EPA Document# EPA-740-R1-8007
December 2020
Office of Chemical Safety and Pollution Prevention
Environmental Protection Agency
Final Risk Evaluation for
1,4-Dioxane
CASRN: 123-91-1
December 2020
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TABLE OF CONTENTS
TABLE OF CONTENTS 2
LIST OF TABLES 10
LIST OF FIGURES 13
LIST OF APPENDIX TABLES 13
LIST OF APPENDIX FIGURES 16
ACKNOWLEDGEMENTS 19
ABBREVIATIONS 20
EXECUTIVE SUMMARY 26
1 INTRODUCTION 36
1.1 Physical and Chemical Properties 38
1.2 Uses and Production Volume 39
1.3 Regulatory and Assessment History 40
1.4 Scope of the Evaluation 41
1.4.1 Conditions of Use Included in the Risk Evaluation 41
1.4.2 Exposure Pathways and Risks Addressed by Other EPA-Administered Statutes 47
1.4.3 Conceptual Models 56
1.5 Systematic Review 61
1.5.1 Data and Information Collection 61
1.5.2 Data Evaluation 69
1.5.3 Data Integration 70
2 EXPOSURES 72
2.1 Fate and Transport 72
2.2 Environmental Releases 74
2.2.1 Environmental Releases to Water 75
2.2.1.1 Results for Daily Release Estimate 75
2.2.1.2 Approach and Methodology 77
2.2.1.2.1 Water Release Estimates 77
2.2.1.2.2 Estimates of Number of Facilities 78
2.2.1.2.3 Estimates of Release Days 79
2.2.1.3 Assumptions and Key Sources of Uncertainty for Environmental Releases 81
2.2.1.3.1 Summary of Overall Confidence in Release Estimates 82
2.3 Environmental Exposures 88
2.3.1 Environmental Exposures - Aquatic Pathway 88
2.4 Human Exposures 89
2.4.1 Occupational Exposures 89
2.4.1.1 Occupational Exposures Approach and Methodology 91
2.4.1.1.1 Manufacturing 97
2.4.1.1.2 Import and Repackaging 98
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2.4.1.1.3 Recycling 100
2.4.1.1.4 Industrial Uses 101
2.4.1.1.5 Functional Fluids (Open System) 103
2.4.1.1.6 Functional Fluids (Closed System) 106
2.4.1.1.7 Laboratory Chemicals 106
2.4.1.1.8 Film Cement 108
2.4.1.1.9 Spray Foam Application 110
2.4.1.1.10 Printing Inks (3D) 113
2.4.1.1.11 Dry Film Lubricant 115
2.4.1.1.12 Disposal 116
2.4.1.1.13 Dermal Exposure Assessment 117
2.4.2 General Population Exposure 126
2.4.2.1 General Population Exposure Approach 127
2.4.2.1.1 Modeling Surface Water Concentrations 127
2.4.2.1.2 Measured Surface Water Concentrations 129
2.4.2.1.3 Estimating Incidental Oral Exposures from Swimming 129
2.4.2.1.4 Estimating Dermal Exposures from Swimming 130
2.4.2.2 General Population Exposure Results 131
2.4.3 Consumer Exposures 131
2.4.3.1 Consumer Conditions of Use and Routes of Exposure Evaluated 131
2.4.3.2 Consumer Exposure Modeling Approach 132
2.4.3.2.1 Modeling Air Concentrations and Inhalation Exposure 133
2.4.3.2.2 Modeling Dermal Exposure 134
2.4.3.3 Consumer Exposure Scenarios and Modeling Inputs 135
2.4.3.4 Consumer Exposure Results 139
2.4.3.4.1 Surface Cleaner 139
2.4.3.4.2 Antifreeze 140
2.4.3.4.3 Dish Soap 141
2.4.3.4.4 Dishwashing Detergent 142
2.4.3.4.5 Laundry Detergent 144
2.4.3.4.6 Paints and Floor Lacquer 145
2.4.3.4.7 Textile Dye 146
2.4.3.4.8 Spray Polyurethane Foam 147
3 HAZARDS (EFFECTS) 149
3.1 Environmental Hazards 149
3.1.1 Approach and Methodology 149
3.1.2 Weight of Scientific Evidence 151
3.2 Human Health Hazards 153
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3.2.1 Approach and Methodology 153
3.2.2 Toxicokinetics 155
3.2.3 Hazard Identification 159
3.2.3.1 Non-Cancer Hazards 160
3.2.3.2 Genetic Toxicity and Cancer Hazards 167
3.2.4 Potential Modes of Action for 1,4-Dioxane Toxicity 172
3.2.5 Weight of Scientific Evidence 174
3.2.6 Dose-Response Assessment 178
3.2.6.1 Potentially Susceptible Subpopulations 178
3.2.6.2 Points of Departure for Human Health Hazard Endpoints 178
3.2.6.2.1 Acute/Short-term POD for Inhalation Exposures 178
3.2.6.2.2 Acute/Short-term POD for Dermal Exposures Extrapolated from Inhalation Studies
180
3.2.6.2.3 Acute/Short-term POD for Oral Exposures Extrapolated from Inhalation Studies
181
3.2.6.2.4 Chronic Non-Cancer POD for Inhalation Exposures 182
3.2.6.2.5 Chronic Cancer Unit Risk for Inhalation Exposures i.e., Inhalation Unit Risk (IUR)
186
3.2.6.2.6 Chronic Non-Cancer POD for Dermal Exposures Extrapolated from Chronic
Inhalation Studies 188
3.2.6.2.7 Chronic Non-Cancer POD for Dermal Exposures Extrapolated from Chronic Oral
Studies 189
3.2.6.2.8 Chronic Cancer Unit Risk for Dermal Exposures i.e., Cancer Slope Factor (CSF)
extrapolated from Chronic Inhalation Studies 192
3.2.6.2.9 Chronic Cancer Unit Risk for Dermal Exposures i.e., Cancer Slope Factor (CSF)
extrapolated from Chronic Oral Studies 193
3.2.7 Summary of Human Health Hazards 198
4 RISK CHARACTERIZATION 203
4.1 Environmental Risk 203
4.1.1 Risk Estimation Approach of 1,4-Dioxane 204
4.1.2 Risk Estimation for the Aquatic Environment 204
4.1.3 Risk Estimation for the Sediment Environment 209
4.1.4 Risk Estimation for the Terrestrial Environment 210
4.2 Human Health Risk 210
4.2.1 Human Health Risk Estimation Approach 210
4.2.2 Risk Estimate for Exposures for Occupational Use of 1,4-Dioxane 214
4.2.2.1 Occupational Risk Estimation for Effects of Acute/Short-term Inhalation Exposures 214
4.2.2.2 Occupational Risk Estimation for Non-Cancer Effects Following Chronic Inhalation
Exposures 216
4.2.2.3 Occupational Risk Estimation for Cancer Effects Following Chronic Inhalation
Exposures 218
4.2.2.4 Occupational Risk Estimation for Non-Cancer Effects Following Acute/Short-term
Dermal Exposures 221
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4.2.2.5 Occupational Risk Estimation for Non-Cancer Effects Following Chronic Dermal
Exposures 222
4.2.2.6 Occupational Risk Estimation for Cancer Effects Following Dermal Exposures 223
4.2.3 Risk Estimates for Exposures from Consumer Use of 1,4-Dioxane 224
4.2.3.1 Risk Estimation for Inhalation Exposures to 1,4-Dioxane in Consumer Products 224
4.2.3.2 Risk Estimation for Dermal Exposure to 1,4-Dioxane in Consumer Products 226
4.2.4 Risk Estimates for Exposures from Incidental Exposure to 1,4-Dioxane in Surface Water227
4.3 Assumptions and Key Sources of Uncertainty 231
4.3.1 Key Assumptions and Uncertainties in the Occupational Exposure Assessment 231
4.3.2 Key Assumptions and Uncertainties in the Consumer Exposure Estimation 236
4.3.2.1 Confidence in Consumer Exposure Estimates 239
4.3.3 Key Assumptions and Uncertainties in the General Population Exposure 244
4.3.3.1 Confidence in General Population Exposure Estimates 245
4.3.4 Key Assumptions and Uncertainties in Environmental Risk 246
4.3.5 Key Assumptions and Uncertainties in Human Health Hazards 247
4.3.6 Key Assumptions and Uncertainties in the Human Health Risk Characterization 248
4.4 Potentially Exposed or Susceptible Subpopulations (PESS) 249
4.5 Aggregate and Sentinel Exposures 251
4.6 Risk Conclusions 251
4.6.1 Summary of Environmental Risk 251
4.6.2 Summary of Human Health Risk 254
4.6.2.1 Summary of Risk for Workers and ONUs 254
4.6.2.2 Summary of Risk for Consumer Users and Bystanders 265
4.6.2.3 Summary of Risk for the General Population 270
5 RISK DETERMINATION 271
5.1 Overview 271
5.1.1 Human Health 272
5.1.1.1 Non-Cancer Risk Estimates 272
5.1.1.2 Cancer Risk Estimates 273
5.1.1.3 Determining Unreasonable Risk of Injury to Health 273
5.1.2 Environment 275
5.1.2.1 Determining Unreasonable Risk to Injury to the Environment 275
5.2 Detailed Unreasonable Risk Determinations by Condition of Use 275
5.2,1 Human Health 278
5.2.1.1 Manufacture - Domestic Manufacture - Domestic Manufacture 278
5.2.1.2 Manufacture - Import - Import/Repackaging (Bottle and Drum) 279
5.2.1.3 Processing - Repackaging - Repackaging (Bottle and Drum) 280
5.2.1.4 Processing - Recycling 281
5.2.1.5 Processing - Non-incorporative - Basic organic chemical manufacturing (process
solvent) 282
5.2.1.6 Processing - Processing as a reactant - Polymerization catalyst 283
5.2.1.7 Distribution in Commerce 284
5.2.1.8 Industrial Use - Intermediate Use - Agricultural chemical intermediate; Plasticizer
intermediate; Catalysts and reagents for anhydrous acid reactions, brominations and sulfonations
285
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5.2.1.9 Industrial use - Processing aids, not otherwise listed - Wood pulping; Extraction of
animal and vegetable oils; Wetting and dispersing agent in textile processing; Purification of
process intermediates; Etching of fluoropolymers 286
5.2.1.10 Industrial use - Functional fluids, open system - Metalworking fluid; Cutting and
tapping fluid; Polyalkylene glycol fluid 287
5.2.1.11 Industrial/commercial use - Laboratory chemicals - Chemical reagent, reference
material; Spectroscopic and photometric measurement, liquid scintillation counting medium;
Stable reaction medium, cryoscopic solvent for molecular mass determinations; Preparation of
histological sections for microscopic examination 288
5.2.1.12 Industrial/commercial use - Adhesives and sealants - Film cement 289
5.2.1.13 Industrial/commercial use - Other uses - Spray polyurethane foam 290
5.2.1.14 Industrial/commercial use - Other uses - Printing and printing compositions 290
5.2.1.15 Industrial/commercial use - Other uses - Dry film lubricant 291
5.2.1.16 Consumer use - Arts, crafts and hobby materials - Textile dye 292
5.2.1.17 Consumer use - Automotive care products - Antifreeze 293
5.2.1.18 Consumer use - Cleaning and furniture care products - Surface cleaner 294
5.2.1.19 Consumer use - Laundry and dishwashing products - Dish soap 295
5.2.1.20 Consumer use - Laundry and dishwashing products - Dishwasher detergent 295
5.2.1.21 Consumer use - Laundry and dishwashing products - Laundry detergent 296
5.2.1.22 Consumer use - Paints and coatings - Paint and floor lacquer 297
5.2.1.23 Consumer use - Other uses - Spray Polyurethane Foam 298
5.2.1.24 Disposal - Disposal - Wastewater; Underground injection; Landfill; Incineration .... 298
5.2.2 Environment 299
5.3 Changes to the Unreasonable Risk Determination from Draft Risk Evaluation to Final Risk
Evaluation 300
5.4 Unreasonable Risk Determination Conclusion 301
5.4.1 No Unreasonable Risk Determinations 301
5.4.2 Unreasonable Risk Determinations 302
6 REFERENCES 303
APPENDICES 339
Appendix A REGULATORY HISTORY 339
A.l Federal Laws and Regulations..... .................339
A.2 State Laws and Regulations 344
A.3 International Laws and Regulations........................................ 344
Appendix B EXPOSURE SCENARIO MAPPING TO COU 347
Appendix C LIST OF SUPPLEMENTAL DOCUMENTS 358
Appendix D FATE AND TRANSPORT 359
Appendix E ENVIRONMENTAL EXPOSURES 361
Appendix F ENVIRONMENTAL RISK 371
F.l Environmental Risk Tables 371
Appendix G OCCUPATIONAL EXPOSURES 377
G.l Systematic Review Summary Tables.................. ....377
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G. 1.1 Evaluation of Inhalation Data Sources Specific to 1,4-Dioxane 377
G. 1.2 Evaluation of Cross-Cutting Data Sources 382
G.2 Equations for Calculating Acute and Chronic Inhalation Exposures...... ......384
G.3 Sample Calculations for Calculating Acute and Chronic Inhalation Exposures 389
G.3.1 Example High-End ADC and LADC 389
G.3.2 Example Central Tendency ADC and LADC 390
G.4 Modeling Approach and Parameters for High-End and Central Tendency Inhalation Exposure
Estimates for Import and Repackaging, Functional Fluids (Open System), Spray Foam Application,
and Disposal 391
G.4.1 Model Design Equations 391
G.4.2 Model Parameters 393
G.4.3 Sample Monte Carlo Simulation Result 396
G.5 Approach for Estimating the Number of Workers........................ .................396
G.6 Occupational Exposure Scenario Grouping 402
G.6.1 Manufacturing 404
G.6.2 Import and Repackaging 408
G.6.3 Industrial Uses 411
G.6.4 Functional Fluids (Open System) 415
G.6.5 Laboratory Chemical Use 419
G.6.6 Film Cement 421
G.6.7 Spray Foam Application 423
G.6.8 Printing Inks (3D) 427
G.6.9 Dry Film Lubricant 428
G.6.10 Disposal 431
G.7 Dermal Exposure Assessment Method 439
G.7.1 Incorporating the Effects of Evaporation 439
G.7.2 Calculation of fabs 440
G.7.3 Potential for Occlusion 443
G.7.4 Incorporating Glove Protection 444
G.7.5 Proposed Dermal Dose Equation 445
G.7.6 Equations for Calculating Acute and Chronic (Non-Cancer and Cancer) Dermal Doses ....446
Appendix H CONSUMER EXPOSURES 452
I I. 1 Consumer Inhalation Exposure 452
11.1.1 CEM2.1 andCEM... 452
11.1.2 MCCEM 453
H. 1.2.1 MCCEM Inputs for SPF Scenario 455
H.2 Consumer Dermal i-.xposure ....456
H.3 Measured Emission Data........... .................459
H.4 Cl.M Model Sensitivity Analysis Summary.... .....461
H.4.1 Continuous Variables 461
H.4.2 Categorical Variables 464
Appendix I HUMAN HEALTH HAZARDS 465
I.1 Hazard and Data Quality Summary Tables by study duration/endpoint........... ...................465
I.1.1 Hazard and Data Evaluation Summary for Human Studies 465
1.1.2 Hazard and Data Quality Evaluation Summary for Acute and Short-Term Studies 465
1.1.3 Hazard and Data Evaluation Summary for the Developmental Toxicity Study 467
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1.1.4 Hazard and Data Evaluation Summary for Subchronic and Chronic Non-Cancer Studies. .467
1.1.5 Hazard and Data Evaluation Summary for Genotoxicity Studies 472
1.1.6 Data Evaluation Summary for Chronic Cancer Studies 478
1.1.7 Data Evaluation Summary for Mechanistic Studies 485
1.1.8 Hazard Data Tables 493
Appendix J MODE OF ACTION ANALYSIS 499
J.l Introduction .....499
J.2 Potential MGAs of 1,4-Dioxane Liver Carcinogenicity ................... 499
J. 3 MO A analysis for metabolic saturation, cytotoxicity and proliferative regeneration (MOA1) as
the basis for 1,4-dioxane-induced liver carcinogenicity 500
J.3.1 Description of the hypothesized MOA 500
J.3.2 Description of experimental support for the hypothesized MOA 506
J.3.3 Strength, consistency, and specificity of association 506
J.3.4 Dose-response concordance between observed tumors and events in the proposed MOA..508
J.3.5 Temporal relationship 510
J.3.6 Biological plausibility and coherence 511
J.3.7 Consideration of the Possibility of Other MO As 511
J.3.8 Conclusions About the Hypothesized MOA 511
Appendix K BENCHMARK DOSE ANALYSIS 527
K. 1 BMDS Summary of Centrilobular necrosis of the liver in male F344/DuCij rats Kasai et al.
(2009)531
K.2 BMDS Summary of Squamous cell metaplasia of respiratory epithelium in male F433/DuCij
rats Kasai et al. (2009)................... 534
K.3 BMDS Summary of Squamous cell hyperplasia of respiratory epithelium in male F433/DuCrj
rats Kasai et al. (2009).. ......536
K.4 Benchmark dose analysis of respiratory metaplasia of tie olfactory epithelium in the nasal.
cavity of male F344/DuCrj rats Kasai etal. (2009) ...........539
K.5 BMDS Summary of Hydropic change (lamina propria) Kasai et al. (2009)..... .................547
K.6 BMDS Summary of Nasal cavity squamous cell carcinoma (male F344/DuCrj rats) Kasai et al.
(2009)550
K.7 BMDS Summary of Zymbal gland adenoma (male F344/DuCrj rats) Kasai et al. (2009).......552
K.8 MS-Combo portal of entry tumors Kasai et al. (2009) ...........554
K.9 BMDS Summary of Hepatocellular adenoma or carcinoma (male F344/DtiCtj rats) Kasai et al.
(2009)554
K.10 BMDS Summary of Renal cell carcinoma (male F344/DuCrj rats) Kasai et al. (2009).... 556
K. 11 BMDS Summary of Peritoneal mesothelioma (male F344/DuCrj rats) Kasai et al. (2009) .....558
K.12 BMDS Summary of Mammary gland fibroadenoma (male F344/D«Crj rats) Kasai et al. (2009)
560
K. 13 BMDS Summary of Subcutis fibroma (male F344/DuCrj rats, high dose dropped) Kasai et al.
(2009)563
K.14 MS-Combo Systemic (including liver) Kasai et al. (2009) .564
K.15 MS-Combo Systemic (omitting liver) Kasai et al. (2009) ....................565
K.16 MS-Combo portal of entry - systemic (including liver) Kasai et al. (2009) 566
K, 17 MS-Combo porta! of entry systemic (omitting liver) Kasai et al. (2009)...., ....................567
K, 18 BMDS Summary of Hepatocellular mixed foci in male F344/PnCrj rats Kano et al. (2009)..567
K. 19 BMDS Summary of Cortical tubule degeneration in female OM rats NCI (1978) ............570
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K.20 BMDS Summary of Nasal squamous cell carcinoma in Male F344/DnCrj rats Kano et al.
(2009)572
K.21 BMDS Summary of Peritoneum mesothelioma in Male F344/DuCrj rats Kano et al. (2009) .574
K.22 BMDS Summary of Hepatocellular adenoma or carcinoma in Male F344 DuCrj rats Kano et al.
(2009)576
K.23 BMDS Summary of Subcutis fibroma in Male F344/DuCrj rats Kano et al. (2009).......,.. 578
K.24 BMDS Summary of Nasal squamous cell carcinoma in female F344/DuCr] rats Kano et al.
(2009)579
K.25 BMDS Summary of Mammary adenoma in female F344/DuCrj rats Kano et al. (2009) 582
K.26 BMDS Summary of Hepatocellular adenomas or carcinomas female F344/DuCij rats Kano et
al. (2009) ."..... 1. ......583
K.27 BMDS Summary of Hepatocellular adenomas or carcinomas in male CrjBDFl mice Kano et al.
(2009)585
K.28 BMDS Summary of Hepatocellular adenomas or carcinomas in female CrjBDF J mice Kano et
al. (2009) ...588
K.28.1 Time-to-Tumor Modeling with Multistage Weibull Model 589
K.28.2 BMDS Modeling with Poly3 Adjusted Data 596
K.29 BMDS Summary of Nasal cavity tumors in Sherman rats Kociba et al. (1974)................. .601
K.30 BMDS Summary of Liver tumors in Sherman rats (male and female combined) Kociba et al.
(1974)602
K.31 BMDS Summary of Nasal squamous cell carcinomas in female OM rats (MS models) NCI
(1978)604
K.32 BMDS Summary of Hepatocellular adenoma in female OM rats NCI (1978). ..607
K.33 BMDS Summary of Hepatocellular adenomas or carcinomas in male B6C3F1 mice NCI (1978)
609
K.34 BMDS Summary of Hepatocellular adenomas or carcinomas in female B6C3F1 mice NCI
(1978)611
K.35 MS-Combo Result Kano et al. (2009), Male F344/ DuCrj rats, excluding liver .....613
K.36 MS-Combo Result Kano et al. (2009), Male F344/ DuCrj rats, including liver 613
K.37 MS-Combo Result Kano et al (2009), Female F344/ DuCrj rats, excluding liver ............614
K.38 MS-Combo Result Kano et al. (2009), Female F344/ DuCrj rats, including liver .,..615
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LIST OF TABLES
Table 1-1. Physical and Chemical Properties of 1,4-Dioxane 38
Table 1-2. Production Volume of 1,4-Dioxane in Chemical Data Reporting (CDR) Reporting Period
(2012 to 2015) a 39
Table 1-3. Assessment History of 1,4-Dioxane 40
Table 1-4. Categories and Subcategories of Conditions of Use Included in the Scope of the Risk
Evaluation 44
Table 1-5 Categorical Term Sets used in SQL Querying for 1,4-Dioxane consumer assessment 66
Table 1-6 PECO Statement 1,4-Dioxane Consumer Exposure Assessment (September 2020) 68
Table 2-1. Environmental Fate Characteristics of 1,4-Dioxane 72
Table 2-2. Summary of EPA's Daily Water Release Estimates for Each OES and EPA's Overall
Confidence in these Estimates 76
Table 2-3. Summary of EPA's Estimates for the Number of Facilities for Each OES 79
Table 2-4. Summary of EPA's Estimates for Release Days Expected for Each OES 79
Table 2-5 1,4-Dioxane releases in TRI and DMR (2018) 80
Table 2-6. Summary of Overall Confidence in Release Estimates by OES 82
Table 2-7. Assigned Protection Factors for Respirators in OSHA Standard 29 CFR § 1910.134 95
Table 2-8. Manufacturing Worker Exposure Data Evaluation 97
Table 2-9. Acute and Chronic Inhalation Exposures of Worker for Manufacturing Based on Monitoring
Data 98
Table 2-10. Import and Repackaging Data Source Evaluation 99
Table 2-11. Acute and Chronic Inhalation Exposures of Workers for Import and Repackaging Based on
Modeling 100
Table 2-12. Industrial Uses Data Source Evaluation 102
Table 2-13. Acute and Chronic Inhalation Exposures of Worker for Industrial Uses Based on Monitoring
Data 103
Table 2-14. Functional Fluids (Open System) Data Evaluation 104
Table 2-15. Acute and Chronic Inhalation Exposures of Worker for Open System Functional Fluids
Based on Modeling 104
Table 2-16. Acute and Chronic ONU Inhalation Exposures for Open System Functional Fluids Based on
Monitoring Data 105
Table 2-17. Laboratory Chemicals Data Evaluation 107
Table 2-18. Acute and Chronic Inhalation Exposures of Worker for Laboratory Chemicals Based on
Monitoring Data 108
Table 2-19. Film Cement Data Evaluation 109
Table 2-20. Acute and Chronic Inhalation Exposures of Worker for the Use of Film Cement Based on
Monitoring Data 109
Table 2-21. Acute and Chronic ONU Inhalation Exposures for the Use of Film Cement Based on
Monitoring Data 110
Table 2-22. Spray Foam Application Data Source Evaluation Ill
Table 2-23. Acute and Chronic Inhalation Exposures of Worker for Spray Application Based on
Modeling 112
Table 2-24. Acute and Chronic Non-Sprayer Workers Inhalation Exposures for Spray Applications
Based on Modeling 113
Table 2-25. Use of Printing Inks Data Evaluation 114
Table 2-26. Acute and Chronic Inhalation Exposures of Worker for Use of Printing Inks Based on
Monitoring Data 114
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Table 2-27. Dry Film Lubricant Data Source Evaluation 115
Table 2-28. Acute and Chronic Inhalation Exposures of Workers for the Use of Dry Film Lubricant
Based on Exposure Data 116
Table 2-29. Disposal Data Source Evaluation 116
Table 2-30. Acute and Chronic Inhalation Exposures of Worker for Disposal Based on Modeling 117
Table 2-31 IHSkinPerm© Output Data for Various Dermal Exposure Scenarios of 1,4-Dioxane 120
Table 2-32. Exposure Control Efficiencies and Protection Factors for Different Dermal Protection
Strategies 123
Table 2-33. Estimated Dermal Absorbed Dose1 (mg/day) for Workers in Various Conditions of Use. 126
Table 2-34 Modeled Surface Water Concentrations 128
Table 2-35 Incidental Oral Exposure Factors 130
Table 2-36 Dermal Exposure Factors 131
Table 2-37 Models Used Across Consumer Conditions of Use and Routes of Exposure 132
Table 2-38 Default Modeling Input Parameters 136
Table 2-39 Key Product-Specific Inputs for Inhalation Modeling 137
Table 2-40 Key Product-Specific Inputs for Dermal Modeling 138
Table 2-41 Estimated Inhalation Exposure: Surface Cleaner 139
Table 2-42 Estimated Dermal Exposure: Surface Cleaner 140
Table 2-43 Estimated Inhalation Exposure: Antifreeze 141
Table 2-44 Estimated Dermal Exposure: Antifreeze 141
Table 2-45 Estimated Inhalation Exposure: Dish Soap 141
Table 2-46 Estimated Dermal Exposure: Dish Soap 142
Table 2-47 Estimated Inhalation Exposure: Dishwasher Detergent 143
Table 2-48 Estimated Dermal Exposure: Dishwasher Detergent 143
Table 2-49 Estimated Inhalation Exposure: Laundry Detergent 144
Table 2-50 Estimated Dermal Exposure: Laundry Detergent 145
Table 2-51 Estimated Inhalation Exposure: Paints and Floor Lacquer 145
Table 2-52 Estimated Dermal Exposure: Paints and Floor Lacquer 146
Table 2-53 Estimated Inhalation Exposure: Textile Dye 146
Table 2-54 Estimated Dermal Exposure: Textile Dye 147
Table 2-55 Estimated Inhalation Exposure: SPF 147
Table 2-56 Estimated Dermal Exposure: SPF 148
Table 3-1. Acceptable acute aquatic toxicity studies that were evaluated for of 1,4-Dioxane 150
Table 3-2. Concentrations of Concern (COCs) for Aquatic Toxicity 153
Table 3-3. Acceptable Studies Evaluated for Toxicity of 1,4-Dioxane Following Acute or Short-term
Exposure51 162
Table 3-4. Acceptable Studies Evaluated for Non-Cancer Subchronic or Chronic Toxicity of 1,4-
Dioxane Following Inhalation Exposure 163
Table 3-5. Acceptable Subchronic and Chronic Studies Evaluated for Non-Cancer Toxicity of 1,4-
Dioxane Following Oral Exposure 165
Table 3-6. Acceptable New Studies Evaluated for Genetic Toxicity of 1,4-Dioxane 168
Table 3-7. Studies Evaluated for Cancer Following Inhalation Exposure to 1,4-Dioxane 171
Table 3-8. Studies Evaluated for Cancer Following Oral Exposure to 1,4-Dioxane 172
Table 3-9. Model selection and duration-adjusted HEC estimates for BMCLs (from best fitting BMDS
models) or NOAECs/LOAECs from the 2-year inhalation study by Kasai et al. 2009) in
Male F344/DuCrj rats3 185
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Table 3-10. Dose-response modeling summary results for male rat tumors associated with inhalation
exposure to 1,4-dioxane for two years 187
Table 3-11. Dose-response modeling summary results for oral non-cancer liver, kidney, and nasal effects
and route-to-route extrapolated applied dermal HEDs 191
Table 3-12. Cancer slope factor for dermal exposures extrapolated from studies for male rat tumors
associated with inhalation exposure to 1,4-dioxane for two years 193
Table 3-13. Dose-response modeling summary results for oral CSFs and route-to-route extrapolated
dermal CSFs 196
Table 3-14. Summary of Hazard Identification and Dose-Response Values 198
Table 4-1. Environmental Risk Estimation of 1,4-Dioxane from Industrial Releases into Surface Water
from DMR Facilities in Year 2015 and 2016 207
Table 4-2. Environmental Risk Estimation of 1,4-Dioxane from Direct Industrial Releases into Surface
Water from TRI Facilities in Year 2014 and 2015 208
Table 4-3. Environmental Risk Estimation of 1,4-Dioxane from Indirect Industrial Releases into Surface
Water from TRI Facilities in Year 2014 and 2015 209
Table 4-4. Summary of Parameters for Risk Characterization 210
Table 4-5. Acute/Short-term Inhalation Exposure Risk to Workers; Benchmark MOE = 300 215
Table 4-6. Acute/Short-term Inhalation Exposure Risk to Occupational Non-Users: Non-Cancer;
Benchmark MOE = 300 216
Table 4-7. Chronic Inhalation Exposure Risk to Workers: Non-Cancer; benchmark MOE=30 217
Table 4-8. Chronic Inhalation Exposure Risk to Occupational Non-Users: Non-Cancer; Benchmark
MOE = 30 218
Table 4-9. Inhalation Exposure Risk Estimates to Workers: Cancer; Benchmark Risk = 1 x 10"' 219
Table 4-10. Inhalation Exposures to Occupational Non-Users: Cancer; Benchmark Risk = 1 x 10"4.... 220
Table 4-11. Dermal Exposure Risk Estimates to Workers for Acute/Short-term Exposures Non-Cancer;
Liver Toxicity; Benchmark MOE = 300 221
Table 4-12. Dermal Exposure Risk Estimates to Workers: Non-Cancer; Liver Toxicity Benchmark MOE
= 30 222
Table 4-13. Dermal Exposure Risk Estimates to Workers: Cancer; Benchmark Cancer Risk = 1 x 10"4
223
Table 4-14. Risks from Acute Inhalation Exposure to 1,4-Dioxane in Consumer Products; Benchmark
VIOL 300 224
Table 4-15. Risks from Chronic Inhalation Exposure to 1,4-Dioxane in Consumer Products. Benchmark
Cancer Risk = 1 x 10"6 225
Table 4-16. Risks from Acute Dermal Exposure to 1,4-Dioxane in Consumer Products; Benchmark
VIOL 300 226
Table 4-17. Risks from Chronic Dermal Exposure to 1,4-Dioxane in Consumer Products. Benchmark
Cancer Risk = 1 x 10"6 227
Table 4-18. Risk from Acute Oral Exposure Through Incidental Ingestion of Water; Benchmark MOE =
300 227
Table 4-19. Risk from Acute Dermal Exposure from Swimming; Benchmark MOE = 300 229
Table 4-20. Summary and Uncertainty Rating of Occupational Exposure of 1,4-dioxane for Various
Conditions of Use 234
Table 4-21 Overall Confidence Ratings for Consumer Inhalation Exposure Estimates 240
Table 4-22 Overall Confidence Ratings for Consumer Dermal Exposure Estimates 242
Table 4-23. Summary of Human Health Risk From Occupational Exposures 256
Table 4-24. Summary of Human Health Risks from Consumer Exposures 266
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Table 4-25. Summary of Human Health Risks from Incidental Exposure to 1,4-Dioxane in Surface
Waters 270
LIST OF FIGURES
Figure 1-1. 1,4-Dioxane Life Cycle Diagram 43
Figure 1-2. 1,4-Dioxane Conceptual Model for Industrial and Commercial Activities and Uses: Potential
Exposures and Hazards 58
Figure 1-3. 1,4-Dioxane Conceptual Model for Consumer Activities and Uses: Consumer Exposures and
Hazards 59
Figure 1-4. 1,4-Dioxane Conceptual Model for Environmental Releases and Wastes: Potential
Exposures and Hazards 60
Figure 1-5. Literature Flow Diagram for Environmental Fate and Transport Data Sources 63
Figure 1-6. 1,4-Dioxane Literature Flow Diagram for Engineering Releases and Occupational Exposures
64
Figure 1-7. Literature Flow Diagram for Environmental Hazard Data Sources 65
Figure 1-8. Literature Flow Diagram for Human Health Hazard Data Sources 66
Figure 1-9. Literature Flow Diagram for General Population, Consumer and Environmental Exposure
Data Sources 69
Figure 2-1 Environmental transport, partitioning, and degradation processes for 1,4-dioxane 74
Figure 2-2. An Overview of How EPA Estimated Daily Water Releases for Each OES 75
Figure 2-3 Conceptual diagram showing various key factors that influence dermal exposures in the event
of 1,4-dioxane releases (modified after Chattopadhyay and Taft, 2018) 119
Figure 2-4 Flux of 1,4-dioxane across human skin at various exposure conditions 122
Figure 3-1. EPA Approach to Human Health Hazard Identification and Dose-Response for 1,4-Dioxane
154
Figure 3-2. 1,4-Dioxane Metabolism Pathways 159
Figure 6-1. Hypothesized Liver Tumor MOA1 for 1,4-dioxane 502
Figure 6-2. Comparison of dose levels associated with increased incidence of liver tumor and various
liver toxicity responses in 2-year and 13-week drinking water studies in female mice . 510
LIST OF APPENDIX TABLES
Table A-l. Federal Laws and Regulations 339
Table A-2. State Laws and Regulations 344
Table A-3. Regulatory Actions by other Governments and Tribes 344
Table B-l. Industrial and Commercial Occupational Exposure Scenarios for 1,4-Dioxane 347
Table B-2. Environmental Releases and Wastes Exposure Scenarios for 1,4-Dioxane 356
Table E-l. Summary of 1,4-Dioxane TRI Releases to the Environment in 2015 (lbs) 361
Table E-2. Facility Selection Characterization 363
Table E-3. Summary of Modeled Surface Water Concentrations for DMR Facilities 365
Table E-4. Summary of Modeled Surface Water Concentrations for TRI Facilities - Direct 367
Table G-l. Summary of Inhalation Monitoring Data Sources Specific to 1,4-Dioxane 378
Table G-2. Summary of Cross-Cutting Data Sources 382
Table G-3. Representative Worker Exposure Durations Considered for Risk Assessments 386
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Table G-4. Overview of Average Worker Tenure from U.S. Census SIPP (Age Group 50+) 388
Table G-5. Median Years of Tenure with Current Employer by Age Group 389
Table G-6. Summary of Parameter Values and Distributions Used in the Inhalation Exposure Model 394
Table G-7. SOCs with Worker and ONU Designations for All Conditions of Use Except Dry Cleaning
397
Table G-8. SOCs with Worker and ONU Designations for Dry Cleaning Facilities 398
Table G-9. Estimated Number of Potentially Exposed Workers and ONUs under NAICS 812320 399
Table G-10. Occupational Exposure Scenario Groupings 402
Table G-l 1 2017 1,4-Dioxane Production Monitoring Data BASF (2017) 406
Table G-12. 2007-2011 1,4-Dioxane Production Monitoring Data BASF (2016) 406
Table G-l3. 2016 CDR Data and Assumed Container Types for Repackaging 410
Table G-14. Number of Totes and Containers per Site 410
Table G-15. Industrial Use NAICS Codes 413
Table G-16. DoD and 2002 EU Risk Assessment Industrial Use Inhalation Exposure Data 414
Table G-17. 1997 NIOSH HHE PBZ and Area Sampling Data for Metalworking Fluids 417
Table G-l8. 2011 ESD on Metalworking Fluids Inhalation Exposure Estimates 419
Table G-19. Monitoring Data for Laboratory Chemicals 421
Table G-20. NIOSH HHE PBZ and Area Samples for Film Cement Use 423
Table G-21. Values Used for Daily Site Use Rate for SPF Application 425
Table G-22. Estimated Activity Exposure Durations 426
Table G-23. PBZ Task and TWA Monitoring Data for Dry Film Lubricant Manufacture and Spray
Application atKCNSC 430
Table G-24. NAICS Codes with Workers and ONUs for Disposal 436
Table G-25. 2018 TRI Off-Site Transfers for 1,4-Dioxane 438
Table G-26. Estimated Fraction Evaporated and Absorbed (fabs) using Equation G-20 443
Table G-27. Exposure Control Efficiencies and Protection Factors for Different Dermal Protection
Strategies from ECETOC TRA v3 445
Table 1-1. Summary of Mechanistic Data for 1,4-Dioxane 485
Table 1-2. Cancer Incidence for 1,4-Dioxane Studies with Acceptable Data Quality Ratings1 490
Table 1-3. Incidences of non-neoplastic lesions in male F344 rats exposed to 1,4-dioxane via inhalation
for 2 years (6 hours/day, 5 days/week) Kasai et al. (2009) 494
Table 1-4. Altered hepatocellular foci data in F344/DuCrj rats exposed to 1,4-dioxane via drinking
water for 2 years (ad libitum) Kano et al. (2009) 494
Table 1-5. Incidence of cortical tubule degeneration in female Osborne-Mendel rats exposed to 1,4-
dioxane via drinking water for 2 years (ad libitum) NCI (1978) 494
Table 1-6. Tumor incidence data in male F344 rats exposed to 1,4-dioxane via inhalation for 2 years (6
hours/day, 5 days/week) Kasai et al. (2009) 495
Table 1-7. Tumor Incidence data in male and female F344/DuCij rats and Crj:BDFl mice exposed to
1,4-dioxane via drinking water for 2 years (ad libitum) Kano et al. (2009) 496
Table 1-8. Tumor Incidence data in in male and female Sherman rats (combined) exposed to 1,4-dioxane
via drinking water for 2 years (ad libitum) Kociba et al. (1974) 497
Table 1-9. Tumor Incidence data in male and female B6C3F1 mice, and female Osborne-Mendel rats
exposed to 1,4-dioxane via drinking water for 2 years (ad libitum) NCI (1978) 497
Table J-l. Supporting Evidence for Hypothesized Liver Tumor MOA1 for 1,4-dioxane 503
Table J-2. Liver histopathology and plasma enzymes in male F344/DuCrj rats exposed to 1,4-dioxane by
inhalation for 13 weeks Kasai (2008) 512
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Table J-3. Liver histopathology and plasma enzymes in female F344/DuCrj rats exposed to 1,4-dioxane
by inhalation for 13 weeks Kasai (2008) 513
Table J-4. Liver tumors, histopathology and plasma enzymes in male F344/DuCij rats exposed to 1,4-
dioxane by inhalation for 2 years Kasai et al. (2009) 514
Table J-5. Liver histopathology and plasma enzymes in male F344/DuCrj rats exposed to 1,4-dioxane in
drinking water for 13 weeks Kano et al. (2008) 515
Table J-6. Liver tumors and histopathology in male F344/DuCij rats exposed to 1,4-dioxane in drinking
water for 2 years Kano et al. (2009; JBRC (1998) 516
Table J-7. Liver weights, histopathology and plasma enzymes in female F344/DuCrj rats exposed to 1,4-
dioxane in drinking water for 13 weeks Kano et al. (2008) 517
Table J-8. Liver tumors, histopathology, and plasma enzymes in female F344/DuCij rats exposed to 1,4-
dioxane in drinking water for 2 years Kano et al. (2009; JBRC (1998) 518
Table J-9. Liver histopathology and plasma enzymes in male Crj:BDFl mice exposed to 1,4-dioxane in
drinking water for 13 weeks Kano et al. (2008) 519
Table J-10. Liver tumors, histopathology and plasma enzymes in male Cij :BDF1 mice exposed to 1,4-
dioxane in drinking water for 2 years Kano et al. (2009; JBRC (1998) 520
Table J-l 1. Liver weights, histopathology and plasma enzymes in female Cij :BDF1 mice exposed to
1,4-dioxane in drinking water for 13 weeks Kano et al. (2008) 521
Table J-12. Liver tumors, weights, histopathology and plasma enzymes in female Cij:BDFl mice
exposed to 1,4-dioxane in drinking water for 2 years Kano et al. (2009; JBRC (1998). 522
Table J-13. Tumor and histopathology incidence in male Sherman rats exposed to 1,4-dioxane in
drinking water for 2 years Kociba et al. (1974) 523
Table J-14. Tumor and histopathology incidence in female Sherman rats exposed to 1,4-dioxane in
drinking water for 2 years Kociba et al. (1974) 524
Table J-l5. Tumor and histopathology incidence in male B6C3F1 mice exposed to 1,4-dioxane in
drinking water 90 weeks McConnell (2013) reexamination of slides from NCI 1978). 525
Table J-16. Tumor and histopathology incidence in female B6C3F1 mice exposed to 1,4-dioxane in
drinking water 90 weeks McConnell (2013) reexamination of slides from NCI 1978). 526
Table K-l. Summary of BMD Modeling Results for Centrilobular necrosis of the liver in male
F344/DuCrj rats Kasai et al. (2009) 531
Table K-2. Summary of BMD Modeling Results for Squamous cell metaplasia of respiratory epithelium
in male F433/DuCrj rats Kasai et al. (2009) 534
Table K-3. Summary of BMD Modeling Results for Squamous cell hyperplasia of respiratory epithelium
in male F433/DuCrj rats Kasai et al. (2009) 536
Table K-4. Summary of BMD Modeling Results for Hydropic change (lamina propria) Kasai et al.
(2009) 547
Table K-5. Summary of BMD Modeling Results for Nasal cavity squamous cell carcinoma (male
F344/DuCrj rats) Kasai et al. (2009) 550
Table K-6. Summary of BMD Modeling Results for Zymbal gland adenoma (male F344/DuCij rats)
Kasai et al. (2009) 552
Table K-7. Summary of BMD Modeling Results for Hepatocellular adenoma or carcinoma (male
F344/DuCrj rats) Kasai et al. (2009) 554
Table K-8. Summary of BMD Modeling Results for Renal cell carcinoma (male F344/DuCrj rats) Kasai
et al. (2009) 557
Table K-9. Summary of BMD Modeling Results for Peritoneal mesothelioma (male F344/DuCrj rats)
Kasai et al. (2009) 559
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Table K-10. Summary of BMD Modeling Results for Mammary gland fibroadenoma (male F344/DuCrj
rats) Kasai et al. (2009) 561
Table K-l 1. Summary of BMD Modeling Results for Subcutis fibroma (male F344/DuCrj rats, high
dose dropped) Kasai et al. (2009) 563
Table K-12. Summary of BMD Modeling Results for Hepatocellular mixed foci in male F344/DuCrj
rats Kano et al. (2009) 567
Table K-13. Summary of BMD Modeling Results for Cortical tubule degeneration in female OM rats
NCI (1978) 570
Table K-14. Summary of BMD Modeling Results for Nasal squamous cell carcinoma in Male
F344/DuCrj rats Kano et al. (2009) 572
Table K-15. Summary of BMD Modeling Results for Peritoneum mesothelioma in Male F344/DuCrj
rats Kano et al. (2009) 574
Table K-16. Summary of BMD Modeling Results for Hepatocellular adenoma or carcinoma in Male
F344/DuCrj rats Kano et al. (2009) 576
Table K-17. Summary of BMD Modeling Results for Subcutis fibroma in Male F344/DuCrj rats Kano et
al. (2009) 578
Table K-18. Summary of BMD Modeling Results for Nasal squamous cell carcinoma in female
F344/DuCrj rats Kano et al. (2009) 580
Table K-19. Summary of BMD Modeling Results for Mammary adenoma in female F344/DuCrj rats
Kano et al. (2009) 582
Table K-20. Summary of BMD Modeling Results for Hepatocellular adenomas or carcinomas female
F344/DuCrj rats Kano et al. (2009) 584
Table K-21. Summary of BMD Modeling Results for Hepatocellular adenomas or carcinomas in male
CijBDFl mice Kano et al. (2009) 586
Table K-22. Summary of BMD Modeling Results for Nasal cavity tumors in Sherman rats Kociba et al.
(1974) 601
Table K-23. Summary of BMD Modeling Results for Liver tumors in Sherman rats (male and female
combined) Kociba et al. (1974) 603
Table K-24. Summary of BMD Modeling Results for Nasal squamous cell carcinomas in female OM
rats (MS models) NCI (1978) 605
Table K-25. Summary of BMD Modeling Results for Hepatocellular adenoma in female OM rats NCI
(1978) 607
Table K-26. Summary of BMD Modeling Results for Hepatocellular adenomas or carcinomas in male
B6C3F1 mice NCI (1978) 609
Table K-27. Summary of BMD Modeling Results for Hepatocellular adenomas or carcinomas in female
B6C3F1 mice NCI (1978) 611
LIST OF APPENDIX FIGURES
Figure D-l. EPI Suite™ welcome screen set up for 1,4-dioxane model run 359
Figure G-l. Example of Monte Carlo Simulation results for the Disposal Scenario 396
Figure G-2. Generic Manufacturing Process Flow Diagram 404
Figure G-3. General Process Flow Diagram for Import and Repackaging 408
Figure G-4. Generic Industrial Use Process Flow Diagram 411
Figure G-5. Process Flow Diagram for Open System Functional Fluids 416
Figure G-6. General Laboratory Use Process Flow Diagram 420
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Figure G-7. Process Flow Diagram for Film Cement Application 422
Figure G-8. Process Flow Diagram for Spray Application 424
Figure G-9. Process Flow Diagram for Printing Inks (3D) 427
Figure G-10. Process Flow Diagram for Dry Film Lubricant in Nuclear Weapon Applications 429
Figure G-l 1. Typical Waste Disposal Process 433
Figure G-12. Typical Industrial Incineration Process 434
Figure G-13. General Process Flow Diagram for Solvent Recovery Processes 436
Figure H-l. Elasticities (> 0.05) for Parameters Applied in El 462
Figure H-2. Elasticities (> 0.05) for Parameters Applied in E4 463
Figure H-3. Elasticities (> 0.05) for Parameters Applied in P_DER2b 464
Figure K-l. Plot of incidence rate by dose with fitted curve for the unrestricted LogProbit (left) and
restricted LogLogistic (right) models for Centrilobular necrosis of the liver in male
F344/DuCrj rats Kasai et al. (2009); dose shown in ppm. Restricted LogLogistic has the
lowest AIC but exhibits higher residuals for all dose groups 532
Figure K-2. Plot of incidence rate by dose with fitted curve for LogProbit model for Squamous cell
metaplasia of respiratory epithelium in male F433/DuCij rats Kasai et al. (2009); dose
shown in ppm 534
Figure K-3. Plot of incidence rate by dose with fitted curve for Quantal-Linear model for Squamous cell
hyperplasia of respiratory epithelium in male F433/DuCij rats; dose shown in ppm.... 537
Figure K-4. Plot of incidence rate by dose with fitted curve for LogLogistic model for Hydropic change
(lamina propria) Kasai et al. (2009); dose shown in ppm 548
Figure K-5. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for Nasal
cavity squamous cell carcinoma (male F344/DuCij rats) Kasai et al. (2009); dose shown
in ppm 550
Figure K-6. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for Zymbal
gland adenoma (male F344/DuCrj rats) Kasai et al. (2009); dose shown in ppm 552
Figure K-7. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Hepatocellular adenoma or carcinoma (male F344/DuCrj rats) Kasai et al. (2009); dose
shown in ppm 555
Figure K-8. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for Renal
cell carcinoma (male F344/DuCij rats) Kasai et al. (2009); dose shown in ppm 557
Figure K-9. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Peritoneal mesothelioma (male F344/DuCrj rats) Kasai et al. (2009); dose shown in ppm.
559
Figure K-10. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Mammary gland fibroadenoma (male F344/DuCrj rats) Kasai et al. (2009); dose shown in
ppm 561
Figure K-l 1. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Subcutis fibroma (male F344/DuCrj rats, high dose dropped) Kasai et al. (2009); dose
shown in ppm 563
Figure K-12. Plot of incidence rate by dose with fitted curve for LogLogistic model for Hepatocellular
mixed foci in male F344/DuCrj rats Kano et al. (2009); dose shown in mg/kg-d 568
Figure K-13. Plot of incidence rate by dose with fitted curve for Weibull model for Cortical tubule
degeneration in female OM rats NCI (1978); dose shown in mg/kg-d 570
Figure K-14. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 2° model for Nasal
squamous cell carcinoma in Male F344/DuCrj rats Kano et al. (2009); dose shown in
mg/kg-d 572
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Figure K-15. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 2° model for
Peritoneum mesothelioma in Male F344/DuCrj rats Kano et al. (2009); dose shown in
mg/kg-d 574
Figure K-16. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 2° model for
Hepatocellular adenoma or carcinoma in Male F344/DuCij rats Kano et al. (2009); dose
shown in mg/kg-d 576
Figure K-17. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Subcutis fibroma in Male F344/DuCrj rats Kano et al. (2009); dose shown in mg/kg-d.
578
Figure K-18. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for Nasal
squamous cell carcinoma in female F344/DuCrj rats Kano et al. (2009); dose shown in
mg/kg-d 580
Figure K-19. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Mammary adenoma in female F344/DuCrj rats Kano et al. (2009); dose shown in mg/kg-
d 582
Figure K-20. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 2° model for
Hepatocellular adenomas or carcinomas female F344/DuCrj rats Kano et al. (2009); dose
shown in mg/kg-d 584
Figure K-21. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Hepatocellular adenomas or carcinomas in male CrjBDFl mice Kano et al. (2009); dose
shown in mg/kg-d 586
Figure K-22. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 2° model for Nasal
cavity tumors in Sherman rats Kociba et al. (1974); dose shown in mg/kg-d 601
Figure K-23. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for Liver
tumors in Sherman rats (male and female combined) Kociba et al. (1974); dose shown in
mg/kg-d 603
Figure K-24. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for Nasal
squamous cell carcinomas in female OM rats (MS models) NCI (1978); dose shown in
mg/kg-d 605
Figure K-25. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Hepatocellular adenoma in female OM rats NCI (1978); dose shown in mg/kg-d 607
Figure K-26. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Hepatocellular adenomas or carcinomas in male B6C3F1 mice NCI (1978); dose shown
in mg/kg-d 609
Figure K-27. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Hepatocellular adenomas or carcinomas in female B6C3F1 mice NCI (1978); dose shown
in mg/kg-d 611
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ACKNOWLEDGEMENTS
This report was developed by the United States Environmental Protection Agency (U.S. EPA), Office of
Chemical Safety and Pollution Prevention (OCSPP), Office of Pollution Prevention and Toxics (OPPT)
with support from the Office of Research and Development (ORD).
Acknowledgements
The OPPT Assessment Team gratefully acknowledges participation and/or input from Intra-agency
reviewers that included multiple offices within EPA, Inter-agency reviewers that included multiple
Federal agencies, and assistance from EPA contractors GDIT (Contract No. CIO-SP3,
HHSN316201200013W), ERG (Contract No. EP-W-12-006), Versar (Contract No. EP-W-17-006), ICF
(Contract No. EPC14001), Abt (Contract No. EP-W-16-009), and SRC (Contract No. EP-W-12-003).
Docket
Supporting information can be found in public docket: \ 1 iQ-QPPT-201 ->-P"23.
Disclaimer
Reference herein to any specific commercial products, process or service by trade name, trademark,
manufacturer or otherwise does not constitute or imply its endorsement, recommendation or favoring by
the United States Government.
Authors
Stan Barone (Deputy Division Director), Yvette Selby-Mohamadu (Management Lead), Nikki Bass
(Staff Lead), Yousuf Ahmad, Michelle Angrish, Joseph Avcin, Marcy Card, Sandip Chattopadhyay,
Allen Davis, Jeff Dean, Ingrid Druwe, Jeff Gift, Belinda Hawkins, Brandon Huston, Amuel Kennedy,
Nagalakshmi Keshava, Niva Kramek, Albert Monroe, Aaron Murray, Shannon Rebersak, James
Sanders, Stephanie Sarraino, Alan Sasso, John Stanek, Lily Wang, Susanna Wegner, Cindy Wheeler,
Paul White, Jay Zhao.
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ABBREVIATIONS
°C Degrees Celsius
AAL
Allowable Ambient Levels
ACC
American Chemistry Council
ACGM
American Conference of Governmental Industrial Hygienists
ADC
Average Daily Concentration
ADME
Absorption, Distribution, Metabolism, and Elimination
AEC
Acute Exposure Concentration
AEGL
Acute Exposure Guideline Level
AES
Alkyl Ethoxysulphates
AF
Assessment Factor
AIC
Akaike Information Criterion
APF
Assigned Protection Factor
AQS
Air Quality System
ARD
Acute Retained Doses
AT acute
Acute Averaging Time
atm
atmosphere(s)
ATSDR
Agency for Toxic Substances and Disease Registry
AWD
Annual Working Days
BCF
Bioconcentration Factor
BLS
Bureau of Labor Statistics
BMC
Benchmark Concentration
BMCL
Benchmark Concentration Limit
BMD
Benchmark Dose
BMDL
Benchmark Dose Level
BMDS
Benchmark Dose Modeling Software
BMDU
Benchmark Dose Upper bound
BMR
Benchmark Response
BSER
Best System of Emission Reduction
BW
Body Weight
CAA
Clean Air Act
CASRN
Chemical Abstract Service Registry Number
CBI
Confidential Business Information
CCL
Candidate Contaminant List
CCP
Commercial Chemical Product
CDC
Centers for Disease Control and Prevention
CDR
Chemical Data Reporting
CERCLA
Comprehensive Environmental Response, Compensation and Liability Act
CFR
Code of Federal Regulations
CHIRP
Chemical Risk Information Platform
CNS
Central Nervous System
coc
Concentrations of Concern
cou
Condition of Use
CPS
Current Population Survey
CPSC
Consumer Product Safety Commission
CRD
Chronic Retained Doses
CSCL
Chemical Substances Control Law
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CSF
Cancer Slope Factor
CT
Central Tendency
CWA
Clean Water Act
DAF
Dosimetric Adjustment Factor
DHHS
Department of Health and Human Services
DIY
Do It Yourself
DMBA
Dimethylbenz[a]anthracene
DMR
Discharge Munitions Report
DoD
Department of Defense
DOE
Department of Energy
DOEHRS-M
Defense Occupational and Environmental Health Readiness System - Industrial Hygiene
DOT
Deportment of Transportation
EASE
Estimation and Assessment of Substance Exposure
EC50
Effective Median Concentration
EC
European Commission
ECETOC TRA European Centre for Ecotoxicology and Toxicology of Chemicals Targeted Risk
Assessment
ECHA
European Chemicals Agency
ECHO
Enforcement and Compliance History Online
ECJRC
European Commission Joint Research Centre
ED
Exposure Duration
EF
Exposure Frequency
E-FAST
Exposure and Fate Assessment Screening Tool
ELCR
Excess Lifetime Cancer Risk
EPA
Environmental Protection Agency
EPCRA
Emergency Planning and Community Right-to-Know Act
ERG
Eastern Research Group
ESD
Emission Scenario Document
EU
European Union
EUSES
European Union System for the Evaluation of Substances
fabs
Fraction Absorbed
FDA
Food and Drug Administration
FEI
Finnish Environmental Institute
FFDCA
Federal Food, Drug, and Cosmetic Act
FRS
Facility Registry Service
GACT
Generally Available Control Technology
GC-FID
Gas Chromatography with Flame-Ionization Detection
GDIT
General Dynamics Information Technology
GESTIS
Substance Database; contains information for the safe handling of hazardous substances
and other chemical substances at work
GNIS
Geographic Names Information System
GS
Generic Scenarios
HAP
Hazardous Air Pollutant
HE
High End
HEAA
(3-Hydroxyethoxy Acetic Acid
HEC
Human Equivalent Factor
HED
Human Equivalent Dose
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HEEG
Human Exposure Expert Group
Hg
Mercury
HHE
Health Hazard Evaluation
HPLC
High Performance Liquid Chromatography
HPV
High Production Volume
I arc:
International Agency for Research on Cancer
IBC
Intermediate Bulk Container
ICMM
International Council on Mining and Metal
ICRP
International Commission on Radiological Protection
ICSC
International Chemical Safety Cards
IE
Immature Erythrocytes
IF A
Insitut fur Arbeitsschutz der
IGHRC
Interdepartmental Group on the Health Risks of Chemicals
IH
Industrial Hygiene
IHA
Industrial Hygiene Analyses
ILO
International Labor Organization
IRIS
Integrated Risk Information System
IS
Industry Sector
ISHA
Industrial Safety and Health Act
IUR
Inventory Update Reporting Rule; or Inhalation Unit Risk
JR
Juvenile Rat
KCNSC
Kansas City National Security Campus
kg
Kilogram(s)
Koc
Organic Carbon: Water Partition Coefficient
Kow
Octanol: Water Partition Coefficient
LADC
Lifetime Average Daily Concentration
lb
Pound
LC50
50% Lethal Concentration
LEV
Local Exhaust Ventilation
LOAEC
Lowest Observed Adverse Effect Concentration
LOAEL
Lowest Observed Adverse Effect Level
LOD
Limit of Detection
LOEC
Lowest Observed Effect Concentration
Log Kow
Logarithmic Octanol:Water Partition Coefficient
LT
Lifetime Years
MACT
Maximum Achievable Control Technology
MATC
Maximum Acceptable Toxicant Concentration
mg
Milligram(s)
MGD
Million Gallons Per Day
Hg
Microgram(s)
MIR
Maximum Individual Risk
MNH
Micronucleated Hepatocytes
MNIE
Micronucleated Immature Erythrocytes
MOA
Mode of Action
MOE
Margin of Exposure
MP&M
Metal Products and Machinery
MRL
Minimal Risk Level
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MW
Molecular Weight
MWC
Municipal Waste Combustor
MWF
Metalworking Fluids
NAC
National Advisory Committee
NAICS
North American industrial Classification System
NAS
National Academies of Science
NATA
National Air-Toxics Assessment
NCEA
National Center for Environmental Assessment
ND
Non-detect
NEI
National Emissions Inventory
NESHAP
National Emission Standards for Hazardous Air Pollutants
NHD
National Hydrography Dataset
NICNAS
National Industrial Chemicals Notification and Assessment Scheme
NIOSH
National Institute for Occupational Safety and Health
NIST
National Institute of Standards and Technology
NITE
National Institute of Technology and Evaluation
NNSA
National Nuclear Security Administration
NOEC
No Observed Effect Concentration
NOAEL
No Observed Adverse Effect Level
NP
Not Provided
NPDES
National Pollutant Discharge Elimination System
NPL
National Priorities List
NPRI
Canada's National Pollutant Release Inventory
NRC
National Research Council
NSPS
New Source Performance Standards
NTP
National Toxicology Program
NWIS
National Water Information System
OAR
Office of Air and Radiation
OARS
Occupational Alliance for Risk Science
OCF
One Component Foam
OCSPP
Office of Chemical Safety and Pollution Prevention
ODsite
Operating Days per Site
OECD
Organisation for Economic Co-operation and Development
OEHHA
Office of Environmental Health Hazard Assessment (California)
OEL
Occupational Exposure Limit
OES
Occupational Exposure Scenario
OLEM
Office of Land and Emergency Management
ONU
Occupational non-user
OPP
Office of Pesticides Program
OPPT
Office of Pollution Prevention and Toxics
ORD
Office of Research and Development
OSHA
Occupational Safety and Health Administration
OSWER
Office of Solid Waste and Emergency Response
OW
Office of Water
PAPR
Power Air-Purifying Respirator
PBPK
Physiologically Based Pharmacokinetic
PBT
Persistent Bioaccumulative Toxic
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PBZ
Personal Breathing Zone
PDE
Permitted Daily Exposure
PDM
Probabilistic Dilution Model
PEC
Predicted Environmental Concentration
PECO
Populations, Exposures, Comparators, and Outcomes
PEL
Permissible Exposure Limit
PESO
Pathways and Processes, Exposure, Setting or Scenario, and Outcomes
PESS
Potentially Exposed or Susceptible Subpopulations
PF
Protection Factor
PFIA
Problem Formulation and Initial Assessment
PH
Partial Hepatectomy
PNOR
Particulates, Not Otherwise Regulated
POD
Point of Departure
POTW
Publicly Owned Treatment Works
ppb
Parts per Billion
PPE
Personal Protective Equipment
ppm
Parts per Million
PV
Production Volume
PWS
Public Water System
QAPP
Quality Assurance Project Plan
QSAR
Quantitative Structure Activity Relationship
RA
Risk Assessment
RAR
Risk Assessment Report
RCRA
Resource Conservation and Recovery Act
RDF
Refuse-Derived Fuel
REACH
Registration, Evaluation, Authorisation and Restriction of Chemicals
REL
Recommended Exposure Level
RESO
Receptors, Exposure, Setting or Scenario, and Outcomes
RfC
Reference Concentration
RfD
Reference Dose
RGDR
Regional Gas Dose Ratio
RQ
Risk Quotient
SAR
Supplied-Air Respirator
SCBA
Self-Contained Breathing Apparatus
SDS
Safety Data Sheet
SDWA
Safe Drinking Water Act
SIC
Standard Industrial Classification
SIDS
Screening Information Data Set
SIFT-MS
Selected Ion Flow Tube-Mass Spectrometry
SIPP
Survey of Income and Program Participation
SOC
Standard Occupational Classification
SOP
Standard Operation Procedure
SPFs
Spray Polyurethane Foams
SRC
SRC Inc., formerly Syracuse Research Corporation
STEL
Short-term Exposure Limit
STORET
Storage and Retrieval
STP
Sewage Treatment Plants
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SUSB
Statistics of US Businesses
TCA
1,1,1 -Trichloroethane
TIAC
Time Integrated Air Concentration
TLC
Thin-layer Chromatography
TLV
Threshold Limit Value
TO
Toxic Organic
TRI
Toxics Release Inventory
TSCA
Toxic Substances Control Act
TSDF
Treatment, Storage and Disposal Facility
TWA
Time Weighted Average
UCMR
Unregulated Contaminant Monitoring Rule
UF
Uncertainty Factor
US
United States
VCCEP
Voluntary Children's Chemical Evaluation Program
Vc
Container Volume
Vffl
Molar Volume
voc
Volatile Organic Carbon
VP
Vapor Pressure
WEEL
Workplace Environmental Exposure Level
WHO
World Health Organization
WWTP
Wastewater Treatment Plant
WY
Working Year
Yderm
weight fraction of the chemical of interest in the liquid
Yr
Year
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EXECUTIVE SUMMARY
This final risk evaluation for 1,4-dioxane was performed in accordance with the Frank R. Lautenberg
Chemical Safety for the 21st Century Act and is being issued following public comment and peer
review. The Frank R. Lautenberg Chemical Safety for the 21st Century Act amended the Toxic
Substances Control Act (TSCA), the Nation's primary chemicals management law, in June 2016. Under
the amended statute, EPA is required, under TSCA § 6(b), to conduct risk evaluations to determine
whether a chemical substance presents unreasonable risk of injury to health or the environment, under
the conditions of use, without consideration of costs or other non-risk factors, including an unreasonable
risk to potentially exposed or susceptible subpopulations (PESS), identified as relevant to the risk
evaluation. Also, as required by TSCA § (6)(b), EPA established, by rule, a process to conduct these risk
evaluations. Procedures for Chemical Risk Evaluation Under the Amended Toxic Substances Control
Act (82 FR 33726) (Risk Evaluation Rule). This risk evaluation is in conformance with TSCA § 6(b),
and the Risk Evaluation Rule, and is to be used to inform risk management decisions. In accordance
with TSCA Section 6(b), if EPA finds unreasonable risk from a chemical substance under its conditions
of use in any final risk evaluation, the Agency will propose actions to address those risks within the
timeframe required by TSCA. However, any proposed or final determination that a chemical substance
presents unreasonable risk under TSCA Section 6(b) is not the same as a finding that a chemical
substance is "imminently hazardous" under TSCA Section 7. The conclusions, findings, and
determinations in this final risk evaluation are for the purpose of identifying whether the chemical
substance presents unreasonable risk or no unreasonable risk under the conditions of use, in accordance
with TSCA Section 6, and are not intended to represent any findings under TSCA Section 7.
TSCA § 26(h) and (i) require EPA, when conducting risk evaluations, to use scientific information,
technical procedures, measures, methods, protocols, methodologies and models consistent with the best
available science and to base its decisions on the weight of the scientific evidence.1 To meet these TSCA
§ 26 science standards, EPA used the TSCA systematic review process described in the Application of
Systematic Review in TSCA Risk Evaluations document ( 2018b). The data collection, data
evaluation and data integration stages of the systematic review process are used to develop the exposure,
fate and hazard assessments for risk evaluations.
1,4-Dioxane is a clear volatile liquid used primarily as a solvent and is subject to federal and state
regulations and reporting requirements. 1,4-Dioxane has been reportable as a Toxics Release Inventory
(TRI) chemical under Section 313 of the Emergency Planning and Community Right-to-Know Act
(EPCRA) since 1987. It is designated a Hazardous Air Pollutant (HAP) under the Clean Air Act (CAA),
and is a hazardous substance under the Comprehensive Environmental Response, Compensation and
Liability Act (CERCLA). It was listed on the Safe Drinking Water (SDWA) Candidate Contaminant
List (CCL) and identified in the third Unregulated Contaminant Monitoring Rule (UCMR3).
1 Weight of the scientific evidence means a systematic review method, applied in a manner suited to the nature of the
evidence or decision, that uses a pre-established protocol to comprehensively, objectively, transparently, and consistently
identify and evaluate each stream of evidence, including strengths, limitations, and relevance of each study and to integrate
evidence as necessary and appropriate based upon strengths, limitations, and relevance.
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1,4-Dioxane is currently manufactured, processed, distributed, used in industrial and commercial
processes, and disposed of.2 Manufacturing sites produce 1,4-dioxane in liquid form at concentrations
greater than or equal to 90% [EPA-HQ-OPPT-2016-0723-0012; >017)1 and 1,4-dioxane is also
imported. The total annual production volume is approximately 1 million pounds ( 016c).
1,4-Dioxane may also be found as a contaminant in consumer products. It is present as a result of
byproduct formation during manufacture of ethoxylated chemicals that are subsequently formulated into
products. EPA evaluated the following conditions of use: manufacturing; processing; industrial and
commercial use in functional fluids in open and closed systems, laboratory chemicals, adhesives and
sealants (professional film cement), spray polyurethane foam, printing and printing compositions, and
dry film lubricant; consumer use in arts, crafts, and hobby materials (textile dye), automotive care
products (antifreeze), cleaning and furniture care products (surface cleaner), laundry and dishwashing
products (dish soap, dishwasher detergent, laundry detergent), paints and coatings (paint and floor
lacquer), and other uses (spray polyurethane foam); and disposal of waste materials containing 1,4-
dioxane. EPA has exercised its authority in TSCA Section 6(b)(4)(D) to exclude from the scope of this
risk evaluation conditions of use associated with 1,4-dioxane generated as a byproduct in manufacturing,
industrial and commercial uses. While use of 1,4-dioxane as a process solvent and as an intermediate in
the manufacture of pharmaceuticals was included in the problem formulation and draft risk evaluation,
upon further analysis of the details of these processes, EPA has determined that these uses fall outside
TSCA's definition of "chemical substance." Under TSCA § 3(2)(B)(vi), the definition of "chemical
substance" does not include any food, food additive, drug, cosmetic, or device (as such terms are defined
in section 201 of the Federal Food, Drug, and Cosmetic Act) when manufactured, processed, or
distributed in commerce for use as a food, food additive, drug, cosmetic, or device. EPA has concluded
that 1,4-dioxane use as a process solvent and an intermediate during pharmaceutical manufacturing falls
outside TSCA's definition of a chemical substance when used for these purposes. As a result, the use of
1,4-dioxane as a process solvent and an intermediate during pharmaceutical manufacturing are not
included in the scope of this risk evaluation.
Approach
EPA used reasonably available information (defined in 40 CFR 702.33 in part as "information that EPA
possesses, or can reasonably obtain and synthesize for use in risk evaluations, considering the deadlines
. . .for completing the evaluation . . . "), in a fit-for-purpose approach, to develop a risk evaluation that
relies on the best available science and is based on the weight of the scientific evidence. EPA used
previous analyses as a starting point for identifying key and supporting studies to inform the exposure,
fate and hazard assessments. EPA also evaluated other studies that were published since these reviews.
EPA reviewed reasonably available information and evaluated the quality of the methods and reporting
of results of the individual studies using the evaluation strategies described in Application of Systematic
Review in TSCA Risk Evaluations ( 318b). To satisfy requirements in TSCA Section 26(j)(4)
and 40 CFR 702.51(e), EPA has provided a list of studies considered in carrying out the risk evaluation
and the results of those studies are included in the Systematic Review Data Quality Evaluation
Documents (see Appendix C and related supplemental files).
In the problem formulation and draft risk evaluation, EPA identified the conditions of use and presented
two conceptual models and an analysis plan. These have been updated in the final risk evaluation where
EPA has quantitatively evaluated the risk to the environment and human health, using both monitoring
2 Although EPA has identified both industrial and commercial uses here for purposes of distinguishing scenarios in this
analysis, the Agency interprets the authority over "any manner or method of commercial use" under TSCA section 6(a)(5) to
reach both.
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data and modeling approaches, for the conditions of use identified in Section 1.4.1 of this risk
evaluation.3
Exposure
EPA utilized environmental fate parameters, physical-chemical properties, and/or exposure modeling, to
assess environmental exposures through surface water, sediment, and land-applied biosolids. EPA
evaluated these pathways based on a qualitative assessment of the physical-chemical properties and fate
of 1,4-dioxane in the environment for sediment and land-applied biosolids, and a quantitative exposure
analysis for aquatic organisms. While 1,4-dioxane is present in various environmental media such as
groundwater, surface water, and air, EPA determined during problem formulation that no further
analysis beyond what was presented in the problem formulation document would be done for those
environmental exposure pathways in this risk evaluation. However, risk determinations were not made
as part of problem formulation; therefore, the results from these analyses are presented in this risk
evaluation and are used to inform the risk determination section. Environmental exposure analyses and
information are presented in Sections 2.1, 2.3, and Appendix E.
EPA evaluated acute and chronic inhalation exposures to workers and occupational non-users (ONUs),
and acute and chronic dermal exposures to workers in association with 1,4-dioxane for the conditions of
use identified. ONUs are workers at the facility who neither directly perform activities near the 1,4-
dioxane source area nor regularly handle 1,4-dioxane. The job classifications for ONUs could be
dependent on the conditions of use. EPA used inhalation monitoring data that was from literature
sources where reasonably available and that met data evaluation criteria and modeling approaches to
estimate potential inhalation exposures. EPA also estimated dermal doses for workers in these scenarios
since dermal monitoring data were not reasonably available. These analyses are described in Section
2.4.1.
An evaluation of general population exposures via the ambient water pathway is included in Section
2.4.2. EPA evaluated acute, incidental oral and dermal exposures to the general population from
recreational activites (i.e., swimming) in surface waters. EPA modeled releases associated with the
industrial and commercial conditions of use, as well as surface water monitoring data submitted during
the public comment period of the draft risk evaluation.
EPA evaluated acute and chronic inhalation and dermal exposures to consumers through the use of
consumer products that contain 1,4-dioxane as a contaminant. EPA evaluated acute inhalation exposures
to bystanders where such products may be used. These analyses are described in Section 2.4.3. EPA
used reasonably available information obtained through systematic review to estimate dermal and
inhalation exposure levels.
3 EPA did not identify any "legacy uses" (i.e., circumstances associated with activities that do not reflect ongoing or
prospective manufacturing, processing, or distribution) or "associated disposal" (i.e., future disposal from legacy uses) of 1,4-
dioxane, as those terms are described in EPA's Risk Evaluation Rule, 82 FR 33726, 33729 (July 20, 2017). Therefore, no
such uses or disposals were added to the scope of the risk evaluation for 1,4-dioxane following the issuance of the opinion in
Safer Chemicals, Healthy Families v. EPA, 943 F.3d 397 (9th Cir. 2019). EPA did not evaluate "legacy disposal" (i.e.,
disposals that have already occurred) in the risk evaluation, because legacy disposal is not a "condition of use" under Safer
Chemicals, 943 F.3d 397.
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Hazard
In the environmental hazards section, EPA evaluated the reasonably available information and identified
hazard endpoints for aquatic species, including the derivation of acute and chronic concentrations of
concern (COCs) for aquatic species. The environmental hazard evaluation is presented in Section 3.1.
In the human health hazards section, EPA evaluated the reasonably available information and identified
hazard endpoints including acute/chronic toxicity, non-cancer effects, and cancer for inhalation and
dermal exposure for relevant chronic exposures. EPA used an approach based on the Framework for
Human Health Risk Assessment to Inform Decision Making (U.S. EPA. ^ ) to evaluate, extract and
integrate 1,4-dioxane's human health hazard and dose-response information. EPA reviewed key and
supporting information from previous hazard assessments [EPA IRIS Assessments (U.S. EPA. .V
2010). an ATSDR Toxicological Profile A.TSDR (2012). a Canadian Screening Assessment (Health
Canada. ), a European Union (EU) Risk Assessment Report (ECJRC. 2002). and an Interim AEGL
( 2005b)]. EPA also screened and evaluated new studies that were published since these
reviews (i.e., from 2013 - 2018).
EPA developed a hazard and dose-response analysis for inhalation and oral hazard endpoints identified
based on the weight of the scientific evidence considering EPA, National Research Council (NRC), and
European Chemicals Agency (ECHA) risk assessment guidance and selected the points of departure
(POD) for acute/chronic, non-cancer endpoints, and inhalation unit risk and cancer slope factors for
cancer risk estimates. Potential health effects of 1,4-dioxane exposure described in the literature include
effects on the liver, kidneys, respiratory system, neurological endpoints, and cancer. EPA identified
acute PODs for inhalation, dermal and oral exposures based on acute liver toxicity observed in rats
(Mattie et at. 2012). The chronic POD for inhalation exposures are based on effects on the olfactory
epithelium in rats (Kasai et al.. 2009). EPA provided chronic PODs for dermal exposure that
extrapolated from effects on the olfactory epithelium attributed to systemic delivery following exposure
through inhalation (Kasai et al.. 2.009; Kociba et al.. 1974) and from liver toxicity following exposure
through drinking water (Kano et al.. 2009; Nf I < >< iba et al.. 1974). Derivation of PODs is
described in Section 3.2.6. EPA also considered the reasonable available information for potential
modes of action that would support either a threshold approach or a linear non-threshold approach for
estimating cancer risk (Section 3.2.4 and Appendix J). The risk evaluation ultimately calculated cancer
risk with a linear model using cancer slope factors based on evidence of increased risk of cancer in rats
or mice exposed to 1,4-dioxane through air or drinking water (Kano et al.. 2009; Kasai et al.. 2009).
Risk Characterization
For environmental risk, EPA estimated risks based on a qualitative assessment of the physical-chemical
properties and fate of 1,4-dioxane in the environment for sediment and land-applied biosolids, and a
quantitative comparison of hazards and exposures for aquatic organisms. EPA utilized a risk quotient
(RQ) to compare the environmental concentration to the effect level to characterize the risk to aquatic
organisms. Tables 5-2 in this risk evaluation summarizes the RQs for acute and chronic risks of 1,4-
dioxane for aquatic organisms. EPA included a qualitive assessment describing 1,4-dioxane exposure in
sediments and land-applied biosolids. 1,4-Dioxane is not expected to accumulate in sediments and is
expected to be mobile in soil and to migrate to water or volatilize to air. The results of the risk
characterization are in Section 4.1.
EPA evaluated cancer and non-cancer human health risks for occupational and consumer exposures as
well as acute non-cancer health risks from general population exposures. EPA used a Margin of
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Exposure (MOE) approach to identify potential non-cancer human health risks. This approach allows for
a range of risk estimates. EPA estimated potential cancer risk from chronic exposures to 1,4-dioxane by
multiplying inhalation unit risk or dermal cancer slope factors by the chronic exposure levels. Risk
estimates for each COU were compared to benchmark MOEs or cancer risk benchmarks. EPA identified
cancer and non-cancer risks relative to risk benchmarks for acute and chronic inhalation and dermal
occupational exposures for several COUs. EPA did not identify risks relative to benchmarks for
consumers, bystanders or the general population for any of the COUs evaluated. The results of these
analyses are presented in Section 4.2. Unreasonable risk determinations based on these risk estimates are
presented in Section 5.2.
Uncertainties: 1,4-Dioxane is a multi-site carcinogen and may have more than one MO A. There was a
high degree of uncertainty in each of the MOA hypotheses considered in this evaluation (e.g., mutagenic
mode of action or threshold response to cytotoxicity and regenerative hyperplasia for liver tumors).
Chronic non-cancer risk estimates from inhalation exposures were based on effects in the respiratory
tract attributed to systemic delivery. These effects are relevant to inhalation exposures and are more
sensitive than the other observed systemic effects.
Dermal extrapolation and dermal absorption were also sources of uncertainty in the dermal risk
assessment for both dermal cancer and noncancer estimates of risk. Inhalation to dermal and oral to
dermal route-to-route extrapolations were compared for relevance to dermal exposures.
EPA's assessments, risk estimations, and risk determinations account for uncertainties throughout the
risk evaluation. EPA used reasonably available information, in a fit-for-purpose approach, to develop a
risk evaluation that relies on the best available science and is based on the weight of the scientific
evidence. For instance, systematic review was conducted to identify reasonably available information
related to 1,4-dioxane hazards and exposures. If no applicable monitoring data were identified,
exposure scenarios were assessed using a modeling approach that requires the input of various key
process parameters related to 1,4-dioxane and exposure factors. When possible, default model input
parameters were used based on 1,4-dioxane-specific inputs available in the literature. The consideration
of uncertainties supports the Agency's risk determinations, each of which is supported by substantial
evidence, as set forth in detail in later sections of this final risk evaluation. See Section 4.3 for a
discussion of uncertainties.
Potentially Exposed or Susceptible Subpopulations: TSCA § 6(b)(4) requires that EPA conduct a risk
evaluation to "determine whether a chemical substance presents an unreasonable risk of injury to health
or the environment, without consideration of cost or other non-risk factors, including an unreasonable
risk to a potentially exposed or susceptible subpopulation identified as relevant to the risk evaluation by
the Administrator, under the conditions of use." TSCA § 3(12) defines the term "potentially exposed or
susceptible subpopulation" as "a group of individuals within the general population identified by the
Administrator who, due to either greater susceptibility or greater exposure, may be at greater risk than
the general population of adverse health effects from exposure to a chemical substance or mixture, such
as infants, children, pregnant women, workers, or the elderly."
In developing the risk evaluation, the EPA analyzed the reasonably available information to ascertain
whether some human receptor groups may have greater exposure or greater susceptibility than the
general population to the hazard posed by a chemical. Some subpopulations may be more biologically
susceptible to the effects of 1,4-dioxane due to genetic variability, pre-existing health conditions,
lifestage, or other factors that alter metabolism or increase target organ susceptibility. There is limited
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data on reproductive and developmental toxicity and a lack of quantitative information on how genetics,
pre-existing disease, or other factors may contribute to increased susceptibility. For consideration of the
most highly exposed groups, EPA considered 1,4-dioxane exposures to potentially exposed or
susceptible subpopulations of interest, including workers and ONUs, adult and child consumers and
bystanders, and adults and children in the general population who recreate in surface waters receiving
discharges of 1,4-dioxane. EPA's decision for unreasonable risk are based on high-end exposure
estimates for workers and high intensity use scenarios for consumers and bystanders, because these
exposure estimates represent the high-end of exposures expected for PESS. See additional discussions in
Section 4.4.
Aggregate and Sentinel Exposures: Section 2605(b)(4)(F)(ii) of TSCA requires EPA, as a part of the
Risk Evaluation, to describe whether aggregate or sentinel exposures under the conditions of use were
considered and the basis for their consideration. EPA has defined aggregate exposure as "the combined
exposures to an individual from a single chemical substance across multiple routes and across multiple
pathways (40 CFR Section 702.33)." Exposures to 1,4-dioxane were evaluated by inhalation and dermal
routes separately. Inhalation and dermal exposures are assumed to occur simultaneously for workers and
consumers. Dermal and oral exposures are assumed to occur simultaneously for general population
exposures through swimming. EPA chose not to employ simple additivity of exposure pathways within
a condition of use because of the uncertainties present in the current exposure estimation procedures.
EPA defines sentinel exposure as "the exposure to a single chemical substance that represents the
plausible upper bound of exposure relative to all other exposures within a broad category of similar or
related exposures (40 CFR Section 702.33)." In this Risk Evaluation, EPA considered sentinel exposure
the highest exposure given the details of the conditions of use and the potential exposure scenarios.
Sentinel exposures for workers are the high-end scenarios with no assumption of PPE use within each
OES. EPA considered sentinel exposures in this Risk Evaluation by considering risks to populations
who may have upper bound (e.g., high-end, high intensities of use) exposures. EPA's decision for
unreasonable risk are based on high-end exposure estimates to capture individuals with sentinel
exposure.
Additional details on how aggregate and sentinel exposures were considered in this Risk Evaluation are
provided in Section 4.5.
Unreasonable Risk Determination
In each risk evaluation under TSCA Section 6(b), EPA determines whether a chemical substance
presents an unreasonable risk of injury to health or the environment, under the conditions of use. The
determination does not consider costs or other non-risk factors. In making this determination, EPA
considers relevant risk-related factors, including, but not limited to: the effects of the chemical substance
on health and human exposure to such substance under the conditions of use (including cancer and non-
cancer risks); the effects of the chemical substance on the environment and environmental exposure
under the conditions of use; the population exposed (including any potentially exposed or susceptible
subpopulations, as determined by EPA); the severity of hazard (including the nature of the hazard, the
irreversibility of the hazard); and uncertainties. EPA also takes into consideration the Agency's
confidence in the data used in the risk estimate. This includes an evaluation of the strengths, limitations,
and uncertainties associated with the information used to inform the risk estimate and the risk
characterization. The rationale for the unreasonable risk determination is discussed in Section 5.2. The
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Agency's risk determinations are supported by substantial evidence, as set forth in detail in later sections
of this final risk evaluation.
Unreasonable Risk of Injury to the Environment: Based on its physical-chemical properties, 1,4-dioxane
does not partition to or accumulate in sediments and land-applied biosolids. Therefore, EPA determined
that there is no unreasonable risk to terrestrial organisms from all conditions of use. For all conditions of
use, EPA did not identify any exceedances of benchmarks to aquatic organisms from exposures to 1,4-
dioxane in surface waters. Because the concentrations of 1,4-dioxane in sediment pore water from
environmental releases is assumed to be similar to the concentrations of the overlying water, EPA has
determined that 1,4-dioxane does not present an unreasonable risk to aquatic organisms or sediment-
dwelling organisms under the conditions of use. Based on the risk estimates, the environmental effects
of 1,4-dioxane, the exposures, physical-chemical properties of 1,4-dioxane, and consideration of
uncertainties, EPA determined that there is no unreasonable risk of injury to the environment from all
conditions of use of 1,4-dioxane.
Unreasonable Risks of Injury to Health: EPA's determination of unreasonable risk for specific
conditions of use of 1,4-dioxane listed below are based on health risks to workers, ONUs, consumers,
bystanders, and the general population. For acute and chronic exposures to workers and ONUs, EPA
evaluated unreasonable risks for adverse non-cancer effects based on liver toxicity and effects in the
olfactory epithelium, as well as unreasonable risks of cancer from chronic exposures. For acute
exposures to the general population, consumers, and bystanders, EPA evaluated unreasonable risks for
adverse non-cancer effects based on liver toxicity. For chronic exposures to consumers, EPA evaluated
unreasonable risks of cancer.
Unreasonable Risk of Injury to Health of Workers: EPA evaluated non-cancer effects from acute and
chronic inhalation and dermal occupational exposures and cancer from chronic inhalation and dermal
occupational exposures to determine if there was unreasonable risk of injury to workers' health. The
drivers for EPA's determination of unreasonable risk of injury for workers are liver toxicity, olfactory
epithelium effects, and cancer resulting from acute and chronic inhalation exposures and acute and
chronic dermal exposures.
EPA generally assumes compliance with OSHA requirements for protection of workers, including the
implementation of the hierarchy of controls. OSHA's PEL for 1,4-dioxane, established in 1971, is 100
ppm. OSHA has acknowledged that many of the PELs adopted shortly after enactment of the
Occupational Safety and Health Act in 1970 are outdated and inadequate for ensuring protection of
worker health. OSHA provides an annotated list of PELs on its website, including alternate exposure
levels. For 1,4-dioxane, the alternates provided are the California OSHA PEL of 0.28 ppm and the
A.CG1H TLV of 20 ppm. EPA assumes some use of PPE due to these alternate exposure levels. In
support of this assumption, EPA used reasonably available information indicating that some employers,
particularly in the industrial setting, are providing appropriate engineering or administrative controls or
PPE to their employees consistent with these alternate exposure levels. EPA does not have reasonably
available information to either support or contradict this assumption for each condition of use; however,
EPA does not believe that the Agency must presume, in the absence of such information, a lack of
compliance with existing regulatory programs and practices. Rather, EPA assumes there is compliance
with worker protection standards unless case-specific facts indicate otherwise, and therefore the
alternate exposure levels will result in use of appropriate PPE in a manner that achieves the stated APF
or PF. EPA's decisions for unreasonable risk to workers are based on high-end exposure estimates, in
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order to account for the uncertainties related to whether or not workers are using PPE. EPA's approach
for evaluating risk to workers and ONUs is to use the reasonably available information and professional
judgement to construct exposure scenarios that reflect the workplace practices involved in the conditions
of use of the chemicals and addresses uncertainties regarding availability and use of PPE.
For each condition of use of 1,4-dioxane with an identified risk for workers, EPA assumes, as a baseline,
the use of a respirator with an APF of 10 or 50. Similarly, EPA assumes the use of gloves with PF of 10
in commercial settings and gloves with PF of 20 in industrial settings. However, EPA assumes that for
some conditions of use, the use of appropriate respirators is not a standard industry practice, based on
best professional judgement given the burden associated with the use of supplied-air respirators,
including the expense of the equipment and the necessity of fit-testing and training for proper use.
The unreasonable risk determinations reflect the severity of the effects associated with the occupational
exposures to 1,4-dioxane and incorporate consideration of the PPE that EPA assumes. A full description
of EPA's unreasonable risk determination for each condition of use, including the PPE assumptions, is
in Section 5.2.
Unreasonable Risk of Injury to Health of Occupational Non-Users (ONUs): ONUs are workers who do not
directly handle 1,4-dioxane but perform work in an area where 1,4-dioxane is present. EPA evaluated non-
cancer effects to ONUs from acute and chronic inhalation occupational exposures and cancer from chronic
inhalation occupational exposures to determine if there was unreasonable risk of injury to ONUs' health. The
unreasonable risk determinations reflect the severity of the effects associated with the occupational exposures to
1,4-dioxane and the assumed absence of PPE for ONUs, since ONUs do not directly handle the chemical and
are instead doing other tasks in the vicinity of 1,4-dioxane use. Non-cancer effects and cancer from dermal
occupational exposures to ONUs were not evaluated because ONUs are not dermally exposed to 1,4-dioxane.
For inhalation exposures, EPA, where possible, estimated ONUs' exposures and described the risks separately
from workers directly exposed. When the difference between ONUs' exposures and workers' exposures cannot
be quantified, EPA assumed that ONU's inhalation exposures are lower than inhalation exposures for workers
directly handling the chemical substance, and EPA considered the central tendency risk estimate when
determining ONU risk. A full description of EPA's unreasonable risk determination for each condition of use is
in Section 5.2.
Unreasonable Risk of Injury to Health of Consumers: 1,4-Dioxane may be found as a contaminant in
consumer products. It is present as a result of byproduct formation during manufacture of ethoxylated
chemicals that are subsequently formulated into products. In a supplemental analysis, EPA evaluated
eight consumer uses of products that contain 1,4-dioxane as a contaminant to determine if there was
unreasonable risk of injury to consumers' health. For each of the eight conditions of use, EPA evaluated
non-cancer effects to consumers from acute inhalation and dermal exposures. For four of the conditions
of use, based on the exposure assessment, EPA also evaluated cancer risks to consumers from chronic
inhalation and dermal exposures. A full description of EPA's draft unreasonable risk determination for
each condition of use is in Section 5.
Unreasonable Risk of Injury to Bystanders (from consumer uses): In a supplemental analysis, EPA
evaluated hazards and exposures for bystanders from consumer uses of products that contain 1,4-
dioxane as a contaminant. Bystanders include men, women, and children of all ages. Specifically, EPA
evaluated non-cancer effects to bystanders from acute inhalation exposures from eight consumer uses of
products that contain 1,4-dioxane as a contaminant to determine if there was unreasonable risk of injury
33 of 616
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to bystanders' health. EPA did not estimate chronic inhalation exposures to bystanders because
bystanders would be exposed to lower levels than the user based on the model bystander placement in
the home during the product's use. EPA also did not evaluate non-cancer effects from dermal exposures
to bystanders because bystanders are not dermally exposed to 1,4-dioxane. A full description of EPA's
unreasonable risk determination for each condition of use is in Section 5.
Unreasonable Risk of Injury to Health of the General Population: As part of the Problem Formulation
for 1,4-Dioxane (U.S. EPA. 2018c). EPA found that exposures to the general population may occur from
the conditions of use due to releases to air, water or land. During the course of the risk evaluation
process for 1,4-dioxane, OPPT worked closely with the offices within EPA that administer and
implement regulatory programs under the Clean Air Act (CAA), the Safe Drinking Water Act (SDWA),
the Clean Water Act (CWA), the Comprehensive Environmental Response, Compensation, and Liability
Act (CERCLA), and the Resource Conservation and Recovery Act (RCRA). Through this intra-agency
coordinate, EPA determined that 1,4-dioxane exposures to the general population via drinking water,
ambient air and sediment pathways fall under the jurisdiction of other environmental statutes
administered by EPA, i.e., CAA, SDWA, CERCLA, and RCRA. As explained in more detail in section
1.4.2, EPA believes it is both reasonable and prudent to tailor TSCA risk evaluations when other EPA
offices have expertise and experience to address specific environmental media, rather than attempt to
evaluate and regulate potential exposures and risks from those media under TSCA. EPA believes that
coordinated action on exposure pathways and risks addressed by other EPA-administered statutes and
regulatory programs is consistent with the statutory text and legislative history, particularly as they
pertain to TSCA's function as a "gap-filling" statute, and also furthers EPA aims to efficiently use
Agency resources, avoid duplicating efforts taken pursuant to other Agency programs, and meet the
statutory deadlines for completing risk evaluations. EPA has therefore tailored the scope of the risk
evaluations for 1,4-dioxane using authorities in TSCA Sections 6(b) and 9(b)(1). EPA did not evaluate
hazards or exposures to the general population from ambient air, drinking water, and sediment pathways
for any of the conditions of use in this risk evaluation, and as such the unreasonable risk determinations
for relevant conditions of use do not account for exposures to the general population from ambient air,
drinking water, and sediment pathways.
EPA evaluated acute incidental exposures via oral and dermal routes from recreational swimming in
ambient water that receives discharges from the industrial and commercial conditions of use for 1,4-
dioxane. EPA has determined that this activity presents no unreasonable risk to the general population.
In addition, because 1,4-dioxane has low bioaccumulation potential, EPA has determined that fish
consumption does not present an unreasonable risk to the general population.
Summary of Unreasonable Risk Determinations:
In conducting risk evaluations, "EPA will determine whether the chemical substance presents an
unreasonable risk of injury to health or the environment under each condition of use within the scope of
the risk evaluation..." 40 CFR 702.47. Pursuant to TSCA Section 6(i)(l), a determination of "no
unreasonable risk" shall be issued by order and considered to be final agency action. Under EPA's
implementing regulations, "[a] determination by EPA that the chemical substance, under one or more of
the conditions of use within the scope of the risk evaluation, does not present an unreasonable risk of
injury to health or the environment will be issued by order and considered to be a final Agency action,
effective on the date of issuance of the order." 40 CFR 702.49(d).
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EPA has determined that the following conditions of use of 1,4-dioxane do not present an unreasonable
risk of injury to health or the environment. These determinations are considered final agency action and
are being issued by order pursuant to TSCA Section 6(i)(l). The details of these determinations are in
section 5.2, and the TSCA Section 6(i)(l) order is contained in Section 5.4.1 of this final risk evaluation.
Conditions of I so tlisit Do Not Present sin I 11 re;is<>ii;ihie Kisk
• Distribution in commerce
• Industrial/commercial use: Functional Fluids, open system
• Industrial/commercial use: Other uses - Spray polyurethane foam
• Consumer use: Arts, crafts, and hobby materials - Textile dye
• Consumer use: Automotive care products - Antifreeze
• Consumer use: Cleaning and furniture care products - Surface cleaner
• Consumer use: Laundry and dishwashing products - Dish soap
• Consumer use: Laundry and dishwashing products - Dishwasher detergent
• Consumer use: Laundry and dishwashing products - Laundry detergent
• Consumer use: Paints and coatings - Paint and floor lacquer
• Consumer use: Other uses - Spray polyurethane foam
EPA has determined that the following conditions of use of 1,4-dioxane present an unreasonable risk of
injury. EPA will initiate TSCA Section 6(a) risk management actions on these conditions of use as
required under TSCA Section 6(c)(1). Pursuant to TSCA Section 6(i)(2), the unreasonable risk
determinations for these conditions of use are not considered final agency action. The details of these
determinations are in Section 5.2.
M;iniir:Kiiiriiig tlisit Presents 2111 I nresisonsihle Kisk
• Manufacture: Domestic manufacture
• Manufacture: Import/repackaging
Processing tlisit Presents 2111 I nresisonsihle Kisk
• Processing: Repackaging
• Processing: Recycling
• Processing: Non-incorporative
• Processing: Processing as a reactant
IikIlistriiil ;iml (ommercinl I ses tlisit Present 2111 I nresisonsihle Kisk
• Industrial/commercial use: Intermediate
• Industrial/commercial use: Processing aid
• Industrial/commercial use: Laboratory chemicals
• Industrial/commercial use: Adhesives and sealants
• Industrial/commercial use: Printing and printing compositions
• Industrial/commercial use: Dry film lubricant
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Disposal llinl Presents sin I nrcnsonnblc Kisk
• Disposal
1 INTRODUCTION
This document presents the final risk evaluation for 1,4-dioxane under the Frank R. Lautenberg
Chemical Safety for the 21st Century Act. The Frank R. Lautenberg Chemical Safety for the 21st
Century Act amended the Toxic Substances Control Act, the Nation's primary chemicals management
law, in June 2016.
The Agency published the Scope of the Risk Evaluation for 1,4-dioxane (U.S. EPA. 2017e) in June
2017, and the problem formulation in June, 2018 ( 018c). which represented the analytical
phase of risk evaluation in which "the purpose for the assessment is articulated, the problem is defined,
and a plan for analyzing and characterizing risk is determined' as described in Section 2.2 of the
Framework for Human Health Risk Assessment to Inform Decision Matins. The EPA received
comments on the published problem formulation and draft risk evaluation for 1,4-dioxane and has
considered the comments specific to 1,4-dioxane, as well as more general comments regarding the
EPA's chemical risk evaluation approach for developing the risk evaluations for the first 10 chemicals
the EPA is evaluating.
The problem formulation identified the conditions of use and presented two conceptual models and an
analysis plan. In this risk evaluation, EPA evaluated the risk to workers from inhalation and dermal
exposures by comparing the estimated occupational exposures to acute and chronic human health
hazards. While 1,4-dioxane is present in various environmental media such as groundwater, surface
water, and air, EPA determined during problem formulation that no further analysis of the
environmental release pathways via ambient water or land-applied biosolids for aquatic, sediment-
dwelling, and terrestrial organisms was needed based on a qualitative assessment of the physical-
chemical properties and fate of 1,4-dioxane in the environment and a quantitative comparison of hazards
and exposures for aquatic organisms. The result of these preliminary analyses indicated that risks were
not identified for aquatic, sediment-dwelling, or terrestrial organisms. Screening-level analyses can be
conducted with limited data based on high-end exposure assumptions and were used by EPA during
problem formulation to identify which exposure pathways warrant more analysis. These approaches are
being brought forward from the problem formulation to this document to make final risk determinations
because the initial evaluation was sufficient to make these risk determinations.
EPA used reasonably available information consistent with best available science for physical and
chemical properties, environmental fate properties, occupational exposure, environmental hazard, and
human health hazard studies according to the systematic review process. For human exposure pathways,
EPA evaluated inhalation exposures to vapors and mists for workers and occupational non-users and
dermal exposures for skin contact with liquids for workers. For environmental release pathways, EPA
characterized risks to ecological receptors from surface water, sediment, and land-applied biosolids in
36 of 616
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the risk characterization section of this risk evaluation based on the analyses presented in the problem
formulation.
The document is structured such that Introduction, Section 1, presents the basic physical-chemical
properties of 1,4-dioxane, as well as a background on uses, regulatory history, conditions of use and
conceptual models, with emphasis on any changes since the publication of the problem formulation.
Section 1 also includes a discussion of the systematic review process utilized in this risk evaluation.
Exposures, Section 2, provides a discussion and analysis of the exposures, both human and
environmental, based on the conditions of use for 1,4-dioxane. Hazards, Section 2.4.2.1.4, discusses
environmental and human health hazards of 1,4-dioxane. Risk characterization is in Section 4, which
integrates and assesses reasonably available information on human health and environmental hazards
and exposures, as required by TSCA (15 U.S.C 2605(b)(4)(F)). Section 4 also includes a discussion of
any uncertainties and how they impact the risk evaluation. In Risk Determination, Section 5, the agency
presents the determination of whether the chemical presents an unreasonable risk under the conditions of
use, as required under TSCA (15 U.S.C. 2605(b)(4)).
As per EPA's final rule, Procedures for Chemical Risk Evaluation Under the Amended Toxic
Substances Control Act (82. FR 33726). this risk evaluation was subject to both public comment and peer
review, which are distinct but related processes. EPA provided 60 days for public comment on any and
all aspects of this risk evaluation, including the submission of any additional information that might be
relevant to the science underlying the risk evaluation and the outcome of the systematic review
associated with 1,4-dioxane. This satisfied TSCA (15 U.S.C 2605(4)(H)), which requires the EPA to
provide public notice and an opportunity for comment on a risk evaluation prior to publishing a final
risk evaluation.
Peer review was conducted in accordance with EPA's regulatory procedures for chemical risk
evaluations, including using the EPA Peer Review Handbook and other methods consistent with section
26 of TSCA (See 40 CFR § 702.45). As explained in the Risk Evaluation Rule, the purpose of peer
review is for the independent review of the science underlying the risk assessment. Peer review
addressed aspects of the underlying science as outlined in the charge to the peer review panel such as
hazard assessment, assessment of dose-response, exposure assessment, and risk characterization. Peer-
review supports scientific rigor and enhances transparency in the risk evaluation process.
As the EPA explained in the Risk Evaluation Rule, it is important for peer reviewers to consider how the
underlying risk evaluation analyses fit together to produce an integrated risk characterization, which will
form the basis of an unreasonable risk determination. The EPA believes peer reviewers will be most
effective in this role if they receive the benefit of public comments on risk evaluations prior to peer
review. For this reason, and consistent with standard Agency practice, EPA provided the opportunity for
public comment before peer review on this risk evaluation. The final risk evaluation reflects changes in
response to public comments received on the risk evaluation and/or in response to peer review, which
itself may be informed by public comments. The EPA responded to public and peer review comments
received on the risk evaluation in this final risk evaluation and the associated response to comments
document.
In response to peer review and public comment on the draft risk evaluation, EPA added eight consumer
conditions of use not included in the original draft risk evaluation, as well as general population
exposures from recreational swimming in ambient water. EPA performed a supplemental analysis to the
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draft risk evaluation of 1,4-dioxane to evaluate these additional uses and exposures and provided 20
days for public comment on this supplemental analysis. EPA has exercised its authority in TSCA
Section 6(b)(4)(D) to exclude from the scope of this risk evaluation conditions of use associated with
1,4-dioxane generated as a byproduct in manufacturing, industrial and commercial uses.
EPA solicited input on the first 10 chemicals, including 1,4-dioxane, as it developed use dossiers, scope
documents, and problem formulations. At each step, EPA received information and comments specific
to individual chemicals and of a more general nature relating to various aspects of the risk evaluation
process, technical issues, and the regulatory and statutory requirements. EPA has considered comments
and information received at each step in the process and factored in the information and comments as
the Agency deemed appropriate and relevant including comments on the published problem formulation
of 1,4-dioxane.
1.1 Physical and Chemical Properties
1,4-Dioxane is a clear liquid at room temperature and has a cyclic structure with two oxygen molecules
attached at the first and fourth bonds, each with free electrons (U.S. EPA. 2006b). 1,4-Dioxane typically
volatilize based on its high vapor pressure (40 mm Hg at 25 °C) ( ?). 1,4-Dioxane has a
Log Kow value of -0.27, indicating that this chemical is hydrophilic and readily miscible in water (U.S.
EPA. 2009). A summary of the physical and chemical properties of 1,4-dioxane are listed in Table 2-1.
Table 1-1. Physical and Chemical Properties of 1,4-Dioxane
Properly
Value 11
References
Data Quality
Ualing
Molecular formula
C4H8O2
Molecular weight
88.1 g/mole
Havnes et al. (2
High
Physical form
Colorless liquid; ethereal
O'Neil et al. (2001)
High
Melting point
11.75°C
Havnes et al. (2
High
Boiling point
101.1°C
O'Neil et al. (2006)
High
Density
1.0329 g/cm3 at 20°C
O'Neil et al. (2006)
High
Vapor pressure
40 mm Hg at 25°C
Lewis (2000)
High
Vapor density
3.02 (air=l)
Lewis (2
High
Water solubility
>8.00 x 102 g/L at 25°C
Yalkowskv et al. (2010)
High
Octanol:water partition
coefficient (Log Kow)
-0.27
Hansch et al. (1995)
High
Henry's Law constant
4.8 x 10"6 atm-m3/mole at 25°C
4.93 x 10"4 atm-m3/mole at 40°C
Park et al. (1987) as cited
in Sander(2017)
High
38 of 616
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Flash point
18.3°C (open cup)
Larranaea Md (1
High
Autoflammability
180 °C at atmospheric pressure
uso
High
Viscosity
0.0120 cP at 25°C
O'Neil (7
High
Refractive index
1.4224 at 20°C
Havnes et al. (2
High
Dielectric constant
2.209 Farad per meter
Bruno and PDN (2006)
High
"Measured unless otherwise noted
1.2 Uses and Production Volume
The EPA's Chemical" Data Reporting (CDR) database ( ) reported that there were two
manufacturers producing or importing 1,059,980 pounds of 1,4-dioxane in the U.S. in 2015 (see Table
1-2.). The total volume (in lbs.) of 1,4-dioxane manufactured (including imports) in the U.S. from 2012
to 2015 indicates that production has varied over that time. Historically, 90% of 1,4-dioxane production
was used as a stabilizer in chlorinated solvents such as 1,1,1-trichloroethane (TCA) ("ATSDR. 2012;
however, use of 1,4-dioxane has decreased since TCA was phased out by the Montreal Protocol in 1995
NTP. 2011; ECJRC. 2.002). Based on the lack of information on reported uses (Sapphire Group. 2007).
EPA concludes that many other industrial, commercial and consumer uses have also been discontinued.
Table 1-2. Production Volume of 1,4-Dioxane in Chemical Data Reporting (CDR) Reporting
Period (2012 to 2015) a
Reporting Year
2012
2013
2014
2015
Total Aggregate
Production Volume (lbs.)
894,505
1,043,627
474,331
1,059,980
1 The CDR data for the 2016 rcoortinu period is available via ChemView (httDs://iava.eDa.gov/chemview) (U.S. EPA.
2014a). The CDR numbers in Chem View reflect the original submissions for the 2016 reporting period, including one for
which the CBI claim was subsequently released. The CDR data displayed in Chem View are static data and not updated
regularly.
1,4-Dioxane is currently manufactured, processed, distributed and used in industrial processes and for
industrial and commercial uses. Manufacturing sites produce 1,4-dioxane in liquid form at
concentrations greater or equal to 90% [EPA-HQ-OPPT-2016-0723-0012; 017)1 and 1,4-
dioxane is also imported. Industrial processing includes: 1) Processing as a reactant or intermediate, 2)
Non-incorporative processing, 3) Repackaging, and 4) Recycling. Disposal of waste materials
containing 1,4-dioxane is also a condition of use.
The major conditions of use identified for 1,4-dioxane are:
• Use in processing aids (not otherwise listed) (270,000 lbs.),
• Use in functional fluids in open and closed systems (<150,000 lbs.),
• Use in laboratory chemicals (<150,000 lbs.),
• Use in adhesives and sealants (professional film cement),
• Use in spray polyurethane foam,
39 of 616
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• Use in printing and printing compositions,
• Disposal of waste materials containing 1,4-dioxane, and
• Use in dry film lubricant.
1,3 Regulatory and Assessment History
EPA conducted a search of existing domestic and international laws, regulations and assessments
pertaining to 1,4-dioxane. EPA compiled this summary from data available from federal, state,
international and other government sources, as cited in Appendix A.
Federal Laws and Regulations
1,4-Dioxane is subject to federal statutes or regulations, other than TSCA, that are implemented by other
offices within EPA and/or other federal agencies/departments. A summary of federal laws, regulations
and implementing authorities is provided in Appendix A.l.
State Laws and Regulations
1,4-Dioxane is subject to state statutes or regulations. A summary of state laws, regulations and
implementing authorities is provided in Appendix A.2.
Laws and Regulations in Other Countries and International Treaties or Agreements
1,4-Dioxane is subject to statutes or regulations in countries other than the United States and/or
international treaties and/or agreements. A summary of these laws, regulations, treaties and/or
agreements is provided in Appendix A.3.
EPA identified numerous previous assessments conducted within EPA and by other organizations (see
Table 1-3.). Depending on the source, these assessments may include information on conditions of use,
hazards, exposures and potentially exposed or susceptible subpopulations.
Table 1-3. Assessment History of 1,4-Dioxane
Authoring Organization
Assessment
EPA assessments
EPA, Office of Chemical Safety and Pollution
Prevention (OCSPP), Office of Pollution
Prevention and Toxics (OPPT)
TSCA. Work Plan Chemical Problem Formulation.
and Initial Assessment: 1.4-Dioxe N
( )
EPA, National Center for Environmental
Assessment (NCEA)
Toxicological Review of 1.4-Dioxane (With.
Inhalation Update) (CASK (2013d)
EPA, NCEA
Toxicological review c rtoxane (CAS No.
i - n do i o)
EPA, Office of Water (OW)
Drinking Water Health Advisory (2012a)
Other U.S.-based organizations
National Toxicology Program (NTP)
Report on. Carcinogens. Fourteenth Edition. 1.4-
Dioxane(2016)
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Authoring Organization
Assessment
Auencv lor Toxic Substances and Disease Reuislrv
(AT SDR)
lexicological Profile for 1.4-Dioxane (2012)
National Advisory Committee for Acute Exposure
Guideline Levels for Hazardous
Substances (NAC/AEGL Committee)
Interim Acute Exposure Guideline Level
fir! j ilu, ^ _ )
(2005b')
International
International Cooperation on Cosmetics Regulation
Report of the ICCR Working Group:
Considerations on Acceptable Tra ^ t el ot 14
Dioxane in Cosmet nets (2017)
International Agency for Research on Cancer
(IARC)
IARC Monographs on the Evaluation of
Carcinogenic Risks to Humans Volui ( 9)
Government of Canada, Environment Canada,
Health Canada
Screening Assessment for the Challenge. 1.4-
Dioxane \ 1 4 J'- I i ,2010)
Research Center for Chemical Risk Management,
National Institute of Advanced Industrial Science
and Technology, Japan
Estimating Health Risk from Exposin
Dioxane in Japan (2006)
World Health Organisation (WHO)
ane in Drinking-water (2.005)
Employment, Social Affairs, and Inclusion,
European Commission (EC)
Recommendation from the Scient mmittee
on Occupational Expo: nits for 1.4-dioxane
(2004)
European Chemicals Bureau, Institute for Health
and Consumer Protection
European Union Risk Assessment Report. 1,4-
dioxane. CASK )4-
661-8. (2.002)
National Industrial Chemicals Notification and
Assessment Scheme (NICNAS), Australian
Government
1 4-Dioxane * uoutv Existing Chemical No. 7.
Full Public Rep ( 98)
Organisation for Economic Co-operation and
Development (OECD), Screening Information
Data Set (SIDS)
ane. SIDS initial assessment profile
( 9)
1.4 Scope of the Evaluation
Conditions of Use Included in the Risk Evaluation
TSCA Section 3(4) defines the conditions of use as "the circumstances, as determined by the
Administrator, under which a chemical substance is intended, known, or reasonably foreseen to be
manufactured, processed, distributed in commerce, used, or disposed of." The conditions of use are
described below in Table 1-4..
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Information on additional conditions of use was submitted to EPA during the public comment period for
the problem formulation and noted in the draft risk evaluation. Specifically, EPA received information
indicating that the Department of Energy's Kansas City National Security Campus uses 1,4-dioxane as a
constituent of a dry film lubricant in the manufacture of components for weapons systems. Although not
reflected in the scope or problem formulation, this condition of use is included in this final risk
evaluation.
As explained in the scope document for 1,4-dioxane, EPA anticipates the production of 1,4-dioxane as a
byproduct from ethoxylation of other chemicals and presence as a contaminant in industrial, commercial
and consumer products. In particular, 1,4-dioxane may be produced as a reaction byproduct in chemicals
produced through ethoxylation, including alkyl ether sulphates (AES, anionic surfactants) and other
ethoxylated substances, such as alkyl, alkylphenol and fatty amine ethoxylates; polyethylene glycols and
their esters; and sorbitan ester ethoxylates. 1,4-Dioxane may also be present at residual concentrations in
commercial and consumer products that contain ethoxylated chemicals. Examples of products
potentially containing 1,4-dioxane as a residual contaminant are paints, coatings, lacquers, ethylene
glycol-based antifreeze coolants, spray polyurethane foam, household detergents, cosmetics/toiletries,
textile dyes, foods, agricultural and veterinary products (ATSDR. 2012; Health Canada. 201 ^ {]±\
2.007; ECJRC. 2002).4 In the Draft Risk Evaluation for 1.4-Dioxane. the manufacture of 1,4-dioxane as a
byproduct from ethoxylation of other chemicals, use and disposal of 1,4-dioxane at residual
concentrations in industrial, commercial and consumer products containing ethoxylated chemicals were
excluded from the scope of the risk evaluation.
EPA received peer review and public comments regarding consumer use of materials containing 1,4
dioxane as byproducts, and in response made a policy decision to expand the scope of the risk evaluation
to include consumer COUs. EPA added eight consumer conditions of use not included in the original
draft risk evaluation, as well as general population exposures from recreational swimming in ambient
water. EPA performed a supplemental analysis to the draft risk evaluation of 1,4-dioxane to evaluate
these additional uses and exposures. For each of the eight uses, EPA evaluated non-cancer effects to
consumers from acute inhalation and dermal exposures. For four of the products, based on the exposure
assessment, EPA also evaluated cancer risks to consumers from chronic inhalation and dermal
exposures. EPA will consider other conditions of use where 1,4-dioxane is a byproduct as part of the
future risk evaluations for chemicals that produce it as byproduct.
4 However, under TSCA § 3(2)(B)(vi), the definition of "chemical substance" does not include any food, food additive, drug,
cosmetic, or device (as such terms are defined in section 201 of the Federal Food, Drug, and Cosmetic Act) when
manufactured, processed, or distributed in commerce for use as a food, food additive, drug, cosmetic, or device.
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MFG/IMPORT
PROCESSING
INDUSTRIAL, COMMERCIAL, CONSUMER USES*
RELEASES and WASTE DISPOSAL
Manufacture
(Includes Import)
(1 million lbs.)
Processing as a
Reactant/lntermediate
(Not reported in 2016 CDR)
Repackaging
(270,000 lbs,)
Non-incorporative
Activities
(270,000 lbs.)
Recycling
Processing Aids, Not Otherwise
Listed
(270,000 lbs,)
e.g., wood pulping, etching of
fluoropolymers
Functional Fluids
(Open and Closed Systems)
(<150,000 lbs.)
e.g., hydraulic fluid.
Disposal
Laboratory Chemicals
(<150,000 lbs.)
e.g., laboratory reagent
Adhesives and Sealants
e.g. film cement
Other Uses
e.g., spray polyurethane foam; printing
and printing compositions; dry film
lubricant
See Figure 2-3 for Environmental Releases
and Wastes
Intended industrial uses
Industrial and/or commercial uses
Processing
Manufacture (Includes Import)
Figure 1-1. 1,4-Dioxane Life Cycle Diagram
The life cycle diagram depicts the conditions of use that are within the scope of the risk evaluation during various life cycle stages including
manufacturing, processing, use (industrial or commercial) and disposal. The production volumes shown are for reporting year 2015 from the
2016 CDR reporting period (U.S. EPA. 2016c).
a See Table 1-4. for additional uses that are not mentioned specifically in this diagram, including consumer conditions of use that were evaluated for 1,4-dioxane present
as a byproduct.
-------
Table 1-4. Categories and Subcategories of Conditions of Use Included in the Scope of the
Risk Evaluation
l.il'e Cycle Stage
Category 11
S ii beat ego rv h
References
Manufacture
Domestic manufacture
Domestic manufacture
Use document,
HO-OPPT-2
0723-0003; Public
Comment, EPA-HQ;
OPPT-2016-0723-
0012
Import
Import
Use document i'P V
HG-OPPT-20 k<-
072.3-0003
Repackaging
Public Comment,
EP A-HO-OPPT -
20 l_o;0 A2AaV 1 -
Processing
Processing as a
reactant
Polymerization catalyst
Use document,
HO-OPI
0723-0003
Non-incorporative
Basic organic chemical
manufacturing
(process solvent)
Public Comment,
EP A-HO-OPPT -
2 23-0012
Recycling
Recycling
> * i p \ 0
Distribution in
commerce
Distribution
Distribution
Use document, EPA-
HO-OPI
0723-0003
Industrial use
Intermediate use
Plasticizer intermediate
Use document,
HO-OPPT-2
0723-0003
Catalysts and reagents for
anhydrous acid reactions,
brominations and
sulfonations
Use document, i 'P \-
HO-OPPT-2016-
0723-0003
Processing aids, not
otherwise listed
Wood pulping0
Use document,
HO-OPPT-2
0723-0003
Extraction of animal and
vegetable oils0
Use document,
HO-OPI
072.3-0003
44 of 616
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1 -ile ( vole Slsigc
CiiU'gorv 11
Siihcsilcgorv h
UcTcitikts
Welling and dispersing
agent in textile processing0
I sc document.
HO-OPPT-2
0723-0003
Polymerization catalyst
Use document, EPA-
HO-OPPT-2016-0723-
0003
Purification of process
intermediates
Use document, EPA-
HO-OPPT-2016-0723-
0003
Etching of fluoropolymers
Public Comment,
EP A-HO-OPPT -
2 23-0012
Functional fluids
(open and closed
system)
Polyalkylene glycol
lubricant
Use document,
HO-OPI
072.3-0003
Synthetic metalworking
fluid
Use document k'PV
HQ-QPPT-20 k<-
072.3-0003
Cutting and tapping fluid
Use document,
HO-OPI
0723-0003
Hydraulic fluid
Use document,
HO-OPPT-2
0723-0003
Industrial use,
potential commercial
use
Laboratory chemicals
Chemical reagent
Use document,
HO-OPPT-2016-
0723-0003; Public
Comment. EPA-HO-
OPPT-21 23-
0009
Reference material
Use document,
HO-OPI
0723-0003
Spectroscopic and
photometric measurement
Use document,
HO-OPPT-2
0723-0003; Public
Comment, EPA-HQz
OPPT-2016-0723-
0009
Liquid scintillation
counting medium
Use document i'P V
HO-OPPT-20 k-
072.3-0003
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1 -ile ( vole Slsigc
CiiU'gorv 11
Siihcsilcgorv h
UcTcitikts
Siahlc reaction medium
I sc document.
HO-OPPT-2
0723-0003
Cryoscopic solvent for
molecular mass
determinations
Use document,
HO-OPI
0723-0003
Preparation of histological
sections for microscopic
examination
Use document, t 'P V
HG-QPPI-2016-
0723-0003
Adhesives and
sealants
Film cement
Use document,
HO-OPPT-2016-
0723-0003; Public
Comment. EPA-HO-
OPPT-21 23-
0021
Other uses
Spray polyurethane foam
Printing and printing
compositions, including
3D printing
Dry film lubricant
Use document,
HO-OPI
0723-0003; Public
Comment, EPA-HO-
OPPT-21 23-
00! 2
Consumer uses
Paints and Coatings
Latex Wall Paint or Floor
Lacquer
TSCA Work Plan
Chemical Problem
Cleaning and
Furniture Care
Products
Surface Cleaner
Formulation and
Initial Assessment:
1.4-Dioxane
fCASRN 193-91-'H
Laundry and
Dishwashing Products
Dish Soap
Dishwasher Detergent
Laundry Detergent
| v/ri.ul\i i 1 £* J .y 1 1 |
(2015)
Arts, Crafts and
Hobby Materials
Textile Dye
Automotive Care
Products
Antifreeze
Other Consumer Uses
Spray Polyurethane Foam
Disposal
Disposal
Industrial pre-treatment
^ r M> \ -v„!0 i V)
Industrial wastewater
treatment
Publicly owned treatment
works (POTW)
Underground injection
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Life ("vole S(a«e
Ciilegorv 11
Subcategory h
References
Municipal landfill
Hazardous landfill
Other land disposal
Municipal waste
incinerator
Hazardous waste
incinerator
Off-site waste transfer
a These categories of conditions of use appear in the initial life cycle diagram, reflect CDR codes and broadly
represent conditions of use for 1,4-dioxane in industrial and/or commercial settings.
b These subcategories reflect more specific uses of 1,4-dioxane.
0 These uses were evaluated but are no longer current uses of 1,4-dioxane.
1.4.2 Exposure Pathways and Risks Addressed by Other EPA-Administered
Statutes
In its TSCA Section 6(b) risk evaluations, EPA is coordinating action on certain exposure
pathways and risks falling under the jurisdiction of other EPA-administered statutes or regulatory
programs. More specifically, EPA is exercising its TSCA authorities to tailor the scope of its risk
evaluations, rather than focusing on environmental exposure pathways addressed under other
EPA-administered statutes or regulatory programs or risks that could be eliminated or reduced to
a sufficient extent by actions taken under other EPA-administered laws. EPA considers this
approach to be a reasonable exercise of the Agency's TSCA authorities, which include:
TSCA Section 6(b)(4)(D): "The Administrator shall, not later than 6 months after the
initiation of a risk evaluation, publish the scope of the risk evaluation to be conducted, including
the hazards, exposures, conditions of use, and the potentially exposed or susceptible
subpopulations the Administrator expects to consider.
TSCA Section 9(b)(1): "The Administrator shall coordinate actions taken under this
chapter with actions taken under other Federal laws administered in whole or in part by the
Administrator. If the Administrator determines that a risk to health or the environment associated
with a chemical substance or mixture could be eliminated or reduced to a sufficient extent by
actions taken under the authorities contained in such other Federal laws, the Administrator shall
use such authorities to protect against such risk unless the Administrator determines, in the
Administrator's discretion, that it is in the public interest to protect against such risk by actions
taken under this chapter."
TSCA Section 9(e): "[I]f the Administrator obtains information related to exposures or
releases of a chemical substance or mixture that may be prevented or reduced under another
Federal law, including a law not administered by the Administrator, the Administrator shall
make such information available to the relevant Federal agency or office of the Environmental
Protection Agency."
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TSCA Section 2(c): "It is the intent of Congress that the Administrator shall carry out this
chapter in a reasonable and prudent manner, and that the Administrator shall consider the
environmental, economic, and social impact of any action the Administrator takes or proposes as
provided under this chapter."
TSCA Section 18(d)(1): "Nothing in this chapter, nor any amendment made by the Frank
R. Lautenberg Chemical Safety for the 21st Century Act, nor any rule, standard of performance,
risk evaluation, or scientific assessment implemented pursuant to this chapter, shall affect the
right of a State or a political subdivision of a State to adopt or enforce any rule, standard of
performance, risk evaluation, scientific assessment, or any other protection for public health or
the environment that— (i) is adopted or authorized under the authority of any other Federal law
or adopted to satisfy or obtain authorization or approval under any other Federal law.
TSCA authorities supporting tailored risk evaluations and intra-agency referrals
TSCA Section 6(b)(4)(D)
TSCA Section 6(b)(4)(D) requires EPA, in developing the scope of a risk evaluation, to identify
the hazards, exposures, conditions of use, and potentially exposed or susceptible subpopulations
the Agency "expects to consider" in a risk evaluation. This language suggests that EPA is not
required to consider all conditions of use, hazards, or exposure pathways in risk evaluations.
In the problem formulation documents for many of the first 10 chemicals undergoing risk
evaluation, EPA applied this authority and rationale to certain exposure pathways, explaining
that "EPA is planning to exercise its discretion under TSCA 6(b)(4)(D) to focus its analytical
efforts on exposures that could present the greatest concern and consequently merit a risk
evaluation under TSCA, by excluding, on a case-by-case basis, certain exposure pathways that
fall under the jurisdiction of other EPA-administered statutes." This approach is informed by the
legislative history of the amended TSCA, which supports the Agency's exercise of discretion to
focus the risk evaluation on areas that raise the greatest potential for risk. See June 7, 2016 Cong.
Rec., S3519-S3520. Consistent with the approach articulated in the problem formulation
documents, and as described in more detail below, EPA is exercising its authority under TSCA
to tailor the scope of exposures evaluated in TSCA risk evaluations, rather than focusing on
environmental exposure pathways addressed under other EPA-administered, media-specific
statutes and regulatory programs.
TSCA Section 9(b)(1)
In addition to TSCA Section 6(b)(4)(D), the Agency also has discretionary authority under the
first sentence of TSCA Section 9(b)(1) to "coordinate actions taken under [TSCA] with actions
taken under other Federal laws administered in whole or in part by the Administrator." This
broad, freestanding authority provides for intra-agency coordination and cooperation on a range
of "actions." In EPA's view, the phrase "actions taken under [TSCA]" in the first sentence of
section 9(b)(1) is reasonably read to encompass more than just risk management actions, and to
include actions taken during risk evaluation as well. More specifically, the authority to
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coordinate intra-agency actions exists regardless of whether the Administrator has first made a
definitive finding of risk, formally determined that such risk could be eliminated or reduced to a
sufficient extent by actions taken under authorities in other EPA-administered Federal laws,
and/or made any associated finding as to whether it is in the public interest to protect against
such risk by actions taken under TSCA. TSCA Section 9(b)(1) therefore provides EPA authority
to coordinate actions with other EPA offices without ever making a risk finding, or following an
identification of risk. This includes coordination on tailoring the scope of TSCA risk evaluations
to focus on areas of greatest concern rather than exposure pathways addressed by other EPA-
administered statutes and regulatory programs, which does not involve a risk determination or
public interest finding under TSCA Section 9(b)(2).
In a narrower application of the broad authority provided by the first sentence of TSCA Section
9(b)(1), the remaining provisions of section 9(b)(1) provide EPA authority to identify risks and
refer certain of those risks for action by other EPA offices. Under the second sentence of section
9(b)(1), "[i]f the Administrator determines that a risk to health or the environment associated
with a chemical substance or mixture could be eliminated or reduced to a sufficient extent by
actions taken under the authorities contained in such other Federal laws, the Administrator shall
use such authorities to protect against such risk unless the Administrator determines, in the
Administrator's discretion, that it is in the public interest to protect against such risk by actions
taken under [TSCA]." Coordination of intra-agency action on risks under TSCA Section 9(b)(1)
therefore entails both an identification of risk, and a referral of any risk that could be eliminated
or reduced to a sufficient extent under other EPA-administered laws to the EPA office(s)
responsible for implementing those laws (absent a finding that it is in the public interest to
protect against the risk by actions taken under TSCA).
Risk may be identified by OPPT or another EPA office, and the form of the identification may
vary. For instance, OPPT may find that one or more conditions of use for a chemical substance
present(s) a risk to human or ecological receptors through specific exposure routes and/or
pathways. This could involve a quantitative or qualitative assessment of risk based on
reasonably available information (which might include, e.g., findings or statements by other EPA
offices or other federal agencies). Alternatively, risk could be identified by another EPA office.
For example, another EPA office administering non-TSCA authorities may have sufficient
monitoring or modeling data to indicate that a particular condition of use presents risk to certain
human or ecological receptors, based on expected hazards and exposures. This risk finding could
be informed by information made available to the relevant office under TSCA Section 9(e),
which supports cooperative actions through coordinated information-sharing.
Following an identification of risk, EPA would determine if that risk could be eliminated or
reduced to a sufficient extent by actions taken under authorities in other EPA-administered laws.
If so, TSCA requires EPA to "use such authorities to protect against such risk," unless EPA
determines that it is in the public interest to protect against that risk by actions taken under
TSCA. In some instances, EPA may find that a risk could be sufficiently reduced or eliminated
by future action taken under non-TSCA authority. This might include, e.g., action taken under
the authority of the Safe Drinking Water Act to address risk to the general population from a
chemical substance in drinking water, particularly if the Office of Water has taken preliminary
steps such as listing the subject chemical substance on the Contaminant Candidate List. This sort
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of risk finding and referral could occur during the risk evaluation process, thereby enabling EPA
to use more a relevant and appropriate authority administered by another EPA office to protect
against hazards or exposures to affected receptors.
Legislative history on TSCA Section 9(b)(1) supports both broad coordination on current intra-
agency actions, and narrower coordination when risk is identified and referred to another EPA
office for action. A Conference Report from the time of TSCA's passage explained that section 9
is intended "to assure that overlapping or duplicative regulation is avoided while attempting to
provide for the greatest possible measure of protection to health and the environment." S. Rep.
No. 94-1302 at 84. See also H. Rep. No. 114-176 at 28 (stating that the 2016 TSCA
amendments "reinforce TSCA's original purpose of filling gaps in Federal law," and citing new
language in section 9(b)(2) intended "to focus the Administrator's exercise of discretion
regarding which statute to apply and to encourage decisions that avoid confusion, complication,
and duplication"). Exercising TSCA Section 9(b)(1) authority to coordinate on tailoring TSCA
risk evaluations is consistent with this expression of Congressional intent.
Legislative history also supports a reading of section 9(b)(1) under which EPA coordinates intra-
agency action, including information-sharing under TSCA Section 9(e), and the appropriately-
positioned EPA office is responsible for the identification of risk and actions to protect against
such risks. See, e.g., Senate Report 114-67, 2016 Cong. Rec. S3522 (under TSCA Section 9, "if
the Administrator finds that disposal of a chemical substance may pose risks that could be
prevented or reduced under the Solid Waste Disposal Act, the Administrator should ensure that
the relevant office of the EPA receives that information"); H. Rep. No. 114-176 at 28, 2016
Cong. Rec. S3522 (under section 9, "if the Administrator determines that a risk to health or the
environment associated with disposal of a chemical substance could be eliminated or reduced to
a sufficient extent under the Solid Waste Disposal Act, the Administrator should use those
authorities to protect against the risk"). Legislative history on TSCA Section 9(b)(1) therefore
supports coordination with and referral of action to other EPA offices, especially when statutes
and associated regulatory programs administered by those offices could address exposure
pathways or risks associated with conditions of use, hazards, and/or exposure pathways that may
otherwise be within the scope of TSCA risk evaluations.
TSCA Sections 2(c) & 18(d)(1)
Finally, TSCA Sections 2(c) and 18(d) support coordinated action on exposure pathways and
risks addressed by other EPA-administered statutes and regulatory programs. Section 2(c) directs
EPA to carry out TSCA in a "reasonable and prudent manner" and to consider "the
environmental, economic, and social impact" of its actions under TSCA. Legislative history
from around the time of TSCA's passage indicates that Congress intended EPA to consider the
context and take into account the impacts of each action under TSCA. S. Rep. No. 94-698 at 14
("the intent of Congress as stated in this subsection should guide each action the Administrator
takes under other sections of the bill").
Section 18(d)(1) specifies that state actions adopted or authorized under any Federal law are not
preempted by an order of no unreasonable risk issued pursuant to TSCA Section 6(i)(l) or a rule
to address unreasonable risk issued under TSCA Section 6(a). Thus, even if a risk evaluation
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were to address exposures or risks that are otherwise addressed by other federal laws and, for
example, implemented by states, the state laws implementing those federal requirements would
not be preempted. In such a case, both the other federal and state laws, as well as any TSCA
Section 6(i)(l) order or TSCA Section 6(a) rule, would apply to the same issue area. See also
TSCA Section 18(d)(l)(A)(iii). In legislative history on amended TSCA pertaining to section
18(d), Congress opined that "[t]his approach is appropriate for the considerable body of law
regulating chemical releases to the environment, such as air and water quality, where the states
have traditionally had a significant regulatory role and often have a uniquely local concern." Sen.
Rep. 114-67 at 26.
EPA's careful consideration of whether other EPA-administered authorities are available and
more appropriate for addressing certain exposures and risks is consistent with Congress's intent
to maintain existing federal requirements and the state actions adopted to locally and more
specifically implement those federal requirements, and to carry out TSCA in a reasonable and
prudent manner. EPA believes it is both reasonable and prudent to tailor TSCA risk evaluations
in a manner reflective of expertise and experience exercised by other EPA and State offices to
address specific environmental media, rather than attempt to evaluate and regulate potential
exposures and risks from those media under TSCA. This approach furthers Congressional
direction and EPA aims to efficiently use Agency resources, avoid duplicating efforts taken
pursuant to other Agency and State programs, and meet the statutory deadline for completing
risk evaluations.
EPA-administered statutes and regulatory programs that address specific exposure pathways
and/or risks
During the course of the risk evaluation process for 1,4-dioxane, OPPT worked closely with the
offices within EPA that administer and implement regulatory programs under the Clean Air Act
(CAA), the Safe Drinking Water Act (SDWA), the Clean Water Act (CWA), the Comprehensive
Envionmental Response, Compensation, and Liability Act (CERCLA), and the Resource
Conservation and Recovery Act (RCRA). Through intra-agency coordination, EPA determined
that specific exposure pathways are well-regulated by the EPA statutes described in the
following paragraphs.
Ambient Air Pathway
The CAA contains a list of hazardous air pollutants (HAP) and provides EPA with the authority
to add to that list pollutants that present, or may present, a threat of adverse human health effects
or adverse environmental effects. For stationary source categories emitting HAP, the CAA
requires issuance of technology-based standards and, if necessary, additions or revisions to
address developments in practices, processes, and control technologies, and to ensure the
standards adequately protect public health and the environment. The CAA thereby provides
EPA with comprehensive authority to regulate emissions to ambient air of any hazardous air
pollutant.
1,4-Dioxane is a HAP. See 42 U.S.C. 7412. EPA has issued a number of technology-based
standards for source categories that may emit 1,4-dioxane to ambient air and, as appropriate, has
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reviewed, or will review remaining risks. See Appendix A of this risk evaluation; 42 U.S.C.
7412(f)(2). Because stationary source releases of 1,4-dioxane to ambient air are addressed under
the CAA, EPA is not evaluating emissions to ambient air from commercial and industrial
stationary sources or associated inhalation exposure of the general population or terrestrial
species under any of the conditions of use in this TSCA risk evaluation, and as such the
unreasonable risk determinations for relevant conditions of use do not account for ambient air
exposures to the general population.
Drinking Water Pathway
The SDWA requires EPA to publish a Contaminant Candidate List (CCL) every 5 years. The
CCL is a list of unregulated contaminants that are known or anticipated to occur in public water
systems and that may require regulation. The SDWA specifies that the Agency place those
contaminants on the list that present the greatest health concern. The SDWA also requires EPA
to make Regulatory Determinations (RegDet) to regulate (or not) at least five CCL contaminants
every 5 years. To regulate a contaminant, EPA must conclude in accordance with SDWA Section
1412(b)(1)(A) that the contaminant may have adverse health effects, occurs or is substantially
likely to occur in public water systems at a level of concern, and that regulation, in the sole
judgement of the Administrator, presents a meaningful opportunity for health risk reduction for
persons served by public water systems. If after considering public comment on a preliminary
determination, the Agency makes a determination to regulate a contaminant, the Agency initiates
the process for issuing a drinking water regulation. When proposing and promulgating drinking
water regulations, the Agency must conduct a number of analyses.
Currently, EPA is evaluating 1,4 Dioxane through the SDWA statutory processes for developing
a National Primary Drinking Water regulation. 1,4-Dioxane is currently one of 109 contaminants
listed on EPA's Fourth Contaminant Candidate List (CCL 4), see 81 FR 81099, and was subject
to occurrence monitoring in public water systems under the third Unregulated Contaminant
Monitoring Rule (UCMR 3), see 77 FR 26072. Under UCMR 3, water systems were monitored
for 1,4-dioxane during 2013-2015. Of the 4,915 water systems monitored, 1,077 systems had
detections of 1,4-dioxane in at least one sample.
In March 2020, EPA published Preliminary Regulatory Determinations for Contaminants on the
Fourth Drinking Water Contaminant Candidate List pursuant to SDWA authority, see 85 FR
14098. The Agency did not make a preliminary determination under SDWA for 1,4-dioxane.
EPA will continue to evaluate 1, 4-dioxane prior to making a regulatory determination. Among
other things, the Agency intends to consider the findings in this risk evaluation, the Canadian
guideline technical document and other relevant new science which may provide clarity as to
whether 1,4-dioxane meets all the criteria to establish a NPDWR under SDWA 1412(b)(1)(A).
The Regulatory Determination 4 Support Document (USEPA, 2019a) and the Occurrence Data
from the Third Unregulated Contaminant Monitoring Rule (UCMR 3) (USEPA, 2019b) present
additional information and analyses supporting the Agency's evaluation of 1,4-dioxane.
OCSPP has coordinated with the Office of Water regarding 1,4-dioxane contamination in
drinking water. As noted above, in the Preliminary Regulatory Determinations for Contaminants
on the Fourth Drinking Water Contaminant Candidate List (85 FR 14098 (Mar. 10, 2020)), EPA
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found that 1,4-dioxane is occuring in finished drinking water above a health reference level
and therefore, for purposes of TSCA section 9(b), EPA has found risk from 1,4-dioxane
contamination at certain levels in drinking water that could be addressed under EPA's SDWA
authorities.5 However, EPA has deferred a determination to regulate 1,4-dioxane under SDWA
because SDWA section 1412(b)(l)(B)(ii) requires that EPA determine after opportunity for
public comment that regulation of 1,4-dioxane meets all three criteria for regulation under
SDWA section 1412(b)(1)(A), and EPA is awaiting new information that can inform the
evaluation of these three criteria (i.e. adverse effect, level of public health concern and
meaningful opportunity for health risk reduction). EPA will continue to evaluate 1,4-dioxane
under SDWA authorities to determine whether or not to regulate 1,4-dioxane in drinking water,
and the information produced in the risk evaluation process will be considered by the Office of
Water as part of future SDWA actions.
As described above, EPA has regular analytical processes to identify and evaluate drinking water
contaminants of potential regulatory concern for public water systems under SDWA. The Office
of Water evaluates the regulatory determination criteria under SDWA Section 1412(b)(1)(A) to
determine whether or not to initiate the development of a National Primary Drinking Water
Regulation. EPA promulgates National Primary Drinking Water Regulations (NPDWRs) under
SDWA when the Agency concludes a contaminant may have adverse health effects, occurs or is
substantially likely to occur in public water systems at a level of concern and that regulation, in
the sole judgement of the Administrator, presents a meaningful opportunity for health risk
reduction. For each contaminant with NPDWRs, EPA sets an enforceable Maximum
Contaminant Level (MCL) as close as feasible to a health based, non-enforceable Maximum
Contaminant Level Goals (MCLG) or establishes a treatment technique. Feasibility refers to both
the ability to treat water to meet the MCL and the ability to monitor water quality at the MCL,
SDWA Section 1412(b)(4)(D). Public water systems are generally required to monitor for the
regulated chemical based on a standardized monitoring schedule to ensure compliance with the
maximum contaminant level (MCL). Under SDWA, EPA must also review existing drinking
water regulations every 6 years, and if appropriate, revise them. SDWA, originally passed by
Congress in 1974, thereby is the main federal statute to protect public health by regulating the
5 EPA does not find that the science standards of TSCA section 26(h) and (i) apply to this
finding of risk, the Agency's determination that the risk could be eliminated or reduced to a
sufficient extent by action under the SDWA, or the corresponding tailoring of this risk
evaluation. TSCA sections 26(h) and (i) are triggered by EPA "decisions" made under TSCA
sections 4, 5, and 6, and the risk finding and associated determination described herein are both
made pursuant to TSCA section 9(b). Neither the finding of risk nor the subsequent
determination implements TSCA section 6. Further, following an EPA determination that risk
from drinking water from 1,4-dioxane contamination could be eliminated or reduced to a
sufficient extent by action taken under SDWA, in accordance with TSCA section 9(b)(1), EPA
will take appropriate action under SDWA in lieu of TSCA (absent a public interest finding
described in TSCA section 9(b), which EPA did not make). Thus, TSCA itself compels EPA to
narrow the scope of the risk evaluation following the Agency's section 9(b)(1) determination,
and there is no separate EPA "decision" subject to TSCA sections 26(h) and (i).
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nation's public drinking water supply and authorizing EPA to set national health-based standards
and take other actions to protect against contaminants that may be found in drinking water.
Ambient Water Pathway
EPA develops recommended water quality criteria under section 304(a) of the CWA for
pollutants in surface water that are protective of aquatic life or human health designated uses. A
criterion is a hazard assessment only; i.e., there is no exposure assessment or risk estimation.
When states adopt criteria that EPA approves as part of a state's regulatory water quality
standards, exposure is considered when state permit writers determine if permit limits are needed
and at what level for a specific discharger of a pollutant to ensure protection of the designated
uses of the receiving water. This is the process used under the CWA to address risk to human
health and aquatic life from exposure to a pollutant in ambient waters.
Under Section 304(a) of the Clean Water Act, EPA develops, publishes, and from time to time
revises criteria based on the latest scientific knowledge for surface waters to protect various
designated uses, including those associated with aquatic life or human health. These criteria are
not regulatory, they are recommendations only. States and tribal governments may adopt the
EPA Clean Water Act Section 304(a) criteria guidance or may adopt their own criteria that differ
from EPA's recommendations, subject to EPA's approval, using scientifically defensible
methods. States implement EPA-approved criteria as part of their regulatory water quality
standards, and exposure is considered by states in permits and listing decisions. EPA has not
developed CWA section 304(a) recommended water quality criteria for the protection of aquatic
life or human health for 1,4-dioxane. Human exposure to a receptor using the waters for
recreation and exposures to aquatic life were evaluated in this risk evaluation under TSCA.
Onsite Releases to Land Pathway
The Comprehensive Environmental Response, Compensation, and Liability Act, otherwise
known as CERCLA or Superfund, provides EPA with broad authority to address uncontrolled or
abandoned hazardous-waste sites as well as accidents, spills, and other releases of hazardous
substances, pollutants and contaminants into the environment. Through CERCLA, EPA is
provided authority to conduct a response action and seek reimbursement of cleanup costs from
potentially responsible parties, or in certain circumstances, order a potentially responsible party
to conduct a cleanup.
CERCLA Section 101(14) defines "hazardous substance" by referencing other environmental
statutes, including toxic pollutants listed under CWA Section 307(a); hazardous substances
designated pursuant to CWA Section 311(b)(2)(A); hazardous air pollutants listed under CAA
Section 112; TSCA Section 7; and hazardous wastes having characteristics identified under or
listed pursuant to RCRA Section 3001. See 40 CFR 302.4. CERCLA Sections 102(a) and 103 of
CERCLA also authorizes EPA to promulgate regulations designating as hazardous substances
those substances which, when released into the environment, may present substantial danger to
the public health or welfare or the environment. EPA must also promulgate regulations
establishing the quantity of any hazardous substance the release of which must be reported under
Section 103. Section 103 requires persons in charge of vessels or facilities to report to the
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National Response Center if they have knowledge of a release of a hazardous substance above
the reportable quantity threshold.
1,4-Dioxane is a hazardous substance under CERCLA. Releases of 1,4-dioxane in excess of 100
pounds within a 24-hour period must be reported (40 CFR 302.4, 302.6). The scope of this EPA
TSCA risk evaluation does not include on-site releases to the environment of 1,4-dioxane at
Superfund sites and subsequent exposure of the general population or non-human species. As
such, EPA is not evaluating exposures to the general population or non-human species from this
exposure pathway under any of the conditions of use in the risk evaluation under TSCA, and as
such the unreasonable risk determinations for relevant conditions of use do not account for
exposures to the general population or non-human species from on-site releases to land.
Disposal Pathway
1,4-Dioxane is included on the list of hazardous wastes pursuant to RCRA 3001 (40 CFR §
261.33) as a listed waste on the F and U lists. The general standard in RCRA section 3004(a) for
the technical criteria that govern the management (treatment, storage, and disposal) of hazardous
waste are those "necessary to protect human health and the environment," RCRA 3004(a). The
regulatory criteria for identifying "characteristic" hazardous wastes and for "listing" a waste as
hazardous also relate solely to the potential risks to human health or the environment. 40 C.F.R.
§§ 261.11, 261.21-261.24. RCRA statutory criteria for identifying hazardous wastes require EPA
to "tak[e] into account toxicity, persistence, and degradability in nature, potential for
accumulation in tissue, and other related factors such as flammability, corrosiveness, and other
hazardous characteristics." Subtitle C controls cover not only hazardous wastes that are
landfilled, but also hazardous wastes that are incinerated (subject to joint control under RCRA
Subtitle C and the CAA hazardous waste combustion MACT) or injected into UIC Class I
hazardous waste wells (subject to joint control under Subtitle C and SDWA).
EPA is not evaluating emissions to ambient air from municipal and industrial waste incineration
and energy recovery units or associated exposures to the general population or terrestrial species
under any of the conditions of use in the risk evaluation under TSCA, as these emissions are
regulated under section 129 of the Clean Air Act. CAA section 129 requires EPA to review and,
if necessary, add provisions to ensure the standards adequately protect public health and the
environment for 1,4-dioxane, and as such the unreasonable risk determinations for relevant
conditions of use do not account for exposures to the general population or terrestrial species
from industrial waste incineration and energy recovery units.
EPA is not evaluating on-site releases to land that go to underground injection or associated
exposures to the general population or terrestrial species under any of the conditions of use in its
risk evaluation under TSCA, and as such the unreasonable risk determinations for relevant
conditions of use do not account for exposures to the general population or terrestrial species
from underground injection. Environmental disposal of 1,4-dioxane injected into Class I
hazardous well types are covered under the jurisdiction of RCRA and SDWA and disposal of
1,4-dioxane via underground injection is not likely to result in environmental and general
population exposures. See 40 CFR parts 144, 146.
EPA is not evaluating on-site releases to land from RCRA Subtitle C hazardous waste landfills
or exposures of the general population or terrestrial species from such releases under any of the
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conditions of use in the TSCA evaluation, and as such the unreasonable risk determinations for
relevant conditions of use do not account for exposures to the general population or terrestrial
species from RCRA Subtitle C hazardous waste landfills. Design standards for Subtitle C
landfills require double liner, double leachate collection and removal systems, leak detection
system, run on, runoff, and wind dispersal controls, and a construction quality assurance
program. They are also subject to closure and post-closure care requirements including installing
and maintaining a final cover, continuing operation of the leachate collection and removal
system until leachate is no longer detected, maintaining and monitoring the leak detection and
groundwater monitoring system. Bulk liquids may not be disposed in Subtitle C landfills.
Subtitle C landfill operators are required to implement an analysis and testing program to ensure
adequate knowledge of waste being managed, and to train personnel on routine and emergency
operations at the facility. Hazardous waste being disposed in Subtitle C landfills, including 1,4-
dioxane (listed as a hazardous waste in 40 CFR 261.33), must also meet RCRA waste treatment
standards before disposal. See 40 CFR part 264.
EPA is not evaluating on-site releases to land from RCRA Subtitle D municipal solid waste
(MSW) landfills or exposures of the general population or terrestrial species from such releases
under any of the conditions of use in the TSCA risk evaluation, and as such the unreasonable risk
determinations for relevant conditions of use do not account for exposures to the general
population or terrestrial species from RCRA Subtitle D MSW landfills. While permitted and
managed by the individual states, municipal solid waste landfills are required by federal
regulations to implement some of the same requirements as Subtitle C landfills. MSW landfills
generally must have a liner system with leachate collection and conduct groundwater monitoring
and corrective action when releases are detected. MSW landfills are also subject to closure and
post-closure care requirements, and must have financial assurance for funding of any needed
corrective actions. MSW landfills have also been designed to allow for the small amounts of
hazardous waste generated by households and very small quantity waste generators (less than
220 lbs per month). Bulk liquids, such as free solvent, may not be disposed of at MSW landfills.
See 40 CFR part 258.
EPA is not evaluating on-site releases to land from industrial non-hazardous waste and
construction/demolition waste landfills or associated exposures to the general population or
terrestrial species under any of the conditions of use in the 1,4-dioxane risk evaluation, and as
such the unreasonable risk determinations for relevant conditions of use do not account for
exposures to the general population or terrestrial species from industrial non-hazardous waste
and construction/demolition waste landfills. Industrial non-hazardous and
construction/demolition waste landfills are primarily regulated under authorized state regulatory
programs. States must also implement limited federal regulatory requirements for siting,
groundwater monitoring and corrective action and a prohibition on open dumping and disposal
of bulk liquids. States may also establish additional requirements such as for liners, post-closure
and financial assurance, but are not required to do so. See, e.g., RCRA section 3004(c), 4007; 40
CFR part 257.
1,4,3 Conceptual Models
The conceptual models for this risk evaluation are shown in figures Figure 1-2, Figure 1-3, and
Figure 1-4. EPA considered the potential for hazards to workers and occupational non-users
(ONUs) from inhalation and dermal exposure and hazards to the environment resulting from
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exposure to aquatic species as shown in the preliminary conceptual models and analysis plan of
the 1,4-dioxane scope document Q % \ .JO I «). EPA considered the potential for hazards to
consumers from inhalation and dermal routes and to bystanders from the inhalation route via use
of household products containing 1,4-dioxane as a byproduct and hazards from incidental
exposure to the general population via releases to ambient water as shown in the conceptual
models.
The conceptual models indicate the exposure pathways and exposure routes of 1,4-dioxane to
workers and ONUs from industrial and commercial activities, consumers and bystanders from
use of consumer products, and human and environmental receptors from environmental releases
and wastes. The problem formulation and the draft supplemental analysis to the draft risk
evaluation documents refined the initial conceptual models and analysis plans that were provided
in the scope documents (U.S. EPA. 2018c). EPA has included the mapping tables that described
all possible scenarios and whether they would be further evaluated. This was developed during
problem formulation and is presented in Appendix B. The environmental characterization for the
pathways included in the risk evaluation is described in Section 4.1.
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INDUSTRIAL AND COMMERCIAL EXPOSURE PATHWAY EXPOSURE ROUTE RECEPTORS0 HAZARDS
ACTIVITIES / USES'
Manufacture
(Including Import)
Hazards Potentially Associated
with Acute and/or Chronic
Exposures
Liquid Contact
Dermal
Workers®
Processing:
• Processing as a
reactant/intermediate
• Repackaging
¦ Non-incorporative
activities
Occupational
Non-Users
Vapor/ Mist
Fugitive
Emissions0
Recycling
Processing Aids, Not
Otherwise Listed
Functional Fluids
(Open and Closed Systems)
La boratory Chem i ca Is
Other Industrial or
Commercial Uses
Waste Handling,
Treatment and
Disposal
Wastewater, Liquid Wastes, Solid Wastes
Figure 1-2.1,4-Dioxane Conceptual Model for Industrial and Commercial Activities and Uses: Potential Exposures and
Hazards
The conceptual model presents the exposure pathways, exposure routes and hazards to human receptors from industrial and
commercial activities and uses of 1,4-dioxane that EPA analyzed in this risk evaluation.
a Additional uses of 1,4-dioxane are included in Table 1-4..
b Fugitive air emissions are those that are not stack emissions (emissions that occur through stacks, confined vents, ducts, pipes or other confined air streams),
and include fugitive equipment leaks from valves, pump seals, flanges, compressors, sampling connections, open-ended lines; evaporative losses from surface
impoundment and spills; and releases from building ventilation systems.
0 Based on physical chemical properties, 1,4-dioxane in mists that deposit in the upper respiratory tract will likely be rapidly absorbed in the respiratory tract or
evaporate and were considered in the inhalation exposure assessment.
d Receptors include potentially exposed or susceptible subpopulations.
e EPA considered the effect that engineering/administrative controls and/or personal protective equipment (PPE) have on occupational exposure levels.
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CONSUMER
ACTIVITIES / USES EXPOSURE PATHWAY EXPOSURE ROUTE RECEPTORS3 HAZARDS
Cleaning and Furniture Care
Products
e.g. Surface Cleaner
Consumers
Laundry and Dishwashing
Products
e.g. Dish Soap, Dishwasher
Detergent, Laundry Detergent
Bystanders
Arts, Crafts and Hobby
Materials
e.g. Textile Dye
Automotive Care Products
e.g. Antifreeze
Other Consumer Uses
e.g. Spray Polyurethane Foam,
Antifreeze
Vapor/Mist
Dermal
Liquid Contact
Inhalation
Paints and Coatings
e.g. Latex Wall Paint or Floor
Lacquer
Hazards Potentially
Associated
with Acute and/or Chronic
Exposures
Grey Tex1
KEY:
Pathways and receptors that were not
further analyzed
Pathways that were not further analyzed.
Pathways that were not further analyzed.
Consumer Handling and
Disposal of Waste
Figure 1-3.1,4-Dioxane Conceptual Model for Consumer Activities and Uses: Consumer Exposures and Hazards
The conceptual model presents the exposure pathways, exposure routes and hazards to human receptors from consumer activities and
uses of 1,4-dioxane that EPA analyzed in this risk evaluation.
a Receptors include potentially exposed or susceptible subpopulations.
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RELEASES AND WASTES FROM EXPOSURE PATHWAY EXPOSURE ROUTE RECEPTORS HAZARDS
INDUSTRIAL / COMMERCIAL USES
Direct
discharge
Water/
Sediment
Aquatic
Species
Indirect discharge
Biosolids
Land Di sposal
Soil
General
Population
POTW
Wastewater or
Liquid Wastes a
Incidental Oral,
Dermal
Industrial Pre-
Treatment or
Industrial WWT
Hazards Potentially
Associated with Acute
and Chronic Exposures
Hazards Potentially
Associated with Acute
Exposures
Figure 1-4.1,4-Dioxane Conceptual Model for Environmental Releases and Wastes: Potential Exposures and Hazards
The conceptual model presents the major exposure pathways, exposure routes and hazards to human and environmental receptors from
environmental releases and wastes of 1,4-dioxane that EPA analyzed in the draft risk evaluation and draft supplemental analysis to the
draft risk evaluation. During problem formulation, EPA made refinements to the conceptual models resulting in no further analysis of
the terrestrial exposure pathway following problem formulation. Analyses were conducted using physical and chemical properties,
fate information and surface water modeling during problem formulation. EPA has included the results of the analyses in Section
2.3.1, and Appendix E) and risk characterizations based on these analyses are included in the risk characterization (Section 4.1).
a Industrial wastewater or liquid wastes could be treated on-site and then released to surface water (direct discharge), or pre-treated and released to POTW
(indirect discharge).
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1.5 Systematic Review
TSCA requires EPA to use scientific information, technical procedures, measures, methods,
protocols, methodologies and models consistent with the best available science and base
decisions on the weight of the scientific evidence. Within the TSCA risk evaluation context,
the weight of the scientific evidence is defined as "a systematic review method, applied in a
manner suited to the nature of the evidence or decision, that uses a pre-established protocol
to comprehensively, objectively, transparently, and consistently identify and evaluate each
stream of evidence, including strengths, limitations, and relevance of each study and to
integrate evidence as necessary and appropriate based upon strengths, limitations, and
relevance" (40 C.F.R. 702.33).
To meet the TSCA § 26(h) science standards, EPA used the TSCA systematic review process
described in the Application of Systematic Review in TSCA Risk Evaluations document (U.S.
EPA. 2018b). The process complements the risk evaluation process in that the data
collection, data evaluation and data integration stages of the systematic review process are
used to develop the exposure and hazard assessments based on reasonably available
information. EPA defines "reasonably available information" to mean information that EPA
possesses, or can reasonably obtain and synthesize for use in risk evaluations, considering the
deadlines for completing the evaluation (40 CFR 702.33).
EPA is implementing systematic review methods and approaches within the regulatory
context of the amended TSCA. Although EPA is adopting as many best practices as
practicable from the systematic review community, EPA expects modifications to the process
to ensure that the identification, screening, evaluation and integration of data and information
can support timely regulatory decision making under the aggressive timelines of the statute.
1,5.1 Data and Information Collection
EPA planned and conducted a comprehensive literature search based on chemical descriptors
and key words related to the different discipline-specific evidence supporting the risk
evaluation (e.g., environmental fate and transport; engineering releases and occupational
exposure; exposure to general population, consumers and environmental exposure; and
environmental and human health hazard). EPA then developed and applied inclusion and
exclusion criteria during the title and abstract screening to identify information potentially
relevant for the risk evaluation process. The literature and screening strategy as specifically
applied to 1,4-dioxane is described in the Strategy for Conducting Literature Searches for
1,4-Dioxane: Supplemental File for the TSCA Scope Document and the results of the title and
abstract screening process were published in the 1, 4-Dioxane (CASRN123-91-1)
Bibliography: Supplemental File for the TSCA Scope Document (' r \ I.VI j). EPA
subsequently conducted full-text screening using inclusion/exclusion criteria within
population, exposure, comparator, outcome (PECO) or similar statements that are included in
Appendix F of Problem Formulation of the Risk Evaluation for 1,4-Dioxane (EPA. 2018b).
For studies determined to be on-topic (or relevant) after title and abstract screening, EPA
conducted a full text screening to further exclude references that were not relevant to the risk
evaluation. Screening decisions were made based on eligibility criteria documented in the
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form of the populations, exposures, comparators, and outcomes (PECO) framework or a
modified framework.6 Data sources that met the criteria were carried forward to the data
evaluation stage. The inclusion and exclusion criteria for full text screening for 1,4-dioxane
are available in Appendix F of the Problem Formulation of the Risk Evaluation for 1,4-
Dioxane (U.S. EPA. 2018c).
Although EPA conducted a comprehensive search and screening process as described above,
EPA made the decision to leverage the literature published in previous assessments7 when
identifying relevant key and supporting data8 and information for developing the 1,4-dioxane
risk evaluation. This is discussed in the Strategy for Conducting Literature Searches for 1,4-
Dioxane: Supplemental Document to the JSC-A Scope Document. In general, many of the
key and supporting data sources were identified in the comprehensive lA-Dioxane (123-91-
1) Bibliography: Supplemental File for the TSCA Scope Document ( 017a).
However, there were instances that EPA missed relevant references that were not captured in
the initial categorization of the on-topic references. EPA found additional relevant data and
information using backward reference searching, which was a technique that will be included
in future search strategies. This issue was discussed in Section 4 of the Application of
Systematic Review for TSCA Risk Evaluations. Other relevant key and supporting references
were identified through targeted supplemental searches to support the analytical approaches
and methods in the 1,4-dioxane risk evaluation (e.g., to locate specific information for
exposure modeling) or to identify new data and information published after the date limits of
the initial search.
EPA used previous chemical assessments to quickly identify relevant key and supporting
information as a pragmatic approach to expedite the quality evaluation of the data sources,
but many of those data sources were already captured in the comprehensive literature as
explained above. EPA also considered newer information not taken into account by previous
chemical assessments as described in the Strategy for Conducting Literature Searches for
1,4-Dioxane: Supplemental Document to the TSCA Scope Document. EPA then evaluated the
confidence of the key and supporting data sources as well as newer information instead of
evaluating the confidence of all the underlying evidence ever published on a chemical
substance's fate and transport, environmental releases, environmental and human exposure
and hazards. Such comprehensive evaluation of all of the data and information ever
published for a chemical substance would be extremely labor intensive and could not be
achieved under the TSCA statutory deadlines for most chemical substances especially those
6 A PESO statement was used during the full text screening of environmental fate and transport data sources.
PESO stands for Pathways and Processes, Exposure, Setting or Scenario, and Outcomes. A RESO statement
was used during the full text screening of the engineering and occupational exposure literature. RESO stands
for Receptors, Exposure, Setting or Scenario, and Outcomes.
7 Examples of existing assessments are EPA's chemical assessments (e.g., previous work plan risk assessments,
problem formulation documents), ATSDR's Toxicological Profiles, and EPA's IRIS assessments. This is
described in more detail in the Strategy for Conducting Literature Searches for 1,4-
8 Key and supporting data and information are those that support key analyses, arguments, and/or conclusions in
the risk evaluation.
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that have a data rich database. Furthermore, EPA determined how EPA's evaluation of the
key and supporting data and information and newer information would change the previous
conclusions presented in the previous assessments.
Using this pragmatic approach, EPA evaluated the confidence of the key and supporting data
sources as well as newer information instead of evaluating the confidence of all the
underlying evidence ever published on 1,4-dioxane's fate and transport, environmental
releases, environmental and human exposure and hazards. This allowed EPA to maximize the
scientific and analytical efforts of other regulatory and non-regulatory agencies by accepting
for the most part the relevant scientific knowledge gathered and analyzed by others except
for influential information sources that may have an impact on the weight of the scientific
evidence and ultimately the risk findings. The influential information (i.e., key/supporting)
came from a smaller pool of sources subject to the rigor of the TSCA systematic review
process to ensure that the risk evaluation uses the best available science and the weight of the
scientific evidence.
Figures 1-5, 1-6, 1-7, and 1-8 depict the literature flow diagrams illustrating the results of this
process for the scientific discipline-specific evidence supporting the risk evaluation. Each
diagram provides the total number of references at the start of each systematic review stage
(i.e., data search, data quality evaluation, data extraction/data integration) and those excluded
based on criteria guiding the screening and data quality evaluation decisions.
EPA made the decision to bypass the data screening step for data sources that were highly
relevant to the risk evaluation as described above. These data sources are depicted as
"key/supporting data sources" in the literature flow diagrams. Note that the number of
"key/supporting data sources" were excluded from the total count during the data screening
stage and added, for the most part, to the data evaluation stage depending on the discipline-
specific evidence. The exception was the engineering releases and occupational exposure
data sources that were subject to a combined data extraction and evaluation step (Figure 1-6).
*Key/supporting
data sources (n=l)
Data Search Results (n= 2,940)
Data Screening (n=2,939)
Data Evaluation (n=l)
Excluded References (n=2,939)
Data Extraction/Data Integration (n=l)
Excluded: Ref that are
unacceptable based on the
evaluation criteria (n=0)
Figure 1-5. Literature Flow Diagram for Environmental Fate and Transport Data
Sources
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Following data screening, EPA determined during problem formulation that no environmental
pathways would be further analyzed (U.S. EPA. 2018c). EPA evaluated a biodegradation study that
was a key source in a previous EPA assessment (U.S. EPA. 2015) and is discussed in Section 2.1.
Data sources identified relevant to physical-chemical properties were not included in this literature
flow diagram. The data quality evaluation of physical-chemical properties studies can be found in the
supplemental document, Data Quality Evaluation of Physical-Chemical Properties Studies (Docket:
EPA-HQ-OPPT-2019-0500) and the extracted data are presented in Table 1-1..
* These are key and supporting studies from existing assessments (e.g., EPA IRIS assessments or
ATSDR assessments) that were considered highly relevant for the TSCA risk evaluation. These
studies bypassed the data screening step and moved directly to the data evaluation step.
Excluded References (n=2883)
•Data Sources that were not
integrated (n=44)
Data Search Results (n=2967)
Excluded Ref that are
unacceptable based on
evaluation criteria (n=38)
Data Integration (n-16)
Data Extraction'Data Evaluation (n-98)
Data Screening (n=296 7)
'The quality of data in these sources (n=44) were acceptable for risk assessment purposes, but they were ultimately
excluded from further consideration based on EPAs integration approach for environmental release and occupational
exposure datafinformation EPA s approach uses a hierarchy of preferences that guide decisions about what types of
data/information are included for further analysis, synthesis and integration into the environmental release and
occupational exposure assessments EPA prefers using data with the highest rated quality among those in the higher
level of the hierarchy of preferences (Le data > modeling > occupational exposure limits or release Imits) If warranted.
EPA may use data/information of lower rated quality as supportive evidence in the environmental release and
occupational exposure assessments
Figure 1-6. 1,4-Dioxane Literature Flow Diagram for Engineering Releases and
Occupational Exposures
Literature search results for environmental release and occupational exposure yielded 2,967 data
sources. Of these data sources, 84 were determined to be relevant for the risk evaluation through the
data screening process. These relevant data sources were entered into the data extraction/evaluation
phase. After data extraction/evaluation, EPA identified several data gaps and performed a
supplemental, targeted search to evaluate these gaps (e.g., to locate information needed for exposure
modeling). The supplemental search yielded 14 relevant data sources that bypassed the data screening
step and were evaluated and extracted in accordance with Appendix D: Data Quality Criteria for
Occupational Exposure and Release Data of the Application of Systematic Review for TSCA Risk
Evaluations document.
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EPA's problem formulation laid out the scope of the evaluation and used reasonably
available sources of information to evaluate potential exposures to environmental receptors
(aquatic) pathways from 1,4-dioxane. The confidence of these data sources was considered
acceptable for risk evaluation purposes and thus they were used to support the analyses
during scoping and problem formulation. EPA determined during problem formulation that
certain environmental pathways were within scope but would not be further analyzed based
on quantitative and qualitative analyses covering ecological pathways (U.S. EPA 2018c). In
support of this evaluation, EPA undertook an additional literature search to identify, screen,
and evaluate literature relevant for a consumer exposure assessment of 1,4-dioxane.
Excluded References due to
ECOTOX Criteria
(n = 42)
Excluded References due to
ECOTOX Criteria
(n = 3239)
Data Extraction I Data Integration (n = 9)
Data Evaluation (n = 14)
Full Text Screening (n = 56)
Excluded References
that are out of scope
(n = 5)
Data Search Results (n = 3302)
Title/Abstract Screening (n = 3295)
Figure 1-7. Literature Flow Diagram for Environmental Hazard Data Sources
The environmental hazard data sources were identified through literature searches and screening
strategies using the ECOTOX Standard Operating Procedures. Additional details about the process
can be found in the Strategy for Conducting Literature Searches for 1,4-Dioxane: Supplemental File
for the TSCA Scope Document, EPA-HQ-OPPT-2016-0723. During problem formulation, EPA made
refinements to the conceptual models resulting in no further analysis of the terrestrial exposure
pathway following problem formulation. Such qualitative analyses can be conducted with limited data
during problem formulation to identify which exposure pathways warrant more analysis. Thus,
environmental hazard data sources on terrestrial organisms were excluded from data quality
evaluation.
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n=9
Key/supporting
data sources
(n = 37)
Excluded References (n = 2655)
Data Search Results (n = 2,701)
Excluded: Ref that are
unacceptable based on
evaluation criteria (n = 5)
Data Extraction/Data Integration (n = 41)
Data Evaluation (n = 46)
Data Screening (n = 2,664)
Figure 1-8. Literature Flow Diagram for Human Health Hazard Data Sources
Key and supporting studies (n=37) were identified from existing assessments (e.g., EPA IRIS
assessments, ATSDR assessments) and considered highly relevant for the TSCA risk evaluation.
These studies bypassed the data screening step and moved directly to the data evaluation step.
Supplemental Literature Search for Consumer Exposure
EPA performed a supplemental literature search of peer databases to identify studies related
to consumer exposure. EPA conducted a new comprehensive literature search of databases of
peer reviewed literature based on chemical name and CAS registry numbe related to
exposure to general population, consumers and environmental exposure. EPA filtered the
new literature search results of 1,4-dioxane for consumer specific references using Structured
Query Language (SQL) querying shown in Table 1-5.
Table 1-5 Categorical Term Sets used in SQL Querying for 1,4-Dioxane consumer
assessment
Term Sets
carpet|Drapery|curtain|upholstery|furniture|rug|Suede|cleaner|leather|water proofing| starch
anti-static|candle|matches|bleach|laundry|detergent|Insect repellent|litter|Charcoal|briquettes|lighter
fluid|Drain cleaner|Dishwasher|dishwasliing|dishes|soap|Fabric
dye|softener|Oven cleaner|home|pet|collar|Fertilizer|garden|Fire extinguisher|floor|metal|silver|Food
packaging|packaged food
deodorizer|freshener|disinfectant|spot remover|stain remover| Scouring pad|Toilet|Herbicide|patio| Water
treatment chemicals|Insecticide|swimmingpool|Paint|varnish|remover|tliinner|interior|spray|house
exterior|polyurethane|stain|Ceiling|tile|patching|plaster|caulk|sealer|filler|Dry
wall|Roofing|Refinishing|wall|wallpaper|Insulation|automobile|car|truck|cycle|van
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Antifreeze|Motor oil|Radiator|additives|Automotive paint|Gasoline|diesel
fuel|vehicle|Windshield|washer|Clothes|clothing|shoe|Sheets|towels|diaper|games|toys|chew|ingestljewelry|col
orprint|newsprint|newspaper|photograph|consumer|emission
Categorical term sets were derived from the Exposure Factors Handbook. This included Household
Furnishings, Garment Conditioning Products, Household Maintenance Products, Home Building &
Improvement Products, Automobile-Related Products, and Personal Materials. Cosmetic Hygiene Products,
insecticide, food packaging terminology was excluded for the purposes of this assessment per TSCA section
JI2L
Next, a machine learning model was employed to rank how similar the filtered references
were to a pre-determined set of consumer references (positive seeds), and how unsimilar the
filtered references were to a pre-determined set of non-consumer references (negative seeds).
More information about the machine learning model, the positive and negative seeds are
provided in the Supplemental Analysis File [Consumer References, Data Screening].
References that ranked above a relevancy cut-off (0.1 for all references) were included for
data screening. These approaches reduced the number of references from 21,373 to 239. The
revised literature flow diagram (Table 3) includes the additional SQL querying and machine
learning steps that were used for the consumer assessment.
In addition to the peer database search, EPA utilized previous assessments and performed an
additional gray literature search for the supplemental consumer analysis. Previous
assessments that were identified in support of the development of EPA's 2015 TSCA Work
Plan Chemical Problem Formulation and Initial Assessment of 1,4-Dioxane (U.S. EPA.
2015). were screened and evaluated for use in the supplemental consumer assessment. EPA
conducted an additional consumer gray literature search to identify references with consumer
information related to 1,4-dioxane. Previous assessments and results of the additional gray
literature search for consumer uses resulted in 34 data sources. The revised literature flow
diagram (Table 3) includes the previous assessments, as well as the additional gray literature
results that were used for the consumer assessment.
The 239 references as a result of the machine learning efforts and the 34 references from
previous assessments and the additional gray literature search underwent data screening.
These sources are listed in the Supplemental Analysis File [Consumer References, Data
Screening].
For the consumer supplemental analysis, EPA modified the inclusion and exclusion criteria
for title and abstract screening and full text screening to identify consumer information
potentially relevant for the risk evaluation process. The revised PECO is presented in
l-6Table .
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Table 1-6 PECO Statement 1,4-Dioxane Consumer Exposure Assessment (September
2020)
Pi:(() l.lcmenl
l.\ idence
Population
Human: Consumers and bystanders, including children. Targeted human DODulation
groups may be exposed to 1,4-dixoane.
Ecological: None.
Exposure
ExDected Primary ExDOSure Sources. Pathways, Routes
Source: Consumer use of products containing 1.4 dioxane as a byproduct, and associated
air emissions and dermal contact.
Pathway: Indoor air. contact w ith products.
Routes: Indoor (inhalation), dermal (contact with products)
Comparator
(Scenario)
Human: Consider use/source specific exposure scenarios as well as which receptors are
and are not reasonably exposed across the projected exposure scenarios.
Ecological: None.
Outcomes for
Exposure
Concentration or
Dose
Human: A wide ranee of effects following acute and chronic exposure doses me/ke/dav
and concentrations mg/m3.
Ecological: None.
The results of the data screening efforts resulted in 37 references that were sent to data
evaluation, and 17 references that were evaluated qualitatively. The results of the data
evaluation are included in the Supplemental File {Data Quality Evaluation of Consumer
Exposure Studies] and the list of references evaluated qualitatively are included in the
Supplemental File [Consumer References, Data Screening]. Following data evaluation, 30
references were sent forward for data extraction/integration. The process is depicted below in
Figure 1-9.
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Data Extraction/Data Integration (n - 30}
Data Evaluation (n = 37)
Data Screening (n = 545)
Raw Literature Search Results
(n =85,379)
Consumer Search Results after Machine
Learning (n =239)
Gray literature and previous
assessments (n =34)
Initial Data Search Results (n =272)
Consumer Search Results after SQL
Query (n =8,077)
Literature Search Results (n « 21,373)
Excluded References (n - 481)
Qualitative References {n = 17)
Duplicates (n=10)
Non-consumer references from
Machine Learning
(n = 7,838)
Non-consumer references from
SQL query (n » 13,296)
Patents (n = 20,865)
Duplicates {n = 43,141)
'Excluded References (n = 7)
Unacceptable based on data evaluation criteria (n = 0)
Not primary source, not extractable or
not most relevant (n = 7)
"The quality of data in these sources were acceptable for risk assessment purposes and considered for
integration. The sources; however, were not extracted for a variety of reasons, such as they contained only
secondary source data, duplicate data, or non-extractable data {i.e., charts or figures). Additionally, some
data sources were not as relevant to the PECO as other data sources wtiich were extracted.
Figure 1-9. Literature Flow Diagram for General Population, Consumer and
Environmental Exposure Data Sources
In support of this evaluation, EPA undertook an additional raw literature search (n=85,379) to
identify, screen, and evaluate literature relevant for a consumer exposure assessment of 1,4-dioxane.
Deduplication, SQL querying, and machine learning were employed to reduce the number of
references for data screening. The Consumer Supplemental Search Results after Machine Learning
(n=239) and the gray literature and previous assessments (n=34) represent the additional sources that
were considered for the consumer SLtpplemental analysis, whereas the initial data search results
(n=272) refer to the references that were considered in the draft risk evaluation.
1.5.2 Data Evaluation
During the data evaluation stage, EPA assesses the quality of the data sources using the
evaluation strategies and criteria described in the Application of Systematic Review in TSCA
Risk Evaluations (U.S. EPA, 2018b) For the data sources that passed full-text screening and
the key and supporting data sources, EPA evaluated their quality and each data source
received an overall data quality rating of high, medium, low or unacceptable.
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The results of the data quality evaluations are summarized in Sections 2.1 (Fate and
Transport), 2.2 (Releases to the Environment), 2.3 (Environmental Exposures), 2.4 (Human
Exposures), 3.1 (Environmental Hazards) and 3.2 (Human Health Hazards). Additional
information is provided in the appendices of the main document. Supplemental files9 also
provide details of the data evaluations including individual metric scores and the overall
study score for each data source.
1.5.3 Data Integration
Data integration includes analysis, synthesis and integration of information for the risk
evaluation. During data integration, EPA considers quality, consistency, relevancy,
coherence and biological plausibility to make final conclusions regarding the weight of the
scientific evidence. As stated in the Application of Systematic Review in TSCA Risk
Evaluations (U.S. EPA. 2018b). data integration involves transparently discussing the
significant issues, strengths, and limitations as well as the uncertainties of the reasonably
available information and the major points of interpretation ( a). EPA defines
"reasonably available information" to mean information that EPA possesses, or can
reasonably obtain and synthesize for use in risk evaluations, considering the deadlines for
completing the evaluation (Procedures for Chemical Risk Evaluation Under the Amended
Toxic Substances Control Act (82 FR 33726)).
EPA used previous assessments (see Table 1-3.) to identify key and supporting information
and then analyzed and synthesized available evidence regarding 1,4-dioxane's chemical
properties, environmental fate and transport properties and its potential for exposure and
hazard. EPA's analysis also considered recent data sources that were not considered in the
previous assessments (Section 1.3) as well as reasonably available information on potentially
exposed or susceptible subpopulations.
The exposures and hazards sections describe EPA's analysis of the influential information
{i.e., key and supporting data) that were found acceptable based on the data quality reviews
as well as discussion of other scientific knowledge using the approaches described in
Sections 2.4.1, 3.1.1, and 3.2.1. The exposure section also describes whether aggregate or
9 There are various systematic review supplemental files accompanying the risk evaluation:
Final Risk Evaluation for 1,4-Dioxane, Systematic Review Supplemental File: Updates to the Data Quality Criteria for
Epidemiological Studies
Final Risk Evaluation for 1,4-Dioxane, Systematic Review Supplemental File: Data Quality Evaluation for Engineering
Releases and Occupational Exposure Data Sources
Final Risk Evaluation for 1,4-Dioxane, Systematic Review Supplemental File: Data Quality Evaluation of Environmental
Fiazard Studies
Final Risk Evaluation for 1,4-Dioxane, Systematic Review Supplemental File: Data Quality Evaluation of Environmental
Fate and Transport Studies
Final Risk Evaluation for 1,4-Dioxane, Systematic Review Supplemental File: Data Quality Evaluation of Fhiman Fiealth
Fiazard Studies, Animal and In Vitro Studies
Final Risk Evaluation for 1,4-Dioxane, Systematic Review Supplemental File: Data Quality Evaluation of Epidemiological
Studies
Final Risk Evaluation for 1,4-Dioxane, Systematic Review Supplemental File: Data Quality Evaluation of Consumer
Exposure Studies
Final Risk Evaluation for 1,4-Dioxane, Systematic Review Supplemental File: Data Quality Evaluation of Physical-
Chemical Properties Studies
70 of 616
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sentinel exposures to a chemical substance were considered under the conditions of use
within the scope of the risk evaluation, and the basis for that consideration.
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2 EXPOSURES
2.1 Fate and Transport
EPA gathered and evaluated environmental fate information according to the process described
in the Application of Systematic Review in TSCA Risk Evaluations (U.S. EPA. 2018b).
Reasonably available environmental fate data were selected for use in the current evaluation.
Furthermore, EPA used previous regulatory and non-regulatory 1,4-dioxane assessments to
inform the environmental fate and transport information discussed in this section and Appendix
D. EPA had confidence in the information used in the previous assessments of 1,4-dioxane (see
Table 1-3.) to describe the environmental fate and transport of 1,4-dioxane and thus used it to
make scoping decisions.
Because EPA determined during problem formulation that no environmental pathways would be
further analyzed, EPA limited data extraction and evaluation to key data sources used in previous
assessments (see Table 1-3.), as described in Section 1.5.2. Thus, EPA assessed the quality of a
microcosm study on soil biodegradation (Kelley et at.. 2001) based on the data quality criteria
described in the Application of Systematic Review in TSCA Risk Evaluations (U.S. EPA. 2018b)
and the study was rated 'high' quality. Data quality evaluation information for the sources used
in this assessment can be found in the supplemental document, Data Quality Evaluation of
Environmental Fate and Transport Studies ( 2019c).
Other fate estimates were based on modeling results from EPI Suite™ ( ), a
predictive tool for physical/chemical and environmental fate properties. The inputs and setup of
EPI Suite™ runs for 1,4-dioxane are described in Appendix D. EPI Suite™ was reviewed by the
EPA. Science Advisory Board and the individual models have been peer-reviewed in numerous
articles published in technical journals. Citations for such articles are available in the EPI Suite™
help files.
The 1,4-dioxane environmental fate characteristics and physical-chemical properties used in fate
assessment are presented in Table 2-1.. As part of problem formulation, EPA also analyzed the
sediment and land-applied biosolids pathways. The results of the analyses are described in the
2018 problem formulation for 1,4-dioxane ( 2018c) and presented again in Sections
4.1.3 and 4.1.4. Please note that this section and Sections 4.1.3 and 4.1.4 may also cite other data
sources as part of the reasonably available information on the fate and transport properties of 1,4-
dioxane. EPA did not subject these other data sources to the later phases of the systematic review
process {i.e., data evaluation and integration) based on the aforementioned approach.
Table 2-1. Environmental Fate Characteristics of 1,4-Dioxane
Properly or
Knripoint
Value 11
References
Data Quality
Ualing
Direct
photodegradati on
Not expected to undergo direct
photolysis13
ToxNet Hazardous
Substances Data Bank
Not applicable
72 of 616
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Properly or
Knd point
Value"
References
Qualify
Killing
)-
(2015")
Indirect
photodegradati on
4.6 hours (estimated for
atmospheric degradation)0
>015.
)
High
Hydrolysis half-life
Does not undergo hydrolysisb
1015);
Wilbur et al. (2012.)
Not applicable
Biodegradation
0% in 120 days, 60% in 300
days (aerobic in soil
microcosm)
U.S. EPA (2.015);
Kellev et al. (2001)
High
Bioconcentration
factor (BCF)
3 (estimated via linear
regression from Log Kow)°
0.9 (estimated via Arnot-Gobas
quantitative structure-activity
relationship [QSAR])C
JO 12c)
High
Bioaccumulation
factor (BAF)
0.9 (estimated via Arnot-Gobas
QSAR)°
U.S. EPA (2.015.
)
High
Organic carbon:water
partition coefficient
(log Koc)
0.4 (estimated)0
>015.
)
High
a Measured unless otherwise noted.
bl,4-Dioxane lacks functional groups susceptible to the degradation mechanism
Information was estimated using EPI Suite™ (IIS. EPA. 2012c)
The EPI Suite™ module that estimates chemical removal in sewage treatment plants (STPWIN)
was run using default settings (details available in the STPWIN help file in EPI Suite™) and
estimated that 0.3% of 1,4-dioxane in wastewater will be removed by volatilization while < 2%
of 1,4-dioxane will be removed by adsorption. The organic carbon-water partition coefficient,
log Koc, reported in previous assessments of 1,4-dioxane were in the range of 0.4 - 1.23 (
EPA. 2013 d: AT SDR. 2012; U.S. EPA. 2010; ECJRC. 2002; NICNAS. 19981 and log Koc
values within this range are associated with low sorption to soil, sediment, and suspended solids.
Aerobic biodegradation of 1,4-dioxane is slow or negligible (' v \ .Vi \ \ r OR. JO | j;
NTP. 2011; Health Canada. 2.010; ECJRC. 2.002; NICNAS. 1998) and will not contribute
significantly to removal of 1,4-dioxane in wastewater treatment. Thus, concentrations of 1,4-
dioxane in pore water of biosolids will be essentially equal to concentrations in the associated
wastewater, and the 1,4-dioxane contained in biosolids will almost all be in the aqueous phase
rather than adsorbed to particles. Similarly, 1,4-dioxane concentrations in sediment are expected
to be nearly equal to concentrations in overlying water, with 1,4-dioxane almost exclusively in
the aqueous phase of sediment samples.
Due to its water solubility (>800 g/L; Table 1-1.) and Henry's Law constant (4.8 x 10"6 atm-
m3/mole at 25°C; Table 1-1.), 1,4-dioxane is expected to demonstrate limited volatility from
73 of 616
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water surfaces, moist soil, and other moist surfaces such as land-applied biosolids. Once it enters
the environment, 1,4-dioxane has low potential to sorb to suspended solids and sediment based
on its log Koc and is therefore expected to migrate to surface waters and groundwater.
1,4-Dioxane is expected to volatilize from dry surfaces and dry soil due to its vapor pressure (40
mm Hg at 25°C). In the atmosphere, it is expected to react with hydroxyl radicals with an
indirect photolysis half-life on the order of hours (U.S. EPA. 2012c).
The estimated bioconcentration and bioaccumulation factors are 3 or below (Table 2-1.) and
measured bioconcentration factors for 1,4-dioxane are 0.7 or below (ECJRC. 2002). Therefore,
1,4-dioxane has low bioaccumulation potential.
Overall, 1,4-dioxane is not likely to accumulate in wastewater biosolids, sediment, soil, or biota.
It is expected to persist in soil, sediment, and water, but may slowly biodegrade in aerobic
environments or volatilize from surface water or soil and then degrade by indirect photolysis.
Groundwater
Bioaccumulation
BCF, BAF < 3
Dry Soil
Moist Soil
log KqC = 0.4
Aerobic Biodegradation
Rate = slow
Surface Water
log KqC = 0.4
Sediment
Land-applied biosolids
Photolysis
= 4.6 hours
Henry s"
4.8xl0"6
w constant =
Wi-m3/mole
Figure 2-1 Environmental transport, partitioning, and degradation processes for 1,4-
dioxane.
Figure 2-1 illustrates the transport and partitioning indicated by green arrows and degradation is
indicated by orange arrows. The width of the arrow is a qualitative indication of the likelihood
that the indicated partitioning will occur or the rate at which the indicated degradation will occur
{i.e., wider arrows indicate more likely partitioning or more rapid degradation). Although
transport and partitioning processes (green arrows) can occur in both directions, the image
illustrates the primary direction of transport indicated by partition coefficients. Figure 2-1
considers only transport, partitioning, and degradation within and among environmental media;
sources to the environment such as discharge and disposal are not illustrated.
2.2 Environmental Releases
Releases to the environment from conditions of use (e.g., industrial and commercial processes)
are one component of potential exposure and may be derived from reported data that are
obtained through direct measurement, calculations based on empirical data and/or assumptions
and models.
Under the Emergency Planning and Community Right-to-Know Act (EPCRA) Section 313, 1,4-
dioxane has been a Toxics Release Inventory (TRI)-reportable substance since 1987. The TRI
74 of 616
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database includes information on disposal and other releases of 1,4-dioxane to air, water, and
land, in addition to how it is being managed through recycling, treatment, and burning for energy
recovery. Based on 2015 TRI reporting, an estimated 35,402 lbs. of 1,4-dioxane was released to
surface water from industrial sources. See Table E-l in Appendix E for a TRI summary table and
further details on recent releases of 1,4-dioxane to various media.
2.2.1 Environmental Releases to Water
EPA categorized the conditions of use (COUs) listed in Table 1-4. into 12 Occupational
Exposure Scenarios (OES). For each OES, a daily water release was estimated based on annual
releases, release days, and the number of facilities (Figure 2-2). In this section, EPA describes its
approach and methodology for estimating daily water releases, and for each OES provides a
summary of release days, number of facilities, and daily water releases (Table 2-2.).
OES
Daily Release
Estimate
Release
Days
ESD, GS,
Assumptions
Annual
Releases
TRI, DMR, ESD,
GS
Number of
Facilities
TRI, CDR, DMR,
Census, ESD,
GS*
Figure 2-2. An Overview of How EPA Estimated Daily Water Releases for Each OES
* TRI: Toxics Release Inventory; DMR: Discharge Monitoring Report; ESD: Emission Scenario Document; GS:
Generic Scenario
2.2.1.1 Results for Daily Release Estimate
EPA combined its estimates for annual releases, release days, and number of facilities to estimate
a range for daily water releases for each OES. A summary of these ranges across facilities is
presented in Table 2-2.. The examples of certain OES where water releases are not expected
follows.
Laboratory Uses: EPA expects that releases of 1,4-dioxane from laboratory uses are to air
(through volatile releases into the indoor laboratory air and/or through laboratory fume hoods
to atmospheric air) and liquid wastes of 1,4-dioxane are handled as hazardous waste. EPA
expects commercial and university laboratories to handle their wastes as hazardous waste and
not discharge wastes to POTW via pouring the wastes down the drain.
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Printing Inks (3D): EPA does not expect water releases from 3D printing ink uses. EPA
expects spent printing ink containers, shavings or fragments, or waste scraps to be disposed
of as solid waste. There is some uncertainty as to whether and how much 1,4-dioxane may
remain in 3D printed products and waste scraps. However, due to the volatility of 1,4-
dioxane, EPA expects 1,4-dioxane to evaporate from any printed object, shavings or
fragments, or other printed material deposited to the floor or work surface prior to it being
cleaned and disposed of as solid waste.
Film Cement: EPA assessed no wastewater discharges for this OES. EPA expects the small
glue bottles to be disposed of as solid waste without rinsing them in a sink. There is some
uncertainty as to whether and how much 1,4-dioxane may remain in the small glue bottles
when disposed. However, due to the small quantities of the glue and high volatility of the
1,4-dioxane, EPA expects any residual 1,4-dioxane to evaporate to the air or remain in the
solid waste stream.
Table 2-2. Summary of EPA's Daily Water Release Estimates for Each OES and EPA's
Overall Confidence in these Estimates
Occiipiilidiiiil
l'l\|)OMIIV
Scenario
(OI.S)
I'.sliniiil
Rili;is»
Acros
(kji/sil
Mini in ii in
od l);iil\
¦ Riiiijie
s Silos
I'-cl.ij)
Miixiiiiiiin
Uokiisc
l);i> s
per
Yi-sir
Ki'li'sisi*
Modiii
(hoiiill
Confidence
Null's
Manufacturing
0
2.48
250
Surface
Water
M
Estimates based on TRI and
DMR data.
Import and
Repackaging
0
0
0
N/A
M
Estimates based on TRI and
DMR data.
Recycling
-
-
-
-
-
EPA evaluated recycling as
part of the industrial uses
OES.
Industrial Uses
0
67.7
250
Surface
Water,
POTW,
and Non-
Public
WWT
M
Estimates based on TRI and
DMR data.
Functional
Fluids (Open-
System)
9.92E-4
3.79E-2
247
Surface
Water
and
POTW
M
EPA estimates releases for
three sites reported in DMR
and for additional, unknown
sites not captured in DMR
or TRI using the Emission
Scenario Document on the
Use of Metalworking
Fluids.
Laboratory
Chemical Use
N/A
N/A
N/A
N/A
H
1,4-dioxane could be
released to air; and wastes
disposed of as hazardous
waste for this OES.
Film Cement
N/A
N/A
N/A
N/A
H
EPA expects releases of 1,4-
dioxane to be to air and
wastes disposed of as solid
waste for this OES.
76 of 616
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()ccup;ilion;d
Kxposurc
Scenario
(OI.S)
I'.sliniiilod l);iil\
Rclc;isc
Across Silcs
(kii/silo-(l:i\)
Mini in ii in | Miixiiiiiiin
Kclciisc
l);i\ s
per
Year
Kclc.isc
Mcdiii
()\cr;ill
Confidence
Nolcs
Spray Foam
Application
3.59E-3
260
Surface
Water or
POTW
M
Modeled using the
Application of Spray
Polyurethane Foam
Insulation Generic Scenario.
Printing Inks
(3D)
N/A
N/A
N/A
N/A
H
EPA expects releases of 1,4-
dioxane to be to air and
wastes disposed of as solid
waste for this OES.
Dry Film
Lubricant
N/A
N/A
N/A
N/A
H
Based on conversations the
with only known user, EPA
expects wastes to be
drummed and sent to a
waste handler with residual
wastes releasing to air or
being disposed to landfill.
Disposal
0
0.12
250
Surface
Water
M
Estimates based on TRI and
DMR data.
N/A: Not applicable. EPA does not expect 1,4-dioxane releases to water from this OES.
POTW = Publicly owned treatment works
WWT = wastewater treatment
2.2.1.2 Approach and Methodology
2.2.1.2.1 Water Release Estimates
Where available, EPA used 2018 TR1 ( ) and 2018 DMR ( ) data
to provide a basis for estimating releases. Facilities are only required to report to TRI if the
facility has 10 or more full-time employees, is included in an applicable NAICS code, and
manufactures, processes, or uses the chemical in quantities greater than a certain threshold
(25,000 pounds for manufacturers and processors of 1,4-dioxane and 10,000 pounds for users of
1,4-dioxane). Due to these limitations, some sites that manufacture, process, or use 1,4-dioxane
may not report to TRI and are therefore not included in these datasets.
For the 2018 Discharge Monitoring Report (DMR) ( 16a). EPA used the Water
Pollutant Loading Tool within EPA's Enforcement and Compliance History Online (ECHO) to
query all 1,4-dioxane point source water discharges in 2018. DMR data are submitted by
National Pollutant Discharge Elimination System (NPDES) permit holders to states or directly to
the EPA according to the monitoring requirements of the facility's permit. States are only
required to load major discharger data into DMR and may or may not load minor discharger
data. The definition of major versus minor discharger is set by each state and could be based on
discharge volume or facility size. Due to these limitations, some sites that discharge 1,4-dioxane
may not be included in the DMR dataset.
Where releases are expected but TRI and DMR data were not available or where EPA
determined TRI and DMR data did not sufficiently represent releases of 1,4-dioxane to water for
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a condition of use, releases were estimated using data from literature, relevant Emission Scenario
Documents (ESDs), and Generic Scenarios (GSs).
2.2X2,2 Estimates of Number of Facilities
Where available. EPA used 2016 CDR ( ^ I l'-\ 20T6b\2018 TRI (1 s \ •( 1 :), and
2018 DMR (U.S. EPA. 2016a) data to provide a basis to estimate the number of sites using 1,4-
dioxane within a condition of use. Generally, information for reporting sites in CDR was
sufficient to accurately characterize each reporting site's condition of use. However, information
for determining the condition of use for reporting sites in TRI and DMR is typically more
limited.
In TRI, sites submitting a Form R indicate whether they perform a variety of activities related to
the chemical, including, but not limited to whether they: produce the chemical; import the
chemical; use the chemical as a reactant; use the chemical as a chemical processing aid; and
ancillary or other use. In TRI, sites submitting Form A are not required to designate an activity.
For both Form R and Form A, TRI sites are also required to report the primary North American
Industry Classification System (NAICS) code for their site. For each TRI site, EPA used the
reported primary NAICS code and activity indicators to determine the condition of use at the
site. For instances where EPA could not definitively determine the condition of use because: 1)
the reported NAICS codes could include multiple conditions of use; 2) the site reported multiple
activities; and/or 3) the site did not report activities due to submitting a Form A, EPA made an
assumption on the condition of use to avoid double counting the site. For these sites, EPA
supplemented the NAICS code and activity information with information from company
websites, satellite images, and industry data to determine a "most likely" or "primary" condition
of use.
In DMR, the only information reported on condition of use is each site's Standard Industrial
Classification (SIC) code. EPA could not determine each reporting site's condition of use based
on SIC code alone; therefore, EPA supplemented the SIC code information with the same
supplementary information used for the TRI.
Where the number of sites could not be determined using CDR/TRI/DMR or where these data
sources were determined to insufficiently capture the number of sites within a condition of use,
EPA supplemented the available data with U.S. economic data using the following method:
• Identify the North American Industry Classification System (NAICS) codes for the industry
sectors associated with these uses.
• Estimate total number of sites using the U.S. Census' Statistics of US Businesses (SUSB)
(U.S. Census Bureau. 2015) data on total establishments by 6-digit NAICS.
• Review available ESDs and GSs for established facility estimates for each occupational
exposure scenario.
• Combine the data generated in Steps 1 through 3 to produce an estimate of the number of
sites using 1,4-dioxane in each 6-digit NAICS code, and sum across all applicable NAICS
codes for the condition of use, augmenting as needed with data from the ESDs and GSs, to
arrive at a total estimate of the number of sites within the condition of use.
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Table 2-3. Summary of EPA's Estimates for the Number of Facilities for Each PES
OiTii|>;ilion;il r.\|)osiiiv
SiTiisirio (OI'.S)
Number of
l-'iicililios
Noll's
Manufacturing
2
Based on CDR and TRI reporting (see Appendix G.6.1)
Import and Repackaging
3 to 18
Based on TRI and CDR reporting (see Appendix G.6.2)
Recycling
-
Evaluated as a part of Industrial Uses.
Industrial Uses
24
Based on TRI and DMR reporting (see Appendix G.6.3)
Functional Fluids (Open-System)
89,000
Based on TRI reporting and bounding estimate from the
2011 OECD Emission Scenario Document on the Use of
Metalworking Fluids (see Appendix G.6.4)
Laboratory Chemicals
6,844
Bounding estimate based on CDR, and U.S. Census
Bureau data for NAICS code 541380, Testing Laboratories
(see Appendix G.6.5)
Film Cement
211
Bounding estimate based on U.S. Census Bureau data for
NAICS code 512199, Other Motion Picture and Video
Industries (see Appendix G.6.6)
Spray Foam Application
1,553,559
Bounding estimate based on U.S. Census Bureau data for
NAICS code 238310, Drywall and Insulation Contractors
and the 2018 EPA generic scenario Application of Spray
Polyurethane Foam Insulation (see Appendix G.6.7)
Printing Inks (3D)
10,767
Bounding estimate based on U.S. Census Bureau data for
NAICS code 339113, Surgical Appliance and Supplies
Manufacturing (see Appendix G.6.8)
Dry Film Lubricant
8
Based on conversations with the Kansas City National
Security Campus, a manufacturer and user (see Appendix
G.6.9)
Disposal
14
Based on TRI and DMR reporting (see Appendix G.6.10)
2.2.1.2.3 Estimates of Release Days
EPA referenced Emission Scenario Documents (ESDs) or needed to make assumptions when
estimating release days for each OES. A summary along with a brief explanation is presented in
Table 2-4. below.
Table 2-4. Summary of EPA's Estimates for Release Days Expected for Each OES
OlTII|)illioilill r.\|)OMIIT
SiTiiiirio (OI'.S)
Ki'li'iisi' Dsijs
Noll's
Manufacturing
250
Assumed five days per week and 50 weeks per year with
two weeks per year for shutdown activities.
Import and Repackaging
250
Assumed five days per week and 50 weeks per year with
two weeks per year for shutdown activities.
Recycling
-
Evaluated as a part of Industrial Uses.
Industrial Uses
250
Assumed five days per week and 50 weeks per year with
two weeks per year for shutdown activities.
Functional Fluids (Open-System)
247
2011 OECD Emission Scenario Document on the Use of
Metalworking Fluids
Laboratory Chemicals
250
Assumed five days per week and 50 weeks per year with
two weeks per year for shutdown activities.
Film Cement
250
Assumed five days per week and 50 weeks per year with
two weeks per year for shutdown activities.
Spray Foam Application
260
Based on the 2018 EPA generic scenario Application of
Spray Polyurethane Foam Insulation, estimated average of
3 days spent/year at each work site.
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OiTii|>;ilion;il l.\|)oNurc
Si-i-nsirio (Or.S)
Ki-li-:isi- Dsijs
Noll's
Printing Inks (3D)
250
Assumed five days per week and 50 weeks per year with
two weeks per year for shutdown activities.
Dry Film Lubricant
56
Facility provided dry film lubricant manufacture and
application frequency.
Disposal
250
Assumed 5 days per week and 50 weeks per year.
Table 2-5 shows site-specific 1,4-dioxane releases as per 2018 TRI and DMR documents. For
each Occupational Exposure Scenario (OES), annual releases, release media, the type of water
body, and water use are also tabulated. These releases were reported to the 2018 TRI or DMR,
and these data represent a snapshot in time. Several reported water releases to TRI and DMR are
estimated only. Facilities below a requisite size are not required to report in TRI or DMR and
therefore this map is likely not representative of all the releases in the U.S. for 2018. There were
no releases reported to TRI or DMR for facilities in Alaska or Hawaii during this time period.
Additional information available in the Supplemental File [Exposure Modeling Inputs, Results,
and Risk Estimates for Incidental Ambient Water Exposure].
Table 2-5 1,4-]
Jioxane releases in TRI and DM
R(2018)
( (iill|);iil\
N si mi-
Cilj. Sisili-
OI'.S
Anniisil
Ki-li-sisi-
(kii/> n
NPDIS
Perm il
Number1
Ki-li-sisi-
Mi-disi
Siil>-\\ sili-rshi-(l or
\\ ;ik'i h(i(l\ Nsimi*1
KociTiilioiiiil
/ A(|ii;ilii'
l.ilc I si-1
BASF Corp.
Zachary, LA
Manufacturing
620.06
LA0004057
Surface
Water
Tchefuncta River:
Savannah Branch
Yes / Yes
INEOS Oxide
Plaquemine,
LA
Industrial
Uses
721.70
LAO 115100
Non-
POTW
WWT
Bayou Bourbeaux
No/No
Microdyn-Nadir
Corp
Goleta, CA
Industrial
Uses
24.04
CAZ482715
POTW
None Listed
No/No
Union Carbide
Corp:
St Charles
Operations
Hahnville, LA
Industrial
Uses
828.26
LA0000191
Surface
Water
Bayou Fortier
No/No
Suez Wts
Solutions USA
Inc
Minnetonka,
MN
Industrial
Uses
16920.83
MN0059013
POTW
South Fork Ninemile
Creek
No/No
The Dow
Chemical Co -
Louisiana
Operations
Plaquemine,
LA
Industrial
Uses
647.73
LAG530436
Surface
Water
Bayou Bourbeaux
No/No
Union Carbide
Corp: Institute
Facility
Institute, WV
Industrial
Uses
3818.80
WVG611765
Surface
Water
Rocky Fork
Yes / Yes
Union Carbide
Corp:
Seadrift Plant
Seadrift, TX
Industrial
Uses
503.49
None
Surface
Water
Private Surface Water
No/No
BASF Corp.
Monaca, PA
Industrial
Uses
2.98
PA0092223
Surface
Water
Sixmile Run-Ohio River
-Raccoon Creek
No/No
Cherokee
Pharmaceuticals
LLC
Riverside, PA
Industrial
Uses
1.66
PA0008419
Surface
Water
Susquehanna River
No/No
Dak Americas
LLC
Fayetteville,
NC
Industrial
Uses
7965.95
NC0003719
Surface
Water
Locks Creek-Cape Fear
River
Yes / Yes
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( (iill|);iil\
N;i mo
Cilj. Sliilo
OI'.S
Anniiiil
Kck'sisi*
(k«i/\ n
M'DIS
Perm il
Number1
Kcloiiso
Mi'riiii
Siil>-\\ iiiorshod or
\\;iU'i'ho(l\ \;inuJ
Kocroiilioiiiil
/ A(|iiiilic
l ile I sc1
Insiiiiiie Haul
lusiiiuie. \VV
Industrial
Lses
<>n: 5"
\\'\'()()()()()S(|
Surface
Waler
T\ lor ( reek-kauau ha
Ri\ or - Rock\ Fork
Yes Yes
Kodak Park
Division
Rochester, NY
Industrial
Uses
63.88
NY0001643
Surface
Water
Round Pond Creek,
Paddy Hill Creek
Yes / Yes
Pharmacia &
Upjohn (Former)
North Haven,
CT
Industrial
Uses
1.05
CT0001341
Surface
Water
Quinnipiac River
No/No
Philips
Electronics Plant
Parker County,
TX
Industrial
Uses
0.06
TX0113484
Surface
Water
Rock Creek
No/No
Sanderson Gulch
Drainage
Improvements
Denver, CO
Industrial
Uses
0.03
COG315474
Surface
Water
Bolden Gulch-Muddy
Creek
Yes / Yes
Ametek Inc.
U.S. Gauge
Division
Sellersville, PA
Open System
Functional
Fluid
2.64
PA0056014
Surface
Water
East Branch Perkiomen
Creek
No/No
Lake Reg
Med/Collegevill
e
Collegeville,
PA
Open System
Functional
Fluid
0.24
PA0042617
Surface
Water
Lower Perkiomen Creek
- Donny Brook
No/No
Pall Life
Sciences Inc
Ann Arbor, MI
Open System
Functional
Fluid
5.42
MI0048453
Surface
Water
Honey Creek
Yes / Yes
Beacon Heights
Landfill
Beacon Falls,
CT
Disposal
30.06
CTMIU0161
Surface
Water
Bladens River-Naugatuck
River
No/No
Ingersoll
Rand/Torrington
Facility
Walhalla, SC
Disposal
11.49
SC0049093
Surface
Water
Cane Creek-Little River
No/No
'Further detail on water releases and media of release are available at https://echo.eDa. gov/.
2.2.1.3 Assumptions and Key Sources of Uncertainty for
Environmental Releases
EPA estimated water releases using reported discharges from the 2018 TRI and the 2018 DMR.
TRI and DMR data were determined to have a "medium" confidence rating through EPA's
systematic review process. Due to reporting requirements for TRI and DMR, the number of sites
for a given OES may be underestimated. It is uncertain the extent to which sites not captured in
these databases discharge wastewater containing 1,4-dioxane and whether any such discharges
would be to surface water, POTW, or non-POTW WWT.
In addition, information on the use of 1,4-dioxane at facilities in TRI and DMR is limited;
therefore, there is uncertainty as to whether the number of facilities estimated for a given OES do
in fact represent that specific OES. If sites were categorized under a different OES, the annual
wastewater discharges for each site would remain unchanged; however, average daily discharges
may change depending on the release days expected for the different OES.
Facilities reporting to TRI and DMR only report annual discharges; to assess daily discharges,
EPA estimated the release days and averaged the annual releases over these days. There is
uncertainty that all sites for a given OES operate for the assumed duration; therefore, the average
daily discharges may be higher if sites have fewer release days or lower if they have greater
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release days. TRI-reporting facilities are required to submit their "best available data" to EPA for
TRI reporting purposes. Some facilities are required to measure or monitor emissions or other
waste management quantities due to regulations unrelated to the TRI Program (e.g., permitting
requirements), or due to company policies. These existing, readily available data are often used
by facilities for TRI reporting purposes, as they represent the best available data. When
monitoring or direct measurement data are not readily available or are known to be non-
representative for TRI reporting purposes, the TRI regulations require that facilities determine
release and other waste management quantities of TRI-listed chemicals by making reasonable
estimates. These reasonable estimates may be obtained through various Release Estimation
Techniques, including mass-balance calculations, the use of emission factors, and engineering
calculations. There may be greater uncertainty in data resulting from estimates compared to
monitoring measurements.
Furthermore, 1,4-dioxane concentrations in wastewater discharges at each site may vary from
day-to-day such that on any given day the actual daily discharges may be higher or lower than
the estimated average daily discharge.
In some cases, the number of facilities for a given OES was estimated using data from the U.S.
Census. In such cases, the average daily release calculated from sites reporting to TRI or DMR
was applied to the total number of sites reported in (U.S. Census Bureau. 2015). It is uncertain
how accurate this average release is to actual releases at these sites; therefore, releases may be
higher or lower than the calculated amount.
2.2,1.3,1 Summary of Overall Confidence in Release Estimates
Table 2-6. provides a summary of EPA's overall confidence in its release estimates for each of
the Occupational Exposure Scenarios assessed.
Table 2-6. Summary of Overall Confidence in Release Estimates by OES
Occupational
Kxposure
Scenario (OKS)
Overall Confidence in Release Kslimalcs
Manufacturing
Wastewater discharges are assessed using reported discharges from the
2018 TRI for two sites. TRI data were determined to have a "medium"
confidence rating through EPA's systematic review process. Facilities
reporting to TRI only report annual discharges; to assess daily discharges,
EPA assumed 250 days/yr. of operation and averaged the annual
discharges over the operating days. There is some uncertainty that all sites
manufacturing 1,4-dioxane will operate for this duration; therefore, the
average daily discharges may be higher if sites operate for fewer than 250
days/yr. or lower if they operate for greater than 250 days/yr. Furthermore,
1,4-dioxane concentrations in wastewater discharges at each site may vary
from day-to-day such that on any given day the actual daily discharges
may be higher or lower than the estimated average daily discharge. Based
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Kxposurc
Sccnsirio (OKS)
Overall Confidence in Release Kslimntes
on this information, EPA has a medium confidence in the wastewater
discharge estimates for the two sites in the 2018 TRI.
Import and
Repackaging
Wastewater discharges are assessed using reported discharges from the
2018 TRI and the 2018 DMR. TRI and DMR data were determined to
have a "medium" confidence rating through EPA's systematic review
process. Due to reporting requirements for TRI and DMR, the number of
sites in this OES may be underestimated. It is uncertain the extent that sites
not captured in these databases discharge wastewater containing 1,4-
dioxane and whether any such discharges would be to surface water,
POTW, or non-POTW WWT. Additionally, information on the conditions
of use of 1,4-dioxane at facilities in TRI and DMR is limited; therefore,
there is some uncertainty as to whether all the sites assessed in this section
are performing repackaging (of imported or domestically manufactured
volumes) rather than a different OES. If the sites were categorized under a
different OES, the annual wastewater discharges for each site would
remain unchanged; however, average daily discharges may change
depending on the number of operating days expected for the OES.
Facilities reporting to TRI and DMR only report annual discharges; to
assess daily discharges, EPA assumed 250 days/year of operation and
averaged the annual discharges over the operating days. There is some
uncertainty that all sites importing or repackaging 1,4-dioxane will operate
for this duration; therefore, the average daily discharges may be higher if
sites operate for fewer than 250 days/yr. or lower if they operate for
greater than 250 days/yr. Furthermore, 1,4-dioxane concentrations in
wastewater discharges at each site may vary from day-to-day such that on
any given day the actual daily discharges may be higher or lower than the
estimated average daily discharge. Based on this information, EPA has a
medium confidence in the wastewater discharge estimates.
Recycling
Assessed as part of industrial uses.
Industrial Uses
Wastewater discharges are assessed using reported discharges from the
2018 TRI and the 2018 DMR. TRI and DMR data were determined to
have a "medium" confidence rating through EPA's systematic review
process. Due to reporting requirements for TRI and DMR, the number of
sites in this OES may be underestimated. It is uncertain the extent that sites
not captured in these databases discharge wastewater containing 1,4-
dioxane and whether any such discharges would be to surface water,
POTW, or non-POTW WWT. Additionally, information on the conditions
of use of 1,4-dioxane at facilities in TRI and DMR is limited; therefore,
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Kxposurc
Sccnsirio (OKS)
Overall Confidence in Release Kslimntes
there is some uncertainty as to whether all the sites assessed in this section
are using 1,4-dioxane in an industrial use capacity rather than a different
OES. If the sites were categorized under a different OES, the annual
wastewater discharges for each site would remain unchanged; however,
average daily discharges may change depending on the number of
operating days expected for the OES.
Facilities reporting to TRI and DMR only report annual discharges; to
assess daily discharges, EPA assumed 250 days/yr. of operation and
averaged the annual discharges over the operating days. There is some
uncertainty that all sites using 1,4-dioxane for industrial uses will operate
for this duration; therefore, the average daily discharges may be higher if
sites operate for fewer than 250 days/yr. or lower if they operate for
greater than 250 days/yr. Furthermore, 1,4-dioxane concentrations in
wastewater discharges at each site may vary from day-to-day such that on
any given day the actual daily discharges may be higher or lower than the
estimated average daily discharge. Based on this information, EPA has a
medium confidence in the wastewater discharge estimates.
Functional
Fluids (Open-
System)
Wastewater discharges are assessed using reported discharges from the
2018 TRI and the 2018 DMR. TRI and DMR data were determined to
have a "medium" confidence rating through EPA's systematic review
process. Due to reporting requirements, the number of sites reflected in
TRI and DMR is assessed as an underestimate. EPA included the
estimated 89,000 metal products and machinery facilities estimated by the
ESD on the Use of Metalworking Fluids as a conservative bounding
estimate for the possible range of sites. It is uncertain the extent that sites
not captured in the TRI and DMR databases discharge wastewater
containing 1,4-dioxane and whether any such discharges would be to
surface water, POTW, or non-POTW WWT. Additionally, information on
the conditions of use of 1,4-dioxane at facilities in TRI and DMR is
limited; therefore, there is some uncertainty as to whether all the sites
assessed in this section are using 1,4-dioxane in an open system functional
fluids capacity rather than a different OES. If the sites were categorized
under a different OES, the annual wastewater discharges for each site
would remain unchanged; however, average daily discharges may change
depending on the number of operating days expected for the OES.
Facilities reporting to TRI and DMR only report annual discharges; to
assess daily discharges, EPA assumed 247 days/yr. of operation and
averaged the annual discharges over the operating days. There is some
uncertainty that all sites using 1,4-dioxane for open system functional
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Overall Confidence in Release Kslimntes
fluids will operate for this duration; therefore, the average daily discharges
may be higher if sites operate for fewer than 247 days/yr. or lower if they
operate for greater than 247 days/yr. Furthermore, 1,4-dioxane
concentrations in wastewater discharges at each site may vary from day-to-
day such that on any given day the actual daily discharges may be higher
or lower than the estimated average daily discharge. Based on this
information, EPA has a medium confidence in the wastewater discharge
estimates.
Laboratory
Chemicals
Water releases from laboratory uses are unlikely as laboratories collect and
track spent and unspent chemicals prior to hazardous waste disposal. The
releases of 1,4-dioxane from laboratory uses are to air (through volatile
releases into the indoor laboratory air and/or through laboratory fume
hoods to atmospheric air) and liquid wastes of 1,4-dioxane are handled as
hazardous waste. The commercial analytical laboratories and university
laboratories handle their wastes as hazardous waste and they are not
allowed to discharge wastes to POTW via pouring the wastes down the
drain. Small volume of 1,4-dioxane could be inadvertently spilled inside a
laboratory and fractional amount may not be properly captured through
spill containment techniques, resulting in 1,4-dioxane being discharged to
POTW (through floor or sink drains). EPA does not evaluate exposures
due to spills. Due to the high volatility of 1,4-dioxane, any spilled 1,4-
dioxane not captured by spill containment materials could release to air.
The number of laboratories assessed is based on the U.S. Census Bureau
data for NAICS code 541380, Testing Laboratories. This NAICS code was
chosen based on the main use of 1,4-dioxane in the laboratory setting: as a
reference standard for determination of analytes in bulk pharmaceuticals.
There are other types of laboratories, such as university laboratories and
analytical laboratories, that may use 1,4-dioxane that are not represented in
this NAICS code. However, it is unknown how many of laboratories
within each of these categories use 1,4-dioxane. Thus, it is possible that the
inclusion of only NAICS code 541380 could overrepresent the number of
laboratories that use 1,4-dioxane. The direction of bias, whether the 6,844
number of sites is an underestimate or overestimate of the number of
laboratories using 1,4-dioxane, is unknown. However, EPA has high
confidence in the assessment of no or negligible releases to water or
POTWs. This high confidence in no releases of water mitigates the
uncertainties in the estimate of number of sites. Based on this information,
EPA has a high confidence in the wastewater discharge estimates.
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Kxposurc
Sccnsirio (OKS)
Overall Confidence in Release Kslimntes
Film Cement
EPA assessed no wastewater discharges for this OES. The small glue
bottles could be disposed of as solid waste without rinsing them in a sink.
There is some uncertainty as to whether and what quantity of 1,4-dioxane
could remain in the small glue bottles when disposed. However, due to the
small quantities of the glue and high volatility of the 1,4-dioxane, EPA
expects any residual 1,4-dioxane to evaporate to the air or remain in the
solid waste stream. Small amount of film cement could inadvertently be
spilled inside a facility, but due to the higher viscosity and small quantities
of the substance, it will likely be cleaned up via wiping and disposed of as
solid waste. However, EPA has not identified any data on the quantities or
frequencies of accidental spills and does not evaluate exposures due to
water releases resulting from such spills. Based on this information, EPA
has a high confidence in the release assessment.
Spray Foam
Application
Wastewater discharges are assessed using EPA's container residual model.
EPA defined operating days, operating days per site, foam thickness, and
mass fraction of B-side in final formulation from the Generic Scenario for
Application of Spray Polyurethane Foam Insulation. The parameters for
average roofing area were defined from homeadvisor.com and
houselogic.com. The parameters for density and mass fraction of the 1,4-
dioxane in the B-side formulation were defined from a spray foam
producer's technical fact sheet. This EPA model addresses residual spray
polyurethane foam in the container only and is based on industry averages,
such as roof size. As a result of the model limitations and uncertainties due
to various activities including container cleaning and product handling
could vary dramatically on a site-by-site basis. It is uncertain to the extent
these water releases are over- or underestimated.
EPA determined that there were 17,857 establishments that fell into
NAICS code 238310, for Drywall and Insulation Contractors. The GS
estimates that a contractor spends three days at a job site before moving to
the next job site and further estimates that a contractor works 260 days per
year. Assuming a contractor works at only a single job site at a time, EPA
calculates that a contractor works at approximately 87 job sites per year
(260 working days divided by three days per job site). EPA multiplied the
number of contractors by 87 to determine a bounding limit for the number
of job sites in a year at which all contractors could potentially discharge
container residuals down a drain to a POTW or directly on the ground,
which could eventually reach surface waters. Based on this information,
EPA has a low confidence in the release assessment.
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Overall Confidence in Release Kslimntes
Printing Inks
(3D)
EPA assessed no wastewater discharges for this OES. EPA expects spent
printing ink containers, shavings or fragments, or waste scraps to be
disposed of as solid waste. There is some uncertainty as to whether and
how much 1,4-dioxane may remain in 3D printed products and waste
scraps. However, due to the volatility of 1,4-dioxane, EPA expects 1,4-
dioxane to evaporate from any printed object, shavings or fragments, or
other printed material deposited to the floor or work surface prior to it
being cleaned and disposed of. Based on this information, EPA has a high
confidence in the release assessment.
Dry Film
Lubricant
EPA assessed no wastewater discharges for this OES based on
conversations with the only known facility to use the product. All dry film
lubricant materials are mixed and handled in a laboratory setting
underneath a fume hood. The material is sprayed onto components in a
spray booth with ventilation. Wastes are containerized and handled as
wastes for removal by a waste handler. There is some uncertainty as to
whether and how much 1,4-dioxane may be deposited on the floor or other
surfaces as a result of overspray or spills. However, due to the volatility of
1,4-dioxane and expected spill clean-up methods of the laboratory setting,
EPA expects deposited overspray or spilled 1,4-dioxane to evaporate to the
air or be contained in spill containment materials and handled as waste.
EPA does not evaluate exposures due to spills. Based on this information,
EPA has a high confidence in the release assessment.
Disposal
Wastewater discharges are assessed using reported discharges from the
2018 TRI and the 2018 DMR. TRI and DMR data were determined to
have a "medium" confidence rating through EPA's systematic review
process. Due to reporting requirements for TRI and DMR, the number of
sites in this OES may be underestimated. It is uncertain the extent that sites
not captured in these databases discharge wastewater containing 1,4-
dioxane and whether any such discharges would be to surface water,
POTW, or non-POTW WWT. Additionally, information on the conditions
of use of 1,4-dioxane at facilities in TRI and DMR is limited; therefore,
there is some uncertainty as to whether all the sites assessed in this section
are using 1,4-dioxane in a disposal capacity rather than a different OES. If
the sites were categorized under a different OES, the annual wastewater
discharges for each site would remain unchanged; however, average daily
discharges may change depending on the number of operating days
expected for the OES.
Facilities reporting to TRI and DMR only report annual discharges; to
assess daily discharges, EPA assumed 250 days/yr. of operation and
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Occupational
Kxposure
Scenario (OKS)
Overall Confidence in Release Kslimalcs
averaged the annual discharges over the operating days. There is some
uncertainty that all sites using 1,4-dioxane for disposal will operate for this
duration; therefore, the average daily discharges may be higher if sites
operate for fewer than 250 days/yr. or lower if they operate for greater than
250 days/yr. Furthermore, 1,4-dioxane concentrations in wastewater
discharges at each site may vary from day-to-day such that on any given
day the actual daily discharges may be higher or lower than the estimated
average daily discharge. Based on this information, EPA has a medium
confidence in the wastewater discharge estimates.
2,3 Environmental Exposures
EPA presents an analysis on environmental exposures to aquatic species based on releases to
surface water. The 2014-2015 TRI dataset used as the basis for TRI releases in the first-tier
aquatic exposure modeling was updated using data from TRI Explorer. In response to public
comment, the TRI analysis was also augmented to include indirect discharge sites, i.e., those
reporting off-site waste transfers to POTWs for treatment. 1,4-dioxane is present in
environmental media such as groundwater, surface water, and air. EPA conducted analysis of the
environmental release pathways based on a qualitative assessment of the physical-chemical
properties and fate of 1,4-dioxane in the environment (described in Section 2.1), and a
quantitative comparison of hazards and exposures for aquatic organisms as described in Section
4.1.
2.3.1 Environmental Exposures - Aquatic Pathway
An aquatic exposure assessment was conducted using TRI and DMR release information to
model predicted surface water concentrations near discharging facilities. To examine whether
near-facility surface water concentrations could approach 1,4-dioxane's concentrations of
concern, EPA employed a conservative approach, using available modeling tools and data to
estimate near-facility surface water concentrations resulting from reported releases of 1,4-
dioxane to surface water. High-end surface water concentrations {i.e., those obtained assuming
low receiving water body stream flows) from all \ AS V *„0M_ (l_ _S runs ranged
from 2.37E-08 |ig/L to 11,500 |ig/L. See Appendix E for results of this first-tier analysis,
including the site-specific discharges modeled. Facility-specific release information is shown in
the supplemental file [Aquatic Exposure Screen Facility Information].
In Section 2.2, more recent 2018 TRI and DMR data were used to estimate surface water releases
for Occupational Exposure Scenarios (OES) within the scope of this evaluation. These estimated
releases were as high as 67.7 kg/site/day for 250 days - for the Industrial Uses OES. The releases
modeled as part of this first-tier aquatic exposure assessment (see Appendix E) were generally of
greater magnitude, as they were based on top dischargers (per DMR and TRI), irrespective of
scoped conditions of use or OES. Modeling the maximum water releases from the Industrial Use
OES through E-FAST using conservative assumptions {i.e., 67.7 kg/site/day for 250 days, 24
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unspecified sites, generic SIC code with conservative stream flow assumptions, and 0% removal
during wastewater treatment) results in a high-end surface water concentration of 8,724 |ig/L,
which is still less than the chronic COC of 14,500 |ig/L. Therefore, the incorporation of the more
recent OES release estimates would not have altered the conclusions of the screening-level
assessment undertaken during problem formulation.
National-scale monitoring data from EPA's STOrage and RETreival (STORET) and National
Water Information System (NWIS) for the past ten years, shows that 1,4-dioxane is detected in
surface water. The data points show a detection rate of approximately 6% for this media, with
detections ranging from 0.568 to 100 |ig/L.
2,4 Human Exposures
2.4.1 Occupational Exposures
Occupational exposures could be direct or indirect and the magnitude of exposure for an
occupational worker could be a function of timeframe of exposures. The duration of exposure,
which depends on occupational mobility, could vary for different population groups. ONUs are
workers at the facility who neither directly perform activities near the 1,4-dioxane source area
nor regularly handle 1,4-dioxane. Workers that are directly handling 1,4-dioxane and/or perform
activities near sources of 1,4-dioxane are in the near field and are called workers throughout this
risk evaluation. The near-field is defined as a volume of air within one-meter in any direction of
the worker's head and the far-field comprises the remainder of the room (Tielemans et at.. 2008).
The source areas/exposure zones are determined by several factors such as the quantity of 1,4-
dioxane releases, ventilation of the facility, vapor pressure and emission potential of the
chemical, process temperature, size of the room, job tasks, and modes of chemical dispersal from
activities (Leblanc et ai. 2018). Corn and Esmen (1979) indicated that the assignment of zones is
a professional judgment and not a scientific exercise. The job classifications for occupational
users and non-occupational users are also dependent on the conditions of use of 1,4-dioxane, size
and type of facility, and operation practice. The activities performed by occupational users and
non-occupational users could overlap depending on conditions of use and facility. A large
manufacturing facility includes supervisors, managers, and tradesmen, who may be co-located in
the manufacturing floor, do not perform tasks that result in the same level of exposures as
workers. However, a small or medium facility may have employees who perform activities as
occupational users and non-occupational users throughout the workday. Occupational users and
non-occupational users would not be able to be distinguished in groupings of employees due to
overlapping tasks they typically perform.
EPA evaluated acute and chronic inhalation exposures to workers and ONUs in association with
1,4-dioxane manufacturing, import and repackaging, its use in industrial applications, open
system functional fluids, spray polyurethane foam insulation, laboratory chemicals, film cement,
printing inks (3D), dry film lubricant, and disposal. Appendix G.6 provides additional detail on
the mapping of the conditions of use to the Occupational Exposure Scenario (OES) groups used
in this risk evaluation. EPA used inhalation monitoring data from literature sources where
available and that met data evaluation criteria (see Section 1.5); and modeling approaches to
estimate potential inhalation exposures where inhalation monitoring data were not available.
EPA modeled inhalation exposures using the following models: the EPA AP-42 Loading Model,
the EPA Mass Balance Inhalation Model, and the EPA Total PNOR PEL-Limiting Model. More
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information about these models may be found in Section 2.4.1.1. EPA also estimated dermal
doses for workers in these scenarios since dermal monitoring data were not reasonably available.
EPA modeled dermal doses using the EPA Dermal Exposure to Volatile Liquids Model which
improves upon the existing EPA 2-Hand Dermal Exposure model by accounting for the effect of
evaporation on dermal absorption for volatile chemicals and the potential exposure reduction due
to glove use. More information about this model and how it was used may be found in Section
2.4.1.1.13 and Appendix G.7. EPA does not expect dermal exposures for occupational non-users
due to no direct contact with the chemical.
Components of the Occupational Exposure Assessment
The occupational exposure assessment for each condition of use comprises the following
components:
• Process Description of the condition of use, including the role of the chemical in the use;
process vessels, equipment, and tools used during the condition of use; and descriptions
of the worker activities, including an assessment for potential points of worker exposure.
• Number of Sites that use the chemical for the given condition of use.
• Number of Workers and ONUs potentially exposed to the chemical for the given
condition of use. CDR data to identify the number of sites where exposure may occur and
approximate workers who may be exposed to the chemicals. Unless mentioned otherwise
in this report, the total number of workers and ONUs are number of personnel per site per
day. The details on estimation of the number of workers and ONUs are discussed in
Sections 2.4.1.1 for each condition of use, and Appendix G.5.
• Central tendency and high-end estimates of inhalation exposure to workers and
occupational non-users. See Section 2.4.1.1 for a discussion of EPA's statistical analysis
approach for assessing inhalation exposure.
• Dermal Exposure estimates for multiple scenarios, accounting for simultaneous
absorption and evaporation, and different protection factors of glove use.
• Users include female and male adult workers (>16 years old) exposed to 1,4-dioxane for
8-hour exposure
• ONUs include female and male adult workers (>16 years old) exposed to 1,4-dioxane
indirectly by being in the same work area of the building.
The OSHA respiratory protection standard, 29 CFR § 1910.134(a)(1), requires employers to
utilize the hierarchy of controls for reducing or removing chemical hazards. The hierarchy of
controls indicates that the most effective control is elimination, followed by substitution, and
then engineering controls. These are followed by administrative controls and the use of PPE. The
respiratory protection standard requires the use of feasible engineering controls as the primary
means to control air contaminants. Respirators are required when effective engineering controls
are not feasible. They are the last means of worker protection in the hierarchy of controls. When
effective engineering and administrative controls are not feasible to adequately protect workers
and maintain compliance with other OSHA statutory and regulatory requirements under 29 CFR
§ 1910.1000, employers should utilize respiratory protective equipment (29 CFR § 1910.134).
If information and data indicate that use or handling of a chemical cannot, under worst-case
conditions, release concentrations of a respiratory hazard above a level that would trigger the
need for a respirator or require use of a more protective respirator, employees would not be
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assumed to wear them. Employers also use engineering or administrative controls to bring
employee exposures below permissible exposure limits for airborne contaminants. Respirators
would be used to supplement engineering and administrative controls only when these controls
cannot be feasibly implemented to reduce employee exposure to permissible levels.
2.4.1.1 Occupational Exposures Approach and Methodology
EPA performed a literature search to find descriptions of processes involving 1,4-dioxane and
worker activities that could potentially result in occupational exposures. The on-topic sources
were then screened against inclusion criteria in the RESO (Receptors, Exposures,
Setting/Scenario, Outcomes) statement and the relevant sources were further evaluated using the
data quality criteria in the Application of Systematic Review in TSCA Risk Evaluations (U.S.
EPA. 2018b). EPA identified 98 potentially useful sources based on literature search, of which
65 sources were determined to have potentially useful exposure information (see Figure 1-6)
Sources with an overall confidence score of less than 4 were considered acceptable in the
systematic review. Of these 65 sources, 27 were deemed to be acceptable. Sixteen of the
acceptable sources were determined to have exposure data relevant to the conditions of use and
were therefore used in this evaluation. A summary of the data quality evaluation results for the
1,4-dioxane occupational exposure sources are presented in Appendix G.l ^ Systematic Review
Supplemental File for the TSCA Risk Evaluation: Data Quality Evaluation for Occupational
Exposure and Release Data").
For the integration of occupational exposure data/information, EPA considered any relevant data
that it determined to be acceptable for use. The hierarchy found later in this section under
"General Inhalation Exposures Approach and Methodology" presents the preferences among the
primary types of data/information to be analyzed, synthesized and integrated for the occupational
exposure assessments in this risk evaluation.
Additional Data Sources
EPA used a variety of sources to supplement the data found through the Systematic Review
process. The additional sources included relevant NIOSH Health Hazard Evaluations, Generic
Scenarios, and Emission Scenario Documents. These sources were sometimes used to provide
process descriptions of the conditions of use as well as estimates for the number of sites and
worker counts. An example is shown below.
CDR data were used to provide a basis to estimate the numbers of sites, workers, and ONUs.
EPA supplemented the available CDR data with U.S. economic data using the following
methods:
• Identification of the North American Industry Classification System (NAICS) codes for
the industry sectors associated with the uses;
• Estimation of total employment by industry/occupation combination using the Bureau of
Labor Statistics" Occupational Employment Statistics (OES) data (BLS. 2016);
• Refinement of the OES estimates where they are not sufficiently detailed by using the
U.S. Census' Statistics of US Businesses (SUSB) (U.S. Census Bureau. 2016a) data on
total employment by 6-digit NAICS;
• Use market penetration data (where available) to estimate the percentage of employees
likely to be using 1,4-dioxane instead of other chemicals;
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• Combine the data generated in previous four bullets to produce an estimate of the number
of establishments and employees using 1,4-dioxane in each industry/occupation
combination, and sum these to arrive at a total estimate of the number of employees with
exposure.
Market penetration data for 1,4-dioxane were not available for any condition of use. Without
these data, it is unknown what portion of a given set of sites use 1,4-dioxane. In absence of this
information, EPA generally assumes that all sites involve 1,4-dioxane. Therefore, site, worker,
and ONU numbers considered could be overestimated.
EPA developed occupational exposure values representative of central tendency conditions and
high-end conditions. A central tendency was assumed to be representative of occupational
exposures in the center of the distribution for a given condition of use. EPA used the 50th
percentile (median), mean (arithmetic or geometric), or mode of a distribution as representative
of the central tendency scenario. EPA's preference was to provide the 50111 percentile of the
distribution. However, if the full distribution was not known, EPA assumed that the mean, mode,
or midpoint of the distribution represented the central tendency depending on the statistics
available for the distribution (U.S. EPA. 1992).
A high-end exposure estimate was defined to be representative of occupational exposures that
occur at probabilities above the 90th percentile but below the 99.9th percentile, the exposure of
the individual with the highest exposure ( 32). EPA considered high-end results at
the 95th percentile. If the 95111 percentile was not available, EPA used a different percentile
greater than or equal to the 90th percentile but less than or equal to the 99th percentile, depending
on the statistics available for the distribution. If the full distribution was not known and the
preferred statistics were not available, EPA estimated a maximum or bounding estimate in lieu of
the high-end occupational exposure estimates. In each case, EPA makes clear the actual
percentile that was used.
For occupational exposures, EPA used measured or modeled air concentrations to calculate
exposure concentration metrics essential for risk assessment. These exposures are presented as 8-
hour time weighted averages (TWAs) and used to calculate acute exposure concentrations
(AECs), average daily concentrations (ADCs), and lifetime average daily concentrations
(LADCs). The ADC is used to estimate chronic, non-cancer risks and the LADC is used to
estimate chronic, cancer risks. These calculations required additional parameter inputs, such as
years of exposure, exposure duration and frequency, and lifetime years. See Appendix G.2 for
more information about parameters and equations used to calculate acute and chronic exposures.
For the final exposure result metrics, each of the input parameters (e.g., air concentrations,
working years, exposure frequency, lifetime years) were point estimates (i.e., a single descriptor
or statistic, such as central tendency or high-end). EPA estimated a central tendency and high-
end for each final exposure result metric using deterministic calculations and combinations of
point estimates of each parameter. EPA documented the method and rationale for selecting
parametric combinations to be representative of central tendency and high-end. A probabilistic
approach was generally not used in cases where monitoring-based data were available, but
models for that condition of use were not.
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For occupational exposures, EPA used measured or estimated air concentrations to calculate
exposure concentration metrics required for risk assessment, such as average daily concentration
and lifetime average daily concentration. These calculations required additional parameter
inputs, such as years of exposure, exposure duration and frequency, and lifetime years. EPA
estimated exposure concentrations from monitoring data, modeling, or occupational exposure
limits, and used each of these in its evidence integration to assess the strength of the evidence.
For each use, EPA considered the assessment approach, the quality of the data and models, and
uncertainties in assessment results to determine an overall level of confidence for the full shift
data and modeled estimates. For the inhalation concentration monitoring data, strength of
confidence is improved by the following factors: a) larger number of sites monitored, b) worker
population groups included in monitoring, and c) higher systematic review data quality ratings.
The strength of confidence in monitoring data is reduced by uncertainty of the representativeness
of these data toward the true distribution of inhalation concentrations for the industries and sites
covered by the use. For modeled air concentrations, strength of confidence is improved by the
following factors: a) model validation, and b) full distributions of input parameters. The strength
of confidence in modeled air concentration estimates is reduced by the uncertainty of the
representativeness of the model or parameter inputs toward the true distribution of inhalation
concentrations for the industries and sites covered by the use. For dermal dose rate estimates,
strength of confidence is improved by the use of actual data rather than assumptions for input
parameters. The strength of confidence in dermal potential dose rates is reduced by the
uncertainty of the representativeness of the of the model or parameter inputs toward the true
distribution of dermal doses for the industries and sites covered by the use.
Monitoring data of 1,4-dioxane considered from various types and key sources including the
following:
• Personal sample monitoring data from directly applicable scenarios (e.g., personal
breathing zone (PBZ); non-CBI data from the Manufacturing scenario (such as BASF);
• Area sample monitoring data from directly applicable scenarios (e.g., NIOSH HHE for
the Film Cement scenario);
• Personal sample monitoring data from potentially applicable or similar scenarios (e.g.,
PBZ data from a manufacturing site that makes a chemical that has physical properties
similar to 1,4-dioxane);
• Area samples monitoring data from potentially applicable or similar scenarios (e.g., area
data from a site that processes a chemical that has physical properties similar to 1,4-
dioxane)
Modeling approaches include the following monitoring data and key mathematical
methodologies:
• Surrogate monitoring data from chemicals with similar properties. Surrogate data were
used to estimate the inhalation exposure from the thickness verification step in the Spray
Foam Application condition of use. Appendix G.6.7 provides additional details on this
use of surrogate data.
• Fundamental modeling approaches (e.g., modeling of the Spray Foam Application
scenario); and
• Statistical regression modeling approaches
Occupational exposure limits considered include, but are not limited to, the following:
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• Company-specific OELs (for site-specific exposure assessments, e.g., there is only one
manufacturer who provides to EPA their internal OEL but does not provide monitoring
data)
• OSHA PEL
• Other occupational exposure limits (ACGIH TLV, NIOSH REL, Occupational Alliance
for Risk Science (OARS) workplace environmental exposure level (WEEL) [formerly by
AMA])
EPA reviewed workplace inhalation monitoring data collected by government agencies such as
OSHA and NIOSH, and monitoring data found in published literature (i.e., personal exposure
monitoring data and area monitoring data). Studies were evaluated using the evaluation strategies
laid out in the Application of Systematic Review in TSCA Risk Evaluations ( :018b).
The supplemental file provides details of the data evaluations, including scores for each metric
and the overall study score for each information source.
Exposure values were calculated from the datasets provided in the sources depending on the size
of the dataset. For datasets with six or more data points (U.S. EPA. 1994a; Hawkins et al I' >02),
central tendency and high-end exposures were estimated using the 50th percentile and 95111
percentile, respectively. For datasets with three to five data points, central tendency exposure
was calculated using the 50th percentile and the maximum was presented as the high-end
exposure estimate. These data sets are considered to have relatively more uncertainty than
datasets with more datapoints. For datasets with two data points, the midpoint was presented as a
midpoint value and the higher of the two values was presented as a higher value. These data sets
are generally considered to have high uncertainty. Finally, data sets with only one data point are
considered indicating appropriate rationale, but EPA cannot determine the statistical
representativeness of the values given the small sample size. Existing monitoring data such as
worker breathing zone data may have been collected at areas or facilities where 1,4-dioxane
releases have not occurred. As such these data sets are considered to have uncertainty associated
with them.
EPA estimated exposures using the following models when exposure monitoring data were
unavailable:
• EPA AP-42 Loading Model estimates vapor releases that occur when vapor is displaced
by liquid during container loading. It calculates a vapor generation rate (G) using the
physio-chemical properties of the chemical ( )
• EPA Mass Balance Inhalation Model estimates occupational inhalation exposures
assuming the air immediately around the source of exposure behaves as a well-mixed
zone. EPA used the vapor generation rate (G), calculated using the EPA AP-42 Loading
Model, in conjunction with this model to develop estimates of inhalation exposure (U.S.
).
• EPA Total PNOR PEL-LimitinsModel estimates occupational inhalation exposures to
particulates containing the chemical. The estimate assumes that the worker exposure is
equal to the OSHA Permissible Exposure Limit (PEL) for Particulates, Not Otherwise
Regulated (PNOR), total particulate ( ).
Specific descriptions of the use of these models for each condition of use can be found in
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Sections 2.4.1.1.1 -2.4.1.1.12.
Respiratory Protection
OSHA's Respiratory Protection Standard (29 CFR § 1910.134) provides a summary of respirator
types by their assigned protection factor (APF). OSHA defines the APF to mean: the workplace
level of respiratory protection that a respirator or class of respirators is expected to provide to
employees when the employer implements a continuing, effective respiratory protection program
according to the requirements of the OSHA Respiratory Protection Standard. OSHA
recommends employers utilize the hierarchy of controls for reducing or removing hazardous
exposures. The most effective controls are elimination, substitution, or engineering controls.
Respirators, and any other personal protective equipment, are the last means of worker protection
in the hierarchy of controls and should only be considered when process design and engineering
controls cannot reduce workplace exposure to levels within regulation.
The United States has several regulatory and non-regulatory exposure limits for 1,4-dioxane: an
OSHA PEL of 100 ppm 8-hour TWA (360 mg/m3) with a skin notation, a NIOSH
Recommended Exposure Limit (REL) of 1 ppm (3.6 mg/m3) as a 30-minute ceiling and an
American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Value
(TLV) of 20 ppm TWA (72 mg/m3) (OSI 35). If respirators are necessary in atmospheres
that are not immediately dangerous to life or health, workers must use NIOSH-certified air-
purifying respirators or NIOSH-approved supplied-air respirators with the appropriate APF.
Respirators that meet these criteria include air-purifying respirators with organic vapor
cartridges. Respirators must meet or exceed the required level of protection listed in Table 2-7. to
meet NIOSH recommended a 1 ppm (3.6 mg/m3, 30 minute) ceiling because 1,4-dioxane is a
potential human carcinogen (29 CFR § 1990).
The respirators should be used when effective engineering controls are not feasible as per
OSHA's 29 CFR § 1910.134. The knowledge of the range of respirator APFs is intended to assist
employers in selecting the appropriate type of respirator that could provide a level of protection
needed for a specific exposure scenario. Table 2-7. lists the range of APFs for respirators. The
complexity and burden of wearing respirators increases with increasing APF. The APFs are not
to be assumed to be interchangeable for any conditions of use, any workplace, or any worker or
ONU.
Table 2-7. Assigned Protection Factors for Respirators in OSHA Standard 29 CFR §
1910.134
Type of Respirator
Quarter
Mask
Half
Mask
1 Mil
l-'acepiece
Helmet/
Mood
1 ,oose-
I'illiii"
Kacepiece
1. Air-Purifying Respirator
5
10
50
2. Power Air-Purifying
Respirator (PAPR)
50
1,000
25/1,000
25
3. Supplied-Air Respirator (SAR) or Airline Respirator
Demand mode
10
50
Continuous flow mode
50
1,000
25/1,000
25
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Pressure-demand or other
positive-pressure mode
50
1,000
4. Self-Contained Breathing Apparatus (SCBA)
Demand mode
10
50
50
Pressure-demand or other
positive-pressure mode (e.g.,
open/closed circuit)
10,000
10,000
Source: 29CFR§ 1910.134
The performance of respiratory protective equipment programs varied across industry. The
National Institute for Occupational Safety and Health (NIOSH) and the U.S. Department of
Labor's Bureau of Labor Statistics (BLS) conducted a voluntary survey of U.S. employers
regarding the use of respiratory protective devices between August 2001 and January 2002. The
survey had a 75.5% response rate (NIOSH. 2003). A voluntary survey may not be representative
of all private industry respirator use patterns as some establishments with low or no respirator
use could have chosen to not respond to the survey. Therefore, results of the survey could
potentially be biased towards higher respirator use. NIOSH and BLS estimated about 619,400
establishments used respirators for voluntary or required purposes (including emergency and
non-emergency uses). About 281,800 establishments (45%) were estimated to have had
respirator use for required purposes in the 12 months prior to the survey. The 281,800
establishments estimated to have had respirator use for required purposes were estimated to be
approximately 4.5% of all private industry establishments in the U.S. at the time (NIOSH. 2003).
In a more recent article. Bell et al. (2012) reported cross-industry analysis for 20 companies, the
majority representing small- or medium-sized enterprises, across a number of different sectors.
Four distinct groups emerged from the 20 sites, ranging from learners (low theoretical
competence and practical control - 4 sites), developers (acceptable theoretical competence and
low practical control - 5 sites), and fortuitous (low theoretical competence and acceptable
practical control - two sites), to proficient (acceptable theoretical competence and practical
control - nine sites). None of the companies were achieving optimal control using the respiratory
protective equipment. Widespread inadequacies were found with program implementation,
particularly training, supervision, and maintenance. In a separate study, the University of
Pittsburgh, CDC, and RAND Corporation used the OSHA data base to examine all inspections in
manufacturing in 47 states from 1999 through 2006 (Men del off et al.. 2013); the examination
starts with 1999 because an expanded OSHA respiratory program standard became effective in
late 1998. The article identified inspections and establishments at which respiratory protection
violations were cited, and it compares the prevalence of violations by industry with the
prevalence reported in the BLS survey of respirator use. The pattern of noncompliance across
industries mostly mirrored the survey findings about the prevalence of requirements for
respirator use. The probability of citing a respiratory protection violation was similar across
establishment size categories, except for a large drop for establishments with over 200 workers.
The presence of a worker accompanying the inspector increased the probability that a respiratory
program violation could be cited; the presence of a union slightly decreased it. OSHA's fatality
reports from 1990 to 2012 were analyzed by Cowan et al. (2017) to characterize historical trends
in fatalities associated with respirators. Industry- and time-specific trends were evaluated to
determine the effect on respirator-related fatalities. Cowan et al. (2.017) reported 174 respirator
related deaths, and 79% of the fatalities were associated with asphyxia associated with improper
employee use or lack of employer compliance.
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Estimating the Number of Workers and Occupational Non-Users (ONUs)
EPA used the following steps to estimate the number of workers and ONUs who may be
potentially exposed to 1,4-dioxane in each condition of use: 1) identified the North American
Industry Classification System (NAICS) codes for the industry sectors associated with each
condition of use; 2) estimated total employment by industry/occupation combination using the
Bureau of Labor Statistics" Occupational Employment Statistics (OES) data (BLS. 2016); 3)
refined the OES estimates where they are not sufficiently granular by using the U.S. Census'
(2016b) Statistics of U.S. Businesses (SUSB) data on total employment by 6-digit NAICS; 4)
estimated the percentage of employees likely to be using 1,4-dioxane instead of other chemicals
(i.e., the market penetration of 1,4-dioxane in the condition of use); 5) estimated the number of
sites and number of potentially exposed employees per site; and 6) estimated the number of
potentially exposed employees within the condition of use.
See Appendix G.5 for more information about the approach used to estimate potentially exposed
workers and ONUs.
2A.\AA_ Manufacturing
1,4-Dioxane is commercially manufactured by the acid-catalyzed dehydration of diethylene
glycol, which in turn is obtained from the hydrolysis of ethylene oxide. The information and data
quality evaluation to assess occupational exposures during manufacturing is listed in Table 2-8..
See Appendix G.l for additional details.
Table 2-8. Manufacturing Worker Exposure Data Evaluation
Worker Acli\ il\ or
Siiinplin^ Locution
Diilii Tjpe
Number ol°
Siiinples
l);il;i Qu;ilil\ Killing
Source Reference
Unknown
PBZ Monitoring
28
High
)
Routine duties,
neutralization,
evaporator dump
PBZ Monitoring
4
High
BASF (2017)
N/A
CDR Data - Number of sites
and workers
N/A
High
I S <20160
Occupational exposures to 1,4-dioxane during manufacturing were estimated by evaluating full-
shift, personal breathing zone (PBZ) monitoring data obtained by BASF during internal
industrial hygiene (IH) studies. BASF monitoring data were selected as it is more relevant and
recent compared to the manufacturing data cited in other sources [such as ECJRC (2002)1 and
lack of availability of monitoring data from other U.S. manufacturer. For example, the data cited
in the 2002 EU Risk Assessment ranges from 1976 to 1998 while the data provided by BASF
ranged from 2006 to 2017 (BASF. 2017. 2016; ECJRC. 2002). The BASF data had limitations
including lack of descriptions of worker tasks, exposure sources, and possible engineering
controls. The BASF (2016) workplace monitoring data were real-time PBZ exposure
measurements. The data were assumed to be relevant to worker activities and were 8-hour TWA
measurements. EPA estimated the total number of workers who could be potentially exposed as
78 and the number occupational non-users as 36 ( ;).
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Acute and chronic occupational inhalation exposures during manufacturing of 1,4-dioxane are
summarized in Table 2-9.. EPA calculated the 95th percentile and 50th percentile of the available
30 data points for inhalation exposure monitoring data to assess the high-end and central
tendency exposures, respectively. Using these 8-hour TWA exposure concentrations, EPA
calculated the ADC and LADC using the equations in Appendix G.2. Additional information
regarding the calculations is provided in Appendix G.6.1.
Table 2-9. Acute and Chronic Inhalation Exposures of Worker for Manufacturing Based
on Monitoring Data
l'A|)OMIIV Tj |K'
( cnlnil Tendono
(50lh porconlilc)
(ill Si/ill')
Ili'Ji-ciid
('>5"' Pcrmilik*)
(inti/mM
Diilii Qu;ilil\ Killing
of AssociiiK'd Souive;l
15-minute TWA (Evaporator Dump)
N/A
137*
High
8-hour TWA Exposure Concentrations
0.42
7.7
High
8-hour TWA Acute Exposure
Concentration (AEC)
0.42
7.7
High
Average Daily Concentration (ADC)
0.40
7.4
High
Lifetime Average Daily Concentration
(LADC)
0.16
3.8
High
N/A = not applicable. *: The hieher of the two reported (BASF. 2017) 15-minute short-term exposures values (137
mg/m3 from the evaporator dump step), considered as high-end, short-term exposure.
a See Table 2-8. for corresponding references.
EPA estimated that 78 workers and 36 ONUs could be exposed at sites that manufacture 1,4-
dioxane in the U.S. EPA used worker number estimates reported in CDR and refined them using
BLS and SUSB data for the applicable NAICS codes. Additional information about the steps
used to estimate the number of potentially exposed workers and ONUs are available in Appendix
G.5. Exposure data for ONUs were not available. ONUs are likely to have lower exposures than
workers. ONUs for manufacturing include supervisors, managers, and tradesmen that may be in
the manufacturing area, but do not perform tasks that result in the same level of exposures as
production workers.
Key Uncertainties
The data sets lacked specific descriptions of worker tasks, exposure sources, and possible
engineering controls to provide context. EPA assumed that the 2016 BASF data are PBZ
measurements relevant to worker activities and are 8-hour TWA measurements. This assumption
could underestimate exposures. The sampling rate was missing for some of the 2016 data, so
EPA assumed the same sampling rate was applied for other data in the set. It is uncertain to what
extent the limited monitoring data used to estimate inhalation exposures for this scenario is
representative of occupational exposures in other manufacturing facility of 1,4-dioxane.
2.4.1.1.2 Import and Repackaging
The import of chemicals, such as 1,4-dioxane, involves chemical handling during storage,
transportation, distribution, and packaging and processing. In addition, 1,4-dioxane shipped in
bulk containers could be repackaged into smaller containers for resale, such as drums or bottles
98 of 616
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using automatic, semi-automatic, or manual filling, sealing, labeling, and wrapping. The
shipment methods and regulations of 1,4-dioxane require the material to be properly classed,
described, packaged, marked, labeled, and in condition for shipment (49 CFR § 171-177). To
avoid spilling, 1,4-dioxane needs to be transported in securely sealed glass bottles or equivalent
containers that should themselves be placed inside strong screw-cap or snap-top containers that
will not open when dropped. Both the bottle and the outside container should be appropriately
labelled. Airtight packaging is required by the International Labor Organization's (ILO)
International Chemical Safety Cards (ICSC).
The information and data quality evaluation to assess occupational exposures from import and
repackaging is listed in Table 2-10.. See Appendix G. 1 for more details about the data quality
evaluation.
Table 2-10. Import and Repackaging Data Source Evaluation
\\ orkcr Acli\ il\ or
Siimplinii 1.million
Diilii T\|K'
Number ol° Samples
Diilii Qu;ili(\ Killing
Source Reference'
N/A
CDR Data - Number
of sites and workers
N/A
High
(20160)
EPA modeled central tendency and high-end occupational inhalation exposures for this scenario
using the EPA AP-42 Loading Model and the EPA Mass Balance Inhalation Model (U.S. EPA.
2013b) and the values listed in Appendix G.2. EPA used a Monte Carlo simulation to vary the
saturation factor (f), ventilation rate (Q), and mixing factor (k) and calculated the 95th percentile
and 50th percentile exposures during unloading directly in the simulation to assess the high-end
and central tendency exposures, respectively. See Appendix G.4 for more information about the
Monte Carlo simulation. Since some sites may only repackage into either bottles or drums and
some sites may use both types of containers, EPA estimated exposures for both bottles and
drums. EPA used these values to calculate acute and chronic inhalation exposures in the Monte
Carlo simulation, varying working years (WY) and the number of days, using the equations in
Appendix G.2. EPA determined once per day short-term exposures of 170 to 610 mg/m3 with a
duration of 30 minutes may occur during drum unloading as central tendency and high-end short-
term exposures, respectively. These estimates are presented in Table 2-10.
EPA estimated that the total number of potentially exposed workers could be between 50 to 198
workers, and occupational non-users could be between 12 to 49. EPA used worker number
estimates reported in CDR and refined them using BLS and SUSB data for the applicable
NAICS codes. See Appendix G.5 for more information about the steps used to estimate the
number of potentially exposed workers and ONUs. Additional information including specific
methodology and assumptions for modeling exposures are described in Appendix G.6.2.
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Table 2-11. Acute and Chronic Inhalation Exposures of Workers for Import and
Repackaging Based on Modeling
l'l\|)OMIIV T>|K'
( onli'iil Tcndono
,511"' Porconlilc)
(nig/nr*)
Ili'Jl-lMKl
('>5"' IVivonlilo)
(niii/mM
Diilii Qu;ili(> Killing of
Associiilod Source1
Short-Term Exposure (0.5-hour
TWA)
170
610
N/A - Modeled Data
Bottle 8-hour TWA Exposure
Concentration
9.3
33
N/A - Modeled Data
Drum 8-hour TWA Exposure
11
38
N/A - Modeled Data
Bottle 8-hour Acute Exposure
Concentration (AEC)
9.3
33
N/A - Modeled Data
Drum 8-hour Acute Exposure
Concentration (AEC)
11
38
N/A - Modeled Data
Average Daily Concentration (ADC)
0.46
3.4
N/A - Modeled Data
Lifetime Average Daily
Concentration (LADC)
0.18
1.3
N/A - Modeled Data
a See Table 2-10. for corresponding references.
Exposure data for ONUs were not available. The ONU exposures are anticipated to be lower
than worker exposures, since ONUs do not typically directly handle the chemical. Only
inhalation exposures to vapors or incidental dermal exposures could be applicable to ONUs,
which will likely be less than worker exposures.
Key Uncertainties
EPA modeled inhalation exposures using the EPA AP-42 Loading Model and the EPA Mass
Balance Inhalation Model. Process specifics for import and repackaging at these sites were not
available, therefore, EPA assumed certain process details, such as container sizes and loading
and unloading frequency. Additionally, EPA assumed that the process steps associated with this
scenario occur indoors, without engineering controls, and in an open-system environment where
vapors freely escape. In the absence of industry-specific information, these assumptions provide
for conservative estimates for exposures during this operation. Actual exposures may be less due
to various factors including closed-system loading and unloading, the use of vapor recovery
systems, or the automation of various process steps.
2.4.1.1.3 Recycling
In the Problem hormulation of the Risk Evaluation for 1,4-l)ioxane ( ), EPA
identified recycling as a separate occupational exposure scenario. EPA assessed the exposure
profile and activities of the recycling process to be more equivalent, and in many cases
synonymous with the Industrial Uses group, described in Section 2.4.1.1.4. Operations at
dedicated recycling facilities often mirror the activities performed at industrial use sites as they
receive much of the spent 1,4-dioxane in smaller containers such as 5 5-gallon drums rather than
the bulk containers that a traditional processing site would receive. Any exposures from worker
activities, such as unloading, maintenance, and drumming spent 1,4-dioxane for disposal are
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assessed in Section 2.4.1.1.4.
2.4.1.1.4 Industrial Uses
1,4-Dioxane is used as a process solvent, an intermediate, and a catalyst in several industrial
applications. For this assessment, these uses have been grouped into a broad category called
"industrial uses." The relevant industries and uses include the following:
• Process solvent in basic organic chemical manufacturing;
• Wetting and dispersing agent in textile processing10;
• Wood pulping10;
• Extraction of animal and vegetable oils10;
• Purification of process intermediates;
• Etching of fluoropolymers;
• Agricultural chemical intermediate;
• Polymerization catalyst;
• Plasticizer intermediate;
• Plastics modeling (thermoforming); and
• Catalysts and reagents for anhydrous acid reactions, brominations, and sulfonations.
EPA did not find specific details for most of these processes, but typical operations are expected
to be similar across these uses. For uses grouped in this "industrial uses" category, it is expected
that 1,4-dioxane is received as a solvent, intermediate, or catalyst in its final formulation and
requires no further processing. The 1,4-dioxane is unloaded and fed to intermediate storage or
directly used in the process. If it is being used as an intermediate, it will likely be consumed
during the reaction. For solvents or catalysts, spent 1,4-dioxane will be collected at the end of the
process for reuse or disposal.
The information and data quality evaluation to assess occupational exposures from industrial
uses is listed in Table 2-12.. See Appendix G. 1 for more details about the data quality evaluation.
10 These uses were evaluated but are likely not current uses of 1,4-dioxane.
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Table 2-12. Industrial Uses Data Source Evaluation
\\ orkcr Acli\ ilj or S;mi|)linii l.ocsilion
Diilii Tjpe
Nil in her
ol'
S;i in pies
Diilii
Qu;ili(\
Killing
Source
Reference
Medicine Maiiiilaclui'c
I'li/. and \rea
Momloi'iiig
:u
1 hull
fZUUZ)
Pharmaceutical Production
PBZ Monitoring
<30
High
ECJRC
02)
Use (e.g., as solvent) in other productions
PBZ Monitoring
194
High
ECJRC
02)
Use (e.g., as solvent) in other productions
PBZ Monitoring
49
High
ECJRC
(2002)
Extractant in medicine manufacturing
EASE Modeling
N/A
- estimates
from
modeling
High
ECJRC
N/A
CDR Data - Number of
sites and workers
N/A
High
U.S.
EPA.
(2016c)
N/A = Not Applicable.
Occupational exposure for 1,4-dioxane used as an industrial chemical was determined using
estimates provided in the Ell Risk Assessment for 1,4-dioxane (ECJRC. 2002). The report
proposed a "typical concentration" of 5 mg/m3 and a "reasonable worst-case" concentration of
20 mg/m3 to estimate the inhalation exposures for various industrial uses. These estimates were
based on full-shift monitoring data provided by other sources cited in the report, which covered
use in the pharmaceutical industry and use as a solvent in industrial processes. However, the
report did not provide details about how these values were calculated, therefore, it is unclear
what percentile is represented when an exposure is described as "typical" or "reasonable worst
case" {i.e., 50th and 95th percentile).). These "typical" and "reasonable worst-case" full-shift
estimates were assumed to be 8-hour TWA values and equivalent to central tendency and high-
end values, respectively. Acute and chronic inhalation exposures for Industrial Uses are
calculated using the equations in Appendix G.2. Results of these calculations are summarized
below in Table 2-12.
EPA estimated a total of 768 workers and 312 occupational non-users may be exposed across all
sites. EPA estimated the number of potentially exposed workers and ONUs per site using BLS
and SUSB data for the applicable NAICS codes. EPA used the number of sites reported in the
2018 TRI and 2018 DMR to estimate the total number of workers and ONUs that may be
exposed. Additional information including typical industrial use, monitoring data, and estimation
of high-end inhalation values for 1,4-dioxane used as an industrial chemical are described in
Appendix G.6.3.
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Table 2-13. Acute and Chronic Inhalation Exposures of Worker for Industrial Uses Based
on Monitoring Data
l'l\|)OSIIIV T\ |K'
( onlnil Tendono ¦'
II I KAK: l\|)ic;il
( oniTiili'iilioii)
(ill Si/nr1)
lli»h-i:ii(l
II I RAR: Koiisoiiiihlc
Worst ( ;iso
('oniTiili'iilioii)
(iiiii/mi)
Diilii (|ii;ilil> rsiling of
AssochiK'd Source1'
8-hour TWA Exposure
Concentrations
5.0
20
High
8-hour TWA Acute
Exposure Concentration
(AEC)
5.0
20
High
Average Daily
Concentration (ADC)
4.8
19
High
Lifetime Average Daily
Concentration (LADC)
1.9
9.9
High
a The risk assessment did not provide details about how these values were calculated, therefore, it is unclear what
percentile is represented when an exposure is described as "typical" or "reasonable worst case" (i.e.,50th and 95th
percentile).
b See Table 2-12. for corresponding references.
Exposure data for ONUs were not available. ONU exposures are lower than worker exposures,
since ONUs do not typically directly handle the chemical. Only inhalation exposures to vapors
are expected, which will likely be less than worker exposures.
Key Uncertainties
EPA used estimates based on exposure data from the 2002 EU Risk Assessment for 1,4-dioxane
in order to estimate the inhalation exposures for this scenario. The data sets used are limited and
mostly lacked specific descriptions of worker tasks, exposure sources, and possible engineering
controls to provide context. Most of the datasets were only presented in ranges with key statistics
{i.e., median or average and 90th percentile), so EPA was unable to directly calculate final values
from the raw data and relied on estimates provided in the 2002 EU Risk Assessment. The
assessment also did not explain how the final 8-hour TWA exposure values of 5 and 20 mg/m3
were derived. These values were reported by the EU to be full-shift values, but EPA assumed
them to be 8-hour TWA values.
2.4.1.1.5 Functional Fluids (Open System)
1,4-Dioxane may be a component of functional fluids that are used in open systems such as
metalworking fluids and cutting and tapping fluids based on information safety data sheets
(SDSs) listed in Preliminary Information on Manufacturing, Processing, Distribution, Use, and
Disposal: 1,4-Dioxane ( |).
The information and data quality evaluation used to assess occupational exposures for functional
fluids (open systems) are listed in Table 2-14.. See Appendix G.l for more details about the data
quality evaluation.
103 of 616
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Table 2-14. Functional Fluids (Open System) Data Evaluation
\\ orkcr Acli\ il\ or
S;i in pi ill vi l.oc;iliou
Diilii l \ pi-
Number ol° Samples
l);ilii (|ii;ilit> ruling
Source Reference
Threader, Broaching,
Apex Drill, and
Lunch Tables
Arc;] Monitoring
4
High
Burton and
Driscoll (1997)
Transfer Lines,
Roughing, Four-way,
Multiple, Screw
Machine-Lathing,
and Apex Drill
PBZ Monitoring
6
High
Burton and
Driscoll (1997)
a: PBZ monitoring data were superseded by Monte Carlo simulation. The area monitoring data were used to
estimate ONU exposures.
Occupational exposure for 1,4-dioxane use as an open system functional fluid was modeled
using the EPA AP-42 Loading Model and the EPA Mass Balance Inhalation Model. EPA used a
Monte Carlo simulation to vary the saturation factor (f), ventilation rate (Q), and mixing factor
(k). See Appendix G.4 for more information about the Monte Carlo simulation. EPA calculated
the 95th percentile and 50th percentile exposures during unloading directly in the simulation to
assess the high-end and central tendency exposures, respectively. EPA used these values to
calculate acute and chronic inhalation exposures in the Monte Carlo simulation, varying working
years (WY), using the equations in Appendix G.2. These results are summarized in Table 2-15..
A 1997 NIOSH Health Hazard Evaluation (HHE) report provided personal breathing zone (PBZ)
samples collected at a facility that manufactures axels for trucks and recreational vehicles
(Burton and Driscoll. 1997). The NIOSH HHE sample results were within the 10th percentile of
the distribution11 from the Monte Carlo simulation and contributed a minor effect to the overall
distribution.
Table 2-15. Acute and Chronic Inhalation Exposures of Worker for Open System
Functional Fluids Based on Modeling
l'l\poMiiv l>pe
( culml Tcndcno
,511"' PerccMi l i le)
(mii/mM
lli»h-i:ml
('>5"' Perceiilile)
(inii/in1)
Confidence Killing of
AssochKcd Source11
Short-Term Exposure (Drum Unloading,
0.05 hr)
0.17
0.61
N/A - Modeled Data
8-hour TWA Exposure Concentrations
1.1E-03
3.8E-03
N/A - Modeled Data
8-hour TWA Acute Exposure
Concentration (AEC)
1.1E-03
3.8E-03
N/A - Modeled Data
Average Daily Concentration (ADC)
1.0E-03
3.7E-03
N/A - Modeled Data
Lifetime Average Daily Concentration
(LADC)
3.9E-04
1.5E-03
N/A - Modeled Data
a See Table 2-14. for corresponding references.
11 All points, except one from the HHE study (Burton and Driscoll 1997). were within the 5th percentile from the
Monte Carlo simulation. Only one value was within the 10th percentile.
104 of 616
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The above values could be influenced by 1,4-dioxane's high vapor pressure (40 mm Hg at 25°C)
causing evaporation from droplets in the air, ventilation rate at the work facility, mixing factor,
vapor saturation factor and other working condition variables. The concentration of 1,4-dioxane
in the formulation could vary from 0.01 to 0.1 wt% resulting in a partial pressure that likely
represents an insignificant source of exposure (\ S \ 20 L'.iO- EPA estimated acute and
chronic inhalation exposures using these values directly in the Monte Carlo simulation. EPA
defined bounding estimates of the total number of potentially exposed workers as 69 to
4,094,000, and ONUs as three to 178,000. This estimate is based on worker numbers provided in
the ESD (OECD. 2011) and 2018 DMR. Additional information including typical use, modeling
methodology, and monitoring data are described in Appendix G.6.4.
To assess ONU inhalation exposures, EPA combined the area measurements taken from a variety
of locations in the manufacturing facility into a single sample set with five datapoints (Burton
and Driscoll. 1997). EPA calculated the 50th percentile of this data set to assess the central
tendency exposure and presents the maximum as the high-end exposure (see Section 2.4.1.1).
These results are summarized in Table 2-16.. The ONU exposures were less than the estimated
central tendency and high-end values for workers, as expected.
Table 2-16. Acute and Chronic ONU Inhalation Exposures for Open System Functional
Fluids Based on Monitoring Data
l'l\|)OMII'C Tj |K'
( culml Tcmlcuo
,511"' iVivonlilc)
diiii/mM
lliiih-r.nd
(Miixiiiiuiii)
img/nr')
Diilii (|ii;ili(\ ruling of
Associiilod Source'1
8-hour TWA Exposure
Concentrations
1.5E-4
2.5E-4
N/A - Modeled Data
8-hour TWA Acute
Exposure Concentration
(AEC)
1.5E-4
2.5E-4
N/A - Modeled Data
Average Daily
Concentration (ADC)
1.4E-04
2.4E-04
N/A - Modeled Data
Lifetime Average Daily
Concentration (LADC)
5.7E-05
1.2E-04
N/A - Modeled Data
a See Table 2-14. for corresponding references.
Key Uncertainties
EPA used exposure data for metalworking fluids from the 2011 OECD ESD on the Use of
Metalworking Fluids and from a 1997 NIOSH HHE. Neither dataset specifically addressed
exposures to 1,4-dioxane. EPA used concentrations provided in relevant SDSs to estimate these
exposures. In addition, the HHE was conducted to address concerns regarding adverse human
health effects reported following exposures during use and therefore the measured exposures
may be inherently biased high.
The data did not estimate exposures during chemical unloading; therefore, EPA estimated this
exposure using the EPA AP-42 Loading Model and the EPA Mass Balance Inhalation Model.
These models assume that the unloading of fluid containing 1,4-dioxane occurs indoors, without
engineering controls, and in an open-system environment where vapors freely escape. In the
105 of 616
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absence of industry-specific information, these assumptions provide for conservative estimates
for exposures during this unloading operation. Actual exposures may be less due to various
factors including closed-system unloading, the use of vapor recovery systems, or an automated
unloading process.
2,4,1,1.6 Functional Fluids (Closed System)
EPA identified closed system functional fluids as a condition of use for 1,4-dioxane in the
problem formulation ( 2018c). The Preliminary Information on Manufacturing,
Processing, Distribution, Use, and Disposal: 1,4-Dioxane presented three SDSs for closed
system functional fluids (hydraulic fluids). These SDSs did not list content information for 1,4-
dioxane, which suggests that it is not an intended component in these products (
2017d). BASF manufactures neat 1,4-dioxane (anhydrous, 99.8% minimum) as well as products
that contain 1,4-dioxane. In a public comment from 2017, BASF provided a table of products
that contain residual amounts of 1,4-dioxane. BASF specifically stated that the residual 1,4-
dioxane is a byproduct of the ethoxylation process and is not an intended component. One of
these products (Pluriol E 400™ or equivalent commercial polyethylene glycols) could be used as
a hydraulic or heat transfer fluid and has a residual level of less than 25 ppm (0.0025%) (BASF.
2017). This concentration is lower than the concentration assessed for open system functional
fluids in Section 2.4.1.1.5, which was 0.1%, or 1,000 ppm. Additionally, EPA reviewed 91
literature sources and performed targeted internet searches and did not find any references to the
use of 1,4-dioxane in closed system functional fluids. A closed system precludes exposure as the
transfer device could prohibit the escape of chemicals outside the system. Due to the lack of
evidence supporting its intended use in closed system functional fluids, EPA did not assess
occupational exposures for this use of 1,4-dioxane.
lAAAJ Laboratory Chemicals
1,4-Dioxane is used in a variety of laboratory applications, which include, but are not limited to,
the following:
• Chemical reagent during lab scale reactions;
• Reference material for quality control or calibration;
• Medium for spectroscopic and photometric measurement;
• Liquid scintillation counting medium;
• Stable reaction medium;
• Cryoscopic solvent for molecular mass determinations; and
• Preparation of histological sections for microscopic examination.
Occupational exposure for 1,4-dioxane used as a laboratory chemical for research/development
and analytical applications was determined by evaluating available monitoring data including
short-term and 8-hour TWA exposures for workers in a laboratory setting (ECJRC. 2002;
NICNAS. 1998). The information and data evaluation for exposures to laboratory chemicals by
the workers are listed in Table 2-17.. See Appendix G. 1 for more details about the data quality
evaluation.
106 of 616
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Table 2-17. Laboratory Chemicals Data Evaluation
Worker Acli\ il\ or
S;uii|)linii l ocution
Diilii Tjpe
Number ol° Samples
Diilii (|iiiilil> rsiling
Source Reference
Solvent extraction
and TLC
PBZ Monitoring
Data
Unknown
High
NIC 8)
Laboratory Work
(HPLC)
PBZ and Area
Monitoring Data
1
High
ECJRC (2002)
Laboratory
PBZ and Area
Monitoring Data
305
High
ECJRC (2002)
Laboratory
PBZ and Area
Monitoring Data
29
High
ECJRC (2002.)
N/A
CDR Data - Number
of sites and workers
N/A
High
2016c)
N/A = Not Applicable.
From these monitoring data, EPA estimated concentrations representing central tendency and
high-end estimates of potential occupational inhalation exposures based on the EU risk
assessment monitoring data (ECJRC. 2002) of 1,4-dioxane as laboratory use (see Table 2-18.).
EPA used a mean value to estimate the central tendency exposures. EPA calculated the high-end
value by calculating an 8-hour TWA of the 15-minute short-term peak exposure and the highest
90th percentile value. This calculated value represents an exposure above the 90th percentile,
which is equivalent to a high-end exposure. Using these 8-hour TWA exposure concentrations,
EPA calculated the ADC and LADC. EPA determined a once per day short-term exposure of 166
mg/m3 may occur with a 15-minute duration during degassing of the high-performance liquid
chromatography fluid based on occupational exposures for laboratory use (ECJRC. 2.002). A
submitter to the 2016 CDR reported 1,4-dioxane estimated that at least 50 but less than 100
laboratory workers could be potentially exposed (U.S. EPA. 2016c). EPA used U.S. Census and
BLS data for the NAICS code 541380, Testing Laboratories, and relevant SOC codes to estimate
a total of 6,844 sites, 6,610 workers, and 804 ONUs (see Appendix G.5), which corresponds to
an estimated average of one worker and 0.12 ONUs per site. EPA used these data to calculate a
ratio of 8:1 workers to ONUs. Additional information on various conditions of use including
typical laboratory use, number of workers and ONUs, monitoring data, and estimation of high-
end inhalation value for laboratory chemicals are described in Section 4.2 (Human Health Risk)
and Appendix G.6.5.
Exposure data for ONUs were not available. ONU exposures could be lower than worker
exposures, since ONUs do not typically directly handle the chemical. Only inhalation exposures
to vapors are expected, which are anticipated to be less than worker exposures.
107 of 616
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Table 2-18. Acute and Chronic Inhalation Exposures of Worker for Laboratory Chemicals
Based on Monitoring Data
l'l\|)UMIIV T>|H'
( cnlriil Ti-mk-no
(Moiin Ysiluc)
(iiili/mM
IliiJl-CIHl
(niii/mM
Diilii (|ii;ilil> rnlinii of
Assnchik'd Source1
Short-Term Exposure (15-
minutes)
N/A
166
High
8-hour TWA Exposure
Concentrations
0.11
5.8*
High
Acute Exposure Concentration
(AEC)
0.11
5.8
High
Average Daily Concentration
(ADC)
0.11
5.5
High
Lifetime Average Daily
Concentration (LADC)
0.042
2.8
High
N/A = not applicable.
* NICNAS (1998) did not provide occupational exposure 1.4-dioxane data, however, cited studies where the
hiehest 8-hour TWA value from personal monitoring was 1.8 ppm (approximately 6.5 mg/m3) (Rimatori et aL
.1.994: Hertlein. 1980)
a See Table 2-17. for corresponding references.
Key Uncertainties
EPA used estimates based on exposure data from the 2002 EU Risk Assessment for 1,4-dioxane
(ECJRC. 2002.) to estimate the inhalation exposures for this scenario. The data sets used are
limited, assumed to be 8-hour TWA values, and mostly lacked specific descriptions of worker
tasks, exposure sources, and possible engineering controls to provide context. Most of the
datasets were only presented in ranges with key statistics {i.e., median or average and 90th
percentile), so EPA was unable to directly calculate final values from the raw data and relied on
the statistics provided in the report. Actual exposures could be less due to various factors in
laboratory chemicals including variations with respect to number of workers and ONUs, scale of
operations, and tasks performed for various process/analytical activities.
2.4,1,1.8 Film Cement
Film cement contains a mixture of solvents including 1,4-dioxane. Film cement is used in the
film processing and archiving industries to splice celluloid movie film together (
2017d). Occupational exposure to 1,4-dioxane used in film cement was determined using
monitoring data provided in a NIOSH HHE report (Okawa and Cove. 1982). The information
and data evaluation for worker exposures during use of film cement are presented in Table 2-19..
See Appendix G. 1 for more details about the data quality evaluation.
108 of 616
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Table 2-19. Film Cement Data Evaluation
\\ orker Acli\ il\ or
Sit in pi in vi Locution
I);ilii Tjpe
Nil ill hoi' of
Samples
Diilii (|iiiilil> rilling
Source Reference / Hero
II)
N/A
References data
provided in NIOSH,
1982
N/A
High
N )
MovieLab
Area Monitoring
1
High
Okawa and Cove
52)
MovieLab
PBZ Monitoring
1
High
Okawa and Cove
(1982)
Technicolor
PBZ Monitoring
4
High
Okawa and Cove
^ t4 >82)
a: NIOSH (1982) reported six ooints that were relevant to 1.4-dioxane. Five were oersonal breathine zone ooints
that were used to estimate worker inhalation exposures and one point was an area sample used to estimate the
ONU exposure. Because of the data being a single data set, it was scored as such instead of viewing the two types
of points each as their own data set. Thus, the sample size sub-score was "High" and that supported the overall
score of "High".
The NIOSH HHE report provided five PBZ samples and one area sample collected at two film
laboratories that develop and clean film. Worker activities included film splicing and manual
film cleaning. These values were used to calculate acute and chronic inhalation exposures using
the equations in Appendix G.2. Results of these calculations are shown in Table 2-20.. EPA
estimated a total of 30 workers and 10 ONUs could be exposed across all the sites. EPA
estimated the number of potentially exposed workers and ONUs using BLS and SUSB data for
the applicable NAICS codes. See Appendix G.5 for more information about the steps used to
estimate workers and ONUs. Additional information including methodology for estimating the
number of workers, typical film cement use, monitoring data, and estimation of high-end
inhalation values for 1,4-dioxane used as a film cement are described in Appendix G.6.6.
Table 2-20. Acute and Chronic Inhalation Exposures of Worker for the Use of Film
Cement Based on Monitoring Data
Kxposurc T\ pe
( cnlr;il Tcndcno
(50lh percentile)
(iiiii/mi|)
Ili'Ji-eiKl
(Miixiiiiiini)
(iiiii/mi|)
Diilii (|ii;ilil> rsiling of
Associiiled Sourcehh
8-hour TWA Exposure
Concentrations
1.5
2.8
High
8-hour TWA Acute Exposure
Concentration (AEC)
1.5
2.8
High
Average Daily Concentration
(ADC)
1.5
2.7
High
Lifetime Average Daily
Concentration (LADC)*
0.58
1.4
High
a Analytical detection limits are lower than the concentrations shown in the table. The method detection limits of
1,4-dioxane in air are 530 ppt (1.9E-6 mg/m3) and 0.01 ppb (3.6E-5 mg/m3) by selected ion flow tube-mass
spectrometry (SIFT-MS) and Gas Chromatography with Flame-Ionization detection (GC-FID), respectively. In
109 of 616
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addition, NIOSH method 1602 could be used to determine the concentration of 1,4-dioxane in a 10-L air sample by
GC-FID. Samples are collected by drawing air through a solid sorbent tube containing coconut shell charcoal. The
flow rate is between 0.01 and 0.2 L/minute for a total sample size of 0.5-15 L. 1,4-Dioxane is eluted from the solid
sorbent with agitation using carbon disulfide. The carbon disulfide eluent sample is then injected directly into the
GC-FID. The detection limit is 0.01 mg per sample.
b See Table 2-19. for corresponding references.
* Refer to Equation 5.2 and Appendix G.2 for additional information on estimation of LADC.
Three out of six NIOSH HHE samples have detectable concentrations and three values were non-
detect (Okawa and Co\ i). The values of the three non-detects were considered as half the
detection limit assuming that the average non-detect values could be between the detection limit
and zero, and that the average value of non-detects could be as high as half the detection limit
( ). EPA calculated an upper bound for these measurements and used it to
calculate an 8-hour TWA value. EPA presented this as an 8-hour TWA inhalation exposure
value for ONUs (Table 2-21.). This value was used to calculate acute and chronic inhalation
exposures as per the equations in Appendix G.2. These values are plausible, but EPA cannot
determine the statistical representativeness of the values given the small sample size. Dermal
exposures are not expected for ONUs since they are not expected to directly handle the chemical.
Table 2-21. Acute and Chronic ONU Inhalation Exposures for the Use of Film Cement
Based on Monitoring Data
l'l\|)OMIIV l \|K'
Ceiilnil Teiirienet •'
(ing/iir*)
lli»h-i:n(l 1
(lllli/lll1)
Diilii (|ii;ilil> rsiling of
Assnciiik'd Source1'
8-hour TWA Exposure CoiiceniraUoiib
o.lo
nigh
8-hour TWA Acute Exposure
Concentration (AEC)
0.10
High
Average Daily Concentration (ADC)
0.10
0.10
High
Lifetime Average Daily Concentration
(LADC)
0.040
0.051
High
a These values are plausible, but EPA cannot determine the statistical representativeness of the values given the
sample size of six data. High uncertainty is introduced given that these values are based on non-detects.
b See Table 2-19. for corresponding references.
Key Uncertainties
Three of the NIOSH HHE reported values were non-detects and three were detectable. The
values of the three non-detects were considered as half the detection limit as per the
considerations indicated earlier. The estimated exposures could be overestimates due to the
single area HHE study, lack of statistical representativeness of the values due to limited sample
size, and typical operations that might not involve direct handling of 1,4-dioxane.
2.4.1.1.9 Spray Foam Application
1,4-Dioxane is present in two-component high-pressure, two-component low-pressure, and one
component foam (OCF). The two-component, high-pressure spray polyurethane foams (SPFs),
which are typically used for larger insulation applications, as an air sealant in hybrid insulations,
and in roofing applications (U.S. EPA. 2017c. d). It is unclear how dependent 1,4-dioxane
110 of 616
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emissions are on the specific SPF product or the way it is installed (such as compounds emitted
from the spray foam specimens when they were fresh). (Natdzhiev et at.. 2.017) and Bayer
Material Science (Kartovich et at.. 2.01 la) indicated that 1,4-dioxane is not intentionally added as
reactant and could be present in the foam as a contaminant. However, several technologies and
researchers reported 1,4-dioxane's presence as an ingredient. Polyester polyols are used for
producing polyurethane, and amounts ranged from 0.8 g to 6 g of 1,4-dioxane generated per kg
of polyester polyol formed in the esterification of aromatic phthalic acid depending on the
technology used (2013). The United States Consumer Product Safety Commission (CPSC) and
the National Institute of Standards and Technology (NIST) characterized and quantified 1,4-
dioxane and other chemicals released from SPF after application (Poppendieck. 2017;
Poppendieck et at.. ). These authors reported 1,4-dioxane emission rates from SPF samples.
Researchers from the NRC-Canada reported that tests on spray foam specimens detected 1,4-
dioxane (Won. 2014). CDC/NIOSH reported presence of 1,4-dioxane in bulk sample analysis of
component-B (a polyol blend with an amine catalyst) of the SPF formulation (Martow. 2014).
Monitoring data for worker inhalation exposure to 1,4-dioxane from spray application of SPF
was not identified. Instead, occupational exposure to 1,4-dioxane used in SPFs was estimated.
The information and data quality evaluation used to assess occupational exposures for spray
foam application are listed in Table 2-22.. See Appendix G.l for more details about the data
quality evaluation.
Table 2-22. Spray Foam Application Data Source Evaluation
Worker Acli\ i(\ or Siiinplinii
Locution
Diilii T\|K'
Number of
Siimplos
Diilii
(|ii;ilil>
rsiling
Source Reference
A typical two-story, 2,300-square-foot
house with a medium-pitch roof with a
roof area of about 1,500 square feet
Parameters
used in
modeling
Not applicable -
Monitoring data not
provided
Medium
Huber (20181
An average size house is 1,500 square
feet of roofing
Parameters
used in
modeling
Not applicable -
Monitoring data not
provided
Medium
Home Advisor
(2018)
Mix A-side and B-side in 1:1 ratio
Parameters
used in
modeling
Not applicable -
Monitoring data not
provided
High
OMG Roofing
ducts (2018)
0.1% 1,4-dioxane in B-Side
Parameters
used in
modeling
Not applicable -
Monitoring data not
provided
High
14)
EPA used assumptions and values from the GS on the Application of Spray Polyurethane Foam
Insulation, which used the EPA AP-42 Loading Model, the EPA Mass Balance Inhalation Model,
the EPA TotalPNOR I'l J-Limiting Model (U.S. EPA. 2.018a) and surrogate data to estimate
inhalation exposures during container unloading, spray foam application, and thickness
verification. EPA used a Monte Carlo simulation to vary the saturation factor (f), ventilation rate
(Q), and mixing factor (k) and calculate 50th and 95th percentile 8-hour TWA exposures during
container unloading. See Appendix G.4 for more information about the Monte Carlo simulation.
The results from each activity were combined to construct an 8-hour TWA. EPA used these
111 of 616
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values to calculate acute and chronic inhalation exposures in the Monte Carlo simulation,
varying working years (WY), using the equations in Appendix G.2. These exposure results are
shown in Table 2-23.
EPA estimated a total of 162,518 potentially exposed workers and 15,627 potentially exposed
workers who are non-sprayers but could not be categorized as ONUs. EPA estimated the number
of potentially exposed workers and non-sprayer workers using BLS and SUSB data for the
applicable NAICS codes. EPA considered the total number of establishments and potentially
exposed workers and non-sprayer workers in this NAICS code as bounding estimates of the
number of establishments that use and the number of workers and non-sprayer workers that are
potentially exposed to 1,4-dioxane-based spray polyurethane foam during insulation installation.
These bounding estimates are likely underestimates of the actual number of establishments and
employees potentially exposed to 1,4-dioxane during spray polyurethane foam insulation
installation, since only a single spray polyurethane foam product that contains 1,4-dioxane was
identified. See Appendix G.5 for more information about the steps used to estimate workers and
non-sprayer workers. Additional information including specific methodology for estimating
worker numbers, typical spray foam application methods, modeling assumptions, and estimation
of high-end and central tendency inhalation values for 1,4-dioxane used in spray foam insulation
are described in Appendix G.6.5.
Table 2-23. Acute and Chronic Inhalation Exposures of Worker for Spray Application
Based on Modeling
Mxposuiv T\ |R'
( onli'iil IVndono
(inii/in1)
lliiili-cml
('>5"' IVrccn(ik')
(iiiii/mM
Diilii (|ii;ilil> rilling of
Associiilod Source1
S-liour TWA 1 \posuiv CoiKviiiralioiis
'J.-L-U3
\ A - Modeled Dala
8-hour TWA Acute Exposure
Concentration (AEC)
9.7E-03
1.2E-02
N/A - Modeled Data
Average Daily Concentration (ADC)
9.4E-03
1.1E-02
N/A - Modeled Data
Lifetime Average Daily Concentration
(LADC)
3.6E-03
5.3E-03
N/A - Modeled Data
a See Table 2-22. for corresponding references.
Exposure data from application of SPFs for non-sprayer workers were not available. Per the GS,
it is assumed that some non-sprayer workers could perform tasks related to trimming the cured
spray foam insulation. Exposures were estimated using the EPA Total PNOR PEL-Limiting
Model with the OSHA PEL for total particulates (15 mg/m3). EPA multiplied the OSHA PEL by
the expected concentration of 1,4-dioxane in the mixed SPF (0.0005) and averaged the exposure
over 8 hours, assuming non-sprayer workers are exposed during trimming and not exposed
during the remainder of the 8-hour period. Due to the small sample size of only one estimated
value, EPA calculated an 8-hour TWA inhalation exposure value for non-sprayer workers and
used this value to calculate acute and chronic inhalation exposures using the equations in
Appendix G.2. These values are summarized in Table 2-24.. While these values may be
plausible, due to the small sample size of only one estimated value, EPA could not determine the
statistical representativeness.
112 of 616
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Table 2-24. Acute and Chronic Non-Sprayer Workers Inhalation Exposures for Spray
Applications Based on Modeling
l'l\|)OMIIV l \|K'
(Vnlnil l ondcno •'
(msi/m')
lliiih-r.nd •'
(inii/in1)
Diilii (|ii;ilil> rsiling of
Associiilcd Source h
8-hour TWA Exposure Concentrations
1.9E-03
N/A - Modeled Data
8-hour TWA Acute Exposure
Concentration (AEC)
1.9E-03
N/A - Modeled Data
Average Daily Concentration (ADC)
1.8E-03
N/A - Modeled Data
Lifetime Average Daily Concentration
(LADC)
7.2E-04
9.3E-04
N/A - Modeled Data
a These values are plausible, but EPA cannot determine the statistical representativeness of the values given the
small sample size.
b See Table 2-22. for corresponding references.
Key Uncertainties
Due to a lack of data specific to 1,4-dioxane for this use, EPA used assumptions and values from
the GS on the Application of Spray Polyurethane Foam Insulation, which used the EPA AP-42
Loading Model, the EPA Mass Balance Inhalation Model, theEPA Total PNORPEL-Limiting
Model ( 2018a) and surrogate data to estimate inhalation exposures during container
unloading, spray foam application, thickness verification, and trimming. Values for the
parameters listed in Table G-21 were assumed based on general industry data. These parameter
values may not always be representative of applications specific to spray foam insulations
containing 1,4-dioxane. The estimate for exposures during application did not account for the
potential evaporation of 1,4-dioxane from the mist particulates and the potential inhalation
exposure of the evaporated vapors. EPA assumed that this is not a significant exposure given that
the partial pressure of 1,4-dioxane is likely very low due to the low concentration of 1,4-dioxane
in the mixed spray foam. EPA also estimated exposures during thickness verification using
surrogate data.
The EPA AP-42 Loading Model and the EPA Mass Balance Inhalation Model were used to
estimate inhalation exposures during container unloading. These models assume that the
unloading of fluid containing 1,4-dioxane occurs indoors, without engineering controls, and in an
open-system environment where vapors freely escape. In the absence of industry-specific
information, these assumptions provide for conservative estimates for exposures during this
unloading operation. Actual exposures may be less due to various factors including closed-
system unloading or the use of vapor recovery systems.
2,4.1,1,10 Printing Inks (3D)
1,4-Dioxane is used in solvent-based inks that are used in a type of additive manufacturing
known as material jetting or 3D printing (U.S. EPA. 2017d). A published literature review and
hazard assessment for material jetting measured exposures to a number of chemicals, including
1,4-dioxane, were reported during additive manufacturing. This report provided a single data
point from an 8-hour sampling period for 1,4-dioxane exposure (Ryan and Hubb ). The
sample was collected inside a commercial grade photopolymerization 3D printer enclosure. Ryan
and Hubbard (2016) reported that the 1,4-dioxane concentrations could be higher than the
113 of 616
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observed value in cases of lack of local exhaust ventilation and operation of multiple printers.
Other researchers also supported the observations indicating that the releases of volatile organic
carbons (VOCs) and particulate matters could increase to higher concentration levels depending
on the temperature of the nozzle, extrusion temperature, the type of filament used, and type of
3D printer (2018); (Zhang et at... 2017). The information and data evaluation for worker
exposures during use of printing inks are presented in Table 2-25.. See Appendix G. 1 for more
details about the data quality evaluation.
Table 2-25. Use of Printing Inks Data Evaluation
\\ orkcr Acli\ il\ or
S;i in pi ill vi l.oc;ilion
Diilii l \ pi-
Number ol° Samples
l);ilii (|ii;ilit> ruling
Source Reference
3-D printing
Arc;] Monitoring
Data
1
High
Rvan and
Hubbard (1 )
The scores for this source were assigned "High" and weighted higher than other sub-scores, including the sample
size, which was scored "Medium." The overall confidence score of this source was rated "High" despite single
data set.
EPA used this sample value to calculate acute and chronic inhalation exposures (Table 2-26.) per
the equations shown in Appendix G.2. EPA cannot determine the statistical representativeness of
the values given the small sample size. It is estimated that a total of 59,970 workers, and 20,430
ONUs could be exposed across all the sites. EPA estimated the number of potentially exposed
workers and ONUs using BLS and SUSB data for the applicable NAICS codes. See Appendix
G.5 for more information about the steps used to estimate workers and ONUs. Additional
information including specific methodology for estimating workers, ingredients of inks, use of
3 D printer, and details about the monitoring data for 1,4-dioxane used in printing inks (3D) are
described in Appendix G.6.8.
Table 2-26. Acute and Chronic Inhalation Exposures of Worker for Use of Printing Inks
Based on Monitoring Data
r.xposurc T\ pe
( on!nil
TcihIoiio 11
(in )
lliuh-l nd
(in ii/ni")
Diilii (|ii;ilil> niliiiii of Assochilcri
Soiiito h
8-hour TWA Exposure
Concentrations
0.097
High
8-hour TWA Acute Exposure
Concentration (AEC)
0.097
High
Average Daily Concentration
(ADC)
0.093
High
Lifetime Average Daily
Concentration (LADC)
0.037
0.048
High
a These values are plausible, but EPA cannot determine the variability and uncertainty of the values due to lack of
data. High uncertainty is introduced given that these values are based on one point.
b See Table 2-25. for corresponding references.
Exposure data for ONUs were not available. EPA expected that ONU exposures may be lower
114 of 616
-------
than worker exposures, since ONUs do not typically directly handle the chemical. Only
inhalation exposures to vapors are expected, which will likely be less than worker exposures to
vapors.
Key Uncertainties
The data source used only provided one data point that was used to estimate the inhalation
exposure of workers. EPA cannot determine the statistical representativeness due to limited data.
The representativeness of this value to other 3D printing sites is unknown. Additionally, the
sample provided is not a PBZ sample. Since the sample was taken within the 3D printing
enclosure, the exposure value is likely higher than a worker would typically experience while
operating the 3D printer. EPA considered the available monitoring data as no model is readily
available to predict the release of 1,4-dioxane under this condition of use.
2,4.1,1.11 Dry Film Lubricant
1,4-Dioxane is used as a carrier in the manufacturing and application of a dry film lubricant.
Occupational exposures to 1,4-dioxane during manufacturing and application were estimated by
evaluating PBZ monitoring sample data provided by the U.S. Department of Defense, Kansas
City National Security Campus (KCNSC) (DOE. 2018a). The information and data evaluation
for worker exposures during use of dry film lubricant are presented in Table 2-27.. See Appendix
G. 1 for more details about the data quality evaluation.
Table 2-27. Dry Film Lubricant Data Source Evaluation
Worker Acli\ ii\ or S;uii|)linii
l.ociilioii
Diilii Tjpe
Number ol'Samples
Diilii
(|ii;ilil>
rsiling
Source Reference
Non-nuclear parts manufacturing
for nuclear weapons.
PBZ and Area
Monitoring Data
25
High
DOE (2018a)
Non-nuclear parts manufacturing
for nuclear weapons.
Number of
Workers
N/A - Monitoring
data not provided
High
DOE (2018b)
These data were used to assess inhalation exposures to 1,4-dioxane for this condition of use. The
PBZ samples included two full shift 8-hour TWA samples and five 8-hour TWAs that are
derived from same-day task-based TWA samples, for a total of seven 8-hour TWA samples.
These data are shown in Appendix G.6.9. EPA calculated the 95th percentile and 50111 percentile
of the available data. Acute and chronic inhalation exposures were calculated using the
assumptions and equations listed in Appendix G.2. The dry film lubricant was manufactured six
to eight days per year and the lubricant was applied about 48 days per year for a total exposure
frequency of 56 days per year at the KCNSC-reported facility (DOE. 2018a). This assumption
was used in place of the standard 250 days per year consideration as outlined in Appendix G.2.
The results are summarized in Table 2-28.. Based on information provided by KCNSC, it is
estimated that 16 workers and 64 ONUs could be exposed across all sites (DOE. 2018b).
KCNSC provided monitoring data for workers but did not have monitoring data for ONUs.
Additional information regarding this use, including monitoring data and assumptions made, are
included in Appendix G.6.9.
115 of 616
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Table 2-28. Acute and Chronic Inhalation Exposures of Workers for the Use of Dry Film
Lubricant Based on Exposure Data
l''.\|)OMII'C T>|K'
('iMilr.il TcihIciio
img/nr')
lli rilling of
Associiilcd Source1
S-lioui' TWA L\pos>uiv Coiiceiiirulioiib
U.4"
1.0
nigh
Acute Exposure Concentration (AEC)
0.47
1.6
High
Average Daily Concentration (ADC)
0.10
0.35
High
Lifetime Average Daily Concentration
(LADC)
0.040
0.18
High
a See Table 2-27. for corresponding references.
Information was not available as to whether other Department of Energy (DOE) facilities within
the National Nuclear Security Administration (NNSA) use 1,4-dioxane like the KCNSC.
However, it was assumed the other seven facilities in the NNSA use 1,4-dioxane in the same
manner and workers are exposed at the same levels as at the KCNSC.
Key Uncertainties
EPA confirmed with the KCNSC that the 8-hour TWAs from task samples were representative
of the employee's entire 1,4-dioxane exposure during their shift. EPA was not, however, able to
confirm if other DOE facilities within the NNSA use 1,4-dioxane in addition to the KCNSC.
2,41X12 Disposal
Each of the conditions of use of 1,4-dioxane could generate waste streams containing 1,4-
dioxane that are collected and transported to third-party sites for disposal, treatment, or
recycling. Industrial sites that treat or dispose onsite generated wastes were assessed for the
occupational exposure assessment for each condition of use in Sections 2.4.1.1.1 through
2.4.1.1.11 (except closed functional fluids). The information and data evaluation for worker
exposures during disposal are presented in Table 2-29.. See Appendix G.l for more details about
the data quality evaluation.
Table 2-29. Disposal Data Source Evaluation
\\ orkcr Acli\ il\ or
S;i in pi ill vi l.ociilion
Diilii Tjpc
Number ol'Siimplcs
l);ilii (|ii;ilil\ rsiiing
Source Reference
N/A
TRIData
N/A
Medium
(2016(1)
N/A
DMR Data
N/A
Medium
EPA modeled occupational exposures using the EPA AP-42 Loading Model and the EPA Mass
Balance Inhalation Model to estimate central tendency and high-end 8-hour TWA exposures.
EPA used a Monte Carlo simulation to vary the saturation factor (f), ventilation rate (Q), and
mixing factor (k). See Appendix G.4 for more information about the Monte Carlo simulation.
EPA also estimated the 3.25-minute (0.06 hr) exposures from drum unloading as central
tendency and high-end short-term exposures (see Table 2-30.). EPA used these values to
116 of 616
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calculate acute and chronic inhalation exposures in the Monte Carlo simulation, varying working
years (WY), using the equations in Appendix G.2.
A total of 177 workers and 53 ONUs could be exposed across all the sites. EPA estimated the
number of potentially exposed workers and ONUs using BLS and SUSB data for the applicable
NAICS codes. See Appendix G.5 for more information about the steps used to estimate workers
and ONUs. Additional information including typical disposal methods, TRI data, and
assumptions for estimating exposure values for the disposal of 1,4-dioxane are described in
Appendix G.6.10.
Table 2-30. Acute and Chronic Inhalation Exposures of Worker for Disposal Based on
Modeling
r.\|)(isuiv l \|K'
( cnli'iil TcihIciio
,511"' iVivonlilc)
(niii/mM
Ili'Ji-cnd
('>5"' Percentile)
Diilii (|iiiilil> ruling of
Assochilcri Source ¦'
SIkh'I-Term 1 ApoMire (oiiceiiiralkiii iinw
hrs)
l"u
olu
\. A - Modeled Dula
8-hour TWA Exposure Concentrations
1.9
6.6
N/A - Modeled Data
8-hour TWA Acute Exposure
Concentration (AEC)
1.9
6.6
N/A - Modeled Data
Average Daily Concentration (ADC)
1.8
6.4
N/A - Modeled Data
Lifetime Average Daily Concentration
(LADC)
0.68
2.5
N/A - Modeled Data
a See Table 2-29. for corresponding references.
Exposure data for ONUs were not available. EPA did not model exposures for ONUs, but EPA
expects ONU exposures to be lower than worker exposures, since ONUs do not typically directly
handle the chemical. Only inhalation exposures to vapors are expected, which will likely be less
than worker exposures.
Key Uncertainties
EPA modeled inhalation exposures using the EPA AP-42 Loading Model and the EPA Mass
Balance Inhalation Model. Process specifics for disposal sites were not available, therefore, EPA
assumed certain process details, such as container sizes and unloading frequency. Additionally,
EPA assumed that the process steps associated with this scenario occur indoors, without
engineering controls, and in an open-system environment where vapors freely escape. In the
absence of industry-specific information, these assumptions provide for conservative estimates
for exposures during this operation. Actual exposures may be less due to various factors
including closed-system loading and unloading, the use of vapor recovery systems, or the
automation of various process steps.
2.4,1,1.13 Dermal Exposure Assessment
EPA estimated workers' dermal exposure to 1,4-dioxane for the industrial and commercial use
scenarios considering evaporation of liquid from the surface of the hands and conditions of use
117 of 616
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with and without gloves. OSHA requires employers to utilize the hierarchy of controls, except
under limited circumstances, as a general concept that OSHA accepts as good industrial hygiene
practice for reducing or removing hazardous exposures. OSHA's hierarchy of controls indicate
that the most effective control is elimination, followed by substitution, and then engineering
controls. Gloves are the last course of worker protection in the hierarchy of controls and should
only be considered when process design and engineering controls cannot reduce workplace
exposure to levels within regulation.
General Approach and Methods
Dermal exposure is the absorption and transport of 1,4-dioxane from the outer surface of the skin
to the inner layers of the skin (Figure 2-1). The relatively thin epidermis lacks vascularization
and is generally considered the primary barrier to uptake of chemicals encountered in the
workplace or general environment. The dermis is vascularized and contains the sweat glands and
hair follicles. Dermal absorption 1,4-dioxane through the skin could occur with or without being
noticed by the worker. The rate of dermal absorption depends largely on the outer layer of the
skin called the stratum corneum. The stratum corneum serves an important barrier function by
keeping molecules from passing into and out of the skin, thus protecting the deeper layers of
skin. Theoretical equations and models have been developed to describe the transport of a
diffusing chemical through the skin. 1,4-Dioxane could permeate the skin's diffusional barriers
and enter the systemic circulation via capillaries at the dermo-epidermal junction. The process
begins with diffusion through the stratum corneum and could involve metabolic processes during
traversal of the living epidermis. The released 1,4-dioxane that encounters skin could undergo
many processes including:
a) evaporation from the surface of the skin;
b) uptake (absorption) into the stratum corneum, followed by reversible or irreversible
binding; and
c) penetration into the viable epidermis, followed by metabolism.
Several factors that influence the dermal absorption of 1,4-dioxane are shown in Figure 2-3
(Eleftheriadou et ai. 2.019; W1 06; Semple. 2004). The factors affecting dermal exposure
could vary based on working conditions, process operations and work practices, type and
conditions of chemical releases, and other site-specific conditions. Various models have been
developed to address various factors impacted by risk assessors; chemicals, and other industries
( Vii'teida et al.. JO r\ H^t'theriadou et at.. 2019; Kissel et al.. 2.018; Sueibayashi. 2017;
Chittenden and Riviere. 201 \ I tasch and Bunge. 2015; Chittenden et al.. 2014; Gaiiar and
KastiiiK J0j J; Nltscfae and Kasting. 2013; Mitragotri et al.. 2011).
IHSkinPerm©, developed by the American Industrial Hygiene Association (AIHA), is one of the
available tools that estimates dermal absorption using the dermal loading, the exposure duration,
and physical-chemical properties of chemicals. This model has taken into account losses to
evaporation and estimates the mass that is absorbed. IH SkinPerm© computes dermal risk
assessment for four types of occupational skin exposures found in work environments: a)
deposition over time (e.g., from repeated or continuous emission); b) instantaneous deposition
(e.g., from a splash); c) skin absorption from airborne vapors, and d) estimating absorption of
1,4-dioxane in water. The scenario output parameters are shown in Table 2-31.
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Chemical
Epidermal Layers
Stratum Corneum
Epidermis
Dermis
Subcutis
Deep Tissue
Systematic Circulation via Capillaries
Chemical
• Evaporation
• Sweat Duct .
•:.•••
• fl":' •: ft
r > f\ -'v n. \
Hair Folicle
Chemical Structure,
v Molecular size,
Chemical lipophilidty.
Polarity
Stratum corneum
Stratum lucidum
Stratum
granulosum
- Stratum spinosum
Skin
1
Stratum
basale
Vehicle
i
Temperature, Humidity
Application dose
Anatomical site,
Temperature,
Hydration of stratum
corneum,
Damage to stratum
corneum,
Diseased skin,
Desquamation
Solubility,
Volatility,
PH
Concentration,
Frequency,
Finite or infinite dose.
Skin area dose (film
thickness, concentration).
Total skin area in contact,
Duration of exposure
Figure 2-3 Conceptual diagram showing various key factors that influence dermal
exposures in the event of 1,4-dioxane releases (modified after Chattopadhyav and Taft,
2018).
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Table 2-31 IHSkinPerm© Output Data for Various Dermal Exposure Scenarios of 1,4-
Dioxane
Scenario
1 nil
Deposition o\er
lime (Slir)
Instantaneous
Vaporlo
skin
Water
solution
Total deposition
mg
8560
100
0.19
3560
Fraction absorbed
%
1.05
5.51E-01
96.9
96.9
Amount absorbed
mg
8.99E+01
5.51E-01
1.81E-01
3.45E+3
Kp-lipids (vehicle water)1
cm/hr
4.08E-04
Kp-lipids (vehicle air) 2
cm/hr
1.7
Kp-keratins (vehicle water)3
cm/hr
9.69E-05
Kp-keratins (vehicle air) 4
cm/hr
4.05E-01
Diffusivity through stratum
corneum5
cm2/hr
1.83E-06
Kp-stagnant air6
cm/hr
3.34E+02
Skin/water partition ratio
dimensionless
0.55
Skin/air partition ratio
dimensionless
2300
Permeation coefficient
water7
cm/hr
5.05E-04
Permeation coefficient air8
cm/hr
2.09
1: Kp-lipids (vehicle water) = permeability coefficient is a constant that describes the speed at which 1,4-dioxane
diffuses through the lipid mortar between skin cells.
2: Kp-lipids (vehicle air) = the estimated permeation coefficient of 1,4-dioxane as vapor in air, valid for the
stratum corneum lipid mortar.
3: Kp-keratins (vehicle water) = permeability coefficient is a constant that describes the speed at 1,4-dioxane
diffuses through the dead skin cells. Keratins are a group of tough, fibrous proteins that form the structural
framework of epithelial cells that make up tissues such as the hair, skin, and nails.
4: Kp-keratins (vehicle air) = the estimated permeation coefficient of 1,4-dioxane as vapor in air, valid for the dead
corneocytes of the stratum corneum.
5: Diffusivity through stratum corneum is a dependent variable describing the effective diffusion of 1,4-dioxane
through the stratum corneum.
6: Kp-stagnant air layer = permeability coefficient of 1,4-dioxane through air boundary layer at the skin.
7: Permeation coefficient water = an estimate of 1,4-dioxane dermally absorbed into the stratum corneum from
water.
8: Permeation coefficient air = an estimate of the 1,4-dioxane dermally absorbed from vapor in air.
A tiered approach has been used for dermal exposure assessment. As a first step, dermal
exposures were estimated using methodologies as described in Appendix G.7. Though the fixed
fractional dermal absorption12 has commonly been used, the shortcomings of this practice have
12 After the estimation of chemical contact rates, the absorbed dose has been assumed by researchers (Sahmel and
Boeniger, 2006) to be a fixed fraction of the material encountered, irrespective of load conditions.
120 of 616
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been reported (Frasch et al., 2014; Kissel et aU Thus, in the second step, a sensitivity
analysis was performed by varying the fraction absorbed (Fabs) from 0.3% to 100% of dermal
absorption. The third step was a consideration of dermal absorption test data that included in
vitro and ex vivo studies.
Dermal Test Data Interpretations
The results of dermal absorption parameters and/or flux13 values for 1,4-dioxane obtained from
empirical studies or tests have been varied. Mahdi (2014) performed in vitro dermal absorption
study of dioxane across human skin from the abdominal region that was obtained from white-
skinned females who had undergone tummy tuck surgery (Manhattan Surgical Hospital,
Manhattan, Kansas). The skin was dermatomed to 0.5 mm thickness and stored at -20°C for two
months. The dermatomed skins were thawed at room temperature for 30 min and cut into disks
that were mounted in the flow-through diffusion cell system with exposed skin surface areas of 1
cm2. Mahdi (2014) reported steady state flux of dioxane ranged between 12.157 ± 0.907 and
12.805 ± 1.125 [j,g/cm2/hr. Bronaug 0 showed that the fluxes of dioxane from water in
human skin were low (0.36 ± 0.03 [j,g /cm2/hr) while the flux was high (freshly excised = 1483.4
±311.8 [j,g/cm2/hr; 4 days stored skin = 1263.8 ± 448 [j,g/cm2/hr; 30 days stored skin = 1116.8 ±
109.9 (.ig/cnr/hr) in 4-hr tests performed by Dennerlein et al. (20 i 3) at the Friedrich-Alexander
University, Erlangen-Nurnberg, Germany.
The percutaneous penetration of 1,4-dioxane was investigated by Dennerlein et al. (2013) using
the diffusion cell technique for freshly excised as well as for 4 and 30 days at -20°C stored
human skin (four anonymous female donors, aged 30-59 years after surgical reduction
abdominoplasty). The National Industrial Chemicals Notification and Assessment Scheme
(NICNAS) used the empirical formula (Potts Ro. 1992) to calculate the 1,4-dioxane flux value to
be approximately 300 (.ig/cnr/hr (NICNAS. 1998). The fractional absorption for 1,4-dioxane as
estimated following a theoretical framework provided by Kasting and Miller (2.006) and other
transdermal flux parameters for 1,4-dioxane obtained from test studies are shown in the Figure
2-4.
13 Flux is the rate of mass accumulation per unit area of exposed surface (mass/area/time).
121 of 616
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FIUX i 4-dioxare (freshly excised skin) (Denrierlein et al , 2013
1000
™ 100
21 10
X
-2 1
0
FILIXj (~2-mon1ti stored sk
[Mahtli 2014)
High En
Central Tendency
abs
Figure 2-4 Flux of 1,4-dioxane across human skin at various exposure conditions
Dernuil Exposure Estimation
Vapor absorption during dermal exposure requires that 1,4-dioxane be capable of achieving
concentration in the media at the temperature and atmospheric pressure of the scenario under
evaluation to provide a significant driving force for skin penetration. Because 1,4-dioxane is a
volatile liquid (VP = 40 mmHg and 25°C) the dermal absorption of 1,4-dioxane depends on the
type and duration of exposure. Only a fraction of 1,4-dioxane that contacts the skin will be
absorbed as the chemical readily evaporates from the skin. Dermal absorption may be significant
in cases of repeated contacts or dermal immersion. See Appendix G.7 for more information
about the incorporation of gloves in the dermal exposure assessment. EPA collected and
reviewed available SDSs to inform the evaluation of gloves used in the following conditions of
use:
• Manufacturing;
• Import and Repackaging;
• Spray Foam Application;
• Laboratory Chemicals; and
• Film Cement.
Except for spray foam use, the SDSs recommended the use of protective or chemical resistant
gloves during the handling of 1,4-dioxane or film cement. The spray foam related SDS indicated
that the selection of specific PPE depends on the operation. However, a specific glove material
or protection factor rating was not provided (BASF. 2018b; GAF. 2014; Tedia. 2014; Kodak.
2011). For operations involving the use of larger amounts of 1,4-dioxane (for example,
transferring dioxane from one container to another) or for other potential extended contact, butyl
rubber or double nitrile gloves could be used. It should be noted that Viton™ or equivalent
gloves need to be avoided as 1,4-dioxane degrades synthetic fluoropolymer product.
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To assess dermal exposure, EPA used the EPA Dermal Exposure to Volatile Liquids model (See
Equation 2.4.1-1) to calculate the dermal retained dose. The equation modifies the EPA 2-Hand
Dermal Exposure to Liquids Model by incorporating a "fraction absorbed (fabs)" parameter to
account for the evaporation of volatile chemicals and a "protection factor (PF)" to account for
glove use. Default PF values, which vary depending on the type of glove used and the presence
of employee training program, are shown in Table 2-32.. The additional details to calculate
dermal exposures are described in Sections 4.2.2.4 and 4.2.2.5, and Appendix G.7.
Equation 2.4.1-1. Dermal Dose Equation
D C V ( Qu xfabs) v y v rT
u exp pp ax derm a r I
Where:
S = surface area of contact (cm2)
Qu = quantity remaining on the skin after bulk liquid has been wiped away (mg/cm2-
event)
Yderm = weight fraction of the chemical of interest in the liquid (0 < Yderm < 1)
FT = frequency of events (integer number per day)
fabs = fraction of applied mass that is retained and absorbed systemically (Defaults for
1,4-dioxane: 0.78 for industrial use and 0.86 for commercial use)
PF = glove protection factor (Default: see Table 2-32..)
The fractional absorption (fabs) for 1,4-dioxane is estimated to be 0.86 in commercial settings
with lower indoor wind speeds and 0.78 in industrial settings with higher indoor wind flows
based on a theoretical framework provided by Kasting and Miller (2006). meaning that 86% or
78% of the applied dose is retained by the stratum corneum, the outermost layer of the epidermis
skin, and absorbed systemically.
Table 2-32. Exposure Control Efficiencies and Protection Factors for Different Dermal
Protection Strategies
Dmiiiil Pmk'Clinn ( li;u;ic(i'i is(ics
A H eeled I sor
(.roup
r.lTicieno ("ni
ProK'Clion
l-'iiclor. PI-
a. No gloves used, or any glove / gauntlet without permeation
data and without employee training
0
1
b. Gloves with available permeation data indicating that the
material of construction offers good protection for the
substance
Industrial and
Commercial
Uses
80
5
c. Chemically resistant gloves (i.e., as "b" above) with
"basic" employee training
90
10
d. Chemically resistant gloves in combination with specific
activity training (e.g., procedure for glove removal and
disposal) for tasks where dermal exposure can be expected to
occur
Industrial Uses
Only
95
20
Table 2-33. presents the estimated dermal absorbed dose for workers in various exposure
scenarios. The dose estimates assume one exposure event (applied dose) per work day and that
123 of 616
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approximately seventy-eight to eighty-six percent14 of the applied dose is absorbed through the
skin. The exposure estimates are provided for each condition of use, where the conditions of use
are "binned" based on the maximum possible exposure concentration (Yderm), the likely level of
exposure. The exposure concentration is determined based on EPA's review of currently
available products and formulations containing 1,4-dioxane. For example, EPA found that 1,4-
dioxane concentration in film cements can be as high as 50 percent (Kodak. 2011).
To streamline the dermal exposure assessment, the conditions of use were grouped based on
characteristics known to effect dermal exposure such as the maximum weight fraction of 1,4-
dioxane that could be present in that condition of use, open or closed system use of 1,4-dioxane,
and large or small-scale use. Six different groups or "bins" were created to group conditions of
use based on this analysis.
Bin 1 covers large-scale industrial uses that typically occur in a closed system. For these uses,
dermal exposure is likely limited to chemical loading/unloading activities (e.g., connecting
hoses).
No gloves used: Operators in these industrial uses, while working around closed-system
equipment, may not wear gloves or may wear gloves for abrasion protection or gripping that are
not chemical resistant.
Gloves used with a protection factor of 5, 10, and 20: Operators may wear chemical-resistant
gloves when taking quality control samples or when connecting and disconnecting hoses during
loading/unloading activities.
Bin 2 covers open system functional fluids, which includes metalworking fluids and cutting and
tapping fluids. During these types of open-system operations, workers are expected to be
exposed during chemical loading/unloading; container cleaning; diluting water-based
metalworking fluids; metal shaping operations; rinsing, wiping, and/or transferring the
completed part; changing filters; transferring spent fluids; and cleaning equipment.
No gloves used: Due to the variety of shop types in these uses the actual use of gloves is
uncertain. EPA assumes workers may not wear gloves or may wear gloves for abrasion
protection or gripping that are not chemical resistant during routine operations.
Gloves used with a protection factor of 5, 10, and 20: Workers may wear chemical-resistant
gloves when charging and draining metal shaping equipment, drumming spent metalworking
fluid, and changing filters. EPA assumes gloves may offer a range of protection, depending on
the type of glove and employee training provided.
Bin 3 covers the use of 1,4-dioxane in small-scale industrial uses. Workers may unload small
volumes of nearly pure 1,4-dioxane and directly handle small quantities in research labs.
14 The absorbed fraction (fabs) is a function of indoor air flow rate, which differs for industrial and commercial
settings.
124 of 616
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No gloves used: Operators in these small-scale industrial uses, while working around small
amounts of the chemical, may not wear gloves or may wear gloves for abrasion protection or
gripping that are not chemical resistant.
Gloves used with a protection factor of 5, 10, and 20: Operators may wear chemical-resistant
gloves when taking quality control samples or when transferring small quantities of the chemical.
EPA assumes gloves may offer a range of protection, depending on the type of glove and
employee training provided.
Bin 4 covers the use of 1,4-dioxane in polyurethane spray foam insulation. Workers are expected
to be exposed during chemical unloading, spray application, and trimming activities.
No gloves used: Actual use of gloves in this use is uncertain. EPA assumes workers may not
wear gloves or may wear gloves for abrasion protection or gripping that are not chemical
resistant during routine operations.
Gloves used with a protection factor of 5, 10, and 20: Workers may wear chemical-resistant
gloves when charging application equipment, applying the foam, and trimming cured spray foam
insulation. EPA assumes gloves may offer a range of protection, depending on the type of glove
and employee training provided.
Bin 5 covers the use of 1,4-dioxane in film cements. Workers are exposed during manual
application of the film cement with a small brush. The NIOSH HHE observed splicer operators
had skin contact with 1,4-dioxane and recommended that employees wear neoprene or other
appropriate chemical resistant gloves when handling solvents, including 1,4-dioxane (Qkawa and
Cove, 1982). The NICNAS report concludes that exposures to skin are likely insignificant in
comparison to inhalation exposures for this use (NICNAS. .1.9981
No gloves used: Operators in these small-scale photo shops, while working around small
amounts of the chemical, may not wear gloves or may wear gloves for gripping that are not
chemical resistant.
Gloves used with a protection factor of 5, 10, and 20: Operators may wear chemical-resistant
gloves when transferring small quantities of the chemical, applying the film cement, or trimming
film coated with cured film cement. EPA assumes gloves may offer a range of protection,
depending on the type of glove and employee training provided.
Bin 6 covers the use of 1,4-dioxane in the manufacture and application of dry film lubricants.
Workers are expected to unload and handle small volumes of pure 1,4-dioxane during dry film
lubricant manufacture, mixing, and spray application. Although the process is small-scale and
involved handling of purity of 1,4-dioxane similar to Bin 3, Bin 6 is considered a separate
industrial application as it is part of a larger manufacturing process.
Gloves used with a protection factor of 5, 10, and 20: Operators may wear chemical-resistant
gloves when taking quality control samples, when transferring small quantities of the chemical,
mixing, or spray applying. EPA assumes gloves may offer a range of protection, depending on
the type of glove and employee training provided.
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Scenarios not assessed: The "no gloves" exposure scenario is not included in Bin 6 because
Kansas City National Security Campus, the only known manufacturer, reports that their workers
use gloves in their operation.
As shown in the Table 2-33., the calculated absorbed dose is high, which is due to high
absorption characteristics, miscibility with water, and a lower octanol-water coefficient (-0.27)
( 2014e). Dermal exposure to liquid is not assumed for ON Us, as they do not directly
handle 1,4-dioxane.
Table 2-33. Estimated Dermal Absorbed Dose1 (mg/day) for Workers in Various
Conditions of Use
I'1\|)osiiivs duo lo (>lo\o Poniioaliun/Chomioal
Woi'Jil
l-'raolinn
(Max
liroaklhmuuh (ni^/d;i> )
Prn(oo(i\o
Pm(oo(i\o
Conriiiion of I so
Bin
No (>lo\os
(H; 1)
Pmioo(i\o
(>lo\os :
(>lo\os :
(>lo\os :
(Commercial
(Industrial
-------
from water and dietary sources and reduced by metabolism. A BAF < 1 indicates that
concentrations in fish tissues are expected to be lower than aqueous concentrations and supports
the expectation that fish ingestion is not a primary pathway of human exposure for 1,4-dioxane.
This is consistent with human and rat toxicokinetic data suggesting a short half-life
(approximately 1 hour) for 1,4-dioxane following uptake. Given its hydrophilic properties and
short half-life, 1,4-dioxane is not expected to accumulate in tissue.
2.4.2.1 General Population Exposure Approach
Both estimated {i.e., modeled) and measured levels of 1,4-dioxane in ambient water/surface
water, were used to estimate incidental oral and dermal exposures during recreational activities
such as swimming. Based on the incidental nature of such exposures, this supplemental analysis
focuses on only acute exposures.
2.4.2.1.1 Modeling Surface Water Concentrations
In Section 2.2.1, Environmental Releases to Water, EPA estimates annual releases, release days,
and number of facilities to provide a range of daily water releases for each OES based on 2018
TRI and DMR. Some OES had no predicted releases to surface water (see Table 2-2.). Therefore,
included in this evaluation of general population exposures via ambient water include
discharging sites involved in the following OES: manufacturing, industrial uses, functional fluids
(open-system), spray foam application, and disposal. Table 2-2. shows the range of surface water
release estimates across these OES; however, site-specific discharges are provided and used in
this exposure analysis (see Supplemental File [Exposure Modeling Inputs, Results, and Risk
Estimates for Incidental Ambient Water Exposure]).
Using the described site-specific water release information (kg/site/day) and days of release
based on OES categories and assumptions, environmental modeling was conducted using EPA's
Exposure and Fate Assessment Screening Tool (E-FAST 2014) to predict surface water
concentrations in near-facility ambient water bodies (U.S. EPA... 2014c). For more on the
operation and inputs of the E-FAST model, refer to the Estimating Surface Water Concentrations
Section of Appendix E and the E-FAST 2*- 'Ms documentation Manu A Q v ^ \ .007).
In this evaluation, site-specific stream flows were applied within E-FAST, where available, and
no wastewater treatment removal was applied. E-FAST does not incorporate degradation or
volatilization once released and estimates concentrations at the point of release (not
downstream).
Modeled Surface Water Concentrations
Table 2-34 displays the modeled surface water concentrations obtained from E-FAST, as well as
the site-specific water release inputs. Refer to the Supplemental Files [Exposure Modeling
Inputs, Results, and Risk Estimates for Incidental Ambient Water Exposure and Ambient Water
Exposure Modeling Output from E-FAST].
127 of 616
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Table 2-34 Modeled Surface Water Concentrations
(kTiipsiliunsil
l'l\|)OMIIV
Scenario (OI'.S)
l-'sicilil>
SIC Cock- or
NPDI.S1
l)siil\
Kck'sisi*
(kii/sik'/(l;i\)
l)sl\S of
Ucic'iisc
3IIQ5: Surl'sico
\\ silcr
( oiiccnlrsilion
(fi»/l.)
Manufacturing
BASF
LA0004057
2.48
250
9.67E+01
Industrial Uses
Ineos Oxide
Industrial
POTW
2.89
250
2.17E+02
Microdyn-Nadir
Corp
Industrial
POTW
0.10
250
7.24E+00
St Charles
Operations
(Taft/Star) Union
Carbide Corp
LA0000191
3.31
250
1.11E-02
SUEZ Water
Technologies &
Solutions
Industrial
POTW
67.68
250
5.09E+03
The Dow Chemical
Co - Louisiana
Operations
LA0003301
2.59
250
8.70E-03
Union Carbide Corp
Institute Facility
WV0000078
15.28
250
3.33E+00
Union Carbide Corp
Seadrift Plant
TX0002844
2.01
250
2.41E+01
BASF Corp
PA0092223
0.01
250
3.40E-01
Cherokee
Pharmaceuticals
LLC
PA0008419
0.01
250
2.63E-03
DAK Americas LLC
NC0003719
31.86
250
2.78E+01
Institute Plant
WV0000086
24.53
250
5.27E+00
Kodak Park Division
NY0001643
0.256
250
1.70E-01
Pharmacia & Upjohn
(Former)
CT0001341
0.00
250
2.74E-02
Philips Electronics
Plant
TX0023779
0.00
250
1.00E-01
Sanderson Gulch
Drainage
Improvements
Industrial
POTW
0.00
250
1.00E-02
Open System
Functional Fluids
Ametek Inc. U.S.
Gauge Div
PA0020460
0.01
247
4.00E-01
Lake Reg
Med/Collegeville
PA0042617
0.00
247
1.31E-02
128 of 616
-------
(kTiipsiliunsil
I'1\|)osiiiv
Scensirio (OI'.S)
SIC Cock- or
¦SIMMS'
l)siil\
Kck'sisi*
(Uii/sik'/(l;i\)
l)sl\S of
Kck'sisi*
3IIQ5: Su iI'skt
\\ silcr
( niiiTiilrsilion
(fiii/l.)
Pall Life Sciences
Inc
M1
-------
(see Table 2-34); this range of predicted concentrations encompasses the full range of the surface
water monitoring data submitted during the public comment period.
Additional inputs/exposure factors used to estimate these acute oral exposures are included in
Table 2-35. Supplemental File [Exposure Modeling Inputs, Results, and Risk Estimates for
Incidental Ambient Water Exposure] for additional details on inputs and assumptions. This
evaluation focused on children 11-15 years, as they present most conservative conditions when
considering the age-specific ingestion rate, body weight, and duration of exposure.
Table 2-35 Incidental Oral Exposure Factors
Description
Value
No lex
Age Class
11-15
Selected based on having highest incidental oral ingestion rate during
swimming from the Exposure Factors Handbook, Table 3-7 (EPA. 2019b)
Incidental Ingestion
Rate
152 mL/hr
Upper-percentile hourly incidental ingestion rate from the Exposure Factors
Handbook. Table 3-7 CEP A. 2019b)
Body Weight
56.8 kg
Recommended, mean body weight for children 11-15 from the Exposure
Factors Handbook Table 8-1 (U.S. EPA. 2011a)
Duration of
Exposure
2 hrs/day
High-end default short-term duration default from EPA Swimmer Exposure
Assessment Model (SWIMODEL): based on competitive swimmers in the
child 11-15 age class ( 15)
Daily Incidental
Ingestion Rate
0.304 L/day
0.152 L/day * 2 hrs
The equation used to estimate the acute daily dose rate (ADR) for incidental oral ingestion is shown
below (U.S. EPA. 2007V
ADR
Where,
SWC = Surface water concentration (|ig/L)
IR = Daily ingestion rate (L/day)
CF = 0.001 mg/|ig
BW = Body weight (kg)
2.4.2.1.4 Estimating Dermal Exposures from Swimming
Predicted stream concentrations were used to estimate incidental acute and incidental dermal
exposure from swimming. Predicted surface water concentrations ranges from 2.63E-03 |ig/L to
5.09E+03 |ig/L (see Table 2-34). Additional inputs/exposure factors used to estimate these acute
dermal exposures are included in Table 2-36. Supplemental File {Exposure Modeling Inputs,
Results, and Risk Estimates for Incidental Ambient Water Exposure] for additional details on
inputs and assumptions. This evaluation focused on the adult age class, as they present the most
conservative exposure conditions when considering the age-specific surface area to body weight
ratio and duration of exposure. Default parameterization from OPP's SWIMODEL were utilized
for most inputs as shown in Table 2-36 (EPA. 2015).
SWxIRx CF
BW
130 of 616
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Table 2-36 Dermal Exposure Factors
IH'scriplion
Value
\»les
Age Class
Adult
Selected based on having highest dose based on permeability-based dermal
exposure equation used in SWIMODEL. considering exposed surface area,
duration, and body weight
Skin Surface Area
19,500 cm2
Default dermal contact surface area for the adult ase class in SWIMODEL
(EPA. 2015)
Body Weight
80 kg
Recommended, mean body weight for adult age class (EFH, Table 8-1)
Exposure Duration
3 hrs/day
High-end, short-term default duration from EPA Swimmer Exposure
Assessment Model (SWIMODEL): based on competitive swimmers in the
adult age class (EPA. 2015)
Permeability
Coefficient (Kp)
5.05E-04
cm/hr
Estimated using IHSkinPerm© for 1,4-dioxane dermallv absorbed into the
stratum corneum from water
The equation used to estimate the acute daily dose rate for dermal exposure from swimming shown below
. 2015V
CW x Kp x SA x ET x CF
ADR = w
Where,
CW = Chemical concentration in water (mg/L)
Kp = Permeability coefficient (cm/hr)
SA = Skin surface area exposed (cm2)
ET = Exposure time (hrs/day)
CF = Conversion factor (0.001 L/cm3)
BW = Body Weight (kg)
2.4.2.2 General Population Exposure Results
Estimated acute incidental oral exposures range from 1.41E-08 to 2.73E-02 mg/kg/day, while
estimated acute dermal exposures range from 9.71E-10 to 1.88E-03 mg/kg/day. The highest
exposures are associated with releases from the industrial uses OES. This range of exposure
estimates cover acute oral and dermal doses estimated using both modeled and measured surface
water concentrations. Refer to the Supplemental File [Exposure Modeling Inputs, Results, and
Risk Estimates for Incidental Ambient Water Exposure] and 4.2.4 for the full set of results for all
releasing sites and submitted monitoring data.
2.4.3 Consumer Exposures
As explained in the scope document, 1,4-dioxane may be found as a contaminant in consumer
products that are readily available for public purchase.
2.4.3,1 Consumer Conditions of Use and Routes of Exposure
Evaluated
Eight consumer conditions of use are evaluated based on the uses identified in EPA's 2015
TSCA Work Plan Chemical Problem Formulation and Initial Assessment of 1,4-Dioxane (U.S.
EPA. 2015). An additional systematic review effort was undertaken for consumer exposures to
identify, screen, and evaluate relevant data sources. These conditions of use include surface
cleaner, antifreeze, dish soap, dishwasher detergent, laundry detergent, paint and floor lacquer,
textile dye, and spray polyurethane foam (SPF). 1,4-Dioxane may be found in these products at
131 of 616
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low levels (0.0009 to 0.02%) based on its presence as a byproduct of other formulation
ingredients, i.e., ethoxylated chemicals.
Inhalation exposures to 1,4-dioxane are estimated for household consumers (i.e., product users -
receptors who use a product directly) and bystanders (i.e., receptors who are a non-user that may
be incidentally exposed to the product). Acute inhalation exposures are presented for all
conditions of use, while chronic inhalation exposures are only presented for conditions of use
that are reasonably expected to involve daily use intervals (i.e., surface cleaner, dish soap,
dishwasher detergent, and laundry detergent). Other conditions of use (i.e., SPF, antifreeze,
textile dye, and paint and floor lacquer) are not evaluated over chronic exposure durations based
on expected infrequent and intermittent use frequencies.
Dermal exposures to 1,4-dioxane are estimated for household consumers, or users. Users are
assumed to include adults (21+ years) and children (11-20 years). As with inhalation, acute
dermal exposures are presented for all conditions of use, while chronic inhalation exposures are
only presented for conditions of use that are reasonably expected to involve daily use intervals
(i.e., surface cleaner, dish soap, dishwasher detergent, and laundry detergent). Other conditions
of use (i.e., SPD, antifreeze, textile dye, and paint and floor lacquer) are not evaluated over
chronic exposure durations based on expected infrequent and intermittent use frequencies.
Generally, individuals that have contact with liquid 1,4-dioxane would be users and not
bystanders. Therefore, direct dermal exposures are not expected for bystanders and are only
estimated for users.
2,4.3.2 Consumer Exposure Modeling Approach
Modeling was conducted to estimate exposure from the identified consumer conditions of use.
Acute exposures via inhalation and acute and chronic exposures via dermal contact to consumer
products were estimated using EPA's Consumer Exposure Model (CEM) Version 2.1 (
2019a). along with consumer behavioral pattern data (i.e., use patterns) and product-specific
inputs. An older version of CEM, available within E-FAST 2014, was used to estimate chronic
inhalation exposures and obtain lifetime average daily concentration outputs ( 14c).
EPA's Multi-Chamber Concentration and Exposure Model (MCCEM) was used to estimate
inhalation exposures related to use of SPF based on the availability of measured emission rate
data for that scenario (EPA. 2010). Table 2-37 displays the models used to estimate inhalation
and dermal exposures across the consumer conditions of use.
Table 2-37 Models Used Across Consumer Conditions ofl
so and Routes of Exposure
Consumer Condition
Acule Inhiiliilion
Chronic Inhiiliilion
Acute Dcrniiil
Chronic Dcrniiil
of I sc
I'1\|)omii'c
I'lxpoMirc
l'l\|)OMirc
I'Aposiirc
Surface Cleaner
clm:.i
CLM
clm:.i
clm:.i
Antifreeze
CEM 2.1
—
CEM 2.1
—
Dish Soap
CEM 2.1
CEM
CEM 2.1
CEM 2.1
Dishwasher Detergent
CEM 2.1
CEM
CEM 2.1
CEM 2.1
Laundry Detergent
CEM 2.1
CEM
CEM 2.1
CEM 2.1
Paint and Floor Lacquer
CEM 2.1
—
CEM 2.1
—
Textile Dye
CEM 2.1
—
CEM 2.1
—
SPF
MCCEM
—
CEM 2.1
—
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Emission data were identified and evaluated through systematic review. For some conditions of
use, emission data were used to support estimated exposures and to model emissions of SPF (see
Appendix H. 1.2.1).
2.4.3,2.1 Modeling Air Concentrations and Inhalation Exposure
Consumer Exposure Model
CEM 2.1 and CEM predict indoor air concentrations from consumer product use by
implementing a deterministic, mass-balance calculation utilizing an emission profile determined
by applying appropriate emission scenarios. The model uses a two-zone representation of the
building of use (e.g., residence, school, office), with Zone 1 representing the room where the
consumer product is used (e.g., a utility room) and Zone 2 being the remainder of the building.
The product user is placed within Zone 1 for the duration of use, while a bystander is placed in
Zone 2 during product use. Otherwise, product users and bystanders follow prescribed activity
patterns throughout the simulated period.
For acute exposure scenarios, emissions from each incidence of product usage are estimated over
a period of 72 hours using the following approach that accounts for how a product is used or
applied, the total applied mass of the product, the weight fraction of the chemical in the product,
and the molecular weight and vapor pressure of the chemical. Time weighted averages (TWAs)
were then computed based on these user and bystander concentration time series per available
human health hazard data. For 1,4-dioxane, 8-hour TWAs were quantified for use in risk
evaluation based on alignment of relevant acute human health hazard endpoints. For additional
details on CEM 2.l's underlying emission models, assumptions, and algorithms, please see the
User Guide Section 3: Detailed Descriptions of Models within CEM 2.1 (U.S. EPA. ), also
summarized in Appendix H. The emission models used have been compared to other model
results and measured data; see Appendix D: Model Corroboration of the User Guide Appendices
for the results of these analyses (U.S. EPA. 2019b).
For chronic exposure scenarios, CEM within E-FAST 2014 was used to obtain lifetime average
daily concentrations (LADCs) for the scenarios involving chronic exposures. Emissions are
estimated over a period of 60 days. For cases where the evaporation time estimated exceeds 60
days, the model will truncate the emissions at 60 days. Conversely, for cases where the
evaporation time is less than 60 days, emissions will be set to zero between the end of the
evaporation time and 60 days. For more information on this version of CEM and its chronic
inhalation estimates, refer to the E-FA.ST 2014 Documentation Manual ( E007).
The general steps of the calculation engine within the CEM 2.1 and CEM models include:
• Introduction of the chemical (i.e., 1,4-dioxane into the room of use (Zone 1) through
two possible pathways: (1) overspray of the product or (2) evaporation from a thin
film;
• Transfer of the chemical to the rest of the house (Zone 2) due to exchange of air
between the different rooms;
• Exchange of the house air with outdoor air; and
• Compilation of estimated air concentrations in each zone as the modeled occupant
(i.e., user or bystander) moves about the house per prescribed activity patterns.
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Multi-Chamber Concentration and Exposure Model
The Multi-Chamber Concentration and Exposure Model (MCCEM) estimated indoor air
concentrations of chemicals released from household products (EPA. ). It uses air
infiltration and interzonal air flow rates with user-input emission rates to calculate time-varying
concentrations in several zones or chambers within a residence. Four types of source models are
available in MCCEM - constant, single exponential, incremental, and data entry. For additional
details, see the MCCEM User Guide (EPA. 2019c).
Within MCCEM, the incremental source model is specifically designed for products that are
applied to a surface (as SPF is) rather than products that are placed in an environment (e.g., an
air freshener). This distinction is important because the incremental source model considers the
time or duration of application or use in its calculations of emissions and concentrations, while
the single exponential source model does not. The incremental model assumes a constant
application rate over time, coupled with an emission rate for each instantaneously applied
segment that declines exponentially.
The incremental model can be populated using data derived from the experimental data and
proposed model of emission rates in Karlovich et al. (2i ). See H. 1.2.1 for details on the
underlying equations and applying these data to estimate the emission rate for this scenario.
2,4.3,2,2 Modeling Dermal Exposure
CEM 2.1 contains dermal modeling components that estimate absorbed dermal doses resulting
from dermal contact with chemicals found in consumer products: P_DER2a: Dermal Dose from
a Product Applied to Skin, Fraction Absorbed Model and P_DER2b: Dermal Dose from Product
Applied to Skin, Permeability Model. The selection of the appropriate dermal model was based
on whether an evaluated condition of use is expected to involve dermal contact with impeded or
unimpeded evaporation. For scenarios that are more likely to involve dermal contact with
impeded evaporation (e.g., wiping or cleaning with a chemical soaked rag), the permeability
model is applied. In contrast, for scenarios less likely to involve impeded evaporation, the
fraction absorbed model is applied. For acute exposure scenarios, dermal acute dose rates
(ADRs) are estimated and, for chronic exposure scenarios, lifetime average daily doses (LADDs)
are estimated. See H.2 for a more detailed comparison of these dermal models.
The permeability model estimates the mass of a chemical absorbed and dermal flux based on a
permeability coefficient (Kp) and is based on the ability of a chemical to penetrate the skin layer
once contact occurs. It assumes a constant supply of chemical directly in contact with the skin
throughout the exposure duration. Kp is a measure of the rate of chemical flux through the skin.
The parameter can either be specified by the user (if measured data are reasonably available) or
be estimated within CEM using a chemical's molecular weight and octanol-water partition
coefficient (Kow). The permeability model does not inherently account for evaporative losses
(unless the available flux or Kp values are based on non-occluded, evaporative conditions),
which can be considerable for volatile chemicals in scenarios where evaporation is not impeded.
While the permeability model does not explicitly represent exposures involving such impeded
evaporation, the model assumptions make it the preferred model for an such a scenario. For 1,4-
dioxane, an estimated aqueous dermal permeability coefficient (Kp, 5.05E-04 cm/hr) is used,
based on IHSkinPerm© predictions. For additional details on this model, please see Apppendix
134 of 616
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H.2 and the CEM User Guide Section 3: Detailed Descriptions of Models within CEM (U.S.
19a).
The fraction absorbed model estimates the mass of a chemical absorbed through the applicational
of a fractional absorption factor to the mass of chemical present on or in the skin following a use
event. The initial dose or amount retained on the skin is determined using a film thickness
approach. A fractional absorption factor is then applied the initial dose to estimate absorbed
dose. The fraction absorbed is essentially the measure of two competing processes, evaporation
of the chemical from the skin surface and penetration deeper into the skin. It can be estimated
using an empirical relationship based on Frasch and Bunge (2015). Due to the model's
consideration of evaporative processes, it was considered more representative of dermal
exposure under unimpeded exposure conditions. For additional details on this model, please see
Apppendix H.2 and the CEM User Guide Section 3: Detailed Descriptions of Models within
CEM (U.S. EPA. 2.019a).
2.4.3.3 Consumer Exposure Scenarios and Modeling Inputs
Based on the combination of high-end and central tendency inputs, modeling results are
presented for "high-intensity users" or "moderate-intensity users." High-intensity user scenarios
are characterized by high-end {i.e., 95th percentile or maximum) inputs governing key user
behavior pattern inputs (duration of use, mass of product used). Moderate-intensity user
scenarios are characterized by central tendency {i.e., 50th percentile) inputs governing the key
user behavior pattern inputs of duration of use and mass of product used. Although key inputs
represent high-end or central tendencies, this was a deterministic assessment and exposure
results are not reflective of a distribution.
For acute exposure scenarios, only high-intensity user scenarios that incorporate high-end mass,
duration, and weight fraction inputs are presented. For chronic exposure scenarios, both high-end
and moderate-intensity user scenarios are presented based on model documentation and the
understanding that central tendency parameters may more accurately represent lifetime
exposures. CEM and CEM 2.1 are designed to use central tendency inputs for mass, duration,
use frequency, and weight fraction when estimating lifetime exposures (I. ' < f ^
EPA. 2019a). Chronic high-intensity user scenarios, unlike the acute high-intensity user
scenarios, utilize central tendency weight fraction inputs, where possible.
Some modeling inputs such as the room of use {i.e., Zone 1 volume) and surface area to body
weight ratio exposed in dermal exposure scenarios were held constant across the multiple
iterations of a single product scenario but differed across product scenarios based on their
product-specific nature. Other parameters such as chemical properties, building volume, air
exchange rate, interzonal ventilation rate, and user and bystander activity patterns {i.e.,
movements around the home) were held constant across all exposure scenarios and reflect central
tendency inputs {i.e., median or mean values; see Table 2-38).
For details on default modeling inputs and a sensitivity analysis, see Appendix B and Appendix
C, respectively, of the CEM 2.1 user guide appendices (U.S. EPA. 2019b). The sensitivity
analysis is also summarized in Appendix H.4.
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Table 2-38 Default Modeling In
put Parameters
Piii'iimolor
1 >
Modeling
Piii'iiiiH'lor
Doliiull Value
Modeled
Value
( haracleri/aliou
Reference
I.uiklnm
Characteristic1
1 iiiikliiiu Volume
(m3)
4<>:
( culial Tciidciics
(Mean)
U.S. EPA (201 la)
Air Exchange
Rate (hr1)
0.45
Central Tendency
(Median)
> i r \ i'_cu! o
Interzonal
Ventilation Rate2
(m3/hr)
107
NA
Defaults U.S. EPA. (2019a.
b)
Emission
Characteristics
Background Air
Concentration
(mg/m3)
0
Minimum
Gas Phase Mass
Transfer
Coefficient (m/hr)
Emission Factor
(ug/m2/hr)
Based on chemical properties and estimated
within CEM (for SPF scenario modeled
with MCCEM, see H. 1.2.1)
Saturation
Concentration in
Air (mg/m3)
1.89E+05
Based on
chemical
properties and
estimated within
CEM
Use Patterns
and Exposure
Factors
Receptor Activity
Pattern
Stay at home3
NA
Default U.S. EPA (2019a.
b)
Use Start Time
9 AM4
NA
Frequency of Use
1 event per day
Defaults U.S. EPA (2019a.
b)
Acute Exposure
Duration
1 day
Acute Averaging
Time
1 day
Chronic Exposure
Duration
57 years
Chronic
Averaging Time
78 years
Surface Area to
Body Weight
Ratio
Face, Hands, Arms
Adult (21+): 15.8
Children (16-20): 14.9
Children (11-15): 16.4
Central tendency
(mean)
Both Hands
Adult (21+): 12.4
Children (16-20): 11.6
Children (11-15): 12.7
Central tendency
(mean)
Inside of One Hand
Adult (21+): 3.10
Children (16-20): 2.90
Children (11-15): 3.17
Central tendency
(mean)
10% of Hands
Adult (21+): 1.24
Children (16-20): 1.16
Children (11-15): 1.27
Central tendency
(mean)
136 of 616
-------
NA = not applicable
1 An overall residential building volume of 492 m3 is used to calculate air concentrations in Zone 2 and room volume is
used to calculate air concentrations in Zone 1. The volume of the near-field bubble in Zone 1 was assumed to be 1 m3
in all cases, with the remaining volume of Zone 1 comprising the far-field volume.
2 The default interzonal air flows are a function of the overall air exchange rate and volume of the building, as well as
the "openness" of the room itself. Kitchens, living rooms, garages, schools, and offices are considered more open to the
rest of the home or building of use; bedrooms, bathrooms, laundry rooms, and utility rooms are usually accessed
through one door and are considered more closed.
3 The activity pattern (i.e., zone location throughout the simulated exposure period) for user and bystander was the
default "stay-at-home" resident, which assumes the receptors are primarily in the home (in either Zone 1 or 2)
throughout the day. These activity patterns in CEM were developed based on Consolidated Human Activity Database
(CHAD) data of activity patterns (Isaacs. 20.1.4).
4 Product use was assumed to start at 9 AM in the morning; as such, the user was assumed to be in the room of use
(Zone 1) at that time, regardless of the default activity pattern at 9 AM.
Key product scenario-specific modeling inputs for inhalation modeling are shown in Table 2-39
For scenarios with both acute and chronic exposure estimates, the table includes both high-end
and central tendency inputs for duration, mass, and frequency of use. Please refer to the
Supplemental File [Consumer Exposure Assessment Modeling Input Parameters] for a detailed
listing of all inputs and associated sources.
Table 2-39 Key Product-Specific Inputs for Inha
Consumer
Product
Scenario
l-n nil
Kiinge of
Product ( one.
(|)|)in)
M;i\ 1
Weight
lr;ic(iou
Room of
Use
(\ tilii me.
mJ)
Dui'iilion
of I se
(mill)
Miiss of
Product
I sed
l "l
l're(|iieiic\
of I se
(
-------
CoilSllllHT
Product
Scciiiirio
Iciiiii
Kiiii^c of
Product ( one.
(|)|)in)
M;i\ 1
Weijihl
lr;ic(ion
Room of
I so
(\olllllH'.
mM
Dui'iilion
of I so
(mill)
Miiss ol'
Product
I sod
mi
l"ro(|iione\
ol-1 so
(dii\s/\o
-------
Consumer
Product
Sccn;irio
loiiii
M;i\ 1
Weigh I
l-'mclion
l.\|)(ISC'(l
Sii iT;icc
Arc;i
Diinilion
of I so :
(mill)
Absorption
Iniction ¦'
l-il in
Thickness
(cm)
Pcrmciihililt
Coefficient
(kp. cm/hi)
l'rC(|IICIIC\
of I so
((l;i\s/\o;u)
NA = not applicable
1 The use of "Max" (/'. e., maximum) here does not indicate use of a theoretical maximum or upper limit but refers to the
highest identified weight fraction for a given product type based on the available data. See the Supplemental File
[Consumer Exposure Assessment Modeling Input Parameters].
2 Durations of use were adjusted for dermal exposure for two scenarios: dishwashing detergent and laundry detergent. The
model default durations listed in Table 2-39 above are based on machine run times and would not be appropriate for dermal
contact duration.
3 Absorption fractions are estimated using duration of exposures; therefore, distinct absorption fractions are estimated and
applied for high-end vs. central tendency durations. This term is only used in estimation of dose using the fraction absorbed
model.
4 Dilution fractions were applied to three scenarios: dish soap (0.7%), laundry detergent (1.6%), and textile dye (10%). See
the Supplemental File [Consumer Exposure Assessment Modeling Input Parameters] for details.
2.4.3.4 Consumer Exposure Results
Estimated inhalation and dermal exposures are presented below for all consumer conditions of
use. Scenarios that involve frequent {i.e., daily) exposure intervals present acute and chronic
exposure estimates for consumer users and acute exposure estimates for users and bystanders.
Scenarios that involve intermittent or infrequent exposure intervals present acute exposure
estimates only for users and bystanders.
2.4.3.4.1 Surface Cleaner
Acute and chronic inhalation and dermal exposures to 1,4-dioxane present as a byproduct in
surface cleaner were evaluated. Concentrations of 1,4-dioxane in surface cleaners range from
0.36 to 9 ppm (up to 0.0009%). CEM 2.1 default inputs for all-purpose liquid cleaner were used
as the basis for duration of use and mass of product used. The room of use (Zone 1) is a
bathroom and the dermal surface area reflects the inside of one hand. Note that the bathroom is
selected as the room of use as a measure of conservatism since it has a smaller room volume than
other interior rooms. The weight fractions and other inputs are not specific to bathroom cleaner
but are intended to reflect general surface cleaner. It This scenario assumes dermal contact
during wiping/cleaning activities and may involve inhibited evaporation from the skin surface.
Inhalation exposure estimates are presented below. See the Supplemental File [Consumer
Exposure Modeling Results and Risk Estimates'] for exposure results and associated risk
estimates.
Table 2-41 Esl
imated Inhalation Exposure: Surface Cleaner
Scoiiiirio
Description
Diinilion of I sc
(mill)
Weigh!
Iniction
Miiss I scd
-------
Scenario
Description
Diinilioii of I so
(mill)
Weight
Irnction
Miiss I sod
(li)
Product I scr
or li\sl;ni(lcr
X-lir M;i\
T\\ A
(iiiti/mM
1 .A IX"
(mii/mM
High-Intensity
User
High End
(30)
Max 1
(9.0E-06)
High End
(300)
User
...
1.0E-03
Moderate-
Intensity User
Central Tendency
(15)
Max
(9.0E-06)
Central
Tendency
(200)
User
...
5.6E-04
Although, generally, mean weight fractions were utilized in all chronic modeling (high-intensity and moderate-
intensity user scenarios), a mean could not be estimates for this scenario based on source information.
Dermal exposure estimates are presented below and are based on the permeability model within
CEM2.1. Seethe Supplemental File [Consumer Exposure Modeling Results and Risk Estimates]
for exposure results and associated risk estimates, including those based on the fraction absorbed
model within CEM 2.1.
Table 2-42 Estimated Dermal Exposure: Surface Cleaner
Scenario Description
Diir;ilion of I so
(mill)
Weight
Irnction
("")
Receptor
ADR
(m^/k^/(lii>)
I.ADD
(m^/k^/(lii>)
Acute
High-Intensity User
High End
(30)
Max
(9.0E-06)
Adult (>21 years)
7.7E-06
—
Children (16-20 years)
7.2E-06
—
Children (11-15 years)
7.9E-06
—
Chronic
High-Intensity User
High End
(30)
Max1
(9.0E-06)
Adult (>21 years)
—
5.6E-06
Moderate-Intensity
User
Central Tendency
(15)
Max
(9.0E-06)
Adult (>21 years)
—
2.3E-06
Although, generally, mean weight fractions were utilized in all chronic modeling (high-intensity and moderate-
intensity user scenarios), a mean could not be estimates for this scenario based on source information.
2,4.3,4,2 Antifreeze
Acute inhalation and dermal exposures to 1,4-dioxane present as a byproduct in antifreeze were
evaluated. Concentrations of 1,4-Dioxane in antifreeze range from 0.01 to 86 ppm (up to
0.0086%). CEM 2.1 default inputs for anti-freeze liquid were used as the basis for duration of
use and mass of product used. The room of use (Zone 1) is a garage and the dermal surface area
reflects the inside of one hand. This scenario assumes dermal contact during pouring activities
and is not expected to involve inhibited evaporation from the skin surface.
Inhalation exposure estimates are presented below. See the Supplemental File [Consumer
Exposure Modeling Results and Risk Estimates] for exposure results and associated risk
estimates.
140 of 616
-------
Table 2-43 Estimated Inhalation Exposure: Ant
ifreeze
Sccn.irio
Description
Diii'iilion of I so
(iniii)
WciiilK
lr;ic(ion
Miiss I sod
Product I scr
or li\sl;imlcr
X-lir M;i\
T\\ A
(inii/in1)
Acute
High-Intensity
User
High End
(15)
Max
(8.6E-05)
High End
(150)
User
1.6E-02
Bystander
4.0E-03
Dermal exposure estimates are presented below and are based on the fraction absorbed model
within CEM 2.1. See the Supplemental File [Consumer Exposure Modeling Results and Risk
Estimates] for exposure results and associated risk estimates, including those based on the
permeability model within CEM 2.1.
Table 2-44 Estimated Dermal Exposure: Antifreeze
Sceiiiii'io Description
Diii'iilion of I se
Wcijihl
l-'mclion
<";.)
Rcccplor
AI)K
(iniii)
(m^/k^/(l:i>)
Acute
Adult (>21 years)
5.12E-04
High-Intensity User
High End
(15)
Max
(150)
Children (16-20 years)
4.80E-04
Children (11-15 years)
5.24E-04
2.4.3.4.3 Dish Soap
Acute and chronic inhalation and dermal exposures to 1,4-dioxane present as a byproduct in dish
soap were evaluated. Concentrations of 1,4-dioxane in dish soap range from 0.7 to 204 ppm (up
to 0.02%). CEM 2.1 default inputs for hand dishwashing soap/liquid serves as the basis for
duration of use and an American Cleaning Institute exposure and risk screening methods
document serves as the basis for mass of product used during hand dishwashing. The room of
use (Zone 1) is a kitchen and the dermal surface area reflects both hands. A 0.7% dilution factor
is applied. This scenario assumes immersive dermal contact in the 0.7% dish soap solution
during washing activities and may involve inhibited evaporation from the skin surface.
Inhalation exposure estimates are presented below. See the Supplemental File [Consumer
Exposure Modeling Results and Risk Estimates] for exposure results and associated risk
estimates.
Table 2-45 Esl
timated Inhalation Exposure: Dish Soap
Scciiiirio
Description
Duriilion of I sc
(iniii)
WciiilK
li;ic(ion
Miiss I scd
(»)
Product
I scr or
li>sliiiulcr
X-lir M;i\
TW A
diiii/mM
I.A DC
(mti/mi)
Acute
141 of 616
-------
Scenario
Description
Dui'iilion of I so
(mill)
Weight
l-'r;iclion
Miiss I sod
Product
I scr or
litsliindcr
X-lir M;i\
T\\ A
(iiiti/mM
1 .A IX"
(inii/in1)
High-Intensity
User
High End
(20)
Max
(2.04E-04)
High End
(84)
User
3.0E-02
—
Bystander
5.4E-03
—
Chronic
High-Intensity
User
High End
(20)
Central
Tendency
(2.40E-05)
High End
(84)
User
—
7.1E-04
Moderate-
Intensity User
Central Tendency
(10)
Central
Tendency
(2.40E-05)
Central
Tendency
(48)
User
—
3.3E-04
Dermal exposure estimates are presented below and are based on the permeability model within
CEM2.1. Seethe Supplemental File [Consumer Exposure Modeling Results and Risk Estimates]
for exposure results and associated risk estimates, including those based on the fraction absorbed
model within CEM 2.1.
Table 2-46 Estimated Dermal Exposure: Dish Soap
Seen:i rio Dose ri pi ion
l)iir;ilion of I se
(mill)
WciiilH
l-'niclion
.11/ i
I /o)
Receplor
\I)R
(m^/k^/d;i>)
I.ADI)
(m^/k^/dii>)
Acute
High-Intensity User
High End
(20)
Max
(2.04E-04)
Adult (>21 years)
3.1E-06
—
Children (16-20 years)
2.9E-06
—
Children (11-15 years)
3.1E-06
—
Chronic
High-Intensity User
High End
(20)
Central
Tendency
(2.40E-05)
Adult (>21 years)
—
2.6E-07
Moderate-Intensity
User
Central Tendency
(10)
Central
Tendency
(2.40E-05)
Adult (>21 years)
—
1.1E-07
2.4.3.4.4 Dishwashing Detergent
Acute and chronic inhalation and dermal exposures to 1,4-dioxane present as a byproduct in
dishwashing detergent were evaluated. Concentrations of 1,4-dioxane in dishwashing detergent
range from 0.86 to 9.7 ppm (up to 0.001%). CEM 2.1 default inputs for on machine dishwashing
detergent (liquid/gel) were used as the basis for duration of use and mass of product used. The
room of use (Zone 1) is a kitchen and the dermal surface area reflects 10% of hands. This
scenario assumes brief dermal contact during loading activities and is not expected to involve
inhibited evaporation from the skin surface.
142 of 616
-------
Inhalation exposure estimates are presented below. See the Supplemental File [Consumer
Exposure Modeling Results and Risk Estimates] for exposure results and associated risk
estimates.
Table 2-47 Estimated Inhalation Exposure: Dishwasher Detergent
Sccn;irin
Description
Dui'iilion of I so
(mill)
WeiiilK
l-'r;iclion
Miiss I sod
I'rnriucl
I ser or
8-hr M;i\
T\\ A
I.ADC
1")
si ;i ndoi*
img/nr')
Acute
High-Intensity
High End
Max
High End
User
6.9E-04
—
User
(50)
(9.7E-06)
(40)
Bystander
1.2E-04
—
Chronic
High-Intensity
User
High End
(50)
Central
Tendency
(5E-06)
High End
(40)
User
—
7.1E-05
Moderate-
Intensity User
Central Tendency
(45)
Central
Tendency
(5E-06)
Central
Tendency
(20)
User
—
2.9E-05
Dermal exposure estimates are presented below and are based on the fraction absorbed model
within CEM 2.1. See the Supplemental File [Consumer Exposure Modeling Results and Risk
Estimates] for exposure results and associated risk estimates, including those based on the
permeability model within CEM 2.1.
Table 2-48 Estimated Dermal Exposure: Dishwasher Detergent
Scenario Description
Duriilion «l" I se 1
(iniii)
WciiilH
l-'niclion
("")
Keceplor
ADR
(m^/k^/(lii>)
I.ADD
(m^/k^/(lii>)
Acute
High-Intensity User
(1)
Max
(9.7E-06)
Adult (>21 years)
3.2E-06
—
Children (16-20 years)
3.0E-06
—
Children (11-15 years)
3.3E-06
—
Chronic
High-Intensity User2
(1)
Central
Tendency
(5E-06)
Adult (>21 years)
—
1.2E-06
Moderate-Intensity
User2
(1)
Central
Tendency
(5E-06)
Adult (>21 years)
—
9.9E-07
1 The exposure duration applied for dermal exposures to dishwashing detergent were adjusted to 1 minute, as the
scenario default exposure duration is based on the run time of a dishwasher, not on expected dermal contact time.
2 For this scenario, the distinct chronic dermal estimates are a result of a difference in frequency of use (365 days/yr
for high-intensity users and 300 days/yr for moderate-intensity users).
143 of 616
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2.4.3.4.5 Laundry Detergent
Acute and chronic inhalation and dermal exposures to 1,4-dioxane present as a byproduct in
laundry detergent were evaluated. Concentrations of 1,4-dioxane in laundry detergent range from
0.05 to 14 ppm (up to 0.0014%). CEM 2.1 default inputs for laundry detergent (liquid) were used
as the basis for duration of use and mass of product used. The room of use (Zone 1) is a utility
room and the dermal surface area reflects both hands. A 1.6% dilution factor is applied. This
scenario assumes immersive dermal contact in the 1.6% laundry detergent solution during hand
washing activities and may involve inhibited evaporation from the skin surface.
Inhalation exposure estimates are presented below. See the Supplemental File [Consumer
Exposure Modeling Results and Risk Estimates] for exposure results and associated risk
estimates.
Table 2-49 Estimated Inhalation Exposure: Laundry Detergent
Scenario
Description
Dui'iilion of I so
(mill)
Weigh l
l-'mclion
Miiss I sod
I'roriucl
I ser or
X-lir M;i\
1 W A
I.AIK
1")
|}\s(;iii(kr
img/m')
Acute
High-Intensity
High End
Max
High End
User
1.5E-03
—
User
(50)
(1.4E-05)
(20)
Bystander
2.7E-04
—
Chronic
High-Intensity
User
High End
(50)
Central
Tendency
(6E-06)
High End
(20)
User
—
1.3E-04
Moderate-
Intensity User
Central Tendency
(45)
Central
Tendency
(6E-06)
Central
Tendency
(10)
User
—
7.1E-05
Dermal exposure estimates are presented below and are based on the permeability model within
CEM 2.1. Seethe Supplemental File [Consumer Exposure Modeling Results and Risk Estimates]
for exposure results and associated risk estimates, including those based on the fraction absorbed
model within CEM 2.1.
144 of 616
-------
Table 2-50 Estimated Dermal Exposure: Launt
ry Detergent
Scenario Description
Dui'iilion of I so 1
(iniii)
Wcifihl
l-'i'iiclion
Rcccplor
APR
(mu/ku/(lii>)
LAPP
(mu/ku/(lii>)
Acute
High-Intensity User
High End
(20)
Max
(1.4E-05)
Adult (>21 years)
4.8E-07
—
Children (16-20 years)
4.5E-07
—
Children (11-15 years)
4.9E-07
—
Chronic
High-Intensity User
High End
(20)
Central
Tendency
(6E-06)
Adult (>21 years)
—
1.5E-07
Moderate-Intensity
User
Central Tendency
(10)
Central
Tendency
(6E-06)
Adult (>21 years)
—
6.2E-08
1 The exposure duration applied for dermal exposures to laundry detergent were adjusted to equal the default exposures
times for dish soap, as this dermal exposure scenario is intended to approximate dermal contact from hand washing of
clothing, whereas the default exposure durations for the laundry detergent scenario are based on run times of the
washing machine.
2,4,3.4.6 Paints and Floor Lacquer
Acute inhalation and dermal exposures to 1,4-dioxane present as a byproduct in paints or floor
lacquer were evaluated. Concentrations of 1,4-dioxane in paints and floor lacquer range from
0.02 to 30 ppm (up to 0.003%). Westat Survey data on latex paint were used as the basis for
duration of use and mass of product used. The room of use (Zone 1) is a bedroom and the dermal
surface area reflects the face, hands, and arms. This scenario assumes dermal contact during
painting activities and is not expected to involve inhibited evaporation from the skin surface.
Inhalation exposure estimates are presented below. See the Supplemental File [Consumer
Exposure Modeling Results and Risk Estimates] for exposure results and associated risk
estimates.
Table 2-51 Estimated Inhalation Exposure: Paints and Floor Lacquer
Sccn.irio
Pcscriplinn
Diii'iilion of I so
(iniii)
WciiilK
l-'i'iiclion
Miiss I sod
Proriucl I scr
or li\sl:iii(ler
X-lir M;i\
T\\ A
(inii/in1)
Acute
High-Intensity
User
95th Percentile
(810)
Max
(3E-05)
95th Percentile
(26025)
User
2.0E-02
Bystander
7.5E-03
Dermal exposure estimates are presented below and are based on the fraction absorbed model
within CEM 2.1. See the Supplemental File [Consumer Exposure Modeling Results and Risk
Estimates] for exposure results and associated risk estimates, including those based on the
permeability model within CEM 2.1.
145 of 616
-------
Table 2-52 Estimated Dermal Exposure: Paints and Floor Lacquer
Scenario Description
Dui'iilion nl' I sc
(mill)
Wciiihl
l-'i'iiclion
Receplor
ADR
(m^/k^/(lii>)
Acute
High-Intensity User
95th Percentile
(810)
Max
(3E-05)
Adult (>21 years)
1.96E-03
Children (16-20 years)
1.85E-03
Children (11-15 years)
2.03E-03
2.4.3.4.7 Textile Dye
Acute inhalation and dermal exposures to 1,4-dioxane present as a byproduct in textile dye were
evaluated. An identified concentration of 1,4-dioxane in textile dye is 4.7 ppm (up to 0.00047%).
CEM 2.1 default inputs for textile and fabric dyes were used as the basis for duration of use and
mass of product used. The room of use (Zone 1) is a utility room and the dermal surface area
reflects both hands. A 10% dilution factor is applied. This scenario assumes immersive dermal
contact in the 10% dye solution during dyeing activities and may involve inhibited evaporation
from the skin surface.
Inhalation exposure estimates are presented below. See the Supplemental File [Consumer
Exposure Modeling Results and Risk Estimates] for exposure results and associated risk
estimates.
Table 2-53 Estimated Inhalation Exposure: Textile Dye
Sceiiiirio
Description
Duriilion of I se
(iniii)
Wei fill 1
l-'riiclion
Miiss I sod
(Si)
Producl I ser
or li\sl:iii(ler
X-lir M;i\
1W A
(ill si/ill')
Acute
High-Intensity
High End
Max
High End
User
8.5E-04
User
(20)
(4.7E-06)
(100)
Bystander
1.5E-04
Dermal exposure estimates are presented below and are based on the permeability model within
CEM 2.1. Seethe Supplemental File [Consumer Exposure Modeling Results and Risk Estimates]
for exposure results and associated risk estimates, including those based on the fraction absorbed
model within CEM 2.1.
146 of 616
-------
Table 2-54 Estimated Dermal Exposure: Textile I
>ye
Sceii;irio Description
Diii'iiliou of I so
(mill)
Wei jili I
lr;ic(ion'
.11/ i
I .'<»)
Receptor
\I)R
(iii}i/kii/(l:i> 1
Acute
High-Intensity User
High End
(20)
Max
(4.7E-06)
Adult (>21 years)
6.4E-07
Children (16-20 years)
6.0E-07
Children (11-15 years)
6.5E-07
2.4.3.4.8 Spray Polyurethane Foam
Acute inhalation and dermal exposures to 1,4-dioxane present as a byproduct in SPF were
evaluated. Concentrations of 1,4-dioxane in SPF range from <0.5 to 500 ppm (up to 0.05% in
mixed SPF) and the selected weight fraction aligns with that used in the occupational exposure
assessment. Three rooms of use (Zone 1) were assumed: the basement, the attic, and the garage.
The dermal surface area reflects the face, hands, and arms. Duration of use is based on loading
rate and application surface area, but it aligns well with the durations assumed in the
occupational exposure assessment (see Appendix G for more details). This scenario assumes
dermal contact during application activities and are not expected to involve inhibited evaporation
from the skin surface.
While application of SPF insulation products may primarily be occupational, a "do it yourself'
or DIY installation of SPF is possible. There are consumer products available that may expose
consumers (users and bystanders) to 1,4-dioxane.
Inhalation exposure estimates are presented below. See the Supplemental File [Consumer
Exposure Modeling Results and Risk Estimates] for exposure results and associated risk
estimates.
Table 2-55 Estimated Inhalation Exposure: SPF
Sceiiiirio
Description
Diii'iilion of I se
(iniii)
Wei fill 1
l-'i'iiclion
Miiss I sod
-------
Scon;irio
Description
Dui'iilioii of I so
(mill)
WeiiilK
Irnction
Miiss I sod
l "l
Product I soi-
or li\sl;indcr
X-lir M;i\
T\\ A
(niii/mM
Durations of us>o arc nol described u;> "liigh-end" in those bceiiunob because llies arc nol ba^cd on a
distribution; however, they are based on loading rates and application surface areas and align with occupational
exposure scenario durations (excluding time for set-up and without considering multiple jobs per day).
3 Mass of use was not an input in MCCEM as it was in the CEM model. These masses instead reflect the total
mass of chemical released in each exposure setting. These were estimated using loading ratios, application
surface areas, emission rate per square inch, and decay rate per hour. Please refer to the Supplemental File
\Consumer Exposure Assessment Modeling Input Parameters] for more details.
Dermal exposure estimates are presented below and are based on the fraction absorbed model
within CEM 2.1. See the Supplemental File [Consumer Exposure Modeling Results and Risk
Estimates] for exposure results and associated risk estimates, including those based on the
permeability model within CEM 2.1.
Table 2-56 Estimated Dermal Exposure: SPF
Scenario Description
Diii'iilion of I so
(mill)
Wei jili I
liiiction
1 11/ V
I /<»)
Rccoplor
\I)R
(in»/kii/d;i\)
Acute
Basement, Attic,
Garage1
(360, 360, 180)2
Max
(5.0E-04)
Adult (>21 years)
1.0E-03
Children (16-20 years)
9.7E-04
Children (11-15 years)
1.0E-03
1 SPF scenarios are not described in the same manner as the other product scenarios, as they are based on
home application areas: basement, attic, and garage, each with distinct air exchange rates and interzonal
ventilation rates. For dermal exposures, there is no difference across these scenarios, as the maximum
fraction absorbed is estimated and applied for either duration (360 or 180 minutes).
2 Durations of use are not described as "high-end" in these scenarios because they are not based on a
distribution; however, they are based on loading rates and application surface areas and align with
occupational exposure scenario durations (excluding time for set-up and without considering multiple
jobs per day).
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3 HAZARDS (Effects)
3.1 Environmental Hazards
3.1.1 Approach and Methodology
As part of problem formulation, EPA reviewed and characterized the environmental hazards
associated with 1,4-dioxane. EPA identified the following sources of environmental hazard data
for 1,4-dioxane: Health Canada (Health Canada. 2010; ECJRC. 2002; OECD. 1999; NICNAS.
1998). European Union risk assessment report (ECJRC. 2002). SIDS initial assessment profile
for 1,4 Dioxane (OECD. 1999). and National Industrial Chemicals Notification and Assessment
Scheme (Health Canada. 2010; ECJRC. 2002; OECD. 1999; NICNAS. 1998). These sources
concluded that the hazard of 1,4-dioxane to aquatic organisms is low. Also, 1,4-dioxane's
potential hazard to terrestrial organism is low due to the chemical's potential to migrate to
groundwater from soil environments. These conclusions pertaining to 1,4-dioxane's low hazard
effects to the environment resulted in determining that the chemical was a low priority for
ecotoxicity. Although the assessment documents mentioned above provide detailed information
regarding the environmental hazard of 1,4-dioxane to aquatic and terrestrial organisms, they do
not account for additional and more recent information published on the chemical. EPA
conducted a systematic review on 1,4-dioxane as described in the Application of Systematic
Review in TSCA Risk Evaluations ( b) and Strategy for Assessing Data Quality in
TSCA Risk Evaluations ( )
EPA completed the review of environmental hazard data/information sources during risk
evaluation using the data quality review evaluation metrics and the rating criteria described in the
Application of Systematic Review in TSCA Risk Evaluations ( E018b). Studies were
assigned an overall quality level of high, medium, or low. The data quality evaluation results are
outlined in Supplemental File: Data Quality Evaluation of Environmental Hazard Studies (U.S.
1). With the data available, EPA only used studies with an overall quality level of
high or medium for quantitative analysis during data integration. Studies assigned an overall
quality level of low were used qualitatively to characterize the environmental hazards of 1,4-
dioxane. Any study assigned an overall quality level of unacceptable was not used for data
integration.
Toxicity to Aquatic Organisms
EPA identified nine high quality studies that contained aquatic toxicity data (i.e., fish, aquatic
invertebrates, algae). Aquatic toxicity studies considered in this assessment are summarized in
Table 3-1..
This assessment evaluated studies that followed standard test guidelines (e.g., Office of
Chemical Safety and Pollution Prevention (OCSPP)), Organisation for Economic Co-operation
and Development [OECD]). Also, non-standard toxicity tests that followed procedures were
evaluated that were determined to be scientifically sound according to the Application of
Systematic Review in TSCA Risk Evaluations document ( b).
Page 149 of 616
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able 3-1. Acceptable acute aquatic toxicil
v studies that were evaluat
ted for of 1.4-Dioxane
Test
Organism
Duration
llndpoini
II a/ard
Value
(ing/l.) 1
I'.ITecl T\ pe
Reference
1'\ a In at ion Ranking
Acute2
Fish
96-hour LC50
13,000
Mortality
High
96-hour LOEC
10,000
96-hour LC50
10,000
Mortality
Dawson et al. (.1.977)
High
6,700
96-hour LC50
1,236
Mortality
Brooke (1987)
High
9,872
96-hour LC50
9,850
Mortality
Geieer et al. (1990)
High
10,800
Invertebrat
es
24-hour EC50
8,450
Behavior,
Equilibrium
Bringmann and Kuehii
(1982)
High
24-hour LC50
4,700
Immobilization
Bringmann and KuJin
High
48-hour EC50
4,269
Mortality
Brooke (1987)
High
Chronic2
Fish
32-day MATC
>145
Growth/Weight
Dow Chemical (1989a)
High
Hatchability
Survival
Development
28-day LOEC
565
Survival
Johnson et al. (1993)
High
Algae3
Short-term
8-day LOEC
575
Population,
growth rate
Brin gnian and Knhn
High
8-day EC50
575
Population
Bringmann and KuJin
(.1.978)
High
8-day EC50
575
Population
8-day LOEC
5,600
Population,
Growth Rate
8-day
5,600
Population
10-day
5,600
Biomass
'Values in the table are presented in the number of significant figures reported by the study authors.
2Acute and chronic hazard data are reported for fish and invertebrates
3Because algae can cycle through several generations in hours to days, the data for algae was assessed together regardless
of duration (i.e., 48-hrs to 96-hrs).
Toxicity to Fish
Four high quality studies were evaluated to characterize the acute toxicity of 1,4-dioxane
exposure to fish. The acute 96-hour LC50 values for fish range from 1,236 mg/L for fathead
minnow (Pimephalespromelas) to 6,700 mg/L for inland silversides (Menidia beryllina).
Two high quality studies were evaluated to characterize the chronic toxicity of 1,4-dioxane
exposure to fish. In a chronic study, medaka (Oryzias latipes) were exposed to measured
concentrations of 1,4-dioxane ranging from 50 mg/L to 6,933 mg/L for 28 days under flow-
Page 150 of 616
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through conditions. There were effects on growth and survival (Johnson et ai, 1993). A low
observed effect concentration (LOEC) of 565 mg/L was reported. In another study, fathead
minnows (P. promelas) were exposed to 1,4-dioxane for 32 days to mean measured
concentrations of 3, 27.6, 40.3, 65.3, 99.7 and 145 mg/L to observe the effects on embryonic
development (i.e., hatching, larval development, and larval survival) under flow-through
conditions. No effects were observed based on larval survival so a maximum acceptable toxicant
concentration (MATC) of 145 mg/L was calculated (Dow Chemical. 1989a).
Invertebrates
Three high quality studies that were evaluated to characterize the toxicity of 1,4-dioxane to
aquatic invertebrates. Brooke (1987) reported a 48-hour ECso of 4,269 mg/L to Daphnia magna
and a 96-hour LCso of 2,274 mg/L to amphipods (Gammarus pseudolimnaeus). The amphipod
study is also a receptor for the benthic environment. Also, a 24-hour ECso of 4,700 mg/L was
reported by Bringmann and Kuhn (1977).
Toxicity to Algae Species
To assess the toxicity of 1,4-dioxane to algae, two acceptable high studies were evaluated.
Bringmann and Kunn (1977. 1978) studied the effects of 1,4-dioxane exposure on population
growth rate in Microcystis aeruginosa and Scenedesmus quadricauda. In M. aeruginosa, cell
inhibition occurred after 8-days of exposure and S. quadricauda at nominal concentrations under
static conditions. The ECso of 575 mg/L and 5,600 mg/L were reported forM aeruginosa and S.
quadricauda, respectively.
Algae data in this assessment for 1,4-dioxane were assessed as acute and chronic endpoints
regardless of duration and not separated into acute and chronic, because durations normally
considered acute for other species (e.g., 48, 72 hours) can encompass several generations of
algae.
3 J .2 Weight of Scientific Evidence
The evaluation for environmental hazard data for 1,4-dioxane using the data quality review
evaluation metrics and the rating criteria is described in the Application of Systematic Review in
TSCA Risk Evaluations (U.S. EPA. 2018b). During data integration stage of the systematic
review process, EPA analyzed, synthesized, and integrated information regarding 1,4-dioxane's
toxicity. This involved evaluating evidence for quality and relevance, using a Weight of the
Scientific Evidence (WoE) approach (U.S. EPA. 2018b).
During data evaluation of the relevant 1,4-dioxane studies, a rating of high, medium, or low for
quality based on the TSCA criteria described in the Application of Systematic Review in TSCA
Risk Evaluations was applied ( ). Only data/information rated as high, medium,
or low for quality was used for the environmental risk assessment. While integrating
environmental hazard data for 1,4-dioxane, EPA gave more weight and consideration to relevant
data/information rated high or medium for quality. Any information rated as unacceptable was
not used to characterize the hazard of 1,4-dioxane. The factors for determining if environmental
data/information were relevant, were based on whether the source had biological,
physical/chemical, and environmental relevance ( ):
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• Biological relevance - correspondence among the taxa, life stages, and processes
measured or observed and the assessment endpoint.
• Physical/chemical relevance - correspondence between the chemical or physical agent
tested and the chemical or physical agent constituting the stressor of concern.
• Environmental relevance - correspondence between test conditions and conditions in the
region of concern ( ).
EPA used this weight-of-evidence approach to assess hazard data and develop COCs. Given the
available data, EPA only used studies assigned an overall quality level of high or medium to
derive COCs for each taxonomic group. To calculate COCs, EPA derived geometric means for
each trophic level that had comparable toxicity values (e.g., multiple ECsos measuring the same
or comparable effects from various species within a trophic level). EPA did not use non-
definitive toxicity values (e.g., EC50 > 48 mg/L) to derive geometric means because these
concentrations of 1,4-dioxane were not high enough to establish an effect on the test organism.
To assess aquatic toxicity from acute exposures, data for three taxonomic groups were available:
fish, aquatic invertebrates and algae. For each taxonomic group, data were available for these
species as shown in Table 3-1. For acute or short-term exposure, the most biologically relevant
species are Microcystis aeruginosa (B lineman and Kuhn. 1977) and Daphnia magna (Brooke.
1987V
The effects of 1,4-dioxane via the sediment pathway were not quantitatively assessed because
1,4-dioxane is expected to remain in aqueous phase and not adsorb to sediment due to its water
solubility (>800 g/L) and low partitioning to organic matter (Log Koc = 0.4). As stated in
Sections 2.1 and 5.4.2Appendix E, 1,4-dioxane concentrations in sediment pore water are
expected to be similar to the concentrations in the overlying water and any detection of the
chemical in sediments is likely from pore water and not the sorption potential to the sediment
solids.
To assess aquatic toxicity from chronic exposures, data for three three fish studes were
evaluated. The most sensitive species were a 28-day LOEC of 565 mg/L measuring growth and
survival in P. promelas (Dow Chemk 9a).
To assess the toxicity of 1,4-dioxane to algae, data for two species were available from high
quality studies. The most sensitive endpoint reported for algae (Microcystis aeruginosa) was a 8-
day EC50 of 575 mg/L from Bringman and Kuhn (1977).
Concentrations of Concern (COC)
The concentrations of concern (COCs) for aquatic species were calculated based on the
environmental hazard data for 1,4-dioxane, using the weight of evidence approach described
above and using EPA methods (Suter. 2016; U.S. EPA. 2013c. 2012d). For 1,4-dioxane, EPA
derived an acute COC, a chronic COC, and an algal COC (see Table 3-2.).
After weighing the scientific evidence and selecting the appropriate toxicity values from the
integrated data to calculate an acute and chronic COC, an assessment factor (AF) was applied
according to EPA methods (Suter. 2016; U.S. EPA. 2013c. 2012d). The application of UFs
provides a lower bound effect level that would likely encompass more sensitive species not
Page 152 of 616
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specifically represented by the available experimental data. Assessment factors also account for
differences in inter- and intra-species variability, as well as lab oratory-to-fi eld variability. These
AFs are dependent on the availability of datasets that can be used to characterize relative
sensitivities across multiple species within a given taxa or species group. However, they are
often standardized in TSCA risk evaluations because of the limited data available for most
industrial chemicals. For fish and aquatic invertebrates (e.g., daphnia), the acute COC values are
divided by an AF of 5. For chronic COCs, an AF of 10 is used (U.S. EPA. 2013c. 2012d).
Table 3-2. Concentrations of Concern (COCs) for Aquatic Toxicity
l'.ii\ in > 111111-111 ill
lo\ici(\
r.lTecls
lla/iird
Value
ASM'SMIK'III
l-aclor
( onceii I ra I ion
of Concern
<(()()
UtTcmuv
Scoiv
Algae (Short-term)
Microcystis aeruginosa
8-day ECso
Growth
Rate
575 mg/L
10
57,500 ng/L
Bring man and
K11I111 (1977)
High
Chronic toxicity
(Pimephales promelas)
32-d LOEC
Grow and
Survival
145 mg/L
10
14,500 (ig/L
Dow Chemical
< i"^9a)
High
The concentrations of concern (COCs) for aquatic species were calculated based on the
environmental hazard for 1,4-dioxane using the weight of evidence approach described above
and EPA methods (Suter. 2016; U.S. EPA. 2013c. 2012d). For 1,4-dioxane algae was the most
biological and environmental relevant species for short-term exposure to the chemical. As stated
in the previous section, algae endpoint was assessed separately and was not evaluated for an
acute or chronic COCs because durations normally considered acute for other species (e.g., 48,
72 hours) can encompass several generations of algae.
The short-term toxicity to algae concentrations of concern (COC) was derived from an 8-day
algae study where the EC50 is 575 mg/L (Geiger et at.. 1990). This value was then divided by the
assessment factor (AF) of 10 for algae.
The algal COC = (575 mg/L) / AF of 10 = 57.5 mg/L x 1000 = 57,500 |ig/L or ppb.
• The algal COC is 57,500 ppb.
For the chronic COC, the lowest chronic toxicity value is from a chronic 32-day MATC fathead
minnow study of > 145 mg/L (Brooke. 1987). This value was divided by an assessment factor of
10 then multiplied by 1,000 to convert from mg/L to |ig/L or ppb.
The lowest value for 32-day fish MATC = 145 mg/L / 10 = 14.5 x 1000 = 14,500 |ig/L or ppb.
Therefore, the chronic COC for 1,4-dioxane is 14,500 ppb based on the lowest chronic toxicity
value.
3,2 Human Health Hazards
3.2.1 Approach and Methodology
EPA used the approach described in Figure 3-1 to evaluate, extract and integrate 1,4-dioxane's
human health hazard and dose-response information. This approach is based on the Application
Page 153 of 616
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of Systematic Review in TSCA Risk Evaluations (U.S. EPA, 2018b) and the Framework for
Human Health Risk Assessment to Inform Decision Making ( 014d).
WSMmBMEBttm
Systematic
Review
Stage
Dili;! iifu.itimi
: After ftUI-text screening.
• Ij-'fh 1! i
' quality evaluation criteria
; to assess the confidence of
i key and supporting studies f
\ identified from previous I
assessments a« wdl as
ii«-\v Xt.;\
; considered in tile previous 1
Output of
Systematic
Review
Stage
Study Quality
Summary
Table (High.
Medium and
Low)
(Appendix F-
I)
Data J
i.xtraetirttt \
Extract data from
key, supporting
and new studies I
Data
ntegrate hazard aitonnatiou by considering QtiaJity (i.e.,
Higtbs, limitations), consistency, relevancy, coherence and
il) j ] Host' Ri-spnnM-
i iu•!: jou-n::! Vn.»tv\is
h.t.nid» identified j j . >!% s<-.
dm nu
scopmir problem *. v.m.pv.u.^ v,„«
formulation and j adequate data;
identify nen lw nds- \ | Selection ofFODs
Data
Summaries foi
Adverse
Endpoints
(Appendix F
Summary of
Results and
PODs
(Sections
J.2.5, 4.2.6
and 5.2.1)
wot
Narrative by
Adverse
Endpoint
(Section 4,2.4)
Ki>k 1 hr\r.HU'fi^afi«tt!
An.dv.\K
Determine the qualitative
.iii.i iJlY.hnV.UW
health risks and include, as
:!! •!'(c J .I-.-CM =•>;"•!<-f
* Data quality
Uncertainties
Figure 3-1. EPA Approach to Human Health Hazard Identification and Dose-Response for
1,4-Dioxane
Specifically, EPA reviewed key and supporting information from previous hazard assessments
[EPA IRIS Assessments (U.S. EPA. 2013 d.; ), an AT SDR Toxicological Profile (ATSDR.
2012). a Canadian Screening Assessment (Health Canada.: ), a European Union (EU) Risk
Assessment Report ECJRC (2.002). and an Interim AEGL (U.S. EPA. 2005b)l. EPA also
screened and evaluated new studies that were published since these reviews, as identified in the
literature search conducted for 1,4-dioxane (1,4-Dioxane (CASRN123-91-1) Bibliography:
Supplemental File for the TSCA Scope Document, EP A-HQ-QPPT-2016-0723).
The new literature was screened against inclusion criteria in the PECO statement and the relevant
studies (e.g., potentially useful for dose-response) were further evaluated using the data quality
criteria for human, animal, and in vitro studies described in the Application of Systematic Review
in TSCA Risk Evaluations ( 18b). EPA skipped the screening step of the key and
supporting studies and entered them directly into the data evaluation step based on their
relevance to the risk evaluation. Hazard studies by all routes of exposure were included since
inhalation exposures are directly relevant to workers and oral exposures can be used in route-to-
route extrapolation for dermal risk to workers.
EPA considered studies of low, medium, or high confidence for hazard identification and dose-
response analysis. Information that was rated unacceptable was not included in the risk
evaluation. Appendix I presents the information on human health hazard endpoints (acute, non-
cancer, and cancer) for all acceptable studies (with low, medium, or high scores).
EPA has not developed data quality criteria for all types of hazard information. This is the case
for toxicokinetics and many types of mechanistic data which EPA typically uses for qualitative
Page 154 of 616
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support when synthesizing evidence. As appropriate, EPA summarized and qualitatively
evaluated the quality of these data to determine the extent to which they could contribute to
hazard characterization.
Following the data quality evaluation, EPA extracted the toxicological information from each
relevant study (Figure 3-1. EPA Approach to Human Health Hazard Identification and Dose-
Response for 1,4-Dioxane). In the last step, the strengths and limitations of the data are evaluated
for each endpoint and a weight-of-the-scientific evidence narrative is developed. Also, data for
each selected hazard endpoint is modeled to determine the dose-response relationship (Appendix
K). Finally, the results are summarized, and the uncertainties are presented.
Adverse health effects associated with inhalation exposure to 1,4-dioxane were identified by
considering the quality and weight-of-the-scientific evidence to identify key endpoints. The
potential mode of action (MOA) for cancer was evaluated according to the framework for MOA
analysis described in the EPA Guidelines for Carcinogen Risk Assessi ( 1.005a).
Information for each adverse hazard endpoint (acute and chronic non-cancer and cancer) was
evaluated and integrated with information on toxicokinetics and MOA in a weight-of-the-
scientific evidence narrative (Section 3.2.3). Information on MOA was evaluated in Section
3.2.4. The evidence for genotoxicity is summarized in Appendix 1.1.5.
Data for the dose-response assessment were selected from the key studies and dose-response
modeling was performed, when the data were amenable to modeling, for adverse hazard
endpoints from those studies (Section 3.2.6). The dose-response assessment included analyses of
the non-cancer and cancer endpoints for inhalation and oral exposures identified in the hazard
identification. Limited toxicological data are available by the dermal route, so the dose-response
data from oral exposures were used to extrapolate to dermal exposures according to the European
Chemical Agency's Guidance on information requirements and chemical safety assessment,
Chapter R 8: Characterisation of dose [concentration]-response for human health (ECHA.
2008).
3,2,2 Toxicokinetics
EPA accepted conclusions about the validity of toxicokinetic data and physiologically-based
pharmacokinetic (PBPK) models based on previous peer reviews. In the 2013 EPA IRIS
assessment of 1,4-dioxane ( Hid), the quality of the toxicokinetic data (published
through 2013) and PBPK models were evaluated according to established standard operating
procedures (SOPs) and a quality assurance project plan. SOPs for identification, organization,
and evaluation of absorption, distribution, metabolism, and elimination (ADME) and
toxicokinetic studies and models have since been updated and consolidated into An Umbrella
Quality Assurance Project Plan (QAPP) for PBPK Models (U.S. EPA. 2.018D. In addition, the
IRIS assessment followed procedures contained in Approaches for the Application of
Physiologically Based Pharmacokinetic (PBPK) Models and Supporting Data in Risk
Assessment ( 06a).
In addition to the toxicokinetic studies summarized in the IRIS assessment, two additional
toxicokinetic studies identified in the literature search (Goem et at. 2016; Take et at.. 2012) were
considered in the weight-of-the-scientific evidence evaluation.
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Absorption
Following inhalation exposure, 1,4-dioxane enters systemic circulation. In a study with four
adult male volunteers exposed to a concentration of 50 ppm, uptake of 1,4-dioxane into plasma
was rapid and approached steady-state conditions by 6 hours (Young et at.. 1977). In a slightly
larger study (6 individuals/group), volunteers were exposed to 20 ppm 1,4-dioxane for 8 hours.
Mean blood concentrations were 0.98 mg/L after 4 hours and 1.1 mg/L after 8 hours, indicating
that blood concentrations were approaching steady state within four hours. Volunteers in the
same study who exercised for 10 minutes during each hour of the exposure had higher mean
blood concentrations, reaching 1.48 mg/L after 4 hours and 1.47 mg/L after 8 hours (Goen et at..
2016; 1977; Young et at.. 1976). Systemic uptake of 1,4-dioxane following inhalation exposure
has also been demonstrated in animal studies. In rats inhaling 50 ppm 1,4-dioxane for 6 hours,
plasma concentrations averaged 7.3 (.ig/mL (Young et at.. 1978a. b). In male rats exposed to 250
ppm, 1,4-dioxane reached steady-state blood concentrations within three hours (Take et at..
2012).
No human data are available to evaluate oral absorption of 1,4-dioxane. In male rats
administered [14C]-l,4-dioxane via oral gavage at single doses of 10, 100, or 1,000 mg/kg or as
17 consecutive doses of 10 or 1,000 mg/kg/day, 75-98% of the administered radioactivity
(depending on dose) was recovered in the urine while only 1-2% of administered radioactivity
was recovered in feces, indicating that 1,4-dioxane is highly absorbed by the gastrointestinal
tracts (Young et at... 1978a. b). Another study in male rats showed that, following a single oral
gavage dose of 65 mg/kg-bw, maximum blood concentrations peaked 60 minutes after exposure.
1,4-Dioxane was still detected in blood at 480 minutes but not at 720 minutes following exposure
(Take et at.. ).
Dermal absorption studies using human skin {in vitro) and nonhuman primates (in vivo)
measured reduced absorption compared to other routes of exposure, due in part to evaporation of
1,4-dioxane. Bronaugh (1982) measured in vitro penetration of 1,4-dioxane through excised
human skin under occluded and unoccluded conditions. Absorption was recorded 205 minutes
after application of radiolabeled 1,4-dioxane dissolved in lotion. Dermal penetration of 1,4-
dioxane in lotion was 3.2% of the applied dose for the occluded condition and 0.3% for the
unoccluded situation. In this study, rapid evaporation was observed, decreasing the amount
available for dermal absorption. Marzutti et at (1981) exposed rhesus monkeys to radiolabeled
1,4-dioxane (in methanol or skin lotion vehicle) for 24 hours under unoccluded conditions on the
forearm. Approximately 2-3% of the original radiolabel was cumulatively recovered in urine
over a 5-day period, but it is not clear how the study accounted for metabolism. In this risk
evaluation, a tiered approach was used to characterize dermal absorption in the dermal exposure
assessment (see Section 2.4.1.1.13).
Distribution
There are no data available on the distribution of 1,4-dioxane in human tissues. Based on limited
data in animal studies, 1,4-dioxane is expected to evenly distribute to major organs.
Take et al. (: observed distribution to multiple systemic tissues (lung, liver, brain, kidney,
and abdominal fat) in rats following administration via inhalation, oral, or combined inhalation
and oral exposures. 1,4-Dioxane concentrations in these tissues reached steady state after 180
minutes of inhalation exposure. 1,4-Dioxane in these tissues remained detectable 120 minutes
Page 156 of 616
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after exposure ended but was non-detectable after 360 minutes. Following a single oral gavage
exposure, 1,4-dioxane reached peak concentrations in all of these tissues 60 minutes after
exposure and was no longer detectable in tissue 720 minutes after exposure. Intraperitoneal (i.p.)
injection studies in rats found roughly even distribution of radiolabeled 1,4-dioxane in the tissues
observed (whole blood, brain, liver, kidney, spleen, lung, colon, testes and skeletal muscle) with
no evidence of appreciable accumulation of 1,4-dioxane or HEAA in tissues (Mikheev et at..
1990; Woo et at.. 1977b; Mikheev et at.. 1990; Woo et at.. 1977b).
It is not known whether 1,4-dioxane or metabolites can cross the placenta or enter breast milk.
1,4-Dioxane is quickly eliminated and is hydrophilic, properties that suggest that it may be less
likely to be detected in breast milk following exposure. However, PBPK modeling based on
experimentally derived partition coefficients for 1,4-dioxane suggest a high degree (18%) of
lactational transfer of 1,4-dioxane (Fisher et at... 1997). There are currently no measurements of
1,4-dioxane in milk following human or animal exposures available for comparison to this model
prediction.
Metabolism
1,4-Dioxane is metabolized in humans and rats by oxidation (Figure 4-2) (Goen et at.. 2.016;
Braun ar ig. 1977; Woo et at.. 1977c). The primary metabolite of 1,4-dioxane in systemic
circulation appears to be HEAA. HEAA may tautomerize to the potentially reactive lactone 1,4-
dioxane-2-one, but the equilibrium is heavily weighted towards metabolism to HEAA under
physiological conditions (Woo et at.. 1977c; Young et at.. 1977). The majority of 1,4-dioxane
that enters systemic circulation is metabolized. HEAA content detected in urine exceeded
concentrations of 1,4-dioxane by a ratio of 118:1 in workers exposed to a TWA of 1.6 ppm for
7.5 hours (Young et at... 1976) and by a ratio of 3,100:1 in rats inhaling 50 ppm 1,4-dioxane for 6
hours (Young et at.. 1978a. b). In adult male volunteers exposed to 50 ppm for 6 hours (Young et
at.. 1977). over 99% of inhaled 1,4-dioxane (assuming negligible exhaled excretion) appeared in
the urine as HEAA. The linear elimination of 1,4-dioxane in both plasma and urine indicated that
1,4-dioxane metabolism was a nonsaturated, first-order process at this exposure level.
Induction of CYP450 increases the amount of HEAA in urine and suppression of CYP450
decreases the amount of HEAA in urine, demonstrating that 1,4-dioxane metabolism is in part
mediated by CYP450 (1978. 1977c). Following oral exposure, 1,4-dioxane induces several
CYP450 isomers in liver microsomes including CYP2B1/2, CYP2C11, CYP2E1, and CYP3A,
but not CYP4A1 (Nannetti et at.. 2005). EPA evaluated two new metabolism studies (data
evaluation results in Appendix I) that measured in vitro hepatic microsomal CYP2E1 enzyme
activity (Patit et al.. 2015; Shah et at.. 2015). 1,4-Dioxane exhibited dose-dependent inhibition of
the CYP2E1-mediated p-nitrophenol hydrolase activity (Patil et al.. 2015) and inhibited the
metabolism of water-soluble substrates of CYP450 in liver microsomes (Shah et al.. 2015).
Local metabolism of 1,4-dioxane may result in tissue-specific metabolites that could contribute
to tissue-specific toxicity. Following oral exposure in rats, 1,4-dioxane induced CYP2E1
expression and increase CYP2E1 mRNA in kidneys and nasal mucosa, indicating induction is
mediated by transcriptional control. In contrast, 1,4-dioxane induced CYP2E1 without any
change in mRNA in liver tissue and there was no CYP2E1 induction in lung tissue (Nannetti et
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at., 2005). Differences in CYP2E1 induction mechanisms in liver, kidney, and nasal mucosa
suggest that induction is controlled in a tissue-specific manner.
Metabolism of 1,4-dioxane generally appears to follow first-order kinetics, and there is some
evidence for metabolic saturation following oral or intravenous (i.v.) exposure at high doses.
Also, as i.v. doses increase, the percentage of urinary HEAA decreases, while the percentage of
1,4-dioxane in exhaled air increases (Young et ai. 1978a). This effect was observed in rats after
a single i.v. dose and occurred when blood levels were near 100 (.ig/mL (Young et at.. 1978b;
Kociba et aL 1975).
In contrast, no evidence of metabolic saturation has been reported following inhalation exposure.
In a 13-week inhalation study, metabolic saturation was not observed at plasma concentrations
up to 730 and 1,054 (.ig/mL in male and female rats, respectively (Kasai et at.. 2008). Following
12 weeks of inhalation exposure to 400-3200 ppm 1,4-dioxane, plasma concentrations increased
linearly with dose, consistent with first-order kinetics. The lack of metabolic saturation in the
Kasai et al. (2008) study is likely attributed to 1) enhanced metabolism due to induction of P450
enzymes (including CYP2E1) by 13 weeks of repeated inhalation exposure to 1,4-dioxane,
and/or 2) toxicokinetic differences between oral and inhalation exposures (first-pass metabolism
following oral ingestion may enhance the saturation effect because the liver receives higher
Take et at. (2012) exposed rats to 1,4-dioxane by inhalation and oral gavage (single-route and
simultaneous multi-route exposures) and observed a synergistic effect of combined exposures on
systemic concentrations. During multi-route exposures (which resulted in high systemic
concentrations of 1,4-dioxane), ingested 1,4-dioxane was not cleared as rapidly as it was under
oral-only exposure. There was less of an impact of combined exposures on the clearance of
inhaled 1,4-dioxane. This difference in clearance rates between inhalation and oral exposure
routes further indicates a first-pass effect on the rate of metabolism of 1,4-dioxane from oral
exposure.
exposure).
COOH
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Figure 3-2. 1,4-Dioxane Metabolism Pathways
1= 1,4-dioxane; II = diethylene glycol; 111 = p-hydroxyethoxy acetic acid (HEAA); IV = 1,4-
dioxane-2-one; V = l,4-dioxane-2-ol; VI = hydroxyethoxy acetaldehyde
Elimination
Elimination of 1,4-dioxane in humans and rats is primarily via urine in the form of the metabolite
HEAA (Goen et at.. 2.016; 1978a; Young et at.. 1976). The elimination half-life of 1,4-dioxane in
plasma was approximately 1 hour in humans and rats and elimination of HEAA in urine was 2.7
hours (Young et at. 1977). These short half-lives of 1,4-dioxane and the metabolite HEAA
indicate that repeated daily exposures would not be expected to result in the accumulation of 1,4-
dioxane or HEAA in workers' bodies. First-order kinetics, in which the amount eliminated will
be dependent on the maximum blood/plasma concentration and not on time may also explain the
lack of accumulation.
Physiologically-Based Pharmacokinetic (PBPK) Models
EPA did not use PBPK models for the derivation of points of departure (PODs) for 1,4-dioxane
or use a PBPK model for route-to-route or cross-species extrapolation in this risk evaluation. The
2010 and 2013 EPA IRIS assessments of 1,4-dioxane evaluated several empirical toxicokinetic
models, PBPK models, and supporting data (Sweeney et at.. 2008; Fisher 7; Leung and
Paustenbach. 1990; Reitz et at... 1990; 1978a; Young et at.. 1977) and concluded that none were
adequate for use in dose-extrapolation between species.
Recent toxicokinetics studies include Take et al. (2012) and Goen et at. (2016). Take et at.
Q provides time course toxicokinetic data in multiple tissues for rats exposed via inhalation,
oral ingestion, and combined inhalation and oral ingestion. Goen et al. (2016) provides blood and
urine data from human volunteers exposed via inhalation at a 1,4-dioxane concentration of 20
ppm for approximately 8 hours (with data spanning 24 hours). EPA reviewed the data in Goen. et
al. (2 and concluded that observations in this more recent study are generally consistent with
data from a previous study (Young et al.. 1977). EPA concluded the inadequacies and
calibration issues in the human PBPK model previously considered by EPA (2013d) would not
be resolved by the additional data in Goen. et al. (2016). Significant uncertainties remain
regarding the appropriate internal dose metric that would be used. Specifically, there are
uncertainties on whether the parent compound or metabolite (or some combination of both) are
responsible for the observed effects of 1,4-dioxane, and uncertainty whether organ-specific or
blood concentrations should be used.
3.2.3 Hazard Identification
For the human health hazard identification, EPA identified key and supporting studies from
previous peer reviewed assessments and new studies published since 2009 (the year the most
recent searches for oral studies were completed for the IRIS assessment) and evaluated them
against the data quality criteria. This section summarizes the key, supporting and new studies,
data on non-cancer hazards (Section 3.2.3.1), genetic toxicity and cancer hazards (Section
3.2.3.2) along with the results of the data quality evaluation (Appendix I). Potential modes of
action for 1,4-dioxane toxicity related to the cancer endpoints were evaluated (Section 3.2.4).
EPA reviewed the oral and inhalation studies to include in the weight-of-the-scientific evidence
analysis, route-to-route extrapolation, and for the cancer classification.
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3.2.3.1
Non-Cancer Hazards
EPA reviewed the reasonably available toxicity data on 1,4-dioxane by the inhalation, oral, and
dermal routes of exposure from acute, short term, subchronic, and chronic studies. No dermal
toxicity studies were identified for 1,4-dioxane. The identified hazard endpoints in the studies
were evaluated for consistency and relevance to humans, according to the Application of
Systematic Review in TSCA Risk Evaluations (U. S. EPA. 2018b). The results of the data quality
evaluation for the non-cancer studies (key and supporting studies and new studies) are described
here and included in the data extraction summary tables in Appendix I. Study quality of
controlled human exposure studies were not quantitatively evaluated because EPA has not yet
developed data quality criteria for this type of study. While EPA could not quantiatively evaluate
their study quality, those studies are included in this discussion to provide a more complete
picture of the available evidence for 1,4-dioxane toxicity.
Toxicity Following Acute and Short-Term Exposure
EPA evaluated studies describing the acute and short-term toxicity of 1,4-dioxane in humans and
in experimental animals. Each of these studies is discussed below, followed by a summary table
(Table 3-3.) of the studies that EPA concluded were the highest quality and suitable for carrying
forward with evidence integration in Section 3.2.5.
Controlled human studies reported few perceivable signs or symptoms following acute exposures
to 1,4-dioxane. When effects were observed, acute exposure primarily caused irritation to the
eyes, nose, and throat depending on the exposure duration and concentration. For example,
Errtstgard et al. (2006) reported that 12 volunteers (6 men and 6 women) exposed to 1,4-dioxane
at 20 ppm (i.e., 72 mg/m3) for two hours at rest produced no symptoms of irritation, headache,
fatigue, or nausea, whereas Young et al. (1977) reported eye irritation in 4 healthy male
volunteers exposed for 6 hours to 50 ppm (180 mg/m3). Further, Yant . and Wirth and
Klimmer (1936) reported that exposures of greater than 1000 ppm (3603 mg/m3) for short
durations (minutes) elicited irritation of mucous membranes in human volunteers. In contrast to
the controlled human volunteer studies, Johnstoi reported the fatality of one worker
after 1 week of occupational exposures to 1,4-dioxane, which was used as a cleaning agent. The
mean measured air concentration in the area was 470 ppm (1694 mg/m3) (range, 208-650 ppm,
749-2342 mg/m3). An autopsy on the worker revealed pathological effects in the liver, kidney,
lung, and brain.
In experimental animals, acute and short-term exposures to 1,4-dioxane have been shown to
cause comparable signs of toxicity as identified in acutely exposed humans, including eye and
nasal irritation, clinical signs of central nervous system (CNS) depression (including staggered
gait, narcosis, paralysis, coma, and death), liver and kidney degeneration and necrosis, and death
(li < 2013a. 2005b).
The available acute toxicity studies in experimental animals include inhalation studies aimed at
identifying adverse effects other than mortality (i.e., Mattie et al. ( ); Drew et al. (1978)).
Drew et al. (1978) performed an acute 4-hour inhalation (whole body) exposure study in male
Sprague-Dawley rats. Animals (15 animals serving as their own controls)) were exposed to 1,4-
dioxane vapors (>99% pure) at concentrations of 0, 3603 or 7207 mg/m3. The authors reported
Page 160 of 616
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an increase in the activities of several serum enzymes associated with liver function in all treated
animals compared to controls.
Mattie et al. (2012) performed an acute 6-hour inhalation (whole body) exposure study in
male/female F344/DuCrl rats. Animals (10/sex/group) were exposed to 1,4-dioxane vapors
(>99% pure) at 0, 429, 1013, 2875, 7920 or and 21,630 mg/m3. Effects were limited to vacuolar
changes in the nasal cavities (olfactory and respiratory epithelium) at two days post-exposure,
but not in rats after a two-week recovery period.
The available short-term toxicity studies in experimental animals include two-week inhalation
studies in adult rats (i.e., Mattie et al. (2012); Goldberg !)) and one oral (gavage)
developmental toxicity study in female rats exposed on gestation days 9 to 15 (i.e., Giavini et al.
5)).
Mattie et al. (2012) performed a two-week inhalation (whole body) toxicity study in male/female
F344/DuCrl rats. Animals (16/sex/group) were exposed to 1,4-dioxane vapors (>99% pure) at 0,
378, 5599, and 11,690 mg/m3 for 6 hours/day, 5 days/week, for two weeks. Animals were
sacrificed on post-exposure day 1 or day 14. The authors reported lesions in the nasal cavity,
kidney, and liver (including hepatic single cell necrosis) in the exposed animals on post-exposure
day 1. Liver effects were still present in exposed animals on post-exposure day 14. The authors
identified a LOAEC of 378 mg/m3, based on the liver effects.
In a separate two-week inhalation (whole body) toxicity study, Goldberg et al. (1964) exposed
female Sprague-Dawley (CFE) rats (8/group) to 1,4-dioxane vapors (purity not stated) at
concentrations of 0, 5405, 10,810, or 21,620 mg/m3 for 4 hours/day, 5 days/week, for two weeks.
The authors identified a NOAEC of 5405 mg/m3, based on CNS effects (i.e., decreased
avoidance behavior) in the mid- and high-concentration exposure groups.
In a developmental toxicity study, Giavini et al. (1985) administered 1,4-dioxane (99% pure) by
oral gavage to pregnant Sprague Dawley rats (18-20 per dose group) at dose levels of 0, 250,
500, or 1,000 mg/kg/d on gestation days 6-15. In the high-dose group, dams' food consumption
decreased at early timepoints and increased at later timepoints while maternal weight gain
slightly decreased. Fetal birth weight and ossification of the sternebrae significantly decreased at
the highest dose. There was a of doubling in the rate of hemisternibrae in the 500 mg/kg/d dose
group relative to the lower dose group, though this effect was not statistically significant. The
authors identified a NOAEL of 500 mg/kg/d and a LOAEL of 1,000 mg/kg/d based on the
reduced fetal weights and delayed ossification.
Of the available acute and short-term studies, EPA concluded that the studies performed in
experimental animals represented the highest quality data from which to assess potential risks to
workers. EPA considered the human exposure studies as supporting information, given the
general consistency of effects seen in humans and experimental animals. However, there were
limitations with the human studies that precluded their use for quantitative risk assessment,
including for example, the absence of measures of systemic effects (e.g., serum chemistry
panels). Therefore, EPA selected the studies listed in Table 3-3. (described in more detail in
Appendix I) with a data quality rating of medium or high for evidence integration and evaluation.
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Table 3-3. Acceptable Studies Evaluated for Toxicity of 1,4-Dioxane Following Acute or
Short-term Exposure3
\( I I I.
Data Source
Study Description b
Hazards Evaluated; Effects reported;
POD
Data Quality Rating
Drew et at
4-hour inhalation
(whole body) study in
rats; 0, 3603 or 7207
mg/m3
Clinical Chemistry; Increased serum liver
enzymes; LOAEC = 3603 mg/m3
Medium
Mattle et at
(2012)
6-hour inhalation
(whole body) study in
rats; 0, 429, 1013,
2875, 7920 and
21,630 mg/m3
Body Weight, Irritation, Hepatic, Renal,
Respiratory; Vacuolar change in olfactory
and respiratory epithelium (2 rats at two
days but not 2 weeks after exposure);
NOAEC = 2875 mg/m3
Medium
SIIOK I- I I.KM
Data Source
Study Description
Hazards Evaluated; Effects reported;
POD
Data Quality Rating
Mattle et at
10-day inhalation
(whole body) study in
rats; 6 hours/day, 5
days/week for two
weeks; 0, 378, 5599
and 11,690 mg/m3
Irritation, Hepatic, Renal, Respiratory;
Lesions in nasal cavity, liver, and kidney;
hepatic single cell necrosis; LOAEC = 378
mg/m3
High
Goldberg et at
i I'M)
10-day inhalation
(whole body) study in
rats; 4 hours/day, 5
days/week for two
weeks; 0, 5405,
10,810 or 21,620
mg/m3
Body Weight, Neurological/ Behavior;
Decreased avoidance response; NOAEC =
5405 mg/m3
Medium
i)i:m:i.opmi:m.\i.
Data Source
Study Description
Hazards Evaluated; Effects reported;
POD
Data Quality Rating
Giavini et at
(1.985)
Oral (gavage)
developmental study
in rats (gestation days
6 to 15); 0, 250, 500,
or 1000 mg/kg-d
Prenatal Development; Delayed
ossification of the sternebrae and reduced
fetal body weight; NOAEL = 500 mg/kg-d
High
a For further details, see the data extraction summary table in Appendix I.
b Concentrations in ppm were converted to mg/m3 using the following equation: ppm*mw (88. l)/24.45. 24.45 is
the gas constant at 760 mm Hg (101 kPa) atmospheric pressure and at 25 °C.
Subchronic and Chronic Non-Cancer Hazards- Inhalation
EPA evaluated studies describing the subchronic and chronic inhalation toxicity of 1,4-dioxane
in animal studies. The results of the data evaluation are given in Table 3-4. and in the data
extraction summary table in Appendix I.
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Table 3-4. Acceptable Studies Evaluated for Non-Cancer Subchronic or Chronic Toxicity
of 1,4-Dioxane Following Inhalation Exposure
D.ilii Source
Study Description
ll;i/:iril K\itlunled
Qunlilv
killing
Kasai et al.
(2008)
13-week inhalation
study in rats
Mortality, Systemic Hepatic, Renal,
Respiratory, Hematology, Clinical Chemistry
High
Kasai et al.
2-year chronic
toxicity/cancer
inhalation bioassay in
rats
Mortality, Systemic, Hepatic, Renal,
Respiratory, Hematological and Immune,
Clinical Chemistry/Biochemistry, Nutrition and
Metabolic, Reproductive, Cancer
High
In Kasai et al. (2.008). 6-week-old F344/DuCij rats (10/sex/group) were exposed to vaporized
1,4-dioxane (>99% pure) at concentrations of 0, 100, 200, 400, 800, 1600, 3200, or 6400 ppm (0,
360, 721, 1441, 2883, 5765, 11,530 or 23,060 mg/m3, respectively) for 6 hours/day, 5 days/week,
for 13 weeks in whole body inhalation chambers. All rats in the 6400 ppm (23,060 mg/m3) group
died by the end of the first week of exposure; at lower doses, mortality rates were not affected.
The study authors determined the most sensitive endpoint to be nuclear enlargement in the
respiratory epithelium, which was noted in both sexes, and identified a LOAEC of 100 ppm (360
mg/m3). EPA considers the toxicological significance of this effect to be equivocal, as it is found
in any cell responding to stress {i.e., adaptive response), transcribing mRNA (i.e., biomarker of
exposure), or undergoing proliferation {i.e., normal cell cycle) ( i). While the
proliferation may be in response to a carcinogenic agent, the impact on the progression from
initiated cell to tumor remains unclear. Therefore, EPA considers the NOAEC for this study to
be 100 ppm (360 mg/m3) based on statistically significantly increased relative lung weights (7-
13%) in females at 200 ppm (721 mg/m3) and higher (p < 0.01 or 0.05). Dose-related increases in
vacuolization of the olfactory epithelium was observed at the same concentrations with
statistically significant increased observed at 800 ppm (2883 mg/m3) and higher (p < 0.01).
Atrophy of the olfactory epithelium was also seen, although the dose-response was less clear.
In a 2-year chronic study (Kasai et al.. 2009). male 6-week-old F344/DuCrj rats were exposed to
vaporized 1,4-dioxane (>99% pure) at concentrations of 0, 50, 250, or 1250 ppm (0, 180, 900, or
4500 mg/m3, respectively) for 6 hours/day, 5 days/week, for 104 weeks in whole body inhalation
chambers. Increased mortality was seen in the 1250 ppm (4504 mg/m3) group. Noncancer effects
were seen in the nasal cavity, liver, and kidneys. Based on chronic nasal toxicity, including
atrophy, respiratory metaplasia, and nuclear enlargement in the olfactory epithelium, and nuclear
enlargement in the respiratory epithelium, the study authors identified the LOAEC to be 50 ppm
(180 mg/m3). The study authors did not identify a NOAEC. As described above, the EPA does
not typically consider nuclear enlargement alone to be an adverse effect. Thus, EPA concluded
that the LOAEC for this study is 50 ppm (180 mg/m3) based on respiratory metaplasia and
atrophy of the olfactory epithelium, which were both statistically significantly increased from
controls (p < 0.01). Effects on the liver (histopathologic changes, including preneoplastic
changes, increased weight, and altered liver enzyme) and kidneys (including histopathologic
lesions, changes in kidney weight, serum chemistry, and urinalysis indices) in this study were
observed at concentrations higher than those associated with olfactory and respiratory effects
(Kasai et al.. 2009).
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EPA review of non-cancer inhalation hazards indicates that sub-chronic or chronic inhalation
exposure to 1,4-dioxane is associated with effects in the olfactory epithelium, liver, and kidneys
(Kasai et at.. 2.009) and changes in body weight and relative lung weight (Kasai et at.. 2008). The
most sensitive endpoints—respiratory metaplasia and atrophy of the olfactory epithelium—
occurred at 50 ppm (180 mg/m3) after chronic (2-year) inhalation exposure in rats (Kasai et at..
2009).
Subchronic and Chronic Non-Cancer Hazards - Dermal
No repeated-dose dermal toxicity studies were identified on 1,4-dioxane. The available data
suggest that delivery of 1,4-dioxane via the inhalation and oral routes of exposure result in
comparable toxic endpoints. EPA performed route-to-route extrapolation to derive dermal PODs
based on data from oral and inhalation exposures studies. There are uncertainties associated
extrapolation from either of these routes. The available inhalation studies were performed by
whole body exposure rather than nose only exposure, which may have led to additional dosing
by the oral and dermal routes of exposure, due to deposition on fur and the grooming behavior of
rodents. EPA does not have information about the extent of 1,4-dioxane exposure through the
oral pathway during whole body exposure, but inhalation doses used as the basis for dermal POD
derivation in route-to-route extrapolation may underestimate total exposures achieved in whole
body inhalation studies. Unlike dermal exposures, chemicals go through first pass metabolism
after oral exposure before entering systemic circulation. EPA does not know which of these
routes is most representative of risks from dermal exposures. It should also be noted that EPA
was unable to conclude with certainty that comparable toxic endpoints would be associated with
the dermal route of exposure, considering the expected quantitative ADME differences and the
absence of an adequate PBPK model. Notwithstanding these uncertainties, EPA considered
route-to-route extrapolation appropriate, considering the comparable toxic endpoints identified in
the available repeated-dose oral/inhalation toxicity studies and the uncertainty with the putative
toxicant {i.e., 1,4-dioxane or a metabolite(s)).
Subchronic and Chronic Non-Cancer Hazards - Oral
The toxicity of 1,4-dioxane following oral exposure was evaluated in several subchronic or
chronic drinking water studies (2009; Kano et at.. 2008; JBRC. 1998; NCI. 1978; Kociba et at..
1974; Argus et at.. 1965). These studies and results of the data quality evaluation are presented in
Table 3-5. and in Appendix I.
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Table 3-5. Acceptable Subchronic and Chronic Studies Evaluated for Non-Cancer Toxicity
of 1,4-Dioxane Fol
owing Oral Exposure
Diilii Souitc
Sluclj Description
llii/iii'd l.\;ilii;ilcd
Diilii
Qu;ili(\
Killing
Kociba et al. (1974)
2-year drinking water study in rats
Mortality, Body Weight, Hepatic,
Renal, Cancer
High
Kano et al. (2009):
also reported as
JBRC (1998)
2-year drinking water chronic
toxicity/ cancer bioassay in rats and
mice
Body Weight, Hepatic, Renal,
Hematological, Respiratory, Cancer
High
NCI (1978)
110-week (rats) or 90-week
(mouse) drinking water chronic
toxicity/ cancer bioassay
Mortality, Gastrointestinal, Hepatic,
Renal, Respiratory, Cancer
Low
Argus et al. (1965)
64.5-week drinking water cancer
bioassay in rats
Hepatic, Renal, Hematological,
Respiratory, Cancer
Medium
Argus et al. (1973)
13 month drinking water study in
rats
Hepatic, Renal, Respiratory, Cancer
Low
Kano et al. (2008)
13-week drinking water study in
rats
Body Weight, Hepatic, Renal,
Respiratory, Nervous System,
Hematological
Medium
Dow Chemical
(1989c)
11-week drinking water repeat
dose oral in vivo DNA repair in rats
Body Weight, Hepatic, Genotoxicity
Medium
1 Male rat data were evaluated as unacceptable.
1,4-Dioxane (purity not reported) was administered to 6-8-week-old Sherman rats (60/sex/dose)
for up to 716 days via drinking water at concentrations of 0, 0.01, 0.1, or 1% (Kociba et al.
1974). The authors calculated the mean daily doses for males and females to be 0, 9.6, 94, or
1015 mg/kg-d and 0, 19, 148, or 1599 mg/kg-d, respectively. Mortality was increased in the
high-dose groups. Noncancer effects occurred in the liver and kidneys. The most sensitive
endpoints, regeneration of the liver (as indicated by hepatocellular hyperplastic nodule
formation) and kidney (specifically, the renal tubular epithelium), were reported in male rats.
The authors identified a LOAEL of 94 mg/kg-d and a NOAEL of 9.6 mg/kg-d.
Male and female rats (35/sex/dose) and mice (50/sex/dose) were administered 1,4-dioxane
(>99.95% pure) for 110 or 90 weeks, respectively, via drinking water at concentrations of 0, 0.5,
or 1% (NCI. 1978). Investigators calculated the average daily intakes of 1,4-dioxane to be as
follows: male rats received 0, 240, or 530 mg/kg-d; female rats received 0, 350, or 640 mg/kg-d;
male mice received 0, 720, or 830 mg/kg-d (decreased dose spacing due to decreased water
consumption in high-dose mice); and female mice received 0, 360, or 860 mg/kg-d. Mortality
was increased among treated rats. Noncancer effects were observed in the stomach (males only),
liver (females only), and kidneys (both sexes). Based on gastric ulcers and renal cortical tubular
degeneration in male rats, the authors determined the LOAEL in this study is 240 mg/kg-d; a
NOAEL was not established (NCI. 1978). Increased mortality also occurred in mice. Noncancer
effects on the respiratory system (pneumonia and rhinitis) were noted in both sexes, resulting in a
LOAEL of 380 mg/kg-d. A NOAEL was not established in this study (M 3).
Results from a two-year drinking water study conducted on F344/DuCij rats and Crj :BDF1 mice
(50/sex/dose) by the Japan Bioassay Research Center ( 3) have also been published as
Page 165 of 616
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Yamazaki et al. (1994) and Kano et al. (2009). 1,4-Dioxane (>99% pure) was administered at
concentrations of 0, 200, 1000, or 5000 ppm; these concentrations were reported by Kano et al.
(2.009) to be the following approximate doses: male rats received 0, 11, 55, or 274 mg/kg-d;
female rats received 0, 18, 83, or 429 mg/kg-d; male mice received 0, 49, 191, or 677 mg/kg-d;
and female mice received 0, 66, 278, or 964 mg/kg-d.
In rats, slower growth rates and decreased terminal body weight were noted in high-dose groups
of both sexes, as were changes in hematology and clinical chemistry and increased relative liver
weight. Noncancer effects were observed in the nasal cavity, liver, and kidneys. Based on the
liver effects (mixed cell foci and increased relative liver weight) in males, the LOAEL in this
study is 55 mg/kg-d; the NOAEL is 11 mg/kg-d (Kano et al.. 2009).
In mice, mortality was increased in females at the highest dose. Growth rates, terminal body
weights, and water consumption were decreased in both sexes. Changes in hematology and
clinical chemistry occurred in both sexes, as did increased lung weights. Respiratory, kidney, and
liver effects also were observed. The LOAEL for female mice in this study is 278 mg/kg-d,
based on inflammation in the nasal cavity; the NOAEL is 66 mg/kg-d. The LOAEL for male
mice in this study is 191 based on changes in serum liver enzymes; the NOAEL is 49 mg/kg-d
(Kano et al.. 2009).
Argus et al. (1965) administered 1,4-dioxane (purity not reported) to 26 adult male Wistar rats
for 64.5 weeks via drinking water at a concentration of 1%, which was calculated to be
equivalent to 640 mg/kg-d. Noncancer effects were noted in the liver, kidney, and lungs. The
LOAEL is 640 mg/kg-d based on glomerulonephritis and histological changes (enlarged
hyperchromic nuclei and large cells with reduced cytoplasmic basophilia) observed in the liver at
the only dose tested.
A follow-up study (Argus et al.. 1973) exposed male Sprague Dawley rats (28-32/group) to 1,4-
dioxane (purity not reported) for up to 13 months via drinking water at concentrations of 0, 0.75,
1, 1.4, or 1.8%, which are calculated to be equivalent to 0, 430, 574, 803, or 1032 mg/kg-d.
Noncancer effects on the liver, kidney and lung were observed. The LOAEL is 430 mg/kg-d,
based on histopathological lesions in the liver and kidney at the lowest dose tested. A NOAEL
was not identified in this study.
Kano et al. (2.008) administered 1,4-dioxane (>99% pure) to 6-week-old F344/DuCrj rats and
Cij:BDFl mice (10/sex/group) for 13 weeks via drinking water at concentrations of 0, 640, 1600,
4000, 10000, or 25000 ppm. The investigators calculated the approximate daily intake of 1,4-
dioxane to be as follows: male rats received doses of 0, 52, 126, 274, 657, or 1554 mg/kg-d;
female rats received 0, 83, 185, 427, 756, or 1614 mg/kg-d; male mice received 0, 86, 231, 585,
882, or 1570 mg/kg-day, and female mice received 0, 170, 387, 898, 1620, or 2669 mg/kg-day.
Significant decreases in food and water consumption were noted among high-dose rats of both
sexes, with final body weights reduced in the two highest dose levels. Respiratory, olfactory,
brain, liver, and kidney effects were noted in rats. Nuclear enlargement of the respiratory
epithelium of the nasal cavity (reported as at least 4 times the size in diameter as normal nuclei)
and hepatocyte swelling were the most sensitive effects reported in male rats. As with the
inhalation studies, the EPA does not consider nuclear enlargement to be an adverse effect; thus,
Page 166 of 616
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based on liver histopathology findings, the LOAEL is 126 mg/kg-day and the NOAEL is 52
mg/kg-day.
Decreased body weights and water consumption were also noted in mice. Several clinical
chemistry parameters were changed and respiratory, olfactory, lung, and liver effects were seen.
The most sensitive effects in mice, nuclear enlargement and degeneration of bronchial
epithelium, occurred in females at 387 mg/kg-day, making the NOAEL 170 mg/kg-day (Kano et
at.. 20081
Male SD rats (4-6/group) were administered 1,4-dioxane (>99% pure) in drinking water at doses
of 0, 10, or 1000 mg/kg-d for 11 weeks, 7 days/week (Dow Chemical. 1989c). Positive {i.e.,
dimethylnitrosamine) and vehicle controls were run concurrently. Repeated dosing at 1000
mg/kg-day 1,4-dioxane resulted in increased liver to body weight ratio and increased (1.5 fold)
hepatic DNA synthesis with minimal hepatocellular swelling.
The EPA review of non-cancer oral hazards indicate that the key endpoints for 1,4-dioxane occur
in the nasal cavity, lungs, liver, kidneys, and brain. The most sensitive effects were in the liver
(degeneration and necrosis of hepatocytes) and kidneys (degeneration and necrosis of renal
tubular cells) and occurred at 94 mg/kg-d; the NOAEL for liver and kidney effects is 9.6 mg/kg-
d (Kociba et at.. 1974).
3.2.3.2 Genetic Toxicity and Cancer Hazards
Genetic Toxicity
The genotoxicity of 1,4-dioxane has been tested in over 40 in vitro and in vivo studies. Briefly,
1,4-dioxane has been tested for genotoxic potential using various in vitro systems including
prokaryotic organisms (S. typhimurium strains and E. coli strains), non-mammalian eukaryotic
organisms, and mammalian cells, and in vivo systems using several strains of mice and rats. EPA
previously evaluated these data in the IRIS assessment of 1,4-dioxane and concluded that 1,4-
dioxane is either nongenotoxic or weakly genotoxic based on a weight-of-the-evidence analysis
of the in vitro and in vivo genotoxicity studies ( E013d). That conclusion was based on
the observations that 1,4-dioxane was not genotoxic in the large majority of in vitro systems
tested, and that positive genotoxic responses were generally observed in the presence of
cytotoxicity. It was not genotoxic in half of the available in vivo mammalian assays, although
several studies have shown positive effects at or above doses of 1000 mg/kg/d.
In this risk evaluation, EPA considered the conclusions of the 2013 IRIS assessment and
evaluated the data quality for the studies used to support those conclusions (Appendix 1.1.5).
EPA also identified and evaluated two key studies that were published after 2013 and had an
acceptable data quality rating, shown in Table 3-6. These studies include two in vivo
micronucleus assays that assessed the genotoxic potential of 1,4-dioxane in bone marrow and in
liver (Itoh and Hattori. iO I") and two in vivo mutagenicity assays (Itch and Hattori. 20l%K
ai. 2018). Each of these studies is summarized below, followed by EPA's interpretation of how
these studies add to the weight-of-the-scientific evidence evaluation from the IRIS assessment on
the potential for 1,4-dioxane to cause genotoxicity and/or mutagenicity.
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Table 3-6. Acce
jtable New Studies Evaluated for Genetic Toxicity of 1,4-Dioxane
Diilii Source
Study Description
llii/iirils K\:ilu;ilcd
rinilin^s
Qiiiility
R:tlin
-------
the results of Itoh and Hattori (2019) and the results of other investigations, noted above and
summarized in the IRIS assessment, EPA concluded that the available bone marrow
micronucleus assays suggest that 1,4-dioxane is genotoxic in vivo at high doses. The discrepant
findings across studies may be due to methodological differences in the studies and/or
differences in the sensitivity between specific strains of rats and mice.
In separate studies, Itoh and Hattori (2019) performed liver micronucleus assays to explore the
potential mode of action by which 1,4-dioxane induced liver adenomas and carcinomas in
chronically exposed rodents. The authors used three different study designs, including the
juvenile rat (JR) method, the dosing before partial hepatectomy (pre-PH) method, and the dosing
after PH (post-PH) method. In each of these studies, animals were administered either one or two
doses of 1,4-dioxane by gavage (water vehicle; 10 mL/kg) at dose levels of 1000, 2000, or 3000
mg/kg. Diethylnitrosamine served as the positive control for clastogenicity in the JR and pre-PH
studies, whereas carbendazim served as the positive control for aneugenicity in the post-PH
study. In the JR study, animals were dosed on days 1 and 2, and livers were harvested on day 6.
In the pre-PH study, animals were dosed on day 1, PH was performed on day 2, and livers were
harvested on day 6. In the post-PH study, PH was performed on day -1, animals were dosed on
day 1, and livers were harvested on day 4. For each of the studies, the authors evaluated liver-to-
body weight ratios {i.e., relative liver weight), micronucleated hepatocytes (MNH) among 2000
hepatocytes (excluding metaphase and nuclear fragment cells), and classified hepatocytes as
mononucleated, binucleated, or multinucleated {i.e., 3 or more nuclei). In the JR study, dose-
dependent and statistically significant increases in MNH were observed in all treated animals. No
changes were reported in relative liver weight or hepatocyte classifications. In the pre- and post-
PH studies, dose-dependent, statistically significant increases in MNH were observed in all
treated animals. In the pre-PH study, no changes in relative liver weights were reported, although
binucleated hepatocytes were increased, albeit not statistically, in the high dose group. In the
post-PH study, statistically significant increases in relative liver weights were reported in the
low- and mid-dose groups; however, no changes in hepatocyte classification were observed.
Based on these results, the authors concluded that 1,4-dioxane is clastogenic in the liver.
The MNH findings reported by Itoh and Hattori (2019) are consistent with the liver micronucleus
assay results summarized in the IRIS assessment. For example, Morita and Hayashi (1998)
reported dose-dependent and statistically significant increases in MNH in pre-PH male CD-I
mice administered 1,4-dioxane by gavage at dose levels of 2000 and 3000 mg/kg. Unlike Itoh
and Hattori (2.019). Morita and Hayashi (1998) did not identify MNH in mice that received a
dose of 1000 mg/kg. Additionally, Roy et al. (2005) reported dose-dependent and statistically
significant increases in MNH in male CD-I mice administered 1,4-dioxane for five days at dose
levels of 2500 or 3500 mg/kg-d. The authors did not identify MNH in mice administered 1500
mg/kg-d. Therefore, EPA concluded that the findings reported by Itoh and Hattori (2019)
indicate that 1,4-dioxane is genotoxic in vivo in high dose experiments.
Itoh and Hattori (2019) also evaluated the potential of 1,4-dioxane (purity not stated) to induce
gene mutations in the in vivo Pig-a assay. Male F344 rats were dosed by gavage (saline vehicle;
10 mL/kg-bw) on day 1 with 1000, 2000, or 3000 mg/kg. Prior to dosing {i.e., day -1), peripheral
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blood was sampled, as pre-treatment control values. Animals were then dosed on day 1 and
peripheral blood was sampled on post-treatment days 15 and 20.
7,12-Dimethylbenz[a]anthracene (DMBA) served as the positive control. Erythrocytes were
screened by flow cytometry analysis for CD59 negative cells, a marker of mutation in the Pig-a
gene. No statistically significant differences were found at any dose level of 1,4-dioxane or
sampling time compared to controls. DMBA-treated animals exhibited the expected statistically
significant increase in CD59 negative cells on post-treatment days 15 and 20.
In a separate in vivo gene mutation assay, Gi et al. (2018) administered various doses of 1,4-
dioxane (purity > 99.9%) to gpt delta transgenic F344 rats in drinking water for 16 weeks. The
daily intake values were 0, 18.7, 92.3, and 440.2 mg/kg-d in one experiment, and 0, 0.02, 0.2, 1.9
mg/kg-d in a second experiment. A positive control was not included in these experiments. Body
weights and liver-to-body weight ratios were statistically significantly decreased or increased,
respectively, in animals from the high-dose group {i.e., 440.2 mg/kg-d) compared to controls.
The gpt mutation frequency in packaged phages from hepatic DNA and GST-P-positive foci per
unit area of liver were increased in a dose-dependent manner and achieved statistical significance
in the high-dose group compared to controls. The spectra of mutations in the high-dose group
included statistically significant increases in A:T to G:C transitions and A:T to T:A transversions
in the high-dose group. In the mid-dose group {i.e., 92.3 mg/kg-d), the gpt mutation frequency
was not statistically significantly different than the control values, although a statistically
significant increase in A:T- to -T:A transversion frequency was reported. No additional
statistically significant changes in mutation frequency were identified in the low dose group for
transitions {i.e., G:C to A:T), transversions {i.e., A:T to C:G, G:C to C:G), deletions {i.e., single
or > double base pairs), or insertions {i.e., single base pairs). Among several cell proliferation,
cell cycle regulation, and DNA damage repair gene expression changes studied in the livers of
gpt delta transgenic rats, a significant increase in PCNA was observed in the high-dose group.
The authors interpreted these findings as support that 1,4-dioxane is a genotoxic carcinogen that
induces hepatocarcinogenesis through a mutagenic mode of action.
Based on the above studies, the negative results reported by Itoh and Hattori (2.019) are
consistent with the negative results from the in vitro gene mutation studies summarized in the
IRIS assessment. However, it is unclear whether the doses used by Itoh and Hattori (2019). albeit
significantly high (up to 3,000 mg/kg), provided sufficient delivery to the bone marrow to induce
mutations in the Pig-a gene. In contrast, Gi et al., (2.018) reported positive in vivo mutagenicity
findings in transgenic rats administered 1,4-dioxane by drinking water at the highest intake dose
of 440 mg/kg/d. Gi et al., reported no genotoxic or mutagenic effect in transgenic animals in the
lowest dose group (18.7 mg/kg/day).
Based on the weight of scientific evidence, EPA concluded that there is some evidence for
genotoxicity in vivo at high doses, but there is insufficient evidence to conclude that 1,4-dioxane
is mutagenic or induces cancer through a mutagenic mode of action.
Carcinogenicity via Inhalation Exposure
A human study of breast cancer incidence in participants in the California Teacher Study (active
and retired female teachers and administrators) from 1995-2011, (n=l 12,378 women) examined
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the association between breast cancer and exposure to ambient air concentrations ofl,4-dioxane
(Garcia et at.. 2015) (Table 3-7.). Exposure was determined using the National-Scale Air Toxics
Assessment Modeled air concentrations. No significant association was found between breast
cancer incidence and modeled annual average ambient air concentrations of 1,4-dioxane based
on participant's residential address. Though these data provide some insight on low-level
exposures to 1,4-dioxane, they are not particularly informative with regard to any association
between occupational exposures and the potential for developing breast cancer. Two
occupational studies ( ,013d; Buffier et at... 1978; Thiess et at.. 1976) were
inconclusive about cancer risk from 1,4-dioxane but they were limited by small sample sizes.
In the key inhalation cancer study for this risk evaluation (Kasai et at.. 2009). groups of male
F344 rats (50/group) were exposed to 0, 50, 250 and 1250 ppm (0, 180, 900 and 4500 mg/m3) of
1,4-dioxane for 6 hours/day, 5 days/week, for 2 years. The incidences of the following tumors
were increased: hepatomas; nasal squamous cell carcinomas; renal cell carcinomas; peritoneal
mesotheliomas; mammary gland fibroadenomas; Zymbal gland adenomas; and subcutis
fibroin as. In the key inhalation cancer study for this risk evaluation (Kasai et at... 2009). groups of
male F344 rats (50/group) were exposed to 0, 50, 250 and 1250 ppm (0, 180, 900 and
4500 mg/m3) of 1,4-dioxane for 6 hours/day, 5 days/week, for 2 years. The incidences of the
following tumors were increased: hepatomas; nasal squamous cell carcinomas; renal cell
carcinomas; peritoneal mesotheliomas; mammary gland fibroadenomas; Zymbal gland
adenomas; and subcutis fibromas.
Table 3-7. Studies Evaluated for Cancer Following Inhalation Exposure to 1,4-Dioxane
Diilii
Source
Study Description
llii/;ircls K\:ilu:ilcd
l)iil;i Qiiiililv
killing
Garcia et al.
(2015)
Cohort study of
hazardous air
pollutants and
breast cancer risk in
California teachers
Breast cancer incidence
High
Kasai et al.
(2009)
2-year inhalation
bioassay- male rats
Cancer- liver, nasal, renal, peritoneal,
mammary gland, Zymbal gland, and skin
High
Carcinogenicity via Dermal Exposure
No dermal carcinogenicity studies were identified for 1,4-dioxane. Therefore, as stated above
under Section 3.2.3.1, EPA applied a route-to-route extrapolation from the oral and inhalation
carcinogenicity studies to derive dermal PODs.
Carcinogenicity via Oral Exposure
EPA evaluated the available carcinogenicity studies on 1,4-dioxane by the oral route of
exposure, including Kociba et al. (1974). JBRC (1998). Kano (2009). and NCI (1978). These
studies (Table 3-8.) provide data regarding the carcinogenic effects of 1,4-dioxane by the oral
route of exposure and are summarized in Section 3.2.3.1. EPA used these studies for deriving
dermal PODs as discussed under Section 3.2.6.
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Table 3-8. Studies Evaluated for Cancer Following Oral Exposure to 1,4-Dioxane
Source
Sluilv Description
llii/iirils
l):il:i Qiiiilitv
Ritlinji
Kociba et al. (1974)
2-year drinking water study-
Sherman rats (60/sex/group)
Cancer- liver, respiratory
High
IBRC (1998). Kano
et al. (2009)
2-year drinking water study-
F344/DuCij rats and Crj:BDFl
mice (50/sex/group)
Cancer- liver, nasal,
peritoneum, mammary
gland, skin
High
NCI (1978)
2-year drinking water study-
Osborne-Mendel rats
(35/sex/group) and B6C3F1 mice
(50/sex/group)
Cancer- liver, nasal,
testis/epididymis
Low
Kociba et al. (1974) administered 1,4-dioxane to 6-8-week old Sherman rats (60/sex/group) via
drinking water for two years. The incidences of hepatocellular carcinomas and squamous cell
carcinoma of the nasal turbinates were increased among the high-dose group (1%; equivalent to
an average dose (male and female) of 1,307 mg/kg/d). No increase in tumor formation was seen
in the mid-dose group. Zero tumors occurred in the low-dose group.
As noted previously, Kano et al. (2009) is one of several publications based on a 2-year drinking
water study performed by the Japan Bioassay Research Center. Groups of F344/DuCij rats and
Cij:BDFl mice (50/sex/group) were exposed to 1,4-dioxane (>99% pure) at levels of 0, 200,
1000, or 5000 ppm and 0, 500, 2000, or 8000 ppm, respectively. Increased incidences of
hepatocellular adenomas and carcinomas and tumors (squamous cell carcinomas) of the nasal
cavity occurred in high-dose male and female rats. Peritoneal mesotheliomas in males also were
increased at the highest dose, and males showed increasing trends in mammary gland
fibroadenoma and subcutis fibroma, a fibroma or mass underneath the cutis layer of the skin.
Females showed an increased incidence of mammary gland adenoma or fibroadenoma.
3.2.4 Potential Modes of Action for 1,4-Dioxane Toxicity
EPA evaluated the evidence supporting plausible modes of action (MOA) of 1,4-dioxane
carcinogenicity for specific tumor locations using the modified Hill criteria for MOA analysis
described in EPA's Guidelines for Carcinogen Risk Assessment ( '005a). EPA
considered available evidence from animal cancer bioassays, genotoxicity studies, specific
MOAs proposed in the literature, and the analysis previously presented in the IRIS Toxicological
Review of 1,4 Dioxane (U.S. EPA. 2013d).
EPA specifically considered MOAs for liver and nasal tissue carcinogenicity of 1,4-dioxane.
There is insufficient chemical-specific information about kidney, peritoneal, mammary gland,
zymbal gland or subcutis tumors to support MOA analysis for these tumor types.
Potential MOAs for 1,4-dioxane liver carcinogenicity
Liver tumors are a principal tumor site of 1,4-dioxane, and the liver is the site for which the most
information exists. The MOA for 1,4-dioxane induction of liver tumors was previously
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considered inconclusive ( 1013d). In this risk evaluation, EPA considered evidence for
several of the potential MO As for 1,4-dioxane liver carcinogenicity (see Appendix J), including:
Metabolic saturation, cytotoxicity and proliferative regeneration. In this hypothesized
MO A, metabolic saturation leads to the accumulation of the parent compound 1,4-dioxane,
which causes liver tumors through cytotoxicity and subsequent regenerative proliferation.
Dourson et al. (20t ; 2.014) (proposed specific key events and compiled evidence from
animal bioassays (McConnell. 2013; Kociba et al.. 1974). EPA evaluated the current
evidence for this proposed MO A for 1,4-dioxane carcinogenicity in depth (Appendix J) using
the framework for MOA analysis described in the EPA Guidelines for Carcinogen Risk
Assessment (U.S. EPA. 2005a).
Based on evidence that cytotoxicity is not a necessary key event, the lack of consistent dose-
response concordance between key events in the MOA and carcinogenicity, data gaps in
support of specific key events, and the plausibility of alternate MO As that would also be
consistent with experimental observations, EPA determined that existing evidence is not
sufficient to support the MOA for liver tumors proposed by Dourson et al. (2017; 2014).
Cell proliferation in the absence of cytotoxicity. It is possible that 1,4-dioxane or a
metabolite leads to cell proliferation in the absence of cytotoxicity. This potential MOA has
not been articulated in the peer-reviewed literature and there is insufficient information to
determine the specific key events through which 1,4-dioxane may lead to proliferation.
Mutagenicity and other forms of genotoxicity. As described in Section 4.2.3.2, EPA
concluded that there is some evidence for genotoxicity in vivo at high doses, but insufficient
evidence to determine whether 1,4-dioxane is mutagenic or induces cancer through a
mutagenic MOA.
CAR/PXR-mediated effects. The nuclear receptors CAR and PXR have been proposed as
mediators of 1-4-dioxane induced liver toxicity and carcinogenicity. Mechanistic evidence
from other chemicals indicates that CAR agonists may lead to proliferation and liver tumors
in the absence of cell death (Elcombe et al..! ). While this is a plausible MOA for 1,4-
dioxane carcinogenicity, the key events in the MOA linking 1,4-dioxane to CAR-mediated
carcinogenicity have not been clearly articulated in the literature and 1,4-dioxane has not
been identified as a CAR agonist. One 16-week drinking water exposure study in transgenic
rats evaluated a panel of CYP enzymes that are induced by nuclear receptors CAR, PXR,
PPARa, or AhR and found no changes in mRNA expression of these CYPs in rat livers
following 1,4-dioxane exposure (Gi et al.. 2018). No studies have evaluated this mechanism
in the presence of tumor formation.
EPA considered evidence for these potential MO As (see Appendix J) and concluded that there is
insufficient evidence to determine the MOA of 1,4-dioxane liver carcinogenicity.
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Potential MOAs for 1,4-dioxane carcinogenicity in nasal tissue
EPA also considered evidence for specific MOAs of 1,4-dioxane carcinogenicity in nasal tissue.
Tumors in the nasal cavity have been observed in rats and mice following drinking water (Kano
et at... 2009) exposure and in rats following inhalation exposure (Kasai et at.. 2009). Kasai et al.
(2.009) and Kano et al. (2.009) consider several potential key events that may contribute to
carcinogenicity in nasal tissue, including:
• biotransformation of 1,4-dioxane to toxic metabolites in nasal tissue, which is rich in
metabolic enzymes
• cell injury followed by regenerative hyperplasia
• long-term stimulation of the nasal epithelia with high concentrations of 1,4-dioxane
and/or its metabolites
• indirect interactions with DNA, such as genomic instability associated with alterations in
cell cycling.
There is insufficient mechanistic information to fully evaluate the extent to which any these key
events may contribute to nasal tumors, but evidence from the 2-year bioassays provide some
clues that are relevant for MOA. The wide distribution of tumors reported throughout the nasal
cavity and the consistency of nasal tumor incidence across oral and inhalation exposures (Kasai
et al.. 2009; Kano et al, 2009) suggests that nasal tumors may be the result of systemic delivery
rather than portal of entry delivery. In addition, several of the nasal tumor types observed in
these studies are rare. A two-year study on the effects of 1,4-dioxane exposure via drinking
water, reported increased incidence of several rare nasal tumors that had never been observed in
the laboratory's historical control data, including esthesioneuroepithelioma, rhabdomyosarcoma
and sarcoma (not otherwise specified) in rats and esthesioneuroepithelioma and adenocarcinoma
in mice (Kano et al.. 2.009). Rare tumor types such as these are unlikely to be explained by a
generic cytotoxic response that is more common.
EPA concluded that there is insufficient evidence to determine the MOA of 1,4-dioxane
carcinogenicity in nasal tissue.
Overall MOA conclusions
There is currently insufficient information to determine the MOA of 1,4-dioxane carcinogenicity
for any tumor location. 1,4-Dioxane carcinogenicity may be mediated by different MOAs for
different tumor sites and the role of metabolites in the carcinogenicity of 1,4-dioxane in different
tissue types is unknown. In the absence of other information about MOA, EPA often takes the
health-protective approach of assuming a linear no-threshold risk model consistent with a
mutagenic MOA. To characterize the sensitivity of 1,4-dioxane cancer models to assumptions
about MOA, EPA developed dose-response for both linear and threshold cancer models for liver
tumors (see Appendix K). Cancer risk calculations in Section 5.2 and subsequent risk
determinations are based on a linear no-threshold model in the absence of sufficient evidence for
any of the hypothesized MOAs.
3.2.5 Weight of Scientific Evidence
The weight-of-the-scientific evidence evaluation provides a narrative concluding with the
recommended approach to dose-response assessment. The information on human health hazard
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was integrated using a weight-of-the-scientific evidence strategy where the strengths, limitations
and relevance of the data were analyzed and summarized across studies within each hazard
endpoint in narrative form. The best available human health hazard science was selected for
dose-response modeling based on integrating the results of the data quality evaluation, MOA
information and weight-of-the-scientific evidence. Liver, kidney, and nasal toxicity were the
primary noncancer health effects associated with exposure to 1,4-dioxane. The weight-of-the-
scientific evidence is presented for acute toxicity (2 studies), chronic toxicity (7 studies), and
carcinogenicity (4 studies).
Acute and Short-term Toxicity
EPA evaluated studies on the acute and short-term effects from exposures to 1,4-dioxane in
humans and experimental animals. The available human studies indicated that 1,4-dioxane
exposures at 72 mg/m3 for two hours was well tolerated in human volunteers, with no signs or
symptoms of adverse effects, whereas exposures at 180.2 mg/m3 for six hours caused eye
irritation in human volunteers (Ermstgard et ai. 2006; Young et at.. 1977). Johnstone (1959)
reported the fatality of one worker after one week of exposures to high concentrations of 1,4-
dioxane (i.e., 1700 mg/m3). An autopsy on the worker showed pathological effects in the liver,
kidney, and brain.
Each of the human studies provide supporting information for comparable effects seen in
experimental animals; however, they were not carried forward for concentration-response
analyses because of inherent limitations with each. For example, the controlled human exposure
studies were based on single concentration exposures and only assessed visible signs of
impairment and participant reported symptoms. No evaluations were performed for signs of
potential systemic effects (e.g., serum chemistry panels).
As shown in Table 3-3., acute and short-term exposures to 1,4-dioxane in experimental animals
have been shown to cause irritation of the mucous membranes and adverse effects on the liver
and kidney (Mattie et at.. 2012). Of the available studies on experimental animals, EPA selected
the high quality short-term exposure study conducted by Mattie et al. (2012) instead of the
medium quality short-term study conducted by Goldberg et al. (1964) as the basis for dose-
response analysis for several reasons. Mattie et al. (. ) exposed male/female rats to 1,4-
dioxane at concentrations of 0, 378, 5599, or 11,690 mg/m3 for 6 hours/day, 5 days/week for two
weeks and assessed effects on the nasal cavity, liver, and kidney. In contrast, Goldberg et al.
(1964) exposed female rats to 1,4-dioxane at concentrations of 0, 5405, 10,810, or 21,620 mg/m3
for 4 hours/day, 5 days/week, for two weeks and only assessed effects on neurological function.
EPA concluded that the exposure duration used by Mattie et al. (2012) was more comparable to
short-term worker exposures (i.e., 8 hours/day, 5 days/week). Further, the range of exposure
concentrations used by Mattie et al. Q ) encompassed the concentrations used in the acute,
single exposure rat studies, where liver effects (i.e., 4-hour LOAEC = 3603 mg/m3) or
respiratory effects (i.e., NOAEC 2875 mg/m3) were reported (Mattie et al.. 2012; Drew et al..
1978). In contrast, the lowest concentration (i.e., 5405 mg/m3) used by Goldberg et al. (1964)
exceeded both of these concentrations, and as noted above, the authors only assessed effects on
neurological function. Therefore, EPA selected the short-term effect levels from Mattie et al.
Q ) as the basis for dose-response assessment and quantification of potential risks to workers
from acute/short-term exposures to 1,4-dioxane, as discussed in Section 3.2.6.
Chronic Toxicity
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Key chronic non-cancer effects observed following inhalation and oral exposures to 1,4-dioxane
include centrilobular necrosis in the liver, degeneration of the olfactory epithelium, and
degeneration of the kidney (2009; Kasai et at.. 2009; Kano et ai. 2008; N [8; Kociba et at..
1974; 1973; Argus et at.. 19651
Non-cancer liver effects reported in the oral or inhalation exposure studies included degeneration
and necrosis, hepatocyte swelling, cells with hyperchromic nuclei, spongiosis hepatis,
hyperplasia, and clear and mixed cell foci of the liver (Kano et at.. 2008; NCI. 1978; Kociba et
at.. 1974; Argus et at.. 1973; 19651
Lesions in the olfactory epithelium and respiratory epithelium were reported in both inhalaltion
and drinking water exposure studies (Kasai et at.. 2009). The uniform distribution of nasal
lesions throughout the olfactory and respiratory epithium (rather than distribution consistent with
airflow), the consistency of effects in oral and inhalation studies, and the fact that 1,4-dioxane is
absorbed into systemic circulation following inhalation exposure indicates that these nasal
lesions may be primarily the result of systemic delivery rather than portal of entry effects.
Kidney toxicity was noted following inhalation and oral exposures (Kasai et at.. 2009; NCI.
1978; Kociba et at.. 1974; 197 \ l^nis et at.. 1965). and kidney damage at high doses is
characterized by degeneration of the cortical tubule cells, necrosis with hemorrhage, and
glomerulonephritis (M 3; Kociba et at.. 1974; Argus et at.. 1965). The lowest dose
reported to produce kidney damage is 94 mg/kg-day (Kociba et at... 1974). Cortical tubule
degeneration was seen at higher doses in the NCI (1978) bioassay (240 mg/kg-d, male rats), and
glomerulonephritis was reported for rats given doses of > 430 mg/kg-d (Argus et at.. 1973;
1965).
EPA considered two high quality studies that evaluated the noncancer effects of inhalation
exposure to 1,4-dioxane, including one 13-week exposure study in male and female rats (Kasai et
at.. 2008) and one 2-year exposure study in male rats (Kasai et at.. 2009). Both studies reported
effects in the olfactory epithelium and respiratory epithelium at the lowest doses tested. EPA
performed dose-response assessment using information from in the 2-year exposure study (Kasai
et at.. 2009) because it evaluated effects at lower doses and the conditions of the study are most
representative of long-term occupational exposures.
EPA evaluated seven studies that address the noncancer effects of 1,4-dioxane following oral
exposure, including two high quality two-year drinking water exposure studies (Kano et at..
2009; Kociba et at.. 1974) one medium quality 13-week drinking water study (Kano et at... 2008).
one medium quality 63-week drinking water study in rat (Argus et at... 1965). one medium
quality developmental toxicity study (Giavini et at.. 1985). and two low quality drinking water
studies in mice (NCI. 1978) and rats (Argus et at.. 1973; 1965). The NCI study was rated as low
quality because of differences in the study timing for control and treated animals and fluctuations
in treatment levels due to variation in water intake. The Argus study was rated as low quality due
to insufficient data reporting and a lack of information on test substance purity, animal
husbandry conditions, health outcomes in control groups, or statistical methods.
Giavini et al. (1985) provide some evidence of developmental toxicity at the highest dose tested
in the presence of slight maternal toxicity. There are data limitations for reproductive and
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developmental endpoints, including a lack of multigenerational reproduction studies or
neurodevelopmental studies.
The most sensitive endpoints identified among the oral exposure studies were liver and kidney
toxicity reported in Kociba et al. (1974) and Kano et al. (2009). EPA performed dose-response
assessment on the three two-year drinking water exposure studies (Kano et al.. 2009; N( 8;
Kociba et al.. 1974) as well as the 13-week drinking water study (Kano et al.. 2008) because
these are studies that identified the most sensitive chronic effects of oral exposure.
Cancer Classification
EPA re-evaluated the reasonably available evidence according to the Guidelines for Carcinogen
Risk Assessment (U.S. EPA. 2005a) that was previously summarized in the IRIS assessment
(L 2013d). Evidence from the human studies did not support or refute an association
between occupational or general population exposure and increased risk of cancer, and by itself
does not establish a clear causal relationship. 1,4-Dioxane exposure in animal studies leads to
tumors in multiple tissues at multiple sites (Table 3-8.) other than the initial points of contact
(oral and inhalation) in males and females. There are data gaps for the potential carcinogenic
effects of 1,4-dioxane from inhalation and dermal exposure in humans and from dermal exposure
in animals.
Human occupational studies examining the association between 1,4-dioxane exposure and
increased cancer risk are inconclusive because they are limited by small cohort size and a small
number of reported cancer cases (Buffier et al. 1978; Thiess et al.. 1976). A large, high quality
cohort study (Garcia et al.. 2015) found no association between exposure to ambient levels of
1,4-dioxane in air and breast cancer rates. This study looked only at breast cancer rates following
ambient levels of exposure and as such cannot be used to extrapolate to all cancers or to evaluate
risks from higher levels of exposure relevant to occupational settings.
Studies in multiple animal species show that chronic exposure to 1,4-dioxane induces tumors in
multiple tissues by both oral and inhalation exposure (Table 3-7. and Table 3-8.). In accordance
with the Guidelines for Carcinogen Risk Assessment (U.S. EPA. 2005a). EPA concluded that
1,4-dioxane is "likely to be carcinogenic to humans" based on animal evidence of
carcinogenicity at multiple sites, in multiple species, and multiple routes of exposure. This is
consistent with the conclusions in EPA's IRIS assessment ( ) and conclusions of
other agencies. The NTP classifies 1,4-dioxane as "reasonably anticipated to be a human
carcinogen" (NTP. 2016). I ARC classifies 1,4-dioxane as "possibly carcinogenic to humans
(L\!ill Jiic!2), and NIOSH classifies it as a "potential occupational carcinogen" (NIOSH. 2004).
This hazard was carried forward for dose-response analysis. In the dose-response assessment,
EPA modeled cancer risk using data from four two-year cancer bioassays (Kano et al.. 2009;
Kasai et al. 2009; NCI. 1978; Kociba et al.. 1974).
Page 177 of 616
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3,2.6 Dose-Response Assessment
3.2.6.1 Potentially Susceptible Subpopulations
Certain human subpopulations may be more susceptible to exposure to 1,4-dioxane than others.
Some individuals may be more biologically susceptible to the effects of 1,4-dioxane due to
lifestage, genetic variability or pre-existing health conditions that increase variability in human
response to chemical exposures. Variations in CYP enzyme expression may contribute to
susceptibility because multiple CYP enzymes are involved in metabolism of 1,4-dioxane,
including CYP2E1. There are large variations in CYP2E1 expression and functionality in
humans (Lipscomb et at.. 2003) and similar variation in other CYPs involved in 1,4-dioxane
metabolism are possible.
Pre-existing conditions affecting the liver may also impair metabolism in some individuals. For
example, fatty liver disease has been associated with reduced CYP function. Other pre-existing
conditions affecting the kidneys, upper respiratory system, and other organs targeted by 1,4-
dioxane could make some individuals more susceptible. Although data are limited, the available
evidence from gestational exposures to 1,4-dioxane provides some evidence of the potential for
developmental toxicity. The offspring of pregnant women may therefore be at greater risk from
exposure. The variability in human susceptibility to 1,4-dioxane, including variability in CYPs,
is reflected in the selection of the uncertainty factor for human variability included in the
benchmark margin of exposure (MOE).
3.2.6.2 Points of Departure for Human Health Hazard Endpoints
The dose-response assessment included analysis of all non-cancer and cancer endpoints,
followed by an overall synthesis that includes a characterization of the risk estimates across
endpoints, the strength of the mode of action information of each endpoint, and the anticipated
relevance of each endpoint to humans, including potentially exposed or susceptible populations
and lifestages. EPA evaluated the data from studies described in Section 3.2 to characterize the
dose-response relationships of 1,4-dioxane for oral and inhalation exposures. EPA first
determined whether each hazard endpoint in the key studies had adequate information to perform
dose-response analysis. This was informed by the IRIS assessment ( 013d). which
evaluated dose-response data within the studies identified in Section 3.2. EPA defines a POD as
the dose-response point that marks the beginning of a low-dose extrapolation. This point can be
the lower bound on the dose for an estimated incidence, or a change in response level from a
dose-response model {i.e., BMD), aNOAEL or a LOAEL for an observed incidence or change in
the level of response.
3.2.6.2.1 Acute/Short-term POD for Inhalation Exposures
EPA identified Mattie et al. (2012) as the highest quality study and most relevant for use in
deriving an acute inhalation point of departure (POD). Mattie et al. (2012) reported a LOAEC of
104.8 ppm (378 mg/m3) for liver effects in male/female rats exposed to 1,4-dioxane for 6-
hour/day for 5 days/week for 2 weeks. This is the most sensitive endpoint reported in the
available acute and short-term toxicity studies. EPA assumed that the selection of this endpoint
for dose-response analysis and risk characterization would be protective of potential acute/short-
term effects to the nasal cavity, lungs, and brain.
Page 178 of 616
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EPA evaluated the endpoints in Mattie et al. (2.012) to determine whether the data were amenable
to BMD modeling. Single cell necrosis of the liver in female rats, the most sensitive liver toxicity
endpoint in the study, was not amenable to BMD modeling because the response rate is high
(87.5%) at the lowest exposure concentration, and all non-control concentrations have nearly the
same response level. The data do not provide dose-response information near the benchmark
response rate (BMR) of 10%. Consistent with EPA's Benchmark Dose Technical Guidance (
EPA. 2012b) section 2.1.5, the data provide little useful information about the dose-response
relationship at lower doses. EPA therefore used a LOAEC approach to identify a point of
departure based on short-term effects of 1,4-dioxane on liver toxicity.
EPA applied a duration adjustment to the LOAEC to normalize the concentration from the
exposure conditions used by Mattie et al. (2012) to that of workers {i.e., 8 hours/day, 5
days/week). The duration adjusted POD (PODadj) was calculated as follows:
„ „ „ „ „ „ 6 hours
PODadj = POD x —
8 hours
Where,
PODadj = the duration adjusted LOAECadj
POD = the LOAEC
Following EPA's Methods for Derivation of Inhalation Reference Concentrations and
Application of Inhalation Dosimetry (U.S. EPA. 1994b). EPA converted the PODadj value of
78.7 ppm (283.5 mg/m3) to a human equivalent concentration (PODhec) using the regional gas
dose ratio (RGDR) approach for extrarespiratory effects by calculating a dosimetric adjustment
factor (DAF), which is based on the ratio between the animal and human blood:air partition
coefficients, as shown below:
DAF = W£M
(Hb/g)H
where:
(Hb/g)A = the animal blood:air partition coefficient, and
(Hb/g)H = the human blood:air partition coefficient
Sweeney et al. (2008) measured the blood:air partition coefficients for 1,4-dioxane in rats (i.e.,
(Hb/g)A = 1861) and humans (i.e., (Hb/g)A = 1666). The resulting DAF equates to 1.117;
however, when the DAF is greater than 1, EPA applies a default value of 1 (U.S. EPA. 1994b)
(see Table 3-9.).
The resulting acute inhalation PODhec is 78.7 ppm (283.5 mg/m3) and was considered protective
of liver effects from short-term worker exposures.
Page 179 of 616
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EPA applied a composite uncertainty factor (UF) of 300 for the acute inhalation benchmark
MOE for short-term/acute effects, based on the following considerations:
• An interspecies uncertainty/variability factor of 3 (UFa) was applied for animal-to-human
extrapolation to account for toxicodynamic differences between species. This uncertainty
factor is comprised of two separate areas of uncertainty to account for differences in the
toxicokinetics and toxicodynamics of animals and humans. In this assessment, the
toxicokinetic uncertainty was accounted for by the calculation of an HEC and application
of a DAF as outlined in the RfC methodology (U.S. EPA. 1994b). As the toxicokinetic
differences are thus accounted for, only the toxicodynamic uncertainties remain, and an
UFa of 3 is retained to account for this uncertainty.
• A default intraspecies uncertainty/variability factor (UFh) of 10 was applied to account
for variation in sensitivity within human populations due to limited information on the
impact of gender, age, health status, or genetic makeup.
• A LOAEC-to-NOAEC uncertainty factor (UFl) of 10 was applied because the POD from
the principle study was a LOAEC.
The acute inhalation benchmark MOE of 300 was used to interpret the MOE risk estimates for
each short-term/acute use scenario.
3,2,6,2,2 Acute/Short-term POD for Dermal Exposures Extrapolated from Inhalation
Studies
In the absence of data from dermal exposure studies, EPA generated an acute dermal POD for
1,4-dioxane by extrapolating from the acute inhalation POD derived from the Mattie et al. ( )
study. The acute inhalation POD was used to derive an absorbed human equivalent dose (HED).
Route-to-route extrapolation is considered appropriate. While there is no specific EPA guidance
on extrapolating from one route to another, EPA considered guidance from other countries.
Three criteria from IGH.RC (2006) are considered here: 1) there are not adequate toxicty data
available by the dermal route, 2) the effects are systemic and 3) while there are first pass effects
in oral studies this extrapolation uses an inhalation study where there are not first pass effects
(see Section 4.2.2). The fraction of dioxane absorbed through skin in human exposures is
accounted for in the exposure estimates in Section 2.4. EPA therefore developed dermal PODs in
terms of absorbed dermal HEDs (rather than applied dermal HEDs which would account for
dermal absorption).
The acute inhalation PODhec of 78.7 ppm (283.5 mg/m3) for liver effects from short-term
occupational exposures was converted to an absorbed dermal HED using the following equation:
dermal HED (mg/kg-d) = absorbed inhalation dose ^ body weight
where the absorbed inhalation dose = PODhec (mg/m3) x inhalation volume x 100% (inhalation
absorption) and body weight is 80 kg. Inhalation volume is 10 m3 (i.e., 1.25 m3/hour over an 8
hour shift) based on REACH guidance on information requirements and chemical safety
assessment (ECHA. 2010). The inhalation absorption estimates were based on experimental data
by the inhalation route (i.e., Young et al., 1977: 1976) where 1,4-dioxane is readily absorbed in
humans), however the available studies did not measure the parameters needed for a quantitative
Page 180 of 616
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estimate of the fraction absorbed. Given this qualitative estimate and the absence of quantitative
inhalation absorption data, 100% inhalation absorption is assumed.
The resulting acute absorbed dermal HED is 35.4 mg/kg/day and is considered protective of liver
effects and other systemic effects from short-term exposures.
EPA applied the same composite uncertainty factor (UF) of 300 for the acute dermal benchmark
MOE for short-term/acute effects as the inhalation POD based on the following considerations:
• An interspecies uncertainty/variability factor of 3 (UFa) was applied for animal-to-human
extrapolation to account for toxicodynamic differences between species. This uncertainty
factor is comprised of two separate areas of uncertainty to account for differences in the
toxicokinetics and toxicodynamics of animals and humans. In this assessment, the
toxicokinetic uncertainty in the inhalation study was accounted for by the calculation of
an HEC and application of a DAF as outlined in the RfC methodology (U.S. EPA.
1994b). As the toxicokinetic differences are thus accounted for, only the toxicodynamic
uncertainties remain, and an UFA of 3 is retained to account for this uncertainty.
• A default intraspecies uncertainty/variability factor (UFh) of 10 was applied to account
for variation in sensitivity within human populations due to limited information on the
impact of gender, age, health status, or genetic makeup.
• A LOAEC-to-NOAEC uncertainty factor (UFl) of 10 was applied because the POD from
the principle study was a LOAEC.
The acute inhalation benchmark MOE of 300 was used to interpret the MOE risk estimates for
each short-term/acute use scenario.
3.2.6.2.3 Acute/Short-term POD for Oral Exposures Extrapolated from Inhalation Studies
In the absence of data from oral exposure studies, EPA generated an acute oral POD for 1,4-
dioxane by extrapolating from the acute inhalation POD derived from the Mattie et al. (2012)
study. The acute inhalation POD was used to derive an oral human equivalent dose (HED) using
an approach consistent with the approach used to derive the acute dermal POD.
The acute inhalation PODhec of 78.7 ppm (283.5 mg/m3) for liver effects from short-term
occupational exposures was converted to an oral HED using the following equation:
oral HED (mg/kg-d) = absorbed inhalation dose ^ body weight
where the absorbed inhalation dose = PODhec (mg/m3) x inhalation volume x 100% (inhalation
absorption) and body weight is 80 kg. Inhalation volume is 10 m3 (i.e., 1.25 m3/hour over an 8
hour shift). 100% inhalation absorption is assumed.
The resulting acute oral HED is 35.4 mg/kg/day and is considered protective of liver effects and
other systemic effects from short-term exposures.
EPA applied the same composite uncertainty factor (UF) of 300 for the acute oral benchmark
MOE for short-term/acute effects as the inhalation POD based on the following considerations:
Page 181 of 616
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• An interspecies uncertainty/variability factor of 3 (UFa) was applied for animal-to-human
extrapolation to account for toxicodynamic differences between species. This uncertainty
factor is comprised of two separate areas of uncertainty to account for differences in the
toxicokinetics and toxicodynamics of animals and humans. In this assessment, the
toxicokinetic uncertainty in the inhalation study was accounted for by the calculation of
an HEC and application of a DAF as outlined in the RfC methodology (
1994b). As the toxicokinetic differences are thus accounted for, only the toxicodynamic
uncertainties remain, and an UFA of 3 is retained to account for this uncertainty.
• A default intraspecies uncertainty/variability factor (UFh) of 10 was applied to account
for variation in sensitivity within human populations due to limited information on the
impact of gender, age, health status, or genetic makeup.
• A LOAEC-to-NOAEC uncertainty factor (UFl) of 10 was applied because the POD from
the principle study was a LOAEC.
The acute inhalation benchmark MOE of 300 was used to interpret the MOE risk estimates for
each short-term/acute use scenario.
3.2.6.2.4 Chronic Non-Cancer POD for Inhalation Exposures
EPA performed dose-response analyses on the noncancer endpoints reported by Kasai et al.,
(2009). which included effects in the respiratory tract (i.e., squamous cell metaplasia of the nasal
respiratory epithelium, squamous cell hyperplasia of the nasal respiratory epithelium, respiratory
metaplasia of the nasal olfactory epithelium, atrophy of the nasal olfactory epithelium, hydropic
change in the lamina propria and sclerosis in the lamina propria of the nasal cavity) and the liver
(i.e., centrilobular necrosis of the liver). EPA selected this two-year inhalation toxicity study
because it is most relevant for deriving inhalation points of departure (PODs) for long-term
human exposures.
EPA evaluated the noncancer endpoints to determine whether the data were amenable to BMD
modeling. For the data sets that were amenable to BMD modeling, EPA followed the benchmark
dose modeling software (BMDS) guidance (U.S. EPA. ) and used BMDS version 2.704. A
benchmark response (BMR) of 10% extra risk was used for all endpoints to estimate the
BMCLio (the lower 95% bound on the concentration estimated to produce a 10% increased
incidence over background) (see Table 3-9.). For the data sets that were not amenable to BMD
modeling, the NOAECs and LOAECs were used as the inhalation PODs (see Table 3-9.).
Additional information on the BMD methods and criteria used for assessing adequacy of model
fit can be found in Appendix K (Benchmark Dose Analysis).
Duration adjustments were applied to the PODs (i.e., BMCLios, NOAECs, or LOAECs) to
normalize the concentrations from the exposure conditions used by (Kasai et al.. 2.009) (i.e., 6
hours/day, 5 days/week) to that of workers (i.e., 8 hours/day, 5 days/week) (see Table 3-9.). The
adjusted PODs (i.e., PODadjs) were calculated as follows:
PODadj = POD x —
8 hours
Page 182 of 616
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Where,
PODadj = the duration adjusted BMCLadj, NOAECadj, or LOAECadj
POD = the BMCLio, NOAEC, or LOAEC
Following EPA's Methods for Derivation of Inhalation Reference Concentrations and
Application of Inhalation Dosimetry (U.S. EPA. 1994b). EPA converted the PODadj to a human
equivalent concentration (PODhec). The HEC was calculated by the application of a dosimetric
adjustment factor (DAF), a ratio of animal and human physiologic parameters which is
dependent on the nature of the contaminant (particle or gas) and the target site (e.g., systemic or
portal of entry). 1,4-Dioxane is miscible with water and has a high blood:air partition coefficient.
Typically, highly water-soluble and directly reactive chemicals (i.e., Category 1 gases) partition
predominantly into the upper respiratory tract, induce portal-of-entry effects, and do not
accumulate significantly in the blood. 1,4-Dioxane induces effects in the respiratory tract, liver,
and kidneys, and it has been measured in the blood after inhalation exposure (Kasai et at. 2008).
The observations of systemic effects and measured blood levels resulting from 1,4-dioxane
exposure indicate that this compound is absorbed into the bloodstream and distributed
throughout the body. Thus, 1,4-dioxane might be best described as a water-soluble and non-
directly reactive gas. Gases such as these are readily taken up into respiratory tract tissues and
can also diffuse into the blood (Mediosky and Bond. 2001). Observations from rat inhalation
studies suggest that nasal effects are primarily due to systemic delivery. Kasai et al. (2.009)
reported uniformly distributed lesions in the olfactory epithelium and respiratory epithelium
lacking an anterior-posterior gradient. Typically, for highly soluble and reactive gases, injury
follows the main inspiratory airstreams and the majority of chemical is removed in the airways.
Therefore, sites of injury typically correlate with airflow patterns where chemical delivery rates
are highest. Lesions induced by inhaled irritants also typically show an anterior-posterior
gradient. The uniform distribution of nasal lesions following 1,4-dioxane exposure suggests that
lesions may result primarily from systemic delivery. For the purposes of dosimetric
extrapolation, EPA therefore treated 1,4-dioxane as a systemic acting gas.
EPA used the RGDR approach for systemic effects by calculating a DAF based on the ratio
between the animal and human blood:air partition coefficients, as shown below:
DAP = ^-Hb/3)A
(Hb/g)H
where:
(Hb/g)A = the animal blood:air partition coefficient, and
(Hb/g)H = the human blood:air partition coefficient
As noted previously, the measured blood:air partition coefficients in rats (i.e., (Hb/g)A = 1861)
and humans (i.e., (Hb/g)A = 1666) results in a DAF of 1.117. Therefore, EPA applied a default
value of 1 (U.S. EPA. 1994b) (see Table 3-9.).
Page 183 of 616
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Of the available PODhec values, EPA selected the PODhec of 12.8 mg/m3 for effects on the
olfactory epithelium (i.e., metaplasia and atrophy). These effects were the most pronounced and
sensitive endpoints in the two-year inhalation study reported by Kasai et al. (2009). EPA
considered these respiratory effects relevant for worker exposures. Given that other systemic
effects occurred at higher concentration levels, basing the chronic PODhec on respiratory effects
should be protective against other systemic effects in workers.
EPA applied a composite UF of 30 for the chronic inhalation benchmark MOE, based on the
following considerations:
• An interspecies uncertainty factor (UFa) of 3 to account for species differences in animal
to human extrapolation. An interspecies uncertainty/variability factor of 3 (UFa) was
applied for animal-to-human extrapolation to account for toxicodynamic differences
between species. This uncertainty factor is comprised of two separate areas of uncertainty
to account for differences in the toxicokinetics and toxicodynamics of animals and
humans. In this assessment, the toxicokinetic uncertainty was accounted for by the
calculation of an HEC and application of a dosimetric adjustment factor as outlined in the
RfC methodology ( Mb). As the toxicokinetic differences are thus accounted
for, only the toxicodynamic uncertainties remain, and an UFa of 3 is retained to account
for this uncertainty.
• A default intraspecies uncertainty/variability factor (UFh) of 10 was applied to account
for variation in sensitivity within human populations due to limited information on the
impact of gender, age, health status, or genetic makeup.
• A Subchronic-to-Chronic uncertainty factor (UFs) was not applied because the key study
used a chronic exposure protocol.
The chronic inhalation benchmark MOE of 30 was used to interpret the MOE risk estimates for
each chronic use scenario.
Page 184 of 616
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Table 3-9. Model selection and duration-adjusted HEC estimates for BMCLs (from best
fitting BMDS models) or NOAECs/LOAECs from the 2-year inhalation study by Kasai et
»1. (
Endpoinl
UMR
Model1'
IJ.MC
in
(ppm)
r
UMCI.m,
or
NOAEC/
LOAEC
(ppm)'
IJMCLuu
or
NOAEC mi,/
LOAEC mi,
(worker
ppm)'1
liMC I.,,,,
or
NOAEC,,,,/
LOAEC ,,,,
(worker
m »/nr()'
licnchmurk
moi:
Respiratory Effects
Squamous
cell
metaplasia;
respiratory
epithelium
10%
Log
Probit
218
160
120
432.4
30
Squamous
cell
hyperplasia;
respiratory
epithelium
10%
Quantal
Linear
679
429
323
1163.9
30
Respiratory
metaplasia:
olfactory
epithelium
10%
BMDLh
6.47
4.74
3.56
12.8
30
Atrophy;
olfactory
epitheliumf
"
LOAEC
--
50
37.5
135.1
300
Hydropic
change;
lamina
10%
Log
Logistic
68.5
46.8
35.1
126.5
30
propria
Sclerosis;
lamina
_
NOAEC
_
50
37.5
135.1
30
propria8
Liver Effects
Centrilobular
necrosis;
10%
Log
Probit
232
44.0
33.0
119
30
Liver
Bold and shaded cells indicate the PODs selected for use in risk characterization
a Data quality evaluations for all endpoints are high (see Appendix I).
bBest fitting models were determined using current BMDS guidance (U.S. EPA, 2012b).
cBMCio = Concentration at specified extra risk (benchmark dose); BMCLio = 95% lower bound on concentration at specified
extra risk.
dPODADj (ppm) = BMCL or LOAEC or NOAEC x 6 hours 8 hours.TODadj (ppm) values were converted to mg/m3 values
based on the following: PODadj (ppm) x molecular weight of 1,4-dioxane (88.1 g/mole) 24.45 (gas constant at 760 mm Hg
and at 25 °C).
TODhec (mg/m3) = BMCLadj x DAF (i.e., (Hb/g)A - (Hb/g)H)
f Atrophy of the olfactory epithelium was not amenable to BMD modeling because the response rate is high (80%) at the
lowest exposure concentration, and all non-control concentrations have nearly the same response level. The data do not
provide dose-response information near the benchmark response rate (BMR) of 10%). Consistent with EPA's Benchmark Dose
Technical Guidance (U.S. EPA, 2012b") section 2.1.5. the data provide little useful information about the dose-response
relationship at lower doses.
Page 185 of 616
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B Only one BMDS model (dichotomous Hill) could provide a statistically adequate fit to these data, however this model fit
implied a high degree of curvature immediately below the observed LOAEL, a pattern that the experimental data could not
support or refute. Due to the uncertainty in model shape, a BMDL value is not proposed for this endpoint.
11 Of the adequately fitting models (p-value >0.1), "the AIC values for gamma, multistage, quantal-linear, and Weibull models
are equivalent and the lowest and, in this case, essentially represent the same model" and, because they all result in the same
BMDL value of 4.7 ppm
1 BMP modeling for respiratory metaplasia of the olfactory epithelium is in Appendix K.4
3.2.6.2.5 Chronic Cancer Unit Risk for Inhalation Exposures i.e., Inhalation Unit Risk
(IUR)
EPA performed dose-response analyses on the cancer endpoints reported by Kasai et al. (2009).
1,4-Dioxane was associated with a statistically significant increase in the incidences and/or
statistically significant dose-response trends for tumors in the respiratory tract and auditory canal
(i.e., nasal cavity squamous cell carcinomas and Zymbal gland (auditory sebaceous gland)
adenomas) and other systemic tumors (i.e., hepatocellular adenomas and carcinomas, renal cell
carcinomas, peritoneal mesotheliomas, and mammary gland fibroadenomas, and subcutis
fibromas). All tumors were considered of independent origin and included in the multi-tumor
analysis. The incidences of adenomas and carcinomas were combined according to EPA's
Guidelines for Carcinogen Risk Assessment which advises that etiologically similar tumor types,
i.e., benign and malignant tumors of the same cell type, can be combined due to the possibility
that benign tumors could progress to the malignant form ( 1005a; McConnell et al..
1986V
BMD modeling was used to fit the dose-response data and calculate the inhalation PODs. The
multistage cancer models available in the BMDS (version 2.704) were fit to the incidence data
for each tumor type observed in rats exposed to 1,4-dioxane via inhalation (Kasai et al.. 2009) to
determine the degree (e.g., 1st, 2nd, or 3rd) of the multistage model that best fit the data. In
accordance with the EPA Guidelines for Carcinogen Risk Assessment ( )05a). a
benchmark response (BMR) of 10% was used to estimate the BMCLio (the lower 95% bound on
the concentration estimated to produce a 10% increase in tumor incidence over background). The
results of the model that best characterized the cancer incidences were selected (see Table 3-10.).
Suitable multistage model fits were obtained for all tumor types included in the inhalation unit
risk analysis. Additional information on the BMD methods and criteria used for assessing
adequacy of model fit can be found in Appendix K (Benchmark Dose Analysis).
As discussed for the noncancer dose-response analyses, the BMCLio values were converted to
duration adjusted values (i.e., BMCLadjs) and dosimetrically adjusted to BMCLhecs, using the
same methods applied to the noncancer endpoints (as discussed above under "Chronic Inhalation
- Non-Cancer") (see Table 3-10.).
U.S. EPA (2013d) applied a linear low-dose approach to derive inhalation unit risk values. This
approach is used when the mode of action (MOA) is unknown or unclear. The inhalation unit
risk (IUR) for humans is defined as the slope of the line drawn from the inhalation POD
(BMCLhec) through the origin. To calculate the IUR, the benchmark response rate (0.1) was
divided by the BMCLhec values (see Table 3-10.).
Given the multiplicity of tumor sites, basing the overall IUR on one tumor site may
underestimate risk. Consistent with recommendati ons of the NRC (1994) and EPA's Guidelines
Page 186 of 616
-------
for Carcinogen Risk Asses. ( 2005a), EPA estimated the total risk and upper
bound risk for multiple tumor sites. The MS-Combo model (which is implemented using BMDS)
was utilized to calculate the concentration associated with a specified composite risk (the risk of
developing any combination of tumors at any site), under the assumption that tumors in different
tissues arise independently. MS-Combo is a peer-reviewed (Versar. 2011) module within BMDS
that employs a combined probability function to calculate composite risk using the best-fitting
BMDS multistage model parameters determined for each individual tumor. MS-Combo was
applied to the best-fitting models for each tumor type from the (Kasai et at.. 2009) study.
To test the sensitivity of the model to inclusion of liver tumor data, MS-Combo was run twice:
first to evaluate combined cancer risk for all tumor sites and then to evaluate risk for all tumor
sites excluding liver tumors (see Table 3-10.). This approach allows EPA to characterize the
impact alternate nonlinear MO As for liver carcinogenicity could have on overall cancer risk of
1,4-dioxane.
Note that the BMCLadj, was calculated assuming a worker exposure scenario of 40 hours per
week i.e.,8 hours per day for 5 days per week. Therefore, the BMCLhec and IUR estimates are
appropriate for comparison with exposure scenarios of comparable duration. The IUR estimate is
not the same as the EPA IRIS assessment where the IUR is estimated for a continuous exposure
(i.e., 24 hours per day for 7 days per week).
Table 3-10. Dose-response modeling summary results for male rat tumors associated with
inhalation exposure to 1,4-dioxane for two years
Tumor T\ |K"'
Mullislii^o
Model
Decree1'
i;m( I,,
(ppm)'
UM( I.im
(ppm)'
liM( Urn
(worker
ppm )¦'
IJMCI.iih
(worker
niii/iir1)'-
11 K
l-'sl iniiile1
(.iiii/m-4)1
\asal wi\ ii) squamous
1
llu"
(¦ ill
4~3
1 ~U4
5.8~L-OS
cell carcinoma
Zymbal gland adenoma
1
1975
958
719
2591
3.86E-08
Hepatocellular adenoma
1
253
182
137
492
2.03E-07
or carcinoma
Renal cell carcinoma
1
1975
958
719
2589
3.86E-08
Peritoneal mesothelioma
1
82.2
64.4
48
174
5.75E-07
Mammary gland
fibroadenoma
1
1635
703
527
1900
5.26E-08
Subcutis fibroma
1
142
81.9
61.4
221
4.52E-07
MS-Combo for all tumor Ivpcs
38.9
31.3
23.5
84.6
1.18E-06
(including liver)1'
MS-Combo for all tumor types
46.0
35.9
26.9
97.0
1.03E-06
(omitting liver)1
Bold and shaded cells indicate the IURs selected for use in risk characterization
aTumor incidence data from Kasai et al. (2009). Data quality evaluations for all endpoints are high (see Appendix I).
' Best-fitting multistage model degree following current BMDS guidance (U.S. EPA. 2014b. 2012b). Model
selections for renal cell carcinoma and Zymbal gland adenoma differ from the (U.S. EPA. 2013d) IRIS
assessment.
°BMCio = Concentration at specified extra risk (benchmark dose); BMCLio = 95% lower bound on concentration
at specified extra risk.
dBMCLADj (ppm) = BMCLio x 6 hours ^
8 hours.
"BMCLadj (ppm) values were converted to mg/m3 values based on the following: BMCLadj (ppm) x molecular
weight of 1,4-dioxane (88.1 g/mole) gas constant at 760 mm Hg and at 25 °C).
Page 187 of 616
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fThe inhalation unit risk ((ig/m3)"1 was derived from the BMCLhec, the 95% lower bound on the concentration associated with
a 10% extra cancer risk. Specifically, by dividing the BMR (0.10) by the BMCLhec. Thus, representing an upper bound,
continuous lifetime exposure estimate of cancer potency.
sBMCLhec (mg/m3) = BMCLadj x DAF (i.e., (Hb/g)A - (Hb/g)H)
hMS-combo model for all tumor types including liver is in Appendix K. 16
'MS-Combo model for all tumor types excluding liver is in Appendix K.17
3.2.6.2,6 Chronic Non-Cancer POD for Dermal Exposures Extrapolated from Chronic
Inhalation Studies
The Kasai et al., (2009) study was used in deriving inhalation PODs for long-term human
exposures. EPA extrapolated from an inhalation to dermal exposure to derive an absorbed human
equivalent dose (HED). Systemic effects (including centrilobular necrosis of the liver and
respiratory lesions believed to result primarily from systemic delivery) were used for route-to-
route extrapolation. As described above (Section 4.2.6.2.3), EPA treated 1,4-dioxane as a
systemic acting gas because experimental observations reported in Kasai et al., (2009) indicate
that respiratory lesions result primarily from systemic delivery rather than portal of entry
exposures. These respiratory endpoints are therefore relevant to systemic delivery from dermal
exposures.
The chronic inhalation BMCLhec of 12.8 mg/m3 for respiratory metaplasia (see Table 3-9.) from
chronic inhalation exposures was converted to an absorbed dermal HED using the following
equation:
dermal HED (mg/kg-d) = inhalation BMDLhec (mg/m3) x inhalation volume x 100% (inhalation
absorption)^- body weight
where the inhalation volume is for an 8-hour exposure x 1.25 m3/hour and the body weight is 80
kg. The absorption estimates were based on experimental data by the inhalation route (i.e.,
Young etal., (1977; 1976) where 1,4-dioxane is readily absorbed in humans. However, the
available studies did not measure the parameters needed for a quantitative estimate of the
fraction absorbed. Given this qualitative estimate and the absence of quantitative inhalation
absorption data, 100% inhalation absorption is assumed.
The resulting chronic dermal HED of 1.6 mg/kg/day was considered protective of systemic
respiratory, liver and kidney effects from chronic worker exposures.
EPA applied the same composite uncertainty factor (UF) of 30 for the chronic dermal benchmark
MOE as the chronic inhalation systemic because the dermal POD was extrapolated from the
systemic effects in the inhalation study, based on the following considerations:
• An interspecies uncertainty/variability factor of 3 (UFa) was applied for animal-to-human
extrapolation to account for toxicodynamic differences between species. This uncertainty
factor is comprised of two separate areas of uncertainty to account for differences in the
toxicokinetics and toxicodynamics of animals and humans. In this assessment, the
toxicokinetic uncertainty in the inhalation study was accounted for by the calculation of
an HEC and application of a DAF as outlined in the RfC methodology (U.S. EPA.
Page 188 of 616
-------
1994b). As the toxicokinetic differences are thus accounted for, only the toxicodynamic
uncertainties remain, and an UFA of 3 is retained to account for this uncertainty.
• A default intraspecies uncertainty/variability factor (UFh) of 10 was applied to account
for variation in sensitivity within human populations due to limited information on the
impact of gender, age, health status, or genetic makeup; and
• A LOAEC-to-NOAEC uncertainty factor (UFl) was not needed, i.e., a value of 1 was
applied because a BMDL was derived and used.
• A Subchronic-to-Chronic uncertainty factor (UFs) was not applied because the key study
used a chronic exposure protocol.
The chronic inhalation benchmark MOE of 30 was used to interpret the MOE risk estimates for
each chronic use scenario.
3,2,6,2,7 Chronic Non-Cancer POD for Dermal Exposures Extrapolated from Chronic
Oral Studies
EPA generated oral human equivalent doses (HEDs) based on dose-response analysis of liver,
kidney, and respiratory effects reported in several chronic oral studies. These were then
translated to absorbed dermal HEDs via route-to-route extrapolation.
The non-cancer endpoints for dose response analysis from the studies by Kano et al. (2009;
2008). Kociba et al. (1974). and NCI (1978) were increased liver enzymes, nasal inflammation
and other nasal effects (atrophy of nasal olfactory epithelium, nuclear enlargement of nasal
respiratory epithelium, nasal adhesion), hepatocellular mixed foci, hepatocyte swelling,
degeneration and necrosis of renal tubular cells and hepatocytes, and cortical tubule
degeneration. NOAELs and LOAELs were obtained from Appendix I for those data that were
not amenable to benchmark dose modeling (see Appendix K for guidance and criteria used for
assessing adequacy of model fit). The highest dose in Kano et al. (2009) was removed from all
analyses because of concerns regarding decreased water intake rate at the highest dose. Because
all LOAELs and NOAELs were in the low-dose region, the exclusion of this data point only
impacted BMD analyses. BMDS modeling was performed on the available data using BMDS
version 2.704 and following current BMDS guidance ( 2012b). Following EPA's
Recommended Use of Body Weight314 as the Default Method in Derivation of the Oral Reference
Dose ( ), human equivalent doses were calculated by multiplying rodent doses
by (BWa/BWh)0'25 (where BWa is the bioassay-specific rodent body weight, and BWn is the
default human body weight of 80 kg). The EPA IRIS assessment (U.S. EPA. ) did not
apply BW3/4 scaling to noncancer oral data since the guidance was finalized after the oral portion
of the 1,4-dioxane ( 13d) IRIS assessment was posted (2013 was the completion
year for the inhalation update).
As shown in Table 3-11., the oral HEDs were converted to absorbed dermal HEDs using the
following equation:
Absorbed dermal HED (mg/kg-d) = oral HED (mg/kg-d) x 100% (oral absorption)
Page 189 of 616
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The absorption estimates were based on experimental data by the oral {i.e., Young et al., 1978a,
b) route of exposure. Young et al. (1978a, b) estimated the oral absorption of 1,4-dioxane in rats
to be nearly complete. Given this qualitative estimate and the absence of quantitative oral
absorption data in experimental animals or humans, 100% oral absorption was assumed. Because
oral absorption was assumted to be 100%, the extrapolated absorbed dermal HEDs are equal to
the oral HEDs calculated for each endpoint.
EPA applied a composite UF of 30 for the chronic dermal benchmark MOE, based on the
following considerations:
• An interspecies uncertainty/variability factor of 3 (UFa) was applied for animal-to-human
extrapolation to account for pharmacodynamic differences between species. This
uncertainty factor is comprised of two separate areas of uncertainty to account for
differences in the toxicokinetics and toxicodynamics of animals and humans. In this
assessment, the toxicokinetic uncertainty was accounted for by the calculation of an HED
and application of BW3 4 scaling ( ). As the toxicokinetic differences are
thus accounted for, only the toxicodynamic uncertainties remain, and an UFA of 3 is
retained to account for this uncertainty.
• A default intraspecies uncertainty/variability factor (UFh) of 10 was applied to account
for variation in sensitivity within human populations due to limited information on the
impact of gender, age, health status, or genetic makeup.
• A Subchronic-to-Chronic uncertainty factor (UFs) was not applied because the key study
used a chronic exposure protocol.
The chronic dermal benchmark MOE of 30 was used to interpret the MOE risk estimates for
each use scenario.
Overall POD Selection for Chronic Non-Cancer Dermal Exposures
EPA evaluated dermal HEDs extrapolated both from oral (Table 3-11.) and inhalation (Section
3.2.6.2.6) studies and selected an absorbed dermal HED of 1.6 mg/kg-day based on respiratory
metaplasia of the olfactory epithelium reported in male rats in by Kasai et al., (2009) following
inhalation exposure. This was the most sensitive systemic endpoint identified. Based on the
uniform distribution of lesions relative to airflow, respiratory metaplasia was considered to be
primarily a result of systemic delivery as opposed to a portal of entry effect and therefore
relevant to systemic effects from dermal exposures. It is possible that portal of entry effects
contribute to the respiratory toxicity in this study, however, the selected POD is supported by
very similar PODs (less than a two-fold difference) derived from dose-response data on
hepatocellular toxicity following drinking water exposure. Two independent studies (Koeiba et
al mo et al.. 2.009) arrived at essentially identical PODs for hepatocellular toxicity in
male rats following oral drinking water exposure, with both rounding to 2.6 mg/kg/day. The
selected absorbed dermal HED of 1.6 mg/kg/day was considered protective of all systemic
effects {i.e., kidney, liver and respiratory effects) from chronic dermal worker exposures.
Page 190 of 616
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Table 3-11. Dose-response modeling summary results for oral non-cancer liver, kidney, and nasal effects and route-to-route
extrapolated applied dermal HEDs i
Study
(data quality)
(lender/strain/
species
r.ndpoinl
liMU
Model
mil)
(mg/kg-d)
KM 1)1. or
NOAKI.
(mg/kg-d)
li\\ \
(s):l
Oral
IIKI)1'
(mg/kg-
d)
Absorbed
Dermal
IIKI)1
(mg/kg-d)
Kano et a I.
(2009); j'BRC
11 (high)
Male F344/DuCij
rats
Increases in serum liver enzymes
(GOT, GPT, LDH, and ALP)
--
NOAELd
--
55
432
14.9
14.9
Atrophy of nasal olfactory
epithelium; nasal adhesion and
inflammation
NOAEL
55
14.9
14.9
Hepatocellular mixed cell foci'
10%
Log
Logistic"
16.7
9.57
2.6
2.6
--
NOAEL
--
11
3.0
3.0
Female Cij:BDFl
mice
Nasal inflammation
--
NOAEL
--
66
35.9
9.6
9.6
Male Cij:BDFl
mice
Increases in serum liver enzymes
(GOT, GPT, LDH, and ALP)
--
NOAEL
--
49
47.9
7.7
7.7
Kano et a I.
(2008) (medium)
Male F344/DuCij
rats
Nuclear enlargement of nasal
respiratory epithelium
--
NOAEL
--
52
335
13.2
13.2
Hepatocyte swelling
—
NOAEL
—
52
335
13.2
13.2
Kociba et al.
(liigh)
Male Sherman
rats
Degeneration and necrosis of
renal tubular cells and
hcpalocvlcs'
NOAEL
9.6
405
2.6
2.6
NCI (1978) (low)
Female OM rats
Cortical tubule degeneration
10%
Weibull
596
452
310
113
113
Bold and shaded cells indicate the PODs selected for potential use in risk characterization
1 Bodv weishts are studv-specific time weishted averaees. For Kano et al. (2009) and NCI (1978). these were obtained from Table 5-9 of the (U.S. EPA. 2013d) IRIS
assessment. For Kano et al. (2008). the published bodv weight at the LOAEL or NOAEL for the species/sex was used. For Kociba et al. (1974). the time weighted average
BW of male rats was approximated by digitizing data from the published growth curve (low-dose and control animals).
' POD=dose x (BWa/BWh)0 25. BWa = studv-specific values (see above). BWh=80 ks. The oral assessment of (U.S. EPA, 2013d). which preceded the inhalation update
portion of the assessment and the BW3/4 scaline euidance (U.S. EPA. 201 lb) did not perform this conversion.
0 Applied dermal HED (mg/kg-d) = oral HED (mg/kg-d) x 100% (oral absorption)
dNOAELs listed in this table were obtained from Appendix I. These endpoints were not amenable to benchmark dose modeling.
e Highest dose omitted.
fBMD modeling for hepatocellular mixed cell foci is in Appendix K. 18; degeneration and necrosis of renal tubular cells and hepatocytes is based on a NOAEL
Page 191 of 616
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3.2.6.2.8 Chronic Cancer Unit Risk for Dermal Exposures i.e., Cancer Slope Factor (CSF)
extrapolated from Chronic Inhalation Studies
EPA used route-to-route extrapolation to generate dermal CSFs for all systemic tumors based on
the lURs derived from a 2-year inhalation cancer bioassay in male rats (Kasai et at.. 2009). As
described above in Section 3.2.6.2.3), EPA treated 1,4-dioxane as a systemic acting gas because
experimental observations reported in Kasai et al. (2009) indicate that respiratory toxicity results
primarily from systemic delivery rather than portal of entry exposures. Respiratory tumors were
therefore considered relevant to systemic delivery from dermal exposures and are included in
this analysis.
The BMCLs that were used to calculate inhalation IURs were converted from inhalation air
concentrations to doses based on inhalation volume and body weights for male rats (Kasai et al..
2009). Following Guidelines for Carcinogen Risk Assessment (U.S. EPA. 2005a). human
equivalent doses were calculated for each tumor type by multiplying rodent doses by
(BWa/BWh)0'25 (where BWa is the bioassay-specific rodent body weight, and BWn is the default
human body weight of 80 kg).The human equivalent doses were adjusted to absorbed dermal
exposures (i.e., internal doses) by multiplying by the percent of inhalation absorption. The
absorbed dermal human equivalent dose was used as the point of departure (POD). To calculate a
cancer slope factor (CSF), the benchmark response rate (0.1) was divided by the POD. A CSF is
a plausible upper bound lifetime cancer risk from chronic ingestion of a chemical per unit of
mass consumed per unit body weight, per day (mg/kg day).
The BMCLhecs (see Table 3-11.) were converted to absorbed dermal HEDs using the following
equations:
animal BMDL (mg/kg-d) = inhalation BMCL (mg/m3) x animal inhalation volume animal
body weight x 3.60 mg/m3 per ppm
BMDLhed (mg/kg-d) = animal BMDL (mg/kg-d) x animal body weight x (human body weight
animal body weight)'74 ^ human body weight
dermal BMDLhed (mg/kg-d) = human equivalent BMDL x inhalation absorption
dermal CSF (mg/kg-d)"1 = BMR / dermal BMDLhed (mg/kg-d)
where the animal inhalation volume is for the exposure duration of the animal study (6 hours / 24
hours) x 0.36 m3/day for rats, the animal body weight for rats is 0.380 kg, the human body
weight is 80 kg.
The inhalation absorption estimates were based on experimental data by the inhalation route (i.e.,
Young et al., 1977; 1976) where 1,4-dioxane is readily absorbed in humans, however the
available studies did not measure the parameters needed for a quantitative estimate of the
fraction absorbed. Given this qualitative estimate and the absence of quantitative inhalation
absorption data, 100% inhalation absorption is assumed. Because of this, the BMDLheds are
equal to the dermal BMDLheds. To convert the dermal BMDLhed to a dermal CSF, EPA used a
BMR of 10%.
Page 192 of 616
-------
The resulting cancer slope factors for dermal exposures are shown below in Table 3-12. and the
slope factors for the combined systemic tumors 1.4E-2 per mg/kg/day (including liver) and 1.2E-
2 per mg/kg/day (omitting liver) are considered protective of all tumor types for chronic worker
exposures.
Table 3-12. Cancer slope factor for dermal exposures extrapolated from studies for male
rat tumors associated with inhalation exposure to 1.4-dioxane for two years
Systemic liffects
IHtiii ;il
Aniiiiiil
liMDI.iiiV1
mini,,,,,'
Dei'iiiiil ( SI-"
liMMm
H\ll> I.1'
I worker
(worker
l-'sliniiile'
Tumor T\ pr1
(ppni)1'
iii^/k^/(l:i\)
m;i/kii/(l;i\)
dnii/k;i/(l;i\) 1
\asal wi\ iis squamous coll carcinoma
(¦ ill
sr
141
141
~ 1L-04
Zymbal gland adenoma
958
817
214
214
4.7E-04
Hepatocellular adenoma or carcinoma
182
155
41
41
2.4E-03
Renal cell carcinoma
958
817
214
214
4.7E-04
Peritoneal mesothelioma
64.4
55
14
14
7.1E-03
Mammary gland fibroadenoma
703
599
157
157
6.4E-04
Subcutis fibroma
81.9
70
18
18
5.6E-03
MS-Combo svslemic (including liver)'
31.3
27
7
7
1.4E-02
MS-Combo svslemic (omitting liver)'
35.9
31
8
8
1.2E-02
Bold and shaded cells indicate the PODs selected for potential use in risk characterization
aTumor incidence data from Kasai et al. (2009). Data quality evaluations for all endpoints
bBMCLio = 95% lower bound on concentration at specified extra risk as shown in Table 3-9..
are high (see Appendix I).
canimal BMDL (mg/kg/day) calculated with equations above
dBMDLHED (mg/kg/day) calculated with equations above using allometric BW3'4 scaling
eThe CSF (mg/kg/day)"1 was derived from the BMCLhec, the 95% lower bound on the concentration associated with a 10% extra
cancer risk. Specifically, by dividing the BMR (0.10) by the BMDLhed. Thus, representing an upper bound, continuous lifetime
exposure estimate of cancer potency.
f MS-Combo models for all tumors including and excluding liver are in Appendix K.16 and Appendix K.17
3.2.6.2.9 Chronic Cancer Unit Risk for Dermal Exposures i.e., Cancer Slope Factor (CSF)
extrapolated from Chronic Oral Studies
EPA generated oral CSFs based on data from cancer bioassays in rats and mice. Oral CSFs were
then converted to dermal CSFs by route-to-route extrapolation. Based on data from chronic 2-
year drinking water studies in F344 rats and Crj :BDF 1 mice (Kano et at.. 2009). Sherman rats
(Kociba et al.. 1974). OM rats and B6C3Fi mice (N 'S), 1,4 dioxane produced a
statistically significant increase in incidence and/or a statistically significant dose-response trend
for the following tumor types: nasal squamous cell carcinomas, peritoneal mesotheliomas,
hepatomas, and subcutis fibromas. All tumors were considered of independent origin and
included in the multi-tumor analysis. The incidence of adenomas and carcinomas were combined
according to EPA's Guidelines for Carcinogen Risk Assessment (U.S. EPA. 2005a) which
advises that etiologically similar tumor types, i.e., benign and malignant tumors of the same cell
type, can be combined due to the possibility that benign tumors could progress to the malignant
form ( )Q5a; McConnell et al.. 1986).
BMD modeling was used to fit the dose-response data and calculate the POD. The multistage
cancer models available in the BMDS (version 2.704) were fit to the incidence data for each
tumor type observed to determine the degree (e.g., 1st, 2nd, or 3rd) of the multistage model that
Page 193 of 616
-------
best fit the data. In accordance with the EPA Guidelines for Carcinogen Risk Assessment (U.S.
>05a). a benchmark response (BMR) of 10% was used to estimate the BMDL10 (the
lower 95% bound on the dose estimated to produce a 10% increase in tumor incidence over
background) and the results of the model that best characterized the cancer incidences were
selected. Liver tumors in female mice reported in (Kano et at... 2009) were not initially amenable
to multistage models due to the steep slope and apparent plateau of the response. EPA therefore
used individual animal data obtained from study authors to model the time-to-tumor effect in this
dataset using the Multistage Weibull Model and applying an Extra Risk of 50% as the BMR to
avoid excess extrapolation. Ultimately suitable multistage model fits were obtained for all tumor
types included in the analysis. Additional information on BMD methods and model selection,
and guidance and criteria used for assessing adequacy of model fit, can be found in Appendix K
(Benchmark Dose Analysis).
Following Guidelines for Carcinogen Risk Assessment ( '05a). human equivalent
doses were calculated for each tumor type by multiplying rodent doses by (BWa/BWh)0'25
(where BWa is the bioassay-specific rodent body weight, and BWn is the default human body
weight of 80 kg). The human equivalent dose was used as the point of departure (POD). To
calculate a cancer slope factor (CSF), the benchmark response rate (0.1) was divided by the
POD. A CSF is a plausible upper bound lifetime cancer risk from chronic ingestion of a chemical
per unit of mass consumed per unit body weight, per day (mg/kg day).
Given the multiplicity of tumor sites, basing the overall CSF on one tumor site may
underestimate risk. Consistent with recommendations of the NRC (1994) and EPA's Guide lines
for Carcinogen Risk Assessment ( 35a). the total risk and upper bound risk for
multiple tumor sites was estimated in a manner similar to that for inhalation (see above). Briefly,
MS-Combo model (which is implemented using BMDS) was utilized to calculate the dose
associated with a specified composite risk (the risk of developing any combination of tumors at
any site), under the assumption that tumors in different tissues arise independently. For studies
that observed liver tumors, MS-Combo was applied twice to evaluate uncertainties related to
model choice and mechanisms: one MS-Combo model run included all tumors, while an
additional model run excluded liver tumors.
The dose-response modeling results for cancer hazards from oral exposure in rats (Table 3-13.)
indicate that the CSF from MS-Combo including or excluding the liver tumors is within a factor
of 2. Female rats appear to be about two times less sensitive than males. In mice, only liver
tumors were reported and modeling is therefore focused on liver tumors. Female mice appear to
be more sensitive to liver tumors than male mice.
As shown in Table 3-13., the oral CSFs were converted to absorbed dermal CSFs using the
following equation:
Dermal CSF (mg/kg-d)"1 = oral CSF (mg/kg-d)"1 ^ 100% (oral absorption)
The absorption estimate was based on experimental data by the oral (i.e., Young et al., 1978a. b)
route of exposure as previously discussed. Because inhalation absorption is assumed to be 100%,
the dermal CSFs are equal to the oral CSFs.
Page 194 of 616
-------
Overall Cancer Slope Factor Selection for Chronic Cancer Risk from Dermal Exposures
EPA evaluated dermal CSF extrapolated from inhalation (Section 4.2.6.2.7) and oral (Section
4.2.6.2.8) exposure studies and selected a dermal CSF of 1.2E-1 (mg/kg-d)"1 based on liver
tumors in female mice exposed via drinking water (Kama et at.. 2009)). Female mice appear to be
the most sensitive group tested in drinking water studies, but they were not tested in inhalation
exposure studies. Cancer slopes derived from combined systemic tumors in male and female rats
exposed via drinking water are approximately an order of magnitude less sensitive, with a CSF
of 1 .OE-2 in female rats and 2.1 E-2 in male rats.
Dermal cancer risks extrapolated from inhalation (Section 3.2.6.2.8) and oral studies (Section
3.2.6.2.9) calculated in male rats are generally consistent (less than a two fold difference). For
example, the CSFs calculated for combined systemic tumors (including the liver) in male rats are
1.4E-2 (mg/kg/day)"1 in the inhalation study and 2.1E-2 (mg/kg/day)"1 in the drinking water
study. CSFs calculated for combined systemic tumors omitting liver in male rats were 1.2E-2
(mg/kg/day)"1 in the inhalation study and 1.3.E-2 (mg/kg/day)"1 in the drinking water study.
These are shown in the summaries in Table 3-12. and Table 3-13.. Overall, the selected dermal
CSF based on liver tumors in female mice is expected to be protective of other systemic tumors
types.
Page 195 of 616
-------
Table 3-13. Dose-response modeling summary results for oral CSFs and route-to-route extrapolated dermal CSFs.
S||I(I\ Uliilii c|ii;ilil\) '
(ioiidoi'/sli'iiin/
species
lliidpoiiii
liMK
MS"
BMI)
diiii/kii-
(1)
IJMIM.
(1)
IJW V
(»)
POD1'
(1)
Onil ( Sl-
im s»/kj»-tl 1
IH-niiiil
(SI
(mti/kii-
(1)1
Kano 6t al (20091
Male F344/
DuCrj rats
Nasal squamous cell
carcinoma
10%
2
365
242
432
65.6
1.5E-03
1.5E-03
Peritoneal
mesothelioma
10%
2
77.7
35.4
9.60
1.0E-02
1.0E-02
Hepatocellular
adenoma or
carcinoma
10%
2
61.7
28.3
7.67
1.3E-02
1.3E-02
Subcutis fibroma
10%
1
154
85.0
23.0
4.3E-03
4.3E-03
MS-Combo
(excluding liver)
10%
N/A
55.2
28.1
7.62
1.3E-02
1.3E-02
MS-Combo
(including liver)
10%
N/A
35.1
17.8
4.83
2.1E-02
2.1E-02
Female F344/
DuCij rats
Nasal squamous cell
carcinoma
10%
1
376
214
267
51.4
1.9E-03
1.9E-03
(high)
Mammary gland
adenoma
10%
1
177
99.1
23.8
4.2E-03
4.2E-03
Hepatocellular
adenoma or
carcinoma
10%
2
79.8
58.1
14.0
7.1E-03
7.1E-03
MS-Combo
(excluding liver)
10%
N/A
120
76.5
18.4
5.4E-03
5.4E-03
MS-Combo
(including liver)
10%
N/A
57.6
41.6
10.0
1.0E-02
1.0E-02
Female
Crj:BDFl mice
Hepatocellular
adenoma or
carcinoma'1
50%
1
35.5
27.0
35.9
3.93
1.2 E-01
1.2 E-01
Male Crj:BDFl
mice
Hepatocellular
adenoma or
carcinoma
10%
1
71.0
44.0
47.9
6.88
1.5E-02
1.5E-02
Page 196 of 616
-------
Sluclj (diilii (|ii;ili(\ C
(•iMidor/siriiin/
spocics
I'lnripoini
liMK
MS"
mil)
(m ii/k Ji-
ll)
mini.
(niii/kii-
(1)
IJW V
<»)
POD1'
diiii/kii-
(1)
()r;il ( Sl-
im s»/kj»-tl 1
Dorm ill
(SI
(niii/kii-
(1)1
Kociba et al.
Sherman rats
(M+F)
Nasal squamous cell
carcinomas
10%
2
1981
1314
325
332
3.0E-04
3.0E-04
(1974) (hieh)
Hepatocellular
carcinoma
10%
1
940
584
147
6.8E-04
6.8E-04
NCI (1978) (low)
Female OM
rats
Nasal squamous cell
carcinoma
10%
1
176
122
310
30.4
3.3E-03
3.3E-03
Hepatocellular
adenoma
10%
1
132
94.1
23.5
4.3E-03
4.3E-03
Male B6C3Fi
mice
Hepatocellular
adenoma or
carcinoma
10%
1
164
117
32
16.5
6.1E-03
6.1E-03
Female B6C3Fi
mice
Hepatocellular
adenoma or
carcinoma
10%
1
49.1
38.8
30
5.40
1.9E-02
1.9E-02
Bold and shaded cells indicate the PODs selected for potential use in risk characterization
a Applies to all of the endpoints listed in this table for each study. See Appendix I.
bPOD=dose x (BWa/BWh)0 25. BWh=80 kg. BWa values are study-specific (obtained from Table 5-9 of the 1,4-Dioxane IRIS assessment)
0 Dermal CSF (mg/kg-d)"1 = Oral CSF (mg/kg-d)"1 ^ 100% (oral absorption).
d Model for hepatocellular adenoma or carcinoma in female mice is in Appendix K.28; Liver tumors in female mice were not initially amenable to multistage
models due to the steep slope and apparent plateau of the response. EPA therefore used individual animal data obtained from study authors to model the time-to-
tumor effect in this dataset using the Multistage Weibull Model and applying an Extra Risk of 50% as the BMR to avoid excess extrapolation.
Page 197 of 616
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3,2,7 Summary of Human Health Hazards
The results of the hazard identification and dose-response are summarized in Table 3-14..
Table 3-14. Summary of Hazard Identification and Dose-Response Values
Kxposure
Route
Knilpoinl
Type
1 lii/iird
POD/MIX /Slope
l-'siclor1
Vsilue
I nils
lienchniiirk
moi:1'
lisisis lor Selection
Key Sluily
Inhalation
Short-term
Acute inhalation
PODhec
283.5
mg/m3
300
(UFl= 10; UFa
= 3; UFh = 10)
Systemic liver effect; Study duration
relevant to worker short-term exposures
Mattie et
al. (2 )
Dermal
Short-term
Acute dermal PODhed
extrapolated from an
inhalation study
35.4
mg/kg/day
300
(UFl= 10; UFa
= 3; UFh = 10)
Oral
Short-term
Acute oral PODhed
extrapolated from an
inhalation study
35.4
mg/kg/day
300
(UFl= 10; UFa
= 3; UFh = 10)
Inhalation
Non-Cancer
Human Equivalent
Concentration (HEC)
12.8
mg/m3
30
(UFa 3= 3; UFH
= 10)
POD relevant for olfactory epithelium
effects (i.e.. metaplasia and atrophy)
Kasai et
al. (2009)
Cancer
Inhalation Unit Risk
(IUR)
1.18E-06
(Mg/m3)"1
N/A
Result of combined cancer modeling for
male rats (including liver)
Kasai et
al. (2009)
1.03E-06
(Mg/m3)"1
N/A
Result of combined cancer modeling for
male rats (excluding liver)
Kasai et
al. (2.009)
Dermal
Non-Cancer
Human Equivalent
Dose (HED)
extrapolated from an
inhalation study
1.6
mg/kg/day
30
(UFa = 3; UFh
= 10)
POD for systemic effects in the nasal
cavity (respiratory metaplasia of the
olfactory epithelium) in male rats
Kociba et
)
Kasai et
al. (2009)
Page 198 of 616
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Kxposure
Route
Knilpoinl
Type
1 lii/iird
POD/MIX /Slope
l-'siclor1
Vsilue
I nils
lienchniiirk
moi:1'
lisisis lor Selection
Key Sluily
Human Equivalent
Dose (HED)
extrapolated from oral
studies
2.6
mg/kg/day
30
(UFA = 3; UFH
= 10)
PODs for hepatocellular and renal
toxicity (degeneration and necrosis of
renal tubular cells and hepatocytes;
hepatocellular mixed cell foci) following
drinking water exposure in male ratsc
Kano et
Kociba et
Cancer Slope Factor
(CSF) extrapolated
from an oral study
1.2E-01
(mg/kg-d)"
i
N/A
Cancer model for liver tumors in female
mice (the most sensitive sex/species);
Kano et
al. (2009)
Cancer
Cancer Slope Factor
(CSF) extrapolated
from an inhalation
study
1.4E-02
(mg/kg-d)"
1
N/A
Result of combined cancer modeling for
male rats (including liver)
Kasai et
al. (2009)
1.2E-02
(mg/kg-d)"
i
N/A
Result of combined cancer modeling for
male rats (excluding liver)
Kasai et
al. (2.009)
aHECs are adjusted from the study conditions as described above in Section 3.2.6.2.
bUFs = subchronic to chronic UF; UFa = interspecies UF; UFh = intrasDCcies UF; UFt. = LOAEL to NOAEL UF (U.S. EPA. 2(>02N)
0 Data from both drinking water studies independently arrived at the same POD for liver effects
N/A is shown in the benchmark MOE column for cancer endpoints because EPA did not use MOEs for cancer risks, see Section 4.2 for more information.
Page 199 of 616
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Primary Strengths
There is a robust set of high quality chronic and sub-chronic studies in rats and mice. Available
evidence demonstrates consistent systemic toxicity and tumor formation in rats exposed via
inhalation and in both rats and mice exposed via drinking water. While data on 1,4-dioxane
toxicity from acute exposures are limited, the acute PODs are supported by no effect levels
reported in acute inhalation exposure studies in human volunteers.
Where possible, dose-response information used to identify PODs is based on BMD modeling.
To calculate cancer risk, EPA assumed that different tumor types are independent and applied
cancer models that integrate risk from all tumor types to calculate total cancer risk.
The systemic liver toxicity, nasal lesions and cancer endpoints that serve as the basis for the
selected PODs are assumed to be relevant to humans. Inhalation studies that are used as the basis
for PODs demonstrate that these effects occur through an exposure route that is relevant to the
occupational exposure scenarios. Furthermore, toxicokinetic studies described in Section 3.2.2
demonstrate that systemic absorption and metabolism following inhalation exposure is similar in
rats and humans.
The quality of the studies, consistency of effects, relevance of effects for human health,
coherence of the effects observed and biological plausibility of the observed effects of 1,4-
dioxane contribute to the overall confidence in the PODs.
Primary Limitations
Several limitations contribute to uncertainty around the selected PODs. For example, there are
limited data on reproductive and developmental endpoints. There are no multi-generation
reproduction studies or developmental neurotoxicity studies. There is a single developmental
study that finds evidence of delayed ossification at high doses in the presence of maternal
toxicity. EPA does not know if the selected PODs are adequately protective of sensitive
endpoints that have not yet been tested.
There is limited information about dermal toxicity of 1,4-dioxane. In the absence of dermal
toxicity studies, EPA relied on extrapolation from inhalation and oral exposure studies to derive
dermal PODs. While route-to-route extrapolation introduces some additional uncertainty around
dermal PODs, the primary sources of uncertainty are likely to underestimate the POD rather than
overestimate the POD. For example, a primary source of uncertainty related to extrapolation
from inhalation to dermal exposure is the relative efficiency of absorption through the lungs vs.
absorption through the skin. Absorption through lungs is generally expected to be more efficient
for solvents. Extrapolation from inhalation or oral to dermal exposure is therefore expected to be
a relatively conservative approach. Similarly, a primary source of uncertainty related to
extrapolation from oral studies is the presence of first-pass metabolism. In this risk evaluation,
oral-to-dermal extrapolation was based on liver toxicity. Given first pass metabolism, it is
unlikely that dermal exposure would result in greater exposure to the liver than oral exposures.
There is also uncertainty around the MOA of 1,4-dioxane carcinogenicity at all tumor cites. A
MOA consistent with a threshold model has been proposed for liver tumors, but EPA concluded
that there is insufficient evidence to identify an MOA. Sensitivity analysis demonstrates that
inclusion or exclusion of liver tumors does not have a substantial impact on inhalation unit risk.
Page 200 of 616
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This suggests that MOA conclusions for liver tumors have a relatively small impact on overall
inhalation cancer risk estimates.
Overall Confidence in Selected PODs
EPA qualitatively evaluated overall confidence in each of the selected PODs based on the quality
of the key studies, the confidence in the dose-response models, the consistency of effects across
studies, species and exposure routes, the relevance of effects for human health, and the
coherence and biological plausibility of the effects observed.
Acute Non-Cancer
EPA has medium confidence in the acute inhalation POD. This POD is based on liver toxicity
reported in a high quality study that evaluated effects of short-term (rather than acute) inhalation
exposure. The POD is based on a LOAEC because the data were not amenable to BMD
modeling and a UF of 10 was applied to the benchmark MOE to account for LOAEC to NOAEC
extrapolation. The selected POD is below no effect levels identified for neurological effects
reported in a medium quality short-term inhalation exposure study in rats (Goldberg »'t A J3j4).
No effect levels reported in acute inhalation exposure studies in humans (Ernstgard et al. (2006);
Young e ) also indicate that the selected POD, in combination with the benchmark
MOE of 300, is protective of acute irritation or inflammatory effects in humans.
EPA has medium confidence in the acute oral and dermal PODs which are extrapolated from the
acute inhalation POD. The systemic liver toxicity identified in short-term inhalation studies is a
systemic effect that is relevant for systemic toxicity from oral and dermal exposures. While there
are uncertainties related to dosimetric extrapolation from an inhalation study, the approach is
more likely to overestimate risk than underestimate risk. For example, absorption through lungs
is generally expected to be more efficient for solvents. The oral and dermal PODs derived under
the assumption of 100% absorption may therefore be artificially low, but are unlikely to be
artificially high.
Chronic Non-Cancer
EPA has high confidence in the chronic inhalation POD. This POD is derived from BMD
modeling of respiratory metaplasia in the olfactory epithelium in a high quality chronic
inhalation study in rats (Kasai et at. 2009). The lesions in the olfactory epithelium reported in
this chronic study are relevant to humans and are consistent with effects observed in the
subchronic inhalation study and in drinking water exposure studies.
EPA has high confidence in the chronic dermal POD. This POD is derived from the chronic
inhalation POD. Based on the systemic uptake of 1,4-dioxane following inhalation exposure, the
uniform distribution of nasal lesions observed, and the observation of nasal lesions following
both inhalation and oral exposures, the nasal lesions are believed to be primarily due to systemic
exposure and therefore relevant for systemic toxicity from dermal exposure. While there is some
uncertainty around the extent to which portal of entry effects may contribute to these nasal
lesions, the selected POD is also strongly supported by very similar PODs derived from systemic
effects observed in oral studies. Two oral exposure studies independently served as the basis for
derivation of PODs of 2.6 mg/kg/day based on hepatocellular toxicity in male rats (Kano et al..
2009; Kociba et al.. 1974). The selected chronic dermal POD of 1.6 mg/kg/day was therefore
considered protective of all observed systemic effects.
Page 201 of 616
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Cancer
EPA has high confidence in the cancer inhalation unit risk based on results of a high quality
study in male rats. Tumors observed in this study are consistent with tumor types reported in
drinking water studies in rats and mice. EPA evaluated inhalation cancer risk using the MS-
Combo model to integrate risk of all tumor types reported in this study. A sensitivity analysis
demonstrates that excluding liver tumors from this analysis does not substantially change overall
cancer risk estimates. This means that applying a threshold model based on alternate MOA
conclusions for liver tumors would not substantially alter overall inhalation cancer risk
conclusions.
EPA has medium-high confidence in the oral and dermal cancer slope factors. These cancer
slope factors are derived from tumors in female mice observed in a high quality drinking water
cancer bioassay. Because liver tumor incidence in female mice was high even at the lowest dose
tested, data were not readily amenable to EPA's standard modeling approaches. EPA therefore
modeled dose-response using a time-to-tumor analysis that incorporates individual animal data.
To avoid excess extrapolation, EPA applied an Extra Risk of 50% as the BMR.
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4 RISK CHARACTERIZATION
4.1 Environmental Risk
The purpose of the environmental risk characterization is to determine whether there are risks
above benchmarks to the aquatic environment from levels of 1,4-dioxane found in surface water
based on the fate properties, relatively high potential for release, and the availability of
environmental monitoring data and hazard data, and to describe any uncertainties or other
considerations relevant to the risk estimate. EPA estimated risks based on a qualitative
assessment of the physical-chemical properties and fate of 1,4-dioxane in the environment for
sediment and land-applied biosolids, and a quantitative comparison of hazards and exposures for
aquatic organisms. These analyses were conducted as part of problem formulation, and
reassessed based on SACC recommendations on the risk evaluation. The results of the analyses
are presented in Sections 2.3.1 and 4.1, Appendix E, and Appendix F.
The environmental exposure of 1,4-dioxane is summarized in Section 2.3 and Appendix E. As
previously stated, only the aquatic pathway was quantitatively evaluated. For this assessment, a
first-tier ecological aquatic exposure assessment was conducted using release estimates and
measured effluent concentrations from EPA's Toxics Release Inventory (TRI) and Discharge
Monitoring Report (DMR) Pollutant Loading Tool, respectively to predict surface water
concentrations near a discharge facility (see section 2.3.1). The first-tier approach uses
conservative assumptions and readily available data and models.
Summary of the Environmental Hazard of 1,4-Dioxane:
An environmental hazard assessment is summarized in Section 3.1 of this document. A total of
nine acceptable aquatic environmental hazard studies were identified for 1,4-dioxane. EPA's
evaluation of these studies was mostly high or medium during data quality evaluation (see Table
3-1. in Section 3.1 and "Systematic Review Supplemental File: Data Quality Evaluation of
Environmental Hazard Studies CASRN: 123-91-1"). The 1,4-Dioxane (123-91-1) Systematic
Review: Supplemental File for the TSCA Risk Evaluation Document provides details of the data
evaluations for each study, including scores for each metric and the overall study score.
Acceptable aquatic toxicity studies show that acute exposure to aquatic invertebrates are low.
The 48-hour LCso values range from 4,269 mg/L to 8,450 mg/L. In addition, acute exposure of
1,4-dioxane to fish is low. The 96-hour LCso values range from 1,236 mg/L to 13,000 mg/L.
The chronic toxicity of 1,4-dioxane to fish is low. The chronic values range from >145 mg/L to
565 mg/L, based on growth, weight hatchability, survival, and developmental endpoints.
In algae species, the toxicity of 1,4-dioxane is low with values ranging from 575 mg/L to 5,600
mg/L (with the more sensitive value of 575 mg/L used to represent algal species as a whole).
Summary of Concentrations of Concern Level of 1,4-Dioxane:
In section 3.1.2, EPA evaluated the environmental hazard data by applying a weight of scientific
evidence approach (WoE). After weighing the evidence and selecting the appropriate toxicity
values from the integrated data to calculate an acute and chronic COC, an assessment factor (AF)
Page 203 of 616
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is applied according to EPA methods (Suter, s ^ r \ 2013c, 2.012d). The application of
AFs provides a lower bound effect level that would likely encompass more sensitive species not
specifically represented by the available experimental data. These concentrations of concern for
acute and chronic ecotoxicity are summarized in Table 3-2. of this assessment.
For 1,4-dioxane, the algae endpoint was the most biological and environmental relevant species
for short-term exposure to the chemical. The short-term or acute COC for the algae endpoint is
57,500 |ig/L. The chronic COC was derived from a 32-day LOEC fish study of 14,500 |ig/L.
Given 1,4-dioxane's conditions of use under TSCA outlined in problem formulation (
2018d). EPA determined that environmental exposures are expected for aquatic species and risk
estimations are discussed in the following section.
4.1.1 Risk Estimation Approach of 1,4-Dioxane
To assess the environmental risk of 1,4-dioxane, EPA evaluated the environmental hazard
(Section 3.1) and environmental exposure data (Section 2.3). EPA used modeled exposure data
from Exposure and Fate Assessment Screening Tool (E-FAST) to characterize the exposure of
1,4-dioxane to aquatic species. Environmental risks are estimated by calculating a risk quotients
(RQ). Modeled data were used to represent surface water concentrations near facilities actively
releasing 1,4-dioxane to surface water. RQs were calculated using surface water concentrations
and the COCs calculated in the hazard section of this document (see Section 4.1.2). The RQ is
defined as:
RQ = Predicted Environmental Concentration / Effect Level or COC
For this assessment, RQ values that are equal to 1 (RQ = 1) indicates that environmental
exposures are the same as the COC. If the RQ is above 1 {i.e., RQ >1), the exposure is greater
than the COC. If the RQ is below 1 {i.e., R<1), the exposure is less than the COC. The COCs
for aquatic organisms shown in Table 3-2. and the environmental concentrations shown in
Section 2.3.1 and Appendix E, were used to calculate RQs (U.S. EPA. 1998).
EPA considered the biological relevance of the species that the COCs were based on when
integrating the COCs with surface water concentration data to produce RQs. For example,
certain biological factors affect the potential for adverse effects in aquatic organisms. Life-
history and the habitat of aquatic organisms influences the likelihood of exposure above the
hazard benchmark in an aquatic environment.
Frequency and duration of exposure also affect potential for adverse effects in aquatic
organisms, especially for chronic exposures.
4.1.2 Risk Estimation for the Aquatic Environment
To characterize potential environmental risk of 1,4-dioxane to aquatic organisms, EPA
calculated RQs based on modeled data from E-FAST for sites that had surface water discharges
of 1,4-dioxane according to Toxic Release Inventory (TRI) and Discharge Monitoring Report
(DMR) release information to model predicted surface water concentrations near discharging
Page 204 of 616
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facilities. EPA employed a first-tier aquatic exposure assessment. Based on the top ten DMR
discharging facilities in 2015 and 2016, predicted surface water concentrations, which were
based on the 7Q10 stream flow, ranged from 18.8 to 11,500 |ig/L for acute release scenarios and
0.095 to 5,762 |ig/L for chronic release scenarios. Based on the top TRI discharging facilities in
2014 and 2015 (including direct and indirect dischargers), predicted surface water concentrations
ranged from 1.26 to 9,734 |ig/L for acute release scenarios and 2.37E-08 to 4,879 |ig/L for
chronic release scenarios. The estimated surface water concentrations derived from chronic
release scenarios (i.e., those assuming 20 days or more of annual release days) were compared
against the chronic COC of 14,500 |ig/L using E-FAST's high-end Probabilistic Dilution Model
(PDM).
The environmental exposure assessment predicts conservative surface water concentrations for a
set of facilities that reports recent releases of 1,4-dioxane via DMR and/or TRI (see Appendix
E). The dataset of facilities were queried from the Enforcement and Compliance History Online
(ECHO) Water Pollutant Loading Tool. The DMR includes pollutant loading information for
more than 60,000 DMR reporting facilities (industrial and municipal point source dischargers)
regulated under the Clean Water Act. It contains wastewater monitoring and other facility data,
as reported on facility specific DMRs. TRI contains reporting information on facilities in specific
industry sectors which employ more than 10 full-time equivalent employees and manufacture,
process, or use more than 25,000 lbs. per year of a TRI-listed chemical.
The analysis was conducted using the top direct and indirect dischargers of 1,4-dioxane from
DMR and TRI covering the two most current and complete reporting years available at the time
of problem formulation (i.e., 2015 and 2016 for DMR and 2014 and 2015 for TRI). As many of
the facilities overlapped between the DMR and TRI sets, and between the assessment years, a
total of 39 unique facilities were assessed. Detailed information on the selected facilities are
summarized in Table E-2.
Page 205 of 616
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Estimation of Environmental Concentrations of 1,4-Dioxane in Surface Water:
The estimation of environmental concentrations of 1,4-dioxane in surface water underlying this
aquatic risk characterization is discussed in Section 2.3.1 and Appendix E. Tables E-3, E-4, and
E-5 presents the results of the first-tier aquatic exposure assessment. Based on the top ten DMR
discharging facilities in 2015 and 2016, predicted surface water concentrations, which were
based on the 7Q10 stream flow, ranging from 18.8 to 11,500 |ig/L for acute release scenarios and
0.095 to 5,762 |ig/L for chronic release scenarios. Based on the top TRI discharging facilities in
2014 and 2015 (including direct and indirect dischargers), predicted surface water concentrations
ranged from 1.26 to 9,734 |ig/L for acute release scenarios and 2.37E-08 to 4,879 |ig/L for
chronic release scenarios. The estimated surface water concentrations derived from chronic
release scenarios {i.e., those assuming 20 days or more of annual release days) were compared
against the chronic COC of 14,500 |ig/L using E-FAST's high-end Probabilistic Dilution Model
(PDM).
The environmental releases of 1,4-dioxane into the aquatic environment occur from industrial
use and are discharged directly to surface water or indirectly to wastewater treatment plants.
Table 4-1., Table 4-2., and Table 4-3. summarize the modeled or estimated exposure scenarios
and the RQ values from facilities that manufacture and release of 1,4-dioxane into surface water.
Only the minimum and maximum concentrations of 1,4-dioxane from these facilities are
summarized in the tables. All facilities from this analysis are provided in Appendix F of this
assessment.
Environmental Risk Estimation of 1,4-Dioxane from Industrial Releases into Surface Water from
DRM Reporting:
Table 4-1., Table 4-2., and Table 4-3. below, summarize the estimated surface water
concentrations of 1,4-dioxane. In this section, only the maximum predicted environmental
concentrations (PNEC) values of 1,4-dioxane in surface water were calculated to derive risk for
acute and chronic exposures for aquatic organisms. For acute exposure, algae represent the most
relevant and sensitive species that is susceptible to 1,4-dioxane exposures and fish for chronic
exposures.
Table 4-1. summarizes the estimated surface water concentrations of 1,4-dioxane due to
discharge from DMR facilities in 2015 and 2016. The parameters in this table are identical to the
values that are reported in Table El in Appendix E. The calculated RQ values in the tables are
included.
The data provided in the table was collected from 10 facilities in 2015 and 2016. Eastman Kodak
in New York reported the lowest concentrations of 1,4-dioxane that resulted in acute exposures
to algae and chronic exposure to fish in 2015 and 2016. DAK Americas, LLC in South Carolina,
reported the maximum concentrations of 1,4-dioxane that resulted in acute and chronic
exposures for the same years. Therefore, risk from acute exposure to the aquatic species from
releases to surface water were not identified because predicted concentrations did not exceed the
acute COC of 57,500 |ig/L. Risk from chronic exposures to aquatic species were not identified
despite the 20 days of exceedences (20/365 days/year during use) because the predicted
environmental concentration (surface water concentrations) of 5,762 |ig/L did not exceed the
chronic COC of 14,500 |ig/L (RQ<1).
Page 206 of 616
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Table 4-1. Environmental Risk Estimation of 1,4-Dioxane from Industrial Releases into
Surface Water from DMR Facilities in Year 2015 and 2016
\;inu\ I.iiiiiliiiii, ;iihI II)
uf .Uli\ c Ri-kiisi-r l';iiilil\
Il-TAST Inputs ;¦ lid Risulls
RQ
l)ii\s ill'
Rl'll'MM' ¦'
Ri-k'iisi- ¦'
(k^/(lil\ )
III"1 IVnviilik-
7QI0
CiiiHi'iilniliiiii
(ii«/l.»
l):i\s
l".\ivi-il;iiui-
ldii\s/\ r)
AI»;k-
(AuiU'I
(¦()(' =
57,500 ii»/l.
1 ish
(('hriinio
(¦()(' =
14,500
ii»/1.
Minimum Acute and Chronic Risk Quotient Values Reported from 10 DMR Facilities Reported in 2015
Eastman Kodak
NY0001643
(SIC 3861)
1
20
18.78
NA
6.90E-05
1.74E-05
20
1
0.95
0
6.90E-06
1.74E-06
250
0.1
0.0949
0
0
0
Maximum Acute and Chronic Risk Quotient Values Reported from 10 DMR Facilities in 2015
Dak Americas LLC
SC0026506
(SIC 2821)
10b
920
10,900"
NA
0.031731
0.0080017
20
460
5,428.91
0
0.0025379
0.00064
250
37
434.22
0
0.0002966
7.48E-05
Minimum Acute and Chronic Risk Quotient Values Reported from 10 DMR Facilities Reported in 2016
Eastman Kodak
NY0001643
(SIC 3861)
1
79
74.46
NA
0.001295
0.0051352
20
3.9
3.7
0
6.43478 E-05
0.0002552
250
0.3
0.28
0
4.86957 E-06
1.93103 E-
05
Maximum Acute and Chronic Risk Quotient Values Reported from 10 DMR Facilities in 2016
Dak Americas LLC
SC0026506
(SIC 2821)
10"
977
11,500
NA
0.2
0.7931034
20
488
5,761.65
0
0.1002026
0.3973552
250
39
461.36
0
0.0080237
0.0318179
a. Days of release (1, 20, or 250) are EPA assumptions that provide a range of potential surface water concentrations; days of release were
not reported in DMR. The release (kg/day) is based on the per day based on total annual loading (lbs/yr), as reported in DMR Pollutant
Loading Tool, and is divided by the assumed number of release days prior to modeling.
b. The Dak chemicals site acute scenario was re-run for a 10-day acute scenario based on input from EPA engineers related to the lowest
number of operating days assumed for facilities falling within this standard industrial category {i.e., 10 days per year). Therefore,
maximum surface water concentrations based on this site reflect an assumed 10 days per year of release instead of 1 day.
Environmental Risk Estimation of 1,4-Dioxane from Direct Industrial Releases into
Surface Water:
Table 4-2. summarizes the estimation of direct releases of 1,4-dioxane into surface water from
industrial use from facilities during 2014 and 2015. There were 10 facilities reporting per year.
The Dow Chemical Company in Louisiana reported the minimum acute and chronic
concentrations of 1,4-dioxane in 2015 and 2016. The minimum acute exposure concentrations
were 1.26 |ig/L (2014) and 1.36 |ig/L (2015). The minimum chronic exposure concentrations
were 0.004 |ig/L for 2014 and 2015.DAK Americas, LLC in South Carolina, reported the
maximum acute and chronic concentrations of 1,4-dioxane for the 2014 and 2015. The maximum
acute exposure concentrations were 9,734 |ig/L (2014) and 9,557 |ig/L (2015). The maximum
chronic exposure concentrations were 4,861 |ig/L (2014) and 4,779 |ig/L (2015). As previously
stated, the maximum estimated surface water concentrations that was reported for 2014 to 2015
for acute and chronic exposure to aquatic organisms will be used to derive the risks of 1,4-
dioxane in surface water.
Page 207 of 616
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Risk from acute exposures to the aquatic species from releases to surface water were not
identified because concentrations did not exceed the acute COC of 57,500 |ig/L. Risk from
chronic exposures to the environment were not identified despite the 20 days of exceedences
(20/365 days/year during use) because the predicted environmental concentration (surface water
concentrations) of 0.49 |ig/L does not exceed the chronic COC of 14,500 |ig/L (RQ<1).
Table 4-2. Environmental Risk Estimation of 1,4-Dioxane from Direct Industrial Releases
into Surface Water from TRI Facilities in Year 2014 and 2015
\;U1K\ I.iil'illiiill. ;ill(l II)
ul'Ai'liM' Ri-k-iisi-r l';nilil\
I'.-I'AS T lll|)llls ;iihI Ri-sulls
RQ
l)il>S III'
Ri-k'iisi- ¦'
Ri-k'usi- ¦'
(k^/il;i\)
10"' IVrivulik-
7QI0
CoiHi-nlniliiin
I ii»/I.I
l);i\s
l!\ivi-il;iiui-
(il;i\s/\ r)
.\l»iu-
( ()( =
57,500 ii»/l.
I'isli ('liniiik'
<¦()(¦ =
14,500 u«/l.
Minimum lane and Chronic Risk Quotient 1 allies ReportedJrom 10 TRI laci lilies in 2014a
The DOW Chemical Co.
Louisiana Operations
LA0003301 b
1
312
1.26
NA
2.19E-05
8.69E-05
20
16
0.0648
0
1.13E-06
4.47E-06
250
1
0.00405
0
7.04E-08
2.79E-07
Maximum Acute and Chronic Risk Quotient Values Reported from 10 TRI Facilities in 2014a
DAK Americas LLC
Cooper River Plant
SC0026506
10c
825
9,734
NA
1.69E-01
6.71E-01
20
412
4,861.36
0
8.45E-02
3.35E-01
250
33
389.4
0
6.77E-03
2.69E-02
Minimum Acute and Chronic Risk Quotient Values Reported from 10 TRI Facilities in 2015
The DOW Chemical Co.
Louisiana Operations
LA0003301 b
1
337
1.36
NA
2.37E-05
9.38E-05
20
17
0.0688
0
1.20E-06
4.74E-06
250
1
0.00405
0
7.04E-08
2.79E-07
Maximum Acute and Chronic Risk Quotient Values Reported from 10 TRI Facilities in 2015
DAK Americas LLC
Cooper River Plant
SC0026506
10c
810
9,557
NA
1.66E-01
6.59E-01
20
405
4778.76
0
8.31E-02
3.30E-01
250
32
377.58
0
6.57E-03
2.60E-02
a. Days of release (1, 20, or 250) are EPA assumptions that provide a range of potential surface water concentrations; days of release were
not reported to TRI. The release (kg/day) is based on the per day based on annual releases to surface water (lbs/yr), as reported to TRI,
and is divided by the assumed number of release days prior to modeling.
b. The NPDES provided in DMR's Pollutant Loading Tool for the facility THE DOW CHEMICAL CO - LOUISIANA OPERATIONS
(NPDES LA0116602) was not found in E-FAST 2014; however, a facility name and location search within E-FAST 2014 returned a
different NPDES (LA0003301) associated with this facility name and location, so it was applied for modeling.
c. ARKEMA Inc (KY0003603), Dow Chemical Co Freeport (TX0006483), Honeywell International (LA0000329), and Westlake Vinyls
Inc (KY0003484 ) facilities, which were included in the risk evaluation based on previous data extraction, did not have reported surface
water discharges in TRI explorer per 2015 release report and were therefore removed.
Environmental Risk Estimation of 1,4-Dioxane from Indirect Industrial Releases into
Surface Water from TRI Reporting:
Table 4-3. summarizes the estimation of indirect releases of 1,4-dioxane concentration into
surface water from industrial use from TRI facilities during 2014 and 2015. There were six
facilities in 2014 and 10 facilities in 2015. Evonik Materials Corp., in Wisconsin and Heritage
Thermal Services in Ohio, reported the minimum chronic environmental concentrations in 2014
and 2015, respectively. SUEZ WTS Solutions USA, Inc., in Indiana reported the maximum
chronic environmental concentrations in during 2014 and 2015. There were no acute
Page 208 of 616
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environmental concentrations reported for indirect surface water releases of 1,4-dioxane during
2014 and 2015.
The minimum chronic environmental concentration was 2.37 E-08 |ig/L and the maximum
environmental concentration was 3789 |ig/L. For this assessment, the maximum surface water
concentrations that was reported from 2014 to 2015 for acute and chronic exposures will be used
to derive the risks of 1,4-dioxane in surface water.
Risks from acute exposures to aquatic species were not identified because there were no indirect
releases of 1,4-dioxane to surface water. Risk from chronic exposures to the environment were
not identified despite the 250 days of exceedences (250/365 days/year during use) because the
predicted environmental concentration (surface water concentrations) of 3,789 |ig/L does not
exceed the chronic COC of 14,500 |ig/L (RQ<1).
Table 4-3. Environmental Risk Estimation of 1,4-Dioxane from Indirect Industrial Releases
into Surface Water from TRI Facilities in Year 2014 and 2015
ViiiK'. 1 .m;ilion, ;iihI IDnl'
Ri-Ii-simt l-'milin
NPDI.S I sid in IM AST
ins
POTW
l-'-l-WS'T lupins ;ind Ki-sulis
RQ
l);i\siil'
Ri'k'sisi'
Ri'k'iisi-
(k)
7QI0
Ciini'i'iilnili
llll
(ii»/l.)
l)il\S
I!\ivi-d;i mi-
ld;^ s/\ r)
COC= 14,500
ii»/l.
AI»;k-
<¦<)<¦ =
57,500
lisli
(lininii.
COC =
14,500
ii»/l.
Minimum Acute and Chronic Risk Quotient Values Reported from 6 TRI Facilities in 2014
Evonik Materials Corp.
WI0060453
Milton
Waterworks
250
0.001
0.00586
0
1.02E-07
4.04E-07
Maximum Acute and Chronic Risk Quotient Values Reported from 6 TRI Facilities in 2014a
SUEZ WTS Solutions USA
Inc.
Ind. POTW
(SIC 4952)b
Blue Lake
WWTP
250
30
3788.66
4
6.59E-02
2.61E-01
Minimum Acute and Chronic Risk Quotient Values Reported from 10 TRI Facilities in 2015
Heritage Thermal Services
OH0024970
East Liverpool
WWTP
250
2.39E-07
2.37E-08
0
4.12E-13
1.63E-12
Maximum Acute and Chronic Risk Quotient Values Reported from 10 TRI Facilities in 2015
SUEZ WTS Solutions USA
Inc.
Ind. POTW
(SIC 4952)b
Blue Lake
WWTP
250
27
3409.79
3
5.93E-02
2.35E-01
a. Days of release (250) are EPA assumptions that provide a range of potential surface water concentrations; days of release were not reported
to TRI. The release (kg/day) is based on the per day based on annual releases to surface water (lbs/yr), as reported to TRI, and is divided by
the assumed number of release days prior to modeling.
b. SIC for industrial POTWs was used for the facility because the facility was not found in E-FAST 2014.
4,1.3 Risk Estimation for the Sediment Environment
EPA did not quantitatively assess exposure of 1,4-dioxane to sediment-dwelling organisms
because the chemical is expected to remain in aqueous phases and has low potential to sorb to
sediment due to its water solubility (> 800 g/L) and organic matter partition coefficient (log Koc
= 0.4). Sediment monitoring data suggest that 1,4-dioxane is present in sediments, but because
1,4-dioxane has low partitioning to organic matter (log Koc = 0.4) it is likely that 1,4-dioxane
detected in sediment is in the pore water and rather than sorbed to the sediment solids. It is
expected that the concentrations of 1,4-dioxane in sediment pore water from environmental
releases is similar to the concentrations of the overlying water.
Page 209 of 616
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4.1,4 Risk Estimation for the Terrestrial Environment
EPA did not quantitatively assess exposure of 1,4-dioxane to terrestrial organisms through soil,
water or land-applied biosolids. Because activated sludge and biosolids (processed sludge) have
high water content and 1,4-dioxane has low potential to sorb to sludge solids, most of the 1,4-
dioxane in biosolids is expected to be in the aqueous phase of the biosolids as opposed to sorbed
to the solids. Further, 1,4-dioxane released from wastewater treatment via biosolids is expected
to be negligible compared to the 1,4-dioxane released with effluents: of the 1,4-dioxane in
influent wastewater, it is expected that < 2% will be removed with biosolids and associated water
and > 95% will be present in the effluent. Concentrations of 1,4-dioxane during biosolids
processing may decrease through volatilization to air during transport, processing (including
dewatering and digestion), handling, and application to soil (which may include spraying). 1,4-
Dioxane released to the terrestrial pathway via land-applied biosolids has low potential to sorb to
soil due to its low partitioning to organic matter (estimated log Koc = 0.4). 1,4-Dioxane is thus
expected to be mobile in soil and migrate to surface waters and groundwater or volatilize to air.
4.2 Human Health Risk
4,2,1 Human Health Risk Estimation Approach
1,4-Dioxane hazard and dose-response assessments were developed based on EPA, National
Research Council (NRC), and European Chemicals Agency (ECHA) risk assessment guidance.
Studies conducted via the inhalation and oral routes of exposure were evaluated in this
assessment. The dose-response assessment used for selection of PODs for non-cancer and cancer
endpoints and the benchmark dose analyses used in the risk characterization are described in
Section 3.2.6.
The use scenarios, populations of interest and toxicological endpoints that were selected for
determining potential risks from acute and chronic exposures are presented in Table 4-4..
Table 4-4. Summary of Parameters for Risk Characterization
Populations and
To\icolo<>ical Approach
Occupational Kxposure Scenarios lor 1,4-l)io\anc I ses at
Industrial or Commercial l-'acililics (see Section (.i h)
Population of Interest and
Exposure Scenario:
Users:
Acute- Healthv female and male adult workers (>16 vears old) exposed
to 1,4-dioxane for a single 8-hour exposure
Chronic- Healthv female and male adult workers (>16 vears old)
exposed to 1,4-dioxane for the entire 8-hour workday for 260 days per
year for 40 working years
Occupational Non-User:
Acute or Chronic- Healthv female and male adult workers (>16 vears
old) exposed to 1,4-dioxane indirectly by being in the same work area
of the building
Page 210 of 616
-------
Populations and
Toxicological Approach
Occupational Kxposure Scenarios lor 1,4-l)io\ane I ses at
Industrial or Commercial l-'acililics (see Section (i
Health Effects of Concern,
Concentration and Time
Duration
Acute/Short-term PODs:
Short-term inhalation HEC is 78.7 ppm (284 mg/m3)
Based on liver toxicity following short-term inhalation exposure in rats;
2-Week duration of study is relevant to typical short-term worker
exposures
Short-term dermal HED is 35.4 mg/kg-d
Extrapolated from short-term inhalation HEC based on systemic liver
toxicity
Short-term oral HED is 35.4 mg/kg-d
Extrapolated from short-term inhalation HEC based on systemic liver
toxicity
Chronic Non-Cancer PODs:
Inhalation 8-hour HEC: 12.8 mg/m3 (olfactory epithelium effects {i.e..
metaplasia and atrophy) from Table 3-14.)
Dermal 8-hour HED: 1.6 mg/kg-d
Extrapolated from inhalation POD based on olfactory epithelium effects
attributed to systemic delivery
Health Effects of Concern,
Concentration and Time
Duration (cont.)
Cancer Health Effects.
Inhalation Unit Risk (from Table 3-10.): 1.0E-06 (fig/m3)"1
Based on consistent results of MS-Combo models for combined tumor
risk in male rats including livertumors (1.18E-6 ((ig/m3)1) and
excluding livertumors (1.0E-6 ((ig/m3)"1)
Dermal cancer slope factor3 (from Table 3-13.): 1.2E-01 (mg/kg-d)"1
Extrapolated from an oral cancer slope factor based on female mouse
liver tumors in a drinking water study; An alternate CSF of 1.2E-02 was
extrapolated from inhalation studies.
Non-Cancer Margin of
Exposure (MOE)
Uncertainty Factors (UF)b
Acute/Short-term Inhalation Benchmark MOE = 300
UFa = 3; UFh = 10; UFL= 10
Acute/Short-term Dermal Benchmark MOE = 300
UFA = 3; UFH = 10; UFL= 10
Acute/Short-term Oral Benchmark MOE = 300
UFA = 3; UFH = 10; UFL= 10
Chronic Inhalation Benchmark MOE = 30
UFa = 3; UFh = 10
Chronic Dermal Benchmark MOE = 30
UFa = 3; UFh = 10
Page 211 of 616
-------
Populations and
To\icolo<>ical Approach
Occupational Kxposure Scenarios lor 1,4-l)io\anc I ses at
Industrial or Commercial l-'acililics (see Section (i
Cancer Benchmark0
Inhalation and Dermal.
1 x 10"4 excess cancer risk for worker populations
1 x 10"6 excess cancer risk for consumers
a A route-to-route extrapolation was performed on the oral and inhalation cancer slope factors as described above in
Section 3.2.6.2.
b UFA=interspecies uncertainty/variability; UFH=intraspecies uncertainty/variability; UFL=LOAEL-to-NOAEL
uncertainty; See Section 3.2.6 for more detailed rationale for selection of uncertainty factors applied to each POD
and Section 5.1.1.1 for additional explanation of the benchmark MOE approach.
0 See Section 5.1.1.2 for rationale for selection of the cancer benchmark
EPA used a Margin of Exposure (MOE) approach to identify potential non-cancer risks. The
MOE is the ratio of the non-cancer POD divided by a human exposure dose.
The acute and chronic MOE (MOEaCute or MOEchronic) for non-cancer inhalation and dermal risk
were calculated using Equation 4.2.1-1.
Equation 4.2.1-1 Equation to Calculate Margin of Exposure for Non-Cancer Risks
Following Acute or Chronic Exposures
Non — cancer Hazard value (POD)
MOEacuteorchronlc = Human Exposure
Where:
MOE = Margin of exposure (unitless)
Hazard value (POD) = HEC (mg/m3) or HED (mg/kg-d)
Human Exposure = Exposure estimate (in mg/m3 or mg/kg-d) from
occupational exposure assessment
MOEs allow for the presentation of a range of risk estimates. EPA used MOEs15 to estimate non-
cancer risks from acute and chronic exposures based on the following: the HECs/HEDs
identified for each each health effects domain; the endpoint/study-specific UFs applied to the
HECs/HEDs per the review of the EPA Reference Dose and Reference Concentration Processes
2002); and the exposure estimates calculated for 1,4-dioxane conditions under the
conditions of use (see Section 2).
The Acute Exposure Concentration (AEC) was used to estimate acute/short-term inhalation risks,
whereas the Average Daily Concentration/Dose (ADC)/D) was used to estimate chronic non-
cancer inhalation/dermal. For occupational exposure calculations, the 8-hour TWA was used to
calculate MOEs for risk estimates for acute and chronic exposures. Evaluation of non-cancer
15 Margin of Exposure (MOE) = (Non-cancer hazard value, POD) (Human Exposure). Equation 4.2.1-1. The
benchmark MOE is used to interpret the MOEs and consists of the total UF shown in Table 4-4.
Page 212 of 616
-------
risks from acute consumer and general population exposures were also based on an 8-hour
exposure.
For acute and chronic non-cancer effects, potential risks for adverse effects were based on liver
toxicity and effects in the olfactory epithelium. Risk estimates for effects in the liver and
olfactory epithelium were calculated from studies that were rated under the data quality criteria
as "Medium" or "High." The liver and olfactory epithelium endpoints used as the basis from
which to estimate risks were chosen based on the quality of the key studies, the confidence in the
dose-response models, the consistency of effects across studies, species and exposure routes, the
relevance of effects for human health, and the coherence and biological plausibility of the effects
observed, as discussed in Section 3.2.7.
EPA interpreted the MOE risk estimates for each use scenario in reference to benchmark MOEs.
Benchmark MOEs are the total UF for each non-cancer POD. The MOE estimate was interpreted
as a human health risk 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 was equal to or exceeded the benchmark MOE. Typically, the
larger the MOE, the more unlikely it is that a non-cancer adverse effect would occur.
Extra cancer risks for repeated exposures to 1,4-dioxane were estimated using Equation 4.2.1-2.
Estimates of extra cancer risks are interpreted as the incremental probability of an individual
developing cancer over a lifetime following exposure to 1,4-dioxane (i.e., incremental or extra
individual lifetime cancer risk).
Equation 4.2.1-2 Equation to Calculate Cancer Risks
Inhalation Cancer Risk = Human Exposure x IUR
or
Dermal Cancer Risk = Human Exposure x CSF
Where:
Risk = Extra cancer risk (unitless)
Human exposure = Occupational exposure estimate (LADC in |ig/m?)
IUR = Inhalation unit risk (1 x 10"() per |ig/m3)
CSF = Cancer slope factor (1.2 x 10"' per mg/kg-d)
The range of IURs considered in Table 4-4. were 1.18 x 10"6 to 1.0 x 10"6 (|ig/m3)"'. Therefore, a
rounded value of 1 x 10"6 per |ig/m3 was used for calculation of inhalation cancer risks. The
range of CSFs considered in Table 4-4. were 1.2 x 10"2 to 1.2 x 10"1 (mg/kg-d)"1 for the different
extrapolations from inhalation or oral studies and for different combinations of tumor types. The
CSF 1.2 x 10-1 (mg/kg-d)"1 was used for calculation of dermal cancer risks.
To determine the level of personal protection needed by workers to reduce the high-end
exposures to below the level of concern, EPA evaluated the impact of respirator and glove use on
risks from inhalation and dermal exposure. Typical APF values of 1, 10 and 50 and glove PF
values of 1, 5, 10, and 20 were compared to the calculated MOEs and benchmark MOE to
Page 213 of 616
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determine the level of APF or glove PF required to reduce exposure so that risk is below the
benchmark MOE.
4,2.2 Risk Estimate for Exposures for Occupational Use of 1,4-Dioxane
4,2,2.1 Occupational Risk Estimation for Effects of Acute/Short-term
Inhalation Exposures
1,4-Dioxane exposure is associated with acute effects. Based on the weight of the scientific
evidence analysis of the reasonably available toxicity studies from humans and animals, the key
acute/short-term exposure effect is liver toxicity {i.e., single cell necrosis).
The study that serves as the basis for acute/short-term health concerns (Mattie et al..! ) is of
high data quality. Risk estimates for acute inhalation exposures to 1,4-dioxane were determined
for the occupational exposure scenarios. Based on the POD reported by Mattie et al. (2012) {i.e.,
LOAEC = 378 mg/m3), EPA calculated an acute HEC of 283.5 mg/m3 and an acute inhalation
benchmark MOE of 300.
Comparing the 8-hour acute exposures (AEC concentrations) for the use scenarios to the
acute/short-term HEC for liver effects gives the calculated MOEs shown in Table 4-5. for workers
and Table 4-6. for ONUs.
Page 214 of 616
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Table 4-5. Acute/Short-term Inhalation Exposure Risk to Workers; Benchmark MOE = 300
Kxposure Scenario
lull Shift
( onI Till
Tendency
Shi)AIX
/in*)
lli»h-
Kml
C
-------
Table 4-6. Acute/Short-term Inhalation Exposure Risk to Occupational Non-Users: Non-Cancer; Benchmark MOE = 300
Kxposnrc Scenario
ADC (m
Ceiilnil Tendency
.i/nr4)
1 li<>li-end
Citlcuhtl
( cnlnil Tendency
ed MOi:
1 li»h-ciul
Manufacturing
-
-
-
-
Import/Repackaging
-
-
-
-
Industrial Use
-
-
-
-
Open System Functional Fluids
0.00015
0.00025
1,903,645
1,128,664
Spray Application
0.0019s
151,467
Lab Chemicals
-
-
-
-
Film Cementc
0.10a
2,726
Use of Printing Inks (3D)
-
-
-
-
Disposal
-
-
-
-
a EPA cannot separately determine a central tendency and high-end estimate.
- EPA does not have ONU-specific estimates for these exposure scenarios and relies on central tendency worker exposure scenarios without PPE
to predict risk to ONUs
4,2.2.2 Occupational Risk Estimation for Non-Cancer Effects Following Chronic Inhalation Exposures
Chronic non-cancer risk estimates for inhalation exposures to 1,4-dioxane were derived for occupational scenarios using estimated
inhalation average daily concentrations (ADCs). The central and high-end ADC exposure estimates were compared to the inhalation
hazard POD of 12.8 mg/m3 using a benchmark MOE of 30. Table 4-7. and Table 4-8. show the exposure estimates used for workers
and ONUs and the resulting MOEs. The definition of high-end exposures varies by exposure scenario as to the percentile of the
distribution. EPA calculated MOEs for workers with and without respirators.
Page 216 of 616
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Table 4-7. Chronic Inhalation Exposure Risk to Workers: Non-Cancer; benchmark MQE=30
Kxposnre Scenario
ai;
(m»/
(Clll Till
Tendency
K
m()
1 li»h-ciul
C'iilciihi
(110 ITS
C on I r;il
Tendency
ed MOi:
)ir;ilor)'
High-end
C'iilciiliile
(AIM
Con I nil
Tendency
d MOi:
10)'
1 li»h-ciul
Ciilciihi
(AP
Cent nil
Tendency
led MOI!
T 50)'
1 ligli-end
Manufacturing
0.40
7.44
32.1
1.7
321
17
1,604
86.1
Import/Repackaging
(Bottle)
0.46
3.39
27.6
3.8
276
38
1,381
189
Import/Repackaging
(Drum)
0.46
3.39
27.6
3.8
276
38
1,381
189
Industrial Use
4.8
19.2C
2.66
0.67
26.6
6.7
133.1
33.3
Open System Functional
Fluids
0.0010
0.0038
12,491
3,511
124,906
35,111
624,528
175,555
Spray Application
0.0094
0.011
1,368
1,126
11,264
13,684
68,421
56,318
Lab Chemicals
0.11
5.53d
121
2.32
1,210
23.15
6,051
116
Film Cement
1.46
2.70e
8.75
4.74
87.5
47.4
437
237
Use of Printing Inks
(3D)
0.093b
137
1,370
6,848
Dry Film Lubricant
0.1
0.35
127
37.1
1,270
371
6,349
1,855
Disposal
1.80
6.39
7.1
2.0
71
20
356
100
Bold: Calculated MOEs were below the benchmark MOE.
a MOEs were calculated with Equation 5-1 briefly that is: "Central Tendency ADC (|ig/m3)" or "High-end ADC (|ig/m3)" POD (|ig/m3)
b EPA cannot determine the statistical representativeness of the values given the small sample size.
0 The risk assessment did not provide details about how these values were calculated, therefore, it is unclear what percentile is represented when an exposure is
described as "reasonable worst case."
d For this scenario the high-end was the 90th percentile.
e For this scenario the high-end was the maximum value.
Page 217 of 616
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f MOEs with respirator use were calculated by multiplying the MOE without a respirator by the respirator APF
Table 4-8. Chronic Inhalation Exposure Risk to Occupational Non-Users: Non-Cancer: Benchmark MOE = 30
Kxposnre Scenario
ADC (m
Ceiilnil Tendency
^/nr()
1 li»h-cncl
Ciilcnliil
( cnlr;il Tendency
ed MOi:
1 li»h-eiul
Manufacturing
-
-
-
-
Import/Repackaging
-
-
-
-
Industrial Use
-
-
-
-
Open System Functional Fluids
0.00014
0.00024
89,230
52,904
Spray Application
0.00183
7,100
Lab Chemicals
-
-
-
-
Film Cementc
0.10a
128
Use of Printing Inks (3D)
-
-
-
-
Disposal
-
-
-
-
a EPA cannot separately determine a central tendency and high-end estimate.
- EPA does not have ONU-specific estimates for these exposure scenarios and relies on central tendency worker exposure scenarios without PPE to predict risk
to ONUs
4.2.2.3 Occupational Risk Estimation for Cancer Effects Following Chronic Inhalation Exposures
Chronic cancer risk estimates for inhalation exposures to 1,4-dioxane were derived for occupational scenarios using estimated
inhalation lifetime average dose concentrations (LADC). Cancer risk was calculated for the central and high-end LADC exposure
estimates. Table 4-9. shows the calculated cancer risks for central and high-end exposures. The definition of high-end percentile of the
exposure distribution varies by exposure scenario. EPA calculated cancer risk for workers with and without respirators.
Page 218 of 616
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Table 4-9. Inhalation Exposure Risk Estimates to Workers: Cancer; Benchmark Risk = 1 x 10 4
Kxposurc Scenario
I.A
(MS
Con (ml
Tendency
DC
nr()
1 li»h-cnil
C;in
(no re
Ccn(r;il
Tendency
cor Risk
spirnlor)'
1 li»h-ciul
C.incei
(AIM
Ceil ir ill
Tendency
Risk
IO)h
1 li^h-end
Ciiiict
(Al»
Cenlral
Tendency
>r Risk
¦" 50)"'
1 li»h-encl
\ hinii laclii ii ny
I5l>
38 14
I.6K-04
I.8K-04
l.«)|-:-03
3.8K-03
1 Ji:-03
4).*)i-:-o3'1
i m:-d5
3.5
i/)i:-(M
3 5F-<)(i
2 fiF-i)5
2.0l-:-(M
1 lidlISlI'Kll I sc
\M \ 1
3 SI:-
-------
Table 4-10. Inhalation Exposures to Occupational Non-Users: Cancer; Benchmark Risk = 1 x 10 4
Risk Scenario
OM population
Ccnlnil Tendency
I.AIK
Iligh-Knil LADC
Cenlnd Tendency
Ciincer Risk-1
1 li»h-Liul Ciincer
Risk'
Manufacturing
-
-
-
-
-
Import/Repackaging
-
-
-
-
-
Industrial Use
-
-
-
-
-
Open System
Functional Fluids
178,000
0.06
0.12
5.7E-08
1.2E-07
Spray Foam
Application
15627
0.72
0.92
7.2E-07
9.2E-07
Lab Chemicals
-
-
-
-
-
Film Cement
10
40
50
3.98E-05
5.14E-05
Use of Printing Inks
(3D)
-
-
-
-
-
Dry Film Lubricant
-
-
-
-
-
Disposal
-
-
-
-
-
11 Cancer risk was calculated as follows: "Central Tendency LADC (|ig/m3)" or "High-end LADC (|ig/m3)" x IUR (i.e., 1 x 10"6 per |ig/m')
- EPA does not have ONU-specific estimates for these exposure scenarios and relies on worker exposure scenarios without PPE to predict risk to ONUs.
Page 220 of 616
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4.2,2.4 Occupational Risk Estimation for Non-Cancer Effects
Following Acute/Short-term Dermal Exposures
1,4-Dioxane exposure is associated with acute effects. Based on the weight of the scientific
evidence analysis of the reasonably available toxicity studies from humans and animals, the key
acute/short-term exposure effect is liver toxicity {i.e., single cell necrosis).
The study that serves as the basis for acute/short-term health concerns from dermal exposures is
an inhalation study (Mattie et at.. 2012). EPA extrapolated from the inhalation POD reported by
Mattie etal. (2012.) {i.e., LOAEC = 378 mg/m3), to calculate an acute dermal HED of 35.4
mg/kg/day and an acute dermal benchmark MOE of 300.
EPA calculated risk estimates for acute dermal exposures to 1,4-dioxane by comparing the 8-hour
acute retained dose (ARD) for each exposure scenario to the acute/short-term HED for liver
effects. The resulting MOEs are shown in Table 4-11..
Wearing gloves could have important consequences for dermal uptake. EPA calculated MOEs for
each worker exposure scenario with and without glove use by applying glove protection factors of
1, 5, 10, and 20. Glove protection factors are based on the ratio of uptake through the unprotected
skin to the corresponding uptake through the hands when protective gloves are worn. The
protection factor provided by gloves is unlikely to be constant for a glove type but could be
influenced by the work situation and the duration of the exposure (see Table 2-32. for a summary
of the conditions corresponding to each glove protection factor).
Table 4-11. Dermal Exposure Risk Estimates to Workers for Acute/Short-term Exposures
Non-Cancer; Liver r
"oxicity; Bene
imark MOE = 300
Kxposuiv Scenario
Con (nil
TcihIsiiicy/
1 li'Ji-Kntl
No (ilo\os
I'rolecliM'
(11()\ OS
I'roloclno
(;io\cs,
Commorcinl
I sers
I'roleclhe
(11()\ OS.
1 ikIii si riiil
I sers
-------
Spray Foam
Application
CT
4,415
22,075
44,151
88,301
HE
1,472
7,358
14,717
29,434
Film Cement
CT
8.8
44.2
88.3
177
HE
2.9
14.8
29.4
58.9
Dry Film Lubricant
CT
4.8
24.1
48.3
96.6
HE
1.6
8.0
16.1
32.2
Disposal
CT
4.8
24.1
48.3
96.6
HE
1.6
8.0
16.1
32.2
Bold: The MOE is below the benchmark MOE
4.2.2.5 Occupational Risk Estimation for Non-Cancer Effects
Following Chronic Dermal Exposures
The dermal 8-hour HED is extrapolated from the inhalation HEC based on effects in the
olfactory epithelium attributed to systemic delivery following inhalation exposure. The POD of
12.8 mg/m3 for inhalation exposures was extrapolated to estimate a dermally absorbed dose of
1.6 mg/kg-d by adjusting for the differences between the inhalation and dermal routes. Table
4-12. outlines the non-cancer dermal risk estimates to workers with and without gloves.
Table 4-12. Dermal Exposure Risk Estimates to Workers: Non-Cancer; Liver Toxicity
Benchmark MOE = 30
Kxposure Scenario
C'en (ml
Tendency/
lli»h-l-:nd
No (iloxcs
I'roleclhe
(Jo\cs
I'roledhe
(Jo\cs,
Coninierciiil
I sers
I'roleclhe
(Jo\cs,
1 nd ii si riiil
I sers
(PI- 1)
(PI- 5)
(PI' Hi)
d>r :<))
\ klllll 1 LICllI II IliJ
CT
0.23
I.I
2.3
4.5
HE
0.08
0.38
0.76
1.5
Import/Repackaging
(Bottle)
CT
18.92
ni
IXW |w
37S »
HE
0.59
2.96
5.9|
11.82
Import/Repackaging
(Drum)
CT
<).46
47 3()
ni
IXW |w
HE
0.33
1.63
3.26
6.52
Industrial Use
CT
0.23
I.I
2.3
4.5
HE
0.08
0.38
0.76
1.5
Functional Fluids
(Open System)
CT
227
1,135
2,270
4,451
HE
75.7
378
757
1,514
Lab Chemical Use
CT
0.21
1.0
2.1
4.2
HE
0.07
0.35
0.69
1.4
Use of Printing Inks
(3D)
CT
0.21
1.0
2.1
4.2
HE
0.07
0.35
0.69
1.4
Spray Foam
Application
CT
208
1,038
2,075
4,151
HE
69.2
346
692
1,384
Film Cement
CT
0.42
2.1
4.2
8.3
Page 222 of 616
-------
Kxposure Scenario
Ceil (ml
Tendency/
Mi»h-l-:nd
No (iloxcs
I'roleclhe
(¦Iom»s
I'roleclhe
(Jo\cs,
Commercial
I sers
I'roleclhe
Cloxcs,
Indus! rial
I sers
(PI- 1)
(IT 5)
r :o)
mi:
(1.14
0.6')
1.4
2.8
Dr\ him 1 .uhlicaiil
(T
1.0
5.1
10.1
20.3
mi:
0.34
1.7
3.4
6.8
Disposal
(T
0.23
I.I
2.3
4.5
HE
0.08
0.38
0.76
1.5
Bold: The MOE is below the benchmark MOE
4.2,2.6 Occupational Risk Estimation for Cancer Effects Following
Dermal Exposures
To estimate cancer risks from dermal exposure, EPA considered the exposure in all use scenarios
for dermal exposure. For each of these scenarios, exposure under conditions with varying levels
of PPE were used. Dermal exposure is assumed to decrease after volatilization of 1,4-dioxane
from the skin. The degree of volatilization was predicted to be 22% based on the physical
chemical properties of 1,4-dioxane. EPA also accounted for dermal absorption as described
above in the risk estimates for chronic non-cancer effects following dermal exposures. The
results of the cancer risk analysis for dermal exposures is presented in Table 4-13..
Table 4-13. Dermal Exposure Risk Estimates to Workers: Cancer; Benchmark Cancer
Risk = 1 x 10 4
Kxposure Scenario
Central
Tendency/
1 li»h-Kiul
No (ilmcs
I'roleclhe
(Jo\es
l'rolecli\e
(;io\es.
Coninierciid
I sers
l'rolecli\e
Cloxes,
Induslriid
I sers
r i)
r 5)
(Pl; Hi)
(Pi; :o)
Manulacluriiiij
(I
0.34
0.07
0.03
0.02
mi:
1.33
0.27
0.13
0.07
1 in purl RqxicLujiiiiJ
(IJollk")
(I
4.I3K-3
8.27K-4
4.I3K-4
2.071:-4
mi:
0.17
0.03
0.02
0.01
1 ill purl RqxicLujiiiiJ
(Drum)
(T
8.27K-3
1.65K-3
8.27K-4
4.I3K-4
mi:
0.31
0.06
0.03
0.02
Induslruil I sc
(I
0.34
0.07
0.03
0.02
mi:
1.33
0.27
0.13
0.07
Functional Fluids
(Open System)
CT
3.4E-4
6.9E-5
3.4E-5
1.7E-5
HE
1.3E-3
2.7E-4
1.3E-4
6.7E-5
Lab Chemical Use
CT
0.38
0.08
0.04
0.02
HE
1.5
0.29
0.15
0.07
Use of Printing Inks
(3D)
CT
0.38
0.08
0.04
0.02
HE
1.5
0.29
0.15
0.07
CT
3.8E-4
7.5E-5
3.8E-5
1.9E-5
Page 223 of 616
-------
Exposure Scenario
S|im\ l-'mim
Appl iclUioii
Central
Tendency/
1 li'Ji-Knd
No (Jlo\cs
Protectee
(Jo\es
Protect i\e
(;io\cs.
Commercial
I sers
Protect i\e
(Joxes.
Indnstriiil
I sers
r i)
/m3)
moi:
Surface Cleaner
High-Intensity
User
User
5.0E-03
5.7E+04
Bystander
9.5E-04
3.0E+05
Antifreeze
High-Intensity
User
User
1.6E-02
1.8E+04
Bystander
4.0E-03
7.2E+04
Dish Soap
High-Intensity
User
User
3.0E-02
9.3E+03
Bystander
5.4E-03
5.2E+04
Dishwasher
Detergent
High-Intensity
User
User
6.9E-04
4.1E+05
Bystander
1.2E-04
2.3E+06
Laundry Detergent
User
1.5E-03
1.9E+05
Page 224 of 616
-------
High-Intensity
User
Bystander
2.7E-04
1.1E+06
Paint and Floor
Lacquer
High-Intensity
User
User
2.1E-02
1.4E+04
Bystander
7.5E-03
3.8E+04
Textile Dye
High-Intensity
User
User
8.5E-04
3.3E+05
Bystander
1.5E-04
1.9E+06
Spray Polyurethane
Foam
Basement
User
8.9E-01
317
Bystander
7.4E-01
384
Attic
User
1.9E-01
1.5E+03
Bystander
7.1E-02
4.0E+03
Garage
User
1.6E-01
1.7E+03
Bystander
1.2E-01
2.5E+03
For consumer products that are used regularly, EPA also evaluated chronic cancer risks. EPA
evaluated cancer risk from chronic inhalation exposure using an inhalation unit risk of 1.0E-06
((ig/m3)"1. Calculated MOE values for chronic exposure above the cancer benchmark for
consumers (1 x 10"6) would indicate a consumer safety concern.
Table 4-15. Risks from Chronic Inhalation Exposure to 1,4-Dioxane in Consumer
Products. Benchmark Cancer Risk = 1 x 10"6
Consumer
Condition of I so
SiTinirio
Lifetime A\ersi«»e Dsiilv
C Oil coiil in lion
(I.ADC. in»/nr()
Csinccr Risk
Surface Cleaner
High-Intensity User
1.0E-03
1.0E-06
Moderate-Intensity
User
5.6E-04
5.6E-07
Dish Soap
High-Intensity User
7.1E-04
7.1E-07
Moderate-Intensity
User
3.3E-04
3.3E-07
Dishwasher
Detergent
High-Intensity User
7.1E-05
7.1E-08
Moderate-Intensity
User
2.9E-05
2.9E-08
Laundry Detergent
High-Intensity User
1.3E-04
1.3E-07
Moderate-Intensity
User
7.1E-05
7.1E-08
Bold: Cancer risk exceeds the benchmark of 1 x 10~6.
Page 225 of 616
-------
4,2.3,2 Risk Estimation for Dermal Exposure to 1,4-Dioxane in
Consumer Products
Risks from acute and chronic dermal exposure to 1,4-dioxane in consumer products are shown in
Table 4-16., and Table 4-17., respectively.
EPA evaluated risk from acute dermal exposure using a POD of 35.4 mg/kg/day based on liver
toxicity reported in Mattie et al. (2012). Calculated MOE values below the benchmark MOE of
300 would indicate a risk concern for acute exposures.
Table 4-16. Risks from Acute Dermal Exposure to 1,4-Dioxane in Consumer Products;
Benchmark MOE=300
Consumer
Condition of I so
Scenario
Receptor
Acute Dose Ksile
moi:
Surface Cleaner
High-Intensity User
Adult (>21 years)
7.7E-06
4.6E+06
Child (16-20 years)
7.2E-06
4.9E+06
Child (11-15 years)
7.9E-06
4.5E+06
Antifreeze
High-Intensity User
Adult (>21 years)
5.1E-04
6.9E+04
Child (16-20 years)
4.8E-04
7.4E+04
Child (11-15 years)
5.2E-04
6.8E+04
Dish Soap
High-Intensity User
Adult (>21 years)
3.1E-06
1.2E+07
Child (16-20 years)
2.9E-06
1.2E+07
Child (11-15 years)
3.1E-06
1.1E+07
Dishwasher
Detergent
High-Intensity User
Adult (>21 years)
3.2E-06
1.1E+07
Child (16-20 years)
3.0E-06
1.2E+07
Child (11-15 years)
3.3E-06
1.1E+07
Laundry Detergent
High-Intensity User
Adult (>21 years)
4.8E-07
7.4E+07
Child (16-20 years)
4.5E-07
7.9E+07
Child (11-15 years)
4.9E-07
7.2E+07
Paint and Floor
Lacquer
High-Intensity User
Adult (>21 years)
2.0E-03
1.8E+04
Child (16-20 years)
1.9E-03
1.9E+04
Child (11-15 years)
2.0E-03
1.7E+04
Textile Dye
High-Intensity User
Adult (>21 years)
6.4E-07
5.6E+07
Child (16-20 years)
6.0E-07
5.9E+07
Child (11-15 years)
6.5E-07
5.4E+07
Spray Polyurethane
Foam
Basement, Attic or
Garage
Adult (>21 years)
1.0E-03
3.5E+04
Child (16-20 years)
9.7E-04
3.7E+04
Page 226 of 616
-------
Child (11-15 years)
1.1E-03
3.3E+04
For consumer products that are used regularly, EPA also evaluated chronic cancer risks. EPA
evaluated cancer risk from chronic inhalation exposure using a dermal cancer slope factor of
0.12 (mg/kg-d)1. Calculated MOE values for chronic exposure that are above the cancer
benchmark for consumers (1 x 10"6) would indicate a risk concern.
Table 4-17. Risks from Chronic Dermal Exposure to 1,4-Dioxane in Consumer Products.
Benchmark Cancer Risk = 1 x 10"6
C onsumer C ondition
or I so
Scenario
Lifetime .\\crage
Daily Dose
(nig/kg/day)
Cancer Risk (Cancer
Slope Factor = O.I2)
Surface Cleaner
High-Intensity User
5.6E-06
6.7E-07
Moderate-Intensity User
2.3E-06
2.8E-07
Dish Soap
High-Intensity User
2.6E-07
3.2E-08
Moderate-Intensity User
1.1E-07
1.3E-08
Dishwasher Detergent
High-Intensity User
1.2E-06
1.4E-07
Moderate-Intensity User
9.9E-07
1.2E-07
Laundry Detergent
High-Intensity User
1.5E-07
1.8E-08
Moderate-Intensity User
6.2E-08
7.4E-09
4.2,4 Risk Estimates for Exposures from Incidental Exposure to 1,4-Dioxane in
Surface Water
The following sections present the risk estimates for acute dermal and inhalation exposures that
may occur from incidental contact with surface water. Calculated MOE values below the
benchmark MOE (300) would indicate a potential safety concern.
Risks from acute oral exposure through incidental ingestion of surface water are shown in Table
4-18. and risks from acute dermal exposure through swimming in surface water are shown in
Table 4-19..
Table 4-18. Risk from Acute Oral Exposure Through Incidental Ingestion of Water;
Benchmark MOE = 300
oi:s
Facility/Data
Source
Surface Water
Concentration
(MS/'-)
Drinking Water
Acute Dose.
Child 11-15
(m»/k»/day);i
moi:
(Oral POD 35.4
m»/k»/day)
Site-Specific Modeling - Estimated Surface Water Concentrations
Manufacturing
BASF
9.7E+01
5.2E-04
6.8E+04
Industrial Uses
Ineos Oxide
2.2E+02
1.2E-03
3.0E+04
Industrial Uses
Microdyn-Nadir
Corp
7.2E+00
3.9E-05
9.1E+05
Page 227 of 616
-------
oi:s
Source
Surface Water
Concentration
(Jili/U
Drinking Water
Acute Dose,
C liikl 11-15
moi:
(Oral POD 35.4
m»/k»/ihiv)
Industrial Uses
St Charles
Operations
(Taft/Star) Union
Carbide Corp
1.1E-02
5.9E-08
6.0E+08
Industrial Uses
SUEZ Water
Technologies &
Solutions
5.1E+03
2.7E-02
1.3E+03
Industrial Uses
The Dow Chemical
Co - Louisiana
Operations
8.7E-03
4.7E-08
7.6E+08
Industrial Uses
Union Carbide Corp
Institute Facility
3.3E+00
1.8E-05
2.0E+06
Industrial Uses
Union Carbide Corp
Seadrift Plant
2.4E+01
1.3E-04
2.7E+05
Industrial Uses
BASF Corp
3.4E-01
1.8E-06
2.0E+07
Industrial Uses
Cherokee
Pharmaceuticals
LLC
2.6E-03
1.4E-08
2.5E+09
Industrial Uses
DAK Americas
LLC
2.8E+01
1.5E-04
2.4E+05
Industrial Uses
Institute Plant
5.3E+00
2.8E-05
1.3E+06
Industrial Uses
Kodak Park
Division
1.7E-01
9.1E-07
3.9E+07
Industrial Uses
Pharmacia &
Upjohn (Former)
2.7E-02
1.5E-07
2.4E+08
Industrial Uses
Philips Electronics
Plant
1.0E-01
5.4E-07
6.6E+07
Industrial Uses
Sanderson Gulch
Drainage
Improvements
1.0E-02
5.4E-08
6.6E+08
Open System
Functional Fluids
Ametek Inc. U.S.
Gauge Div
4.0E-01
2.1E-06
1.7E+07
Open System
Functional Fluids
Lake Reg
Med/Collegeville
1.3E-02
7.0E-08
5.1E+08
Open System
Functional Fluids
Pall Life Sciences
Inc
4.3E-02
2.3E-07
1.5E+08
Open System
Functional Fluids
Modeled Release
Estimates
2.9E+00
1.5E-05
2.3E+06
Spray Foam
Application
Modeled Release
Estimates
2.7E-01
1.5E-06
2.5E+07
Disposal
Beacon Heights
Landfill
5.3E-01
2.8E-06
1.3E+07
Page 228 of 616
-------
oi:s
racility/Data
Source
Surface Water
Concentration
Drinking W aler
Acute Dose,
C hild 11-15
(m "/kg/day)-'
moi:
(Oral POD 35.4
(ms/I)
nig/kg/day)
Disposal
Ingersoll
Rand/T orrington
Fac
3.5E+00
1.9E-05
1.9E+06
High-End of Submitted Monitoring Data -
Measured Surface Water Concentrations
—
STORET
1.0E+02
5.4E-04
6.6E+04
—
Sun et al. 2016
1.4E+03
7.5E-03
4.7E+03
North Carolina
Department of
Environmental
1.0E+03
5.5E-03
6.4E+03
—
Quality
Minnesota
Department of
Environmental
4.4E+00
2.4E-05
1.5E+06
—
Quality
aDose is based on hig
i end incidental intake rate
Table 4-19. Risk from Acute Dermal Ex
posure from Swimming; Benchmark MOE = 300
oi:s
l-'acility/Data
Source
Surface W ater
C oncent ration
Dermal Acute
Dose. Adult
moi:
(Dermal I'OI)
(MS/'-)
(nig/kg/day)
nig/kg/day)
Site-Specific Modeling - Estimated Surface Water Concentrations
Manufacturing
BASF
9.7E+01
3.6E-05
9.9E+05
Industrial Uses
Ineos Oxide
2.8E+02
8.0E-05
4.4E+05
Industrial Uses
Microdyn-Nadir
Corp
7.2E+00
2.7E-06
1.3E+07
Industrial Uses
St Charles
Operations
(Taft/Star) Union
Carbide Corp
1.1E-02
4.1E-09
8.6E+09
Industrial Uses
SUEZ Water
Technologies &
Solutions
5.1E+03
1.9E-03
1.9E+04
Industrial Uses
The Dow Chemical
Co - Louisiana
8.7E-03
3.2E-09
1.1E+10
Operations
Industrial Uses
Union Carbide Corp
Institute Facility
3.3E+00
1.2E-06
2.9E+07
Industrial Uses
Union Carbide Corp
Seadrift Plant
2.4E+01
8.9E-06
4.0E+06
Industrial Uses
BASF Corp
3.4E-01
1.3E-07
2.8E+08
Page 229 of 616
-------
oi:s
racility/Data
Source
Surface \Yater
Concent ration
(MS/'-)
Dermal Acute
Dose. Adult
(nig/kg/day)
moi:
(Dermal I'OI)
35.4
m»/k»/da\)
Industrial Uses
Cherokee
Pharmaceuticals
LLC
2.6E-03
9.7E-10
3.6E+10
Industrial Uses
DAK Americas
LLC
2.8E+01
1.0E-05
3.4E+06
Industrial Uses
Institute Plant
5.3E+00
2.0E-06
1.8E+07
Industrial Uses
Kodak Park
Division
1.7E-01
6.3E-08
5.6E+08
Industrial Uses
Pharmacia &
Upjohn (Former)
2.7E-02
1.0E-08
3.5E+09
Industrial Uses
Philips Electronics
Plant
1.0E-01
3.7E-08
9.6E+08
Industrial Uses
Sanderson Gulch
Drainage
Improvements
1.00E-02
3.7E-09
9.6E+09
Open System
Functional Fluids
Ametek Inc. U.S.
Gauge Div
4.0E-01
1.5E-07
2.4E+08
Open System
Functional Fluids
Lake Reg
Med/Collegeville
1.3E-02
4.8E-09
7.3E+09
Open System
Functional Fluids
Pall Life Sciences
Inc
4.3E-02
1.6E-08
2.2E+09
Open System
Functional Fluids
Modeled Release
Estimates
2.9E+00
1.1E-06
3.4E+07
Spray Foam
Application
Modeled Release
Estimates
2.7E-01
10.0E-08
3.6E+08
Disposal
Beacon Heights
Landfill
5.3E-01
2.0E-07
1.8E+08
Disposal
Ingersoll
Rand/T orrington
Fac
3.5E+00
1.3E-06
2.8E+07
High-End of Submitted Monitoring Data - Measured Surface Water Concentrations
—
STORET
1.0E+02
3.7E-05
9.6E+05
—
Sun et al. 2016
1.4E+03
5.2E-04
6.8E+04
North Carolina
Department of
Environmental
Quality
1.0E+03
3.8E-04
9.3E+04
Minnesota
Department of
Environmental
Quality
4.4E+00
1.6E-06
2.2E+07
Page 230 of 616
-------
4.3 Assumptions and Key Sources of Uncertainty
There were uncertainties related to environmental risk for 1,4-dioxane, with some leading to
potentially underestimating risk and some leading to potentially overestimating risk. As
mentioned in Section 3.1.7, there were uncertainties regarding the hazard data for aquatic
species; however, some of the uncertainty was mitigated by the use of multiple lines of evidence
supporting the assessment of hazard.
There were also uncertainties around surface water concentrations used to determine the
environmental risk. EPA used E-FAST. In some ways the E-FAST estimates are underestimating
exposure, because data used in E-FAST only included TRI and DMR data and no monitoring
data. DMR data are submitted by NPDES permit holders to states or directly to the EPA
according to the monitoring requirements of the facility's permit. States are only required to load
major discharger data into DMR and may or may not load minor discharger data. The definition
of major vs. minor discharger is set by each state and could be based on discharge volume or
facility size. Due to these limitations, some sites that discharge may not be included in the DMR
dataset.
The characterization of assumptions, variability and uncertainty may raise or lower the
confidence of the risk estimates. This section describes the assumptions and uncertainties in the
exposure assessment, hazard/dose-response and risk characterization.
4,3,1 Key Assumptions and Uncertainties in the Occupational Exposure
Assessment
EPA addressed variability in the occupational exposure models by identifying key model
parameters to apply a statistical distribution that mathematically defines the parameter's
variability. EPA defined statistical distributions for parameters using documented statistical
variations where available. Uncertainty is "the imperfect knowledge or lack of precise knowledge
of the real world either for specific values of interest or in the description of the system" (40
CFR § 702.33). It can be described qualitatively or quantitatively (U.S. EPA. 2001). The
following sections discuss uncertainties in each of the assessed 1,4-dioxane use scenarios.
Number of Workers and ONUs
There are several uncertainties surrounding the estimated number of workers potentially exposed
to 1,4-dioxane, as outlined below.
First, BLS OES employment data for each industry/occupation combination are only available at
the 3-, 4-, or 5-digitNAICS level, rather than the full 6-digitNAICS level. This lack of
granularity could result in an overestimation of the number of exposed workers if some 6-digit
NAICS are included in the less granular BLS estimates but are not, in reality, likely to use 1,4-
dioxane for the assessed applications. EPA addressed this issue by refining the OES estimates
using total employment data from the U.S. Census SUSB. However, this approach assumes that
the distribution of occupation types (SOC codes) in each 6-digitNAICS is equal to the
distribution of occupation types at the parent 5-digit NAICS level. If the distribution of workers
in occupations with 1,4-dioxane exposure differs from the overall distribution of workers in each
NAICS, then this approach will result in uncertainty. Furthermore, market penetration data were
unavailable, therefore, EPA was unable to estimate the number of establishments within each
Page 231 of 616
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NAICS code that used 1,4-dioxane instead of other chemicals. This would result in a systematic
overestimation of the count of exposed workers. For manufacturing and import/re-packaging,
CDR data provided information to better estimate the number of workers.
Second, EPA's judgments about which industries (represented by NAICS codes) and
occupations (represented by SOC codes) are associated with the uses assessed in this report are
based on EPA's understanding of how 1,4-dioxane is used in each industry. Designations of
certain industries/occupations with few exposures might erroneously be included, or some
industries/occupations with exposures might erroneously be excluded. This not expected to
systematically either overestimate or underestimate the count of exposed workers.
Analysis of Exposure Monitoring Data
This risk evaluation uses existing worker exposure monitoring data to assess exposure to 1,4-
dioxane during manufacturing, industrial use, open system functional fluid, laboratory chemical,
film cement, and 3D printing ink applications. To analyze the exposure data, EPA categorized
each PBZ and area data point as either "worker" or "occupational non-user." The categorizations
are based on descriptions of worker job activity as provided in literature and EPA's judgment. In
general, PBZ samples are categorized as "worker" and area samples are categorized as
"occupational non-user."
Exposure data for ONUs were not available for most scenarios. EPA assumes that these
exposures are expected to be lower than worker exposures, since ONUs do not typically directly
handle the 1,4-dioxane nor are they in the immediate proximity of 1,4-dioxane.
Some data sources may be inherently biased, such as data directly from industry or in response to
reported issues. For example, NIOSH HHEs for the open system functional fluids and film
cement uses were conducted to address concerns regarding adverse human health effects
reported following exposures during use. Both HHEs were requested by the United
Paperworkers International Union and Film Technicians Union, respectively.
Some monitoring data are incomplete and required assumptions to fill in the gaps. For example,
the monitoring data from BASF for the manufacturing condition of use required EPA to make
assumptions on worker activities and sampling rates for certain datapoints similar to others
mentioned in the data set.
The 2002 EU Risk Assessment (ECJRC. 2002). did not provide complete datasets. This
assessment provided limited summary statistics for different datasets, i.e., a range of the
monitoring data, an arithmetic average or median, and the 90th percentile. The EU report
provided limited information about processes involved in each dataset with corresponding
worker activities. Finally, this report provided recommendations for "typical" and "reasonable
worst case" exposures but did not provide details for how these values were calculated.
Because of these limitations, EPA acknowledges that the reported inhalation exposure
concentrations for the industrial scenario uses may not be representative for the exposures in all
industries within that group.
Page 232 of 616
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Some scenarios have limited exposure monitoring data in literature, if any {i.e., use in 3D
printing inks). Where there are few data points available, it is unlikely the results will be
representative of worker exposure across the industry depending on the sample collection
location (PBZ or source zone), monitoring time and other conditions to represent the work
situation and the duration of the exposure.
The 95th and 50th percentile exposure concentrations were calculated using reasonably available
data. The 95th percentile exposure concentration is intended to represent a high-end exposure
level, while the 50th percentile exposure concentration represents typical exposure level. The
underlying distribution of the data, and the representativeness of the available data, are not
known.
EPA calculated ADC values assuming a high-end exposure duration of 260 days per year over
40 years and LADC values assuming a high-end exposure duration of 260 days per year over 78
years. Repackaging and import is an exception, since the exposure duration depends on the
number of containers being unloaded. The high-end exposure duration value for this exposure
scenario is 90 days (one container unloaded per day). See Section 2.4.1.1.2 for more information.
This assumes the workers and occupational non-users are regularly exposed during their entire
working lifetime, which likely results in an overestimate. Individuals may change jobs during
their career such that they are no longer exposed to 1,4-dioxane, and that actual ADC and LADC
values become lower than the estimates presented.
Modeling Dermal Exposures
The EPA Dermal Exposure to Volatile Liquids Model used for modeling dermal exposures offers
an improvement over the existing EPA 2-HandDermal Exposure models by accounting for the
effect of evaporation on dermal absorption for volatile chemicals and the potential exposure
reduction due to glove use. The passage of a chemical through the skin barrier is dependent on
many factors. The skin is not uniform in terms of thickness. For example, epidermis to dermis
ratio, density of hair follicles, and many other parameters could affect permeability. Other factors
that could influence the dermal uptake include temperature and the presence of other materials
on the skin. A detailed description of dermal exposure assessment method is shown in Appendix
G.7. To address the uncertainty due to lack of monitoring data, a film-thickness approach was
used. This approach considered a thin film of product on a defined skin area. A multiplicative
factor was incorporated to the EPA model to include the proportion of 1,4-dioxane remaining on
the skin after the bulk liquid has fallen from the hand that cannot be removed by wiping the skin.
The model assumes an infinite dose scenario and does not consider the transient exposure and
exposure duration effect.
Uncertainties of Occupational Exposure of 1,4-dioxane for Various Conditions of Use
The summary and uncertainty rating of occupational exposure of 1,4-dioxane indicating
strengths, challenges, whether modelling or monitoring preformed, representativeness and
confidence of data assessed, and overall rating for various conditions of use are shown in Table
4-20..
Page 233 of 616
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Table 4-20. Summary and Uncertainty Rating of Occupational Exposure of 1,4-dioxane for
Various Conditions of Use
Occupational
Exposure
Scenario
Manufacturing
Strength
PBZ sampthg
Biji Hals qjaliry
Sojceoi
internal] oi
available direciy
from manufacturer
CDR presided
emptee counts te
specific
ranuficiLTng site
Data from nulsple
facitliBS
Challenge
Data s provided
from wie sconce
Inhalation Exposure
Monitoring
Modeling
Representativeness
Data (!) Surrogate Worker ONU Worker ONU
Many data points
*ere at or became
limit of detected
/
(32)
/
as1)
ROitra raoManng data
avatoMefcrwoik
envraiwent
Higher
/
Import and
R»pac«3giing
cdr orc.iaed
ernpfcryee counts te
specific rapcr: and
Repackaging sites
No Monitorng Data
EPA mooes are not
specific to liraoit
and Repacking
Ei?litr
Monte Caito
simuiatksn of
models B vary
specific parameter
Relies on process
and prctec&dn
assumptions
Assesses exposure cased
on lading and unloading
ont/. Assures contr&ied
and ctss&a systems *or a*l
ottier operations.
/
May underestimate
wcrterenposje
Lower
Industrial Use
Aggregated daa
IHlK
FBI Samping
Nomcnitonnq data
ttrtis CoU;
Sjrroqate dats^ir;
manulaBjring
Higter
Data Itom multiple
fadaes
Data >s provfled
#wn one source
*394)
~
Roifine rnoniteriig data
avaiatSe&uoFK
environment
/
CDR prowled
Mipfcuee counts for
specific
manuQduHi siies
Many data points
'*ereatc?t3e«*ttie
limit of detection
Functional
Fluids (Open
System)
PBZ samplhg
Ail Oa& points are
atarteloBlteSnit
ofdetecSm
f/ode! assesses exposure
Cased on loading and
unloosing ont/. Assumes
csnCroiied and ttosed
systems fir al offer
opefatioK.
Higher
Sou-ceo!
intern ad on
ava lacle direct y
from manufiiciu-er
~
(19)
~
(«>
~
(4)
Sampfe; representative of
ireialworKing suid. bfjt not
necessarily mete Iwfliiiig
Ruid wth 1,4-dBiane
content
~
Lower
Specific water
adivhes for eacfc
sarrpie
Sampling caca is
fiwn one facility
RC'X.re monitoring data
j.alattetewi'li
en'.timment
Laboratory
Cnemicala
CDRpiciidefl
empfcyee counts te
Datasets liniEd,
adiinq specific
/
/
Assesses exposure Casec
on Isacing and uSoad'rsg
Page 234 of 616
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Inhalation Exposure
Strength
specific ndustiai
processrvq
agentokl sites
FEZ samples
Challenge
dessipbons of
worker tasks and
eiossure sources
Monitoring
Modeling
Representative ness
Data (f) Surrogate Worker ONU Worker ONU
corraanson wti
oilier lajoralsres is
-Kit pcrisicfe dL61Q
lack of infonratwi
Mast daiasets
oro,idec in a raige
May underestimate
worker eiposue
(335)
(335)
only. Assumes cofitrorted
and dosed sj'stems *or all
otter ope-?atk>ns.
/
Lower
F cwrir:
Job opetjbyis are
prated
Tfeeoiihesix
sanples *e*e iwt-
detecB
"n"seei:nesis samples
were non-sexes
Soj'ceoi
infcrmatai includes
caa from mtitipie
film semen usets
Data s owy from
one reference
FEZ sampling
Lack of statistical
recuse ttoeness
due tone small
datasetoPBZand
I Area samples
/
(6)
/
(5)
/
(1)
Assesses exposure Pased
on loading aid uncaring
ont/. Assumes controlea
and closed systems for all
other operations.
/
Higher
«
M
Sp«j Foam
Application
Liiissrie G5 on
tre .Appiicacon of
SpTjy Polyuietiane
Foam na.ation
Nomonnorng data
Seles on rrcdets.
swogaledala. aid
qere-al industry
data wncn may net
oe rspr&^itato
Higher
/e
/
/
comcines
esGBislKd "Todels
Mil Monte Carlo
simulations
Mode; is based on a
relevant generc scenario
/
Estrrason does roc
account for ffle
wtertal
evaporation of 1,4.-
dosane (torn tfe
rnisi eamctes and
•esLltnq inhalation
esq>osure
Use sf printing
inks
One data pan:
enr.s
Lack of statist cat
¦ecesertxveres-
due to Tie small
dataset 1 Area
sample
/
(1}
/
(1)
Sample puled Sm irfKr-
workings o< equipment
fiat is a part sf?s routine
viorkerwranrrefit
/
Higher
\
Page 235 of 616
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Occupational
Exposure
Scenario
Strength
Challenge
Inhalation Exposure
Representativeness
Dermal
Exposure
Modeling
Overall
Monrtorin
n
Modeling
Worker ¦
ONU"
Rating
Data {#)
Surrogate Worker
ONU
Worker
ONU
FBI sampes are B-
l-our TWAs
Direct caiwsation *ith
1 Higher 1
Captures 100% of
urmm users, fcul
n>igienists regarding
sample data
Dry Film
Lubrcsaton
Soijrteof
info-matim
a.; title cirect y
torn manufacturer
and user
uncfear if oner
DOE fsciilies are
also 1 ,<-dioi2ne dry
fimiutficarrtuseis
(7)
X
~
V)
X
X
X
Rouwe mentoring data
avaiabie wort;
envKmraent
~
X
u
Lower
Combine?
esGSisheo Todels
No p*ocess details
were available for
dispose sites
Ketieson
arrogate data, and
genesal industry data
which may iks be
rep-esentatve
Higher
m
Disposal
X
X
X
X
X
M
wn Monte Carlo
simulations
EPA mooes are not
SKDffctO
disposa;.Tenahg
Assesses exposure Casec
on tsading and unloading
only. Assumes centrales
and closed systems isr 31
other iterations.
X
L
EPA assj-nptiora
may He overty
conseivatNe
L
.ower
a: Dermal exposure estimates, which are based on high-end/central tendency parameters and commercial/industrial
settings, have medium level of confidence.
b: ONU exposure estimates, which are based on central tendency paraments, have low levels of confidence,
c: Two data points were short term samples.
d: A monte carlo model was performed on this to determine fit of data,
e: Surrogate data were used to determine foam thickness and input to models.
4.3.2 Key Assumptions and Uncertainties in the Consumer Exposure Estimation
EPA's approach recognizes the need to include uncertainty analysis. One important distinction
for such an analysis is variability versus uncertainty - both aspects need to be addressed.
Variability refers to the inherent heterogeneity or diversity of data in an assessment. It is a
quantitative description of the range or spread of a set of values and is often expressed through
statistical metrics, such as variance or standard deviation, that reflect the underlying variability
of the data. Uncertainty refers to a lack of data or an incomplete understanding of the context of
the risk evaluation decision. Variability cannot be reduced, but it can be better characterized.
Uncertainty can be reduced by collecting more or better data. Quantitative methods to address
uncertainty include non-probabilistic approaches such as sensitivity analysis and probabilistic or
stochastic methods. Uncertainty can also be addressed qualitatively, by including a discussion of
factors such as data gaps and subjective decisions or instances where professional judgment was
used. Uncertainties associated with approaches and data used in the evaluation of consumer
exposures are described below.
Deterministic v.v. Stochastic
With deterministic approaches like the one applied in this evaluation of consumer exposure, the
output of the model is fully determined by the choices of parameter values and initial condi tions.
Stochastic approaches feature inherent randomness, such that a given set of parameter values and
initial conditions can lead to an ensemble of different model outputs.
Page 236 of 616
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Aggregate Exposure
Background levels of 1,4-dioxane in indoor and outdoor air are not considered or aggregated in
this analysis; therefore, there is a potential for underestimating consumer inhalation exposures,
particularly for populations living near a facility emitting 1,4-dioxane or living in a home with
other sources of 1,4-dioxane, such as other 1,4-dioxane-containing products stored and/or used in
the home such as personal care products that are not covered under TSCA. Similarly, inhalation
and dermal exposures were evaluated on a product-specific basis and are based on use of a single
product type within a day, not multiple products. There was no aggregation of dermal and
inhalation exposure to single products either.
Dermal Exposure Approach
For dermal exposure scenarios using the permeability model that may involve dermal contact
with impeded evaporation based on professional considerations of the formulation type and
likely use pattern, there is uncertainty surrounding the application of exposure durations for such
scenarios. The exposure durations modeled are based on reported durations of product use,
unless otherwise specified, and may not reflect reasonable durations of dermal contact with
impeded evaporation. The exposure duration modeled could exceed a reasonable duration of
such dermal contact with a wet rag, for example.
For scenarios using the absorption fraction model that are less likely to involve dermal contact
with impeded evaporation, there is uncertainty surrounding the assumption that the entire mass
present in the thin film is absorbed and retained in the stratum corneum following a use event.
The fractional absorption factor estimated based on Frasch and Bunge (2015) is intended to be
applied to the mass retained in the stratum corneum after exposure; it does not account for
evaporation from the skin surface during the exposure event. Therefore, the assumption that the
entire amount of chemical present in the thin film on the skin surface is retained in the stratum
corneum may lead to uncertainty in the absorbed dose estimate.
Product Concentration Data
The products evaluated are largely based on EPA's 2015 TSCA Work Plan Chemical Problem
Formulation and Initial Assessment of 1,4-Dioxane ( >15). EPA conducted an
additional systematic review focused on identifying data on 1,4-dioxane presence in consumer
products and associated exposures and/or emissions. Because 1,4-dioxane is present in consumer
products as a byproduct and not as an ingredient, there is more uncertainty than typical when
identifying and using concentration information. Unlike other chemicals that are ingredients in
consumer products with readily available reported concentration ranges in SDSs for each product
category, 1,4-dioxane concentrations have been sourced from a variety of primary and secondary
sources such as governmental risk assessments, SDSs, literature reviews, emission studies, etc.
There are limited reasonably available data and they are not necessarily complete or consistently
updated and general internet searches cannot guarantee entirely comprehensive product
identification. According to reasonably available information, there may be uncertainty in the
range of weight fractions modeled for consumer dish soap and laundry detergent. Therefore, it is
possible that the entire universe of products that contain 1,4-dioxane as a byproduct may not
have been identified, or that certain changes in the universe of products may not have been
captured, due to market changes or research limitations. Maximum identified weight fractions
Page 237 of 616
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were used in acute high-intensity user scenarios and mean weight fractions were used in chronic
high-intensity and moderate-intensity user scenarios, where possible. While weight fractions are
described as "maximum" in tables, these reflect only the maximum levels identified from
available literature and other sources and may not capture the true maximum in specific products
or batches. There is uncertainty about how these means and maximums broadly reflect typical
products and there is also uncertainty about whether the true upper end is captured in the ranges
identified through the available sources. For the range of weight fractions identified, see the
Supplemental File [Consumer Exposure Assessment Modeling Input Parameters],
Emission Rate
The higher-tier Multi-Chamber Concentration and Exposure Model (MCCEM) is used in the
estimation of inhalation exposures from SPF application only. For other product scenarios, key
data {i.e., chamber emission data) were not reasonably available. Therefore, the model used
(CEM 2.1) estimates emission rate based on chemical properties and emission profiles matching
the formulation type and use method.
The emission rate data derived from Karlovich et al. {2i ) is based on occupational-grade
products, so there is some uncertainty surrounding the application to consumers. High-pressure
SPF may not be available to consumers, unlike one-component or low-pressure foams. Each
foam type is anticipated to have unique exposure profiles and therefore there is uncertainty
surrounding how the emission and exposure profile may have differed, had EPA identified and
used emission rate data from low-pressure or one-component SPF products. The product for
which 1,4-dioxane emission data were collected is an open-cell foam. The initial emission rate
and decay constant estimates were based on a modeled relationship, as measured emission data
were not available during application.
Dilution Factor
For most product scenarios, the dilution factor is not considered. For dish soap, laundry
detergent, and textile dye, all of which are expected to be used in aqueous solutions during hand
washing or dyeing activities, dilution factors are incorporated. For dish soap, a dilution factor of
0.7% is applied based on assuming a mass of 28 g (~1 oz) is used in one gallon of water for hand
washing of dishes. For laundry detergent, a dilution factor of 1.6% is applied based on assuming
a high-end mass of 60 g (oz) is used in one gallon of water for hand washing of laundry. These
estimations incorporate a conservative water use assumption.
Chronic Exposure Estimations
Chronic (lifetime) inhalation and dermal exposures were estimated for four product scenarios:
surface cleaner, dish soap, dishwasher detergent, and laundry detergent. The inclusion of lifetime
exposure estimates for these conditions of use is based on the anticipated daily or near-daily use
of these products. This differs from expected intermittent exposure pattern associated with the
other evaluated consumer conditions of use. Lifetime exposure estimates are calculated assuming
the exposure event occurs for 365 or 300 days per year for high-end or central tendency
frequencies, respectively, for an expopsure duration 57 years. The exposure scenarios still
assume one exposure event per day and therefore may not capture users that continuously use
products throughout the day. This exposure is averaged over a period of 78 years {i.e., averaging
time). The models employed (CEM 2.1 and CEM) typically utilize central tendency inputs for
Page 238 of 616
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weight fraction, duration, frequency, and mass when estimating lifetime exposures (
2019a; :007). Central tendency inputs for weight fraction were used in estimating
chronic exposures, across high- and moderate-intensity user scenarios.
4.3.2.1 Confidence in Consumer Exposure Estimates
The considerations and overall confidence ratings for the inhalation consumer exposure
scenarios are displayed in Table 4-21. Ratings are based on the strength of the models employed,
as well as the quality and relevance of the modeling parameterization. CEM, CEM 2.1, and
MCCEM are peer reviewed, publicly available, and were designed to estimate inhalation and
dermal exposures from household uses of products and articles.
Systematic review identified several studies reporting emission rates or chamber concentrations
of 1,4-dioxane from spray foam and paint products and findings as they relate to the current
evaluation are summarized in Appendix H.3. Although measured chamber or test room
concentrations are not directly comparable to the 8-hr TWAs estimated for the various consumer
exposure scenarios, on the whole, these emission studies bolster confidence in the predicted air
concentrations for the SPF and paint and floor lacquer conditions of use.
The predicted 8-hr TWAs for SPF range from 160 to 890 |ig/m3 for users. These predicted
estimates fall within the range predicted in Karlovich et al. (201 lb) for samples measured at four
and 12 hours. Peppendieck et al. (2017) also reported measured air concentrations that
encompass the modeled consumer exposure estimates, with concentrations from non-ideal
closed-cell spray foam ranging from 500 to 1,000 |ig/m3 over the first 48 hours. Won et al.
(2014) reported levels of 1,4-dioxane well below the CEM 2.1 predictions, from 0.25 to 44.68
|ig/m3 at six hours for various insulation products including foam board and two-component
open- and closed-cell spray foams.
The predicted 8-hr TWAs for paint and floor lacquer is 20 |ig/m3 for users, which is roughly one
order of magnitude greater than concentrations measured in Won et al. (2014) (0.8 - 1.74 |ig/m3
at six hours), but aligns with the measured air concentration five hours after application of the
two-component epoxy floor paint (21 |ig/m3). The predicted TWA also falls within the range of
air concentrations taken five hours after application in the Danish EPA's 2020 Follow-Up study,
which reported levels from 7 to 460 |ig/m3 at five hours.
The considerations and overall confidence ratings for the dermal consumer exposure scenarios
are displayed in Table 4-22. Ratings are based on the strength of the models employed, as well
as the quality and relevance of the modeling parameterization. CEM 2. lis peer reviewed,
publicly available, and was designed to estimate inhalation and dermal exposures from
household uses of products and articles.
Page 239 of 616
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Table 4-21 Overall Confidence Ratings for Consumer Inhalation Exposure Estimates
Consumer Product
()\i-r;ill C onlidence
()\i-r;ill ('onllrii'iKT
Scoiiiirio-Spociric Considcra (ions
()\oi'iii'cliinu Considerations
Scenario
Acule
('limine
Surface (leaner
Mndeiale In 1 ligli
Mnderale
• Duration and niabb inpub obtained from
the Westat Survey from its solvent-type
cleaning fluids and degreasers category.
• Weight fraction range obtained from
few sources.
• There ib u nee nanus
regarding how the maximum
and mean from identified
weight fraction sources
reflects the existing range or
Antifreeze
Moderate to High
NA
• Duration and mass inputs obtained from
CEM 2.1 scenario-specific defaults.
• Weight fraction range obtained from
few sources.
captures actual maximum
concentrations.
• Use of CEM (not CEM 2.1)
to estimate lifetime inhalation
Dish Soap
Moderate to High
Moderate
• Duration and mass inputs obtained from
CEM 2.1 scenario-specific defaults.
• Weight fraction range obtained from
several sources.
exposures (LADCs) did not
estimate exposure to
bystanders; however,
bystanders would be exposed
to lower levels than the
presented user exposures
based on their placement in
the home during use (Zone
2).
• Use of central tendency
weight fractions for chronic
exposure scenarios bolsters
confidence, as it does not
assume use of the highest
identified concentration daily
or near-daily intervals over
57 years.
Dishwasher Detergent
Moderate to High
Moderate
• Duration and mass inputs obtained from
CEM 2.1 scenario-specific defaults.
• Exposure duration assumes user is in the
room of use (kitchen) during the
machine's run time (50 min).
• Weight fraction range obtained from
several sources.
Laundry Detergent
Moderate to High
Moderate
• Duration and mass inputs obtained from
CEM 2.1 scenario-specific defaults.
• Exposure duration assumes user is in the
room of use (utility) during the
machine's runtime (50 min).
• Weight fraction range obtained from
several sources.
Paint and Floor
High
NA
• Duration and mass inputs obtained from
Lacquer
the Westat Survey from its latex paint
category.
• Weight fraction data obtained from
American Coatings Association public
submission (Nekoomaram and
Wieroniev. 2015).
Page 240 of 616
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Consumer Product
()\cr;ill C onlidence
()\i-r;ill ("oiilldeiico
Scoii;irio-SpeciTie Consider;! (ions
()\cr;i rcliin^ Considerations
Scenario
Acule
Chronic
• Measured emission data align with 8-hr
TWA for users.
Textile Dye
Moderate
NA
• Duration and mass inputs obtained from
CEM 2.1 scenario-specific defaults.
• Single weight fraction source.
SPF
High
NA
• Initial emission rate and decay constant
are based on a modeled relationship.
• No emission or concentration data were
available for 1,4-dioxane during
application.
• Emission data on 1,4-dioxane from
Karlovich et al.. (20.1. lb) is from open
cell foam.
• Duration inputs based on the SPF
occupational exposure assessment.
• Application area specific air exchange
rates and ventilation rates applied.
• Product and chemical specific emission
rate applied.
• Used higher-tier MCCEM model to
estimate air concentrations.
• Weight fraction based on occupational
exposure assessment.
• Measured and predicted emission data
encompass predicted range of 8-hr
TWAs for users.
Page 241 of 616
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Table 4-22 Overall Confidence Ratings for Consumer Dermal Exposure Estimates
Consumer Product
()\cr;ill Confidence
()\cr;ill Confidence
Scciiiiriu-Spccific Consider;! (ions
()\ci';ii'chin^ Cunsidci'iiliuns
Scenario
Anile
Chronic
Surface Cleaner
Moderate
Low to Moderate
• Duration input obtained from the Westat
Survey from its solvent-type cleaning
fluids and degreasers category.
• Exposure duration assumes dermal
contact may occur during the entire
activity duration.
• Weight fraction range obtained from
few sources.
• There is uncertainty
regarding how the maximum
and mean from identified
weight fraction sources
reflects the existing range or
captures actual maximum
concentrations.
• An estimated permeability
Antifreeze
Moderate
NA
• Duration input obtained from CEM 2.1
scenario-specific defaults.
• Exposure duration assumes dermal
contact may occur during the entire
activity duration.
• Weight fraction range obtained from
few sources.
coefficient is used in dermal
modeling.
• There are uncertainties
associated with both dermal
models applied (see Section
2.4.3.6).
• Use of central tendency
Dish Soap
Moderate
Low to Moderate
• Duration input obtained from CEM 2.1
scenario-specific defaults.
• Dilution fraction of 3% may be a
conservative assumption.
• Weight fraction range obtained from
several sources.
weight fractions for chronic
exposure scenarios bolsters
confidence, as it does not
assume use of the highest
identified concentration daily
or near-daily intervals over
57 years.
Dishwasher Detergent
Moderate
Low to Moderate
• Duration input obtained from CEM 2.1
scenario-specific defaults.
• Exposure duration adjusted to one
minute to approximate contact time
during loading of liquid detergent.
• Weight fraction range obtained from
several sources.
Laundry Detergent
Moderate
Low to Moderate
• Duration input obtained from CEM 2.1
scenario-specific defaults.
• Exposure duration adjusted to equal dish
soap exposure durations to approximate
contact time during hand washing of
laundry.
Page 242 of 616
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Consumer Product
Scenario
()\cr;ill Confidence
Acuk"
()\cr;ill Confidence
( lironic
Scoiiiii'io-Spociric Considerations
()\oi'iii'chinu Consider;! lions
• Chronic exposure scenario assumes
hand washing of laundry daily or near
daily.
• Weight fraction range obtained from
several sources.
Paint and Floor
Lacquer
Moderate
NA
• Duration and mass inputs obtained from
the Westat Survey from its latex paint
category.
• Exposure duration assumes dermal
contact may occur during the entire
activity duration.
• Weight fraction data obtained from
American Coatings Association public
comment submission (Nekoomaram and
Wieroniev. 2015).
Textile Dye
Moderate
NA
• Duration and mass inputs obtained from
CEM 2.1 scenario-specific defaults.
• Dilution fraction of 10% likely a
conservative assumption.
• Single weight fraction source.
SPF
Moderate
NA
• Duration inputs based on the SPF
occupational exposure assessment.
• Exposure duration assumes dermal
contact may occur during the entire
activity duration.
• Weight fraction based on occupational
exposure assessment.
Page 243 of 616
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4,3.3 Key Assumptions and Uncertainties in the General Population Exposure
EPA's approach recognizes the need to include uncertainty analysis. One important distinction
for such an analysis is variability versus uncertainty - both aspects need to be addressed.
Variability refers to the inherent heterogeneity or diversity of data in an assessment. It is a
quantitative description of the range or spread of a set of values and is often expressed through
statistical metrics, such as variance or standard deviation, that reflect the underlying variability
of the data. Uncertainty refers to a lack of data or an incomplete understanding of the context of
the risk evaluation decision. Variability cannot be reduced, but it can be better characterized.
Uncertainty can be reduced by collecting more or better data. Quantitative methods to address
uncertainty include non-probabilistic approaches such as sensitivity analysis and probabilistic or
stochastic methods. Uncertainty can also be addressed qualitatively, by including a discussion of
factors such as data gaps and subjective decisions or instances where professional judgment was
used. Uncertainties associated with approaches and data used in the evaluation of general
population exposures are described below.
Modeling Inputs and Assumptions
Releases modeled using E-FAST 2014 were predicted based on engineering site-specific
estimates based on DMR and TRI reporting databases. These data that form the basis for
engineering estimates are self-reported by facilities subject to minimum reporting thresholds;
therefore, they may not capture releases from certain facilities not meeting reporting thresholds
(i.e., environmental releases may be underestimated). The modeled releases are based on
occupational exposure scenarios (i.e., industrial and/or commercial conditions of use) and are not
intended to reflect contributions from the use and/or disposal of consumer products. These
release estimates, however, are described as having a medium level of confidence in Section
2.2.1.3.1.
E-FAST 2014 estimates surface water concentrations at the point of release, without accounting
for post-release environmental fate or degradation processes such as volatilization,
biodegradation, photolysis, hydrolysis, or partitioning. Additionally, E-FAST does not estimate
stream concentrations based on the potential for downstream transport and dilution. These
considerations tend to lead to higher predicted surface water concentrations. Dilution is
incorporated, but it is based on the stream flow applied. Therefore, there is uncertainty regarding
the level of 1,4-dioxane that would be predicted downstream of a releasing facility or after
accounting for potential volatilization from the water surface, which is dependent on the degree
of mixing in a receiving water body.
The ambient water analysis assumes that members of the general population are incidentally
exposed via swimming in ambient waters, but there is uncertainty surrounding the likelihood that
such recreation and contact would occur at or near the point of release. If such activities occurred
further from the point of release, this analysis may overestimate the water concentrations that
swimmers would be exposed to.
EPA's SWIMODEL was used as the source for exposure duration. This model is intended to
assess exposure from swimming in pools, not ambient water bodies, so there is uncertainty about
the application of swimming pool duration data in this analysis.
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Monitoring Data
The surface water monitoring data that were submitted during the draft's public comment period
and SACC review were utilized but relative contributions from specific industrial and/or
consumer sources of 1,4-dioxane are unknown.
Aggregate Exposure
Background levels of 1,4-dioxane from other sources are not considered or aggregated in this
analysis; therefore, there is a potential for underestimating exposures, particularly for
populations living near a facility emitting 1,4-dioxane or living in a home with other sources of
1,4-dioxane, such as other 1,4-dioxane-containing products stored and/or used in the home such
as personal care products that are not covered under TSCA. Similarly, there was no aggregation
of incidental oral and dermal exposures from swimming, which would be expected to be
concurrent.
4.3,3,1 Confidence in General Population Exposure Estimates
Confidence ratings for general population ambient water exposure scenarios are informed by
uncertainties surrounding inputs and approaches used in modeling surface water concentrations
and estimating incidental oral and dermal doses. In Section 2.2.1.3.1, confidence ratings are
assigned to these estimated daily releases (kg/site-day) on a per occupational exposure scenario
(OES) basis and reflect moderate confidence.
Other considerations that impact confidence in the ambient water exposure scenarios include the
model used (E-FAST 2014) and its associated default and user-selected values and related
uncertainties. As described, there are uncertainties related to the ability of E-FAST 2014 to
incorporate downstream fate and transport. Of note, as stated on the EPA's E-FAST 2014
website, "modeled estimates of concentrations and doses are designed to reasonably overestimate
exposures, for use in an exposure assessment in the absence of or with reliable monitoring data."
Regarding the assumption that members of the general population could reasonably be expected
to swim at or near the point of release, there is relatively low confidence due to uncertainty.
EPA utilized the SWIMODEL default duration parameters to estimate incidental dermal and oral
exposures to the general population from swimming in ambient water bodies. The model's
default duration inputs were based on swimming pool use patterns rather than freshwater bodies,
so there is low to moderate confidence that these parameters accurately reflect the ambient water
body recreation activities covered in this supplemental analysis.
There are surface water monitoring data available that reflect ambient water exposure levels in
the United States (see Section 2.4.2.3). These data were submitted from only two states (NC and
MN) and may reflect multiple sources of 1,4-dioxane in surface water that may or may not be
related to within-scope occupational exposure scenarios. Because these monitoring data reflect
surface water conditions at specific sampling sites during a specific sampling period, they may
not reflect current levels of 1,4-dioxane in surface water. The modeled surface water
concentration ranges obtained from E-FAST modeling (2.63E-03 - 5.09E+03 |ig/L) encompass
the full range of the surface water monitoring data submitted during public comment period.
Based on the above considerations, the general population ambient water exposure assessment
scenarios have an overall low to moderate confidence.
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4,3,4 Key Assumptions and Uncertainties in Environmental Risk
The available environmental toxicity data for 1,4-dioxane indicate that the hazard to aquatic
organisms is low. While the EPA has determined that sufficient data are available to characterize
the overall environmental hazards of 1,4-dioxane, there are limited chronic toxicity studies
available for assessing the long-term effects of 1,4-dioxane to aquatic species that may create
some uncertainty associated with this assessment.
National-scale monitoring data from EPA's STOrage and RETreival (STORET) and National
Water Information System (NWIS) for the past ten years, shows that 1,4-dioxane is detected in
surface water. The data points show a detection rate of approximately 6% for this media, with
detections ranging from 0.568 to 100 |ig/L. However, some samples within this dataset have
method detection limits above the highest detection level of 100 |ig/L. Public commenters
pointed out that some of these MDLs may exceed the chronic COC of 14,500 |ig/L rEPA-HQ-
OPPT-2019-0238-00581. Non-detects from this dataset were not considered, so there is some
uncertainty surrounding potential levels of 1,4-dioxane from such samples.
As described in Appendix E and Section 2.3.1, a screening-level aquatic exposure assessment
was undertaken during problem formulation to evaluate ecological exposures in the U.S. that
may be associated with releases of 1,4-dioxane to surface waters.
This assessment was intended as a first-tier, or screening-level, evaluation. Discharging or
releasing facilities were chosen from two data sources: EPA's Discharge Monitoring Report
(DMR) and Toxic Release Inventory (TRI). The top ten (by annual release/discharge amount)
facilities were selected for use in exposure modeling; therefore, not all reporting sites were
modeled, and the selected sites were not cross-walked with the conditions of use included in the
occupational engineering assessment. These top dischargers were selected from two recent
complete years of TRI and DMR reporting, which at the time of modeling included 2014-2015
for TRI and 2015-2016 for DMR.
EPA's Exposure and Fate Assessment Screening Tool, Version 2014 ( 14c) was
used for predicting stream concentrations resulting from the selected releasers. The predicted
stream concentrations reflect concentrations in the receiving water body at the point of the
release, incorporating any immediate dilution based on stream flow. Downstream transport
and/or dilution are not modeled, nor are any post-release fate or removal processes such as
degradation, photolysis, hydrolysis, or volatilization.
For the purposes of this assessment, the number of release days was based on conservative
assumptions. The reported annual release amounts from TRI and DMR were converted to kg and
divided by the assumed number of release days (1, 20, or 250) to obtain the necessary kg/site-day
release input. These assumptions are not based on associated industry-specific data or standards,
but on screening-level assumptions to capture worst-case environmental concentrations for acute
and chronic release scenarios. One day of release is the worst-case release assumption for an
acute scenario, appropriate for comparison against an acute COC, while 20 days of release is the
worst-case release assumption for a chronic scenario, appropriate for comparison against a
chronic COC. 250 days of release may be more typical for facilities that operate and release
effluent frequently, such as POTWs or treatment plants.
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4.3,5 Key Assumptions and Uncertainties in Human Health Hazards
Data are limited for some chronic toxicological endpoints. While not required here, there is no
multi-generation reproductive/developmental study. In the only available developmental study in
mammals (Giavini etal... 1985). effects of 1,4-dioxane included delayed ossification of the
sternebrae and reduced fetal body weight. These effects only reached statistical significance at
the highest dose tested (1000 mg/kg-day) in the presence of slight maternal toxicity. Although
there is some limited evidence of developmental toxicity, there is a lack of data for several
reproductive and developmental endpoints, including neurodevelopmental effects.
There is also a lack of data on toxicity of 1,4-dioxane from dermal exposures. EPA therefore
extrapolated from evidence from oral and inhalation studies to derive dermal PODs. As
described in Section 3.2.7, route-to-route extrapolation introduces several sources of uncertainty,
including differences in absorption through different routes of exposure (e.g., first-pass
metabolism following oral exposure) and uncertainty related to exposure methods (e.g., whole
body inhalation exposure in animal studies may result in additional exposure via dermal and oral
exposure routes that are unaccounted for in POD derivation). EPA did not apply additional
uncertainty factors to address uncertainties related to route-to-route extrapolation because these
sources of uncertainty are likely to underestimate rather than overestimate the POD for 1,4-
dioxane.
One source of uncertainty for cancer risk estimates is the mode of action (MO A) for 1,4-dioxane
carcinogenicity. EPA concluded that there is insufficient information to support a specific MOA
for any of the tumor types associated with 1,4-dioxane exposure. A clearer understanding of the
MOA for carcinogensis at each tumor location could inform selection of linear or non-linear
models for BMD modeling to determine the dose-response relationship at low doses. For
example, there is uncertainty on whether the toxic moiety is 1,4-dioxane or one or more
metabolites and whether cytotoxicity is a necessary key event in the progression to observed
liver tumors. Additionally, cancer dose-response was performed on a set of tissue types that are
not all present in humans (i.e., Zymbal gland). However, in the absence of information to
indicate otherwise, and considering similar cell types are prevalent throughout the respiratory
tract of rats and humans, nasal, liver, renal, peritoneal, mammary gland, Zymbal gland, and
subcutis tumors were all considered relevant to humans. Inclusion of Zymbal gland tumors is
consistent with EPA's Guidelines for Carcinogenic Risk Assessment (U.S. EPA... 2005a). which
does not always require site concordance between humans and animals.
In the reasonably available studies for inhalation and oral cancer hazard, there were issues such
as mortality at the high doses (NCI. 1978; Kociba et at... 1974). EPA was unable to use the data
from male rats in the NCI (1978) study due to high levels of mortality, and the doses were too
close together due to drinking water intake.
EPA performed BMD modeling for all non-cancer data that were amenable to modeling. EPA
made several assumptions related to modeling, including selection of BMRs and appropriate
model fits. The assumptions and uncertainties related to BMD modeling for each endpoint are
described in detail in Appendix K. The acute liver toxicity as well as some of the chronic
respiratory and olfactory effects were not able to be estimated with BMD modeling and were
instead based on a LOAEC or a NOAEC. This resulted in greater uncertainty and a higher
Page 247 of 616
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benchmark MOE for those endpoints. The endpoint EPA selected as the basis for the acute PODs
relies on a LOAEC and therefore requires an additional uncertainty factor of LOAEC and
NOAEC extrapolation. The endpoint EPA ultimately selected as the basis for the chronic
inhalation POD was evaluated with BMD modeling.
EPA performed BMD modeling for data on all cancer endpoints (Kano et at.. 2.009; Kasai et at..
2009) as relevant to humans. EPA ran the multi-tumor BMD models with and without liver
tumors to determine the sensitivity of the result to the inclusion of liver tumors. For some
tumors, the human relevance and/or pathology is not well understood such as subcutis fibroma,
which is a skin tumor that occurred following both inhalation and oral exposure.
Subcutis fibromas were observed in both oral and inhalation studies of chronic duration. The
high concentration group for subcutis fibroma inhalation data (Kasai et at.. 2009) was omitted
from the dose-response analysis Q s \ 201 *b). The incidence data were monotonic non-
decreasing functions of dose for the control (0 ppm), low (50 ppm), and mid-dose (250 ppm);
however, the incidence rate at the high dose (1,250 ppm) was lower than observed at the mid-
dose. No BMDS model exhibited reasonable fit to the data without dropping the high dose. The
need to drop the high dose creates uncertainty regarding the endpoint.
Nasal tumors were seen in both oral and inhalation studies of chronic duration. The MOA for
nasal tumors is uncertain. It has been suggested that direct exposure of the nasal tissues to liquid
during drinking water studies of 1,4-dioxane where sipper tubes have been used may have
confounded findings at the portal of entry in the nose (Sweeney et at.. 2008). However, nasal
tumors occurred in both oral and inhalation studies. 1,4-dioxane is a volatile chemical and it is
unknown how much drinking water exposure may be due to liquid, vapor, or aerosols.
There are a number of datasets where effect incidence was only observed in the highest exposure
group [zymbal gland adenomas and renal cell carcinomas from the inhalation data by Kasai et al.
(2009). cortical tubule degeneration from the oral data by NCI (1978). and nasal tumors from the
oral data by Kano et al. (2009) and Kociba et al. (1974)1.
As described in Section 3.2.7, EPA has medium-high confidence in hazard PODs used as the
basis for risk characterization.
4.3.6 Key Assumptions and Uncertainties in the Human Health Risk
Characterization
The uncertainty factors that are the basis of benchmark MOEs used in the risk evaluation account
for some sources of uncertainty for non-cancer hazards.
For chronic non-cancer risks, EPA used a benchmark MOE of 30, based on an uncertainty factor
of 3 for interspecies variability and an uncertainty factor of 10 for interindividual variability.
Chronic non-cancer risk estimates from inhalation exposures were based on effects in the
olfactory epithelium and respiratory epithelium. These effects were attributed to systemic
delivery of 1,4-dioxane and are therefore assumed to be relevant to both inhalation and dermal
exposures.
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For acute non-cancer risks, EPA used a benchmark MOE of 300 based on uncertainty factors of
3 for interspecies variability, 10 for interindividual variability, and 10 for extrapolation from a
LOEALtoaNOAEL.
For cancer risk estimates, in the absence of a known MO A for liver tumors or other tumor types,
a linear low-dose extrapolation approach was used to estimate the dose-response at doses below
the observable range. There was a high degree of uncertainty in any of the MOA hypotheses
considered in this evaluation (e.g., mutagenic mode of action or threshold response to
cytotoxicity and regenerative hyperplasia for liver tumors). Linear extrapolation is the default
approach when there is uncertainty about the MOA. 1,4-Dioxane is a multi-site carcinogen and
may have more than one MOA. EPA estimates for excess cancer risk were based on the
assumption of linearity in the relationship between 1,4-dioxane exposure and the probability of
cancer. To understand the impact of assuming a linear dose-response for liver tumors, EPA
presents combined cancer risk estimates that do not include the liver tumors. As seen in Table
3-10., excluding liver tumors from the combined linear model has a minimal impact on the
overall inhalation cancer risk estimate.
Route-to-route extrapolation of dermal cancer and non-cancer PODs from oral and inhalation
studies introduced several potential sources of uncertainty. There is a lack of information about
how differences in absorption, metabolism and distribution to target tissues alter toxicity of 1,4-
dioxane across routes of exposure. While EPA does not have data to quantify these uncertainties,
they are expected to overestimate rather than underestimate dermal risk.
Dermal absorption and permeation could provide sources of uncertainty in the dermal risk
assessment for both dermal cancer and noncancer estimates of risk. The transdermal flux
parameters reported by researchers varied depending on the test conditions (Section 2.4.1.1.13
and Figure 2-2).
There is also some uncertainty related to the potential impact of 1,4-dioxane on potentially
exposed and susceptible subpopulations. EPA applied an intraspecies uncertainty factor of 10 to
all non-cancer PODs to account for variation in sensitivity across gender, age, health status, or
genetic makeup, but the actual magnitude of the impact of these factors on susceptibility is
unknown. Workers were identified as relevant potentially exposed or susceptible subpopulations,
but EPA did not specifically identify women of reproductive age or pregnant women who may
work with 1,4-dioxane or children ages 16 to 21 because EPA does not have information to
indicate that 1,4-dioxane would preferentially affect women or developing children.
4.4 Potentially Exposed or Susceptible Subpopulations (PESS)
TSCA § 6(b)(4) requires that EPA conduct a risk evaluation to "determine whether a chemical
substance presents an unreasonable risk of injury to health or the environment, without
consideration of cost or other non-risk factors, including an unreasonable risk to a potentially
exposed or susceptible subpopulation identified as relevant to the risk evaluation by the
Administrator, under the conditions of use" TSCA § 3(12) states that "the term 'potentially
exposed or susceptible subpopulation' means a group of individuals within the general
population identified by the Administrator who, due to either greater susceptibility or greater
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exposure, may be at greater risk than the general population of adverse health effects from
exposure to a chemical substance or mixture, such as infants, children, pregnant women,
workers, or the elderlyEPA believes that the statutory directive to consider potentially
exposed or susceptible subpopulations (PESS) and the statutory definition of PES S inherently
include environmental justice populations. Thus, EPA's consideration of PESS in this risk
evaluation addresses the requirements of the Executive Order 12898.
Previous EPA assessments for 1,4-dioxane found no direct evidence that specific populations
and lifestages are more susceptible to 1,4-dioxane (EPA IRIS Assessments ( 2013d.
2010)). Information on induction of liver enzymes, genetic polymorphisms and gender
differences is inadequate to quantitatively assess toxicokinetic or toxicodynamic differences in
1,4-dioxane hazard between animals and humans and the potential variability in human
susceptibility.
As discussed in Section 3.2.6.1, some subpopulations may be more biologically susceptible to
the effects of 1,4-dioxane due to genetic variability, pre-existing health conditions, lifestage,
pregnancy, or other factors that alter metabolism or increase target organ susceptibility. For
example, people with liver disease may be more susceptible due to reduced metabolism of 1,4-
dioxane and increased susceptibility of a target organ. EPA does not have sufficient quantitative
information about these potential sources of susceptibility to quantitatively incorporate them into
the risk evaluation. Populations with liver sensitivities or other underlying health issues within
the worker and ONU populations would be expected to have increased susceptibility to 1,4-
dioxane.
In developing the risk evaluation, the EPA qualitatively analyzed the reasonably available
information to ascertain whether some human receptor groups may have greater exposure or
greater susceptibility than the general population to the hazard posed by a chemical. Exposures
of 1,4-dioxane would be expected to be higher amongst workers and ONUs using 1,4-dioxane as
compared to the general population. EPA's decision for unreasonable risk are based on high-end
exposure estimates for workers and high intensity use scenarios for consumers and bystanders in
order to capture individuals who are PESS. Members of the general population incidentally
exposed to 1,4-dioxane through recreational activities in ambient water containing 1,4-dioxane
are also subject to greater exposure. The general population analysis considered and used the age
group that resulted in the highest exposure estimates for the purposed of risk characterization and
risk determination. For example, while recommended intake rates for oral ingestion during
swimming were available for ages 6 years and greater, the 11-15 age class was selected for
exposure and risk characterization based on the combination of intake, duration, and body weight
for that age class resulting in the highest estimated exposures. Likewise, consumers and
bystanders exposed to 1,4-dioxane through the use of household products that contain 1,4-
dioxane as a byproduct are also considered PESS due to their greater exposure. Additionally,
high-intensity users {i.e., those using consumer products for longer durations or in great
amounts) are evaluated. Consumers are considered to include children and adults, ages 11 and
up, while bystanders in the home exposed via inhalation could include children and adults of all
ages.
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4.5 Aggregate and Sentinel Exposures
Section 2605(b)(4)(F)(ii) of TSCA requires the EPA, as a part of the risk evaluation, to describe
whether aggregate or sentinel exposures under the conditions of use were considered and the
basis for their consideration. The EPA has defined aggregate exposure as "the combined
exposures to an individual from a single chemical substance across multiple routes and across
multiple pathways (40 CFR § 702.33)."
For each COU, EPA evaluated risks from dermal and inhalation exposures independently.
Inhalation and dermal exposures are assumed to occur simultaneously for workers and
consumers. Dermal and oral exposures are assumed to occur simultaneously for general
population exposures through swimming. EPA chose not to employ simple additivity of risk
exposure pathways within a condition of use because of the uncertainties present in the current
exposure estimation procedures. There is currently no PBPK model available to facilitate
evaluation of aggregate exposure from simultaneous exposure through inhalation and dermal
contact with 1,4-dioxane. Without a PBPK model containing a dermal compartment to account
for toxicokinetic processes the true internal dose for any given exposure cannot be determined,
and aggregating exposures by simply adding exposures from multiple routes could
inappropriately overestimate total exposure. This lack of aggregation across exposoure routes
may lead to an underestimate of exposure.
EPA also did not consider aggregate exposure among individuals who may be exposed both in
an occupational and consumer context because there is insufficient information reasonably
available as to the likelihood of this scenario or the relative distribution of exposures from each
pathway.
The EPA defines sentinel exposure as "the exposure to a single chemical substance that
represents the plausible upper bound of exposure relative to all other exposures within a broad
category of similar or related exposures (40 CFR § 702.33)." In terms of this risk evaluation, the
EPA considered sentinel exposures by evaluating exposures to populations who may have upper
bound exposures. EPA characterized high-end exposures using both monitoring data and
modeling approaches. Where statistical data are available, EPA typically uses the 95th percentile
value of the available dataset to characterize high-end exposure for a given condition of use. For
consumer and bystander exposures, EPA characterized sentinel exposure through a "high-
intensity use" category based on both product and user-specific. EPA's decision for unreasonable
risk are based on high-end exposure estimates to capture individuals with sentinel exposure.
4.6 Risk Conclusions
4,6.1 Summary of Environmental Risk
EPA's analysis of environmental risk, in Section 4.1 identified risk to aquatic organisms (acute
RQ > 1, or a chronic RQ > 1 and 20 days or more of exceedance for the chronic COC). EPA did
not identify RQs greater than 1 for aquatic organisms near any facilities. These facilities are
presented in Tables 4-1,4-1 and 4-3.
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EPA did not identify acute or chronic risks to fish, invertebrates or algae in the surface water
where monitored data were reasonably available. There were no exceedances of the acute COC (
57,000 ppb), or chronic COC (14,500 ppb) in surface water.
Table 4-1. Environmental Risk Estimation of 1,4-Dioxane from Industrial Releases into
Surface Water from DMR Facilities in Year 2015 and 2016
Name, Location, and ID
of Active Releaser Facility
E-FAST Inputs and Results
RQ
Days of
Release a
Release a
(kg/day)
10th Percentile
7Q10
Concentration
(Mg/L)
Days
Exceedance
(days/yr)
Algae
(Acute)
coc =
57,500 |ig/L
Fish
(Chronic)
coc =
14,500
Hg/L
Minimum Acute and Chronic Risk Quotient Values Reported from 10 DMR Facilities Reported in 2015
Eastman Kodak
NY0001643
(SIC 3861)
1
20
18.78
NA
6.90E-05
1.74E-05
20
1
0.95
0
6.90E-06
1.74E-06
250
0.1
0.0949
0
0
0
Maximum Acute and Chronic Risk Quotient Values Reported from 10 DMR Facilities in 2015
Dak Americas LLC
SC0026506
(SIC 2821)
10b
920
10,900 b
NA
0.031731
0.0080017
20
460
5,428.91
0
0.0025379
0.00064
250
37
434.22
0
0.0002966
7.48E-05
Minimum Acute and Chronic Risk Quotient Values Reported from 10 DMR Facilities Reported in 2016
Eastman Kodak
NY0001643
(SIC 3861)
1
79
74.46
NA
0.001295
0.0051352
20
3.9
3.7
0
6.43478 E-05
0.0002552
250
0.3
0.28
0
4.86957 E-06
1.93103 E-
05
Maximum Acute and Chronic Risk Quotient Values Reported from 10 DMR Facilities in 2016
Dak Americas LLC
SC0026506
(SIC 2821)
10"
977
11,500
NA
0.2
0.7931034
20
488
5,761.65
0
0.1002026
0.3973552
250
39
461.36
0
0.0080237
0.0318179
Days of release (1, 20, or 250) are EPA assumptions that provide a range of potential surface water concentrations; days of release were
not reported in DMR. The release (kg/day) is based on the per day based on total annual loading (lbs/yr), as reported in DMR Pollutant
Loading Tool, and is divided by the assumed number of release days prior to modeling.
The Dak chemicals site acute scenario was re-run for a 10-day acute scenario based on input from EPA engineers related to the lowest
number of operating days assumed for facilities falling within this standard industrial category (i.e., 10 days per year). Therefore,
maximum surface water concentrations based on this site reflect an assumed 10 days per year of release instead of 1 day.
Table 4-2. Environmental Risk Estimation of 1,4-Dioxane from Direct Industrial Releases
into Surface Water from TRI Facilities in Year 2014 and 2015
Name, Location, and ID
of Active Releaser Facility
E-FAST Inputs and Results
RQ
Days of
Release a
Release a
(kg/day)
10th Percentile
7Q10
Concentration
(Mg/L)
Days
Exceedance
(days/yr)
Algae
coc =
57,500 |ig/L
Fish Chronic
coc =
14,500 ng/L
Minimum Acute and Chronic Risk Quotient Values Reported from 10 TRI Facilities in 2014a
The DOW Chemical Co.
Louisiana Operations
LA0003301 b
1
312
1.26
NA
2.19E-05
8.69E-05
20
16
0.0648
0
1.13E-06
4.47E-06
250
1
0.00405
0
7.04E-08
2.79E-07
Page 252 of 616
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Name, Location, and ID
of Active Releaser Facility
E-FAST Inputs and Results
RQ
Days of
Release a
Release a
(kg/day)
10th Percentile
7Q10
Concentration
(Mg/L)
Days
Exceedance
(days/yr)
Algae
coc =
57,500 |ig/L
Fish Chronic
coc =
14,500 ng/L
Maximum Acute and Chronic Risk Quotient Values Reported from 10 TRI Facilities in 2014a
DAK Americas LLC
Cooper River Plant
SC0026506
10c
825
9,734
NA
1.69E-01
6.71E-01
20
412
4,861.36
0
8.45E-02
3.35E-01
250
33
389.4
0
6.77E-03
2.69E-02
Minimum Acute and Chronic Risk Quotient Values Reported from 10 TRI Facilities in 2015
The DOW Chemical Co.
Louisiana Operations
LA0003301 b
1
337
1.36
NA
2.37E-05
9.38E-05
20
17
0.0688
0
1.20E-06
4.74E-06
250
1
0.00405
0
7.04E-08
2.79E-07
Maximum Acute and Chronic Risk Quotient Values Reported from 10 TRI Facilities in 2015
DAK Americas LLC
Cooper River Plant
SC0026506
10c
810
9,557
NA
1.66E-01
6.59E-01
20
405
4778.76
0
8.31E-02
3.30E-01
250
32
377.58
0
6.57E-03
2.60E-02
a. Days of release (1, 20, or 250) are EPA assumptions that provide a range of potential surface water concentrations; days of release were
not reported to TRI. The release (kg/day) is based on the per day based on annual releases to surface water (lbs/yr), as reported to TRI,
and is divided by the assumed number of release days prior to modeling.
b. The NPDES provided in DMR" s Pollutant Loading Tool for the facility THE DOW CHEMICAL CO - LOUISIANA OPERATIONS
(NPDES LA0116602) was not found in E-FAST 2014; however, a facility name and location search within E-FAST 2014 returned a
different NPDES (LA0003301) associated with this facility name and location, so it was applied for modeling.
c. ARKEMA Inc (KY0003603), Dow Chemical Co Freeport (TX0006483), Honeywell International (LA0000329), and Westlake Vinyls
Inc (KY0003484 ) facilities, which were included in the risk evaluation based on previous data extraction, did not have reported surface
water discharges in TRI explorer per 2015 release report and were therefore removed from the list of assessed sites.
Table 4-3. Environmental Risk Estimation of 1,4-Dioxane from Indirect Industrial Releases
into Surface Water from TRI Facilities in Year 2014 and 2015
Name, Location, and ID of
Receiving
E-FAST Inputs and Results
RQ
Active Releaser Facility
NPDES Used in E-FAST
POTW
Days of
Releasea
Release a
(kg/day)
7Q10
Concentrati
on
Days
Exceedance
(days/yr)
COC = 14,500
Hg/L
Algae
COC =
57,500
Hg/L
Fish
Chronic
COC =
14,500
Hg/L
Minimum Acute and Chronic Risk Quotient Values Reported from 6 TRI Facilities in 2014
Evonik Materials Corp.
Milton
250
0.001
0.00586
0
1.02E-07
4.04E-07
WI0060453
Waterworks
Maximum Acute and Chronic Risk Quotient Values Reported from 6 TRI Facilities in 2014a
SUEZ WTS Solutions USA
Blue Lake
250
30
3788.66
4
6.59E-02
2.61E-01
Inc.
WWTP
Ind. POTW
(SIC 4952)b
Minimum Acute and Chronic Risk Quotient Values Reported from 10 TRI Facilities in 2015
Heritage Thermal Services
East Liverpool
250
2.39E-07
2.37E-08
0
4.12E-13
1.63E-12
OH0024970
WWTP
Maximum Acute and Chronic Risk Quotient Values Reported from 10 TRI Facilities in 2015
SUEZ WTS Solutions USA
Blue Lake
250
27
3409.79
3
5.93E-02
2.35E-01
Inc.
WWTP
Ind. POTW
(SIC 4952)b
Page 253 of 616
-------
Name, Location, and ID of
Receiving
E-FAST Inputs and Results
RQ
Active Releaser Facility
POTW
Days of
Release a
7Q10
Days
Algae
Fish
NPDES Used in E-FAST
Releasea
(kg/day)
Concentrati
Exceedance
coc =
Chronic
on
(days/yr)
57,500
coc =
COC = 14,500
Hg/L
14,500
Hg/L
Hg/L
a. Days of release (250) are EPA assumptions that provide a range of potential surface water concentrations; days of release were not reported
to TRI. The release (kg/day) is based on the per day based on annual releases to surface water (lbs/yr), as reported to TRI, and is divided
by the assumed number of release days prior to modeling.
b. SIC for industrial POTWs was used for the facility because the facility was not found in E-FAST 2014.
4.6.2 Summary of Human Health Risk
4.6.2.1 Summary of Risk for Workers and ONUs
Table 4-23. summarizes the representative risk estimates for inhalation and dermal exposures for
all occupational exposure scenarios. Risk estimates that indicate potential risk (i.e. MOEs less
than the benchmark MOE or cancer risks greater than the cancer risk benchmark) are highlighted
by holding the number and shading the cell in gray. The occupational exposure assessment and
risk characterization are described in more detail in Sections 2.4.1 and 4.2, respectively. Specific
links to the relevant risk characterization sections are listed in Table 4-23. in the Occupational
Exposure Scenario column.
Risk estimates for each inhalation and dermal exposure scenario for workers are presented both
with and without PPE. EPA calculated risks based on respirator APFs of 1, 10, or 50 and glove
PFs of 1, 5, 10 or 20. The lowest protection factor that results in no indication of risk relative to
the benchmark is shown (i.e., if risks do not exceed the benchmark for APF 10 and above, the
risk estimate for APF 10 is shown).
Inhalation
Cancer risks for central tendency and high-end worker inhalation exposures exceed the cancer
benchmark for manufacturing, import/repackaging, industrial use, film cement, and disposal.
High-end inhalation exposures also exceed the cancer benchmark for lab chemicals and dry film
lubricant. With respirator use (APF 50), cancer risk is reduced to below the benchmark for all
worker exposure scenarios expect for high-end industrial use exposures.
For acute and chronic inhalation exposures, MOEs indicate non-cancer risks to workers relative
to the benchmarks for central tendency and high-end exposures predicted for import/repackaging
(bottle and drum), industrial use, film cement, and disposal. MOEs also indicate risks relative to
the benchmarks for high-end exposures predicted for manufacturing, lab chemicals, and dry film
lubricant. MOEs calculated based on respirator use (APF 50), do not indicate non-cancer risk
relative to the benchmarks for any acute or chronic worker inhalation exposures.
Occupational non-users are expected to have lower levels of exposure than workers in most
instances, but exposures could not always be quantified. When separate ONU exposure estimates
were not reasonably available, EPA provided risk estimates for ONUs based on central tendency
exposures for workers without PPE. These instances are indicated with footnotes in Table 4-23..
MOEs for ONU-specific exposure scenarios for spray foam application, functional fluids, and
film cement do not indicate risk relative to the benchmark. Upper-bound ONU exposure
estimates based on central tendency exposures for workers indicate inhalation risks for ONUs in
Page 254 of 616
-------
manufacturing, import/repackaging (bottle and drum), industrial use, and disposal exposure
scenarios. ONUs are assumed not to wear respirators.
Dermal
Cancer risk from central tendency and high end dermal exposures exceeds the cancer benchmark
of 10"4, indicating risk for all occupational exposure scenarios in the absence of glove use. With
glove use (PF 5 and above), cancer risk is reduced to below the benchmark for functional fluids
and spray foam application exposure scenarios. Glove use does not reduce cancer risk to below
the cancer benchmark for any other worker exposure scenarios.
Noncancer risks for central tendency and high-end acute and chronic dermal exposures are below
the benchmark MOEs, indicating risk for workers in the following exposure scenarios:
manufacturing, import/repackaging (bottle and drum), industrial use, lab chemical use, use of 3D
printing inks, film cement, dry film lubricant, and disposal. For most of these scenarios, glove
use (up to PF 20) is not sufficient to reduce risks from acute or chronic exposures relative to the
benchmark. Glove use would only be expected to reduce chronic non-cancer risk relative to the
benchmark MOE for import/repackaging scenarios. No acute or chronic non-cancer risk is
identified for dermal exposures associated with spray foam application or functional fluids,
regardless of glove use. EPA did not calculate risks of dermal exposure for ONUs because ONUs
are assumed to have no direct dermal contact with 1,4-dioxane.
Page 255 of 616
-------
Table 4-23. Summary of Human Health Ris
i. From Occupational Exposures
l.ilc Cycle
Csilcgory
Subc:ilo«>orios
Occn p:ition ill
Kxposurc
Sceiiiirio
Popiihition
Kxposurc
Roulo
iiiul
Dui'iilion
Kxposurc
l.e\el
Risk Kstiniiitos lor No I'l'K
Risk l-isliin:i(cs with I'PK
Aculc \on-
c.inccr
(bench in ;irk
moi: =
300)
Chronic
\on-csinccr
(hcnchimirk
M()i: = 30)
Csincer
(hciuhniit rk
= I04)
Aculc Non-
ciinccr
(hcnchimirk
moi: =
300)
Chronic
Non-csinccr
(hcnchnnirk
M()i: = 30)
Ciinccr
(bench in :irk
= I04)
Manufacture/
Domestic
manufacture
Domestic
manufacture
Section
2.4.1.1.1 and
4.2 -
Manufacturing
Worker
Inhalation
8-hr
TWA
Central
Tendency
684
32.1
1.59E-04
f\X43
(AIM 10)
321
(AIM 10)
1 5^L-i)5
(AIM 10)
High-End
36.7
1.72
3.81 E-03
367
(APF 10)
86.1
(APF 50)
7.63 E-05
(APF 50)
Dermal
Central
Tendency
4.83
0.23
0.34
96.6
(PF 20)
4.54
(PF 20)
1.72E-02
(PF 20)
High-End
1.61
7.57E-02
1.33
32.2
(PF 20)
1.51
(PF 20)
6.67E-02
(PF 20)
ONUb
Inhalation
8-hr
TWA
Central
Tendency
684
32.1
1.59E-04
N/A
N/A
N/A
High-End
N/A
N/A
N/A
Manufacture/
Import
Import
Section
2.4.1.1.2 and
4.2 - Import/
Worker
Inhalation
8-hr
TWA
Central
Tendency
30.6
27.6
1.75E-04
306
(APF 10)
276
(APF 10)
1.75E-05
(APF 10)
Page 256 of 616
-------
Risk Estimates lor No I'l'E
Risk Estimates with I'l'E
Life Cycle
Sin *»o/
Category
Subcategories
Occupational
Exposure
Scenario
Population
Exposure
Route
:t ml
Duration
Exposure
l.e\el
Anile Non-
cancer
(benchmark
moi: =
300)
Chronic
Non-cancer
(hen chin :i r k
MOE = 30)
Cancer
(hen cli in ark
= I04)
Acute Non-
cancer
(hen chin a rk
MOE =
300)
Chronic
Non-cancer
(benchmark
MOE = 30)
Cancer
(benchmark
= It)4)
Repackaging
(Bottle)
Repackaging
(Bottle)
High-End
S.5S
3.77
1.32E-03
129
(APF 50)
37.7
(APF 10)
2.0 IL-05
(APF 50)
Dermal
Central
Tendency
4.83
18.9
4.13E-03
96.6
(PF 20)
94.6
(PF 5)
2.07E-04
(PF 20)
High-End
1.61
0.59
0.17
32.2
(PF 20)
11.8
(PF 20)
8.54E-03
(PF 20)
Inhalation
Central
Tendency
30.6
27.6
1.75E-04
N/A
N/A
N/A
ONUb
8-hr
TWA
High-End
"
"
"
N/A
N/A
N/A
Inhalation
8-hr
TWA
Central
Tendency
26.7
27.6
1.75E-04
1,334
(APF 50)
276
(APF 10)
1.75E-05
(APF 10)
Section
2.4.1.1.2 and
4.2-
Import/Repack
aging (Drum)
Worker
High-End
7.44
3.77
1.32E-03
372
(APF 50)
37.7
(APF 10)
2.64E-05
(APF 50)
Manufacture/
Import
Import
Repackaging
Dermal
Central
Tendency
4.83
9.46
8.27E-03
96.6
(PF 20)
47.3
(PF 5)
4.13E-04
(PF 20)
(Drum)
High-End
1.61
0.33
0.31
32.2
(PF 20)
6.52
(PF 20)
1.55E-02
(PF 20)
ONUb
Inhalation
8-hr
Central
Tendency
26.7
27.6
1.75E-04
N/A
N/A
N/A
TWA
High-End
--
--
~
N/A
N/A
N/A
Processing
Processing/
Repackaging
(Bottle)
Section
2.4.1.1.2 and
4.2 - Import/
Worker
Inhalation
8-hr
TWA
Central
Tendency
30.6
27.6
1.75E-04
306
(APF 10)
276
(APF 10)
1.75E-05
(APF 10)
Page 257 of 616
-------
Risk Estimates lor No I'l'E
Risk Estimates with I'l'E
Life Cycle
Sin *»o/
Category
Subcategories
Occupational
Exposure
Scenario
Population
Exposure
Route
:t ml
Duration
Exposure
l.e\el
Anile Non-
cancer
(benchmark
moi: =
300)
Chronic
Non-cancer
(hen chin :i r k
MOE = 30)
Cancer
(hen cli in ark
= I04)
Acute Non-
cancer
(hen chin a rk
MOE =
300)
Chronic
Non-cancer
(benchmark
MOE = 30)
Cancer
(benchmark
= It)4)
Repackaging
(Bottle)
High-End
S.5S
3.77
1.32 E-03
129
(APF 50)
37.7
(APF 10)
2.(> IL-05
(APF 50)
Dermal
Central
Tendency
4.83
18.9
4.13E-03
96.6
(PF 20)
94.6
(PF 5)
2.07E-04
(PF 20)
High-End
1.61
0.59
0.17
32.2
(PF 20)
11.8
(PF 20)
8.54 E-03
(PF 20)
Inhalation
Central
Tendency
30.6
27.6
1.75E-04
N/A
N/A
N/A
ONUb
8-hr
TWA
High-End
"
"
"
N/A
N/A
N/A
Inhalation
8-hr
TWA
Central
Tendency
26.7
27.6
1.75E-04
1,334
(APF 50)
276
(APF 10)
1.75E-05
(APF 10)
Section
2.4.1.1.2 and
4.2-
Import/Repack
aging (Drum)
Worker
High-End
7.44
3.77
1.32E-03
372
(APF 50)
37.7
(APF 10)
2.64E-05
(APF 50)
Processing
Processing/
Repackaging
(Drum)
Dermal
Central
Tendency
4.83
9.46
8.27E-03
96.6
(PF 20)
47.3
(PF 5)
4.13E-04
(PF 20)
High-End
1.61
0.33
0.31
32.2
(PF 20)
6.52
(PF 20)
1.55E-02
(PF 20)
ONUb
Inhalation
8-hr
Central
Tendency
26.7
27.6
1.75E-04
N/A
N/A
N/A
TWA
High-End
--
--
~
N/A
N/A
N/A
Processing/
Recycling
Section
2.4.1.1.4 and
Worker
Inhalation
8-hr
TWA
Central
Tendency
56.8
2.66
1.91 E-03
568
(APF 10)
133
(APF 50)
3.82E-05
(APF 50)
Recycling
4.2 - Industrial
Use
High-End
14.2
0.67
9.86E-03
710
(APF 50)
33.3
(APF 50)
1.97E-04
(APF 50)
Page 258 of 616
-------
Life Cycle
Sin *»o/
Category
Subcategories
Occupational
Kxposure
Scenario
Population
Kxposure
Route
:t ml
Duration
Kxposure
l.e\el
Risk Kslimales lor No I'l'K
Risk Estimates with I'l'K
Acute Non-
cancer
(benchmark
moi: =
300)
Chronic
Non-cancer
(benchmark
M()K = 30)
Cancer
(hen cli in ark
= 10 4)
Acute Non-
cancer
(benchmark
moi: =
300)
Chronic
Non-cancer
(benchmark
M()i: = 30)
Cancer
(benchmark
= It)4)
IX* nil ill
(en Hill
TcikIciicn
4.83
0.23
0.34
9(>.6
(PF 20)
4.54
(Pi; :<))
I.72K-02
(Pi: :<))
lliuh-Likl
1.61
7.57 K-02
1.33
32.2
(m :o)
1.51
(Pi: :<))
6.67 E-02
(Pi: :<))
ONUb
Inhalation
8-hr
TWA
Central
Tendency
56.8
2.66
1.91 E-03
N/A
N/A
N/A
High-End
~
--
--
N/A
N/A
N/A
Processing/
Non-
Incorporative
Basic organic
chemical
manufacturing
(process solvent)
Section
2.4.1.1.4 and
4.2 - Industrial
Use
Worker
Inhalation
8-hr
TWA
Central
Tendency
56.8
2.66
1.91 E-03
568
(APF 10)
133
(APF 50)
3.82E-05
(APF 50)
High-End
14.2
0.67
9.86 E-03
710
(APF 50)
33.3
(APF 50)
1.97E-04
(APF 50)
Dermal
Central
Tendency
4.83
0.23
0.34
96.6
(PF 20)
4.54
(PF 20)
1.72E-02
(PF 20)
High-End
1.61
7.57E-02
1.33
32.2
(PF 20)
1.51
(PF 20)
6.67E-02
(PF 20)
ONUb
Inhalation
8-hr
TWA
Central
Tendency
56.8
2.66
1.91 E-03
N/A
N/A
N/A
High-End
--
--
--
N/A
N/A
N/A
Processing/
Processing as a
reactant
Polymerization
catalyst
Section
2.4.1.1.4 and
4.2 - Industrial
Use
Worker
Inhalation
8-hr
TWA
Central
Tendency
56.8
2.66
1.91 E-03
568
(APF 10)
133
(APF 50)
3.82E-05
(APF 50)
High-End
14.2
0.67
9.86 E-03
710
(APF 50)
33.3
(APF 50)
1.97E-04
(APF 50)
Dermal
Central
Tendency
4.83
0.23
0.34
96.6
(PF 20)
4.54
(PF 20)
1.72E-02
(PF 20)
High-End
1.61
7.57E-02
1.33
32.2
(PF 20)
1.51
(PF 20)
6.67E-02
(PF 20)
Page 259 of 616
-------
Life Cycle
Sin *»o/
Category
Subcategories
Occii|);itioii;il
Kxposure
Scenario
Population
Kxposure
Route
:t ml
Dui'iition
Kxposure
l.e\el
Risk Kslimales lor No I'l'E
Risk Estimates with I'l'K
Acute Non-
cancer
(ben chili si rk
moi: =
3(H))
Chronic
Non-cancer
(benchniiirk
MOI-: = 30)
Cancer
(ben cli in ark
= I04)
Acute Non-
cancer
(ben chin a rk
moi: =
300)
Chronic
Non-cancer
(benchmark
M()i: = 30)
Cancer
(benchmark
= It)4)
ONUb
Inhalation
8-hr
TWA
Central
Tendency
56.8
2.66
1.91E-03
N, A
N/A
N,A
High-End
--
--
~
N/A
N/A
N/A
Industrial Use/
Intermediate
Use
Agricultural
chemical
intermediate
Plasticizer
intermediate
Catalysts and
reagents for
anhydrous acid
reactions,
brominations
and sulfonations
Section
2.4.1.1.4 and
4.2 - Industrial
Use
Worker
Inhalation
8-hr
TWA
Central
Tendency
56.8
2.66
1.91 E-03
568
(APF 10)
133
(APF 50)
3.82E-05
(APF 50)
High-End
14.2
0.67
9.86E-03
710
(APF 50)
33.3
(APF 50)
1.97E-04
(APF 50)
Dermal
Central
Tendency
4.83
0.23
0.34
96.6
(PF 20)
4.54
(PF 20)
1.72E-02
(PF 20)
High-End
1.61
7.57E-02
1.33
32.2
(PF 20)
1.51
(PF 20)
6.67E-02
(PF 20)
ONUb
Inhalation
8-hr
TWA
Central
Tendency
56.8
2.66
1.91 E-03
N/A
N/A
N/A
High-End
--
--
--
N/A
N/A
N/A
Industrial Use/
Processing
aids, not
otherwise
listed
Wood pulping
Extraction of
animal and
vegetable oils
Wetting and
dispersing agent
in textile
processing
Purification of
process
intermediates
Etching of
fluoropolymers
Section
2.4.1.1.4 and
4.2 - Industrial
Use
Worker
Inhalation
8-hr
TWA
Central
Tendency
56.8
2.66
1.91 E-03
568
(APF 10)
133
(APF 50)
3.82E-05
(APF 50)
High-End
14.2
0.67
9.86 E-03
710
(APF 50)
33.3
(APF 50)
1.97E-04
(APF 50)
Dermal
Central
Tendency
4.83
0.23
0.34
96.6
(PF 20)
4.54
(PF 20)
1.72E-02
(PF 20)
High-End
1.61
7.57E-02
1.33
32.2
(PF 20)
1.51
(PF 20)
6.67E-02
(PF 20)
ONUb
Inhalation
8-hr
TWA
Central
Tendency
56.8
2.66
1.91 E-03
N/A
N/A
N/A
High-End
N/A
N/A
N/A
Page 260 of 616
-------
Life Cycle
Sin *»o/
Category
Subcategories
Occii|);itioii;il
Exposure
Scenario
Population
Exposure
Route
:t ml
Dui'iition
Exposure
l.e\el
Risk Estimates lor No I'l'E
Risk Estimates with I'l'E
Acute Non-
cancer
(ben chili si rk
moi: =
300)
Chronic
Non-cancer
(benchniiirk
MOE = 30)
Cancer
(ben cli in ark
= I04)
Acute Non-
cancer
(benchmark
MOE =
300)
Chronic
Non-cancer
(benchmark
MOE = 30)
Cancer
(benchmark
= It)4)
Industrial Use/
Functional
Fluids, Open
System
Metalworking
fluid
Cutting and
tapping fluid
Polyalkylene
glycol fluid
Section
2.4.1.1.5 and
4.2-
Functional
Fluids, Open
System
Worker
Inhalation
8-hr
TWA
Central
Tendency
266,475
12,491
3.88E-07
2,664,753
(APF 10)
124,906
(APF 10)
3.88E-08
(APF 10)
High-End
74,906
3,511
1.45E-06
749,065
(APF 10)
35,111
(APF 10)
1.45E-07
(APF 10)
Dermal
Central
Tendency
4,830
227
3.45E-04
24,149
(PF 5)
1,135
(PF 5)
6.89E-05
(PF 5)
High-End
1,610
75.7
1.33E-03
8,050
(PF 5)
378
(PF 5)
6.67E-05
(PF 20)
ONUc
Inhalation
8-hr
TWA
Central
Tendency
1,903,645
89,230
5.70E-08
N/A
N/A
N/A
High-End
1,128,664
52,904
1.24E-07
N/A
N/A
N/A
Industrial Use,
Potential
Commercial
Use/
Laboratory
Chemicals
Chemical
reagent
Reference
material
Spectroscopic
and photometric
measurement
Liquid
scintillation
counting
medium
Stable reaction
medium
Section
2.4.1.1.7 and
4.2 - Lab
Chemicals
Worker
Inhalation
8-hr
TWA
Central
Tendency
2,582
121
4.20E-05
25,818
(APF 10)
1,210
(APF 10)
4.20E-06
(APF 10)
High-End
49.4
2.32
2.83E-03
494
(APF 10)
116
(APF 50)
5.67E-05
(APF 50)
Dermal
Central
Tendency
4.42
0.21
0.38
88.3
(PF 20)
4.15
(PF 20)
1.88E-02
(PF 20)
High-End
1.47
6.92E-02
1.46
29.4
(PF 20)
1.38
(PF 20)
7.29E-02
(PF 20)
ONUb
Inhalation
8-hr
TWA
Central
Tendency
2,582
121
4.20E-05
N/A
N/A
N/A
High-End
N/A
N/A
N/A
Page 261 of 616
-------
Risk Estimates lor No I'l'E
Risk Estimates with I'l'E
Life Cycle
Sin *»o/
Category
Subcategories
Occii|);itioii;il
Exposure
Scenario
Population
Exposure
Route
:t ml
Dui'iition
Exposure
l.e\el
Acute Non-
cancer
(ben chili si rk
moi: =
300)
Chronic
Non-cancer
(benchniiirk
MOE = 30)
Cancer
(ben cli in ark
= I04)
Acute Non-
cancer
(benchmark
MOE =
300)
Chronic
Non-cancer
(benchmark
MOE = 30)
Cancer
(benchmark
= It)4)
Cryoscopic
solvent for
molecular mass
determinations
Preparation of
histological
sections for
microscopic
examination
Inhalation
8-hr
TWA
Central
Tendency
187
8.75
5.82E-04
1,866
(APF 10)
87.5
(APF 10)
5.82E-05
(APF 10)
Industrial Use,
Section
2.4.1.1.8 and
4.2 - Film
Worker
High-End
101
4.74
1.38E-03
1,012
(APF 10)
47.4
(APF 10)
2.77E-05
(APF 50)
Potential
Commercial
Use/
Film cement
Dermal
Central
Tendency
8.83
0.42
0.19
177
(PF 20)
8.30
(PF 20)
9.42E-03
(PF 20)
Adhesives and
Sealants
Cement
High-End
2.94
0.14
0.73
58.9
(PF 20)
2.77
(PF 20)
3.65E-02
(PF 20)
ONUc
Inhalation
8-hr
Central
Tendency
2,726
128
3.98E-05
N/A
N/A
N/A
TWA
High-End
2,726
128
5.14E-05
N/A
N/A
N/A
Industrial Use,
Section
Inhalation
8-hr
TWA
Central
Tendency
29,194
1,368
3.63E-06
291,939
(APF 10)
13,684
(APF 10)
3.63E-07
(APF 10)
Potential
Commercial
Use/
Other Uses
Spray
polyurethane
foam
2.4.1.1.9 and
4.2 - Spray
Foam
Application
Worker
High-End
24,030
1,126
5.25E-06
240,300
(APF 10)
11,264
(APF 10)
5.25E-07
(APF 10)
Dermal
Central
Tendency
4,415
208
3.77E-04
22,075
(PF 5)
1,038
(PF 5)
7.54E-05
(PF 5)
Page 262 of 616
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Life Cycle
Sin *»o/
CsHcgorv
Subcategories
Occii|);itioii;il
Exposure
Scenario
Population
Exposure
Route
:t ml
Dui'iition
Exposure
l.e\el
Risk Estimates lor No I'l'E
Risk Estimates with I'l'E
Acute Non-
cancer
(ben chili si rk
moi: =
300)
Chronic
Non-cancer
(benchniiirk
M()E = 30)
Cancer
(benchniiirk
= 10 4)
Acute Non-
can cer
(benchniiirk
moi: =
300)
Chronic
Non-cancer
(benchniiirk
M()i: = 30)
Cancer
(benchniiirk
= It)4)
High-End
1,472
69.2
1.46E-03
7,358
(PF 5)
346
(PF 5)
7.29E-05
(PF 20)
ONUc
Inhalation
8-hr
TWA
Central
Tendency
151,467
7,100
7.17E-07
N/A
N/A
N/A
High-End
151,467
7,100
9.25E-07
N/A
N/A
N/A
Industrial Use,
Potential
Commercial
Use/
Other Uses
Printing and
printing
compositions
Section
2.4.1.1.10 and
4.2 - Use of
Printing Inks
(3D)
Worker
Inhalation
8-hr
TWA
Central
Tendency
2,922
137
3.71E-05
29,218
(APF 10)
1,370
(APF 10)
3.71E-06
(APF 10)
High-End
2,922
137
4.79E-05
29,218
(APF 10)
1,370
(APF 10)
4.79E-06
(APF 10)
Dermal
Central
Tendency
4.42
0.21
0.38
88.3
(PF 20)
4.15
(PF 20)
1.88E-02
(PF 20)
High-End
1.47
6.92E-02
1.46
29.4
(PF 20)
1.38
(PF 20)
7.29E-02
(PF 20)
ONUb
Inhalation
8-hr
TWA
Central
Tendency
2,922
137
3.71E-05
N/A
N/A
N/A
High-End
--
--
--
N/A
N/A
N/A
Industrial Use,
Potential
Commercial
Use/ Other
Uses
Dry film
lubricant
Section
2.4.1.1.11 and
4.2 - Dry Film
Lubricant
Worker
Inhalation
8-hr
TWA
Central
Tendency
607
127
4.01E-05
6,068
(APF 10)
1,270
(APF 10)
4.01E-06
(APF 10)
High-End
177
37.1
1.77E-04
1,773
(APF 10)
371
(APF 10)
1.77E-05
(APF 10)
Dermal
Central
Tendency
4.83
1.01
7.72E-02
96.6
(PF 20)
20.3
(PF 20)
3.86E-03
(PF 20)
High-End
1.61
0.34
0.30
32.2
(PF 20)
6.76
(PF 20)
1.49E-02
(PF 20)
ONUb
Inhalation
8-hr
TWA
Central
Tendency
607
127
4.01E-05
N/A
N/A
N/A
High-End
--
--
--
N/A
N/A
N/A
Page 263 of 616
-------
Life Cycle
Sin *»o/
Category
Subcategories
Occii|);itioii;il
Kxposure
Scenario
Population
Kxposure
Route
:t ml
Dui'iition
Kxposure
l.e\el
Risk Kslimales lor No I'l'K
Risk Estimates with I'l'K
Acute Non-
cancer
(bench in ark
moi: =
300)
Chronic
Non-cancer
(benchmark
M()K = 30)
Cancer
(ben chili ark
= I04)
Acute Non-
cancer
(ben chin a rk
moi: =
300)
Chronic
Non-cancer
(benchmark
MOI-: = 30)
Cancer
(benchmark
= It)4)
Disposal/
Disposal
Wastewater
Underground
injection
Landfill
Recycling
Incineration
Section
2.4.1.1.12 and
4.2 - Disposal
Worker
Inhalation
8-hr
TWA
Central
Tendency
152
7.11
6.S0E-04
1,517
(APF 10)
71.1
(APF 10)
0.80L-05
(APF 10)
High-End
42.8
2.00
2.54E-03
428
(APF 10)
100
(APF 50)
5.08E-05
(APF 50)
Dermal
Central
Tendency
4.83
0.23
0.34
96.6
(PF 20)
4.54
(PF 20)
1.72E-02
(PF 20)
High-End
1.61
7.57E-02
1.33
32.2
(PF 20)
1.51
(PF 20)
6.67E-02
(PF 20)
ONUb
Inhalation
8-hr
TWA
Central
Tendency
152
7.11
6.80E-04
N/A
N/A
N/A
High-End
--
--
--
N/A
N/A
N/A
a Details on whether modelling or monitoring preformed, representativeness and confidence of data for various occupational expo sure life cycle categories are shown in Table 4-13.
b ONU-specific exposure estimates were not reasonably available. Risk estimates for ONUs are based on central tendency values for workers without PPE.
0 Based on ONU-specific exposure estimates. N/A = Not Applicable; ONUs are assumed to not wear respiratory protection.
Page 264 of 616
-------
4,6,2,2 Summary of Risk for Consumer Users and Bystanders
Table 4-24. summarizes risk estimates for inhalation and dermal exposures for all consumer
exposure scenarios. Risk estimates that indicate potential risk {i.e. MOEs less than the
benchmark MOE or cancer risks greater than the cancer risk benchmark) are highlighted by
bolding the number and shading the cell in gray. The consumer exposure assessment and risk
characterization are described in more detail in Sections 2.4.3 and 4.2.3, respectively.
Page 265 of 616
-------
Table 4-24. Summary of Human Health Risks from Consumer Exposures
Dermal Risk Kslimales
Inhalation Risk Kslimalcs
Assessed
Condition of
I so
Chronic
Acute MOK
Chronic
Category
Scenario Descriptor
Receptor
Acute MOK
Benchmark
Cancer
Risk"
MIX = 2S4
m j*/nr*
Cancer
Risk'1
11)0
Benchmark
Benchmark
inn
Benchmark
li:-uf,
Paints and
Coatings
Paint and
Floor Lacquer
High-Intensity User
Adult
(>21 years)
1.8E+04
NA
1.4E+04
NA
High-Intensity User
Child
(16-20 years)
1.9E+04
NA
NA
NA
High-Intensity User
Child
(11-15 years)
1.7E+04
NA
NA
NA
High-Intensity User
Bystander
NA
NA
3.8E+04
NA
Cleaning and
Furniture
Surface
Cleaner
High-Intensity User
Adult
(>21 years)
4.6E+06
6.7E-07
5.7E+04
1.0E-06
Care
Products
Moderate-Intensity
User
Adult
(>21 years)
NA
2.8E-07
NA
5.6E-07
High-Intensity User
Child
(16-20 years)
4.9E+06
NA
NA
NA
High-Intensity User
Child
(11-15 years)
4.5E+06
NA
NA
NA
High-Intensity User
Bystander
NA
NA
3.0E+05
NA
Laundry and
Dishwashing
Dish Soap
High-Intensity User
Adult
(>21 years)
1.2E+07
3.2E-08
9.3E+03
7.1E-07
Products
Moderate-Intensity
User
Adult
(>21 years)
NA
1.3E-08
NA
3.3E-07
High-Intensity User
Child
(16-20 years)
1.2E+07
NA
NA
NA
High-Intensity User
Child
(11-15 years)
1.1E+07
NA
NA
NA
High-Intensity User
Bystander
NA
NA
5.2E+04
NA
Page 266 of 616
-------
Dermal Risk Kslimnles
Inhalation Risk Kslimales
Cntcjiorv
Assessed
Condition of
I so
Scenario Descriptor
Receptor
Acute MOK
Benchmark
>i)i)
Chronic
("sincer
Risk'1
Benchmark
ll-l-iit.
Acute MOK
MIX = 2S4
nig/nr'
Benchmark
11)1)
Chronic
Cancer
Risk'1
Benchmark
Dishwasher
Detergent
High-Intensity User
Adult
(>21 years)
1.1E+07
1.4E-07
4.1E+05
7.1E-08
Moderate-Intensity
User
Adult
(>21 years)
NA
1.2E-07
NA
2.9E-08
High-Intensity User
Child
(16-20 years)
1.2E+07
NA
NA
NA
High-Intensity User
Child
(11-15 years)
1.1E+07
NA
NA
NA
High-Intensity User
Bystander
NA
NA
2.3E+06
NA
Laundry
Detergent
High-Intensity User
Adult
(>21 years)
7.4E+07
1.8E-08
1.9E+05
1.3E-07
Moderate-Intensity
User
Adult
(>21 years)
NA
7.4E-09
NA
7.8E-08
High-Intensity User
Child
(16-20 years)
7.9E+07
NA
NA
NA
High-Intensity User
Child
(11-15 years)
7.2E+07
NA
NA
NA
High-Intensity User
Bystander
NA
NA
1.1E+06
NA
Arts, Crafts,
and Hobby
Textile Dye
High-Intensity User
Adult
(>21 years)
5.6E+07
NA
3.4E+05
NA
Materials
High-Intensity User
Child
(16-20 years)
5.9E+07
NA
NA
NA
High-Intensity User
Child
(11-15 years)
5.4E+07
NA
NA
NA
High-Intensity User
Bystander
NA
NA
1.9E+06
NA
Page 267 of 616
-------
Dermal Risk Kslimnles
Inhibition Risk Kslimnles
Assessed
Condition of
I so
Chronic
Acute MOK
Chronic
Cntcjiorv
Scenario Descriptor
Receptor
Acute MOK
Benchmark
("sincer
Risk'1
MIX = 2S4
nig/nr'
Cancer
Risk'1
>i)i)
Benchmark
ll-l-iit.
Benchmark
11)1)
Benchmark
Other
Consumer
Spray
Polyurethane
Basement
Adult
(>21 years)
3.5E+04
NA
317
NA
Uses
Foam
Bystander
NA
NA
384
NA
Child
(16-20 years)
3.7E+04
NA
NA
NA
Child
(11-15 years)
3.3E+04
NA
NA
NA
Attic
Adult
(>21 years)
3.5E+04
NA
1.5E+03
NA
Bystander
NA
NA
4.0E+03
NA
Child
(16-20 years)
3.7E+04
NA
NA
NA
Child
(11-15 years)
3.3E+04
NA
NA
NA
Garage
Adult
(>21 years)
3.5E+04
NA
1.7E+03
NA
Bystander
NA
NA
2.5E+03
NA
Child
(16-20 years)
3.7E+04
NA
NA
NA
Child
(11-15 years)
3.3E+04
NA
NA
NA
Antifreeze
High-Intensity User
Adult
(>21 years)
6.9E+04
NA
1.8E+04
NA
High-Intensity User
Child
(16-20 years)
7.4E+04
NA
NA
NA
High-Intensity User
Child
(11-15 years)
6.8E+04
NA
NA
NA
High-Intensity User
Bystander
NA
NA
7.2E+04
NA
Page 268 of 616
-------
Cntcjiorv
Assessed
Condition of
I so
Scenario Descriptor
Receptor
Dermal Risk Kslimnles
1 iih;ihitioil Risk Kslimnles
Acute MOK
Benchmark
>i)i)
Chronic
Csincer
Risk'1
Benchmark
Acute MOK
MIX = 2S4
nig/nr'
Benchmark
11)1)
Chronic
Cancer
Risk'1
Benchmark
NA= Not Applicable
Bold: Cancer risk exceeds the benchmark of 1 x 10"6
a Risks from chronic exposure were evaluated only for consumer products that are used regularly
Page 269 of 616
-------
4,6.2,3 Summary of Risk for the General Population
EPA considered reasonably available information to characterize general population exposures
and risk.
Table 4-25. summarizes potential risks from acute exposures from incidental ingestion of or
dermal contact with 1,4-dioxane in surface water. Calculated MOE values below the benchmark
MOE (300) would indicate a potential safety concern. None of the surface water concentration
estimates indicate risks from acute exposures to the general population. EPA did not identify
releases to surface waters from OESs that are not included in this table (including for
import/repackaging, recycling, film cement, printing inks, dry film lubricants, and laboratory
chemical use).
Table 4-25. Summary of Human Health Risks from Incidental Exposure to 1,4-Dioxane in
Surface Waters
oi:s
l-~!icilit>/l>!it:i Source
Acute MOE
Oral Exposure
Benchmark 300
Acme MOE
Dermal Exposure
Benchmark 300
Site-Specific Modeling - Estimated Surface Water Concentrations
Manufacturing
BASF
6.8E+04
9.9E+05
Industrial Uses
Ineos Oxide
3.0E+04
4.4E+05
Industrial Uses
Microdyn-Nadir Corp
9.1E+05
1.3E+07
Industrial Uses
St Charles Operations (Tafit/Star)
Union Carbide Corp
6.0E+08
8.6E+09
Industrial Uses
SUEZ Water Technologies &
Solutions
1.3E+03
1.9E+04
Industrial Uses
The Dow Chemical Co - Louisiana
Operations
7.6E+08
1.1E+10
Industrial Uses
Union Carbide Corp Institute Facility
2.0E+06
2.9E+07
Industrial Uses
Union Carbide Corp Seadrifit Plant
2.7E+05
4.0E+06
Industrial Uses
BASF Corp
2.0E+07
2.8E+08
Industrial Uses
Cherokee Pharmaceuticals LLC
2.5E+09
3.6E+10
Industrial Uses
DAK Americas LLC
2.4E+05
3.4E+06
Industrial Uses
Institute Plant
1.3E+06
1.8E+07
Industrial Uses
Kodak Park Division
3.9E+07
5.6E+08
Industrial Uses
Pharmacia & Upjohn (Former)
2.4E+08
3.5E+09
Industrial Uses
Philips Electronics Plant
6.6E+07
9.6E+08
Industrial Uses
Sanderson Gulch Drainage
Improvements
6.6E+08
9.6E+09
Open System
Functional Fluids
Ametek Inc. U.S. Gauge Div
1.7E+07
2.4E+08
Open System
Functional Fluids
Lake Reg Med/Collegeville
5.1E+08
7.3E+09
Open System
Functional Fluids
Pall Life Sciences Inc
1.5E+08
2.2E+09
Page 270 of 616
-------
Acute MOi:
Acute MOI!
oi:s
Facility/Data Source
Oral Kxposure
Benchmark 300
Dermal Kxposure
Benchmark 300
Open S\slem
Functional Fluids
Modeled Release l.sliiiiales
2.3E+Ut>
3.4E+U7
Spray Foam
Application
Modeled Release Estimates
2.5E+07
3.6E+08
Disposal
Beacon Heights Landfill
1.3E+07
1.8E+08
Disposal
Ingersoll Rand/Torrington Fac
1.9E+06
2.8E+07
High-End of Submitted Monitoring Data - Measured Surface Water Concentrations
STORET
6.6E+04
9.6E+05
Sun et al. 2016
4.7E+03
6.8E+04
North Carolina Department of
Environmental Quality
6.4E+03
9.3E+04
Minnesota Department of
Environmental Quality
1.5E+06
2.2E+07
5 RISK DETERMINATION
5,1 Overview
In each risk evaluation under TSCA Section 6(b), EPA determines whether a chemical substance
presents an unreasonable risk of injury to health or the environment, under the conditions of use.
These determinations do not consider costs or other non-risk factors. In making these
determinations, EPA considers relevant risk-related factors, including, but not limited to: the
effects of the chemical substance on health and human exposure to such substance under the
conditions of use (including cancer and non-cancer risks); the effects of the chemical substance
on the environment and environmental exposure under the conditions of use; the population
exposed (including any potentially exposed or susceptible subpopulations (PESS)); the severity
of hazard (including the nature of the hazard, the irreversibility of the hazard); and uncertainties.
EPA also takes into consideration the Agency's confidence in the data used in the risk estimate.
This includes an evaluation of the strengths, limitations, and uncertainties associated with the
information used to inform the risk estimate and the risk characterization. This approach is in
keeping with the Agency's final rule, Procedures for Chemical Risk Evaluation Under the
Amended Toxic Substances Control Act (82 FR 33726).16
This section describes the final unreasonable risk determinations of the conditions of use in the
scope of the risk evaluation. The final unreasonable risk determinations are based on the risk
estimates in the final risk evaluation, which may differ from the risk estimates in the draft risk
16 This risk determination is being issued under TSCA section 6(b) and the terms used, such as unreasonable risk,
and the considerations discussed are specific to TSCA. Other statutes have different authorities and mandates and
may involve risk considerations other than those discussed here.
Page 271 of 616
-------
evaluation due to peer review and public comments. Therefore, the final unreasonable risk
determinations of some conditions of use may differ from those in the draft risk evaluation.
5.1.1 Human Health
EPA's risk evaluation identified cancer and non-cancer adverse effects from acute and chronic
inhalation and dermal exposure to 1,4-dioxane. The health risk estimates for all conditions of use
are in 4.6.2 (Table 4-23. and Table 4-24.).
EPA generally identified as Potentially Exposed or Susceptible Subpopulations: workers and
ONUs, including men and women of reproductive age, and adolescents; and consumers and
bystanders, including men, women, and children of any age.
EPA evaluated exposures to workers, ONUs, consumers, and bystanders using reasonably
available monitoring and modeling data of inhalation and dermal exposures, as applicable. For
example, EPA assumed that ONUs and bystanders do not have direct contact with 1,4-dioxane;
therefore non-cancer effects and cancer from dermal exposures to 1,4-dioxane are not expected.
The description of the data used for human health exposure is in Section 2.4. Uncertainties in the
analysis are discussed in Section 4.3 and considered in the unreasonable risk determination for
each condition of use presented below, including the fact that the dermal model used does not
address variability in exposure duration and frequency.
As discussed in Section 1.4.2, EPA did not assess exposures from ambient air, drinking water,
and sediment pathways because they fall under the jurisdiction of other environmental statutes
administered by EPA, i.e., CAA, SDWA, RCRA, and CERCLA. However, EPA has not
developed recommended ambient water quality criteria for the protection of human health for
1,4-dioxane. Exposure to the general population via surface water can occur through recreational
activities (e.g., swimming) and through consuming fish. EPA considered reasonably available
information and environmental fate properties to characterize general population exposure
through the surface water pathway. EPA evaluated the human health risks of potential acute and
chronic incidental exposures via oral and dermal routes from recreational swimming in bodies of
water that receive discharges from the industrial and commercial conditions of use of 1,4-
dioxane and determined that these risks are not unreasonable. In addition, because 1,4-dioxane
has low bioaccumulation potential, EPA has determined that the human health risks from fish
ingestion are not unreasonable.
5.1.1.1 Non-Cancer Risk Estimates
The risk estimates of non-cancer effects (MOEs) refers to adverse health effects associated with
health endpoints other than cancer, including to the body's organ systems, such as
reproductive/developmental effects, cardiac and lung effects, and kidney and liver effects. The
MOE is the point of departure (POD) (an approximation of the no-observed adverse effect level
(NOAEL) or benchmark dose level (BMDL)) for a specific health endpoint divided by the
exposure concentration for the specific scenario of concern. Section 3.2.6 presents the PODs for
non-cancer effects for 1,4-dioxane and Section 4.2 presents the MOEs for non-cancer effects.
The MOEs are compared to a benchmark MOE. The benchmark MOE accounts for the total
uncertainty in a POD, including, as appropriate: (1) the variation in sensitivity among the
members of the human population (i.e., intrahuman/intraspecies variability); (2) the uncertainty
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in extrapolating animal data to humans {i.e., interspecies variability); (3) the uncertainty in
extrapolating from data obtained in a study with less-than-lifetime exposure to lifetime exposure
{i.e., extrapolating from subchronic to chronic exposure); and (4) the uncertainty in extrapolating
from a lowest observed adverse effect level (LOAEL) rather than from a NOAEL. A lower
benchmark MOE {e.g., 30) indicates greater certainty in the data (because fewer of the default
UFs relevant to a given POD as described above were applied). A higher benchmark MOE {e.g.,
1000) would indicate more uncertainty for specific endpoints and scenarios. However, these are
often not the only uncertainties in a risk evaluation. The benchmark MOE for 1,4-dioxane for
acute exposures is 100 (accounting for interspecies and intraspecies variability and LOAEL-to-
NOAEL uncertainty), while the benchmark MOE for chronic exposures is 30 (accounting for
interspecies and intraspecies variability). Additional information regarding the benchmark MOE
is in Section 4.2.
5.1.1.2 Cancer Risk Estimates
Cancer risk estimates represent the incremental increase in probability of an individual in an
exposed population developing cancer over a lifetime (excess lifetime cancer risk (ELCR))
following exposure to the chemical. Standard cancer benchmarks used by EPA and other
regulatory agencies are an increased cancer risk above benchmarks ranging from 1 in 1,000,000
to 1 in 10,000 {i.e., lxlO"6 to lxlO"4) depending on the subpopulation exposed.17 EPA used 1x10"
6 as the benchmark for the cancer risk to consumers and bystanders from consumer use of
cleaning and furniture care products and laundry and dishwashing products. EPA used 1 x 10"4as
the benchmark for the purposes of this unreasonable risk determination for individuals in
industrial and commercial work environments. This cancer benchmark is consistent with the
2017 NIOSH chemical carcinogen policy.18 It is important to note these benchmarks are not
bright lines and EPA has discretion to make unreasonable risk determinations based on other
benchmarks as appropriate.
5.1.1.3 Determining Unreasonable Risk of Injury to Health
Calculated risk estimates (MOEs or cancer risk estimates) can provide a risk profile by
presenting a range of estimates for different health effects for different conditions of use. A
calculated MOE that is less than the benchmark MOE supports a determination of unreasonable
risk of injury to health, based on non-cancer effects. Similarly, a calculated cancer risk estimate
that is greater than the cancer benchmark supports a determination of unreasonable risk of injury
to health from cancer. Whether EPA makes a determination of unreasonable risk depends upon
other risk-related factors, such as the endpoint under consideration, the reversibility of effect,
17 As an example, when EPA's Office of Water in 2017 updated the Human Health Benchmarks for Pesticides, the
benchmark for a "theoretical upper-bound excess lifetime cancer risk" from pesticides in drinking water was
identified as 1 in 1,000,000 to 1 in 10,000 over a lifetime of exposure (EPA. Human Health Benchmarks for
Pesticides: Updated 2017 Technical Document (pp.5). (EPA 822-R -17 -001). Washington, DC: U.S. Environmental
Protection Agency, Office of Water. January 2017. https://www.epa.gov/sites/production/files/2015-
10/documents/hh-benchmarks-techdoc.pdf). Similarly, EPA's approach under the Clean Air Act to evaluate residual
risk and to develop standards is a two-step approach that "includes a presumptive limit on maximum individual
lifetime [cancer] risk (MIR) of approximately 1 in 10 thousand" and consideration of whether emissions standards
provide an ample margin of safely to protect public health "in consideration of all health information, including the
number of persons at risk levels higher than approximately 1 in 1 million, as well as other relevant factors" (54 FR
38044, 38045, September 14, 1989).
18 NIOSH Current intelligence bulletin 68: NIOSH chemical carcinogen policy (Whittaker et al. 2016). Note that the
NIOSH Recommended Exposure Limit (REL) for 1,4-dioxane was established prior to this guidance.
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exposure-related considerations (e.g., duration, magnitude, or frequency of exposure, or
population exposed), and the confidence in the information used to inform the hazard and
exposure values. A calculated MOE greater than the benchmark MOE or a calculated cancer risk
estimate less than the cancer benchmark, alone do not support a determination of unreasonable
risk, since EPA may consider other risk-based factors when making an unreasonable risk
determination.
When making an unreasonable risk determination based on injury to health of workers (who are
one example of PESS), EPA also makes assumptions regarding workplace practices and
exposure controls, including engineering controls or use of PPE (see limitations and use practices
under Respiratory Protection subheading in Section 2.4.1.1). EPA's decisions for unreasonable
risk to workers are based on high-end exposure estimates, in order to capture not only exposures
for PESS but also to account for the uncertainties related to whether or not workers are using
PPE. However, EPA does not assume that ONUs use PPE. Once EPA has applied the appropriate
PPE assumption for a particular condition of use in each unreasonable risk determination, in
those instances when EPA assumes PPE is used, EPA also assumes that the PPE is used in a
manner that achieves the stated APF or PF.
In the 1,4-dioxane risk characterization, liver toxicity was used as the most sensitive endpoint for
non-cancer adverse effects from acute inhalation and dermal exposures. For chronic inhalation
and dermal exposures to workers and ONUs, olfactory epithelium effects were used. However,
additional risks associated with other adverse respiratory and liver effects were identified for
chronic inhalation and dermal exposures. Determining unreasonable risk by using olfactory
epithelium effects for workers and ONUs will also include the unreasonable risk from other
endpoints resulting from chronic inhalation and dermal exposures.
The 1,4-dioxane unreasonable risk determination considers the uncertainties associated with the
reasonably available information to justify the linear cancer dose-response model when
compared to other available models. The cancer analysis is described in Section 3.2.4. EPA
considered cancer risk estimates from chronic inhalation or dermal exposures in the unreasonable
risk determination.
When making a determination of unreasonable risk, the Agency has a higher degree of
confidence where uncertainty is low. Similarly, EPA has high confidence in the hazard and
exposure characterizations when, for example, the basis for characterizations is measured or
based on monitoring data or a robust model and the hazards identified for risk estimation are
relevant for conditions of use. Where EPA has made assumptions in the scientific evaluation,
whether or not those assumptions are protective is also a consideration. Additionally, EPA
considers the central tendency and high-end exposure levels when determining the unreasonable
risk. High-end risk estimates (e.g., 95th percentile) are generally intended to cover individuals or
sub-populations with greater exposure (i.e., PESS) and central tendency risk estimates are
generally estimates of average or typical exposure.
EPA may make a determination of no unreasonable risk for conditions of use where the
substance's hazard and exposure potential, or where the risk-related factors described previously,
lead the Agency to determine that the risks are not unreasonable.
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5,1,2 Environment
EPA used environmental fate parameters, physical-chemical properties, modelling, and
monitoring data to assess ambient water exposure to aquatic organisms. Further analysis was not
conducted for biosolids, soil and sediment pathways based on a qualitative assessment of the
physical-chemical properties and fate of 1,4-dioxane in the environment. However, a quantitative
comparison of hazards and exposures for aquatic organisms in surface water was evaluated. EPA
calculated a risk quotient (RQ) to compare environmental concentrations against an effect level
in surface water for the most biological relevant species. Exposures of 1,4-dioxane to aquatic
organisms from surface water are assessed and presented in this risk evaluation and used to
inform the risk determination. These analyses are described in Sections 2.1, 2.3, and 4.1.
5.1.2.1 Determining Unreasonable Risk to Injury to the Environment
An RQ equal to 1 indicates that the exposures are the same as the concentration that causes
effects. An RQ less than 1, when the exposure is less than the effect concentration, supports a
determination that there is no unreasonable risk of injury to the environment. An RQ greater than
1, when the exposure is greater than the effect concentration supports a determination that there
is unreasonable risk of injury to the environment. Consistent with EPA's human health
evaluations, other risk-based factors may be considered (e.g., confidence in the hazard and
exposure characterization, duration, magnitude, uncertainty) for purposes of making an
unreasonable risk determination.
EPA considered the effects on the aquatic, sediment dwelling and terrestrial organisms. EPA
provides estimates for environmental risk in Section 4.1 and Table 4-2..
5,2 Detailed Unreasonable Risk Determinations by Condition of Use
Table 5-1. Categories and Subcategories of Conditions of Use Included in the Scope of
the Risk Eva
uation
Life Cycle
Stage
Category 11
Subcategory b
Unreasonable
Risk
Detailed Risk
Determination
Manufacture
Domestic
manufacture
Domestic manufacture
Yes
Sections 5.2.1.1 and
5.2.2.
Import/repackaging
Import/repackaging/bottl
e and drum
Yes
Sections 5.2.1.2 and
5.2.2.
Processing
Repackaging
Repackaging/bottle and
drum
Yes
Sections 5.2.1.3 and
5.2.2.
Recycling
Recycling
Yes
Sections 5.2.1.4 and
5.2.2.
Non-incorporative
Basic organic chemical
manufacturing (process
solvent)
Yes
Sections 5.2.1.5 and
5.2.2.
Processing as a
reactant0
Polymerization catalyst
Yes
Sections 5.2.1.6 and
5.2.2.
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Table 5-1. Categories and Subcategories of Conditions of Use Included in the Scope of
the Risk Eva
uation
Life Cycle
Stage
Category"
Subcategory b
Unreasonable
Risk
Detailed Risk
Determination
Distribution in
commerce
Distribution
Distribution
No
Sections 5.2.1.7 and
5.2.2.
Industrial/
Intermediate 0
Agricultural chemical
Yes
Sections 5.2.1.8 and
commercial use
Plasticizer
5.2.2.
Catalysts and reagents
for anhydrous acid
reactions, brominations,
and sulfonations
Processing aids, not
Wood pulping
Yes
Sections 5.2.1.9 and
otherwise listed0
Extraction of animal and
vegetable oils
5.2.2.
Wetting and dispersing
agent in textile
processing
Polymerization catalyst
Purification of process
intermediates
Etching of
fluoropolymers
Functional fluids,
Metalworking fluid
No
Sections 5.2.1.10 and
open system
Cutting and tapping
fluid
5.2.2.
Polyalkylene glycol
fluid
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Table 5-1. Categories and Subcategories of Conditions of Use Included in the Scope of
the Risk Eva
uation
Life Cycle
Stage
Category"
Subcategory b
Unreasonable
Risk
Detailed Risk
Determination
Industrial/
Laboratory
Chemical reagent
Yes
Sections 5.2.1.11 and
commercial use
chemicals
Reference material
5.2.2.
Spectroscopic and
photometric
measurement
Liquid scintillation
counting medium
Stable reaction medium
Cryoscopic solvent for
molecular mass
determinations
Preparation of
histological sections for
microscopic
examination
Industrial/
commercial use
Adhesives and
sealants
Film cement
Yes
Sections 5.2.1.12 and
5.2.2.
Other uses
Spray polyurethane
foam
No
Sections 5.2.1.13 and
5.2.2.
Printing and printing
compositions
Yes
Sections 5.2.1.14 and
5.2.2.
Dry film lubricant
Yes
Sections 5.2.1.15 and
5.2.2.
Consumer users
Arts, crafts, and
hobby materials
Textile dye
No
Sections 5.2.1.16 and
5.2.2.
Automotive care
products
Antifreeze
No
Sections 5.2.1.17 and
5.2.2.
Cleaning and
furniture care
products
Surface cleaner
No
Sections 5.2.1.18 and
5.2.2.
Laundry and
dishwashing
Dish soap
No
Sections 5.2.1.19 and
5.2.2.
products
Dishwasher detergent
No
Sections 5.2.1.20 and
5.2.2.
Laundry detergent
No
Sections 5.2.1.21 and
5.2.2.
Paints and coatings
Paint and floor lacquer
No
Sections 5.2.1.22 and
5.2.2.
Other consumer
uses
Spray polyurethane
foam
No
Sections 5.2.1.23 and
5.2.2.
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Table 5-1. Categories and Subcategories of Conditions of Use Included in the Scope of
the Risk Eva
uation
Life Cycle
Stage
Category"
Subcategory b
Unreasonable
Risk
Detailed Risk
Determination
Disposal
Disposal
Industrial pre-treatment
Yes
Sections 5.2.1.24 and
5.2.2.
Industrial wasterwater
treatment
Publicly owned
treatment works
(POTW)
Underground injection
Municipal landfill
Hazardous landfill
Other land disposal
Municipal waste
incinerator
Hazardous waste
incinerator
Off-site waste transfer
a These categories of conditions of use appear in the Life Cycle Diagram, reflect CDR codes, and broadly represent
additional information regarding all conditions of use of 1,4-dioxane.
b These subcategories reflect more specific information regarding the conditions of use of 1,4-dioxane.
0 While use of 1,4-dioxane as a process solvent and as an intermediate in the manufacture of pharmaceuticals
was included in the problem formulation and draft risk evaluation, upon further analysis of the details of these
processes, EPA has determined that these uses fall outside TSCA's definition of "chemical substance." Under
TSCA § 3(2)(B)(vi), the definition of "chemical substance" does not include any food, food additive, drug,
cosmetic, or device (as such terms are defined in section 201 of the Federal Food, Drug, and Cosmetic Act)
when manufactured, processed, or distributed in commerce for use as a food, food additive, drug, cosmetic, or
device. EPA has concluded that 1,4-dioxane use as a process solvent and an intermediate during
pharmaceutical manufacturing falls outside TSCA's definition of a chemical substance when used for these
purposes. As a result, the use of 1,4-dioxane as a process solvent and an intermediate during pharmaceutical
manufacturing are not included in the scope of this risk evaluation.
5,2.1 Human Health
5.2.1.1 Manufacture - Domestic Manufacture - Domestic Manufacture
Section 6(b)(4)(A) unreasonable risk determination for domestic manufacture of 1,4-dioxane:
Presents an unreasonable risk of injury to health (workers and ONUs).
For workers, EPA found that there was an unreasonable risk of non-cancer effects (liver
toxicity and olfactory epithelium effects) from acute and chronic dermal exposures and
cancer from chronic dermal exposures at the central tendency and high-end, even when
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assuming use of PPE. For occupational non-users (ONUs), EPA found that there was an
unreasonable risk of cancer from chronic inhalation exposures at the central tendency.
EPA's determination that the domestic manufacturing of 1,4-dioxane presents an unreasonable
risk is based on the comparison of the risk estimates for non-cancer effects and cancer to the
benchmarks (Table 4-23.). As explained in Section 5.1., EPA also considered the health effects
of 1,4-dioxane, the exposures from the condition of use, and the uncertainties in the analysis
(Section 4.3), including uncertainties related to the exposures for ONUs:
• For workers, when assuming the use of gloves with PF of 20, the risk estimates for acute
and chronic non-cancer effects and cancer from dermal exposures at the high end and
central tendency support an unreasonable risk determination.
• For workers, when assuming the use of respirators with APF of 50, the risk estimates of
non-cancer effects from acute and chronic inhalation exposures at the high-end and the
risk estimates for cancer from chronic inhalation exposures at the high-end do not support
an unreasonable risk determination. Respirators with APF of 50 and gloves with PF of 20
are the maximum assumed personal protective equipment for workers at manufacturing
facilities, based on process and work activity descriptions at a manufacturing facility.
• The inhalation exposure was assessed using full-shift personal breathing zone (PBZ)
monitoring data reflective of current operations at one manufacturing facility, and there is
uncertainty of how well the data represents activities at other manufacturing facilities.
• The dermal exposure was assessed using modeled data.
• Based on EPA's analysis, the data for worker and ONU inhalation exposure could not be
distinguished; however, ONU inhalation exposures are assumed to be lower than
inhalation exposures for workers directly handling the chemical substance. To account
for this uncertainty, EPA considered the workers' central tendency estimate of inhalation
exposures when determining ONU risk.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is an unreasonable risk of
injury to health (workers and ONUs) from the domestic manufacture of 1,4-dioxane.
5.2.1.2 Manufacture - Import - Import/Repackaging (Bottle and Drum)
Section 6(b)(4)(A) unreasonable risk determination for import/repackaging of 1,4-dioxane (bottle
and drum): Presents an unreasonable risk of injury to health (workers and ONUs).
For workers, EPA found that there was an unreasonable risk of non-cancer effects (liver
toxicity and olfactory epithelium effects) from acute and chronic dermal exposures and
cancer from chronic dermal exposures, even when assuming use of PPE. For occupational
non-users (ONUs), EPA found that there was an unreasonable risk of non-cancer effects
(liver toxicity) from acute inhalation exposures and cancer from chronic inhalation
exposures at the central tendency.
EPA's determination that the import/repackaging of 1,4-dioxane presents an unreasonable risk is
based on the comparison of the risk estimates for non-cancer effects and cancer to the
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benchmarks (Table 4-23.). As explained in Section 5.1., EPA also considered the health effects
of 1,4-dioxane, the exposures from the condition of use, and the uncertainties in the analysis
(Section 4.3), including uncertainties related to the exposures for ONUs:
• For workers, when assuming the use of gloves with PF of 20, the risk estimates for non-
cancer effects and cancer from dermal exposures support an unreasonable risk
determination.
• For workers, when assuming the use of respirators with APF of 50, the risk estimates of
non-cancer effects from acute and chronic inhalation exposures at the high-end and the
risk estimates for cancer from chronic inhalation exposures at the high-end do not support
an unreasonable risk determination. Respirators with APF of 50 and gloves with PF of 20
are the maximum assumed personal protective equipment for workers at
import/repackaging facilities, based on professional judgment regarding practices at
import/repackaging facilities.
• Inhalation and dermal exposures were assessed using modeled data.
• Based on EPA's analysis, the data for worker and ONU inhalation exposure could not be
distinguished; however, ONU inhalation exposures are assumed to be lower than
inhalation exposures for workers directly handling the chemical substance. To account
for this uncertainty, EPA considered the workers' central tendency estimate of inhalation
exposures when determining ONU risk.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is an unreasonable risk of
injury to health (workers and ONUs) from the import/repackaging of 1,4-dioxane.
5.2.1.3 Processing - Repackaging - Repackaging (Bottle and Drum)
Section 6(b)(4)(A) unreasonable risk determination for repackaging (bottle and drum) of 1.4-
dioxane: Presents an unreasonable risk of injury to health (workers and ONUs).
For workers, EPA found that there was an unreasonable risk of non-cancer effects (liver toxicity
and olfactory epithelium effects) from acute and chronic dermal exposures at the central tendency
and high-end and cancer from chronic inhalation exposures at the high-end and dermal exposures
at the central tendency and high-end, even when assuming use of PPE. For ONUs, EPA found that
there was an unreasonable risk of non-cancer effects (liver toxicity and olfactory epithelium
effects) from acute and chronic inhalation exposures and cancer from chronic inhalation
exposures at the central tendency.
EPA's determination that the repackaging of 1,4-dioxane presents an unreasonable risk based on
the comparison of the risk estimates for non-cancer effects and cancer to the benchmarks (Table
4-23.). As explained in Section 5.1., EPA also considered the health effects of 1,4-dioxane, the
exposures from the condition of use, and the uncertainties in the analysis (Section 4.3), including
uncertainties related to the exposures for ONUs:
• For workers, when assuming the use of gloves with PF of 20, the risk estimates for non-
cancer effects from acute and chronic dermal exposures and cancer from chronic dermal
exposures at the central tendency and high-end support an unreasonable risk
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determination. Similarly, for workers, even when assuming the use of respirators with
APF of 50, the risk estimates for cancer from chronic inhalation exposures at the high-
end support an unreasonable risk determination.
• For workers, when assuming use of respirators with APF of 50, the risk estimates of non-
cancer effects from acute and chronic inhalation exposures at the high-end do not support
an unreasonable risk determination. Respirators with APF of 50 and gloves with PF of 20
are the maximum assumed personal protective equipment for workers at repackaging
facilities, based on professional judgment regarding practices at repackaging facilities.
• Inhalation exposures were assessed based on exposure data from the 2002 EU Risk
Assessment for 1,4-dioxane. The data sets used were limited and mostly lacked specific
descriptions of worker tasks, exposure sources, and possible engineering controls. The
values were reported to be full-shift values, which EPA assumed to be 8-hour time-
weighted average (TWA) values.
• Dermal exposures were assessed using modeled data.
• Based on EPA's analysis, the data for worker and ONU inhalation exposure could not be
distinguished; however, ONU inhalation exposures are assumed to be lower than
inhalation exposures for workers directly handling the chemical substance. To account
for this uncertainty, EPA considered the workers' central tendency estimate of inhalation
exposures when determining ONU risk.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is an unreasonable risk of
injury to health (workers and ONUs) from the repackaging of 1,4-dioxane.
5.2.1.4 Processing - Recycling
Section 6(b)(4)(A) unreasonable risk determination for the recycling of 1,4-dioxane: Presents an
unreasonable risk of injury to health (workers and ONUs).
For workers, EPA identified an unreasonable risk of non-cancer effects (liver toxicity and
olfactory epithelium effects) from acute and chronic dermal exposures at the central tendency and
high-end and cancer from chronic inhalation exposures at the high-end and dermal exposures at
the central tendency and high-end, even when assuming use of PPE. For ONUs, EPA identified an
unreasonable risk of non-cancer effects (liver toxicity and olfactory epithelium effects) from acute
and chronic inhalation exposures and cancer from chronic inhalation exposures at the central
tendency.
EPA's determination that the recycling of 1,4-dioxane presents an unreasonable risk based on the
comparison of the risk estimates for non-cancer effects and cancer to the benchmarks (Table
4-23.). As explained in Section 5.1., EPA also considered the health effects of 1,4-dioxane, the
exposures from the condition of use, and the uncertainties in the analysis (Section 4.3), including
uncertainties related to the exposures for ONUs:
• For workers, when assuming the use of gloves with PF of 20, the risk estimates for non-
cancer effects from acute and chronic dermal exposures and cancer from chronic dermal
exposures at the central tendency and high-end support an unreasonable risk
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determination. Similarly, for workers, even when assuming the use of respirators with
APF of 50, the risk estimates for cancer from chronic inhalation exposures at the high-
end support an unreasonable risk determination.
• For workers, when assuming use of respirators with APF of 50, the risk estimates of non-
cancer effects from acute and chronic inhalation exposures at the high-end do not support
an unreasonable risk determination. Respirators with APF of 50 and gloves with PF of 20
are the maximum assumed personal protective equipment for workers at recycling
facilities, based on professional judgment regarding practices at a recycling facility.
• Inhalation exposures were assessed based on exposure data from the 2002 EU Risk
Assessment for 1,4-dioxane. The data sets used were limited and mostly lacked specific
descriptions of worker tasks, exposure sources, and possible engineering controls. The
values were reported to be full-shift values, which EPA assumed to be 8-hour time-
weighted average (TWA) values.
• Dermal exposures were assessed using modeled data.
• Based on EPA's analysis, the data for worker and ONU inhalation exposure could not be
distinguished; however, ONU inhalation exposures are assumed to be lower than
inhalation exposures for workers directly handling the chemical substance. To account
for this uncertainty, EPA considered the workers' central tendency estimate of inhalation
exposures when determining ONU risk.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is an unreasonable risk of
injury to health (workers and ONUs) from the recycling of 1,4-dioxane.
5.2.1.5 Processing - Non-incorporative - Basic organic chemical manufacturing
(process solvent)
Section 6(b)(4)(A) unreasonable risk determination for non-incorporative processing of 1.4-
dioxane: Presents an unreasonable risk of injury to health (workers and ONUs).
For workers, EPA found that there was an unreasonable risk of non-cancer effects (liver toxicity
and olfactory epithelium effects) from acute and chronic dermal exposures at the central tendency
and high-end and cancer from chronic inhalation exposures at the high-end and dermal exposures
at the central tendency and high-end, even when assuming use of PPE. For ONUs, EPA found that
there was an unreasonable risk of non-cancer effects (liver toxicity and olfactory epithelium
effects) from acute and chronic inhalation exposures and cancer from chronic inhalation
exposures at the central tendency.
EPA's determination that the non-incorporative processing of 1,4-dioxane presents an
unreasonable risk is based on the comparison of the risk estimates for non-cancer effects and
cancer to the benchmarks (Table 4-23.). As explained in Section 5.1., EPA also considered the
health effects of 1,4-dioxane, the exposures from the condition of use, and the uncertainties in
the analysis (Section 4.3), including uncertainties related to the exposures for ONUs:
• For workers, when assuming the use of gloves with PF of 20, the risk estimates for non-
cancer effects from acute and chronic dermal exposures and cancer from chronic dermal
exposures at the central tendency and high-end support an unreasonable risk
Page 282 of 616
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determination. Similarly, for workers, even when assuming the use of respirators with
APF of 50, the risk estimates for cancer from chronic inhalation exposures at the high-
end support an unreasonable risk determination.
• For workers, when assuming use of respirators with APF of 50, the risk estimates of non-
cancer effects from acute and chronic inhalation exposures at the high-end do not support
an unreasonable risk determination. Respirators with APF of 50 and gloves with PF of 20
are the maximum assumed personal protective equipment for workers at non-
incorporative processing facilities, based on professional judgment regarding practices at
non-incorporative processing facilities.
• Inhalation exposures were assessed based on exposure data from the 2002 EU Risk
Assessment for 1,4-dioxane. The data sets used were limited and mostly lacked specific
descriptions of worker tasks, exposure sources, and possible engineering controls. The
values were reported to be full-shift values, which EPA assumed to be 8-hour time-
weighted average (TWA) values.
• Dermal exposures were assessed using modeled data.
• Based on EPA's analysis, the data for worker and ONU inhalation exposure could not be
distinguished; however, ONU inhalation exposures are assumed to be lower than
inhalation exposures for workers directly handling the chemical substance. To account
for this uncertainty, EPA considered the workers' central tendency estimate of inhalation
exposures when determining ONU risk.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is an unreasonable risk of
injury to health (workers and ONUs) from the non-incorporative processing of 1,4-dioxane.
5.2.1.6 Processing - Processing as a reactant - Polymerization catalyst
Section 6(b)(4)(A) unreasonable risk determination for the processing as a reactant of 1.4-
dioxane: Presents an unreasonable risk of injury to health (workers and ONUs).
For workers, EPA found that there was an unreasonable risk of non-cancer effects (liver toxicity
and olfactory epithelium effects) from acute and chronic dermal exposures at the central tendency
and high-end and cancer from chronic inhalation exposures at the high-end and dermal exposures
at the central tendency and high-end, even when assuming use of PPE. For ONUs, EPA found that
there was an unreasonable risk of non-cancer effects (liver toxicity and olfactory epithelium
effects) from acute and chronic inhalation exposures and cancer from chronic inhalation
exposures at the central tendency.
EPA's determination that the processing as a reactant of 1,4-dioxane presents an unreasonable
risk is based on the comparison of the risk estimates for non-cancer effects and cancer to the
benchmarks (Table 4-23.). As explained in Section 5.1., EPA also considered the health effects
of 1,4-dioxane, the exposures from the condition of use, and the uncertainties in the analysis
(Section 4.3), including uncertainties related to the exposures for ONUs:
• For workers, when assuming the use of gloves with PF of 20, the risk estimates for non-
cancer effects from acute and chronic dermal exposures and cancer from chronic dermal
Page 283 of 616
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exposures at the central tendency and high-end support an unreasonable risk
determination. Similarly, for workers, even when assuming the use of respirators with
APF of 50, the risk estimates for cancer from chronic inhalation exposures at the high-
end support an unreasonable risk determination.
• For workers, when assuming use of respirators with APF of 50, the risk estimates of non-
cancer effects from acute and chronic inhalation exposures at the high-end do not support
an unreasonable risk determination. Respirators with APF of 50 and gloves with PF of 20
are the maximum assumed personal protective equipment for workers at processing
facilities that process 1,4-dioxane as a reactant, based on professional judgment regarding
practices at processing facilities that processes 1,4-dioxane as a reactant.
• Inhalation exposures were assessed based on exposure data from the 2002 EU Risk
Assessment for 1,4-dioxane. The data sets used were limited and mostly lacked specific
descriptions of worker tasks, exposure sources, and possible engineering controls. The
values were reported to be full-shift values, which EPA assumed to be 8-hour time-
weighted average (TWA) values.
• Dermal exposures were assessed using modeled data.
• Based on EPA's analysis, the data for worker and ONU inhalation exposure could not be
distinguished; however, ONU inhalation exposures are assumed to be lower than
inhalation exposures for workers directly handling the chemical substance. To account
for this uncertainty, EPA considered the workers' central tendency estimate of inhalation
exposures when determining ONU risk.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is an unreasonable risk of
injury to health (workers and ONUs) from the processing as a reactant of 1,4-dioxane.
5.2.1.7 Distribution in Commerce
Section 6(b)(4)(A) unreasonable risk determination for distribution in commerce of 1,4-dioxane:
Does not present an unreasonable risk of injury to health (workers and ONUs).
For the purposes of the unreasonable risk determination, distribution in commerce of 1,4-dioxane
is the transportation associated with the moving of 1,4-dioxane in commerce. EPA is assuming
that workers and ONUs will not be handling 1,4-dioxane because the loading and unloading
activities are associated with other conditions of use and EPA assumes transportation of 1,4-
dioxane is in compliance with existing regulations for the transportation of hazardous materials
(49 CFR 172). Emissions are therefore minimal during transportation, so there is limited
exposure (with the exception of spills and leaks, which are outside the scope of the risk
evaluation). Based on the limited emissions from the transportation of chemicals, EPA
determines there is no unreasonable risk of injury to health (workers and ONUs) from the
distribution in commerce of 1,4-dioxane.
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5.2.1.8 Industrial Use - Intermediate Use - Agricultural chemical intermediate;
Plasticizer intermediate; Catalysts and reagents for anhydrous acid
reactions, brominations and sulfonations
Section 6(b)(4)(A) unreasonable risk determination for industrial use of 1.4-dioxane as an
intermediate: Presents an unreasonable risk of injury to health (workers and ONUs).
For workers, EPA found that there was an unreasonable risk of non-cancer effects (liver toxicity
and olfactory epithelium effects) from acute and chronic dermal exposures at the central tendency
and high-end and cancer from chronic inhalation exposures at the high-end and dermal exposures
at the central tendency and high-end, even when assuming use of PPE. For ONUs, EPA found that
there was an unreasonable risk of non-cancer effects (liver toxicity and olfactory epithelium
effects) from acute and chronic inhalation exposures and cancer from chronic inhalation
exposures at the central tendency.
EPA's determination that the industrial use of 1,4-dioxane as an intermediate presents an
unreasonable risk is based on the comparison of the risk estimates for non-cancer effects and
cancer to the benchmarks (Table 4-23.). As explained in Section 5.1., EPA also considered the
health effects of 1,4-dioxane, the exposures from the condition of use, and the uncertainties in
the analysis (Section 4.3), including uncertainties related to the exposures for ONUs:
• For workers, when assuming the use of gloves with PF of 20, the risk estimates for non-
cancer effects from acute and chronic dermal exposures and cancer from chronic dermal
exposures at the central tendency and high-end support an unreasonable risk
determination. Similarly, for workers, even when assuming the use of respirators with
APF of 50, the risk estimates for cancer from chronic inhalation exposures at the high-
end support an unreasonable risk determination.
• For workers, when assuming use of respirators with APF of 50, the risk estimates of non-
cancer effects from acute and chronic inhalation exposures at the high-end do not support
an unreasonable risk determination. Respirators with APF of 50 and gloves with PF of 20
are the maximum assumed personal protective equipment for workers at industrial use
facilities, based on professional judgment regarding practices at industrial use facilities.
• Inhalation exposures were assessed based on exposure data from the 2002 EU Risk
Assessment for 1,4-dioxane. The data sets used were limited and mostly lacked specific
descriptions of worker tasks, exposure sources, and possible engineering controls. The
values were reported to be full-shift values, which EPA assumed to be 8-hour time-
weighted average (TWA) values.
• Dermal exposures were assessed using modeled data.
• Based on EPA's analysis, the data for worker and ONU inhalation exposure could not be
distinguished; however, ONU inhalation exposures are assumed to be lower than
inhalation exposures for workers directly handling the chemical substance. To account
for this uncertainty, EPA considered the workers' central tendency estimate of inhalation
exposures when determining ONU risk.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is an unreasonable risk of
injury to health (workers and ONUs) from the industrial use of 1,4-dioxane as an intermediate.
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5.2.1.9 Industrial use - Processing aids, not otherwise listed - Wood pulping;
Extraction of animal and vegetable oils; Wetting and dispersing agent in
textile processing; Purification of process intermediates; Etching of
fluoropolymers
Section 6(b)(4)(A) unreasonable risk determination for the industrial use of 1.4-dioxane as a
processing aid: Presents an unreasonable risk of injury to health (workers and ONUs).
For workers, EPA found that there was an unreasonable risk of non-cancer effects (liver toxicity
and olfactory epithelium effects) from acute and chronic dermal exposures at the central tendency
and high-end and cancer from chronic inhalation exposures at the high-end and dermal exposures
at the central tendency and high-end, even when assuming use of PPE. For ONUs, EPA found that
there was an unreasonable risk of non-cancer effects (liver toxicity and olfactory epithelium
effects) from acute and chronic inhalation exposures and cancer from chronic inhalation
exposures at the central tendency.
EPA's determination that the industrial use of 1,4-dioxane as a processing aid presents an
unreasonable risk is based on the comparison of the risk estimates for non-cancer effects and
cancer to the benchmarks (Table 4-23.). As explained in Section 5.1., EPA also considered the
health effects of 1,4-dioxane, the exposures from the condition of use, and the uncertainties in
the analysis (Section 4.3), including uncertainties related to the exposures for ONUs:
• For workers, when assuming the use of gloves with PF of 20, the risk estimates for non-
cancer effects from acute and chronic dermal exposures and cancer from chronic dermal
exposures at the central tendency and high-end support an unreasonable risk
determination. Similarly, for workers, even when assuming the use of respirators with
APF of 50, the risk estimates for cancer from chronic inhalation exposures at the high-
end support an unreasonable risk determination.
• For workers, when assuming use of respirators with APF of 50, the risk estimates of non-
cancer effects from acute and chronic inhalation exposures at the high-end do not support
an unreasonable risk determination. Respirators with APF of 50 and gloves with PF of 20
are the maximum assumed personal protective equipment for workers at industrial use
facilities, based on professional judgment regarding practices at industrial use facilities.
• Inhalation exposures were assessed based on exposure data from the 2002 EU Risk
Assessment for 1,4-dioxane. The data sets used were limited and mostly lacked specific
descriptions of worker tasks, exposure sources, and possible engineering controls. The
values were reported to be full-shift values, which EPA assumed to be 8-hour time-
weighted average (TWA) values.
• Dermal exposures were assessed using modeled data.
• Based on EPA's analysis, the data for worker and ONU inhalation exposure could not be
distinguished; however, ONU inhalation exposures are assumed to be lower than
inhalation exposures for workers directly handling the chemical substance. To account
for this uncertainty, EPA considered the workers' central tendency estimate of inhalation
exposures when determining ONU risk.
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In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is an unreasonable risk of
injury to health (workers and ONUs) from the industrial use of 1,4-dioxane as a processing aid.
5.2.1.10 Industrial use - Functional fluids, open system - Metalworking fluid;
Cutting and tapping fluid; Polyalkylene glycol fluid
Section 6(b)(4)(A) unreasonable risk determination for the industrial use of 1,4-dioxane as a
functional fluid in an open system: Does not present an unreasonable risk of injury to health
(workers and ONUs).
For workers, EPA found that there was no unreasonable risk of non-cancer effects (liver toxicity
and olfactory epithelium effects) from acute or chronic inhalation or dermal exposures or cancer
from chronic inhalation exposures at the central tendency or high-end, even when PPE is not
used. In addition, for workers, EPA found that there was no unreasonable risk of cancer from
chronic dermal exposures at the central tendency and high-end, when assuming use of PPE. For
ONUs, EPA found that there was no unreasonable risk of non-cancer effects or cancer from
chronic inhalation exposures at the central tendency and high-end.
EPA's determination that the industrial use of 1,4-dioxane as a functional fluid in an open system
does not present an unreasonable risk is based on the comparison of the risk estimates for non-
cancer effects and cancer to the benchmarks (Table 4-23.). As explained in Section 5.1., EPA
also considered the health effects of 1,4-dioxane, the exposures from the condition of use, and
the uncertainties in the analysis (Section 4.3):
• For workers, when assuming use of gloves with PF of 20, the risk estimates for cancer
from chronic dermal exposures at the central tendency and the high-end do not support an
unreasonable risk determination. Respirators with APF of 50 and gloves with PF of 20
are the maximum assumed personal protective equipment for workers at industrial
facilities using functional fluids, based on professional judgment regarding practices at
industrial facilities using functional fluids.
• Inhalation exposures were assessed using modeled data along with personal breathing
zone (PBZ) samples from a 1997 NIOSH Health Hazard Evaluation (HHE) report on a
facility that manufactured axles for trucks and recreational vehicles.
• Dermal exposures were assessed using modeled data.
• ONU inhalation exposures were assessed by combining area measurements from the
1997 NIOSH HHE report into a single sample set with five datapoints.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is no unreasonable risk of
injury to health (workers and ONUs) from the industrial use of 1,4-dioxane as a functional fluid
in an open system.
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5.2.1.11 Industrial/commercial use - Laboratory chemicals - Chemical
reagent, reference material; Spectroscopic and photometric measurement,
liquid scintillation counting medium; Stable reaction medium, cryoscopic
solvent for molecular mass determinations; Preparation of histological
sections for microscopic examination
Section 6(b)(4)(A) unreasonable risk determination for the industrial use of 1.4-dioxane as a
laboratory chemical: Presents an unreasonable risk of injury to health (workers); does not
present an unreasonable risk of injury to health (ONUs)
For workers, EPA found that there was an unreasonable risk of non-cancer effects (liver toxicity
and olfactory epithelium effects) from acute and chronic dermal exposures and cancer from
chronic dermal exposures at the central tendency and high-end, even when assuming the use of
PPE. For ONUs, EPA found that there was no unreasonable risk of non-cancer effects or cancer from
acute or chronic inhalation exposures at the central tendency.
EPA's determination that the industrial/commercial use of 1,4-dioxane as a laboratory chemical
presents an unreasonable risk is based on the comparison of the risk estimates for non-cancer
effects and cancer to the benchmarks (Table 4-23.). As explained in Section 5.1., EPA also
considered the health effects of 1,4-dioxane, the exposures from the condition of use, and the
uncertainties in the analysis (Section 4.3), including uncertainties related to the exposures for
ONUs:
• For workers, when assuming the use of gloves with PF of 20, the risk estimates for non-
cancer effects from acute and chronic dermal exposures and cancer from chronic dermal
exposures at the central tendency and high-end support an unreasonable risk
determination.
• For workers, when assuming use of respirators with APF of 50, the risk estimates of non-
cancer effects from acute and chronic inhalation exposures and cancer effects from
chronic exposures at the high-end do not support an unreasonable risk determination.
Respirators with APF of 50 and gloves with PF of 20 are the maximum assumed personal
protective equipment for workers at industrial/commercial facilities using laboratory
chemicals, based on professional judgment regarding practices at industrial/commercial
facilities using laboratory chemicals.
• Inhalation exposures were assessed based on exposure data from the 2002 EU Risk
Assessment for 1,4-dioxane. The data sets used were limited and mostly lacked specific
descriptions of worker tasks, exposure sources, and possible engineering controls. Most
of the datasets were only presented in ranges with key statistics, so EPA was unable to
directly calculate final values from the raw data and relied on the statistics provided in
the report.
• Dermal exposures were assessed using modeled data.
• Based on EPA's analysis, the data for worker and ONU inhalation exposure could not be
distinguished; however, ONU inhalation exposures are assumed to be lower than
inhalation exposures for workers directly handling the chemical substance. To account
for this uncertainty, EPA considered the workers' central tendency estimate of inhalation
exposures when determining ONU risk.
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In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is an unreasonable risk of
injury to health (workers) from the industrial/commercial use of 1,4-dioxane as a laboratory
chemical.
5.2.1.12 Industrial/commercial use - Adhesives and sealants - Film cement
Section 6(b)(4)(A) unreasonable risk determination for the industrial/commercial use of 1.4-
dioxane as an adhesive or sealant: Presents an unreasonable risk of injury to health
(workers); does not present an unreasonable risk of injury to health (ONUs)
For workers, EPA found that there was an unreasonable risk of non-cancer effects (liver toxicity
and olfactory epithelium effects) from acute and chronic dermal exposures and cancer from
chronic dermal exposures at the central tendency and high-end, even when assuming the use of
PPE. For ONUs, EPA found that there was no unreasonable risk of non-cancer effects or cancer from
chronic inhalation exposures at the high end or central tendency.
EPA's determination that the industrial/commercial use of 1,4-dioxane as an adhesive or sealant
presents an unreasonable risk is based on the comparison of the risk estimates for non-cancer
effects and cancer to the benchmarks (Table 4-23.). As explained in Section 5.1., EPA also
considered the health effects of 1,4-dioxane, the exposures from the condition of use, and the
uncertainties in the analysis (Section 4.3):
• For workers, when assuming the use of gloves with PF of 20, the risk estimates for non-
cancer effects from acute and chronic dermal exposures and cancer from chronic dermal
exposures at the central tendency and high end support an unreasonable risk
determination.
• For workers, when assuming use of respirators with APF of 10, the risk estimates of non-
cancer effects from acute and chronic inhalation exposures do not support an
unreasonable risk determination. Similarly, for workers, when assuming use of
respirators with APF of 50, the risk estimates for cancer from chronic inhalation
exposures do not support an unreasonable risk determination. Respirators with APF of 50
and gloves with PF of 20 are the maximum assumed personal protective equipment for
workers at industrial/commercial facilities using film cement, based on professional
judgment regarding practices at industrial/commercial facilities using film cement.
• Inhalation exposures were assessed using personal breathing zone (PBZ) and area
samples from a 1982 NIOSH Health Hazard Evaluation (HHE) report.
• Dermal exposures were assessed using modeled data.
• To assess ONU exposure, EPA calculated an upper bound for the NIOSH HHE samples
and used it to calculate an 8-hour time-weighted average (TWA) value. The 8-hour TWA
was used to calculate acute and chronic inhalation exposures for ONUs.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is an unreasonable risk of
injury to health (workers) from the industrial/commercial use of 1,4-dioxane as an adhesive or
sealant.
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5.2.1.13
Industrial/commercial use - Other uses - Spray polyurethane foam
Section 6(b)(4)(A) unreasonable risk determination for the industrial/commercial use of 1.4-
dioxane in spray polyurethane foam: Does not present an unreasonable risk of injury to health
(workers and ONUs).
For workers, EPA found that there was no unreasonable risk of non-cancer effects (liver toxicity
and olfactory epithelium effects) from acute or chronic inhalation or dermal exposures or cancer
from chronic inhalation exposures at the central tendency or high-end, even when PPE is not
used. In addition, for workers, EPA found that there was no unreasonable risk of cancer from
chronic dermal exposures at the central tendency and high-end when assuming use of PPE. For
ONUs, EPA found that there was no unreasonable risk of non-cancer effects or cancer from
chronic inhalation exposures at the central tendency and high-end.
EPA's determination that the industrial use of 1,4-dioxane as a spray polyurethane foam does not
present an unreasonable risk is based on the comparison of the risk estimates for non-cancer
effects and cancer to the benchmarks (Table 4-23.). As explained in Section 5.1., EPA also
considered the health effects of 1,4-dioxane, the exposures from the condition of use, and the
uncertainties in the analysis (Section 4.3):
• For workers, when assuming use of gloves with PF of 20, the risk estimates for cancer
from chronic dermal exposures at the central tendency and high-end do not support an
unreasonable risk determination. Respirators with APF of 10 and gloves with PF of 20
are the maximum assumed personal protective equipment for workers applying spray
polyurethane foam, based on professional judgment regarding practices for workers
applying spray polyurethane foam.
• Worker and ONU inhalation exposures were assessed using modeled and surrogate data.
• Dermal exposures were assessed using modeled data.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is no unreasonable risk of
injury to health (workers and ONUs) from the industrial use of 1,4-dioxane in spray
polyurethane foam.
5.2.1.14 Industrial/commercial use - Other uses - Printing and printing
compositions
Section 6(b)(4)(A) unreasonable risk determination for the industrial/commercial use of 1.4-
dioxane in printing and printing compositions: Presents an unreasonable risk of injury to
health (workers); does not present an unreasonable risk of injury to health (ONUs)
For workers, EPA found that there was an unreasonable risk of non-cancer effects (liver toxicity
and olfactory epithelium effects) from acute and chronic dermal exposures and cancer from
chronic dermal exposures at the central tendency and high-end, even when assuming the use of
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PPE. For ONUs, EPA found that there was no unreasonable risk of non-cancer effects or cancer from
chronic inhalation exposures at the central tendency.
EPA's determination that the industrial/commercial use of 1,4-dioxane in printing and printing
compositions presents an unreasonable risk is based on the comparison of the risk estimates for
non-cancer effects and cancer to the benchmarks (Table 4-23.). As explained in Section 5.1.,
EPA also considered the health effects of 1,4-dioxane, the exposures from the condition of use,
and the uncertainties in the analysis (Section 4.3), including uncertainties related to the
exposures for ONUs:
• For workers, when assuming the use of gloves with PF of 20, the risk estimates for non-
cancer effects from acute and chronic dermal exposures and cancer from chronic dermal
exposures at the central tendency and high-end support an unreasonable risk
determination. Gloves with PF of 20 are the maximum assumed personal protective
equipment for workers at industrial/commercial facilities doing printing and using
printing compositions, based on professional judgment regarding practices at
industrial/commercial facilities doing printing and using printing compositions.
• For workers, the risk estimates of non-cancer effects from acute and chronic inhalation
exposures and cancer from chronic inhalation exposures at the central tendency and high-
end do not support an unreasonable risk determination, even without assuming the use of
PPE.
• Inhalation exposures were assessed using a single data point from a published literature
review and hazard assessment for material jetting that measured exposures to a number of
chemicals including 1,4-dioxane.
• Dermal exposures were assessed using modeled data.
• Based on EPA's analysis, the data for worker and ONU inhalation exposure could not be
distinguished; however, ONU inhalation exposures are assumed to be lower than
inhalation exposures for workers directly handling the chemical substance. To account
for this uncertainty, EPA considered the workers' central tendency estimate of inhalation
exposures when determining ONU risk. However, as previously noted, the risk estimates
for workers of non-cancer effects from acute and chronic inhalation exposures and cancer
from chronic inhalation exposures at the high-end also do not support an unreasonable
risk determination, even without the use of PPE.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is an unreasonable risk of
injury to health (workers) from the industrial/commercial use of 1,4-dioxane in printing and
printing compositions.
5.2.1.15 Industrial/commercial use - Other uses - Dry film lubricant
Section 6(b)(4)(A) unreasonable risk determination for the industrial/commercial use of 1.4-
dioxane in dry film lubricants: Presents an unreasonable risk of injury to health (workers);
does not present an unreasonable risk of injury to health (ONUs)
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For workers, EPA found that there was an unreasonable risk of non-cancer effects (liver toxicity
and olfactory epithelium effects) from acute and chronic dermal exposures and cancer from
chronic dermal exposures at the central tendency and high-end, even when assuming the use of
PPE. For ONUs, EPA found that there was no unreasonable risk of non-cancer effects or cancer from
chronic inhalation exposures at the central tendency.
EPA's determination that the industrial/commercial use of 1,4-dioxane in dry film lubricants
presents an unreasonable risk is based on the comparison of the risk estimates for non-cancer
effects and cancer to the benchmarks (Table 4-23.). As explained in Section 5.1., EPA also
considered the health effects of 1,4-dioxane, the exposures from the condition of use, and the
uncertainties in the analysis (Section 4.3), including uncertainties related to the exposures for
ONUs:
• For workers, when assuming the use of gloves with PF of 20, the risk estimates for non-
cancer effects from acute and chronic dermal exposures and cancer from chronic dermal
exposures at the central tendency and high-end support an unreasonable risk
determination.
• For workers, when assuming use of respirators with APF of 10, the risk estimates of non-
cancer effects from acute inhalation exposure and cancer effects from chronic exposures
at the high end do not support an unreasonable risk determination. Respirators with APF
of 10 and gloves with PF of 20 are the maximum assumed personal protective equipment
for workers at industrial/commercial facilities using 1,4-dioxane in dry film lubricants,
based on process and work activity descriptions at industrial/commercial facilities using
1,4-dioxane in dry film lubricants.
• Inhalation exposures were assessed using personal breathing zone (PBZ) monitoring
sample data provided by the U.S. Department of Defense, Kansas City National Security
Campus. Information was not available as to whether other facilities within the National
Nuclear Security Administration (NNSA) use 1,4-dioxane like the KCNSC.
• Dermal exposures were assessed using modeled data.
• Based on EPA's analysis, the data for worker and ONU inhalation exposure could not be
distinguished; however, ONU inhalation exposures are assumed to be lower than
inhalation exposures for workers directly handling the chemical substance. To account
for this uncertainty, EPA considered the workers' central tendency estimate of inhalation
exposures when determining ONU risk.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is an unreasonable risk of
injury to health (workers) from the industrial/commercial use of 1,4-dioxane in dry film
lubricants.
5.2.1.16 Consumer use - Arts, crafts and hobby materials - Textile dye
Section 6(b)(4)(A) unreasonable risk determination for the consumer use of 1,4-dioxane in
textile dye: Does not present an unreasonable risk of injury to health (consumers and
bystanders).
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For consumers, EPA found that there was no unreasonable risk of non-cancer effects (liver
toxicity) from acute inhalation or dermal exposures at the high-intensity use. For bystanders,
EPA found that there was no unreasonable risk of non-cancer effects (liver toxicity) from acute
inhalation exposures at the high intensity use.
EPA's determination that the consumer use of 1,4-dioxane in textile dye does not present an
unreasonable risk is based on the comparison of the risk estimates for non-cancer effects to the
benchmarks (Table 4-24.). As explained in Section 5.1., EPA also considered the health effects
of 1,4-dioxane, the exposures from the condition of use, and the uncertainties in the analysis
(Section 4.3):
• Chronic exposures were not evaluated for this condition of use because daily use
intervals are not reasonably expected to occur.
• Inhalation exposures to consumers and bystanders were evaluated with the Consumer
Exposure Model Version 2.1 (CEM 2.1). The magnitude of inhalation exposures to
consumers and bystanders depends on several factors, including the concentration of
1,4-dioxane in products used, use patterns (including frequency, duration, amount of
product used, room of use, and local ventilation), and application method.
• Dermal exposures to consumers were evaluated with the CEM (Fraction Absorbed).
Dermal exposures to consumers result from dermal contact not involving impeded
evaporation while using the product. The magnitude of dermal exposures depends on
several factors, including skin surface area, film thickness, concentration of 1,4-dioxane
in product used, dermal exposure duration, and estimated fractional absorption.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is no unreasonable risk of
injury to health (consumers and bystanders) from the consumer use of 1,4-dioxane in textile
dye.
5.2.1.17 Consumer use - Automotive care products - Antifreeze
Section 6(b)(4)(A) unreasonable risk determination for the consumer use of 1,4-dioxane in
antifreeze: Does not present an unreasonable risk of injury to health (consumers and
bystanders).
For consumers, EPA found that there was no unreasonable risk of non-cancer effects (liver
toxicity) from acute inhalation or dermal exposures at the high-intensity use. For bystanders,
EPA found that there was no unreasonable risk of non-cancer effects (liver toxicity) from acute
inhalation exposures at the high intensity use.
EPA's determination that the consumer use of 1,4-dioxane in antifreeze does not present an
unreasonable risk is based on the comparison of the risk estimates for non-cancer effects to the
benchmarks (Table 4-24.). As explained in Section 5.1., EPA also considered the health effects
of 1,4-dioxane, the exposures from the condition of use, and the uncertainties in the analysis
(Section 4.3):
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• Chronic exposures were not evaluated for this condition of use because daily use
intervals are not reasonably expected to occur.
• Inhalation exposures to consumers and bystanders were evaluated with the Consumer
Exposure Model Version 2.1 (CEM 2.1). The magnitude of inhalation exposures to
consumers and bystanders depends on several factors, including the concentration of
1,4-dioxane in products used and use patterns (including frequency, duration, amount of
product used, and local ventilation).
• Dermal exposures to consumers were evaluated with the CEM (Fraction Absorbed).
Dermal exposures to consumers result from dermal contact not involving impeded
evaporation while using the product. The magnitude of dermal exposures depends on
several factors, including skin surface area, film thickness, concentration of 1,4-dioxane
in product used, dermal exposure duration, and estimated fractional absorption.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is no unreasonable risk of
injury to health (consumers and bystanders) from the consumer use of 1,4-dioxane in antifreeze.
5.2.1.18 Consumer use - Cleaning and furniture care products - Surface
cleaner
Section 6(b)(4)(A) unreasonable risk determination for the consumer use of 1,4-dioxane in
general purpose cleaners: Does not present an unreasonable risk of injury to health (consumers
and bystanders).
For consumers, EPA found that there was no unreasonable risk of non-cancer effects (liver
toxicity) from acute inhalation or dermal exposures or of cancer from chronic inhalation or
dermal exposures at the high intensity use. For bystanders, EPA found that there was no
unreasonable risk of non-cancer effects (liver toxicity) from acute inhalation exposures at the
high intensity use.
EPA's determination that the consumer use of 1,4-dioxane in surface cleaner does not present
an unreasonable risk is based on the comparison of the risk estimates for non-cancer effects and
cancer to the benchmarks (Table 4-24.). As explained in Section 5.1., EPA also considered the
health effects of 1,4-dioxane, the exposures from the condition of use, and the uncertainties in
the analysis (Section 4.3):
• Inhalation exposures to consumers and bystanders were evaluated with the Consumer
Exposure Model Version 2.1 (CEM 2.1). The magnitude of inhalation exposures to
consumers and bystanders depends on several factors, including the concentration of
1,4-dioxane in products used and use patterns (including frequency, duration, amount of
product used, and local ventilation).
• Dermal exposures to consumers were evaluated with the CEM (Fraction Absorbed).
Dermal exposures to consumers result from dermal contact not involving impeded
evaporation while using the product. The magnitude of dermal exposures depends on
several factors, including skin surface area, film thickness, concentration of 1,4-dioxane
in product used, dermal exposure duration, and estimated fractional absorption.
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In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is no unreasonable risk of
injury to health (consumers and bystanders) from the consumer use of 1,4-dioxane in surface
cleaner.
5.2.1.19 Consumer use - Laundry and dishwashing products - Dish soap
Section 6(b)(4)(A) unreasonable risk determination for the consumer use of 1,4-dioxane in dish
soap: Does not present an unreasonable risk of injury to health (consumers and bystanders).
For consumers, EPA found that there was no unreasonable risk of non-cancer effects (liver
toxicity) from acute inhalation or dermal exposures or of cancer from chronic inhalation or
dermal exposures at the high intensity use. For bystanders, EPA found that there was no
unreasonable risk of non-cancer effects (liver toxicity) from acute inhalation exposures at the
high intensity use.
EPA's determination that the consumer use of 1,4-dioxane in dish soap does not present an
unreasonable risk is based on the comparison of the risk estimates for non-cancer effects and
cancer to the benchmarks (Table 4-24.). As explained in Section 5.1., EPA also considered the
health effects of 1,4-dioxane, the exposures from the condition of use, and the uncertainties in
the analysis (Section 4.3):
• Inhalation exposures to consumers and bystanders were evaluated with the Consumer
Exposure Model Version 2.1 (CEM 2.1). The magnitude of inhalation exposures to
consumers and bystanders depends on several factors, including the concentration of
1,4-dioxane in products used and use patterns (including frequency, duration, amount of
product used, and local ventilation).
• Dermal exposures to consumers were evaluated with the CEM (Fraction Absorbed).
Dermal exposures to consumers result from dermal contact not involving impeded
evaporation while using the product. The magnitude of dermal exposures depends on
several factors, including skin surface area, film thickness, concentration of 1,4-dioxane
in product used, dermal exposure duration, and estimated fractional absorption.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is no unreasonable risk of
injury to health (consumers and bystanders) from the consumer use of 1,4-dioxane in dish soap.
5.2.1.20 Consumer use - Laundry and dishwashing products - Dishwasher
detergent
Section 6(b)(4)(A) unreasonable risk determination for the consumer use of 1,4-dioxane in
dishwasher detergent: Does not present an unreasonable risk of injury to health (consumers and
bystanders).
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For consumers, EPA found that there was no unreasonable risk of non-cancer effects (liver
toxicity) from acute inhalation or dermal exposures or of cancer from chronic inhalation or
dermal exposures at the high intensity use. For bystanders, EPA found that there was no
unreasonable risk of non-cancer effects (liver toxicity) from acute inhalation exposures at the
high intensity use.
EPA's determination that the consumer use of 1,4-dioxane in dishwasher detergent does not
present an unreasonable risk is based on the comparison of the risk estimates for non-cancer
effects and cancer to the benchmarks (Table 4-24.). As explained in Section 5.1., EPA also
considered the health effects of 1,4-dioxane, the exposures from the condition of use, and the
uncertainties in the analysis (Section 4.3):
• Inhalation exposures to consumers and bystanders were evaluated with the Consumer
Exposure Model Version 2.1 (CEM 2.1). The magnitude of inhalation exposures to
consumers and bystanders depends on several factors, including the concentration of
1,4-dioxane in products used and use patterns (including frequency, duration, amount of
product used, and local ventilation).
• Dermal exposures to consumers were evaluated with the CEM (Fraction Absorbed).
Dermal exposures to consumers result from dermal contact not involving impeded
evaporation while using the product. The magnitude of dermal exposures depends on
several factors, including skin surface area, film thickness, concentration of 1,4-dioxane
in product used, dermal exposure duration, and estimated fractional absorption.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is no unreasonable risk of
injury to health (consumers and bystanders) from the consumer use of 1,4-dioxane in
dishwasher detergent.
5.2.1.21 Consumer use - Laundry and dishwashing products - Laundry
detergent
Section 6(b)(4)(A) unreasonable risk determination for the consumer use of 1,4-dioxane in
laundry detergent: Does not present an unreasonable risk of injury to health (consumers and
bystanders).
For consumers, EPA found that there was no unreasonable risk of non-cancer effects (liver
toxicity) from acute inhalation or dermal exposures or of cancer from chronic inhalation or
dermal exposures at the high intensity use. For bystanders, EPA found that there was no
unreasonable risk of non-cancer effects (liver toxicity) from acute inhalation exposures at the
high intensity use.
EPA's determination that the consumer use of 1,4-dioxane in laundry detergent does not present
an unreasonable risk is based on the comparison of the risk estimates for non-cancer effects and
cancer to the benchmarks (Table 4-24.). As explained in Section 5.1., EPA also considered the
health effects of 1,4-dioxane, the exposures from the condition of use, and the uncertainties in
the analysis (Section 4.3):
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• Inhalation exposures to consumers and bystanders were evaluated with the Consumer
Exposure Model Version 2.1 (CEM 2.1). The magnitude of inhalation exposures to
consumers and bystanders depends on several factors, including the concentration of
1,4-dioxane in products used and use patterns (including frequency, duration, amount of
product used, and local ventilation).
• Dermal exposures to consumers were evaluated with the CEM (Fraction Absorbed).
Dermal exposures to consumers result from dermal contact not involving impeded
evaporation while using the product. The magnitude of dermal exposures depends on
several factors, including skin surface area, film thickness, concentration of 1,4-dioxane
in product used, dermal exposure duration, and estimated fractional absorption.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is no unreasonable risk of
injury to health (consumers and bystanders) from the consumer use of 1,4-dioxane in laundry
detergent.
5.2.1.22 Consumer use - Paints and coatings - Paint and floor lacquer
Section 6(b)(4)(A) unreasonable risk determination for the consumer use of 1,4-dioxane in paint
and floor lacquer: Does not present an unreasonable risk of injury to health (consumers and
bystanders).
For consumers, EPA found that there was no unreasonable risk of non-cancer effects (liver
toxicity) from acute inhalation or dermal exposures at the high-intensity use. For bystanders,
EPA found that there was no unreasonable risk of non-cancer effects (liver toxicity) from acute
inhalation exposures at the high intensity use.
EPA's determination that the consumer use of 1,4-dioxane in paint and floor lacquer does not
present an unreasonable risk is based on the comparison of the risk estimates for non-cancer
effects to the benchmarks (Table 4-24.). As explained in Section 5.1., EPA also considered the
health effects of 1,4-dioxane, the exposures from the condition of use, and the uncertainties in
the analysis (Section 4.3):
• Chronic exposures were not evaluated for this condition of use because daily use
intervals are not reasonably expected to occur.
• Inhalation exposures to consumers and bystanders were evaluated with the Consumer
Exposure Model Version 2.1 (CEM 2.1). The magnitude of inhalation exposures to
consumers and bystanders depends on several factors, including the concentration of
1,4-dioxane in products used and use patterns (including frequency, duration, amount of
product used, and local ventilation).
• Dermal exposures to consumers were evaluated with the CEM (Fraction Absorbed).
Dermal exposures to consumers result from dermal contact not involving impeded
evaporation while using the product. The magnitude of dermal exposures depends on
several factors, including skin surface area, film thickness, concentration of 1,4-dioxane
in product used, dermal exposure duration, and estimated fractional absorption.
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In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is no unreasonable risk of
injury to health (consumers and bystanders) from the consumer use of 1,4-dioxane in paint and
floor lacquer.
5.2.1.23 Consumer use - Other uses - Spray Polyurethane Foam
Section 6(b)(4)(A) unreasonable risk determination for the consumer use of 1,4-dioxane in
spray polyurethane foam: Does not present an unreasonable risk of injury to health (consumers
and bystanders).
For consumers, EPA found that there was no unreasonable risk of non-cancer effects (liver
toxicity) from acute inhalation and dermal exposures at the high-intensity use. For bystanders,
EPA found that there was no unreasonable risk of non-cancer effects (liver toxicity) from acute
inhalation exposures at the high intensity use.
EPA's determination that the consumer use of 1,4-dioxane in spray polyurethane foam does not
present an unreasonable risk is based on the comparison of the risk estimates for non-cancer
effects to the benchmarks (Table 4-24.). As explained in Section 5.1., EPA also considered the
health effects of 1,4-dioxane, the exposures from the condition of use, and the uncertainties in
the analysis (Section 4.3):
• Chronic exposures were not evaluated for this condition of use because daily use
intervals are not reasonably expected to occur.
• Inhalation exposures to consumers and bystanders were evaluated with the Consumer
Exposure Model Version 2.1 (CEM 2.1). The magnitude of inhalation exposures to
consumers and bystanders depends on several factors, including the concentration of
1,4-dioxane in products used and use patterns (including frequency, duration, amount of
product used, and local ventilation).
• Dermal exposures to consumers were evaluated with the CEM (Fraction Absorbed).
Dermal exposures to consumers result from dermal contact not involving impeded
evaporation while using the product. The magnitude of dermal exposures depends on
several factors, including skin surface area, film thickness, concentration of 1,4-dioxane
in product used, dermal exposure duration, and estimated fractional absorption.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is no unreasonable risk of
injury to health (consumers and bystanders) from the consumer use of 1,4-dioxane in spray
polyurethane foam.
5.2.1.24 Disposal - Disposal - Wastewater; Underground injection; Landfill;
Incineration
Section 6(b)(4)(A) unreasonable risk determination for the disposal of 1,4-dioxane: Presents an
unreasonable risk of injury to health (workers and ONUs).
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For workers, EPA found that there was an unreasonable risk of non-cancer effects (liver toxicity
and olfactory epithelium effects) from acute and chronic dermal exposures and cancer from
chronic dermal exposures, even when assuming use of PPE. For ONUs, EPA found that there was
an unreasonable risk of non-cancer effects and cancer from chronic inhalation exposures at the
central tendency.
EPA's determination that the disposal of 1,4-dioxane presents an unreasonable risk is based on
the comparison of the risk estimates for non-cancer effects and cancer to the benchmarks (Table
4-23.). As explained in Section 5.1., EPA also considered the health effects of 1,4-dioxane, the
exposures from the condition of use, and the uncertainties in the analysis (Section 4.3), including
uncertainties related to the exposures for ONUs:
• For workers, when assuming the use of gloves with PF of 20, the risk estimates for non-
cancer effects from acute and chronic dermal exposures and cancer from chronic dermal
exposures at the central tendency and high-end support an unreasonable risk
determination.
• For workers, when assuming use of respirators with APF of 50, the risk estimates of non-
cancer effects from acute and chronic inhalation exposures do not support an
unreasonable risk determination. Similarly, for workers, when assuming use of
respirators with APF of 50, the risk estimates for cancer from chronic inhalation
exposures do not support an unreasonable risk determination. Respirators with APF of 50
and gloves with PF of 20 are the maximum assumed personal protective equipment for
workers at disposal facilities, based on professional judgment regarding practices at
disposal facilities.
• Inhalation and dermal exposures were assessed using modeled data.
• Based on EPA's analysis, the data for worker and ONU inhalation exposure could not be
distinguished; however, ONU inhalation exposures are assumed to be lower than
inhalation exposures for workers directly handling the chemical substance. To account
for this uncertainty, EPA considered the workers' central tendency estimate of inhalation
exposures when determining ONU risk.
In summary, the risk estimates, the health effects of 1,4-dioxane, the exposures, and
consideration of uncertainties support EPA's determination that there is an unreasonable risk of
injury to health (workers and ONUs) from the disposal of 1,4-dioxane.
5.2.2 Environment
6(b)(4)(A) unreasonable risk determination for all conditions of use of 1,4-dioxane: Does not
present an unreasonable risk of injury to the environment (aquatic, sediment dwelling, and
terrestrial organisms).
For all conditions of use, EPA found that there were no exceedances of benchmarks to aquatic
organisms from exposures to 1,4-dioxane. The RQ values for acute and chronic risks are 0.2 and
0.397, respectively, based on the best available science.
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The high volatility, high water solubility and low Log Koc of 1,4-dioxane suggest that 1,4-
dioxane will only be present at low concentrations in sediment and land-applied biosolids.
In summary, the risk estimates, the environmental effects of 1,4-dioxane, the exposures, physical
chemical properties of 1,4-dioxane and consideration of uncertainties support a determination
that there is no unreasonable risk for the environment from all conditions of use of 1,4-dioxane.
5,3 Changes to the Unreasonable Risk Determination from Draft Risk
Evaluation to Final Risk Evaluation
In this final risk evaluation, EPA made changes to the unreasonable risk determination for 1,4-
dioxane following the publication of the draft risk evaluation, as a result of the analysis
following peer review and public comments. In particular, in November 2020, EPA issued a
Draft Supplemental Analysis to the Draft Risk Evaluation of 1,4-Dioxane that covered eight
consumer conditions of use not included in the original draft risk evaluation, as well as general
population exposures from recreational swimming in ambient water. The consumer conditions of
use presented in the supplemental analysis are use of 1,4-dioxane in textile dye, antifreeze,
surface cleaner, dish soap, dishwasher detergent, laundry detergent, paint and floor lacquer, and
spray polyurethane foam. As a result of the supplemental analysis, this final risk evaluation
includes risk determinations for the general population in Section 5.1.1 and for the eight
consumer conditions of use at Sections 5.2.1.15-5.2.1.23.
In addition, while use of 1,4-dioxane as a process solvent and as an intermediate in the
manufacture of pharmaceuticals was included in the problem formulation and draft risk
evaluation, upon further analysis of the details of these processes, EPA has determined that these
uses fall outside TSCA's definition of "chemical substance." Under TSCA § 3(2)(B)(vi), the
definition of "chemical substance" does not include any food, food additive, drug, cosmetic, or
device (as such terms are defined in section 201 of the Federal Food, Drug, and Cosmetic Act)
when manufactured, processed, or distributed in commerce for use as a food, food additive, drug,
cosmetic, or device. EPA has concluded that 1,4-dioxane use as a process solvent and an
intermediate during pharmaceutical manufacturing falls outside TSCA's definition of a chemical
substance when used for these purposes. As a result, the use of 1,4-dioxane as a process solvent
and an intermediate during pharmaceutical manufacturing are not included in the scope of this
risk evaluation.
Finally, EPA is correcting two minor errors that appeared in the risk determination table in the
draft risk evaluation. The "Etching of fluoropolymers" condition of use was inadvertently
omitted from the "Industrial use: Processing aids, not otherwise listed" subcategory. Also,
"Hydraulic fluid" should not have appeared under the "Industrial use: Functional fluids (open
system)" subcategory. Hydraulic fluid is a closed system functional fluid and, as noted in the risk
determination table in the draft risk evaluation, EPA determined that functional fluid use in
closed systems was not a condition of use for 1,4-dioxane.
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5.4 Unreasonable Risk Determination Conclusion
5.4.1 No Unreasonable Risk Determinations
TSCA Section 6(b)(4) requires EPA to conduct risk evaluations to determine whether chemical
substances present unreasonable risk under their conditions of use. In conducting risk
evaluations, "EPA will determine whether the chemical substance presents an unreasonable risk
of injury to health or the environment under each condition of use within the scope of the risk
evaluation..40 CFR 702.47. Pursuant to TSCA Section 6(i)(l), a determination of "no
unreasonable risk" shall be issued by order and considered to be final agency action. Under
EPA's implementing regulations, "[a] determination by EPA that the chemical substance, under
one or more of the conditions of use within the scope of the risk evaluation, does not present an
unreasonable risk of injury to health or the environment will be issued by order and considered to
be a final Agency action, effective on the date of issuance of the order." 40 CFR 702.49(d).
EPA has determined that the following conditions of use of 1,4-dioxane do not present an
unreasonable risk of injury to health or the environment:
• Distribution in commerce (Section 5.1.1, Section 5.2.1.7, Section 5.2.2, Section 4,
Section 3)
• Industrial/commercial use: Functional fluids, open system (Section 5.1.1, Section
5.2.1.10, Section 5.2.2, Section 4, Section 3, and Section 2.4.1.1.5)
• Industrial/commercial use: Other uses: Spray polyurethane foam (Section 5.1.1, Section
5.2.1.13, Section 5.2.2, Section 4, Section 3, and Section 2.4.1.1.9)
• Consumer use: Arts, crafts, and hobby materials - Textile dye (Section 5.1.1, Section
5.2.1.16, Section 5.2.2, Section 4, Section 3, and Section 2.4.3.4.7)
• Consumer use: Automotive care products - Antifreeze (Section 5.1.1, Section 5.2.1.17,
Section 5.2.2, Section 4, Section 3, and Section 2.4.3.4.2)
• Consumer use: Cleaning and furniture care products - Surface cleaner (Section 5.1.1,
Section 5.2.1.18, Section 5.2.2, Section 4, Section 3, and Section 2.4.3.4.1)
• Consumer use: Laundry and dishwashing products - Dish soap (Section 5.1.1, Section
5.2.1.19, Section 5.2.2, Section 4, Section 3, and Section 2.4.3.4.3)
• Consumer use: Laundry and dishwashing products - Dishwasher detergent (Section
5.1.1, Section 5.2.1.20, Section 5.2.2, Section 4, Section 3, and Section 2.4.3.4.4)
• Consumer use: Laundry and dishwashing products - Laundry detergent (Section 5.1.1,
Section 5.2.1.21, Section 5.2.2, Section 4, Section 3, and Section 2.4.3.4.5)
• Consumer use: Paints and coatings - Paint and floor lacquer (Section 5.1.1, Section
5.2.1.22, Section 5.2.2, Section 4, Section 3, and Section 2.4.3.4.6)
• Consumer use: Other uses - Spray polyurethane foam (Section 5.1.1, Section 5.2.1.23,
Section 5.2.2, Section 4, Section 3, and Section 2.4.3.4.8)
This subsection of the final risk evaluation therefore constitutes the order required under TSCA
Section 6(i)(l), and the "no unreasonable risk" determinations in this subsection are considered
to be final agency action effective on the date of issuance of this order. All assumptions that went
into reaching the determinations of no unreasonable risk for these conditions of use, including
any considerations excluded for these conditions of use, are incorporated into this order.
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The support for each determination of no unreasonable risk is set forth in Section 5.2 of the final
risk evaluation, "Detailed Unreasonable Risk Determinations by Condition of Use." This
subsection also constitutes the statement of basis and purpose required by TSCA Section 26(f).
5,4,2 Unreasonable Risk Determinations
EPA has determined that the following conditions of use of 1,4-dioxane present an unreasonable
risk of injury:
• Manufacture: Domestic manufacture
• Manufacture: Import/repackaging (bottle and drums)
• Processing: Repackaging (bottle and drums)
• Processing: Recycling
• Processing: Non-incorporative
• Processing: Reactant
• Industrial use: Intermediate
• Industrial use: Processing aid
• Industrial use: Laboratory chemicals
• Industrial/commercial use: Adhesives or sealants
• Industrial/commercial use: Printing and printing compositions
• Industrial/commercial use: Dry film lubricant
• Disposal
EPA will initiate TSCA Section 6(a) risk management actions on these conditions of use as
required under TSCA Section 6(c)(1). Pursuant to TSCA Section 6(i)(2), the "unreasonable risk"
determinations for these conditions of use are not considered final agency action.
Page 302 of 616
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Wirth. W; Klimmer. O. (1936). [On the toxicology of organic solvents. 1,4 dioxane (diethylene
dioxide)]. Archiv fuer Gewerbepathologie und Gewerbehygiene 17: 192-206.
Won. DNoGYaWCoP. (2014). Material Emissions Testing: VOCs from Wood, Paint, and
Insulation Materials. National Research Council of Canada.
http://dx.doi.Org/https://doi.org/10.4224/23002015.
Woo. Yt; Arcos. JC: Argus. MF. (1977a). Metabolism in vivo of dioxane: identification of p-
dioxane-2-one as the major urinary metabolite. Biochem Pharmacol 26: 1535-1538.
Woo. YT; Arcos. JC: Argus. MF; Griffin. GW: K. N. (1977b). Structural identification of p-
dioxane-2-one as the major urinary metabolite of p-dioxane. Naunyn-Schmiedebergs
Arch Pharmacol 299: 283-287. http://dx.doi.org, )500322.
Woo. s. MF; Arcos. JC. (1977c). Tissue and subcellular distribution of 3H-dioxane in
the rat and apparent lack of microsome-catalyzed covalent binding in the target tissue.
Life Sci 21: 1447-1456. http://dx.doi.org/10.1016/0024-3205(77)90199-0.
Woo. YT; Argus. MF; Arcos. JC. (1978). Effect of mixed-function oxidase modifiers on
metabolism and toxicity of the oncogen dioxane. Cancer Res 38: 1621-1625.
Yatkowsky. SH; He. Y; Jain. P. (2010). Handbook of aqueous solubility data (2nd ed.). Boca
Raton, FL: CRC Press. http://dx.doi.( t/EBK 1439802458.
Yamazaki. K; Ohno. H; Asakura. M; Narum: ibayashi. H; Fujita. H; Ohnishi. M; Katagiri.
T; Senoh. H; Yamanouchi. K; Nakavame imamoto. S; Noguchi. T; Nagano. K;
Enomoto. M; Sakabe. H. (1994). Two-year toxicological and carcinogenesis studies of
1,4-dioxane in F344 rats and BDF1 mice. In K Sumino; S Sato; NG Shinkokai (Eds.),
Proceedings: Second Asia-Pacific Symposium on Environmental and Occupational
Health 22-24 July, 1993: Kobe (pp. 193-198). Kobe, Japan: Kobe University School of
Medicine, International Center for Medical Research.
Yant. WP; Schrenk. HH; Waite. CP; 1 (1930). Acute response of guinea pigs to vapors
of some new commercial organic compounds: VI. Dioxan. Public Health Rep 45: 2023-
2032.
Yoon. JS; Mason. J encia. R; Woodruff. RC; Zimmering. S. (1985). Chemical
mutagenesis testing in Drosophila. IV. Results of 45 coded compounds tested for the
National Toxicology Program. Environ Mutagen 7: 349-367.
http://dx.doi.org h« i^02/em.2860070 * 10
Page 336 of 616
-------
Young, ID; Braun., WH; Gehring, PI. (1978a). The dose-dependent fate of 1,4-dioxane in rats. J
Environ Pathol Toxicol 2: 263-282.
Your urn. WH; Gehring. PI. (1978b). Dose—dependent fate of 1,4-dioxane in rats(b). J
Toxicol Environ Health A 4: 709-726. http://dx.doi. 80/15287397809529693.
Young. ID; Braun. WH; Gehring. PI; Horval . (1976). 1,4-Dioxane and beta-
hydroxyethoxyacetic acid excretion in urine of humans exposed to dioxane vapors.
Toxicol Appl Pharmacol 38: 643-646. http://dx.doi.org, 10 101 00 I I 008Xf76)90195-2.
Young. JD; Braun. WH; Ramp v. LW; Chenoweth. I au. GE. (1977). Pharmacokinetics of
1,4-dioxane in humans. J Toxicol Environ Health 3: 507-520.
http://dx.doi.org/10.1080/152.87397709529583.
Zhang. Q; Sharma. G; Wong. IPS; Davis \\ k. Kiswas. P; Weber. RJ. (2018).
Investigating particle emissions and aerosol dynamics from a consumer fused deposition
modeling 3D printer with a lognormal moment aerosol model. Aerosol Sci Technol 52:
1099-1111. http://dx.d0i.0rg/h.ttp://d0i.0rg/l0.1080/0278682.6.
Zhang. O; Wong '^r iU\tl V * P4ack. MS; Weber. RJ. (2017). Characterization of particle
emissions from consumer fused deposition modeling 3D printers. Aerosol Sci Technol
51: 1275-1286. http://dx.doi.org/10.1080/02786826.2017.1342029.
Zim.merm.ann. FK; Mayer. VW; Scheel. I; Resnick. MA. (1985). Acetone, methyl ethyl ketone,
ethyl acetate, acetonitrile and other polar aprotic solvents are strong inducers of
aneuploidy in Saccharomyces cerevisiae. MutatRes 149: 339-351.
http://dx.doi.on 10 J 0 L* 0027 > 10?, ,YS 190150-2.
WHO. (2005). 1,4-Dioxane in drinking water. (WHO/SDE/WSH/05.08/120). Geneva,
Switzerland.
WHO. (2006). Protecting groundwater for health: Managing the quality of drinking-water
sources. London, UK.
http://apps.who.int/iris/bitstream/10665/43186/1/9241546689 eng.pdf
Wilbur. S; Jones. D; Risher. IF; Crawford J, 1'emcza K 1 iados. F; Diamond. GL; Citra. M;
Osier. MR; Lockwciwt I 1 * (2012). Toxicological Profile for 1,4-Dioxane. Atlanta (GA):
Agency for Toxic Substances and Disease Registry (US).
Williams. GM; Hirota. N; Rice. JM. (1979). The resistance of spontaneous mouse hepatocellular
neoplasms to iron accumulation during rapid iron loading by parenteral administration
and their transplantability. Am J Pathol 94: 65-74.
Wirth. W; Ktimmer. O. (1936). [On the toxicology of organic solvents. 1,4 dioxane (diethylene
dioxide)]. Archiv fuer Gewerbepathologie und Gewerbehygiene 17: 192-206.
Woo. Yt; Arcos. JC; Argus. MF. (1977a). Metabolism in vivo of dioxane: identification of p-
dioxane-2-one as the major urinary metabolite. Biochem Pharmacol 26: 1535-1538.
Woo. YT; Arcos. JC; Argus. MF; Griffin. GW; K. N. (1977b). Structural identification of p-
dioxane-2-one as the major urinary metabolite of p-dioxane. Naunyn-Schmiedebergs
Arch Pharmacol 299: 283-287. http://dx.doi.org, )322
Woo. YT; Argus. MF; Arcos. JC. (1977c). Tissue and subcellular distribution of 3H-dioxane in
the rat and apparent lack of microsome-catalyzed covalent binding in the target tissue.
Life Sci 21: 1447-1456. http://dx.doi.org 024-3205(77)90199-0
Woo. YT; Argus. MF; Arcos. JC. (1978). Effect of mixed-function oxidase modifiers on
metabolism and toxicity of the oncogen dioxane. Cancer Res 38: 1621-1625.
Yalkowsky. SH; He. Y; Jain. P. (2010). Handbook of aqueous solubility data (2nd ed.). Boca
Raton, FL: CRC Press. http://dx.doi.( t/EEK 1439802458
Page 337 of 616
-------
Yamazaki, K; Ohno, H; Asakura, M; Narum: ibayashi, H; Fujita, H; Ohnishi, M; Katagiri,
T; Senoh. H; Yamanouchi. K; Nakayame imamoto. S; Noguchi. T; Nagano. K;
Enomoto. M; Sakabe. H. (1994). Two-year toxicological and carcinogenesis studies of
1,4-dioxane in F344 rats and BDF1 mice. In K Sumino; S Sato; NG Shinkokai (Eds.),
Proceedings: Second Asia-Pacific Symposium on Environmental and Occupational
Health 22-24 July, 1993: Kobe (pp. 193-198). Kobe, Japan: Kobe University School of
Medicine, International Center for Medical Research.
Yant. WP; Schrenk. HH; Waite. CP; 1 . (1930). Acute response of guinea pigs to vapors
of some new commercial organic compounds: VI. Dioxan. Public Health Rep 45: 2023-
2032.
Yoon. IS; Mason. J encia. R; Woodruff. RC; Zimmering. S. (1985). Chemical
mutagenesis testing in Drosophila. IV. Results of 45 coded compounds tested for the
National Toxicology Program. Environ Mutagen 7: 349-367.
http://dx.doi.org 1 « i^02/em.2860070 * 10
Your un. WH; Gehring. PI. (1978a). The dose-dependent fate of 1,4-dioxane in rats. J
Environ Pathol Toxicol 2: 263-282.
Your un. WH; Gehring. PI. (1978b). Dose—dependent fate of 1,4-dioxane in rats(b). J
Toxicol Environ Health A 4: 709-726. http://dx.doi.org i»l^0/15287397809529693
Your^ 'Is Pi am. WH; Gehring. PI; Horvalli Ur I *;miel. K1 (1976). 1,4-Dioxane and beta-
hydroxyethoxyacetic acid excretion in urine of humans exposed to dioxane vapors.
Toxicol Appl Pharmacol 38: 643-646. http://dx.doi.org, 10 101 o/00-t I 008X(76)90195-2
Your^ M * ^ am. WH; Ramr^ < \\; Chenoweth. MB; Blau. GE. (1977). Pharmacokinetics of
1,4-dioxane in humans. J Toxicol Environ Health 3: 507-520.
http://dx.doi.org/10.1080/15287397709529583
Zhang. Q; S harm a. G; Wong. IPS; Davis \\ , BLick. MS; Biswas. P; Weber. RJ. (2018).
Investigating particle emissions and aerosol dynamics from a consumer fused deposition
modeling 3D printer with a lognormal moment aerosol model. Aerosol Sci Technol 52:
1099-1111. http://dx.doi.org/http://doi.org/10.1080/02786826.
Zhang. O; Wong. IPS; I)a\ ack. MS; Weber. RJ. (2017). Characterization of particle
emissions from consumer fused deposition modeling 3D printers. Aerosol Sci Technol
51: 1275-1286. http://dx.doi.org/10.1080/02786826.2017.1342.029
Zimmermann. FK; Mayer. ¥W; Scheet. I; Resnick. (1985). Acetone, methyl ethyl ketone,
ethyl acetate, acetonitrile and other polar aprotic solvents are strong inducers of
aneuploidy in Saccharomyces cerevisiae. MutatRes 149: 339-351.
http://dx.doi.org/10 fOU'OOT MO i85)90150-2
Page 338 of 616
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APPENDICES
Appendix A REGULATORY HISTORY
A.l Federal Laws and Regulations
Table A-l. Federal Laws and Regulations
Statutes/
Regulations
Description of Authority/Regulation
Description of Regulation
EPA Regulations
TSCA - Section
6(b)
EPA is directed to identify and begin risk
evaluations on 10 chemical substances
drawn from the 2014 update of the TSCA
Work Plan for Chemical Assessments.
1,4-Dioxane is on the initial
list of chemicals to be
evaluated for risk under TSCA
(81 FR 91927, December 19,
2016).
TSCA - Section
8(a)
The TSCA Section 8(a) CDR Rule requires
manufacturers (including importers) to give
EPA basic exposure-related information on
the types, quantities and uses of chemical
substances produced domestically and
imported into the United States.
1,4-Dioxane manufacturing
(including importing),
processing distribution and use
information is reported under
the CDR rule information
about chemicals in commerce
in the United States.
TSCA - Section
8(b)
EPA must compile, keep current and
publish a list (the TSCA Inventory) of each
chemical substance manufactured or
processed in the United States.
1,4-Dioxane was on the initial
TSCA Inventory and therefore
was not subject to EPA's new
chemicals review process.
TSCA - Section
8(e)
Manufacturers (including importers),
processors and distributors must
immediately notify EPA if they obtain
information that supports the conclusion
that a chemical substance or mixture
presents a substantial risk of injury to
health or the environment.
Ten substantial risk reports
from 1989 to 2004 U.S. EPA.
(2014a) Accessed April 13,
2017.
EPCRA - Section
313
Requires annual reporting from facilities in
specific industry sectors that employ 10 or
more full time equivalent employees and
that manufacture, process or otherwise use
a TRI-listed chemical in quantities above
threshold levels.
1,4-Dioxane is a listed
substance subject to reporting
requirements under 40 CFR §
372.65 effective as of January
01, 1987.
Federal Food,
Drug, and
Cosmetic Act
FFDCA governs the allowable residues of
pesticides in food. Section 408 of the
FFDCA provides EPA with the authority to
In 1998, 1,4-dioxane was
removed from the list of
pesticide product inert
Page 339 of 616
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Si :i lull's/
Ucgiihilions
Description of Aiilhorily/Uo^uhilion
Description of Requisition
(J 1 IKA)
Section 408
scl lolcianccs (rules that csUiblish
maximum allowable residue limits) or
exemptions from the requirement of a
tolerance, for all residues of a pesticide
(including both active and inert
ingredients) that are in or on food. Prior to
issuing a tolerance or exemption from
tolerance, EPA must determine that the
tolerance or exemption is "safe." Sections
408(b) and (c) of the FFDCA define "safe"
to mean the Agency has reasonable
certainty that no harm will result from
aggregate exposures to the pesticide
residue, including all dietary exposure and
all other exposure (e.g., non-occupational
exposures) for which there is reliable
information. Pesticide tolerances or
exemptions from tolerance that do not meet
the FFDCA safety standard are subject to
revocation. In the absence of a tolerance or
an exemption from tolerance, a food
containing a pesticide residue is considered
adulterated and may not be distributed in
interstate commerce.
ingicdicnls because il was no
longer being used in pesticide
products. 1,4-Dioxane is also
no longer exempt from the
requirement of a tolerance (the
maximum residue level that
can remain on food or feed
commodities under 40 CFR
Part 180, Subpart D).
CAA - Section
111(b)
Requires EPA to establish new source
performance standards (NSPS) for any
category of new or modified stationary
sources that EPA determines causes, or
contributes significantly to, air pollution,
which may reasonably be anticipated to
endanger public health or welfare. The
standards are based on the degree of
emission limitation achievable through the
application of the best system of emission
reduction (BSER) which (considering the
cost of achieving reductions and
environmental impacts and energy
requirements) EPA determines has been
adequately demonstrated.
1,4-Dioxane is subject to the
NSPS for equipment leaks of
volatile organic compounds
(VOCs) in the synthetic
organic chemicals
manufacturing industry for
which construction,
reconstruction or modification
began after 1/5/1981 and on or
before 11/7/2006 (40 CFR Part
60, Subpart VV).
CAA - Section
112(b)
Defines the original list of 189 hazardous
air pollutants (HAP). Under 112(c) of the
CAA, EPA must identify and list source
categories that emit HAP and then set
1,4-Dioxane is listed as a HAP
under section 112 (42 U.S.C. §
7412) of the CAA.
Page 340 of 616
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Si :i lull's/
Ucgiihilions
Description of Aiilhorily/Uo^uhilion
Description of Requisition
emission standards for those listed source
categories under CAA section 112(d).
CAA section 112(b)(3)(A) specifies that
any person may petition the Administrator
to modify the list of HAP by adding or
deleting a substance.
CAA - Section
112(d)
Section 112(d) states that the EPA must
establish (NESHAPs for each category or
subcategory of major sources and area
sources of HAPs [listed pursuant to
Section 112(c)], The standards must
require the maximum degree of emission
reduction that the EPA determines to be
achievable by each particular source
category. Different criteria for maximum
achievable control technology (MACT)
apply for new and existing sources. Less
stringent standards, known as generally
available control technology (GACT)
standards, are allowed at the
Administrator's discretion for area sources.
There are a number of source-
specific NESHAPs that are
applicable to 1,4-dioxane,
including:
Organic Hazardous Air
Pollutants from the Synthetic
Organic Chemical
Manufacturing Industry (40
CFR Part 63, Subpart F),
Organic Hazardous Air
Pollutants from the Synthetic
Organic Chemical
Manufacturing Industry for
Process Vents, Storage
Vessels, Transfer Operations,
and Wastewater (40 CFR Part
63, Subpart G)
Off-Site Waste and Recovery
Operations (40 CFR Part 63,
Subpart DD),
Wood Furniture Manufacturing
Operations (40 CFR Part 63,
Subpart JJ),
Pharmaceuticals Production
(40 CFR Part 63, Subpart
GGG),
Group IV Polymers and Resins
(thermoplastic product
manufacturing) (40 CFR Part
63, Subpart JJJ),
Organic Liquids Distribution
(Non-gasoline) (40 CFR Part
63, Subpart EEEE),
Miscellaneous Organic
Chemical Manufacturing (40
CFR Part 63, Subpart FFFF),
Page 341 of 616
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Si :i lull's/
Ucgiihilions
Description of Aiilhorily/Uo^uhilion
Description of Requisition
Site Remediation (40 CFR Pai l
63, Subpart GGGGG), and
Miscellaneous Coating
Manufacturing (40 CFR Part
63, Subpart HHHHH).
Comprehensive
Environmental
Response,
Compensation
and Liability Act
(CERCLA) -
Sections 102(a)
and 103
Authorizes EPA to promulgate regulations
designating as hazardous substances those
substances which, when released into the
environment, may present substantial
danger to the public health or welfare or
the environment. EPA must also
promulgate regulations establishing the
quantity of any hazardous substance the
release of which must be reported under
Section 103.
Section 103 requires persons in charge of
vessels or facilities to report to the National
Response Center if they have knowledge of
a release of a hazardous substance above
the reportable quantity threshold.
1,4-Dioxane is a hazardous
substance under CERCLA.
Releases of 1,4-dioxane in
excess of 100 pounds must be
reported (40 CFR 302.4).
Safe Drinking
Water Act
(SDWA) -
Section 1412(b)
Every 5 years, EPA must publish a list of
contaminants that: (1) are currently
unregulated, (2) are known or anticipated
to occur in public water systems (PWSs)
and (3) may require regulations under
SDWA. EPA must also determine whether
to regulate at least five contaminants from
the list every 5 years.
1,4-dioxane was identified on
both the Third (2009) and
Fourth (2016) Contaminant
Candidate List (CCL) (74 FR
51850, October 8, 2009) (81
FR 81099, November 17,
2016).
SDWA - Section
1445(a)
Every 5 years, EPA must issue a new list of
no more than 30 unregulated contaminants
to be monitored by PWSs. The data
obtained must be entered into the National
Drinking Water Contaminant Occurrence
Database.
1,4-dioxane was identified in
the third Unregulated
Contaminant Monitoring Rule
(UCMR3), issued in 2012 (77
FR 26072, May 2, 2012).
RCRA - Section
3001
Directs EPA to develop and promulgate
criteria for identifying the characteristics of
hazardous waste, and for listing hazardous
waste, considering toxicity, persistence,
and degradability in nature, potential for
accumulation in tissue and other related
factors such as flammability, corrosiveness,
and other hazardous characteristics.
In 1980, 1,4-dioxane became a
listed hazardous waste in 40
CFR § 261.33 - Discarded
commercial chemical products,
off-specification species,
container residues, and spill
residues thereof (U108) (45 FR
33084).
Page 342 of 616
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Si :i lull's/
Regulations
Description of Aiilhorit.Y/Ucgiilalion
Description of Regulation
Other federal regulations
FFDCA
Provides the U.S. Food and Drug
Administration (FDA) with authority to
oversee the safety of food, drugs and
cosmetics.
FDA established a limit of
10 mg/kg on the amount of
1,4-dioxane that can be present
in the food additive glycerides
and polyglycides of
hydrogenated vegetable oils
(21 CFR § 172.736 and 71 FR
12618, March 13,2006).
Occupational
Safety and Health
Act
Requires employers to provide their
workers with a place of employment free
from recognized hazards to safety and
health, such as exposure to toxic chemicals,
excessive noise levels, mechanical dangers,
heat or cold stress or unsanitary conditions.
Under the Act, OSHA can issue
occupational safety and health standards
including such provisions as PELs,
exposure monitoring, engineering and
administrative control measures and
respiratory protection.
In 1971, OSHA established a
PEL for 1,4-dioxane of 100
ppm or 360 mg/m3 as an 8-
hour, TWA (29 CFR §
1910.1001).
While OSHA has established a
PEL for 1,4-dioxane, OSHA
has recognized that many of its
PELs are outdated and
inadequate for ensuring the
protection of worker health.
1,4-Dioxane appears in
OSHA's annotated PEL tables,
wherein OSHA recommends
that employers follow the
California OSHA limit of 0.28
ppm, the NIOSH REL of 1
ppm as a 30-minute ceiling or
the ACGM TLV of 20 ppm (8-
hour TWA).
Atomic Energy
Act
The Atomic Energy Act authorizes the
Department of Energy to regulate the
health and safety of its contractor
employees
10 CFR § 851.23, Worker
Safety and Health Program,
requires the use of the 2005
ACGIH TLVs if they are more
protective than the OSHA
PEL.
Federal
Hazardous
Materials
Transportation
Act
Section 5103 of the Act directs the
Secretary of Transportation to:
Designate material (including an explosive,
radioactive material, infectious substance,
flammable or combustible liquid, solid or
gas, toxic, oxidizing or corrosive material
and compressed gas) as hazardous when
The Department of
Transportation (DOT) has
designated 1,4-dioxane as a
hazardous material, and there
are special requirements for
marking, labeling and
transporting it (49 CFR Part
Page 343 of 616
-------
Statutes/
Regulations
Description of Authority/Regulation
Description of Regulation
the Secretary determines llial transporting
the material in commerce may pose an
unreasonable risk to health and safety or
property.
Issue regulations for the safe
transportation, including security, of
hazardous material in intrastate, interstate
and foreign commerce.
171, 40 CIR § 173.202 and 40
CFR § 173.242).
A.2 State Laws and Regulations
Table A-2. State Laws and Regulations
Stale Actions
Description of Action
Stale PELs
California PEL. 0.28 ppm (Cal Code Regs. Title 8, § 5155).
State Right-to-Know
Acts
New Jersey (8:59 N.J. Admin. Code § 9.1), Pennsylvania (34 Pa.
Code § 323).
State air regulations
Allowable Ambient Levels (AAL): New Hampshire (RSA 125-1:6,
ENV-A Chap. 1400), Rhode Island (12 R.I. Code R. 031-022).
State drinking/ground
water limits
Massachusetts (310 Code Mass. Regs. § 22.00), Michigan (Mich.
Admin. Code r.299.44 and r.299.49, 2017).
Chemicals of high
concern to children
Several states have adopted reporting laws for chemicals in children's
products that include 1,4-dioxane, such as Oregon (Toxic-Free Kids
Act, Senate Bill 478, 2015) Vermont (Code Vt. R. § 13-140-077) and
Washington State (Wash. Admin. Code § 173-334-130).
Other
In California, 1,4-dioxane was added to the Proposition 65 list in
1988 (Cal. Code Regs, title 27, § 27001).
A.3 International Laws and Regulations
Table A-3. Regulatorv Actions bv other Governments and Tribes
Country /Organization
Requirements and Restrictions
Canada
1,4-Dioxane is on the Cosmetic Ingredient Hotlist as a substance
prohibited for use in cosmetics. 1,4-Dioxane is also included in
Canada's National Pollutant Release Inventory (NPRI), the
publicly-accessible inventory of pollutants released, disposed of
and sent for recycling by facilities across the country
Page 344 of 616
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Country/Organization
Requirements and Restrictions
[Government of Canada (1 1,4-Dioxane. Accessed April
18, 2017],
Australia
In 1994, 1,4-dioxane was assessed. A workplace product
containing more than 0.1% 1,4-dioxane is classed as a
hazardous substance. 1,4-Dioxane is in Class 3, (Packing Group
II) under the Australian Dangerous Goods Code [1,4-Dioxane.
Priority Existing Chemical No. 7. Full Public Report][l,4-
Dioxane. Priority Existing Chemical No. 7. Full Public Report
1998Y|.
Japan
1,4-dioxane is regulated in Japan under the following
legislation:
Act on the Evaluation of Chemical Substances and Regulation
of Their Manufacture, etc. (Chemical Substances Control Law;
CSCL)
Act on Confirmation, etc. of Release Amounts of Specific
Chemical Substances in the Environment and Promotion of
Improvements to the Management Thereof
Industrial Safety and Health Act (ISHA)
Air Pollution Control Law
Water Pollution Control Law
[National Institute of Technology and Evaluation (NITE)
Chemical Risk Information Platform (CHIRP)MTK (2015),
Accessed April 18, 2017],
Republic of Korea
The Ministry of the Environment recently adopted a provisional
water quality standard for human health of 50 |ig/L 1,4-dioxane
in drinking water An et al. (2014).
Australia, Austria, Belgium,
Canada, Denmark, European
Union (EU), Finland, France,
Germany, Hungary, Ireland,
Italy, Japan, Latvia, New
Zealand, People's Republic of
China, Poland, Singapore,
South Korea, Spain, Sweden,
Switzerland, The
Netherlands, Turkey, United
Kingdom
Occupational exposure limits for 1,4-dioxane Insitut fur
sitsschutz der (IFA) Deutschen Gesetzlichen
Unfall versicherung (2017)(GESTIS International limit values
for chemical agents (Occupational exposure limits, OELs)
database. Accessed April 18, 2017).
WHO
Established a tolerable daily intake of 16 |ig 1,4-dioxane/kg
body weight based on a no-observed-adverse-effect level
(NOAEL) of 16 mg/kg body weight per day for hepatocellular
tumors observed in a long-term drinking-water study in rats.
Page 345 of 616
-------
Country/Organization
Requirements and Restrictions
The WHO water quality guideline is 0.05 mg/L 1,4-dioxane in
drinking water WHO (2005).
Page 346 of 616
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Appendix B EXPOSURE SCENARIO MAPPING TO COU
As part of the Problem Formulation, EPA considered if each unique combination of exposure pathway, route, and receptor in the
lifecycle of 1,4-dioxane would be further evaluated and includes all possible exposure scenarios for each condition of use. EPA
provided the mapping tables that described all possible scenarios developed during problem formulation in tables B-l and B2. EPA
used readily available fate, engineering, exposure and/or toxicity information to determine whether to conduct further analysis on each
exposure scenario.
Industrial and Commercial Occupational Exposure Scenarios for 1,4-Dioxane
EPA has identified release/occupational exposure scenarios and mapped them to relevant conditions of use in Table B-l below. As
presented in the Release/Exposure Scenario column of this table, representative release/exposure scenarios each with 5-6 unique
combinations of exposure pathway, route, and receptor will be further analyzed. EPA further refined the mapping/grouping of
industrial and commercial occupational exposure scenarios based on factors (e.g., process equipment and handling, magnitude of
production volume used, and exposure/release sources) corresponding to conditions of use as additional information is identified
during risk evaluation.
Table B-l. Industrial and Commercial Occupational Ex
josure Scenarios for 1,4-Dioxane
l .ilo ( >clo
S(;i»e
Csili'Sion
Siihciilofion
Koloiisc/
r.\|)ONIMY
Scenario
l'l\|)OMir
c
PiUliNin
r.xpnsurc
Rnnle
Km'plor
I-'ii rl her
l-'\illllill ifill?
K;ilion;ik' lor I-'im'Mkt 1'\ ;iIn;ilion / no
I'llrlher l-'.\iiliiiilion
Manufacture
Domestic
Manufacture
or Import
Domestic
Manufacture or
Import
Manufacture of
1,4-dioxane via
acid catalyzed
conversion of
ethylene glycol
by ring closure
Repackaging of
import
containers
Liquid
Contact
Dermal
Workers
Yes
Workers are expected to routinely handle
liquids containing 1,4-dioxane.
Manufacture
Domestic
Manufacture
or Import
Domestic
Manufacture or
Import
Vapor
Dermal
Workers
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Manufacture
Domestic
Manufacture
or Import
Domestic
Manufacture or
Import
Vapor
Inhalation
Workers
Yes
Due to high volatility (VP = 40 mmHg)
at room temperature, inhalation exposure
from \ ;i|k>r should bo linHicr c\ alualcd
Manufacture
Domestic
Manufacture
or Import
Domestic
Manufacture or
Import
Liquid
( miiacl
Dermal
<>\l
<< )ccupali
onal \on-
l sen
\n
Dermal e\pnsnre is c\pcclcd In he
primariK in workers dircclk m\ ol\cd m
handling llic chemical
Page 347 of 616
-------
Manufacture
Domestic
Manufacture
or Import
Domestic
Manufacture or
Import
Vapor
Dermal
ONU
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Manufacture
Domestic
Manufacture
or Import
Domestic
Manufacture or
Import
Vapor
Inhalation
ONU
Yes
Due to high volatility (VP = 40 mmHg)
at room temperature, inhalation exposure
from vapor should be further evaluated.
Manufacture
Domestic
Manufacture
or Import
Domestic
Manufacture or
Import
\lls|
Dermal In
halation ()
nil
Workers.
()\l
\o
Misi uenernliou is uni e\peeled
Processing
Processing
as a Reactant
Polymerization
catalyst
Polymer
manufacture
Liquid
Contact
Dermal
Workers
Yes
Workers are expected to routinely handle
liquids containing 1,4-dioxane.
Processing
Processing
as a Reactant
Vapor
Dermal
Workers
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Processing
Processing
as a Reactant
Vapor
Inhalation
Workers
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
However, potential for exposure may be
low in scenarios where 1,4-dioxane is
consumed as a chemical intermediate or
used as a catalyst.
Processing
Processing
as a Reactant
Liquid
( oiiinel
Dermal
<>\l
\o
Domini e\pnsiire is e\peeled In he
prininrik in workersdireelh ui\ol\ediu
hniidhim llie chemical
Processing
Processing
as a Reactant
Vapor
Dermal
ONU
No
The ahsorpuon of 1 4-diovine \ apor \ la
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Processing
Processing
as a Reactant
Vapor
Inhalation
ONU
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
However, potential for exposure may be
low in scenarios where 1,4-dioxane is
consumed as a chemical intermediate or
used as a catalyst.
Page 348 of 616
-------
Processing
Processing
as a Reactant
\lisi
Dermal In
halation ()
nil
Workers.
()\l
\o
Misi ueiicraliou is noi e\peeled
Processing
Liquid
Contact
Dermal
Workers
\ es
W orkers are c\pecled in loiiiiucK handle
liquids containing 1,4-dioxane.
Processing
Vapor
Dermal
Workers
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Processing
Non-
incorporativ
e
Basic organic
Vapor
Inhalation
Workers
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
Processing
chemical
manufacturing
(process
Basic organic
chemical
manufacture
Liquid
( ouiacl
Dermal
<>\l
\o
Dermal exposure is e\pccled in he
priniai'iK lo workers diieclK ui\ol\ediii
haiidliuu 1 lie chemical.
Processing
Repackaging
solvent)
Bulk to
Repackaging to
large and small
Vapor
Dermal
ONU
No
The absorption of 1,4-dioxane \ apor \ la
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Processing
packages, then
distribute
containers
Vapor
Inhalation
ONU
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
Processing
\lisi
Dermal In
halation ()
nil
Workers.
<>\l
\o
Misi ueiieraliou is uoi c\pecled
Processing
Recycling
Recycling
Liquid
Conlael
Dermal
Workers
Yes
W orkers are c\pecled lo loiiiiucK handle
liquids conlaiiun^ 1,4-dioxaiie.
Processing
Recycling
Recycling
Recycling of
process solvents
containing 1,4-
dioxane
Vapor
Dermal
Workers
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Processing
Recycling
Recycling
Vapor
Inhalation
Workers
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
Processing
Recycling
Recycling
Liquid
( ouiacl
Dermal
<>\l
\o
Dermal exposure is expected lo he
primarily lo workersdireelK ui\ol\ediu
haiidhuu I lie chemical
Processing
Recycling
Recycling
Vapor
Dermal
(JM
No
The absorption of 14-dio\aue \ apor \ la
skin is expected to be orders of
Page 349 of 616
-------
magnitude lower than via inhalation and
will not be further analyzed.
Processing
Recycling
Recycling
Vapor
Inhalation
ONU
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
Processing
Recycling
Recycling
Mist
Dermal/In
halation/O
ral
Workers,
ONU
Yes
EPA requires additional information on
industry practices for recycling waste
solvents containing 1,4-dioxane to
determine if exposures to mists are
possible.
Distribution
in commerce
Distribution
Distribution
Distribution of
bulk shipment
of 1,4-dioxane
Liquid
Contact,
Vapor,
Mist
Dermal/In
halation/O
ral
Workers,
ONU
Yes
EPA will further analyze activities
resulting in exposures associated with
distribution in commerce (e.g., loading,
unloading) throughout the various
lifecycle stages and conditions of use
(e.g., manufacturing, processing,
industrial use) rather than as a single
distribution scenario.
Industrial use
Intermediate
Use
Processing
aids, not
otherwise
listed
Agricultural
chemical
intermediate
Plasticizer
intermediate
Catalysts and
reagents for
anhydrous acid
reactions,
brominations
and sulfonations
Polymerization
catalyst
Agricultural
product
manufacture
Plasticizer
manufacture
Anhydrous acid,
bromination and
sulfonation
reaction
chemical
manufacture
Polymer
Manufacture
Liquid
Contact
Dermal
Workers
Yes
Workers are expected to routinely handle
liquids containing 1,4-dioxane.
Industrial use
Vapor
Dermal
Workers
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Industrial use
Vapor
Inhalation
Workers
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
However, potential for exposure may be
low in scenarios where 1,4-dioxane is
consumed as a chemical intermediate or
used as a calaU s|
Industrial use
Liquid
( ouiacl
Dermal
<>\l
\n
Dermal exposure is e\pecled in he
priuiaiiK lo workers direclK ui\ ol\ed m
haiidliuu 11 ic chemical
Industrial use
Vapor
Dermal
ONU
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
Page 350 of 616
-------
magnitude lower than via inhalation and
will not be further analyzed.
Industrial use
Vapor
Inhalation
ONU
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
However, potential for exposure may be
low in scenarios where 1,4-dioxane is
consumed as a chemical intermediate or
used as a catalyst.
Industrial use
\lisi
Dermal In
halation ()
nil
Workers.
()\l
\n
Misi ueiieralmii is imi e\pecled
Industrial use
Processing
aids, not
otherwise
listed
Wood pulping19
Extraction of
animal and
vegetable oils15
Wetting and
dispersing agent
in textile
processing15
Wood pulping
Extraction of
animal and
vegetable oils
Textile
processing
Liquid
Contact
Dermal
Workers
Yes
Workers are expected to routinely handle
liquids containing 1,4-dioxane.
Industrial use
Processing
aids, not
otherwise
listed
Vapor
Dermal
Workers
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Industrial use
Processing
aids, not
otherwise
listed
Vapor
Inhalation
Workers
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
Industrial use
Processing
aids, not
otherwise
listed
Liquid
( oniacl
Dermal
ONI
Yes
Dermal e\pnsure is e\pecled in he
primarih in workersdireclk iii\nl\edin
haiidlinu I lie chemical
Industrial use
Processing
aids, not
otherwise
listed
Vapor
Dermal
ONU
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Industrial use
Processing
aids, not
otherwise
listed
Vapor
Inhalation
ONU
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
19 These uses were evaluated but are likely not current uses of 1,4-dioxane.
Page 351 of 616
-------
Industrial use
Processing
aids, not
otherwise
listed
Mist
Dermal/In
halation/O
ral
Workers,
ONU
Yes
Mist generation may occur during these
processes.
Industrial use
Processing
aids, not
otherwise
listed
Liquid
Contact
Dermal
Workers
Yes
Workers are expected to routinely handle
liquids containing 1,4-dioxane.
Industrial use
Processing
aids, not
otherwise
listed
Vapor
Dermal
Workers
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Industrial use
Processing
aids, not
otherwise
listed
Vapor
Inhalation
Workers
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
Industrial use
Processing
aids, not
otherwise
listed
Etching of
fluoropolymers
Etching of
fluoropolymers
Liquid
( nulacl
Dermal
ONI
\n
Dermal c\posiiie is e\pecled In he
primariK lo workers direclK in\ ol\ed in
handlnm I lie chemical
Industrial use
Processing
aids, not
otherwise
listed
Vapor
Dermal
ONU
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Industrial use
Processing
aids, not
otherwise
listed
Vapor
Inhalation
ONU
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
Industrial use
Processing
aids, not
otherwise
listed
Mist
Dermal/In
halation/O
ral
Workers,
ONU
Yes
Mist generation may occur during these
processes.
Industrial use
Functional
fluids
(closed/open
system)
Polyalkylene
glycol lubricant
Cutting and
Use of
Liquid
Contact
Dermal
Workers
Yes
Workers are expected to routinely handle
liquids containing 1,4-dioxane.
Industrial use
Functional
fluids
(closed/open
system)
Tapping Fluid
Synthetic
metalworking
lubricants
Use of
metalworking
Vapor
Dermal
Workers
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Page 352 of 616
-------
Industrial use
Functional
fluids
(closed/open
system)
fluid
Hydraulic fluid
fluids
Vapor
Inhalation
Workers
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated
Industrial use
Functional
fluids
(closed/open
system)
Servicing
hydraulic
equipment and
charging
Liquid
( ouiacl
Dermal
<>\l
\o
Dermal exposure is expecled in he
priuiarik in workersdircclK iu\nl\ediu
haudliuu 11 ic chemical
Industrial use
Functional
fluids
(closed/open
system)
hydraulic fluids
in original
equipment
manufacture
Vapor
Dermal
ONU
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Industrial use
Functional
fluids
(closed/open
system)
Vapor
Inhalation
ONU
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
Industrial use
Functional
fluids
(closed/open
system)
Mist
Dermal/In
halation/O
ral
Workers,
ONU
Yes
Mist exposure can occur during open
system uses and potentially while
charging and servicing equipment with
hydraulic fluid.
Industrial
use, potential
commercial
use
Laboratory
chemicals
Chemical
reagent
Reference
Liquid
Contact
Dermal
Workers
Yes
Workers are expected to routinely handle
liquids containing 1,4-dioxane.
Industrial
use, potential
commercial
use
Laboratory
chemicals
material
Spectroscopic
and photometric
Vapor
Dermal
Workers
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Industrial
use, potential
commercial
use
Laboratory
chemicals
measurement
Liquid
scintillation and
Laboratory
chemical use
Vapor
Inhalation
Workers
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
Industrial
use, potential
commercial
use
Laboratory
chemicals
counting
medium
Stable reaction
Liquid
( ouiacl
Dermal
ONI
\o
Dermal e\posmv is expected in he
priuiarih in workersdireclK iu\nl\ediu
haiidliuu I lie chemical
Industrial
use, potential
commercial
use
Laboratory
chemicals
medium
Cryoscopic
solvent for
Vapor
Dermal
ONU
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Page 353 of 616
-------
Industrial
use, potential
commercial
use
Laboratory
chemicals
molecular mass
determinations
Preparation of
Vapor
Inhalation
ONU
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated
Industrial
use, potential
commercial
use
Laboratory
chemicals
histological
sections for
microscopic
examination
\lls|
Dermal In
halation ()
nil
Workers.
<>\l
\o
Misi ueiieralioii is noi e\pecled
Industrial
use, potential
commercial
use
Liquid
Contact
Dermal
Workers
Yes
Workers are expected to routinely handle
liquids containing 1,4-dioxane.
Industrial
use, potential
commercial
use
Vapor
Dermal
Workers
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Industrial
use, potential
commercial
use
Vapor
Inhalation
Workers
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
Industrial
use, potential
commercial
use
Adhesives
and sealants
Other Uses
Film cement
Industrial and
commercial
small brush
application
Liquid
( oniacl
Dermal
<>\l
\o
Dermal e\posnre is e\pecled in he
priniarik in workersdireclk ni\nl\ediii
handling llie chemical
Industrial
use, potential
commercial
use
Vapor
Dermal
ONU
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Industrial
use, potential
commercial
use
Vapor
Inhalation
ONU
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
Industrial
use, potential
commercial
use
\lls|
Dermal In
halation ()
nil
Workers.
<>\l
\o
Misi ueneralinn is nni e\pecled
Industrial
use, potential
commercial
use
Other Uses
Spray
polyurethane
foam
Application of
spray
polyurethane
foam through a
Liquid
Contact
Dermal
Workers
Yes
Workers are expected to routinely handle
liquids containing 1,4-dioxane.
Page 354 of 616
-------
Industrial
use, potential
commercial
use
Printing and
printing
nozzle
Use of Printing
Inks
Vapor
Dermal
Workers
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Industrial
use, potential
commercial
use
compounds
Vapor
Inhalation
Workers
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
Industrial
use, potential
commercial
use
Liquid
( oiiiacl
Dermal
<>\l
\o
Dermal c\posurc is e\peeled In he
primariK in workers direclK m\ ol\ed m
haiidhim 11 ic chemical
Industrial
use, potential
commercial
use
Vapor
Dermal
ONU
No
The absorption of 1,4-dioxane \ apor \ la
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Industrial
use, potential
commercial
use
Vapor
Inhalation
ONU
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
Industrial
use, potential
commercial
use
Mist
Dermal/In
halation/O
ral
Workers,
ONU
Yes
Mist generation may occur during these
processes.
Manufacture,
processing,
use, Disposal
Emissions to
air
Air
Industrial pre-
Liquid
Contact
Dermal
Workers
Yes
Workers are expected to routinely handle
liquids containing 1,4-dioxane.
Manufacture,
processing,
use, Disposal
Wastewater
treatment
Industrial
wastewater
Worker
Handling of
wastes
Vapor
Dermal
Workers
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
magnitude lower than via inhalation and
will not be further analyzed.
Manufacture,
processing,
use, Disposal
Solid wastes
and liquid
treatment
Publicly owned
Vapor
Inhalation
Workers
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated.
Manufacture,
processing,
use, Disposal
wastes
treatment works
(POTW)
Liquid
( oiiiacl
Dermal
<>\l
\o
Dermal e\posme is e\peeled In he
primariK in workersdireclK in\ol\edin
haiidhim 11 ic chemical
Manufacture,
processing,
use, Disposal
Underground
Injection
Vapor
Dermal
ONU
No
The absorption of 1,4-dioxane vapor via
skin is expected to be orders of
Page 355 of 616
-------
Municipal
landfill
Hazardous
landfill
magnitude lower than via inhalation and
will not be further analyzed.
Manufacture,
processing,
use, Disposal
Vapor
Inhalation
ONU
Yes
Due to high volatility at room
temperature, inhalation exposure from
vapor should be further evaluated
Manufacture,
processing,
use, Disposal
\lisi
Dermal In
halation ()
nil
Workers.
()\l
\o
Misi ueiieralion is noi e\pecled
Environmental Releases and Wastes Exposure Scenarios for 1,4-Dioxane
Table B-2. During problem formulation, EPA used readily available fate, exposure and/or toxicity information to determine whether to
conduct further analysis on each exposure scenario. EPA has identified release/environmental exposure scenarios and mapped them to
relevant conditions of use in the table below.
Table B-2. Environmental Releases and Wastes Exposure Scenarios for 1,4-Dioxane
l.ifcocle Si;i»e
I so
Release
l'l\|)OMIIV
PiKhwin
l'l\|)OMIIV
Route
Reeeplor
l-'urlher
l.\;ilu;i(ion?
R;ilion;ile for l-'urlher
l-'.\iiliiiilion / no l-'urlher
l-'.\;i In ;i 1 ion
Manufacturing
and Processing
TBD
Industrial wastewater
treatment operations
Water
N/A
Aquatic
Species
No
Conservative screening
indicates low potential for risk
to aquatic organisms.
Manufacturing
and Processing
TBD
Industrial wastewater
treatment operations
Water, Air
N/A
Terrestrial
Species
No
Ingestion of water and
inhalation of air are not
expected to be primary
exposure routes for terrestrial
organisms (see OPP tool).
Manufacturing
and Processing
TBD
Industrial wastewater
treatment operations
Sediment
N/A
Terrestrial
Species
No
1,4-Dioxane has low sorption to
soil, sludge, and sediment and
will instead stay in the
associated aqueous phases.
Manufacturing
and Processing
TBD
Industrial wastewater
treatment operations
Sediment
Aquatic
Species
No
Manufacturing
and Processing
TBD
Industrial wastewater
treatment operations
Biosolids
disposed to soil,
migration to
groundwater
N/A
Terrestrial
Species
No
1,4 dioxane is not expected to
remain in soil for long periods
of time due to migration to
groundwater and volatilization
from soil.
Page 356 of 616
-------
Manufacturing
and Processing
TBD
Industrial pre-treatment,
then transfer to Publicly
Owned Treatment
Works (POTW)
Water
N/A
Aquatic
Species
No
Conservative screening
indicates low potential for risk
to aquatic organisms.
Manufacturing
and Processing
TBD
Industrial pre-treatment,
then transfer to Publicly
Owned Treatment
Works (POTW)
Water, Air
N/A
Terrestrial
Species
No
Ingestion of water and
inhalation of air are not
expected to be primary
exposure routes for terrestrial
organisms (see OPP tool).
Manufacturing
and Processing
TBD
Industrial pre-treatment,
then transfer to Publicly
Owned Treatment
Works (POTW)
Sediment
N/A
Terrestrial
Species
No
1,4-Dioxane has low sorption to
soil, sludge, and sediment and
will instead stay in the
associated aqueous phases.
Manufacturing
and Processing
TBD
Industrial pre-treatment,
then transfer to Publicly
Owned Treatment
Works (POTW)
Sediment
Aquatic
Species
No
Manufacturing
and Processing
TBD
Industrial pre-treatment,
then transfer to Publicly
Owned Treatment
Works (POTW)
Biosolids
disposed to soil,
migration to
groundwater
N/A
Terrestrial
Species
No
1,4-dioxane is not expected to
remain in soil for long periods
of time due to migration to
groundwater and volatilization
from soil.
Disposal
TBD
Municipal landfill,
Hazardous Landfill, and
other land disposal
Soil
N/A
Terrestrial
Species
No
2015 TRI data indicates 3 sites
reporting 13,422 lbs to landfill.
However, 1,4-dioxane has low
sorption to soil.
Page 357 of 616
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Appendix € LIST OF SUPPLEMENTAL DOCUMENTS
1. Summary of External Peer Review and Public Comments and Disposition for 1,4-Dioxane:
Response to Support Risk Evaluation for 1,4-Dioxane
2. Final Risk Evaluation for 1,4-Dioxane Systematic Review Supplemental File: Updates to the
Data Quality Criteria for Epidemiological Studies
3. Final Risk Evaluation for 1,4-Dioxane Systematic Review Supplemental File: Data Quality
Evaluation for Environmental Releases and Occupational Exposure Data Sources
4. Final Risk Evaluation for 1,4-Dioxane Systematic Review Supplemental File: Data Quality
Evaluation of Environmental Hazard Studies
5. Final Risk Evaluation for 1,4-Dioxane Systematic Review Supplemental File: Data Quality
Evaluation of Environmental Fate and Transport Studies
6. Final Risk Evaluation for 1,4-Dioxane Systematic Review Supplemental File: Data Quality
Evaluation of Human Health Hazard Studies, Animal and In Vitro Studies
7. Final Risk Evaluation for 1,4-Dioxane Systematic Review Supplemental File: Data Quality
Evaluation of Epidemiological Studies
8. Final Risk Evaluation for 1,4-Dioxane Systematic Review Supplemental File: Data Quality
Evaluation of Consumer Exposure Studies
9. Final Risk Evaluation for 1,4-Dioxane Systematic Review Supplemental File: Consumer
References, Data Screening
10. Final Risk Evaluation for 1,4-Dioxane Supplemental Information File on Aquatic Exposure
Screen Facility Information
11. Final Risk Evaluation for 1,4-Dioxane Supplemental Information File on Occupational Risk
Calculations
12. Final Risk Evaluation for 1,4-Dioxane Supplemental Information File on Ambient Water
Exposure Modeling Outputs from E-FAST
13. Final Risk Evaluation for 1,4-Dioxane Supplemental Information File on Exposure Modeling
Inputs, Results, and Risk Estimates for Incidental Ambient Water Exposure
14. Final Risk Evaluation for 1,4-Dioxane Supplemental Information File on Consumer Exposure
Assessment Modeling Input Parameters
15. Final Risk Evaluation for 1,4-Dioxane Supplemental Information File on Consumer Exposure
Modeling Results and Risk Estimates
16. Final Risk Evaluation for 1,4-Dioxane Systematic Review Supplemental File: Data Quality
Evaluation of Physical-Chemical Properties Studies
-------
Appendix D FATE AND TRANSPORT
EPI Suite™ model inputs
To set up EPI Suite™ for estimating fate properties of 1,4-dioxane, 1,4-dioxane was identified using the
"Name Lookup" function. The physical-chemical properties were input based on the values in Table
1-1.. Water solubility was not entered because it is listed as >800 g/L, a value that is not valid to input.
EPI Suite™ was run using default settings {i.e., no other parameters were changed or input).
PhysProp
AOPWIN
Show
Structure
Output
Fugacity
Help
EPI Suite - Welcome Screen
Clear Input Fields
Input CAS# 000123-91-1
Input Smiles: |Q(CCOC1)C1
Input Chem Name ' ¦** UioHorie
Name Lookup
Henry LC:
Melting Point:
Boiling Point:
0.0000048 atm-m /mole
11.75 Celsius
101.1 Celsius
Water Solubility:
Vapor Pressure: j
Log Kow:
40 mm Hg
-0.271
Water Depth: I
Wind Velocity: [~
Current Velocity:
~r
5 r
~r
1
meters
0.5 meters/sec
meters/sec
o
0.05
Output
r Full
lV Summary
c
EPI Links
The Estimation Programs Interface (EPI) SuiteTM was developed by the OS Environmental Protection Agency's Office of Pollution Prevention
and Toxics and Syracuse Research Corporation (SRC). It is a screening-level tool, intended for use in applications such as to quickly screen
chemicals for release potential and "bin" chemicals by priority for future work. Estimated values should not be used when experimental
(measured) values are available.
EPI SuiteTM cannot be used for all chemical substances. The intended application domain is organic chemicals. Inorganic and organometallic
chemicals generally are outside the domain.
Important information on the performance, development and application of EPI SuiteTM and the individual programs within it can be
found under the Help tab. Copyright 2000-2012 Onited States Environmental Protection Agency for EPI SuiteTM and all component
programs except BioHCWIN and KOAWIN.
Figure D-l. EPI Suite™ welcome screen set up for 1,4-dioxane model run
As part of problem formulation, EPA also analyzed the sediment, land application and biosolids
pathways. The results of the analyses are described in the 2018 problem formulation for 1,4-dioxane
U.S. EPA (2018c) and presented below. Fate and transport were not further analyzed in this risk
evaluation.
Sediment Pathways
1,4-Dioxane is expected to remain in aqueous phases and not adsorb to sediment due to its water
solubility (> 800 g/L) and low partitioning to organic matter (log Koc = 0.4). Limited sediment
monitoring data for 1,4-dioxane that are available suggest that 1,4-dioxane is present in sediments, but
because 1,4-dioxane does not partition to organic matter (log Koc = 0.4) and biodegrades slowly [<10%
biodegradation in 29 days EC HA (1996)1, 1,4-dioxane concentrations in sediment pore water are
expected to be similar to the concentrations in the overlying water. Thus, the 1,4-dioxane detected in
sediments is likely from the pore water and not 1,4-dioxane that was sorbed to the sediment solids.
Land-Applied Biosolids Pathway
Page 359 of 616
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1,4-Dioxane is not expected to adsorb to soil and sediment due to its low partitioning to organic matter
(estimated log Koc = 0.4), so 1,4-dioxane in biosolids is expected to be in the aqueous phase associated
with the biosolids rather than adsorbed to the organic matter. The aqueous phase represents > 95% of
biosolids, or > 70% if the biosolids are dewatered, and at the time of removal the water in the biosolids
will contain the same concentration of 1,4-dioxane as the rest of the wastewater at the activated sludge
stage of treatment. However, the volume of water removed with biosolids represents < 2% of
wastewater treatment plant influent volume ), and is < 1% of influent volume when the
sludge is dewatered and the excess water is returned to treatment, a process that is commonly used NRC
5). Thus, the water released from a treatment plant via biosolids is negligible compared to that
released as effluent. By extension the 1,4-dioxane released from wastewater treatment via biosolids is
expected to be negligible compared to the 1,4-dioxane released with effluents: of the 1,4-dioxane in
influent wastewater, it is expected that < 2% will be removed with biosolids and associated water and >
95% will be present in the effluent (see Section 2.1, Fate and Transport). Further, the concentrations of
1,4-dioxane in biosolids may decrease through volatilization to air during transport, processing
(including dewatering and digestion), handling, and application to soil (which may include spraying).
When 1,4-dioxane is released in the environment, it is expected to be mobile in soil and migrate to
surface waters and groundwater or volatilize to air. 1,4-Dioxane is expected to volatilize readily from
dry soil and surfaces due to its vapor pressure (40 mm Hg). Overall, the exposures to surface water from
biosolids will be negligible compared to the direct release of WWTP effluent to surface water.
Page 360 of 616
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Appendix E ENVIRONMENTAL EXPOSURES
Systematic Review for Environmental Exposures
The flow of publications on environmental exposure through systematic review is illustrated in Section
1.5.1. On-topic literature obtained from Systematic Review were screened via title/abstract screening
and full-text screening for relevance and usability. Through scoping and problem formulation, EPA
determined that no environmental pathways would be further analyzed. Therefore, none of the 272
studies proceeded to data evaluation per the environmental exposure PECO statement, which was
updated to reflect the results of the aquatic exposure screen and the determination not to further analyze
this pathway.
First-tier Ecological Aquatic Exposure Assessment for 1,4-Dioxane
While recent monitoring data on ambient surface water levels indicate relatively low levels, EPA used
release estimates and measured effluent concentrations from EPA's Toxics Release Inventory (TRI) and
Discharge Monitoring Report (DMR) Pollutant Loading Tool, respectively, to predict surface water
concentrations near such discharging facilities. This first-tier aquatic exposure assessment evaluates
ecological exposures in the US associated with releases of 1,4-dioxane to surface water. This first-tier,
screening approach uses conservative assumptions and readily available data and models. In this
assessment, conservative surface water concentrations are estimated for facilities that release the 1,4-
dioxane to surface water bodies. The assessment was conducted using the top ten discharging facilities
that submit DMRs, as well as the top ten releasers that report to the TRI. The 2015-2016 DMR data with
facilities and associated release amounts were identified using EPA's Enforcement and Compliance
History Online (ECHO) Water Pollutant Loading Tool. The 2014-2015 TRI dataset was updated using
data from TRI Explorer. In response to public comment, the TRI analysis was also augmented to include
the top indirect discharging sites, i.e., those reporting off-site waste transfers to POTWs for treatment.
Surface water concentrations were estimated using EPA's Exposure and Fate Assessment Screening
Tool. Version 2 )14c). The two most recent years with complete data at the time of the
problem formulation analysis were 2014 and 2015 for TRI and 2015 and 2016 for DMR. In Section 2.2,
more recent 2018 TRI and DMR data were used to estimate surface water releases for Occupational
Exposure Scenarios (OES) within the scope of this evaluation. These estimated releases ranged from 0-
67.7 kg/site/day across all OES, with the highest release volume associated with Industrial Uses. The
releases modeled as part of this first-tier aquatic exposure assessment were within this range, as they
were based on top direct and indirect dischargers. It is not expected that the incorporation of the more
recent OES release estimated would have altered the conclusions of the screening-level aquatic exposure
assessment undertaken during problem formulation.
Table E-l shows the environmental release data from TRI reported in the 1,4-Dioxane Problem
Formulation document.
Table E-l
. Summary of 1,4-Dioxane T
il Releases to the Environment in 2015 (lbs
Number of
Facilities
Air Releases
Water
Releases
Land Disposal
Other
Releases"
Total On-
and On-site
Disposal or
Other
Releases Kc
Slack Air
Releases
Fugitive
Air
Releases
Class I
U nderground
Injection
RCRA
Subtitle C
Landfills
All other
Land
Disposal''
Subtotal
46,219
16,377
563,976
13,376
49
Totals
49
62,596
35,402
577,400
0
675,399
Page 361 of 616
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Data source: 2015 TRI Data (updated March 2017) 017g).
" Terminology used in these columns may not match the more detailed data element names used in the TRI public data and analysis access points.
b These release quantities include releases due to one-time events not associated with production such as remedial actions or earthquakes.
c Counts release quantities once at final disposition, accounting for transfers to other TRI reporting facilities that ultimately dispose of the chemical waste.
Predicted surface water concentrations ranged from 1.26 to 11,500 ug/L for acute scenarios and 2.37E-
08 to 5,762 |ig/L for chronic release scenarios for the set of top dischargers modeled, based on the two
complete years of most recent data available at the time the analysis was conducted during problem
formulation (2014-2016). These concentrations were predicted using conservative assumptions to
inform whether further evaluation of the aquatic exposure pathway is supported.
Facility Selection
This assessment predicts conservative surface water concentrations for a set of facilities reporting recent
releases of 1,4-dioxane via DMR and/or TRI. The DMR dataset of facilities were queried from ECHO'S
Water Pollutant Loading Tool. DMR includes pollutant loading information for more than 60,000 DMR
reporting facilities (industrial and municipal point source dischargers) regulated under the Clean Water
Act. It contains wastewater monitoring and other facility data, as reported on facility-specific DMRs.
TRI data were retrieved from TRI Explorer for TRI reporters. TRI contains reporting information on
facilities in specific industry sectors which employ more than 10 full-time equivalent employees and
manufacture, process, or use more than 25,000 lbs per year of a TRI-listed chemical.
The analysis was conducted using the top direct and indirect dischargers of 1,4-dioxane from DMR and
TRI covering the two most current and complete reporting years available at the time of problem
formulation (i.e., 2015 and 2016 for DMR and 2014 and 2015 for TRI). As many of the facilities
overlapped between the DMR and TRI sets, and between the assessment years, a total of 24 unique
facilities were assessed. Table E-2 below summarizes characterizing information.
Page 362 of 616
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Table E-2. Facility Selection Characterization
Parameter
DMR - 2015
DMR - 2016
TRI - 20141
TRI - 20151
Universe of Facilities
No. of Facilities
54
61
56
50
No. of Facilities with annual
loading >0
26
31
21
22
Annual Loading:
Maximum
95th percentile
50th percentile
Minimum
20,974
20,733
38.6
0.000074
30,319
25,047
16.6
0.15
122,130.36
26,962.0
184.0
0.01
165,416.24
21,349.2
544.5
0.000132
No. of Facilities in Top 5th
percentile for discharging
1
2
2
2
Facilities Selected
Number Selected
10
10
18
20
Annual Loading/Release
Percentile % (Range)
64-100%
70-100%
0-100%
0-100%
SIC Represented
N=5
2821,4952,
2869, 2899,
3861
N=5
2821,4952,
2869, 3861,
blank (landfill)
N=3
2821,2869,
2899, 2879,
2865, 2599,
3569, 3599,
3821,3841,
3081,2843
N=14
2821, 2869, 2865,
2899, 2599, 3569,
3599, 3821, 3841,
3081, 2834, 2835,
2843, 4953
NAICS Represented
N=7
325211, 325199,
325320, 325110,
333999, 326113,
325613
N=8
325211,325199,
325110,333999,
326113,325412,
325613,562213
No. ofPOTWs
4
5
0
0
No. of non-POTWs
6
5
18
20
-No. of direct dischargers
(non- POTW)
6
4
10
10
-No of indirect dischargers
(non- POTW)
0
1 (Beacon
landfill -
discharges to
POTW)
8
10
States Represented
N=5
CA, NY, MO,
SC, WV
N=6
CA, CT, PA,
NY, SC, WV
N=10
WV, SC, LA,
NC, TN, AL,
MN, MS, MD,
WI
N=13
WV, SC, LA, TX,
NC, TN, AL, MN,
NY, MD, MS, WI,
OH
1 TRI facility counts include indirect and direct dischargers.
As described, this approach used only the top ten dischargers for a given release data source and reporting
year. However, for the TRI direct surface water releases, the top ten facilities modeled represented > 99%
of the total releases to surface water for all reporting sites during the time period modeled. Because there
were at most ten facilities reporting off-site waste transfer to POTW - treatment during the years
examined, all of those were captured in this effort. Additionally, the top ten dischargers modeled based
on DMR reporting represented >95% of the total releases to surface water reported across all sites for the
years modeled. Therefore, most reported surface water releases were captured in this first-tier assessment.
Furthermore, the modeled sites reflect a variety of watersheds in 18 states.
Page 363 of 616
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The following basic information was collected for each facility and is shown in the supplemental file titled
1,4-D Supplemental - Aq Screen Facility Information 062419:
• DMR: Site name, location (city, state, latitude, longitude), NPDES code, SIC code, NAICS Code, FRS
ID, average effluent concentration (mg/L), maximum effluent concentration (mg/L), total pounds (lbs/yr),
average flow (MGD), flag for potential outlier, and max allowable load (lbs/yr).
• TRI: Site name, location (city, state, latitude, longitude), NPDES code, NAICS Code, FRS ID, TRI
Facility ID, and Direct TRI Pounds (lbs/yr).
• Receiving Water Information: Waterbody Number (REACH code) and Waterbody Name (from GNIS).
Estimating Surface Water Concentrations
Surface water concentrations were estimated for multiple scenarios using E-FAST U.S. EPA. (2014c).
which can be used to estimate site-specific, near-facility surface water concentrations based on estimated
loadings of 1,4-dioxane into receiving water bodies. Both direct discharges (i.e., facility releases to
surface water) and indirect discharges (i.e., facility transfers to other sites/POTWs for treatment and
subsequent release to surface water) were included based on TRI reporting. DMR reporting includes
direct discharges only, as volumes are being reported under a facility's NPDES permit. The reported
annual loading estimates for DMR facilities are calculated by using the reported effluent concentrations
and facility effluent flows. For TRI, the reported releases are based on monitoring, emission factors,
mass balance and/or other engineering calculations. These reported annual loading amounts (lbs/year)
were first converted to release inputs required by E-FAST (kg/day) by converting from lbs to kgs and
dividing by the number of release days for a given scenario. The reported annual loading amounts
(lbs/year) are shown in the supplemental file, Supplemental File: Aquatic Exposure Screen Facility
Information, while the release inputs (kg/day) are shown in Tables E-3, E-4, and E-5. The referenced
supplemental file also provides a column showing the reported release converted from lbs to kgs and an
example EFAST output file for one of the sites modeled.
E-FAST U.S. EPA. (2014c) incorporates stream dilution at the point of release using stream flow
distribution data contained within the model. The stream flow data have not been updated recently and
may differ from current values obtained from NHD or USGS gages. Site-specific stream flow data are
applied using a National Pollutant Discharge Elimination System (NPDES) code. If a specific
discharger's NPDES code could not be identified within the E-FAST database, a surrogate site or
generic Standard Industrial Classification (SIC) code was applied (i.e., Industrial POTW).
E-FAST 2014 can incorporate wastewater treatment removal efficiencies. Wastewater treatment
removal is assumed to be 0% for all direct discharges this exercise, as reported direct loadings/releases
are assumed to account for any pre-release treatment. Indirect releases were assessed using TRI Explorer
data on transfers to POTW using 2% wastewater treatment removal based on fate predictions. Therefore,
for volumes transferred off-site to POTWs, a 2% wastewater treatment removal rate was applied within
E-FAST. Because the days of release and/or operation are not reported in these sources, E-FAST U.S.
EPA. (2014c) is run assuming hypothetical release-day scenarios (i.e., assuming 1, 20, and 250 days for
most facilities and 250 days for Wastewater/Sewage Treatment Plants/Publicly Owned Treatment
Works [WWT/STP/POTW]). For WWTP/STP/POTW facilities, it is assumed that a lower number of
release and/or operation days is unlikely. Refer to the E-FAST 2014 Documentation Manual for
equations used in the model to estimate surface water concentrations 4 v \ v _>01 jo).
The modeled surface water concentrations presented in Tables E-3, Table E-4, and E-5 are associated
with a low flow - 7Q10, which is an annual minimum seven-day average stream flow over a ten-year
recurrence interval. The 7Q10 stream flow is used to derive the presented surface water concentrations.
Page 364 of 616
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No post-release degradation or removal mechanisms (e.g., hydrolysis, aerobic degradation, photolysis,
volatilization) are applied in the calculation of the modeled surface water concentrations.
Modeled Surface Water Concentrations
Tables E-3, E-4, and E-5 present the results of this first-tier aquatic exposure assessment. Based on the
top ten DMR discharging facilities in 2015 and 2016, predicted surface water concentrations, which
were based on the 7Q10 stream flow, ranged from 18.8 to 11,500 |ig/L for acute release scenarios and
0.095 to 5,762 |ig/L for chronic release scenarios. Based on the top TRI discharging facilities in 2014
and 2015 (including direct and indirect dischargers), predicted surface water concentrations ranged from
1.26 to 9,734 |ig/L for acute release scenarios and 2.37E-08 to 4,879 |ig/L for chronic release scenarios.
The estimated surface water concentrations derived from chronic release scenarios (i.e., those assuming
20 days or more of annual release days) were compared against the chronic COC of 14,500 |ig/L using
E-FAST's high-end Probabilistic Dilution Model (PDM).
It is assumed that these modeled surface water concentrations are higher than those that would be
present from non-point sources based on the conservative nature of the estimation approaches including
the following: surface water concentrations would be expected to decrease downstream and this
modeling analysis does not account for downstream transport and fate processes; non-zero wastewater
removal rates would be applied for any indirect releases that pass through a treatment facility before
release; and assuming a low-end number of release days (i.e., 1 day per year) assumes the total annual
loading estimate occurs over 1 day. Furthermore, the modeled levels, for some sites, exceed the
maximum levels reported in the literature cited in Section 2.3.1.
Table E-3. Summary of Modeled Surface Water Concentrations for DMR Facilities
Facility
E-F AST Inputs and Results
NPDES Used in E-F AST
Name
Days of
Releasea
Releasea
(kg/day)
7Q10
Concentration
(Mg/L)
Days Exceedance
(days/yr)
COC = 14,500 fig/L
Reporting Year 2016
WV0000132
(SIC 2821)
M and G Polymers
USA, LLC
1
13,753
968.17
NA
20
688
48.41
0
250
55
3.87
0
SC0026506
(SIC 2821)
10b
977
11.500
NA
Dak Americas LLC
20
488
5.761.65
0
250
39
461.36
0
SC0046311c
(SIC 4952)
Lake City
Wastewater
Treatment Plant
250
5.4
695.88
0
WV0000086
(SIC 2869)
1
271
81.19
NA
Institute Plant
20
14
4.07
0
250
1.1
0.33
0
NY0001643
(SIC 3861)
1
79
74.46
NA
Eastman Kodak
20
3.9
3.7
0
250
0.3
0.28
0
PA0026492
The Scranton Sewer
250
0.2
1.85
0
(SIC 4952)
Authority
CA0054011
(SIC 4952)
Los Coyotes Water
Reclamation Plant
250
0.2
1.45
20
CTMTU0161
Beacon Heights
250
0.2
1.10
0
Page 365 of 616
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Facility
E-FAST Inputs and Results
NPDES Used in E-FAST
Name
Days of
Releasea
Releasea
(kg/day)
7Q10
Concentration
(Mg/L)
Days Exceedance
(days/yr)
COC = 14,500 fig/L
(SIC Blank) ¦=> CT0101061 d
Landfill ¦=> Beacon
Falls WPCF
CA0053911
(SIC 4952)
San Jose Creek
Water Reclamation
Plant
250
0.1
0.47
20
CA0056227
(SIC 4952)
Donald C Tillman
WRP
250
0.1
1.49
0
Reporting Year 2016
Min
74.46 (acute)
0.28 (chronic)
Max
11.500 (acute)
5.762 (chronic)
Reporting Year 2015
WV0000132
(SIC 2821)
M and G Polymers
USA, LLC
1
9,514
669.75
NA
20
476
33.49
0
250
38
2.68
0
SC0026506
(SIC 2821)
Dak Americas LLC
10b
920
10.900
NA
20
460
5.428.91
0
250
37
434.22
0
SC0046311c
(SIC 4952)
Lake City
Wastewater
Treatment Plant
250
4.3
554.12
0
SC0002798
(SIC 2821)
Auriga Polymers,
Inc.
1
155
521.38
NA
20
7.8
26.22
0
250
0.6
2.02
0
WV0000086
(SIC 2869)
Institute Plant
1
92
27.42
NA
20
4.6
1.38
0
250
0.4
0.12
0
CA0054011
(SIC 4952)
Los Coyotes Water
Reclamation Plant
250
0.1
0.73
20
CA0053953
(SIC 4952)
LA-Glendale WRP
250
0.1
2.93
0
CA0056227
(SIC 4952)
Donald C Tillman
WRP
250
0.1
1.49
0
MOO 101184
(SIC 2899)
Buckman
Laboratories, Inc.
1
20
1.819.84
NA
20
1
90.99
0
250
0.1
9.1
0
NY0001643
(SIC 3861)
Eastman Kodak
1
20
18.78
NA
20
1
0.95
0
250
0.1
0.0949
0
Reporting Year 2015
Min
18.78 (acute)
0.0949 (chronic)
Max
10.900 (acute)
5.429 (chronic)
a. Days of release (1, 20, or 250) are EPA assumptions that provide a range of potential surface water concentrations; days of release were not reported in
DMR. The release (kg/day) is based on the per day based on total annual loading (lbs/yr), as reported in DMR Pollutant Loading Tool, and is divided
by the assumed number of release days prior to modeling.
b. The Dak chemicals site acute scenario was re-run for a 10-day acute scenario based on input from EPA engineers related to the lowest number of
operating days assumed for facilities falling within this standard industrial category (i.e., 10 days per year). Therefore, maximum surface water
concentrations based on this site reflect an assumed 10 days per year of release instead of 1 day.
c. Flow data were not available in E-FAST 2014 for NPDES SC0046311 (Lake City Wastewater Treatment Plant) and an appropriate surrogate was not
readily identified. Therefore, a generic SIC code (4952 - Industrial POTW) was applied in E-FAST.
Page 366 of 616
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d. NPDES CTMIU0161 (Beacon Heights Landfill) is not in the E-FAST 2014 database. This site is a landfill and is in the Superfund program. Leachate
collected from this site is sent through a leachate transportation line to the local sewer system and to the Beacon Falls Treatment Plant (Beacon Falls
WPCF; NPDES CT0101061). https://cumulis.epa.gov/supercpad/SiteProfiles/index.cfm?fuseaction=second.Cleanup&id=0100180#bkground
Table E-4. Summary of Modeled Surface Water Concentrations for TRI Facilities - Direct
NPDES Used in E-
FAST
Name
Days of
Release11
Releasea
(kg/day)
7Q10 Concentration
(Mg/L)
Days
Exceedance
(days/yr)
COC = 14,500
Hg/L
Reporting Year 2015 b
WV0000132
APG Polytech LLC
1
9767
687.59
NA
20
488
34.35
0
250
39
2.75
0
SC0026506
DAK Americas LLC
Cooper River Plant
10c
810
9.557
NA
20
405
4778.76
0
250
32
377.58
0
LA0036421 d
BASF Corp.
1
5361
21.7
NA
20
268
1.09
0
250
21
0.0868
0
LA0000191
St Charles Operations
(TAFT/STAR)
Union Carbide Corp.
1
817
3.31
NA
20
41
0.17
0
250
3.3
0.0134
0
TX0002844 e
Union Carbide Corp.
Seadrift Plant
1
640
7685.62
NA
20
32
96.07
NA
250
2.6
7.81
NA
NC0003719
DAK Americas LLC
10c
44
56.19
NA
20
22
28.16
0
250
1.8
2.30
0
LA0003301f
The DOW Chemical
Co. - Louisiana
Operations
1
337
1.36
NA
20
17
0.0688
0
250
1
0.00405
0
SC0002798
Auriga Polymers Inc.
1
157
527.77
NA
20
8
26.89
0
250
1
3.36
0
NC0001112
Invista SA RL -
Wilmington
1
99
480.86
NA
20
5
24.29
0
250
0.4
1.94
0
TN0002640
Eastman Chemical Co.
1
56
28.91
NA
20
3
1.55
0
250
0.2
0.10
0
Reporting Year 2015
Min
1.36 (acute)
0.00405 (chronic)
Max
9.557 (acute)
4.778.76 (chronic)
Reporting Year 2014 g
WV0000132
APG Polytech LLC
1
12,200
858.87
NA
20
611
43.01
0
250
49
3.45
0
SC0026506
DAK Americas LLC
Cooper River Plant
10c
825
9.734
NA
20
412
4.861.36
0
250
33
389.4
0
LA0036421 d
BASF Corp.
1
1199
4.85
NA
Page 367 of 616
-------
Days
NPDES Used in E-
FAST
Name
Days of
Releasea
Releasea
(kg/day)
7Q10 Concentration
(Mg/L)
Exceedance
(days/yr)
COC = 14,500
Ug/L
20
60
0.24
0
250
4.8
0.0194
0
St Charles Operations
1
784
3.17
NA
LA0000191
(TAFT/STAR)
Union Carbide Corp.
20
39
0.16
0
250
3.1
0.012
0
The DOW Chemical
1
312
1.26
NA
LA0003301f
Co. - Louisiana
20
16
0.0648
0
Operations
250
1
0.00405
0
DAK Americas LLC.
Cedar Creek
10c
17
22.14
NA
NC0003719
20
9
11.52
0
250
0.7
0.9
0
1
83
279.01
NA
SC0002798
Auriga Polymers Inc.
20
4
13.45
0
250
0.3
1.01
0
1
67
34.58
NA
TN0002640
Eastman Chemical Co.
20
3
1.55
0
250
0.3
0.15
0
Bayer Crop Science
LP.
1
66
19.76
NA
WV0000086
20
3
0.90
0
250
0.3
0.0898
0
Invista SA RL -
Wilmington
1
44
213.72
NA
NC0001112
20
2
9.71
0
250
0.2
0.97
0
Reporting Year 2014
Min
1.26 (acute)
0.00405 (chronic)
Max
9.734 (acute)
4.861.36 (chronic)
a. Days of release (1, 20, or 250) are EPA assumptions that provide a range of potential surface water concentrations; days of release were not
reported to TRI. The release (kg/day) is based on the per day based on annual releases to surface water (lb^yr), as reported to TRI, and is
divided by the assumed number of release days prior to modeling.
b. ARKEMA Inc (KY0003603), Dow Chemical Co Freeport (TX0006483), Honeywell International (LA0000329), and Westlake Vinyls Inc
(KY0003484 ) facilities, which were included in the draft risk evaluation based on previous data extraction, did not have reported surface
water discharges in TRI explorer per 2015 release report and were therefore removed from the list of assessed sites.
c. The Dak chemicals site acute scenario was re-run for a 10-day acute scenario based on input from EPA engineers related to the lowest
number of operating days assumed for facilities falling within this standard industrial category (i.e., 10 days per year). Therefore, maximum
surface water concentrations based on this site reflect an assumed 10 days per year of release instead of 1 day.
d. For facility BASF CORP (LA0004057), E-FAST appears to show that this facility discharging to Bayou Baton Rouge. Communications
with the Louisiana Department of Environmental Quality confirmed this site discharges process waters to the Mississippi River via pipeline,
so an appropriate surrogate, the Baton Rouge POTW (NPDES LA0036421), was used in E-FAST for the purposes of applying stream flow.
e. The facility UNION CARBIDE CORP SEADRIFT PLANT does not have a NPDES listed in DMR; however, a facility name and location
search within E-FAST 2014 returned a NPDES (TX0002844), which was used for modeling.
f. The NPDES provided in DMR's Pollutant Loading Tool for the facility THE DOW CHEMICAL CO - LOUISIANA OPERATIONS
(NPDES LA0116602) was not found in E-FAST 2014; however, a facility name and location search within E-FAST 2014 returned a
different NPDES (LA0003301) associated with this facility name and location, so it was applied for modeling.
g. ARKEMA Inc (KY0003603), Catlettsburg Refining LLC (KY0070718), Dow Chemical Co Freeport (TX0006483), Eagle US 2 LLC
(LA0000761), Honeywell International (LA0000329), and Westlake Vinyls Inc ( KY0003484 ) facilities, which were included in the draft
risk evaluation based on previous data extraction, did not have reported surface water discharges in TRI explorer per 2014 release report
and were therefore removed from the list of assessed sites.
Table E 5. Summary of Modeled Surface Water Concentrations for Facilities - Indirect
Page 368 of 616
-------
NPDES Used
in E-FAST
Facility Name
Receiving POTW
Days of
Releasea
Releasea
(kg/day)
7Q10
Concentration
(Hg/L)
Days
Exceedance
(days/yr)
coc =
14,500 jig/L
Reporting Year 2015
AL0048593
Indorama Ventures
Decatur Utilities
Dry Creek WWTP
250
300
15.95
0
Ind. POTW
(SIC 4952) b
SUEZ WTS
Solutions USA Inc.
Blue Lake WWTP
250
27
3409.79
3
Ind. POTW
(SIC 4952) c
Nan Ya Plastics
Corp. America
Lake City
WWTP
250
7
884.02
0
Ind. POTW
(SIC 4952) b
Mitsubishi
Polyester Film Inc.
Pelham
WWTP
250
2
252.58
0
NY0087971
AMRI Rensselaer
Inc.
Rensselaer Co.
250
0.4
0.0573
0
MD0021601
Solvay USA Inc.
Patapsco
WWTP
250
0.1
0.76
0
Ind. POTW
(SIC 4952) b
DAK Americas
Mississippi Inc.
Hancock County
Port and Harbor
Commission
250
0.1
12.63
0
WI0025411
Aldrich Chemical
Co. LLC
Sheboygan
Regional
WWTP
250
0.004
0.012
NA
WI0060453
Evonik Materials
Corp.
Milton Waterworks
250
0.001
0.0586
0
OH0024970
Heritage Thermal
Services
East Liverpool
WWTP
250
2.39E-07
2.37E-08
0
Reporting Year 2015
Min
2.37E-08 (chronic)
Max
3.410 (chronic)
Reporting Year 2014
AL0048593
Indorama Ventures
Decatur Utilities
Dry Creek WWTP
250
222
11.8
0
Ind. POTW
(SIC 4952) b
SUEZ WTS
Solutions USA Inc.
Blue Lake WWTP
250
30
3788.66
4
Ind. POTW
(SIC 4952) c
Nan Ya Plastics
Corp. America
Lake City
WWTP
250
8
1010.31
0
Ind. POTW
(SIC 4952) b
Mitsubishi
Polyester Film Inc.
Pelham
WWTP
250
1
126.29
0
Ind. POTW
(SIC 4952) b
DAK Americas
Mississippi Inc.
Hancock County
Port and Harbor
Commission
250
0.1
12.63
0
MD0021601
Solvay USA Inc.
Patapsco
WWTP
250
0.1
0.76
0
WI0025411
Aldrich Chemical
Co. LLC
Sheboygan
Regional
WWTP
250
0.004
0.012
NA
WI0060453
Evonik Materials
Corp.
Milton Waterworks
250
0.001
0.00586
0
Reporting Year 2014
Min
0.0059 (chronic)
Max
3.789 (chronic)
a. Days of release (250) are EPA assumptions that provide a range of potential surface water concentrations; days of release were not reported to
TRI. The release (kg/day) is based on the per day based on annual releases to surface water (lbs/yr), as reported to TRI, and is divided by the
assumed number of release days prior to modeling,
b. SIC for industrial POTWs was used for the facility because the facility was not found in E-FAST 2014.
Page 369 of 616
-------
c. SIC for industrial POTWs was used for NAN YA PLASTICS CORP AMERICA because flow data were not available in E-FAST 2014 for
NPDES SC0046311 (Lake City Wastewater Treatment Plant) and an appropriate surrogate was not readily identified.
Page 370 of 616
-------
Appendix F ENVIRONMENTAL RISK
F.l Environmental Risk Tables
Table F-l. Environmental Risk Estimation of 1,4-Dioxane from Industrial Releases into Surface Water
from DMR Facilities in Year 2015
Name, Location, and ID
of Active Releaser Facility
E-FAST Inputs and Results
RQ
Days of
Release a
Release a
(kg/day)
10th Percentile
7Q10
Concentration
(Mg/L)
Days
Exceedance
(days/yr)
Algae
coc =
57,500 |ig/L
Fish Chronic
coc =
14,500 ng/L
M and G Polymers USA,
LLC
WV0000132
(SIC 2821)
1
9,514
669.75
NA
0.0328069
0.008273
20
476
33.49
0
0.0026276
0.0006626
250
38
2.68
0
0.0634621
0.0160035
Dak Americas LLC
SC0026506
(SIC 2821)
10b
920
10,900 b
NA
0.031731
0.0080017
20
460
5,428.91
0
0.0025379
0.00064
250
37
434.22
0
0.0002966
7.48E-05
Lake City Wastewater
Treatment Plant
SC0046311c
(SIC 4952)
250
4.3
554.12
0
0.0106966
0.0026974
Auriga Polymers,
Inc.SC0002798
(SIC 2821)
1
155
521.38
NA
0.0005379
0.0001357
20
7.8
26.22
0
4.14E-05
1.04E-05
250
0.6
2.02
0
0.0063172
0.001593
Institute Plant
WV0000086
(SIC 2869)
1
92
27.42
NA
0.0003172
0.00008
20
4.6
1.38
0
2.76E-05
6.96E-06
250
0.4
0.12
0
6.90E-06
1.74E-06
Los Coyotes Water
Reclamation Plant
CA0054011
(SIC 4952)
250
0.1
0.73
20
6.90E-06
1.74E-06
LA-Glendale WRP
CA0053953
(SIC 4952)
250
0.1
2.93
0
6.90E-06
1.74E-06
Donald C Tillman WRP
CA0056227
(SIC 4952)
250
0.1
1.49
0
0.0013793
0.0003478
Buckman Laboratories,
Inc.M00101184
(SIC 2899)
1
20
1,819.84
NA
6.90E-05
1.74E-05
20
1
90.99
0
6.90E-06
1.74E-06
250
0.1
9.1
0
0.0013655
0.0003443
Eastman Kodak
NY0001643
(SIC 3861)
1
20
18.78
NA
6.90E-05
1.74E-05
20
1
0.95
0
6.90E-06
1.74E-06
250
0.1
0.0949
0
0
0
c. Days of release (1, 20, or 250) are EPA assumptions that provide a range of potential surface water concentrations; days of release were
not reported in DMR. The release (kg/day) is based on the per day based on total annual loading (lbs/yr), as reported in DMR Pollutant
Loading Tool, and is divided by the assumed number of release days prior to modeling.
d. The Dak chemicals site acute scenario was re-run for a 10-day acute scenario based on input from EPA engineers related to the lowest
number of operating days assumed for facilities falling within this standard industrial category (i.e., 10 days per year). Therefore,
maximum surface water concentrations based on this site reflect an assumed 10 days per year of release instead of 1 day.
e. Flow data were not available in E-FAST 2014 for NPDES SC0046311 (Lake City Wastewater Treatment Plant) and an appropriate
surrogate was not readily identified. Therefore, a generic SIC code (4952 - Industrial POTW) was applied in E-FAST.
f. NPDES CTMIU0161 (Beacon Heights Landfill) is not in the E-FAST 2014 database. This site is a landfill and is in the Superfund
program. Leachate collected from this site is sent through a leachate transportation line to the local sewer system and to the Beacon Falls
Treatment Plant (Beacon Falls WPCF; NPDES CT0101061).
https://cumulis.epa.gov/supercpad/SiteProfiles/index.cfm?fuseaction=second.Cleanup&id=0100180#bkground
Page 371 of 616
-------
Name, Location, and ID
of Active Releaser Facility
E-FAST Inputs and Results
RQ
Days of
Release a
Release a
(kg/day)
10th Percentile
7Q10
Concentration
(Mg/L)
Days
Exceedance
(days/yr)
Algae
coc =
57,500 |ig/L
Fish Chronic
coc =
14,500 ng/L
Table F-2. Environmental Risk Estimation of 1,4-Dioxane from Industrial Releases into Surface Water
from DMR Facilities in Year 2016
Name, Location, and
ID of Active Releaser
Facility
E-FAST Inputs and Results
RQ
Days of
Release a
Release a
(kg/day)
10th Percentile
7Q10
Concentration
(Mg/L)
Days
Exceedance
(days/yr)
Algae
COC = 57,500
Hg/L
Fish Chronic
COC = 14,500
Hg/L
M and G Polymers
USA, LLC
WV0000132
(SIC 2821)
1
13,753
968.17
NA
0.0168377
0.0667703
20
688
48.41
0
0.0008419
0.0033386
250
55
3.87
0
6.73E-05
0.0002669
Dak Americas LLC
SC0026506
(SIC 2821)
10"
977
11,500
NA
0.2
0.7931034
20
488
5,761.65
0
0.1002026
0.3973552
250
39
461.36
0
0.0080237
0.0318179
Lake City Wastewater
Treatment Plant
SC0046311c
(SIC 4952)
250
5.4
695.88
0
0.0121023
0.0479917
Institute Plant
WV0000086
(SIC 2869)
1
271
81.19
NA
0.001412
0.0055993
20
14
4.07
0
7.07826 E-05
0.0002807
250
1.1
0.33
0
5.73913 E-06
2.27586 E-05
Eastman Kodak
NY0001643
(SIC 3861)
1
79
74.46
NA
0.001295
0.0051352
20
3.9
3.7
0
6.43478 E-05
0.0002552
250
0.3
0.28
0
4.86957 E-06
1.93103 E-05
Hie Scranton Sewer
Authority
PA0026492
(SIC 4952)
250
0.2
1.85
0
3.21739 E-05
0.0001276
Los Coyotes Water
Reclamation Plant
CA0054011
(SIC 4952)
250
0.2
1.45
20
2.52174 E-05
0.0001
Beacon Heights
Landfill
Beacon Falls WPCF
CTMIU0161
(SIC Blank)
CT0101061 d
250
02
1.10
0
1.91E-05
7.59E-05
San Jose Creek Water
Reclamation Plant
CA0053911
(SIC 4952)
250
0.1
0.47
20
8.17E-06
3.24138 E-05
Donald C Tillman
WRP
CA0056227
(SIC 4952)
250
0.1
1.49
0
2.59E-05
0.0001028
Page 372 of 616
-------
Name, Location, and
ID of Active Releaser
Facility
E-FAST Inputs and Results
RQ
Days of
Release a
Release a
(kg/day)
10th Percentile
7Q10
Concentration
(Mg/L)
Days
Exceedance
(days/yr)
Algae
COC = 57,500
Hg/L
Fish Chronic
COC = 14,500
Hg/L
e. Days of release (1, 20, or 250) are EPA assumptions that provide a range of potential surface water concentrations; days of release were
not reported in DMR. The release (kg/day) is based on the per day based on total annual loading (lbs/yr), as reported in DMR Pollutant
Loading Tool, and is divided by the assumed number of release days prior to modeling.
f. The Dak chemicals site acute scenario was re-run for a 10-day acute scenario based on input from EPA engineers related to the lowest
number of operating days assumed for facilities falling within this standard industrial category (i.e., 10 days per year). Therefore,
maximum surface water concentrations based on this site reflect an assumed 10 days per year of release instead of 1 day.
g. Flow data were not available in E-FAST 2014 for NPDES SC0046311 (Lake City Wastewater Treatment Plant) and an appropriate
surrogate was not readily identified. Therefore, a generic SIC code (4952 - Industrial POTW) was applied in E-FAST.
h. NPDES CTMIU0161 (Beacon Heights Landfill) is not in the E-FAST 2014 database. This site is a landfill and is in the Superfiind
program. Leachate collected from this site is sent through a leachate transportation line to the local sewer system and to the Beacon Falls
Treatment Plant (Beacon Falls WPCF; NPDES CT0101061).
https://cumulis.epa.gov/supercpad/SiteProfiles/index.cfm?fiiseaction=second.Cleanup&id=0100180#bkground
Table F-3. Environmental Risk Estimation of 1,4-Dioxane from Direct Industrial Releases into
Surface Water from TRI Facilities in Year 2014a
Name, Location, and
E-FAST Inputs and Results
RQ
ID of Active
Days of
Release b
7Q10
Days
Algae
Fish Chronic
Releaser Facility
Release b
(kg/day)
Concentration
Exceedance
coc =
COC = 14,500 ng/L
NPDES Used in
(Mg/L)
(days/yr)
coc =
57,500 ng/L
E-FAST
14,500 ng/L
APG Polytech LLC
1
12,200
858.87
NA
1.49E-02
5.92E-02
WV0000132
20
611
43.01
0
7.48E-04
2.97E-03
250
49
3.45
0
6.00E-05
2.38E-04
DAK Americas LLC
10c
825
9,734
NA
1.69E-01
6.71E-01
Cooper River Plant
20
412
4,861.36
0
8.45E-02
3.35E-01
SC0026506
250
33
389.4
0
6.77E-03
2.69E-02
BASF Corp.
1
1199
4.85
NA
8.43E-05
3.34E-04
LA0036421 d
20
60
0.24
0
4.17E-06
1.66E-05
250
4.8
0.0194
0
3.37E-07
1.34E-06
St Charles Operations
1
784
3.17
NA
5.51E-05
2.19E-04
(TAFT/STAR)
Union Carbide Corp.
LA0000191
20
39
0.16
0
2.78E-06
1.10E-05
250
3.1
0.012
0
2.09E-07
8.28E-07
The DOW Chemical
1
312
1.26
NA
2.19E-05
8.69E-05
Co.
Louisiana Operations
LA0003301e
20
16
0.0648
0
1.13E-06
4.47E-06
250
1
0.00405
0
7.04E-08
2.79E-07
DAK Americas LLC.
10c
17
22.14
NA
3.85E-04
1.53E-03
Cedar Creek
NC0003719
20
9
11.52
0
2.00E-04
7.94E-04
250
0.7
0.9
0
1.57E-05
6.21E-05
Auriga Polymers Inc.
1
83
279.01
NA
4.85E-03
1.92E-02
SC0002798
20
4
13.45
0
2.34E-04
9.28E-04
250
0.3
1.01
0
1.76E-05
6.97E-05
Eastman Chemical
1
67
34.58
NA
6.01E-04
2.38E-03
Co.
TN0002640
20
3
1.55
0
2.70E-05
1.07E-04
250
0.3
0.15
0
2.61E-06
1.03E-05
Bayer Crop Science
1
66
19.76
NA
3.44E-04
1.36E-03
LP.
WV0000086
20
3
0.90
0
1.57E-05
6.21E-05
250
0.3
0.0898
0
1.56E-06
6.19E-06
Invista SA RL -
1
44
213.72
NA
3.72E-03
1.47E-02
Wilmington
NC0001112
20
2
9.71
0
1.69E-04
6.70E-04
250
0.2
0.97
0
1.69E-05
6.69E-05
Page 373 of 616
-------
Name, Location, and
E-FAST Inputs and Results
RQ
ID of Active
Days of
Release b
7Q10
Days
Algae
Fish Chronic
Releaser Facility
Release b
(kg/day)
Concentration
Exceedance
coc =
COC = 14,500 ng/L
(Mg/L)
(days/yr)
57,500 ng/L
NPDES Used in
coc =
E-FAST
14,500 ng/L
d. ARKEMA Inc (KY0003603). Catlettsburg Refining LLC (KY0070718). Dow Chemical Co Freeport (TX0006483). Eagle US 2 LLC (LA0000761).
Honeywell International (LA0000329), and Westlake Vinyls Inc ( KY0003484 ) facilities, which were included in the risk evaluation based on
previous data extraction, did not have reported surface water discharges in TRI explorer per 2014 release report and were therefore removed from the
list of assessed sites.
e. Days of release (1, 20, or 250) are EPA assumptions that provide a range of potential surface water concentrations; days of release were not reported
to TRI. The release (kg/day) is based on the per day based on annual releases to surface water (lbs/yr), as reported to TRI, and is divided by the
assumed number of release days prior to modeling.
f. ARKEMA Inc (KY0003603), Dow Chemical Co Freeport (TX0006483), Honeywell International (LA0000329), and Westlake Vinyls Inc
(KY0003484 ) facilities, which were included in the risk evaluation based on previous data extraction, did not have reported surface water discharges
in TRI explorer per 2015 release report and were therefore removed from the list of assessed sites.
g. For facility BASF CORP (LA0004057), E-FAST appears to show that this facility discharging to Bayou Baton Rouge. Communications with the
Louisiana Department of Environmental Quality confirmed this site discharges process waters to the Mississippi River via pipeline, so an appropriate
surrogate, the Baton Rouge POTW (NPDES LA0036421), was used in E-FAST for the purposes of applying stream flow.
h. The NPDES provided in DMR's Pollutant Loading Tool for the facility THE DOW CHEMICAL CO - LOUISIANA OPERATIONS (NPDES
LAO 116602) was not found in E-FAST 2014; however, a facility name and location search within E-FAST 2014 returned a different NPDES
(LA0003301) associated with this facility name and location, so it was applied for modeling.
Table F-5. Environmental Risk Estimation of 1,4-Dioxane from Direct Industrial Releases into Surface
Water from TRI Facilities in Year 2015b
Name, Location, and ID
of Active Releaser Facility
NPDES Used in
E-FAST
E-FAST Inputs and Results
RQ
Days of
Releasea
Release a
(kg/day)
7Q10
Concentration
(M«/L)
Days
Exceedance
(days/yr)
COC =
14,500 ng/L
Algae
COC =
57,500 ng/L
Fish Chronic
COC = 14,500
Hg/L
APG Polytech LLC
WV0000132
1
9767
687.59
NA
1.20E-02
4.74E-02
20
488
34.35
0
5.97E-04
2.37E-03
250
39
2.75
0
4.78E-05
1.90E-04
DAK Americas LLC
Cooper River Plant
SC0026506
10c
810
9,557
NA
1.66E-01
6.59E-01
20
405
4778.76
0
8.31E-02
3.30E-01
250
32
377.58
0
6.57E-03
2.60E-02
BASF Corp.
LA0036421 d
1
5361
21.7
NA
3.77E-04
1.50E-03
20
268
1.09
0
1.90E-05
7.52E-05
250
21
0.0868
0
1.51E-06
5.99E-06
St Charles Operations
(TAFT/STAR)
Union Carbide Corp
LA0000191
1
817
3.31
NA
5.76E-05
2.28E-04
20
41
0.17
0
2.96E-06
1.17E-05
250
3.3
0.0134
0
2.33E-07
9.24E-07
Union Carbide Corp.
Seadrift Plant
TX0002844 e
1
640
7685.62
NA
1.34E-01
5.30E-01
20
32
96.07
NA
1.67E-03
6.63E-03
250
2.6
7.81
NA
1.36E-04
5.39E-04
DAK Americas LLC
NC0003719
10c
44
56.19
NA
9.77E-04
3.88E-03
20
22
28.16
0
4.90E-04
1.94E-03
250
1.8
2.30
0
4.00E-05
1.59E-04
The DOW Chemical Co.
Louisiana Operations
LA0003301f
1
337
1.36
NA
2.37E-05
9.38E-05
20
17
0.0688
0
1.20E-06
4.74E-06
250
1
0.00405
0
7.04E-08
2.79E-07
Auriga Polymers Inc.
SC0002798
1
157
527.77
NA
9.18E-03
3.64E-02
20
8
26.89
0
4.68E-04
1.85E-03
250
1
3.36
0
5.84E-05
2.32E-04
Invista SA RL -
Wilmington
NC0001112
1
99
480.86
NA
8.36E-03
3.32E-02
20
5
24.29
0
4.22E-04
1.68E-03
250
0.4
1.94
0
3.37E-05
1.34E-04
Eastman Chemical Co.
TN0002640
1
56
28.91
NA
5.03E-04
1.99E-03
20
3
1.55
0
2.70E-05
1.07E-04
250
0.2
0.10
0
1.74E-06
6.90E-06
Page 374 of 616
-------
Name, Location, and ID
of Active Releaser Facility
NPDES Used in
E-FAST
E-FAST Inputs and Results
RQ
Days of
Releasea
Release a
(kg/day)
7Q10
Concentration
Days
Exceedance
(days/yr)
coc =
14,500 p,g/L
Algae
coc =
57,500 ng/L
Fish Chronic
COC = 14,500
Hg/L
h. Days of release (1, 20, or 250) are EPA assumptions that provide a range of potential surface water concentrations; days of release were not reported
to TRI. The release (kg/day) is based on the per day based on annual releases to surface water (lbs/yr), as reported to TRI, and is divided by the
assumed number of release days prior to modeling.
i. ARKEMA Inc (KY0003603), Dow Chemical Co Freeport (TX0006483), Honeywell International (LA0000329), and Westlake Vinyls Inc
(KY0003484 ) facilities, which were included in the risk evaluation based on previous data extraction, did not have reported surface water discharges
in TRI explorer per 2015 release report and were therefore removed from assessed sites.
j. The Dak chemicals site acute scenario was re-run for a 10-day acute scenario based on input from EPA engineers related to the lowest number of
operating days assumed for facilities falling within this standard industrial category (i.e., 10 days per year). Therefore, maximum surface water
concentrations based on this site reflect an assumed 10 days per year of release instead of 1 day.
k. For facility BASF CORP (LA0004057), E-FAST appears to show that this facility discharging to Bayou Baton Rouge. Communications with the
Louisiana Department of Environmental Quality confirmed this site discharges process waters to the Mississippi River via pipeline, so an appropriate
surrogate, the Baton Rouge POTW (NPDES LA0036421), was used in E-FAST for the purposes of applying stream flow.
1. The fecility UNION CARBIDE CORP SEADRIFT PLANT does not have a NPDES listed in DMR; however, a facility name and location search
within E-FAST 2014 returned a NPDES (TX0002844). which was used for modeling,
m. The NPDES provided in DMR's Pollutant Loading Tool for the facility THE DOW CHEMICAL CO - LOUISIANA OPERATIONS (NPDES
LAO 116602) was not found in E-FAST 2014; however, a facility name and location search within E-FAST 2014 returned a different NPDES
(LA0003301) associated with this facility name and location, so it was applied for modeling.
Table 4-5. Summary of Modeled Surface Water Concentrations for Facilities - Indirect -
Reporting Year 2014
Name, Location, and ID of
Receiving
E-FAST
Inputs and Results
RQ
Active Releaser Facility
POTW
Days of
Release a
7Q10
Days
Algae
Fish
NPDES Used in E-FAST
Releasea
(kg/day)
Concentratio
n
(Mg/L)
Exceedance
(days/yr)
COC = 14,500
Hg/L
coc =
57,500
Hg/L
Chronic
coc =
14,500
Hg/L
Reporting Year 2014
Indorama Ventures
Decatur Utilities
250
222
11.8
0
2.05E-04
8.14E-04
AL0048593
Dry Creek
WWTP
SUEZ WTS Solutions USA Inc.
Blue Lake
250
30
3788.66
4
6.59E-02
2.61E-01
Ind. POTW
WWTP
(SIC 4952)b
Nan Ya Plastics Corp. America
Lake City
250
8
1010.31
0
1.76E-02
6.97E-02
Ind. POTW
WWTP
(SIC 4952)c
Mitsubishi Polyester Film Inc.
Pelham
250
1
126.29
0
2.20E-03
8.71E-03
Ind. POTW
WWTP
(SIC 4952)b
DAK Americas Mississippi Inc.
Hancock County
250
0.1
12.63
0
2.20E-04
8.71E-04
Ind. POTW
Port and Harbor
(SIC 4952)b
Commission
Solvay USA Inc.
Patapsco
250
0.1
0.76
0
1.32E-05
5.24E-05
MD0021601
WWTP
Aldrich Chemical Co. LLC
Sheboygan
250
0.004
0.012
NA
2.09E-07
8.28E-07
WI0025411
Regional
WWTP
Evonik Materials Corp.
Milton
250
0.001
0.00586
0
1.02E-07
4.04E-07
WI0060453
Waterworks
d. Days of release (250) are EPA assumptions that provide a range of potential surface water concentrations; days of release were not reported to TRI.
The release (kg/day) is based on the per day based on annual releases to surface water (lbs/yr), as reported to TRI, and is divided by the assumed number
of release days prior to modeling.
e. SIC for industrial POTWs was used for the facility because the facility was not found in E-FAST 2014.
f. SIC for industrial POTWs was used for NAN YA PLASTICS CORP AMERICA because flow data were not available in E-FAST 2014 for NPDES
SC0046311 (Lake City Wastewater Treatment Plant) and an appropriate surrogate was not readily identified.
Page 375 of 616
-------
Table F-6. Environmental Risk Estimation of 1,4-Dioxane from Direct Industrial Releases into
Surface Water from TRI Facilities in Year 2014
Name, Location, and ID of
Receiving
E-FAST
Inputs and Results
RQ
Active Releaser Facility
POTW
Days of
Release a
7Q10
Days
Algae
Fish
NPDES Used in E-FAST
Releasea
(kg/day)
Concentratio
n
(Mg/L)
Exceedance
(days/yr)
COC = 14,500
Hg/L
coc =
57,500
Hg/L
Chronic
coc =
14,500
Hg/L
Indorama Ventures
Decatur Utilities
250
300
15.95
0
2.77E-04
1.10E-03
AL0048593
Dry Creek
WWTP
SUEZ WTS Solutions USA Inc.
Blue Lake
250
27
3409.79
3
5.93E-02
2.35E-01
Ind. POTW
WWTP
(SIC 4952)b
Nan Ya Plastics Corp. America
Lake City
250
7
884.02
0
1.54E-02
6.10E-02
Ind. POTW
WWTP
(SIC 4952)c
Mitsubishi Polyester Film Inc.
Pelham
250
2
252.58
0
4.39E-03
1.74E-02
Ind. POTW
WWTP
(SIC 4952)b
AMRI Rensselaer Inc.
Rensselaer Co.
250
0.4
0.0573
0
9.97E-07
3.95E-06
NY0087971
Solvay USA Inc.
Patapsco
250
0.1
0.76
0
1.32E-05
5.24E-05
MD0021601
WWTP
DAK Americas
Hancock County
250
0.1
12.63
0
2.20E-04
8.71E-04
Mississippi Inc.
Port and Harbor
Ind. POTW
Commission
(SIC 4952)b
Aldrich Chemical Co. LLC
Sheboygan
250
0.004
0.012
NA
2.09E-07
8.28E-07
WI0025411
Regional
WWTP
Evonik Materials Corp.
Milton
250
0.001
0.0586
0
1.02E-06
4.04E-06
WI0060453
Waterworks
Heritage Thermal Services
East Liverpool
250
2.39E-07
2.37E-08
0
4.12E-13
1.63E-12
OH0024970
WWTP
a. Days of release (250) are EPA assumptions that provide a range of potential surface water concentrations; days of release were not reported to TRI.
The release (kg/day) is based on the per day based on annual releases to surface water (lbs/yr), as reported to TRI, and is divided by the assumed number
of release days prior to modeling.
b. SIC for industrial POTWs was used for the facility because the facility was not found in E-FAST 2014.
c. SIC for industrial POTWs was used for NAN YA PLASTICS CORP AMERICA because flow data were not available in E-FAST 2014 for NPDES
SC0046311 (Lake City Wastewater Treatment Plant) and an appropriate surrogate was not readily identified.
Page 376 of 616
-------
Appendix G OCCUPATIONAL EXPOSURES
G.l Systematic Review Summary Tables
G.l.l Evaluation of Inhalation Data Sources Specific to 1,4-Dioxane
EPA has reviewed acceptable sources for 1,4-dioxane inhalation exposure data according to the data
quality evaluation criteria found in The Application of Systematic Review in TSCA Risk Evaluations U.S.
EPA. (2018b). Table G-l summarizes the results of this evaluation. The data quality evaluation indicated
the sources included are of medium to high confidence and are used to characterize the occupational
inhalation exposures of 1,4-dioxane.
Page 377 of 616
-------
Table G-l. Summary of Inhalation Monitoring Data Sources Specific to 1,4-Dioxane
l);il;i
Omt;iII l)iil;i
Rim
Oiui|>;iliim;il
l!\|)iisuiv
Sivn.iriii
T\ |K" III'
S.impk-
Worker Aiii\ ii\
or S;iiii|)lin^
1 .i >c;i 1 i< • ll
l.4-l)io\;MK'
Airlxinu-
Cuiii'i'iilnilhiii
NiiihIkt ill"
Siinipk's
T\ |K" III'
Mi';isinvnu'iil
S.illipk-
Tiim-
Si ill I'l l'
lilinlil'iiT
1'nim l);il;i
r.Uniiliim
i|ii;ilil\ niiin^
In mi l);il:i
l'\lr;iiiiim
K;iliun;ik' 1'iir
llll'lllsillll /
I.Mlusiim
(msi/m1) 1
;inil
l!\:i ln:i 1 it i n
mill
l.\;i ln:i 1 ii i n
Included -
Referenced in
1
Laboratory
Chemicals
Personal
Solvent extraction
and TLC
1.8 ppm
(highest value)
Unknown
Unknown
Unknown
NICNA
S, 1998
NICNAS
(1998)
High
comparison to
other available
data in the
Laboratory
Chemical
OES.
Included -
Referenced in
2
Film Cement
Personal
Film cement
application
<1 ppm
Unknown
Unknown
Unknown
NICNA
S, 1998
NICNAS
0998)
High
comparison to
other available
data in the
Film Cement
OES.
Metal cleaning
surface, Medicine
Included -
Recommended
central
tendency and
high-end
values used to
estimate
inhalation
exposures for
industrial use
3
Industrial Use
Area
and
Personal
manufacture, Shirt
cleaning area,
textile
industry,
Pharmaceutical
production
Manufacture of
magnetic tapes,
Use (e.g., as
solvent) in other
productions
Central
Tendency: 5
mg/m3
High-end: 20
mg/m3
Eight
datasets -
each has
between 2
and 194
samples per
set
Full-shift and
Short term
6-8 hour
for full
shift,
0-0.5 hour
for short
term
ECJRC,
2002
ECJRC
(2002)
High
Included -
4
Industrial Use
EASE
Modelin
g
Extractant in
medicine
manufacturing
36-180 mg/m3
Not
applicable -
estimates
from
modeling
unknown
Not
applicable
- estimates
from
modeling
ECJRC,
2002
ECJRC
(2002)
High
Modeling
estimates are
considered/ref
erenced, but
not used in
exposure
calculations.
Page 378 of 616
-------
l);il;i
Omt;iII I);iI;i
Oi'Ui|>;iliiin;il
I".\|)IISIIIV
Sivn;irin
Worker Aiii\ il\
or S;uii|)lin^
l.iiiiiliiiii
l.4-l)iii\;iiu-
Idinlil'iiT
(|ii;ilil\ |-;ilink-
Ci uii i-iil nil inn
S;ini|)k's
Mi-;imiiviiu-iiI
Tinu-
l'.\lr;iiliiiii
I'.Mriiiiiim
(msi/nr1) ¦'
;iihI
l".\:i ln:i 1 ii i n
mill
r.\iiiiiiiiimi
Included -
Mean, 90th
Three
datasets -
6-8 hour
for full
shift,
0-0.5 hour
for short
term
percentile, and
short-term
5
Laboratory
Chemicals
Area
and
Personal
Laboratory Work
0-166 mg/m3
each has
between 1
and 305
Full-shift and
Short term
ECJRC,
2002
ECJRC
(2002)
High
peak values
used to
estimate
samples per
inhalation
set
exposures for
laboratory
chemical use
Included -
6
Open System
Functional
Fluids
Area
and
Personal
Threader,
broaching, Apex
drill, lunch tables
(for area)
Transfer lines,
roughing, four-
way, multiple,
screw machine-
lathing, and apex
drill (for pbz)
0.14 to 0.23
mg/m3 (area)
0.24 to 0.53
(PBZ)
These are
exposures to
MWF, not
dioxane
specifically
6 PBZ, 4 area
Full-shift
~ 7 hours
sample
time
Burton,
1997
Burton
and
Driscoll
(1997)
High
Used in
conjunction
with 1,4-
dioxane
weight
fraction to
estimate
inhalation
exposures
during use of
metalworking
fluids
Included -
7
Printing Inks
(3D)
Area
3-D printing
27 ppbv
1
Full-shift
8
Ryan &
Hubbard
,2016
Rvan and
Hubbard
(201 )
High
Used to
estimate
inhalation
exposures for
3-D printing
ink use
Included -
8
Film Cement
Area
and
Personal
Splicing
less than 1 ppm
4 pbz, 1 area
Full-shift
6 hours
Okawa,
1982
Okawa
and Cove
(1982)
High
Data used to
estimate
exposures for
film cement
application.
Page 379 of 616
-------
Rim
()i'i'll|>;iliiill;il
I".\|)IISIIIV
Sivn;iriii
T\ |K" ol'
S;illl|>k-
Worker .Uli\ il\
or S;iiii|)lin^
l.iii'iiliiui
l.4-l)iii\;iiu-
Airhiinu-
Ci uii i-iil nil inn
(msi/nr1) ¦'
NiiiiiIkt ill'
S;iiii|)k's
T\ |K" III'
Mi-;imiiviiu-iiI
S;illl|)k-
Tinu-
Si ill I'l l'
l);il;i
Idinlil'iiT
I'll Mil Dillil
r.Uniiliiui
;iihI
l'\:i ln:i 1 ii i n
Omt;iII I);iI;i
(|ii;ilil\ r;ilin»
I'l l Mil l);il;i
I'.Mriiiiiim
mill
l".\iiliiiiiimi
R;iliiin;ik- 1'nr
liH'lusiiin /
I'.M'liisiiui
9
Manufacturing
Personal
Unknown
provided in
report, most
less than 2
ug/sample
28
Full-shift
Time listed
for each
sample
BASF,
2016
BASF
(2016)
High
Included -
Data used to
estimate
exposures for
manufacturing
10
Manufacturing
Personal
Routine duties,
neutralization,
evaporator dump
0.39 ppm (15-
min STEL)
<0.056 ppm (8-
hour TWA)
38 ppm (15-min
STEL)
0.23 ppm (8-
hour TWA)
4
Short-term,
Full-shift
15-min
STEL, 8-
hour TWA
BASF,
2017
BASF
(2017)
High
Included -
Data used to
estimate
exposures for
manufacturing
11
Spray Foam
Application
Not
applicab
le -
Monitor
ing data
not
provided
a typical two-
story, 2,300-
square-foot
house with a
medium-pitch roof
— has a roof area
of about 1,500
square
feet
Not applicable
- Monitoring
data not
provided
Not
applicable -
Monitoring
data not
provided
Not applicable
- Monitoring
data not
provided
Not
applicable
Monitorin
g data not
provided
Huber,
2018
Huber
(2018)
Medium
Included -
Used as an
input in
calculations to
model
exposures
during spray
foam use
12
Spray Foam
Application
Not
applicab
le -
Monitor
ing data
not
provided
an average size
house is 1,500
square feet of
roofing
Not applicable
- Monitoring
data not
provided
Not
applicable -
Monitoring
data not
provided
Not applicable
- Monitoring
data not
provided
Not
applicable
Monitorin
g data not
provided
HomeA
dvisor,
2018
Home Ad
visor
(2018)
Medium
Included -
Used as an
input in
calculations to
model
exposures
during spray
foam use
13
Spray Foam
Application
Not
applicab
le -
Monitor
ing data
not
provided
Mix A-side and B-
side in 1:1 ratio
Not applicable
- Monitoring
data not
provided
Not
applicable -
Monitoring
data not
provided
Not applicable
- Monitoring
data not
provided
Not
applicable
Monitorin
g data not
provided
OMG
Roofing
Products
,2018
OMG
Roofing
ducts
(2018)
High
Included -
Used as an
input in
calculations to
model
exposures
Page 380 of 616
-------
l);il;i
Om'|';iII I>;i 1
()i'i'll|>;iliiill;il
I".\|)IISIIIV
Sivn;iriii
Worker .Uli\ il\
or S;iiii|)lin^
l.iii'iiliiui
l.4-l)io\;iiu-
Idinlil'iiT
(|ii;ilil\ |-;ilink-
('iiiH'iiilniliiui
S;iiii|)k's
Mi-;imiiviiu-iiI
Tinu-
r.Uniiliiui
I'.Mriiiiiim
(iiifi/m *) ¦'
;iihI
l'\:i ln:i 1 ii i n
mill
r.\iiiiiiiiimi
during spray
foam use
Not
applicab
le -
Monitor
ing data
not
provided
Not
Included -
14
Spray Foam
Application
0.1% 1,4-dioxane
in B-Side
Not applicable
- Monitoring
data not
provided
applicable -
Monitoring
data not
provided
Not applicable
- Monitoring
data not
provided
Not
applicable
Monitorin
g data not
provided
GAF,
2014
GAF
(2014)
High
Used as an
input in
calculations to
model
exposures
during spray
foam use
Included -
Manufacture,
Data used to
estimate
exposures for
dry film
lubrication
manufacture
and use
15
Dry Film
Lubrication
Area
and
personal
Application - also
provides specific
activity
descriptions
<0.031 to 50
ppm
25
8-hour TWA,
Short-term
tasks
8 hours,
varied
DOE,
2018a
DOE
(2018a)
High
Not
Not
applicable
Monitorin
g data not
provided
16
Dry Film
Lubrication
applicab
le -
Monitor
ing data
not
provided
Up to 10 workers
potentially
exposed.
Not applicable
- Monitoring
data not
provided
Not
applicable -
Monitoring
data not
provided
Not applicable
- Monitoring
data not
provided
DOE,
2018b
DOE
(2018b)
High
Included -
Used in dry
film
lubrication
scenario
Page 381 of 616
-------
G.1.2 Evaluation of Cross-Cutting Data Sources
EPA has reviewed acceptable sources for data that are relevant to all chemicals in this first wave of risk
evaluations under the amended TSCA according to the data quality evaluation criteria found in The
Application of Systematic Review in TSCA Risk Evaluations U.S. EPA. (2018b). Table G-2 summarizes
the results of this evaluation. The data quality evaluation indicated the sources included are of medium
to high confidence and are used to characterize the occupational inhalation exposures of 1,4-dioxane.
Table G-2. Summary of Cross-Cutting Data Sources
Uow
Data Source
Reference
Overall
Data quality
rating from
Data
Extraction
and
Evaluation
1
Chemical Data Reporting (CI)R) Data
(2016c)
High
2
RY 2016 Toxics Release Inventory (TRI) Data
U.S. EPA.
(2016e)
Medium
3
Defense Occupational and Environmental Health Readiness System -
Industrial Hygiene (DOEHRS-IH); Provided to EPA from DOD; 2018
DoD (2018)
High
4
Bureau of Labor Statistics (BLS). 2014b. Employee Tenure News
Release, September 18, 2014.
http://www.bls.gov/news.release/archives/tenure_09182014.htm
(Accessed February 19, 2016).
(2014)
High
5
Bureau of Labor Statistics (BLS). 2015. Hours and Employment by
Industry Tables - August 6, 2015. Available at
http://www.bls.gov/lpc/tables.htm (Accessed December 30, 2015).
(2015)
High
6
Census Bureau. 2012b. Code Lists and Crosswalks - Census 2012
Detailed Industry Code List. Available at
http://www.census.gov/people/io/methodology/ (Accessed January 28,
2016).
U.S. Census
N/Aa
Bureau
)
7
Census Bureau. 2016a. Survey of Income and Program Participation -
Data. Available at http://www.census.gov/programs-
surveys/sipp/data.html (Accessed February 1, 2016).
U.S. Census
Bureau
(2016a)
High
8
Census Bureau. 2016b. Survey of Income and Program Participation -
SIPP Introduction and History. Available at
http://www.census.gov/programs-surveys/sipp/about/sipp-introduction-
history.html (Accessed February 1, 2016).
U.S. Census
Bureau
(2016b)
N/Ab
9
Bureau of Labor Statistics (BLS). 2016. May 2016 Occupational
Employment and Wage Estimates: National Industry-Specific Estimates.
Available at http://www.bls.gov/oes/tables.htm (Accessed May 14,
2018).
(2016)
High
Page 382 of 616
-------
10
Census Bureau. 2015. Statistics of U.S. Businesses (SUSB). Available at
https://www.census.gov/data/tables/2015/econ/susb/2015-susb-
annual.html (Accessed May 14, 2018).
U.S. Census
Bureau
(2015")
High
11
Cherrie JW, Semple S, Brouwer D (2004) Gloves and dermal exposure
to chemicals: Proposals for Evaluating Workplace Effectiveness. Annals
of Occupational Hygiene 48: 607-615.
Cherrie et
al. (2004")
High
12
Dancik Y, Bigliardi PL, Bigliardi-Qi M (2015) What happens in the
skin? Integrating skin permeation kinetics into studies of developmental
and reproductive toxicity following topical exposure. Reproductive
Toxicology. 58: 252-281.
Dancik et
al. ( )
High
13
Environmental Protection Agency [EPA] (2013) ChemSTEER User
Guide: Chemical Screening Tool for Exposures and Environmental
Release.
U.S. EPA.
(2013b")
High
14
Frasch HF, Bunge AL (2015). The Transient Dermal Exposure II: Post-
Exposure Absorption and Evaporation of Volatile Compounds. Journal
of Pharmaceutical Sciences 104: 1499-1507.
Frasch. and
Bunge
(2015")
High
15
Frasch HF (2012). Dermal Absorption of Finite Doses of Volatile
Compounds. JPharm Sci. 2012 July; 101(7): 2616-2619.
Frasch
)
High
16
Frasch HF, Dotson GS, Barbero AM (2011). In Vitro Human Epidermal
Penetration of 1-Bromopropane. Journal of Toxicology and
Environmental Health, Part A, 74:1249-1260.
Frasch et al.
(901 n
\ wV/ 1 1 )
High
17
Garrod ANI, Phillips AM, Pemberton JA (2001). Potential Exposure of
Hands Inside Protective Gloves - a Summary of Data from Non-
Agricultural Pesticide Surveys. Ann. Occup Hyg., Vol. 45, No. 1, pp. 55-
60.
Garrod et
al. (2001")
High
18
Kasting GB, Miller MA (2006) Kinetics of finite dose absorption
through skin 2: Volatile Compounds. Journal of Pharmaceutical Sciences
95: 268-280.
Kasting and
Miller
(2006")
High
19
Marquart H, Franken R, Goede H, Fransman W, Schinkel (2017)
Validation of the dermal exposure model in ECETOC TRA. Annals of
Work Exposures and Health. 61: 854-871.
Marauart et
al. ( )
High
20
Baldwin, P. E., and A. D. Maynard. 1998. A Survey of Wind Speeds in
Indoor Workplaces. The Annals of Occupational Hygiene, 42(5), 303-
313.
Baldwin
and
Maynard
(1998")
High
a This is a crosswalk of codes. Does not provide data. Does not need to be evaluated.
b This is a history and introduction of the U.S. Census Bureau's SIPP program. Does not provide data. Does
not need to be evaluated.
Page 383 of 616
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G.2 Equations for Calculating Acute and Chronic Inhalation
Exposures
This report assessed 1,4-dioxane exposures to workers in occupational settings, presented as 8-
hour time weighted average (TWA). The 8-hour TWA exposures were used to calculate acute
exposure, average daily concentration (ADC) for chronic, non-cancer risks, and lifetime average
daily concentration (LADC) for chronic, cancer risks.
Acute workplace exposures were assumed to be equal to the contaminant concentration in air (8-
hour TWA), per Equation G-l.
Equation G-l
C X ED
AEC = —
acute
Where:
AEC = acute exposure concentration
C = contaminant concentration in air (8-hour TWA)
ED = exposure duration (8 hour/day)
ATacute = acute averaging time (8 hour/day)
ADC and LADC were used to estimate workplace chronic exposures for non-cancer and cancer
risks, respectively. These exposures were estimated as follows:
Equation G-2
C x ED x EF x WY
ADC or LADC = — —
AT or ATc
Where:
ADC = average daily concentration (8-hour TWA) used for chronic non-cancer risk
calculations
LADC = lifetime average daily concentration (8-hour TWA) used for chronic cancer risk
calculations
C = contaminant concentration in air (8-hour TWA)
ED = exposure duration (8 hour/day)
EF = exposure frequency (250 days/year, except where noted)
WY = exposed working years per lifetime (50th percentile = 31; 95th percentile = 40)
AT = averaging time, non-cancer risks (WY x 260 days/yr x 8 hour/day)
ATC = averaging time, cancer risks (LT x 260 days/year x 8 hour/day; where LT = 78
years)
Exposure Duration (ED)
EPA used an exposure duration of 8 hours per day for averaging full-shift exposures.
Page 384 of 616
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Exposure Frequency (EF)
Exposure frequency (EF) is expressed as the number of days per year a worker is exposed to the
chemical being assessed. In some cases, it could be reasonable to assume a worker is exposed to
the chemical on each working day. In other cases, it could be more appropriate to estimate a
worker's exposure to the chemical occurs during a subset of the worker's annual working days.
The relationship between exposure frequency and annual working days could be described as
follows:
Equation G-3
EF = fx AWD
Where:
EF = exposure frequency, the number of days per year a worker is exposed to the
chemical (day/yr)
f = fractional number of annual working days during which a worker is exposed to
the chemical (dimensionless)
AWD = annual working days, the number of days per year a worker works (day/yr)
BLS ) provides data on the total number of hours worked and total number of employees by
each industry NAICS code20. These data are available from the 3- to 6-digit NAICS level.
Dividing the total, annual hours worked by the number of employees yields the average number
of hours worked per employee per year for each NAICS.
EPA has identified approximately 140 NAICS codes applicable to the multiple conditions of use
for the ten chemicals currently undergoing risk evaluation. For each NAICS code of interest,
EPA looked up the average hours worked per employee per year at the more specific NAICS
code hierarchy {i.e., 4-digit, 5-digit, or 6-digit). EPA converted the working hours per employee
to working days per year per employee assuming employees work an average of eight hours per
day. The average number of days per year worked, or AWD, ranged from 169 to 282 days per
year, with a 50th percentile value of 250 days per year. EPA repeated this analysis for all NAICS
codes at the 4-digit level. The average AWD for all 4-digit NAICS codes ranges from 111 to 282
days per year, with a 50th percentile value of 228 days per year. Two hundred fifty days per year
is approximately the 75th percentile.
In the absence of industry-specific data, EPA assumed that the fractional number of annual
working days during which a worker is exposed to the 1,4-dioxane (f) is equal to one for all
conditions of use.
EPA used an exposure frequency of 250 days per year for all exposure scenarios in this
assessment with the exception of the import and re-packaging scenario. EPA estimated 1 to 18
sites could import and re-package 1,4-dioxane (see Section 2.4.1.1.2 for additional details).
20 NAICS is a 2- through 6-digit hierarchical classification system, offering five levels of detail. Each digit in the
code is part of a series of progressively narrower categories, and the more digits in the code signify greater
classification detail. The first two digits designate the economic sector, the third digit designates the sub sector, the
fourth digit designates the industry group, the fifth digit designates the NAtCS industry, and the sixth digit
designates the national industry.
Page 385 of 616
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These sites could receive the chemical in totes and may re-package it in bottles or drums. For
central tendency exposures, EPA assumed 18 sites and that each site repackaged into either
bottles or drums. Based on standard loading and unloading rates, EPA used an exposure
frequency of 2 days for sites that repackaged into bottles and 3 days for sites that repackaged into
drums to calculate ADC and LADC. For high-end exposures, EPA assumed 1 site re-packaged
into both bottles and drums. EPA used a weighted exposure frequency the account for 32 days
for re-packaging into bottles and 58 days for re-packaging into drums to calculate ADC and
LADC.
Working Years (WY)
Table G-3 lists the various worker exposure durations considered/recommended for risk and
exposure assessments. The variations in worker exposure duration could be caused by various
factors including issues of individual risk, population risk, type and nature of exposure, duration
of time at a single location, activity patterns, and other factors. A more realistic portrayal of the
reasonable length of exposure that would occur at the location(s) of maximal impact requires
consideration of newer data and assessment of more realistic exposure scenario.
Table G-3. Representative Worker Exposure Durations Considered for Risk Assessments
Worker Exposure
Duration (years)
Remarks
Reference
45
OSHA performed critical analysis and addressed
comments of American Chemistry Council (ACC),
Chamber of Commerce, and others.
Federal Register.
2016
40
Based on threshold of toxicological concern
classification to Cramer classes that requires detailed
knowledge about structural chemical classes.
Protective for a worker population, which consists
typically of people who are healthy and within
certain age limits.
ECETOC (2006}
30
-
Mallongi et al.
^ns, \u Ln. i)
25-30
-
Baciocchi et al.
(2010)
25
Supplemental guidance to provide a standard set of
default values that were intended to be used for
calculating reasonable maximum exposure levels for
use in exposure assessments when site-specific data
are lacking. Exposure assessments were based on
recommendations in Exposure Factors Handbook
>01laY
>014f.
)
25
Offsite worker based on point estimate and
stochastic risks. Risk assessments were conducted
OEB 312)
Page 386 of 616
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for different durations of exposure based on
estimates of how long people live at a single location
(9 years for the average, 30 years for a high-end
estimate, and 70 years for a lifetime).
20
Monte Carlo Analysis
Washburn et al.
8)
EPA utilized a triangular distribution for exposed working years per lifetime (also could be
referred as worker exposure duration) values considering the recent information available at the
Current Population Survey (CPS) from the Bureau of Labor Statistics (BLS), Survey of Income
and Program Participation (SIPP) and relevant resources from U.S. Census Bureau (Census). The
key parameters of the triangular distribution are following:
Minimum value: BLS CPS tenure data with current employer as a low-end estimate of the
number of lifetime working years: 10.4 years;
Mode value: The 50th percentile tenure data with all employers from SIPP as a mode value for
the number of lifetime working years: 36 years; and
Maximum value: The maximum average tenure data with all employers from SIPP as a high-end
estimate on the number of lifetime working years: 44 years.
This triangular distribution revealed a 50th percentile value of 31 years and a 95th percentile value
of 40 years. These values were used for central tendency and high-end ADC and LADC
calculations, respectively (see Appendix G.4 on Modeling Approach and Parameters for High-
end and Central Tendency Inhalation Exposure Estimates).
The BLS 2014) provided information on employee tenure with current employer obtained from
the CPS. The CPS is a monthly sample survey of about 60,000 households that provides
information on the labor force status of the civilian non-institutional population age 16 and over;
CPS data are released every two years. The data are available by demographics and by generic
industry sectors but are not available by NAICS codes.
The U.S. Census' 2.016a) SIPP provided information on lifetime tenure with all employers. SIPP
is a household survey that collects data on income, labor force participation, social program
participation and eligibility, and general demographic characteristics through a continuous series
of national panel surveys of between 14,000 and 52,000 households isus Bureau
(2016b). EPA analyzed the 2008 SIPP Panel Wave21 1, a panel that began in 2008 and covers the
interview months of September 2008 through December 2008 U.S. Census Bureau (2016a. b).
For this panel, lifetime tenure data are available by Census Industry Codes, which could be
cross-walked with NAICS codes.
21 SIPP is administered in panels and conducted in waves. Within a SIPP panel, the entire sample is interviewed over
a 4-year period which includes a group of annual interviews conducted during a 4-month period. These groups of
interviews are called waves. The first time an interviewer contacts a household is Wave 1; the second time is Wave
2, and so forth.
Page 387 of 616
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SIPP data included fields for the industry in which each surveyed, size and characteristics of this
population, work patterns, worker age, and years of work experience with all employers over the
surveyed individual's lifetime.22 Census household surveys used different industry codes than the
NAICS codes used in its firm surveys, so these were converted to NAICS using a published
crosswalk U.S. Census Bureau (2012). EPA calculated the average tenure for the following age
groups: 1) workers age 50 and older; 2) workers age 60 and older; and 3) workers of all ages
employed at time of survey. EPA used tenure data for age group "50 and older" to determine the
high-end lifetime working years, because the sample size in this age group is often substantially
higher than the sample size for age group "60 and older". For some industries, the number of
workers surveyed, or the sample size, was too small to provide a reliable representation of the
worker tenure in that industry. The data with sample size of less than five were excluded from
this analysis.
Table G-4 summarized the average tenure for workers age 50 and older from SIPP data.
Although the tenure could differ for any given industry sector, no significant variability was
observed between the 50th and 95th percentile values of average tenure across manufacturing and
non-manufacturing sectors.
Table G-4. Overview of Average Worker Tenure from U.S. Census SIPP (Age Group 50+
Industry Sectors
Working Years
Average
50,h
Percentile
95"'
Percentile
Maximum
\11 industry sectors relevant to the
10 chemicals undergoing risk
evaluation
35.9
36
39
44
Manufacturing sectors (NAICS 31-
33)
35.7
36
39
40
Non-manufacturing sectors
(NAICS 42-81)
36.1
36
39
44
Source: U.S. Census Bureau (2016a")
Note: Industries where sample size is less than five are excluded from this analysis.
BLS CPS data provided the median years of tenure that wage and salary workers had been with
their current employer. Table G-5 presented CPS data for all demographics (men and women) by
age group from 2008 to 2012. To estimate the low-end value on number of working years, EPA
used the available recent' r ^ s ) CPS data for workers age 55 to 64 years, which
indicated a median tenure of 10.4 years with their current employer. The use of this low-end
value represented a scenario where workers were only exposed to the chemical of interest for a
portion of their lifetime working years, as they could change job(s) or move from one industry to
another throughout their career.
22 The number of years of work experience was calculated considering the difference between the year first worked
and the current data year (i.e., 2008). Any intervening months, when not working, were subtracted thereafter.
Page 388 of 616
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Table G-5. Median Years of Tenure with Current Employer by Age Group
Age
January 2008
January 2010
January 2012
January 2014
16 years and over (<25)
4.1
4.4
4.6
4.6
16 to 17 years
0.7
0.7
0.7
0.7
18 to 19 years
0.8
1.0
0.8
0.8
20 to 24 years
1.3
1.5
1.3
1.3
25 years and over (<65)
5.1
5.2
5.4
5.5
25 to 34 years
2.7
3.1
3.2
3.0
35 to 44 years
4.9
5.1
5.3
5.2
45 to 54 years
7.6
7.8
7.8
7.9
55 to 64 years
9.9
10.0
10.3
10.4
65 years and over
10.2
9.9
10.3
10.3
Source: BLS (2014)
G.3 Sample Calculations for Calculating Acute and Chronic
Inhalation Exposures
Sample calculations for high-end and central tendency acute and chronic exposure
concentrations for one setting, Industrial Uses, are demonstrated below. The explanation of the
equations and parameters used is provided in Appendix G.2. The final values will have two
significant figures since they are based on values from modeling.
G.3.1 Example High-End ADC and LADC
Calculate AEChe:
Calculate ADChe:
CHE x ED
AEChe =
AT,
acute
20H!|x
_ m3 day
At lhe — zz
8
day
mg
AEChe = 20—r-
Mb m3
CHE xEDxEF x EWY
ADChe =
AT
Page 389 of 616
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20 x 8-^x 250^^x 40years mn
m3 day year J _ mg
Uo years x 260^x8^-)
\ 7 year day J
Calculate LADChe:
CHE xEDxEFx EWY
LADChe =
AT,
LADC
20 x 8-t— x 250^^ x 40 years mn
m3 day year * _ccm9
HE~ (78 years x 260^X8^1)
\ 7 year day J
G.3.2 Example Central Tendency ADC and LADC
Calculate AECct:
Cct x ED
AECct =
AT
ri1 acute
5mgxehr_
m3 day
AtLCT — j—
8
day
mg
AECct = 5—-
m3
Calculate ADCct:
Cct xEDxEFx EWY
ADCct = -±L~
AT.
ADC
5mx8 *>L x 250^x31 years
m3 day year * _ mg
CT IsiyearsxlM^xB^i)
\ 7 year day J
Calculate LADCct:
Page 390 of 616
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CCT xEDxEFx EWY
LADCct = —
AT,
LADC
5 mx 8tolx25o^x31 years
m3 day year J _ mg
LADCct = ~r " T* E r~ = L9
78yearsx 260^X8^)
V 17 year day J
3
G.4 Modeling Approach and Parameters for High-End and Central
Tendency Inhalation Exposure Estimates for Import and
Repackaging, Functional Fluids (Open System), Spray Foam
Application, and Disposal
This appendix presents the approach for high-end and typical inhalation exposure estimation. This
approach is based on the application of established EPA AP-42 Loading Model, EPA Mass Balance Model
(Fehrenbacher, M.C.), and Monte Carlo simulation.
This approach is intended to assess air releases and associated inhalation exposures associated with
interior container loading scenarios at industrial and commercial facilities. Inhalation exposure to
chemical vapor is a function of physical properties of substance, various EPA default constants, and other
model parameters. While physical properties are fixed for a substance, some model parameters, such as
ventilation rate (Q), mixing factor (k) and vapor saturation factor (f), are expected to vary from one facility
to another. This approach addresses variability for these parameters using a Monte Carlo simulation.
An individual model input parameter could either have a discrete value or a distribution of values. EPA
assigned statistical distributions based on available literature data or engineering judgment to address the
variability in Q, k, f, and exposed working years per lifetime (WY). A Monte Carlo simulation (a type of
stochastic simulation) was conducted to capture variability in the model input parameters. The simulation
was conducted using the Latin hypercube sampling, a statistical method for generating a near-random
sample of parameter values from a multidimensional distribution, in @RISK Industrial Edition, Version
7.0.0 (Palisade, Ithaca, New York). The Latin hypercube sampling method is a statistical method for
generating a sample of possible values from a multi-dimensional distribution forces the samples drawn to
correspond more closely with the input distribution and thus converges faster on the true statistics of the
input distribution. Latin hypercube sampling is a stratified method, meaning it guarantees that its
generated samples are representative of the probability density function (variability) defined in the model.
EPA performed 100,000 iterations of the model to capture the range of possible input values {i.e.,
including values with low probability of occurrence).
From the distribution resulted from the Monte Carlo simulation, the 95th and 50th percentile values are
selected to represent a high-end exposure, and central tendency exposure level respectively. The statistics
were calculated directly in @RISK. The following subsections detail the model design equations and
parameters used for Inhalation exposure estimates.
G.4.1 Model Design Equations
The EPA Mass Balance Model includes the following equations for estimating mass concentration of the
chemical vapor in air (mg/m3):
Page 391 of 616
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Equation G-4
MW
— C v X
Vm
Where
Cm = =mass concentration of chemical vapor in air [mg/m3]
Cv = =volumetric concentration of chemical vapor in air [ppm]
MW= molecular weight of chemical [g/mol]
Vm =molar volume [L/mol]
Equation G-5
170,000 xTxG
Cv ~ MW xQxk
T = temperature [K]
G = average vapor generation rate [gm/sec]
MW = molecular weight of chemical [g/mol]
Q = ventilation rate [ftVmin]
k = mixing factor [Dimensionless]
Average vapor generation rate needed for EPA Mass Balance Model, is calculated from following EPA
AP-42 Loading Model:
Equation G-6
f x MW x (3,785.4 x Vc) x r x X x (jgfi)
G =
3,600 xTxR
G = average vapor generation rate [gm/sec]
f = saturation factor [Dimensionless]
MW= molecular weight of chemical [g/mol]
Vc =container volume [gallon]
r =container loading/unloading rate [number of containers/hr]
X =vapor pressure correction factor [ Dimensionless], assumed to be equal to weight fraction of
component
VP = vapor pressure (at temperature, T) [mm Hg]
T = temperature [K]
R = universal gas constant [atm-cm3/mol-K]
Mass concentration of the chemical vapor in air calculated from Equation G-4, subsequently used in
following equations to estimate acute exposure concentration (AEC), average daily concentration (8-hour
TWA) used for chronic non-cancer risk calculations (ADC) and lifetime average daily concentration (8-
hour TWA) used for chronic cancer risk calculations (LADC):
Equation G-7
C X ED
AEC = —
acute
Where:
Page 392 of 616
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AEC = acute exposure concentration [mg/m3]
C = contaminant concentration in air (8-hour TWA) [mg/m3]
ED = exposure duration [hr/day]
ATacute = acute averaging time [hr/day]
ADC and LADC are used to estimate workplace chronic exposures for non-cancer and cancer risks,
respectively. These exposures are estimated as follows:
Equation G-8
ADC orLADC =
C x ED x EF x WY
AT orATC
= average daily concentration (8-hour TWA) used for chronic non-cancer risk calculations
Where:
ADC
[mg/m3]
LADC = lifetime average daily concentration (8-hour TWA) used for chronic cancer risk
calculations [mg/m3]
C = contaminant concentration in air (8-hour TWA) [mg/m3]
ED = exposure duration [hour/day]
EF = exposure frequency [days/yr]
WY = exposed working years per lifetime [yr/LT]
AT = averaging time, non-cancer risks [hr]
ATC = averaging time, cancer risks [hr]
Equation G-9
AT = WY X 260
d i
hr
x 8
day
yr
AT = averaging time, non-cancer risks [hr]
WY = exposed working years per lifetime [yr/LT]
Equation G-10
ATc = LTX 260
d i
hr
x 8
day
yr
ATC = averaging time, cancer risks [hr]
LT= lifetime = 78 [yr]
Refer to Appendix G.2 for equations used to calculate acute and chronic inhalation exposures, details
about Equation G-8 and Equation G-9, and the basis for various parameters used in the calculations.
G.4.2 Model Parameters
Table G-6 summarizes the model parameters and their values for the Monte Carlo simulation. High-end
and typical exposure are estimated by selecting the 50th and 95th percentile values from the output
distribution.
Page 393 of 616
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Table G-6. Summary of Parameter Values and Distributions Used in the Inhalation Exposure Model
Constant
Model
Parameter
Values
Variable Model Parameter Values
Input Parameter
Symbol
Unit
Rational / Basis
Value
Basis
Lower
Upper
Mode
Distributio
Bound
Bound
n Type
Molecular Weight
MW
g/mol
88.1
—
—
—
—
—
Physical Property
Physical Property. The vapor pressure of 1,4-
Vapor Pressure
VP
mm Hg
—
30
40
—
—
dioxane was needed at 293K (30 minHg) and
at 298K (40 mmHg).
Molar Volume at 298
K
Vm
L/mol
24.45
—
—
—
—
—
Physical Constant
Gas Constant
R
atm-cm3/mol-
K
82.05
—
—
—
—
—
Temperature
T
K
298
—
—
—
—
—
Process Parameter
Container Volume
Vc
gallons
1 or 55
—
—
—
—
—
Value is determined by the selected container
type for given exposure scenario
Container
Loading/Unloading
Rate
r
Containers / lir
20 or
60
—
—
—
—
—
Value is determined by the selected container
type
Ventilation Rate23
Q
ft3/min
—
—
500
10000
3000
Triangular
1. General ventilation rates in industry ranges
Mixing Factor
k
Dimensionless
—
—
0.1
1
0.5
Triangular
from a low of 500 ft3/min to over 10,000
ft3/min; a typical value is 3,000.
2. Mixing Factor ranges from 0.1 to 1.
3. Saturation factor ranges from 0.5 for
submerged loading to 1.45 for splash loading.
Saturation Factor
f
Dimensionless
0.5
1.45
0.5
Triangular
Underlying distribution of these parameters
are not known, EPA assigned triangular
distributions, since triangular distribution
requires least assumptions and is completely
defined by range and mode of a parameter.
23 Ventilation rate procedure is a prescriptive design procedure in which air rates are dependent on space type, occupancy, and floor area. Airflow for ventilation could be
calculated by various methods including area method, air change method, occupancy method, and heat removal method.
Page 394 of 616
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Input Parameter
Symbol
Unit
Constant
Model
Parameter
Values
Variable Model Parameter Values
Rational / Basis
Value
Basis
Lower
Bound
Upper
Bound
Mode
Distributio
n Type
(ASHRAE. 2016 ; ACGIH. 2019)
Vapor Pressure
Correction Factor
X
Dimensionless
1
—
—
—
—
—
For Import & Repackaging and Disposal
Vapor Pressure
Correction Factor
X
Dimensionless
0.001
—
—
—
—
—
For Functional Fluids (open System) and
Spray Foam Application
Exposed Working
Years per Lifetime
MY
years
—
—
10
44
31
Triangular
See Appendix G.2 of this Report
Contaminant
concentration in air
(8-hour TWA)
C
mg/m3
—
—
—
—
—
Calculated
Refer Appendix G.2 for "Equations for
Calculating Acute and Chronic Inhalation
Exposures"
Exposure Duration
ED
lir/day
8
—
—
—
—
—
Acute averaging
Time
A t'acute
lir/day
8
—
—
—
—
—
Averaging Time,
non-cancer risks
AT
hr
—
—
—
—
—
Calculated
Averaging Time,
cancer risks
ATC
hr
—
—
—
—
—
Calculated
Exposure Frequency
EF
days/yr
250
—
—
—
—: Not Applicable
Page 395 of 616
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G.4.3 Sample Monte Carlo Simulation Result
Average Daily Concentration (ADC)
35%
30%
25%
S- 20%
15%
10%
5%
0% I-
0.0
50th Percentile Value = 0.36 mg/m3
95th Percentile Value = 0.93 mg/m3
1—1-
0.5
1.0
ADC (mg/m3)
1.5
2.0
Figure G-l. Example of Monte Carlo Simulation results for the Disposal Scenario
G.5 Approach for Estimating the Number of Workers
This appendix summarizes the methods that EPA used to estimate the number of workers who
are potentially exposed to 1,4-dioxane in each of its conditions of use. The method consists of
the following steps:
Identify the North American Industry Classification System (NAICS) codes for the industry
sectors associated with each condition of use.
Estimate total employment by industry/occupation combination using the Bureau of Labor
Statistics' Occupational Employment Statistics (OES) data BLS (2016).
Refine the OES estimates where they are not sufficiently granular by using the U.S. Census'
2016b) Statistics of U.S. Businesses (SUSB) data on total employment by 6-digit NAICS.
Estimate the percentage of employees likely to be using 1,4-dioxane instead of other chemicals
{i.e., the market penetration of 1,4-dioxane in the condition of use).
Estimate the number of sites and number of potentially exposed employees per site.
Estimate the number of potentially exposed employees within the condition of use.
Step 1: Identifying Affected NAICS Codes
Page 396 of 616
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As a first step, EPA identified NAICS industry codes associated with each condition of use. EPA
generally identified NAICS industry codes for a condition of use by:
Querying the U.S. Census Bureau's NAICS Search tool using keywords associated with each
condition of use to identify NAICS codes with descriptions that match the condition of use.
Referencing EPA Generic Scenarios (GS's) and Organisation for Economic Co-operation and
Development (OECD) Emission Scenario Documents (ESDs) for a condition of use to identify
NAICS codes cited by the GS or ESD.
Reviewing Chemical Data Reporting (CDR) data for the chemical, identifying the industrial
sector codes reported for downstream industrial uses, and matching those industrial sector codes
to NAICS codes using Table D-2 provided in the CDR reporting instructions.
Each condition of use section in the main body of this report identifies the NAICS codes EPA
identified for the respective condition of use.
Step 2: Estimating Total Employment by Industry and Occupation
BLS's 2016) OES data provide employment data for workers in specific industries and
occupations. The industries are classified by NAICS codes (identified previously), and
occupations are classified by Standard Occupational Classification (SOC) codes.
Among the relevant NAICS codes (identified previously), EPA reviewed the occupation
description and identified those occupations (SOC codes) where workers are potentially exposed
to 1,4-dioxane. Table G-7 shows the SOC codes EPA classified as occupations potentially
exposed to 1,4-dioxane. These occupations are classified into workers (W) and occupational non-
users (O). All other SOC codes are assumed to represent occupations where exposure is unlikely.
Table G-7. SOCs with Worker and ONU Designations for All Conditions of Use Except
Dry Cleaning
SOC
Occupation
Designation
11-9020
Construction Managers
O
17-2000
Engineers
O
17-3000
Drafters, Engineering Technicians, and Mapping Technicians
0
19-2031
Chemists
0
19-4000
Life, Physical, and Social Science Technicians
0
47-1000
Supervisors of Construction and Extraction Workers
0
47-2000
Construction Trades Workers
w
49-1000
Supervisors of Installation, Maintenance, and Repair Workers
0
49-2000
Electrical and Electronic Equipment Mechanics, Installers, and
Repairers
w
49-3000
Vehicle and Mobile Equipment Mechanics, Installers, and Repairers
w
49-9010
Control and Valve Installers and Repairers
w
49-9020
Heating, Air Conditioning, and Refrigeration Mechanics and Installers
w
49-9040
Industrial Machinery Installation, Repair, and Maintenance Workers
w
49-9060
Precision Instrument and Equipment Repairers
w
Page 397 of 616
-------
49-9070
Maintenance and Repair Workers, General
W
49-9090
Miscellaneous Installation, Maintenance, and Repair Workers
W
51-1000
Supervisors of Production Workers
O
51-2000
Assemblers and Fabricators
w
51-4020
Forming Machine Setters, Operators, and Tenders, Metal and Plastic
w
51-6010
Laundry and Dry-Cleaning Workers
w
51-6020
Pressers, Textile, Garment, and Related Materials
w
51-6030
Sewing Machine Operators
0
51-6040
Shoe and Leather Workers
0
51-6050
Tailors, Dressmakers, and Sewers
0
51-6090
Miscellaneous Textile, Apparel, and Furnishings Workers
0
51-8020
Stationary Engineers and Boiler Operators
w
51-8090
Miscellaneous Plant and System Operators
w
51-9000
Other Production Occupations
w
W = worker designation
O = ONU designation
For dry cleaning facilities, due to the unique nature of work expected at these facilities and that
different workers may be expected to share among activities with higher exposure potential (e.g.,
unloading the dry-cleaning machine, pressing/finishing a dry-cleaned load), EPA made different
SOC code worker and ONU assignments for this condition of use. Table G-8 summarizes the
SOC codes with worker and ONU designations used for dry cleaning facilities.
Table G-8. SOCs with Worker and ONU Designations for Dry Cleaning Facilities
SOC
Occupation
Designation
41-2000
Retail Sales Workers
O
49-9040
Industrial Machinery Installation, Repair, and Maintenance Workers
w
49-9070
Maintenance and Repair Workers, General
w
49-9090
Miscellaneous Installation, Maintenance, and Repair Workers
w
51-6010
Laundry and Dry-Cleaning Workers
w
51-6020
Pressers, Textile, Garment, and Related Materials
w
51-6030
Sewing Machine Operators
0
51-6040
Shoe and Leather Workers
0
51-6050
Tailors, Dressmakers, and Sewers
0
51-6090
Miscellaneous Textile, Apparel, and Furnishings Workers
0
W = worker designation
O = ONU designation
After identifying relevant NAICS and SOC codes, EPA used BLS data to determine total
employment by industry and by occupation based on the NAICS and SOC combinations. For
example, there are 110,640 employees associated with 4-digit NAICS 8123 (Drycleaning and
Laundry Services) and SOC 51-6010 (Laundry and Dry-Cleaning Workers).
Using a combination of NAICS and SOC codes to estimate total employment provides more
accurate estimates for the number of workers than using NAICS codes alone. Using only NAICS
codes to estimate number of workers typically result in an overestimate, because not all workers
employed in that industry sector will be exposed. However, in some cases, BLS only provide
Page 398 of 616
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employment data at the 4-digit or 5-digit NAICS level; therefore, further refinement of this
approach may be needed (see next step).
Step 3: Refining Employment Estimates to Account for lack of NAICS Granularity
The third step in EPA's methodology was to further refine the employment estimates by using
total employment data in the U.S. Census Bureau's 2016b) SUSB. In some cases, BLS OES's
occupation-specific data are only available at the 4-digit or 5-digit NAICS level, whereas the
SUSB data are available at the 6-digit level (but are not occupation-specific). Identifying specific
6-digit NAICS will ensure that only industries with potential 1,4-dioxane exposure are included.
As an example, OES data are available for the 4-digit NAICS 8123 Dryclecming and Laundry
Services, which includes the following 6-digit NAICS:
NAICS 812310 Coin-Operated Laundries and Drycleaners;
NAICS 812320 Drycleaning and Laundry Services (except Coin-Operated);
NAICS 812331 Linen Supply; and
NAICS 812332 Industrial Launderers.
In this example, only NAICS 812320 is of interest. The Census data allow EPA to calculate
employment in the specific 6-digit NAICS of interest as a percentage of employment in the BLS
4-digit NAICS.
The 6-digit NAICS 812320 comprises 46% of total employment under the 4-digit NAICS 8123.
This percentage can be multiplied by the occupation-specific employment estimates given in the
BLS OES data to further refine our estimates of the number of employees with potential
exposure.
Table G-9 illustrates this granularity adjustment for NAICS 812320.
Table G-9. Estimated Number of Potentially Exposed Workers and ONUs under NAICS
812320
NAIC
S
soc
CODE
SOC Description
Occupation
Designation
Employment
by SOC at 4-
digit NAICS
level
% of Total
Employmen
t
Estimated
Employmen
t by SOC at
6-digit
NAICS level
8123
41-2000
Retail Sales Workers
O
44,500
46.0%
20,459
Page 399 of 616
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8123
49-9040
Industrial Machinery
Installation, Repair, and
Maintenance Workers
W
1,790
46.0%
823
8123
49-9070
Maintenance and Repair
Workers, General
W
3,260
46.0%
1,499
8123
49-9090
Miscellaneous Installation,
Maintenance, and Repair
Workers
W
1,080
46.0%
497
8123
51-6010
Laundry and Dry-Cleaning
Workers
W
110,640
46.0%
50,867
8123
51-6020
Pressers, Textile, Garment,
and Related Materials
W
40,250
46.0%
18,505
8123
51-6030
Sewing Machine Operators
O
1,660
46.0%
763
8123
51-6040
Shoe and Leather Workers
0
Not Reported for this NAICS Code
8123
51-6050
Tailors, Dressmakers, and
Sewers
0
2,890
46.0%
1,329
8123
51-6090
Miscellaneous Textile,
Apparel, and Furnishings
Workers
0
0
46.0%
0
Total Potentially Exposed Employees
206,070
94,740
Total Workers
72,190
Total Occupational Non-Users
22,551
Note: numbers may not sum exactly due to rounding.
W = worker
O = occupational non-user
Source :BLS ( . msus Bureau (2016b")
Step 4: Estimating the Percentage of Workers Using 1,4-Dioxane Instead of Other
Chemicals
In the final step, EPA accounted for the market share by applying a factor to the number of
workers determined in Step 3. This accounts for the fact that 1,4-dioxane may be only one of
multiple chemicals used for the applications of interest. EPA was unable to identify market
penetration data for any of the conditions of use. In the absence of market penetration data for a
given condition of use, EPA assumed 1,4-dioxane may be used at up to all sites and by up to all
workers calculated in this method as a bounding estimate. This assumes a market penetration of
100%. Market penetration is discussed for each condition of use in the main body of this report.
Step 5: Estimating the Number of Workers per Site
EPA calculated the number of workers and occupational non-users in each industry/occupation
combination using the formula below (granularity adjustment is only applicable where SOC data
are not available at the 6-digit NAICS level):
Number of Workers or ONUs in NAICS/SOC (Step 2) x Granularity Adjustment Percentage
(Step 3) = Number of Workers or ONUs in the Industry/Occupation Combination
EPA then estimated the total number of establishments by obtaining the number of
establishments reported in the U.S. Census Bureau's SUSB 2016b) data at the 6-digit NAICS
level.
Page 400 of 616
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EPA then summed the number of workers and occupational non-users over all occupations
within a NAICS code and divided these sums by the number of establishments in the NAICS
code to calculate the average number of workers and occupational non-users per site.
Step 6: Estimating the Number of Workers and Sites for a Condition of Use
EPA estimated the number of workers and occupational non-users potentially exposed to 1,4-
dioxane and the number of sites that use 1,4-dioxane in a given condition of use through the
following steps:
Obtaining the total number of establishments by:
Obtaining the number of establishments from SUSB 2016b) at the 6-digit NAICS level (Step 5)
for each NAICS code in the condition of use and summing these values; or
Obtaining the number of establishments from the Toxics Release Inventory (TRI), Discharge
Monitoring Report (DMR) data, National Emissions Inventory (NEI), or literature for the
condition of use.
Estimating the number of establishments that use 1,4-dioxane by taking the total number of
establishments from Step 6. A and multiplying it by the market penetration factor from Step 4.
Estimating the number of workers and occupational non-users potentially exposed to 1,4-dioxane
by taking the number of establishments calculated in Step 6.B and multiplying it by the average
number of workers and occupational non-users per site from Step 5.
Page 401 of 616
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G.6 Occupational Exposure Scenario Grouping
OES grouping corresponds to the defined use scenarios for the occupational exposure
assessment.
Table G-10. Occupational Exposure Scenario Groupings
Life Cycle S(a«e
Category
Subcategory
OLS Grouping
Manufacture
Domestic Manufacture
Domestic Manufacture
Manufacturing
Manufacture
Import
Import
Import and
Repackaging
Repackaging
Processing
Recycling
Recycling
Non-Incorporative
Pharmaceutical and
medicine manufacturing
(process solvent)
Processing
Basic organic chemical
manufacturing (process
solvent)
Processing as a
reactant
Pharmaceutical
intermediate
Polymerization catalyst
Agricultural chemical
intermediate
Intermediate Use
Plasticizer intermediate
Industrial Use
Catalysts and reagents for
anhydrous acid reactions,
brominations and
sulfonations
Industrial Use
Wood pulping24
Extraction of animal and
vegetable oils20
Processing aids, not
otherwise listed
Wetting and dispersing
agent in textile
processing20
Purification of
pharmaceuticals
Etching of fluoropolymers
Industrial Use
Metalworking fluid
24 These uses were evaluated but are likely not current uses of 1,4-dioxane.
Page 402 of 616
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Functional Fluids,
Open System
Cutting and Tapping Fluid
Polyalkylene Glycol Fluid
Functional Fluids,
Open System
Industrial Use
Functional Fluids,
Closed System a
Hydraulic Fluid a
Functional Fluids,
Closed System a
Industrial Use,
Potential
Commercial Use
Laboratory Chemicals
Chemical Reagent
Reference material
Spectroscopic and
photometric measurement
Liquid scintillation
counting medium
Stable Reaction medium
Cryoscopic solvent for
molecular mass
determinations
Preparation of histological
sections for microscopic
examination
Laboratory Chemicals
Industrial Use,
Potential
Commercial Use
Adhesives and
Sealants
Film Cement
Film Cement
Industrial Use,
Potential
Commercial Use
Other Uses
Spray Polyurethane Foam
Spray Application
Industrial Use,
Potential
Commercial Use
Other Uses
Printing and Printing
Compositions
Use of Printing Inks
(3D)
Industrial Use,
Potential
Commercial Use
Other Uses
Dry Film Lubricant
Dry Film Lubricant
Disposal
Disposal
Wastewater
Underground Injection
Landfill
Recycling
Incineration
Disposal
a EPA did not find evidence to support the intended use of 1,4-dioxane in closed-system functional fluids;
therefore, occupational exposures and environmental releases were not assessed for this scenario. See Section
2.4.1.1.6.
Page 403 of 616
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G.6.1 Manufacturing
There are three methods to produce 1,4-dioxane, but it is typically manufactured for industrial
purposes via an acid-catalyzed conversion of ethylene glycols in a closed system. The other two
methods25 are used to make substituted 1,4-dioxane and are not known to be used for industrial
production ECJRC (2002).
A typical acid-catalyzed conversion of ethylene glycols process is carried out in a heated vessel
at a temperature between 266 and 392 °F (130 and 200 °C) and a pressure between 0.25 and 1.1
atm (25 and 1 10 kPa) ECJRC (2002). At the BASF Facility in Zachary, Louisiana, 1,4-dioxane is
produced using this method with diethylene glycol and concentrated sulfuric acid (Figure G-2).
After synthesis, 1,4-dioxane is further purified in a multi-step process that includes multiple
distillation and neutralization steps to remove water and volatile byproducts BASF (: ).
Feed
Tank
Feed
Tank
Final
Product
Tank
Storage
Reactor
Condenser
Neutralizer
Tank
Settling
Tank
Distillation
Column
Evaporator
Boiler
Multiple
Distillation Steps
Figure G-2. Generic Manufacturing Process Flow Diagram
Source: Modeled after BASF (2017')
Number of Potentially Exposed Workers and Occupational Non-Users
The CDR 016c) reports two manufacturing sites, each reporting 50 to 100 workers.
Based on data from the Bureau of Labor Statistics (BLS) for NAICS code 325199 (All Other
Basic Organic Chemical Manufacturing and related SOC codes), there could be an average of 39
workers and 19 ON Us per site U.S. EPA. (2016c). The BLS data indicated that there could be an
25 Substituted 1,4-Dioxane can be prepared by ring closure of 2-chloro-2'-hydroxydiethyl ether through heating with
20% sodium hydroxide, and by catalyzed cyclo-dimerization of ethylene oxide either over NaHSO/i, SiF4, or BF3, or
at an elevated temperature with an acidic cation-exchange resin.
Page 404 of 616
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average of 57 potentially exposed workers and ONUs per site, which is consistent with the range
reported in CDR 2016c). Using the BLS data, EPA estimated that 78 workers and 36 ONUs
could be exposed over all sites that manufacture 1,4-dioxane in the U.S., 2018, BASF provided
additional information regarding the manufacture of 1,4-dioxane. In this public comment, BASF
indicated that the Zachary, Louisiana site would cease manufacturing of 1,4-dioxane by the end
of 2018; and BASF might direct its customers to import the chemical from a BASF site in
Germany. Though the public comment stated that BASF is the sole domestic producer of 1,4-
dioxane, CDR 2016c) lists a second domestic manufacturer; therefore, EPA assesses exposures
from the two 1,4-dioxane manufacturing sites in the US BASF (2018a; U.S. EPA. (2016c).
Worker and Occupational Non-User Activities
BASF provided limited monitoring data related to certain steps in the production process, such as
neutralization and evaporator dumping. However, specific descriptions of these worker tasks
were not provided p \SF (201 ). The European Union Risk Assessment Report ECJRC (2002.)
provided detailed description of the 1,4-Dioxane manufacturing processes at the sites in Europe.
The report stated that the primary ways workers could be exposed are during drumming,
maintenance, sampling, and from the system "breathing." Dermal and inhalation exposures are
expected during drumming from connecting and disconnecting the transfer line, and during any
leakages 002).
ONUs include employees that work at the site where 1,4-dioxane is manufactured, but they do
not directly handle the chemical and are therefore expected to have lower exposures. ONUs for
manufacturing include supervisors, managers, and tradesmen that may be in the manufacturing
area, but do not perform tasks that result in the same level of exposures as production workers.
Worker and Occupational Non-User Exposure Assessment
EPA used full-shift, personal breathing zone (PBZ) monitoring data provided by BASF to assess
occupational inhalation exposures. These data ranged from 2006 to 2011 and covered the
manufacturing facility under two different corporate ownerships, Ferro Corp and BASF. BASF
also provided monitoring data in a public comment from 2017. The public comment states that
these data are from "periodic monitoring of employees performing tasks that could present
exposure to Dioxane" V* L • ,-\Q! *.'.)• EPA assumed that these monitoring data were originated
via PBZ measurements. In addition, EPA reviewed European manufacturing monitoring data
cited in the European Union Risk Assessment ECJRC (2002) for 1,4-dioxane ranging between
1976 to 1998. After the review, EPA chose monitoring data from the more recent time period in
this risk evaluation that are representative of U.S. manufacturing over the older European data.
The production monitoring data of 1,4-dioxane from BASF plant at Zachary, Louisiana is
summarized in Table G-l 1 '17). BASF 2016) provided additional monitoring data from
multiple Industrial Hygiene Analyses (IHA) reports from 2008 to 2011. It also provided
monitoring data from 2006 and 2007 from the previous owner of the manufacturing site (Ferro
Corp), but did not provide job descriptions, exposure sources, or possible engineering controls
used in relation to these data points to refine the exposure assessment BASF (2016). The data are
summarized in Table G-12.
Page 405 of 616
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Tsihlc Ci-I I 2017 l.4-l)i»\;iiu' Production Monitoring
Date Monitored
Process Tiisk Monitored
Res
ppm
nils
Sample Tjpe
2/24/2017
Neutralization step
0.39
1.4
15-min TWA
2/24/2017
Routine duties during production
(including neutralization step)
<0.056
<0.20
8-hour TWA
2/28/2017
Evaporator dump step
38
137
15-min TWA
2/28/2017
Routine duties during production
(including evaporator dump step)
0.23
0.828
8-hour TWA
a Calculated using 3.6 (mg/m3)/ppm conversion factor NIOSH (2005)
Source: F (2.017-)
Table (>-12. 2007-2011 1.4-l)io\:ino Production Monitoring l):it;i
Report
Mass of
l.4-dio\iine
(fiti)
Sampling
lime
(mill)
Ho« rsile
icm¦Vmiii)
Total air
\oliiine
siimpled (1.)
Raw iiir
concentration
(mii/m ') •'
Raw iiir
concentration
(PPm)11
Adjusted iiir
coiiceiil rill ion
diiii/mM
ILIA
L2/L8/2008
13
48"
34.5
lo.8
U.~~
o.:i
0.85
26
484
34.5
16.7
1.56
0.43
1.71
LHA
0L/L2/20L0
<2
490
34.5
16.9
<0.12
<0.04
<0.13
6
508
34.5
17.5
0.34
0.1
0.38
6
397
34.5
13.7
0.44
0.12
0.48
<2
487
34.5
16.8
<0.12
0.04
<0.13
<2
471
34.5
16.2
<0.12
0.04
<0.14
LHA
05/L4/20L0
<2
480
34.50
-
<0.12 d
0.0335
<0.13
7
480
34.50
-
0.42 d
0.117
0.46
120
483
34.50
-
7.20 d
2.00
7.91
LHA
LL/09/20L0
<2
419
34.50
-
<0.14 d
<0.038
<0.15
<2
445
34.50
-
<0.13 d
<0.036
<0.14
<2
443
34.50
-
<0.13 d
<0.036
<0.14
<2
450
34.50
-
<0.13 d
<0.036
<0.14
IHA
08/05/2011
21
493
34.50
-
1.23 d
0.342
1.36
6
443
34.50
-
0.39d
0.109
0.43
<2
474
34.50
-
<0.12 d
<0.033
<0.13
Ferro
summary
(2006 -
2007)
-
480
-
-
0.25e
0.07
0.28
-
480
-
-
3.63 e
1.01
4.00
-
480
-
-
0.36e
0.1
0.40
-
480
-
-
1.8e
0.5
1.98
Page 406 of 616
-------
Report
Msissof
l.4-dio\;inc
(iilil
Siiinplinii
(i nu-
dum)
Hon rsilc
(ciirVmin)
Tolsil ;iir
\ olu me
siimplod (1.)
K:i\\ iiii'
co iH'iwi trillion
(in > •'
Kiiw :iir
coiKTiilriilion
(ppm)''
Adjusted :iir
cciiicon 1 r;il ion
diiii/mM
-
480
-
-
0.43 e
0.12
0.47
-
480
-
-
0.9e
0.25
0.99
-
480
-
-
6.84e
1.9
7.52
-
480
-
-
24.1e
6.7
26.5
<2 b'c
480
34.5 c
-
<0.14e
0.04c
<0.16
<2b-°
480
34.50
-
<0.14e
0.04c
<0.16
-
-
-
-
1.55
0.43
1.7
" The duration corresponds to the sample time listed for this concentration.
b Non-detect
0 Assumed values
dEPA calculated raw air concentrations in mg/m3 by using sampling durations on the associated chain of custody
sheets and assuming the same sampling rate (34.5 cc/min) given in the other two IHA reports.
e Converted ppm results to units of mg/m3 by multiplying by 3.60 mg/m3 per ppm.
fEPA divided the 28 raw TWA air concentrations by 0.91 (assuming the same desorption efficiency for all samples)
to generate adjusted air concentrations in mg/m3.
The cells marked are not available and/or not applicable.
Source: ? (20161
BASF provided data from 28 PBZ samples BASF (2016). Based on the provided sampling
durations, EPA assumed that these samples were 8-hour TWAs. Of the 28 samples, the 11
samples dated 2006 and 2007 showed results only in units of ppm in a tabular summary from the
previous owner of the manufacturing site (Ferro Corp). EPA converted these ppm results to units
of mg/m3 by multiplying by 3.60 mg/m3 per ppm for 1,4-dioxane.
The two BASF Industrial Hygiene Analysis (IHA) reports dated 12/18/2008 and 1/12/2010
showed a total of 7 samples with mass units in |ig, sampling rates of 34.5 cc/min, sampling
durations in minutes (ranging from 6.5 to >8 hours) and calculated sample volumes in units of
liters and TWA air concentrations in ppm.
The remaining 10 samples in the three IHA reports dated 05/14/2010, 11/09/2010 and
08/05/2011 were given as |ig/sample mass results only without sampling rates, sample volumes,
or other parameters or units. EPA calculated raw air concentrations in mg/m3 by using sampling
durations on the associated chain of custody sheets and assuming the same sampling rate (34.5
cc/min) given in the two older IHA reports (dated 12/18/2008 and 1/12/2010).
The IHA report (dated 12/18/2008) indicates that the sampling results do not account for
desorption efficiency, shown as 0.91. It appears that none of the reports make such a correction.
EPA divided the 28 raw TWA air concentrations by 0.91 (assuming the same desorption
efficiency for all samples) to generate adjusted air concentrations in mg/m3.
To assess occupational inhalation exposures, EPA assembled the BASF 8-hour TWA monitoring
data from Table G-l 1 and the adjusted air concentration values from Table G-12 to a single
sample set with 30 data points. EPA calculated the 95th percentile and 50th percentile of this data
Page 407 of 616
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set to assess the high-end and central tendency exposures, respectively. EPA estimated acute and
chronic inhalation exposures using these values and the equations in Appendix G.2. The EU Risk
Assessment 302.) estimated that the central tendency inhalation exposure was 0.2
mg/m3 and a reasonable high-end exposure was 10 mg/m3 (full-shift) EC IRC (2002). These
values were based on measured data and support the values that EPA calculated for this
assessment. These values are summarized in Section 2.4.1.1.1.
BASF reported two 15-minute short-term exposures (refer Table G-l 1). EPA used the higher of
these two values, 137 mg/m3 from the evaporator dump step, as a high-end short-term exposure
value in this risk assessment. EPA did not use the other short-term exposure value (1.4 mg/m3) to
estimate a central tendency, short-term exposure, since the statistical significance of this sample
is unclear (z'.e.,low end of range, median, etc.).
Although BASF stated that they would cease manufacturing 1,4-dioxane at their Zachary,
Louisiana site by the end of 2018, EPA used the exposure monitoring data from this site as
representative of 1,4-dioxane manufacturing across the U.S. manufacturing facilities.
G.6.2 Import and Repackaging
Commodity chemicals are typically imported into the United States in bulk via water, air, land,
and intermodal shipments Tomer and Kane (2015). These shipments take the form of oceangoing
chemical tankers, railcars, tank trucks, and intermodal tank containers. Chemicals shipped in
bulk containers may be repackaged into smaller containers for resale, such as drums or bottles.
Domestically manufactured commodity chemicals may be shipped within the United States in
liquid cargo barges, railcars, tank trucks, tank containers, intermediate bulk containers
(IBCs)/totes, and drums. Both imported, and domestically manufactured commodity chemicals
may be repackaged by wholesalers for resale; for example, repackaging bulk packaging into
drums or bottles. The exact shipping and packaging methods specific to 1,4-dioxane are not
known, so for this risk evaluation, EPA assessed the repackaging of 1,4-dioxane from bulk
packaging to drums and bottles at wholesale repackaging sites (see Figure G-3). The import and
repackaging uses are grouped because repackaging is the only routine activity of an importer that
would lead to an exposure.
Smaller containers
shipped to customers
for use
1,4-Dioxane received
in rail cars, tanks, or
totes
Unloaded from larger
containers and loaded
into smaller containers
Figure G-3. General Process Flow Diagram for Import and Repackaging
During repackaging, workers could be exposed while connecting and disconnecting hoses and
transfer lines to containers and packaging to be unloaded (e.g., railcars, tank trucks, totes),
intermediate storage vessels (e.g., storage tanks, pressure vessels), and final packaging containers
(e.g., drums, bottles). Workers near loading racks and container filling stations are potentially
exposed to fugitive emissions from equipment leaks and displaced vapor as containers are filled.
These activities are potential sources of worker exposure through dermal contact with liquid and
inhalation of vapors. In addition, ONUs may include employees that work at the site where 1,4-
dioxane is repackaged, but they do not directly handle the chemical and are therefore expected to
Page 408 of 616
-------
have lower inhalation exposures and are not expected to have dermal exposures. ONUs for
repackaging include supervisors, managers, and tradesmen that may be in the repackaging area
but do not perform tasks that result in the same level of exposures as repackaging workers.
Number of Potentially Exposed Workers and Occupational Non-Users
Two companies reported selling a portion of their PV to Industry Sector (IS) code IS46 for
wholesale and retail sale in the 2016 CDR. While one CDR submitter reported the industrial use
type for the wholesale sites as "processing - repackaging", the other reported "not known or
reasonably ascertainable." EPA assumes both sets of wholesale sites repackage their shipments
of 1,4-dioxane. Each CDR submitter reported selling 1,4-dioxane to fewer than 10 wholesale
sites with at least 50 but less than 100 workers potentially exposed. It is possible some portion of
the wholesale sites indicated by the two CDR submitters may overlap; for example, both CDR
submitters may sell to the same wholesaler. Two facilities in the 2018 TRI with NAICS Code
325199, all other basic organic chemical manufacturing, reported a TRI activity of repacking. A
third facility did not report any TRI activities but had the same NAICS Code, and is assumed to
repackage 1,4-dioxane as well. Therefore, EPA assesses an overall range of wholesale sites
repackaging 1,4-dioxane of three to 18. Similarly, the range of reported potentially exposed
workers is 50 to 198 016c).
CDR IS code IS46 corresponds to NAICS codes for wholesale and retail trade and transportation
and warehousing. EPA assumes NAICS Code 424690, other chemical and allied products
merchant wholesalers, is the most relevant NAICS code for wholesalers who repackage and sell
1,4-dioxane. Using U.S. Census and BLS data, EPA estimates a total of 9,517 establishments,
27,214 workers, 10,359 ONUs, a ratio of 3:1 workers to ONUs for this NAICS code. Using the
range of three to 18 sites, EPA calculates a range of nine to 51 workers and three to 20 ONUs
over all sites (a total of 12 to 71 potentially exposed employees). This range is less than the
estimated range reported to CDR of 50 to 198 potentially exposed employees. Therefore, EPA
assesses the range of total potentially exposed employees of 50 to 198 and applies the ratio of 3:1
workers to ONUs to estimate a range of 38 to 149 workers and 12 to 49 ONUs.
Worker and Occupational Non-User Exposure Assessment
Exposure data for this scenario are not available. Therefore, EPA modeled inhalation exposures
using the EPA AP-42 Loading Model and the EPA Mass Balance Inhalation Model and varied
the saturation factor (f), ventilation rate (Q), mixing factor (k) using a Monte Carlo simulation.
See Appendix G.4 for more information about the Monte Carlo simulation. These models use
default parameter values and standard assumptions to develop estimates of inhalation exposures
for container loading and unloading operations.
Table G-13 summarizes the 2016 CDR data reported for the PV of 1,4-dioxane sold to
wholesalers and the container types assumed by EPA for the purposes of this risk evaluation U.S.
EPA. (2016c). EPA assumed Tedia and BASF both ship 1,4-dioxane to wholesalers using 550-gal
totes. This assumption yields a similar order of magnitude of the number of shipping containers
sent to wholesalers: approximately 32 totes for Tedia and approximately 58 totes for BASF. EPA
assumes Tedia's shipments are repackaged into 1-gal bottles since this volume is often sold for
laboratory use. EPA assumes BASF's shipments are repackaged into 55-gal drums as the market
for this volume is unknown. Table G-14 estimates the number of each type of container per site.
Page 409 of 616
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Table G-13. 2016 CDR Data and Assumed Container Types for Repackaging
( /\r)
of PV Sold in
\\ Molesters iiiid
Uep;iek;i^ed
Assumed luilhil
( oiiliiiuer Tjpe
iind Volume h
Assumed
Kep;iek;i^ed
( oiiliiiuer Tjpe
iiud Volume
Number ol'
Kep;iek;i^ed
( ouiiiiiiers
Tedia
151,265
Up to 100%a
Totes
(550 gal)
Bottles
(1 gal)
17,598
BASF
908,710
30%
Totes
(550 gal)
Drums
(55 gal)
577
a In the 2016 CDR, Tedia appears to report that up to 100% of its PV is shipped to each of its two end-use markets:
shipped directly to pharmaceutical and medicine manufacturing and shipped to wholesalers for resale to laboratory
use. Therefore, EPA assesses the entire PV (Manufacture + Imports) as the upper bound for repackaging for
laboratory use.
b Container types are not specified. These types are assumed based on PV and market.
Source: U.S. EPA. (2016c)
Table G-14. Number of Totes and Containers per Site
Compiiin
Nil ill her of To
1 sile
les I uloiided per
•iile
IS siles
Number of Kep;iek;i^e(
Sile
1 sile
1 ( oniiiiners per
IS siles
Tedia
32
2
17,598
978
BASF
58
3
577
32
To calculate central tendency and high-end exposures from repackaging 1,4-dioxane from totes
to drums and small containers, EPA modeled full-shift and short-term exposures using the
equations and parameters in Appendix G.2 and a Monte Carlo simulation. EPA assumed that
workers may be exposed to vapors from the breathing of smaller containers as they are loaded;
therefore, EPA assessed exposures for loading bottles and drums.
EPA assumed that one tote could be unloaded per day and the totes could be loaded directly into
the bottles or drums; therefore, the rate of unloading would be equal to the rate at which the
bottles or drums are loaded. Assuming default loading rates of 60 bottles per hour and 20 drums
per hour, it would take an estimated 9.2 hours to unload one tote into 550 bottles and 0.5 hours to
unload one tote into 10 drums. EPA assumed the bottles are loaded over the course of a full-shift.
Using the Monte Carlo simulation, EPA estimated the central tendency and high-end exposures
for unloading totes into bottles were 9.3 and 33 mg/m3, respectively. For repackaging into drums,
EPA averaged the 30-minute exposure over an 8-hour shift, assuming the workers are exposed to
1,4-dioxane while repackaging and then not exposed for the rest of the shift. The central
tendency and high-end 8-hour TWA exposures for unloading from totes into drums are 11 and
38 mg/m3, respectively. EPA also considered the 30-minute exposures of 170 and 610 mg/m3 to
be central tendency and high-end short-term exposures.
Since different container types may be used, the number of sites may range from 1 to 18 sites,
which also affects the number of days used to calculate acute and chronic inhalation exposures.
To account for this, EPA used the equations in Appendix G.4 along with a Monte Carlo
Page 410 of 616
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simulation to vary the number of sites using a uniform distribution (i.e.,integers only). The
results of these calculations are summarized in Section 2.4.1.1.2.
G.6.3 Industrial Uses
In the absence of available information, EPA assumes that industrial operations are similar in
this category. For uses grouped in the Industrial Uses category, EPA expected that 1,4-dioxane is
received as a solvent, intermediate, or catalyst in its final formulation and requires no further
processing. The 1,4-dioxane is then unloaded and sent to intermediate storage or used
immediately in the process. If used as an intermediate, 1,4-dioxane is likely consumed during the
reaction. For solvents or catalysts, spent 1,4-dioxane would be collected at the end of the process
for reuse, disposal, or recycling. Figure G-4 shows a basic process flow diagram for Industrial
Use.
Filtering/Recycling
(Optional)
Collection and
disposal of waste
1,4-Dioxane
received and
unloaded
Process Steps
(Intermediate
Destroyed)
Collection of spent
1,4-dioxane
(Optional)
Charged to
intermediate storage
(Optional)
Figure G-4. Generic Industrial Use Process Flow Diagram
Specific process description information is available for some uses of 1,4-dioxane. For example,
during wood pulping, 1,4-dioxane is used in an aqueous solution in organosolv pulping to extract
lignin from chipped wood. The solution is usually mixed in a ratio of 96 parts 1,4-dioxane to
four parts water (by volume). A ratio of 9:1, 1,4-dioxane to water, may also be used to increase
lignin yield, but the product will also have a higher carbohydrate content. During this process,
milled wood is mechanically stirred in an aqueous dioxane solution. The wood chip-dioxane
suspension is centrifuged and the remaining solids are washed again in a fresh aqueous dioxane
solution. The extract is dried to produce crude milled wood lignin Obst and Kirk (1988).
In pharmaceutical and medicine manufacturing, 1,4-dioxane is used as an intermediate, a process
solvent, and a solvent for purification. Pharmaceutical processes vary across the industry, but
nearly all process are batch operations. In general, pharmaceutical manufacture includes one or
more chemical reactions, followed by product separation, purification, and drying
|).
Specific worker exposure scenarios in the US are unknown but could be similar to those
described in the 2002 EU Risk Assessment for 1,4-Dioxane. Possible exposure scenarios
described in this assessment in industrial processes that use 1,4-dioxane as a solvent include
unloading 1,4-dioxane, sampling, maintenance activities, and drumming or loading spent 1,4-
dioxane for disposal ECJRC (2002). These exposure activities are related to the process flow
diagram shown in Figure G-4.
ONUs include employees that work at the site where 1,4-dioxane is used in an industrial setting
as a solvent, chemical intermediate, or catalyst, but they do not directly handle the chemical and
are therefore expected to have lower exposures. ONUs for industrial use include supervisors,
Page 411 of 616
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managers, and tradesmen that may be in the processing area, but do not perform tasks that result
in the same level of exposures as production workers.
In Table 2-9 of Problem Formulation of the Risk Evaluation for 1,4-Dioxane U.S. EPA. (2018e).
EPA identified several conditions of use that may produce a mist. Some of those uses were
included within this Industrial Uses group; namely, wood pulping26, extraction of animal and
vegetable oils22, wetting and dispersing agent in textile processing22, etching of fluoropolymers,
and recycling. Mist generation is not expected from the process steps shown in Figure G-4 or the
wood pulping process description. Therefore, exposures to mists from any use within the
industrial uses group were not assessed for workers or ONUs.
Number of Potentially Exposed Workers and Occupational Non-Users
The two listed manufacturers in the 2016 Chemical Data Reporting (CDR) database reported
three downstream industrial uses in the following two sectors; pharmaceutical and medicine
manufacturing, and all other basic inorganic chemical manufacturing. Each sector is listed as
having fewer than 10 sites, with one industrial use employing 50 to 100 workers and two with
100 to 500 workers each 1016c). These three sectors only estimate workers for two of
the industries that may fall in the industrial uses category, therefore, this range of 250 to 1,100
total workers could underrepresent the workers exposed in all the industries related to this use
category.
EPA identified NAICS codes that were relevant to this condition of use and refined the number
of workers using relevant SOC codes. Table G-15 identifies the relevant NAICS. BLS data
indicate an average of 32 workers and 13 ONUs per site. The number of establishments within
these NAICS codes that use 1,4-dioxane-based solvents, intermediates, and catalysts are
unknown. A total of 24 sites in these NAICS codes reported discharging 1,4-dioxane in the 2018
TRI and 2018 DMR. EPA assumed this represents the total number of sites that use 1,4-dioxane
in this condition of use and estimates a total of 768 workers and 312 ONUs may be exposed
during these operations.
26 These uses were evaluated but are likely not current uses of 1,4-dioxane.
Page 412 of 616
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Table G-15. Industrial Use NAICS Codes
NAICS Code
NAICS Description
311224
Soybean and Other Oilseed Processing
311613
Rendering and Meat Byproduct Processing
313110
Fiber, Yarn and Thread Mills
322121
Pulp and Paper (except groundwood, newsprint) combined Manufacturing
325180
Other Basic Inorganic Chemical Manufacturing
325199
All Other Basic Organic Chemical Manufacturing
325320
Pesticide and Other Agricultural Chemical Manufacturing
32541 la
Medicinal and Botanical Manufacturing
325412
Pharmaceutical Preparation Manufacturing
325510
Paint and Coating Manufacturing
325992a
Photographic Film, Paper, Plate, and Chemical Manufacturing
325998
All Other Miscellaneous Chemical Product and Preparation Manufacturing
3261303
Laminated Plastics Plate, Sheet (except Packaging), and Shape Manufacturing
327910b
Abrasive Product Manufacturing
334413
Semiconductor and Related Device Manufacturing
3359913
Carbon and Graphite Product Manufacturing
a - Data only available at the 4-digit NAICS level. Workers/site and ONUs/site numbers account for
%granularity.
b - BLS data unavailable (total workers and ONUs). Averaged workers/site and ONUs/site for the other
NAICS Codes.
Worker and Occupational Non-User Exposure Assessment
The 2002 EU Risk Assessment provided a summary of some exposure data relevant to the
conditions of use outlined in Section 2.4.1.1.4. The Finnish Environmental Institute and an
unnamed company provided the datasets, and the data provided ranged from 1989 to 1998. Some
of the exposure data cover uses that are not applicable to this Industrial Uses group; therefore,
EPA selected data for the uses related to this group. Select data specific to this Industrial Uses
group are summarized in Table G-16.
Page 413 of 616
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Table G-16. DoD and 2002 EXT Risk Assessment Industrial Use Inhalation Exposure Data
Industries or Tsisk
Number of
Siimpk-s
1'.*
posmv l.c\ols in
A\er;iiie
lii/mM
yo"1 |K'iYcnlilc
Sou itc
Medicine manufacture3
20 b
1.8-18
6.5
ECJRC (2002)
Pharmaceutical
production3
<30c
<3.6
ECJRC (2002)
Use (e.g., as solvent)
in other productions'1
194°
<0.01-184
0.11e
1.8
ECJRC (2002)
Use (e.g., as solvent)
in other productions'1
49°
<0.04-7.2
0.07 e
0.62
ECJRC (2002)
Plastic Thermoforming
1
<72
DoD (2018)
" The 2002 EU Risk Assessment does not provide information about these uses to describe the difference between
medicine and pharmaceutical manufacture. EPA assumes the processes are similar. These datasets also come from
different sources in the report.
b Fixed and personal samples.
0 Personal samples.
d These datasets were provided by the same company, but as separate datasets from different time periods.
e These were medians.
The 2002 European Union Risk Assessment provided calculated exposure estimates using
exposure data from similar scenarios and the Estimation and Assessment of Substance Exposure
(EASE) model. The EASE model was developed by the US Health and Safety Executive with
the Health and Safety Laboratory. It predicts expected dermal and inhalation exposures for a
wide range of substances and scenarios using situational information related to the chemical
Tickner et al. (2005). The scenario considers exposures specifically from activities related to the
use of 1,4-dioxane as an extractant medicine manufacturing. The assessment assumes that it is an
essentially closed system which may be breached and local exhaust ventilation (LEV) is used.
Using these assumptions, the model calculated an inhalation exposure of 36 to 180 mg/m3
ECJRC (20021
EPA reached out to the Department of Defense (DoD) for monitoring data for TSCA chemicals.
The DoD provided monitoring data from its Defense Occupational and Environmental Health
Readiness System - Industrial Hygiene (DOEHRS-IH), which collects occupational and
environmental health risk data from each service branch. The dataset provided by the DoD to
EPA included one sample for 1,4-dioxane exposure. The sample was a personal sample taken
December 4, 2015 from a plastic thermoforming process. The total sampling time was 104
minutes and the measured result was <20,000 ppb (72 mg/m3) DoD (2018).
The 2002 EU Risk Assessment states that the inhalation estimates from EASE appear to
considerably overestimate the exposures and recommends a central tendency exposure of 5
mg/m3 (full- shift) and a reasonable high-end exposure of 20 mg/m3 (full-shift) for the end use of
1,4-dioxane, mainly based on the highest exposure level during medicine manufacture ECJRC
(2002). This recommended range agrees well with the exposure data in Table G-16, except for
Page 414 of 616
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one of the data points. The exposure level of 184 mg/m3 is likely an outlier because the value is
two magnitudes larger than the 90th percentile of the range; 1.8 mg/m3. Therefore, the proposed
range of 5 to 20 mg/m3 was used to estimate the inhalation exposures for the Industrial Uses
group. These central tendency and reasonable high-end estimates were assumed to be equivalent
to central tendency and high-end values, respectively and representing an 8-hour TWA value.
Acute and chronic inhalation exposures for Industrial Uses were calculated using the equations
in Appendix G.2. Results of these calculations are summarized in Section 2.4.1.1.4.
G.6.4 Functional Fluids (Open System)
EPA assessed the industrial use of metalworking fluids in the metal products and machinery
(MP&M) industry U.S. EPA. ( ). Metalworking fluids (formulations ranging from straight
oils to water-based fluids, which include soluble oils and semisynthetic/synthetic fluids) are used
to reduce heat and friction and to remove metal particles in industrial machining and grinding
operations. Cutting and tapping fluids are a subset of metalworking fluids that are used for the
machining of internal and external threads using cutting tools like taps and thread-mills. In
general, industrial metal shaping operations include machining, grinding, deformation, blasting,
and other operations and may use different types of metalworking fluids to provide cooling and
lubrication and to assist in metal shaping and protect the part being shaped from oxidation
OECD ('. ). Of the three open-system functional fluids identified in the Preliminary
Information on Manufacturing, Processing, Distribution, Use, and Disposal: 1,4-Dioxane U.S.
I), only one (a cutting and tapping fluid) has a safety data sheet (SDS) with
information indicating the 1,4-dioxane content ranges from 0.01 to 0.1 wt%. While some cutting
and tapping fluids may be used by consumers in a DIY setting, there are no consumer uses
reported to the CDR U.S. EPA. (2017dY
The Emission Scenario Document (ESD) on the Use of Metalworking Fluids provided a generic
process description of the industrial use of metalworking fluids in the metal products and
machinery (MP&M) industries OECD (2011). Metalworking fluids are typically received in
containers ranging from 5-gallon pails to bulk containers. Water-based metalworking fluids are
unloaded and diluted with water on-site before being transferred into the trough of the
metalworking machine. Straight oils are not diluted and instead transferred directly into the
trough. The metalworking fluids are pumped from the trough and usually sprayed directly on the
part during metal shaping. The fluid stays on the part and may drip dry before being rinsed or
wiped clean. Any remaining metalworking fluid is usually removed during a cleaning or
degreasing operation OECD (2011). A generic process flow diagram is shown in Figure G-5.
Workers could unload the metalworking fluid from containers; clean containers; dilute water-
based metalworking fluids; transfer fluids to the trough; perform metal shaping operations; rinse,
wipe, and/or transfer the completed part; change filters; transfer spent fluids; and clean
equipment C ).
Page 415 of 616
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Filtering/Recycling
Metalworking
Fluid
Part
Rinsed/Dried
Dilute with Water
(Water-Based Only)
Disposal of Spent
Metalworking Fluid
Sprayed onto
Part During
Metal Shaping
Charged to Metal
Shaping Machine
Trough
Figure G-5. Process Flow Diagram for Open System Functional Fluids
ONUs include employees that work at the site where 1,4-dioxane is used in an industrial setting
as an open-system functional fluid, but these employees typically do not directly handle the
chemical and are therefore expected to have lower exposures. ONUs for open-system functional
fluids include supervisors, managers, and tradesmen that may be in the processing area but do
not perform tasks that result in the same level of exposures as machinists.
Since 1,4-dioxane has a high vapor pressure (40 mm Hg at 2525°C), workers could be exposed
to 1,4-dioxane when handling liquid metalworking fluid, such as unloading, transferring, and
diluting neat fluids, and disposing spent fluids and cleaning machines and troughs. However, due
to 1,4-dioxane's low content in metalworking fluids (0.01 to 0.1 wt%), the 1,4-dioxane partial
pressure could be low and would reduce exposure to 1,4-dioxane vapors.
The greatest source of potential exposure is during metal shaping operations. The high machine
speeds can generate airborne mists of the metalworking fluids to which workers could be
exposed. Additionally, the high vapor pressure of 1,4-dioxane could lead to its evaporation from
the airborne mist droplets, potentially creating a fog of vapor and mist. However, the low
concentration of 1,4-dioxane in metalworking fluids could lead to a low partial pressure, which
would mitigate the evaporation of the 1,4-dioxane from the mist droplets.
Number of Potentially Exposed Workers and Occupational Non-Users
Three facilities reported 1,4-dioxane releases in the 2018 DMR, but due to the reporting
requirements of DMR, EPA expects this number to represent the minimum (DMR, 2018). EPA
estimated 89,000 MP&M industrial sites in the in the US as an upper bounding estimate OECD
(2011). The ESD does not provide total workers in the industry but cites a NIOSH study of 79
small machine shops, which observed an average of 46 machinists per site. The ESD also cites
an EPA effluent limit guideline development for the MP&M industry, which estimated a single
shift supervisor per shift, who could perform tasks such as transferring and diluting neat
metalworking fluids, disposing spent metalworking fluids, and cleaning the machines and
troughs OECD (2011).
Since the machinists perform the metal shaping operations, during which metalworking fluid
mists are generated, EPA assesses the machinists as workers, as they have the highest potential
exposure. EPA assessed the single shift supervisor per site as an ONU, as this employee is not
expected to have as high an exposure as the machinists. Assuming two shifts per day (hence two
Page 416 of 616
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shift supervisors per day), EPA assesses 46 workers and two ON Us per site OECD ( ).
Although it is possible the shift supervisors may perform some tasks that may lead to direct
handling of the metalworking fluid as outlined in the ESD, EPA assesses these shift supervisors
as ONUs as their exposures are expected to be less than that of the machinist. With the above
distinction between machinests and supervisors, EPA used the worker-to-ONU ratio of 23-to-l.
The number of establishments within this NAICS code that use metalworking fluids and the
number of those establishments that use 1,4-dioxane-based metalworking fluids are unknown.
EPA estimates three to 89,000 total sites per the ESD and estimates a total of 69 to 4,094,000
workers and three to 178,000 ONUs. Therefore, EPA provides the total number of
establishments and potentially exposed workers and ONUs as bounding estimates, both high and
low, of the number of establishments that use and the number of workers and ONUs that are
potentially exposed to 1,4-dioxane-based metalworking fluids during metal shaping operations.
Worker and Occupational Non-Users Exposure Assessment
EPA assessed worker exposures EPA AP-42 Loading Model and the EPA Mass Balance
Inhalation Model and varied the saturation factor (f), ventilation rate (Q), mixing factor (k) using
a Monte Carlo simulation (see Appendix G.4) These models use default parameter values and
assumptions to provide screening level assessments of inhalation exposures for container
unloading operations. EPA estimated 77 containers per site per year using default values and
equations provided in the ESD and assumes that one container is unloaded per day, resulting in
an exposure duration of 3 minutes (0.054 hours). EPA presents these values, 0.17 and 0.61
mg/m3, as central tendency and high-end short-term exposures, respectively. The simulation also
estimated 0.0011 and 0.0038 mg/m3 as 50th and 95th percentile 8-hour TWA exposures. EPA
used these values to calculate acute and chronic inhalation exposures in the Monte Carlo
simulation, varying working years (WY), using the equations in Appendix G.2. See Section
2.4.1.1.5 for a summary of the results.
A 1997 NIOSH HHE provided PBZ and area data for workers at the Dana Corporation, Spicer
Axle Division facility in Fort Wayne, Indiana. NIOSH conducted PBZ and area measurements of
water-soluble synthetic metalworking fluids and oil mists from conventional metalworking
fluids. These data are of the total concentration of oil mists or synthetic metalworking fluid
particulates in the air Burton and Driscoll (1997). The NIOSH HHE does not identify 1,4-
dioxane as a component of the metalworking fluids used at the facility (although NIOSH did
identify 1,4-dioxane as a component of a flow-coat paint used at the facility). To estimate
potential 1,4-dioxane exposures, the concentration of the synthetic metalworking fluid or oil mist
was multiplied by 0.1%, the high-end concentration of 1,4-dioxane in metalworking fluids
identified by EPA U.S. EPA. ('. ). These data are summarized in Table G-17.
Table G-17. 1997 NIOSH HHE PBZ and Area Sampling Data for Metalworking Fluids
.lol> Deseripl ion/Area
Sample
lime (lir)
Sample
Volume
(1.)
( oneenlralion im^/nr'i;|
('oneenlralion of
l.4-l)io\ane
(111^/111') 1 h
Sample
Tj pe
Metalworking Fluids
Several Operations at
Transfer Lines/ Dept.
6.70
804
0.53
0.00053
Personal
Page 417 of 616
-------
661
Roughing/Dept. 661
6.77
812
0.43
0.00043
Personal
Four-Way/Dept. 541
6.53
784
0.46
0.00046
Personal
Multiple/ Dept. 373
5.98
718
0.22
0.00022
Personal
Screw Machine-
Lathing/Dept. 171
6.28
754
0.24
0.00024
Personal
Apex Drill/Dept. 151
6.22
746
0.24
0.00024
Personal
Threader/ Dept. 373
6.08
730
0.14
0.00014
Area
Broaching/ Dept. 375
5.82
698
0.17
0.00017
Area
Apex Drill/Dept. 354
6.15
738
0.23
0.00023
Area
Lunch Tables/ Dept.
375
5.68
682
0.21
0.00021
Area
Oil Mists
Lathing/H3
6.92
830
0.08
0.00008
Personal
Burr Drill/H6
6.63
796
0.1
0.0001
Personal
Gear Cutter/K6
6.50
780
0.23
0.00023
Personal
Burnisher/K6
6.48
778
0.13
0.00013
Personal
Screw Machine
6.32
758
0.13
0.00013
Personal
Gear Cutter/N9
6.37
764
0.3
0.0003
Personal
Gear Cutter/N7
6.40
768
0.25
0.00025
Personal
Gear Cutter/Grinder
6.03
724
0.26
0.00026
Personal
Gleason Cutting
Machines/N5
6.10
732
0.33
0.00033
Area
a The duration corresponds to the sample time listed for this concentration.
b Calculated by multiplying concentration by 0.1%, the expected concentration of 1,4-dioxane.
Source: Burton and Driscoll (1997)
EPA compared the distribution of 8-hour TWA results produced by the Monte Carlo simulation
with the 8-hour TWA values calculated from the NIOSH HHE sample measurements and
observed that all of the NIOSH HHE results are less than the 10th percentile of the Monte Carlo
distribution. This indicates that the NIOSH HHE sample results are insignificant compared to the
distribution produced by the Monte Carlo simulation and contribute a minor effect on the overall
final estimate.
EPA compiled the five area measurements from Table G-17 into a single dataset and calculated
the 50th and 95th percentile to estimate central tendency and high-end ONU inhalation exposures.
EPA used these values to calculate acute and chronic exposures using the equations in Appendix
G.2. See Section 2.4.1.1.5 for a summary of the results.
The 2011 OECD ESD on the Use of Metalworking Fluids estimates typical and high-end
exposures for different types of metalworking fluids. These estimates are provided in Table G-18
Page 418 of 616
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and are based on a NIOSH study of 79 small metalworking facilities. The concentrations for
these estimates are for the solvent-extractable portion and do not include water contributions.
EPA assumes the concentration data available is before dilution and is therefore already equal to
the concentration of the dioxane in the mist.
Table G-18. 2011 ESP on Metalworking Fluids Inhalation Exposure Estimates
Tj |>o of
\k'(;il\\orkinii I'luid
T>pio;il Misl
( 11 neon li'ii lit hi
(mii inisl/ni ") ¦'
T\pio;il l.4-l)io\;ino
( < i neon li'ii lit hi
h
lli»h-i:ii(l Misl
( (inoonlriilion
(mii inisl/ni V
lliuh-lnd 1.4-
l)io\iino
( (inoonlriilion
(niii /in')h
Conventional
Soluble
0.19
0.00019
0.87
0.00087
Semi-Synthetic
0.20
0.00020
0.88
0.00088
Synthetic
0.24
0.00024
1.10
0.0011
Straight Oil
0.39
0.00039
1.42
0.0014
a Geometric Mean
b Calculated by multiplying concentration by 0.1%, the expected concentration of 1,4-dioxane.
0 90th Percentile
Source: QECD ( )
G.6.5 Laboratory Chemical Use
The laboratory worker activities may include preparing the mobile phase by degassing with
helium, nitrogen, or processing reactions in an ultrasonic bath ECJRC (2002). In addition to
these applications and others listed in Section 2.4.1.1.7, EPA expects conditions of use could
involve activities such as unloading small quantities of chemicals; applications/filling and
emptying using small volumes for laboratory activities such as preparing samples, performing
small scale reactions, or for quality control or calibration purposes; and loading waste 1,4-
dioxane into containers for recycling or disposal. TWA exposures typically are small, as the
majority of workers could only be exposed intermittently to 1,4-dioxane due to the infrequency
of such applications and filling and emptying of the solvent reservoir is reportedly carried out in
a fume cupboard. In addition to laboratory analysts/workers, ONUs may include supervisors,
laboratory managers, and laboratory analysts and technicians that perform other tasks in a
laboratory setting where 1,4-dioxane is used but do not directly handle the chemical and are
therefore expected to have lower exposures.
Descriptions of the specific process for how 1,4-dioxane is used in each of these conditions of
use are not available. In general, 1,4-dioxane could be received in small containers and used in
small quantities on a lab bench under a fume cupboard or hood. After use, the waste 1,4-dioxane
is collected and disposed of or recycled (see Figure G-6). Quantities used in laboratory use could
be disposed of with other laboratory liquid waste and/or diluted under certain occasions, but
quantities used by individual laboratories would be typically small.
Page 419 of 616
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1,4-Dioxane
Used in small
Waste 1,4-dioxane
received in small
>
quantities for various
~
collected and disposed
containers
lab uses
of or recycled
Figure G-6. General Laboratory Use Process Flow Diagram
Number of Potentially Exposed Workers and Occupational Non-Users
A single submitter to the 2016 CDR reported selling an unknown volume of 1,4-dioxane for use
as a laboratory chemical. The submitter estimated selling 1,4-dioxane to fewer than 10 sites
(through the use of wholesalers and retailers). The submitter further estimated that at least 50 but
less than 100 laboratory workers could be potentially exposed U.S. EPA. (2016c). EPA used U.S.
Census and BLS data for the NAICS code 541380, Testing Laboratories, and relevant SOC
codes to estimate a total of 6,844 sites, 6,610 workers, and 804 ONUs, which corresponds to an
estimated average of one worker and 0.12 ONUs per site. EPA used these data to calculate a
ratio of 8:1 workers to ONUs. EPA applied this ratio to the total number of workers reported in
CDR to estimate total of 44 to 89 workers and 6 to 11 ONUs.
The number of establishments within this NAICS code that use 1,4-dioxane-based laboratory
chemicals are unknown. Therefore, EPA used the total number of establishments and potentially
exposed workers and ONUs in this NAICS code as bounding estimates for the number of
establishments that use and the number of workers and ONUs that are potentially exposed to 1,4-
dioxane-based laboratory chemicals in a laboratory setting. These bounding estimates likely
overestimate the actual number of establishments and employees potentially exposed during the
use of 1,4-dioxane as a laboratory chemical.
Worker and Occupational Non-User Exposure Assessment
The EU Risk Assessment 2002) provides monitoring data for laboratory work activities from the
Finnish Environmental Institute (FEI) and an unnamed company. Table G-19 summarizes the
exposure levels. The assessment states that the first data point (laboratory work) is probably from
the use of 1,4-dioxane as the mobile phase in HPLC and dilution ventilation was present but does
not provide any context about specific worker activities for the rest of the data ECJRC (2002)
reported: "[t]he Finnish Environmental Institute (FEI, 1996) provided some exposure data
during the use of 1,4-dioxane in a cleaning agent, during the use in a laboratory (probably as
the mobile phase in HPLC), and during medicine manufacturing (as an extractant). Company A
(1997/1998) provided exposure data during the use of the substance in a laboratory, in the
pharmaceutical industry ...". The EU risk assessment grouped the laboratory use with
pharmaceutical manufacturing; therefore, the risk assessment did not provide recommended
central tendency or high-end values specific to laboratory use. The high concentrations in the
monitoring data were considered outliers and the highest concentrations short-term peak
exposures. An additional risk assessment report for 1,4-dioxane N ) did not provide
occupational exposure data but cited a study where the highest 8-hour TWA value from personal
monitoring was 1.8 ppm (approximately 6.5 mg/m3) Rimatori et al. (1994; Hertlein (1980).
Page 420 of 616
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Table G-19. Monitoring Data for Laboratory Chemicals
Industries or Task
Number of Samples
K\po<>
U;in<>c
lire l.e\i
Menu
'Is (111 "/ill *)
percentile
Laboratory Work (HPLC)
1
165 a
Laboratory
305
0-166
0.11
0.58
Laboratory
29
<0.07-0.18
<0.07
0.15
a Only a single measurement was provided for laboratory work associated with HPLC use.
Source: ECJRC (2002.)
Based on the monitoring data available from the Ell risk assessment ECJRC (2002). EPA used
0.11 mg/m3 and 5.7 mg/m3 to assess the central tendency and high-end exposures, respectively.
EPA calculated the high-end value by calculating an 8-hour TWA of the 15-minute short-term
peak exposure and the 90th percentile value of 0.58 mg/m3 per Equation G-l 1.
Equation G-ll. High-End Inhalation Value for Laboratory Chemicals
(o.25 hr xl66^?) +(7.75 hr *0.58^?) _ ^mg
8 hours m3
This calculated, high-end value compares with the highest 8-hour TWA reported in the NICNAS
report of 6.5 mg/m3. Acute and chronic inhalation exposures for laboratory uses are calculated
using the equations in Appendix G.2 and sample calculations are found in Appendix G.3. Results
of these calculations are summarized in Section 2.4.1.1.7.
G.6.6 Film Cement
The Preliminary Information on Manufacturing, Processing, Distribution, Use, and Disposal:
1,4-Dioxane lists one SDS for film cement, which contains 1,4-dioxane at a concentration of
45% to 50% U.S. EPA. (2.017d). Film cement is used in the film processing and archiving
industries to splice celluloid movie film together. This splicing processing is typically done by
hand in an open process. Film is cut using a special tool, then the cement is applied to the edges
of the film by hand using a small brush. The pieces of film are joined together by closing the tool
and heating to 35 °C to dry the cement. Film is also cleaned, which may be done using a sonic
cleaner or as a manual operation. One site in Australia reports using 12 liters of the cement per
year NICNAS (1998; Qkawa and Co\ c j Lr>S2). A 1980 NIOSH HHE of two U.S. film
laboratories observed upwards of 100 splices conducted by an employee per day and estimated
less than 10 mL of cement used by an employee per shift Qkawa and Coy E). See Figure
G-l.
Page 421 of 616
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Film cut using special
tool
Automated or manual
film cleaning
Cut and glued film
edges joined, heated
to facilitate drying
Film cement manually
applied to the film
edge using a small
brush
Film cement
containing 1,4-
Dioxane received in
bottles
Figure G-7. Process Flow Diagram for Film Cement Application
The National Industrial Chemicals Notification and Assessment Scheme (NICNAS) reported that
the splicing operation at a site in Australia was manual NICNAS (1998). Workers processed and
cut the film, applied the cement, and joined the cut film pieces together using the heated tool.
Workers would also manually clean the film using solvents. Two American film laboratories also
used a similar process; therefore, EPA expects worker activities in the U.S. to be similar. These
exposures are based on the activities shown in the process flow diagram in Figure G-7.
ONUs include employees that work at the film processing lab where 1,4-dioxane is used in a
film cement, but they do not directly handle the chemical and are therefore expected to have
lower exposures. ONUs for film laboratories include supervisors, laboratory managers, and
laboratory workers that perform other tasks but do not directly handle 1,4-dioxane.
Number of Potentially Exposed Workers and Occupational Non-Users
NICNAS estimated up to 10 laboratories perform the film cement processing in Australia, with
about three workers potentially exposed up to eight hours per day per site Nlj 38). The
report also stated that an unknown additional number of workers could be exposed at these sites.
The film laboratory could deploy up to four workers to handle duties related to film splicing
Okawa and Coy I). EPA identified NAICS code 512199, Other Motion Picture and Video
Industries, as the relevant NAICS code for this use. Data from the U.S. Census Bureau for the
Statistics for U.S. Businesses (SUSB) for this code indicated 211 sites and 1,238 total
employees. Due to the diversity of operations covered by this NAICS code, this could be an
overestimate for the total number of sites and workers that perform this specific operation using
film cement containing 1,4-dioxane. It is assumed that all U.S. film laboratories use a process
similar to the one outlined in the NICNAS report and therefore have a similar number of workers
per site. EPA estimated a total of 30 workers and 10 ONUs for all sites.
The number of establishments within this NAICS code that splice film and the number of those
establishments that use 1,4-dioxane-based film cement are unknown. Therefore, EPA provides
the total number of establishments and potentially exposed workers and ONUs in this NAICS
code as bounding estimates of the number of establishments that use and the number of workers
and ONUs that are potentially exposed to 1,4-dioxane-based film cement during film splicing
operations. These bounding estimates could overestimate the actual number of establishments
and employees potentially exposed to 1,4-dioxane during film splicing operations.
Worker and Occupational Non-User Exposure Assessment
The NICNAS report N ) did not have Australian air monitoring data but referenced
a NIOSH HHE that collected data in 1980 from two U.S. film laboratories Okawa and Cove
2). EPA noted that these are historic monitoring data and that processing technologies may
have changed. The HHE identified 1,4-dioxane as a component in the film cement used in film
Page 422 of 616
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splicing. However, the HHE did not specify the concentration of 1,4-dioxane in the formulation.
EPA calculated values for samples that were non-detects using the flow rate, and limit of
detection from NIOSH Method 1602 NIOSH (1994). From the measured and calculated values,
EPA calculated 8-hour TWA values (see Table G-20).
Table G-20. NIOSH HHE PBZ and Area Samples for Film Cement Use
l.ociilion
Job 1 iilo or
O|)or;i(ion
Siimplo
Tj |)l'
Siimplo
Dui'iilion
(lir)
( OIKTIIII'illioil
(mii/m M •'
Ciilciiliilod
( niHTiiInition
img/iiv') •'
X-llour
T\\ A
img/iiv')
Technicolor
Splicer
(Behind glass
doors)
PBZ
5.67
3.1
3.1
2.2
Technicolor
Splicer (Main
Room)
PBZ
1.67
NDb
1.0 c
0.95 d
Technicolor
Splicer (Main
Room)
PBZ
4.25
1.4
1.4
Technicolor
Manual Film
Cleaning
PBZ
6.42
3.5
3.5
2.81
MovieLab
Splicer
PBZ
5.58
NDb
0.30 c
0.21
MovieLab
Splicing
General Area
Area
5.50
NDb
0.30 c
0.21
a The duration corresponds to the sample time listed for this concentration.
b ND - non-detect
0 EPA calculated a value for non-detects using limit of detection of 0.01 mg/sample NICK M).
d These two samples are for the same operator; therefore, EPA averaged them together for the 8-hour TWA
calculation.
Source: Okawa and Co\ c i V sS2)
Due to the small size of the data set (five data points), EPA calculated the 50111 percentile to
assess the central tendency exposure and presented the maximum as the high-end exposure. EPA
used these values to calculate acute and chronic inhalation exposures using the equations in
Appendix G.2. The results of these calculations are summarized in Section 2.4.1.1.8.
The one area sample result was a non-detect Okawa and Cove (1982). which means the
concentration was lower than the level of detection for the method at that time. EPA calculated
an upper bound for this value using half of the method detection limit. EPA considered this value
as an 8-hour TWA exposure value for ONUs. This value is plausible, but EPA cannot determine
the statistical representativeness of the value given the small sample size. This value was used to
calculate acute and chronic inhalation exposures as per the equations in Appendix G.2. The
results of these calculations are summarized in Section 2.4.1.1.8. Dermal exposures are not
expected for ONUs.
G.6.7 Spray Foam Application
There are three main types of spray polyurethane foam (SPF): two-component high-pressure,
two-component low-pressure, and one OCF. The low-pressure and OCF types are available for
DIY-use, but the high-pressure type is only available for professional use. A safety data sheet
Page 423 of 616
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(SDS) identified in the Preliminary Information on Manufacturing, Processing, Distribution,
Use, and Disposal: 1,4-Dioxane indicate that 1,4-dioxane is present in open- and closed-cell
SPFs, which are subsets of two-component high-pressure SPFs S I 7c. d). While one
SDS has been identified where 1,4-dioxane was listed as an ingredient, it could also be an
impurity/byproduct and the concentration could vary by the type of SPF.
This type of SPF is used for larger insulation applications, as an air sealant in hybrid insulations,
and in roofing applications. The components are typically stored in 55-gallon drums. The
operator pumps both components (sides A and B) through heated tubes from the supply tanks
into a nozzle. 1,4-Dioxane is a component in Side B with concentrations typically around 0.1%
U.S. EPA. (2017c. d). Sides A and B begin to react in the nozzle and are sprayed at elevated
pressures and temperatures (>150 °F and 1,200 psi). Closed-cell foam could be applied in layers.
As the foam cures, it expands up to 120 times its original size. After curing, the foam could be
trimmed or cut. Trimmings and waste foam are collected and disposed. See Figure G-8 for a
typical process flow diagram for spray foam application.
Figure G-8. Process Flow Diagram for Spray Application
Worker activities for the application of high-pressure SPF include transferring the component
containing 1,4-dioxane from the drum to the supply tank, applying the spray foam mixture,
trimming foam after it cures, and disposing of trimmings and waste that may contain 1,4-dioxane
i ^ i r \t 4018a, 2otV).
Non-sprayer workers include employees that work at the site where 1,4-dioxane is used during
spray foam application, but do not directly handle the chemical and are therefore expected to
have lower exposures. Non-sprayer workers for spray foam application include construction
managers, engineers, drafters, supervisors, and workers performing other tasks that may be in the
area where the spray foam is being applied, but do not perform tasks that result in the same level
of exposures as workers. Non-sprayer workers may also perform trimming tasks after the
insulation has cured.
Number of Potentially Exposed Workers and Non-Sprayer Workers
Data for the number of potentially exposed workers and non-sprayer workers are unknown. EPA
reviewed BLS data for NAICS code 238310, Drywall and Insulation Contractors, along with
relevant SOC codes, which estimated 17,857 establishments, 162,518 workers, and 15,627 non-
sprayer workers. EPA estimated nine workers and one non-sprayer worker per establishment.
Spj|* Rt( J~
Page 424 of 616
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The number of establishments within this NAICS code that install spray polyurethane foam
installation and the number of those establishments that use 1,4-dioxane-based spray
polyurethane foam are unknown. Therefore, EPA considered the total number of establishments
and potentially exposed workers and non-sprayer workers in this NAICS code as bounding
estimates of the number of establishments that use and the number of workers and non-sprayer
workers that are potentially exposed to 1,4-dioxane-based spray polyurethane foam during
insulation installation. These bounding estimates are likely overestimates of the actual number of
establishments and employees potentially exposed to 1,4-dioxane during spray polyurethane
foam insulation installation, since only a single spray polyurethane foam product that contains
1,4-dioxane was identified.
Worker and Non-Sprayer Worker Exposure Assessment
Monitoring data for inhalation exposure to 1,4-dioxane from spray application of SPF is not
known. EPA assumed that the spray foam containing 1,4-dioxane is only used for roofing
applications, per the technical data sheet for the spray polyurethane foam identified in the
Preliminary Information on Manufacturing, Processing, Distribution, Use, and Disposal: 1,4-
Dioxane U.S. EPA. (2017c). EPA used assumptions and values from the 2018 GS on the
Application of Spray Polyurethane Foam Insulation to calculate the use rate per site U.S. EPA.
(2.018a). These values and relevant parameters are summarized in Table G-21.
Table G-21. Values Used for Daily Site Use Rate for SPF Application
I'sirsiiiK'tcr
Sy in hoi
\ ill no
I nil
Operating days per site
ODsite
3 a
days/site
Roofing area
A
1500 b
ft2
SPF density
P
3.2 c
lb/ft3
SPF thickness
t
0.33 a
ft
Mass fraction of 1,4-dioxane in B-side
Fchem, B-Side
0.001 d
dimensionless
Mass fraction of B-side in mixed SPF
FB-Side
0.5 c
dimensionless
Mass fraction of 1,4-dioxane in mixed
SPF
Fchem, SPF
0.0005 a
dimensionless
Use rate of SPF per site
QsPF.site
718.5a
kg spf/site
Daily Use Rate of 1,4-dioxane per site
Qchem,site
0.12 a
kg chem/site-day
Number of drums B-side unloaded per
site-job
NDrums
1.7 a
drums/site-job
Unloading rate for drums
r
20 a
drums/hour
a U.S. EPA. (2018a)
b Horn eAdvi sor (2018; Huber (2018)
c OMG Roofing Products (2018)
d ¦* U ^4 I)
Per the GS, EPA modeled inhalation exposures from unloading using the EPA AP-42 Loading
Model and the EPA Mass Balance Inhalation Model and varied the saturation factor (f),
Page 425 of 616
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ventilation rate (Q), mixing factor (k) using a Monte Carlo simulation. See Appendix G.4 for
more information about the Monte Carlo simulation. These models use default parameter values
and assumptions to provide screening level assessments of inhalation exposures for container
unloading operations. Assuming an unloading rate of 20 drums/hour and one drum/site, EPA
estimates that workers will be exposed for less than two minutes during drum unloading.
EPA also used the EPA Total PNOR PEL-LimitingModel with the OSHA PEL for particulates
(15 mg/m3) to estimate inhalation exposures to mists during application. EPA estimates an
exposure of 0.0075 mg/m3 to mists during application. This estimate does not account for the
potential evaporation of 1,4-dioxane from the mist particulates and the potential inhalation
exposure of the evaporated vapors. 1,4-Dioxane has a high vapor pressure (40 mmHg at25 °C);
however, the weight % of 1,4-dioxane in the SPF particulates is very low (0.05 wt% in the mixed
SPF. Therefore, the partial pressure of 1,4-dioxane is low enough so that inhalation might not be
a significant route of exposure.
EPA estimated exposures from thickness verification using surrogate exposure data provided in
the GS from a different chemical with similar properties. 1,2-Dichloroethane (1,2-DCE) has a
vapor pressure of 61 mmHg and a molecular weight of 98.96 grams per mole, which is similar to
the physical properties of 1,4-dioxane (VP = 40 mmHg at 25 °C, MW = 88.1 g/mol). The
exposure data for the surrogate chemical showed a central tendency exposure of 0.044 mg/m3
and a high-end exposure of 0.077 mg/m3. EPA used Equation G-12 to estimate central tendency
and high-end exposures to 1,4-dioxane during foam thickness verification. EPA assumes an
exposure duration of one hour.
Equation G-12
w MWchem interest ^ VPchem interest ^ ^chem interest
^•m_cheminterest ~ ^m_surrogate * MWT v~~i/P v V
'surrogate x * "surrogate x ^ surrogate
EPA calculated central tendency and high-end 8-hour TWA exposure assuming that the drum is
unloaded at the beginning of the day and the remainder of the 8-hour shift is spent applying the
spray foam insulation and verifying the thickness of the insulation. See Table G-22 for estimated
exposure durations for each activity. EPA used these values to calculate acute and chronic
inhalation exposures in the Monte Carlo simulation, varying working years (WY), using the
equations in Appendix G.2. See Section 2.4.1.1.6 for a summary of the results.
Table G-22. Estimated Activity Exposure Durations
Activity
Kxposurc Duration (hours)
Drum Unloading
0.028
Spray Foam Application
6.97
Thickness Verification
1.0
Exposure data for non-sprayer workers were not available. Per the GS, EPA assumed that some
non-sprayer workers may perform tasks related to trimming the cured spray foam insulation.
EPA used the EPA Total PNOR PEL-Limiting Model with the OSHA PEL for particulates (15
Page 426 of 616
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mg/m3) to estimate inhalation exposures to particulates during trimming. An exposure of
particulates at the rate of 0.0075 mg/m3 considered to occur during trimming. EPA averaged this
exposure over an 8-hour shift, assuming this exposure occurs over one hour and that non-sprayer
workers are not exposed to 1,4-dioxane during the rest of the shift. EPA presents this as an 8-
hour TWA inhalation exposure value for non-sprayer workers. This value is plausible, but EPA
cannot determine the statistical representativeness of the value given the small sample size. This
value was used to calculate acute and chronic inhalation exposures as per the equations in
Appendix G.2. Only inhalation exposures to vapors are expected, which could be less than
worker exposures.
G.6.8 Printing Inks (3D)
The Preliminary Information on Manufacturing, Processing, Distribution, Use, and Disposal:
1,4-Dioxane identified one SDS for an inkjet printing cartridge used in standard inkjet printers
that may contain 1,4-dioxane. However, the SDS does not indicate that 1,4-dioxane is an
intended ingredient in this cartridge 1 \ O'! t *)• Recent articles identified 1,4-dioxane as
a major component in inks used in additive manufacturing, also known as three-dimensional
(3D) printing He et al. (2016; Ryan and Hubbard (2016; Ruggiero et al. (20He et al. (2013).
Therefore, EPA assessed exposures related to the use of 1,4-dioxane as a component in printing
inks in additive printing manufacturing.
1,4-Dioxane could be present in solvent-based inks that are used in a type of additive
manufacturing known as material jetting. The concentration of 1,4-dioxane in these inks ranges
from 75% to 99.5%, based on the solvent system He et al. (2.016; Ruggiero et al. (2015; He et al.
(2013). In this process, the ink could be made on site or received in cartridges or syringes (Figure
G-9). The liquid ink is charged to a cartridge in the material printer. The printing head deposits
the ink one drop at a time on the substrate. Each drop is cured to form a solid structure using an
outside energy source, such as ultraviolet light or heat. The final product is cleaned in a bath of a
concentrated, highly corrosive material to remove support structures He et al. (2016).
Finished products cleaned
with corrosives, packaged,
and sent to customers
Printing ink containing
1,4-Dioxane received in
cartridges, or syringes or
made on site
Cartridge installed or
printing ink injected into
the cartridge in material
printer
Printing ink applied to
substrate via material jetting,
ink cured as it is applied
(1,4-dioxane evaporated)
Figure G-9. Process Flow Diagram for Printing Inks (3D)
This type of 3D printing ink is used in research labs to print biomedical products, such as
bioresorbable or biodegradable stents, implants, and scaffolds for tissue recovery. Making these
devices using this method allows for lower production costs and increased customization
Ruggiero et ;il 1 He et al. (2013). Workers could be exposed while charging the ink to the
cartridges in the material printer, during the 3D printing process, and when disposing of spent
cartridges and syringes. If the ink is made on site, workers could be exposed during this step in
the process. ONUs include employees that work at the site where 1,4-dioxane is used in a
laboratory setting, but they do not directly handle the chemical and are therefore expected to
have lower exposures. ONUs for laboratory use include supervisors, laboratory managers, and
laboratory workers that perform other tasks but do not directly handle 1,4-dioxane.
Number of Potentially Exposed Workers and Occupational Non-Users
Page 427 of 616
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EPA uses U.S. Census and BLS data for the NAICS code 339113, surgical appliance and
supplies manufacturing, and relevant SOC codes to estimate a total of 10,767 sites, 59,970
workers, and 20,430 ONUs, which corresponds to an estimated average of six workers and two
ONUs per site. The number of establishments within this NAICS code that print biomedical
products and the number of those establishments that use 1,4-dioxane-based 3D printing inks are
unknown. Therefore, EPA provided the total number of establishments and potentially exposed
workers and ONUs in this NAICS code as bounding estimates of the number of establishments
that use and the number of workers and ONUs that are potentially exposed to 1,4-dioxane-based
3D printing ink in biomedical product 3D printing. These bounding estimates could overestimate
the actual number of establishments and employees potentially exposed to 1,4-dioxane during
biomedical product 3D printing.
Worker and Occupational Non-User Exposure Assessment
A literature review and hazard assessment for material jetting identified exposure data for a
number of chemicals, including 1,4-dioxane, during additive manufacturing. A piece of tubing
was placed inside the unventilated 3D printer enclosure and attached to a 1.4-L Toxic Organic-
15 (TO-15) canister, which was placed directly adjacent to the printer. Air Method, Toxic
Organics-15 (TO-15) is an EPA method for sampling and analyzing volatile organic compounds
(VOCs) using specially prepared canisters and gas chromatography/mass spectrometry. The air
was sampled for an 8-hour period while the printer ran continuously. Since there was only a
single sample run, only a single data point is available. 1,4-Dioxane was present inside the
printer enclosure at a level of 27 ppb (0.097 mg/m3). The printer did not have local exhaust
ventilation and relied on general ventilation. 1,4-dioxane levels could be higher if more printers
were operating in the same area without local exhaust ventilation and could reach the NIOSH
REL of 1 ppm. However, Ryan and Hubbard 2016) indicated that the results were based on a
preliminary study and acknowledged that more statistically defensible sampling could be
performed to better understand exposures during this process.
EPA presented this value as an 8-hour TWA exposure for workers. This value is plausible, but
EPA cannot determine the statistical representativeness of the value given the small sample size.
Additionally, this sample was taken inside the 3D printing enclosure and likely represents a
higher exposure than what workers operating the 3D printer would typically experience. EPA
used this value to calculate acute and chronic inhalation exposures as per the equations in
Appendix G.2. Results of these calculations are summarized in Section 2.4.1.1.10.
Exposure data for ONUs were not available. EPA expects that ONU exposures are expected to
be lower than worker exposures, since ONUs do not typically directly handle the chemical. Only
inhalation exposures to vapors are expected, which could be less than worker exposures.
G.6.9 Dry Film Lubricant
The DOE's KCNSC indicated use of 1,4-dioxane as a carrier in the manufacture and application
of a dry film lubricant. The KCNSC is one of eight sites that comprise the DOE's NNSA, which
manufacture 85% of non-nuclear components of nuclear weapons KCNSC (2018).
The facility stated that the dry film lubricant was used on non-nuclear components for nuclear
weapons. The manufacture of the dry film typically initiated by mixing 1,4-dioxane and other
Page 428 of 616
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solvents to create a solvent blend, which generally contained 16% 1,4-dioxane. The solvent
blend was used to manufacture concentrated dry film lubricant with a final 1,4-dioxane
concentration of 4% to 5%. Twelve half-pint containers of concentrated dry film lubricant were
produced in each run DOE (2018a).
Prior to spray application of the dry film lubricant, the facility mixed about 1.5 pints of pure 1,4-
dioxane with a half-pint container of concentrated dry film lubricant. The dry film lubricant and
dioxane mixture was sprayed in a vented paint booth either by hand or an automated system onto
the applicable parts. If the dry film lubricant needed to be removed from a part immediately after
spraying, it was cleaned in an ultrasonic bath filled with one gallon of dioxane for three to five
minutes and then rinsed in alcohol. The dioxane from the ultrasonic cleaner was disposed of in
chemical waste containers. After application, parts were cured in an oven for one hour during
which the 1,4-dioxane was evaporated and vented from the oven stack DOE (2018a).
Dry Film Manufacture
Dry Film Application
Send to
chemical
storage
location
Package
intoK pint
containers,
yield 12.
1,4-dioxane
disposed of
in waste
containers
Receive
1,4-dioxane
in Igal
container
Receive
1,4-dioxane
in Igal
container
Clean spray
equipment with
1,4-dioxane
Cure dry film in oven.
1,4-dioxa ne vented
from oven stack
Manufacture dry
film concentrate.
Contains 4-5%
1,4-dioxane
Use 1 gallon of
1,4-dioxane in
ultra soniccleaner
to remove dry film
1,4-dioxane blended
with other solvents.
Solution contains
16% 1,4-dioxane
Mix 1,4-dioxane with
concentrated dry
film in half gallon
containerin 3:1 ratio
Spray dry film and
1,4-dioxane mixture.
1,4-dioxane is vented
through fume hood
Figure G-10. Process Flow Diagram for Dry Film Lubricant in Nuclear Weapon
Applications
Process flow diagram for dry film lubricant at the KCNSC is shown in Figure G-10. Workers
activities included mixing, packaging, pouring, and spraying the dry film lubricant. If any part
needed to have the dry film lubricant removed soon after spraying, the worker could use a small
ultrasonic bath containing 1,4-dioxane. In addition, workers routinely cleaned the spray gun with
1,4-dioxane. KCNSC estimated that the dry film lubricant was manufactured six to eight times
per year in one-gallon batches and each batch could take about an hour to manufacture.
According to KCNSC, the dry film lubricant was applied, on average, once per week for a
minimum of two hours and a maximum of six hours. These estimates included the mixing,
application, and clean-up steps as described in Figure G-10. Factoring in holidays and down
time, KCNSC estimated dry film lubricant application to be about 48 times per year DOE
(2018a). It was assumed this process and these worker activities could be similar to other sites
that produce and use 1,4-dioxane-based dry film lubricants.
ONUs include employees that work at the site where 1,4-dioxane is used in dry film lubricants,
but they do not directly handle the chemical and are therefore expected to have lower exposures.
Page 429 of 616
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ONUs for dry film lubricant manufacture and use include supervisors, managers, and workers
that perform other tasks but do not directly handle 1,4-dioxane.
Number of Potentially Exposed Workers and Occupational Non-Users
KCNSC provided an estimate of ten exposed or potentially exposed workers at the facility. This
estimate includes three to four employees in the chemical material area where the dry film
lubricant is formulated and another five to six employees who work in the paint shop where the
dry film lubricant is spray applied DOE (2018b). KCNSC estimated that only one employee in
each area is exposed as a worker with the rest considered ONUs.
The KCNSC is one of eight facilities in DOE's NNSA KCNSC (2018). EPA believes that the
operations at different DOE/NNSA facilities vary substantially and that it is unlikely that the
operations at the KCNSC are similar to any of the other facilities. However, the KCNSC 2018)
does not have additional information on operations at the other DOE facilities, so it is unknown
if other DOE NNSA sites use 1,4-dioxane in a similar way. As conservative, EPA assumed all
eight facilities could use 1,4-dioxane for this application and therefore, EPA assessed a total of
16 workers and 64 ONUs potentially exposed to 1,4-dioxane across all NNSA sites. This may be
an overestimate of workers and ONUs.
Worker and Occupational Non-User Exposure Assessment Methodology and Results
KCNSC provided the results of 20 area samples and 12 PBZ monitoring sample measurements to
EPA DOE (2018a). EPA used these data to assess inhalation exposures to 1,4-dioxane for this
condition of use. The PBZ samples included two full shift 8-hour TWA samples and five 8-hour
TWAs that are derived from same-day task-based TWA samples, for a total of seven 8-hour
TWA results, which are included below in Table G-23.
The 20 area samples KCNSC provided were gathered using a direct reading method. Direct
reading instruments provide real-time monitoring using calibrated devices that record multiple
single point readings. These readings do not provide time-weighted average results. Therefore,
EPA did not use the area measurements.
Table G-23. PBZ Task and TWA Monitoring Data for Dry Film Lubricant Manufacture
Process
Tsisk
Siimple
Collodion
Ditlc
Siimple
Duration
(mill)
Siimple
Result
(m "/m1)
( itlculitlccl
-------
Application
Material mixing, spray
application
9/14/2010
30
2.1
0.47
Application
Spray application
9/14/2010
17
3.2
Application
Equipment cleaning,
pour material into step
can
9/14/2010
62
1.6
Application
Material preparation
inside hood or closed
mixing
9/21/2010
60
1.8
0.68
Application
Spray application
9/21/2010
60
1.8
Application
All cleaning steps with
exception of pouring
material into
equipment reservoir;
opening step can (step
can is mixed VOCs)
9/21/2010
50
2.2
Application
Material preparation
inside hood or closed
mixing, pouring
material into
equipment container
inside the hood, and
spray application
10/11/2010
60
1.1
0.25
Application
All cleaning steps
10/11/2010
23
2.5
Application
Material preparation
and spray application
12/1/2011
395
np
1.9
Application
Material preparation,
spray application, and
cleanup
5/16/2013
425
np
0.97
SIP: not provided.
EPA estimated the 95th percentile and 50th percentile of the calculated 8-hour TWA results to
assess the high-end and central tendency exposures, respectively. These values were used to
calculate acute and chronic inhalation exposures as per the equations in Appendix G.2. As
referenced in Section 2.4.1.1.11, KCNSC indicated that the facility manufactured the dry film
lubricant six to eight days per year and applied it about 48 days per year for a total exposure
frequency of 56 days per year. This value was used in place of the standard 250 days per year
assumption outlined in Appendix G.2. Results of these calculations are summarized in Section
2.4.1.1.11.
G.6.10 Disposal
Each of the conditions of use of 1,4-dioxane may generate waste streams of the chemical that are
Page 431 of 616
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collected and transported to third-party sites for disposal, treatment, or recycling. Industrial sites
that treat or dispose onsite wastes that they themselves generate are assessed in each condition of
use assessment in Sections 2.4.1.1.1 through 2.4.1.1.12. Wastes containing 1,4-dioxane that are
generated during a condition of use and sent to a third-party site for treatment, disposal, or
recycling could include the following:
Wastewater: 1,4-Dioxane may be contained in wastewater discharged to POTW or other, non-
public treatment works for treatment. Industrial wastewater containing 1,4-dioxane discharged to
a POTW may be subject to EPA or authorized NPDES state pretreatment programs. The
assessment of wastewater discharges to POTWs and non-public treatment works of 1,4-dioxane
is included in each of the condition of use assessments in Sections 2.4.1.1.1 through 2.4.1.1.12.
Solid Wastes: Solid wastes are defined under RCRA as any material that is discarded by being:
abandoned; inherently waste-like; a discarded military munition; or recycled in certain ways
(certain instances of the generation and legitimate reclamation of secondary materials are
exempted as solid wastes under RCRA). Solid wastes may subsequently meet RCRA's definition
of hazardous waste by either being listed as a waste at 40 CFR § 261.30 to § 261.35 or by
meeting waste-like characteristics as defined at 40 CFR § 261.20 to 261.24. Solid wastes that are
hazardous wastes are regulated under the more stringent requirements of Subtitle C of RCRA,
whereas non-hazardous solid wastes are regulated under the less stringent requirements of
Subtitle D of RCRA.
1,4-Dioxane is listed as a hazardous waste on the U list at 40 CFR § 261.30. This list designates
specific unused commercial chemical products (CCP) that are pure or a commercial grade
formulation as hazardous waste. The hazardous waste code for 1,4-dioxane is U108.
Wastes Exempted as Solid Wastes under RCRA: Certain conditions of use of 1,4-dioxane
may generate wastes of 1,4-dioxane that are exempted as solid wastes under 40 CFR § 261.4(a).
For example, the generation and legitimate reclamation of hazardous secondary materials of 1,4-
dioxane may be exempt as a solid waste.
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2018 TRI data lists off-site transfers of 1,4-dioxane to land disposal, wastewater treatment,
incineration, and recycling facilities (see Figure G-l 1). About 69% of off-site transfers were
incinerated, 19% sent to land disposal, and less than 1% is recycled off-site U.S. U.S. EPA
(2016c).
Recycling
Hazardous Waste
Generation
Hazardous Waste
Transportation
Treatment
Disposal
Figure G-ll. Typical Waste Disposal Process
Source: U.S. EPA (2017d)
Municipal Waste Incineration
Municipal waste combustors (MWCs) that recover energy are generally located at large facilities
comprising an enclosed tipping floor and a deep waste storage pit. Typical large MWCs may
range in capacity from 250 to over 1,000 tons per day. Workers do not generally directly handle
waste materials at the large facilities. Trucks may dump the waste directly into the pit, or waste
may be tipped to the floor and later pushed into the pit by a worker operating a front-end loader.
A large grapple from an overhead crane is used to grab waste from the pit and drop it into a
hopper, where hydraulic rams feed the material continuously into the combustion unit at a
controlled rate. The crane operator also uses the grapple to mix the waste within the pit, in order
to provide a fuel consistent in composition and heating value, and to pick out hazardous or
problematic waste.
Facilities burning refuse-derived fuel (RDF) conduct on-site sorting, shredding, and inspection of
the waste prior to incineration to recover recyclables and remove hazardous waste or other
unwanted materials. Sorting is usually an automated process that uses mechanical separation
methods, such as trommel screens, disk screens, and magnetic separators. Once processed, the
waste material could be transferred to a storage pit, or it could be conveyed directly to the hopper
for combustion.
Tipping floor operations may generate dust. Air from the enclosed tipping floor, however, is
continuously drawn into the combustion unit via one or more forced air fans to serve as the
primary combustion air and minimize odors. Dust and lint present in the air is typically captured
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in filters or other cleaning devices in order to prevent the clogging of steam coils, which are used
to heat the combustion air and help dry higher-moisture inputs Kitto (1992).
Hazardous Waste Incineration
Commercial scale hazardous waste incinerators are generally two-chamber units, a rotary kiln
followed by an afterburner, that accept both solid and liquid waste. Liquid wastes are pumped
through pipes and are fed to the unit through nozzles that atomize the liquid for optimal
combustion. Solids may be fed to the kiln as loose solids gravity fed to a hopper, or in drums or
containers using a conveyor ETC (2018; Heritage (2018).
Incoming hazardous waste is usually received by truck or rail, and an inspection is required for
the waste received. Receiving areas for liquid waste generally consist of a docking area,
pumphouse, and storage facilities. For solids, conveyor devices are typically used to transport
incoming waste ETC (2.018; Heritage (2018).
Smaller scale units that burn municipal solid waste or hazardous waste (such as infectious and
hazardous waste incinerators at hospitals) could require more direct handling of the materials by
facility personnel. Units that are batch-loaded require the waste to be placed on the grate prior to
operation and may involve manually dumping waste from a container or shoveling waste from a
container onto the grate. See Figure G-12.
Emissions Stack
Gas Temperature
Reduction
Waste Storage
* Scrubber Water or
Ash Handling
Ash Handling
Combustion
Feed Preparation
Heat Recovery
Disposal Disposal
Figure G-12. Typical Industrial Incineration Process
Municipal Waste Landfill
Municipal solid waste landfills are discrete areas of land or excavated sites that receive
household wastes and other types of non-hazardous wastes (e.g., industrial and commercial solid
wastes). Standards and requirements for municipal waste landfills include location restrictions,
composite liner requirements, leachate collection and removal system, operating practices,
groundwater monitoring requirements, closure-and post-closure care requirements, corrective
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action provisions, and financial assurance. Non-hazardous solid wastes are regulated under
RCRA Subtitle D, but states may impose more stringent requirements.
Municipal solid wastes may be first unloaded at waste transfer stations for temporary storage,
prior to being transported to the landfill or other treatment or disposal facilities.
Hazardous Waste Landfill
Hazardous waste landfills are excavated or engineered sites specifically designed for the final
disposal of non-liquid hazardous wastes. Design standards for these landfills require double liner,
double leachate collection and removal systems, leak detection system, run on, runoff and wind
dispersal controls, and construction quality assurance program U.S. EPA. (2018a). There are also
requirements for closure and post-closure of a landfill facility, such as the addition of a final
cover over the landfill and continued monitoring and maintenance. These standards and
requirements prevent potential contamination of groundwater and nearby surface water
resources. Hazardous waste landfills are regulated under Part 264/265, Subpart N.
Solvent Recovery
Waste solvents are generated when it becomes contaminated with suspended and dissolved
solids, organics, water, or other substances U.S. EPA. (1980). Waste solvents could be restored to
a condition that permits reuse via solvent reclamation/recycling I _S ; 1980). The recovery
process could involve an initial vapor recovery (e.g., condensation, adsorption and absorption) or
mechanical separation (e.g., decanting, filtering, draining, setline and centrifuging) step followed
by distillation, purification and final packaging U.S. EPA. (1980). Worker activities include
unloading of waste solvents and loading of reclaimed solvents. Figure G-13 illustrates a typical
solvent recovery process flow diagram 980).
Page 435 of 616
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Storage
Tank
Venl
Fugitive
Emissions
Reclaimed
Solvent
~ Incinerator Stack
* Fugitive Emissions
Storage
and
Handling
Storage
and
Handling
Waste
Disposal
Initial
Treatment
Figure G-13. General Process Flow Diagram for Solvent Recovery Processes
U.S. Source: U.S. EPA (1980)
Number of Potentially Exposed Workers and Occupational Non-Users
The total number of sites that treat and dispose wastes containing 1,4-dioxane is unknown. For
reporting year 2018, six hazardous waste treatment and disposal facilities, one solid waste
combustor and incinerator, four cement plants, and one facility listed under Ground or Treated
Mineral Earth Manufacturing report released of 1,4-dioxane to the TRI U.S. EPA (2016c). Table
G-24 presented the estimated number of workers and ONUs at these facilities based on EPA's
analysis of typical employment in those industry sectors. It is possible that additional hazardous
waste treatment facilities treated and disposed 1,4-dioxane but did not meet the TRI reporting
threshold for reporting year 2018. Therefore, the total number of workers and ONUs potentially
exposed to 1,4-dioxane could be greater than 1177 workers and 53 ONUs.
Table G-24. NAICS Codes with Wor
ters and ONUs
'or Disposal
NAICS
Code
NAICS Description
Total
Sites
Total
Workers
Total
ONUs
Number of
Sites that
Reported 1,4-
Dioxane
Workers
Potentially
Exposed to
1,4-Dioxane
ONUs
Potentially
Exposed to
1,4-Dioxane
562211
Hazardous Waste
Treatment and Disposal
892
8,054
4,836
6
54
30
562213
Solid Waste Combustors
and Incinerators
102
1,356
814
1
13
8
327310
Cement Manufacturing
233
5,080
781
4
88
12
Page 436 of 616
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NAICS
Coclc
NAICS Description
Toial
Silcs
Tolal
\\ orkcrs
lolal
ONI s
Nil in hoi' ol
Silos llial
Reported 1.4-
Dioxanc
Workers
Polcnlialh
llxposed lo
l.4-l)io\ane
ONI s
Poien I ia 11>
llxposed lo
l.4-l)io\ane
327992
Ground or Treated
Mineral Earth
Manufacturing a
231
-
-
1
22
3
Grand Totals
3,052
19,820
9,631
12
177
53
aBLS data are not available for the 327992 NAICS code and EPA assessed the number of
workers and ONUs at cement manufacturing facilities as similar.
Worker and Occupational Non-User Activities
At waste disposal sites, workers are potentially exposed via dermal contact with wastes
containing 1,4-dioxane or via inhalation of 1,4-dioxane vapor. Depending on the concentration
of 1,4-dioxane in the waste stream, the route and level of exposure could be similar to that
associated with container unloading activities. The assessments of worker exposure from
chemical unloading activities are in the following sections.
Municipal Waste Incineration
At municipal waste incineration facilities, there could be one or more technicians present on the
tipping floor to oversee operations, direct trucks, inspect incoming waste, or perform other tasks
as warranted by individual facility practices. These workers may wear protective gear such as
gloves, safety glasses, or dust masks. Specific worker protocols are largely up to individual
companies, although state or local regulations may require certain worker safety standards be
met. Federal operator training requirements pertain more to the operation of the regulated
combustion unit rather than operator health and safety.
Workers are potentially exposed via inhalation to vapors while working on the tipping floor.
Potentially-exposed workers include workers stationed on the tipping floor, including front-end
loader and crane operators, as well as truck drivers. The potential for dermal exposures is
minimized by the use of trucks and cranes to handle the wastes.
Hazardous Waste Incineration
More information is needed to determine the potential for worker exposures during hazardous
waste incineration and any requirements for personal protective equipment. There is likely a
greater potential for exposures while operating smaller scale incinerators that involve more direct
handling of the wastes by the worker.
Municipal and Hazardous Waste Landfill
At landfills, typical worker activities may include operating refuse vehicles to weigh and unload
the waste materials, operating bulldozers to spread and compact wastes, and monitoring,
inspecting, and surveying and landfill site CatRecycle (2018).
Worker and Occupational Non-User Exposure Assessment
Bulk Shipments of Liquid Hazardous Waste
It is assumed that the 1,4-dioxane wastes that are generated, transported, and treated or disposed
Page 437 of 616
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as hazardous waste are done so via bulk liquid shipments. For example, a facility that uses 1,4-
dioxane as a processing aid could generate and store the waste processing aid as relatively pure
1,4-dioxane and have it shipped to hazardous waste treatment, storage and disposal facilities
(TSDFs).
Exposure data for this scenario are not known; therefore, the EPA AP-42 Loading Model and the
EPA Mass Balance Inhalation Model were used to estimate inhalation exposures. These models
use default parameter values and assumptions to provide screening level assessments of
inhalation exposures for container loading and unloading operations. EPA used a Monte Carlo
simulation to vary the saturation factor (f), ventilation rate (Q), mixing factor (k), and working
years (WY). See Appendix G.4 for more information about the Monte Carlo simulation.
It is assumed that any exposures related to on-site waste treatment and disposal are addressed in
the assessments for those uses in this report; therefore, this section assesses exposures to workers
for wastes transferred from the use site to an off-site waste treatment and disposal facility. Table
G-25 lists the off-site waste transfers reported in the 2018 TRI. EPA used the total value reported
in this table as the PV for this assessment. It is assumed that the waste chemical is typically
transported to the treatment and disposal sites in 55-gallon drums that estimated 2,427 drums per
year. The 2018 TRI reported 12 waste treatment and disposal sites, resulting in an average of 388
drums per site per year. Facilities are only required to report to TRI if the facility has 10 or more
full-time employees, is included in an applicable NAICS code, and manufactures, processes, or
uses the chemical in quantities greater than a certain threshold (25,000 lb/yr for the manufacture
or processing of the chemical, or 10,000 lb/yr for otherwise use of the chemical). Some sites that
use 1,4-dioxane in this Industrial Uses category may not meet these qualifications and therefore
are not required to report to TRI.
Table G-25. 2018 TRI Off-Site Transfers for 1,4-Dioxane
()IT-Siie Transfer
Total Quanlil> Ki-purli-ri (II))
Land Disposal
543,252
Incineration
1,941,760
Recycled
8,043
Other
1,896
Total
2,494,951
U.S. Source: U.S. EPA. (2016c)
EPA assumed that 1.75 drums are unloaded per site per day. Assuming a default unloading rate
of 20 drums per hour, it would take an estimated 5.4 minutes (0.09 hours) for each site to a single
drum each day. EPA estimated this exposure using the equations and parameters in Appendix
G.2 and averaged the 5.4-minute exposures over an 8-hour shift, assuming the workers are
exposed to 1,4-dioxane while unloading and then not exposed for the rest of the shift. The central
tendency and high-end 8-hour TWA exposures for unloading drums are 1.87 and 6.64 mg/m3,
respectively. EPA also presents the 5.4-minute exposures as central tendency and high-end short-
term exposures EPA used these values to calculate acute and chronic inhalation exposures in the
Monte Carlo simulation, varying working years (WY), using the equations in Appendix G.2.
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Results of these calculations are summarized in Section 2.4.1.1.12.
Modeling was not performed to estimate exposures for ONUs. ONU exposures would be lower
than worker exposures, since ONUs do not typically directly handle the chemical. Only
inhalation exposures to vapors are expected, which would be less than worker exposures.
Municipal Solid Wastes
Certain commercial conditions of use of 1,4-dioxane could generate solid wastes that might be
sent to municipal waste combustors or landfills. For example, spent spray polyurethane foam
insulation containers or spray foam trimmings containing residual 1,4-dioxane used by
contractors and technicians could be disposed as household hazardous waste as it is exempted as
a hazardous waste under RCRA. While some municipalities may have collections of household
hazardous wastes to prevent the comingling of household hazardous wastes with municipal waste
streams, some users could inappropriately dispose of household hazardous wastes in the
municipal waste stream.
EPA was not able to quantitatively assess worker or ONU exposures to 1,4-dioxane within
municipal solid waste streams. The quantities of 1,4-dioxane could be diluted among the
comingled municipal solid waste stream.
G.7 Dermal Exposure Assessment Method
This proposed method was developed through review of relevant literature and consideration of
existing exposure models, such as EPA models and the European Centre for Ecotoxicology and
Toxicology of Chemicals Targeted Risk Assessment (ECETOC TRA).
G.7.1 Incorporating the Effects of Evaporation
Current EPA dermal models do not incorporate the evaporation of material from the dermis. The
dermal potential dose rate, Dexp (mg/day), is calculated as U.S. EPA. C ):
Equation G-13
Dexp — S x Qu x Yderm x FT
Where:
S is the surface area of contact (cm2; defaults: 535 cm2 (Central tendency); 1,070 cm2 (high end).
These values represent the surface area of one side of both hands (central tendency) and the full
surface area of both sides of both hands (high end)), respectively, for the average adult male U.S.
13b").
Qu is the quantity remaining on the skin (mg/cm2-event; defaults: 1.4 mg/cm2-event (central
tendency); 2.1 mg/cm2-event (high end)).
Yderm's the weight fraction of the chemical of interest in the liquid (0 < Yderm < 1).
FT is the frequency of events (integer number per day).
Here Qu does not represent the quantity remaining after evaporation, but represents the quantity
remaining after the bulk liquid has fallen from the hand that cannot be removed by wiping the
skin (e.g., the film that remains on the skin).
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One way to account for evaporation of a volatile solvent would be to add a multiplicative factor
to the EPA model to represent the proportion of chemical that remains on the skin after
evaporation,/abs (0
-------
For this scenario, Frasch 2012.) calculated the fraction of applied mass that is absorbed, based on
the infinite limit of time {i.e., infinite amount of time available for absorption after exposure):
Equation G-16
mabs( °°) 2 + fx
Tabs ~ Mq ~ 2 + 2x
Where:
Mabs is the mass absorbed
Mq is the initial mass applied
f is the relative depth of penetration in the stratum corneum {f= 0.1 can be assumed)
c is as previously defined
Note the simple algebraic solution in Equation G-16 provides a theoretical framework for the
total mass that is systemically absorbed after exposure to a small finite dose (mass/area) of
chemical, which depends on the relative rates of evaporation, permeation, and the initial load. At
"infinite time", the applied dose is either absorbed or evaporated Frasch (: ). The finite dose
is a good model for splash-type exposure in the workplace Frasch and Bunge (2015).
The fraction of the applied mass that evaporates is simply the complement of that absorbed:
Equation G-17
Wlevap (°°) _ _ _ — fx
~ ~'abs ~ 2 + 2x
Where:
mevap is the mass evaporated
The fraction absorbed can also be represented as a function of dimensionless time x (Dt/h2), as
shown in Equation G-18.
Equation G-18
™abs „ V 1 -J - r, ( X2+K2 \ (COSll - f)A„ - COSA,, \
6 " \2+K2+x) { J.K J
where the eigenvalues An are the positive roots of the equation:
Equation G-19
Xn ¦ cot (2n) + x = 0
Equation G-18 and Equation G-19 must be solved analytically. It should be noted that the
dimensionless time x is not a representation of exposure duration for a work activity; rather, it
represents the amount of time available for absorption after the initial exposure dose is applied.
Since most dermal risk assessments are typically more concerned with the quantity absorbed,
rather than the time course of absorption, the simple algebraic solution is recommended over the
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analytical solution.
Large Doses (Case 2: MO > Msat)
For large doses (Mo > Msat), the chemical saturates the upper layers of the stratum corneum, and
any remaining amount forms a residual layer (or pool) on top of the skin. The pool acts as a
reservoir to replenish the top layers of the membrane as the chemical permeates into the lower
layer. In this case, absorption and evaporation approach steady-state values as the dose is
increased, similar to an infinite dose scenario.
The steady-state fraction absorbed can be approximated by Equation G-20:
Equation G-20
fabsM =
Table G-26 presents the estimated absorbed fraction calculated using the steady-state
approximation for large doses (Equation G-20) for 1,4-dioxane.
Page 442 of 616
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Table G-26. Estimated Fraction Evaporated and Absorbed (fabs) using Equation G-20
Chemical Name
1,4-Dioxane
CASRN
123-91-1
Molecular Formula
C4H8O2
Molecular Weight (g/mol)
88.1
Pvp (torr)
40
Universal gas constant, R (L*atm/K*mol)
0.0821
Temperature, T (K)
303
Log Kow
-0.27
Koct
0.5
Sw (g/L)
800
Sw (|ig/cm3)
800,000
Industrial Setting
u (m/s)a
0.1674
Evaporative Flux, y
0.28
Fraction Evaporated
0.22
Fraction Absorbed
0.78
Commercial Setting
u (m/s)a
0.0878
Evaporative Flux, /
0.17
Fraction Evaporated
0.14
Fraction Absorbed
0.86
a EPA used air speeds from Baldwin and Mavnard 1998): t
le 50th percentile of industrial
occupational environments of 16.74 cm/s is used for industrial settings and the 50th percentile
of commercial occupational environments of 8.78 cm/s is used for commercial settings.
G.7.3 Potential for Occlusion
Occlusion refers to skin covered directly or indirectly by impermeable films or substances.
Chemical protective gloves are one of the most widely used forms of PPE intended to prevent
skin exposure to chemicals. Gloves can prevent the evaporation of volatile chemicals from the
skin. Chemicals trapped in the glove may be broadly distributed over the skin (increasing S in
Equation G-13), or if not distributed within the glove, the chemical mass concentration on the
skin at the site of contamination may be maintained for prolonged periods of time (increasing Qu
in Equation G-13). Conceptually, occlusion is similar to the "infinite dose" study design used in
in vitro and ex vivo dermal penetration studies, in which the dermis is exposed to a large,
continuous reservoir of chemical.
The protective measures could produce negative events due to the nature of occlusion, which
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often causes stratum corneum hyper-hydration and reduces the protective barrier properties of
the skin. Many gloves do not resist the penetration of low molecular weight chemicals: those
chemicals may enter the glove and become trapped on the skin under occlusion for many hours.
Breakthrough times for glove materials are often underestimates of the true breakthrough times,
because the measurements do not consider increased temperature and flexing of the material
during use, which is not accounted for in tests to determine breakthrough times. Occlusion by
gloves raises skin temperature and hydration leading to a reduction in its natural barrier
properties. The impact of occlusion on dermal uptake is complex: continuous contact with the
chemical may degrade skin tissues, increasing the rate of uptake, but continuous contact may
also saturate the skin, slowing uptake Dancik et al. ( ). Wearing gloves which are internally
contaminated can lead to increased systemic absorption due to increased area of contact and
reduced skin barrier properties, and repeated skin contact with chemicals can give higher than
expected exposure if evaporation of the carrier occurs and the concentration in contact with the
skin increases. These phenomena are dependent upon the chemical, the conditions of use and
environmental conditions. It is probably not feasible to incorporate these sources of variability in
a screening-level population model of dermal exposure without chemical-specific studies.
EPA does not expect occlusion scenarios to be a reasonable occurrence for all conditions of use.
Specifically, occlusion is not expected at sites using chemicals in closed systems where the only
potential of dermal exposure is during the connecting/disconnecting of hoses used for
unloading/loading of bulk containers (e.g., tank trucks or rail cars) or while collecting quality
control samples including manufacturing sites, repackaging sites, sites processing the chemical
as a reactant, formulation sites, and other similar industrial sites. Occlusion is also not expected
to occur at highly controlled sites, such as pharmaceuticals manufacturing sites, where, due to
purity requirements, the use of engineering controls is expected to limit potential dermal
exposures. EPA also does not expect occlusion at sites where contact with bulk liquid chemical
is not expected such as research laboratories where workers are only expected to handle the
small quantities of the chemical in controlled environments and not the actual bulk liquid
chemical.
G.7.4 Incorporating Glove Protection
Data about the frequency of effective glove use - that is, the proper use of effective gloves - is
very limited in industrial settings. Initial literature review suggests that there is unlikely to be
sufficient data to justify a specific probability distribution for effective glove use for a chemical
or industry. Instead, the impact of effective glove use should be explored by considering
different percentages of effectiveness (e.g., 25% vs. 50% effectiveness).
Gloves only offer barrier protection until the chemical breaks through the glove material. Using a
conceptual model, Cherrie et al. 2004) proposed a glove workplace protection factor - the ratio
of estimated uptake through the hands without gloves to the estimated uptake though the hands
while wearing gloves: this protection factor is driven by flux, and thus varies with time. The
ECETOC TRA model represents the protection factor of gloves as a fixed, assigned protection
factor equal to 5, 10, or 20 Marquart et al. (2017). Where, similar to the APR for respiratory
protection, the inverse of the protection factor is the fraction of the chemical that penetrates the
glove.
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The protection afforded by gloves can be incorporated into the EPA model (Equation G-13) by
modification of Qu with a protection factor, PF (unitless, PF > 1):
Equation G-21
Dexp = s x x Yderm x FT
Given the limited state of knowledge about the protection afforded by gloves in the workplace, it
is reasonable to utilize the PF values of the ECETOC TRA model Marquart et al. (20171 rather
than attempt to derive new values. Table G-27 presents the PF values from ECETOC TRA
model (version 3). In the exposure data used to evaluate the ECETOC TRA model, Marquart et
al. 2017) reported that the observed glove protection factor was 34, compared to PF values of 5
or 10 used in the model.
Table G-27. Exposure Control Efficiencies and Protection Factors for Different Dermal
Protection Strategies from ECETOC TRA v3
Dermal Protection Characteristics
Affected User
Group
Indicated
Efficiency (%)
Protection
Factor, PF
a. Any glove / gauntlet without permeation data and
without employee training
Both industrial and
professional users
0
1
b. Gloves with available permeation data indicating that
the material of construction offers good protection for
the substance
80
5
c. Chemically resistant gloves (i.e., as "b" above) with
"basic" employee training
90
10
d. Chemically resistant gloves in combination with
specific activity training (e.g., procedure for glove
removal and disposal) for tasks where dermal exposure
can be expected to occur
Industrial users only
95
20
G.7.5 Proposed Dermal Dose Equation
Accounting for all parameters above, the proposed, overall equation for estimating dermal
exposure is:
Equation G-22
( Qu x fabs)
Dexp = S x x Yderm x FT
EPA proposes to present exposure estimates for the following deterministic dermal exposure
scenarios:
Dermal exposure without the use of protective gloves (Equation G-22, PF = 1)
Dermal exposure with the use of protective gloves (Equation G-22, PF = 5)
Dermal exposure with the use of protective gloves and employee training (Equation G-22, PF =
20 for industrial users and PF = 10 for professional users)
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EPA assumes the following parameter values for Equation G-22 in addition to the parameter
values presented in Table G-26:
S, the surface area of contact (cm2): 535 cm2 (central tendency) and 1,070 cm2 (high end),
representing the toal surface area of both hands.
Qu, the quantity remaining on the skin: 1.4 mg/cm2-event (central tendency) and 2.1 mg/cm2-
event (high end). These are the midpoint value and high-end of range value, respectively, used in
the EPA/OPPT dermal contact with liquids models 2013b).
Yderm, the weight fraction of the chemical of interest in the liquid: EPA will assess a unique
value of this parameter for each occupational scenario or group of similar occupational scenarios.
FT, the frequency of events: 1 event per day. Equation G-22 shows a linear relationship between
FT and Dexp; however, this fails to account for time between contact events. Since the chemical
simultaneously evaporates from and absorbs into the skin, the dermal exposure is a function of
both the number of contact events per day and the time between contact events. EPA did not
identify information on how many contact events may occur and the time between contact
events. Therefore, EPA assumes a single contact event per day for estimating dermal exposures.
G.7.6 Equations for Calculating Acute and Chronic (Non-Cancer and
Cancer) Dermal Doses
Equation E-12 estimates dermal potential dose rates (mg/day) to workers in occupational
settings. The potential dose rates are then used to calculate acute retained doses (ARD), and
chronic retained doses (CRD) for non-cancer and cancer risks.
Acute retained doses are calculated using Equation G
Equation G-23
Where:
ARD = acute retained dose (mg/kg-day)
Dexp = dermal potential dose rate (mg/kg)
BW = body weight (kg)
CRD is used to estimate exposures for non-cancer and cancer risks. CRD is calculated as
follows:
Equation G-24
Dexv x EF x WY
CRD = p
BW x (AT or ATC)
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Equation G-25
day
AT = WY x 365——
yr
Equation G-26
day
ATC = LTx 365—-
yr
Where:
CRD
= Chronic retained dose used for chronic non-cancer or cancer risk calculations
EF
= Exposure frequency (day/yr)
WY
= Working years per lifetime (yr)
AT
= Averaging time (day) for chronic, non-cancer risk
ATc
= Averaging time (day) for cancer risk
LT
= Lifetime years (yr) for cancer risk
Table XX summarizes the default parameter values used to calculate each of the above acute or
chronic exposure estimates. Where multiple values are provided for EF, it indicates that EPA
may have used different values for different conditions of use. The rationales for these
differences are described below in this section.
Table G-28: Worker Exposure Parameters
Pa rani el er Name
Sy in hoi
Value
1 nil
Exposure Frequency
EF
250
258 (50th percentile) to 293 (95th
percentile) (dry cleaning only)
125 to 150 (DoD - oil analysis
only)
30 to 36 (DoD - water pipe repair
only)
days/yr
Working years
WY
31 (50111 percentile)
40 (95th percentile)
years
Lifetime Years, cancer
LT
78
years
Body Weight
BW
80 (average adult worker)
72.4 (woman of childbearing age)
kg
Averaging Time, non-
cancer
AT
11,315 (central tendency)51
14,600 (high-end)b
day
Averaging Time, cancer
ATC
28,470
day
a Calculated using the 50th percentile value for working years (WY)
b Calculated using the 95th percentile value for working years (WY)
Exposure Frequency (EF)
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EPA generally uses an exposure frequency of 250 days per year with two notable exceptions: dry
cleaning and DoD uses. EPA assumed dry cleaners may operate between five and six days per
week and 50 to 52 weeks per year resulting in a range of 250 to 312 annual working days per
year (AWD). Taking into account fractional days exposed (f) resulted in an exposure frequency
(EF) of 258 at the 50th percentile and 293 at the 95th percentile. For the two DoD uses,
information was provided indicating process frequencies of two to three times per week (oil
analysis) and two to three times per month (water pipe repair). EPA used the maximum
frequency for high-end estimates and the midpoint frequency for central tendency estimates. For
the oil analysis use this resulted in 125 days/yr at the central tendency and 150 days/yr at the
high-end. For the water pipe repair, this resulted in 30 days/yr at the central tendency and 36
days/yr at the high-end.
EF is expressed as the number of days per year a worker is exposed to the chemical being
assessed. In some cases, it may be reasonable to assume a worker is exposed to the chemical on
each working day. In other cases, it may be more appropriate to estimate a worker's exposure to
the chemical occurs during a subset of the worker's annual working days. The relationship
between exposure frequency and annual working days can be described mathematically as
follows:
Equation G-27
EF = fx AWD
Where:
EF = exposure frequency, the number of days per year a worker is exposed to the
chemical (day/yr)
f = fractional number of annual working days during which a worker is exposed to
the chemical (unitless)
AWD = annual working days, the number of days per year a worker works (day/yr)
BLS ) provides data on the total number of hours worked and total number of employees by
each industry NAICS code. These data are available from the 3- to 6-digit NAICS level (where
3-digit NAICS are less granular and 6-digit NAICS are the most granular). Dividing the total,
annual hours worked by the number of employees yields the average number of hours worked
per employee per year for each NAICS.
EPA has identified approximately 140 NAICS codes applicable to the multiple conditions of use
for the ten chemicals undergoing risk evaluation. For each NAICS code of interest, EPA looked
up the average hours worked per employee per year at the most granular NAICS level available
(i.e., 4-digit, 5-digit, or 6-digit). EPA converted the working hours per employee to working days
per year per employee assuming employees work an average of eight hours per day. The average
number of days per year worked, or AWD, ranges from 169 to 282 days per year, with a 50th
percentile value of 250 days per year. EPA repeated this analysis for all NAICS codes at the 4-
digit level. The average AWD for all 4-digit NAICS codes ranges from 111 to 282 days per year,
with a 50th percentile value of 228 days per year. 250 days per year is approximately the 75th
percentile. In the absence of industry- and PCE-specific data, EPA assumes the parameter/is
equal to one for all conditions of use except dry cleaning. Dry cleaning used a uniform
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distribution from 0.8 to 1 for f. The 0.8 value was derived from the observation that the weighted
average of 200 day/yr worked (from BLS/Census) is 80% of the standard assumption that a full-
time worker works 250 day/yr. The maximum of 1 is appropriate as dry cleaners may be family
owned and operated and some workers may work as much as every operating day.
Working Years (WY)
EPA has developed a triangular distribution for working years. EPA has defined the parameters
of the triangular distribution as follows:
Minimum value: BLS CPS tenure data with current employer as a low-end estimate of the
number of lifetime working years: 10.4 years;
Mode value: The 50th percentile tenure data with all employers from SIPP as a mode value for
the number of lifetime working years: 36 years; and
Maximum value: The maximum average tenure data with all employers from SIPP as a high-end
estimate on the number of lifetime working years: 44 years.
This triangular distribution has a 50th percentile value of 31 years and a 95th percentile value of
40 years. EPA uses these values for central tendency and high-end ADC and LADC calculations,
respectively.
The BLS 2014) provides information on employee tenure with current employer obtained from
the Current Population Survey (CPS). CPS is a monthly sample survey of about 60,000
households that provides information on the labor force status of the civilian non-institutional
population age 16 and over; CPS data are released every two years. The data are available by
demographics and by generic industry sectors but are not available by NAICS codes.
The U.S. Census' 2016a) Survey of Income and Program Participation (SIPP) provides
information on lifetime tenure with all employers. SIPP is a household survey that collects data
on income, labor force participation, social program participation and eligibility, and general
demographic characteristics through a continuous series of national panel surveys of between
14,000 and 52,000 households U.S. Census Bureau (2016b). EPA analyzed the 2008 SIPP Panel
Wave 1, a panel that began in 2008 and covers the interview months of September 2008 through
December 2008 U.S. Census Bureau (2016a. b). For this panel, lifetime tenure data are available
by Census Industry Codes, which can be cross-walked with NAICS codes.
SIPP data include fields for the industry in which each surveyed, employed individual works
(TJBIND1), worker age (TAGE), and years of work experience with all employers over the
surveyed individual's lifetime.28 Census household surveys use different industry codes than the
NAICS codes used in its firm surveys, so these were converted to NAICS using a published
crosswalk isus Bureau (2016b). EPA calculated the average tenure for the following age
28 To calculate the number of years of work experience EPA took the difference between the year first worked
(TMAKMNYR) and the current data year (/'. e., 2008). EPA then subtracted any intervening months when not
working (ETIMEOFF).
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groups: 1) workers age 50 and older; 2) workers age 60 and older; and 3) workers of all ages
employed at time of survey. EPA used tenure data for age group "50 and older" to determine the
high-end lifetime working years, because the sample size in this age group is often substantially
higher than the sample size for age group "60 and older". For some industries, the number of
workers surveyed, or the sample size, was too small to provide a reliable representation of the
worker tenure in that industry. Therefore, EPA excluded data where the sample size is less than
five from our analysis.
Table G-29 summarizes the average tenure for workers age 50 and older from SIPP data.
Although the tenure may differ for any given industry sector, there is no significant variability
between the 50th and 95th percentile values of average tenure across manufacturing and non-
manufacturing sectors.
Table G-29: Overview of Average Worker Tenure from U.S. Census SIPP (Age Group 50+)
Working Years
Industry Sectors
Average
50"'
Percentile
95"11
Percentile
.Maximum
All industry sectors relevant to the 10
chemicals undergoing risk evaluation
35.9
36
39
44
Manufacturing sectors (NAICS 31-33)
35.7
36
39
40
Non-manufacturing sectors (NAICS 42-
81)
36.1
36
39
44
Source: Census Bureau, 2016a.
Note: Industries where sample size is less than five are excluded from this analysis.
BLS CPS data provides the median years of tenure that wage and salary workers had been with
their current employer. Table G-30 presents CPS data for all demographics (men and women)
by age group from 2008 to 2012. To estimate the low-end value on number of working years,
EPA uses the most recent (2014) CPS data for workers age 55 to 64 years, which indicates a
median tenure of 10.4 years with their current employer. The use of this low-end value
represents a scenario where workers are only exposed to the chemical of interest for a portion of
their lifetime working years, as they may change jobs or move from one industry to another
throughout their career.
Table G-30: Median Years of Tenure with Current Employer by Age Group
Age
January 200S
January 2010
January 2012
January 2014
16 years and
over
4.1
4.4
4.6
4.6
16 to 17 years
0.7
0.7
0.7
0.7
18 to 19 years
0.8
1.0
0.8
0.8
20 to 24 years
1.3
1.5
1.3
1.3
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25 years and
over
5.1
5.2
5.4
5.5
25 to 34 years
2.7
3.1
3.2
3.0
35 to 44 years
4.9
5.1
5.3
5.2
45 to 54 years
7.6
7.8
7.8
7.9
55 to 64 years
9.9
10.0
10.3
10.4
65 years and
over
10.2
9.9
10.3
10.3
Source: BLS, 2014b.
Lifetime Years (LT)
EPA assumes a lifetime of 78 years for all worker demographics.
Body Weight (BW)
EPA assumes a body weight of 80 kg for all average worker demographics and 72.4 kg for
women of childbearing age.
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Appendix H CONSUMER EXPOSURES
For additional consumer modeling support files, please see the following supplemental
documents: Supplemental Analysis to the Draft Risk Evaluation for 1,4-Dioxane - Consumer
Exposure Assessment Model Input Parameters; Supplemental Analysis to the Draft Risk
Evaluation for 1,4-Dioxane - Exposure Modeling Results and Risk Estimates for Consumer
Exposures.
H.I Consumer Inhalation Exposure
H.1.1 CEM 2.1 and CEM
The Consumer Exposure Models ( and ) predict indoor air
concentrations from consumer product use by implementing a deterministic, mass-balance
calculation utilizing an emission profile determined by implementing appropriate emission
scenarios. The model uses a two-zone representation of the building of use (e.g., residence,
school, office), with Zone 1 representing the room where the consumer product is used (e.g., a
utility room) and Zone 2 being the remainder of the building. The product user is placed within
Zone 1 for the duration of use, while a bystander is placed in Zone 2 during product use.
Otherwise, product users and bystanders follow prescribed activity patterns throughout the
simulated period. Each zone is considered well-mixed. Product users are exposed to airborne
concentrations estimated within the near-field during the time of use and otherwise follow their
prescribed activity pattern. Bystanders follow their prescribed activity pattern and are exposed to
far-field concentrations when they are in Zone 1. Background concentrations can be set to a non-
zero concentration if desired.
The general steps of the calculation engine within the CEM models include:
• Introduction of the chemical (i.e., 1,4-dioxane) into the room of use (Zone 1) through two possible
pathways: (1) overspray of the product or (2) evaporation from a thin film;
• Transfer of the chemical to the rest of the house (Zone 2) due to exchange of air between the
different rooms;
• Exchange of the house air with outdoor air; and
• Compilation of estimated air concentrations in each zone as the modeled occupant (i.e., user or
bystander) moves about the house per prescribed activity patterns.
For acute exposure scenarios, emissions from each incidence of product usage are estimated over
a period of 72 hours using the following approach that accounts for how a product is used or
applied, the total applied mass of the product, the weight fraction of the chemical in the product,
and the molecular weight and vapor pressure of the chemical. Time weighted averages (TWAs)
were then computed based on these user and bystander concentration time series per available
human health hazard data. For 1,4-dioxane, 8-hour TWAs were quantified for use in risk
evaluation based on alignment of relevant acute human health hazard endpoints. For additional
details on CEM 2.l's underlying emission models, assumptions, and algorithms, please see the
User Guide Section 3: Detailed Descriptions of Models within CEM 2.1 U.S. EPA. (2019a). The
emission models used have been compared to other model results and measured data; see
Appendix D: Model Corroboration of the User Guide Appendices for the results of these
analyses U.S. EPA. (2019bY
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For chronic exposure scenarios, CEM within E-FAST 2014 was used to obtain lifetime average
daily concentrations (LADCs) for the scenarios involving chronic exposures. Emissions are
estimated over a period of 60 days. For cases where the evaporation time estimated exceeds 60
days, the model will truncate the emissions at 60 days. Conversely, for cases where the
evaporation time is less than 60 days, emissions will be set to zero between the end of the
evaporation time and 60 days. For more information on this version of CEM and its chronic
inhalation estimates, refer to the E-FAST 2014 Documentation Manual (U.S. EPA. 2007).
Emission Models in CEM 2.1
Based on the suite of product scenarios developed to evaluate the 1,4-dioxane consumer
conditions of use, the specific emission models applied for the purposes of this evaluation
include: El: Emission from Product Applied to a Surface Indoors Incremental Source Model and
E4: Emission from Product Added to Water.
Product Scenarios in CEM
Based on the suite of product scenarios developed to evaluate the 1,4-dioxane consumer
conditions of use, the specific models applied for the purposes of this evaluation include: Product
Applied to Surface - Incremental Source Model and Product Added to Water - Constant Rate
Model.
CEM 2.1's El model and CEM's Product Applied to Surface - Incremental Source Model are
analogous and are generally applicable for liquid products applied to a surface such as cleaners.
These emission models assume a constant application rate over a user-specified duration of use
and an emission rate that declines exponentially over time, at a rate that depends on the chemical
molecular weight and vapor pressure.
CEM 2.1's E4 model and CENM's Product Added to Water - Constant Rate Model assume
emission at a constant rate over a duration that depends on the chemical's molecular weight and
vapor pressure. If this estimated duration is longer than the user-specified duration of use,
chemical emissions are truncated at the end of the product use period and the remaining chemical
mass is assumed to go down the drain. These emission models are applied for use scenarios such
as laundry and dishwashing detergent, dish soap, and textile dye.
H.1.2 MCCEM
The Multi-Chamber Concentration and Exposure Model (MCCEM) estimates indoor air
concentrations of chemicals released from household products EPA. (2010). It uses air infiltration
and interzonal air flow rates with user-input emission rates to calculate time-varying
concentrations in several zones or chambers within a residence. Four types of source models are
available in MCCEM - constant, single exponential, incremental, and data entry. For additional
details, see the MCCEM User Guide 019c).
Within MCCEM, the incremental source model is specifically designed for products that are
applied to a surface (as SPF is) rather than products that are placed in an environment (e.g., an
air freshener). This distinction is important because the incremental source model considers the
time or duration of application or use in its calculations of emissions and concentrations, while
Page 453 of 616
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the single exponential source model does not. The incremental model assumes a constant
application rate over time, coupled with an emission rate for each instantaneously applied
segment that declines exponentially. The equation for the time-varying emission rate resulting
from the combination of constant application and exponentially declining emissions (Evans.
1996) utilized in the single exponential incremental model is shown below. This is a
simplification of the overall incremental model in MCCEM that considers two emission decay
constants and rates to capture emissions from both the evaporation and diffusion phases.
However, the SPF scenario is better modeled by a single decay constant after application.
MxWFxCF
ER(t) = x
|(l — e~k<-t~tstart'>) — ((l — e~k(-t~<-tstart+ta))) x //(t))]
Where:
ER(t)
M
WF
CF
tstart
ta
k
t
H{t)
Emission rate at time t (mg/min)
Mass of product used (g)
Weight fraction of chemical in product (unitless)
Conversion factor (1000 mg/g)
Time of start of application (min)
= Application time (min)
First-order rate constant for emissions decline (min1)
= Time (min)
0/1 value used to indicate if product is actively in use
= 0 if t - (tstart + ta)< 0
= 1 if t - (tstart + ta)> 0
The incremental model can be populated using experimental data and proposed model of
emission rates in Karlovich et al. ! ). In this study, the authors measured air concentrations
of 1,4-dioxane after taking samples from an open-cell SPF product applied to a cardboard box
and placed in a small-scale environmental chamber. These concentrations were used to develop a
mathematical relationship between the emission factor and loading factor based on the volume
and airflow of the chamber.
Where:
EF
r
°chamber
LF
ACH
EF =
-chamber
LF X ACH
Emission Factor (|ig/m2-hr)
Chamber concentration (|ig/m3)
Loading factor (m2/m3)
air changes per hour
Based on the chamber air flow rate, foam sample surface area, and indoor air assumptions, the
above equation can be reworked to find predicted air concentrations:
-air, predicted
EF x 0.5
03
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The concentration data can be used to determine decay rates by fitting the data to a time series
concentration function associated with MCCEM's incremental model. The general mass-balance
equation for a test chamber can be integrated assuming an initial concentration of zero to the
following:
Karlovich et al. ) collected air samples 4, 12, 24, and 48 hours after placing the sample in
the chamber. Predicted indoor air concentrations (1,479, 663, 201, and 40 |ig/m3, respectively)
were fitted to the concentration equation above to identify the initial emission rate and decay
constant, 73.868 |ig/hr and 0.1 hr"1, respectively. The emission rate was normalized to the
applied surface area of SPF in the study (25 square inches) to find an emission rate per square
inch of SPF applied, 2.955 |ig/in2/hr. This initial emission rate and decay constant can then be
scaled appropriately to find the total mass applied in each application setting (attic, basement,
and garage).
H.l.2.1 MCCEM Inputs for SPF Scenario
Product and Exposure Settings
The suggested values for house volume (492 m3) and air exchange rate (0.45 ACH) are central
values from the Exposure Factors Handbook (EPA. ). A two-story house is assumed for all
cases. The attic volume is assumed to be half the volume of one story, or 123 m3. The basement
volume is assumed to be the volume of one story, or 246 m3. The assumed garage volume (118
m3) is the average volume of one- and two-car garages in 15 single-family homes with attached
garages, as reported by Batterman et al. 2007. The attic and garage are assumed to be outside of
the standard house volume as they are not modeled to be conditioned or finished.
• For the attic scenario, interzonal airflow rates were applied based on measured air change
rates at a variety of temperatures and wind speeds for vented and unvented attics (Walker et
al. 2005). The central measured value at wind speeds of 2-3 m/s was about 1.5 air changes
per hour (ACH) for the unvented attic and about 6.0 ACH for the vented. The latter case is
used in this scenario as most US homes are assumed to have vented attics. When multiplied
by the volume of the attic, this 6.0 ACH rate corresponds to an interzonal airflow rate of 738
m3/hr between the attic and outdoors. Walker et al. also considered the airflow between
unconditioned attics and the remainder of the houses, measuring an average of about 0.125
ACH at standard temperatures of 20-25°C. This corresponds to an interzonal airflow rate of
61.5 m3/hr between the attic and the rest of the house (ROH). The suggested value of 0.45
C(t) = — x (e~kt - e v
Where:
C(t)
E0
V
Q
k
t
Concentration (|ig/m3)
Initial emission rate (ng/hr)
Volume of the chamber (m3)
Airflow rate into and out of the chamber (m3/hr)
First-order rate constant (hr1)
Time (hr)
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ACH was applied for the rest of the house and outdoors, corresponding to an interzonal
airflow rate of 221.4 m3/hr.
• For the basement scenario, interzonal airflow rates were applied using an algorithm
developed in a study estimating the distributions for residential air exchange rates (Koontz
and Rector. 2005). The estimated interzonal airflow rate between both basements and
garages is estimated at 109 m3/hr. The suggested value of 0.45 ACH was applied for the rest
of the house and outdoors, corresponding to an interzonal airflow rate of 110.7 m3/hr.
• For the garage scenario, interzonal airflow rates were informed by the results of a study
measuring the airtightness of garages on a variety of homes under induced pressurized
conditions (Emmerich et al. 2003). The average airtightness measured with the blower door
was 48 ACH at 50 Pa, which corresponds to an air exchange rate of about 2.5 ACH and 295
m3/hr under normal conditions. The suggested value of 0.45 ACH was applied for the rest of
the house and outdoors, corresponding to an interzonal airflow rate of 221.4 m3/hr.
A typical floor or ceiling loading ratio of 0.41 m2/ m3 (i.e., for a ceiling height of 2.44 m; EPA,
2011), when multiplied by the upstairs volume of 246 m3, gives an estimated attic floor area of
100.9 m2 (1086 sq. feet or 156,384 sq. inches). The same ratio applies to the garage ceiling,
giving an estimated area of 48.4 m2 (521 sq. feet or 75,024 sq. inches) when multiplied by the
garage volume of 118 m3. The basement volume (246 m3) and ceiling height (2.44 m) indicate a
floor area of 100.8 m2, corresponding to dimensions of 7.9 m by 12.8 m. The wall area is 2.44 m
x (7.9 m x 2 + 12.8 m x 2) = 101 m2 or 1087 sq. ft. or 156,528 sq. inches. These areas of
application surface were multiplied by the emission rate per square inch over the decay rate per
hour to determine the total mass of 1,4-dioxane released in each setting: 4523.752659 mg in the
attic, 4527.918177 mg in the basement, and 2170.234931 mg in the garage.
Use Patterns and Exposure Factors
An installation rate of 3 sq. ft./min or 180 sq. ft./hour is assumed, based on an instructional video
for DIY spray foam insulation installation. Corresponding estimates for the duration of
installation are 6 hours for the attic floor, 6 hours for basement walls, and 3 hours for the garage
ceiling. Each application was modeled to start at 9 AM. It is assumed that the user would be in
the room of use during the time of application and in the rest of the house for the remainder of
the model run. This assumption of staying at home produces a conservative estimate of exposure.
Bystander exposure is based on the assumption that the bystander is home during the application
period but spends the entire time in the rest of the house and no time in the room of use.
In MCCEM, a breathing rate of 15.083 m3/day was estimated based on the recommended mean
long-term exposure inhalation values in the 2011 Exposure Factors Handbook (EPA. 2011).
H.2 Consumer Dermal Exposure
Two models were used to evaluate consumer dermal exposures, the Fraction Absorbed model
(P_DE2a within CEM) and the Permeability model (P_DER2b within CEM). A brief comparison
of these two dermal models through the calculation of acute dose rates (ADRs) is provided
below. They have been applied to distinct exposure conditions, with the permeability model
applied to scenarios likely to involve occluded dermal contact where evaporation may be
inhibited and the fraction absorbed model applied to scenarios less likely to involve occluded
dermal contact.
Page 456 of 616
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The dermal models described below were run for all consumer conditions of use to provide a
comparison between the two results while recognizing each model is unique in its approach to
estimating dermal exposure and may not be directly comparable. Keeping these limitations in
mind, the full suite of exposure results from both models is shown for all conditions of use in
Supplemental Analysis to the Draft Risk Evaluation for 1,4-Dioxane - Exposure Modeling
Results and Risk Estimates for Consumer Exposures.xlsx.
Because neither model considers the mass of chemical as an input in the absorbed dose
equations, both have the potential to overestimate the dermal absorption by modeling a mass
which is larger than the mass used in a scenario. Therefore, when utilizing either of the CEM
models for dermal exposure estimations, a mass check is necessary outside of the CEM model to
make sure the mass absorbed does not exceed the typical mass used for a given scenario.
CEM Absorption Fraction Model (P_DER2a)
The fraction absorbed model estimates the mass of a chemical absorbed through the applicational
of a fractional absorption factor to the mass of chemical present on or in the skin following a use
event. The initial dose or amount retained on the skin is determined using a film thickness
approach. A fractional absorption factor is then applied to estimate the absorbed dose from the
initial dose. The fraction absorbed is essentially the measure of two competing processes,
evaporation of the chemical from the skin surface and penetration deeper into the skin. It can be
estimated using an empirical relationship based on Frasch and Bunge 2.015). Due to the model's
consideration of evaporative processes, dermal exposure under unimpeded exposure conditions
was considered to be more representative. For additional details on this model, please see
Appendix H and the CEM User Guide Section 3: Detailed Descriptions of Models within CEM
( 2019a).
The acute form of the absorption fraction model is given below:
SA
AR x Fabs x w x FQac x Dil xWFx EDac x CF1
Ar\D — P VV
Where:
ADR
= Acute daily dose rate (mg/kg-day)
AR
= Amount retained in the skin (g/cm2, film thickness [cm] multiplied by product density)
F abs
= Absorption fraction (see below)
Dac
= Duration of use (min/event)
SA/BW
= Surface area to body weight ratio (cm2/kg)
FQac
= Frequency of use (events/day, 1 for acute exposure scenarios)
Dil
= Product dilution fraction (unitless)
WF
= Weight fraction of chemical in product (unitless)
EDac
= Exposure duration (1 day for acute exposure scenarios)
CF1
= Conversion factor (1,000 mg/g)
ATcr
= Averaging time (1 day for acute exposure scenarios)
The fraction absorbed (Fabs) term is estimated using the ratio of evaporation from the stratum
corneum to the dermal absorption rate through the stratum corneum, as informed by gas phase
Page 457 of 616
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mass transfer coefficient, vapor pressure, molecular weight, water solubility, real gas constant,
and permeability coefficient.
3 +1
FR.
i_expC_a__i_)
xabs
3(1 +X)
Where:
X = Ratio of the evaporation rate from the stratum corneum (SC) to the dermal absorption rate
a = Constant (2.906)
Dac = Duration of use (min/event)
ti:ig = Lag time for chemical transport through SC (hr)
CFi = Conversion factor (60 min/hr)
The chronic form of the dermal absorption fraction model is given below:
C/l
AR x Fabs x -nTjT x FQcr x Dil x WF x EDcr x CF1
LADD = — ^^
ATcr X CF2
Where:
LADD = Lifetime average daily dose (mg/kg-day)
Dcr = Duration of use (min/event)
FQCT = Frequency of use (events or days/year)
EDcr = Exposure duration (57 years)
CF2 = Conversion factor (365 days/yr)
ATcr = Averaging time (78 years)
CEM Permeability Model (P_DER2b)
The permeability model estimates the mass of a chemical absorbed and dermal flux based on a
permeability coefficient (Kp) and is based on the ability of a chemical to penetrate the skin layer
once contact occurs. It assumes a constant supply of chemical directly in contact with the skin
throughout the exposure duration. Kp is a measure of the rate of chemical flux through the skin.
The parameter can either be specified by the user (if measured data are reasonably available) or
be estimated within CEM using a chemical's molecular weight and octanol-water partition
coefficient (Kow). The permeability model does not inherently account for evaporative losses
(unless the available flux or Kp values are based on non-occluded, evaporative conditions),
which can be considerable for volatile chemicals in scenarios where evaporation is not impeded.
While the permeability model does not explicitly represent exposures involving such impeded
evaporation, the model assumptions make it the preferred model for an such a scenario. For
additional details on this model, please see Appendix H and the CEM User Guide Section 3:
Detailed Descriptions of Models within CEM ( 1019a).
The acute form of the dermal permeability model is given below:
SA
KpXD^xpx-srrrX FQac x Dil x WF x EDac x CF1
ADR = —
ATac X CF2
Where:
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ADR = Potential acute dose rate (mg/kg-day)
Kp = Permeability coefficient (cm/hr)
Dac = Duration of use (min/event)
p = Density of formulation (g/cm3)
SA/BW = Surface area to body weight ratio (cm2/kg)
FQac = Frequency of use (events/day, 1 for acute exposure scenarios)
Dil = Product dilution fraction (unitless)
WF = Weight fraction of chemical in product (unitless)
EDac = Exposure duration (1 day for acute exposure scenarios)
CF1 = Conversion factor (1,000 mg/g)
CF2 = Conversion factor (60 min/hr)
ATac = Averaging time (1 day for acute exposure scenarios)
The chronic form of the dermal permeability model is given below:
C/l
Kv x Dcr x p x -nTjT x FQcr x Dil x WF x EDcr x CF1
LADD = —
A I'cr X C. /* 2 X CF%
Where:
LADD
= Lifetime average daily dose (mg/kg-day)
Dcr
= Duration of use (min/event)
FQcr
= Frequency of use (events or days/year)
EDcr
= Exposure duration (57 years)
CF3
= Conversion factor (365 days/yr)
ATcr
= Averaging time (78 years)
H.3 Measured Emission Data
Systematic review identified several studies reporting emission rates or chamber emission
concentrations of 1,4-dioxane from spray foam and paint samples. These emission data are
summarized below. These data are not directly comparable to the predicted 8-hr TWAs presented
for consumer exposure scenarios, as the 8-hr TWAs are zone-integrated to account for the
activity patterns of the user or bystander (i.e., the presented TWAs account for a user or
bystander's movement throughout the house - Zones 1 and 2 - for the 8-hr period).
As described above, Karlovich et al. \ ) identified 1,4-dioxane in emissions from a two-
component open-cell SPF hours and days after application. Chamber concentrations and
emission factors were calculated from these sampling results. The emission factors were then
used to predict indoor air concentrations (1,479, 663, 201, and 40 |ig/m3 for samples measured at
4, 12, 24, and 48 hours, respectively).
Naldzhiev et al. 2019) analyzed volatile organic compound presence in and emissions from three
spray foam insulation products. Authors measured 1,4-dioxane in a two-component closed-cell
SPF product, both in the raw material (i.e., mixed spray foam, pre-application) and in the
headspace from the cured foam. Air concentrations were not reported, but findings confirm 1,4-
dioxane's presence in closed-cell SPF products. 1,4-Dioxane was not detected in the other two
products tested including a commercially available, two-component closed-cell spray foam and a
commercially available, one-component spray foam.
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Poppendieck et al. 2017) reported concentrations of 1,4-dioxane in micro-chamber air sampling
of a high-pressure closed-cell spray foam. Initial concentrations {i.e., at sampling time 0) were
just above 100 |ig/m3 and fell below 50 |ig/m3 after roughly 48 hours of sampling. In the authors'
related final report Poppendieck (2017). additional 1,4-dioxane chamber concentrations were
reported for a "non-ideal" closed-cell spray foam. The non-ideal foam samples were submitted
by the Consumer Product Safety Commission (CPSC) to reflect non-ideal preparation or
application conditions such as off-ratio mixing of two-component foams, low substrate
temperature, and incorrect nozzle pressure or temperature. Chamber concentrations measured
from the non-ideal closed-cell foam were higher, falling between 500 and 1,000 |ig/m3 at
sampling time 0, -500 |ig/m3 at 48 hours, and falling below 250 |ig/m3 around 175 hours.
Won et al. 2014) tested 30 building materials for 121 VOCs and reported measured chamber
concentrations and emission factors for 1,4-dioxane in two of the product types covered in this
consumer evaluation: foam insulation and paint. Chamber concentrations of 1,4-dioxane from
various insulation products ranged from 0.25 to 44.68 |ig/m3 at six hours, with the highest level
measured from a two-component, closed-cell foam. Chamber concentrations of 1,4-dioxane from
various paint products ranged from 0.80 to 1.74 |ig/m3 at six hours, with the highest level
measured from an interior latex paint. Study authors cite mean emission rates of 15.72 |ig/m2/hr
and 1.97 |ig/m2/hr for insulation and paint, respectively.
The Danish EPA's 2018 Survey and Risk Assessment of Chemical Substances in Chemical
Products Used for "Do-It-Yourself' Projects in the Home EPA. (2018a) measured respiratory
zone concentrations during a realistic use of specific products in a test room and then measured
subsequent emissions in a climate chamber after five hours, three days, and 28 days. During
application of water-based, two-component epoxy floor paint, respiratory zone levels of 1,4-
dioxane were 220 |ig/m3. At five hours, levels decreased to 21 |ig/m3. In a 2020 follow-up
survey, the Danish EPA 2.019a) tested additional products and reported chamber concentrations
of 1,4-dioxane from two-component paint and lacquer ranging from 7 to 460 |ig/m3 at five hours.
Following application of floor polish, levels of 1,4-dioxane were measured at 68-70 |ig/m3 at five
hours.
Although measured chamber or test room concentrations are not directly comparable to the 8-hr
TWAs estimated for the various consumer exposure scenarios, on the whole, these emission
studies bolster confidence in the predicted air concentrations for the SPF and paint and floor
lacquer conditions of use.
The predicted 8-hr TWAs for SPF range from 160 to 890 |ig/m3 for users. These predicted
estimates fall within the range predicted in Karlovich et al., 201 lb) for samples measured at four
and 12 hours. Peppendieck et al. 2017) also reported measured air concentrations that encompass
the modeled consumer exposure estimates, with concentrations from non-ideal closed-cell spray
foam ranging from 500 to 1,000 |ig/m3 over the first 48 hours. Won et al. 2014) reported levels
of 1,4-dioxane well below the CEM 2.1 predictions, from 0.25 to 44.68 |ig/m3 at six hours for
various insulation products including foam board and two-component open- and closed-cell
spray foams.
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The predicted 8-hr TWA for paint and floor lacquer is 20 |ig/m3 for users, which is roughly one
order of magnitude greater than concentrations measured in Won et al. 2014) (0.8 - 1.74 |ig/m3
at six hours), but aligns with the Danish EPA's measured air concentration five hours after
application of the two-component epoxy floor paint (21 |ig/m3) EPA. (2018a). The predicted
TWA also falls within the range of air concentrations taken five hours after application in the
Danish EPA's 2020 Follow-Up study, which reported levels from 7 to 460 |ig/m3 at five hours.
H.4 CEM Model Sensitivity Analysis Summary
The CEM 2.1 developers conducted a detailed sensitivity analysis for CEM, as described in
Appendix C of the CEM User Guide U.S. EPA. (2019b). The CEM developers included results of
model corroboration analysis in Appendix D of the CEM User Guide U.S. EPA. (2.019b).
In brief, the analysis was conducted on continuous variables and categorical variables that were
used in CEM emission or dermal models. A base run of different CEM models using various
product or article categories, along with CEM defaults, was used. Individual variables were
modified, one at a time, and the resulting Acute Dose Rate (ADR) and Chronic Average Daily
Dose (CADD) were compared to the corresponding results for the base run. Benzyl alcohol, a
VOC, was used as an example for product models such as those applied in this evaluation of 1,4-
dioxane.
The tested model parameters were increased by 10%. The measure of sensitivity for continuous
variables such as mass of product used, weight fraction, and air exchange rate was "elasticity,"
defined as the ratio of percent change in each result to the corresponding percent change in
model input. A positive elasticity indicates that an increase in the model parameter resulted in an
increase in the model output, whereas a parameter with negative elasticity is associated with a
decrease in the model output. For categorical variables such as receptor activity pattern {i.e.,
work schedule) and room of use, the percent difference in model outputs for different category
pairs was used as the measure of sensitivity.
The results are summarized below for the inhalation and dermal models used to evaluate
consumer exposures to 1,4-dioxane {i.e., emission models El and E3 and the dermal
permeability model P_DER2b. For full results and additional background, refer to Appendix C
of the CEM User Guide 317b).
H.4.1 Continuous Variables
For acute exposures generated from emission model El, WF (weight fraction) and M acute
(mass of product used) have the greatest positive elasticities of the tested parameters. The next
most sensitive parameters demonstrate negative elasticity and include: Vol Building (building
volume); AER_Zone2 (air exchange rate in Zone 2); AER Zonel (air exchange rate in Zone 1);
Vol Zonel (room of use, or Zone 1 volume). Inhalation exposures from liquid products applied
to surface such as surface cleaner were modeled using El.
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El Elasticity for ADR and CADD
-0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1
Elasticity (% change in dose/% change in variable)
¦ ADR Negative ~ ADR Positive ~ CADD Negative ~ CADD Positive
WF
VP*
VP
Vol_Zonel
Vol_Building
Q_zl2
MW*
MW
MChronic
M_Acute
AER_Zone2
AER Zonel
1.2
Figure H-l. Elasticities (> 0.05) for Parameters Applied in El
For acute exposures generated from emission model E4, WF (weight fraction), M acute (mass of
product used), VP (vapor pressure), and MW (molecular weight) have the greatest positive
elasticities of the tested parameters. The next most sensitive parameters demonstrate negative
elasticity and include: Vol Zonel (room of use volume); Qzl2 (interzonal ventilation rate);
Vol Building (building volume); AER_Zone2 (air exchange rate in Zone 2); AER Zonel (air
exchange rate in Zone 1). Inhalation exposures from products added to water such as laundry
detergent and dish soap were modeled using E4.
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E4 Elasticity for ADR and CADD
=¦ WF
VP*
J VP
i VolZonel
VolBuilding
Q_zl2
MW*
MW
^^MChronic
, MAcute
DurationChronic
i DurationAcute
AER_Zone2
AERZonel
-0.4 -0.2 0 0.2 0.4 0.6 0.8 1 1.2
Elasticity (% change in dose/% change in variable)
¦ ADR Negative ¦ ADR Positive ¦ CADD Negative ~ CADD Positive
Figure H-2. Elasticities (> 0.05) for Parameters Applied in E4
For acute exposures generated from the dermal permeability model, the chemical properties that
inform absorption rate, or absorption rate estimates, have the greatest elasticities. For 1,4-
dioxane, dermal exposures from consumer product formulations were modeled using a measured
Kp (permeability coefficient). Therefore, LogKow (octanol/water partition coefficient) and MW
(molecular weight) were not used to estimate skin penetration.
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MW*
LogKow*
-2.0 -1.0 0.0 1.0 2.0 3.0
Elasticity (% change in dose/% change in variable)
¦ ADR Megative M ADR Positive ~ CADD Negative ~ CADD Positive
Figure H-3. Elasticities (> 0.05) for Parameters Applied in P_DER2b
H.4.2 Categorical Variables
For categorical variables there were multiple parameters that affected other model inputs. For
example, varying the room type changed the ventilation rates, volume size and the amount of
time per day that a person spent in the room. Thus, each modeling result was calculated as the
percent difference from the base run. Among the categorical variables, the most sensitive
parameters included receptor type (adult vs. child), room of use (Zone 1) selection, and
application of the near-field bubble within Zone 1. However, these types of variables were held
constant within a given product modeling scenario and were applied using consistent
assumptions across all modeling scenarios.
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Appendix I HUMAN HEALTH HAZARDS
1.1 Hazard and Data Quality Summary Tables by study duration/endpoint
1.1.1 Hazard and Data Evaluation Summary for Human Studies
Target Organ/
System
Outcome/ Endpoint
Study Population
Exposure
Results
Reference
Data Quality
Evaluation
ADME/PBPK
Half-lives of 1,4-dioxane
determined in plasma and
urine
4 Caucasian males, ages 40-
49, scientists and businessmen
at Dow Chemical, Freeport,
Texas
Subjects exposed to 50ppm
1,4-dioxane in air for 6 hrs
Half-life determined for 1,4-
D in plasma, statistical
significance relative to an
unexposed population is not
applicable
Young et
•I l!< ' )
Medium
Cancer
Breast cancer incidence
Participants in the California
Teacher Study cohort, 1995-
201 l,(n=l 12,378 women)
National-Scale Air Toxics
Assessment Modeled air
concentrations
No significant association
between breast cancer
incidence and 1,4-D
exposure
Garcia et
High
1.1.2 Hazard and Data Quality Evaluation Summary for Acute and Short-Term Studies
The acute, short-term table focuses on a single IS
OAEL or LOAEL per study wit
i footnotes related to other effects measured/observed.
Target Organ/
System1
Study
Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations"
Duration
Effect Dose or
Concentration
(NOAEL,
LOAEL, LCso)
(mg/m3 or
mg/kg-bw/day)
(Sex)
Effect
Reference
Data
Quality
Evaluation
Hepatic
Acute
Rat, CD-I, M
(n= unknown
treated and
controls)
Inhalation,
vapor,
whole-
body
3603 or 7207
mg/m3 (1000 or
2000 ppm)
4 hours
LOAEC = 3603
mg/m3 (M)
Increased
serum liver
enzymes
w et
8)
Medium
-------
Target Organ/
System1
Study
Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations3
Duration
Effect Dose or
Concentration
(NOAEL,
LOAEL, LCso)
(mg/m3 or
mg/kg-bw/day)
(Sex)
Effect
Reference
Data
Quality
Evaluation
Respiratory '¦ 0
Acute
Rat,
F344/DuCrl
(n =
10/sex/conc.)
Inhalation,
vapor,
whole-
body
0, 429, 1013,
2875, 7920,
21,630 mg/m3 (0,
119, 281,798,
2198, 6002 ppm)
6 hours
NOAEC = 2875
mg/m3
Vacuolar
change in
olfactory and
respiratory
epithelium (2
rats at two days
but not 2 weeks
after exposure)
Mattie et
al. (20121
Medium
Hepatic, renal,
respiratory b c
Short-term
Rat, Fischer
344 rats (n=
64 treated and
controls)
Inhalation,
vapor,
whole-
body
0, 378, 5599,
11,690 mg/m3 (0,
105, 1554, 3245
ppm)
6h/d,
5 d/wk for
2 wk,
assessed
Id and
2wk post
exposure
LOAEC = 378
mg/m3
Lesions in nasal
cavity, liver,
and kidney;
hepatic single
cell necrosis
Mattie et
al. (2012)
High
Neurologicald
Short-term
Rat, CFE,e
F (n = 8)
Inhalation,
vapor,
whole-
body
5405, 10,810,
21,620 mg/m3
(1500, 3000, 6000
ppm)
4 hrs/day,
5 days a
week for
10
exposures
NOAEC = 5405
mg/m3
Decreased
avoidance
response
Goldberg
et al.
>4)
Medium
a Concentrations in ppm were converted to mg/m3 using the following equation: ppm*mw (88. l)/24.45. 24.45 is the gas constant at 760 mm Hg (101 kPa) atmospheric pressure
and at 25 °C.
b The neurological/behavioral endpoints from these studies received an unacceptable rating and therefore, were not included in the above table and body weight changes
not reported.
0 No effects on hepatic, renal, hematology, clinical chemistry endpoints.
d Body weight changes were observed at the highest concentration.
e Presumed to be Sprague-Dawley rats.
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1.1.3 Hazard and Data Evaluation Summary for the Developmental Toxicity Study
Target Organ/
System
Study
Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Effect Dose or
Concentration
(NOAEL,
LOAEL, LCso)
(mg/m3 or
mg/kg-bw/day)
(Sex)
Effect
Reference
Data
Quality
Evaluation
Reproductive
toxicity (adverse
effects on
development of
the offspring)
Developm
ental
Rat, Sprague
Dawley, F
(n=18-
20/group)
Oral,
gavage
0, 250, 500 or
1000 mg/kg-
bw/day
GDs 6-15
NOAEL=500
mg/kg-bw/day
(F)
LOAEL= 1,000
mg/kg-bw/day
(F)
Delayed
ossification of
the sternebrae
and reduced
fetal body
weight
Giavini et
5)
High
1.1.4 Hazard and Data Evaluation Summary for Subchronic and Chronic Non-Cancer Studies
The endpoints in the tables below focus on hepatic, renal and respiratory endpoints, the critical endpoints for 1,4-dioxane. NOAELs (or
LOAELs) are provided for each critical endpoint; BMD modeling has also been conducted for some studies (as presented elsewhere).
Although additional endpoints may have been reported or examined in these studies, they are observed less often or are less sensitive and
have not been included in this table.
Page 467 of 616
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INHALATION
Target Organ/
System
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations"
Duration
Effect Dose or
Concentration
(NOAEL,
LOAEL, LCso)
(mg/m3 or
mg/kg-bw/day)
(Sex)
Effect
Reference
Data Quality
Evaluation
Respiratory
Subchronic
Rat,
F344/DuCij,
M/F
(n=20/group)
Inhalation,
vapor,
whole
body
0, 360, 721, 1441,
2883, 5765,
11,530 or 23,060
mg/m3
(0, 100, 200, 400,
800, 1600, 3200
or 6400 ppm)
6
hours/day,
5
days/week
for 13
weeks
NOAEC= 360
(M/F) mg/m3
Increased
relative lung
weight
Kasai et
al. (2.008)
High
Respiratory
Chronic
Rat,
F344/DuCij,
M
(n=50/group)
Inhalation,
vapor,
whole
body
0, 180, 900 or
4500 mg/m3
(0, 50, 250 or
1250 ppm)
6
hours/day,
5
days/week
for 2 years
LOAEC= 180
mg/m3 (M)
Nasal cavity:
atrophy and
metaplasia in
olfactory
epithelium
Kasai et
al. (2009)
High
Hepatic
Subchronic
Rat,
F344/DuCij,
M/F
(n=20/group)
Inhalation,
vapor,
whole
body
0, 360, 721, 1441,
2883, 5765,
11,530 or 23,060
mg/m3
(0, 100, 200, 400,
800, 1600, 3200
or 6400 ppm)
6
hours/day,
5
days/week
for 13
weeks
NOAEC (F) =
2883
mg/m3
Liver focib
Kasai et
al. (2008)
High
Hepatic
Chronic
Rat,
F344/DuCij,
M
(n=50/group)
Inhalation,
vapor,
whole
body
0, 180, 900 or
4500 mg/m3
(0, 50, 250 or
1250 ppm)
6
hours/day,
5
days/week
for 2 years
NOAEC = 901
mg/m3
Liver foci,
spongiosis
hepatis,
necrosis,
increased
enzymes and
liver weight
Kasai et
al. (2009)
High
Renal
Subchronic
Rat,
F344/DuCij,
M/F
(n=20/group)
Inhalation,
vapor,
whole
body
0, 360, 721, 1441,
2883, 5765,
11,530 or 23,060
mg/m3
(0, 100, 200, 400,
800, 1600, 3200
or 6400 ppm)
6
hours/day,
5
days/week
for 13
weeks
NOAEC (F) =
5765
mg/m3
Hydropic
change in
proximal
tubule
Kasai et
High
Page 468 of 616
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Target Organ/
System
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations3
Duration
Effect Dose or
Concentration
(NOAEL,
LOAEL, LCso)
(mg/m3 or
mg/kg-bw/day)
(Sex)
Effect
Reference
Data Quality
Evaluation
Renal
Chronic
Rat,
F344/DuCr j,
M
(n=50/group)
Inhalation,
vapor,
whole
body
0, 180, 900 or
4500 mg/m3
(0, 50, 250 or
1250 ppm)
6
hours/day,
5
days/week
for 2 years
NOAEC = 901
mg/m3 0
hydropic
change and
decreased
urine pH
Kasai et
al. (2009)
High
11 Concentrations in ppm were converted to mg/m3 using the following equation: ppm*mw (88. l)/24.45. 24.45 is the gas constant at 760 mm Hg (101 kPa) atmospheric pressure
and at 25 °C.
b Liver weights were increased at > 2912 mg/mg3 (800 ppm); single cell necrosis, centrilobular swelling and increased liver enzymes seen at 11,650 mg/m3
0 Nuclear enlargement of proximal tubule observed at 910 mg/m3
ORAL
Target Organ/
System1
Study
Type
Species/
Strain/Sex
(Number/
group)2
Exposure
Route
Doses/
Concentrations3
Duration4
Effect Dose or
Concentration
(NOAEL,
LOAEL,
LCso)5 (mg/m3
or mg/kg-
bw/day) (Sex)
Effect6
Reference7
Data Quality
Evaluation8
Hepatic
Chronic
Rat, Wistar, M
(n=26 treated, 9
controls)
Oral,
drinking
water
0 or 640 mg/kg-
bw/day
63 weeks
LOAEL= 640
mg/kg-bw/day
(M)
Hepatocytes
with enlarged
hyperchromic
nuclei
Argus et
< 5)
Medium
Hepatic
Chronic
Rat, Sprague
Dawley, M
(n=30/group)
Oral,
drinking
water
0, 430, 574, 803
or 1032 mg/kg-
bw/day
13 months
LOAEL= 430
mg/kg-bw/day
(M)
Hepatocyto-
megaly
Argus et
< )
Low
Hepatic
Chronic
Rat, Sherman,
MZF
(n=120/group)
Oral,
drinking
water
0, 9.6, 94 or 1015
mg/kg-bw/day
(M);
0, 19, 148 or 1599
mg/kg-bw/day (F)
2 years
NOAF.I .= 9.6
mg/kg-bw/day
(M)
LOAEL = 94
mg/kg-bw/day
(M)
Degeneration
and necrosis
of
hepatocytes
Kociba
et al.
(1974)
High
Page 469 of 616
-------
Target Organ/
System1
Study
Type
Species/
Strain/Sex
(Number/
group)2
Exposure
Route
Doses/
Concentrations3
Duration4
Effect Dose or
Concentration
(NOAEL,
LOAEL,
LCso)5 (mg/m3
or mg/kg-
bw/day) (Sex)
Effect6
Reference7
Data Quality
Evaluation8
Hepatic
Sub
chronic
Rat,
F344/DuCij,
MZF
(n=20/group)
Oral,
drinking
water
0, 52, 126, 274,
657 or 1554
mg/kg-bw/day
(M);
0, 83, 185, 427,
756 or 1614
mg/kg-bw/day (F)
13 weeks
NOAEL= 52
mg/kg-bw/day
(M)
LOAEL= 126
mg/kg-bw/day
(M)
Hepatocyte
swelling
Kano et
al. (2008)
Medium
Hepatic
Chronic
Rat,
F344/DuCij,
MZF
(n=100/group)
Oral,
drinking
water
0, 11, 55 or 274
mg/kg-bw/day
(M);
0, 18, 83 or 429
mg/kg-bw/day (F)
2 years
NOAF.I ,= 11
mg/kg-bw/day
(M)
LOAEL= 55
mg/kg-bw/day
(M)
Mixed cell
liver foci
Kano et
al. (2.009;
>8)
High/High
Hepatic
Chronic
Rat,
F344ZDuCij,
MZF
(n=100/group)
Oral,
drinking
water
0, 11, 55 or 274
mg/kg-bw/day
(M);
0, 18, 83 or 429
mg/kg-bw/day (F)
2 years
NOAEL= 55
mg/kg-bw/day
(M)
LOAEL= 274
mg/kg-bw/day
(M)
Increases in
serum liver
enzymes
(GOT, GPT,
LDH and
ALP)
Kano et
al. (2009;
JBRC
>8)
HighZHigh
Hepatic
Chronic
Mouse,
Crj:BDFl,MZF
(n=100/group)
Oral,
drinking
water
0, 49, 191 or 677
mg/kg-bw/day
(M);
0, 66, 278 or 964
mg/kg-bw/day (F)
2 years
NOAEL= 49
mg/kg-bw/day
(M)
LOAEL= 191
mg/kg-bw/day
(M)
Increases in
serum liver
enzymes
(GOT, GPT,
LDH and
ALP)
Kano et
al. (2009;
JBRC
>8)
HighZHigh
Renal
Chronic
Rat, Wistar, M
(n=26 treated, 9
controls)
Oral,
drinking
water
0 or 640 mg/kg-
bw/day
63 weeks
LOAEL= 640
mg/kg-bw/day
(M)
Glomerulo-
nephritis
js et
5)
Medium
Renal
Chronic
Rat, Sprague
Dawley, M
(n=30/group)
Oral,
drinking
water
0, 430, 574, 803
or 1032 mg/kg-
bw/day
13 months
LOAEL= 430
mg/kg-bw/day
(M)
Glomerulo-
nephritis
js et
D
Low
Page 470 of 616
-------
Target Organ/
System1
Study
Type
Species/
Strain/Sex
(Number/
group)2
Exposure
Route
Doses/
Concentrations3
Duration4
Effect Dose or
Concentration
(NOAEL,
LOAEL,
LCso)5 (mg/m3
or mg/kg-
bw/day) (Sex)
Effect6
Reference7
Data Quality
Evaluation8
Renal
Chronic
Rat, Sherman,
MZF
(n=120/group)
Oral,
drinking
water
0, 9.6, 94 or 1015
mg/kg-bw/day
(M);
0, 19, 148 or 1599
mg/kg-bw/day (F)
2 years
NOAF.I ,= 9.6
mg/kg-bw/day
(M)
LOAEL= 94
mg/kg-bw/day
(M)
Degeneration
and necrosis
of renal
tubular cells
Kociba
et al.
)
High
Respiratory
Chronic
Rat,
F344/DuCij,
MZF
(n=20/group)
Oral,
drinking
water
0, 52, 126, 274,
657 or 1554
mg/kg-bw/day
(M);
0, 83, 185, 427,
756 or 1614
mg/kg-bw/day (F)
13 weeks
NOAEL= 52
mg/kg-bw/day
(M)
LOAEL= 126
mg/kg-bw/day
(M)
Kano et
al. (2.008)
Medium
Respiratory
Chronic
Rat,
F344ZDuCij,
MZF
(n=100/group)
Oral,
drinking
water
0, 11, 55 or 274
mg/kg-bw/day
(M);
0, 18, 83 or 429
mg/kg-bw/day (F)
2 years
NOAEL= 55
mg/kg-bw/day
(M)
LOAEL= 274
mg/kg-bw/day
(M)
Atrophy of
nasal
olfactory
epithelium;
nasal
adhesion and
inflammation
Kano et
al. (2009;
JBRC
>8)
High; High
Respiratory
Sub
chronic
Mouse,
Crj:BDFl,MZF
(n=20/group)
Oral,
drinking
water
0, 86, 231, 585,
882 or 1570
mg/kg-bw/day
(M);
0, 170, 387, 898,
1620 or 2669
mg/kg-bw/day (F)
13 weeks
NOAEL= 170
mg/kg-bw/day
(F)
LOAEL= 387
mg/kg-bw/day
(F)
Kano et
al. (2008)
Medium
Respiratory
Chronic
Mouse,
B6C3F1, MZF
(n=100/group)
Oral,
drinking
water
0, 720 or 830
mg/kg-bw/day
(M);
0, 380 or 860
mg/kg-bw/day (F)
90 weeks
LOAEL= 380
mg/kg-bw/day
(F)
Pneumonia
and rhinitis
NCI
F8)
Low
Page 471 of 616
-------
Target Organ/
System1
Study
Type
Species/
Strain/Sex
(Number/
group)2
Exposure
Route
Doses/
Concentrations3
Duration4
Effect Dose or
Concentration
(NOAEL,
LOAEL,
LCso)5 (mg/m3
or mg/kg-
bw/day) (Sex)
Effect6
Reference7
Data Quality
Evaluation8
Respiratory
Chronic
Mouse,
Crj:BDFl, M/F
(n=100/group)
Oral,
drinking
water
0, 49, 191 or 677
mg/kg-bw/day
(M);
0, 66, 278 or 964
mg/kg-bw/day (F)
2 years
NOAEL= 66
mg/kg-bw/day
(F)
LOAEL= 278
mg/kg-bw/day
(F)
Nasal
inflammation
Kano et
al. (2009:
JBRC
1 rvv>
High
1.1.5 Hazard and Data Evaluation Summary for Genotoxicity Studies
l arge! Organ/
Sjslem
Sind> Tjpe
Species/
Si rain/Cell
(>pe (Number/
(•roup if
rclc\ anl)
l-lxposure
Route
Doses/
Conccnlralions
Duralion
r.lTecl
Conccnlralion/
Result
r.lTecl
measured
Reference
Dala Qu:ilil>
l'.\ alualion
Genotoxicity
Short Term
S. typhimurium
strains TA98,
TA100,
TA1535,
TA1537
In vitro
0, 10,000
ug/plate
1 week
Negative
Reverse
Mutation
Haworth et
al. (1983)
High
Genotoxicity
Short Term
S. typhimurium
strains TA98,
TA100,
TA1530,
TA1535,
TA1537
In vitro
ND
NR
False-negative
Mutagenesis
(Ames assay)
Khudolev et
al. (19871
Medium
Genotoxicity
Acute
S. typhimurium
strains TA98,
TA100,
TA1535,
TA1537
In vitro
0, 5,000 (ig/plate
30 minutes
Negative
Reverse
mutation
Merita and
Havashi
8)
High
Genotoxicity
Acute
S. typhimurium
In vitro
0, 103 mg
24 hours
Negative
Reverse
Nestmann et
Medium
Page 472 of 616
-------
T;ir«ic( Orgsin/
Sjslcni
Siuclj Tjpe
Speck's/
Si min/Ccll
(\pc (Nil m her/
Croup il°
rele\ iinl)
l-lxposure
Rome
Doses/
(oiiccnlnilions
Diimlion
r.iTcci
(oiicciilnilion/
Result
I'.ITecl
measured
Reference
Diilii
l'.\ iiliiiilion
strains TA100,
TA1535
mutation
al. (1984)
Genotoxicity
Short Term
S. typhimurium
strains TA98,
TA100,
TA1535,
TA1537,
TA1538
In vitro
0, 5.17, 15.5,
31.0, 62, 103 mg
48 hours
Negative
Reverse
mutation
Stott et al.
High
I 1 *'N1): Dow
Chemical
9d)
Genotoxicity
Short Term
E. coliK-12
uvrB/recA
In vitro
1,150 mmol/L
1 day
Negative
DNA Repair
Hellmer and
Bolcsfoldi
High
Genotoxicity
Acute
E. coli
WP2/WP2uvrA
In vitro
0, 5,000 ug/plate
24 hours
Negative
Reverse
Mutation
Morita and
Havashi
(1998)
High
Genotoxicity
Acute
P. phosphoreum
M169
In vitro
ND
18 hours
Negative
Mutagenicity,
DNA damage
Kwan et al.
0)
unacceptable
Genotoxicity
Short Term
S. cerevisiae
D61.M
In vitro
0, 1.48, 1.96,
2.44,2.91, 3.38,
4.31,4.75%
7 days
Negative
Aneuploidy
Zimmerman,
n et al
5)
unacceptable
Genotoxicity
Acute
D.
melanogaster
In vitro
0, 1, 1.5,2, 3,
3.5% in sucrose
media
24 hours
I.OAF.I. at 2%
Meiotic
nondisjunction
Munoz and
Harnett
(2.002)
High
Genotoxicity
D.
melanogaster
In vitro
35,000 ppm in
feed, 7 days or
50,000 ppm (5%
in water) by
injection
Sex-linked
recessive lethal
test
i et al.
5)
Medium
Genotoxicity
Acute
Male CDF
Fischer 344 rat
In vitro
10° to 10"8 Molar
18 hours
Negative
Unscheduled
DNA synthesis
Stott et al.
(h'Nl): Dow
High
Page 473 of 616
-------
Tsirgcl Orgsin/
Stsicm
Siuclj Tjpe
Speck's/
Si min/Ccll
lj|K' (Nil m her/
(.roup if
rclc\ iinl)
l'l\pOMIIV
Koulo
Doses/
('<>iiiTiilr;ilioiis
Diimlion
r.iTcci
( oiicoii 1 r;i 1 ion/
Result
r.nw-i
mciisiiml
UcTi'ivikv
Diilii (,)u;ili(>
l-'.\ iiliiiilion
hepatocytes
Chemical
9d)
Genotoxicity
Acute
Rat hepatocytes
In vitro
0,0.03,0.3,3,
10, 30 mM
3 hours
LOAEL at 0.3
mM
DNA damage;
single-strand
breaks
measured by
alkaline elution
Sina et al.
3)
High
Genotoxicity
Short Term
Primary
hepatocyte
culture from
male F344 rats
In vitro
0,0.001,0.01,
0.1, 1 mM
5 days
Negative
DNA repair
et al. (1991)
High
Genotoxicity
Short Term
L5178Y mouse
lymphoma cells
In vitro
0, 5,000 ug/mL
48 hours
Negative
Forward
mutation assay
Mcgregor et
it \ s ' s )
High
Genotoxicity
Acute
L5178Y mouse
lymphoma cells
In vitro
0, 5,000 ug/mL
24 hours
Negative
Forward
mutation assay
Morita and
Havashi
(1998)
High
Genotoxicity
Short Term
BALB/3T3
cells
In vitro
0,0.25,0.5, 1.0,
2.0 mg/mL
48 hours
LOAEL at 0.5
mg/mL
Cell
transformation
Sheu et al.
5)
High
Genotoxicity
Acute
CHO cells
In vitro
0, 1,050, 3,500,
10,500 ug/L
2 hours
Negative
SCE
Galloway et
al. (1987)
High
Genotoxicity
Short Term
CHO cells
In vitro
0, 1,050, 3,500,
10,500 ug/L
26 hours
Negative
Chromosomal
aberration
Galloway et
al. (1987)
High
Genotoxicity
Short Term
CHO cells
In vitro
0, 5,000 ug/mL
26 hours
Negative
SCE
Morita and
Havashi
(1998)
High
Genotoxicity
Short Term
CHO cells
In vitro
0, 5,000 ug/mL
44 hours
Negative
Chromosomal
aberration
Morita and
Havashi
8}
High
Page 474 of 616
-------
Tsirgcl Orgsin/
Stsicm
Siuclj Tj|K'
Speck's/
Si min/Ccll
lj|K' (Nil m her/
Croup il°
rclc\ iinl)
r.\|)ONIMV
Koulo
Doses /
('<>iiiTiilr;ilioiis
Diimlion
r.iTcci
( oiicoii 1 r;i 1 ion/
Result
r.nw-i
mciisiiml
UcTi'ivikv
Diilii (,)u;ili(>
l-'.\ iiliiiilion
Genotoxicity
Short Term
CHO cells
In vitro
0, 5,000 ug/mL
44 hours
Negative
Micronucleus
formation
Morita and
Havashi
8)
High
Genotoxicity
Acute
Calf thymus
DNA
In vitro
0.04
pmol/mg/DNA
16 hours
Negative
Covalent
binding to DNA
Woo et al.
0 )
Unacceptable
Genotoxicity
Acute
Female Sprague
Dawley Rat
In vivo
0, 168, 840,
2,550, 4,200
mg/kg
21 hours
LOAEL at
2,550 mg/kg
DNA damage;
single-strand
breaks
measured by
alkaline elution
Kitchin and
Brown
(1990)
Medium
Genotoxicity
Subchronic
Male Sprague
Dawley Rat
In vivo
0, 10, 100, 1000
mg/kg
11 weeks
Negative
DNA alkylation
in hepatocytes
Stott et al.
1); Dow
Chemical
(1989d)
High
Genotoxicity
Short Term
Male B6C3F1
Mouse
In vivo
0, 500, 1,000,
2,000 mg/kg
daily dose; 0,
2,000, 3,000,
4,000 mg/kg
single injection
48 hours
Negative up to
daily doses of
2,000, Single
dose of 4,000
mg/kg
Micronucleus
formation in
bone marrow
McFee et al.
(1994)
High
Genotoxicity
Short Term
Male and
female C57BL6
Mouse; Male
BALB/c Mouse
In vivo
0, 450, 900,
1,800, 3,600
mg/kg
(C57BL6); 0,
5,000 mg/kg
(BALB/c)
48 hours
LOAEL of 900
mg/kg
(C57BL6);
Negative up to
5,000 mg/kg
(BALB/c)
Micronucleus
formation in
bone marrow
Mirkova
4)
High
Genotoxicity
Short Term
Male CD1
Mouse
In vivo
0, 500, 1,000,
2,000, 3,200
mg/kg
72 hours
Negative up to
3,200 mg/kg
Micronucleus
formation in
peripheral
blood
Morita
4)
High
Genotoxicity
Short Term
Male CD1
In vivo
0, 1,000, 2,000,
7 days
LOAEL at
Micronucleus
Morita and
High
Page 475 of 616
-------
Tsirgcl Orgsin/
Stsicm
Siuclj Tj|K'
Speck's/
Si min/Ccll
lj|K' (Nil m her/
Croup il°
rclc\ iinl)
l'l\|)OMIIV
Koulo
Doses /
('<>iiiTiilr;ilioiis
Diimlion
r.iTcci
( oiicoii 1 r;i 1 ion/
Result
r.nw-i
mciisiiml
UcTi'ivikv
Diilii (,)u;ili(>
l-'.\ iiliiiilion
Mouse
or 3,000 mg/kg
2,000 mg/kg
formation in
hepatocytes
Havashi
8)
Genotoxicity
Short Term
Male CD1
Mouse
In vivo
0, 1,000, 2,000,
or 3,000 mg/kg
7 days
Negative
Micronucleus
formation in
peripheral
blood
Merita and
Havashi
8)
High
Genotoxicity
Acute
Male CBA and
C57BL6 Mouse
In vivo
0, 1,800, 3,600
mg/kg
24 hours
Negative
Micronucleus
formation in
bone marrow
Tin well and
Ashbv
(1994)
High
Genotoxicity
Short Term
Male CD1
Mouse
In vivo
0, 1,500, 2,500,
3,500 mg/kg per
day for 5 days
6 days
I.OAF.I. of
1,500 mg/kg-
day for 5 days
Micronuclei
formation in
bone marrow
Roy et al.
(2005)
High
Genotoxicity
Short Term
Male CD1
Mouse
In vivo
0, 1,500, 2,500,
3,500 mg/kg per
day for 5 days
6 days
I.OAF.I. of
2,500 mg/kg-
day for 5 days
Micronuclei
formation in
hepatocytes
Rov et al.
(2005)
High
Genotoxicity
Subchronic
Male Sprague
Dawley Rat
In vivo
0, 10, 100, 1,000
mg/kg-day for 11
weeks
11 weeks
Negative
DNA repair in
hepatocytes
Stott et al.
I I^Kl); Dow
Chemical
9d)
High
Genotoxicity
Acute
Male F344 Rat
In vivo
0, 10, 100, 1,000
gm/kg for 2 or
12 hours;
12 hours
Negative
DNA repair in
hepatocytes
(autoradiograph
)
Goldsworthv
et al. CI991)
High
Genotoxicity
Short Term
Male F344 Rat
In vivo
0, 1,500 mg/kg-
day for 8 days +
1,000 mg/kg
gavage dose 12
hours prior to
sacrifice
8 days
Negative
DNA repair in
nasal epithelial
cells from the
nasoturbinate or
maxilloturbinat
e
Goldsworthv
et al. (1991)
Unacceptable
Genotoxicity
Short Term
Male F344 Rat
In vivo
0, 1,000 mg/kg
2 weeks
I.OAF.I. of
Replicative
Goldsworthv
High
Page 476 of 616
-------
Tsirgcl Orgsin/
Stsicm
Sluclj Tjpe
Speck's/
Si min/Ccll
lj|K' (Nil m her/
(.roup if
rclc\ iinl)
r.xposuiv
Koulo
Doses/
('<>iiiTiilr;ilioiis
Diimlion
r.iTcci
( oiicoii 1 r;i 1 ion/
Result
r.nwi
mciisiiml
UcTi'ivikv
Diilii (,)u;ili(>
l-'.\ iiliiiilion
for 24 or 48
hours; 1,500
mg/kg-day for 1
or 2 weeks
1,000 mg/kg for
24 or 48 hours;
1,500 mg/kg-
day for 1 or 2
weeks
DNA synthesis
{i.e., cell
proliferation) in
hepatocytes
et al. (1991)
Genotoxicity
Short Term
Male F344 Rat
In vivo
0, 1,500 mg/kg-
day for 2 weeks
2 weeks
1,500 mg/kg-
day for 2 weeks
Replicative
DNA synthesis
(i.e., cell
proliferation) in
nasal epithelial
cells
Goldsworthv
et al. (1991)
Unacceptable
Genotoxicity
Acute
Male Sprague
Dawley Rat
In vivo
0, 10, 100 mg/rat
24 hours
I.OAF.I. of 10
mg/rat
RNA synthesis;
inhibition of
RNA
polymerase A
andB
Kurt et al.
D
Unacceptable
Genotoxicity
Short Term
Male F344 Rat
In vivo
0, 1,000, 1,500,
2,000, 4,000
mg/kg
48 hours
I.OAF.I. of
1,000 mg/kg
DNA synthesis
in hepatocytes
Miyaeawa et
ilLi
High
Genotoxicity
Short Term
Male F344 Rat
In vivo
0, 1,000, 2,000
mg/kg
48 hours
I.OAF.I. of
2,000 mg/kg
DNA synthesis
in hepatocytes
Uno et al.
4)
Medium
Genotoxicity
Short Term
Male Sprague
Dawley Rat
In vivo
0, 10, 100, or
1,000 mg/kg.
11 weeks
I.OAF.I. of
1,000 mg/kg-
day for 11
weeks
DNA synthesis
in hepatocytes
Stott et al.
1); Dow
Chemical
9d)
High
Genotoxicity
Short term
Male
F344/DuCrlCrlj
rats
In vivo
1000, 2000, 3000
mg/kg
6 days
I.OAF.I. of
1,000 mg/kg
Liver
micronucleus
test by juvenile
rat method
Itoh and
Hattori
(2.019)
High
Genotoxicity
Short term
Male
F344/DuCrlCrlj
In vivo
1000, 2000, 3000
mg/kg
24 or 48 hours
I.OAF.I. of
3,000 mg/kg
Bone marrow
micronucleus
Itoh and
Hattori
High
Page All of 616
-------
Tsirgcl ()r«i;in/
Stslcm
Sluclj l>|)0
Speck's/
Si min/Ccll
lj|K' (Nil m her/
Croup if
rclc\ iinl)
l'l\|)OMIIV
Uoule
Doses/
(oiiccnlnilions
Diimlion
r.iTcci
( oiicoii 1 i~;i 1 ion/
Result
r.nw-i
mciisiiml
UcTi'micc
Diilii (,)u;ili(>
l-'.\ iiliiiilion
rats
test
(2.019)
Genotoxicity
Short term
Male
F344/DuCrlCrlj
rats
In vivo
1000, 2000, 3000
mg/kg
15 or 30 days
No effect at any
doses tested
Mutagenicity
by Pig-a gene
mutation assay
Itoh and
Hattori
(2.019)
High
Genotoxicity
Long Term
Male gpt delta
transgenic F344
rats
In vivo
0, 200, 1,000,
5,000 ppm
16 weeks
Positive at
5,000 ppm
Increased
relative mRNA
expression
levels
Gi et al.
(2018)
High
Genotoxicity
Long Term
Male gpt delta
transgenic F344
rats
In vivo
0, 0,2, 2, or 20
ppm
16 weeks
Negative up to
20 ppm
Mutagenesis
Gi et al.
(2.018)
High
Genotoxicity
Long Term
Male gpt delta
transgenic F344
rats
In vivo
0, 2, 20, 200,
2,000, 5,000 ppm
16 weeks
Positive at
2,000 ppm
Increased GST-
P-positive foci
induction and
cell
proliferation
Gi et al.
(2.018)
High
SIR- not reported; ND - not determined
1.1.6 Data Evaluation Summary for Chronic Cancer Studies
Cancer Incidence for 1,4-Dioxane Studies with Acceptable Data Quality Ratings1
Study
Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Cancer
Incidence
Effect
Reference
Data
Quality
Evaluation
Chronic
Rat, Wistar,
M
(n=26 treated,
9 controls)
Oral,
drinking
water
0 or 640 mg/kg-
bw/day
63 weeks
6/26
treated rats
Hepatocellular
carcinomas
us et
Medium
Page 478 of 616
-------
Study
Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Cancer
Incidence
Effect
Reference
Data
Quality
Evaluation
Chronic
Rat, Wistar,
M
(n=26 treated,
9 controls)
Oral,
drinking
water
0 or 640 mg/kg-
bw/day
63 weeks
1/26
treated rats
Transitional cell
carcinoma in kidney's
pelvis
us et
5)
Medium
Chronic
Rat, Wistar,
M
(n=26 treated,
9 controls)
Oral,
drinking
water
0 or 640 mg/kg-
bw/day
63 weeks
1/26
treated rats
Leukemia
us et
5)
Medium
Chronic
Rat, Sprague
Dawley, M
(n=30/group)
Oral,
drinking
water
0, 430, 574, 803
or 1032 mg/kg-
bw/day
13
months
5/28-32
rats (dose
not
specified)
Liver
•\ mus et
)
Low
Chronic
Rat,
F344/DuCij ,
MZF, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or
274 mg/kg-
bw/day (M) 0,
18, 83, or 429
mg/kg-bw/day
(F)
2 years
3,4,7,32
(M, 50
rats/ dose)
3,1,6,48
(F, 50 rats/
dose)
Hepatocellular adenoma
Kano et
al. (2009;
JBRt
0998)
High
Chronic
Rat,
F344/DuCij ,
M/F, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or
274 mg/kg-
bw/day (M) 0,
18, 83, or 429
mg/kg-bw/day
(F)
2 years
0,0,0,14
(M, 50
rats/ dose)
0,0,0,10
(F, 50 rats/
dose)
Hepatocellular carcinoma
Kano et
al. (2009;
)
High
Chronic
Rat,
F344/DuCij ,
M/F, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or
274 mg/kg-
bw/day (M) 0,
18, 83, or 429
mg/kg-bw/day
(F)
2 years
3,4,7,39
(M, 50
rats/ dose)
3,1,6,48
(F, 50 rats/
dose)
Either hepatocellular
adenoma or carcinoma
Kano et
al. (2009;
JBRC
>8)
High
Page 479 of 616
-------
Study
Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Cancer
Incidence
Effect
Reference
Data
Quality
Evaluation
Chronic
Rat,
F344/DuCij ,
MZF, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or
274 mg/kg-
bw/day (M) 0,
18, 83, or 429
mg/kg-bw/day
(F)
2 years
1,1,0,4 (M,
50 rats/
dose)
3,2,1,3 (F,
50 rats/
dose)
Mammary gland-
Fibroadenoma
Kano et
al. (2009;
>8)
High
Chronic
Rat,
F344/DuCij ,
M/F, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or
274 mg/kg-
bw/day (M) 0,
18, 83, or 429
mg/kg-bw/day
(F)
2 years
0,1,2,2 (M,
50 rats/
dose)
6,7,10,16
(F, 50 rats/
dose)
Mammary gland-
Adenoma
Kano et
al. (2.009;
)
High
Chronic
Rat,
F344/DuCij ,
M/F, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or
274 mg/kg-
bw/day (M) 0,
18, 83, or 429
mg/kg-bw/day
(F)
2 years
1,2,2,6 (M,
50 rats/
dose)
8,8,11,18
(F, 50 rats/
dose)
Mammary gland- Either
fibroadenoma or
adenoma
Kano et
al. (2009;
JBRC
m)
High
Chronic
Rat,
F344/DuCij ,
M/F, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or
274 mg/kg-
bw/day (M) 0,
18, 83, or 429
mg/kg-bw/day
(F)
2 years
2,2,5,28
(M, 50
rats/ dose)
1,0,0,0 (F,
50 rats/
dose)
Peritoneum-
Mesothelioma
Kano et
al. (2009;
JBRC
)
High
Chronic
Rat,
F344/DuCij ,
M/F, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or
274 mg/kg-
bw/day (M) 0,
18, 83, or 429
mg/kg-bw/day
(F)
2 years
0,0,0,3 (M,
50 rats/
dose)
0,0,0,7 (F,
50 rats/
dose)
Nasal- Squamous cell
carcinoma
Kano et
al. (2.009;
JBRt
High
Page 480 of 616
-------
Study
Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Cancer
Incidence
Effect
Reference
Data
Quality
Evaluation
Chronic
Rat,
F344/DuCij ,
MZF, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or
274 mg/kg-
bw/day (M) 0,
18, 83, or 429
mg/kg-bw/day
(F)
2 years
0,0,0,2 (M,
50 rats/
dose)
0,0,0,0 (F,
50 rats/
dose)
Nasal- Sarcoma
Kano et
al. (2009;
>8)
High
Chronic
Rat,
F344/DuCij ,
M/F, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or
274 mg/kg-
bw/day (M) 0,
18, 83, or 429
mg/kg-bw/day
(F)
2 years
0,0,0,1 (M,
50 rats/
dose)
0,0,0,0 (F,
50 rats/
dose)
Nasal-
Rhabdomyosarcoma
Kano et
al. (2.009;
)
High
Chronic
Rat,
F344/DuCij ,
M/F, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or
274 mg/kg-
bw/day (M) 0,
18, 83, or 429
mg/kg-bw/day
(F)
2 years
0,0,0,1 (M,
50 rats/
dose)
0,0,0,1 (F,
50 rats/
dose)
Nasal-
Esthesioneuroepithelioma
Kano et
al. (2009;
JBRC
m)
High
Chronic
Rat,
F344/DuCij,
M (n=
50/group)
Inhalation,
vapor,
whole
body
0, 180, 900, or
4500 mg/m3
(0, 50, 250, or
1250 ppm)
6
hours/dy,
5
days/wk,
for 2
years
0,0,1,6(50
rats per
dose
group)
Nasal squamous cell
carcinoma
Kasai et
al. (2009)
High
Chronic
Rat,
F344/DuCij,
M (n=
50/group)
Inhalation,
vapor,
whole
body
0, 180, 900, or
4500 mg/m3 (0,
50, 250, or
1250 ppm)
6
hours/dy,
5
days/wk,
for 2
years
1,2,3,21
(50 rats per
dose
group)
Hepatocellular adenoma
Kasai et
al. (2.009)
High
Page 481 of 616
-------
Study
Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Cancer
Incidence
Effect
Reference
Data
Quality
Evaluation
Chronic
Rat,
F344/DuCij,
M (n=
50/group)
Inhalation,
vapor,
whole
body
0, 180, 900, or
4500 mg/m3 (0,
50, 250, or
1250 ppm)
6
hours/dy,
5
days/wk,
for 2
years
0,0,1,2 (50
rats per
dose
group)
Hepatocellular carcinoma
Kasai et
al. (2009)
High
Chronic
Rat,
F344/DuCij,
M (n=
50/group)
Inhalation,
vapor,
whole
body
0, 180, 900, or
4500 mg/m3 (0,
50, 250, or
1250 ppm)
6
hours/dy,
5
days/wk,
for 2
years
0,0,0,4 (50
rats per
dose
group)
Renal cell carcinoma
Kasai et
al. (2.009)
High
Chronic
Rat,
F344/DuCij,
M (n=
50/group)
Inhalation,
vapor,
whole
body
0, 180, 900, or
4500 mg/m3 (0,
50, 250, or
1250 ppm)
6
hours/dy,
5
days/wk,
for 2
years
2,4,14,41
(50 rats per
dose
group)
Peritoneal mesothelioma
Kasai et
al. (2009)
High
Chronic
Rat,
F344/DuCij,
M (n=
50/group)
Inhalation,
vapor,
whole
body
0, 180, 900, or
4500 mg/m3 (0,
50, 250, or
1250 ppm)
6
hours/dy,
5
days/wk,
for 2
years
1,2,3,5 (50
rats per
dose
group)
Mammary gland
fibroadenoma
Kasai et
al. (2009)
High
Chronic
Rat,
F344/DuCij,
M (n=
50/group)
Inhalation,
vapor,
whole
body
0, 180, 900, or
4500 mg/m3 (0,
50, 250, or
1250 ppm)
6
hours/dy,
5
days/wk,
for 2
years
0,0,0,1(50
rats per
dose
group)
Mammary gland
adenoma
Kasai et
al. (2.009)
High
Page 482 of 616
-------
Study
Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Cancer
Incidence
Effect
Reference
Data
Quality
Evaluation
Chronic
Rat,
F344/DuCij,
M (n=
50/group)
Inhalation,
vapor,
whole
body
0, 180, 900, or
4500 mg/m3 (0,
50, 250, or
1250 ppm)
6
hours/dy,
5
days/wk,
for 2
years
0,0,0,4 (50
rats per
dose
group)
Zymbal gland adenoma
Kasai et
al. (2009)
High
Chronic
Rat,
F344/DuCij,
M (n=
50/group)
Inhalation,
vapor,
whole
body
0, 180, 900, or
4500 mg/m3 (0,
50, 250, or
1250 ppm)
6
hours/dy,
5
days/wk,
for 2
years
1,4,9,5 (50
rats per
dose
group)
Subcutis fibroma
Kasai et
al. (2.009)
High
Chronic
Rat, Sherman,
M/F,
(n=120/group)
Oral,
drinking
water
0, 9.6, 94, or
1015 mg/kg-
bw/day (M)
0, 19, 148, or
1599 mg/kg-
bw/day (F)
2 years
2/106,
0/110,
1/106,
12/66
Hepatic tumors (all
types)
Kociba et
)
High
Chronic
Rat, Sherman,
M/F,
(n=120/group)
Oral,
drinking
water
0, 9.6, 94, or
1015 mg/kg-
bw/day (M)
0, 19, 148, or
1599 mg/kg-
bw/day(F)
2 years
1/106,
0/110,
1/106,
10/66
Hepatocellular carcinoma
Kociba et
)
High
Chronic
Rat, Sherman,
M/F,
(n=120/group)
Oral,
drinking
water
0, 9.6, 94, or
1015 mg/kg-
bw/day (M)
0, 19, 148, or
1599 mg/kg-
bw/day (F)
2 years
0/106,
0/110,
0/106, 3/66
Nasal carcinoma
Kociba et
)
High
Page 483 of 616
-------
Study
Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Cancer
Incidence
Effect
Reference
Data
Quality
Evaluation
Chronic
Mouse,
B6C3F1, M/F
(n=100/group)
Oral,
drinking
water
0, 720 or 830
mg/kg-bw/day
(M);
0, 380 or 860
mg/kg-bw/day
(F)
90 weeks
2/49,
18/50,
24/47 (M)
0/50,
12/48,
29/37 (F)
Hepatocellular carcinoma
NCI
r8)
Low
Chronic
Mouse,
B6C3F1, M/F
(n=100/group)
Oral,
drinking
water
0, 720 or 830
mg/kg-bw/day
(M);
0, 380 or 860
mg/kg-bw/day
(F)
90 weeks
8/49,
19/50,
28/47 (M)
0/50,
21/48,
35/37 (F)
Hepatocellular adenoma
or carcinoma
NCI
r8)
Low
Chronic
Rat, Osborne-
Mendel, F2
(n=70/group)
Oral,
drinking
water
0, 350 or 640
mg/kg-bw/day
(F)
110
weeks
0/34,
10/35, 8/35
(F)
Nasal cavity squamous
cell carcinoma
NCI
(1978)
Low
Chronic
Rat, Osborne-
Mendel, F2
(n=70/group)
Oral,
drinking
water
0, 350 or 640
mg/kg-bw/day
(F)
110
weeks
0/31,
10/33,
11/32 (F)
Hepatocellular carcinoma
NCI
r8)
Low
1 Unacceptable studies are not included in this table.
2The results for male rats were considered unacceptable and are not included in this table.
Page 484 of 616
-------
1.1.7 Data Evaluation Summary for Mechanistic Studies
Table 1-1. Summary of Mechanistic Data for 1,4-Dioxane
Target Organ/
System
Study
Type
Species/
Strain/Cell type
(Number/
Group if
relevant)
Exposure
Route
Doses/
Concentrations
Duration
Effect
Concentration/
Result
Effect
measured
Reference
Data Quality
Evaluation
Genotoxicity
Short-
term
Fly, Drosphilia
melanogaster, F
(n=50/treatment
group)
In vitro
1, 1.5,2, 3 or
3.5% 1,4-dioxane
(in 4% sucrose
aqueous solution)
24 hrs
LOAEL = 1.5%
solution (F)
Increased
meiotic non-
disjunction
in oocytes
Munoz
and
Barnett
(2002)
High
Genotoxicity
Acute
Male CDF
Fischer 344 rat
hepatocytes
In vitro
10° to 10"8 Molar
18 hours
Negative for
DNA damage
Unscheduled
DNA
synthesis
Dow
Chemical
!9b)
Medium
Hepatic
Acute
Rat liver
microsomes (n =
3 trials/dose)
In vitro
0,0.1,0.25,0.5,
0.75 or l%v/v
10 min
ACso (MET) =
0.25% v/v; 29.4
mM
ACso (IMI) =
0.10% v/v; 11.7
mM
Decrease in
CYP450
activity
measured
with
metoprolol
(MET) or
imipramine
(IMI)
metabolism
Shah et
al. C )
High
Hepatic
Not
reported
Rat liver
microsomes
(n= 3
trials/dose)
In vitro
0,0.1,0.25,0.5,
0.75 or l%v/v
Not
Reported
ACso = <0.10%
v/v; <11.7 mM
Decrease in
P-
nitrophenol
hydroxylase
activity
measured
with p-
nitrophenol
metabolism
Patil et al.
(2015)
High
Page 485 of 616
-------
Target
Study
Species/
Exposure
Doses/
Duration
Effect
Effect measured
Reference
Data
Organ/
Type
Strain/Cell
Route
Concentrations
Concentration/
Quality
System
type (Number/
Group if
relevant)
Result
Evaluation
Genotoxicity
Acute
Male CDF
Fischer 344 rat
hepatocytes
In vitro
10° to 10"8
Molar
18 hours
Negative for
DNA damage
Unscheduled
DNA synthesis
Dow
Chemical
J ' *(10 (pg
248-261)
Medium
Genotoxicity
Short Term
S. typhimurium
strains TA98,
TA100,
TA1535,
TA1537
In vitro
0, 10,000
ug/plate
1 week
Negative up to
10,000 ug/plate
Reverse
Mutation
Haworth et
I)
High
Genotoxicity
Short Term
S. typhimurium
strains TA98,
TA100,
TA1530,
TA1535,
TA1537
In vitro
ND
NR
False-negative
Mutagenesis
(Ames assay)
Khudolev et
I)
Medium
Genotoxicity
Acute
S. typhimurium
strains TA98,
TA100,
TA1535,
TA1537
In vitro
0, 5,000 (ig/plate
30
minutes
Negative up to
5,000 (ig/plate
Reverse
mutation
Merita and
Havashi
>8)
High
Genotoxicity
Acute
S. typhimurium
strains TA100,
TA1535
In vitro
0, 103 mg
24 hours
Negative up to
103 mg
Reverse
mutation
Nestmann et
i)
Medium
Genotoxicity
Short Term
S. typhimurium
In vitro
0, 5.17, 15.5,
NR
Negative up to
Reverse
Stott et al.
High
strains TA98,
31.0, 62, 103 mg
103 mg
mutation
;i)
TA100,
TA1535,
TA1537,
TA1538
Genotoxicity
Short Term
E. coliK-12
uvrB/recA
In vitro
1,150 mmol/L
1 day
Negative up to
1,150 mmol/L
DNA Repair
Hellmer and
Bolcsfoldi
i\^K)
High
Genotoxicity
Acute
E. coli
WP2/WP2uvrA
In vitro
0, 5,000 ug/plate
24 hours
Negative up to
5,000 ug/plate
Reverse
Mutation
Merita and
Havashi
>8)
High
Page 486 of 616
-------
Genotoxicity
Acute
P. phosphoreum
M169
In vitro
ND
18 hours
Negative
Mutagenicity,
DNA damage
Kwan et al.
>0)
Unacceptable
Genotoxicity
Short Term
S. cerevisiae
D61.M
In vitro
0, 1.48, 1.96,
2.44, 2.91,3.38,
4.31,4.75%
7 days
Negative up to
4.75%
Aneuploidy
Zimmermann
et al. {1985)
Unacceptable
Genotoxicity
Acute
D.
melanogaster
In vitro
0, 1, 1.5,2, 3,
3.5% in sucrose
media
24 hours
LOAEL at 2%
Meiotic
nondisjunction
Munoz and
Barnett
(2002)
High
Genotoxicity
D.
melanogaster
In vitro
35,000 ppm in
feed, 7 days or
50,000 ppm (5%
in water) by
injection
Sex-linked
recessive lethal
test
\ oom et al.
!5)
Medium
Genotoxicity
Acute
Rat hepatocytes
In vitro
0,0.03,0.3,3,
10, 30 mM
3 hours
LOAEL at 0.3
mM
DNA damage;
single-strand
breaks measured
by alkaline
elution
Sina et al.
13)
High
Genotoxicity
Short Term
Primary
hepatocyte
culture from
male F344 rats
In vitro
0,0.001,0.01,
0.1, 1 mM
5 days
Negative up to
ImM
DNA repair
Golds-worthy
euil i r-'M)
High
Genotoxicity
Short Term
L5178Y mouse
lymphoma cells
In vitro
0, 5,000 ug/mL
48 hours
Negative up to
5,000 ug/mL
Forward
mutation assay
Mcgreeor et
It )!' 1)
High
Genotoxicity
Acute
L5178Y mouse
lymphoma cells
In vitro
0, 5,000 ug/mL
24 hours
Negative up to
5,000 ug/mL
Forward
mutation assay
Merita and
Havashi
>8)
High
Genotoxicity
Short Term
BALB/3T3
cells
In vitro
0, 0.25, 0.5, 1.0,
2.0 mg/mL
48 hours
LOAEL at 0.5
mg/mL
Cell
transformation
Sheu et al.
!8)
High
Genotoxicity
Acute
CHO cells
In vitro
0, 1,050, 3,500,
10,500 ug/L
2 hours
Negative up to
10,500 ug/mL
SCE
Galloway et
High
Z)
Genotoxicity
Short Term
CHO cells
In vitro
0, 1,050, 3,500,
10,500 ug/L
26 hours
Negative up to
10,500 ug/mL
Chromosomal
aberration
Galloway et
2)
High
Genotoxicity
Short Term
CHO cells
In vitro
0, 5,000 ug/mL
26 hours
Negative up to
5,000 ug/mL
SCE
Merita and
Havashi
l!(>D
High
Page 487 of 616
-------
Genotoxicity
Short Term
CHO cells
In vitro
0, 5,000 ug/mL
44 hours
Negative up to
5,000 ug/mL
Chromosomal
aberration
Morita and
Havashi
>8)
High
Genotoxicity
Short Term
CHO cells
In vitro
0, 5,000 ug/mL
44 hours
Negative up to
5,000 ug/mL
Micronucleus
formation
Morita and
Havashi
>8)
High
Genotoxicity
Acute
Calf thymus
DNA
In vitro
0.04
pmol/mg/DNA
16 hours
Negative up to
0.04
pmol/mg/DNA
(bound)
Covalent binding
to DNA
Woo et al.
>)
Unacceptable
Genotoxicity
Acute
Female Sprague
Dawley Rat
In vivo
0, 168, 840,
2,550, 4,200
mg/kg
21 hours
LOAEL at
2,550 mg/kg
DNA damage;
single-strand
breaks measured
by alkaline
elution
Kitchin and
Brown
< r^0)
Medium
Genotoxicity
Subchronic
Male Sprague
Dawley Rat
In vivo
0, 10, 100, 1000
mg/kg
11 weeks
Negative up to
1,000 mg/kg
DNA alkylation
in hepatocytes
Stott et al.
ID
High
Genotoxicity
Short Term
Male B6C3F1
Mouse
In vivo
0, 500, 1,000,
2,000 mg/kg
daily dose; 0,
2,000, 3,000,
4,000 mg/kg
single injection
48 hours
Negative up to
daily doses of
2,000, Single
dose of 4,000
mg/kg
Micronucleus
formation in
bone marrow
McFee et al.
>4)
High
Genotoxicity
Short Term
Male and
female C57BL6
Mouse; Male
BALB/c Mouse
In vivo
0, 450, 900,
1,800, 3,600
mg/kg
(C57BL6); 0,
5,000 mg/kg
(BALB/c)
48 hours
LOAEL of 900
mg/kg
(C57BL6);
Negative up to
5,000 mg/kg
(BALB/c)
Micronucleus
formation in
bone marrow
Mirkova
>4)
High
Genotoxicity
Short Term
Male CD1
Mouse
In vivo
0, 500, 1,000,
2,000, 3,200
mg/kg
72 hours
Negative up to
3,200 mg/kg
Micronucleus
formation in
peripheral blood
Morita
>4)
High
Genotoxicity
Short Term
Male CD1
Mouse
In vivo
0, 1,000, 2,000,
or 3,000 mg/kg
7 days
LOAEL at
2,000 mg/kg
Micronucleus
formation in
hepatocytes
Morita and
Havashi
>8)
High
Genotoxicity
Short Term
Male CD1
Mouse
In vivo
0, 1,000, 2,000,
or 3,000 mg/kg
7 days
Negative up to
3,000 mg/kg
Micronucleus
formation in
peripheral blood
Morita and
Havashi
1)
High
Page 488 of 616
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Genotoxicity
Acute
Male CBA and
C57BL6 Mouse
In vivo
0, 1,800, 3,600
mg/kg
24 hours
Negative up to
3,600 mg/kg
Micronucleus
formation in
bone marrow
Tinwell and
Ashbv
ii!!'24)
High
Genotoxicity
Short Term
Male CD1
Mouse
In vivo
0, 1,500, 2,500,
3,500 mg/kg per
day for 5 days
6 days
LOAEL of
1,500 mg/kg-
day for 5 days
Micronuclei
formation in
bone marrow
Roy et al.
(2.005)
High
Genotoxicity
Short Term
Male CD1
Mouse
In vivo
0, 1,500, 2,500,
3,500 mg/kg per
day for 5 days
6 days
LOAEL of
2,500 mg/kg-
day for 5 days
Micronuclei
formation in
hepatocytes
Roy et al.
(2005)
High
Genotoxicity
Subchronic
Male Sprague
Dawley Rat
In vivo
0, 10, 100, 1,000
mg/kg-day for
11 weeks
11 weeks
Negative up to
1,000 mg/kg-
day for 11
weeks
DNA repair in
hepatocytes
Stott et al.
;i)
High
Genotoxicity
Acute
Male F344 Rat
In vivo
0, 10, 100, 1,000
gm/kg for 2 or
12 hours;
12 hours
Negative up to
1,000 mg/kg for
2 or 12 hours
DNA repair in
hepatocytes
(autoradiograph)
Goldsworthv
A J >()
High
Genotoxicity
Short Term
Male F344 Rat
In vivo
0, 1,500 mg/kg-
day for 8 days +
1,000 mg/kg
gavage dose 12
hours prior to
sacrifice
8 days
Negative up to
1,500 mg/kg-
day for 8 days +
1,000 mg/kg
gavage dose 12
hours prior to
sacrifice
DNA repair in
nasal epithelial
cells from the
nasoturbinate or
maxilloturbinate
Goldsworthv
et si! 1)
Unacceptable
Genotoxicity
Short Term
Male F344 Rat
In vivo
0, 1,000 mg/kg
for 24 or 48
hours; 1,500
mg/kg-day for 1
or 2 weeks
2 weeks
LOAEL of
1,000 mg/kg for
24 or 48 hours;
1,500 mg/kg-
day for 1 or 2
weeks
Replicative
DNA synthesis
{i.e., cell
proliferation) in
hepatocytes
Goldsworthv
et vil i 1)
High
Genotoxicity
Short Term
Male F344 Rat
In vivo
0, 1,500 mg/kg-
day for 2 weeks
2 weeks
1,500 mg/kg-
day for 2 weeks
Replicative
DNA synthesis
{i.e., cell
proliferation) in
nasal epithelial
cells
Goldsworthv
euil i r-'M)
Unacceptable
Genotoxicity
Acute
Male Sprague
Dawley Rat
In vivo
0, 10, 100
mg/rat
24 hours
LOAEL of 10
mg/rat
RNA synthesis;
inhibition of
RNA
polymerase A
andB
Kiirl et al.
;i)
Unacceptable
Page 489 of 616
-------
Genotoxicity
Short Term
Male F344 Rat
In vivo
0, 1,000, 1,500,
2,000, 4,000
mg/kg
48 hours
LOAEL of
1,000 mg/kg
DNA synthesis
in hepatocytes
Miyaeawa et
9)
High
Genotoxicity
Short Term
Male F344 Rat
In vivo
0, 1,000, 2,000
mg/kg
48 hours
LOAEL of
2,000 mg/kg
DNA synthesis
in hepatocytes
Uno et al.
>4)
Medium
Genotoxicity
Short Term
Male Sprague
Dawley Rat
In vivo
0, 10, 100, or
1,000 mg/kg.
11 weeks
LOAEL of
1,000 mg/kg-
day for 11
weeks
DNA synthesis
in hepatocytes
Stott et al.
;i)
High
Genotoxicity
Long Term
Male gpt delta
transgenic F344
rats
In vivo
0, 200, 1,000,
5,000 ppm
16 weeks
Positive at
5,000 ppm
Increased
relative mRNA
expression levels
Gi et al.
(2018)
High
Genotoxicity
Long Term
Male gpt delta
transgenic F344
rats
In vivo
0, 0,2, 2, or 20
ppm
16 weeks
Negative up to
20 ppm
Mutagenesis
Gi et al.
(2.018)
High
Genotoxicity
Long Term
Male gpt delta
transgenic F344
rats
In vivo
0, 2, 20, 200,
2,000, 5,000
ppm
16 weeks
Positive at 2,000
ppm
Increased GST-
P-positive foci
induction and
cell proliferation
Gi et al.
(2018)
High
Table 1-2. Cancer Incidence for 1,4-Dioxane Studies with Acceptable Data Quality Ratings1
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Cancer
Incidence
Effect
Reference
Data Quality
Evaluation
Chronic
Rat, Wistar, M
(n=26 treated, 9
controls)
Oral,
drinking
water
0 or 640 mg/kg-
bw/day
63 weeks
6/26 treated
rats
Hepatocellular carcinomas
us et
5)
Medium
Chronic
Rat, Wistar, M
(n=26 treated, 9
controls)
Oral,
drinking
water
0 or 640 mg/kg-
bw/day
63 weeks
1/26 treated
rats
Transitional cell
carcinoma in kidney's
pelvis
us et
5)
Medium
Chronic
Rat, Wistar, M
(n=26 treated, 9
controls)
Oral,
drinking
water
0 or 640 mg/kg-
bw/day
63 weeks
1/26 treated
rats
Leukemia
lis et
5)
Medium
Chronic
Rat, Sprague
Dawley, M
(n=30/group)
Oral,
drinking
water
0, 430, 574, 803 or
1032 mg/kg-
bw/day
13 months
5/28-32 rats
(dose not
specified)
Liver
us et
3)
Low
Page 490 of 616
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Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Cancer
Incidence
Effect
Reference
Data Quality
Evaluation
Chronic
Rat, F344/DuCij ,
MZF, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or 274
mg/kg-bw/day (M)
0, 18, 83, or 429
mg/kg-bw/day (F)
2 years
3,4,7,32 (M,
50 rats/ dose)
3,1,6,48 (F,
50 rats/ dose)
Hepatocellular adenoma
Kano et al.
(2009;
(1998)
High
Chronic
Rat, F344/DuCij ,
M/F, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or 274
mg/kg-bw/day (M)
0, 18, 83, or 429
mg/kg-bw/day (F)
2 years
0,0,0,14 (M,
50 rats/ dose)
0,0,0,10 (F,
50 rats/ dose)
Hepatocellular carcinoma
Kano et al.
(2009;
>8)
High
Chronic
Rat, F344/DuCij ,
M/F, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or 274
mg/kg-bw/day (M)
0, 18, 83, or 429
mg/kg-bw/day (F)
2 years
3,4,7,39 (M,
50 rats/ dose)
3,1,6,48 (F,
50 rats/ dose)
Either hepatocellular
adenoma or carcinoma
Kano et al.
(2009;
(1998)
High
Chronic
Rat, F344/DuCij ,
M/F, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or 274
mg/kg-bw/day (M)
0, 18, 83, or 429
mg/kg-bw/day (F)
2 years
1,1,0,4 (M,
50 rats/ dose)
3,2,1,3 (F, 50
rats / dose)
Mammary gland-
Fibroadenoma
Kano et al.
(2009;
>8)
High
Chronic
Rat, F344/DuCij ,
M/F, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or 274
mg/kg-bw/day (M)
0, 18, 83, or 429
mg/kg-bw/day (F)
2 years
0,1,2,2 (M,
50 rats/ dose)
6,7,10,16 (F,
50 rats/ dose)
Mammary gland-
Adenoma
Kano et al.
(2009;
(1998)
High
Chronic
Rat, F344/DuCij ,
M/F, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or 274
mg/kg-bw/day (M)
0, 18, 83, or 429
mg/kg-bw/day (F)
2 years
1,2,2,6 (M,
50 rats/ dose)
8,8,11,18 (F,
50 rats/ dose)
Mammary gland- Either
fibroadenoma or adenoma
Kano et al.
(2009;
>8)
High
Chronic
Rat, F344/DuCij ,
M/F, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or 274
mg/kg-bw/day (M)
0, 18, 83, or 429
mg/kg-bw/day (F)
2 years
2,2,5,28 (M,
50 rats/ dose)
1,0,0,0 (F, 50
rats / dose)
Peritoneum-
Mesothelioma
Kano et al.
(2009;
(1998)
High
Chronic
Rat, F344/DuCij ,
M/F, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or 274
mg/kg-bw/day (M)
0, 18, 83, or 429
mg/kg-bw/day (F)
2 years
0,0,0,3 (M,
50 rats/ dose)
0,0,0,7 (F, 50
rats/ dose)
Nasal- Squamous cell
carcinoma
Kano et al.
(2.009;
>8)
High
Page 491 of 616
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Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Cancer
Incidence
Effect
Reference
Data Quality
Evaluation
Chronic
Rat, F344/DuCij ,
MZF, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or 274
mg/kg-bw/day (M)
0, 18, 83, or 429
mg/kg-bw/day (F)
2 years
0,0,0,2 (M,
50 rats/ dose)
0,0,0,0 (F, 50
rats / dose)
Nasal- Sarcoma
Kano et al.
(2009;
(1998)
High
Chronic
Rat, F344/DuCij ,
M/F, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or 274
mg/kg-bw/day (M)
0, 18, 83, or 429
mg/kg-bw/day (F)
2 years
0,0,0,1 (M,
50 rats/ dose)
0,0,0,0 (F, 50
rats / dose)
Nasal-
Rhabdomyosarcoma
Kano et al.
High
(2009;
>8)
Chronic
Rat, F344/DuCij ,
M/F, (n=
100/group)
Oral,
drinking
water
0, 11, 55, or 274
mg/kg-bw/day (M)
0, 18, 83, or 429
mg/kg-bw/day (F)
2 years
0,0,0,1 (M,
50 rats/ dose)
0,0,0,1 (F, 50
rats / dose)
Nasal-
Esthesioneuroepithelioma
Kano et al.
High
(2009;
(1998)
Chronic
Rat, F344/DuCij,
M (n= 50/group)
Inhalation,
vapor, whole
body
0, 180, 900, or
4500 mg/m3
(0, 50, 250, or 1250
ppm)
6 hours/dy,
5 days/wk,
for 2 years
0,0,1,6 (50
rats per dose
group)
Nasal squamous cell
carcinoma
Kasai et al.
High
(2009)
Chronic
Rat, F344/DuCij,
M (n= 50/group)
Inhalation,
vapor, whole
body
0, 180, 900, or
4500 mg/m3 (0, 50,
250, or 1250 ppm)
6 hours/dy,
5 days/wk,
for 2 years
1,2,3,21 (50
rats per dose
group)
Hepatocellular adenoma
Kasai et al.
High
(2009)
Chronic
Rat, F344/DuCij,
M (n= 50/group)
Inhalation,
vapor, whole
body
0, 180, 900, or
4500 mg/m3 (0, 50,
250, or 1250 ppm)
6 hours/dy,
5 days/wk,
for 2 years
0,0,1,2 (50
rats per dose
group)
Hepatocellular carcinoma
Kasai et al.
High
(2009)
Chronic
Rat, F344/DuCij,
M (n= 50/group)
Inhalation,
vapor, whole
body
0, 180, 900, or
4500 mg/m3 (0, 50,
250, or 1250 ppm)
6 hours/dy,
5 days/wk,
for 2 years
0,0,0,4 (50
rats per dose
group)
Renal cell carcinoma
Kasai et al.
High
(2009)
Chronic
Rat, F344/DuCij,
M (n= 50/group)
Inhalation,
vapor, whole
body
0, 180, 900, or
4500 mg/m3 (0, 50,
250, or 1250 ppm)
6 hours/dy,
5 days/wk,
for 2 years
2,4,14,41 (50
rats per dose
group)
Peritoneal mesothelioma
Kasai et al.
(2009)
High
Chronic
Rat, F344/DuCij,
M (n= 50/group)
Inhalation,
vapor, whole
body
0, 180, 900, or
4500 mg/m3 (0, 50,
250, or 1250 ppm)
6 hours/dy,
5 days/wk,
for 2 years
1,2,3,5 (50
rats per dose
group)
Mammary gland
fibroadenoma
Kasai et al.
(2.009)
High
Chronic
Rat, F344/DuCij,
M (n= 50/group)
Inhalation,
vapor, whole
body
0, 180, 900, or
4500 mg/m3 (0, 50,
250, or 1250 ppm)
6 hours/dy,
5 days/wk,
for 2 years
0,0,0,1 (50
rats per dose
group)
Mammary gland adenoma
Kasai et al.
(2009)
High
Page 492 of 616
-------
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Cancer
Incidence
Effect
Reference
Data Quality
Evaluation
Chronic
Rat, F344/DuCij,
M (n= 50/group)
Inhalation,
vapor, whole
body
0, 180, 900, or
4500 mg/m3 (0, 50,
250, or 1250 ppm)
6 hours/dy,
5 days/wk,
for 2 years
0,0,0,4 (50
rats per dose
group)
Zymbal gland adenoma
Kasai et al.
(2009)
High
Chronic
Rat, F344/DuCij,
M (n= 50/group)
Inhalation,
vapor, whole
body
0, 180, 900, or
4500 mg/m3 (0, 50,
250, or 1250 ppm)
6 hours/dy,
5 days/wk,
for 2 years
1,4,9,5 (50
rats per dose
group)
Subcutis fibroma
Kasai et al.
(2009)
High
Chronic
Rat, Sherman,
MZF,
(n=120/group)
Oral,
drinking
water
0, 9.6, 94, or 1015
mg/kg-bw/day (M)
0, 19, 148, or 1599
mg/kg-bw/day (F)
2 years
2/106, 0/110,
1/106, 12/66
Hepatic tumors (all types)
Kociba et
)
High
Chronic
Rat, Sherman,
MZF,
(n=120/group)
Oral,
drinking
water
0, 9.6, 94, or 1015
mg/kg-bw/day (M)
0, 19, 148, or 1599
mg/kg-bw/day (F)
2 years
1/106, 0/110,
1/106, 10/66
Hepatocellular carcinoma
Kociba et
al 1)
High
Chronic
Rat, Sherman,
MZF,
(n=120/group)
Oral,
drinking
water
0, 9.6, 94, or 1015
mg/kg-bw/day (M)
0, 19, 148, or 1599
mg/kg-bw/day (F)
2 years
0/106, 0/110,
0/106, 3/66
Nasal carcinoma
Kociba et
)
High
Chronic
Mouse, B6C3F1,
MZF
(n=100/group)
Oral,
drinking
water
0, 720 or 830
mg/kg-bw/day (M);
0, 380 or 860
mg/kg-bw/day (F)
90 weeks
2/49, 18/50,
24/47 (M)
0/50, 12/48,
29/37 (F)
Hepatocellular carcinoma
NCI
r8)
Low
Chronic
Mouse, B6C3F1,
MZF
(n=100/group)
Oral,
drinking
water
0, 720 or 830
mg/kg-bw/day (M);
0, 380 or 860
mg/kg-bw/day (F)
90 weeks
8/49, 19/50,
28/47 (M)
0/50, 21/48,
35/37 (F)
Hepatocellular adenoma
or carcinoma
NCI
?8)
Low
Chronic
Rat, Osborne-
Mendel, F2
(n=70/group)
Oral,
drinking
water
0, 350 or 640
mg/kg-bw/day (F)
110 weeks
0/34, 10/35,
8/35 (F)
Nasal cavity squamous
cell carcinoma
NCI
r8)
Low
Chronic
Rat, Osborne-
Mendel, F2
(n=70/group)
Oral,
drinking
water
0, 350 or 640
mg/kg-bw/day (F)
110 weeks
0/31, 10/33,
11/32 (F)
Hepatocellular carcinoma
NCI
r8)
Low
1 Unacceptable studies are not included in this table.
2The results for male rats were considered unacceptable and are not included in this table.
1.1.8 Hazard Data Tables
Page 493 of 616
-------
Table 1-3. Incidences of non-neoplastic lesions in male F344 rats exposed to 1,4-dioxane via inhalation for 2 years (6 hours/day, 5
days/week) Kasai et ai. (2009)
Tissue
Endpoint
Concentration (ppm) and incidence
0 ppm
50 ppm
250 ppm
1250 ppm
Liver
Centrilobular necrosis
1
3
6
12
Nasal
Squamous cell metaplasia; respiratory epithelium
0
0
7
44
Squamous cell hyperplasia; respiratory epithelium
0
0
1
10
Respiratory metaplasia; olfactory epithelium
11
34
49
48
Atrophy; olfactory epithelium
0
40
47
48
Hydropic change; lamina propia
0
2
36
49
Sclerosis, lamina propia
0
0
22
40
Data quality evaluations for this study were determined to high (see Appendix G)
N=50 for all data.
Table 1-4. Altered hepatocellular foci data in F344/DuCrj rats exposed to 1,4-dioxane via drinking water for 2 years (ad libitum)
Kano et ai, (2009)
Endpoint Male Female
ppm
0
200
1000
5000
0
200
1000
5000
mg/kg-d
0
11
55
274
0
18
83
429
Mixed cell
foci
2
8
14
13
1
1
3
11
Data quality evaluations for this study were determined to high (see Appendix G)
N=50 for all data.
Table 1-5. Incidence of cortical tubule degeneration in female Osborne-Mendel rats exposed to 1,4-dioxane via drinking water for 2
Species and endpoint
Dose (mg/kg-d) and incidence
Female Osborne-Mendel
rats
Dose (mg/kg-d)
0 mg/kg-d
350 mg/kg-d
640 mg/kg-d
Page 494 of 616
-------
Kidney
Cortical tubule degeneration
0/31
0/34
10/32
Data quality evaluations for B6C3F1 mice (male and female) and OM rats (female) from this study were determined to be low (see Appendix G). Data in for male OM
rats were determined to be unacceptable and are not included in this table.
Table 1-6. Tumor incidence data in male F344 rats exposed to 1,4-dioxane via inhalation for 2 years (6 hours/day, 5 days/week) Kasai
Endpoint
Concentration (ppm) and incidence (%)
Concentration (ppm)
0 ppm
50 ppm
250 ppm
1250 ppm
Nasal cavity
Squamous cell carcinoma
0/50 (0%)
0/50 (0%)
1/50 (2%)
6/50 (12%)
Liver
Hepatocellular adenoma
1/50 (2%)
2/50 (4%)
3/50 (6%)
21/50 (42%)
Hepatocellular carcinoma
0/50 (0%)
0/50 (0%)
1/50 (2%)
2/50 (4%)
Hepatocellular adenoma or
carcinoma*
1/50 (2%)
2/50 (4%)
4/50 (8%)
22/50 (44%)
Kidney
Renal cell carcinoma
0/50 (0%)
0/50 (0%)
0/50 (0%)
4/50 (8%)
Peritoneum
Mesothelioma
2/50 (4%)
4/50 (8%)
14/50 (28%)
41/50 (82%)
Mammary gland
Fibroadenoma
1/50 (2%)
2/50 (4%)
3/50 (6%)
5/50 (10%)
Adenoma
0/50 (0%)
0/50 (0%)
0/50 (0%)
1/50 (2%)
Zymbal gland
Adenoma
0/50 (0%)
0/50 (0%)
0/50 (0%)
4/50 (8%)
Subcutis
Fibroma
1/50 (2%)
4/50 (8%)
9/50 (18%)
5/50 (10%)
Data quality evaluations for this study were determined to high (see Appendix G).
Page 495 of 616
-------
incidences of hepatocellular adenomas or carcinomas were corrected to account for rats that exhibited both adenomas and carcinomas (data were provided to U.S. EPA
by communication with the study author Kasai (2008)
Table 1-7. Tumor Incidence data in male and female F344/DuCrj rats and CrjrBDFl mice exposed to 1,4-dioxane via drinking water
Species and endpoint
Dose (mg/kg-d) and incidence (%)
Male F344/DuCrj rats
Dose (mg/kg-d)
0 mg/kg-d
11 mg/kg-d
55 mg/kg-d
274 mg/kg-d
Nasal cavity
Squamous cell carcinoma
0/50 (0%)
0/50 (0%)
0/50 (0%)
3/50 (6%)
Liver
Hepatocellular adenoma
3/50 (6%)
4/50 (8%)
7/50(14%)
32/50 (64%)
Hepatocellular carcinoma
0/50 (0%)
0/50 (0%)
0/50 (0%)
14/50 (28%)
Hepatocellular adenoma or carcinoma
3/50 (6%)
4/50 (8%)
7/50 (14%)
39/50 (78%)
Subcutis
Fibroma
5/50 (10%)
3/50 (6%)
5/50 (10%)
12/50 (24%)
Peritoneum
Mesothelioma
2/50 (4%)
2/50 (4%)
5/50 (10%)
28/50 (56%)
Female F344/DuCrj rats
Dose (mg/kg-d)
0 mg/kg-d
18 mg/kg-d
83 mg/kg-d
429 mg/kg-d
Nasal cavity
Squamous cell carcinoma
0/50 (0%)
0/50 (0%)
0/50 (0%)
7/50 (14%)
Liver
Hepatocellular adenoma
3/50 (6%)
1/50 (2%)
6/50 (12%)
48/50 (96%)
Hepatocellular carcinoma
0/50 (0%)
0/50 (0%)
0/50 (%)
10/50 (20%)
Hepatocellular adenoma or carcinoma
3/50 (6%)
1/50 (2%)
6/50 (12%)
48/50 (96%)
Mammary gland
Adenoma
6/50 (12%)
7/50 (14%)
10/50 (20%)
16/50 (32%)
Female Crj:BDFl mice
Dose (mg/kg-d)
0 mg/kg-d
66 mg/kg-d
278 mg/kg-d
964 mg/kg-d
Liver
Hepatocellular adenoma
5/50 (10%)
31/50 (62%)
20/50 (40%)
3/50 (6%)
Hepatocellular carcinoma
0/50 (0%)
6/50 (12%)
30/50 (60%)
45/50 (90%)
Hepatocellular adenoma or carcinoma
5/50 (10%)
35/50 (70%)
41/50 (82%)
46/50 (92%)
Male Crj:BDFl mice
0 mg/kg-d
49 mg/kg-d
191 mg/kg-d
677 mg/kg-d
Liver
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Hepatocellular adenoma
9/50 (18%)
17/50 (34%)
23/50 (46%)
11/50 (22%)
Hepatocellular carcinoma
15/50 (30%)
20/50 (40%)
23/50 (46%)
36/50 (72%)
Hepatocellular adenoma or carcinoma
23/50 (46%)
31/50 (62%)
37/50 (74%)
40/50 (80%)
Data quality evaluations for this study were determined to high (see Appendix G).
Table 1-8. Tumor Incidence data in in male and female Sherman rats (combined) exposed to 1,4-dioxane via drinking water for 2
years (ad libitum) Kociba et ai, (1974)
Endpoint
Dose (mg/kg-d, average of male and female) and incidence (%)
Dose (mg/kg-d):
0 mg/kg-d
14 mg/kg-d
121 mg/kg-d
1307 mg/kg-d
Liver
Hepatic tumors (all types)
2/106 (2%)
0/110 (0%)
1/106 (0.9%)
12/66 (18%)
Hepatocellular carcinoma
1/106 (0.9%)
0/110 (0%)
1/106 (0.9%)
10/66 (15%)
Cholangiocarcinoma
1/106 (0.9%)
0/110 (0%)
0/106(0%)
0/66 (0%)
Cholangioma
0/106 (0%)
0/110 (0%)
0/106(0%)
2/66 (3%)
Nasal turbinates
Squamous cell carcinoma
0/106 (0%)
0/110 (0%)
0/106 (0%)
3/66 (5%)
Data quality evaluations for this study were determined to high (see Appendix G).
Table 1-9. Tumor Incidence data in male and female B6C3F1 mice, and female Osborne-Mendel rats exposed to 1,4-dioxane via
drinking water for 2 years (ad libitum) M
< *'8)
Species and endpoint
Dose (mg/kg-d) and incidence (%)
Male B6C3F1 mice
Dose (mg/kg-d)
0 mg/kg-d
720 mg/kg-d
830 mg/kg-d
Liver
Hepatocellular adenoma
6/49 (12%)
1/50 (2%)
4/47 (9%)
Hepatocellular carcinoma
2/49 (4%)
18/50 (36%)
24/47 (51%)
Hepatocellular adenoma or carcinoma
8/49 (16%)
19/50 (38%)
28/47 (60%)
Female B6C3F1 mice
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Dose (mg/kg-d)
0 mg/kg-d
380 mg/kg-d
860 mg/kg-d
Liver
Hepatocellular adenoma
0/50 (0%)
9/48 (19%)
6/37 (16%)
Hepatocellular carcinoma
0/50 (0%)
12/48 (25%)
29/37 (78%)
Hepatocellular adenoma or carcinoma
0/50 (0%)
21/48 (44%)
35/37 (95%)
Female Osborne-Mendel rats
Dose (mg/kg-d)
0 mg/kg-d
350 mg/kg-d
640 mg/kg-d
Nasal turbinate
Squamous cell carcinoma
0/34 (0%)
10/35 (29%)
8/35 (23%)
Liver
Hepatocellular adenoma
0/31 (0%)
10/33 (30%)
11/32 (34%)
Data quality evaluations for B6C3F1 mice (male and female) and OM rats (female) from this study were determined to be low (see Appendix G). Data in for male OM
rats were determined to be unacceptable and are not included in this table.
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Appendix J MODE OF ACTION ANALYSIS
J,1 Introduction
EPA evaluated proposed modes of action (MOAs) for 1,4-dioxane carcinogenicity using the
MO A framework proposed in EPA's Guidelines for Carcinogen Risk Assessment U.S. EPA.
(2005a). The MOA framework is an analytic tool that applies modified Hill criteria for causality
to evaluate whether available data support a hypothesized carcinogenic MOA. This MOA
analysis for 1,4-dioxane considers evidence from animal cancer bioassays, genotoxicity studies,
proposed key events, MOAs published in the peer-reviewed literature, and the analysis
previously presented in EPA's IRIS Toxicological Review of 1,4 Dioxane U.S. EPA. (2013d).
1,4-Dioxane is a multisite carcinogen associated with increased incidences of liver tumors,
kidney tumors, nasal cavity tumors, and peritoneal mesothelioma in rats and increased incidences
of liver tumors in mice. EPA does not have sufficient information to determine whether
carcinogenic effects of 1,4-dioxane at each tumor site are mediated by the parent compound,
metabolites, or both. The most well-developed MOAs for 1,4-dioxane carcinogenicity focus on
the MOA for liver tumors. Therefore, this MOA analysis focuses on plausible MOAs of 1,4-
dioxane liver carcinogenicity.
J.2 Potential MOAs of 1,4-Dioxane Liver Carcinogenicity
EPA considered four of the plausible MOAs for liver carcinogenicity of 1,4-dioxane, including
metabolic saturation and cytotoxicity followed by regenerative proliferation, proliferation in the
absence of cytotoxicity, mutagenic and other genotoxic mechanisms, and CAR/PXR-mediated
effects:
• MOA1: Metabolic saturation, cytotoxicity and proliferative regeneration. In this
hypothesized MOA, metabolic saturation leads to the accumulation of the parent compound
1,4-dioxane, which causes liver tumors through cytotoxicity and subsequent regenerative
proliferation. Dourson et al. 2017; 2014) proposed specific key events and compiled evidence
from animal bioassays McConnell (2013; Kociba et al. (1974). EPA used the framework for
MOA analysis described in EPA's Guidelines for Carcinogen Risk Assessme
(2005a) to further evaluate the current evidence for this proposed mode of action (MOA) for
1,4-dioxane carcinogenicity.
• MOA2: Cell proliferation in the absence of cytotoxicity. It is possible that 1,4-dioxane or a
metabolite leads to cell proliferation in the absence of cytotoxicity. This potential MOA has
not been articulated in the peer-reviewed literature and there is insufficient information to
determine the specific key events through which 1,4-dioxane or its metabolites may lead to
proliferation.
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• M0A3: Mutagenicity and other forms of genotoxicity. As described in Section 4.2.3.2, EPA
concluded that there is insufficient data to determine whether 1,4-dioxane is mutagenic or
induces cancer through a mutagenic MOA. In the absence of other information about MO A,
EPA often takes the health protective approach of assuming a linear no-threshold risk model
consistent with a mutagenic MOA.
• MOA4: CAR/PXR mediated effects. The nuclear receptors CAR and PXR have been
proposed as mediators of liver toxicity and carcinogenicity. Mechanistic evidence from other
chemicals indicates that CAR agonists may lead to proliferation and liver tumors in the
absence of cell death Elcombe et al. (20.1.4). While this is a plausible MOA for 1,4-dioxane
carcinogenicity, the key events in the MOA linking 1,4-dioxane to CAR-mediated
carcinogenicity have not been clearly articulated in the literature, and 1,4-dioxane has not
been identified as a CAR agonist. One 16-week drinking water exposure study in transgenic
rats evaluated a panel of CYP enzymes that are induced by nuclear receptors CAR, PXR,
PPARa, or AhR and found no changes in mRNA expression of these CYPs in rat livers
following 1,4-dioxane exposure Gi et al. (20.1.8). No studies have evaluated this mechanism in
the presence of tumor formation. EPA concluded that there is insufficient chemical-specific
data to meaningfully evaluate this proposed MOA.
Of these potential MOAs, cytotoxicity and proliferative regeneration (MOA1) is the one most
widely discussed in the literature. Therefore, the rest of this analysis focuses on evaluating the
available evidence for MO Al.
J .3 MOA analysis for metabolic saturation, cytotoxicity and
proliferative regeneration (MOA1) as the basis for 1,4-
dioxane-induced liver carcinogenicity
J.3.1 Description of the hypothesized MOA
In this proposed MOA, metabolic saturation leads to accumulation of the parent compound 1,4-
dioxane. Accumulated 1,4-dioxane then causes cytotoxicity by an undetermined mechanism.
Cytotoxicity is followed by regenerative proliferation, leading to liver tumors. The proposed
MOA and the strength of evidence for each key event is summarized in Figure 6-1. Evidence in
support of each key event is summarized in Table J-l..
In a previous analysis, EPA determined that evidence in support of this MOA was inconclusive
U.S. EPA. (2005a). New supplemental data that were not available to EPA at the time of the
previous review have since been published. Dourson et al. 2017; 2014) proposed specific key
events for this MOA and compiled supporting evidence from animal bioassays. Dourson et al.
support this MOA hypothesis using previously unavailable liver histopathology data from
translated Japanese Bioassay Research Center (JBRC) study reports (the data underlying Kano et
al. (2008) and Kano et al. (2009)) and reanalyzed liver histopathology data from the 1978 NCI
study McConne )
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In addition, previously unpublished incidence data from Kociba 1974) and an unpublished 90
day ACC study were made available to EPA and the public through the public comment process
for this risk evaluation. EPA reviewed these submissions and concluded that while they provide
some information that is relevant to mechanism, they do not provide information in support of a
specific MOA. The hepatic nuclear injury reported in unpublished Kociba data does not seem to
coincide with other liver toxicity, and does not seem to be an early event or precondition for the
other changes to occur. The 90-day ACC study reported liver toxicity and corresponding changes
in gene expression, but these effects are not specific to carcinogenicity. The study did not
contribute evidence that the events reported in the study were key events and necessary sufficient
precursors to tumor formation
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0
Regenerative cell
proliferation
| Preneoplastic foci
development and
clonal expansion
Hyperplasia
Tumor formation
Denotes events
that have limited
or inconsistent
evidence
-*• Hypothetical linkage
Legend
Denotes insufficient evidence
to inform whether events
that could occur as part of TK
orMOA
Data Gap
HEAA elimination
in urine
Hepatocellular
Toxicity
1,4-Dioxane
absorption
Metabolic saturation &
1,4-Dioxane
accumulation in the
blood
Metabolism by
CYP2B1/2, CYP2C11,
CYP2E1, CYP3A
Toxicokinetics
Hypothesized Liver Tumor MOA1
Caused by 1,4-dioxane
Figure 6-1. Hypothesized Liver Tumor MOA1 for 1,4-dioxane
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Table J-l. Supporting Evidence for Hypothesized Liver Tumor MOA1 for 1,4-dioxane
Key Event
Event Description
Key Event Relationship/Supporting Data
Reference
Exposure &
absorption
Inhalation
1,4-dioxane exposure
and absorption
1,4-dioxane exposure may occur via breathing of contaminated air or via dermal
absorption
AT SDR (2012)
A. Metabolism
Metabolism by
CYP2B1/2,
CYP2C11, CYP2E1,
CYP3A
Increased activity of CYP450 isozymes (i.e.,CYP2B1/2, CYP2C11, CYP2E1, CYP3A)
metabolize 1,4-dioxane into (3-hydroxyethoxy acetic acid (HEAA) and other metabolites
possibly including diethylene glycol and diglycolic acid
Nannelli et al. (2005;
Woo et al , r ' <0
B.
Excretion
1,4-dioxane metabolite, HEAA is excreted in urine
Nannelli et al. (2005;
YOU! 1,
b; Woo t a;
Woo et *
You! )
C
Metabolic saturation
and accumulation of
1,4-dioxane
Metabolic capacity exceeded leading to accumulation of 1,4-dioxane
Nannelli et al. (2005;
Goldsworthv et al.
(1991; Kociba et al.
(1975)
1
Hepatocellular
Toxicity
Hepatocellular toxicity marked by the following: there were hepatotoxicity findings
from two 2-year studies where male and female rats received oral doses of 1,4-dioxane
in drinking water Kano et al. (2008; Kociba et al. (1974). These findings
included anisonucleosis, a morphological manifestation of nuclear injury characterized
by variation in the size of the cell nuclei. This nuclear change was coincident with
findings of hepatocyte swelling (vacuolar degeneration) and hepatocellular necrosis.
Further support for liver toxicity were findings of increased serum levels of the
enzymes ALT (GPT), AST (GOT), ALP, GGT, and LDH in male and female rats
receiving oral 1,4-dioxane exposures in drinking water Kano et al. (2008; JBRC
(1998) Lundberg et al. (1986; Kociba et il « s ») and receiving 1,4-Dioxane
K
1
(
Lasai et al. (2009;
,asai (2008; JBRC
1998; Stott et al.
IS : ;wetal.
1978)
inhalation exposures Kasai et al. (2009; Kasai et al. (2008; Drew et al.
(1978). While, serum levels, in general, were significantly increased by <2-fold, it is
Page 503 of 616
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clear that the liver is affected because: 1) the liver is the only organ common to ALT,
AST, ALP, GGT, and LDH Whalan (2000); and 2) there were concurrent
histopathology findings (vacuolization, nuclear enlargement, and necrosis) supporting
1,4-Dioxane hepatotoxicity.
2
Regenerative cell
proliferation
Increases in cell proliferation in hepatocytes were reported using replicative DNA
synthesis as a surrogate marker at doses observed to be tumorigenic. Inconsistency in
characterization of histopathology.
:n
c
c
(
c
(
IcConnell (2013;
livaeawa et al.
)8;
ioldsworthy et al.
1991; Stott et al.
1981; Kociba et al.
1975; Kociba et al.
1974)
3
Hyperplasia
Hepatocyte hyperplasia observed with clear and mixed foci development. Liver
hyperplasia in rats and mice
McConnell (2013;
Kano et al. (2008;
JBRC (1998;
Yamazaki et al.
)
4
Preneoplastic foci
development and
clonal expansion
Evidence (limited, 1 study) of foci development and clonal expansion observed at high
(1000 mg/kg/day) dose in a tumor promotion study.
Additional evidence of foci development in rats includes acidophilic, mixed, and
basophilic hepatocellular foci changes reported following inhalation or oral drinking
water exposures. These findings were not dose-responsive, but were correlative with
increased incidence of hepatocellular adenoma and/or carcinoma at the highest
administered dose.
Kano et al. (2009;
Kasai et al. (2009;
Lundbere et al.
(1987)
5
Tumor formation
Hepatic adenomas and carcinomas formed
McConnell (2013;
Kano et al. (2009;
JBRC (1998;
Yamazaki et al.
(1994; 'N 78;
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Kociba et al. (1975;
Koci ).
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J.3.2 Description of experimental support for the hypothesized MOA
J.3.3 Strength, consistency, and specificity of association
As summarized in Table 1-1, there is experimental evidence that is consistent with several of the key
events in the proposed MOA. This section describes and evaluates the evidence in support of each key
event, including the level of statistical and biological significance of the data, and the consistency and
specificity of observations across studies.
Strength of evidence for 1,4-dioxane metabolism, excretion, and metabolic saturation (Key Events A,
B, and C in Table J-l.)
Toxicokinetic studies indicate that while metabolism of 1,4-dioxane follows first-order kinetics at lower
doses, higher oral doses exhibit nonlinear Michaelis-Menten kinetics Young et al. (1978a. b; Kociba et
al. (1975). Dourson et al. 2017; 2014) concluded that this is an indication of metabolic saturation and
that liver toxicity primarily occurs following metabolic saturation at high doses that are not relevant for
human exposures. Conversely, there is no clear evidence for metabolic saturation in inhalation studies.
In a 13-week inhalation study, metabolic saturation was not observed at plasma concentrations of up to
730 and 1,054 (.ig/mL in male and female rats, respectively Kasai (2008). Following inhalation exposure
to 400-3200 ppm 1,4-dioxane, plasma concentrations increased linearly with dose, consistent with first-
order kinetics. The lack of metabolic saturation following inhalation exposure may be due to enzyme
induction and/or due to toxicokinetic differences between inhalation and oral exposures related to first-
pass metabolism. Increased incidence of liver tumors in male rats was reported following inhalation
exposure to 1250 ppm 1,4-dioxane Kasai et al. (2009). well within the range of exposure that followed
first order kinetics in Kasai et al. 2008). This evidence in inhalation exposure studies suggests that
metabolic saturation may not be a necessary key event for liver tumor formation.
Based on toxicokinetic evidence for metabolic saturation and the lack of increase in toxicity following
induction of CYP450 metabolism, Dourson et al. 2017; 2014) proposed that the parent compound is the
toxic moiety. This is consistent with the fact that 1,4-Dioxane is known to be metabolized by CYP450s
into beta-hydroxyethoxyacetic acid (HEAA) which is then excreted through urine. Alternate metabolic
pathways for 1,4-dioxane may also be present. One plausible explanation for the lack of increased
toxicity following CYP induction is the possibility that toxicity is mediated by metabolites generated
through alternate metabolic pathways. Therefore, liver toxicity due to metabolites of 1,4-dioxane cannot
be ruled out.
Strength of evidence for hepatocellular toxicity (Key Event 1 in Table J-l.)
Evidence for hepatocellular toxicity following 1,4-dioxane exposure includes significant increases in
cytoplasmic vacuolar degeneration, hepatocellular necrosis and non-neoplastic lesions, and/or increased
liver enzymes Kasai et al. (2009; Kano et al. (2008; Kasai (200 *, H ij 8; Stott et a I >! *1; Drew
et al. (1978). In 13-week studies Kano et al. (2008; Kasai (2008). evidence for cytotoxicity in the liver
was reported at dose levels above those associated with tumor formation in subsequent cancer bioassays.
While evidence of cytotoxicity was also observed in some 2-year cancer bioassays McConnell (2013;
Kociba et al. (1974). it was not consistently seen as a precursor to carcinogenic lesions in all studies. For
example, liver tumors in female mice were observed in the absence of hepatocellular toxicity Kano et al.
(2009). As discussed below, the dose-response relationships to tumor formation are not established in rat
and mouse data and are inconsistent among bioassays and across exposure duration, suggesting it is not
necessary key event in the MOA of 1,4-dioxane liver carcinogenesis. Evidence for liver tumors in the
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absence of hepatocellular toxicity is consistent with the alternate hypothesis articulated in MOA2 (see
Section J.2).
There is insufficient information on metabolic and mechanistic processes that may lead to cytotoxicity in
rodents exposed to 1,4-dioxane. There is no clear evidence that metabolic saturation is a necessary
precursor to cytotoxicity, as represented by the dashed line between these key events in Figure 6-1.
Hypothesized Liver Tumor MOA1 for 1,4-dioxane. There are also no in vitro or in vivo assays that have
conclusively identified the toxic moieties resulting from 1,4-dioxane exposure. The mechanism of a
cytotoxic response to 1,4-dioxane is therefore unknown. This data gap is represented by the black box in
Figure 6-1.
Strength of evidence for regenerative cell proliferation (Key Event 2 in Table J-l.)
Evidence in rat bioassays supports the occurrence of cell proliferation prior to liver tumor formation,
McConnell (2013; Miyagawa et al. (199S, S i l v ; Goldsworthy it « s s, Stott ci jL • ]
Kociba et al. (1975; Kociba et ); however, the dose-response relationship for induction of cell
proliferation has not been characterized, and it is unknown if there is a dose-response relationship
between cell proliferation and liver tumors in the 2-year cancer bioassays in rat and mouse studies.
Increases in cell proliferation in hepatocytes were reported using replicative DNA synthesis as a
surrogate marker at doses observed to be tumorigenic. It is unknown whether the increased rates of
DNA synthesis observed in response to 1,4-dioxane exposure represent a true increase in cellular
proliferation rates or if this increase is a cellular response to DNA damage and the repair of those
lesions. It is also unknown whether observed cell proliferation is a direct response to cytotoxicity and
whether it is caused by 1,4-dioxane or a metabolite. Cell proliferation in the absence of cytotoxicity
would be consistent with the alternate hypothesis articulated in MOA2 (see Section J.2).
Strength of evidence for hyperplasia (Key Event 3 in Table J-l.)
Hepatocyte hyperplasia was reported in rats and mice following 1,4-dioxane exposure in several studies
McConn Hum , U-, > * _8; Yamazaki et al. (1994; NC 3); however, the hyperplasia originally
reported by Yamazaki et al.and JBRC was subsequently reexamined histopathologically and changed to
hepatocellular adenoma and altered hepatocellular foci Kano et al. (2009). EPA also considered
previously unavailable incidence data from Kociba et al. 1974). This new data suggests there may be a
dose-response relationship between 1,4-dioxane and bile duct epithelial hyperplasia, but did not show a
dose-response relationship between 1,4-dioxane and hepatocellular hyperplasia or demonstrate that
hyperplasia precedes tumor formation.
Strength of evidence for preneoplastic foci development and clonal expansion (Key Event 4 in Table
J-l.)
The sequence of cellular events leading to hepatocarcinogenesis are represented by increased clear and
acidophilic foci, glycogen depletion, increased cellular proliferation linked with the gradual appearance
of mixed and basophilic cell foci Bannasch et al. (1982.). There is limited evidence of foci development
and clonal expansion following 1,4-dioxane exposure in a tumor promotion study. Following initiation
with diethylnitrosoamine, a high dose (1000 mg/kg/day by oral gavage) of 1,4-dioxane administered to
rats 5 times a week for 6 weeks was associated with a significant increase in the number and volume of
foci Lundberg et al. (1987).There is also evidence available in rats for acidophilic, mixed, and basophilic
foci development Kano et al. (2009; Kasai et al. (2009) (Tables 1-4, 1-6 and 1-8) and glutathione S-
transferase placental form (GST-P)-positive foci Kano et al. (2008)that are a possible early predictor of
hepatocarcinogenicity Ito et al. (2000). These findings were not dose-responsive, but were correlative
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with increased incidence of hepatocellular adenoma and/or carcinoma at the highest administered dose.
Foci development and progression to hepatocarcinogenesis is an unclear process that may be reversible,
persistent, transient, and/or progressive. Further, foci of altered hepatocytes may progress to
hepatocarcinogenesis with or without an intermediary neoplastic nodular stage (that may lag for weeks
or months after foci development and before progression to hepatocarcinomas). The presence of
basophilic foci is marked by a strong increase in glucose 6 phosphate dehydrogenase activity, suggesting
a switch from glycogenolysis to pentose phosphate pathway and glycolysis as the predominant
metabolic pathways Bannasch et £ 2). Neoplastic nodules (also known as hyperplastic nodules)
contain a mixture of precancerous and diverse intermediary cells Bannasch et al. (1980) and in the rat
liver, is morphologically similar to human hepatic adenomas whereas comparable nodules in mice have
been classified as hepatocellular nodules Walker et al. (1973). neoplastic nodules Bannasch et i 9),
or adenomas Williams ))• While the observations of foci, nodules and adenomas in rats is
expected to be relevant to humans, mice are more susceptible to the development of spontaneous
carcinomas and liver nodules following carcinogen exposure Ohmori et al. (1981; Grasso and Crampton
2). Therefore, the human applicability of the mouse data from McConnell (2013) may be further
reduced in addition to study design characteristics described below. While the current available evidence
consistently identified foci development correlative with tumor formation in rats in the absence of a
dose- response relationship, it is assumed that foci development is a precursor to hepatocarcinogenesis..
Strength of evidence for tumor formation (Key Event 5 in Table J-l.)
There is clear and consistent evidence of a significant increase in liver tumor formation (including
adenomas and carcinomas) in rats and mice exposed to 1,4-dioxane through drinking water and in rats
exposed through inhalation McConnell (2013; Kano et al. (200' , J" 8; Yamazaki et al. (1994;
NCI (1978; Kociba ^ ll > s , ' d?a et al. (1974). While a significant increase in liver tumor
formation has been observed in male and female rats and mice following 1,4-dioxane exposure, female
mice appear to be most sensitive Kano et al. (2009).
J.3.4 Dose-response concordance between observed tumors and events in the proposed
MOA
This section considers the dose-response relationships for key events and tumor incidence in each of the
cancer bioassay datasets, and examines the concordance of data across studies.
Dose response data indicate that hepatocellular toxicity and non-neoplastic lesions may not be a
necessary precursor to carcinogenic lesions in liver following 1,4-dioxane exposure. As described
previously 2013d). the doses in hepatotoxicity studies where cytotoxicity and cell
proliferation were observed were greater than doses associated with increased tumor incidence in cancer
bioassays.
Bioassays of 1,4- dioxane in rats and mice conducted by the JBRC (Tables 1-2 through 1-12) provide the
most substantial basis for evaluating liver cancer induction by 1,4-dioxane. These studies utilized both
rats and mice Kano et al. (2009). both ingestion Kano et al. (2009) and inhalation Kasai et al. (2009)
exposure pathways, and include chronic duration cancer studies Kano et al. (2009; Kasai et al. (2009) as
well as 13-week sub-chronic studies Kano et al. (2008; Kasai (2008) to evaluate toxic effects. In 13-
week drinking water and inhalation studies in rats and mice, evidence of liver toxicity included
hepatocycte swelling, single cell necrosis in the liver and increased liver enzymes, (Figure 6-2), however
these effects are not consistently demonstrated in 2-year cancer bioassays at or below doses associated
with liver tumor formation. Liver tumors identified in 2-year rodent liver bioassays occurred in the
absence of reported lesions related to cytotoxicity Kano et al. (200 , s^t ij f 8). Liver adenomas
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observed in female mice in a 2-year drinking water study Kano et al. (2009) occurred at doses below
those associated with increased plasma ALT in the same study (Figure 6-2). Observations of increased
incidence of liver tumors below doses associated with hepatocellular toxicity suggest that cytotoxicity
may not be a necessary key event in 1,4-dioxane exposure leading to liver carcinogenesis.
Dourson et al. 2017) compared doses that caused liver toxicity in the 13-week JBRC studies to doses
associated with liver tumors in 2-year rat JBRC studies, by adjusting doses from 13-week studies to
"chronic equivalents". Based on comparison to time-adjusted doses in sub-chronic studies, Dourson et
al. 2017) concluded that hepatocellular toxicity occurs below doses associated with liver tumor
formation; however, this approach for time-adjusting doses is not clearly explained or justified. EPA
does not typically apply a scaling factor to compare sub-chronic and chronic dose rates in different
studies. There remains a lack of consistent dose-response data for hepatocellular toxicity at dose levels
comparable to doses associated with liver tumor formation.
Other studies do report evidence consistent with hepatocellular toxicity at doses below those associated
with tumor formation (Tables 1-13 through 1-16). In one 2-year study, mild hepatocellular vacuolar
degeneration and necrosis were reported at doses as low as 94 mg/kg/day, below doses associated
increased incidence of hepatocellular carcinomas in male rats exposed via drinking water Kociba et al.
|). A re-evaluation of mouse pathology data from the NCI, 1978 study McConnell (2013) also
established the presence of previously unreported non-neoplastic lesions in mice exposed chronically to
1,4-dioxane in drinking water, but the following study limitations limit confidence in the dose-response
relationship between these effects and tumor formation:
• Dose spacing in males was not adequate for characterizing a dose-response relationship likely
due to decreased drinking water consumption in the high-dose male group leading to a high dose
only slightly greater than the low-dose group (830 and 720 mg/kg/d, respectively).
• A dose-response relationship was not apparent for hyperplastic foci in the liver of male and
female mice. The combined incidence for total foci in males was higher for the low dose group
than the high dose group, and in females the incidence for combined total foci were
approximately the same.
• Female mouse data are confounded by the presence of murine hepatitis infection and should not
be combined with male mice to evaluate dose response patterns.
EPA also considered dose-response information for cell proliferation. Some data support the occurrence
of cell proliferation prior to liver tumor formation in rat models H i v ij -, Kociba et al. (1974). but
the dose-response relationship for induction of cell proliferation has not been characterized or the
relationship between cell proliferation and liver tumors is unknown.
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Liver tumor and toxicity responses, Female Mice, Kano et al (2008, 2009)
Adenomas and carcinomas - 2 year study
"E
.
o
>
-------
J.3.6 Biological plausibility and coherence
The proposed MOA is biologically plausible and experimental evidence supports several of the
proposed key events, but several critical inconsistencies and data gaps remain. For example, several
studies demonstrate that liver tumors may occur in the absence of cytotoxicity, indicating that
cytotoxicity may not be a necessary key event. In addition, the mechanisms that lead to observed
cytotoxicity and proliferation following 1,4-dioxane exposure are not clearly established. It is also
unknown whether these mechanisms are primarily mediated by metabolites or by the parent compound.
J.3.7 Consideration of the Possibility of Other MO As
Some of the experimental evidence in support of the proposed MOA may be explained by alternate key
events:
• Metabolite-mediate toxicity. Alternate (non CYP-mediated) metabolic pathways may play a
role in producing active metabolites that contribute to the carcinogenicity of 1,4-dioxane through
a range of plausible MO As. The mutagenicity or genotoxicity of potential metabolites of 1,4-
dioxane are not known.
• Proliferation in the absence of cytotoxicity. Evidence for liver carcinogenesis in the absence of
cytotoxicity in some studies suggests an alternate MOA in which 1,4-dioxane or a metabolite
induce proliferation through alternate mechanisms. This is consistent with what is proposed in
MOA2 (see Section J.2).
• Nuclear receptors. One plausible MOA of liver carcinogenicity of 1,4-dioxane is activation of
nuclear receptors CAR/PXR. While there is evidence that CAR/PXR-mediated pathways can
contribute to liver carcinogenesis, there is no direct evidence on the potential for 1,4-dioxane to
lead to CAR/PXR activation. This is consistent with what is proposed in MOA4 (see Section
J.2).
• DNA damage. Several studies show that 1,4-dioxane exposure increased DNA synthesis in rat
hepatocytes at dose levels (1,000 mg/kg/d) higher than doses that promoted liver tumors
Mivaeawa et al. (.1.999; Uno et al. (.1.994; Goldsworthv et al. (.1.991; Stott et al. (.1.98.1.) and this result has
been interpreted as increased cell proliferation. However, it is unknown whether the increased
rates of DNA synthesis observed in response to 1,4-dioxane exposure represent a true increase in
cellular proliferation, or if the increase is a cellular response to DNA damage and the repair of
hepatic lesions. In in vitro screening assays (ToxCast), 1,4-dioxane was observed to increase the
transcriptional activity of the p53 tumor suppressor protein in human colon cancer cells
(HCT116) 24 hours after 1,4-dioxane exposure, indicative of an active DNA damage and repair
response (https://comptox.epa.gov/dashboard accessed 03/27/2019). These studies do not rule
out MO As for either mutagenicity or cytotoxicity and regenerative proliferation.
J.3.8 Conclusions About the Hypothesized MOA
Integrating data across studies, dose-response relationships between cytotoxicity and tumor formation
are not well established in the rat and mouse data and are inconsistent across bioassays and exposure
durations. Though several publications 2017; Dourson et al. (2.014; McConnell (2013) provide evidence
of cytoplasmic vacuolar degeneration and hepatocellular necrosis in rat and non-neoplastic lesions, the
animal data does not support a dose-response relationship between cell proliferation, hyperplasia, and
liver tumors in rat and mouse studies.
Based on evidence that cytotoxicity is not a necessary key event, a lack of consistent dose-response
concordance between key events in the MOA and carcinogenicity, remaining data gaps in support of
Page 511 of 616
-------
specific key events, and the plausibility of alternate MO As that would also be consistent with
experimental observations, EPA determined that existing evidence is not sufficient to support the MOA
for liver tumors proposed by Dourson et al. 2017; 2014).
Table J-2. Liver histopathology and plasma enzymes in male F344/DuCrj rats exposed to 1,4-
ioxane hv inhalation for 13 weeks
/1AAO
)
Air com*, (ppm)
Control
KM)
2(H)
400
soo
1.600
3.200
Lslimukxl inhaled dose
(alveolar) (mg/kg-day)a
0
27
54
110
210
430
870
Body weight (g)
323 ± 14
323 ± 14
304 ±
11*
311 ± 19
317 ± 12
312 ± 14
301 ±
11**
Liver (% of BW)
2.6 ±
0.07
2.7 ±
0.09
2.6 ±
0.08
2.7 ±
0.08
2.7 ±
0.08*
2.8 ±
0.09**
3.0 ±
0.10**
Liver Histopathology (grade)b
Hepatocyte swelling
0/10
0/10
0/10
0/10
0/10
1/10
10/10**
(1.0)
Vacuolic change
None reported
Single cell necrosis
0/10
0/10
0/10
0/10
0/10
1/10
(1.0)
8/10**
(1.0)
Plasma enzyme levels
AST/GOT (IU/1)
73 ±8
5± 14
73 ± 10
72 ±5
72±3
70±4
73± 4
ALT/GPT (IU/1)
27 ±3
27±4
27±4
28±1
27±2
27±2
30± 2*
a Alveolar ventilation in rats calculated as QPC*BW°75 (l/hr) where normalized rate QPC =13 and BW is weight in kg
Sweeney et al. (2008). Alveolar inhaled dose = Cone (converted to mg/1) * alveolar ventilation (l/hr)/ BW (kg) * 6 hr
exposure * 5/7 days per week. Assumes ventilation not reduced with inhaled conc.
b Values in parentheses average severity grade in affected animals; l=slight, 2=moderate, 3=severe.
Page 512 of 616
-------
Table J-3. Liver histopathology and plasma enzymes in female F344/DuCrj rats exposed to 1,4-
dioxane by inhalation for 13 weeks )
Air com*, (ppm)
Conl rol
100
200
400
soo
1.600
3.200
Body weight (g)
187 ± 5
195 ±8
174 ±
10**
180 ± 5
175 ±
6**
173 ±
8**
168 ±
4**
Liver (% of BW)
2.4 ±
0.08
2.3 ±
0.09
2.4 ±
0.09
2.4 ±
0.07
2.5 ±
0.08**
2.6 ±
0.14**
2.9 ±
0.14**
Liver Histopathology (grade)"
Hepatocyte swelling
0/10
0/10
0/10
0/10
0/10
1/10
8/10**
(1.0)
Vacuolic change
None reported
Single cell necrosis
0/10
0/10
0/10
0/10
0/10
0/10
3/10**
(1.0)
Plasma enzyme levels
AST/GOT (IU/1)
64 ±6
65±3
74± 14*
69 ±5
68±6
70±5
76± 5**
ALT/GPT (IU/1)
23 ±3
21±2
26± 10
25 ±3
24±4
25±3
30± 3**
* p < 0.05; **p < 0.01, per authors. Cancer incidence using Fishers exact test, noncancer incidence Chi-square test.
11 Values in parentheses average severity grade in affected animals; l=slight, 2=moderate, 3=severe.
Page 513 of 616
-------
Table J-4. Liver tumors, histopathology and plasma enzymes in male F344/DuCrj rats exposed to
1.4-dioxane In inhalation for 2 years )
Air concentration (ppm)
Control
50
250
1250
Estimated inhaled dose (alveolar)
(mg/kg-day)a
0
13
64
324
Survival, 2 yr
37/50
37/50
28/50
25/50
Body weight, 2 yr (g)
383 ± 50
383 ± 53
376 ±38
359 ±29*
Liver (% of body weight), 2 yr
3.6 ± 0.7
3.9 ± 1.1
3.6 ±0.5
4.5 ± 0.7**
Liver Tumors
Hepatocellular adenoma
1/50
2/50
3/50
21/50**
Hepatocellular carcinoma
0/50
0/50
1/50
2/50
Either adenoma or carcinoma
Not reported
Liver Histopathologyb
Nuclear enlargement,
centrilobular
0/50
0/50
1/50
30/50**
Necrosis, centrilobular
1/50
3/50
6/50
12/50**
Spongiosis hepatis
7/50
6/50
13/50
19/50**
Clear cell foci
15/50
17/50
20/50
23/50
Acidophilic cell foci
5/50
10/50
12/50
25/50**
Basophilic cell foci
17/50
20/50
15/50
44/50 **
Mixed-cell foci
5/50
3/50
4/50
14/50
Plasma enzymes
AST/GOT (IU/1)
67 ±31
95 ±99
95 ± 116
98± 52**
ALT/GPT (IU/1)
37 ± 12
42 ±21
49 ±30
72± 36**
ALP (IU/L)
185 ±288
166 ± 85
145 ±71
212± 109**
y-GTP (IU/L)
6 ± 3
8 ± 5
10 ± 8
40 ±26**
* p < 0.05; **p < 0.01, per authors. Cancer incidence using Fishers exact test, noncancer incidence Chi-square test.
a Alveolar ventilation in rats calculated as QPC*BW0 75 (1/hr) where normalized rate QPC =13 and BW is weight in kg
Sweeney et al. (2008). Alveolar inhaled dose = Cone (converted to mg/1) * alveolar ventilation (1/hr)/ BW (kg) * 6 hr
exposure * 5/7 days per week. Assumes ventilation not reduced with inhaled conc.
b Values in parentheses average severity grade in affected animals; l=slight, 2=moderate, 3=severe.
Page 514 of 616
-------
Table J-5. Liver histopathology and plasma enzymes in male F344/DuCrj rats exposed to 1,4-
dioxane in drinking water for 13 weeks )
Dose (m );|
0
52
126
274
657
1.554
DW conc. (ppm)
Control
640
1600
4000
10000
25000
Body weight (g)
331 ±
13
335 ±9
337 ±7
322 ± 15
309 ± 7**
263 ±22**
Liver (% of BW)
2.5 ±
0.07
2.5 ±0.07
2.5 ±0.08
2.5 ±0.07
2.6 ±0.04*
2.7 ± .12**
Liver Histopathology (grade)
b
Hepatocyte swelling
0/10
0/10
9/10* *( 1.0)
10/10**(1.1)
10/10**(2.0)
10/10**(2.9)
Vacuolic change
0/10
0/10
1/10(1.0)
0/10
10/10**(1.5)
10/10**(3.0)
Single cell necrosis
0/10
0/10
0/10
5/10* (1.0)
2/10(1.0)
10/10**(1.1)
Plasma Enzymes
AST/GOT (IU/1)
75 ± 16
79 ± 15
80 ±9
78 ± 11
83 ±6
104 ± 15**
ALT/GPT (IU/1)
26 ± 5
27 ±4
29 ±3
28 ±3
29 ±2
43 ± 9 **
* p < 0.05; **p < 0.01, per authors. Cancer incidence using Fishers exact test, noncancer incidence Chi-square test.
a Concentration in drinking-water multiplied by the daily volume of water consumed divided by body weight.
b Values in parentheses average severity grade in affected animals; l=slight, 2=moderate, 3=severe.
Page 515 of 616
-------
Table J-6. Liver tumors and histopathology in male F344/DuCrj rats exposed to 1,4-dioxane in
years
)
Dose (m«/k«-diiv):i
0
11
55
274
DW concentration (ppm)
Control
200
1000
5000
Survival, 2 yr
40/50
45/50
35/50
22/50
Body weight, 2 yr (g)
428 ± 36
433 ±32
410± 53
391± 71**
Liver (% of body weight), 2 yr
2.9 ±0.3
3.0 ± 0.6
3.3 ± 0.5**
5.0 ± 1.1**
Liver Tumors
Hepatocellular adenoma
3/50
4/50
7/50
32/50**
Hepatocellular carcinoma
0/50
0/50
0/50
14/50**
Either adenoma or carcinoma
3/50
4/50
7/50
39/50**
Liver Histopathologyd
Spongiosis hepatis
12/50
20/50
25/50 *
40/50**
Clear cell foci
3/50
3/50
9/50
8/50
Acidophilic cell foci
12/50
8/50
7/50
5/50
Basophilic cell foci
7/50
11/50
8/50
16/50 *
Mixed-cell foci
2/50
8/50
14/50 **
13/50 **
Plasma Enzymesc
AST/GOT (IU/1)
67
67
68
172 **
ALT/GPT (IU/1)
18
19
29
68 **
y-GTP (IU/L)
6
7
8
57**
* p < 0.05; **p < 0.01, per authors. Cancer incidence using Fishers exact test, noncancer incidence Chi-square test.
a Concentration in drinking-water multiplied by the daily volume of water consumed divided by body weight.
b Values in parentheses average severity grade in affected animals; l=slight, 2=moderate, 3=severe.
0 LDH, ALP, CPK also significantly elevated at high dose only in male and female rats, ALP also
elevated in high dose female rats
d Samples originally identified as liver hyperplasia in Yamazaki et al. 1994) and JBRC 1998) were re-examined according
to updated criteria and reclassified as either hepatocellular adenoma or altered foci in Kano et al. 2009)
Page 516 of 616
-------
Table 3-1. Liver weights, histopathology and plasma enzymes in female F344/DuCrj rats exposed
)
Dose (m»/k»-diiv):i
0
S3
185
427
756
1.614
DW conc. (ppm)
Control
640
1600
4000
10000
25000
Body weight (g)
194 ±6
197 ±7
188 ± 8
183 ± 7**
172± 7**
155 ±7**
Liver (% of BW)
2.3 ±
0.05
2.4 ±0.08
2.6 ±0.1**
2.4 ±0.07*
2.6 ± .08**
2.9 ±0.1**
Liver Histopathology (grade)b
Hepatocyte swelling
0/10
0/10
1/10(1.0)
0/10
9/10* *(1.0)
9/9**(l 7)
Vacuolic change
0/10
0/10
0/10
0/10
0/10
9/9**(2.2)
Single cell necrosis
2/10(1.0)
0/10
1/10(1.0)
5/10 (1.0)
5/10(1.2)
8/9**(i 5)
Plasma Enzymes
AST/GOT (IU/1)
88 ± 19
87 ±30
89 ± 18
87 ±29
93 ± 14
139 ± 35**
ALT/GPT (IU/1)
17 ± 4
17 ± 5
20 ± 5
22 ±6
30 ± 6**
50 ± 8**
* p < 0.05; **p < 0.01, per authors. Cancer incidence using Fishers exact test, noncancer incidence Chi-square test.
a Concentration in drinking-water multiplied by the daily volume of water consumed divided by body weight.
b Values in parentheses average severity grade in affected animals; l=slight, 2=moderate, 3=severe.
Page 517 of 616
-------
Table J-8. Liver tumors, histopathology, and plasma enzymes in female F344/DuCrj rats exposed
)
Dose (m«/k«-diiv):i
0
18
83
429
DW concentration (ppm)
Control
200
1000
5000
Survival, 2 yr
38/50
37/50
38/50
24/50
Body weight, 2 yr (g)
303 ±41
301 ±38
296 ± 29
242 ±42**
Liver (% of body weight), 2 yr
2.7 ±0.7
2.6 ±0.6
2.7 ±0.4
7.3 ± 2.3**
Liver Tumors
Hepatocellular adenoma
3/50
1/50
6/50
48/50**
Hepatocellular carcinoma
0/50
0/50
0/50
10/50**
Either adenoma or carcinoma
3/50
1/50
6/50
48/50**
Liver Histopathologyd
Spongiosis hepatis
0/50
0/50
1/50
20/50**
Clear cell foci
0/50
1/50
1/50
8/50
Acidophilic cell foci
1/50
1/50
1/50
1/50
Basophilic cell foci
23/50
27/50
31/50
8/50**
Mixed-cell foci
1/50
1/50
5/50
4/50
Plasma Enzymesc
AST/GOT (IU/1)
122
117
118
813**
ALT/GPT (IU/1)
32
32
34
244**
y-GTP (IU/L)
4
4
5
70**
* p < 0.05; **p < 0.01, per authors. Cancer incidence using Fishers exact test, noncancer incidence Chi-square test.
a Concentration in drinking-water multiplied by the daily volume of water consumed divided by body weight.
b Values in parentheses average severity grade in affected animals; l=slight, 2=moderate, 3=severe.
0 LDH, ALP, CPK also significantly elevated at high dose only in male and female rats, ALP also
elevated in high dose female rats
d Samples originally identified as liver hyperplasia in Yamazaki et al. 1994) and JBRC 1998) were re-examined according
to updated criteria and reclassified as either hepatocellular adenoma or altered foci in Kano et al. 2009)
Page 518 of 616
-------
Table J-9. Liver histopathology and plasma enzymes in male CrjrBDFl mice exposed to 1,4-
dioxane in drinking water for 13 weeks )
Dose (m«/k«-diiv):i
0
86
231
585
882
1.570
DW conc. (ppm)
Control
640
1600
4000
10000
25000
Body weight (g)
30.9 ±
2.6
32.3 ±3.0
31.3 ± 3.3
30.7 ±4.0
29.4 ±2.5
22.2
±2.0**
Liver (% of BW)
3.6 ±
0.26
3.7 ± 0.21
3.8 ±0.21
3.9 ±0.23
3.8 ±0.16
3.9 ±0.37
Liver Histopathology (grade)b
Hepatocyte swelling
0/10
0/10
0/10
10/10**(1.1)
10/10**(1.0)
9/9**(2 o)
Single cell necrosis
0/10
0/10
0/10
5/10**(1.0)
10/10**(1.0)
9/9**(l 0)
Plasma Enzymes
AST/GOT (IU/1)
48 ± 10
49 ± 1
144 ± 8
43 ± 10
44 ±6
70± 12**
ALT/GPT (IU/1)
11 ±2
13 ±3
10 ± 2
12 ±2
13 ±2
25 ± 9**
* p < 0.05; **p < 0.01, per authors. Cancer incidence using Fishers exact test, noncancer incidence Chi-square test.
11 Concentration in drinking-water multiplied by the daily volume of water consumed divided by body weight.
b Values in parentheses average severity grade in affected animals; l=slight, 2=moderate, 3=severe.
Page 519 of 616
-------
Table J-10. Liver tumors, histopathology and plasma enzymes in male CrjrBDFl mice exposed to
)
Dose (m«/k«-diiv):i
0
49
191
677
DW concentration (ppm)
Control
500
2000
8000
Survival, 2 yr
31/50
33/50
25/50
26/50
Body weight, 2 yr (g)
48.7 ±6.1
47.3 ±6.8
44.1 ±7.6*
27.0 ±3.0**
Liver (% of body weight), 2 yr
4.4 ±2.6
4.9 ±2.4
6.2 ±4.3*
6.5 ±2.6*
Liver Tumors
Hepatocellular adenoma
9/50
17/50
23/50 **
11/50
Hepatocellular carcinoma
15/50
20/50
23/50
36/50 **
Either adenoma or carcinoma
23/50
31/50
37/50c
40/50 **
Liver Histopathologyd
Angiectasis
2/50
3/50
4/50
16/50
Plasma Enzymesc
AST/GOT (IU/1)
288
180
333**
2994**
ALT/GPT (IU/1)
110
78
136**
512**
* p < 0.05; **p < 0.01, per authors. Cancer incidence using Fishers exact test, noncancer incidence Chi-square test.
11 Concentration in drinking-water multiplied by the daily volume of water consumed divided by body weight.
b Values in parentheses average severity grade in affected animals; l=slight, 2=moderate, 3=severe.
0 LDH, ALP, and CPK also elevated in mid and high dose male and female mice.
d Samples originally identified as liver hyperplasia in Yamazaki et al. 1994) and JBRC 1998) were re-examined according
to updated criteria and reclassified as either hepatocellular adenoma or altered foci in Kano et al. 2009)
Page 520 of 616
-------
Table J-ll. Liver weights, histopathology and plasma enzymes in female CrjrBDFl mice exposed
)
Dose (m«/k«-diiv):i
0
170
3S7
898
1.620
2.669
DW conc. (ppm)
Control
640
1600
4000
10000
25000
Body weight (g)
20.0 ±
1.2
20.5 ± 1.1
20.3 ± 1.1
21.0 ± 1.6
20.8 ± 1.6
19.5 ± 1.2
Liver (% of BW)
4.6 ±
0.26
4.4 ±0.19
4.6 ±0.28
4.6 ±0.19
4.4 ±0.34
4.3 ±0.10
*
Liver Histopathology (grade)b
Hepatocyte swelling
0/10
1/10(1.0)
1/10 (1.0)
10/10**(1.0)
10/10**(1.0)
9/10**(2.0)
Single cell necrosis
0/10
0/10
0/10
7/10**(1.0)
10/10**(1.0)
9/10**(1.0)
Plasma enzyme levels
AST/GOT (IU/1)
88 ± 19
87 ±30
89 ± 18
87 ±29
93 ± 14
139 ± 35**
ALT/GPT (IU/1)
17 ± 4
17 ± 5
20 ± 5
22 ±6
30 ± 6**
50 ± 8**
* p < 0.05; **p < 0.01, per authors. Cancer incidence using Fishers exact test, noncancer incidence Chi-square test.
11 Concentration in drinking-water multiplied by the daily volume of water consumed divided by body weight.
b Values in parentheses average severity grade in affected animals; l=slight, 2=moderate, 3=severe.
Page 521 of 616
-------
Table J-12. Liver tumors, weights, histopathology and plasma enzymes in female CrjrBDFl mice
)
Dose (m«/k«-diiv):i
0
66
278
964
DW concentration (ppm)
Control
500
2000
8000
Survival, 2 yr
29/50
29/50
17/50
5/50
Body weight, 2 yr (g)
303 ±41
301 ±38
296 ± 29
242 ±42**
Liver (% of body weight), 2 yr
4.5 ± 1.2
4.4 ± 1.4
5.1 ±0.94
6.6 ±2.0**
Liver Tumors
Hepatocellular adenoma
5/50
31/50 **
20/50 **
3/50
Hepatocellular carcinoma
0/50
6/5 0c
30/50a
45/50 **
Either adenoma or carcinoma
5/50
35/50a
41/50a
46/50 **
Liver histopathologyd
No nonneoplastic lesions
reported
Plasma enzymesc
AST/GOT (IU/1)
107
150
1518**
724**
ALT/GPT (IU/1)
29
39
442 **
175**
* p < 0.05; **p < 0.01, per authors. Cancer incidence using Fishers exact test, noncancer incidence Chi-square test.
a Concentration in drinking-water multiplied by the daily volume of water consumed divided by body weight.
b Values in parentheses average severity grade in affected animals; l=slight, 2=moderate, 3=severe.
0 LDH, ALP, and CPK also elevated in mid and high dose male and female mice.
d Samples originally identified as liver hyperplasia in Yamazaki et al. 1994) and JBRC 1998) were re-examined according
to updated criteria and reclassified as either hepatocellular adenoma or altered foci in Kano et al. 2009)
Page 522 of 616
-------
Table J-13. Tumor and histopathology incidence in male Sherman rats exposed to 1,4-dioxane in
years
)
Dose (m«/k«-diiv):i
0
10
94
1020
DW concentration (ppm)
Control
100
1000
10,000
Survival, 2 yr
20/60
24/60
14/60
1/60
Body weight, 2 yr (g)b
378 ±40
377 ± 57
387 ±68
-
Liver (% of body weight), 2 yrb
2.5 ±0.3
2.6 ±0.3
2.7 ±0.5
-
Liver Tumors
Hepatocellular carcinoma
(No adenomas reported)
1/60
0/60
0/60
6/60*
Liver Histopathologyc
Hepatocellular vacuolar
degeneration
4/60 (1)
1/60 (1)
14/60(1.4)
17/60(1.7)
Hepatocellular necrosis
2/60 (1.5)
6/60 (1.2)
12/60(1.7)
24/60(1.7)
Hepatocellular anisonucleosis
1/60
1/60
0/60
15/60
Bile duct epithelial hyperplasia
4/60
0/60
3/60
10/60
Elevated nodules (gross path)
1/60
1/60
2/60
7/60
Hepatocellular hyperplastic nodules
1/60
1/60
2/60
1/60
* p < 0.05; **p <0.01; p< 0.001, for tumor findings per authors. Not indicated for noncancer results.
a Concentration in drinking-water multiplied by the daily volume of water consumed divided by body weight. Based on
measurements for days 114-198, reported in Kociba et al. 1974). Table 1.
b Based on surviving animals at final sacrifice
0 Values in parentheses average severity grade in, affected animals; l=minimal, 2=moderate, 3=severe.
The term hepatocellular cytoplasmic degeneration as used by Kociba includes both "hepatocyte swelling" and "vacuolic
change". For comparison these changes were diagnosed separately in Kano 2008) for male and female rats, and swelling
was seen at a lower dose than vacuolic change in that study.
Page 523 of 616
-------
Table J-14. Tumor and histopathology incidence in female Sherman rats exposed to 1,4-dioxane in
years
)
Dose (m«/k«-diiv):i
0
19
I4S
160(1
DW concentration (ppm)
Control
100
1000
10,000
Survival, 2 yr
37/60
36/60
32/60
3/60
Body weight, 2 yr (g)b
285 ± 47
289 ± 42
280 ± 47
212 ±42**
Liver (% of body weight), 2 yrb
2.9± 0.7
2.9 ±0.5
3.0 ±0.4
5.8 ± 1.5*
Liver Tumors
Hepatocellular carcinoma
(adenomas not reported)
0/60
0/60
1/60
4/60
Liver Histopathology0 (All counts numbers out of 60 animals)
Hepatocellular vacuolar
degeneration
5/60(1.2)
4/60(1.0)
14/60(1.3)
25/60(1.8)
Hepatocellular necrosis
1/60 (3)
2/60(1.0)
11/60(1.3)
31/60 (2.0)
Hepatocellular anisonucleosis
0/60
0/60
2/60
19/60
Bile duct epithelial hyperplasia
6/60
1/60
6/60
13/60
Elevated nodules (gross path)
0/60
0/60
2/60
12/60
Hepatocellular hyperplastic nodules
0/60
0/60
1/60
8/60
* p < 0.05; **p < 0.01; p< 0.001, per authors.
a Concentration in drinking-water multiplied by the daily volume of water consumed divided by body weight. Based on
measurements for days 114-198, reported in Kociba et al. 1974). Table 1.
b Based on surviving animals at final sacrifice
0 Values in parentheses average severity grade in affected animals; l=slight, 2=moderate, 3=severe.
Page 524 of 616
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Table J-15. Tumor and histopathology incidence in male B6C3F1 mice exposed to 1,4-dioxane in
) reexamination of slides from NCI )
Dose (m«/k«-diiv):i
0
720
830
DW concentration (ppm)
Control
5000
10000
Survival, 91 weeks'3
48/50
45/50
46/50
Body weight, 91 weeks (g)
39
35
35
Liver (% of body weight), 2 yr
NA
NA
NA
Liver Tumors: NCI (1978) - McConnell (2013)°
Hepatocellular adenoma
6/49 -- 2/44
1/50 - 1/48
4/47 - 3/48
Hepatocellular carcinoma
2/49 - 4/44
18/50*** -
16/48
24141*** -2114%
Either adenoma or carcinoma
8/49 - 5/44
19/50* - 17/48
28/47*** -22/48
Liver Histopathology (McConnell, 2013)d
Hepatocellular hypertrophy
3/44(1.5)
41/43 (1.6)
41/42 (1.7)
Hepatocyte glycogen (scored as
"none")
11/44
32/43
35/42
Hepatocellular necrosis
4/48 (1.0)
37/41 (1.7)
33/40 (1.5)
Inflammation
4/48 (1.0)
37/41 (1.7)
32/40 (1.5)
Kupffer cell hyperplasia
4/48 (1.2)
29/43 (1.3)
31/42 (1.6)
Hepatocellular foci, total®
4/44
13/43
7/42
* p < 0.05; **p <0.01; **p <0.01; ***p < 0.001, per NCI 1978), using Fishers exact test. Significance not provided by NCI
for adenomas alone. Significance results not provided in McConnell 2013).
11 Concentration in drinking-water multiplied by the daily volume of water consumed divided by body weight.
b From graph
0 Tumor count from original NCI study followed by count from reread of slides by McConnell
d Frequency for lesions scored minimal or greater. Values in parentheses average severity grade in affected animals;
l=minimal, 2=mild, 3=moderate, 4=marked. Statistical significance not reported. McConnell reported severity averaged
across both affected and nonaffected (severity=0) animals, here this value is divided by fraction affected to apply to affected
animals only.
e Basophilic, eosinophilic, clear cell and mixed cell foci combined, considered as preneoplastic indicators
NA: Not available
Page 525 of 616
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Table J-16. Tumor and histopathology incidence in female B6C3F1 mice exposed to 1,4-dioxane in
drinking water 90 weeks McConiieii (2013) reexamination of slides from NCI 1978)
Dose (m«/k«-d:iv):i
0
380
S20
DW concentration (ppm)
Control
5000
10000
Survival, 91 weeks
45/50
39/50
28/50
Body weight, 91 weeks (g)b
37
36
27
Liver (% of body weight), 2 yr
NA
NA
NA
Liver Tumors: NCI (1978) - McConnell (2013)°
Hepatocellular adenoma
0 /50 - 0/49
9/48 - 7/45
6/37-11/37
Hepatocellular carcinoma
0 /50 - 0/49
12/48*** -7/45
29/37*** -23/37
Either adenoma or carcinoma
0/50 - 0/49
21/48*** -
14/45
35/37*** -29/37
Liver Histopathology (McConnell, 2013)d
Hepatocellular hypertrophy
0/46
17/37 (1.2)
29/30 (1.7)
Hepatocyte glycogen (scored as
"none")
18/46
17/37
21/30
Hepatocellular necrosis
27/46(1.0)
17/37 (1.3)
17/19 (1.3)
Inflammation
26/46(1.1)
17/37 (1.3)
16/19 (1.3)
Kupffer cell hyperplasia
0/46
1/37 (1)
9/30 (1.7)
Hepatocellular foci, total®
1/46
10/37
8/30
* p < 0.05; **p <0.01; **p < 0.01, per NCI 1978), using Fishers exact test. Significance not provided by NCI for adenomas
alone. Significance results not provided in McConnell 20131.
a Concentration in drinking-water multiplied by the daily volume of water consumed divided by body weight.
b From graph
0 Tumor count from original NCI study followed by count from reread of slides by McConnell
d Frequency for lesions scored minimal or greater. Values in parentheses average severity grade in affected animals;
l=minimal, 2=mild, 3=moderate, 4=marked. McConnell reported severity averaged across both affected and nonaffected
(severity=0) animals, here this value is divided by fraction affected to apply to affected animals only.
e Basophilic, eosinophilic, clear cell and mixed cell foci combined, considered as preneoplastic indicators
Page 526 of 616
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Appendix K BENCHMARK DOSE ANALYSIS
U.S. EPA relied on the following guidance and support documents for data requirements and other
considerations for dose-response modeling: EPA's Benchmark Dose Technical Guidance U EPA
£2012b), EPA's Methods for Derivation of Inhalation Reference Concentrations and Application of
Inhalation Dosimetry * r N1 \ j 4b). EPA's Review of the Reference Dose and Reference
Concentration Processes U.S. EPA. (2002), Guidelines for Carcinogen Risk Assessment U.S. EPA.
(2005a). and EPA's Recommended Use of Body Weight3 4 as the Default Method in Derivation of the
Oral Reference Dose U.S. EPA. (2 ).
For studies that had suitable data, dose-response analysis was performed and point of departures (PODs)
were identified. The POD, an estimated dose (expressed in human-equivalent terms) near the lower end
of the observed range without significant extrapolation to lower doses, is used as the starting point for
subsequent extrapolations and analyses. PODs can be a NOAEL or LOAEL for an observed incidence,
or change in level of response, or the lower confidence limit on the dose at the benchmark dose (BMD).
The preferred approach is to use dose response modeling to incorporate as much of the data set as
possible into the analysis to yield a POD. EPA evaluates a range of dose response models thought to be
consistent with underlying biological processes to determine how best to empirically model the dose
response relationship in the range of the observed data. If the procedure fails to yield reliable results,
expert judgment or alternative analyses are used. For example, a model fit may be considered poor if the
goodness-of-fit p value is below a critical value (i.e., <0.1), or the largest scaled residual exceeds 2 in
absolute value [ ) §2.3.5], If none of the models provide a reasonable fit to certain
datasets, the dose-response modeling may be re-done using only data for the lower doses, or the
NOAEL/LOAEL could be used as the POD.
In general, the benchmark response level (BMR) at which the POD is calculated is guided by the
severity of the endpoint. As stated in EPA's Benchmark Dose Technical Guidance U.S. EPA. (2012b).
EPA does not currently have explicit guidance to assist in making such judgments for the selection of
response levels for most applications (e.g., for calculating reference doses). However, the guidance
provides general principles to consider for different types of data. For dichotomous data, a response
level of 10% extra risk is generally used for minimally adverse effects, 5% or lower for more severe
effects. For continuous data, a response level is ideally based on an established definition of biologic
significance. In the absence of such definition, one control standard deviation from the control mean is
often used for minimally adverse effects, one-half standard deviation for more severe effects. For cancer
data, U.S. EPA's Guidelines for Carcinogen Risk Assessment U.S. EPA. (2005a) address BMRs for
cancer risk estimation. Standard values near the low end of the observable range are generally used (for
example, 10% extra risk for cancer bioassay data, 1% for epidemiologic data, lower for rare cancers).
For 1,4-dioxane, both linear and nonlinear approaches were evaluated for the human health endpoints
because comparing both approaches can provide insights into uncertainties related to model choice and
mechanisms. Information regarding the degree of change in the selected endpoints that is considered
biologically significant was not available. Therefore, a BMR of 10% extra risk was selected under the
assumption that it represents a minimally biologically significant response level U.S JJP \ (2012b).
Decision trees summarizing the general progression of steps in a BMD/BMDL calculation are presented
below.
Page 527 of 616
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Noncancer
Basic statistical background and guidance on choosing a model structure for the data being analyzed,
fitting models, comparing models, and calculating confidence limits to derive a BMDL to use as a POD
is outlined in EPA's Benchmark Dose Technical Guidance 12b) Sections 2.3.9 and 2.5.
Empirical models that provide the best fit to the dose-response data are typically used in the absence of
data to develop a biologically-based model. While these models are empirical, parameters are typically
constrained on some of them for the purposes of strengthening the biological plausibility of the results
{i.e., many toxic effects exhibit a monotonic dose-response), and to prevent imprecise BMDs/BMDLs
resulting from steeply supralinear models ITJ.S. EPA. (2012b) §2.3.3.3], Consistent with EPA's
Benchmark Dose Technical Guidance 112b), initial runs of the LogProbit and Dichotomous
Hill models did not constrain their slope parameter, whereas initial runs of the Gamma, Weibull, and
LogLogistic models constrained their slope or power parameters to be >1.
For each candidate endpoint/study the following steps were taken:
Goodness-of-fit was assessed for all models [U.S. EPA (20.1.2b) §2.3.5]
Models having a goodness-of-fit p value of less than 0.1 were rejected.29
Models not adequately describing the dose response relationship (especially in the low-dose region)
were rejected based on examining the dose-group scaled residuals30 and graphs of models and data.
The models that remained (after rejecting those that did not meet the recommended default statistical
criteria for adequacy and fail in visual inspection of model fit) were used for determining the BMDL.
The default selection criteria are listed below [ 012b) §2.3.9]:
If the BMDL estimates from the remaining models were sufficiently close (generally defined as being
within threefold, as in the case of this assessment), it was assumed there was no particular influence of
the individual models on the estimates. In this case, the model with the lowest AIC was chosen.
If the BMDL estimates from the remaining models were not sufficiently close, it was assumed there was
some model dependence {i.e., model uncertainty) of the estimate. In this case, if there was no clear
remaining biological or statistical basis on which to choose among them, the lowest BMDL was selected
as a reasonable conservative estimate (U.S. EPA (2012b) Section 2.3.9).
In some cases, modeling attempts did not yield useful results. When this occurred, the NOAEL (or
LOAEL) was used as a candidate POD.
Modeling considerations specific to noncancer data
The highest dose in the oral study by Kano et al. (2009) was removed from all analyses because of
concerns regarding decreased water intake rate at the highest dose. Data in male OM rats from the NCI
3} study were not modeled, because the data quality was determined to be unacceptable (see
Appendix G).
29 For the yl goodness-of-fit test and a p-value of a, the critical value is the 1- a percentile of the yl distribution at the
appropriate degrees of freedom. Models are rejected if there are large values of yl corresponding to p-values less than 0.1, the
limiting probability of a Type I error (false positive) selected for this purpose.
30 Scaled residuals reported by BMDS for dichotomous responses are defined as (Observed - Expected)/SE, where
"Expected" is the predicted number of responders and SE equals the estimated standard error of that predicted number. For
dichotomous models, the estimated standard error is equal to V|n /pp/(\-pp)\. where n is the sample size, and p is the
model-predicted probability of response. Model fit is considered questionable if the scaled residual value for any dose group,
particularly the control or low dose group, is greater than 2 or less than -2.
Page 528 of 616
-------
For inhalation data that were not amenable to BMD modeling, NOAECs/NOAELs and
LOAECs/LOAELs were obtained from Appendix G.
Cancer
Following EPA's Benchmark Dose Technical Guidance U.S. EPA. (2012b) Sections 2.3.9 and 2.5, and
EPA's Choosing Appropriate Stage of a Multistage Model for Cancer Modeling 14b):
All orders of the Multistage model up to two less than the number of dose groups were fit (e.g., up to
model order k-2 if there are k dose groups).
If all parameter (y, pi, .., pk-2) estimates were positive, then the model with the lowest AIC was chosen
as the best-fitting model if at least one of the models provides an adequate fit to the data. Consistent with
EPA's guidance when there is an a priori reason to prefer a specific model(s) [U.S. EPA (2012b) §2.3.5
and §2.3.9], Multistage models having a goodness-of-fit p value of less than 0.05 were rejected.
Otherwise (i.e., if any parameter is estimated to be zero and is thus at a boundary), the following
procedure (2) was followed:
Model fits of order 1 and 2 (linear and quadratic, respectively) were examined for adequate fit. The
linear model parameters (y, pi), and the quadratic model parameters (y, pi, P2) were examined.
If only one of the models exhibited adequate fit, that model was chosen.
If both models exhibited adequate fit:
The model with the lowest AIC was chosen if all of the parameters (y , pi,and P2) were positive.
Otherwise, the model with the lower BMDL (more health protective) was chosen. If the BMD/BMDL
ratio is larger than 3, the matter was referred to EPA statisticians and health assessors for a decision.
The MS-Combo model (which is implemented using BMDS) was utilized to calculate the dose
associated with a specified composite risk (the risk of developing any combination of tumors at any
site), under the assumption that tumors in different tissues arise independently. MS-Combo is a peer-
reviewed Versar (2011) module within BMDS that employs a combined probability function to calculate
composite risk using the best-fitting BMDS multistage model parameters determined for each individual
tumor.
Modeling considerations specific to cancer data for the oral route
The U.S. EPA. (2013d) IRIS assessment applied all available noncancer models and did not evaluate
multiple tumors using MS-Combo. Thus, points of departure differ from the '2013d) IRIS
assessment.
Subcutis fibroma in male rats exposed via drinking water from the Kama et at. (2009) study exhibited a
statistically significant (p<0.01) increasing trend by the Peto test. It should be noted that these data were
not used for dose-response of the oral portion of the U.S. EPA. (2013 d) IRIS assessment. However, data
for subcutis fibroma from the Kasai et al. (2009) study was modeled for the inhalation update of the
EPA. (2013d) IRIS assessment.
Female mouse hepatocellular carcinoma data from Kano et al. (2009) were not initially amenable to
modeling due to the difficulties that were previously noted in the I S i'P \ ;2013d) IRIS assessment.
Specifically, this endpoint exhibited a low control group incidence, and a high (70% incidence) response
rate at the lowest dose followed by a plateau. While the U.S. EPA. (2013d) IRIS assessment did perform
BMD modeling on these data, it was necessary to increase the BMR, omit the highest dose group, and
apply a non-multistage model. EPA therefore used individual animal data obtained from study authors to
Page 529 of 616
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model the time-to-tumor effect in this dataset using the Multistage Weibull Model and applying an Extra
Risk of 50% as the BMR to avoid excess extrapolation.
For studies that observed liver tumors, which were amenable to BMD modeling, MS-Combo was
applied twice to evaluate uncertainties related to model choice and mechanisms: one MS-Combo model
run included all tumors, while an additional model run excluded liver tumors.
The Kano et al. (2009) data are based on the data of the laboratory report by JBRC 1998). which were
also published as conference proceedings Yamazaki et al. (1994). There are data discrepancies between
these publications. This is explained in 0 of the \. S i' P \ ^ 2013 d) IRIS assessment. It was determined
that the differences in tumor counts have a negligible impact on the final PODs. The analysis presented
here assumes that the data by Kano et al. (2009) (which was used in the IRIS assessment) are a suitable
representation of the 2-year drinking water bioassay data.
Data in male OM rats from the NCI (1978) study were not modeled, because the data quality was
determined to be unacceptable (see Appendix G).
Modeling considerations specific to cancer data for the inhalation route
The U.S. EPA. (2013d) IRIS assessment applied MS-Combo to the inhalation cancer data (the model
was not available during the development of the oral assessment, which preceded the inhalation update).
However, MS-Combo under BMDS version 2.704 produced slightly different results from the U.S. EPA.
(2013d) IRIS assessment. This was due to differences in multistage model selection using current
guidance U.S. EPA. (2014b. 2012b). and differences in software versions (MS-Combo under BMDS
version 2.2Beta was used for the •• v \ <2.013d) IRIS assessment).
MS-Combo was applied to the BMD modeling results from the Kasai et al. (2009) study. To evaluate
uncertainties related to model choice and mechanisms, MS-Combo was applied twice: one model run
included all tumors, while an additional model run excluded liver tumors.
Incidences of tumors in rats (hepatocellular adenomas or carcinomas) from the Kasai et al. (2009) study
were corrected to account for rats that exhibited both adenomas and carcinomas. These data were
provided to U.S. EPA by a personal communication with the study author Kasai (2008). and were
extracted from Table 5-8 of 013d).
The high concentration group for subcutis fibroma was omitted from the dose-response analysis. As
noted in the U.S. U.S. EPA. (2013d) IRIS assessment, the incidence data for subcutis fibroma were
monotonic non-decreasing functions of dose for the control (0 ppm), low (50 ppm), and mid-dose (250
ppm); however, the incidence rate at the high dose (1,250 ppm) was lower than observed at the mid-
dose. No BMDS model exhibited a reasonable fit to the data without dropping the high dose.
Page 530 of 616
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K.1 BMDS Summary of Centrilobular necrosis of the liver in male
F344/DuCrj rats ¥ " ' " )
Table K-l. Summary of BMD Modeling Results for Centrilobular necrosis of the liver in male
F344/DuCrj rats
Kasai et al. (2009)
Model3
Goodness of fit
BMDiopct
(ppm)
BMDLiopct
(ppm)
Basis for model selection
/?-value
AIC
Gammab
0.510
129.69
502
308
Lowest BMDL model chosen
when adequate-fitting models
are not sufficiently close in
range.
Dichotomous -Hill
0.746
130.40
220
59.6
Logistic
0.279
131.04
795
609
LogLogistic
0.568
129.47
453
259
Probit
0.299
130.89
756
567
LogProbit
0.952
130.31
232
44.0
Weibull"
Quantal-Lineard
0.510
129.69
502
308
Multistage 3oe
Multistage 2of
0.510
129.69
502
308
The restricted dichotomous Hill results are reported here because the unrestricted dichotomous Hill model resulted in zero
degrees of freedom (number of estimated parameters equal to number of dose groups), precluding the derivation of a p-value
and AIC for that model.
a Selected model in bold; scaled residuals for selected model for doses 0, 50,250, and 1250 ppm were -0.01, 0.03, -0.04, 0.02,
respectively.
b The Gamma model may appear equivalent to the Weibull model, however differences exist in digits not displayed in the table.
This also applies to the Multistage 3° model. This also applies to the Multistage 2° model. This also applies to the Quantal-
Linear model.
c For the Weibull model, the power parameter estimate was 1. The models in this row reduced to the Quantal-Linear model.
d The Quantal-Linear model may appear equivalent to the Gamma model, however differences exist in digits not displayed in
the table. This also applies to the Multistage 3° model. This also applies to the Multistage 2° model.
e For the Multistage 3° model, the beta coefficient estimates were 0 (boundary of parameters space). The models in this row
reduced to the Multistage 2° model.
f The Multistage 2° model may appear equivalent to the Gamma model, however differences exist in digits not displayed in the
table. This also applies to the Weibull model. This also applies to the Quantal-Linear model.
Page 531 of 616
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LogProb it Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Log-Logistic Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
LogProb it
Figure K-l. Plot of incidence rate by dose with fitted curve for the unrestricted LogProbit (left)
and restricted LogLogistic (right) models for Centrilobular necrosis of the liver in male
F344/DuCrj rats Kasai et al. (2009); dose shown in ppm. Restricted LogLogistic has the lowest
AIC but exhibits higher residuals for all dose groups.
Page 532 of 616
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LogProbit Model. (Version: 3.4; Date: 5/21/2017)
The form of the probability function is: P[response] = Background + (1-Background) *
CumNorm(Intercept+Slope*Log(Dose)),where CumNorm(.) is the cumulative normal distribution
function
Slope parameter is not restricted
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 232.245
BMDL at the 95% confidence level = 43.9928
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
background
0.0201374
0.02
intercept
-2.9660E+00
-2.9443E+00
slope
0.309189
0.305751
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-62.15
4
Fitted model
-62.15
3
0.00361134
1
0.95
Reduced
model
-69.3
1
14.305
3
0
AIC: = 130.305
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0.0201
1.007
1
50
-0.01
50
0.0589
2.943
3
50
0.03
250
0.1221
6.105
6
50
-0.04
1250
0.2389
11.946
12
50
0.02
ChiA2 = 0 d.f = 1 P-value = 0.9521
Page 533 of 616
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K.2 BMDS Summary of Squamous cell metaplasia of respiratory
epithelium in male F433/DuCrj rats Kasai et al. (2009)
Table K-2. Summary of BMD Modeling Results for Squamous cell metaplasia of respiratory
epithelium in male F433/DuCrj rats Kasai et al. (2009)
Model8
Goodness of fit
BMDiopct
(ppm)
BMDLiopct
(ppm)
Basis for model selection
/?-value
AIC
Gamma
0.868
81.687
218
150
Lowest AIC. BMDL estimates
for models not excluded (based
on goodness-of-fit p values
less than 0.1, or high scaled
residuals) are sufficiently
close.
Dichotomous -Hill
1.000
83.189
241
162
Logistic
0.0464
89.415
370
289
LogLogistic
0.914
81.525
218
158
Probit
0.0779
87.936
338
268
LogProbit
0.989
81.230
218
160
Weibull
0.768
82.124
218
145
Multistage 3°
0.619
82.688
231
140
Multistage 2°
0.619
82.688
231
141
Quantal-Linear
0.0198
92.922
87.7
68.8
a Selected model in bold; scaled residuals for selected model for doses 0, 50,250, and 1250 ppm were 0, -0.14, 0.03, -0.02,
respectively.
LogProbit Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Log Pro bit
1
0.8
0.6
0.4
0.2
O
O
200
400
600
800
1000
1200
Figure K-2. Plot of incidence rate by dose with fitted curve for LogProbit model for Squamous cell
metaplasia of respiratory epithelium in male F433/DuCrj rats Kasai et al. (2009); dose shown in
ppm.
LogProbit Model. (Version: 3.4; Date: 5/21/2017)
Page 534 of 616
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The form of the probability function is: P[response] = Background + (1-Background) *
CumNorm(Intercept+Slope*Log(Dose)),where CumNorm(.) is the cumulative normal distribution
function
Slope parameter is not restricted
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 217.79
BMDL at the 95% confidence level = 159.619
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
background
0
0
intercept
-8.8618E+00
-6.7651E+00
slope
1.40803
1.09006
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-38.59
4
Fitted model
-38.62
2
0.041197
2
0.98
Reduced
model
-113.55
1
149.916
3
<.0001
AIC: = 81.23
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0
0
0
50
0
50
0.0004
0.02
0
50
-0.14
250
0.1384
6.922
7
50
0.03
1250
0.8808
44.038
44
50
-0.02
ChiA2 = 0.02 d.f = 2 P-value = 0.9894
Page 535 of 616
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K.3 BMDS Summary of Squamous cell hyperplasia of respiratory
epithelium in male F433 DuCrj rn(s ' " )
Table K-3. Summary of BMD Modeling Results for Squamous cell hyperplasia of respiratory
epithelium in male F433/DuCrj rats Kasai et ai. (2009)
Model3
Goodness of fit
BMDiopct
(ppm)
BMDLiopct
(ppm)
Basis for model selection
/?-value
AIC
Gamma
0.961
63.981
761
487
Lowest AIC. BMDL estimates
for models not excluded (based
on goodness-of-fit p values
less than 0.1, or high scaled
residuals) are sufficiently
close.
Note: Dichotomous Hill did
not converge
Dichotomous -Hill
1.000
65.844
316
280
Logistic
0.582
65.208
1013
847
LogLogistic
0.960
63.988
760
473
Probit
0.631
65.018
962
786
LogProbit
0.987
63.893
704
437
Weibull
0.956
64.001
776
486
Multistage 3ob
0.926
64.099
812
481
Multistage 2°c
0.926
64.099
812
481
Quantal-Linear
0.795
63.342
679
429
a Selected model in bold; scaled residuals for selected model for doses 0, 50,250, and 1250 ppm were 0, -0.62, -0.67, 0.44,
respectively.
b The Multistage 3° model may appear equivalent to the Multistage 2° model; however, differences exist in digits not displayed
in the table.
c The Multistage 2° model may appear equivalent to the Multistage 3° model; however, differences exist in digits not displayed
in the table.
For results based on a power or slope parameter that hits the bound of 1, EPA 201.2b) states (footnote 10) ".. .the nominal
coverage of the confidence interval is not exact (asymptotically) and could be much less than intended if the true (unknown)
parameter is <1, and this should also be reported"
Page 536 of 616
-------
Quantal Linear Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
0
200
400
600
800
1000
1200
Figure K-3. Plot of incidence rate by dose with fitted curve for Quantal-Linear model for
Squamous cell hyperplasia of respiratory epithelium in male F433/DuCrj rats; dose shown in
ppm.
Page 537 of 616
-------
Quantal Linear Model using Weibull Model (Version: 2.17; Date: 6/23/2017)
The form of the probability function is: P[response] = background + (1-background)* [1-EXP(-
slope*dose)]
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 679.311
BMDL at the 95% confidence level = 429.287
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0
0.0192308
Slope
0.000155099
0.000174603
Power
n/a
1
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-29.92
4
Fitted model
-30.67
1
1.49818
3
0.68
Reduced
model
-42.6
1
25.3487
3
<.0001
AIC: = 63.3423
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0
0
0
50
0
50
0.0077
0.386
0
50
-0.62
250
0.038
1.902
1
50
-0.67
1250
0.1762
8.812
10
50
0.44
ChiA2 = 1.03 d.f = 3 P-value = 0.7945
Page 538 of 616
-------
K.4 Benchmark dose analysis of respiratory metaplasia of the olfactory
epithelium in the nasal cavity of male F344/DuCrj rats sai et al.
(2009)
As reported in the EPA 1,4-dioxane IRIS assessment, no models in the software provided adequate fits
to the data for the incidence of respiratory metaplasia of the olfactory epithelium in male rats (%2 p >
0.1) when all dose groups are included in the analysis ( 2013d) Table F-8). While the model
uncertainty associated with data for which the response at the lowest non-control dose (34/50) is 46%
higher than the control response (11/50) was acknowledged, the IRIS assessment determined that
modeling this dataset without the high dose group would be consistent with BMD Technical Guidance
Document U.S. EPA. (2012b). As a result, all models were fit to the incidence data with the highest dose
group omitted (U.S. EPA (2.013d). Table F-9). Using BMDS 2.1.1, it was determined that, of the
adequately fitting models (p-value > 0.1), "the AIC values for gamma, multistage, quantal-linear, and
Weibull models in Table F-9 are equivalent and the lowest and, in this case, essentially represent the
same model" and, because they all result in the same BMDL value of 4.7 ppm, "consistent with the
Benchmark Dose Technical Guidance )12b). any of them with equal AIC values (gamma,
multistage, quantal-linear, or Weibull) could be used to identify a POD for this endpoint." This report
confirms these findings of BMDS 2.1.1 for this dataset using the latest version of BMDS, BMDS 3.1.
The table below shows the BMR, BMD, BMDL, p-value, AIC and scaled residual for the dose-group
nearest the BMD (the 50 ppm dose group) for the suite of BMDS dichotomous models available in
BMDS 3.1 using standard model restriction settings (default settings in BMDS 3.1) recommended in the
EPA BMD technical guidance U.S. EPA. (2012b). The Gamma, Multistage and Weibull models all
converge to the same BMD and goodness-of-fit results, the same (lowest) AIC value and the same
BMDL estimate of 4.7 ppm, which is virtually the same result obtained from BMDS 2.1.1 in the 2013
IRIS assessment (ILSJ. \ >,013d) Table F-9). Several aspects of this analysis support dropping the
highest dose group data, including the inability to adequately fit the dose-response data for all four dose
groups (see U.S. EPA (2.013d) Table F-8), acceptable fit (p-value >0.1) to the dose-response data when
the highest dose group is removed (see table summary of BMD modeling results below), visual
inspection of the plots for the acceptable models with the three models with the lowest AIC (see detailed
results for individual Gamma, Multistage and Weibull models below), and the low scaled residuals (-
0.106) reported for these models at the (50 ppm) dose group nearest the BMD. In general, models that
result in low scaled residuals for dose groups near the BMD are preferred ( 312b) Sections
2.3.5 and 2.5.). The concern over model uncertainty due to the nearly 10-fold difference between the
BMD and the lowest non-control dose group is partially offset in this case by the fact that six different
models, including three saturated models (models for which p-values could not be derived due to the use
of as many or more parameters than dose groups, resulting in 0 degrees of freedom), reported BMDLs
within a very small range of 3-5 ppm.
Page 539 of 616
-------
Summary of BMD modeling results for respiratory metaplasia of olfactory epithelium in the nasal
Model
Restriction
BM
R
BMD
(ppm)
BMDL
(ppm)
P -Value
AIC
Scaled
Residual
for Dose
Group near
BMD
BMDS Recommendation Notes
Gamma
Restricted
0.1
6.468
4.737
0.581
129.46
-0.106
Lowest AIC
BMDL lOx lower than lowest non-zero
dose
Multistage
Degree 22
Restricted
0.1
6.468
4.737
0.581
129.46
-0.106
Multistage
Degree 1
Restricted
0.1
6.468
4.737
0.581
129.46
-0.106
Weibull
Restricted
0.1
6.468
4.737
0.581
129.46
-0.106
Log-Logistic
Restricted
0.1
14.207
3.771
NA
131.18
-1.24E-05
BMDL lOx lower than lowest non-zero
dose
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Dichotomous
Hill
Restricted
0.1
14.204
3.771
NA
131.18
-0.0002
Log-Probit
LTnrestricted
0.1
12.211
3.075
NA
131.18
-8.44E-07
Logistic
LTnrestricted
0.1
12.520
9.345
0.012
133.58
-1.031
Goodness of fit p-value <0.1
Probit
LTnrestricted
0.1
15.288
11.687
0.007
136.12
-1.511
1 High dose response was not included because of inadequate model fits and the fact that maximal response was reached at the mid-dose.
2 Multistage 2 is the same model as Multistage 1 due to parameter convergence.
Data
Respiratory metaplasia
Respiratory metaplasia of the olfactory epithelium (male F344 rats.
Kasai et al.,2009))
Dose
N
Incidence
[Dose]
[N]
[Incidence]
0
50
11
50
50
34
250
50
49
Page 540 of 616
-------
Restricted Gamma
User Input
Info
Model
Restricted Gamma
Dataset
Name
Respiratory metaplasia
User
notes
Respiratory metaplasia
of olfactory epithelium
(male F344 rats, Kasai et
al„ 2009))
Model Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Background
Estimated
Model Data
Dependent
Variable
ppm
Independent
Variable
Respiratory
metaplasia
Total # of
Observations
3
Model Results
Benchmark Dose
BMD
6.468479372
BMDL
4.737250177
BMDU
15.58341107
AIC
129.46256
P-value
0.581473595
D.O.F.
1
Chi2
0.303858409
Model Parameters
# of Parameters
4
Variable
Estimate
g
0.226248926
a
1
b
0.016288297
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.226248926
11.31244628
11
50
-0.105608
50
0.657306883
32.86534417
34
50
0.3380978
250
0.986813734
49.34068668
49
50
-0.422369
Analysis of Deviance
Page 541 of 616
-------
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-62.59082662
0
_
_
_
Fitted Model
-62.73127999
2
0.28090675
1
0.5961075
Reduced Model
-99.1058899
1
73.0301266
2
<0.0001
1
Frequentist Gamma Model with BMR of 10% Extra Risk for the
BMD and 0.95 Lower Confidence Limit for the BMDL
0.9
0.8
0.7
8 0.6
g. 0.5
w
cc 0.4
0.3
0.2
0.1
0
50 100 150 200 250
Dose
Estimated Probability Response at BMD • Data BMD BMDL
Page 542 of 616
-------
Restricted Multistage 1
User Input
Info
Model
Restricted Multistage 1
Dataset
Name
Respiratory metaplasia
User
notes
Respiratory metaplasia
of olfactory epithelium
(male F344 rats, Kasai et
al. 2009))
Model Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Background
Estimated
Model Data
Dependent
Variable
ppm
Independent
Variable
Respiratory
metaplasia
Total # of
Observations
3
Model Results
Benchmark Dose
BMD
6.468474487
BMDL
4.737235003
BMDU
9.087463619
AIC
129.46256
P-value
0.581473253
D.O.F.
1
Chi2
0.303858959
Model Parameters
# of Parameters
2
Variable
Estimate
g
0.226248831
bl
0.01628831
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.226248831
11.31244157
11
50
-0.105606
50
0.657307053
32.86535263
34
50
0.3380953
250
0.986813773
49.34068863
49
50
-0.422372
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Page 543 of 616
-------
Full Model
-62.59082662
0
_
_
_
Fitted Model
-62.73127999
2
0.28090675
1
0.5961075
Reduced Model
-99.1058899
1
73.0301266
2
<0.0001
1
Frequentist Multistage Degree 1 Model with BMR of 10% Extra
Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
0.9
0.8
0.7
8 0.6
I 0.5
tn
£ 0.4
0.3
n 9 <
u.z
0.1
0
50 100 150 200 250
Dose
Estimated Probability Response at BMD Linear Extrapolation • Data BMD BMDL
Page 544 of 616
-------
Restricted Weibull
User Input
Info
Model
Restricted Weibull
Dataset
Name
Respiratory metaplasia
User
notes
Respiratory metaplasia
of olfactory epithelium
(male F344 rats, Kasai et
al„ 2009))
Model Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Background
Estimated
Model Data
Dependent
Variable
ppm
Independent
Variable
Respiratory
metaplasia
Total # of
Observations
3
Model Results
Benchmark Dose
BMD
6.468485055
BMDL
4.737254339
BMDU
13.26149794
AIC
129.46256
P-value
0.581473996
D.O.F.
1
Chi2
0.303857764
Model Parameters
# of Parameters
3
Variable
Estimate
g
0.226249018
a
1
b
0.016288283
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.226249018
11.31245092
11
50
-0.105609
50
0.657306679
32.86533396
34
50
0.3381008
250
0.986813688
49.3406844
49
50
-0.422365
Page 545 of 616
-------
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-59.3166114
0
-
-
-
Fitted Model
-59.31661362
2
4.4538E-06
2
0.9999978
Reduced Model
-123.8201329
1
129.007043
3
<0.0001
1
Frequentist Weibull Model with BMR of 10% Extra Risk for the
BMD and 0.95 Lower Confidence Limit for the BMDL
0.9
0.8
0.7
8 0.6
I 0.5
tn
& 0.4
0.3
0.2 (
0.1
0
50 100 150 200 250
Dose
Estimated Probability Response at BMD • Data BMD BMDL
Page 546 of 616
-------
K.5 BMDS Summary of Hydropic change (lamina propria) Kasai et al.
(2009)
Table K-4. Summary of BMD Modeling Results for Hydropic change (lamina propria) Kasai et al.
Model8
Goodness of fit
BMDiopct
(ppm)
BMDLiopct
(ppm)
Basis for model selection
/?-value
AIC
Gamma
2.00E-
04
98.344
52.0
28.8
Lowest AIC. BMDL estimates
for models not excluded (based
on goodness-of-fit p values
less than 0.1, or high scaled
residuals) are sufficiently
close.
Dichotomous -Hill
1.000
91.894
73.1
49.3
Logistic
0
117.96
89.3
70.6
LogLogistic
0.682
90.539
68.5
46.8
Probit
0
136.59
92.6
74.4
LogProbit
0.346
91.588
63.1
44.6
Weibull
0.0033
100.23
39.1
24.0
Multistage 3ob
Multistage 2°
Quantal-Linear
0.0256
99.348
28.8
22.7
a Selected model in bold; scaled residuals for selected model for doses 0, 50,250, and 1250 ppm were 0, -0.33, 0.32, -0.74,
respectively.
b For the Multistage 3° model, the beta coefficient estimates were 0 (boundary of parameters space). The models in this row
reduced to the Multistage 2° model.
Page 547 of 616
-------
Log-Logistic Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Log-Logistic
1
0.8
0.6
0.4
0.2
0
0
200
400
600
800
1000
1200
Figure K-4. Plot of incidence rate by dose with fitted curve for LogLogistic model for Hydropic
change (lamina propria) Kasai et al. (2009); dose shown in ppm.
LogLogistic Model. (Version: 2.15; Date: 3/20/2017)
The form of the probability function is: P[response] = background+(l-background)/[l+EXP(-intercept-
slope*Log(dose))]
Slope parameter is restricted as slope >= 1
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 68.5266
BMDL at the 95% confidence level = 46.7808
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
background
0
0
intercept
-1.2132E+01
-1.1575E+01
slope
2.3501
2.19638
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-42.95
4
Fitted model
-43.27
2
0.645129
2
0.72
Reduced
model
-136.94
1
187.976
3
<.0001
Page 548 of 616
-------
AIC: = 90.5388
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0
0
0
50
0
50
0.0503
2.515
2
50
-0.33
250
0.6994
34.969
36
50
0.32
1250
0.9903
49.515
49
50
-0.74
ChiA2 = 0.77 d.f = 2 P-value = 0.6819
Page 549 of 616
-------
K.6 BMDS Summary of Nasal cavity squamous cell carcinoma (male
F344/DuCrj rats) Kasai et al. (2009)
Table K-5. Summary of BMD Modeling Results for Nasal cavity squamous cell carcinoma (male
F344/DuCrj rats) Kasai et al. (2009)
Model8
Goodness of lit
BMDiopct
(ppm)
BMDLiopct
(ppm)
Basis for model selection
/?-value
AIC
One
0.961
49.031
1107
630
Lowest AIC. All parameter
estimates positive in both models.
Two
0.909
50.828
1087
642
a Selected model in bold; scaled residuals for selected model for doses 0, 50,250, and 1250 ppm were 0, -0.49, -0.16, 0.18,
respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Multistage Cancer
Linear extrapolation
0.25
0.2
0.15
0.1
0.05
O
O
200
400
600
800
1000
1200
Figure K-5. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Nasal cavity squamous cell carcinoma (male F344/DuCrj rats) Kasai et al. (2009); dose shown in
ppm.
Page 550 of 616
-------
Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (l-background)*[l-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 1107.04
BMDL at the 95% confidence level = 629.948
BMDU at the 95% confidence level = 2215.11
Taken together, (629.948, 2215.11) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.000158743
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0
0
Beta(l)
0.0000951733
0.000104666
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-23.25
4
Fitted model
-23.52
1
0.534383
3
0.91
Reduced
model
-30.34
1
14.1894
3
0
AIC: = 49.0308
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0
0
0
50
0
50
0.0047
0.237
0
50
-0.49
250
0.0235
1.176
1
50
-0.16
1250
0.1122
5.608
6
50
0.18
ChiA2 = 0.3 d.f = 3 P-value = 0.9607
Page 551 of 616
-------
K.7 BMDS Summary of Zymbal gland adenoma (male F344/DuCrj rats)
Kasai et al. (2009)
Table K-6. Summary of BMD Modeling Results for Zymbal gland adenoma (male F344/DuCrj
rats) Kasai et al. (2009)
Model8
Goodness of lit
BMDiopct
(ppm)
BMDLiopct
(ppm)
Basis for model selection
/?-value
AIC
One
0.800
31.663
1975
958
Lowest BMDL. Some parameter
values were zero for both models.
Two
0.982
30.217
1435
999
a Selected model in bold; scaled residuals for selected model for doses 0, 50,250, and 1250 ppm were 0, -0.36, -0.82, 0.45,
respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Multistage Cancer
Linear extrapolation
0.2
0.15
0.1
0.05
O
O
500
1000
1500
2000
dose
09:22 08/09 2018
Figure K-6. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Zymbal gland adenoma (male F344/DuCrj rats) Kasai et al. (2009); dose shown in ppm.
Page 552 of 616
-------
Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (l-background)*[l-EXP(-
betal *doseAl -beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 1974.78
BMDL at the 95% confidence level = 957.63
BMDU at the 95% confidence level = 5118.88
Taken together, (957.63, 5118.88) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.000104424
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0
0
Beta(l)
0.0000533531
0.0000700345
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-13.94
4
Fitted model
-14.83
1
1.78598
3
0.62
Reduced
model
-19.61
1
11.3387
3
0.01
AIC: = 31.6629
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0
0
0
50
0
50
0.0027
0.133
0
50
-0.36
250
0.0132
0.662
0
50
-0.82
1250
0.0645
3.226
4
50
0.45
ChiA2 = 1 d.f = 3 P-value = 0.8004
Page 553 of 616
-------
K.8 MS-Combo portal of entry tumors Kasai et al. (2009)
Portal of entry tumors (nasal cavity squamous cell carcinoma, zymbal gland adenoma)
Output information
Tumor Output Directory
C:\Users\
\Documents\MODELS\14dioxane\inhalation\
Tumor Output File Name
kasai noliv POE.out
Combined BMD and BMDL Calculations
Combined Log-Likelihood
-38.34685652
Combined Log-likelihood Constant
32.84040568
Benchmark Dose Computation
Specified effect
0.1
Risk Type
Extra risk
Confidence level
0.95
BMD
709.372
BMDL
448.544
Multistage Cancer Slope Factor
0.000222944
**** Start of combined BMD and BMDL Calculations.****
Combined Log-Likelihood -38.346856517733208
Combined Log-likelihood Constant 32.840405681643567
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
C onfi dence 1 evel = 0.95
BMD = 709.372
BMDL = 448.544
BMDU = 1218.18
Multistage Cancer Slope Factor = 0.000222944
K.9 BMDS Summary of Hepatocellular adenoma or carcinoma (male
F344/DuCrj rats) Kasai et al. (2009)
Table K-7. Summary of BMD Modeling Results for Hepatocellular adenoma or carcinoma (male
F344/DuCrj rats) Kasai et al. (2009)
Model8
Goodness of lit
BMDiopct
(ppm)
BMDLiopct
(ppm)
Basis for model selection
/?-value
AIC
One
0.693
127.86
253
182
Lowest AIC. All parameter
estimates positive in both models.
Two
0.764
129.16
377
190
a Selected model in bold; scaled residuals for selected model for doses 0, 50,250, and 1250 ppm were 0.16, 0.1, -0.76, 0.34,
respectively.
Page 554 of 616
-------
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Multistage Cancer
Linear extrapolation
0.6
0.5
0.4
0.3
0.2
0.1
0
0
200
400
600
800
1000
1200
Figure K-7. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Hepatocellular adenoma or carcinoma (male F344/DuCrj rats) Kasai et al. (2009); dose shown in
ppm.
Page 555 of 616
-------
Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (l-background)*[l-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 252.799
BMDL at the 95% confidence level = 182.256
BMDU at the 95% confidence level = 371.457
Taken together, (182.256, 371.457) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.000548678
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0.0170678
0.00480969
Beta(l)
0.000416776
0.0004548
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-61.53
4
Fitted model
-61.93
2
0.792109
2
0.67
Reduced
model
-82.79
1
42.5066
3
<.0001
AIC: = 127.86
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0.0171
0.853
1
50
0.16
50
0.0373
1.867
2
50
0.1
250
0.1143
5.716
4
50
-0.76
1250
0.4162
20.81
22
50
0.34
ChiA2 = 0.73 d.f = 2 P-value = 0.6928
K.10 BMDS Summary of Renal cell carcinoma (male F344/DuCrj rats)
Kasai et ai (2009)
Page 556 of 616
-------
Table K-8. Summary of BMD Modeling Results for Renal cell carcinoma (male F344/DuCrj rats)
Kasai et al. (2009)
Model8
Goodness of lit
BMDiopct
(ppm)
BMDLiopct
(ppm)
Basis for model selection
/?-value
AIC
One
0.800
31.663
1975
958
Lowest BMDL. Some parameter
values were zero for both models.
Two
0.982
30.217
1435
999
a Selected model in bold; scaled residuals for selected model for doses 0, 50,250, and 1250 ppm were 0, -0.36, -0.82, 0.45,
respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Multistage Cancer
Linear extrapolation
0.2
0.15
0.1
0.05
O
O
500
1000
1500
2000
dose
09:08 08/09 2018
Figure K-8. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Renal cell carcinoma (male F344/DuCrj rats) Kasai et al. (2009); dose shown in ppm.
Page 557 of 616
-------
Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (1-background)* [1-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 1974.78
BMDL at the 95% confidence level = 957.63
BMDU at the 95% confidence level = 5118.88
Taken together, (957.63, 5118.88) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.000104424
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0
0
Beta(l)
0.0000533531
0.0000700345
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-13.94
4
Fitted model
-14.83
1
1.78598
3
0.62
Reduced
model
-19.61
1
11.3387
3
0.01
AIC: = 31.6629
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0
0
0
50
0
50
0.0027
0.133
0
50
-0.36
250
0.0132
0.662
0
50
-0.82
1250
0.0645
3.226
4
50
0.45
ChiA2 = 1 d.f = 3 P-value = 0.8004
K.l 1 BMDS Summary of Peritoneal mesothelioma (male F344/DuCrj
rats) : ~)
Page 558 of 616
-------
Table K-9. Summary of BMD Modeling Results for Peritoneal mesothelioma (male F344/DuCrj
rats) Kasai et al. (2009)
Model8
Goodness of lit
BMDiopct
(ppm)
BMDLiopct
(ppm)
Basis for model selection
/?-value
AIC
One
0.851
155.43
82.2
64.4
Lowest AIC. All parameter
estimates positive in both models.
Two
0.805
157.17
96.2
65.1
a Selected model in bold; scaled residuals for selected model for doses 0, 50,250, and 1250 ppm were 0.25, -0.33, -0.29, 0.26,
respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
1
Multistage Cancer
Linear extrapolation
0.8
0.6
0.4
0.2
O
O
200
400
600
800
1000
1200
dose
09:20 08/09 2018
Figure K-9. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Peritoneal mesothelioma (male F344/DuCrj rats) Kasai et al. (2009); dose shown in ppm.
Page 559 of 616
-------
Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (1-background)* [1-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 82.2057
BMDL at the 95% confidence level = 64.3808
BMDU at the 95% confidence level = 107.497
Taken together, (64.3808, 107.497) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.00155326
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0.033631
0.0172414
Beta(l)
0.00128167
0.00135351
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-75.55
4
Fitted model
-75.72
2
0.326905
2
0.85
Reduced
model
-123.01
1
94.9105
3
<.0001
AIC: = 155.433
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0.0336
1.682
2
50
0.25
50
0.0936
4.681
4
50
-0.33
250
0.2986
14.928
14
50
-0.29
1250
0.8053
40.265
41
50
0.26
ChiA2 = 0.32 d.f = 2 P-value = 0.8509
K.I 2 BMDS Summary of Mammary gland fibroadenoma (male
F344/DuCrj rats) " )
Page 560 of 616
-------
Table K-10. Summary of BMD Modeling Results for Mammary gland fibroadenoma (male
F344/DuCrj rats) Kasai et al. (2009)
Model8
Goodness of lit
BMDiopct
(ppm)
BMDLiopct
(ppm)
Basis for model selection
/?-value
AIC
One
Two
0.790
86.290
1635
703
All (equivalent) models provide
adequate fit.
a Selected model in bold; scaled residuals for selected model for doses 0, 50,250, and 1250 ppm were -0.47, 0.2, 0.43, -0.15,
respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Multistage Cancer
Linear extrapolation
0.2
0.15
0.1
0.05
O
O
200
400
600
800
1000
1200
1400
1600
dose
09:21 08/09 2018
Figure K-10. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Mammary gland fibroadenoma (male F344/DuCrj rats) Kasai et al. (2009); dose shown in ppm.
Page 561 of 616
-------
Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (1-background)* [1-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 1635.46
BMDL at the 95% confidence level = 703.034
BMDU at the 95% confidence level = 1247200000
Taken together, (703.034, 1247200000) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.000142241
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0.0315836
0.0335609
Beta(l)
0.0000644224
0.0000591694
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-40.9
4
Fitted model
-41.14
2
0.486662
2
0.78
Reduced
model
-42.6
1
3.3895
3
0.34
AIC: = 86.29
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0.0316
1.579
1
50
-0.47
50
0.0347
1.735
2
50
0.2
250
0.0471
2.353
3
50
0.43
1250
0.1065
5.326
5
50
-0.15
ChiA2 = 0.47 d.f = 2 P-value = 0.7904
Page 562 of 616
-------
K.13 BMDS Summary of Subcutis fibroma (male F344/DuCrj rats, high
dose dropped) Kasai et al. (2009)
Table K-ll. Summary of BMD Modeling Results for Subcutis fibroma (male F344/DuCrj rats,
high dose dropped) Kasai et al. (2009)
Model8
Goodness of lit
BMDiopct
(ppm)
BMDLiopct
(ppm)
Basis for model selection
/?-value
AIC
One
0.525
89.209
142
81.9
Model provides adequate fit.
a Selected model in bold; scaled residuals for selected model for doses 0, 50, and 250 ppm were -0.28, 0.54, -0.2, respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
0.35
Multistage Cancer
Linear extrapolation
0.3
0.25
0.2
0.15
0.1
0.05
O
O
50
100
150
200
250
Figure K-ll. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Subcutis fibroma (male F344/DuCrj rats, high dose dropped) Kasai et al. (2009); dose shown in
ppm.
Page 563 of 616
-------
Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (l-background)*[l-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 141.762
BMDL at the 95% confidence level = 81.9117
BMDU at the 95% confidence level = 364.364
Taken together, (81.9117, 364.364) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.00122083
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0.0262055
0.0327631
Beta(l)
0.00074322
0.000673665
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-42.41
3
Fitted model
-42.6
2
0.389155
1
0.53
Reduced
model
-46.53
1
8.23466
2
0.02
AIC: = 89.2094
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0.0262
1.31
1
50
-0.28
50
0.0617
3.086
4
50
0.54
250
0.1913
9.566
9
50
-0.2
ChiA2 = 0.41 d.f = 1 P-value = 0.5245
K.14 MS-Combo Systemic (including liver) Kasai et al. (2009)
Systemic tissue tumors, including liver (hepatocellular adenoma or carcinoma, renal cell carcinoma,
peritoneal mesothelioma, mammary gland fibroadenoma, subcutis fibroma)
Output information
Tumor Output Directory
C :\Users\ \Documents\MODELS\14dioxane\inhalation\
Tumor Output File Name
kasai systemic wliver.out
Page 564 of 616
-------
Combined BMD and BMDL Calculations
Combined Log-Likelihood
-236.2277997
Combined Log-likelihood Constant
209.8734852
Benchmark Dose Computation
Specified effect
0.1
Risk Type
Extra risk
Confidence level
0.95
BMD
41.1654
BMDL
32.7682
Multistage Cancer Slope Factor
0.00305174
**** Start of combined BMD and BMDL Calculations.****
Combined Log-Likelihood -236.22779970471757
Combined Log-likelihood Constant 209.87348521364675
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
C onfi dence 1 evel = 0.95
BMD = 41.1654
BMDL = 32.7682
BMDU = 53.265
Multistage Cancer Slope Factor = 0.00305174
K.15 MS-Combo Systemic (omitting liver) KasaietaL_(2009)
Systemic tissue tumors, excluding liver (renal cell carcinoma, peritoneal mesothelioma, mammary gland
fibroadenoma, subcutis fibroma)
Output information
Tumor Output Directory
C :\Users\ \Documents\MODELS\14dioxane\inhalation\
Tumor Output File Name
Kasai noliv systemic.out
Combined BMD and BMDL Calculations
Combined Log-Likelihood
-174.2976237
Combined Log-likelihood Constant
154.3867855
Benchmark Dose Computation
Specified effect
0.1
Risk Type
Extra risk
Confidence level
0.95
BMD
49.1727
BMDL
37.8668
Multistage Cancer Slope Factor
0.00264083
**** Start of combined BMD and BMDL Calculations.****
Combined Log-Likelihood -174.29762368979428
Combined Log-likelihood Constant 154.38678553667452
Benchmark Dose Computation
Page 565 of 616
-------
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 49.1727
BMDL = 37.8668
BMDU = 66.6769
Multistage Cancer Slope Factor = 0.00264083
K.16 MS-Combo portal of entry + systemic (including liver) Kasai et al.
(2009)
Portal of entry tumors (nasal cavity squamous cell carcinoma, zymbal gland adenoma) and systemic
tissue tumors, including liver (hepatocellular adenoma or carcinoma, renal cell carcinoma, peritoneal
mesothelioma, mammary gland fibroadenoma, subcutis fibroma)
Output information
Tumor Output Directory
C: \Users\ \Documents\MODELS\ 14dioxane\inhalation\
Tumor Output File Name
Kasai all.out
Combined BMD and BMDL Calculations
Combined Log-Likelihood
-274.5746562
Combined Log-likelihood Constant
242.7138909
Benchmark Dose Computation
Specified effect
0.1
Risk Type
Extra risk
Confidence level
0.95
BMD
38.9076
BMDL
31.2841
Multistage Cancer Slope Factor
0.00319651
**** Start of combined BMD and BMDL Calculations.****
Combined Log-Likelihood -274.57465622245081
Combined Log-likelihood Constant 242.71389089529029
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 38.9076
BMDL = 31.2841
BMDU = 49.6547
Multistage Cancer Slope Factor = 0.00319651
Page 566 of 616
-------
K.17 MS-Combo portal of entry + systemic (omitting liver) Kasai et al.
(2009)
Portal of entry tumors (nasal cavity squamous cell carcinoma, zymbal gland adenoma) and systemic
tissue tumors, excluding liver (renal cell carcinoma, peritoneal mesothelioma, mammary gland
fibroadenoma, subcutis fibroma)
Output information
Tumor Output Directory
C: \Users\ \Documents\MODELS\ 14dioxane\inhalation\
Tumor Output File Name
kasai noliv.out
Combined BMD and BMDL Calculations
Combined Log-Likelihood
-212.6444802
Combined Log-likelihood Constant
187.2271912
Benchmark Dose Computation
Specified effect
0.1
Risk Type
Extra risk
Confidence level
0.95
BMD
45.985
BMDL
35.8978
Multistage Cancer Slope Factor
0.00278569
**** Start of combined BMD and BMDL Calculations.****
Combined Log-Likelihood -212.64448020752749
Combined Log-likelihood Constant 187.22719121831807
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 45.985
BMDL = 35.8978
BMDU = 61.1203
Multistage Cancer Slope Factor = 0.00278569
K.18 BMDS Summary of Hepatocellular mixed foci in male F344/DuCrj
rats Kano et al. (2009)
Table K-12. Summary of BMD Modeling Results for Hepatocellular mixed foci in male
F344/DuCrj rats Kano et al. (2009)
Page 567 of 616
-------
Model8
Goodness of fit
BMDiopct
(mg/kg-d)
BMDLiopct
(mg/kg-d)
Basis for model selection
/?-value
AIC
Gammab
Weibull"
Multistage 2°
Quantal-Linear
0.220
125.50
19.2
11.8
Lowest AIC. BMDL estimates
for models not excluded (based
on goodness-of-fit p values
less than 0.1, or high scaled
residuals) are sufficiently
close.
Logistic
0.107
126.75
30.9
23.3
LogLogistic
0.275
125.20
16.7
9.57
Probit
0.114
126.61
29.4
21.8
LogProbit
(restricted)
0.0555
127.84
33.2
21.8
LogProbit
N/Ad
126.06
7.06
error®
Note: There were not enough degrees of freedom to run the Dichotomous Hill model
a Selected model in bold; scaled residuals for selected model for doses 0,11, and 55 mg/kg-d were -0.44, 0.91, -0.42,
respectively.
b For the Gamma and Weibull models, the power parameter estimates were 1 (boundary of parameter space).For the Gamma
model, the power parameter estimate was 1. The model is equivalent to the Quantal-Linear model.
c For the Weibull and Gamma models, the power parameter estimates were 1 (boundary of parameter space).For the Weibull
model, the power parameter estimate was 1. The models in this row reduced to the Quantal-Linear model.
d No available degrees of freedom to calculate a goodness of fit value.
e BMD or BMDL computation failed for this model.
For results based on a power or slope parameter that hits the bound of 1, EPA 2012b) states (footnote 10) ".. .the nominal
coverage of the confidence interval is not exact (asymptotically) and could be much less than intended if the true (unknown)
parameter is <1, and this should also be reported"
Log-Logistic Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Log-Logistic
0.4
0.3
0.2
0.1
O
O
10
20
30
40
50
Figure K-12. Plot of incidence rate by dose with fitted curve for LogLogistic model for
Hepatocellular mixed foci in male F344/DuCrj rats Kano et al. (2009); dose shown in mg/kg-d.
LogLogistic Model. (Version: 2.15; Date: 3/20/2017)
The form of the probability function is: P[response] = background+(l-background)/[l+EXP(-intercept-
slope*Log(dose))]
Page 568 of 616
-------
Slope parameter is restricted as slope >= 1
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 16.7141
BMDL at the 95% confidence level = 9.56614
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
background
0.054099
0.04
intercept
-5.0135E+00
-4.7777E+00
slope
1
1
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-60.03
3
Fitted model
-60.6
2
1.14263
1
0.29
Reduced
model
-65.95
1
11.8442
2
0
AIC: = 125.199
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0.0541
2.705
2
50
-0.44
11
0.1186
5.928
8
50
0.91
55
0.3073
15.367
14
50
-0.42
ChiA2 =1.19 d.f = 1 P-value = 0.275
Page 569 of 616
-------
K.19 BMDS Summary of Cortical tubule degeneration in female OM rats
NCI (1978)
Table K-13. Summary of BMD Modeling Results for Cortical tubule degeneration in female OM
Model8
Goodness of fit
BMDiopct
(mg/kg-d)
BMDLiopct
(mg/kg-d)
Basis for model selection
/?-value
AIC
Gamma
0.945
41.971
525
437
Lowest AIC. BMDL estimates for
models not excluded (based on
goodness-of-fit p values less than
0.1. or high scaled residuals) are
sufficiently close.
For the two models that have
identical (lowest) AICs, the
difference in BMDLs is minor
(452 vs 447).
Logistic
1.000
43.750
617
472
LogLogistic
1.000
41.750
592
447
Probit
1.000
43.750
596
456
LogProbit
1.000
43.750
584
436
Weibull
1.000
41.750
596
452
Multistage 2°
0.144
48.197
399
298
Quantal-Linear
0.0300
52.304
306
189
Note: There were not enough degrees of freedom to rim the Dichotomous Hill model
a Selected model in bold; scaled residuals for selected model for doses 0, 350, and 640 mg/kg-d were 0, -0.02, 0, respectively.
Weibull Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
0.5
0.4
0.3
0.2
0.1
O
O
100
200
300
400
500
600
dose
14:12 08/10 2018
Figure K-13. Plot of incidence rate by dose with fitted curve for Weibull model for Cortical tubule
degeneration in female OM rats NCI (1978); dose shown in mg/kg-d.
Page 570 of 616
-------
Weibull Model using Weibull Model (Version: 2 17; Date: 6/23/2017)
The form of the probability function is: P[response] = background + (1-background)* [1-EXP(-
slope*doseApower)]
Power parameter is restricted as power >=1
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 596.445
BMDL at the 95% confidence level = 452.359
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0
0.030303
Slope
1.1545E-51
7.5210E-10
Power
18
3.09322
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-19.87
3
Fitted model
-19.88
1
0.000487728
2
1
Reduced
model
-32.19
1
24.6247
2
<.0001
AIC: = 41.75
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0
0
0
31
0
350
0
0
0
34
-0.02
640
0.3125
9.999
10
32
0
ChiA2 = 0 d.f = 2 P-value = 0.9999
Page 571 of 616
-------
K.20 BMDS Summary of Nasal squamous cell carcinoma in Male
F344/DuCrj rats Kano et al. (2009)
Table K-14. Summary of BMD Modeling Results for Nasal squamous cell carcinoma in Male
F344/DuCrj rats Kano et al. (2009)
Model8
Goodness of lit
BMDiopct
(mg/kg-d)
BMDLiopct
(mg/kg-d)
Basis for model selection
/?-value
AIC
One
0.862
26.028
582
256
Lowest BMDL. Some parameter
values were zero for both models.
Two
0.988
24.951
365
242
a Selected model in bold; scaled residuals for selected model for doses 0,11, 55, and 274 mg/kg-d were 0, -0.07, -0.35, 0.07,
respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Multistage Cancer
Linear extrapolation
0.15
0.1
0.05
O
O
50
100
150
200
250
300
350
Figure K-14. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 2° model for
Nasal squamous cell carcinoma in Male F344/DuCrj rats Kano et al. (2009); dose shown in mg/kg-
d.
Page 572 of 616
-------
Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (1-background)* [1-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 365.191
BMDL at the 95% confidence level = 242.296
BMDU at the 95% confidence level = 1348.53
Taken together, (242.296, 1348.53) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.000412718
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0
0
Beta(l)
0
0
Beta(2)
7.9002E-07
8.3465E-07
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-11.35
4
Fitted model
-11.48
1
0.253836
3
0.97
Reduced
model
-15.58
1
8.45625
3
0.04
AIC: = 24.9506
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0
0
0
50
0
11
0.0001
0.005
0
50
-0.07
55
0.0024
0.119
0
50
-0.35
274
0.0576
2.879
3
50
0.07
ChiA2 = 0.13 d.f = 3 P-value = 0.988
Page 573 of 616
-------
K.21 BMDS Summary of Peritoneum mesothelioma in Male F344/DuCrj
rats Kano et al. (2009)
Table K-15. Summary of BMD Modeling Results for Peritoneum mesothelioma in Male
F344/DuCrj rats Kano et al. (2009)
Model8
Goodness of lit
BMDiopct
(mg/kg-d)
BMDLiopct
(mg/kg-d)
Basis for model selection
/?-value
AIC
One
0.362
140.83
41.0
30.5
Lowest AIC. All parameter
estimates positive in both models.
Two
0.814
140.75
77.7
35.4
a Selected model in bold; scaled residuals for selected model for doses 0,11, 55, and 274 mg/kg-d were 0.13, -0.19, 0.07, -0.01,
respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
0.6
0.5
0.4
0.3
0.2
0.1
Multistage Cancer
Linear extrapolation
15:45 08/08 2018
Figure K-15. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 2° model for
Peritoneum mesothelioma in Male F344/DuCrj rats Kano et al. (2009); dose shown in mg/kg-d.
Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (1-background)* [1-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 77.7277
BMDL at the 95% confidence level = 35.4296
BMDU at the 95% confidence level = 118.349
Taken together, (35.4296, 118.349) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.0028225
Page 574 of 616
-------
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0.0366063
0.0358706
Beta(l)
0.000757836
0.000816174
Beta(2)
7.6893E-06
7.4706E-06
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-67.35
4
Fitted model
-67.37
3
0.056567
1
0.81
Reduced
model
-95.78
1
56.8663
3
<.0001
AIC: = 140.747
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0.0366
1.83
2
50
0.13
11
0.0455
2.275
2
50
-0.19
55
0.0972
4.859
5
50
0.07
274
0.5605
28.027
28
50
-0.01
ChiA2 = 0.06 d.f = 1 P-value = 0.8135
Page 575 of 616
-------
K.22 BMDS Summary of Hepatocellular adenoma or carcinoma in Male
F344/DuCrj rats Kano et al. (2009)
Table K-16. Summary of BMD Modeling Results for Hepatocellular adenoma or carcinoma in
Male F344/DuCrj rats Kano et al. (2009)
Model8
Goodness of lit
BMDiopct
(mg/kg-d)
BMDLiopct
(mg/kg-d)
Basis for model selection
/?-value
AIC
One
0.0978
152.84
23.8
18.3
Lowest AIC. All parameter
estimates positive in both models.
Two
0.816
149.81
61.7
28.3
a Selected model in bold; scaled residuals for selected model for doses 0,11, 55, and 274 mg/kg-d were -0.13, 0.18, -0.06, 0.01,
respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Multistage Cancer
Linear extrapolation
0.8
0.6
0.4
0.2
O
O
50
100
150
200
250
Figure K-16. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 2° model for
Hepatocellular adenoma or carcinoma in Male F344/DuCrj rats Kano et al. (2009); dose shown in
mg/kg-d.
Page 576 of 616
-------
Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (l-background)*[l-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 61.6807
BMDL at the 95% confidence level = 28.2577
BMDU at the 95% confidence level = 85.9896
Taken together, (28.2577, 85.9896) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.00353886
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0.0645254
0.0651805
Beta(l)
0.000672524
0.000611007
Beta(2)
0.0000167903
0.0000170394
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-71.88
4
Fitted model
-71.91
3
0.0535945
1
0.82
Reduced
model
-115.64
1
87.528
3
<.0001
AIC: = 149.814
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0.0645
3.226
3
50
-0.13
11
0.0733
3.665
4
50
0.18
55
0.1431
7.157
7
50
-0.06
274
0.7794
38.971
39
50
0.01
ChiA2 = 0.05 d.f = 1 P-value = 0.8161
Page 577 of 616
-------
K.23 BMDS Summary of Subcutis fibroma in Male F344/DuCrj rats
Kano et al. (2009)
Table K-17. Summary of BMD Modeling Results for Subcutis fibroma in Male F344/DuCrj rats
Kano et al. (2009)
Model8
Goodness of lit
BMDiopct
(mg/kg-d)
BMDLiopct
(mg/kg-d)
Basis for model selection
/?-value
AIC
One
0.662
147.64
154
85.0
Lowest AIC. All parameter
estimates positive for both models.
Two
0.440
149.44
198
86.6
a Selected model in bold; scaled residuals for selected model for doses 0,11, 55, and 274 mg/kg-d were 0.66, -0.57, -0.21, 0.11,
respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Multistage Cancer
Linear extrapolation
0.4
0.35
0.3
0.25
0.2
0.15
0.1
0.05
O
O
50
100
150
200
250
dose
16:03 08/08 2018
Figure K-17. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Subcutis fibroma in Male F344/DuCrj rats Kano et al. (2009); dose shown in mg/kg-d.
Page 578 of 616
-------
Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (l-background)*[l-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 153.921
BMDL at the 95% confidence level = 84.9898
BMDU at the 95% confidence level = 443.236
Taken together, (84.9898, 443.236) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.00117661
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0.0752804
0.0733151
Beta(l)
0.00068451
0.000713137
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-71.41
4
Fitted model
-71.82
2
0.818155
2
0.66
Reduced
model
-75.35
1
7.88672
3
0.05
AIC: = 147.639
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0.0753
3.764
5
50
0.66
11
0.0822
4.111
3
50
-0.57
55
0.1094
5.472
5
50
-0.21
274
0.2334
11.671
12
50
0.11
ChiA2 = 0.82 d.f = 2 P-value = 0.6624
K.24 BMDS Summary of Nasal squamous cell carcinoma in female
F344/DuCrj rats "")
Page 579 of 616
-------
Table K-18. Summary of BMD Modeling Results for Nasal squamous cell carcinoma in female
F344/DuCrj rats Kano et al. (2009)
Model8
Goodness of lit
BMDiopct
(mg/kg-d)
BMDLiopct
(mg/kg-d)
Basis for model selection
/?-value
AIC
One
0.618
45.660
376
214
Lowest BMDL. Some parameter
values were zero for both models.
Two
0.961
43.075
366
275
a Selected model in bold; scaled residuals for selected model for doses 0,18,83, and 429 mg/kg-d were 0,-0.5,-1.08, 0.6,
respectively.
0.3
0.25
0.2
0.15
0.1
0.05
O
O 50 100 150 200 250 300 350 400 450
dose
16:32 08/08 2018
Figure K-18. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Nasal squamous cell carcinoma in female F344/DuCrj rats Kano et al. (2009); dose shown in
mg/kg-d.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Multistage Cancer
Linear extrapolation
Page 580 of 616
-------
Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (l-background)*[l-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 375.811
BMDL at the 95% confidence level = 213.836
BMDU at the 95% confidence level = 752.01
Taken together, (213.836, 752.01) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.000467648
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0
0
Beta(l)
0.000280355
0.00036949
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-20.25
4
Fitted model
-21.83
1
3.16408
3
0.37
Reduced
model
-30.34
1
20.1894
3
0
AIC: = 45.6604
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0
0
0
50
0
18
0.005
0.252
0
50
-0.5
83
0.023
1.15
0
50
-1.08
429
0.1133
5.666
7
50
0.6
ChiA2 = 1.78 d.f = 3 P-value = 0.6184
Page 581 of 616
-------
K.25 BMDS Summary of Mammary adenoma in female F344/DuCrj rats
Kano et al. (2009)
Table K-19. Summary of BMD Modeling Results for Mammary adenoma in female F344/DuCrj
rats Kano et al. (2009)
Model8
Goodness of lit
BMDiopct
(mg/kg-d)
BMDLiopct
(mg/kg-d)
Basis for model selection
/?-value
AIC
One
Two
0.856
194.22
177
99.1
All (equivalent) models have
adequate fit.
a Selected model in bold; scaled residuals for selected model for doses 0,18, 83, and 429 mg/kg-d were -0.27, -0.05, 0.46, -
0.13, respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
0.5
Multistage Cancer
Linear extrapolation
0.4
0.3
0.2
0.1
O
50
100
150
200
250
300
350
400
450
dose
16:37 08/08 2018
Figure K-19. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Mammary adenoma in female F344/DuCrj rats Kano et al. (2009); dose shown in mg/kg-d.
Page 582 of 616
-------
Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (l-background)*[l-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 176.663
BMDL at the 95% confidence level = 99.1337
BMDU at the 95% confidence level = 501.523
Taken together, (99.1337, 501.523) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.00100874
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0.133161
0.136033
Beta(l)
0.000596394
0.000570906
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-94.96
4
Fitted model
-95.11
2
0.305898
2
0.86
Reduced
model
-98.68
1
7.4409
3
0.06
AIC: = 194.222
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0.1332
6.658
6
50
-0.27
18
0.1424
7.121
7
50
-0.05
83
0.175
8.751
10
50
0.46
429
0.3288
16.442
16
50
-0.13
ChiA2 = 0.31 d.f = 2 P-value = 0.8559
K.26 BMDS Summary of Hepatocellular adenomas or carcinomas female
F344/DuCrj rats : "
Page 583 of 616
-------
Table K-20. Summary of BMD Modeling Results for Hepatocellular adenomas or carcinomas
female F344/DuCrj rats Kano et al. (2009)
Model8
Goodness of lit
BMDiopct
(mg/kg-d)
BMDLiopct
(mg/kg-d)
Basis for model selection
/?-value
AIC
One
1.00E-
04
114.09
25.6
19.9
lst-degree multistage has inadequate
p-value. 2nd-degree multistage
exhibits adequate fit.
Two
0.452
91.590
79.8
58.1
a Selected model in bold; scaled residuals for selected model for doses 0,18, 83, and 429 mg/kg-d were 0.9, -0.76, -0.41, 0.2,
respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Multistage Cancer
Linear extrapolation
1
0.8
0.6
0.4
0.2
O
O
50
100
150
200
250
300
350
400
450
Figure K-20. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 2° model for
Hepatocellular adenomas or carcinomas female F344/DuCrj rats Kano et al. (2009); dose shown in
mg/kg-d.
Page 584 of 616
-------
Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (l-background)*[l-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 79.8299
BMDL at the 95% confidence level = 58.085
BMDU at the 95% confidence level = 94.0205
Taken together, (58.085, 94.0205) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.00172161
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0.0362773
0.0281572
Beta(l)
0
0
Beta(2)
0.0000165328
0.0000173306
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-42.99
4
Fitted model
-43.79
2
1.60218
2
0.45
Reduced
model
-120.43
1
154.873
3
<.0001
AIC: = 91.5898
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0.0363
1.814
3
50
0.9
18
0.0414
2.071
1
50
-0.76
83
0.14
7.001
6
50
-0.41
429
0.954
47.701
48
50
0.2
ChiA2 = 1.59 d.f = 2 P-value = 0.4516
K.27 BMDS Summary of Hepatocellular adenomas or carcinomas in male
CrjBDFl mice " )
Page 585 of 616
-------
Table K-21. Summary of BMD Modeling Results for Hepatocellular adenomas or carcinomas in
Model8
Goodness of lit
BMDiopct
(mg/kg-d)
BMDLiopct
(mg/kg-d)
Basis for model selection
/?-value
AIC
One
Two
0.153
250.55
71.0
44.0
All (equivalent) models have
adequate fit.
a Selected model in bold; scaled residuals for selected model for doses 0,49,191, and 677 mg/kg-d were -1.22, 0.6, 1.22, -0.64,
respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Multistage Cancer
Linear extrapolation
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0
100
200
300
400
500
600
700
Figure K-21. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Hepatocellular adenomas or carcinomas in male CrjBDFl mice Kano et al. (2009); dose shown in
mg/kg-d.
Page 586 of 616
-------
Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (l-background)*[l-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 70.9911
BMDL at the 95% confidence level = 44.0047
BMDU at the 95% confidence level = 150.117
Taken together, (44.0047, 150.117) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.00227248
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0.545889
0.573756
Beta(l)
0.00148414
0.00123152
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-121.37
4
Fitted model
-123.28
2
3.80413
2
0.15
Reduced
model
-128.86
1
14.9718
3
0
AIC: = 250.551
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0.5459
27.294
23
50
-1.22
49
0.5777
28.887
31
50
0.6
191
0.658
32.899
37
50
1.22
677
0.8337
41.687
40
50
-0.64
ChiA2 = 3.76 d.f = 2 P-value = 0.1527
Page 587 of 616
-------
K.28 BMDS Summary of Hepatocellular adenomas or carcinomas in
female CrjBDFl mice ' . "" )
The IRIS 1,4-Dioxane assessment modeled liver tumors (adenomas or carcinomas) in female mice from
Kano et al. 2009). and this site was the most sensitive tumor endpoint for the oral CSF. An adequate fit
could not be obtained with any multistage (MS) models at the time due to the steep slope and apparent
plateau of the response to a probability less than 100%, so non-MS models were applied. For the current
assessment, EPA performed time-to-tumor analysis that provides a better model fit.
EPA obtained individual animal data, with liver tumor incidence, time of death and pathologically
diagnosed cause of death, from the study institute JBRC (emails dated October 30 and November 1,
2019, from Dr. Kano, JBRC to Paul White, CPHEA, ORD, U.S. EPA). EPA used two methods to model
the time-to-tumor effect in this data set. They were the MSW model (Multistage Weibull Model) and
Poly3 method (/.e.,BMDS modeling with Poly3-adjusted data). The results were summarized in Table
1.
Extra risk of 0.5 (ER50%) was selected as the primary Benchmark Response (BMR) to calculate CSF to
avoid excess extrapolation; this is also consistent with the IRIS assessment. Sensitivity analysis was also
done by calculating CSF at other BMRs (/.
-------
Comparison of modeling result
ts with dif
erent approaches.
Method
BMR
BMD
BMDL
BMDU
BMDL
HEDa
Oral
CSF
MSW (Stagel)
ER10%
5.39
4.10
7.14
0.62
0.162
ER20%
11.42
8.69
15.12
1.31
0.153
ER30%
18.25
13.89
24.17
2.09
0.143
ER40%
26.13
19.90
34.62
2.99
0.134
ER50%
35.46
27.00
46.98
4.06
0.123
BMDS Modeling with Poly3
Adjusted Data
(Log-Logistic Model)
ER10%
2.52
1.43
11.25
0.22
0.464
ER20%
5.65
3.22
18.72
0.49
0.412
ER30%
9.64
5.53
26.43
0.83
0.361
ER40%
14.96
8.60
35.31
1.29
0.309
ER50%
22.38
12.90
46.52
1.94
0.258
IRIS Assessment
(Log-Logistic Model)
ER10%
5.54
3.66
N/A
0.55
0.182
ER50%
49.9
32.9
N/A
4.95
0.101
a Human equivalent doses (HEDs) were calculated from the administered animal doses using a body weight scaling factor (BW0.75) U. S . EP A.
(20 1 Ih) This was accomplished using the following equation: HED=animal dose (mg/kg) * [animal BW (kg)/human BW (kg)]"0.25. For all
calculations, a human BW of 70 kg and a female mice BW of 35.9 kg were used Ka.nO 6t 3.1. (2009).
K.28.1 Time-to-Tumor Modeling with Multistage Weibull Model
The MSW time-to-tumor model is a multistage in dose and Weibull in time, which is used to model both
the dose and the time of appearance of a detectable tumor. With this model, the probability of observing
a tumor prior to some specific observation time, t, upon exposure to a carcinogen at dose level, is
given by the function:
G(t, d) = G(t, d, c, /?„, /?,,..., pt) = 1 - expj- r° £ p,d'j
The MSW time-to-tumor model was conducted using the MultiStage-Weibull software, which was
based on Weibull models drawn from Krewski et al. (1983) and downloaded from the EPA's BMDS
website. The model with the lowest AIC was selected from models fit up to stages n -1, where n was
the number of dose groups. Parameters were estimated using the method of maximum likelihood.
Before fitting the MSW time-to-tumor models, each animal was classified into one of four response
categories: "I" (hepatocellular carcinoma and/or adenoma were detected when the mouse was removed
from the study due to unscheduled death - where the hepatocellular tumor was judged not to be the cause
of death - or final sacrifice), "U" (the presence or absence of hepatocellular carcinoma and/or adenoma
could not be determined when the mouse was removed from the study due to unscheduled death or final
sacrifice or other reasons), "C" (neither hepatocellular carcinoma nor adenoma was detected when the
mouse was removed from the study due to unscheduled death or final sacrifice), and "F" (hepatocellular
carcinoma and/or adenoma was judged to be the cause of death). See Table 2 for details.
Page 589 of 616
-------
Using SAS software, the individual animal tumor data {i.e.,hepatocellular carcinoma and/or adenoma
in female mice) was prepared for the MSW modeling by merging and cleaning results from
0064deadr.xlsx (11012019 email from Dr. Kano) and 0064Mouse HepaticTumor.xlsx (10302019 email
from Dr. Kano). The merged data set was also manually verified. Stage 1, 2 and 3 MSW time-to-tumor
models were fit to the data, but only Stagel and 3 converged to yield estimated parameters. Stage 1 was
selected as the best fitting model because it had a lower AIC value (See Table 3).
Extra risk 50% (ER50%) was used as the primary BMR with the MSW time-to-tumor modeling
(Outputl). Tumor incidental risks of ER 10%, 20%, 30% and 40% were also extrapolated and
compared to ER50% as a sensitivity analysis. (See Table 1)
EPA's gofplot_msw(), also available for download from the EPA's BMDS website, was used to
generate plots to visually assess goodness-of-fit for the MSW time-to-tumor models. Probability vs.
Time (PR) Plot is the default plot for gofplot_msw() program, where the fitted distribution function was
plotted against time, separately for each dose level. Since both fatal and incidental contexts occurred in
the data, two smooth curves and two series of points were plotted. The solid curve and filled points were
for the fatal tumor response, while a dashed line and unfilled points were for the incidental tumor
response (Figure 1). In keeping with usual EPA practice, the risk estimates in the memo apply to all (not
just diagnosed as fatal) hepatocellular tumors, hence the "incidental" which reflects both fatal and non-
fatal tumors is the measure of direct importance here. The BMD50 and BMDL50 for total hepatocellular
tumors were located between the control dose and the 1st dose (66 mg/kg/day) - the BMD and BMDL
being, respectively, a factor of 1.9 and 2.4 below the 1st test dose. This was judged a reasonable degree
of extrapolation. A Dose-Response (DR) Plot was also generated (Figure 2) to show the incidental risk
probability in relation to dose for a fixed time (/'.e.,105 weeks in this case), with the BMD and BMDL
values displayed.
Table 2: Individual Animal Data with Hepatocellular Carcinoma and/or Adenoma in
Female Mice, Kano et at (2009).
Administered
Tumor
Week at
Animal ID
Dose (mg/kg-d)
Contexta
Death
2001
0
c
91
2002
0
c
105
2003
0
c
105
2004
0
c
55
2005
0
c
99
2006
0
I
105
2007
0
c
89
2008
0
c
105
2009
0
c
105
2010
0
c
93
2011
0
c
105
2012
0
c
105
2013
0
c
102
2014
0
c
105
2015
0
c
105
2016
0
c
105
2017
0
c
105
2018
0
c
105
2019
0
c
105
2020
0
c
105
2021
0
c
105
2022
0
c
105
2023
0
c
99
2024
0
I
95
2025
0
c
105
Page 590 of 616
-------
2026
2027
2028
2029
2030
2031
2032
2033
2034
2035
2036
2037
2038
2039
2040
2041
2042
2043
2044
2045
2046
2047
2048
2049
2050
2101
2102
2103
2104
2105
2106
2107
2108
2109
2110
2111
2112
2113
2114
2115
2116
2117
2118
2119
2120
2121
2122
2123
2124
2125
2126
2127
2128
2129
2130
2131
2132
2133
2134
2135
2136
2137
2138
2139
2140
2141
2142
2143
2144
90
73
70
105
105
100
105
98
87
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
66
78
105
105
82
105
91
84
105
105
75
105
98
105
105
105
75
105
98
105
105
105
84
105
96
105
105
85
78
105
100
105
96
105
103
105
105
96
75
105
105
105
77
105
105
105
105
85
97
72
105
105
105
105
105
105
105
105
98
Page 591 of 616
-------
2145
2146
2147
2148
2149
2150
2201
2202
2203
2204
2205
2206
2207
2208
2209
2210
2211
2212
2213
2214
2215
2216
2217
2218
2219
2220
2221
2222
2223
2224
2225
2226
2227
2228
2229
2230
2231
2232
2233
2234
2235
2236
2237
2238
2239
2240
2241
2242
2243
2244
2245
2246
2247
2248
2249
2250
2301
2302
2303
2304
2305
2306
2307
2308
2309
2310
2311
2312
2313
66
66
66
66
66
66
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
278
964
964
964
964
964
964
964
964
964
964
964
964
964
79
91
102
105
97
105
103
56
105
96
105
105
50
92
94
71
75
97
105
105
95
102
96
105
105
105
93
100
103
102
105
95
90
71
99
73
47
96
93
92
97
105
105
83
104
70
105
63
92
105
105
85
105
105
105
99
84
56
100
90
85
61
98
91
Page 592 of 616
-------
2314
964
F
78
2315
964
F
97
2316
964
F
91
2317
964
F
87
2318
964
F
80
2319
964
I
81
2320
964
I
61
2321
964
F
95
2322
964
I
58
2323
964
F
101
2324
964
F
95
2325
964
F
73
2326
964
I
105
2327
964
F
74
2328
964
C
47
2329
964
F
86
2330
964
C
67
2331
964
F
96
2332
964
F
84
2333
964
F
95
2334
964
F
75
2335
964
F
95
2336
964
I
70
2337
964
I
97
2338
964
I
90
2339
964
F
90
2340
964
F
83
2341
964
C
69
2342
964
I
105
2343
964
I
105
2344
964
I
105
2345
964
F
83
2346
964
I
105
2347
964
C
32
2348
964
I
68
2349
964
F
84
2350
964
F
62
a Tumor context:
C: Neither hepatocellular carcinoma nor adenoma was detected when the mouse was removed from the study due to scheduled sacrifice or unscheduled
death.
U: The presence or absence of hepatocellular carcinoma and/or adenoma could not be determined when the mouse was removed from the study due to
scheduled sacrifice or unscheduled death or other reasons.
I: Hepatocellular carcinoma and/or adenoma were detected when the mouse was removed from the study due to scheduled sacrifice or unscheduled death.
Table 3: Different Stages of MSW Time-to-tumor Models with Hepatocellular Carcinoma
and/or Adenoma in Female Mice, Kano et al. (2009)
MSW
Stage
Log(Likelihood)
#Parameter
AIC
BMDso
BMDLso
BMDUso
Incidental
Risk
1
-245.823
4
499.65
35.46
27.00
46.98
2
Moc
el did not work with estimated parameters.
3
-244.279
6
500.56
38.27
28.55
52.46
Outputl: Stagel MSW Time-to-tumor Model, with Hepatocellular Carcinoma and/or
Adenoma in Female Mice, Kano et al. (2009), BMR= ER50%
Page 593 of 616
-------
Multistage Weibull Model. (Version: 1.6.1; Date: 11/24/2009)
Solutions are obtained using donlp2-intv, (c) by P. Spellucci
Input Data File: LatestLiverFMicelIncidentalER50.(d)
Fri Nov 01 14:45:29 2019
Timer to Tumor Model, Liver Tumors, "0064deadr.xlsx" and "0064Mouse HepaticTumor.xlsx", Female Mice
The form of the probability function is:
P[response] = l-EXP{-(t - tj)^ *
(beta_0+beta_l*doseAl)}
The parameter betas are restricted to be positive
Dependent variable = CONTEXT
Independent variables = DOSE, TIME
Total number of observations = 200
Total number of records with missing values = 0
Total number of parameters in model = 4
Total number of specified parameters = 0
Degree of polynomial = 1
Maximum number of iterations = 64
Relative Function Convergence has been set to: 2.22045e-016
Parameter Convergence has been set to: 1,49012e-008
Default Initial Parameter Values
c = 6
t_0 = 27.5556
betaO = 1.12014e-013
beta 1 = 1.39427e-014
Asymptotic Correlation Matrix of Parameter Estimates
c t_0 betaO betal
c 1 -0.85 -0.99 -1
t_0 -0.85 1 0.84 0.87
betaO -0.99 0.84 1 0.99
beta 1 -1 0.87 0.99 1
Parameter Estimates
95.0% Wald Confidence Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit
c 5.5329 0.997498 3.57784 7.48796
t_0 37.8608 5.78378 26.5248 49.1968
betaO 9.5028e-013 4.45516e-012 -7.78167e-012 9.68223e-012
beta 1 1.28255e-013 5.8095e-013 -1.01039e-012 1.2669e-012
Log(likelihood) # Param AIC
Fitted Model -245.823 4 499.646
Data Summary
CONTEXT
C F I U Total Expected Response
DOSE
0 45 0 5 0 50 5.17
66 15 1 34 0 50 31.50
2.8e+002 9 9 32 0 50 42.74
9.6e+002 4 29 17 0 50 45.04
Minimum observation time for F tumor context = 62
Benchmark Dose Computation
Risk Response = Incidental
Risk Type = Extra
Specifiedeffect= 0.5
Page 594 of 616
-------
Confidence level = 0.9
Time = 105
BMD = 35.4583
BMDL = 27.0033
BMDU = 46.9785
Incidental Risk: Latest Data, Female Mice Liver Tumor
points show nonparam. est. for Incidental (unfilled) and Fatal (filled)
Dose = 0.00 Dose = 66.00
Figure 1: Probability vs. Time Plot for MSW Time-to-tumor Models with Hepatocellular
Carcinoma and/or Adenoma in Female Mice, Kano et al. (2009)
Page 595 of 616
-------
BMD for Incidental Risk atT=105, Extra Risk level = 0.5, conf. level = 0.9
points show nonparametric estimate for nearest times at obsvd. doses
Latest Data, Female Mice Liver Tumor
MSW Model for Incidental Risk
LO
o
re
W
£
re
+¦>
c
-------
power of 3 (thus, the name"poly-3") was assumed, which was found to be representative for a large
number of cancer types fPortier et at.. 1986). Algebraically,
Nadj = Xi Wi
Where
i indicates the animal number
Wi= 1 if tumor is present
wi= (ti/T)3 if tumor is absent at time of death (ti)
T indicates the duration of study
Benchmark dose software version 3.1.1 (BMDS 3.1.1) was used to analyze the poly-3 adjusted data
(Table 4). This analysis was conducted using maximum likelihood optimization and profile likelihood-
based confidence intervals. Standard forms of these models31 (defined below) were run in BMDS 3.1.1,
applying EPA model selection procedures 012b). See Table 5 for results.
Standard Dichotomous Models Applied to Poly3 Adjusted Liver Tumor Data:
Gamma-restricted
Log-Logistic-restricted
Multistage-restricted; from degree = 1 to degree = # dose groups - 1
Weibull-restricted
Dichotomous Hill-unrestricted
Logistic
Log-Probit-unrestricted
Probit
General Model Options Used for Poly3 Adjusted Liver Tumor Data:
Benchmark Response (BMR): 10%, 20%, 30%, 40% and 50% Extra Risk
Confidence Level: 0.95
Background: Estimated
Model Restrictions and Model Selection
Restrictions for BMDS 3.1.1 models are defined in the BMDS 3.1.1 User Guide and are applied in
accordance with EPA BMD Technical Guidance U.S. EPA. (2012b). For each BMD analysis, a single
preferred model was chosen from among the preferred standard set of models (noting instances where
consideration of non-standard models may be justified) in accordance with EPA BMD Technical
Guidance 312b).
This process leaded to the selection of log-logistic (restricted) as providing the preferred BMDS model
suite estimates, with BMD and BMDL of 22 and 13 mg/kg-d respectively, and with a BMDL based
human oral cancer slope factor of 0.26 per mg/kg-d.
Table 4: Poly3 adjusted data
31 The set of standard models are identified in accordance with EPA BMD technical guidance (EPA, 2012) and are the default
models in BMDS 3.1.1.
Page 597 of 616
-------
Administered Dose
(mg/kg/day)
Poly3 Adjusted Sample
Size
Tumor Incidence
0
41.98
5
66
44.69
35
278
44.33
41
964
46.66
46
Table 5: BMDS Modeling results with poly3 adjusted Hepatocellular Carcinoma and/or
Adenoma in Female Mice, Kano et al. (2009)
Model
Restriction
BMR
BMD
BMDL
BMDL
P
Value
AIC
Scaled
Residual
near
BMD
BMDS Recommendation Notes
Gamma
Restricted
ER50%
66.86
50.56
92.38
<0.0001
128.17
2.71
Questionable
Goodness of fit p-value <0.1
Residual for Dose Group Near BMD > 2
Log-Logistic
Restricted
ER50%
22.38
12.90
46.52
0.692
114.15
0.00
Viable - Recommended
Lowest AIC
BMDL 3x lower than lowest non-zero
dose
Multistage
Degree 3
Restricted
ER50%
66.86
50.56
92.39
<0.0001
128.17
2.71
Questionable
Goodness of fit p-value <0.1
Residual for Dose Group Near BMD > 2
Multistage
Degree 2
Restricted
ER50%
66.86
50.56
92.39
<0.0001
128.17
2.71
Questionable
Goodness of fit p-value <0.1
IResidual for Dose Group Near BMD| > 2
Multistage
Degree 1
Restricted
ER50%
66.86
50.56
92.38
<0.0001
128.17
2.71
Questionable
Goodness of fit p-value <0.1
IResidual for Dose Group Near BMD| > 2
Weibull
Restricted
ER50%
66.86
50.56
92.39
<0.0001
128.17
2.71
Questionable
Goodness of fit p-value <0.1
Residual for Dose Group Near BMD > 2
Dichotomous
Hill
LTnrestricted
ER50%
22.38
2.65
46.52
NA
116.15
0.00
Questionable
BMD/BMDL ratio > 3
BMDL 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero
dose
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Logistic
LTnrestricted
ER50%
116.27
88.79
157.57
<0.0001
142.49
3.25
Questionable
Goodness of fit p-value <0.1
Residual for Dose Group Near BMD > 2
Residual at control > 2
Log-Probit
LTnrestricted
ER50%
18.13
1.62
43.10
0.810
114.05
0.00
Questionable
BMD/BMDL ratio > 3
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero
dose
Probit
LTnrestricted
ER50%
167.86
132.96
227.20
<0.0001
151.63
3.27
Questionable
Goodness of fit p-value <0.1
Residual for Dose Group Near BMD > 2
Residual at control > 2
Page 598 of 616
-------
Output2: Log-Logistic Modeling Output with Poly3 Adjusted Hepatocellular Carcinoma
and/or Adenoma in Female Mice, Kano et al. (2009)
User Input
Info
Model
frequentist Log-
Logistic vl.l
Dataset Name
DataSet Namel
User notes
[Add user notes
here]
Dose-Response
Model
P[dose] = g+(l-
g)/[l+exp(-a-
b*Log(dose))l
Model Options
Risk Type
Extra Risk
BMR
0.5
Confidence Level
0.95
Background
Estimated
Model Data
Dependent Variable
[Dosel
Independent Variable
!Incidencel
Total # of
Observations
4
Model Results
Benchmark Dose
BMD
22.37990188
BMDL
12.89695219
BMDU
46.52457822
AIC
114.1506984
P-value
0.692090927
D.O.F.
1
Chi2
0.156831139
Model Parameters
# of Parameters
3
Variable
Estimate
Page 599 of 616
-------
£
0.119231882
a
-3.128607576
b
1.006577601
Goodness of Fit
Dose
Estimated Probability
Expected
Observed
Size
Scaled Residual
0
0.119231882
5.004814738
5
41.9754739
-0.002293231
66
0.778151202
34.77721655
35
44.6921067
0.080206021
278
0.935377478
41.46629827
41
44.3310848
-0.284855247
964
0.980494043
45.75140244
46
46.6615813
0.263154636
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-53.99521585
4
_
_
_
Fitted Model
-54.07534919
3
0.160266692
1
0.688911098
Reduced Model
-106.1971175
1
104.4038034
3
<0.0001
Frequentist Log-Logistic Model with BMR of 50% Extra Risk for the
BMD and 0.95 Lower Confidence Limit for the BMDL
Estimated Probability
^^Response at BMD
O Data
BMD
BMDL
100
200
300
400
500
Dose
600
700
800
900
Figure 3: Dose-Response Plot for Log-Logistic Model with Poly3 Adjusted Hepatocellular
Carcinoma and/or Adenoma in Female Mice, Kano et al. (2009)
Page 600 of 616
-------
K.29 BMDS Summary of Nasal cavity tumors in Sherman rats Kociba et
al. (1974)
Table K-22. Summary of BMD Modeling Results for Nasal cavity tumors in Sherman rats Kociba
et al. (1974)
Model8
Goodness of lit
BMDiopct
(mg/kg-d)
BMDLiopct
(mg/kg-d)
Basis for model selection
/?-value
AIC
One
0.916
27.352
3465
1525
Lowest BMDL. Both models have
some parameter values of zero
Two
0.998
26.493
1981
1314
a Selected model in bold; scaled residuals for selected model for doses 0,14,121, and 1307 mg/kg-d were 0, -0.02, -0.2, 0.02,
respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Multistage Cancer
Linear extrapolation
0.14
0.12
0.1
0.08
0.06
0.04
0.02
O
O
500
1000
1500
2000
dose
11:22 08/10 2018
Figure K-22. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 2° model for
Nasal cavity tumors in Sherman rats Kociba et al. (1974); dose shown in mg/kg-d.
Page 601 of 616
-------
Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (1-background)* [1-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 1980.96
BMDL at the 95% confidence level = 1314.37
BMDU at the 95% confidence level = 8538.89
Taken together, (1314.37, 8538.89) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.0000760821
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0
0
Beta(l)
0
0
Beta(2)
2.6849E-08
2.7310E-08
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-12.2
4
Fitted model
-12.25
1
0.0850948
3
0.99
Reduced
model
-17.58
1
10.7433
3
0.01
AIC: = 26.4929
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0
0
0
106
0
14
0
0.001
0
110
-0.02
121
0.0004
0.042
0
106
-0.2
1307
0.0448
2.959
3
66
0.02
ChiA2 = 0.04 d.f = 3 P-value = 0.9977
K.30 BMDS Summary of Liver tumors in Sherman rats (male and female
combined)" " )
Page 602 of 616
-------
Table K-23. Summary of BMD Modeling Results for Liver tumors in Sherman rats (male and
female combined) Kociba et al. (1974)
Model8
Goodness of lit
BMDiopct
(mg/kg-d)
BMDLiopct
(mg/kg-d)
Basis for model selection
/?-value
AIC
One
0.384
85.119
940
584
Lowest AIC. All parameter
estimates positive in both models.
Two
0.311
86.287
1042
629
a Selected model in bold; scaled residuals for selected model for doses 0,14,121, and 1307 mg/kg-d were 0.92, -0.78, -0.62,
0.28, respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Multistage Cancer
Linear extrapolation
0.25
0.2
0.15
0.1
0.05
0
O
200
400
600
800
1000
1200
Figure K-23. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Liver tumors in Sherman rats (male and female combined) Kociba et al. (1974); dose shown in
mg/kg-d.
Page 603 of 616
-------
Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (1-background)* [1-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 940.125
BMDL at the 95% confidence level = 583.576
BMDU at the 95% confidence level = 1685.88
Taken together, (583.576, 1685.88) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.000171357
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0.00386835
0.000925988
Beta(l)
0.000112071
0.000124518
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-39.39
4
Fitted model
-40.56
2
2.34056
2
0.31
Reduced
model
-53.53
1
28.2732
3
<.0001
AIC: = 85.1187
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0.0039
0.41
1
106
0.92
14
0.0054
0.597
0
110
-0.78
121
0.0173
1.832
1
106
-0.62
1307
0.1396
9.213
10
66
0.28
ChiA2 =1.92 d.f = 2 P-value = 0.3838
K.31 BMDS Summary of Nasal squamous cell carcinomas in female OM
rats (MS models) )
Page 604 of 616
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Table K-24. Summary of BMD Modeling Results for Nasal squamous cell carcinomas in female
OM rats (MS models) N<
(1978)
Model8
Goodness of lit
BMDiopct
(mg/kg-d)
BMDLiopct
(mg/kg-d)
Basis for model selection
/?-value
AIC
One
0.180
84.800
176
122
Model has adequate fit.
a Selected model in bold; scaled residuals for selected model for doses 0, 350, and 640 were 0,1.47, -1.13, respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
0.5
Multistage Cancer
Linear extrapolation
0.4
0.3
0.2
0.1
0
0
100
200
300
400
500
600
Figure K-24. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Nasal squamous cell carcinomas in female OM rats (MS models) NCI (1978); dose shown in
mg/kg-d.
Page 605 of 616
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Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (1-background)* [1-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 176.281
BMDL at the 95% confidence level = 122.274
BMDU at the 95% confidence level = 271.474
Taken together, (122.274, 271.474) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.000817837
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0
0.0569154
Beta(l)
0.000597685
0.00042443
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-39.75
3
Fitted model
-41.4
1
3.29259
2
0.19
Reduced
model
-47.92
1
16.3252
2
0
AIC: = 84.7996
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0
0
0
34
0
350
0.1888
6.607
10
35
1.47
640
0.3179
11.125
8
35
-1.13
ChiA2 = 3.44 d.f=2 P-value = 0.1795
Page 606 of 616
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K.32 BMDS Summary of Hepatocellular adenoma in female OM rats
NCI (1978)
Table K-25. Summary of BMD Modeling Results for Hepatocellular adenoma in female OM rats
NCI (1978)
Model8
Goodness of lit
BMDiopct
(mg/kg-d)
BMDLiopct
(mg/kg-d)
Basis for model selection
/?-value
AIC
One
0.591
84.697
132
94.1
Model has adequate fit.
a Selected model in bold; scaled residuals for selected model for doses 0, 350, and 640 mg/kg-d were 0, 0.8, -0.64, respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Multistage Cancer
Linear extrapolation
0.5
0.4
0.3
0.2
0.1
O
O
100
200
300
400
500
600
dose
17:08 08/08 2018
Figure K-25. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Hepatocellular adenoma in female OM rats NCI (1978); dose shown in mg/kg-d.
Page 607 of 616
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Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (1-background)* [1-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 132.359
BMDL at the 95% confidence level = 94.0591
BMDU at the 95% confidence level = 194.33
Taken together, (94.0591, 194.33) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.00106316
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0
0.0385912
Beta(l)
0.00079602
0.000670869
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-40.83
3
Fitted model
-41.35
1
1.02868
2
0.6
Reduced
model
-50.43
1
19.1932
2
<.0001
AIC: = 84.6972
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0
0
0
31
0
350
0.2432
8.024
10
33
0.8
640
0.3992
12.774
11
32
-0.64
ChiA2 = 1.05 d.f = 2 P-value = 0.5908
Page 608 of 616
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K.33 BMDS Summary of Hepatocellular adenomas or carcinomas in male
B6C3F1 mice NCI (1978)
Table K-26. Summary of BMD Modeling Results for Hepatocellular adenomas or carcinomas in
male B6C3F1 mice NCI
[1978)
Model8
Goodness of lit
BMDiopct
(mg/kg-d)
BMDLiopct
(mg/kg-d)
Basis for model selection
/?-value
AIC
One
0.0762
180.62
164
117
Model has adequate fit.
a Selected model in bold; scaled residuals for selected model for doses 0, 720, and 830 mg/kg-d were 0.08, -1.28, 1.23,
respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Multistage Cancer
Linear extrapolation
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
100
200
300
400
500
600
700
800
Figure K-26. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Hepatocellular adenomas or carcinomas in male B6C3F1 mice NCI (1978); dose shown in mg/kg-
d.
Page 609 of 616
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Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (1-background)* [1-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 164.285
BMDL at the 95% confidence level = 117.371
BMDU at the 95% confidence level = 265.631
Taken together, (117.371, 265.631) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.000851999
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0.15914
0.142253
Beta(l)
0.000641327
0.000710746
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-86.72
3
Fitted model
-88.31
2
3.17505
1
0.07
Reduced
model
-96.72
1
19.9875
2
<.0001
AIC: = 180.618
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0.1591
7.798
8
49
0.08
720
0.4701
23.505
19
50
-1.28
830
0.5062
23.792
28
47
1.23
ChiA2 = 3.14 d.f = 1 P-value = 0.0762
Page 610 of 616
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K.34 BMDS Summary of Hepatocellular adenomas or carcinomas in
female B6C3F1 mice NCI (1978)
Table K-27. Summary of BMD Modeling Results for Hepatocellular adenomas or carcinomas in
'emale
B6C3F1 mice NCI (1978)
Model8
Goodness of lit
BMDiopct
(mg/kg-d)
BMDLiopct
(mg/kg-d)
Basis for model selection
/?-value
AIC
One
0.0548
89.986
49.1
38.8
Model has adequate fit.
a Selected model in bold; scaled residuals for selected model for doses 0, 380, and 860 mg/kg-d were 0,-1.67, 1.73,
respectively.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Multistage Cancer
Linear extrapolation
1
0.8
0.6
0.4
0.2
O
O
100
200
300
400
500
600
700
800
900
Figure K-27. Plot of incidence rate by dose with fitted curve for Multistage-Cancer 1° model for
Hepatocellular adenomas or carcinomas in female B6C3F1 mice NCI (1978); dose shown in
mg/kg-d.
Page 611 of 616
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Multistage Model. (Version: 3.4; Date: 05/02/2014)
The form of the probability function is: P[response] = background + (1-background)* [1-EXP(-
betal*doseAl-beta2*doseA2..)]
The parameter betas are restricted to be positive
Benchmark Dose Computation.
BMR = 10% Extra risk
BMD = 49.1018
BMDL at the 95% confidence level = 38.8015
BMDU at the 95% confidence level = 62.9223
Taken together, (38.8015, 62.9223) is a 90% two-sided confidence interval for the BMD
Multistage Cancer Slope Factor = 0.00257722
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Background
0
0
Beta(l)
0.00214576
0.00345682
Analysis of Deviance Table
Model
Log(likelihoo
d)
# Param's
Deviance
Test d.f.
p-value
Full model
-40.68
3
Fitted model
-43.99
1
6.63483
2
0.04
Reduced
model
-91.61
1
101.861
2
<.0001
AIC: = 89.986
Goodness of Fit Table
Dose
Est. Prob.
Expected
Observed
Size
Scaled Resid
0
0
0
0
50
0
380
0.5575
26.762
21
48
-1.67
860
0.842
31.155
35
37
1.73
ChiA2 = 5.81 d.f = 2 P-value = 0.0548
Page 612 of 616
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K.35 MS-Combo Result Kano et al. (2009), Male F344/ DuCrj rats,
excluding liver
Output information
Tumor Output Directory
C:\Users\ \Documents\MODELS\14dioxane\oral\kano MSC\
Tumor Output File Name
Kano M nasal perit subcut.out
Combined BMD and BMDL Calculations
Combined Log-Likelihood
-150.6683784
Combined Log-likelihood
Constant
135.326183
Benchmark Dose Computation
Specified effect
0.1
Risk Type
Extra risk
Confidence level
0.95
BMD
55.1605
BMDL
28.1197
Multistage Cancer Slope
Factor
0.00355622
**** Start of combined BMD and BMDL Calculations.****
Combined Log-Likelihood -150.66837843809108
Combined Log-likelihood Constant 135.32618295034047
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
C onfi dence 1 evel = 0.95
BMD = 55.1605
BMDL = 28.1197
BMDU = 88.9926
Multistage Cancer Slope Factor = 0.00355622
K.36 MS-Combo Result Kano et al. (2009), Male F344/ DuCrj rats,
including liver
Output information
Tumor Output Directory
C:\Users\ \Documents\MODELS\14dioxane\oral\kano MSC\
Page 613 of 616
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Tumor Output File Name
Kano M all.out
Combined BMD and BMDL Calculations
Combined Log-Likelihood
-222.5755927
Combined Log-likelihood
Constant
200.3198288
Benchmark Dose Computation
Specified effect
0.1
Risk Type
Extra risk
Confidence level
0.95
BMD
35.099
BMDL
17.8487
Multistage Cancer Slope
Factor
0.00560264
**** Start of combined BMD and BMDL Calculations.****
Combined Log-Likelihood -222.57559271275764
Combined Log-likelihood Constant 200.31982880189281
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 35.099
BMDL = 17.8487
BMDU = 55.9726
Multistage Cancer Slope Factor = 0.00560264
K.37 MS-Combo Result Kano et al. (2009), Female F344/ DuCrj rats,
excluding liver
Output information
Tumor Output Directory
C:\Users\ \Documents\MODELS\14dioxane\oral\kano MSC\
Tumor Output File Name
Kano Frat mam nas.out
Combined BMD and BMDL Calculations
Combined Log-Likelihood
-116.9411818
Combined Log-likelihood
Constant
105.6980867
Page 614 of 616
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Benchmark Dose Computation
Specified effect
0.1
Risk Type
Extra risk
Confidence level
0.95
BMD
120.172
BMDL
76.5303
Multistage Cancer Slope
Factor
0.00130667
**** Start of combined BMD and BMDL Calculations.****
Combined Log-Likelihood -116.94118175960915
Combined Log-likelihood Constant 105.69808670837932
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 120.172
BMDL = 76.5303
BMDU = 231.101
Multistage Cancer Slope Factor = 0.00130667
K.38 MS-Combo Result Kano et al. (2009), Female F344/ DuCrj rats,
including liver
Output information
Tumor Output Directory
C:\Users\ \Documents\MODELS\14dioxane\oral\kano MSC\
Tumor Output File Name
kano F all.out
Combined BMD and BMDL Calculations
Combined Log-Likelihood
-160.736061
Combined Log-likelihood
Constant
143.1853353
Benchmark Dose Computation
Specified effect
0.1
Page 615 of 616
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Risk Type
Extra risk
Confidence level
0.95
BMD
57.6028
BMDL
41.6426
Multistage Cancer Slope
Factor
0.00240139
**** Start of combined BMD and BMDL Calculations.****
Combined Log-Likelihood -160.73606100858856
Combined Log-likelihood Constant 143.18533527241118
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 57.6028
BMDL = 41.6426
BMDU = 70.5585
Multistage Cancer Slope Factor = 0.00240139
Page 616 of 616
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