and occupational dermal exposure assessments used the 50th percentile
body weight value for pregnant women in their first trimester, which is 74 kg. EPA/OPPT
obtained this value from the 2011 edition of EPA's Exposure Factors Handbook (Table 8-29)
(EPA, 2011a).
Duration of Dermal Contact
For the occupational dermal exposure assessment, EPA/OPPT assumed a low-end value of 1
hr/day, which is a reasonable assumption considering the initial contact time with the paint
stripper plus the time after direct contact when the thin film evaporates from and absorbs into
the skin. EPA/OPPT assumed a high-end value of 8 hrs/day (i.e., a full shift). The mid-range
value is 4 hrs/day (the calculated mid-point of 4.5 was rounded to 4 hrs/day). The low-end and
high-end values are consistent with EPA/OPPT's documented standard model assumptions for
occupational dermal exposure modeling (EPA, 1991a).
Associated Background and Uncertainties
A survey of a single graffiti removal company in Sweden found 87% of graffiti removers use
gloves. Only a small fraction of these workers used gloves made of optimal material for
protection against NMP and some used cloth or leather gloves. A majority of the workers
reported splashes to skin with varying frequency (occasional to several times per week). Some
workers encountered exposures through clothing "soaked" with stripper formulations. The
survey results may be reasonable to assume applicable to NMP-paint stripping uses in other
types of work settings (Anundi et al., 2000).
Data and information (e.g., types and prevalence of glove materials used, ranges of protections
provided by glove materials, splash amounts contacting skin and associated frequencies and
durations, liquid exposures through wet clothing) are inadequate to make reasonable
parameter assumptions needed to model quantitative estimates of dermal liquid exposure to
workers who routinely wear gloves. Therefore, EPA/OPPT employed a "what-if" type
assumption of 90 percent reduction of hand exposure due to use of gloves made of materials
most effective to protect against NMP. Data and information on prevalence and types of
respirators used are also incomplete. Therefore, EPA/OPPT employed a "what-if" type
assumption that the use of respirators providing an assigned protection factor (APF) of 10 will
reduce inhalation concentrations by a factor of 10 when this type of respirator is properly used.
D-7 Occupational Inhalation Exposure Literature Data
EPA/OPPT used existing exposure data to estimate occupational exposures to NMP by
inhalation. Several exposure studies were identified through a literature search. Exposure
studies were only identified for the following industries and settings:
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• Professional contractors;
• Wood furniture stripping;
• Graffiti removal; and
• Non-specified workplace settings.
Table_Apx D-9 summarizes the NMP inhalation exposure data obtained from the literature
search. These data, including references, are discussed in detail in the sections that follow.
Table_Apx D-9 Summary of NMP Inhalation Exposure Data Identified in the Literature
Industry
Category
Professional
Contractors
(in home)
Professional
Contractors
(in home)
Professional
Contractors
(in home)
Professional
Contractors
(in home)
Professional
Contractors
(in home)
Professional
Contractors
(in home)
Professional
Contractors
(in home)
Professional
Contractors
(chamber
test)
Professional
Contractors
(chamber
test)
Professional
Contractors
Use
Description
Floor
stripping
Floor
stripping
Floor
stripping
Floor
stripping
Floor
stripping
Floor
stripping
Floor
stripping
Manual
stripping
Manual
stripping
Manual
stripping
Airborne
Concentration
(mg/m3)
9.3
17.4
5.7
21.1
12.6
21.1
14.2
39
37
37
Characterization
Personal sample; 48-
min sample
Personal sample; 93-
min sample. Stripping
solution was applied
during this sample.
Personal sample; 64-
min sample. The
window was opened
during this sample.
Personal sample; 46-
min sample. Stripping
solution was applied
during this sample.
Personal sample; 47-
min sample
Personal sample; 52-
min sample
Personal sample; 43-
min sample
Personal sample; 129-
min sample
Personal sample; 130-
min sample
Personal sample; 143-
min sample
Notes
Mean of these four samples is
13.4 mg/m3 (3.3 ppm).
US NIOSH study of a flooring
contractor, conducted in 1993.
Mean of these three samples is
16.2 mg/m3 (4.0 ppm). A coat of
stripping solution was applied to
the floor during each sampling
period; windows and doors were
closed.
US NIOSH study of a flooring
contractor, conducted in 1993.
Consumer exposures; Brush
application - use as surrogate for
workers.
Consumer exposures; Brush
application - use as surrogate for
workers.
Consumer exposures; Brush
application - use as surrogate for
workers.
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Industry
Category
(chamber
test)
Furniture
stripping
Non-specific
Workplace
Settings
Non-specific
Workplace
Settings
Non-specific
Workplace
Settings
Graffiti
removal
Graffiti
removal
Graffiti
removal
Graffiti
removal
Graffiti
removal
Graffiti
removal
Use
Description
Furniture
stripping
Paint
stripping
Paint
stripping
Paint
stripping
Graffiti
removal
Graffiti
removal
Graffiti
removal
Graffiti
removal
Graffiti
removal
Graffiti
removal
Airborne
Concentration
(mg/m3)
1.0-3.8
64
280
0.01-6
0.01-30
0.56
1.78
1
4.71
9.9
Characterization
TWAs range 125-167
min
Highest value in range;
8-hr TWA; personal
breathing zones
Highest value in range;
1-hr peak samples
Range; Sampling time
not presented
Short-term; Sampling
time not presented
Personal sampling; 8-hr
TWA; average for 6
workers
Personal sampling; 8-hr
TWA; average for 3
workers
Personal sampling; 8-hr
TWA; average for 25
workers
Personal sampling; 15-
min (ST), average of 40
samples
Personal sampling; 15-
min (ST), 1 sample
Notes
Study of two shops in Germany.
Dipping for paint stripping and
degreasing. Study conducted in
the UK.
Study conducted in the UK.
Depot 1 and 2. Geometric
mean=0.4 mg/m3; Range=0-1.68
mg/m3.
Poorly ventilated, semi-confined
spaces.
Study conducted in Sweden in
2000.
Depot 3 and 4. Geometric
mean=1.5 mg/m3; Range=0.61-
2.56 mg/m3.
Poorly ventilated, semi-confined
spaces.
Study conducted in Sweden in
2000.
Underground stations. Geometric
mean=0.67 mg/m3; Range=0.03-
4.52 mg/m3.
Poorly ventilated, semi-confined
spaces.
Study conducted in Sweden in
2000.
Geometric mean=1.97 mg/m3;
Standard deviation=6.17 mg/m3;
Range=0.01-24.61 mg/m3.
Poorly ventilated, semi-confined
spaces.
Study conducted in Sweden in
2000.
Sometimes workers worked in
semi-confined spaces. Did not
wear respirators.
Study conducted in Sweden in
1992.
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Industry
Category
Use
Description
Airborne
Concentration
(mg/m3)
Characterization
Notes
Note: Complete references can be found in the descriptive paragraphs, below
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°C 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).
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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, one of
which contained NMP (other ingredients in this product 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 8 hrs (EPA, 1994a). Although this investigation simulated in-home consumer paint
stripping of wood products, EPA/OPPT used these data as surrogate data for in-home paint
stripping performed by professional contractors.
In the MRI investigation, the only NMP-based paint stripper was brush applied. The breathing
zone concentrations of NMP measured by gas chromatography with flame ionization detection
(GC-FID) from time-integrated samples ranged from 37 to 39 mg/m3 (9.1 to 9.6 ppm) (sampling
times ranging from 129 to 143 minutes). The stationary length-of-task concentrations ranged
from 38 to 45 mg/m3 (9.4 to 11.1 ppm). The stationary, 8-hr TWA concentrations ranged from
46 to 74 mg/m3 (11.3 to 18.2 ppm) (EPA, 1994a). Section E-l of Appendix E discusses the
investigation's fourfold discrepancy in the NMP measurement results by Fourier transform
infrared (FTIR) versus GC-FID. Based on the explanation provided by MRI regarding this
discrepancy, EPA/ OPPT decided that time-integrated GC-FID sampling results summarized
above are likely more reliable.
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Wood Furniture Stripping
A literature search conducted by the NMP Producers Group identified a 2004 German study
that measured NMP exposures of workers in two furniture paint stripping shops. The personal
sample concentrations ranged from 1.0 to 3.8 mg/m3 (0.24 to 0.93 ppm) and the sampling time
ranged from 125 to 167 minutes (NMP Producers Group, 2012).
Paint Stripping in Graffiti Removal
Studies conducted in 1993 and 2000 in Sweden examined inhalation exposures to workers in
graffiti removal companies. The 1993 study examined all 12 workers at a single company. Only
a single NMP personal measurement was obtained for a single worker: a 15-min sample
concentration of 9.9 mg/m3 (2.44 ppm) (Anundi et al., 1993). The 2000 study conducted
personal air sampling of 38 workers associated with five graffiti removal companies. The
workers removed graffiti at public transportation depots and underground stations. The study
authors observed the workers, at times, conducted graffiti removal in poorly ventilated, semi-
confined spaces. The 8-hr TWA personal air samples for the 38 workers ranged from 0.03 to
4.52 mg/m3, with a standard deviation of 0.89 mg/m3, an arithmetic mean of 1.01 mg/m3 and a
geometric mean of 0.66 mg/m3. Additionally, 40 15-min samples were taken, with a range of
0.01 to 24.61 mg/m3, a standard deviation of 6.17 mg/m3, an arithmetic mean of 4.71 mg/m3
and a geometric mean of 1.97 mg/m3. Table_Apx D-10 summarizes the NMP personal air
measurements collected at the public transportation depots and underground stations during
the 2000 study (Anundi et al., 2000).
Table_Apx D-10 NMP Personal Air Measurements Obtained during Graffiti Removal (Anundi et al.,
2000)
Depot 1 and 2
Mean
(mg/m3)
0.56
Geometric
Mean Low
(mg/m3) (mg/m3)
0.4 0
High
(mg/m3)
1.68
Number of
Workers
Exposed
6
Depot 3 and 4
Mean
(mg/m3)
1.78
Geometric
Mean Low
(mg/m3) (mg/m3)
1.5 0.61
High
(mg/m3)
2.56
Number of
Workers
Exposed
3
Underground Stations
Mean
(mg/m3)
1.0
Geometric
Mean Low
(mg/m3) (mg/m3)
0.67 0.03
High
(mg/m3)
4.52
Number of
Workers
Exposed
25
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A literature search conducted by the NMP Producers Group identified a 2004 UK study of
graffiti removal, which resulted in short-term exposures ranging from 0.01 to 30 mg/m3 (0.002
to 7.4 ppm) (NMP Producers Group, 2012)
Paint Stripping in Non-specific Workplace Settings
Some NMP exposure data were identified for which workplace 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 World Health Organization (WHO) report identified NMP exposures in a non-specified paint
stripping industry in the literature. Personal breathing zone samples had 8-hr TWA exposures as
high as 64 mg/m3 (16 ppm) and 1-hr peak exposures as high as 280 mg/m3 (69 ppm) (WHO,
2001). The NMP Producers Group literature search results were in general agreement with the
WHO report. The NMP Producers 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 a 2004 UK study were identified ranging from 0.01 mg/m3
(0.002 ppm) to 6 mg/m3 (1.5 ppm) associated with dipping for paint stripping and degreasing,
but the sampling time was not specified (NMP Producers Group, 2012).
OSHA IMIS Data
EPA/OPPT searched the OSHA's Integrated Management Information System (IMIS) database
for OSHA and state health inspection data for NMP inhalation exposures. However, the limited
NMP exposure data in the IMIS database (42 IMIS sampling data points range from non-detect
to 4.3 ppm TWA (17 mg/m3)) did not include any industries that matched the NAICS or SIC
codes identified as relevant for paint stripping. Therefore, the IMIS data were not included in
the risk analyses.
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 was 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 was solved for as follows:
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Equation D-l Mass Balanced Concentration of NMP
m yPM /l,000ma\ 1000 mo/
C = — = ' v\..'
v RT V g ) v kmol J
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 1
million. At ambient conditions (1 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.
Appendix E CONSUMER EXPOSURE ASSESSMENT
E-l Estimation of Emission Profiles for Paint
Removers/Strippers
In the absence of actual air monitoring data for consumer use of an NMP paint stripper,
EPA/OPPT reviewed several air monitoring studies for consumer paint strippers that used DCM-
containing products, including EPA (1994a), EC (2004), a Consumer Product Safety Commission
study (as cited in EPA, 1996; and Riley et al., 2000) and a study conducted in the Netherlands by
van Veen et al. (2002). EPA/OPPT determined, however, that data from most of 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.
EPA/OPPT identified one study as particularly useful for the estimation of emission profiles; a
1993 study conducted by MRI involved a series of chamber tests performed on five paint
stripping products, including two containing DCM and one containing NMP ("Wood Finisher's
Pride") (EPA, 1994a). For each test, both near real-time (continuous) samples and time-
integrated samples were collected at breathing-zone height during paint stripping operations
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that were conducted according to manufacturer label instructions. The test chamber was
intended to represent an enclosed consumer room with a nominal ventilation rate of 0.5 air
changes/hr. The near real-time air concentrations were measured using a Fourier transform
infrared (FTIR) spectrometer. The time-integrated samples were collected on activated charcoal
sorbent tubes using personal and stationary samplers and were analyzed by gas
chromatography with flame ionization detection (GC-FID). Additional stationary samplers inside
the chamber and in the supply air of the chamber were run for an 8-hr period, but these results
were not deemed useful for this analysis and are not discussed herein.
EPA/OPPT considered the data from the three NMP runs conducted in the MRI study (identified
as Runs 10,11 and 12 in the MRI study and this appendix) for use in this emission modeling
analysis. As described below, predicted NMP air concentrations from paint stripping were
derived from time-varying emission profiles that were estimated by fitting the experimental
chamber study data to exponential equations.
Conceptual Approach
Exponential Decay of Emissions. In evaluating the experimental data, an exponential-emission
model was chosen because of the general shape of the concentration profile and its similarity
to other emission behaviors (e.g., for chemicals released from applied paint). The equation for
an exponentially decaying emission rate has the following form:
Equation E-l Exponential Decay of Emissions
E = E0e~kt
Where:
Eo = initial emission rate (the emission rate at t = 0), mg/hr
k = first-order rate constant, hr1
t = time since application, hrs
Integrating Equation E-l to a time of infinity gives the total released mass represented by the
exponential, as follows:
Equation E-2 Total Mass Released
Mass Released = E0/k
Or:
Equation E-3 Initial Emission Rate
EO = (Mass Released^) * k
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The single-compartment, mass-balance equations for the time-varying air concentration for
single- and double-exponential representations of the emissions are given in Equation E-4 and
Equation E-5 (EPA, 1997), respectively:
Equation E-4 Air Concentration for a Single Exponential as a Function of Time
-
Where:]
V = chambervolume, m3
Q = air flow rate in and out of the chamber, m3/hr
Equation E-5 Air Concentration for a Double Exponential as a Function of Time
' ~ ~
Where:
Eoi = initial emission rate for the first exponential, mg/hr
£02 = initial emission rate for the second exponential, mg/hr
ki = first-order rate constant for the first exponential, hr1
l<2 = first-order rate constant for the second exponential, hr1
The analysis of DCM emissions from the same MRI study (EPA, 1994a) achieved a good fit to the
chamber data using a single exponential. For NMP, a double exponential was necessary due to
its lower volatility and the resulting longer tail for the emission profile, as demonstrated by the
results for Runs 10, 11 and 12 of the MRI study. The first exponential was used to represent the
rapid rise during application and the second exponential was used to capture the extended
slower release from the target surface after application. In fitting Equation E-5 to the chamber
data, EPA/OPPT took the measured chamber volume (35.68 m3) and measured air exchange
rate for the chamber (0.56 air changes/hr) as "known constants" in solving for the values of Eoi,
ki, Eo2 and fe that provided the best fit to the data.
Data from MRI Chamber Studies Used for Estimation. Each NMP chamber run (Runs 10-12)
involved sequential application of a paint stripper to each of four quarters of a 4-ft by 8-ft
panel. This application sequence was repeated, for a total of eight applications or segments. For
each of the eight segments, there was a 1-min application, followed by approximately a 30-min
effect time and then by a 4-min scraping time. This sequence resulted in an elapsed time of
approximately 35 minutes from the start of each segment through completion of that
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segment's stripping sequence. As illustrated in Table_Apx E-l, the total for all 8 sequences was
112 minutes (1 hr and 52 minutes). This total was consistent with the duration of stripping
operations reported by MRI (107 minutes for Run 10, 112 minutes for Run 11 and 113 minutes
for Run 12).
Table_Apx E-l Sequence of Stripping Activities for MRI study
Description
Quarter 1, 1st Sequence
Quarter 2, 1st Sequence
Quarter 3, 1st Sequence
Quarter 4, 1st Sequence
Quarter 1, 2nd Sequence
Quarter 2, 2nd Sequence
Quarter 3, 2nd Sequence
Quarter 4, 2nd Sequence
Segment
1
2
3
4
5
6
7
8
Application
Time (min)
Start
0
11
22
33
44
55
66
77
End
1
12
23
34
45
56
67
78
Effect Time
(min)
Start
1
12
23
34
45
56
67
78
End
31
42
53
64
75
86
97
108
Scrape Time
(min)
Start
31
42
53
64
75
86
97
108
End
35
46
57
68
79
90
101
112
Total Time
(min)
Start
0
11
22
33
44
55
66
77
End
35
46
57
68
79
90
101
112
Air samples were collected and analyzed by two methods: (1) near real-time samples analyzed
with an FTIR spectrometer, averaged over4-min intervals; and (2) time-integrated samples,
collected on charcoal sorbent tubes for subsequent analysis by GC-FID. As an example,
Figure_Apx E-l and Table_Apx E-2 provides a comparison of the FTIR results (graphical format)
and the GC-FID results (tabular format) for Run 10, as reported in the MRI study. The time-
series plot of concentrations measured by FTIR near the breathing zone, with units of ppm on
the y-axis, suggested a time-averaged concentration on the order of 40-45 ppm; by comparison,
the concentrations measured by GC-FID from time-integrated samples ranged from ~40-45
mg/m3 (~9-ll ppm) for the different sampling locations in the chamber, including the breathing
zone. This apparent fourfold discrepancy for NMP samples was in contrast to results for DCM-
containing products that were tested, in which case the FTIR and GC-FID sampling results for
DCM agreed within ±15 percent.
The most likely reason for the discrepancy was described in section 7.2 of the MRI study (EPA,
1994a):
The air concentrations measured by the FTIR appeared to agree with the integrated samples,
with the exception ofN-methyl-pyrrolidone. The FTIR NMP air concentration data were higher
than the data measured by the integrated air sample results. This may have been due to
difficulties in preparing standards of semi-volatile compounds in air. The NMP that was injected
into the Tedlar bag may not have fully vaporized due to saturation. This would have created
positive bias to the data.
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Air Concentration vs. Time
Run No. 10 • Wood Fmshefs Pride
Tlme(hre)
Figure_Apx E-l Results from FTIR Samples (EPA, 1994a)
Table_Apx E-2 Results from GC-FID Samples (EPA, 1994a)
Sampling
Location in
Test Chamber
Inlet Side
Outlet Side
Breathing Zone
Time-integrated
Concentration
mg/m3
38
45
39
ppm
9.4
11
10
Data Adjustment
For each chamber test, MRI also collected ancillary data on chamber airflow rates, as well as
temperature and humidity. A review by EPA of the original laboratory data led to the discovery
that MRI had applied temperature and humidity corrections to the data from Runs 10 and 11,
but not to the Run 12 data. The reason why these corrections were not applied to the Run 12
data was not disclosed in the MRI report to the EPA (1994a).
Because the average temperature and RH levels were quite similar for Runs 10 and 11 (see
Table_Apx E-3), MRI used the same correction factor (0.839) for both. Table_Apx E-3 further
indicates that average temperature and RH levels for Run 12 were very close to those for Run
10. Consequently, EPA chose to apply the same correction factor (0.839) to the FTIR samples for
Run 12. Figure_Apx E-2 shows the corrected (by MRI) data for Runs 10 and 11 together with
both the uncorrected and corrected (by EPA) data for Run 12.
Page 157 of 281
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Table_Apx E-3 Table 1 from the MRI Report to EPA (EPA, 1994a)
Table 1, TEST CHAMBER ENVIRONMENTAL CUNUII IONS
Run"
Air Exchange
No. Rate Per Hour
1
2
3
4
5
6
7
8
9
10
11
12
13
14
16
D.76
0.62
0.61
0.57
0.57
0.58
0.56
0,54
0.55
0.5(5
0.54
0.57
0,55
0.54
0.54
Tern
Average
76.6
76.8
766
75.9
75.B
76.2
75.8
767
76.3
7Rfi
75.9
766
76.6
76.1
75.8
lerature (ck
Maximum
77.2
775
77.2
76.7
76.6
77.0
76.6
77.3
77.0
77 S
76.6
775
77.4
76.9
76.6
**y
Minimum
76.1
76.3
76,1
7S.1
75.3
75.5
75.0
75.9
75.2
75 3
75.3
76.0
76.0
75.6
75.1
Relative Humidity (%}
Average
59.2
56.8
614
60.2
60,0
£6,1
60.Q
57.$
59.3
61.8
65.4
62.7
55.9
566
•MR
Maximum
64.4
62.9
63.9
65.6
65 1
58,9
66.6
64.7
622
655
69.6
68.2
67.7
70.2
fisa
Minimum
55.1
543
58.0
57.9
57.6
54.3
58.0
54.7
56.1
56.0
57.3
553
46.3
47.8
43?
350
300
£
A
£
re
5
100
Corrected (by MRI) NMP Run 10
• Corrected (by MRI) NMP Run 11
D Uncorrected NMP Run 12
• Corrected (by EPA) NMP Run 12
Figure_Apx
Pride
123456
Time, hours
E-2 Uncorrected (Run 12) and Corrected (All Runs) FTIR Results for NMP - Wood Finisher's
Given the fourfold discrepancy in the NMP measurement results by FTIR vs. GC-FID methods
and the explanation provided by MRI, EPA/OPPT decided to take the GC-FID results as the
baseline for the analysis because it was not dependent on the Tedlar bag calibration step. This
allowed for a rescaling of the FTIR results, such that the average concentrations from the two
methods for the same time period in any given run would match. The adjustment was applied
Page 158 of 281
-------
to the FTIR results on a run-by-run basis; that is, the rescaling factor was allowed to vary across
runs.
The corrected FTIR results for all runs, along with the rescaled FTIR results for Runs 10 and 12,
are displayed in Figure_Apx E-3. The results from the three runs were very consistent, with the
single exception of an apparent "artificial rise" in the time series for Run 11, shortly before an
elapsed time of 3 hrs. This deviation was explained in the MRI report (page 36) as follows:
NMP air concentration data collected during run no. 11 sharply increases at approximately 2.7 h
into the run. The vacuum in the White cell was above 2 in. Hg during the first period. The vacuum
was corrected at 2.7 h by the FTIR operator. All data collected prior to the adjustment have a
negative bias.
For this reason, EPA/OPPT decided to exclude Run 11 from any subsequent analysis and used
only the rescaled results from Runs 10 and 12. The Run 10 results were adjusted by a
multiplicative factor of 0.2207 and the Run 12 results were adjusted by a factor of 0.2365 to
account for the FTIR miscalibration.
fO
00
c
o
'•p
-
I
u
c
o
u
J2
E
350
300
250
200
150
100
A'
A Corrected (by MRI) NMP Run 10
• Corrected (by MRI) NMP Run 11
• Corrected (by EPA) NMP Run 12
A NMP Run 10 Re-Scaled Data
D NMP Run 12 Re-Scaled Data
0
0
1
23456
Time, hours
Figure_Apx E-3 Corrected and Rescaled FTIR Results for NMP - Wood Finisher's Pride (Brush
Application)
Estimation Procedure for Brush Application
As noted earlier, each NMP chamber study involved eight approximately 1-min applications of
the paint stripper, with each successive application starting about 11 minutes after the previous
one. The emissions from each application were represented by a double exponential, with each
Page 159 of 281
-------
pair of exponentials identical to the other seven pairs but having a different start time that was
set at the midpoint of the 1-min application period. Based on this approach, the start times of
the eight NMP double exponentials were 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 Wood Finisher's Pride, the fitting process involved:
1. Using the rescaled FTIR concentrations for Runs 10 and 12.
2. Calculating the mass of NMP applied during the test and assigning l/8th of the applied
mass to each of the eight double exponentials.
3. Obtaining the best fit to the combined concentration time series for Runs 10 and 12 by
applying a non-linear least squares (NLS) procedure; this procedure iteratively solves for
the values of Eoi, ki, £02 one/ fe (see Equation E-5) that minimize the sum of the squared
differences between predicted and measured values across the entire time series.
The resulting fit is shown as a dashed line in Figure_Apx E-4, with the underlying eight
exponentials shown in the lower part of the figure and with the sum of these exponentials
shown as the dashed line. The line of best fit can be barely seen in some portions of the time
series because it aligns so well with the measured values (R2 = 0.97). The fitted model
parameters for the Wood Finisher's Pride case are shown in Table_Apx E-4. The NLS fit implies
that ~87 percent of the applied NMP mass would theoretically be emitted if the emissions were
allowed to continue indefinitely, with the majority (86.2%) associated with the 2nd exponential.
80
A NMP Run 10 Re-Scaled Data
n NMP Run 12 Re-Scaled Data
Eight Underlying Exponentials
0123456
Time, hours
Figure_Apx E-4 NLS Fit of Exponential-emissions Model to Rescaled FTIR Results for Wood Finisher's
Pride
Page 160 of 281
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Table_Apx E-4 Fitted Parameters to the Rescaled MRI (EPA, 1994) Results for Wood Finisher's Pride
Product
Wood
Finisher's
Pride
Mass of
Product
Applied, g
896
NMP Mass
Applied, g
403
1st Exponential
NMP Fraction
Released
0.0070
Ist-Order
Rate
Constant, hr1
32.825
2nd Exponential
NMP Fraction
Released
0.8625
Ist-Order
Rate
Constant, hr1
0.0024
A numerical integration of the fitted "sum of 8 exponentials" that is shown above in Figure_Apx
E-4 yields the theoretical cumulative mass released over time for Wood Finisher's Pride, as
shown in Figure_Apx E-5. The numerical integration indicates that ~1.2% of the applied NMP
mass would be released through hour 3 of the chamber experiments, as compared to the
theoretical maximum release (i.e., at time = oo) of 87% (i.e., sum of the two release fractions in
Table_Apx E-4). Immediate removal of the scrapings on completion of paint stripping, as
assumed for the modeling exercise, results in truncation of the emissions governed by the 2nd
exponential and, thus, a considerable reduction in the modeled user and non-user exposures
relative to those that would have been incurred had the scrapings been assumed to remain in
the residence for a longer duration.
00
•5
QC
* T
IB
n
z
1
n -
— —Sum of 2nd Exponentials
f^^
/*^
7^/'""'
/»*"""" ^'^
X'l---^'""'^
- 1.4%
•o
V
- 1.2% =_
a
- 1.0% *
- 0.8% •«
in
s
- 0.6% -Q!
ec
n
- 0.4% J
a.
- 0.2% |
n n%
0 0.5 1 1.5 2 2.5 3
Time, hours
Figure_Apx E-5 Theoretical Cumulative Mass of NMP Released from Wood Finisher's Pride
Page 161 of 281
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Estimation Procedure for Spray Application
Chamber data are not available for spray application of NMP paint strippers; consequently, the
exposure estimates for the spray scenario were generated by inserting two values for the
emissions parameters. The objective of this approach was to develop a reasonable range of
exposure estimates for user and nearby non-user. Within the user and non-user scenarios (6
&7) the difference between the a & b versions is only the emission parameters. The consumer
behavior patterns are meant to create upper end exposures, so all the scenarios are termed as
upper end, but 6 b and 7b use higher emission parameters as well.
The primary relevant differences between spray and brush applications of similar products
relate to the surface areas associated with alternative application methods, product
composition (i.e., NMP content) and use behavior (i.e., duration of application). For both the
upper- and lower-emission parameter scenarios, the underlying double-exponential emissions
model developed for the brush application was assumed to be equally valid for the spray
application. The underlying assumptions are as follows:
1. The first exponential primarily represents the rapid-volatilization component of the
emissions that occurs primarily when the paint stripper is first exposed to the air and
the NMP at the surface of the bulk product "flashes off." In the case of brush
application, this component includes the releases when the can is first opened as well as
the releases when the product is being agitated as it is applied to the surface with a
brush. For the spray application, the first exponential is intended to represent the
release from the droplets as they are created at the nozzle and fly through the air, until
they re-coalesce on the surface. It is reasonable to assume that the surface area of the
product during spray application is at least an order of magnitude greater than that for
brush application during the application phase.
2. The second exponential primarily represents the slower-volatilization component of
emissions that occur while the paint stripper is sitting on the target's surface during the
effect period. It is reasonable to assume that the bulk product behaves similarly for
brush and spray applications during this effect period.
An additional assumption made in extrapolating NMP emissions from the brush application to
the spray application was that the total mass ultimately released (assuming that the product is
left undisturbed on the surface being stripped for an extended duration) is the same for the
two methods. It is possible that a greater fraction of the applied NMP mass might be released
for the spray scenario, due to the larger surface area that is exposed to air during stripper
application. On the other hand, the total NMP emissions governed by the second exponential
likely would be quite similar for the two methods because (1) the release rate is slow and (2)
much of the theoretical mass release never actually occurs, due to the (assumed) removal of
scrapings from the house immediately after scraping is completed.
The product-composition and use-behavior aspects of the brush vs. spray applications were
compiled from product-specific information (see section E-3 of this appendix); these differences
Page 162 of 281
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are captured in certain model parameters (e.g., mass of NMP in the applied product).
Incorporating the assumptions discussed here, the exponentials developed to represent
emissions for the brush application were modified as follows to provide lower- and upper
exposure estimates for the spray application:
1. Lower Estimate (6a and 7a): The equations developed for the brush application were
used with the same model-emission parameters (i.e., fraction of applied NMP mass
released and rate constants for the first and second exponentials) while modifying the
product-composition and use parameters (i.e., fraction of NMP in the product, amount of
product applied and duration of application) to reflect differences associated with the
method of application.
2. Upper Estimate (6b and 7b): The equations developed for the brush application were
used with the same model-emission parameters, as above, with one exception - the
mass assigned to the first exponential was increased by a multiple of 10, to account for
an assumed tenfold increase in exposed surface area during the spray application. The
total (theoretical) NMP mass released was assumed to be the same as that for the lower
case. In other words, the additional mass assigned to the first exponential was "taken
away" from the second. In essence, these assumptions simply "remove" approximately
6% of the mass from the second (slower) release and "reassign" that mass to the first
(faster) release.
Two spray scenarios have been defined to estimate the range of expected upper-end exposures
for the product user (Scenario 6) and for the nearby non-user (Scenario 7). For each spray
scenario,
"Part a" (i.e., Scenario 6a) indicates the lower estimate and "Part b" the upper estimate.
The resulting model parameters for spray application are listed in Table_Apx E-5. The model
parameters imply that ~87 percent of the applied NMP mass would theoretically be emitted if
the emissions were allowed to continue indefinitely, with the 0.7% associated with the first
exponential for the lower case and 7.0% for the upper case.
Page 163 of 281
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Table_Apx E-5 Assumed Model Parameters for Estimates of User and Non-user Exposures for a Spray-
applied Product Containing NMP
Scenario
Description
Scenario 6:
Upper-end for
User
Scenario 7:
Upper-end for
User & Non-user
Emission
parameter
Assumption
Lower(6a)
Upper (6b)
Lower (7a)
Upper (7b)
1st Exponential for NMP
Fraction
Released
0.0070
0.070
0.0070
0.070
Rate Constant,
hr1
32.825
32.825
2nd Exponential for NMP
Fraction
Released
0.8625
0.7995
0.8625
0.7995
Rate Constant,
hr1
0.0024
0.0024
Discussion and Conclusions
NMP Mass Released from Brush-on Paint Stripper
From the exponential fits to the rescaled FTIR data, it was estimated that 0.7% of the applied
NMP mass was accounted for by the sum of the 1st exponentials. For the 2nd exponentials, the
percent accounted for depended on the duration of the activity and resulting exposure, as the
off-gassing following application is very slow. The theoretical maximum for the sum of the 2nd
exponentials was 86.3%, assuming that the emissions continued to infinity. Three hours after
the start of the run, ~1.2% of the applied NMP mass was accounted for by the combined sums
for the two exponentials. Integrating the two exponentials to a time of infinity yielded a
predicted potential release of 87% of the applied NMP mass.
Limitations Associated with Brush-on Paint Stripper
There is considerable uncertainty in the FTIR sampling results for NMP due to calibration issues
noted previously. In EPA/OPPT's opinion, rescaling the FTIR results to match the GC-FID results
on a time-integrated basis (i.e., effectively ignoring the calibration data for the FTIR) was a
reasonable approach to address the calibration issues. An implicit assumption with this
approach was that the FTIR results properly reflected the relative (but not absolute)
magnitudes of the time-varying NMP concentrations.
Limitations Associated with Spray-on Paint Stripper
Because no chamber data are available for NMP-containing spray products, EPA/OPPT used
professional judgment to estimate a range of upper-end exposures that might be expected. The
lower estimate for the spray product assumed the same release characteristics as for the brush
product, adjusted for differences in product mass, NMP weight fraction and duration of
Page 164 of 281
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application. The upper estimate used the same product-composition and use parameters but
increased the fraction of mass associated with the first exponential (rapid NMP release) by a
multiple often, by moving approximately 6% of the NMP mass from the second exponential
(slower release) to the first. The spray application had the same limitations as the brush
application, as well as an additional limitation - the two emission parameter estimates, which
were developed using professional judgment, may not have accounted for all relevant factors
governing NMP emissions and, thus, may have underestimated the magnitude of the upper
emission parameters.
E-2 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 was denoted as X, the result for the halved case
as %X and the result for the doubled case as 2X. Computing and averaging the two differences
from the base case gave the following result:
Equation E-6 Sensitivity Analysis of Linear Variables
3
([X - 1/2X] + [2X - X])/2 = -X or 75% of X
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:
Equation E-7 Sensitivity Analysis for Discrete Variables
\Y-X\
v x 100%
X
Where Y is the output associated with the change in location pattern from the base case.
Page 165 of 281
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E-3 Inhalation Exposure Scenario Inputs
Model Inputs
Method of Application. A review of product labels and technical data sheets indicated that
paint-stripping products can be applied using either brush-on or spray-on (i.e., aerosol or
trigger-pump) application methods. The MRI chamber tests EPA (1994b) did not include any
applications involving NMP-containing spray-on strippers. EPA/OPPT considered extrapolating
results from tests of other chemicals (e.g., DCM) that included both application methods.
Consequently, EPA/OPPT used professional judgment to estimate the expected range of user
and non-user upper-end exposures resulting from spray-on applications, as described and
discussed in section E-l of this appendix.
Application Amount (Product Mass)
The product application mass (grams of product) was determined using application rates (g/ft2)
calculated from the chamber tests in EPA (1994a) 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 %
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 4
and 5. As previously mentioned, the application amounts assumed in this assessment for
Scenarios 1 through 3 are a product of application rates calculated from the EPA (1994a)
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 8 ft2).
Because there were no EPA (1994a) chamber tests for NMP-containing spray-on strippers, the
DCM brush/spray ratio (540 g/722 g) was applied to the NMP brush rate of 108 g/ft2 to estimate
a spray rate for Scenarios 6 & 7, resulting in an estimated NMP spray application rate of 81 g/ft2.
This estimated spray rate is within the range of rates recommended on the Savogran Company
website for paint strippers in general - 1 gallon per 50 to 100 ft2 (~ 42 to 83 g/ft2, based on a
nominal density of 1.1 g/cm3)13.
13 See the following URL: http://www.savogran.com/lnformation/removerfaq.html
Page 166 of 281
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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 x 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 x 2.5 ft2 for front + 2.5 x 1.5 ft2 for top + 2 x 4.5 x 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 hrs).
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 (Old House Online, 2012).
The application time was derived from the EPA (1994b). From the protocol description in that
report, it was deduced that the NMP stripper was brush-applied at a rate of 2 ft2/min and spray-
applied at a rate of 4 ft2/min. It was further assumed that the scrape time was double the brush
application time, meaning that the surface was scraped at a rate of 1 ft2/min. For the bathtub
case (Scenarios 4 and 5), 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_Apx E-6.
Page 167 of 281
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Table_Apx E-6 Time Schedule for Paint Stripping with Repeat Application
Scenario
1. Brush application to coffee
table in workshop, central
tendency scenario
2. Brush application to coffee
table in workshop, upper-end
scenario for user
3. Brush application to chest in
workshop, upper-end scenario
for user & non-user
4. Brush application to bathtub
in bathroom, upper-end to
bounding scenario for user &
non-user; Csat = 1,013 mg/m3
5. Brush application to bathtub
in bathroom, upper-end to
bounding scenario for user &
non-user; Csat = 640 mg/m3
6. Spray application to coffee
table in workshop, upper-end
scenario for user
7. Spray application to chest in
workshop, upper-end scenario
for user & non-user
Elapsed Time From Time Zero, Minutes (Product User Location)
Apply 1
0-5
(workshop)
0-5
(workshop)
0-12.5
(workshop)
0-18
(bathroom)
0-18
(bathroom)
0-2.5
(workshop)
0-6.25
(workshop)
Wait 1
5-35
(ROM)
5-35
(workshop)
12.5-42.5
(ROM)
18-48
(ROM)
18-48
(ROM)
2.5-32.5
(workshop)
6.25-36.25
(ROM)
Scrape 1
35-45
(workshop)
35-45
(workshop)
42.5-67.5
(workshop)
48-84
(bathroom)
48-84
(bathroom)
32.5-42.5
(workshop)
36.25-61.25
(workshop)
Apply 2
45-50
(workshop)
45-50
(workshop)
67.5-80
(workshop)
84-102
(bathroom)
84-102
(bathroom)
42.5-45
(workshop)
61.25-67.5
(workshop)
Wait 2
50-80
(ROM)
50-80
(Workshop)
80-110
(ROM)
102-132
(ROM)
102-132
(ROM)
45-75
(workshop)
67.5-97.5
(ROM)
Scrape 2
80-90
(workshop)
80-90
(workshop)
110-135
(workshop)
132-168
(bathroom)
132-168
(bathroom)
75-85
(workshop)
97.5-122.5
(workshop)
Note:
Scenarios 6 and 7 provide two spray estimates; each scenario has a lower (Part a) and an upper (Part b) estimate for the
emission parameters. See section E-l of this Appendix for a detailed description.
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 (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
Page 168 of 281
-------
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 EPA (1994a) data indicates an NMP release fraction of 0.8695 for brush-on (see
section E-l of this appendix). The resultant mass applied for different application targets is
summarized in Table D-5. The resultant mass applied for the assumed spray-on scenarios (see
section E-l of this appendix) is summarized in Table_Apx E-7.
Table_Apx E-7 NMP Mass Released for Brush-on Application, by Application Target
Target (Surface Area)
Coffee table (10 ft2)
Chest of drawers (25 ft2)
Bathroom tub (36 ft2)
Application
Rate, g/ft2
108
108
108
NMP Weight
Fraction a
0.25 | 0.50
0.50
0.5
Release Fraction
0.8695
0.8695
0.8695
NMP Mass
Released, g
234.6 | 469.5
1173.8
1690.3
Notes:
a For the coffee-table case, two weight fractions are given, one for central and one for upper-end.
Table_Apx E-8 NMP Mass Released for Spray-on Application, by Application Target
Target (Surface Area)
Coffee table (10 ft2)
Chest of drawers (25 ft2)
Application
Rate, g/ft2
81
81
NMP Weight
Fraction
0.53
0.53
Release Fraction
0.8695
0.8695
NMP Mass
Released, g
373.3
933.2
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
ROM. 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 x
20 feet with an 8-foot ceiling (20 x 12 x 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 ROM, 438 m3, is determined by subtraction (492 to 54 m3).
Page 169 of 281
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For the bathroom scenario, the bathroom volume was set at nine m3 for consistency with that
reported in a CDC/NIOSH case (CDC, 2012b).
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/hr and 0.18/hr -
that were used in assigning the indoor-outdoor airflow rate for the ROM 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/hr,
was obtained by multiplying the room volume of 54 m3 by the 90th percentile (1.26/hr) 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 EPA
(1995):
Equation E-8 Interzonal Airflow Rate
Q = (0.078 + 0.31 * ACH) * House Volume
where Q is the interzonal airflow rate, in m3/hr and ACH is the air exchange rate, in 1/hr.
Substitution of the central air exchange rate of 0.45/hr and the house volume of 492 m3 yields
an estimated interzonal airflow rate of 107 m3/hr. The corresponding number for the upper-end
Page 170 of 281
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case, with an air exchange rate of 0.18/hr, was 65.8 m3/hr. Figure_Apx E-6 depicts the volumes
and airflows that were used for the workshop scenarios.
Central Values
68
m3/hr
Room of
Use
(54m3)
k. -^_
107
m3/hr
k.
Rest of
House
(438m3)
197
m3/hr
Values for Upper-end
Concentration
Room of
68 Use
m3/hr (54m3)
65.8
m3/hr
k.
Scenarios
Rest of
House 78-8
(438m3) m3/hr
-j k.
•^ ^- denotes air flow
Figure_Apx E-6 Zone Volumes and Airflow Rates for Workshop Scenarios
As previously mentioned, the bathroom scenario (Figure_Apx E-7) is more complex. While
working in close proximity to the target (bathtub) for an extended period, the product user is
typically exposed to elevated concentrations in the immediate vicinity of the application area, a
concept that has been termed the "source cloud" in the scientific literature. There is
considerable evidence of a source-cloud effect around sources (Cheng et al., 2011; Furtaw et
al., 1996; Matthews et al., 1989), which generally relates the size of the source cloud and the
ratio of the near- vs. far-field concentrations to the room turbulence (e.g., due to natural and
mechanical ventilation) and other mixing forces such as thermal gradients.
16
Rest of
Bathroom
35
ms/hr
Rest of
House
869
m
80
m3/hr
"Source
Cloud"
(l
Denotes airflow
Figure_Apx E-7 Zone Volumes and Airflow Rates for Bathroom Scenario
Several studies have investigated methods for modeling a source cloud, including use of a
virtual compartment around the source (Cherrie, 1999), rough partitioning (Musy et al., 1999)
and a zero-equation turbulence model (Chen and Xu, 1998). The virtual-compartment method
also has been discussed in ASTM Standard Practice D 6178-97 (ASTM, 1997). Although the ideal
Page 171 of 281
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size of the virtual compartment has not been discussed in the literature, Furtaw et al. (1996)
successfully represented concentrations using a sphere around the source (with an unspecified
volume). Thus, both the presence of higher concentrations near a source and the concept of
using a source cloud to better represent these near-field elevated concentrations appear to be
well founded in the scientific literature.
For the purpose of this exposure assessment, a source cloud is used for the bathroom scenario
to better represent the user's exposure to NMP emitted from the paint stripper. The bathroom
scenario involves application of a relatively large amount of the product within a semi-enclosed,
concave workspace, resulting in accumulation of the heavier-than-air NMP vapors toward the
lower tub surfaces in particular (see the vertical stratification analysis earlier in this section).
Moreover, accessibility constraints and the concave shape of the workspace would require the
user to work in close proximity to the surface being stripped, particularly when working on the
lower portions of the tub. For these reasons, a source-cloud representation is appropriate for
the bathroom scenario. The source cloud representation was not deemed necessary for the
workshop scenarios because work areas within such a space typically are not so confined and
are less likely to promote localized accumulation of NMP vapors.
Recognizing that the source cloud is not a well-defined area, but rather a gradual transition
between near- and far-field concentrations and further recognizing that the purpose of this
volume is to represent average air concentrations in the breathing zone of the product user,
the approach to defining the virtual volume was to establish some geometry around the source
that represents the approximate work space. Figure_Apx E-8 shows a schematic representation
of the bathtub and virtual compartment representing the source cloud. Consistent with this
representation, a source-cloud volume of 1.0 m3 was assumed the bathroom scenario.
Matthews et al. (1989) analyzed the impact of a central, forced-air heating, ventilating and air
conditioning (HVAC) system on the distribution of air velocities in three of their six study homes
(the remaining three homes were not included in the analysis because in two cases the fan was
operated continuously and in the third a probe malfunctioned). In Figure_Apx E-9, the results
for the three analyzed homes are presented at three different indoor locations (basement,
kitchen and master bedroom). For the bedroom (most similar of the three locations to the
bathroom), the Matthews results include a median air velocity of 1.8 cm/sec with the fan off
and 6.1 cm/sec with the fan on.
Page 172 of 281
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Virtual Compartment
;x5'0" (1m3)
Bathtub (Top = 2'8" x 5')
Sfl
Figure_Apx E-8 Modeling Representation of the Bathtub and Virtual Compartment (aka "Source
Cloud")
Page 173 of 281
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I «
5
o
o
§ 0.1
0.4
O.Z
BASEMENT
MEDIAN MAXIMUM
HVAC FLOW FLOW
D WT 4J W*
• ON 15.0 n.»
Ill
II
KITCHEN
OFF
ON
5.3
7.3
34.3
SC l
I
HVAC OFF and ON flows
for Master Bedroom
J J
Alfl VELOCITY (cm/MCl
Figure_Apx E-9 Air Velocity Distributions from Matthews et al. (1989)
With the fan cycling on and off the air velocity would be between 1.8 and 6.1 cm/sec, with the
average velocity dependent on the on-time for the fan. As of 2008, at least 25% of US homes
did not have a central, forced-air heating system ((EPA, 2011a) Table 19-13). Homes with
alternative systems (e.g., steam or hot-water system; baseboard/portable electric heat) would
be expected to have a velocity similar to that for the fan-off case. Similarly, ~40% of US homes
had either no cooling equipment or room/window cooling units ((EPA, 2011a) Table 19-15).
Consequently, a velocity of 1.8 cm/sec (65 m/hr) was used for the bathroom scenario, to
represent such homes as well as those with a central forced-air system that is off during paint
stripping either by intent or due to mild weather.
The assumed airflow rate between the source cloud and the rest of the bathroom was based on
a relationship developed by Matthews et al. (1989), who determined experimentally that such
an airflow could be estimated as the product of the room air velocity (m/hr) and the entry/exit
surface area (m2). An assumed air velocity of 65 m/hr, representing the fan-off case, together
with an assumed entry/exit surface area of 5 ft by 2 ft, 8 in (13.35 ft2 or 1.24 m2) yields an
estimated airflow rate of 80 m3/hr between the source cloud and the rest of the bathroom.
Page 174 of 281
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Based on professional judgment, the interzonal airflow rate between the bathroom and rest of
the house (35 m3/hr) was assumed to be ~2/3 lower than that for the workshop central
scenarios (107 m3/hr), given the small bathroom volume. The indoor-outdoor airflows were
based on air exchange rate of 0.18 ACH assumed for upper-end concentration 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 ROM as a central-
tendency assumption for the user (Scenario 1), in the workshop as an upper-end assumption
for the user (Scenario 2) and in the ROM of the house for Scenarios 3, 4 and 5, which were
developed to model upper-end concentrations primarily for the non-user. The user was placed
in the ROM 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 scenario (Scenario 2), 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
WEST AT (1987) and Abt (1992) surveys with a median value of zero minutes spent in the room
after using the product (EPA, 2011a).
The non-user was assumed to be in the ROM 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 ROM 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 4 and 5 were used to estimate upper-end NMP concentrations,
primarily for the non-user; 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 to airborne concentrations.
MCCEM prevents airborne concentrations of NMP from exceeding its saturation concentration
through the input of a saturation-constraint value. The model normally will apply the emission
Page 175 of 281
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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 was used to estimate the value for the saturation concentration:
Equation E-9 Saturation Concentration
VP
r ,760mmatm
^sat
MW x 1,000 ^*L x 1,000 -=j
(RxT)
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.
Scenario 4 imposes a saturation concentration constraint corresponding to the vapor pressure
reported in Table 1-1 of this report of 0.190 mmHg that, using Equation E-9 results in a
saturation concentration of 1013 mg/m3 at 25°C.
NMP's saturation concentration is affected by the level of relative humidity. An NMP Initial
Assessment Report by the OECD (2007) indicates that several studies have 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 humidity) and 0 mg/l (0 ppm) in
Page 176 of 281
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humidity saturated air (100% relative humidity BASFAG, 1989,1992,1995a, 1995b;
BASFAG, 1995c).
Based on the cited findings, the OECD report concludes:
Thus, the vapor saturation ofNMP 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.
BASF AG conducted the studies and associated data cited by OECD; however, the studies are
unpublished and are not readily available. To examine this potential relative humidity impact,
Scenario 5 imposes a saturation concentration constraint of 640 mg/m3, representing the upper
end of the saturation concentration values associated with "normal humidity conditions." This
concentration corresponds to an estimated RH, calculated by interpolation, of approximately 42
percent.
E-4 Inhalation Model Outputs and Exposure Calculations
Exposure Calculations
TWA concentrations are only used for model evaluation during sensitivity analysis and to
present information to allow for the characterization of the different exposure scenarios. The
TWA numbers are not used in the PBPK model or in the risk assessment calculations, but they
are helpful to translate the model results into concentrations that are routinely used in
exposure assessment models and in air monitoring. The PBPK model used the minute by minute
airborne concentrations that were calculated by the model directly without relying on longer
time period averages.
Maximum TWA concentrations for different averaging periods, described below, were
calculated from the 1-min averages for both the user and non-user based on their respective
exposure concentration time series. The calculations took into account the possibility that the
user can change zones within a 1-min interval (e.g., at an elapsed time of 6.25 min). The
exposure concentration was calculated for each 1-minute interval in the modeling period
(24 hrs or 1,440 1-min intervals) as follows:
For each time interval, / to / +1, for / = 0 to 1,440:
Equation E-10 Maximum Time Weighted Concentrations
4. \(CROH,i + CROH,i+l
+
)/ If., F
/2 *v *M+l
Where:
ECi,i+i = the exposure concentration over the time interval / to i +1
Ci/i and Ci/i+i = the concentrations in the use zone at times / and i+1, respectively
Page 177 of 281
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CROW,/ and CROHJ+I = the concentrations in the ROM zone at times / and i+1, respectively
Fi,i+i = the fraction of time spent in the use zone during the time interval / to i+1
These calculations, illustrated in Figure D-9, were implemented for each of the five scenarios.
C D
Model Result;
H I I
Activity Pattern .ind piTuin.il f tMuriilrjIioiT,
Ouldows 21 (Woriutap) Z2(ROH) Time
|mg/m'| rog/na, (mg/mi) (rota)
AvgZlConc AvgUCone
(Wofkihop) (HOH]
InVm'l
0
0016667
0.033333
0.05
O.CKS6667
0.083333
0.1
O.I1«C7
O.I33J33
0.15
0166667
0.113333
0.2
0.216666
0133333
0.250001
0..
l325
019737
0.27561
0.36689J
0.4 JOS I
O.SS6935
0.71478
0.853921
1.00322
1.1559
1.315S
1.4710
1.62241
7.42E-S9
I.07E-5J
1.41
Fraction of Time
Spent in Use Zone
6.S9E-S*
7.ME-58
S.07E-58
S.79E-5S
9.50E-5S
1.02E-5J
I.OSE-57
1.15E-57
1.21E-57
1.27E-S7
0.283332
0.3
0316666
0.33U34
03499W
0.366667
03S3333
0.400001
62.3374
(S059J2
5S7S6S
S«.97S6
55.IM2
S3.W07
51.7M3
50169
1.76909
1.910655
2.046KS
2.177995
2.303SS
2.42475
2-J4077
1.9S013
2.1I37S
2.24221
2,36555
2.JS395
1.S97S9
19,0 - 20,0
20.0-21.0
21.0-22.0
22,0-23,0
23.0-24.0
240-25,0
765635
J34324
7.524105
1253765
17.942
23,4853
29,02535
34.4S345
39,8174
45.00595
50.03995
54.917
J0.2462J575
1003221
.15591
31596
1.47106
1.622415
76909
1910655
2,046955
2.177995
2.303K
2.42475
2,54077
0.00066821
0.005352095
0.01M57585
00434693
0.0812601
013253
0.197377
0.275411
0.366S955
0.470519
0 5S69355
0.714788
4.8539215
1003221
1 15891
1.31596
1.47106
1622415
1.J6909
1910655
2.04«S5
2.177995
2.303SS
2.42475
2.54077
Figure_Apx E-10 Example of the Personal Concentration Calculation as Defined in Equation C-13
TWA Concentrations
In addition to the maximum 1-minute concentration and the 24-hr average concentration to
which the user and non-user were exposed, a maximum TWA exposure concentration also was
calculated for each of the following averaging periods: 10 minutes, 30 minutes, 1 hr, 4 hrs and
8 hrs. The maximum 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 min length of the averaging period) TWA concentration values within the 24-hr
(1,440-min) time series. For example, there are 1,430 10-min averaging periods (1,440-10), the
first of which is for time 0 to 10 minutes, the second of which is for time 1 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-specific and user-exposure concentrations predicted by MCCEM for Scenarios 1-5 are
presented in Figure_Apx E-10 through Figure_Apx E-13 at the end of this section. The non-
user's exposure concentration is the same as that shown for Zone 2 (ROM). The user's time-
Page 178 of 281
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related exposure concentration follows the same pattern for all scenarios except Scenario 2: (1)
an initial rise associated with the first stripper application; (2) a sharp decline when the user
leaves the work area; (3) a lesser rise associated with the first scraping, immediately followed
by a sharper rise associated with the second stripper application; and (4) a lesser rise associated
with the second scraping. For scenario 2, the user does not leave the work area between
stripper applications; thus, in this case the user's exposure concentration time series exactly
matches that in Zone 1 (Workshop), until the user moves to the ROM immediately following the
second scraping.
Figure_Apx E-10 shows the zone-specific and user's exposure-concentration results for Scenario
1 (brush application in the workshop with central parameter values). The non-user exposure
concentrations for this scenario, as well as for those shown in subsequent figures, are assumed to
be the same as the concentrations in the ROM. Figure_Apx E-ll shows the zone-specific and
exposure-concentration results for Scenario 2 for the workshop with parameter values (NMP
weight fraction and user location during wait period) selected to estimate upper-end
concentrations for the user. The maximum 1-min user exposure for Scenario 2 (33.4 mg/m3) is
higher than that for Scenario 1 (12.6 mg/m3) by about a factor of 2.5. The maximum
1-min non-user exposure for Scenario 2 (4.1 mg/m3) is higher than that for Scenario 1
(2.0 mg/m3) by a factor of 2.
Figure_Apx E-12 shows the zone-specific and exposure-concentration results for Scenario 3 for
the workshop with parameter values (surface area for stripper target and air exchange rate for
ROM, non-user exposure = concentration in ROM) selected to estimate upper-end
concentrations for the non-user. In this case the maximum 1-min exposure for the non-user
(10.4 mg/m3) is more than twice that for either of the previous scenarios; the maximum user
exposure (76 mg/m3) also increases by more than a factor of two relative to Scenario 2.
Figure_Apx E-13 shows the zone-specific and exposure-concentration results for the bathroom
case with a bathtub stripping activity. Scenario 4 imposes a saturation-concentration constraint
of 1,013 mg/m3 (250 ppm) whereas Scenario 5 imposes a constraint of 640 mg/m3 (158 ppm).
The saturation concentration is never reached in Scenario 4, with a predicted peak
concentration of 807 mg/m3 (199 ppm). For Scenario 5, the saturation concentration is reached
within the source cloud but remains lower than the saturation concentration in the bathroom.
The maximum 1-min exposure estimates for these two scenarios are 797 mg/m3for the user
(for Scenario 4) and 31 mg/m3 for the non-user (for both scenarios).
Figure_Apx E-14 (Scenario 6) and Figure_Apx E-15 (Scenario 7) show zone-specific and
exposure-concentration results for a spray application in the workshop. As noted previously,
each scenario has a lower (6a, 7a) and an upper (6b, 7b) estimate for the emission parameters
that are used for these upper-end exposure estimates. The maximum 1-min exposure estimates
for these two scenarios- 387 mg/m3 for the user and 62 mg/m3 for the non-user- both are
associated with Scenario 7b.
Page 179 of 281
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—Zl (Workshop)
-Z2(ROH)
8 12
Time, hours
16
20
24
•User Exposure
12
Time, hours
16
20
24
Figure_Apx E-ll Scenario 1, Brush Applied: Modeled NMP Concentrations and User Exposure for Stripper Application in Workshop Using
Parameter Values Selected for Central Tendency Exposure.
—Zl (Workshop)
-Z2(ROH)
12
Time, hours
16
20
24
12
Time, hours
Figure_Apx E-12 Scenario 2, Brush Applied: Modeled NMP Concentrations and User Exposure for Stripper Application in Workshop Using
Parameter Values Selected for Upper-end User Exposure.
Page 180 of 281
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0.
100
80
g 40
20
Zl (Workshop)
Z2 (RON)
100
16
20
24
Time, hours
Time, hours
Figure_Apx E-13 Scenario 3, Brush Applied: Modeled NMP Concentrations for Stripper Application in Workshop using Parameter Values
Selected for Upper-end User and Non-User Exposures.
Page 181 of 281
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900
800
l-o-,
g-600
2 500
! 400
§
« 300 \\
1 ,00 \\
100 I
0 +
0
a) Scenar
900
800
tq
"3 700
= 600
1 5°°
S 400 -U
3 P
300 I
1
z 200 1
100 I
Zl (Source Cloud)
— -Z2 (Bathroom)
Z3 (ROM)
|
Csat = 1013 mg/m3
V
$A
3^
4 8 12 16 20 2
Time, hours
io 4, Saturation Concentration Constraint at 1,013 mg>
^^^Zl (Source Cloud)
— -Z2 (Bathroom)
Z3 (ROH)
J Csat = 640 mg/m3
I
I >,
V A
900
E
0
e
<3 300
0.
z 200 -
100
0 -
4 c
'm3
900
I5 700
i
* 500
0
u
OL 300
z 200
100
o -
I
^^~User Exposure
C5at= 1013 mg/m3
.
rl
J |
4 8 12 16 20 2
Time, hours
^^User Exposure
Jt
li
h
20
24
0 4 8 12 16
Time, hours
b) Scenario 5, Saturation Concentration Constraint at 640 mg/m3
8 12 16
Time, hours
20
24
Figure_Apx E-14 Modeled NMP Concentrations for Scenarios 4 and 5, Brush Application in Bathroom using Parameter Values selected for
Upper-end to Bounding User and Non-User Exposures.
Page 182 of 281
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o
0.
•Zl (Workshop)
•Z2 (ROH)
0
16
20
24
12
Time, hours
a) Scenario 6a, User Upper-end Concentrations and Exposure, Lower Estimate
300
—Zl (Workshop)
-Z2 (ROH)
300
16
20
24
12
Time, hours
12
Time, hours
b) Scenario 6b, User Upper-end Concentrations and Exposure, Upper Estimate
Figure_Apx E-15 Modeled NMP Concentrations for Scenarios 6a and 6b, Spray Application to Coffee Table in Workshop using Lower and
Upper Estimates for Emission Parameter Values selected for Upper-end User Exposures.
Page 183 of 281
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100
O.
-Zl (Workshop)
-22 (ROH)
100
90
80
i 70
r eo -
; so
: 40 -
', 30 -
20
10
0
-User Exposure
16
20
24
0
12
Time, hours
16
20
24
a) Scenario 7a, User and Non-user Upper-end Concentrations and Exposure, Lower Estimate for Emission Parameters
I
-
0.
z
-Zl (Workshop)
-Z2(ROH)
600
550
500
"E450 -
"^400
§350 -
a
2 300
§ 250
e
u 200
S 150
•z.
100
50
0
•User Exposure
16
20
24
12
Time, hours
16
20
24
b) Scenario 7b, User and Non-user Upper-end Concentrations and Exposure, Upper Estimate for Emission Parameters
Figure_Apx E-16 Modeled NMP Concentrations for Scenarios 7a and 7b, Spray Application to Chest in Workshop using Lower and Upper
Estimates fir Parameter Values selected for Upper-end User and Non-user Exposures.
Page 184 of 281
-------
E-5 MCCEM Inhalation Modeling Case Summaries
NMP Summaries
Formula:
CASRN:
Molecular Weight:
Density:
Appearance:
Melting Point:
Boiling Point:
Conversion units: 1 ppm =
Saturation Concentration:
Saturation Concentration:
C5H9NO
872-50-4
99.13 g/mol
1.028 g/cm2 (liquid)
clear liquid
-24 °C = -11 °F = 249 K
203°C=397°F = 476K
4.054397 mg/m3
~1,013 mg/m3 (equivalent to a vapor pressure of 0.190 Torr at
25 °C, used in Scenario 5, based on (OECD, 2007). See section E-
3)
~640 mg/m3 (representing the upper end of the saturation
concentration values associated with "normal humidity
conditions." See section E-3)
E-5-1 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
ROM-outdoors
Workshop-ROM
68 m3/h
197.1 m3/h (0.45 ACH)
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 x 0.25 (wt fraction) = 270 g
Page 185 of 281
-------
Total NMP mass released (theoretical, both exponentials) = 1,080 g x 0.25 (wt fraction) x 0.8695
(release fraction, theoretical) = 234.8 g
For each of the 2 applications:
ki = 32.83/hr
% Mass for Exponential 1 = 0.7% = 0.007*1,080*0.25 (wt fraction) * 0.5 (half per application)
= 0.95 g or 0.8% of released NMP
Eoi = Mass * ki = 0.95*32.83 = 31.1 g/hr (NOTE: only k and Mass are needed as MCCEM inputs)
k2 = 0.00237/hr
% Mass for Exponential 2 = 86.2% = 0.862*1,080*0.25 (wt fraction) * 0.5 (half per application)
= 116.4 g or 99.2% of released NMP
E02 = Mass * k2 = 116.4*0.00237 = 0.276 g/hr (NOTE: only k and Mass are needed as MCCEM
inputs)
Application Times and Activity Patterns:
Episode
1) Coffee Table, Brush-On,
Workshop, User ROM during wait
time, 0.45 ACH, 0.25 Weight
Fraction
Elapsed Time from Time Zero, Minutes (Product User Location)
Apply 1
0-5 (Use)
Wait 1
5-35
(ROM)
Scrape 1
35-45
(Use)
Apply 2
45-50
(Use)
Wait 2
50-80
(ROM)
Scrape 2
80-90
(Use)
User in ROM at the end of Scraping 2
User in ROM for the remainder of the run (22 hrs, 30 minutes)
Model RunTime:
0-24 hrs
User takes out scrapings after 90 minutes; emissions truncated.
MCCEM Results Summary
Personal Exposures (maximum values over first 24 hrs):
These values were generated for comparison purposes only as described in section E-4.
In mg/m3
Individual
User
Other
1 min
12.6
2.0
10 min
6.8
2.0
30 min
3.6
2.0
Ihr
3.5
1.9
4hr
1.8
1.3
8hr
1.1
0.8
24 hr
0.4
0.3
Inppm
Individual
User
Other
1 min
3.1
0.5
10 min
1.7
0.5
30 min
0.9
0.5
Ihr
0.9
0.5
4hr
0.5
0.3
8hr
0.3
0.2
24 hr
0.1
0.1
Page 186 of 281
-------
0
>Z1 (Workshop)
•Z2(ROH)
12
Time, hours
16
20
24
0
0
'User Exposure
4
8
12
Time, hours
16
20
24
Page 187 of 281
-------
E-5-2 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
ROM volume = 492 - 54 = 438 m3
Airflows:
Workshop-outdoors
ROM-outdoors
Workshop-ROM
68 m3/h
197.1 m3/h (0.45 ACH)
107 m3/h
NMP Mass Released:
Coffee Table = 10 sq ft surface area
Applied product mass = 1,080 g
Applied NMP = 1,080 g x 0.5 (wt fraction) = 540 g
Total NMP mass released (both exponentials) = 1,080 g x 0.5 (wt fraction) x 0.8695 (release
fraction, theoretical) =469.5 g
For each of the 2 applications:
ki = 32.83/hr
% Mass for Exponential 1 = 0.7% = 0.007*1,080*0.5 (wt fraction) * 0.5 (half per application)
= 1.90 g or 0.8% of released NMP
Eoi = Mass * ki = 1.86*32.83 = 62.2 g/hr (NOTE: only k and Mass are needed as MCCEM inputs)
k2 = 0.00237/hr
% Mass for Exponential 2 = 86.2% = 0.862*1,080*0.5 (wt fraction) * 0.5 (half per application)
= 232.9 g or 99.2% of released NMP
E02 = Mass * k2 = 232.9*0.00237 = 0.553 g/hr (NOTE: only k and Mass are needed as MCCEM
inputs)
Page 188 of 281
-------
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
Elapsed Time from Time Zero, Minutes (Product User Location)
Apply 1
0-5 (Use)
Wait 1
5-35 (Use)
Scrape 1
35-45
(Use)
Apply 2
45-50
(Use)
Wait 2
50-80
(Use)
Scrape 2
80-90
(Use)
User in ROM at the end of Scraping 2
User in ROM for the remainder of the run (22 hrs, 30 minutes)
Model RunTime:
0-24 hrs
User takes out scrapings after 90 minutes; emissions truncated.
MCCEM Results Summary
Personal Exposures (maximum values over first 24 hrs):
These values were generated for comparison purposes only as described in section E-4.
In mg/m3
Individual
User
Other
1 min
33.4
4.1
10 min
31.1
4.1
30 min
24.2
4.0
Ihr
19.1
3.9
4hr
8.3
2.6
8hr
4.4
1.5
24 hr
1.5
0.5
Inppm
Individual
User
Other
1 min
8.2
1.0
10 min
7.7
1.0
30 min
6.0
1.0
Ihr
4.7
1.0
4hr
2.0
0.6
8hr
1.1
0.4
24 hr
0.4
0.1
Page 189 of 281
-------
Plots:
0
0
0
4
>Z1 (Workshop)
>Z2 (ROM)
8
12
Time, hours
16
20
24
>User Exposure
8
12
Time, hours
16
20
24
Page 190 of 281
-------
E-5-3 NMP Scnario 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
ROM-outdoors
Workshop-ROM
68 m3/h
78.8 m3/h (0.18 ACH)
65.8m3/h
NMP Mass Released:
Chest = 25 sq ft surface area
Applied product mass = 2,700 g
Applied NMP = 2,700 g x 0.5 (wt fraction) = 1,350 g
Total NMP mass released (both exponentials) = 2,700 g x 0.5 (wt fraction) x 0.8695 (release
fraction, theoretical) =1173.8 g
For each of the 2 applications:
ki = 32.83/hr
% Mass for Exponential 1 = 0.7% = 0.007*2,700*0.5 (wt fraction) * 0.5 (half per application)
= 4.74 g or 0.8% of released NMP
Eoi = Mass * ki = 4.739*32.83 =155.6 g/hr (NOTE: only k and Mass are needed as MCCEM
inputs)
k2 = 0.00237/hr
% Mass for Exponential 2 = 86.2% = 0.862*2,700*0.5 (wt fraction) * 0.5 (half per application)
= 582.2 g or 99.2% of released NMP
E02 = Mass * k2 = 582.2*0.00237 = 1.382 g/hr (NOTE: only k and Mass are needed as MCCEM
inputs)
Page 191 of 281
-------
Application Times and Activity Patterns:
Episode
3) Chest, Brush-On, Workshop,
User in ROM during wait time, 0.18
ACH, 0.5 Weight Fraction
Elapsed Time from Time Zero, Minutes (Product User Location)
Apply 1
0-12.5
(Use)
Wait 1
12.5-42.5
(ROM)
Scrape 1
42.5-67.5
(Use)
Apply 2
67.5-80
(Use)
Wait 2
80-110
(ROM)
Scrape 2
110-135
(Use)
User in ROM at the end of Scraping 2
User in ROM for the remainder of the run (21 hrs, 45 minutes)
Model RunTime:
0-24 hrs
User takes out scrapings after 135 minutes; emissions truncated.
MCCEM Results Summary
Personal Exposures (maximum values over first 24 hrs):
These values were generated for comparison purposes only as described in section E-4.
In mg/m3
Individual
User
Other
1 min
76.0
10.4
10 min
51.4
10.4
30 min
32.7
10.3
Ihr
25.4
10.2
4hr
15.6
8.3
8hr
10.3
6.2
24 hr
3.9
2.5
In ppm
Individual
User
Other
1 min
18.7
2.6
10 min
12.7
2.6
30 min
8.1
2.5
Ihr
6.3
2.5
4hr
3.9
2.1
8hr
2.5
1.5
24 hr
1.0
0.6
Page 192 of 281
-------
Plots:
o
u
z
100
80
60 -
40
20
II (Workshop)
Z2(ROH)
0
0
100
80 -
o
u
a.
0
16
20
8
12
Time, hours
16
20
24
24
Page 193 of 281
-------
E-5-4 NMP Scenario 4. 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 1013 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
Source cloud - bathroom
Source cloud - outdoors
ROM-outdoors
Bathroom-ROH
1.6 m3/h
80 m3/h
0
86.9 m3/h
(0.18 ACH)
35 m3/h
NMP Mass Released:
Bathtub = 36 sq ft surface area
Applied product mass = 3,888 g
Applied NMP = 3,888 g x 0.5 (wt fraction) = 1,944 g
Total NMP mass released (both exponentials) = 3,888 g x 0.5 (wt fraction) x 0.8695 (release
fraction, theoretical) = 1690.3 g
For each of the 2 applications:
ki = 32.83/hr
% Mass for Exponential 1 = 0.7% = 0.007*3,888*0.5 (wt fraction) * 0.5 (half per application)
= 6.82 g or 0.8% of released NMP
Eoi = Mass * ki = 6.82*32.83 = 224.0 g/hr (NOTE: only k and Mass are needed as MCCEM
inputs)
k2 = 0.00237/hr
% Mass for Exponential 2 = 86.2% = 0.862*3,888*0.5 (wt fraction) * 0.5 (half per application)
= 838.3 g or 99.2% of released NMP
E02 = Mass * k2 = 838.3*0.00237 = 1.99 g/hr (NOTE: only k and Mass are needed as MCCEM
inputs)
Page 194 of 281
-------
Application Times and Activity Patterns:
Episode
4) Bathtub, Brush-On, Bathroom +
Source Cloud, User in ROM during
wait time, 0.18 ACH, 0.50 Weight
Fraction
Elapsed Time from Time Zero, Minutes (Product User Location)
Apply 1
0-18 (Use)
Wait 1
18-48
(ROM)
Scrape 1
48-84
(Use)
Apply 2
84-102
(Use)
Wait 2
102-132
(ROM)
Scrape 2
132-168
(Use)
User in ROM at the end of Scraping 2
User in ROM for the remainder of the run (21 hrs 12 minutes)
Model RunTime:
0-24 hrs
User takes out scrapings after 168 minutes; emissions truncated.
MCCEM Results Summary
Personal Exposures (maximum values over first 24 hrs):
These values were generated for comparison purposes only as described in section E-4.
In mg/m3
Individual
User
Other
1 min
796.8
30.7
10 min
691.7
30.7
30 min
365.96
30.5
Ihr
234.4
30.1
4hr
136.0
25.9
8hr
77.4
20.4
24 hr
28.6
9.4
In ppm
Individual
User
Other
1 min
196.5
7.6
10 min
170.6
7.6
30 min
90.2
7.5
Ihr
57.8
7.4
4hr
33.5
6.4
8hr
19.1
5.0
24 hr
7.1
2.3
Page 195 of 281
-------
Plots:
1000
0
0
Zl (Source Cloud)
Z2 (Bathroom)
Z3 (ROM)
1000
900
<. 700
I
* 600
re
a.
400
100
0
0
Exposure
Csat= 1013 mg/m3
8 12 16
Time, hours
20
24
Page 196 of 281
-------
E-5-5 NMP Scenario 5. 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
Source cloud - bathroom
Source cloud - outdoors
ROM-outdoors
Bathroom-ROH
1.6 m3/h
80 m3/h
0
86.9 m3/h
(0.18 ACH)
35 m3/h
NMP Mass Released:
Bathtub = 36 sq ft surface area
Applied product mass = 3,888 g
Applied NMP = 3,888 g x 0.5 (wt fraction) = 1,944 g
Total NMP mass released (both exponentials) = 3,888 g x 0.5 (wt fraction) x 0.8695 (release
fraction, theoretical) = 1690.3 g
For each of the 2 applications:
ki = 32.83/hr
% Mass for Exponential 1 = 0.7% = 0.007*3,888*0.5 (wt fraction) * 0.5 (half per application)
= 6.82 g or 0.8% of released NMP
Eoi = Mass * ki = 6.82*32.83 = 224.0 g/hr (NOTE: only k and Mass are needed as MCCEM
inputs)
k2 = 0.00237/hr
% Mass for Exponential 2 = 86.2% = 0.862*3,888*0.5 (wt fraction) * 0.5 (half per application)
= 838.3 g or 99.2% of released NMP
E02 = Mass * k2 = 838.3*0.00237 = 1.99 g/hr (NOTE: only k and Mass are needed as MCCEM
inputs)
Page 197 of 281
-------
Application Times and Activity Patterns:
Episode
5) Bathtub, Brush-On, Bathroom +
Source Cloud, User in ROM during
wait time, 0.18 ACH, 0.50 Weight
Fraction
Elapsed Time from Time Zero, Minutes (Product User Location)
Apply 1
0-18 (Use)
Wait 1
18-48
(ROM)
Scrape 1
48-84
(Use)
Apply 2
84-102
(Use)
Wait 2
102-132
(ROM)
Scrape 2
132-168
(Use)
User in ROM at the end of Scraping 2
User in ROM for the remainder of the run (21 hrs 12 minutes)
Model RunTime:
0-24 hrs
User takes out scrapings after 168 minutes; emissions truncated.
MCCEM Results Summary
Personal Exposures (maximum values over first 24 hrs):
These values were generated for comparison purposes only as described in section E-4.
In mg/m3
Individual
User
Other
1 min
640.0
30.7
10 min
627.8
30.7
30 min
344.6
30.5
Ihr
223.8
30.1
4hr
133.2
25.9
8hr
76.0
20.4
24 hr
28.1
9.4
Inppm
Individual
User
Other
1 min
157.9
7.6
10 min
154.9
7.6
30 min
85.0
7.5
Ihr
55.2
7.4
4hr
32.8
6.4
8hr
18.7
5.0
24 hr
6.9
2.3
Page 198 of 281
-------
1000
900
mE 800
M
o
'•p
ra
+*
g
u
400
100 -
0
Exposure
mg/rrr
8
12
Time, hours
16
20
24
Page 199 of 281
-------
E-5-6 NMP Scenario 6a. 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
ROM volume = 492 - 54 = 438 m3
Airflows:
Workshop-outdoors
ROM-outdoors
Workshop-ROM
68 m3/h
197.1 m3/h (0.45 ACH)
107 m3/h
NMP Mass Released:
Coffee Table = 10 sq ft surface area
Applied product mass = 810 g
Applied NMP = 810 g x 0.53 (wt fraction) = 429.3 g
Total NMP mass released (both exponentials) = 810 g x 0.53 (wt fraction) x 0.8695 (release
fraction, theoretical) =373.3 g
For each of the 2 applications:
ki = 32.83/hr
% Mass for Exponential 1 = 0.7% = 0.007 *810 *0.53 (wt fraction) * 0.5 (half per application)
= 1.5g
Eoi = Mass * ki = 1.5*32.83 =49.245 g/hr (NOTE: only k and Mass are needed as MCCEM inputs)
k2 = 0.00237/hr
% Mass for Exponential 2 = 86.25% = 0.8625 *810 *0.53 (wt fraction) * 0.5 (half per application)
= 185.1 g
E02 = Mass * k2 = 185.1*0.00237=0.439 g/hr (NOTE: only k and Mass are needed as MCCEM inputs)
Application Times and Activity Patterns:
Episode
6a) Coffee Table, Spray-On,
Workshop, User in workshop
during wait time, 0.45 ACH, 0.53
Weight Fraction
Elapsed Time from Time Zero, Minutes (Product User Location)
Apply 1
0-2.5
(Use)
Wait 1
2.5 -32.5
(Use)
Scrape 1
32.5-42.5
(Use)
Apply 2
42.5-45
(Use)
Wait 2
45-75
(Use)
Scrape 2
75-85
(Use)
User in ROM at the end of Scraping 2
User in ROM for the remainder of the run (22 hrs, 35 minutes)
Page 200 of 281
-------
Model RunTime:
0-24 hrs
User takes out scrapings after 85 minutes; emissions truncated.
MCCEM Results Summary
Personal Exposures (maximum values over first 24 hrs):
These values were generated for comparison purposes only as described in section E-4.
In mg/m3
Individual
User
Other
1 min
27.3
3.2
10 min
25.3
3.2
30 min
19.5
3.2
Ihr
15.9
3.1
4hr
6.5
2.0
8hr
3.5
1.2
24 hr
1.2
0.4
In ppm
Individual
User
Other
1 min
6.7
0.8
10 min
6.2
0.8
30 min
4.8
0.8
Ihr
3.9
0.8
4hr
1.6
0.5
8hr
0.9
0.3
24 hr
0.3
0.1
Plots:
S
3
50
40 -
30
20
10
0
0
•Zl (Workshop)
>Z2(ROH)
12
Time, hours
16
20
24
Page 201 of 281
-------
0
4
12
Time, hours
16
20
24
Page 202 of 281
-------
E-5-7 New Scenario 6b. 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
ROM volume = 492 - 54 = 438 m3
Airflows:
Workshop-outdoors
ROM-outdoors
Workshop-ROM
68 m3/h
197.1 m3/h (0.45 ACH)
107 m3/h
NMP Mass Released:
Coffee Table = 10 sq ft surface area
Applied product mass = 810 g
Applied NMP = 810 g x 0.53 (wt fraction) = 429.3 g
Total NMP mass released (both exponentials) = 810 g x 0.53 (wt fraction) x 0.8695 (release
fraction, theoretical) =373.3 g
For each of the 2 applications:
ki = 32.83/hr
% Mass for Exponential 1 = 7% = 0.07 *810 *0.53 (wt fraction) * 0.5 (half per application)
= 15.0g
Eoi = Mass * ki = 15*32.83 =492.45 g/hr (NOTE: only k and Mass are needed as MCCEM inputs)
k2 = 0.00237/hr
% Mass for Exponential 2 = 79.95% = 0.7995 *810 *0.53 (wt fraction) * 0.5 (half per application)
= 171.6 g
E02 = Mass * k2 = 171.6*0.00237=0.41 g/hr (NOTE: only k and Mass are needed as MCCEM inputs)
Application Times and Activity Patterns:
Episode
6b) Coffee Table, Spray-On,
Workshop, User in workshop
during wait time, 0.45 ACH, 0.53
Weight Fraction
Elapsed Time from Time Zero, Minutes (Product User Location)
Apply 1
0-2.5
(Use)
Wait 1
2.5 -32.5
(Use)
Scrape 1
32.5-42.5
(Use)
Apply 2
42.5-45
(Use)
Wait 2
45-75
(Use)
Scrape 2
75-85
(Use)
User in ROM at the end of Scraping 2
User in ROM for the remainder of the run (22 hrs, 35 minutes)
Page 203 of 281
-------
Model RunTime:
0-24 hrs
User takes out scrapings after 85 minutes; emissions truncated.
MCCEM Results Summary
Personal Exposures (maximum values over first 24 hrs):
These values were generated for comparison purposes only as described in section E-4.
In mg/m3
Individual
User
Other
1 min
245.9
26.4
10 min
224.0
26.4
30 min
160.9
26.0
Ihr
138.6
24.8
4hr
53.3
16.2
8hr
28.3
9.6
24 hr
9.5
3.3
In ppm
Individual
User
Other
1 min
60.6
6.5
10 min
55.3
6.5
30 min
39.7
6.4
Ihr
34.2
6.1
4hr
13.2
4.0
8hr
7.0
2.4
24 hr
2.3
0.8
Plots:
]
o
j
0.
300
250
200
150
100
50 -
Page 204 of 281
-------
300
4
8
12
Time, hours
16
20
24
Page 205 of 281
-------
E-5-8 NMP Scenario 7a 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
ROM-outdoors
Workshop-ROM
68 m3/h
78.8 m3/h (0.18 ACH)
65.8m3/h
NMP Mass Released:
Chest = 25 sq ft surface area
Applied product mass = 2,025 g
Applied NMP = 2,025 g x 0.53 (wt fraction) = 1,073.25 g
Total NMP mass released (both exponentials) = 2,025 g x 0.53 (wt fraction) x 0.8695 (release
fraction, theoretical) = 933.19 g
For each of the 2 applications:
ki = 32.83/hr
% Mass for Exponential 1 = 0.7% = 0.007 *2025 *0.53 (wt fraction) * 0.5 (half per application)
= 3.76g
Eoi = Mass * ki = 3.76*32.83 =123.322 g/hr (NOTE: only k and Mass are needed as MCCEM inputs)
k2 = 0.00237/hr
% Mass for Exponential 2 = 86.25% = 0.8625 *2025*0.53 (wt fraction) * 0.5 (half per application)
= 462.84 g
E02 = Mass * k2 = 462.84*0.00237=1.097 g/hr (NOTE: only k and Mass are needed as MCCEM inputs)
Application Times and Activity Patterns:
Episode
7a) Coffee Table, Spray-On,
Workshop, User in ROH during wait
time, 0.18 ACH, 0.53 Weight
Fraction
Elapsed Time from Time Zero, Minutes (Product User Location)
Apply 1
0-6.25
(Use)
Wait 1
6.25-36.25
(ROH)
Scrape 1
36.25-
61.25
(Use)
Apply 2
61.25-
67.5 (Use)
Wait 2
67.5-97.5
(ROH)
Scrape 2
97.5-
122.5
(Use)
User in ROH at the end of Scraping 2
User in ROH for the remainder of the run (21 hrs, 57.5 minutes)
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Model RunTime:
0-24 hrs
User takes out scrapings after 122.5 minutes; emissions truncated.
MCCEM Results Summary
Personal Exposures (maximum values over first 24 hrs):
These values were generated for comparison purposes only as described in section E-4.
In mg/m3
Individual
User
Other
1 min
44.6
7.9
10 min
25.9
7.9
30 min
21.0
7.9
Ihr
15.9
7.7
4hr
9.2
5.4
8hr
5.3
3.3
24 hr
1.8
1.1
In ppm
Individual
User
Other
1 min
11.0
2.0
10 min
6.4
2.0
30 min
5.2
1.9
Ihr
3.9
1.9
4hr
2.3
1.3
8hr
1.3
0.8
24 hr
0.4
0.3
Plots:
]
o
j
0.
100
0
Page 207 of 281
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100
90 -
80 -
70
60
s
c
o
u
50 -
•User Exposure
12
Time, hours
16
20
24
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E-5-9 NMP Scenario 7b 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
ROM-outdoors
Workshop-ROM
68 m3/h
78.8 m3/h (0.18 ACH)
65.8m3/h
NMP Mass Released:
Chest = 25 sq ft surface area
Applied product mass = 2,025 g
Applied NMP = 2,025 g x 0.53 (wt fraction) = 1,073.25 g
Total NMP mass released (both exponentials) = 2,025 g x 0.53 (wt fraction) x 0.8695 (release
fraction, theoretical) = 933.19 g
For each of the 2 applications:
ki = 32.83/hr
% Mass for Exponential 1 = 7% = 0.07 *2025 *0.53 (wt fraction) * 0.5 (half per application)
= 37.56 g
Eoi = Mass * ki = 37.56*32.83 = 1233.22 g/hr (NOTE: only k and Mass are needed as MCCEM inputs)
k2 = 0.00237/hr
% Mass for Exponential 2 = 79.95% = 0.7995 *2025 *0.53 (wt fraction) * 0.5 (half per application)
= 429.03 g
E02 = Mass * k2 = 429.03*0.00237=1.02 g/hr (NOTE: only k and Mass are needed as MCCEM inputs)
Application Times and Activity Patterns:
Episode
7b) Coffee Table, Spray-On,
Workshop, User in ROH during wait
time, 0.18 ACH, 0.53 Weight
Fraction
Elapsed Time from Time Zero, Minutes (Product User Location)
Apply 1
0-6.25
(Use)
Wait 1
6.25-36.25
(ROH)
Scrape 1
36.25-
61.25
(Use)
Apply 2
61.25-
67.5 (Use)
Wait 2
67.5-97.5
(ROH)
Scrape 2
97.5-
122.5
(Use)
User in ROH at the end of Scraping 2
User in ROH for the remainder of the run (21 hrs, 57.5 minutes)
Page 209 of 281
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Model RunTime:
0-24 hrs
User takes out scrapings after 122.5 minutes; emissions truncated.
MCCEM Results Summary
Personal Exposures (maximum values over first 24 hrs):
These values were generated for comparison purposes only as described in section E-4.
In mg/m3
Individual
User
Other
1 min
386.8
62.0
10 min
168.9
61.9
30 min
118.9
61.0
Ihr
100.1
58.4
4hr
61.6
39.9
8hr
35.4
24.2
24 hr
12.0
8.3
In ppm
Individual
User
Other
1 min
95.4
15.3
10 min
41.7
15.3
30 min
29.3
15.1
Ihr
24.7
14.4
4hr
15.2
9.8
8hr
8.7
6.0
24 hr
3.0
2.0
Plots:
c
o
o
u
0.
Zl (Workshop)
Z2(ROH)
12 16
Time, hours
20
24
Page 210 of 281
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600
550
500
"E450
"|400
§350
| 300
§250
B
3 200
•User Exposure
8
12
Time, hours
16
20
24
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Appendix F TOXICOLOGY STUDIES
F-l Literature Collection
Several high quality risk and hazard assessments were available for NMP, including RIVM
Proposal for a Restriction of NMP (RIVM, 2013), the OECD Screening Information Data Set
(OECD, 2007), OEHHA MADL (OEHHA, 2003) and the WHO Concise International Chemical
Assessment Document (CICAD) for NMP (WHO, 2001). The assessments were surveyed to
determine which endpoint or endpoints yielded relevant, sensitive and consistent effects. As
described in section 3.1.2, EPA/OPPT determined developmental toxicity endpoints are the
most sensitive, relevant and consistent across multiple studies. Every publicly available study
evaluating developmental toxicity endpoints was obtained for EPA/OPPT review. In addition, a
small number of recent toxicological studies were identified by peer reviewers and public
commenters and were also considered in the assessment.
F-2 Study Quality and Selection Considerations
Toxicological studies were evaluated for quality, considering soundness, applicability and utility,
clarity and completeness and uncertainty and variability (EPA, 2014a). Specifically, each
laboratory animal-based study was reviewed considering the following factors:
• the adequacy of study design,
• test animals (e.g., species, strain, source, sex, age/lifestage/embryonic stage),
• environment (e.g., husbandry, culture medium),
• test substance (e.g., identification, purity, analytical confirmation of stability and
concentration),
• treatment (e.g., dose levels, controls, vehicle, group sizes, duration, route of
administration),
• endpoints evaluated (e.g., schedule of evaluation, randomization and blinding
procedures, assessment methods) and
• reporting (quality and completeness)
The evaluation also included a number of considerations, as described below in Table_Apx F-l
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Table_Apx F-l Study Quality Considerations
Feature
Exa mple Questions
Exposure
Quality
•Were the exposures well designed and tightly
controlled?
•Was the test article/formulation adequately identified
and characterized? Are co-exposures expected as a
result of test article composition?
• Is the administration route relevant to human
exposure?
•Are the exposure levels relevant?
• Inhalation exposure: Were analytical concentrations in
the test animals' breathing zone measured and reported
(i.e., not just target or nominal concentrations)?
• Inhalation exposure: For aerosol studies, were the mass
median aerodynamic diameter and geometric standard
deyjatrgjijeggrtgd?
• Inhalation exposure: Was the chamber type appropriate?
Dynamic chambers should be used; static chambers are not
recommended.
• Inhalation exposure: Were appropriate methods used to generate
the test article and measure the analytical concentration?
• Diet/Water Exposure: Was consumption measured to allow for
accurate dose determinations? Were stability and homogeneity
of the test substance maintained? Was palatability an issue?
•Gavage Exposure: Was an appropriate vehicle used? Are there
any toxkokinetk differences due to bolus dosing? Consider
relevance to human exposures.
Test Animals
•Were the test animals appropriate foi evaluation of the
specified effecl(s)?
•Were the species, strain, sex, and/or age of the test
animals appropriate for the effect{s) measured?
•Were the control and exposed populations matched in
all aspects other than exposure?
• Were an appropriate number of animals examined, based on
what is knownabout the particular endpoint(s) in question?
•Were there any notable issues regarding animal housing or food
and water consumption?
Study Design
• Is the study design appropriate for the effect(s) and
chemical analyzed?
•Were exposure frequency and duration appropriate for
the effect)s) measured?
•Were anticipated confounding factors caused by
selection bias controlled for in the study design (e.g.,
correction for potential litter bias; randomization of
treatment groups)?
• Was the timing of the endpoint evaluation (e.g., latency
from exposure) appropriate?
•Was it a Good laboratory Practices (GLP) study?
• Was it designed according to established guidelines (e.g., EPA,
OECO)? Was it designed to specifically test the endpoint(s)in
question?
• Did the study design include other experimental procedures (e.g.,
surgery) that may influence the results of the toxicity endpoint(s)
in question? Were they controlled for?
•Was the study design able to detect the most sensitive effects in
the most sensitive population);)?
•Were multiple exposure groups tested? Was justification for
exposure group spacing given? Was recovery or adaptation
tested?
Toxicity
Endpoints
•Are the protocols used for evaluating a specific
endpoint reliable and the study endpoints chosen
relevant to humans?
•Are the endpoints measured relevant to humans? Do
the endpoints evaluate an adverse effect on the health
outcome in question?
•Were the outcomes evaluated according to established
protocols? If not, were the approaches biologically
sound? Were any key protocol details omitted?
• Were all necessary control experiments performed to allow for
selective examination of the endpoint in question?
•As appropriate, were steps taken to minimize experimenter bias
(e.g., blinding}?
• Does the methodotagy employed represent the most appropriate
and discriminating option for the chosen endpoint?
Data
Presentation
and Analysis
•Were statistical methods and presentation of data
sufficient to accurately define the direction and
magnitude of the observed effect(s)?
•Are the statistical methods and comparisons
appropriate?
•Was sufficient sampling performed to detect a
biologically relevant effect (e.g..appropriate number of
slides examined)?
• Does the data present pooled groups that should be displayed
separately (e.g., pooled exposure groups; pooled sexes) and/or
analyzed separately?
•Wasan unexpectedly high/low level of within-study variability
and/or variation from historical measures reported or explained?
• As appropriate, were issues such as systemic and maternal
toxicity (e.g., body weight) considered?
Reporting
•Are descriptions of study methods and results for all
endpoints sufficient to allow for study quality
evaluations?
•Were the details of the exposure protocols and
equipment provided?
•Were test animal specifics adequately presented?
•Are the protocols for all study endpoints clearly
described? Is sufficient detail provided to reproduce the
exppnmentjsj?
•Are the statistical methods applied for data analysis provided and
applied in a transparent manner? Was variability reported?
• Did the study evaluate a unique cohort of animals (i.e., are
multiple studies linked)?
•Are group sizes and results reported quantitatively for each
exposure group, time-point, and endpoint examined?
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F-3 Developmental Toxicity Studies Considered for Use in Risk
Assessment
The studies summarized in this section were identified for consideration in the dose-response
assessment, as described in section 3.1.3.
F-3-1 Oral Toxicity Studies
Sitarek et al., 2012
Sitarek et al. (2012) examined the reproductive toxicity of NMP by oral gavage in female Wistar
rats. Females were exposed to aqueous NMP solutions of 0,150, 450 and 1,000 mg/kg bw/day
(26% of the LDso). The number of females in the exposure groups was 24, 26, 28 and 22 animals
respectively. Exposures were 5 days/week 2 weeks before mating, 1 week of mating, 3 weeks of
gestation and 3 weeks of lactation. The litter size was reduced to 8 pups 4 days after birth.
Offspring were assessed for litter weight, mean pup weight and mortality. The 0, 150 and 450
mg/kg bw/day dams were sacrificed after 21 days of lactation. Females from the 1,000 mg/kg
bw/day group with no delivery were sacrificed 25 days after mating. Major organs were
selected for histopathology.
Two of the females in the high dose group died during the experiment. No other animals died.
Water and food consumption was reduced in the 1,000 mg/kg bw/day but not the other
exposure groups. At day 20 of gestation, all treated female BW values were significantly less
than controls but did not differ on day 21 of lactation in the low and mid dose females. The
percent BW gain for this period is presented in Table_Apx F-2 below. Organ weights in the
1,000 mg/kg bw/day group were not evaluated because they were sacrificed on day 25 after
insemination. Absolute and relative organ weights in the 150 and 450 mg/kg bw/day groups
were not different from control with the exception of increased relative thyroid weights in 450
mg/kg females. However, the thyroid was not examined histopathologically so the significance
of this single finding is uncertain. Hematocrit values were statistically significantly different
from control at the 150 and 450 mg/kg bw/day doses (Sitarek et al., 2012).
Microscopic examination of the 1,000 mg/kg bw/day females revealed normal lungs, liver,
kidneys, spleen, brain and adrenal glands. However, they had a lower number of corpora lutea
in comparison to control, low and mid dose females. Infiltrations of mononuclear cells,
granulocytes and early resorptions were noted in the uterine mucosa and myometrium were
also noted in the 1,000 mg/kg bw/day females. The NOAEL for the dams is 450 mg/kg bw/day
(Sitarek etal., 2012).
The reproductive performance of females is detailed in Table_Apx F-2. Fertility and offspring
viability were drastically affected in 1,000 mg/kg bw/day females. Only 15 of 22 inseminated
Page 214 of 281
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females became pregnant and only 7 of them gave birth to a total of 3 live-born and 5 stillborn.
The live born fetuses did not survive to day 4 of lactation. The percent of pregnant females in
the 450 mg/kg bw/day was less than control. The percent of pups that survived to day 4 and
day 21 was significantly less than control in the 150 and 450 mg/kg bw/day females. The pup
body weights on day 4 were significantly lower than control in the low and mid dose groups but
recovered by day 21 in the 150 mg/kg bw/day group. The LOAEL for developmental effects on
the offspring is 150 mg/kg, based on viability of offspring (Sitarek et al., 2012).
Table_Apx F-2 Reproductive Performance of Females, Summarized from Sitarek et al, 2012
Dose mg/kg
bw/day
0
150
450
1,000
Number of Animals
Mating females
with males
Pregnant
females
Died females*
Live pups per
litter
Dead pups per
litter
Sex ratio (F : M)
24
22
0
11.5±3.5a
0.18 ±0.85
132 : 125
26
24
0
10.4 ±2.6
0
112:137
28
20
0
10.5 ±3.4
0.13 ±0.34
105:107
22
15
2
0.33±0.82b
0.80±l.lb
5:3
Indices
Fertility %c
Viability %d
Lactation %e
Body weight
gain of mothers
from 0 to 20 GD
(% control)
91.7
94.0
96.1
100
92.3
86.4b
78.2b
87.7
71.4b
71.6b
43.4b
75.6
68.2b
0
0
40.8
Notes:
*Two nonpregnant females died in the 30th and in the 32nd day of experiment, respectively.
a Mean ±SD.
b Significantly different (p < 0.05) from control value.
c Fertility index = percentage of pregnant females in mating females group
d Viability index = percentage of pups born alive that survived to 4 days
e Lactation index = percentage of pups alive at 4 days that survived to 21 days
F, female; M, male; GD, gestation day.
Sitarek and Stetkiewicz, 2008
Sitarek and Stetkiewicz (2008) examined the reproductive toxicity of NMP in male lmp:WIST
rats. Male rats, 24 per dose, were exposed by gavage to aqueous NMP solutions of 0, 100, 300
and 1,000 mg/kg bw/day (identified as 25% of the LDso) for 5 days/week, 10 weeks before
Page 215 of 281
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mating and 1 week during mating. Males were paired in a 1:1 ratio except 1,000 mg/kg bw/day
males were paired with 2 females. Females were not treated. At the end of mating, the males
were sacrificed and macroscopic examination of internal organs, hematocrit with absolute and
relative organ weight data collected. Testis and epididymis were examined histopathologically.
Postnatal development of the offspring was examined through the end of lactation on day 28.
On day 4 the litter size was reduced to 8 animals. Pups were examined on days 1, 4, 7, 14 and
21 for body weight, day of pinna detachment, incisor eruption and lid slit opening.
The body weight gain of all treated males was significantly lower than control. The food intake
in the 100 and 300 mg/kg bw/day was 8-12% higher than control during the first weeks but did
not differ later in the study. At 100 mg/kg bw/day water intake was 8-25% lower than control
during the study whereas it was 12-16% lower only during weeks 6, 9 and 10 of exposure.
Hematocrit value was higher only in the 1,000 mg/kg bw/day group. Absolute and relative testis
weights were lower only in the high dose. Absolute and relative epididymis weights were higher
at the 2 lower doses but lower at the high dose. Significant decreases in major organ weights
were seen at the high dose. The absolute brain weight was increased at 100 and 300 mg/kg
bw/day but decreased at 1,000 mg/kg bw/day. Relative brain weights were increased at all
doses. Relative liver weights were increased in the mid and high doses.
There appears to be an inconsistency in reporting. The paper states that body weight is lower in
all exposed males and refers to Figure 1. Figure 1 illustrates change in body weight, while Table
1 lists body weights, but the table and figure do not seem to agree; Figure 1 shows significant
differences between all exposures groups and the control group but Table 1 shows differences
only between the control and high dose group. Because of this apparent discrepency,
EPA/OPPT considers making any definitive conclusions with regard to body weight and organ
weights (detailed in Table 1 of the publication) are problematic.
There was a significant lack of reproductive performance in the 1,000 mg/kg bw/day group
where only 2 of 44 mated females produced progeny and the total number of pups was 6. The
other sperm-positive females (as evidenced by the presence of sperm in their vaginal smears)
did not produce live litters. At 100 and 300 mg/kg bw/day the percent of fertile females, pups
born per litter and survival from 4-21 days did not differ from controls. However, the percent of
pups born that survived to day 4 (94.0, 95.9 and 80.9 in the 0, 100 and 300 mg/kg bw/day
groups respectively) was significantly lower at 300 mg/kg bw/day. None of the 1,000 mg/kg
pups survived to day 4. Other measures of growth and development (body weight day of pinna
detachment, incisor eruption and lid slit opening) did not differ from control in the 100 and 300
mg/kg bw/day groups. The NOAEL for developmental effects was 100 mg/kg bw/day and the
LOAEL was 300 mg/kg bw/day (reduced pup survival from day 0-4) (Sitarek and Stetkiewicz,
2008).
At 1,000 mg/kg bw/day the seminiferous epithelium was extensively damaged and stages of
spermatogenesis could not be determined. Sertoli cells and a small number of spermatogonia
and spermatocytes were observed. Early and late spermatids were not found in the tubules,
possibly due to the inhibition of the spermatocyte to spermatid stage of spermatogenesis.
Page 216 of 281
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Interstitial edema foci and intercellular edema was observed in the parabasal zone of the
seminiferous epithelium of 3/24 rats at 300 mg/kg bw/day and 2/24 rats at the 100 mg/kg
bw/day groups; the statistical significance of this finding was not evaluated (Sitarek and
Stetkiewicz, 2008).
NMP Producers Group, 1999a
In an OECD 416 guideline study, groups of 30 Sprague-Dawley rats per sex were given NMP via
the diet at initial dose levels of 0, 50,160 or 500 mg/kg bw/day for 10 weeks prior to
premating, during mating, gestation and lactation and during the rest period between
pregnancies. Concentrations were adjusted regularly in response to body weight gain. The
highest dose was reduced to 350 mg/kg bw/day due to severe pup mortality in the first litter
(Fla). The parental animals for the second generation were selected from pups of the second
litter (Fib).
NMP had no adverse effects on reproductive performance or fertility of the FO or Fl parental
animals of all substance-treated groups and as demonstrated by the clinical and
histopathological examinations. The parental Sprague-Dawley rats were not systemically
affected after reduction to 350 mg/kg bw/day. Parental toxicity in the Wistar rats consisted of
reduced body weight gain and food intake as well as kidney findings in form of impaired organ
weight and histopathological findings. Developmental toxicity was evidenced by increased pup
mortality and reduced body weight gain, including corresponding effects in the investigated
organs, in pups treated at 500/350 mg/kg bw/day. Thus, the NOAEL for reproductive
performance/fertility was 350 mg/kg bw/day. The NOAEL for systemic (parental) and
developmental toxicity was 160 mg/kg bw/day (NMP Producers Group, 1999a).
NMP Producers Group, 1999b
In an OECD 416 guideline study, groups of 25 Wistar rats per sex were given NMP via the diet at
initial dose levels of 0, 50, 160 or 500 mg/kg bw/day for 10 weeks prior to premating, during
mating, gestation and lactation and during the rest period between pregnancies.
Concentrations were adjusted regularly in response to body weight gain. The highest dose was
reduced to 350 mg/kg bw/day due to severe pup mortality in the first litter (Fla). The parental
animals for the second generation were selected from pups of the second litter (Fib).
NMP had no adverse effects on reproductive performance or fertility of the FO or Fl parental
animals of all substance-treated groups and as demonstrated by the clinical and
histopathological examinations. The Wistar rats revealed signs of systemic toxicity in each of
the high dose groups at 500 mg/kg bw/day and also after reduction to 350 mg/kg bw/day.
Parental toxicity in the Wistar rats consisted of reduced body weight gain and food intake as
well as kidney findings in form of impaired organ weight and histopathological findings.
Developmental toxicity was evidenced by increased pup mortality and reduced body weight
gain, including corresponding effects in the investigated organs, in pups treated at 500/350
mg/kg bw/day. Thus, the NOAEL for reproductive performance/fertility was 350 mg/kg bw/day.
The NOAEL for systemic (parental) and developmental toxicity was 160 mg/kg bw/day (NMP
Producers Group, 1999b).
Page 217 of 281
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Saillenfait et al., 2002
In an OECD 414 guideline study, pregnant Sprague-Dawley rats were treated via gavage with
aqueous NMP solutions of 0, 125, 250, 500 or 750 mg/kg bw/day during gestational days 6
through 20. Females were observed daily for signs of toxicity. On GD 21 females were killed and
the uterus was removed and weight; contents were examined for implantation sites,
resorptions, live/dead fetuses and corpora lutea/ovary. Live fetuses were weighed, sexed and
evaluated for external and skeletal anomalies. Half of the live fetues/litter were preserved for
internal evaluation.
Significant decreases in maternal body weight gain and food consumption were observed at
250, 500 and 750 mg/kg bw/day. Post implantation losses and the number of resorptions were
increased at 500 mg/kg bw/day. The rate of fetal malformations (external, skeletal, soft tissue)
was increased at >500 mg/kg bw/day. Malformations included external (anasarca, anal atresia),
soft tissue (persistent truncus arteriosus) and skeletal findings (fusion or absence of cervical
arches were most prominent). Reduced fetal weights were observed at >250 mg/kg bw/day,
delayed ossification of skull bones and sternebrae and an increase in skeletal variations at >500
mg/kg bw/day. There was also a very low proportion of live fetuses and an increase in the rate
of soft tissue variations at 750 mg/kg bw/day. The NOAEL for maternal toxicity and
developmental toxicity, based on fetal body weight, is 125 mg/kg bw/day. The NOAEL for
malformations was 250 mg/kg bw/day (Saillenfait et al., 2002).
Exxon Biomedical Sciences, 1992
Groups of 25 pregnant Sprague-Dawley (Crl:CD®BR) rats received an aqueous NMP solution at
dose levels of 0, 40,125 or 400 mg/kg bw/day by gavage during gestation days 6 - 15. Reduced
body weight gain was observed between gestational days 6 - 15 in dams, reduced fetal body
weights and an increase in fetal growth retardation were noted at the high dose only. The
incidence of malformations was comparable among all groups. The NOAEL for maternal and
developmental toxicity was 125 mg/kg bw/day (Exxon Biomedical Sciences, 1992).
F-3-2 Inhalation Toxicity Studies
Saillenfait et al., 2003
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 (CDs) 6 through 20 (Saillenfait et al., 2003). For exposures, the
females were transferred to stainless-steel wire-mesh exposure cages and the cages were
moved into the 200 L stainless-steel exposure chambers. NMP vapors were generated and
delivered at constant rate with an infusion pump and concentrations were monitored with a
gas chromatograph. Because NMP has a low vapor pressure, particle formation was monitored
by measuring and comparing in the number of particles in the exposure chamber between
Page 218 of 281
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control and exposure doses; no differences were observed so it was concluded that exposures
were to vapor.
Slight maternal toxicity was evidenced by significantly decreased body weight gain in the dams
on CDs 6 through 13 at 243 and 486 mg/m3 as well as decreased food consumption at 486
mg/m3 on CDs 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 (Saillenfait et al., 2003).
Mass et al., 1995
Pregnant rats were exposed by whole-body inhalation to NMP at 151 ppm (612 mg/m3) for six
hrs/day from GD 4 to 20. The concentration of N-methylpyrrolidone in the chamber was
monitored continuously and the pregnant animals were observed daily after exposure for signs
of toxicity and body weight and food consumption. On day 21 of pregnancy, the rats were
sacrificed. All rats were examined for macroscopic changes body weight, weight of intact
uterus, number of corpora lutea, number of implantations and fetuses alive, dead or resorbed.
Live fetuses were weighed, their sex determined, examined for gross external malformations
and then dissected.
No clinical signs of maternal toxicity were observed and there were no statistically significant
differences regarding the number of corpora lutea, implantations, resorptions or live fetuses
per dam. There was in the exposed group, a higher incidence of preimplantation loss (87% of
the exposed dams compared to 55% of dams in the control group (P<0.05)). In addition, the
mean fetal body weight, adjusted for litter size, was significantly lower in the exposed group.
Delayed ossification was generally observed among litters of NMP-exposed rats (Mass et al.,
1995).
Mass et al., 1994
Mass 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 PND 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. Because only one dose was
Page 219 of 281
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used, a NOAEL for neurotoxicity could not be determined. Also, this study did not include
exposures during embryogenesis and organgogenesis (pre GD 7) that may contribute to
postnatal development outcomes (Mass et al., 1994).
Du Pont, 1990
The DuPont (1990) study included both a reproductive and developmental component. For the
developmental component, 10 male and 10 female rats were exposed via whole body to 10, 52
or 116 ppm (42, 206 or 470 mg/m3 analytical) for six hrs/day seven days/week in two-
generation reproductive effects study. For the reproductive effects component, males and
females were exposed throughout the breeding period. Exposures continued for females
through pregnancy, ending on GD 20. Exposures were continued on PND 4 through PND 21.
There was no exposure after weaning of the Fl generation. Fl rats were mated with controls of
the opposite sex to produce the F2 generation. In a parallel developmental toxicity study, males
or females were exposed to 0 or 116 ppm during the breeding period and mated with
unexposed partners. Exposure to pregnant females continued through GD 20, as described
above. At GD 21, all females were sacrificed and a detailed examination of fetal development of
the offspring was conducted.
The two-generation reproduction study did not identify 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. 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.
Significant reductions in fetal and pup body weight were observed. For the pups, while there
was a significant trend for reduced body weight, the results were only significant at the high
and low exposures. The delays persisted through 21 days after birth. Interestingly, the decrease
in body weight was greatest in those pups where both parents were exposed to NMP pre-
conception; pups born to dams exposed to NMP pre-conception and pups born to males
exposed to NMP pre-conception, exhibited slightly decreased body weights, but the differences
were not significant. A delay in skeletal ossification was also noted, considered likely to be
related to delays in growth.
Despite the apparent absence of effects on reproductive parameters, there was a slight
increase in the number of early resorptions and a slight decrease in the number of live fetuses,
both indicative of fetal mortality. In addition, there was an increase in skeletal malformations,
not related to delays in ossification. There were no increases in visceral malformations (DuPont,
1990).
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Lee et al, 1987
Lee et al. (1987) includes the results of three separate studies: teratogenicity, subchronic
exposure and a 2-year carcinogenicity study. In the teratogenicity study, rats were exposed to
100 and 360 mg/m3 (25 and 89 ppm, respectively) of NMP for six hrs/day from GD 6 through 15
(Lee et al., 1987). Exposures were to vapor and a trace of aerosol, but the particle size
distribution was not analyzed. However, in the subchronic 28-day study, 95 percent of the
particles were <10 u.m in diameter.
In the dams, sporadic lethargy and irregular respiration were observed during the first three
days of exposure in both dose groups, but not seen during the remainder of the exposure
period or during the 10-day recovery period. Hence, these minor signs of neurotoxicity,
behavior and clinical findings, were considered to be reversible. 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 and the corpora lutea were
formed following ovulation and prior to GD 6. Fetal body weight was increased at 100 mg/m3,
but not at 360 mg/m3. The number of resorptions per litter was lowest in the high dose group.
There were no treatment-related increases in variations or defects in organs or skeletal
anomalies. The maternal and fetal NOAEL for six hrs of exposure was 360 mg/m3 (Lee et al.,
1987).
F-3-3 Dermal Toxicity Studies
Becci et al., 1981
Rats were exposed dermally for 8 hrs to 75, 237 and 750 mg/kg bw/day from GD 6 through 15.
Dams had collars to prevent oral ingestion (Becci et al., 1981; Becci et al., 1982; DuPont, 1992;
FDRL, 1979; 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
bw/day, 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
bw/day. 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 bw/day exposure group died before
GD 20. In the 1,100 mg/kg bw/day exposure group, 65 of 66 fetuses were resorbed. The NOAEL
of 237 mg/kg bw/day is essentially within a factor of 4+ of a totally lethal outcome for the fetus.
F-4 Human Case Report
Solomon et al. (1996) is a case report of a pregnant woman whose fetus died in utero at week
31 of pregnancy. She was exposed throughout pregnancy to NMP by inhalation and dermal
exposure. The exposure levels were unknown. However, during week 16 of the pregnancy she
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cleaned up a spill of NMP using latex gloves that dissolved in the NMP. She was ill for the next 4
days and experienced malaise, headache, nausea and vomiting.
This case-report is well-documented, ruled out reasonable complicating factors and provides
some evidence that NMP may be fetotoxic. The lack of quantitative exposure data precludes its
use in the risk assessment other than to note the qualitative support for NMP fetotoxicity that
might come about from exposures to levels causing frank toxicity.
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Appendix G HUMAN EXPOSURE STUDIES
EPA/OPPT evaluated the human NMP exposure studies that were used in the development of
the PBPK model, for ethics according to the standards established in the Acute Exposure
Guideline Levels (AEGL) Standing Operating Procedures (SOP) (NAS, 2001) and recommendation
5-7 issued by the National Academy of Sciences (NAS) in the report "Intentional Human Dosing
Studies for EPA Regulatory Purposes: Scientific and Ethical Issues" (NAS, 2004). In addition, the
ethics reviews that EPA has completed are comparable to the principles and procedures for
performing ethics reviews of intentional dosing human studies developed for reviews
conducted by the Human Studies Review Board (HSRB).
The outcome of the NMP risk assessment ethics reviews was that there was no clear and
convincing evidence that the research was fundamentally unethical or significantly deficient
relative to the ethical standards prevailing when the studies were conducted. A summary of
each study is presented below.
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G-l Review of Akkeson et al., 2004
Akesson, B., Carnerup, M. A. and Jonsson, B. A. (2004). Evaluation of exposure biomarkersfrom
percutaneous absorption of N-methyl-2-pyrrolidone. Scand. J. Work Environ. Health 30, 306-
312.
The objective of the study was to evaluate the toxicokinetic properties of NMP and its
metabolites in humans after dermal exposure to pure and diluted NMP. The authors used the
information to evaluate different biomarkers of exposure to NMP. Although the societal benefit
of the study was not explicitly discussed, it was presumed that the toxicokinetic information
may be used to identify occupational exposures to NMP, inform proper measures to reduce
exposures and/or support the derivation of occupational exposure limits for NMP.
A total of 18 healthy volunteers participated in the study, which were comprised of 6 females
aged 43-47 years and 12 males aged 27-56 years. Healthy volunteers were selected after a
health examination. Women were tested for pregnancy before the study and presumably
excluded if they were pregnant. Subjects provided written, informed consent before
participating in the study. No reference was made about the subject recruitment process and
risk/benefit considerations.
Participants were exposed dermally on the forearm to either 300 mg of pure NMP or 300 mg of
NMP in a 50% water solution for 6 hrs. Blood and urine samples were collected on the day of
exposure and up to 9 days post exposure and analyzed for NMP and 3 metabolites. None of the
participants reported irritation. The application site was slightly red for about 4 hrs after
exposure and slight dryness was observed that disappeared in 4 days on average.
Despite the gaps in the documentation of ethical information, there was no clear and
convincing evidence that the research was fundamentally unethical (e.g. intended to seriously
harm participants) or significantly deficient to the standards prevailing at the time the study
was conducted (e.g. study collected informed consent from volunteers).
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G-2 Review of Akkeson and Jonsson, 2000
Akesson, B. and Jonsson, B. A. (2000). Biological monitoring of N-methyl-2-pyrrolidone using 5-
hydroxy-N-methyl-2-pyrrolidone in plasma and urine as the biomarker. Scand. J. Work Environ.
Health 26, 213-218.
The objective of the study was to evaluate the toxicokinetic properties of the main NMP
metabolite (i.e., 5-hydroxy-l-methyl-2-pyrrolidone or 5-HNMP). The study also assessed
whether 5-HNMP can be used as a biomarker to monitor human exposure to NMP. Although
the societal benefit of the study was not explicitly discussed, it was presumed that the
toxicokinetic information may be used to identify occupational exposures to NMP, inform
proper measures to reduce exposures and/or support the derivation of occupational exposure
limits for NMP.
Six male volunteers in the age range of 28-41 yrs participated in the study. The investigators
conducted a general health examination to potential participants and selected those that were
healthy (risk minimization measure). Subjects gave written, informed consent prior to
participating in the study. No reference was made about the subject recruitment process and
risk/benefit considerations.
Subjects were exposed in an inhalation chamber to 0, 10, 25 and 50 mg/m3 NMP for 8 hrs with
at least two weeks between exposures. It seems that the investigators considered experimental
exposure human studies reporting mild irritation at 50 mg/m3 NMP when deciding to set the
highest test concentration at 50 mg/m3. In addition, the Swedish occupational exposure level
for NMP was 200 mg/m3 and the German limit was 90 mg/m3 at the time of the exposures.
Plasma and urine were collected during and after exposure and analyzed for the presence of
5-HNMP.
The study did not report health effects in the NMP-exposed subjects. Maximal plasma and urine
levels of the metabolite occurred 1 hr and 0-2 hrs, respectively, after the end of the exposure.
Half-times of plasma and urine levels were 6.3 and 7.3 hrs, respectively.
Despite gaps in documentation of ethical information, there was no clear and convincing
evidence that the research was fundamentally unethical (e.g., intended to seriously harm
participants) or significantly deficient to the standards prevailing at the time the study was
conducted (e.g., study collected informed consent from volunteers).
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G-3 Review of Akesson and Paulsson, 1997
Akesson, B. and Paulsson, K. (1997). Experimental exposure of male volunteers to N-methyl-2-
pyrrolidone (NMP): Acute effects and pharmacokinetics of NMP in plasma and urine. Occup. Environ.
Med. 54, 236-240.
The objective of the study was to evaluate the acute effects of inhalation exposure to NMP in humans as
well as measure plasma and urine concentrations of NMP during and after exposure. The long term goal
is to develop a system for biological monitoring of human exposure. Although the societal benefit of the
study was not explicitly discussed, it was presumed that the toxicokinetic information may be used to
identify occupational exposures to NMP, inform proper measures to reduce exposures and/or support
the derivation of occupational exposure limits for NMP.
Six male volunteers in the age range of 28-41 yrs participated in the study. The investigators conducted
a general health examination to potential participants and selected those that were healthy (risk
minimization measure). Subjects gave written, informed consent prior to participating in the study. No
reference was made about the subject recruitment process and risk/benefit considerations.
Subjects were exposed in an inhalation chamber to 0, 10, 25 and 50 mg/m3 NMP for 8 hrs on 4 different
days. Plasma and urine were collected during and after exposure. Nasal volume changes were measured
by acoustic rhinometry and airway resistance was measured by spirometry. Volunteers filled out a
questionnaire to report symptoms before the exposure and then every two hrs for 16 hrs.
None of the exposures caused discomfort to the eyes or upper airways. There were no changes in nasal
volume and airway resistance at any dose. NMP elimination was suggestive of a non-linear pattern. At
the end of exposure, half lives in urine ranged from 2.9-5.8 hrs and 3.5 to 6.6 in plasma. The NMP was
metabolized before excretion; only 2% was excreted as the parent compound.
Despite gaps in the documentation of ethical information, there was no clear and convincing evidence
that the research was fundamentally unethical (e.g., intended to seriously harm participants) or
significantly deficient to the standards prevailing at the time the study was conducted (e.g., study
collected informed consent from volunteers).
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G-4 Review of Bader et al., 2005
Bader, M., Keener, S. A. and Wrbitzky, R. (2005). Dermal absorption and urinary elimination of N-methyl-
2-pyrrolidone. Int. Arch. Occup. Environ. Health 78, 673-676.
The objective of the study was to evaluate the dermal absorption of NMP and its urinary elimination.
Although the societal benefit of the study was not explicitly discussed, it was presumed that the
toxicokinetic information may be used to identify occupational exposures to NMP, inform proper
measures to reduce exposures and/or support the derivation of occupational exposure limits for NMP.
A total of 7 healthy volunteers participated in the study and consisted of 4 females and 3 males, average
age of 38 yrs. There is no mention of confirmation of pregnancy status for the female subjects. It was
presumed that no pregnant women participated in the study since the investigators disclosed the
developmental toxicity of NMP in animals. Healthy volunteers were selected after a health examination.
None of the subjects reported dermal sensitization to chemicals during the medical evaluation. Subjects
provided written, informed consent prior to participating in the study. They were notified about the
irritating properties of NMP as well as the observed developmental effects in animals. No reference was
made about the subject recruitment process and risk/benefit considerations.
Subjects were dermally exposed to 1,045 mg of NMP by applying the solvent on a medical cellulose pad
and placing it on the back of the hand. The site of application was occluded with aluminum foil. The
duration of exposure was 2 hrs. An occupational physician examined the participants during the study.
The concentration of NMP in the urine was measured for 26 hrs after the beginning of the exposure.
The study reported a ti/2 of 3.2 hrs for NMP in the urine. Also, participants reported feelings of heat,
prickling and itchiness during the exposure. Moderate swelling of the skin was observed at the site of
application and one participant developed local erythema. The symptoms resolved in 24 hrs.
Despite gaps in the documentation of ethical information, there was no clear and convincing evidence
that the research was fundamentally unethical (e.g., intended to seriously harm participants) or
significantly deficient to the standards prevailing at the time the study was conducted (e.g., study
collected informed consent from volunteers).
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G-5 Review of Bader and van Thriel, 2006
Bader, M. and van Thriel, C. (2006). Human volunteer study on biomarkers of N-methyl-2-pyrrolidone
(NMP) after inhalation exposure. Report for the NMP Producers Group, Washington, DC. This is a
supplemental study supporting the following initial study:
Bader M. and van Thriel, C. (2006) Human volunteer study on chemosensory effects and evaluation of a
threshold limit value in biological material of N-methyl-2-pyrrolidone (NMP) after inhalational and
dermal exposure. Final Report to the NMP Producers Group, c/o Bergeson & Campbell, P.C., 1203
Nineteenth Street, NW, Suite 300, Washington, DC, USA.
Note that the initial study was not reviewed. We assumed that the ethical information in the initial study
and the supplemental study would be consistent between each other.
The purpose of this study was to provide additional biomonitoring data for NMP and its main
metabolites in urine and plasma. The study results were then used for a physiologically- based
pharmacokinetic model. Although the societal benefit of the study was not explicitly discussed, it was
presumed that the biomonitoring information may be used to may be used to identify occupational
exposures to NMP, inform proper measures to reduce NMP exposures and/or support the derivation of
occupational exposure limits for NMP.
Eight healthy non-smoking male volunteers, age 23-29, participated in the study. Seven of the eight
volunteers also participated in the main study, noted in section 5.1. Subjects underwent a medical
evaluation prior to exposure. The study design was approved by the Ethics Committee of the University
of Dortmund. The report stated that all participants were informed about the sampling procedures and
possible risks, with written informed consent obtained prior to the experiments. No reference was made
about the subject recruitment process and specific risk/benefit considerations.
An environmental chamber was used and subjects were exposed to three concentrations of NMP (10, 40
and 80 mg/m3) for 6 hours via inhalation and dermal exposure. The three concentrations were
presented to the volunteers in ascending order, with an exposure-free period of 1 week between two
subsequent sessions. Blood and urine samples were collected at intervals from the start of the study to
48 hours from the first exposure.
The concentrations of NMP and two major metabolites 5-HNMP and 2-HMSI were measured in plasma
and urine. The protocol did not include any assessment of health effects and there was no mention of
observed adverse health effects.
Despite gaps in the documentation of ethical information, there was no clear and convincing
evidence that the research was fundamentally unethical (e.g., intended to seriously harm participants)
or significantly deficient to the standards prevailing at the time the study was conducted (e.g., study
collected informed consent from volunteers).
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G-6 Review of Bader et al., 2007
Bader, M., Wrbitzky, R., Blaszkewicz, M. and van Thriel, C. (2007). Human experimental exposure study
on the uptake and urinary elimination of N-methyl-2-pyrrolidone (NMP) during simulated workplace
conditions. Arch. Toxicol. 81, 335-346.
The purpose of the study was to assess the elimination of NMP under workplace conditions and
determine an effective biomonitoring scheme. Although the societal benefit of the study was not
explicitly discussed, it was presumed that the toxicokinetic information may be used to identify
occupational exposures to NMP, inform proper measures to reduce exposures and/or support the
derivation of occupational exposure limits for NMP.
Sixteen male volunteers in the average age of 26.5 ± 2.4 years participated in the study. Subjects
underwent a medical evaluation to check their fitness status and the presence of respiratory, skin and
cardiovascular problems. Subjects were excluded from the study if they had respiratory problems, skin
diseases or cardiovascular diseases (e.g., hypertension) (risk minimization measure). The study was
carried out following the principles of the Declaration of Helsinki. The study design was approved by the
Ethics Committee of the University of Dortmund. No reference was made about the subject recruitment
process and risk/benefit considerations.
Subjects were exposed to 10, 40 and 80 mg/m3 NMP under an exposure paradigm that mimicked
workplace exposures. The study tested NMP inhalation concentrations that were at or below the
German workplace limit value (80 mg/m3). Exposures were whole body to resting individuals for an
initial period of 4 hrs, a 30 min break and a subsequent exposure for 4 hrs. This exposure paradigm was
repeated on another day with 6 periods of 10-min exercise on a bicycle at 76 Watts. In addition,
participants were exposed to a baseline concentration of 25 mg/m3 NMP and peak exposures of 160
mg/m3 NMP for four 15-min periods with a 2 hr break between peak exposures. During the experiment,
the study volunteers took neuropsychological test batteries and ratings to evaluate NMP's potential
chemosensory effects. In addition, urine was collected and NMP and its main metabolites, 5-hydroxy-N-
methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI), were analyzed. Urine
samples were collected at the beginning, during and up to 40 hrs after exposure.
The study did not report any effects for the exposed participants. NMP, 5-HNMP and 2-HMSI showed
close correlation between their post-shift concentrations and exposures to airborne NMP. In addition,
the study demonstrated that the total uptake of NMP was increased after moderate exercise. The
authors suggested that dermal absorption has a significant contribution to the uptake of NMP in whole-
body inhalation exposures based on differences between the estimated and the observed total amount of
urinary metabolites.
The study was conducted in accordance with the Declaration of Helsinki, was reviewed by an ethics
committee and subjects provided informed consent. There was no clear and convincing evidence that
the research was fundamentally unethical (e.g., intended to seriously harm participants) or significantly
deficient to the standards prevailing at the time the study was conducted.
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G-7 Review of Bader et al., 2008
Bader, M., Wrbitzky, R., Blaszkewicz, M., Schaper, M. and van Thriel, C. (2008). Human volunteer study
on the inhalational and dermal absorption of N-methyl-2-pyrrolidone (NMP) from the vapour phase.
Arch. Toxicol. 82, 13-20.
The purpose of the study was to determine the dermal absorption of airborne NMP vapor. Although the
societal benefit of the study was not explicitly discussed, it was presumed that the toxicokinetic
information may be used to identify occupational exposures to NMP, inform proper measures to reduce
exposures and/or support the derivation of occupational exposure limits for NMP.
Sixteen male volunteers ranging from 22-30 years participated in the study. Subjects underwent a
medical evaluation to check their fitness status and the presence of respiratory and skin problems.
Subjects were excluded from the study if they had respiratory problems or skin diseases (risk
minimization measure). The study was carried out following the principles of the Declaration of Helsinki.
The study design was approved by the Ethics Committee of the University of Dortmund and subjects
gave written, informed consent. No reference was made about the subject recruitment process and
risk/benefit considerations.
Subjects were exposed whole body to 80 mg/m3 NMP while wearing long pants and cotton shirts and
being on a resting state or doing exercise in a bicycle. Initial exposure was for 4 hrs following a break of
30 minutes. Subjects were subsequently exposed to NMP for an additional 4 hrs. The tested NMP
inhalation concentration was the German workplace limit value (80 mg/m3) at that time. The exercising
individuals were exposed to NMP during the 8-hr exposure interval while exercising in the bicycle for 6 x
10 min periods. These exposure conditions measured both inhalation and dermal absorption of airborne
NMP. For dermal-only exposures to NMP, the participants wore a face mask with activated carbon
filtered air to eliminate the inhalation component of absorption. Urine was collected up to 48 hrs after
the beginning of exposure. The urine was analyzed for NMP and its main metabolites, 5-hydroxy-N-
methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI).
The study did not report any effects for the exposed participants. The study findings suggested that
dermal absorption has a significant contribution to the uptake of NMP in whole-body inhalation
exposures.
The study was conducted in accordance with the Declaration of Helsinki, was reviewed by an ethics
committee and subjects provided informed consent. There was no clear and convincing evidence that
the research was fundamentally unethical (e.g., intended to seriously harm participants) or significantly
deficient to the standards prevailing at the time the study was conducted.
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G-8 Review of Xiaofeietal., 2000
Xiaofei, E., Wada, Y., Nozaki, J., Miyauchi, H., Tanaka, S., Seki, Y. and Koizumi, A. (2000). A linear
pharmacokinetic model predicts usefulness of N-methyl-2-pyrrolidone (NMP) in plasma or urine as a
biomarker for biological monitoring for NMP exposure. J. Occup. Health 42, 321-327.
The purpose of the study was to construct a simple pharmacokinetic model for NMP. Although the
societal benefit of the study was not explicitly discussed, it was presumed that the toxicokinetic
information may be used to identify occupational exposures to NMP, inform proper measures to reduce
exposures and/or support the derivation of occupational exposure limits for NMP.
Workers at two factories were monitored for a week during their normal work routines. In one factory
four workers and five volunteers who stayed in the room were assessed. In a second factory 8 workers
were evaluated. The age range of the participants was 20-56 yrs. The sex of the volunteers was not
identified. This was an observational study with the exception of the volunteers who stayed in the room
with the workers. Participants underwent annual medical checkups including measurements for red
blood cells, white blood cells, hemoglobin, liver enzymes, total cholesterol, HDL cholesterol, triglyceride,
electrocardiogram and plain chest roentgenogram. None of them had abnormal values. No reference
was made about the subject recruitment process, risk/benefit considerations or independent review by
ethics committee.
Personal exposures to NMP were measured with a diffusive sampler with activated charcoal. Weekly
time-weighted averages air concentrations ranged from 0.04 to 0.69 ppm. Blood and urine samples
were collected over the course of the study and analyzed for NMP concentration. Workers were
protected with gloves and apron, although one of the workers had dermatitis after dermal exposure to
NMP. The study did not report additional information about NMP-associated health symptoms. The
authors concluded that the measured NMP values were compared to the pharmacokinetic model
predictions. Thus, the model successfully predicted the NMP plasma and urine levels.
Despite the lack of documentation of ethical information, there was no clear and convincing evidence
that the research was fundamentally unethical (e.g., intended to seriously harm participants) or
significantly deficient to the standards prevailing at the time the study was conducted.
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Appendix H BENCHMARK DOSE ANALYSIS
H-l Benchmark Dose Modeling of Fetal/Pup Body Weight
Changes for Chronic Exposures
BMD modeling was performed using USEPA's BMD Software package (version 2.5), in a manner
consistent with EPA guidelines (EPA, 2012a). Continuous models were used to fit dose-response
data for fetal/pup body weight changes. A BMR of 5% was used because this is a developmental
endpoint (Kavlock et al., 1995) see section 0. A BMR of 1 standard deviation is also shown for
comparison. Daily AUC for NMP in blood, averaged over the exposure period until the day of
measurement (e.g. GD6-20 for Becci et al. (1982) or GD5-21 for Saillenfait et al. (2003)), was
used as an appropriate dose measure for this endpoint. The doses and response data used for
the modeling are presented in Table_Apx H-l.
Table_Apx H-l Fetal Body Weight Data Selected for Dose-Response Modeling for NMP
Reference
Saillenfait et al.,
2003
Saillenfait et al.,
2002
Saillenfait et al.,
2002 and 2003
pooled
DuPont 1990
Dose
AUC (hr mg/L)
0
158
323
668
0
1144
2503
5674
9231
0
158
323
668
1144
2503
5674
9231
0
51
268
633
Number of
litters
24
20
19
25
21
21
24
25
8
45
20
19
25
21
24
25
8
39
16
15
22
Fetal body weight (g)
Mean ± Standard Deviation
5.671 ±0.370
5.623 ±0.358
5.469 ±0.252
5.393 ±0.446
5.73 ±0.5
5. 59 ±0.22
5. 18 ±0.35
4.02 ±0.21
3. 01 ±0.39
5.698 ± 0.44
5.623 ±0.358
5.469 ±0.252
5.393 ±0.446
5. 59 ±0.22
5. 18 ±0.35
4.02 ±0.21
3. 01 ±0.39
7.48 ±0.701
7.03 ±0.705
7.13 ±0.695
6.66 ±0.616
Page 232 of 281
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Becci et al., 1982
0
561
2052
7986
24
22
23
22
3.45 ±0.20
3.49 ±0.24
3. 54 ±0.29
2.83 ±0.39
The best fitting model was selected based on Akaike information criterion (AIC; lower value
indicates a better fit), chi-square goodness of fit p-value (higher value indicates a better fit),
ratio of the BMCBMCL (lower value indicates less model uncertainty) and visual inspection. A
comparison of model fits obtained for each data set of fetal/pup body weight changes is
provided in Table_Apx H-2 to Table_Apx H-6. The best-fitting models, based on the criteria
described above, are indicated in bold. For each of the best fitting models the model version
number, model form, benchmark dose calculation, parameter estimates and estimated values
are shown.
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H-l-1 Results for Saillenfait et al., 2003
Table_Apx H-2 Model Predictions for Fetal Body Weights in Rats Exposed to NMP by Inhalation Using
Daily Average AUC as the Dose Metric (Saillenfait et al., 2003)
BMR = 5% Relative Deviation (RD) and for Comparison 1 Standard Deviation (SD)
Model"
Linear
Exponential
(M2)
Exponential
(M4)
Exponential
(M3)
Power
Polynomial 3°b
Polynomial 2°
Hill
Exponential
(M5)
Goodness of fit
P-
value
0.952
0.948
0.948
0.815
0.812
0.789
N/AC
N/AC
AIC
-84.637
-84.629
-84.629
-82.682
-82.680
-82.665
-80.737
-80.737
BMR = 5% RD
BMDsRD (hr
mg/L)
642
641
641
653
653
652
649
643
BMDLsRD(hr
mg/L)
411
405
284
406
413
412
176
168
BMR=1SD
BMDisD (hr
mg/L)
747
749
749
745
744
738
889
error
BMDLiso (hr
mg/L)
456
451
381
453
458
457
error
error
Basis for model
selection
The Linear model
was selected
based on lowest
AIC and highest p-
value.
Notes:
a Modeled variance case presented (BMDS Test 2 p-value = 0.0670), selected model in bold; scaled residuals for
selected model for doses 0, 158.3, 322.6 and 668.2 hr mg/L were 0.0675, 0.316, -0.654 and 0.24, respectively.
b For the Polynomial 3° model, the b3 coefficient estimates was 0 (boundary of parameters space). The models in
this row reduced to the Polynomial 2° model.
c No available degrees of freedom to calculate a goodness of fit value.
Page 234 of 281
-------
Linear u odei. vjnn BUR oro.ns p. el. Dev. njrtne BUD and n.95 Lower commence Limit rartne BM DL
c
c
•
•
100 2DG
09:26 10/21 2014
Figure_Apx H-l Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body
Weight in Rats Exposed to NMP via Inhalation (Saillenfait et al., 2003)
BMR = 5% Relative Deviation; Daily Average AUC as Dose Shown in hr mg/L
Equation H-l Linear Model. (Version: 2.19; Date: 06/25/2014)
The form of the response function is: Y[dose] = beta_0 + beta_l*dose
A modeled variance is fit
Benchmark Dose Computation.
BMR = 5% Relative deviation
BM 0 = 642.052
BMDL at the 95% confidence level = 411.487
Parameter Estimates
Variable
lalpha
rho
beta_0
beta_l
Estimate
10.9507
-7.59357
5.66546
-0.000441199
Default Initial
Parameter Values
-1.98661
0
5.66303
-0.00043693
Table of Data and Estimated Values of Interest
Dose
0
158.3
322.6
N
24
20
20
Obs Mean
5.67
5.62
5.47
Est Mean
5.67
5.6
5.52
Obs Std Dev
0.37
0.36
0.25
Est Std Dev
0.33
0.346
0.363
Scaled Resid
0.0675
0.316
-0.654
Page 235 of 281
-------
668.2
25
5.39
5.37
0.45
0.404
0.24
Likelihoods of Interest
Model
Al
A2
A3
fitted
R
Log(likelihood)
45.950356
49.530515
46.368255
46.318536
41.618363
# Param's
5
8
6
4
2
AIC
-81.900712
-83.061031
-80.736511
-84.637072
-79.236727
Tests of Interest
Test
Testl
Test 2
Test3
Test 4
2*log(Likelihood
Ratio)
15.8243
7.16032
6.32452
0.099439
Test df
6
3
2
2
p-value
0.01473
0.06696
0.04233
0.9515
Page 236 of 281
-------
H-l-2 Results for Saillenfait et al., 2002
Table_Apx H-3 Model Predictions for Fetal Body Weights in Rats Exposed to NMP by Gavage Using
Daily Average AUC as the Dose Metric (Saillenfait et al., 2002)
BMR = 5% Relative Deviation (RD) and for Comparison 1 Standard Deviation (SD)
Model"
Exponential
(M2)
Exponential
(M3)
Exponential
(M4)
Exponential
(M5)
Hill
Power
Polynomial 4°b
Polynomial 3°c
Polynomial 2°
Linear
Goodness of fit
p-value
0.00183
0.325
0.00183
0.966
0.962
0.0479
0.0295
0.0687
AIC
-98.750
-109.49
-98.750
-109.73
-109.73
-105.66
-104.68
-106.63
BMDsRD
(hr mg/L)
741
1329
741
1637
1660
1114
962
938
BMDURD
(hr mg/L)
693
1035
691
1184
1194
904
895
895
BMDisD (hr
mg/L)
1028
1578
1028
1880
1895
1381
1233
1210
BMDLiso (hr
mg/L)
876
1245
876
1400
1409
1070
1038
1036
Basis for model selection
The Exponential (M5)
model was selected
based on lowest AIC with
highest p-value.
Notes:
a Modeled variance case presented (BMDS Test 2 p-value = 1.26E-04), selected model in bold; scaled residuals for
selected model for doses 0, 1144, 2503, 5674 and 9231 hr mg/L were -0.1399, 0.1248, -0.02274, 0.1033 and -
0.1213, respectively.
b For the Polynomial 4° model, the b4 and b3 coefficient estimates were 0 (boundary of parameters space). The
models in this row reduced to the Polynomial 2° model.
c For the Polynomial 3° model, the b3 coefficient estimates was 0 (boundary of parameters space). The models in
this row reduced to the Polynomial 2° model.
Page 237 of 281
-------
Exponential Model 5. vjnn BUR oro.ns p. el. Dev. nrtne BUD and D.95 Lnwer confidence Level lor Br.i DL
c
c
•
•
Exponential
BMDL BMD
4OOO ennn
dose
09:43 10/21 201*
Figure_Apx H-2 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body
Weight in Rats Exposed to NMP via Gavage (Saillenfait et al., 2002)
BMR = 5% Relative Deviation; Daily Average AUC as Dose Shown in hr mg/L
Equation H-2 Exponential Model. (Version: 1.9; Date: 01/29/2013)
The form of the response function is: Y[dose] = a * [c-(c-l) * exp(-(b * dose)Ad)]
A modeled variance is fit
Benchmark Dose Computation.
BMR = 5% Relative deviation
BM 0 = 1637.32
BMDL at the 95% confidence level = 1184.3
Parameter Estimates
Variable
Inalpha
rho
a
b
c
d
Estimate
-3.80738
1.00208
5.74092
0.000143148
0.405685
1.67614
Default Initial
Parameter Values
-2.38723
0.0548918
6.0165
0.000073183
0.000500291
1
Page 238 of 281
-------
Table of Data and Estimated Values of Interest
Dose
0
1144
2503
5674
9231
N
21
21
24
25
8
Obs Mean
5.73
5.59
5.18
4.02
3.01
Est Mean
5.741
5.58
5.182
4.014
3.021
Obs Std Dev
0.5
0.22
0.35
0.21
0.39
Est Std Dev
0.3577
0.3527
0.3398
0.299
0.2593
Scaled Resid
-0.1399
0.1248
-0.02274
0.1033
-0.1213
Likelihoods of Interest
Model
Al
A2
A3
R
5
Log(likelihood)
59.67563
71.17728
60.86644
-42.05093
60.86544
# Param's
6
10
7
2
6
AIC
-107.3513
-122.3546
-107.7329
88.10186
-109.7309
Tests of Interest
Test
Testl
Test 2
Test3
Test 7a
2*log(Likelihood
Ratio)
226.5
23
20.62
0.001995
Test df
8
4
3
1
p-value
0.0001
0.0001264
0.0001261
0.9644
Page 239 of 281
-------
H-l-3 Results for Saillenfait et al., 2002 and 2003 combined
Table_Apx H-4 Model Predictions for Fetal Body Weights in Rats Exposed to NMP by Gavage or
Inhalation using Daily Average AUC as the Dose Metric (Saillenfait et al., 2002 and 2003)
BMR = 5% Relative Deviation (RD) and for Comparison 1 Standard Deviation (SD)
Model"
Exponential
(M2);
Exponential
(M4)b
Exponential (M3)
Exponential
(M5)
Hill
Power
Polynomial 7°c
Polynomial 5°d
Polynomial 4°e
Polynomial 3°f
Polynomial 6°g
Polynomial 2°h
Linear
Goodness of fit
p-value
<0.0001
0.0119
0.0150
0.0138
0.00396
0.00218
0.00218
0.00218
0.00164
AIC
-169.77
-187.12
-187.44
-187.25
-184.48
-183.08
-183.08
-183.08
-182.51
BMDsRD
(hr mg/L)
828
1547
1937
1962
1321
1155
1155
1155
989
BMDLsRD
(hr mg/L)
774
1253
1424
1421
1039
978
978
978
944
BMDiso
(hr mg/L)
1155
1911
2283
2297
1696
1532
1532
1532
1343
BMDLiso
(hr mg/L)
1030
1579
1764
1762
1366
1287
1287
1287
1208
Basis for model
selection
The Exponential (M5)
model was selected
based on lowest AIC.
Notes:
a Modeled variance case presented (BMDS Test 2 p-value = 1.21E-04), selected model in bold; scaled residuals for
selected model for doses 0,156.5, 319, 660.8,1144, 2503, 5674 and 9231 hr mg/L were 1.671, 0.2153, -1.487, -
2.354,1.142, 0.2305, 0.03888 and -0.1112, respectively.
b For the Exponential (M4) model, the estimate of c was 0 (boundary). The models in this row reduced to the
Exponential (M2) model.
c For the Polynomial 7° model, the b7, b6, b5 and b4 coefficient estimates were 0 (boundary of parameters
space). The models in this row reduced to the Polynomial 3° model.
d For the Polynomial 5° model, the b5 and b4 coefficient estimates were 0 (boundary of parameters space). The
models in this row reduced to the Polynomial 3° model.
e For the Polynomial 4° model, the b4 coefficient estimate was 0 (boundary of parameters space). The models in
this row reduced to the Polynomial 3° model.
f The Polynomial 3° model may appear equivalent to the Polynomial 6° model, however differences exist in digits
not displayed in the table. This also applies to the Polynomial 2° model.
8 The Polynomial 6° model may appear equivalent to the Polynomial 7° model, however differences exist in digits
not displayed in the table. This also applies to the Polynomial 5° model. This also applies to the Polynomial 4°
model. This also applies to the Polynomial 3° model. This also applies to the Polynomial 2° model.
h The Polynomial 2° model may appear equivalent to the Polynomial 7° model, however differences exist in digits
not displayed in the table. This also applies to the Polynomial 6° model. This also applies to the Polynomial 5°
model. This also applies to the Polynomial 4° model. This also applies to the Polynomial 3° model.
Page 240 of 281
-------
Exponential Model 5. vjnn BUR oTO.ns P. el. Dev. IDrtne BUD and n.95 Lnwer confidence Level lor BM DL
c
c
•
•
Exponential
OB:42 10/21 2014
Figure_Apx H-3 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body
Weight in Rats Exposed to NMP via Gavage or Inhalation (Saillenfait et al., 2002 and 2003)
BMR = 5% Relative Deviation; Daily Average AUC as Dose Shown in hr mg/L
Equation H-3 Exponential Model. (Version: 1.9; Date: 01/29/2013)
The form of the response function is: Y[dose] = a * [c-(c-l) * exp(-(b * dose)Ad)]
A modeled variance is fit
Benchmark Dose Computation.
BMR = 5% Relative deviation
BM 0 = 1937.29
BMDL at the 95% confidence level = 1423.77
Parameter Estimates
Variable
Inalpha
rho
a
b
c
d
Estimate
-4.03673
1.20539
5.6045
0.000147759
0.446945
1.88381
Default Initial
Parameter Values
-2.36893
0.0584431
5.9829
0.0000728823
0.000503101
1
Page 241 of 281
-------
Table of Data and Estimated Values of Interest
Dose
0
156.5
319
660.8
1144
2503
5674
9231
N
45
20
20
25
21
24
25
8
Obs Mean
5.698
5.62
5.47
5.39
5.59
5.18
4.02
3.01
Est Mean
5.604
5.602
5.595
5.566
5.497
5.163
4.018
3.02
Obs Std Dev
0.4353
0.36
0.25
0.45
0.22
0.35
0.21
0.39
Est Std Dev
0.3755
0.3754
0.3751
0.3739
0.3711
0.3574
0.3072
0.2587
Scaled Resid
1.671
0.2153
-1.487
-2.354
1.142
0.2305
0.03888
-0.1112
Likelihoods of Interest
Model
Al
A2
A3
R
5
Log(likelihood)
104.4887
119.1975
105.8917
-48.75234
99.71803
# Param's
9
16
10
2
6
AIC
-190.9774
-206.3949
-191.7834
101.5047
-187.4361
Tests of Interest
Test
Testl
Test 2
Test3
Test 7a
2*log(Likelihood
Ratio)
335.9
29.42
26.61
12.35
Test df
14
7
6
4
p-value
0.0001
0.0001214
0.0001712
0.01495
Page 242 of 281
-------
H-l-4 Results for DuPont, 1990
Table_Apx H-5 Model Predictions for Fetal Body Weights in Rats Exposed to NMP by Inhalation using
Daily Average AUC as the Dose Metric (DuPont 1990)
BMR = 5% Relative Deviation and for Comparison 1 Standard Deviation (SD)
Model"
Exponential (M2)
Exponential (M3)b
Exponential (M4)
Exponential (M5)
Hill
Power0
Polynomial 3°d
Polynomial 2°e
Linear
Goodness of fit
p-value
0.140
0.0494
0.0494
0.0597
0.138
AIC
27.266
29.191
29.191
28.875
27.288
BMDsRD
(hr mg/L)
315
260
260
58.5
323
BMDLsRD
(hr mg/L)
223
1.16
1.30
4.71E-04
234
BMDiso
(hr mg/L)
594
580
580
609
596
BMDLiso
(hr mg/L)
411
2.61
3.07
1.98E-05
421
Basis for model
selection
The Exponential
model was selected
based on lowest AIC.
Notes:
a Constant variance case presented (BMDS Test 2 p-value = 0.905), selected model in bold; scaled residuals for
selected model for doses 0, 51.18, 267.9 and 633.3 hr mg/L were 0.8831, -1.718, 0.3504 and 0.0002752,
respectively.
b For the Exponential (M3) model, the estimate of d was 1 (boundary). The models in this row reduced to the
Exponential (M2) model.
c For the Power model, the power parameter estimate was 1. The models in this row reduced to the Linear
model.
d For the Polynomial 3° model, the b3 coefficient estimates was 0 (boundary of parameters space). The models
in this row reduced to the Polynomial 2° model. For the Polynomial 3° model, the b3 and b2 coefficient
estimates were 0 (boundary of parameters space). The models in this row reduced to the Linear model.
e For the Polynomial 2° model, the b2 coefficient estimate was 0 (boundary of parameters space). The models in
this row reduced to the Linear model.
Page 243 of 281
-------
Exponential Model 2, vjnn BUR oTO.ns P. el. Dev. IDrtne BUD and n.95 Lnwer confidence Level lor BM DL
c
c
•
•
15:02 09*25 201.»
Figure_Apx H-4 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body
Weight in Rats Exposed to NMP via Inhalation (DuPont 1990)
BMR = 5% Relative Deviation; Daily Average AUC as Dose Shown in hr mg/L
Equation H-4 Exponential Model. (Version: 1.9; Date: 01/29/2013)
The form of the response function is: Y[dose] = a * exp(sign * b * dose)
A constant variance model is fit
Benchmark Dose Computation.
BMR = 5% Relative deviation
BM 0 = 314.897
BMDL at the 95% confidence level = 223.175
Parameter Estimates
Variable
Inalpha
rho(S)
a
b
c
d
Estimate
-0.768852
n/a
7.38373
0.000162889
0
1
Default Initial
Parameter Values
-0.811648
0
6.90878
0.000162077
0
1
Page 244 of 281
-------
Table of Data and Estimated Values of Interest
Dose
0
51.18
267.9
633.3
N
39
16
15
22
Obs Mean
7.48
7.03
7.13
6.66
Est Mean
7.384
7.322
7.068
6.66
Obs Std Dev
0.701
0.705
0.695
0.616
Est Std Dev
0.6808
0.6808
0.6808
0.6808
Scaled Resid
0.8831
-1.718
0.3504
0.0002752
Likelihoods of Interest
Model
Al
A2
A3
R
2
Log(likelihood)
-8.66418
-8.383601
-8.66418
-18.52227
-10.6328
# Param's
5
8
5
2
3
AIC
27.32836
32.7672
27.32836
41.04454
27.26561
Tests of Interest
Test
Testl
Test 2
Test3
Test 4
2*log(Likelihood
Ratio)
20.28
0.5612
0.5612
3.937
Test df
6
3
3
2
p-value
0.002471
0.9053
0.9053
0.1396
Page 245 of 281
-------
H-l-5 Results for Becci et al, 1982
Table_Apx H-6 Model Predictions for Fetal Body Weights in Rats Exposed to NMP Dermally Using Daily
Average AUC as the Dose Metric (Becci et al., 1982)
BMR = 5% Relative Deviation and for Comparison 1 Standard Deviation (SD)
Model"
Hill
Power
Polynomial 3°
Polynomial 2°
Linear
Goodness of fit
p-value
N/Ab
0.371
0.572
0.307
0.00557
AIC
-134.67
-136.67
-138.35
-137.11
-129.09
BMDsRD
(hr mg/L)
7497
7692
5391
4326
2452
BMDLsRD
(hr mg/L)
2302
3783
4018
3919
1944
BMDisD
(hr mg/L)
7695
7864
6015
5087
3331
BMDLiso
(hr mg/L)
2361
4525
4645
4503
2567
Basis for model selection
The Polynomial 3° model
was selected based on
lowest AIC.
Notes:
a Modeled variance case presented (BMDS Test 2 p-value = 0.0101), selected model in bold; scaled residuals for
selected model for doses 0, 588.7, 2156 and 8409 hr mg/L were -0.928, -0.111, 1.08 and -0.03, respectively.
b No available degrees of freedom to calculate a goodness of fit value.
Polynomial Model, with BMR of O.O5 Rel. Dev. for the BMD and O.95 Lower Confidence Limit for the BIN
8.
$
Polynomial
r
O 1000 2000 3000 4OOO 5OOO 6OOO 7OOO 8OOO
dose
14:21 12/10 2014
Figure_Apx H-5 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body
Weight in Rats Exposed to NMP Dermally (Becci et al., 1982)
BMR = 5% Relative Deviation; Daily Average AUC as Dose Shown in hr mg/L
Equation H-5 Polynomial Model. (Version: 2.19; Date: 06/25/2014)
The form of the response function is: Y[dose] = beta_0 + beta_l*dose + beta_2*doseA2 + ...
A modeled variance is fit
Page 246 of 281
-------
Benchmark Dose Computation.
BMR = 5% Relative deviation
BM 0 = 5390.85
BMDL at the 95% confidence level = 4017.68
Parameter Estimates
Variable
lalpha
rho
beta_0
beta_l
beta_2
beta_3
Estimate
2.56784
-4.31376
3.49599
-1.68014E-27
0
-1.11576E-12
Default Initial
Parameter Values
-2.49546
0
3.45
0
-0.000000016108
-2.23106E-13
Table of Data and Estimated Values of Interest
Dose
0
588.7
2156
8409
N
24
22
23
22
Obs Mean
3.45
3.49
3.54
2.83
Est Mean
3.5
3.5
3.48
2.83
Obs Std Dev
0.2
0.24
0.29
0.39
Est Std Dev
0.243
0.243
0.244
0.382
Scaled Resid
-0.928
-0.111
1.08
-0.03
Likelihoods of Interest
Model
Al
A2
A3
fitted
R
Log(likelihood)
70.088658
75.754919
73.734901
73.175965
37.76879
# Param's
5
8
6
4
2
AIC
-130.177316
-135.509838
-135.469801
-138.35193
-71.537581
Tests of Interest
Test
Testl
Test 2
Test3
Test 4
2*log(Likelihood
Ratio)
75.9723
11.3325
4.04004
1.11787
Test df
6
3
2
2
p-value
0.0001
0.01006
0.1327
0.5718
Page 247 of 281
-------
H-2 Benchmark Dose Modeling of Effects for Acute Exposures
Benchmark Dose (BMD) modeling was performed using USEPA's BMD Software package
(version 2.5), in a manner consistent with USEPA guidelines (USEPA, 2012). Dichotomous
models were used to fit fetal mortality and continuous models were used to fit dose-response
data for resorptions. A BMR of 1% was used to address the relative severity of this endpoint
(EPA, 2012a) see section 3.2.3. BMRs of 0.5 and 1 standard deviation are also shown for
comparison. The peak NMP in maternal blood (Cmax) was used as an appropriate dose measure
for these endpoints. The doses and response data used for the modeling are presented in
Table_Apx H-7.
Table_Apx H-7 Skeletal Malformations, Resorptions and Fetal Mortality Data Selected for Dose-
Response Modeling for NMP
Reference and
endpoint
Saillenfait et al.,
2002 and 2003
Resorptions
Sitarek et al.,
2012
fetal mortality
Dose
Cmax (mg/L)
0
15
30
62
120
250
531
831
0
76
265
669
Dose
AUC (hr mg/L)
0
156.5
319
660.8
1144
2503
5674
9231
0
902
3168
8245
Number of
litters
45
20
20
25
21
24
25
5
22
24
20
15
Response
Mean ± Standard
Deviation
3.4 ±7.13
4.3 ±4.1
9.9 ±22.3
7 ±9.4
8.9 ±21.2
4.5 ±6.6
9.4 ±8.9
91 ±16
0.18 ±0.85
0±0
0.13 ±0.34
0.8 ±1.1
The best fitting model was selected based on Akaike information criterion (AIC; lower value
indicates a better fit), chi-square goodness of fit p-value (higher value indicates a better fit),
ratio of the BMCBMCL (lower value indicates less model uncertainty) and visual inspection.
Comparisons of model fits obtained for resorptions and fetal mortality are provided in
Table_Apx H-7 to Table_Apx H-10. The best-fitting models, based on the criteria described
above, are indicated in bold. For each of the best fitting models the model version number,
model form, benchmark dose calculation, parameter estimates and estimated values are
shown.
Page 248 of 281
-------
H-2-1 Results for Saillenfait et al., 2002 and 2003 combined using Cmax
Table_Apx H-8 Model Predictions for Resorptions in Rats Exposed to NMP via Gavage or Inhalation
Using Cmax as the Dose Metric (Saillenfait et al., 2002 and 2003)
BMR = 1% Relative Deviation (RD) and for Comparison 0.5 and 1 Standard Deviation (SD)
Model"
Exponential
(M2)
Exponential
(M3)
Exponential
(M4)
Exponential
(M5)
Hill
Power
Polynomial 4°
Polynomial 3°
Polynomial 2°
Linear
Goodness of fit
p-value
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
AIC
1288.45
1263.09
1364.53
1265.04
1263.03
1263.04
1276.48
1300.17
1336.49
1362.53
BMDiRD
(mg/L)
1.60
247
0.122
326
429
326
128
66.7
19.2
0.121
BMDLiRD
(mg/L)
1.26
97.9
0.0122
215
216
215
77.6
55.2
3.77
0.0122
BMDo.sso
(mg/L)
424
621
58.2
593
558
593
436
359
247
58.2
BMDLo.sso
(mg/L)
349
510
44.5
514
514
514
419
345
215
44.5
BMDisD
(mg/L)
530
685
116
648
582
648
518
452
349
116
BMDLiso
(mg/L)
468
602
89.1
583
548
583
504
435
317
89.1
Basis for
model
selection
Of the
models
that
provided
an
adequat
e fit and
a valid
BMDL
estimate
the Hill
model
was
selected
based on
lowest
AIC.
Notes:
a Modeled variance case presented (BMDS Test 2 p-value = <0.0001), selected model in bold; scaled residuals for
selected model for doses 0, 15.01, 30.34, 61.86, 120, 250, 531 and 831 mg/L were -1.42, -0.619, 1.41, 0.401, 1.1, -
0.599, 0.29 and -0.00443, respectively.
Page 249 of 281
-------
HIM Model, tMtti BM R om.01 RBI. Dev. Tnrtne Bit a ana D.95 Lover confluence Limit nrtne HI.! DL
c
c
•
•
11:00 12/152014
Figure_Apx H-6 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Resorptions
in Rat Exposed to NMP via Gavage or Inhalation (Saillenfait et al., 2002 and 2003)
BMR = 1% Relative Deviation; Cmax as Dose Shown in mg/L
Equation H-6 Hill Model. (Version: 2.17; Date: 01/28/2013)
The form of the response function is: Y[dose] = intercept + v*doseAn/(kAn + doseAn)
A modeled variance is fit
Benchmark Dose Computation.
BMR = 1% Relative deviation
BM 0 = 429.482
BMDL at the 95% confidence level = 215.783
Parameter Estimates
Variable
lalpha
rho
intercept
V
n
k
Estimate
4.75575
0.150826
6.00954
85.8437
18
642.982
Default Initial
Parameter Values
5.10412
0
3.4
87.6
1.9286
992.029
Page 250 of 281
-------
Table of Data and Estimated Values of Interest
Dose
0
15.01
30.34
61.86
120
250
531
831
N
45
20
20
25
22
24
25
25
Obs Mean
3.4
4.3
9.9
7
8.9
4.5
9.4
91
Est Mean
6.01
6.01
6.01
6.01
6.01
6.01
8.67
91
Obs Std Dev
7.13
4.1
22.3
9.4
21.2
6.6
8.9
16
Est Std Dev
12.3
12.3
12.3
12.3
12.3
12.3
12.7
15.2
Scaled Resid
-1.42
-0.619
1.41
0.401
1.1
-0.599
0.29
-0.00443
Likelihoods of Interest
Model
Al
A2
A3
fitted
R
Log(likelihood)
-624.644958
-570.082153
-595.035542
-626.515585
-806.807094
# Param's
9
16
10
5
2
AIC
1267.289916
1172.164306
1210.071083
1263.03117
1617.614189
Tests of Interest
Test
Testl
Test 2
Test3
Test 4
2*log(Likelihood
Ratio)
473.45
109.126
49.9068
62.9601
Test df
14
7
6
5
p-value
0.0001
0.0001
0.0001
O.0001
Page 251 of 281
-------
H-2-2 Results for Saillenfait et al., 2002 and 2003 combined using AUC
Table_Apx H-9 Model Predictions for Resorptions in Rats Exposed to NMP via Gavage or Inhalation
Using AUC as the Dose Metric (Saillenfait et al., 2002 and 2003)
BMR = 1% Relative Deviation (RD) and for Comparison 0.5 and 1 Standard Deviation (SD)
Model"
Exponential
(M2)
Exponential
(M3)
Exponential
(M4)
Exponential
(M5)
Hill
Power
Polynomial
4°
Polynomial
3°
Polynomial
2°
Linear
Goodness of fit
p-value
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
AIC
1286.
5
1263.
1
1360.
1
1265.
0
1265.
0
1263.
0
1271.
7
1292.
4
1329.
7
1358.
1
BMDiRD
(hr
mg/L)
19.8
2466
0.720
3343
4177
3343
1432
743
211
0.720
BMDLiRD
(hr mg/L)
15.8
901
0.0760
2128
2133
2128
135
133
148
0.0760
BMDo.sso
(hr mg/L)
4281
6721
598
6394
6091
6394
4827
3958
2714
598
BMDLo.sso
(hr mg/L)
3524
5432
473
5479
5481
5479
4537
3731
2538
473
BMDisD
(hr mg/L)
5543
7486
1196
7045
6478
7045
5741
4986
3838
1196
BMDLiso
(hr mg/L)
4887
6504
946
6285
5858
6285
5534
4786
3589
946
Basis for
model
selection
Of the
models that
provided an
adequate fit
and a valid
BMDL
estimate, the
Power model
was selected
based on
lowest AIC.
Notes:
a Modeled variance case presented (BMDS Test 2 p-value = <0.0001), selected model in bold; scaled residuals for
selected model for doses 0, 156.5, 319, 660.8, 1144, 2503, 5674 and 9231 hr mg/L were -1.42, -0.62, 1.41, 0.4, 1.1,
-0.603, 0.299 and -0.00462, respectively.
Page 252 of 281
-------
Power P.I Ddei. vtftn BMR oTO.ni Rei. oev. tor the BUD and D.95 Lower confidence Limit Tbrtne BM DL
c
c
•
•
13:0312/152014
Figure_Apx H-7 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Resorptions
in Rat Exposed to NMP via Gavage or Inhalation (Saillenfait et al., 2002 and 2003)
BMR = 1% Relative Deviation; AUC as Dose Shown in hr mg/L
Equation H-7 Power Model. (Version: 2.18; Date: 05/19/2014)
The form of the response function is: Y[dose] = control + slope * doseApower
A modeled variance is fit
Benchmark Dose Computation.
BMR = 1% Relative deviation
BM 0 = 3343.09
BMDL at the 95% confidence level = 2127.52
Parameter Estimates
Variable
lalpha
rho
control
slope
power
Estimate
4.75548
0.150959
6.01205
4.0533 1E-27
7.14249
Default Initial
Parameter Values
5.10412
0
3.4
0.0564664
0.625198
Page 253 of 281
-------
Table of Data and Estimated Values of Interest
Dose
0
156.5
319
660.8
1144
2503
5674
9231
N
45
20
20
25
22
24
25
25
Obs Mean
3.4
4.3
9.9
7
8.9
4.5
9.4
91
Est Mean
6.01
6.01
6.01
6.01
6.01
6.02
8.64
91
Obs Std Dev
7.13
4.1
22.3
9.4
21.2
6.6
8.9
16
Est Std Dev
12.3
12.3
12.3
12.3
12.3
12.3
12.7
15.2
Scaled Resid
-1.42
-0.62
1.41
0.4
1.1
-0.603
0.299
-0.00462
Likelihoods of Interest
Model
Al
A2
A3
fitted
R
Log(likelihood)
-624.644958
-570.082153
-595.035542
-626.519051
-806.807094
# Param's
9
16
10
5
2
AIC
1267.289916
1172.164306
1210.071083
1263.038102
1617.614189
Tests of Interest
Test
Testl
Test 2
Test3
Test 4
2*log(Likelihood
Ratio)
473.45
109.126
49.9068
62.967
Test df
14
7
6
5
p-value
0.0001
0.0001
0.0001
O.0001
Page 254 of 281
-------
H-2-3 Results for Sitarek et al., 2012
Table_Apx H-10 Model Predictions for Fetal Mortality in Rats Exposed to NMP by Gavage Using CmaXas
the Dose Metric (Sitarek et al., 2012)
BMR = 1% Relative Deviation and for Comparison 0.5 and 1 Standard Deviation (SD)
Model"
Exponential
(M2)
Exponential
(M3)
Exponential
(M4)
Exponential
(M5)
Power
Polynomial
2°
Linear
Hill
Goodness of fit
p-value
<0.0001
<0.0001
N/AC
<0.0001
<0.0001
<0.0001
N/AC
AIC
7701.7
1.8E+17
4.2143
11.247
20.871
8.2143
BMDiRD
(mg/L)
0.0578
1.1E+15
errorb
errorb
465
31.9
1.94
464
BMDLiRD
(mg/L)
0.0403
1.1E+15
error
error
83.1
15.0
4.30E-05
83.2
BMDo.sso
(mg/L)
181
3.9E+15
errorb
errorb
634
471
457
633
BMDo.sso
(mg/L)
0.341
3.9E+15
error
error
471
351
241
300
BMDisD
(mg/L)
185
3.9E+15
errorb
errorb
658
666
915
658
BMDisD
(mg/L)
26.4
3.9E+15
error
error
567
496
482
324
Basis for
model
selection
No models
provided an
adequate fit
and a valid
BMDL
estimate,
therefore no
model was
selected.
Notes:
a Modeled variance case presented (BMDS Test 2 p-value = <0.0001, BMDS Test 3 p-value = <0.0001), no model
was selected as a best-fitting model.
b BMD or BMDL computation failed for this model.
c No available degrees of freedom to calculate a goodness of fit value.
Page 255 of 281
-------
Appendix I PBPK MODELING
The PBPK models of Poet et al. (2010) for describing the toxicokinetics of NMP in rats and
humans were revised for use in deriving an occupational exposure limit (OEL). These PBPK
models were initially evaluated and revised by the EPA in 2013 (EPA, 2013c). Further
modifications and calibration were conducted by Dr. Torka Poet in 2014 (personnel
communication). In this update, additional data were considered to further calibrate and
validate the model. Model calibration consists of using data to optimize parameters when those
parameters are unknown or approximated, validation is used to show the fits of the model to
other datasets. The EPA then evaluated the version submitted by Dr. Poet in 2014 and made
some additional corrections and modifications as described below.
These PBPK models simulate the pharmacokinetics of NMP and its metabolite 5HNMP5-HNMP
in rats and humans, described briefly below. The models consist of nine main compartments:
lung, richly perfused tissues, slowly perfused tissues, skin, fat, mammary, placenta, fetus and
liver for NMP with a submodel for 5H-NMP. The model can simulate NMP exposures via the
oral, inhalation and dermal routes. Dermal absorption occurs for contact with NMP liquid and
vapor. Distribution of NMP to tissues is assumed to be flow-limited. The model includes
mathematical descriptions of the growth of fetal and maternal tissues during gestation based
on a previous PBPK model of pregnancy (Gentry et al., 2002). Due to extensive differences
between rat and human gestation periods, separate rat and human models were developed.
NMP metabolism was assumed to occur in the liver. NMP was assumed to be eliminated in
exhaled air and urine. 5H-NMP was assumed to be eliminated by further metabolism and in
urine. The physiological parameter values used in the model were obtained from the literature
(Brown et al., 1997; Gentry et al., 2002) and biochemical constants for absorption, metabolism
and elimination were fit to the available toxicokinetic data (Akesson and Jonsson, 1997; Wells
and Digenis, 1988; Payan et al., 2002; Ghantous et al., 1995; Midgley et al., 1992). Further
description of the PBPK model are available in Poet et al. (2010), (EPA, 2013c) and the
modifications described below.
1-1 Rat Model
Several corrections were made to the model code (.csl file) and supporting scripts (.m) files as
received from Dr. Torka Poet (personnel communication). The first few of these are general and
described here.
Blood Flows
Since the placenta is a separate compartment for the 5-HNMP model, its blood-flow and
volume were subtracted from the sums used for the 'rest of body' for 5-HNMP. Also, the term
for blood flow from the placenta was added to the mixed-venous blood mass balance for 5-
HNMP.
Page 256 of 281
-------
To assure flow mass balance, instead of calculating cardiac output (QC) as an initial amount plus
the change from initial for each compartment, it was just calculated as the sum over all the
compartments:
Equation 1-1 Cardiac Output
! QC = QCINIT + (QFAT - QFATI) + (QMAM - QMAMI) + QPLA+ (QUTR - QUTRI)
QC = QFAT+QLIV+QSLW+QRAP+QSKN+QMAM+QPLA+QUTR ! pms, 8-13-13
Parameter Consolidation
In the provided files, some physiological and chemical-specific parameter were set in separate
scripts; e.g., skin transport parameters in the dermal exposure scripts. This approach creates
the potential for inconsistent parameters between different exposure simulations. Therefore
most parameters are now set in the ratparam.m script except those which are experimental
control variables (eg., air concentration, duration of exposure) and pregnancy-specific
parameters set in preg_rat_params.m. The final set of parameters used and any inconsistencies
with previous values in ratparam.m that may have differed are noted in that script.
Recalibration (performed by T. Poet)
Additional data were used to calibrate and validate the intravenous, oral and dermal routes of
exposure in rats. While plasma and urinary excretion data for major metabolite (5-HNMP) have
also been reevaluated, primary attention has been paid to NMP, since the dose measure of
interest are for the parent chemical. Model parameters for rats are set in the
preg_rat_params.m and ratparam.m code scripts (preg_rat_params first calls ratparam),
included in the acsIX code package available with this assessment. Specific data and modeling
choices for the rat are as follows.
Intravenous Data
All available intravenous data were obtained from studies that administered radiolabeled NMP.
Most of the available studies only provided peak measured concentration and pharmacokinetic
parameters. The study chosen to calibrate the model was that described by Payan (2002), in
which nulliparous rats were exposed to NMP doses ranging from 0.1 to 500 mg/kg. However,
the authors only reported plasma NMP data for the lowest dose. This time-course data set was
used to optimize metabolic rate parameters (VmaxC and Km) to describe the clearance of NMP
from plasma. Unchanged NMP has only been found at very low levels in rat urine, so urinary
elimination was set at a nominal value using a BW-scaled constant of KLNC= 0.0001 kg0.25/h.
KLN = KLNC/(BW0.25) = 0.00014 h-1 for a 0.25-kg rat.
Payan (2002) estimated the post-distribution metabolic rates of NMP from the disappearance
of NMP from plasma in their studies. These estimated rates (Km=200 mg/L and VmaxC=1.5
Page 257 of 281
-------
mg/hr/kgO.75) were used as the seed values for the optimization carried out using the
optimization routines supplied in acsIX (v3.0.2.1; The AEgis Technologies Group, Inc, Huntsville,
AL) in which the model was created. By starting with these values, it was hoped that the dose-
range in that study would be represented and the optimized model would fit across doses. The
final optimized parameters were Km= 225 mg/l and VmaxC=9 mg/hr/kg0-75. Wells (1988)
administered an intravenous dose of 45 mg/kg to rats, which is 450x higher than the dose used
for optimization and this was used to validate the metabolic rates over a large range
(Figure_Apx 1-1).
100
10
Q.
5
Z
0.1
0.01
45 mg/kg simulation
• Wells &Oigenis (1988)
^^ 0,1 mg/kg simulation
Q Payan et al. (2002)
02468
Time (h)
Figure_Apx 1-1 Model Fits to IV Injection Data in Rats
10
12
Oral Data
All available oral exposure data were obtained from studies that administered radiolabeled
NMP. The most valuable data sets are those that specifically measured NMP in blood (dose
measure used in the assessment). NMP is highly metabolized and generally not found in urine
as unchanged NMP. The study chosen to calibrate the oral absorption rate was described by
Midgley et al. (1992). In this study, male and female rats received an oral gavage of 105 mg/kg
(22.5 mg in rats weighing 192-239 g) NMP, co-exposed with 2-pyrrolidinone in a water vehicle.
The authors concluded that 94.5% of the administered radiolabel was absorbed. However,
when a constant (FRACOR) was fit to the data using the PBPK model the optimal value was
found to be 93%.
The data indicate a rapid uptake and a slow elimination of NMP from plasma. Using the
metabolic rate constants optimized to fit the intravenous dosing and the oral bioavailability
measurements of Midgley et al. (1992), the model estimates of plasma NMP clearance resulted
Page 258 of 281
-------
in a much higher AUC than the data indicated (Figure_Apx 1-2). There is no suggestion of extra-
hepatic (i.e., intestinal) metabolism, so another mechanism to describe this absorption pattern
was investigated. NMP is readily absorbed across membranes (see dermal absorption data
discussion below) and for some chemicals absorption has been proposed to occur either in the
stomach or quickly in the intestine, then more slowly during later phases of transport (Levitt,
1997; Staats, 1991; Timchalk, 2002). Therefore the original PBPK model was altered to include
primary (stomach) and secondary (intestine) Gl compartments to describe oral absorption
following the description from Staats (1991). The resulting model predictions are vastly
improved (Figure_Apx 1-2). Using dual oral absorption results in ~75% of the absorbed dose
(after multiplying by 93% bioavailability) being absorbed via the faster process and the
remaining ~25% being more slowly absorbed. Also, an unusually high fraction of the
radioactivity was found in the feed residue for the females in the Ghantous (1995) study, 4.5%,
so the simulated dose for that group was decreased proportionately.
112 nng/kg simulation
Midgley 112 mg/kg data
50 mg/kg (male) simulation
Ghantous 50 mg/kg male data
50 mg/kg (female) simulation
Ghantous 50 mg/kg female data
6 8
Time (hr)
10
12
14
Page 259 of 281
-------
(0
C 3
112 mg/kg simulation
50 mg/kg (female) simulation
• Midgley 112 mg/kg data
V Ghantous 50 mg/kg female data^,
0
20
40 60 80
Time (hr)
Figure_Apx 1-2 Model Fits to Rat Oral PK Data
100
120
Dermal Model & Data
Corrections to the mass balance equations for the rat skin are as indicated in the commented
code copied below. RASK is the rate of changes in the skin compartment. The equation for the
amount in the compartment, ASK, includes the initial condition, ASKO, for the initial dermal
application, but otherwise the correction to RASK makes it the standard format for PBPK
models. As received the code had multiplied CSK rather than CSKV (skin venous blood
concentration) by the blood flow (QSKN) for the rate of efflux in blood and had not separately
calculated CSKV.
Equation 1-2 Rat Skin Model Equations
RASK = QSKN*(CA - CSKV) + RADL ! NOW MINUS CSKV, NOT CSK; PMS 8-21-13
ASK = INTEG(RASK,ASKO) ! Initial value, ASKO, added for Becci et al. (1982)
! exposures; pms 8-14-13
CSK = ASK/VSK I'NMPINSKIN, MG/L'
CSKV = CSK/PSKB ! NMP IN VENOUS BLOOD, PMS 8-22-13
The corresponding flow term for transfer from the skin to the mixed venous blood
compartment was also corrected (i.e., to use CVSK instead of CSK).
While these changes to the skin compartment equations initially degraded the fits to the
dermal exposure considerably, it also appeared that the associated partition coefficients were
Page 260 of 281
-------
not consistent with the measured values reported by Poet et al. (2010), Table 5. They were
recalculated as follows:
Equation 1-3 Rat Skin Partition Coefficients
Skin:liquid, PSKL = 0.42: % value as measured for skin:saline, vs. 450
Skin:blood, PSKB = 0.12: % (skin:saline)/(blood:saline)
Skin:air, PSKA = 55:
% (skin:saline)*(blood:air)/(blood:saline) = (skin:blood)*(blood:air)
Developmental studies for NMP have been conducted by the dermal route (Becci et al., 1982).
In the original PBPK model publication (Poet et al., 2010)(Poet et al., 2010), the dermal route
was assessed using a permeability coefficient (Kp) of 4.7xlO~3 cm/hr that was approximated
from in vitro studies (Payan, 2003). For the current assessment, the in vivo dermal exposure
studies described by Payan (2003) were used to optimize Kp. In this study, rats were exposed to
200 u.lof neat NMP. According to Payan etal., by 24 hrs after dosing, 80% of the NMP applied
had penetrated the skin. The Kp value optimized to these data was estimated to be
4.6xlO"3 cm/hr (Figure_Apx 1-3), which is consistent with the range of Kp values estimated from
the in vitro studies (from 2.0 xlO'3 to 7.7 xlO-3cm/hr: (Payan, 2002)).
600
500
j? 400
300
V)
£L
200
100
Model
O Payan et al. (2003) data
8
24
28
12 16 20
Time (hr)
Figure_Apx 1-3 Model Fits to Dermal PK Data from Payan et al. (2003) in Rats
32
Page 261 of 281
-------
Inhalation
No parameters were optimized to simulate the inhalation exposures of female rats to 104 ppm
NMP for 6 hr (Ghantous, 1995), 100% inhalation bioavailability was assumed. These data, like
the oral exposure data from the same source, appear to be more variable than from other
studies. The model fits to the data are shown in Figure_Apx 1-4.
D.
5!
Z
60
50
40
30
10
— 100 ppm (female) simulation
—• 100 ppm (male) simulation
• Ghantous (1995) female data
D Ghantous (1995) male data
12
15
0369
Time (hr)
Figure_Apx 1-4 Model Simulations vs. Inhalation PK Data from Ghantous (1995) for NMP Inhalation in
Rats
Exposure Control for Bioassay Simulations
Because both Becci et al. (1982) and Saillenfait et al. (2002) explicitly stated that the animal
BWs were measured every 3rd day of gestation and the dermal/oral doses were adjusted
accordingly on those days (as BW increases during pregnancy), corresponding conditional
(if/then) statements were added to the 'GAVD' and 'REAPPLY' discrete blocks, to re-calculate
the doses on those days.
The code for the dermal discrete blocks follows. ASKO is the total absolute amount applied; DSK
is the dose/kg BW. Because Becci et al. (1982) rubbed the material into the skin, it is assumed
to be added directly into the skin compartment (ASK), rather than as a liquid on top. Hence the
dose is given as an addition of ASKO (mg/day applied) to ASK.
Equation 1-4 Dermal Dosing Equations
DISCRETE SKWASH ! PMS, 8-14-13
ASK = 0.0 ! Assume skin washing in Becci et al. (1982) removes all NMP IN skin
Page 262 of 281
-------
if (DAYS.LT.15.0) SCHEDULE REAPPLY.AT.(T+DOSEINTERVAL-TWASH)
END
DISCRETE REAPPLY ! PMS, 8-14-13
IF (ROUND(DAYS).EQ.9.0) ASKO=DSK*BW
IF (ROUND(DAYS).EQ.12.0) ASKO=DSK*BW
IF (ROUND(DAYS).EQ.15.0) ASKO=DSK*BW
ASK = ASK + ASKO
SCHEDULE SKWASH.AT.(T+TWASH)
END
Also, because Becci et al. (1982) washed the skin area exposed to dermal application at the end
of a set time interval, a "SKWASH" discrete block was introduced at which time the amount in
that patch of skin was assumed to be momentarily reduced to zero. During periods of dermal
application, transport from the liquid to the skin was turned on using the pulse function,
DZONE. After removal of the liquid it was assumed that NMP in the skin patch could volatilize
into the otherwise clean air, with the rate defined by the same permeability constants, but
using the skin:air partition coefficient.
The rate of transfer to/from the skin area is then defined by:
Equation 1-5 NMP Dermal Transport
RADL=(KPL*SA/1000.0)*((CSURF-(CSK/PSKL))*DZONE-(1.0-DZONE)*(CSK/PSKA))
! 2ND term, (1.0-DZONE)*(CSK/PSKA), allows for evaporative loss when DZONE=0
The primary part of this equation for transfer when liquid is in contact with the skin,
(KPL*SA/1000.0)*(CSURF-(CSK/PSKL)), is identical to that used previously by McDougal (1986).
Finally, a constant, CONCMGS, was introduced so that the air concentration could be set
directly in mg/m3. This is converted to the concentration in mg/L (CONCMG) in the code and
added to the inhalation exposure, turned on and off using the switch, CIZONE, which is turned
on and off using SCHEDULE/DISCRETE statements:
Equation 1-6 NMP Vapor Exposure Control
Cl = CCH*PULSE(0., DOSEINTERVALJCHNG) + CIZONE*CONCMG ! MG/L
! Added CIZONE*CONCMG, PMS, 8-13-13
1-2 Human Model
Human exposures to NMP will be primarily via the inhalation route; contribution from the
dermal route (vapors or liquid) may also be significant if not primary for some scenarios.
Ingestion of NMP is not expected to be a significant pathway in human populations. Both
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controlled and occupational human exposure data are available from the published literature.
Controlled human biomonitoring studies were used to calibrate NMP and 5-HNMP metabolic
rates and a workplace exposure assessment study was used to validate the model and exposure
scenarios.
1-2-1 Corrections to Human Model Structure
NMP Metabolism and Urinary Elimination
Since the human PK data were consistent with a nearly linear model (first-order kinetics,
including metabolism) estimation of a metabolic saturation constant, Km, using the traditional
Michaelis-Menten equation for metabolism of NMP, was difficult. In particular as estimates of
Km became larger, model fits became less sensitive to variation in its value. Therefore equation
was changed from the standard form, rate = Vmax*C/(Km + C), where C is the concentration of
NMP in the liver, to the equivalent form, rate = VK1*C/(1 + AF1*C), where VK = Vmax/Km and
API = I/Km. These two forms are mathematically identical given the relationship between
parameters just shown. The affinity constant, API, can be easily bounded to be non-negative
and possibly converge to zero, corresponding to an indeterminately large Km. Since VK
represents hepatic metabolism, it was assumed to scale with BW the same as Vmax; i.e., VK1 =
VK1C*BW0.75. The urinary elimination of NMP was assumed to be first order, rather than
saturable, using a rate constant (KUMNE) that was not scaled by BW.
5-HNMP
Since 5-HNMP is not being considered as an internal metric for toxicity and its volume-of-
distribution (VOD) appeared to be over-estimated using the original PBPK model structure and
measured tissue partition coefficients, it's description was replaced with a classical one-
compartment PK model. Further, as the metabolism of 5-HNMP also appeared to be linear and
the data for estimating a Km value even weaker, a transformation of its metabolic rate
equation like that for NMP described just above was assumed, but with the affinity assumed to
be effectively zero, resulting in a first-order metabolic rate equation. As with NMP, the urinary
elimination of 5-HNMP was also assumed to be first-order. The resulting model then becomes:
Equation 1-7 5-HNMP Metabolism and Elimination
d A5H/dt = RAMET1*STOCH - RAMETM1 - RAUHP
(rate of change of amount of 5-HNMP)
CVEN1 = A5H/VOD5H (concentration of 5-HNMP in venous blood)
VOD5H = VOD5HC*BW (volume of distribution assumed to scale with BW)
RAMETM1 = -CVEN1 *VK2, where VK2 = VK2C*BW0.75
(rate of metabolism of 5-HNMP)
RAUHP = KME*CVEN1 (rate of urinary elimination of 5-HNMP)
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RAMET1 = rate of NMP metabolism to 5-HNMP (mg NMP metabolized/h)
STOCH = ratio of 5-HNMP to NMP molecular weights.
Exposure and Timing Control
A table function, RESLVL, was added as a place-holder for reading in defined (consumer)
inhalation exposure time-courses; specifically from EPA exposure assessment modeling.
A constant, GDstart, the day of gestation on which the simulation starts and a variable Gtime,
the hrs into gestation, were added to facilitate separating exposure control from gestation
timing.
A second set of DISCRETE/SCHEDULE blocks were added to allow for split exposure scenarios
(morning/afternoon worker exposure; dual-episode consumer exposures). DZONE, set in the
DISCRETE/SCHEDULE blocks, controls the time within a day when discontinuous exposure
occurs. Czone is the product of DZONE and a pulse function used to control for days/week
exposure in workplace scenarios:
Equation 1-8 Vapor Exposure Scheduling
Czone = pulse(0.0,fullweek,hrsweek)*DZONE ! pms 8-20-13
! for a 5 day/wk exposure, use fullweek=7*24, hrsweek=5*24 (Dayswk=5)
! for a single day, fullweek=lel6, hrsweek=24 (Dayswk=l)
A binary constant, BRUSH, was added to set exposure scenarios when dermal contact with
liquid occurs. For workplace scenarios, exposure to vapor and liquid are assumed to be
simultaneous; i.e., the worker leaves the location with NMP vapor and washes his/her hands
when he/she has finished applying the material.
Skin Compartment
The original skin compartment which is coded to include uptake from liquid-dermal contact was
renamed by adding "L" to the end, SK -> SKL and a second skin compartment to account for
concurrent vapor-skin uptake, SKV, was added. This was done because when the human model
was calibrated for inhalation exposure, an exposed skin surface area of 6700 cm2 was used.
When this surface is reduced to ~ 0, predicted blood levels of NMP are reduced ~ 45%. Thus
vapor uptake through the skin is a significant component of inhalation exposure and there is no
reason to assume, a priori, that this uptake (or desorption) does not occur through a similar
area of exposed skin during workplace and consumer exposures, except for any area that would
have liquid contact or otherwise be occluded (e.g., by protective equipment). So the SKV
compartment allows for simultaneous absorption of vapor-through-skin that does not have
liquid contact and from areas of skin with liquid contact. The surface area of SKV and SKL are
SAV and SAL, respectively. SAL can set directly for different exposure scenarios.
Page 265 of 281
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To account for variations with individual BW, a parameter for the fraction of skin area exposed
to vapor was introduced: SAVC, with SAV = SAVC*TSA, where ISA is the total body surface area.
ISA is calculated for each individual based on BW and height. For EPA simulations, SAVC was
set to 0.25, representing the head, neck, arms and hands, minus any area assumed to have
liquid contact or covered with protective gloves or a face-mask.
The rate for delivery from a liquid film to the 'SKL' skin compartment (also see further below) is
then defined by:
Equation 1-9 NMP Liquid Rate of Delivery to Skin
RADL = (PVL*SAL/1000.0)*(CSURF-(CSKL/PSKL))*Czone*BRUSH
! Net rate of delivery to "L" skin from liquid, when liquid is there
The equations for transfer of vapor (air concentration = Cl) to the SKL compartment, which
occurs during periods with no liquid/spray contact for the SKL compartment are similarly:
Equation 1-10 NMP Vapor Rate of Delivery to Skin
RADVL = (PV*SAL/1000.0)*(CI - (CSKL/PSKA))*(1.0-Czone*BRUSH)
! Net rate of delivery to "L" skin from air, when liquid not present
Since the dermal exposures are to neat or highly concentrated preparations of NMP, it would
not be appropriate to assume that the residual liquid volume on the skin remains constant as
absorption occurs. Further assuming that water penetration of the skin is minimal, the amount
of water in the liquid solution is assumed to remain constant. The initial volume on the skin is
defined by a new constant VLIQO and the density of NMP at 40C (~ skin temperature) = DENSITY
= 1.02xl06 mg/L. To avoid potential divide-by-zero errors, the nominal initial concentration
(CONCL) is reduced by 1 mg/L (1 ppm) when computing the initial amount of NMP and water in
the liquid:
Equation 1-11 NMP Unabsorbed Fraction Remaining on Skin
DDN = (CONCL - 1.0)*VLIQO*FAD
! Subtract 1 mg/L, ~ 1 ppm, from initial cone, to avoid VLIQ -> 0
AH20 = (DENSITY+1.0-CONCL)*VLIQO ! ... and add it to H20. pms 9-16-14
A mass-balance equation was then added to attract the remaining amount and volume on the
skin surface, which is then used to calculate the concentration:
ASURF = INTEG(-RADL, DDN) ! Amount in liquid. DDN is the initial amount.
VLIQ = (AH20 + ASURF)/DENSITY
CSURF = ASURF/VLIQ
This volume balance is important for analysis and calibration of the dermal PK studies where
small volumes (5 or 10 ml) were applied at the beginning of the exposure and not replenished.
However in workplace and consumer user exposures, it is assumed that fresh liquid is
Page 266 of 281
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constantly replacing any NMP that is absorbed, keeping the surface concentration essentially
constant. Therefore the initial volume, VLQO, is set to a large value (106 L) for those scenarios.
The skin partition coefficients were also recalculated as was done for the rat, with rat
parameters for skin:saline and blood:air, but human blood:saline.
Tissue and Blood-Flow Mass Balances
The model had been previously coded with an alveolar blood compartment (ALV), but this was
commented out in the DYNAMIC section. Therefore this volume fraction should not be
subtracted when calculating the slowly-perfused volume. The fraction of blood-flow to slowly
perfused tissue was updated to also account for the SKV compartment; on the other hand a
separate skin compartment is not used for 5-HNMP, so the skin blood flow is NOT subtracted
for the metabolite-slowly-perfused compartment (SLW5). These have all been corrected.
QSKCC (original fractional flow to the skin) had been subtracted twice, both in calculating
QSLWC and then in the calculation of QSLW. The 2nd subtraction created a mass balance error
and hence was removed. On the other hand, placental blood flow is now subtracted, so the
total flow to slowly-perfused continues to total cardiac output minus all other tissue/group
flows.
For tissues for which the volume changes with gestation day, the initial values were corrected
to match the calculation in the DYNAMIC section, which apply at the first time-step. In the
dynamic section, the calculation of QC was corrected to include the *increase* in placental flow
(QPLA - QPLAI) rather than the total placental flow (QPLA), since QCINIT includes QPLAI.
QSLW5 and VSLW5 (5-HNMP slow compartment flow and volume) are now calculated in the
DYNAMIC section by subtraction. The calculation of QC was otherwise left in its original form, in
contrast to the rat PBPK model.
Parameter Consolidation
Like the rat model, the human model physiological and biochemical parameters are now
primarily set in a single script, human_params.m. Initial values for the metabolic and vapor-
absorption (KPV) parameters were obtained by fitting Bader et al. (2006) inhalation data with
the exception of the high-concentration data from one individual, but the data otherwise
grouped without distinction between individuals (further details below). An alternate set of
fitted parameters was obtained by fitting the data for each individual separately, focused on
the low-concentration data and then calculating the average of each parameter across the
individually-fitted values. This subset of parameters is selected by using human_avg_params.m.
Since further analysis of the dermal absorption of liquid NMP showed that this uptake differed
between neat (100%) NMP and diluted (50%) NMP, separate value of PVL were obtained for
neat vs. diluted NMP (also see below). Hence only constants which define specific exposure
scenarios (include skin areas exposed) and PVL are defined in the specific simulation scripts.
Page 267 of 281
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Inhalation Data
A study conducted by the Hannover Medical School, University of Dortmund, Germany (Bader
and van Thriel, 2006) was used to calibrate inhalation parameters of the model. In this study, 8
healthy, non-smoking, male volunteers were exposed to 10, 40 or 80 mg/m3 NMP in an
environmental chamber. Over the course of several weeks, each volunteer was exposed
sequentially to all 3 concentrations. The 8 volunteers were separated into 2 groups of 4 and
each group was exposed in a shared chamber. The exposures were carried out in ascending
concentrations, with a 1-week period between each session. Volunteers wore slacks and T
shirts and thus had arms exposed to vapor. Blood was collected from each volunteer in the
middle of the 6-hr exposure period, at the end of exposure (6 hr) and 1, 2, 3, 18 and 42 hrs after
the end of exposure. Urine was also collected from each volunteer at times up to 42 hrs after
the end of exposure. Because it is relatively rare to have blood and urine data for multiple
exposure levels, multiple time points, in individuals, efforts were made to ensure the exposure
scenarios for these data were modeled as accurately as possible.
To collect the mid-exposure blood samples, volunteers left the chamber one at a time and
moved to another room to have blood drawn and to give a urine sample. The data are
consistent with a sharp drop in concentration for the mid-exposure blood sampling, when the
peak NMP concentration measured at the end of the exposures are considered. In the report,
the time taken to leave the chamber, walk to the new room, donate blood and urine was
suggested to be about 10 minutes. However, exact times were not recorded. The notes indicate
that the time between blood collection and urine collection was at least 5 minutes. In addition,
the recorded times for collection of blood from first collected sample to last (i.e., between the
first and fourth volunteers to leave the chamber) was up to 55 minutes. If the times were
equivalent for each subject and the volunteers only left the chamber as the previous volunteer
returned, this would indicate an average of 12 minutes was needed for sample collection from
each volunteer.
Based on a careful review of the data tables in Bader and van Thriel (2006) and personal
communication with Dr. Michael Bader and Dr. Christoph van Thriel, it was determined that
each subject entered and left the exposure chamber at different times as described just above
and were likely not sampled at exactly the same time after the beginning and end of each
exposure segment. While the total exposure time for each subject was monitored and kept to
exactly 6 h on each exposure day, based on the timing of the blood and urine samples (taken
outside the exposure chamber), it is clear that the study design was not exactly followed. In
particular, while the morning and afternoon exposures were supposed to be 3 h each, the time
between the mid-day and first afternoon blood samples was less than 3 h for some individuals
in some exposures (and the mid-day sample was taken much later after noon for such samples).
In these cases it seemed likely that the individual spent slightly more than 3 h in the chamber in
the morning and slightly less in the afternoon, for that exposure. Based on the recorded data
and communications, the exposure timing used for modeling and simulation was set to 3.1 h for
the morning exposure, a mid-day break of 0.2 h (12 min) and 2.9 h for the afternoon exposure.
Since individual subjects did not enter and exited the chamber at exactly the same time, the
Page 268 of 281
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time of their entrance to the chamber for each exposure was estimated based on the recorded
times of the blood and urine samples. The sample times used for modeling were then
calculated relative to the estimated entry times.
It was also clear that a number of the measurements, especially those of 5-HNMP for the low-
concentration exposure, were recorded as the limit-of-detection (LOD), when the measured
value fell below this limit. This was confirmed with Dr. Bader (personal communication).
Therefore all measurements at/below the LOD were removed from the data set to avoid the
bias they would otherwise introduce.
It also appeared that the high-concentration-exposure (80 mg/m3) for one subject deviated
substantially from the other subjects; see Figure_Apx 1-5 below. Since the blood concentration
at 6 h was well below those of the other subjects and that at 24 h well above (4 subjects had
levels below the LOD), this individual's high concentration set was excluded from analysis of the
grouped data. Blood concentrations at the middle and low exposure for this individual were
among the range of the other subjects, hence included in the group data.
With this one data set removed, the revised model was fit to the group data for exposures at
9.7 and 80 mg/m3, by adjusting the following parameters: PV, VK1C, API, KUMNE, VK2C,
VOD5HC and KME. Since the data for the 40 mg/m3 exposure were consistent with the
80 mg/m3, but the data for 9.7 mg/m3 appeared not to be and it was considered especially
important to describe low-concentration exposures, the 40 mg/m3 data were excluded from
this exercise. The resulting parameter values are as follows, with model fits to the group data
shown in Figure_Apx 1-6, left side. These fits are compared to ones obtained by fitting the data
for each individual separately, where possible using only the low-concentration exposure data
and then calculating the average across the individual fits for each parameter (right side of
Figure_Apx 1-6; details below).
Page 269 of 281
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en
E
*^j>
•o
o
_o
CD
C
Q.
£
z
2,1
1.8
1.5
1.2
0.9
0.6
0.3
10
20
25
15
Time (h)
Figure_Apx 1-5 NMP Blood Concentration Data from Bader and van Thriel (2006)
Curves are simulations for 9.7, 40 and 80 mg/m3 exposures. Squares are individual blood
concentration data for the 80 mg/m3 exposure. Solid squares are from the one individual with
the highest BW and height (102 kg, 190 cm), compared to the other subjects (65-80 kg, 168-
183cm).
Page 270 of 281
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Model fit, 80 mg/m3
Model fit, 40 mg/m3
Modi fit, 9,7 mg/m3
Exp obs 80 ppm
Exp obs 40 mg/rr»3
Exp obs 9,7 mg/m3
Model fit, 80 mg/m3
Model fit, 40 mg/m3
Modi fit, 9,7 mg/m3
Exp obs 80 ppm
Exp obs 40 mg/m3
Exp obs 9.7 mg/m3
10 15
Time (Mrs)
10 15
Time (hrs)
10 15
Time (hrs)
10 15
Time (hrs)
20 30
Time (hrs)
20 30
Time (hrs)
20 30
Time (hrs)
50
10
20 30
Time (hrs)
40
50
Figure_Apx 1-6 Alternate Fits to Collective Data from Bader and van Thriel (2006)
Left panels show fits to the groped data for 9.7 and 80 mg/m3 (data shown). Simulations in right
panel used average of parameters fit to each individual separately, primarily for 9.7 mg/m3 (see
text for details).
Page 271 of 281
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Parameters fitted to group data
for 9.7 and 80 mg/m3 exposures
PV = 1.6 (cm/h)
VKlC = 0.47(L/(h*kg075))
AFl = 0.02(L/mg)
VK2C = 0.035 (L/(h*kg075))
VOD5HC = 0.26(L/kg)
KME = 2.3(L/h)
KUMNE = 0.092 (L/h)
Average of parameters fit to data for each
individual separately, primarily 9.7 mg/m3
PV = 16.4 (cm/h)
VK1C = 0.386 (L/(h*kg075))
API = 0.02 (L/mg) [fixed at group-fit value]
VK2C = 0.0359 (L/(h*kg075))
VOD5HC = 0.243(L/kg)
KME = 2.75 (L/h)
KUMNE = 0.103 (L/h)
In their summary statistics, Bader and van Thriel (2006) reported group-averages of the peak
NMP blood levels as being 0.293 mg/Lfor the 9.7 mg/m3 and 1.585 mg/m3. The ratio of these
two (1.585/0.293 = 5.4), is considerably less than one would expect assuming linearity with
exposure level (80/9.7 = 8.25) and is the opposite of what one would expect due to metabolic
saturation of the conversion of NMP to 5-HNMP. This is not true for the ratio peak 5-HNMP
levels in blood (8.08), however, which is comparable to the relative exposure level. If the
nonlinearity in NMP blood levels were due to more efficient metabolism at the higher exposure
level, then ratio of 5-HNMP blood levels would have been greater than expected.
Since the mechanism for the nonlinearity in blood NMP levels is unclear and it would be
undesirable to under-estimate NMP blood levels and hence human risks at lower exposure
levels, it was decided to estimate parameters using only the low-exposure data, if possible or
with minimal use of the high-exposure data. (For two of the subjects the blood levels of
5-HNMP did not rise above the LOD for the low exposure, making it impossible to estimate
VOD5HC for them. Hence the 80 mg/m3 blood 5-HNMP data were also needed to estimate their
parameters.) Given the observation that the high-exposure data for one subject was disparate
from the other subjects, it also seemed possible that the apparent nonlinearity in the average
PK data was due to the mixing of data from the 8 subjects in the study. Therefore fits focused
on the low-exposure data were conducted separately for each subject. Since limiting to the low-
exposure data would provide almost no information on metabolic saturation and the affinity
(AF1) obtained from the fits to the group data was quite low (0.02 L/mg), AF1 was held at that
group-fit value for this exercise. The resulting parameter values are listed in Table_Apx 1-1 and
fits to the individual data shown in Figure_Apx 1-7 - Figure_Apx 1-10. In order to allow one to see
the fit to the low concentration and otherwise compare the fits across individuals, the y-axis
scale was held constant for each analyte across the individuals, though this meant that the
simulation curves for the higher exposure data sometimes went off the top of the plot.
Page 272 of 281
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Table_Apx 1-1 Estimated PBPK Parameters for Each Subject of the Bader and van Thriel (2006)
Experiments
Subject
1
4
10
12
14
16
17
25
average
VK1C
0.25
0.17
0.22
0.63
0.57
0.45
0.38
0.42
0.386
KUMNE
0.11
0.042
0.069
0.046
0.2
0.06
0.2
0.1
0.103
PV
19
34
35
12
10
0
20
1.5
16.4
VK2C
0.017
0.004
0.027
0.044
0.08
0.08
0.02
0.015
0.0359
KME
3.2
3
2.8
1.9
2.5
1.9
4.3
2.4
2.75
VOD5HC
0.2
0.14
0.12
0.39
0.4
0.2
0.26
0.23
0.243
It is interesting to note that for half of the subjects (#12, #14, #16 and #25), the fits and data for
NMP in blood show that the data are quite consistent with the essentially linear PBPK model,
while for the other half the simulations with parameters fitted to the low-concentration data
over-predict the high-concentration NMP data.
Page 273 of 281
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CO
JC
O.
2.1
1.8
1.5
1.2
0.9
0.6
0.3
Q.
5!
Z
I
/ \
R
\
D
A
Model 80 mg/m3
Model 40 mg/m3
Model 9.7 mg/m3
Exp obs 80 ppm
Exp obs 40 mg/m3
Exp obs 9.7 mg/m3
12 18
Time (h)
12 18 24
Time (h)
24 36 48
Time (h)
140'
120
100
80
60
40
20
0
in
12
24 36
Time (h)
48
Model 80 mg/m3
Model 40 mg/m3
Model 9.7 mg/m3
Exp obs 80 ppm
Exp obs 40 mg/rn3
Exp obs 9.7 mg/m3
Figure_Apx 1-7 Model Fits to Subjects 1 and 4 of Bader and van Thriel (2006)
Model fit separately to each subject. See text for details.
Page 274 of 281
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Model SO mg/m3
Model 40 mg/m3
Model 9.7 mg/m3
Exp obs 80 pprn
Exp obs 40 mg/m3
Exp obs 9.7 mg/m3
Model 80 mg/m3
Model 40 mg/m3
Model 9.7 mg/m3
Exp obs 30 ppm
Exp obs 40 mg/m3
Exp obs 9.7 mg/m3
24 36
Time (h)
24 36
Time (h)
12
24 36
Time(h)
48
12
24 36
Time (h)
Figure_Apx 1-8 Model Fits to Subjects 10 and 12 of Bader and van Thriel (2006)
Model fit separately to each subject. See text for details.
48
Page 275 of 281
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Model 80 mg/m3
Model 40 mg/m3
Model 9.7 mg/m3
Exp obs 80 ppm
Exp obs 40 mg/m3
Exp obs 9.7 mg/m3
Model SO mg/m3
Model 40 mg/m3
Model 9.7 mg/m3
Exp obs 80 pprn
Exp obs 40 mg/m3
Exp obs 9.7 mg/m3
12
Time (h)
6 12 18
Time (h)
_c
0.
5!
Z
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
~ 1.6
f 1.4
*•* 1.2
.E 1
5 0.8
.£ 0.6
| 0.4
Z 0.2
n
n n n n
i A A A A A
(f
&f"
r^^n -v-W" V V V
12 24 36 48
Time (h)
12 24 36 48
Time (h)
4S
12
24 36
Time(h)
Figure_Apx 1-9 Model Fits to Subjects 14 and 16 of Bader and van Thriel (2006)
Model fit separately to each subject. See text for details.
24 36
Time (h)
48
Page 276 of 281
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,-. 2.1
Model SO mg/m3
Model 40 mg/m3
Model 9.7 mg/m3
Exp obs 80 ppm
Exp obs 40 mg/m3
Exp obs 9.7 mg/m3
Model 80 mg/m3
Model 40 mg/m3
Model 9.7 mg/m3
Exp obs 80 ppm
Exp obs 40 mg/m3
Exp obs 9.7 mg/m3
M A A A A A
12
24 36
Time (h)
48
12 24 36 48
Time (h)
24 36
Time(h)
4S
12
24 36
Time (h)
48
Figure_Apx 1-10 Model Fits to Subjects 17 and 25 of Bader and van Thriel (2006)
Model fit separately to each subject. See text for details.
Page 277 of 281
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Dermal Data: Vapor and Liquid
Volunteers in the study described by Akesson and Paulsson (1997) wore shorts and t-shirts and
thus also had dermal (vapor) exposures, as well as inhalation exposures, to NMP. The exposure
concentrations for this study were similar to those of Bader et al. (2005). With only inhalation
exposures, the model under-predicted plasma NMP by about 25%, a vapor permeability
coefficient, which accounts for both the skin permeability and the vapor/skin surface
interaction, (PV) of 1.5 cm/hr was optimized to fit these data and is equivalent to the previously
optimized value (Poet et al., 2010) (Figure_Apx 1-11).
2,7
2,1
"
O
O 0.6
-Q
53 mg/m3
24 mg/m3
10 mg/m3
53 mg/m3
24 mg/m3
10 mg/m3
53 mg 'rn3
24 mg/m3
10 mg/m3
simulation, with dermal
simulation, with dermal
simulation, with dermal
simulation, no dermal
simulation, no dermal
simulation, no dermal
data
data
data
12 15
Time (hr)
18
21
24
Figure_Apx 1-11 Model Fits to Human Inhalation Data of Akesson and Paulsson (1997), With and
Without Dermal Absorption of Vapors
Model parameters were as obtained previously using the data of Bader and van Thriel (2006).
Simulations are shown with dermal absorption of vapors included ("with dermal"; 25% of total
surface area assumed exposed) or turned off ("no dermal").
Akesson et al. (2004) exposed 12 volunteers (6 male and 6 female) to 300 mg NMP either neat
or diluted 50:50 in an aqueous solution. Blood and urine 5-HNMP concentrations were
monitored for up to 9 days. The plasma 5-HNMP concentration was extracted from the figure
using Digitizlt (Braunschweig, Germany). Urinary 5-HNMP concentrations were extrapolated to
total amount eliminated using the assumption that the average urinary flow for an adult is
18 ml/kg-day (Heffernan et al., 2014). Aqueous dilution resulted in a slower time to reach peak
plasma 5-HNMP and a reduction in peak plasma concentration. Because the urinary elimination
constant (KME) for 5-HNMP was seen to vary among subjects when fitting the Bader and van
Thriel (2006) data (see Table HI) and we did not want a lack-of-fit to the urinary elimination
Page 278 of 281
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data (which establish the mass balance, hence total amount absorbed) to adversely impact the
fitting of the 5-HNMP blood levels, KME was also fit to each data set then. Optimized liquid Kp
for neat NMP was 2.05 x ICT3 cm/hr (with KME = 4.54L/hr). To fit the data from the diluted
exposures, a lower Kp of 2.87xlO'4 was needed (with KME = 2.10 L/hr) (Figure_Apx 1-12). These
liquid dermal permeability coefficients were used in estimating human dermal absorption for
neat and diluted NMP absorption, though with KME kept at the average value from the Bader
and van Thriel (2006) study (2.3 L/hr). (Note that KME does not impact NMP blood levels.)
Workplace Observer Study
In a biomonitoring study Xiaofei (2000) followed 4 workers and 5 observers in a lens
manufacturing facility. The workers washed lenses with NMP, working 11-hr shifts with a 1-hr
lunch break (total 12 hrs within the facility). Observers were stated to be in the facility from 8
am to 5 pm for a single day, but the tabulated exposure metrics indicated only 8 h of exposure,
so it was assumed that they also took a 1-hr break (at noon). The mean exposures for the
observers was 0.28 ppm, with a range from 0.24 to 0.32 ppm. The PBPK model underestimated
plasma NMP concentrations for the workers (data not shown) and observer by ~3x when no
dermal exposure is assumed (Figure_Apx 1-13). However, droplets of NMP were noted on the
lenses as the workers were moving those lenses to drying racks. Just assuming that these
droplets were due to some aerosolized NMP and that the observers had a small surface area of
skin exposed to such droplets, 0.2 cm2, gave results that better fitted the blood data during the
exposure, but the clearance after exposure appeared to be too rapid. Assuming that the
average metabolic rate was 1/z of that identified from the Bader and van Thriel (2006) data (i.e.,
VK1C = 0.193 L/h-kgO.75) with an even smaller exposure to aerosol (0.1 cm2 of exposed skin)
resulted in simulations that matched the data well (Figure_Apx 1-13). The lowest individual
VK1C estimated for the Bader and van Thriel (2006) data was 0.17 L/h-kgO.75, so the value used
here is not unreasonable. In summary, the un-adjusted model gave simulations that were
within a factor of three of this data set and the discrepancy can be explained by a reasonable
level of metabolic variability between the two study populations and a small amount of dermal
contact.
Page 279 of 281
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1.2-
1.1-
5 J
| 0.9-
0.8-
I
w
J5
a
c 0.5 -I
0.7-
0.6-
Q.
5:
z
I
in
0.4-
0.3-
0.2-
0.1-
0-
Q.
Z
Z
±
in
Model simulation, men, neat NMP
Model simulation, women, neat NMP
Moodel simulation, men, 50% NMP
Akesson et al 2004 men, neat NMP
Akesson et al 2004 women, neat NMP
Akesson et a! 2004 men, 50% NMP
0
10 15 20
Time (h)
25
30
60-
55-
50-
40-
35-
30-
25-
20-
15-
10-
5-
0-
Model simulation, men, neat NMP
Model simulation, women, neat NMP
Moodel simulation, men, 50% NMP
Akesson et al 2004 men, neat NMP
Akesson et al 2004 women, neat NMP
Akesson et al 2004 men, 50% NMP
0
10
50
60
20 30 40
Time (h)
Figure_Apx 1-12 Model Fits to Human Dermal Exposure Data of Akesson et al. (2004)
Page 280 of 281
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0.12
0.1
0,08
fi: 0.06
Z
•o
g 0.04
S
0.02
•
A
O
0.24 ppm simulation
0.32 ppm simulation
0.28 ppm, modified"
Volunteer A
Volunteer B
Volunteer C
Volunteer D
Volunteer E
6
18
21
24
9 12 15
Time (hr)
Figure_Apx 1-13 Workplace Observer Simulations Representing Subjects of Xioafei et al. (2000)
*Metabolic elimination was reduced to 1/£ that estimated from Bader and van Thriel (2006) data and
0.1 cm2 of skin was assumed exposed to liquid aerosol.
Page 281 of 281
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