TSCA Work Plan Chemical Risk Assessment

N-Methylpyrrolidone:

Paint Stripper Use

CASRN: 872-50-4

March 2015

N O

United States

Environmental Protection Agency

EPA Document# 740-R1-5002

March 2015

Office of Chemical Safety and

Pollution Prevention
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-1 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-1 CONSUMER USES .............................................................................................................................................127

B-2 PAINT STRIPPING APPLICATIONS..........................................................................................................................128

Appendix C STATE NMP REGULATIONS .......................................................................... 129

Appendix D OCCUPATIONAL EXPOSURE ASSESSMENT SUPPORT INFORMATION............. 130

D-1 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-1 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 ROH during wait time, 0.45 ACH, 0.25 

Weight Fraction.............................................................................................................................185

E-5-2 NMP Scenario 2. Coffee Table, Brush-On, Workshop, User in Workshop during wait time, 0.45 

ACH, 0.5 Weight Fraction..............................................................................................................188

E-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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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......................................................................................................194

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......................................................................................................197

E-5-6 NMP Scenario 6a. Coffee Table, Spray-On, Workshop, User in workshop during wait time, 0.45 

ACH, 0.53 Weight Fraction............................................................................................................200

E-5-7 New Scenario 6b. Coffee Table, Spray-On, Workshop, User in workshop during wait time, 0.45 

ACH, 0.53 Weight Fraction............................................................................................................203

E-5-8 NMP Scenario 7a Chest, Spray-On, Workshop, User in ROH during wait time, 0.18 ACH, 0.53 

Weight Fraction.............................................................................................................................206

E-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-1 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-1 REVIEW OF AKKESON ET AL., 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 ET AL., 2005 .........................................................................................................................227

G-5 REVIEW OF BADER AND VAN THRIEL, 2006 ...........................................................................................................228

G-6 REVIEW OF BADER ET AL., 2007 .........................................................................................................................229

G-7 REVIEW OF BADER ET AL., 2008 .........................................................................................................................230

G-8 REVIEW OF XIAOFEI ET AL., 2000........................................................................................................................231

Appendix H BENCHMARK DOSE ANALYSIS...................................................................... 232

H-1 BENCHMARK DOSE MODELING OF FETAL/PUP BODY WEIGHT CHANGES FOR CHRONIC EXPOSURES .................................232

H-1-1 Results for Saillenfait et al., 2003..................................................................................................234

H-1-2 Results for Saillenfait et al., 2002..................................................................................................237

H-1-3 Results for Saillenfait et al., 2002 and 2003 combined.................................................................240

H-1-4 Results for DuPont, 1990...............................................................................................................243

H-1-5 Results for Becci et al., 1982 .........................................................................................................246

H-2 BENCHMARK DOSE MODELING OF EFFECTS FOR ACUTE EXPOSURES...........................................................................248

H-2-1 Results for Saillenfait et al., 2002 and 2003 combined using Cmax ................................................249

H-2-2 Results for Saillenfait et al., 2002 and 2003 combined using AUC................................................252

H-2-3 Results for Sitarek et al., 2012.......................................................................................................255

Appendix I PBPK MODELING......................................................................................... 256

I-1 RAT MODEL ....................................................................................................................................................256

I-2 HUMAN MODEL...............................................................................................................................................263

I-2-1 Corrections to Human Model Structure ........................................................................................264

LIST OF 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 Liquidsa .............................................................33

Table 2-2 Summary of Parameters for Worker Inhalation Exposure Concentrationsa................................................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-1 Aquatic Toxicity Data for NMP - Acute Toxicity.................................................................................122

Table_Apx A-2 Aquatic Toxicity Data for NMP - Chronic Toxicity..............................................................................123

Table_Apx A-3 Aquatic Toxicity Data for NMP - Wildlife...........................................................................................124

Table_Apx B-1 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_Apx C-1 State NMP Regulations......................................................................................................................129

Table_Apx D-1 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-1 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-1 Study Quality Considerations.............................................................................................................213

Table_Apx F-2 Reproductive Performance of Females, Summarized from Sitarek et al, 2012.................................215

Table_Apx H-1 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 

AUC as the 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 

AUC as the 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 

AUC as the Dose Metric (DuPont 1990) ......................................................................................................243

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)................................................................................................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 Cmax as the Dose 

Metric (Sitarek et al., 2012).........................................................................................................................255

Table_Apx I-1 Estimated PBPK Parameters for Each Subject of the Bader and 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 NOAEL and 

LOAELs Identified ..........................................................................................................................................64

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.......................................................................................................65

Figure 3-4 Analysis of Fit: Average Daily AUC vs Fetal or Postnatal Body Weight.......................................................73

LIST OF APPENDIX FIGURES

Figure_Apx D-1 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-1 Results from FTIR Samples (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-11 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-1 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 et al., 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 I-1 Model Fits to IV Injection Data in Rats..............................................................................................258

Figure_Apx I-2 Model Fits to Rat Oral PK Data ..........................................................................................................260

Figure_Apx I-3 Model Fits to Dermal PK Data from Payan et al. (2003) in Rats........................................................261

Figure_Apx I-4 Model Simulations vs. Inhalation PK Data from Ghantous (1995) for NMP Inhalation in Rats.........262

Figure_Apx I-5 NMP Blood Concentration Data from Bader and van Thriel (2006)..................................................270

Figure_Apx I-6 Alternate Fits to Collective Data from Bader and van Thriel (2006)..................................................271

Figure_Apx I-7 Model Fits to Subjects 1 and 4 of Bader and van Thriel (2006).........................................................274

Figure_Apx I-8 Model Fits to Subjects 10 and 12 of Bader and van Thriel (2006).....................................................275

Figure_Apx I-9 Model Fits to Subjects 14 and 16 of Bader and van Thriel (2006).....................................................276

Figure_Apx I-10 Model Fits to Subjects 17 and 25 of Bader and van Thriel (2006)...................................................277

Figure_Apx I-11 Model Fits to Human Inhalation Data of Akesson and Paulsson (1997), With and Without Dermal 

Absorption of Vapors ..................................................................................................................................278

Figure_Apx I-12 Model Fits to Human Dermal Exposure Data of Akesson et al. (2004) ...........................................280

Figure_Apx I-13 Workplace Observer Simulations Representing Subjects of Xioafei et al. (2000)...........................281

LIST OF EQUATIONS

Equation D-1 Mass Balanced Concentration of NMP ................................................................................................153

Equation E-1 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 for a 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-1 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 I-1 Cardiac Output......................................................................................................................................257

Equation I-2 Rat Skin Model Equations .....................................................................................................................260

Equation I-3 Rat Skin Partition Coefficients...............................................................................................................261

Equation I-4 Dermal Dosing Equations......................................................................................................................262

Equation I-5 NMP Dermal Transport .........................................................................................................................263

Equation I-6 NMP Vapor Exposure Control ...............................................................................................................263

Equation I-7 5-HNMP Metabolism and Elimination ..................................................................................................264

Equation I-8 Vapor Exposure Scheduling...................................................................................................................265

Equation I-9 NMP Liquid Rate of Delivery to Skin .....................................................................................................266

Equation I-10 NMP Vapor Rate of Delivery to Skin ...................................................................................................266

Equation I-11 NMP Unabsorbed Fraction Remaining on Skin ...................................................................................266

Page 8 of 281
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-Methyl2-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.

Page 9 of 281
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.

Page 10 of 281
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

BMCL1SD 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

CO2 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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ft2 or sq ft Square foot/feet

FTIR Fourier transform infrared

g Gram(s)

GC-FID Gas chromatography with flame ionization detection

GD Gestation day

H2S 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)

LC50 Lethal concentration 50 percent

LD50 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:air PC

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

TDS 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

UFH 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)

Page 13 of 281
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 Nmethylpyrrolidone, also referred to as 1-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 lbs 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.

1 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 

Page 15 of 281
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 vaporthrough-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, vaporthrough-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)

Page 16 of 281

 
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 vaporthrough-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, vaporthrough-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.

Page 18 of 281
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.

Page 19 of 281
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 

1-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 (lbs) 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-1).

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 [CO2] and 

hydrogen sulfide [H2S]), lube oil extraction;

• Engineering plastics: reaction medium for the production of high-temperature 

polymers such as polyethersulfones, polyamideimides and polyaramids;

• Coatings: solvent for acrylic and epoxy resins, polyurethane paints, waterborne 

paints or finishes, printing inks, synthesis/diluent of wire enamels, coalescing agent;

• Agricultural chemicals: solvent and/or 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.

Page 21 of 281

 
7.747 million lbs 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 nonregulatory 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/methyl.pdf (accessed October 28, 2014) 

Page 22 of 281

 
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. 

Page 23 of 281
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.

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 C5H9ON

Molecular weight 99.13

Physical form Colorless to slightly yellow liquid; slight amine odor

Melting point -24.4 °C

Boiling point 202 °C

Vapor pressure 0.190 mmHg at 25 °C

Log Kow -0.727 at 25 °C

Water solubility 1,000 g/L at 25 °C

Flash point 95 °C (open cup); 91 °C (closed cup)

Source: EC (2000)

N O

Page 24 of 281
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 × 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 × 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.

Page 25 of 281
Table 1-2 Environmental Fate Characteristics of NMP

Property Value

CASRN 872-50-4

Photodegradation 

half-life

5.8 hrs (estimated)

Hydrolysis halflifeStable

Biodegradation Half-life of 4 days in a clay soil

Half-life of 8.7 days in a loam soil

Half-life of 11.5 days in a sandy soil

73% after 28 days (readily biodegradable, OECD 301C, MITI (I))

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)

Bioaccumulation

Bioconcentration 

BAF = 0.9 (estimated)b

BCF = 3.16

Log Koc 0.9 (estimated)b 

Fugacity

(Level III Model)b

Air (%)

Water (%)

Soil (%)

Sediment (%)

<0.1

32.5

67.3

<0.1

Persistencec low

Bioaccumulationc low

Notes:

aOECD (2008)

b EPA (2012b)

c EPA (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.

Page 26 of 281
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. 

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). 

1.3.3.2 Health Effects and Human Receptors

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
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 

Page 28 of 281
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).

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
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
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 

Page 31 of 281
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).

Page 32 of 281
Table 2-1 Summary of Parameters for Worker Dermal Exposure to Liquidsa

Parameter 

Characterization

NMP Weight 

Fraction in Liquid 

Paint Stripper 

Skin Surface Area

Contacting Liquid 

Paint Stripperb

Duration of 

Contact with 

Liquid

Body 

Weight

(Unitless) (cm2) (hrs/day) (kg)

Low end of range 0.25 445 1

74 

(50th

percentile)

Mid-range 0.625 668 4

High end of 

range

1 890 8

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 I-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).

Page 33 of 281
Table 2-2 Summary of Parameters for Worker Inhalation Exposure Concentrationsa

Scenario Parameter 

Characterization

NMP Exposure Concentration

(mg/m3, 8-hr TWA)

b

Miscellaneous stripping 

(assumed mostly indoor)

Low end of range 1.0

Mid-range 32.5

High end of range 64

Graffiti removal

(assumed mostly 

outdoor but may include 

semi-confined spaces)

Low end of range 0.03

Mean 1.01

High end of range 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 

Page 34 of 281
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 

Page 35 of 281
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 

#

Scenario 

description

Liquid 

weight 

fraction

Skin area 

exposeda 

(cm2)

8-hr 

TWA 

(mg/m3)

b

Durationc

Air 

concentrationd

(mg/m3)

1 Miscellaneous 

stripping low 

end of range

25% 445 1 1 hr/day 8

2 Miscellaneous 

stripping 

mid-range

62.5% 668 32.5 4 hr/day 65

3 Miscellaneous 

stripping high 

end of range

100% 890 64 8 hr/day with 

30-min break 64

4 Graffiti 

removal low 

end of range

25% 445 0.03 1 hr/day 0.24

5 Graffiti 

removal 

mean

62.5% 668 1.01 4 hr/day 2.02

6 Graffiti 

removal high 

end of range

100% 890 4.52 8 hr/day with 

30-min break 4.52

Notes:

a Total area potentially exposed to liquid NMP, in the absence of protective gloves. b TWA taken from Table 2-2. cDuration taken from Table 2-1. dAir 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.

Page 36 of 281
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.

Page 37 of 281

 
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 I-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 “upperend” 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.'

Page 38 of 281

 
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., TDS). The information collected from available product 

labels or TDSs 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/ft2 and 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 sprayon 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 

Page 39 of 281
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-1, 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

Page 40 of 281
• 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.

Figure 2-1 Example of Time-varying User Exposure Concentration and Maximum TWA Values for 

Selected Averaging Times

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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 × 30 ft2, two-story house with an 8-foot 

ceiling), workshop (area of product use) volume of 54 m3 (corresponds to 20 × 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 (ROH), 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 ROH 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.,

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consumer stays in workshop versus moving to the ROH), so that if the consumer stayed in the 

workshop during the wait period, inhalation exposures likely would be higher. The model 

response was somewhat less sensitive to the ROH air exchange rate with outdoor air (ROH ACH) for 

the non-user, but not for the user. This outcome could be explained for the non-user as the rate 

of air exchange in the ROH is less of a factor in inhalation exposure because initial exposures to 

the non-user were likely low. For the user, initial exposures were higher and if the user moves 

to the ROH, the rate of air flow in the ROH could reduce inhalation exposures under some 

conditions (i.e., high exchange rates). 

Figure 2-3 Model Sensitivity Results (Percent Change from Base-case Response) for Peak 1-hr TWA for 

Consumer User and Non-user

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
location and ROH 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

Case Description

Type of Application Location of

Product Use Concentration Characterizationa

1 Brush-on Workshop Central tendency

2 Brush-on Workshop User upper-end

3 Brush-on Workshop Non-user upper-end

4 Brush-on Bathroom Upper-end to bounding for user and non-user, 

constrained by Csat = 1,013 mg/m3

5 Brush-on Bathroom Upper-end to bounding for user and non-user, 

constrained by Csat = 640 mg/m3

6 Spray-on Workshop User upper-end b

7 Spray-on Workshop Non-user upper-end b

Notes: 

a Conditions obtained by varying the most sensitive parameters: NMP mass emitted; user location during the 

effect or wait period; and the ROH air exchange rate with outdoors. b Scenarios 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-1 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 ROH air exchange rate with outdoors (i.e., central tendency versus upper-end).

Page 44 of 281
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 ROH 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
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 ROH. Similarly, Scenarios 6 and 7 (for spray-on products) estimated upperend 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, acslX 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.

Page 46 of 281
Table 2-5 NMP Consumer Paint Stripping Scenario Descriptions and Parameters

Case 

ID Scenario 

NMP Released

Stripping Method

Room of Use House User Location 

During Wait 

Periodb

NonUser 

Location

Weight 

Fraction

Surface Area 

Treateda ft2

Application 

Rate, g/ft2

Release 

Fraction

Volume, 

m3

Ventilation/ 

ACH, hr-1

Volume, 

m3

ROH

ACH, hr-1

Brush-on Exposure Scenarios in Workshop

1 Central 0.25 

(central)

10

Coffee table

(central)

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.

54 

(central)

Open windows 

/ 1.26

(Professional 

judgment, 

90th 

percentile)

492 

(central)

0.45

(central)

ROH ROH 

(entire 

time)

2 Upper-end for user 0.5

(upperend)

Workshop

3 Upper-end for 

non-user

25

Chest of drawers 

(upper-end)

Chest: 12.5/ 30/25 min. per application; 

process repeated after completion of first 

scraping. Scrapings removed from house 

after last scraping.

0.18

(low-end)

ROH

Brush-on Exposure Scenario in Bathroom

4 and 

5

Upper-end to bounding 

for user and non-user

0.5

(upperend)

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)

ROH ROH 

(entire 

time)

Spray-on Exposure Scenarios in Workshop

6a Upper-end for user 

(Lower spray volatility) e

0.53

(upperend)

10

Coffee table 

(central)

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.

54 

(central)

Open windows 

/ 1.26

(Professional 

judgment, 

90th 

percentile)

492 

(central)

0.45

(central)

Workshop ROH 

(entire 

time)

6b Upper-end for user 

(Upper spray volatility) e

7a Upper-end for non-user 

(Lower spray volatility) e

0.53

(upperend)

25

Chest of drawers 

(upper-end)

Chest: 6.25/ 30/25 min. per application; 

process repeated after completion of first 

scraping. Scrapings removed from house 

after last scraping.

0.18

(low-end)

ROH

7b Upper-end for 

non-user

(Upper spray volatility) e

Notes: 

a

Surface area values were selected so that the calculated amount of product applied (g) corresponds approximately to the Abt (1992) survey results for amount of paint stripper used (50th percentile value 

of 32 ounces or 1,000 g for the central surface area of 10 ft2 and ~80th percentile value of 80 ounces or 2,500 g for the upper-end surface area of 25 ft2). bFor all scenarios, the user is in the treatment room during the application and scraping times and in the ROH after the last scraping. c

1 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.) e

For 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-1 of Appendix E for a detailed description.

Page 47 of 281
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).

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

Page 48 of 281
• 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 

LD50 values ranged from 5000 to 7000 mg/kg bw and the 4 hr LC50 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 

Page 49 of 281
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. Hass 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. 

Page 50 of 281
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.

Page 51 of 281
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

↓ Male fertilitya

, female 

fecunditya

LOAEL= 500 mg/kg bw/day

NOAEL= 160 mg/kg bw/day

↓ 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

↓ Maternal body weight

LOAEL=350 mg/kg bw/day

NOAEL=160 mg/kg bw/day

↓ Pup body weights

↑ Pup mortality

NMP 

Producer’s 

Group 1999b

Page 52 of 281
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

↓ Mean litter size

↓ 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

↓ Maternal body weight

LOAEL= 400 mg/kg bw/day

NOAEL=125 mg/kg bw/day

↓ Fetal BW

Exxon 

Biomedical 

Sciences, 

1992b

Page 53 of 281
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

↓ Maternal body weight

LOAEL=250 mg/kg bw/day

NOAEL=125 mg/kg bw/day

↓ 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

↓ Maternal body weight

LOAEL=540 mg/kg bw/day

NOAEL=175 mg/kg bw/day for 

Developmental toxicity and 

malformations

IRDC, 1991 b

Rat, 

Wistar

Male 

reproduction

0, 100, 300, 1,000 mg/kg 

bw/day by gavage

Males: premating and 

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

↓ Pup survival PND 0-4

Sitarek and 

Stetkiewicz, 

2008

Page 54 of 281
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, 

Wistar

Female 

reproduction

0, 150, 450, 1,000 mg/kg 

bw/day by gavage

Premating, mating and

gestation days 1-20, 

lactation exposures

LOAEL=450 mg/kg bw/day

NOAEL=150 mg/kg bw/day

↓ Percent of pregnant 

females

LOAEL=150 mg/kg bw/day

NOAEL=not determined

↓ Maternal body weight –

through gestation only, no 

difference during lactation

LOAEL=150 mg/kg bw/day

No NOAEL

↑ Pup mortality PND 0-4 & 0-21

↓ Pup BW PND 0-4

Sitarek et al., 

2012

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

Rat, SD 28-day 

subchronic

0, 258, 516.5, 1,033, 

2,066 mg/kg bw/day by 

gavage

LOAEL=2,066 mg/kg bw/day

NOAEL=1,033 mg/kg bw/day

↓ Testes size

↑ Testicular lesions 

(degeneration of 

seminiferous tubules)d

N/A BASF AG 

1978bb

Rat, SD 28-day 

subchronic 

study

0, 149/161, 429/493, 

1,234/1,548, 

2,019/2,269 mg/kg 

bw/day by diet 

males/females

LOAEL=1,234 mg/kg bw/day

NOAEL=429 mg/kg bw/day

↑ Testes degeneration/

atrophy

N/A Malek et al 

1997b

Rat, SD 3-month 

subchronic 

neurotoxicity

0,169/217, 433/565, 

1,057/1,344 mg/kg

bw/day by diet 

males/females

NOAEL= 1,057/1,344 mg/kg

bw/day e

Highest dose tested

N/A Malley et al., 

1999b

Rat, SD 2-year chronic 

bioassay

0, 66/88, 207/283, 

678/939 mg/kg bw/day by 

diet males/females

LOAEL=678 mg/kg bw/day

NOAEL=207 mg/kg bw/day

↓ Testes size

N/A Malley et al., 

2001b

Page 55 of 281
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/day f

N/A Malek et al., 

1997 b

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/day g

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 

DuPont 1990

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 ossificationa

↑ Skeletal malformationsa

↑ Fetal resorptionsa

Rat, 

Wistar

Developmental 

toxicity

0, 669 mg/m3

(0, 165 ppm) g hrs/day, 

Gestation days 4-20

NOAEC=669 mg/m3

↓Maternal body weight

LOAEC=669 mg/m3

Only dose tested

↑ Preimplantation loss

↓ Fetal BW

↑ Delayed ossification

Hass et al., 

1995

Page 56 of 281
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, 

Wistar

Developmental 

neurotoxicity

0, 612 mg/m3

(0, 151 ppm) 6 hrs/day, 

Gestation days 6-20

NOAEC=612 mg/m3

Only dose tested

Reproductive effects

Maternal body weight

LOAEC=612 mg/m3

Highest dose tested

↓ Fetal, pup BW, delayed 

developmental milestones and 

difficult tasks

Hass et al., 

1994

Rat, SD Developmental 0,122, 243, 487 mg/m3

(0, 30, 60, 120 ppm) 

6 hrs/day on gestation 

day 6-20

NOAEC=487 mg/m3

Highest dose tested

Reproductive effects

LOAEC=243 mg/m3

NOAEC=122 mg/m3

↓Maternal body weight

LOAEC=487 mg/m3

NOAEC=243 mg/m3

↓ Fetal BW

Saillenfait et 

al., 2003

Rat, 

Charles 

River 

CD

28-day 

subchronic 

0, 88, 423, 740 mg/m3

(0, 22, 104, 182 ppm)

LOAEC=88 mg/m3

Lowest dose tested

slight testicular atrophya

N/A Lee et al., 

1987

Rat, 

Wistar

28-day 

subchronic 

0, 10, 30, 101 mg/m3

(0, 2.5, 7.4, 25 ppm)

NOAEC=101 mg/m3

Highest dose tested

N/A BASF AG, 

1993b

Rat, 

Wistar

90-day 

subchronic 

0, 500, 1,000, 

3,000 mg/m3 (123, 247, 

740 ppm)

LOAEC=3,000 mg/m3

NOAEC=1,000 mg/m3

↑testes germinal 

epithelium cellular 

depletion, testicular atrophy

N/A BASF AG, 

1994b

Page 57 of 281
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

↓ Maternal body weight

LOAEL=750 mg/kg bw/day

NOAEL=237 mg/kg bw/day

↑ Incomplete ossification

↓ Fetal and pup BW

↑ Resorptions

↓ Viable offspring

Becci et al., 

1982

Notes:

a Considered biologically, but not statistically significant.

bAs cited in OECD (2007) cDue 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 ↓ BW in males e NOAEL= 169 mg/kg bw/day, LOAEL= 433 mg/kg bw/day for ↓ BW in males f NOAEL= 820 mg/kg bw/day, LOAEL= 2500 mg/kg bw/day for epithelial swelling of distal kidney tubuli g NOAEL= 2500 mg/kg bw/day, LOAEL= 7500 mg/kg bw/dayfor ↓ 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 indepth 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
Table 3-2 Summary of Exposure Pathways, Toxicity Endpoints and Risk Estimation Approach

Receptors

Exposure Pathway and Analytical Approach

Acute Dermal and Inhalation 

Exposures

Chronic Dermal and Inhalation 

Exposures

Worker 

Users and 

Nearby 

Worker

Non-Users Toxic endpoint: Developmental toxicitya

Risk approach: Margin of Exposure 

(MOE)

Toxic Endpoint: Developmental toxicity

Risk approach: Margin of Exposure 

(MOE)

Consumer 

Users and 

Nearby 

Residential 

Non-Users

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
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
Table 3-3 NMP Studies with Evidence for Developmental Toxicity

Study

Fetal Weight

GD 20 - PND 1

Pup Weight

PND 4

Pup Weight

PND 21

Fetal Mortality 

(multiple 

metricsa)

Pup 

Mortality 

PND 4

Pup 

Mortality 

PND 21

Incomplete 

Ossification

Skeletal 

Malformations

ORAL

STUDIES

Sitarek et al.,

2012 -- ↓ ↓ ↑ ↑ ↑ NA NA

Sitarek et al., 

2008

NA NA NA -- ↑ -- NA NA

NMP 

Producers 

Group, 1999a

↓ ↓ ↑ ↑ ↑

NMP 

Producers 

Group, 1999b

↓ ↓ ↑ ↑ ↑

Saillenfait et 

al., 2002 ↓ NA NA ↑ NA NA ↑ ↑

Exxon, 1992 ↓

INHALATION

STUDIES

Saillenfait et 

al., 2003 ↓ NA NA -- NA NA -- --

Hass et 

al.,1995 ↓ NA NA ↑ NA NA ↑ --

Hass et al.,

1994 ↓ ↓ ↓ -- -- -- NA NA

DuPont, 1990 ↓ ↓ ↓ ↑b -- -- ↑ ↑

Lee et al., 

1987 -- NA -- NA -- --

DERMAL

STUDIES

Becci et al.,

1982 ↓ NA NA ↑ NA NA ↑ ↑

Notes:

↓ indicates decrease, ↑ 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
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 GDs 20 or 21 and PNDs 0 or 1 were observed in multiple studies (DuPont, 1990; Hass et al., 

1995; Hass 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 Hass 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 Hass et al. also noted decreased pup body weights

(DuPont, 1990; Hass et al., 1995; Hass 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
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
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
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. Hass 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 et al., 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
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 NMPassociated 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
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 doseresponse 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 (Hass et al., 1995; Hass 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 doseresponse 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; 

Page 68 of 281
• Saillenfait et al., 2002 and

• Saillenfait et al., 2003.

For fetal resorptions and increased fetal mortality EPA/OPPT selected the following studies for 

dose-response analysis:

• Becci et al., 1982;

• Saillenfait et al., 2002;

• Saillenfait et al., 2003 and

• Sitarek et al, 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-methylsuccinimide (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 

Jönsson, 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 

Page 69 of 281
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 semioccluded (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 dermalonly (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), 2.05x10-3 cm/h and 

4.78x10-4 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 

Page 70 of 281
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-methylPage 71 of 281
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. 

Page 72 of 281
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 PODs 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 

Page 73 of 281
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. 

Page 74 of 281
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 Modela BMR

BMD

Internal 

dose 

BMDL

Internal 

dose

POD 

Internal 

dose 

Equivalent 

administered 

dose (route)a

Resorptions

Saillenfait et al. 

2002 and 2003

(GD 6-20, oral 

and inhalation)

Cmax

(mg/L) Hill 1% RD 429 216 216

218 mg/kg

bw/day 

(oral)

AUC (hr 

mg/L) Power 1% RD 3343 2128 2128

217 mg/kg

bw/day 

(oral)

Becci et al., 1982

(GD 6-15, 

dermal)

NOAEL = 237 mg/kg bw/day 662

237 mg/kg

bw/day

(dermal)

612 mg/kg

bw/day 

(oral)b

Fetal Mortality

Sitarek et al., 

2012

(GD1-PND1, oral)

Cmax

(mg/L)

No 

model 

selectedc

1% 

RD N/A N/A N/A 264 mg/kg

bw/day 

(oral)

NOAEL = 450 mg/kg bw/day 265

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 

Page 75 of 281
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.

Page 76 of 281
Table 3-5 Summary of Derivation of the PODs for Decreased Body Weight Following Chronic Exposure 

to NMP

Endpoint and 

reference

(exposure 

duration/route) Modela BMR

BMD

Internal 

dose 

AUC (hr 

mg/L)

BMDL

Internal 

dose 

AUC (hr 

mg/L)

POD

Internal 

dose AUC 

(hr mg/L)

Equivalent applied 

oral dosea

Fetal Body Weight

Saillenfait et al. 

2002 and 2003

(GD 6-20, oral 

and inhalation)

Exponential 

(M5)b

5% 

RD 1937 1424 1424 152 mg/kg bw/day

Saillenfait et al. 

2002

(GD 6-20 oral)

Exponential 

(M5)

5% 

RD 1637 1184 1184 129 mg/kg bw/day

Saillenfait et al. 

2003

(GD 6-20 

inhalation)

Linear 5% 

RD 652 411 411 48 mg/kg bw/day

DuPont 1990

(pre-conception 

exposure, GD

1–20, 

inhalation)

Exponential 

(M2)

5% 

RD 315 223 223 27 mg/kg bw/day 

Becci et al., 

1982

(GD 6-15, 

dermal)

Polynomial 

(3°) 5% RD 5341 4018 4018 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 BMDL of 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.

Page 77 of 281
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 doseresponse 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 (Hines, 2007). Therefore, the

Page 78 of 281
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 endpoints 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.

Page 79 of 281
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 nonusers 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 = Margin of Exposure (unitless)

Hazard value (POD) = PBPK derived from toxicological studies (see Table 3-4 and Table 3-5)

Human Exposure = 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.

Page 80 of 281
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 (ROH) 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.

UFH 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
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
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: EPAHQ-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
Table 4-3 Acute Risk Estimates for Occupational Exposures to NMP-Based Paint Strippers - Miscellaneous Stripping Activities

Exposure Scenario PPE Used Air Concentration

mg/m3a

Exposure, Internal Dose

Blood Cmax, mg-hr/L Margin of Exposure (MOE)

Women of 

Childbearing

Age

Pregnant 

Women

Women of 

Childbearing 

Age

Pregnant 

Women

1) Miscellaneous stripping (assumed 

mostly indoor)

-- low end of parameter range

1 hr/day contact

No respirator, No gloves

8

1.81 1.60 119.5 135.0

With respirator, No gloves 1.75 1.55 123.4 139.6

No respirator, With gloves 0.25 0.23 849.0 951.6

With respirator and gloves 0.20 0.18 1092.8 1233.6

1) Nearby worker non-user NA 0.08 0.07 2619.9 2886.5

2) Miscellaneous stripping (assumed 

mostly indoor)

-- mid-range parameter 

characterization

4 hr/day contact

No respirator, No gloves

65

16.99 16.03 12.7 13.5

With respirator, No gloves 15.75 14.84 13.7 14.6

No respirator, With gloves 2.97 2.87 72.6 75.3

With respirator and gloves 1.89 1.80 114.2 119.7

2) Nearby worker non-user NA 1.53 1.49 141.4 144.8

3) Miscellaneous stripping (assumed 

mostly indoor)

-- high end of parameter range

two 4 hr/day contacts

No respirator, No gloves

64

320.55 294.92 0.7 0.7

With respirator, No gloves 317.44 292.00 0.68 0.74

No respirator, With gloves 21.56 20.79 10.0 10.4

Page 84 of 281
Exposure Scenario PPE Used Air 

Concentration

mg/m3a

Exposure, Internal Dose

Blood Cmax, mg-hr/L Margin of Exposure (MOE)

Women of 

Childbearing

Age

Pregnant 

Women

Women of 

Childbearing 

Age

Pregnant 

Women

With respirator and gloves 19.76 19.03 10.93 11.35

3) Nearby worker non-user

NA 1.95 1.95 111.0 111.0

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 PPE Used Air Concentration

mg/m3

Exposure, Internal Dose

Blood Cmax, mg/L Margin of Exposure (MOE)

Women of 

Childbearing 

Age

Pregnant 

Women

Women of 

Childbearing 

Age

Pregnant 

Women

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

No respirator, No gloves

0.24

1.73 1.53 124.9 141.3

With respirator, No gloves 1.73 1.53 125.1 141.5

No respirator, With gloves 0.17 0.15 1238.8 1399.3

With respirator and gloves 0.17 0.15 1251.0 1413.6

4) Nearby worker non-user NA 0.003 0.002 86051.5 94837.9

Page 85 of 281
Exposure Scenario PPE Used Air Concentration

mg/m3

Exposure, Internal Dose

Blood Cmax, mg/L Margin of Exposure (MOE)

Women of 

Childbearing 

Age

Pregnant 

Women

Women of 

Childbearing 

Age

Pregnant 

Women

5) Graffiti removal (assumed mostly 

outdoor but may include semi-confined 

spaces)

-- mid-range parameter 

characterization

-- 0.625 weight fraction, 668 cm2 skin 

surface area, 4 hr/day contact

No respirator, No gloves

2.02

15.32 14.44 14.1 15.0

With respirator, No gloves 15.28 14.40 14.1 15.0

No respirator, With gloves 1.47 1.40 147.2 154.4

With respirator and gloves 1.43 1.37 150.6 158.1

5) Nearby worker non-user NA 0.05 0.05 4574.2 4678.4

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

No respirator, No gloves

4.52

316.59 291.22 0.7 0.7

With respirator, No gloves 316.37 291.01 0.68 0.74

No respirator, With gloves 19.17 18.47 11.3 11.7

With respirator and gloves 19.05 18.34 11.34 11.78

6) Nearby worker non-user NA 0.14 0.14 1579.2 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
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
Table 4-5 Acute Risk Estimates for Consumer Exposures to NMP-Based Paint Strippers

Exposure Scenario Individual

Peak Blood Exposure

Cmax, mg/L Margin of Exposure (MOE)

Women of 

Childbearing 

Age

Pregnant 

Women

Women of 

Childbearing 

Age

Pregnant 

Women

Scenario #1

Brush application in 

workshop, 

central parameter 

values

User 

without 

gloves

0.65 0.56 333 388

User with 

gloves 0.10 0.08 2244 2613

Nearby 

resident 0.03 0.03 7725 7855

Scenario #2

Brush application in 

workshop, 

upper-end values for 

user

User 

without 

gloves

1.36 1.17 159 184

User with 

gloves 0.26 0.24 836 912

Nearby 

resident 0.06 0.06 3862 3927

Scenario #3

Brush application in 

workshop, upper-end 

values for nearby 

residents

User 

without 

gloves

2.55 2.15 85 101

User with 

gloves 0.56 0.48 385 447

Nearby 

resident 0.19 0.19 1134 1141

Scenario #4

Brush application in 

bathroom, upper-end 

for user and nearby 

residents, constrained 

by Csat = 1,013 mg/m3a

User 

without 

gloves

7.32 6.28 29.5b 34.4

User with 

gloves 4.76 4.12 45.4 52.4

Nearby 

resident 0.62 0.61 350 352

Scenario #5

Brush application in 

bathroom, upper-end 

for user and nearby 

residents, constrained 

by Csat = 640 mg/m3a

User 

without 

gloves

6.98 5.99 30.9 36.1

User with 

gloves 4.42 3.84 48.9 56.3

Nearby 

resident 0.62 0.61 350 352

Scenario #6a User 

without 

gloves

0.18 0.17 1203.8 1295.1

Page 88 of 281
Exposure Scenario Individual

Peak Blood Exposure

Cmax, mg/L Margin of Exposure (MOE)

Women of 

Childbearing 

Age

Pregnant 

Women

Women of 

Childbearing 

Age

Pregnant 

Women

Spray application in 

workshop, upper-end 

values for user 

User with 

gloves 0.17 0.16 1268.4 1354.8

Nearby 

resident 0.04 0.04 4882 4965

Scenario #6b

Spray application in 

workshop, upper-end 

values for user 

User 

without 

gloves

1.55 1.36 139.8 158.5

User with 

gloves 1.47 1.30 147.1 166.0

Nearby 

resident 0.35 0.34 619 630

Scenario #7a

Spray application in 

workshop, upper-end 

values for nearby 

residents

User 

without 

gloves

0.23 0.21 944.6 1029.0

User with 

gloves 0.24 0.22 897.6 980.8

Nearby 

resident 0.12 0.12 1802 1832

Scenario #7b

Spray application in 

workshop, upper-end 

values for nearby 

residents

User 

without 

gloves

1.45 1.36 149.2 159.4

User with 

gloves 1.38 1.30 156.4 166.5

Nearby 

resident 0.88 0.86 246 251

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
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 vaporthrough-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
Table 4-6 Chronic Risk Estimates for Occupational Exposures to NMP-Based Paint Strippers - Miscellaneous Stripping Activities

Exposure Scenario PPE Used Air Concentration

mg/m3a

Exposure, Internal Dose

Blood AUC, mg-hr/L Margin of Exposure (MOE)

Women of 

Childbearing 

Age

Pregnant 

Women

Women of 

Childbearing 

Age

Pregnant 

Women

1) Miscellaneous stripping (assumed 

mostly indoor)

-- low end of parameter range

1 hr/day contact

No respirator, No gloves

8

4.24 4.23 97.0 97.1

With respirator, No gloves 4.09 4.08 100.4 100.7

No respirator, With gloves 0.60 0.61 680.1 676.4

With respirator and gloves 0.46 0.46 892.4 893.2

1) Nearby worker non-user NA 0.20 0.21 2008.6 1968.6

2) Miscellaneous stripping (assumed 

mostly indoor)

-- mid-range parameter 

characterization

4 hr/day contact

No respirator, No gloves

65

75.55 75.09 5.4 5.5

With respirator, No gloves 69.63 69.08 5.9 5.9

No respirator, With gloves 12.95 13.07 31.7 31.5

With respirator and gloves 8.10 8.10 50.7 50.8

2) Nearby worker non-user NA 6.73 6.87 61.1 59.9

3) Miscellaneous stripping (assumed 

mostly indoor)

-- high end of parameter range

two 4 hr/day contacts

No respirator, No gloves

64

4085.28 3969.28 0.1 0.1

With respirator, No gloves 4021.20 3905.60 0.1 0.1

No respirator, With gloves 146.65 145.84 2.8 2.8

Page 91 of 281
Exposure Scenario PPE Used Air 

Concentration

mg/m3a

Exposure, Internal Dose

Blood AUC, mg-hr/L Margin of Exposure (MOE)

Women of 

Childbearing 

Age

Pregnant 

Women

Women of 

Childbearing 

Age

Pregnant 

Women

With respirator and gloves 133.88 133.87 3.1 3.1

3) Nearby worker non-user

NA 13.35 13.62 30.8 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 PPE Used Air Concentration

mg/m3

Exposure, Internal Dose

Blood AUC, mg-hr/L Margin of Exposure (MOE)

Women of 

Childbearing 

Age

Pregnant 

Women

Women of 

Childbearing 

Age

Pregnant 

Women

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

No respirator, No gloves

0.24

4.04 4.03 101.7 102.0

With respirator, No gloves 4.04 4.02 101.8 102.1

No respirator, With gloves 0.41 0.40 1013.6 1015.1

With respirator and gloves 0.40 0.40 1024.5 1026.4

4) Nearby worker non-user NA 0.006 0.006 66048.7 64746.5

Page 92 of 281
Exposure Scenario PPE Used Air Concentration

mg/m3

Exposure, Internal Dose

Blood AUC, mg-hr/L Margin of Exposure (MOE)

Women of 

Childbearing 

Age

Pregnant 

Women

Women of 

Childbearing 

Age

Pregnant 

Women

5) Graffiti removal (assumed mostly 

outdoor but may include semi-confined 

spaces)

-- mid-range parameter 

characterization

-- 0.625 weight fraction, 668 cm2 skin 

surface area, 4 hr/day contact

No respirator, No gloves

2.02

67.64 67.11 6.1 6.1

With respirator, No gloves 67.46 66.92 6.1 6.1

No respirator, With gloves 6.27 6.26 65.5 65.6

With respirator and gloves 6.13 6.11 67.1 67.3

5) Nearby worker non-user NA 0.21 0.21 1981.3 1941.8

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

No respirator, No gloves

4.52

4003.88 3888.80 0.1 0.1

With respirator, No gloves 3999.38 3884.33 0.1 0.1

No respirator, With gloves 129.79 128.82 3.2 3.2

With respirator and gloves 128.91 127.93 3.2 3.2

6) Nearby worker non-user NA 0.94 0.96 438.4 429.7

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

Page 93 of 281
4.2 HUMAN HEALTH RISK CHARACTERIZATION SUMMARY

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-throughskin, 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)

Page 94 of 281

 
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 (intra-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 

Page 95 of 281
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/OPPT from 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). 

Page 96 of 281
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-1), 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 

Page 97 of 281
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 Hass et al. (1994) and Lee et al. (1987)

identified effects that could be linked to neurotoxicity. Hass 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 (Hass 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 of PODs 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 (GDs 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.

Page 100 of 281
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 tanktop 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 intrahuman 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.

Page 101 of 281
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 UFH for toxicodynamic variability of 3. As such, EPA used an intraspecies 

UFH 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 × 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 (t1/2) is approximately 2 1⁄2 hrs, exposures are effectively independent events unless 

Page 102 of 281
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 ASSESSMENT 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)

Page 104 of 281

 
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 30 Minutes 1 Hour 2 Hours 4 Hours 8 Hours

Product Concentration 25% 25% 50% 62.5% 100%

Use Scenario # Consumer 1 Worker 1 Consumer 4 Worker 2 Worker 3

User Population Consumer Worker Consumer Worker Worker

Acute 

Exposure 

Risks MOE 

to:

User 333 119.5 29.5 2.7 0.7

Nearby 

Non-user

7752 2619.9 350 141.4 111.0

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)

Page 105 of 281

 
REFERENCES

Abbas, A. (About.com). 2012. Standard Furniture Measurements. 

http://furniture.about.com/od/furnishingdesignresources/a/measurements.htm

(accessed on October 31, 2012).

Abt. 1992. Methylene chloride consumer products use survey findings. Prepared by Abt 

Associates, Inc., for the U.S. Consumer Product Safety Commission, Bethesda, MD.

AIHA. 2013. Workplace Environmental Exposure Limit (WEEL). WEEL® Values 2011. American 

Industrial Hygiene Association Guideline Foundation. https://www.aiha.org/getinvolved/AIHAGuidelineFoundation/WEELs/Documents/2011WEELValues.pdf (accessed 

on August 20, 2012).

Akesson, B., M. A. Carnerup, and B. A. G. Jönsson. 2004. Evaluation of Exposure Biomarkers 

from Percutaneous Absorption of N-Methyl-2-Pyrrolidone. Scandinavian Journal of Work, 

Environment & Health, 30, 306-312.

Akesson, B., and B. A. G. Jönsson. 1997. Major Metabolic Pathway for N-Methyl-2-Pyrrolidone in 

Humans. Drug Metabolism and Disposition, 25, 267-269.

Akesson, B., and K. Paulsson. 1997. Experimental Exposure of Male Volunteers to N-Methyl-2-

Pyrrolidone (NMP): Acute Effects and Pharmacokinetics of NMP in Plasma and Urine. 

Journal of Occupational and Environmental Medicine, 54(4), 236-240.

American Unfinished Furniture (CaliberCommerce). 2012. Summit Bedroom Collection. Item 

3702w. http://www.furnitureunfinished.com/product_info.php?products_id=1093

(August 8, 2012).

Anundi, H., S. Langworth, G. Johanson, M. L. Lind, B. Akesson, L. Friis, N. Itkes, E. Soderman, B. 

Jonsson, and C. Edling. 2000. Air and Biological Monitoring of Solvent Exposure During 

Graffiti Removal. International Archives of Occupational and Environmental Health, 

73(8), 561-569.

Anundi, H., M. Lind, L. Friis, N. Itkes, S. Langworth, and C. Edling. 1993. High Exposures to 

Organic Solvents among Graffiti Removers. International Archives of Occupational and 

Environmental Health, 65(4), 247-251.

Ash, M., and I. Ash (Editors). 2009. Specialty Chemicals Source Book. Volume 2 (4th ed.). 

Endicott, NY: Synapse Information Resources, Inc.

Page 106 of 281
ASTM (ASTM International). 1997. Standard Practice for Estimation of Short-Term Inhalation 

Exposure to Volatile Organic Chemicals Emitted from Bedding Sets. Designation: D 6178-

97 (Reapproved 2008). West Conshohocken, PA.

Bader, M., S. Keener, and R. Wrbitzky. 2005. Dermal Absorption and Urinary Elimination of NMethyl-2-Pyrrolidone. International Archives of Occupational and Environmental Health, 

78, 673-676.

Bader, M., and C. van Thriel. 2006. Human Volunteer Study on Biomarkers of N-Methyl-2-

Pyrrolidone (NMP) after Inhalational Exposure. Hannover Medical School and University 

of Dortmund, Institute of occupational Physiology, Hannover and Dortmund, Germany.

Bader, M., R. Wrbitzky, M. Blaszkewicz, M. Schaper, and C. van Thriel. 2008. Human Volunteer 

Study on the Inhalational and Dermal Absorption of N-Methyl-2-Pyrrolidone (NMP) from 

the Vapour Phase. Archives of Toxicology, 82(1), 13-20.

BASF AG. 1978. Unpublished Study (Xxv/436), 22 May 1978. Department of Toxicology. (as cited 

in OECD, 2007).

BASF AG. 1988. Unpublished Research (1035/88). Labor Oekologie,. (as cited in Verschuren, 

2009).

BASF AG. 1989. Unpublished Results, Project No. 36i0794/87088, 03 Jan 1989. Department of 

Toxicology (as cited in OECD, 2007).

BASF AG. 1992. Unpublished Results, Project No. 36i0794/87088, 21 Apr 1992. Department of 

Toxicology. (as cited in OECD, 2007).

BASF AG. 1994. Unpublished Results, Project No. 50i0544/90061, 04 Jan 1994. Department of 

Toxicology. (as cited in OECD, 2007).

BASF AG. 1995a. Unpublished Results, N-Methylpyrrolidone: Synopsis of Project Nos. 

36i0587/89023, /89042, /89044, /89045, /89054, /89069, /89070, and Supplement 

Report (Techn. Part), 19 May 1995. Department of Toxicology (as cited in OECD, 2007).

BASF AG. 1995b. Unpublished Results, Project No. 36i0587/89045, 19 May 1995. Department of 

Toxicology. (as cited in OECD, 2007).

BASF AG. 1995c. Unpublished Results, Project No. 36i05876/89023, 19 May 1995. Department 

of Toxicology (as cited in OECD, 2007).

BASF AG. 2001. Unpublished Study, Project No. 00/0969/51/125, Jul 2001. Experimental 

Toxicology and Ecology (as cited in OECD, 2007).

Page 107 of 281
Becci, P., M. Knickerbocker, R. Parent, and L. Burnette. 1981. Teratogenic Evaluation of NMethylpyrrolidone in Sprague-Dawley Rats. Toxicologist, 1, 29-30.

Becci, P., M. Knickerbocker, E. Reagan, R. Parent, and L. Burnette. 1982. Teratogenicity Study of 

N-Methylpyrrolidone after Dermal Application to Sprague-Dawley Rats. Fundamental 

and Applied Toxicology, 2(2), 73-76.

Brown, J. (US Environmental Protection Agency). 2012. Formulations Spreadsheet File Personal 

communication with Conrad Flessner, Washington, DC.

Cal EPA (California Environmental Protection Agency). 2006. Methylene Chloride Consumer 

Product Paint Strippers: Low-VOC, Low Toxicity Alternatives. 

http://www.irta.us/Methylene%20Chloride%20Consumer%20Product%20Paint%20Strip

pers%20REPORT%20ONLY.pdf (accessed on August 7, 2012).

Carney, E., and C. Kimmel. 2007. Interpretation of Skeletal Variations for Human Risk 

Assessment: Delayed Ossification and Wavy Ribs. Birth Defects Research (Part B), 80, 

473-496.

CDC. 2012a. Fatal Exposure to Methylene Chloride among Bathtub Refinishers -- United States, 

2000-2011. Mobidity and Mortality Weekly Report, 61(7), 119-122.

CDC (Centers for Disease Control and Prevention). 2012b. Tub Refinisher Died Due to Methylene 

Chloride Overexposure While Stripping a Bathtub. Michigan Case Report: 10m1013. 

http://www.cdc.gov/niosh/face/stateface/mi/10MI013.html (accessed on August 1, 

2012).

Chen, Q., and W. Xu. 1998. A Zero-Equation Turbulence Model for Indoor Airflow Simulation. 

Energy and Buildings, 28, 137-144.

Cheng, K.-C., V. Acevedo-Bolton, R.-T. Jiang, N. Klepeis, W. Ott, O. Fringer, and L. Hildemann. 

2011. Modeling Exposure Close to Air Pollution Sources in Naturally Ventilated 

Residences: Association of Turbulent Diffusion Coefficient with Air Change Rates. 

ENVIRONMENTAL SCIENCE & TECHNOLOGY, 45, 4016-4022.

Cherrie, J. W. 1999. The Effect of Room Size and General Ventilation on the Relationship 

between near and Far-Field Concentrations. Applied Occupational and Environmental 

Hygiene, 14(8), 539-546.

Daston, G. P., and J. Seed. 2007. Skeletal Malformations and Variations in Developmental 

Toxicity Studies: Interpretation Issues for Human Risk Assessment. Birth Defects Res 

(Part B), 80, 421-424.

Page 108 of 281
Davis, A., J. S. Gift, G. M. Woodall, M. G. Narotsky, and G. L. Foureman. 2009. The Role of 

Developmental Toxicity Studies in Acute Exposure Assessments: Analysis of Single-Day 

Vs. Multiple-Day Exposure Regimens. Regulatory Toxicology and Pharmacology, 54(2), 

134-142.

DuPont (EI du Pont de Nemours and Company,). 1990. 1-Methyl-2-Pyrrolidinone (NMP): 

Reproductive and Developmental Toxicity in the Rat. HLR 294-90. Medical Research 

Project 3872-001/HLR 294-90, unpublished data, 05 Oct 1990.

DuPont (EI Dupont de Nemours and Co.). 1992. Initial Submission: Teratologic Dose RangeFinding Study with N-Methylpyrrolidone in Sprague Dawley Rats with Cover Letter Dated 

09/01/92. Study conducted by Authors of the Study (Required field. Type "author's last 

name, first name initials". OTS0555033.

EC (European Commission). 2000. Iuclid Dataset. 1-Methyl-2-Pyrrolidone.

EC (European Commission). 2004. Effectiveness of Vapour Retardants in Reducing Risks to 

Human Health from Paint Strippers Containing Dichloromethane. Final Report.

http://ec.europa.eu/enterprise/sectors/chemicals/files/studies/etvareadpaint_stripper_dcm_en.pdf (accessed on October 24, 2012).

EC (European Commission). 2007. Impact Assessment of Potential Restrictions on the Marketing 

and Use of Dichloromethane in Paint Strippers. Final Report. 

http://ec.europa.eu/enterprise/sectors/chemicals/files/markrestr/j549_dcm_final_repo

rt_en.pdf.

ECHA (European Chemicals Agency). 2011. Annex XV Dossier. Proposal for Identification of a 

Substance as a Category 1a or 1b CMR, PBT, Vpvb or a Substance of an Equivalent Level 

of Concern, 1-Methyl-2-Pyrrolidone. Helsinki, Finland.

ECHA (European Chemicals Agency). 2014. Opinion on an Annex XV Dossier Proposing 

Restrictions on -Methyl-2-Pyrrolidone. ECHA/RAC/RES-O-0000005316-76-01/F. 

Committee for Risk Assessment (RAC).

Enander, R. T., H. J. Cohen, D. M. Gute, L. C. Brown, A. M. Desmaris, and R. Missaghian. 2004. 

Lead and Methylene Chloride Exposures among Automotive Repair Technicians. Journal 

of Occupational Environmental Hygiene, 1(3), 119-125.

EPA. 1990. N-Methylpyrrolidone; Proposed Test Rule. Federal Register, 55(60), 11398-11487.

EPA (US Environmental Protection Agency). 1991a. Chemical Engineering Branch Manual for the 

Preparation of Engineering Assessments. Volume I. Ceb Engineering Manual. Office of 

Pollution Protection and Toxics, Washington, DC.

Page 109 of 281
EPA (US Environmental Protection Agency). 1991b. Guidelines for Developmental Toxicity Risk 

Assessment. EPA/600/FR-91/001. Risk Assessment Forum, Washington, DC. 

http://www.epa.gov/raf/publications/pdfs/DEVTOX.pdf.

EPA (US Environmental Protection Agency). 1992. Guidelines for Exposure Assessment. 

Washington, DC. 

http://ofmpub.epa.gov/eims/eimscomm.getfile?p_download_id=429103 (August 7, 

2012).

EPA (US Environmental Protection Agency). 1994a. Consumer Exposure to Paint Stripper 

Solvents. EPA Contract No 68-DO-0137. MRI, Washington, DC.

EPA (US Environmental Protection Agency). 1994b. Consumer Exposure to Paint Stripper 

Solvents. Washington, DC.

EPA (US Environmental Protection Agency. National Center for Environmental Assessment). 

1995. Estimation of Distributions for Residential Air Exchange Rates. EPA600R95180.

EPA (US Environmental Protection Agency). 1996. Consumer/Small Shop Paint Stripping Use 

Cluster. Ar-161. Risk Management Report. Public Comment Draft. Washington, DC.

EPA (US Environmental Protection Agency). 1997. Use of Small-Chamber Data to Estimate and 

Model Chemical Emissions from Latex and Alkyd Paints. IE-2812. Washington, DC.

EPA. 1999a. Category for Persistent, Bioaccumulative, and Toxic New Chemical Substances. 

Federal Register, 64(213), 60194-60204.

EPA (US Environmental Protection Agency). 1999b. Category for Persistent, Bioaccumulative, 

and Toxic New Chemical Substances. 64 Federal Register 213, pp. 60194-60204.

EPA (U.S. Environmental Protection Agency). 2001. Risk Assessment Guidance for Superfund: 

Volume 3 - Part a, Process for Conducting Probabilistic Risk Assessment. EPA/540-R-02-

002. Office of Emergency and Remedial Response, Washington, DC. 

http://www.epa.gov/oswer/riskassessment/rags3adt/.

EPA (US Environmental Protection Agency). 2006. Approaches for the Application of 

Physiologically Based Pharmacokinetic (PBPK) Models and Supporting Data in Risk 

Assessment. EPA/600/R-05/043F. National Center for Environmental Assessment, Office 

of Research and Development, Washington, DC.

EPA (US Environmental Protection Agency). 2007. Technical Support Document for Proposed 

Rule: National Emission Standards for Hazardous Air Pollutants: Paint Stripping 

Operations at Area Sources. OAQPS/Sector Policies and Programs Divsion, Research 

Triangle Park, NC. http://www.epa.gov/airtoxics/6h/tsd.pdf.

Page 110 of 281
EPA (US Environmental Protection Agency). 2009. Methodology for Risk-Based Prioritization 

under ChAMP. Office of Pollution Prevention and Toxics, Washington, DC.

EPA (US Environmental Protection Agency). 2010. Multi-Chamber Concentration and Exposure 

Model (Mccem) Version 1.2. http://www.epa.gov/oppt/exposure/pubs/mccem.htm

(accessed on October 31, 2012).

EPA (US Environmental Protection Agency). 2011a. Exposure Factors Handbook: 2011 Edition. 

National Center for Environmental Assessment, Washington, DC. 

http://www.epa.gov/ncea/efh/pdfs/efh-complete.pdf.

EPA (US Environmental Protection Agency). 2011b. Toxicological Review of Dichloromethane 

(Methylene Chloride; CAS No. 75-09-2). EPA/635/R-10/003F. Integrated Risk Information 

System, Office of Research and Development, Washington, DC. 

http://www.epa.gov/iris/toxreviews/0070tr.pdf.

EPA (US Environmental Protection Agency). 2012a. Benchmark Dose Technical Guidance. 

EPA/100/R-12/001. Risk Assessment Forum, Washington, DC. 

http://www.epa.gov/raf/publications/pdfs/benchmark_dose_guidance.pdf.

EPA (US Environmental Protection Agency). 2012b. Estimation Programs Interface SuiteTM for 

Microsoft® Windows, V4.10. Washington, DC. 

http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm (March 19, 2012).

EPA (US Environmental Protection Agency). 2013a. Chemical Data Access Tool: 2-Pyrrolidinon, 

1-Methyl. Office of Chemical Safety and Pollution Prevention, Office of Pollution 

Prevention and Toxics. http://java.epa.gov/oppt_chemical_search/ (12/10/2014).

EPA (US Environmental Protection Agency). 2013b. Pesticide Ecotoxicity Database (Formerly: 

Environmental Effects Database (EEDB)). Environmental Fate and Effects Division, 

Washington, DC. http://www.ipmcenters.org/ecotox/.

EPA (US Environmental Protection Agency). 2013c. TSCA Workplan Chemical Risk Assessment NMethylpyrrolidone: Paint Stripping Use CASRN: 872-50-4. Draft. Office of Pollution 

Prevention and Toxics, Washington, DC.

EPA (US Environmental Protection Agency). 2014a. Framework for Human Health Risk 

Assessment to Inform Decision Making. EPA/100/R-14/001. Office of the Science 

Advisor, Risk Assessment Forum, Washington, DC.

EPA (US Environmental Protection Agency). 2014b. TSCA Work Plan Chemical Risk Assessment. 

Methylene Chloride: Paint Stripping Use. EPA/740/R1/4003. Office of Chemical Safety 

and Pollution Prevention, Office of Pollution Prevention and Toxics.

Page 111 of 281
EWG (Environmental Working Group). 2012. Ewg's Skin Deep Cosmetic Database. Methyl 

Pyrrolidone. 

http://www.ewg.org/skindeep/ingredient/products/703913/METHYL_PYRROLIDONE/

(August 9, 2012).

Exxon Biomedical Sciences. 1991. Project No. 236535, 26 Nov 1991. GAF Corp., Wayne, USA. (as 

cited in OECD, 2007).

Exxon Biomedical Sciences. 1992. Project No. 136534, 05 Jun 1992 (as cited in OECD, 2007). GAF 

Corp., Wayne, USA.

FDRL (Food and Drug Research Laboratories). 1979. Lab. No. 6161, Unpublished Report, 18 Oct 

1979. GAF Corp., Wayne, NJ, USA. (as cited in OECD, 2007).

Frey, H. C., and S. R. Patil. 2002. Identification and Review of Sensitivity Analysis Methods. Risk 

Analysis, 22(3), 553-578.

Furtaw, J., EJ, M. Pandian, D. Nelson, and J. Behar. 1996. Modeling Indoor Air Concentrations 

near Emission Sources in Imperfectly Mixed Rooms. Journal Air & Waste Management 

Association, 46(9), 861-868.

GAF Corp. 1979. Unpublished Study, Contract No. L1393-05, Aug 1976. Aquatic Toxicology 

Laboratory. (as cited in OECD, 2007).

Ghantous, H. 1995. Oral, Dermal, and Inhalation Pharmacokinetics and Disposition of [2-14 C] 

NMP in the Rat. Report for E.I. Du Pont De Nemours and Company. Haskell Laboratory 

for Toxicology and Industrial Medicine, Wilmington, DE.

Harreus, A. L., R. Backes, J. Eichloer, R. Feuerhake, C. Jakel, U. Mahn, R. Pinkos, and R. 

Vogelsang. 2011. 2-Pyrrolidone. Ullmann's Encyclopedia of Industrial Chemistry. 

http://onlinelibrary.wiley.com/doi/10.1002/14356007.a22_457.pub2/abstract

(accessed on August 8, 2012).

Hass, U., B. M. Jakobsen, and S. P. Lund. 1995. Developmental Toxicity of Inhaled NMethylpyrrolidone on Postnatal Development and Behavior in Rats. Neurotoxicology and 

Teratology, 16, 241-249.

Hass, U., S. P. Lund, and J. Elsner. 1994. Effects of Prenatal Exposure to N-Methylpyrrolidone on 

Postnatal Development and Behavior in Rats. Neurotoxicology and Teratology, 16(3), 

241-249.

Hazelton Laboratories America, I. 1979. Unpublished Report, Project No. 257-110, 02 Oct 1979. 

(as cited in OECD, 2007).

Page 112 of 281
Hazelton Laboratories America, I. 1980. Unpublished Report, Project No. 257-109, 11 Feb, 1980

(as cited in OECD, 2007).

Heffernan, A., L. Aylward, L. Toms, P. Sly, M. Macleod, and J. Mueller. 2014. Pooled Biological 

Specimens for Human Biomonitoring of Environmental Chemicals: Opportunities and 

Limitations. Journal of Exposure Science and Environmental Epidemiology, 24(3), 225-

232.

Hines, R. N. 2007. Ontogeny of Human Hepatic Cytochrome P450. J Biochem Mol Toxicol, 21(4), 

169-175.

HLS (Huntingdon Life Sciences (HLS) Ltd,). 1998. [14c]-N-Methylpyrrolidone: Topical Application: 

Dermal Absorption Study in the Rat. Report 982974. (as cited in RIVM, 2013).

HSE (Health and Safety Executive). 2001. Health Risks During Furniture Stripping Using 

Dichloromethane (Dcm). www.hse.gov.uk/pubns/wis19.pdf (August 6, 2012).

IRTA (Institute for Research and Technical Assistance). 2006. Assessment, Development and 

Demonstration of Alternatives for Five Emerging Solvents. 

www.cdph.ca.gov/programs/hesis/Documents/emergingsolvents.pdf (August 6, 2012).

Jonsson, B. A., and B. Akesson. 2003. Human Experimental Exposure to N-Methyl-2-Pyrrolidone 

(NMP): Toxicokinetics of NMP, 5-Hydroxy- N-Methyl-2-Pyrrolidone, N-Methylsuccinimide 

and 2-Hydroxy- N-Methylsuccinimide (2-HMSI), and Biological Monitoring Using 2-HMSI 

as a Biomarker. International Archives of Occupational and Environmental Health, 76(4), 

267-274.

Kavlock, R. J., B. C. Allen, E. M. Faustman, and C. A. Kimmel. 1995. Dose-Response Assessments 

for Developmental Toxicity: IV. Benchmark Doses for Fetal Weight Changes. 

Fundamental and Applied Toxicology, 26, 211-222.

Keener, S., R. Wrbitzky, and M. Bader. 2007. Human Volunteer Study on the Influence of 

Exposure Dilution of Dermally Applied N-Methyl-2-Pyrrolidone (NMP) on the Urinary 

Elimination of NMP Metabolites. International Archives of Occupational and 

Environmental Health, 80(4), 327-334.

Lan, C. H., C. Y. Peng, and T. S. Lin. 2004. Acute Aquatic Toxicity of N-Methyl-2-Pyrrolidinone to 

Daphnia Magna. Bulletin of Environmental Contamination and Toxicology, 73(2), 392-

397.

Lee, K. P., N. C. Chromey, R. Culik, J. R. Barnes, and P. W. Schneider. 1987. Toxicity of N-Methyl2-Pyrrolidone (NMP): Teratogenic, Subchronic, and Two-Year Inhalation Studies. 

Fundamental and Applied Toxicology, 9(2), 222-235.

Page 113 of 281
Levitt, M. D., Li, R., Demaster, E.G., Elson, M., Furne, J., Levitt, D.G. 1997. Use of Measurements 

of Ethanol Absorption from Stomach and Intestine to Assess Human Ethanol 

Metabolism. American Journal of Gastrointestinal and Liver Physiology, 273, G951–957.

Lide, D. 2001. Physical Constants of Organic Compounds. In Crc Handbook of Chemistry and 

Physics, 82nd Edition (pp. 3-206). CRC Press Inc., Boca Raton, FL.

Ligocka, D., D. Lison, and V. Haufroid. 2003. Contribution of CYP2E1 to N-Methyl-2-Pyrrolidone 

Metabolism. Archives of Toxicology, 77(5), 261-266.

Malek, D. E., L. A. Malley, T. W. Slone, G. S. Elliott, G. L. Kennedy, W. Mellert, K. Deckardt, C. 

Gembardt, B. Hildebrand, S. R. Murphy, D. B. Bower, and G. A. Wright. 1997. Repeated 

Dose Toxicity Study (28 Days) in Rats and Mice with N-Methylpyrrolidone (NMP). Drug 

Chemistry and Toxicology, 20(1-2), 63-77.

Malley, L. A., G. L. Kennedy, G. S. Elliott, T. W. Slone, W. Mellert, K. Deckardt, K. Kuttler, B. 

Hildebrand, M. I. Banton, R. J. Parod, and J. C. Griffiths. 2001. Chronic Toxicity and 

Oncogenicity of N-Methylpyrrolidone (NMP) in Rats and Mice by Dietary Administration. 

Drug Chemistry and Toxicology, 24(4), 315-338.

Matthews, T., C. Thompson, D. Wilson, A. Hawthorne, and D. Mage. 1989. Air Velocities inside 

Domestic Environments: An Important Parameter in the Study of Indoor Air Quality and 

Climate. Environment International, 15, 545-550.

McDougal, J. N., Jepson, G.W., Clewell, H.J.-III, MacNaughton, M.G., Andersen, M.E. 1986. A 

Physiological Pharmacokinetic Model for Dermal Absorpotion of Vapors in the Rat. 

Toxicology and Applied Pharmacology, 85, 286-294.

McLanahan, E. D., H. A. El-Masri, L. M. Sweeney, L. Y. Kopylev, H. J. Clewell, J. F. Wambaugh, 

and P. M. Schlosser. 2012. Physiologically Based Pharmacokinetic Model Use in Risk 

Assessment—Why Being Published Is Not Enough. Toxicological Sciences, 126(1), 5-15.

Midgley, I., A. Hood, L. Chasseaud, C. Brindley, S. Baughman, and G. Allan. 1992. Percutaneous 

Absorption of Co-Administered N-Methyl-2-[4c]Pyrrolidinone and S-[14c]Pyrrolidinone in 

the Rat. Food Chemistry and Toxicology, 30(1), 57-64.

MSU/MIFACE (Michigan State University/Michigan Fatality Assessment and Control Evaluation). 

2011. Tub Refinisher Died Due to Methylene Chloride Overexposure While Stripping a 

Bathtub. Report # 10MI013. East Lansing, MI. 

http://www.oem.msu.edu/MiFace/10MI013Report.pdf.

Musy, M., E. Wurtz, and J.-M. Nataf. 1999. An Intermediate Model to Predict Thermal Comfort 

and Air Quality in a Building. Indoor Air, 1, 685-690.

Page 114 of 281
NICNAS. 2013. Human Health Tier Ii Assessment for 2-Pyrrolidinone, 1-Methyl, CAS Number 872-

50-4. Department of Health, National Industrial Chemicals Notification and Assessment 

Scheme (Australia). http://www.nicnas.gov.au/chemical-information/imapassessments/imap-assessment-details?assessment_id=91.

NIH (US Department of Health & Services, National Institute of Health). 2012. Household 

Products Database. N-Methylpyrrolidone. National Library of Medicine, Bethesda, MD. 

http://householdproducts.nlm.nih.gov/cgi-bin/household/brands?tbl=chem&id=1193

(accessed on August 8, 2012).

NIOSH (National Institute for Occupational Safety and Health). 1977. Health Hazard Evaluation 

Determination Report. United Airlines Maintenance Base San Francisco International 

Airport, Burlingame, California. 75-195-396. Cincinnati, OH. 

www.ntis.gov/search/product.aspx?ABBR=PB273779.

NIOSH (National Institute for Occupational Safety and Health). 1990. Walk-Though Survey 

Report: Control of Methylene Chloride in Furniture Stripping at Colonial Furniture 

Stripping. ECTB number: 170-14a. Cincinnati, OH. 

www.cdc.gov/niosh/surveyreports/pdfs/170-14a.pdf.

NIOSH (National Institute for Occupational Safety and Health). 1992. Health Hazard Evaluation. 

Ackerman and Sons, Littleton, Colorado. HETA 92-0360-2372. Scand. J. Work. Environ. 

Health. www.cdc.gov/niosh/hhe/reports/pdfs/1992-0360-2372.pdf.

NIOSH (National Institute for Occupational Safety and Health). 1993. Health Hazard Evaluation. 

Rosebud Company. HETA 93-0844-2411. 

http://www.cdc.gov/niosh/hhe/reports/pdfs/1993-0844-2411.pdf.

NMP Producers Group. 1995. Subchronic Oral Toxicity: 90-Day Feeding and Neurotoxicity Study 

in Rats with N-Methylpyrrolidone (NMP). Unpublished Report. Project No. 9737-001. E. I. 

du Pont de Nemours and Company, Haskell Laboratory for Toxicology and Industrial 

Medicine, Newark, DE. (as cited in OECD, 2007).

NMP Producers Group. 1999a. Two Generation Reproduction Toxicity Study with NMethylpyrrolidone (NMP) in Sprague Dawley Rats - Administration in the Diet. Project 

No. 97-4106. Huntingdon Life Science, East Millestone, NJ. (as cited in RIVM 2013).

NMP Producers Group. 1999b. Two Generation Reproduction Toxicity Study with NMythylpyrrolidone (NMP) in Wistar Rats - Administration in the Diet. Project No. 

70R0056/97008. Department of Toxicology of BASF Aktiengesellschaft, Ludwigshafen, 

Germany. (as cited in RIVM, 2013).

Page 115 of 281
NMP Producers Group. 2012. NMP Exposure Summary. Communication with US EPA , June, 

2012. Scand. J. Work. Environ. Health.

O'Neil, M. J., A. Smith, P. E. Heckelman, and J. R. Obenchain. 2001. N-Methylpyrroline. In The 

Merck Index, 13th Edition (pp. 6141). Merck & Co, Inc, Whitehouse Station, NJ.

OECD (Organization for Economic Co-operation and Development). 2007. SIDS Initial

Assessment Report. 1-Methyl-2-Pyrrolidone.

OECD (Organization for Economic Co-operation and Development). 2008. SIDS Dossier. 2-

Pyrrolidinone, 1-Methyl. http://webnet.oecd.org/hpv/ui/SponsoredChemicals.aspx

(November 26, 2012).

OECD (Organization for Economic Co-operation and Development). 2010. Emission Scenario 

Document on Coating and Application Via Spray Painting in the Automotive Refinishing 

Industry. . Number 11. OECD Environmental Health and Safety Publications. Series on 

Emission Scenario Documents.

OEHHA (Office of Environmental Health Hazard Assessment (California)). 2003. Proposition 65 

Maximum Allowable Dose Level (MADL) for Reproductive Toxicity for NMethypyrrolidone for Dermal and Inhalation Exposures. Reproductive and Cancer 

Hazard Assessment Section.

OEHHA (Office of Environmental Health Hazard Assessment (California)). 2011. Carcinogen 

Identification Committee Consultation: N-Methylpyrrolidone. Carcinogen Identification 

Committee.

Old House Online. 2012. Making Sense of Paint Strippers. 

http://www.oldhouseonline.com/making-sense-of-paint-strippers/ (accessed on June 

13, 2012).

OSHA (Occupational Safety and Health Administration). 2012. Data and Statistics. US 

Department of Labor. http://www.osha.gov/oshstats/index.html (accessed on 

11/17/2014).

Payan, J.-P., Beydon, D., Fabry, J.-P., Boudry, I., Cossec, B., Ferrari, E. 2002. Toxicokinetics and 

Metabolism of N-[(14)C]N-Methyl-2-Pyrrolidone in Male Sprague-Dawley Rats: In Vivo 

and in Vitro Percutaneous Absorption. Drug Metabolism and Disposition, 30, 1418–1424.

Payan, J.-P., Boudry, I., Beydon, D., Fabry, J.-P., Grandclaude, M.-C., Ferrari, E., André, J.-C. 

2003. Toxicokinetics and Metabolism of N-[(14)C]N-Methyl-2-Pyrrolidone in Male 

Sprague-Dawley Rats: In Vivo and in Vitro Percutaneous Absorption. Drug Metabolism 

and Disposition, 31, 659–669.

Page 116 of 281
Poet, T. S., C. R. Kirman, M. Bader, C. van Thriel, M. L. Gargas, and P. M. Hinderliter. 2010. 

Quantitative Risk Analysis for N-Methyl Pyrrolidone Using Physiologically Based 

Pharmacokinetic and Benchmark Dose Modeling. Toxicological Sciences, 113(2), 468-

482.

Pollack-Nelson, C. 1995. Analysis of Methylene Chloride Product Labelling. Ergonomics, 38(11), 

2176-2187.

Riley, D. M., B. Fischhoff, M. J. Small, and P. Fischbeck. 2001. Evaluating the Effectiveness of 

Risk-Reduction Strategies for Consumer Chemical Products. Risk Analysis, 21(2), 357-369.

Riley, D. M., M. J. Small, and B. Fischhoff. 2000. Modeling Methylene Chloride ExposureReduction Options for Home Paint-Stripper Users. Journal of Exposure Analysis and 

Environmental Epidemiology, 10(3), 240-250.

RIVM (National Institute for Public Health and the Environment (RIVM)). 2013. Annex XV 

Restriction Report: Proposal for a Restriction, N-Methylpyrrolidone (NMP). Version 2. 

RIVM, Bureau REACH, The Netherlands.

Saillenfait, A. M., F. Gallissot, I. Langonne, and J. P. Sabate. 2002. Developmental Toxicity of NMethyl-2-Pyrrolidone Administered Orally to Rats. Food Chemistry and Toxicology, 

40(11), 1705-1712.

Saillenfait, A. M., F. Gallissot, and G. Morel. 2003. Developmental Toxicity of N-Methyl-2-

Pyrrolidone in Rats Following Inhalation Exposure. Food Chemistry and Toxicology, 

41(4), 583-588.

Saillenfait, A. M., J. P. Sabate, and F. Gallissot. 2007. Comparative Developmental Toxicities of 

the Three Major Metabolites of N-Methyl-2-Pyrrolidone after Oral Administration in 

Rats. Journal of Applied Toxicology, 27(6), 571-581.

Sitarek, K., J. Stekiewicz, and W. Wasowicz. 2012. Evaluation of Reproductive Disorders in 

Female Rats Exposed to N-Methyl-2-Pyrrolidone. Birth Defects Research (Part B), 95, 

195-201.

Sitarek, K., and J. Stetkiewicz. 2008. Assessment of Reproductive Toxicity and Gonadotoxic 

Potential of N-Methyl-2-Pyrrolidone in Male Rats. International Journal of Occupational 

Medicine and Environmental Health, 21(1), 73-80.

Smithsonian (Smithsonian Museum Conservation Institute). 2012a. Does My Painting Need to 

Be Cleaned? http://si.edu/mci/english/learn_more/taking_care/painting_clean.html

(accessed on July 20, 2012).

Page 117 of 281
Smithsonian (Smithsonian Museum Conservation Institute). 2012b. What Does It Mean to Have 

a Painting Restored and How Do I Pick a Conservator?

http://si.edu/mci/english/learn_more/taking_care/conservation_meaning.html

(accessed on July 20, 2012).

Solomon, G. M., E. P. Morse, M. J. Garbo, and D. K. Milton. 1996. Stillbirth after Occupational 

Exposure to N-Methyl-2-Pyrrolidone. A Case Report and Review of the Literature. Journal 

of Occupational and Environmental Medicine, 38(7), 705-713.

Staats, D. A., Fisher, J.W., Connolly, R.B. 1991. Gastrointestinal Absorption of Xenobiotics in 

Physiologically Based Pharmacokinetic Models. A Two-Compartment Description. Drug 

Metabolism and Disposition, 19, 144-148.

Timchalk, C., Nolan, R.J., Mendrala, A.L., Dittenber, D.A., Brzak, K.A., Mattsson, J.L. 2002. 

Physiologically Based Pharmacokinetic and Pharmacodynamic (PBPK/Pd) Model for the 

Organophosphate Insecticide Chlorpyrifos in Rats and Humans. Toxicol Sci, 66, 34-53.

TNO (European Commision. TNO-STB). 1999. Methylene Chloride: Advantages and Drawbacks 

of Possible Market Restrictions in the EU. STB-99-53 Final. Scand. J. Work. Environ. 

Health, Brussels, Belgium.

USDOC (US Census Bureau). 2007a. 2007 NAICS Index File. North American Industry 

Classification System. US Department of Commerce, Washington, DC. 

http://www.census.gov/cgi-bin/sssd/naics/naicsrch?chart=2007 (accessed on April 20, 

2012).

USDOC (US Census Bureau). 2007b. American Factfinder: 2007 Economic Census. US 

Department of Commerce, Washington, DC.

Van Raaij, M. T. M., A. H. Janssen, and A. H. Piersma. 2003. The Relevance of Developmental 

Toxicity Endpoints for Acute Limit Setting RIVM Report 601900004.

van Veen, M. P., F. Fortezza, E. Spaans, and T. T. Mensinga. 2002. Non-Professional Paint 

Stripping, Model Prediction and Experimental Validation of Indoor Dichloromethane

Levels. Indoor Air, 12(2), 92-97.

Verschuren, K. 2009. Handbook of Environmental Data on Organic Chemicals (5th ed.). New 

York: Wiley & Sons, Inc.

Vincent, R., P. Poirot, I. Subra, B. Rieger, and A. Cicolella. 1994. Occupational Exposure to 

Organic Solvents During Paint Stripping and Painting Operations in the Aeronautical 

Industry. International Archives of Occupational and Environmental Health, 65(6), 377-

380.

Page 118 of 281
W. M. Barr (W.M. Barr and Company). 2009a. Material Safety Data Sheet. Citristrip Stripping 

Gel. Product Code: Cs61040.25. 

http://www.wmbarr.com/ProductFiles/CitriStrip%20Stripping%20Gel%20(CS61040.25)

%205-28-09.pdf (accessed on August 8, 2012).

W. M. Barr (W. M. Barr and Company). 2009b. Material Safety Data Sheet. Klean Strip Klean 

Kutter. Product Code: 130. 

http://www.wmbarr.com/ProductFiles/130%20(Klean%20Kutter).pdf (accessed on 

August 6, 2012).

W. M. Barr (W.M. Barr and Company). 2011. Material Safety Data Sheet. Citristrip Safer Paint 

and Varnish Stripper Aerosol. Product Code: Acsa35.4. 

http://www.wmbarr.com/ProductFiles/ACSA35%204%20CSSafer%20Paint%20and%20V

arnish%20Stripper%20Aerosol.pdf (accessed on August 8, 2012).

Wells, D. A., Digenis, G.A. 1988. Disposition and Metabolism of Double-Labeled [3h and 14c] NMethyl-2-Pyrrolidinone in the Rat. Drug Metabolism and Disposition, 16, 243-249.

WESTAT (WESTAT Inc.). 1987. Household Solvent Products: A National Usage Survey. PB88-

132881. Rockville, MD.

WHO (World Health Organization). 2001. Concise International Chemical Assessment Document 

(CICAD) 35, N-Methyl-2-Pyrrolidone. Geneva, Switzerland. 

www.who.int/entity/ipcs/publications/cicad/en/cicad35.pdf.

Wollbrinck, T. 1993. The Composition of Proprietary Paint Strippers. Journal of the Amercian 

Institute for Conservation, 32(1), 43-57.

Xiaofei, E., Wada, Y., Nozaki, J., Miyauchi, H., Tanaka, S., Seki, Y., 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. Journal of 

Occupational Health, 42, 321–327.

Page 119 of 281
APPENDICES

Page 120 of 281
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-1, Table_Apx A-2 and Table_Apx A-3. 

A-1 Acute Toxicity to Aquatic Organisms

Table_Apx A-1 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-1); 

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 EC50 for the water fleas ranged 

from 1,230 – 4,897 mg/L and the reported 48-hr EC50 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).

Page 121 of 281
Toxicity to Aquatic Plants

Only one study was identified testing the toxicity of NMP to aquatic plants (Table_Apx A-1). 

Green algae (Scenedesmus subspicatus) were exposed to nominal concentrations of NMP under 

static conditions for 96 hrs. A 72-hr EC50 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-1 Aquatic Toxicity Data for NMP - Acute Toxicity

Test Species

Fresh/ 

Salt 

Water

Duration Endpoint

Conc.

(mg/L)

Test 

Analysis Effect References

Fish

Fathead minnow 

(Pimphales promelas)

Fresh 96-hr LC50 1,072 Measured Mortality SRC (1979); 

Verschuren (2009)

Bluegill sunfish (Lepomis 

macrochirus)

Fresh 96-hr LC50 832 Nominal Mortality Dawson et al. (1977)

Orfe 

(Leuciscus idus)

Fresh 96-hr LC50 4,000 Nominal Mortality BASF (1986) 

Verschuren (2009)

Guppies 

(Poecilia reticulata)

Fresh 96-hr LC50 2,673 Nominal Mortality OECD, (2007a); 

Verschuren (2009); 

Weisbrod and Seyring 

(1980)

Rainbow trout 

(Oncorhynchus mykiss)

Fresh 96-hr LC50 >500 Nominal Mortality BASF AAG (1983 as 

cited in OECD 2007a); 

SRC (1979)

Aquatic Invertebrates

Water flea 

(Daphnia magna) Fresh 48-hr EC50 4,897 Nominal Immobiliza

tion

GAF Corp (1979 as 

cited in OECD, 2007a); 

Verschuren (2009)

Water flea 

(Daphnia magna) Fresh 48-hr EC50 1,230 Nominal Immobilization Lan et al., (2004)

Grass shrimp

(Palaemonetes vulgaris) Fresh 48-hr EC50 >299 Nominal Mortality

GAF Corp (1979 as 

cited in OECD, 2007a); 

Verschuren (2009)

Aquatic Plants

Green algae

(Scenedesmus 

subspicatus)

Fresh 72-hr EC50 >500 Nominal Not 

reported

BASF AG(1988a as 

cited in Verschuren, 

2009)

Page 122 of 281
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 Endpoint

Conc.

(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 LD50 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 LC50

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
Table_Apx A-3 Aquatic Toxicity Data for NMP - Wildlife

Test Species Duration Endpoint

Conc.

(mg/kg/bw)

Test 

Analysis Effect References

Avian

Bobwhite quail

(Colinus virginianus) 14-day LD50 2,500 – 5,000 Nominal Mortality

Hazelton Laboratories 

America (1980 as cited in 

OECD, 2007a)

Mallard duck

(Anas platyrhynchus) 8-Day LC50 >5,000 Mortality

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
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-1, Table_Apx B-2 and Table_Apx B-3

were extracted from the 2012 CDR records (EPA, 2013).

Table_Apx B-1 National Chemical Information for NMP from 2012 CDR

Production Volume (aggregate)

184.7 million 

pounds

Maximum Concentration (at manufacture or import site) >90%

Physical form(s) Liquid

Number of reasonably likely to be exposed industrial manufacturing, processing and use 

workers (aggregated) >1,000

Was industrial processing or use information reported? Yes

Was commercial or consumer use information reported? Yes

Table_Apx B-2 Summary of Industrial NMP Uses from 2012 CDR

Industrial Sector [Based on 

North American Industry 

Classification System (NAICS)]

Industrial Function Type of Processing

Adhesives and sealant 

chemicals

Processing-incorporation into 

formulation, mixture or reaction 

product

Adhesives and sealant chemicals

Not Known or Reasonably 

Ascertainable Not Known or Reasonably Ascertainable Not Known or Reasonably Ascertainable

Solvents (for cleaning or 

degreasing) Use-non-incorporative activities Solvents (for cleaning or degreasing)

Solvents (for cleaning or 

degreasing)

Processing-incorporation into 

formulation, mixture or reaction 

product

Solvents (for cleaning or 

degreasing)

Solvents (which become part 

of product formulation or 

mixture)

Processing-incorporation into 

formulation, mixture or reaction 

product

Solvents (which become part of 

product formulation or mixture)

Plating agents and surface 

treating agents

Processing-incorporation into 

formulation, mixture or reaction 

product

Plating agents and surface treating 

agents

Processing aids, not otherwise 

listed Use-non-incorporative activities Processing aids, not otherwise listed

Other (specify) Processing-incorporation into article Other (specify)

Page 125 of 281
Industrial Sector [Based on 

North American Industry 

Classification System (NAICS)]

Industrial Function Type of Processing

Solvents (for cleaning or 

degreasing) Use-non-incorporative activities Solvents (for cleaning or degreasing)

Solvents (which become part 

of product formulation or 

mixture)

Processing-incorporation into article Solvents (which become part of 

product formulation or mixture)

Processing aids, specific to 

petroleum production Use-non-incorporative activities Processing aids, specific to petroleum production

Processing aids, specific to 

petroleum production Use-non-incorporative activities Processing aids, specific to petroleum production

Paint additives and coating 

additives not described by 

other categories

Processing-incorporation into 

formulation, mixture or reaction 

product

Paint additives and coating 

additives not described by other 

categories

Paint and Coating 

Manufacturing

Solvents (which become part of product 

formulation or mixture)

Processing-incorporation into 

formulation, mixture or reaction 

product

Processing aids, not otherwise 

listed Use-non-incorporative activities Processing aids, not otherwise listed

Solvents (which become part 

of product formulation or 

mixture)

Processing-incorporation into 

formulation, mixture or reaction 

product

Solvents (which become part of 

product formulation or mixture)

Processing aids, specific to 

petroleum production Use-non-incorporative activities Processing aids, specific to petroleum production

Intermediates Processing as a reactant Intermediates

Other (specify) Processing as a reactant Other (specify)

Intermediates Processing as a reactant Intermediates

Other (specify)

Processing-incorporation into 

formulation, mixture or reaction 

product

Other (specify)

Other (specify) Processing-incorporation into article Other (specify)

Printing Ink Manufacturing Paint additives and coating additives not 

described by other categories

Processing-incorporation into 

formulation, mixture or reaction 

product

Paint additives and coating 

additives not described by 

other categories

Processing-incorporation into article

Paint additives and coating 

additives not described by other 

categories

Solvents (for cleaning or 

degreasing) Use-non-incorporative activities Solvents (for cleaning or degreasing)

Not Known or Reasonably

Ascertainable Not Known or Reasonably Ascertainable Not Known or Reasonably Ascertainable

Page 126 of 281
Table_Apx B-3 NMP Commercial/Consumer Use Category Summary

Commercial/Consumer Product 

Category

Intended for Commercial 

and/or Consumer Uses or Both

Intended for Use in Children's 

Products in Related Product 

Category

Electrical and Electronic Products Commercial Not Known or Reasonably 

Ascertainable

Batteries Both No

Paints and Coatings Both No

Metal Products not covered elsewhere Commercial No

Adhesives and Sealants Commercial No

Fabric, Textile and Leather Products not 

covered elsewhere Commercial 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 foodcontact 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-1 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
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 Leather cleaner/conditionera

Rubbing compounda

Paint protectanta

Cleaner for fuel injection/carburetora

Arts and crafts products Stripper/paint removera

Home maintenance products Adhesive removera

Paint, varnish, wood stain, etc.a

Wood sealanta

Paint strippera

Graffiti removera

Brush cleanera

Floor finisha

Floor cleanera

Pesticides Fungicidea

Herbicidea

Insecticidea

Cosmetics Polish removerb

Mascarab

Notes:

a

NIH (2012)

b

EWG (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
Appendix C STATE NMP REGULATIONS

Table_Apx C-1 State NMP Regulations

State Regulation Link or Reference

California California’s Proposition 65 list 

because it is known to cause birth 

defects or other reproductive harm

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)

California Proposed a permissible exposure limit 

(PEL) at 1 ppm as an 8-hr timeweighted average (TWA) to reduce 

the risk of developmental effects

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

California Regulations that require employees 

that handle NMP to wear appropriate 

protective gloves

http://www.dir.ca.gov/title8/sb7g2a10.html

(accessed October 28, 2014)

California California lists NMP as an 

informational candidate chemical 

under California’s Safer Consumer 

Products regulations

http://www.dtsc.ca.gov/SCP/ChemList.cfm

(accessed October 28, 2014)

Washington Listed as chemical of high concern 

under the Children’s Safe Product Act

http://www.ecy.wa.gov/programs/swfa/cspa/chcc.html

(accessed October 28, 2014)

Minnesota Listed chemical of high concern 

(development)

http://www.health.state.mn.us/divs/eh/hazardous/topics/toxfreekids/chclist/mdhchc2013.pdf

(accessed September 10, 2014)

New Hampshire Listed toxic air pollutant Regulated Toxic Air Pollutants, New Hampshire Code of Administrative Rules, Chapter CHAPTER 

Env-A 1400, Table-1450-1 2009

New Jersey Listed hazardous substance Environmental Hazardous Substance List,” New Jersey Department of Environmental Protection, 

N.J.A.C. 7:1G-2, as printed in the Community Right to Know Survey Instruction Book, 2005. 

http://web.doh.state.nj.us/rtkhsfs/rtkhsl.aspx

(accessed December 5, 2014)

Pennsylvania Listed hazardous substance 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&objID=552962&mode=2

(accessed December 5, 2014)

Vermont Listed air pollutant Air Pollution Control Regulations, State of Vermont Agency of Natural Resources, A-1: Hazardous 

Air Contaminants. 2014

Page 129 of 281
Appendix D OCCUPATIONAL EXPOSURE ASSESSMENT SUPPORT 

INFORMATION

D-1 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 

Page 130 of 281
literature search, EPA/OPPT defined primary keywords to use in the search queries. The defined 

primary keywords were:

• N-methylpyrrolidone

• 1-Methyl-2-pyrrolidinone

• paint stripp*

EPA/OPPT included both chemical synonyms “N-methylpyrrolidone” and “1-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-1 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.

Page 131 of 281
Table_Apx D-1 Study Quality Criteria and Acceptance Specifications

Quality Criterion Description/Definition Acceptance Specification

Currency (up to 

date)

The information reflects present conditions. Data from all years are acceptable.

Geographic Scope The information reported reflects an area 

relevant to the assessment.

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.

Reliability The information reported is reliable. For 

example, this criterion may include the 

following acceptance specifications:

• The information or data are from a peerreviewed, 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.

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.

Unbiased The information is not biased towards a 

particular product or outcome.

• Objective of the information is clear.

• Methodology is designed to answer a 

specific question.

Comparability The data are comparable to other sources 

that have been identified.

Data sources will not be accepted or 

rejected based on their comparison to 

data from other sources.

Representativeness 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.

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.

Applicability For surrogate data, the data are expected to 

be similar for the industry or property of 

interest.

Surrogate data deemed applicable if they 

are inhalation exposure or airborne 

concentration data of NMP measured 

during paint stripping.

Page 132 of 281
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 2007 NAICS Title Rationale for Inclusion of NAICS with Paint Stripping Activities

238320 Painting and wall covering contractors US Census reports an index entry of “Paint and wallpaper 

stripping” (USDOC, 2007a).

238330 Flooring contractors 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).

811121 Automotive body, paint and interior 

repair and maintenance

NAICS code 811121 is identified for automobile refinishing per 

the OECD Coating Application via Spray-Painting in the 

Automotive Refinishing Industry ESD (OECD, 2010).

811420 Reupholstery and furniture repair US Census reports index entries of “Furniture refinishing shops” 

and “Restoration and repair of antique furniture” (USDOC, 

2007a).

711510 Independent artists, writers and

performers

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).

712110 Museums Research has shown art conservation to use paint strippers 

based on DCM or, preferably, NMP (Wollbrinck, 1993).

336411 Aircraft manufacturing US Census reports an index entry of “Aircraft rebuilding (i.e., 

restoration to original design specifications)” (USDOC, 2007a).

Paint removal during the restoration process may use DCM- or 

NMP-based paint strippers.

336611 Ship building and repairing US Census 2007 NAICS definition includes shipyards involved in 

the construction of ships as well as “their repair and conversion 

and alteration” (USDOC, 2007a). Any paint removal activities 

during repair, conversion and alteration may use DCM- or 

NMP-based paint strippers.

Page 133 of 281
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 (70oC) 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., 

Page 134 of 281
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 highpressure 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 

Page 135 of 281
transferred to other refinishing processes (e.g., sanding, painting, reupholstery) (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-1 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-1 Typical Flow Tray for Applying Stripper to Furniture (IRTA, 2006)

Page 136 of 281
Figure_Apx D-2 Typical Water Wash Booth Used to Wash Stripper and Coating Residue from Furniture 

(IRTA, 2006)

Figure_Apx D-3 Example Diagram of a Dipping Tank for Furniture Stripping (HSE, 2001)

Page 137 of 281
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 NIOSHapproved 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/MSHAapproved 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 

Page 138 of 281
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.

Page 139 of 281
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 2007 NAICS Title 2007 Number of 

Establishments

2007 Average Number of 

Construction Workers

238320 Painting and Wall 

Covering 

Contractors

35,619 174,276

238330 Flooring 

Contractors

14,575 49,085

Source: 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.

Page 140 of 281
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 Shops

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 2007 NAICS Title 2007 Number of 

Establishments

2007 Number of Paid 

Employees

811121 Automotive Body, 

Paint and Interior 

Repair and 

Maintenance

35,581 223,942

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. 

Page 141 of 281
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 2007 NAICS Title 2007 Number of 

Establishments

2007 Number of Paid 

Employees

811420 Reupholstery and 

Furniture Repair

4,693 16,142

Source: USDOC (2007b).

The present-day population of reupholstery and furniture repair establishments that use NMPbased paint strippers and the number of employees within an establishment exposed to NMPbased 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 2007 NAICS Title 2007 Number of 

Establishments

2007 Number of Paid 

Employees

711510 Independent Artists, 

Writers and

Performers

20,612 48,321

712110 Museums 4,664 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 NMPbased 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 

Page 142 of 281
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

Parameters Calculated from 

the Corresponding 2007 

Economic Census Data

2007 

NAICS 

Code

2007 NAICS 

Title

Number of 

Establishments

Average 

Number of 

Production 

Workers

Production 

Workers 

Hrs (1,000 

hr)

Average 

Worker Days 

per Year 

(Assuming

8 hr/day)

Average 

Worker Hrs 

per Day 

(Assuming 250 

Days/yr)

33641

1

Aircraft 

Manufacturi

ng

254 81,456 157,589 242 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 

Page 143 of 281
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

Parameters Calculated 

from the Corresponding 

2007 Economic Census 

Data

2007 

NAICS 

Code

2007 NAICS 

Title

Number of 

Establishment

s

Average 

Number of 

Production 

Workers

Production 

Workers 

Hrs (1,000 

hr)

Average 

Worker Days 

per Year 

(Assuming 

8 Hrs/day)

Average 

Worker Hrs 

per Day 

(Assuming

250 Days/yr)

336611 Ship building 

and repairing

656 65,737 136,929 260 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 

Page 144 of 281
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 palmside of both hands exposed to a liquid.

Page 145 of 281
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

Use 

Description

Airborne 

Concentration 

(mg/m3) Characterization Notes

Professional 

Contractors 

(in home)

Floor 

stripping 9.3 Personal sample; 48-

min sample

Mean of these four samples is 

13.4 mg/m3 (3.3 ppm).

US NIOSH study of a flooring 

contractor, conducted in 1993.

Professional 

Contractors 

(in home)

Floor 

stripping 17.4

Personal sample; 93-

min sample. Stripping 

solution was applied 

during this sample.

Professional 

Contractors 

(in home)

Floor 

stripping 5.7

Personal sample; 64-

min sample. The 

window was opened 

during this sample.

Professional 

Contractors 

(in home)

Floor 

stripping 21.1

Personal sample; 46-

min sample. Stripping 

solution was applied 

during this sample.

Professional 

Contractors 

(in home)

Floor 

stripping 12.6 Personal sample; 47-

min sample

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.

Professional 

Contractors 

(in home)

Floor 

stripping 21.1 Personal sample; 52-

min sample

Professional 

Contractors 

(in home)

Floor 

stripping 14.2 Personal sample; 43-

min sample

Professional 

Contractors 

(chamber 

test)

Manual 

stripping 39 Personal sample; 129-

min sample

Consumer exposures; Brush 

application - use as surrogate for 

workers.

Professional 

Contractors 

(chamber 

test)

Manual 

stripping 37 Personal sample; 130-

min sample

Consumer exposures; Brush 

application - use as surrogate for 

workers.

Professional 

Contractors 

Manual 

stripping 37 Personal sample; 143-

min sample

Consumer exposures; Brush 

application - use as surrogate for 

workers.

Page 147 of 281
Industry 

Category

Use 

Description

Airborne 

Concentration 

(mg/m3) Characterization Notes

(chamber 

test)

Furniture 

stripping

Furniture 

stripping 1.0-3.8 TWAs range 125-167 min Study of two shops in Germany.

Non-specific 

Workplace 

Settings

Paint 

stripping 64

Highest value in range; 

8-hr TWA; personal 

breathing zones

Non-specific 

Workplace 

Settings

Paint 

stripping 280 Highest value in range; 

1-hr peak samples

Non-specific 

Workplace 

Settings

Paint 

stripping 0.01-6 Range; Sampling time 

not presented

Dipping for paint stripping and 

degreasing. Study conducted in 

the UK.

Graffiti 

removal

Graffiti 

removal 0.01-30 Short-term; Sampling time not presented Study conducted in the UK.

Graffiti 

removal

Graffiti 

removal 0.56

Personal sampling; 8-hr 

TWA; average for 6 

workers

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.

Graffiti 

removal

Graffiti 

removal 1.78

Personal sampling; 8-hr 

TWA; average for 3 

workers

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.

Graffiti 

removal

Graffiti 

removal 1

Personal sampling; 8-hr 

TWA; average for 25 

workers

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.

Graffiti 

removal

Graffiti 

removal 4.71

Personal sampling; 15-

min (ST), average of 40 

samples

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.

Graffiti 

removal

Graffiti 

removal 9.9 Personal sampling; 15-

min (ST), 1 sample

Sometimes workers worked in 

semi-confined spaces. Did not 

wear respirators.

Study conducted in Sweden in 

1992.

Page 148 of 281
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 20oC 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).

Page 149 of 281
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-1 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, semiconfined 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)

Geometric 

Mean 

(mg/m3)

Low 

(mg/m3)

High 

(mg/m3)

Number of 

Workers 

Exposed

0.56 0.4 0 1.68 6

Depot 3 and 4

Mean 

(mg/m3)

Geometric 

Mean 

(mg/m3)

Low 

(mg/m3)

High 

(mg/m3)

Number of 

Workers 

Exposed

1.78 1.5 0.61 2.56 3

Underground Stations

Mean 

(mg/m3)

Geometric 

Mean 

(mg/m3)

Low 

(mg/m3)

High 

(mg/m3)

Number of 

Workers 

Exposed

1.0 0.67 0.03 4.52 25

Page 151 of 281
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:

Page 152 of 281
Equation D-1 Mass Balanced Concentration of NMP

CC = mm

vv = yyyyyyRRRR xx �

1,000 mmmm� xx (1000 mmmmmm

kk )

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-1 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 DCMcontaining 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 timeintegrated samples were collected at breathing-zone height during paint stripping operations 

Page 153 of 281
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-1 Exponential Decay of Emissions

EE = EE0ee−kkkk

Where:

E0 = initial emission rate (the emission rate at t = 0), mg/hr

k = first-order rate constant, hr-1

t = time since application, hrs

Integrating Equation E-1 to a time of infinity gives the total released mass represented by the 

exponential, as follows:

Equation E-2 Total Mass Released

MMMMMM RR RR = EE0/k

Or:

Equation E-3 Initial Emission Rate

EE0 = ( MMMMMM RR RR) ∗ kk

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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

CC(tt) = EE0

VV ∗ (

QQ

VV − kk)

(ee−kkkk − ee−QQ

VV )

Where:]

V = chamber volume, 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

CC(tt) = EE01

VV ∗ �

QQ

VV − kk1�

(ee−kk1 − ee−QQ

VV ) +

EE02

VV ∗ (

QQ

VV − kk2)

(ee−kk2 − ee−QQ

VV )

Where:

E01 = initial emission rate for the first exponential, mg/hr

E02 = initial emission rate for the second exponential, mg/hr

k1 = first-order rate constant for the first exponential, hr-1

k2 = first-order rate constant for the second exponential, hr-1

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 E01, 

k1, E02 and k2 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 

Page 155 of 281
segment’s stripping sequence. As illustrated in Table_Apx E-1, 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-1 Sequence of Stripping Activities for MRI study

Description Segment

Application 

Time (min)

Effect Time

(min)

Scrape Time 

(min)

Total Time 

(min)

Start End Start End Start End Start End

Quarter 1, 1st Sequence 1 0 1 1 31 31 35 0 35

Quarter 2, 1st Sequence 2 11 12 12 42 42 46 11 46

Quarter 3, 1st Sequence 3 22 23 23 53 53 57 22 57

Quarter 4, 1st Sequence 4 33 34 34 64 64 68 33 68

Quarter 1, 2nd Sequence 5 44 45 45 75 75 79 44 79

Quarter 2, 2nd Sequence 6 55 56 56 86 86 90 55 90

Quarter 3, 2nd Sequence 7 66 67 67 97 97 101 66 101

Quarter 4, 2nd Sequence 8 77 78 78 108 108 112 77 112

Air samples were collected and analyzed by two methods: (1) near real-time samples analyzed 

with an FTIR spectrometer, averaged over 4-min intervals; and (2) time-integrated samples, 

collected on charcoal sorbent tubes for subsequent analysis by GC-FID. As an example, 

Figure_Apx E-1 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 timeseries 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 (~9-11 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 DCMcontaining 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 of N-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.

Page 156 of 281
Figure_Apx E-1 Results from FTIR Samples (EPA, 1994a)

Table_Apx E-2 Results from GC-FID Samples (EPA, 1994a)

Sampling 

Location in 

Test Chamber

Time-integrated 

Concentration

mg/m3 ppm

Inlet Side 38 9.4

Outlet Side 45 11

Breathing Zone 39 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
Table_Apx E-3 Table 1 from the MRI Report to EPA (EPA, 1994a)

Figure_Apx E-2 Uncorrected (Run 12) and Corrected (All Runs) FTIR Results for NMP – Wood Finisher’s

Pride

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.

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 1/8th 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 E01, k1, E02 and k2 (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.

Figure_Apx E-4 NLS Fit of Exponential-emissions Model to Rescaled FTIR Results for Wood Finisher’s 

Pride

Page 160 of 281
Table_Apx E-4 Fitted Parameters to the Rescaled MRI (EPA, 1994) Results for Wood Finisher’s Pride

Product

Mass of 

Product 

Applied, g

NMP Mass 

Applied, g

1st Exponential 2nd Exponential

NMP Fraction 

Released

1st-Order 

Rate 

Constant, hr-1

NMP Fraction 

Released

1st-Order 

Rate 

Constant, hr-1

Wood 

Finisher’s 

Pride

896 403 0.0070 32.825 0.8625 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 = ∞) 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.

Figure_Apx E-5 Theoretical Cumulative Mass of NMP Released from Wood Finisher’s Pride

Page 161 of 281
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
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
Table_Apx E-5 Assumed Model Parameters for Estimates of User and Non-user Exposures for a Sprayapplied Product Containing NMP

Scenario 

Description

Emission 

parameter

Assumption

1st Exponential for NMP 2nd Exponential for NMP

Fraction 

Released

Rate Constant, 

hr-1

Fraction 

Released

Rate Constant, 

hr-1

Scenario 6:

Upper-end for 

User

Lower(6a) 0.0070

32.825

0.8625

0.0024

Upper (6b) 0.070 0.7995

Scenario 7:

Upper-end for 

User & Non-user

Lower (7a) 0.0070

32.825

0.8625

0.0024

Upper (7b) 0.070 0.7995

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
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 of ten, 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 1⁄2X 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

([XX − 1/2XX] + [2XX − XX])/2 = 3

4

XX oo 75% oo XX

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

|YY − XX|

XX xx 100%

Where Y is the output associated with the change in location pattern from the base case.

Page 165 of 281
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-1 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 1⁄4 

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/Information/removerfaq.html

Page 166 of 281

 
The applied surface areas selected for central and upper-end values were 10 and 25 ft2, 

respectively. The upper-end surface area is 2.5 times higher than the central surface area and 

provides sufficient distinction from the central case. Application targets with surface areas close 

to the two specified surface areas (10 and 25 ft2) were used in the exposure scenarios to reflect 

real-world situations. A coffee table with nominal dimensions of 4 feet × 2.5 feet for the top 

surface was selected for the central case (10 ft2) (Abbas, 2012) and a chest of drawers with 

nominal dimensions of 4 feet high by 2.5 feet wide by 1.5 feet deep (American Unfinished 

Furniture, 2012 shows an illustrative chest of drawers with nearly the same dimensions) was 

selected for the upper-end case (4 × 2.5 ft2 for front + 2.5 × 1.5 ft2 for top + 2 × 4.5 × 1.5 ft2 for 

sides ≈ 25 ft2). For the bathroom scenario, a bathtub surface area of 36 ft2 was calculated 

assuming nominal dimensions of five feet wide by 2.5 feet deep by 1.5 feet high.

Stripping Sequence

The sequence chosen to characterize product application was intended to be consistent with 

labeling instructions. The stripping event consisted of an initial stripping sequence (apply-waitscrape) 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 sprayapplied 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
Table_Apx E-6 Time Schedule for Paint Stripping with Repeat Application

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

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

1. Brush application to coffee 

table in workshop, central 

tendency scenario

0-5

(workshop)

5-35

(ROH)

35-45

(workshop)

45-50

(workshop)

50-80

(ROH)

80-90

(workshop)

2. Brush application to coffee 

table in workshop, upper-end 

scenario for user

0-5

(workshop)

5-35

(workshop)

35-45

(workshop)

45-50

(workshop)

50-80

(Workshop)

80-90

(workshop)

3. Brush application to chest in 

workshop, upper-end scenario 

for user & non-user

0-12.5

(workshop)

12.5-42.5

(ROH)

42.5-67.5

(workshop)

67.5-80

(workshop)

80-110

(ROH)

110-135

(workshop)

4. Brush application to bathtub 

in bathroom, upper-end to 

bounding scenario for user & 

non-user; Csat = 1,013 mg/m3

0-18

(bathroom)

18-48 

(ROH)

48-84

(bathroom)

84-102

(bathroom)

102-132

(ROH)

132-168

(bathroom)

5. Brush application to bathtub 

in bathroom, upper-end to 

bounding scenario for user & 

non-user; Csat = 640 mg/m3

0-18

(bathroom)

18-48 

(ROH)

48-84

(bathroom)

84-102

(bathroom)

102-132

(ROH)

132-168

(bathroom)

6. Spray application to coffee 

table in workshop, upper-end 

scenario for user 

0-2.5

(workshop)

2.5-32.5

(workshop)

32.5-42.5

(workshop)

42.5-45

(workshop)

45-75

(workshop)

75-85

(workshop)

7. Spray application to chest in 

workshop, upper-end scenario 

for user & non-user 

0-6.25

(workshop)

6.25-36.25

(ROH)

36.25-61.25

(workshop)

61.25-67.5

(workshop)

67.5-97.5

(ROH)

97.5-122.5

(workshop)

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-1 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-1 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-1 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) Application

Rate, g/ft2

NMP Weight 

Fraction a Release Fraction NMP Mass 

Released, g

Coffee table (10 ft2) 108 0.25 | 0.50 0.8695 234.6 | 469.5

Chest of drawers (25 ft2) 108 0.50 0.8695 1173.8

Bathroom tub (36 ft2) 108 0.5 0.8695 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) Application

Rate, g/ft2

NMP Weight 

Fraction Release Fraction NMP Mass Released, g

Coffee table (10 ft2) 81 0.53 0.8695 373.3

Chest of drawers (25 ft2) 81 0.53 0.8695 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 

ROH. The house volume chosen for the model runs, 492 m3, was the central value listed in the 

EFH. The volume assigned to the in-house workshop area was 54 m3, corresponding to 12 feet × 

20 feet with an 8-foot ceiling (20 × 12 × 8 = 1,920 ft3 or ~54 m3). This room volume is similar to 

the value reported in Riley et al. (2001) for the mean volume of the room used for paint 

stripping (51 m3). The volume for the ROH, 438 m3, is determined by subtraction (492 to 54 m3).

Page 169 of 281
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 ROH are the mean and 10th

percentile values, respectively, from the EFH. (Note that a low-end ACH would be expected to 

contribute to upper-end concentration estimates.) For the workshop, it was assumed that 

multiple windows were opened. The indoor-outdoor airflow rate assigned to this zone, 68 m3/hr, 

was obtained by multiplying the room volume of 54 m3 by the 90th percentile (1.26/hr) of the airexchange-rate distribution from the EFH, thought to be a reasonable representation of the openwindow 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

QQ = (0.078 + 0.31 ∗ AA AA) ∗ HH VV

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
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.

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.

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 

Room of 

Use

(54 m3)

68

m3/hr

107

m3/hr

Rest of 

House

(438 m3)

197

m3/hr

Central Values

Room of 

Use

(54 m3)

68

m3/hr

65.8

m3/hr

Rest of 

House

(438 m3)

78.8

m3

/hr

Values for Upper-end 

Concentration Scenarios

denotes air flow

Denotes air flow

1.6

m3/hr

Rest of 

Bathroom

(8 m3)

35

m3/hr

Rest of 

House

(483 m

3

)

“Source 

Cloud”

(1 m3)

86.9

m3/hr

80

m3/hr

Page 171 of 281
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
Figure_Apx E-8 Modeling Representation of the Bathtub and Virtual Compartment (aka “Source 

Cloud”)

Page 173 of 281
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. 

HVAC OFF and ON flows

for Master Bedroom

Page 174 of 281
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 ROH as a centraltendency assumption for the user (Scenario 1), in the workshop as an upper-end assumption 

for the user (Scenario 2) and in the ROH 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 ROH during the waiting phase for the central assumption because the user is assumed to 

be aware of potential inhalation health concerns from using paint strippers based on label 

warnings (“Vapor Harmful”) on some labels (which are often for products containing multiple 

active ingredients, not solely NMP) and because the Riley survey (Riley et al., 2001) reported 

that 65 percent of users reported taking breaks outside the work area. Breaks typically involved 

a specific break activity and location, such as going to the kitchen and making a sandwich or

going outside to do yard work. For the upper-end 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 

WESTAT (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 ROH throughout the model run, as was the user for the 

portion of the run after all applying/scraping was completed. For the bathroom scenario, the 

user was assumed to be in the ROH during the wait times.

It was further assumed that the scrapings were removed from the house as soon as scraping 

was completed for the last segment. The implication for modeling purposes is that any 

remaining NMP emissions would be truncated at that time.

Saturation Concentration Constraint

As discussed above, Scenarios 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
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 

CCssss =

� VV

760 mmmm

xx MM xx 1,000 mmmm xx 1,000 LL

mm3�

(RR xx )

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
humidity saturated air (100% relative humidity BASF AG, 1989, 1992, 1995a, 1995b; 

BASF AG, 1995c).

Based on the cited findings, the OECD report concludes:

Thus, the vapor saturation of NMP under normal conditions is considered to be in the 

range of 0.48 - 0.64 mg/l (120 - 160 ppm) depending on humidity and temperature.

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, i to i +1, for i = 0 to 1,440: 

Equation E-10 Maximum Time Weighted Concentrations

EEEEii,ii+11 = �

� 11,ii + 11,ii+11�

22

� � ∗ FFii,ii+11 + �

� RRRRRR,ii + RRRRRR,ii+11�

22

� � ∗ �11 − FFii,ii+11�

Where:

ECi,i+1 = the exposure concentration over the time interval i to i +1

C1,i and C1,i+1 = the concentrations in the use zone at times i and i+1, respectively

Page 177 of 281
CROH,i and CROH,i+1 = the concentrations in the ROH zone at times i and i+1, respectively

Fi,i+1 = the fraction of time spent in the use zone during the time interval i to i +1

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

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 nonuser’s exposure concentration is the same as that shown for Zone 2 (ROH). The user’s timePage 178 of 281
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 ROH 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 ROH. Figure_Apx E-11 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 

ROH, non-user exposure = concentration in ROH) 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/m3 for 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
Figure_Apx E-11 Scenario 1, Brush Applied: Modeled NMP Concentrations and User Exposure for Stripper Application in Workshop Using 

Parameter Values Selected for Central Tendency Exposure. 

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
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
a) Scenario 4, Saturation Concentration Constraint at 1,013 mg/m3

b) Scenario 5, Saturation Concentration Constraint at 640 mg/m3

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
a) Scenario 6a, User Upper-end Concentrations and Exposure, Lower Estimate

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
a) Scenario 7a, User and Non-user Upper-end Concentrations and Exposure, Lower Estimate for Emission Parameters

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: C5H9NO

CASRN: 872-50-4

Molecular Weight: 99.13 g/mol

Density: 1.028 g/cm2 (liquid)

Appearance: clear liquid

Melting Point: -24 °C = -11 °F = 249 K

Boiling Point: 203 °C = 397 °F = 476 K 

Conversion units: 1 ppm = 4.054397 mg/m3

Saturation Concentration: ~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 E3)

Saturation Concentration: ~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 68 m3/h

ROH-outdoors 197.1 m3/h (0.45 ACH)

Workshop-ROH 107 m3/h

NMP Mass Released:

Coffee table = 10 sq ft surface area

Applied product mass = 108 g/sq ft = 1,080 g

Applied NMP = 1,080 g × 0.25 (wt fraction) = 270 g

Page 185 of 281
Total NMP mass released (theoretical, both exponentials) = 1,080 g × 0.25 (wt fraction) × 0.8695

(release fraction, theoretical) = 234.8 g

For each of the 2 applications:

k1 = 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

E01 = Mass * k1 = 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

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

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

1) Coffee Table, Brush-On, 

Workshop, User ROH during wait 

time, 0.45 ACH, 0.25 Weight 

Fraction

0-5 (Use) 5-35 

(ROH)

35-45 

(Use)

45-50 

(Use)

50-80 

(ROH)

80-90 

(Use)

User in ROH at the end of Scraping 2

User in ROH for the remainder of the run (22 hrs, 30 minutes)

Model Run Time:

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 1 min 10 min 30 min 1 hr 4 hr 8 hr 24 hr

User 12.6 6.8 3.6 3.5 1.8 1.1 0.4

Other 2.0 2.0 2.0 1.9 1.3 0.8 0.3

In ppm

Individual 1 min 10 min 30 min 1 hr 4 hr 8 hr 24 hr

User 3.1 1.7 0.9 0.9 0.5 0.3 0.1

Other 0.5 0.5 0.5 0.5 0.3 0.2 0.1

Page 186 of 281
Plots: 

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

ROH volume = 492 – 54 = 438 m3

Airflows:

Workshop-outdoors 68 m3/h

ROH-outdoors 197.1 m3/h (0.45 ACH)

Workshop-ROH 107 m3/h

NMP Mass Released:

Coffee Table = 10 sq ft surface area

Applied product mass = 1,080 g

Applied NMP = 1,080 g × 0.5 (wt fraction) = 540 g

Total NMP mass released (both exponentials) = 1,080 g × 0.5 (wt fraction) × 0.8695 (release 

fraction, theoretical) =469.5 g

For each of the 2 applications:

k1 = 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

E01 = Mass * k1 = 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

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

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

2) Coffee Table, Brush-On, 

Workshop, User in Workshop 

during wait time, 0.45 ACH, 0.5 

Weight Fraction

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

(Use)

45-50 

(Use)

50-80 

(Use)

80-90 

(Use)

User in ROH at the end of Scraping 2

User in ROH for the remainder of the run (22 hrs, 30 minutes)

Model Run Time:

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 1 min 10 min 30 min 1 hr 4 hr 8 hr 24 hr

User 33.4 31.1 24.2 19.1 8.3 4.4 1.5

Other 4.1 4.1 4.0 3.9 2.6 1.5 0.5

In ppm

Individual 1 min 10 min 30 min 1 hr 4 hr 8 hr 24 hr

User 8.2 7.7 6.0 4.7 2.0 1.1 0.4

Other 1.0 1.0 1.0 1.0 0.6 0.4 0.1

Page 189 of 281
Plots: 

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 68 m3/h

ROH-outdoors 78.8 m3/h (0.18 ACH)

Workshop-ROH 65.8 m3/h

NMP Mass Released:

Chest = 25 sq ft surface area

Applied product mass = 2,700 g

Applied NMP = 2,700 g × 0.5 (wt fraction) = 1,350 g

Total NMP mass released (both exponentials) = 2,700 g × 0.5 (wt fraction) × 0.8695 (release 

fraction, theoretical) =1173.8 g

For each of the 2 applications:

k1 = 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

E01 = Mass * k1 = 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

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

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

3) Chest, Brush-On, Workshop, 

User in ROH during wait time, 0.18 

ACH, 0.5 Weight Fraction

0-12.5 

(Use)

12.5-42.5 

(ROH)

42.5-67.5 

(Use)

67.5-80 

(Use)

80-110 

(ROH)

110-135 

(Use)

User in ROH at the end of Scraping 2

User in ROH for the remainder of the run (21 hrs, 45 minutes)

Model Run Time:

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 1 min 10 min 30 min 1 hr 4 hr 8 hr 24 hr

User 76.0 51.4 32.7 25.4 15.6 10.3 3.9

Other 10.4 10.4 10.3 10.2 8.3 6.2 2.5

In ppm

Individual 1 min 10 min 30 min 1 hr 4 hr 8 hr 24 hr

User 18.7 12.7 8.1 6.3 3.9 2.5 1.0

Other 2.6 2.6 2.5 2.5 2.1 1.5 0.6

Page 192 of 281
Plots:

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 1.6 m3/h

Source cloud - bathroom 80 m3/h

Source cloud - outdoors 0

ROH-outdoors 86.9 m3/h (0.18 ACH)

Bathroom-ROH 35 m3/h

NMP Mass Released:

Bathtub = 36 sq ft surface area

Applied product mass = 3,888 g

Applied NMP = 3,888 g × 0.5 (wt fraction) = 1,944 g

Total NMP mass released (both exponentials) = 3,888 g × 0.5 (wt fraction) × 0.8695 (release 

fraction, theoretical) = 1690.3 g

For each of the 2 applications:

k1 = 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

E01 = Mass * k1 = 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

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

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

4) Bathtub, Brush-On, Bathroom + 

Source Cloud, User in ROH during 

wait time, 0.18 ACH, 0.50 Weight 

Fraction 

0-18 (Use) 18-48 

(ROH)

48-84 

(Use)

84-102 

(Use)

102-132 

(ROH)

132-168 

(Use)

User in ROH at the end of Scraping 2

User in ROH for the remainder of the run (21 hrs 12 minutes)

Model Run Time:

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 1 min 10 min 30 min 1 hr 4 hr 8 hr 24 hr

User 796.8 691.7 365.96 234.4 136.0 77.4 28.6

Other 30.7 30.7 30.5 30.1 25.9 20.4 9.4

In ppm

Individual 1 min 10 min 30 min 1 hr 4 hr 8 hr 24 hr

User 196.5 170.6 90.2 57.8 33.5 19.1 7.1

Other 7.6 7.6 7.5 7.4 6.4 5.0 2.3

Page 195 of 281
Plots:

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 1.6 m3/h

Source cloud - bathroom 80 m3/h

Source cloud - outdoors 0

ROH-outdoors 86.9 m3/h (0.18 ACH)

Bathroom-ROH 35 m3/h

NMP Mass Released:

Bathtub = 36 sq ft surface area

Applied product mass = 3,888 g

Applied NMP = 3,888 g × 0.5 (wt fraction) = 1,944 g

Total NMP mass released (both exponentials) = 3,888 g × 0.5 (wt fraction) × 0.8695 (release 

fraction, theoretical) = 1690.3 g

For each of the 2 applications:

k1 = 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

E01 = Mass * k1 = 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

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

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

5) Bathtub, Brush-On, Bathroom + 

Source Cloud, User in ROH during 

wait time, 0.18 ACH, 0.50 Weight 

Fraction 

0-18 (Use) 18-48 

(ROH)

48-84 

(Use)

84-102 

(Use)

102-132 

(ROH)

132-168 

(Use)

User in ROH at the end of Scraping 2

User in ROH for the remainder of the run (21 hrs 12 minutes)

Model Run Time:

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 1 min 10 min 30 min 1 hr 4 hr 8 hr 24 hr

User 640.0 627.8 344.6 223.8 133.2 76.0 28.1

Other 30.7 30.7 30.5 30.1 25.9 20.4 9.4

In ppm

Individual 1 min 10 min 30 min 1 hr 4 hr 8 hr 24 hr

User 157.9 154.9 85.0 55.2 32.8 18.7 6.9

Other 7.6 7.6 7.5 7.4 6.4 5.0 2.3

Page 198 of 281
Plots:

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

ROH volume = 492 – 54 = 438 m3

Airflows:

Workshop-outdoors 68 m3/h

ROH-outdoors 197.1 m3/h (0.45 ACH)

Workshop-ROH 107 m3/h

NMP Mass Released:

Coffee Table = 10 sq ft surface area

Applied product mass = 810 g

Applied NMP = 810 g × 0.53 (wt fraction) = 429.3 g

Total NMP mass released (both exponentials) = 810 g × 0.53 (wt fraction) × 0.8695 (release 

fraction, theoretical) =373.3 g

For each of the 2 applications:

k1 = 32.83/hr

% Mass for Exponential 1 = 0.7% = 0.007 *810 *0.53 (wt fraction) * 0.5 (half per application)

= 1.5 g

E01 = Mass * k1 = 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

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

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

6a) Coffee Table, Spray-On, 

Workshop, User in workshop 

during wait time, 0.45 ACH, 0.53 

Weight Fraction

0-2.5 

(Use)

2.5 -32.5 

(Use)

32.5-42.5 

(Use)

42.5-45 

(Use)

45-75 

(Use)

75-85 

(Use)

User in ROH at the end of Scraping 2

User in ROH for the remainder of the run (22 hrs, 35 minutes)

Page 200 of 281
Model Run Time:

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 1 min 10 min 30 min 1 hr 4 hr 8 hr 24 hr

User 27.3 25.3 19.5 15.9 6.5 3.5 1.2

Other 3.2 3.2 3.2 3.1 2.0 1.2 0.4

In ppm

Individual 1 min 10 min 30 min 1 hr 4 hr 8 hr 24 hr

User 6.7 6.2 4.8 3.9 1.6 0.9 0.3

Other 0.8 0.8 0.8 0.8 0.5 0.3 0.1

Plots:

Page 201 of 281
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

ROH volume = 492 – 54 = 438 m3

Airflows:

Workshop-outdoors 68 m3/h

ROH-outdoors 197.1 m3/h (0.45 ACH)

Workshop-ROH 107 m3/h

NMP Mass Released:

Coffee Table = 10 sq ft surface area

Applied product mass = 810 g

Applied NMP = 810 g × 0.53 (wt fraction) = 429.3 g

Total NMP mass released (both exponentials) = 810 g × 0.53 (wt fraction) × 0.8695 (release 

fraction, theoretical) =373.3 g

For each of the 2 applications:

k1 = 32.83/hr

% Mass for Exponential 1 = 7% = 0.07 *810 *0.53 (wt fraction) * 0.5 (half per application)

= 15.0 g

E01 = Mass * k1 = 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

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

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

6b) Coffee Table, Spray-On, 

Workshop, User in workshop 

during wait time, 0.45 ACH, 0.53 

Weight Fraction

0-2.5 

(Use)

2.5 -32.5 

(Use)

32.5-42.5 

(Use)

42.5-45 

(Use)

45-75 

(Use)

75-85 

(Use)

User in ROH at the end of Scraping 2

User in ROH for the remainder of the run (22 hrs, 35 minutes)

Page 203 of 281
Model Run Time:

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 1 min 10 min 30 min 1 hr 4 hr 8 hr 24 hr

User 245.9 224.0 160.9 138.6 53.3 28.3 9.5

Other 26.4 26.4 26.0 24.8 16.2 9.6 3.3

In ppm

Individual 1 min 10 min 30 min 1 hr 4 hr 8 hr 24 hr

User 60.6 55.3 39.7 34.2 13.2 7.0 2.3

Other 6.5 6.5 6.4 6.1 4.0 2.4 0.8

Plots:

Page 204 of 281
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 68 m3/h

ROH-outdoors 78.8 m3/h (0.18 ACH)

Workshop-ROH 65.8 m3/h

NMP Mass Released:

Chest = 25 sq ft surface area

Applied product mass = 2,025 g

Applied NMP = 2,025 g × 0.53 (wt fraction) = 1,073.25 g

Total NMP mass released (both exponentials) = 2,025 g × 0.53 (wt fraction) × 0.8695 (release 

fraction, theoretical) = 933.19 g

For each of the 2 applications:

k1 = 32.83/hr

% Mass for Exponential 1 = 0.7% = 0.007 *2025 *0.53 (wt fraction) * 0.5 (half per application)

= 3.76 g

E01 = Mass * k1 = 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

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

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

7a) Coffee Table, Spray-On, 

Workshop, User in ROH during wait 

time, 0.18 ACH, 0.53 Weight 

Fraction

0-6.25 

(Use)

6.25-36.25 

(ROH)

36.25-

61.25 

(Use)

61.25-

67.5 (Use)

67.5-97.5 

(ROH)

97.5-

122.5 

(Use)

User in ROH at the end of Scraping 2

User in ROH for the remainder of the run (21 hrs, 57.5 minutes)

Page 206 of 281
Model Run Time:

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 1 min 10 min 30 min 1 hr 4 hr 8 hr 24 hr

User 44.6 25.9 21.0 15.9 9.2 5.3 1.8

Other 7.9 7.9 7.9 7.7 5.4 3.3 1.1

In ppm

Individual 1 min 10 min 30 min 1 hr 4 hr 8 hr 24 hr

User 11.0 6.4 5.2 3.9 2.3 1.3 0.4

Other 2.0 2.0 1.9 1.9 1.3 0.8 0.3

Plots:

Page 207 of 281
Page 208 of 281
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 68 m3/h

ROH-outdoors 78.8 m3/h (0.18 ACH)

Workshop-ROH 65.8 m3/h

NMP Mass Released:

Chest = 25 sq ft surface area

Applied product mass = 2,025 g

Applied NMP = 2,025 g × 0.53 (wt fraction) = 1,073.25 g

Total NMP mass released (both exponentials) = 2,025 g × 0.53 (wt fraction) × 0.8695 (release 

fraction, theoretical) = 933.19 g

For each of the 2 applications:

k1 = 32.83/hr

% Mass for Exponential 1 = 7% = 0.07 *2025 *0.53 (wt fraction) * 0.5 (half per application)

= 37.56 g

E01 = Mass * k1 = 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

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

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

7b) Coffee Table, Spray-On, 

Workshop, User in ROH during wait 

time, 0.18 ACH, 0.53 Weight 

Fraction

0-6.25 

(Use)

6.25-36.25 

(ROH)

36.25-

61.25 

(Use)

61.25-

67.5 (Use)

67.5-97.5 

(ROH)

97.5-

122.5 

(Use)

User in ROH at the end of Scraping 2

User in ROH for the remainder of the run (21 hrs, 57.5 minutes)

Page 209 of 281
Model Run Time:

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 1 min 10 min 30 min 1 hr 4 hr 8 hr 24 hr

User 386.8 168.9 118.9 100.1 61.6 35.4 12.0

Other 62.0 61.9 61.0 58.4 39.9 24.2 8.3

In ppm

Individual 1 min 10 min 30 min 1 hr 4 hr 8 hr 24 hr

User 95.4 41.7 29.3 24.7 15.2 8.7 3.0

Other 15.3 15.3 15.1 14.4 9.8 6.0 2.0

Plots:

Page 210 of 281
Page 211 of 281
Appendix F TOXICOLOGY STUDIES

F-1 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-1

Page 212 of 281
Table_Apx F-1 Study Quality Considerations

Page 213 of 281
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 LD50). 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 et al., 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
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 

24 26 28 22

Pregnant 

females 

22 24 20 15

Died females* 0 0 0 2

Live pups per 

litter 

11.5 ± 3.5a 10.4 ± 2.6 10.5 ± 3.4 0.33 ± 0.82b

Dead pups per 

litter 

0.18 ± 0.85 0 0.13 ± 0.34 0.80 ± 1.1b

Sex ratio (F : M) 132 : 125 112:137 105:107 5:3

Indices

Fertility %c 91.7 92.3 71.4b 68.2b

Viability %d 94.0 86.4b 71.6b 0

Lactation %e 96.1 78.2b 43.4b 0

Body weight 

gain of mothers 

from 0 to 20 GD 

(% control)

100 87.7 75.6 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 Imp: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 LD50) for 5 days/week, 10 weeks before 

Page 215 of 281
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
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

(F1a). The parental animals for the second generation were selected from pups of the second 

litter (F1b). 

NMP had no adverse effects on reproductive performance or fertility of the F0 or F1 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 (F1a). The parental 

animals for the second generation were selected from pups of the second litter (F1b).

NMP had no adverse effects on reproductive performance or fertility of the F0 or F1 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
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 (GDs) 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
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 GDs 6 through 13 at 243 and 486 mg/m3 as well as decreased food consumption at 486 

mg/m3 on GDs 13 through 21. There were no effects on embryo/fetal viability or teratogenic 

effects at any dose. There was a slight body weight decrease in the fetus at 486 mg/m3. The noobserved-adverse-effect level (NOAEL) for maternal toxicity was 122 mg/m3 and the observed 

fetal NOAEL was 243 mg/m3 (Saillenfait et al., 2003).

Hass 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 (Hass et al., 

1995). 

Hass et al., 1994

Hass et al. (1994) investigated the effects of NMP on postnatal development and behavior in 

rats. Dams were exposed by whole-body inhalation to analytically determined levels of 

151 ppm (612 mg/m3) for six hrs/day from GD 7 to 20. Offspring were weighed through 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
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 (Hass 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 twogeneration 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 F1 generation. F1 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 preconception; 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).

Page 220 of 281
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 μm 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 

Page 221 of 281
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.

Page 222 of 281
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.

Page 223 of 281
G-1 Review of Akkeson et al., 2004

Akesson, B., Carnerup, M. A. and Jonsson, B. A. (2004). Evaluation of exposure biomarkers from 

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).

Page 224 of 281
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-1-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).

Page 225 of 281
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/m3NMP 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).

Page 226 of 281
G-4 Review of Bader et al., 2005

Bader, M., Keener, S. A. and Wrbitzky, R. (2005). Dermal absorption and urinary elimination of N-methyl2-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 t1/2 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).

Page 227 of 281
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).

Page 228 of 281
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/m3NMP 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-Nmethyl-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 wholebody 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.

Page 229 of 281
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-Nmethyl-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.

Page 230 of 281
G-8 Review of Xiaofei et al., 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.

Page 231 of 281
Appendix H BENCHMARK DOSE ANALYSIS

H-1 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-1.

Table_Apx H-1 Fetal Body Weight Data Selected for Dose-Response Modeling for NMP

Reference Dose 

AUC (hr mg/L) 

Number of 

litters

Fetal body weight (g) 

Mean ± Standard Deviation 

Saillenfait et al., 

2003

0 24 5.671 ± 0.370

158 20 5.623 ± 0.358

323 19 5.469 ± 0.252

668 25 5.393 ± 0.446

Saillenfait et al., 

2002

0 21 5.73 ± 0.5

1144 21 5.59 ± 0.22

2503 24 5.18 ± 0.35

5674 25 4.02 ± 0.21

9231 8 3.01 ± 0.39

Saillenfait et al., 

2002 and 2003 

pooled

0 45 5.698 ± 0.44

158 20 5.623 ± 0.358

323 19 5.469 ± 0.252

668 25 5.393 ± 0.446

1144 21 5.59 ± 0.22

2503 24 5.18 ± 0.35

5674 25 4.02 ± 0.21

9231 8 3.01 ± 0.39

DuPont 1990 0 39 7.48 ± 0.701

51 16 7.03 ± 0.705

268 15 7.13 ± 0.695

633 22 6.66 ± 0.616

Page 232 of 281
Becci et al., 1982 0 24 3.45 ± 0.20

561 22 3.49 ± 0.24

2052 23 3.54 ± 0.29

7986 22 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 BMC:BMCL (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.

Page 233 of 281
H-1-1 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)

Modela Goodness of fit BMR = 5% RD BMR = 1 SD Basis for model 

selection

pvalueAIC BMD5RD (hr 

mg/L)

BMDL5RD (hr 

mg/L)

BMD1SD (hr 

mg/L)

BMDL1SD (hr 

mg/L)

Linear 0.952 -84.637 642 411 747 456 The Linear model 

was selected 

based on lowest 

AIC and highest pvalue.

Exponential 

(M2)

0.948 -84.629 641 405 749 451

Exponential 

(M4)

0.948 -84.629 641 284 749 381

Exponential 

(M3)

0.815 -82.682 653 406 745 453

Power 0.812 -82.680 653 413 744 458

Polynomial 3°b

Polynomial 2°

0.789 -82.665 652 412 738 457

Hill N/Ac -80.737 649 176 889 error

Exponential 

(M5)

N/Ac -80.737 643 168 error error

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
Figure_Apx H-1 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-1 Linear Model. (Version: 2.19; Date: 06/25/2014)

The form of the response function is: Y[dose] = beta_0 + beta_1*dose

A modeled variance is fit

Benchmark Dose Computation.

BMR = 5% Relative deviation

BMD = 642.052

BMDL at the 95% confidence level = 411.487

Parameter Estimates

Variable Estimate Default Initial 

Parameter Values

lalpha 10.9507 -1.98661

rho -7.59357 0

beta_0 5.66546 5.66303

beta_1 -0.000441199 -0.00043693

Table of Data and Estimated Values of Interest

Dose N Obs Mean Est Mean Obs Std Dev Est Std Dev Scaled Resid

0 24 5.67 5.67 0.37 0.33 0.0675

158.3 20 5.62 5.6 0.36 0.346 0.316

322.6 20 5.47 5.52 0.25 0.363 -0.654

Page 235 of 281
668.2 25 5.39 5.37 0.45 0.404 0.24

Likelihoods of Interest

Model Log(likelihood) # Param's AIC

A1 45.950356 5 -81.900712

A2 49.530515 8 -83.061031

A3 46.368255 6 -80.736511

fitted 46.318536 4 -84.637072

R 41.618363 2 -79.236727

Tests of Interest

Test -

2*log(Likelihood 

Ratio)

Test df p-value

Test 1 15.8243 6 0.01473

Test 2 7.16032 3 0.06696

Test 3 6.32452 2 0.04233

Test 4 0.099439 2 0.9515

Page 236 of 281
H-1-2 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)

Modela Goodness of fit BMD5RD

(hr mg/L)

BMDL5RD

(hr mg/L)

BMD1SD (hr 

mg/L)

BMDL1SD (hr 

mg/L)

Basis for model selection

p-value AIC

Exponential 

(M2)

0.00183 -98.750 741 693 1028 876 The Exponential (M5) 

model was selected 

based on lowest AIC with 

highest p-value. Exponential 

(M3)

0.325 -109.49 1329 1035 1578 1245

Exponential 

(M4)

0.00183 -98.750 741 691 1028 876

Exponential 

(M5)

0.966 -109.73 1637 1184 1880 1400

Hill 0.962 -109.73 1660 1194 1895 1409

Power 0.0479 -105.66 1114 904 1381 1070

Polynomial 4°b

Polynomial 3°c

Polynomial 2°

0.0295 -104.68 962 895 1233 1038

Linear 0.0687 -106.63 938 895 1210 1036

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
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-1) * exp(-(b * dose)^d)]

A modeled variance is fit

Benchmark Dose Computation.

BMR = 5% Relative deviation

BMD = 1637.32

BMDL at the 95% confidence level = 1184.3

Parameter Estimates

Variable Estimate Default Initial 

Parameter Values

lnalpha -3.80738 -2.38723

rho 1.00208 0.0548918

a 5.74092 6.0165

b 0.000143148 0.000073183

c 0.405685 0.000500291

d 1.67614 1

Page 238 of 281
Table of Data and Estimated Values of Interest

Dose N Obs Mean Est Mean Obs Std Dev Est Std Dev Scaled Resid

0 21 5.73 5.741 0.5 0.3577 -0.1399

1144 21 5.59 5.58 0.22 0.3527 0.1248

2503 24 5.18 5.182 0.35 0.3398 -0.02274

5674 25 4.02 4.014 0.21 0.299 0.1033

9231 8 3.01 3.021 0.39 0.2593 -0.1213

Likelihoods of Interest

Model Log(likelihood) # Param's AIC

A1 59.67563 6 -107.3513

A2 71.17728 10 -122.3546

A3 60.86644 7 -107.7329

R -42.05093 2 88.10186

5 60.86544 6 -109.7309

Tests of Interest

Test -

2*log(Likelihood 

Ratio)

Test df p-value

Test 1 226.5 8 <0.0001

Test 2 23 4 0.0001264

Test 3 20.62 3 0.0001261

Test 7a 0.001995 1 0.9644

Page 239 of 281
H-1-3 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)

Modela Goodness of fit BMD5RD

(hr mg/L)

BMDL5RD

(hr mg/L)

BMD1SD

(hr mg/L)

BMDL1SD

(hr mg/L)

Basis for model 

selection

p-value AIC

Exponential 

(M2); 

Exponential 

(M4)b

<0.0001 -169.77 828 774 1155 1030 The Exponential (M5) 

model was selected 

based on lowest AIC.

Exponential (M3) 0.0119 -187.12 1547 1253 1911 1579

Exponential 

(M5)

0.0150 -187.44 1937 1424 2283 1764

Hill 0.0138 -187.25 1962 1421 2297 1762

Power 0.00396 -184.48 1321 1039 1696 1366

Polynomial 7°c

Polynomial 5°d

Polynomial 4°e

Polynomial 3°f

0.00218 -183.08 1155 978 1532 1287

Polynomial 6°g 0.00218 -183.08 1155 978 1532 1287

Polynomial 2°h 0.00218 -183.08 1155 978 1532 1287

Linear 0.00164 -182.51 989 944 1343 1208

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. g 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
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-1) * exp(-(b * dose)^d)]

A modeled variance is fit

Benchmark Dose Computation.

BMR = 5% Relative deviation

BMD = 1937.29

BMDL at the 95% confidence level = 1423.77

Parameter Estimates

Variable Estimate Default Initial 

Parameter Values

lnalpha -4.03673 -2.36893

rho 1.20539 0.0584431

a 5.6045 5.9829

b 0.000147759 0.0000728823

c 0.446945 0.000503101

d 1.88381 1

Page 241 of 281
Table of Data and Estimated Values of Interest

Dose N Obs Mean Est Mean Obs Std Dev Est Std Dev Scaled Resid

0 45 5.698 5.604 0.4353 0.3755 1.671

156.5 20 5.62 5.602 0.36 0.3754 0.2153

319 20 5.47 5.595 0.25 0.3751 -1.487

660.8 25 5.39 5.566 0.45 0.3739 -2.354

1144 21 5.59 5.497 0.22 0.3711 1.142

2503 24 5.18 5.163 0.35 0.3574 0.2305

5674 25 4.02 4.018 0.21 0.3072 0.03888

9231 8 3.01 3.02 0.39 0.2587 -0.1112

Likelihoods of Interest

Model Log(likelihood) # Param's AIC

A1 104.4887 9 -190.9774

A2 119.1975 16 -206.3949

A3 105.8917 10 -191.7834

R -48.75234 2 101.5047

5 99.71803 6 -187.4361

Tests of Interest

Test -

2*log(Likelihood 

Ratio)

Test df p-value

Test 1 335.9 14 <0.0001

Test 2 29.42 7 0.0001214

Test 3 26.61 6 0.0001712

Test 7a 12.35 4 0.01495

Page 242 of 281
H-1-4 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)

Modela Goodness of fit BMD5RD

(hr mg/L)

BMDL5RD

(hr mg/L)

BMD1SD

(hr mg/L)

BMDL1SD

(hr mg/L)

Basis for model 

selection

p-value AIC

Exponential (M2)

Exponential (M3)b

0.140 27.266 315 223 594 411 The Exponential 

model was selected 

based on lowest AIC.

Exponential (M4) 0.0494 29.191 260 1.16 580 2.61

Exponential (M5) 0.0494 29.191 260 1.30 580 3.07

Hill 0.0597 28.875 58.5 4.71E-04 609 1.98E-05

Powerc

Polynomial 3°d

Polynomial 2°e

Linear

0.138 27.288 323 234 596 421

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
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

BMD = 314.897

BMDL at the 95% confidence level = 223.175

Parameter Estimates

Variable Estimate Default Initial 

Parameter Values

lnalpha -0.768852 -0.811648

rho(S) n/a 0

a 7.38373 6.90878

b 0.000162889 0.000162077

c 0 0

d 1 1

Page 244 of 281
Table of Data and Estimated Values of Interest

Dose N Obs Mean Est Mean Obs Std Dev Est Std Dev Scaled Resid

0 39 7.48 7.384 0.701 0.6808 0.8831

51.18 16 7.03 7.322 0.705 0.6808 -1.718

267.9 15 7.13 7.068 0.695 0.6808 0.3504

633.3 22 6.66 6.66 0.616 0.6808 0.0002752

Likelihoods of Interest

Model Log(likelihood) # Param's AIC

A1 -8.66418 5 27.32836

A2 -8.383601 8 32.7672

A3 -8.66418 5 27.32836

R -18.52227 2 41.04454

2 -10.6328 3 27.26561

Tests of Interest

Test -

2*log(Likelihood 

Ratio)

Test df p-value

Test 1 20.28 6 0.002471

Test 2 0.5612 3 0.9053

Test 3 0.5612 3 0.9053

Test 4 3.937 2 0.1396

Page 245 of 281
H-1-5 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)

Modela Goodness of fit BMD5RD

(hr mg/L)

BMDL5RD

(hr mg/L)

BMD1SD

(hr mg/L)

BMDL1SD

(hr mg/L)

Basis for model selection

p-value AIC

Hill N/Ab -134.67 7497 2302 7695 2361 The Polynomial 3° model 

was selected based on 

lowest AIC. Power 0.371 -136.67 7692 3783 7864 4525

Polynomial 3° 0.572 -138.35 5391 4018 6015 4645

Polynomial 2° 0.307 -137.11 4326 3919 5087 4503

Linear 0.00557 -129.09 2452 1944 3331 2567

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.

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_1*dose + beta_2*dose^2 + ...

A modeled variance is fit

 2.6

 2.8

 3

 3.2

 3.4

 3.6

 0 1000 2000 3000 4000 5000 6000 7000 8000

Mean Response

dose

Polynomial Model, with BMR of 0.05 Rel. Dev. for the BMD and 0.95 Lower Confidence Limit for the BM

14:21 12/10 2014

BMDL BMD

 

Polynomial

Page 246 of 281
Benchmark Dose Computation.

BMR = 5% Relative deviation

BMD = 5390.85

BMDL at the 95% confidence level = 4017.68

Parameter Estimates

Variable Estimate Default Initial 

Parameter Values

lalpha 2.56784 -2.49546

rho -4.31376 0

beta_0 3.49599 3.45

beta_1 -1.68014E-27 0

beta_2 0 -0.000000016108

beta_3 -1.11576E-12 -2.23106E-13

Table of Data and Estimated Values of Interest

Dose N Obs Mean Est Mean Obs Std Dev Est Std Dev Scaled Resid

0 24 3.45 3.5 0.2 0.243 -0.928

588.7 22 3.49 3.5 0.24 0.243 -0.111

2156 23 3.54 3.48 0.29 0.244 1.08

8409 22 2.83 2.83 0.39 0.382 -0.03

Likelihoods of Interest

Model Log(likelihood) # Param's AIC

A1 70.088658 5 -130.177316

A2 75.754919 8 -135.509838

A3 73.734901 6 -135.469801

fitted 73.175965 4 -138.35193

R 37.76879 2 -71.537581

Tests of Interest

Test -

2*log(Likelihood

Ratio)

Test df p-value

Test 1 75.9723 6 <0.0001

Test 2 11.3325 3 0.01006

Test 3 4.04004 2 0.1327

Test 4 1.11787 2 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 DoseResponse Modeling for NMP

Reference and 

endpoint

Dose 

Cmax (mg/L) 

Dose 

AUC (hr mg/L)

Number of 

litters 

Response

Mean ± Standard 

Deviation 

Saillenfait et al., 

2002 and 2003

Resorptions

0 0 45 3.4 ± 7.13

15 156.5 20 4.3 ± 4.1

30 319 20 9.9 ± 22.3

62 660.8 25 7 ± 9.4

120 1144 21 8.9 ± 21.2

250 2503 24 4.5 ± 6.6

531 5674 25 9.4 ± 8.9

831 9231 5 91 ± 16

Sitarek et al., 

2012

fetal mortality

0 0 22 0.18 ± 0.85

76 902 24 0 ± 0

265 3168 20 0.13 ± 0.34

669 8245 15 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 BMC:BMCL (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)

Modela Goodness of fit BMD1RD

(mg/L)

BMDL1RD

(mg/L)

BMD0.5SD

(mg/L)

BMDL0.5SD

(mg/L)

BMD1SD

(mg/L)

BMDL1SD

(mg/L)

Basis for 

model 

selection p-value AIC

Exponential 

(M2)

<0.0001 1288.45 1.60 1.26 424 349 530 468 Of the 

models 

that 

provided 

an 

adequat

e fit and 

a valid 

BMDL 

estimate

the Hill 

model 

was 

selected 

based on 

lowest 

AIC.

Exponential 

(M3)

<0.0001 1263.09 247 97.9 621 510 685 602

Exponential 

(M4)

<0.0001 1364.53 0.122 0.0122 58.2 44.5 116 89.1

Exponential 

(M5)

<0.0001 1265.04 326 215 593 514 648 583

Hill <0.0001 1263.03 429 216 558 514 582 548

Power <0.0001 1263.04 326 215 593 514 648 583

Polynomial 4° <0.0001 1276.48 128 77.6 436 419 518 504

Polynomial 3° <0.0001 1300.17 66.7 55.2 359 345 452 435

Polynomial 2° <0.0001 1336.49 19.2 3.77 247 215 349 317

Linear <0.0001 1362.53 0.121 0.0122 58.2 44.5 116 89.1

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
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*dose^n/(k^n + dose^n)

A modeled variance is fit

Benchmark Dose Computation.

BMR = 1% Relative deviation

BMD = 429.482

BMDL at the 95% confidence level = 215.783

Parameter Estimates

Variable Estimate Default Initial 

Parameter Values

lalpha 4.75575 5.10412

rho 0.150826 0

intercept 6.00954 3.4

v 85.8437 87.6

n 18 1.9286

k 642.982 992.029

Page 250 of 281
Table of Data and Estimated Values of Interest

Dose N Obs Mean Est Mean Obs Std Dev Est Std Dev Scaled Resid

0 45 3.4 6.01 7.13 12.3 -1.42

15.01 20 4.3 6.01 4.1 12.3 -0.619

30.34 20 9.9 6.01 22.3 12.3 1.41

61.86 25 7 6.01 9.4 12.3 0.401

120 22 8.9 6.01 21.2 12.3 1.1

250 24 4.5 6.01 6.6 12.3 -0.599

531 25 9.4 8.67 8.9 12.7 0.29

831 25 91 91 16 15.2 -0.00443

Likelihoods of Interest

Model Log(likelihood) # Param's AIC

A1 -624.644958 9 1267.289916

A2 -570.082153 16 1172.164306

A3 -595.035542 10 1210.071083

fitted -626.515585 5 1263.03117

R -806.807094 2 1617.614189

Tests of Interest

Test -

2*log(Likelihood 

Ratio)

Test df p-value

Test 1 473.45 14 <0.0001

Test 2 109.126 7 <0.0001

Test 3 49.9068 6 <0.0001

Test 4 62.9601 5 <0.0001

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)

Modela Goodness of fit BMD1RD

(hr 

mg/L)

BMDL1RD

(hr mg/L)

BMD0.5SD

(hr mg/L)

BMDL0.5SD

(hr mg/L)

BMD1SD

(hr mg/L)

BMDL1SD

(hr mg/L)

Basis for 

model 

selection p-value AIC

Exponential 

(M2)

<0.0001 1286.

5

19.8 15.8 4281 3524 5543 4887 Of the 

models that 

provided an 

adequate fit 

and a valid 

BMDL 

estimate, the 

Power model 

was selected 

based on 

lowest AIC.

Exponential 

(M3)

<0.0001 1263.

1

2466 901 6721 5432 7486 6504

Exponential 

(M4)

<0.0001 1360.

1

0.720 0.0760 598 473 1196 946

Exponential 

(M5)

<0.0001 1265.

0

3343 2128 6394 5479 7045 6285

Hill <0.0001 1265.

0

4177 2133 6091 5481 6478 5858

Power <0.0001 1263.

0

3343 2128 6394 5479 7045 6285

Polynomial 

4°

<0.0001 1271.

7

1432 135 4827 4537 5741 5534

Polynomial 

3°

<0.0001 1292.

4

743 133 3958 3731 4986 4786

Polynomial 

2°

<0.0001 1329.

7

211 148 2714 2538 3838 3589

Linear <0.0001 1358.

1

0.720 0.0760 598 473 1196 946

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
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 * dose^power

A modeled variance is fit

Benchmark Dose Computation.

BMR = 1% Relative deviation

BMD = 3343.09

BMDL at the 95% confidence level = 2127.52

Parameter Estimates

Variable Estimate Default Initial 

Parameter Values

lalpha 4.75548 5.10412

rho 0.150959 0

control 6.01205 3.4

slope 4.05331E-27 0.0564664

power 7.14249 0.625198

Page 253 of 281
Table of Data and Estimated Values of Interest

Dose N Obs Mean Est Mean Obs Std Dev Est Std Dev Scaled Resid

0 45 3.4 6.01 7.13 12.3 -1.42

156.5 20 4.3 6.01 4.1 12.3 -0.62

319 20 9.9 6.01 22.3 12.3 1.41

660.8 25 7 6.01 9.4 12.3 0.4

1144 22 8.9 6.01 21.2 12.3 1.1

2503 24 4.5 6.02 6.6 12.3 -0.603

5674 25 9.4 8.64 8.9 12.7 0.299

9231 25 91 91 16 15.2 -0.00462

Likelihoods of Interest

Model Log(likelihood) # Param's AIC

A1 -624.644958 9 1267.289916

A2 -570.082153 16 1172.164306

A3 -595.035542 10 1210.071083

fitted -626.519051 5 1263.038102

R -806.807094 2 1617.614189

Tests of Interest

Test -

2*log(Likelihood 

Ratio)

Test df p-value

Test 1 473.45 14 <0.0001

Test 2 109.126 7 <0.0001

Test 3 49.9068 6 <0.0001

Test 4 62.967 5 <0.0001

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 Cmax as 

the Dose Metric (Sitarek et al., 2012)

BMR = 1% Relative Deviation and for Comparison 0.5 and 1 Standard Deviation (SD)

Modela Goodness of fit BMD1RD

(mg/L)

BMDL1RD

(mg/L)

BMD0.5SD

(mg/L)

BMD0.5SD 

(mg/L)

BMD1SD

(mg/L)

BMD1SD 

(mg/L)

Basis for 

model 

selection p-value AIC

Exponential 

(M2)

<0.0001 7701.7 0.0578 0.0403 181 0.341 185 26.4 No models 

provided an 

adequate fit 

and a valid 

BMDL 

estimate, 

therefore no 

model was 

selected.

Exponential 

(M3)

<0.0001 1.8E+17 1.1E+15 1.1E+15 3.9E+15 3.9E+15 3.9E+15 3.9E+15

Exponential 

(M4) errorb error errorb error errorb error

Exponential 

(M5)

N/Ac

errorb error errorb error errorb error

Power <0.0001 4.2143 465 83.1 634 471 658 567

Polynomial 

2°

<0.0001 11.247 31.9 15.0 471 351 666 496

Linear <0.0001 20.871 1.94 4.30E-05 457 241 915 482

Hill N/Ac 8.2143 464 83.2 633 300 658 324

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.

I-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 I-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 acslX 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 

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mg/hr/kg0.75) were used as the seed values for the optimization carried out using the 

optimization routines supplied in acslX (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 doserange 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 I-1).

Figure_Apx I-1 Model Fits to IV Injection Data in Rats

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 I-2). There is no suggestion of extrahepatic (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) GI compartments to describe oral absorption 

following the description from Staats (1991). The resulting model predictions are vastly 

improved (Figure_Apx I-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.

Page 259 of 281
Figure_Apx I-2 Model Fits to Rat Oral PK Data

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, ASK0, 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 I-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 !'NMP IN SKIN, 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 I-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 4.7×10-3 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 μl of neat NMP. According to Payan et al., 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 

4.6×10-3 cm/hr (Figure_Apx I-3), which is consistent with the range of Kp values estimated from 

the in vitro studies (from 2.0 ×10-3 to 7.7 ×10-3cm/hr: (Payan, 2002)). 

Figure_Apx I-3 Model Fits to Dermal PK Data from Payan et al. (2003) in Rats

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 I-4.

Figure_Apx I-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. ASK0 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 ASK0 (mg/day applied) to ASK.

Equation I-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

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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 I-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 I-6 NMP Vapor Exposure Control

CI = CCH*PULSE(0., DOSEINTERVAL,TCHNG) + CIZONE*CONCMG ! MG/L 

! Added CIZONE*CONCMG, PMS, 8-13-13

I-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. 

I-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 

AF1 = 1/Km. These two forms are mathematically identical given the relationship between 

parameters just shown. The affinity constant, AF1, 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-ofdistribution (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 onecompartment 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 I-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)

Page 264 of 281
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 I-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=1e16, hrsweek=24 (Dayswk=1)

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.

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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 TSA is the total body surface area.

TSA 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 I-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 = CI) to the SKL compartment, which 

occurs during periods with no liquid/spray contact for the SKL compartment are similarly:

Equation I-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 VLIQ0 and the density of NMP at 40C (~ skin temperature) = DENSITY 

= 1.02x106 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 I-11 NMP Unabsorbed Fraction Remaining on Skin

DDN = (CONCL - 1.0)*VLIQ0*FAD 

! Subtract 1 mg/L, ~ 1 ppm, from initial conc. to avoid VLIQ --> 0

AH20 = (DENSITY+1.0-CONCL)*VLIQ0 ! ... 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 

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constantly replacing any NMP that is absorbed, keeping the surface concentration essentially 

constant. Therefore the initial volume, VLQ0, 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 vaporabsorption (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
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
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 lowconcentration 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 I-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, AF1, 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 I-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 I-6; details below).

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Figure_Apx I-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-

183 cm).

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Figure_Apx I-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).

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Parameters fitted to group data

for 9.7 and 80 mg/m3 exposures

Average of parameters fit to data for each 

individual separately, primarily 9.7 mg/m3

PV = 1.6 (cm/h)

VK1C = 0.47 (L/(h*kg0.75)) 

AF1 = 0.02 (L/mg) 

VK2C = 0.035 (L/(h*kg0.75))

VOD5HC = 0.26 (L/kg)

KME = 2.3 (L/h)

KUMNE = 0.092 (L/h)

PV = 16.4 (cm/h) 

VK1C = 0.386 (L/(h*kg0.75)) 

AF1 = 0.02 (L/mg) [fixed at group-fit value] 

VK2C = 0.0359 (L/(h*kg0.75)) 

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/L for 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 lowexposure 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 I-1 and 

fits to the individual data shown in Figure_Apx I-7 - Figure_Apx I-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.

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Table_Apx I-1 Estimated PBPK Parameters for Each Subject of the Bader and van Thriel (2006) 

Experiments

Subject VK1C KUMNE PV VK2C KME VOD5HC

1 0.25 0.11 19 0.017 3.2 0.2

4 0.17 0.042 34 0.004 3 0.14

10 0.22 0.069 35 0.027 2.8 0.12

12 0.63 0.046 12 0.044 1.9 0.39

14 0.57 0.2 10 0.08 2.5 0.4

16 0.45 0.06 0 0.08 1.9 0.2

17 0.38 0.2 20 0.02 4.3 0.26

25 0.42 0.1 1.5 0.015 2.4 0.23

average 0.386 0.103 16.4 0.0359 2.75 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.

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Figure_Apx I-7 Model Fits to Subjects 1 and 4 of Bader and van Thriel (2006)

Model fit separately to each subject. See text for details.

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Figure_Apx I-8 Model Fits to Subjects 10 and 12 of Bader and van Thriel (2006)

Model fit separately to each subject. See text for details.

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Figure_Apx I-9 Model Fits to Subjects 14 and 16 of Bader and van Thriel (2006)

Model fit separately to each subject. See text for details.

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Figure_Apx I-10 Model Fits to Subjects 17 and 25 of Bader and van Thriel (2006)

Model fit separately to each subject. See text for details.

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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 I-11).

Figure_Apx I-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 DigitizIt (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 H1) and we did not want a lack-of-fit to the urinary elimination 

Page 278 of 281
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 10-3 cm/hr (with KME = 4.54L/hr). To fit the data from the diluted 

exposures, a lower Kp of 2.87x10-4 was needed (with KME = 2.10 L/hr) (Figure_Apx I-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 I-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 1⁄2 of that identified from the Bader and van Thriel (2006) data (i.e., 

VK1C = 0.193 L/h-kg0.75) with an even smaller exposure to aerosol (0.1 cm2 of exposed skin) 

resulted in simulations that matched the data well (Figure_Apx I-13). The lowest individual 

VK1C estimated for the Bader and van Thriel (2006) data was 0.17 L/h-kg0.75, 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.

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Figure_Apx I-12 Model Fits to Human Dermal Exposure Data of Akesson et al. (2004)

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Figure_Apx I-13 Workplace Observer Simulations Representing Subjects of Xioafei et al. (2000)

*Metabolic elimination was reduced to 1⁄2 that estimated from Bader and van Thriel (2006) data and 

0.1 cm2 of skin was assumed exposed to liquid aerosol.

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