EPA Document# EPA-740-R1-7012 May 2018 United States Office of Chemical Safety and Environmental Protection Agency Pollution Prevention Problem Formulation of the Risk Evaluation for 1,4-Dioxane CASRN: 123-91-1 O May, 2018 ------- TABLE OF CONTENTS ACKNOWLEDGEMENTS 5 ABBREVIATIONS 6 EXECUTIVE SUMMARY 8 1 INTRODUCTION 10 1.1 Regul atory Hi story 12 1.2 Assessment History 12 1.3 Data and Information Collection 14 1.4 Data Screening During Problem Formulation 15 2 PROBLEM FORMULATION 16 2.1 Physical and Chemical Properties 16 2.2 Conditions of Use 17 2.2.1 Data and Information Sources 17 2.2.2 Identification of Conditions of Use 17 2.2.2.1 Categories and Subcategories Determined Not to be Conditions of Use During Problem Formulation 18 2.2.2.2 Categories and Subcategories of Conditions of Use Included in the Scope of the Risk Evaluation 18 2.2.2.3 Overview of Conditions of Use and Lifecycle Diagram 21 2.3 Exposures 24 2.3.1 Fate and Transport 24 2.3.2 Releases to the Environment 26 2.3.3 Presence in the Environment and Biota 28 2.3.4 Environmental Exposures 28 2.3.5 Human Exposures 30 2.3.5.1 Occupational Exposures 30 2.3.5.2 Consumer Exposures 31 2.3.5.3 General Population Exposures 31 2.3.5.4 Potentially Exposed or Susceptible Subpopulations 32 2.4 Hazards (Effects) 32 2.4.1 Environmental Hazards 32 2.4.2 Human Health Hazards 35 2.4.2.1 Non-Cancer Hazards 35 2.4.2.2 Genotoxicity and Cancer Hazards 36 2.4.2.3 Potentially Exposed or Susceptible Subpopulations 36 2.5 Conceptual Models 36 2.5.1 Conceptual Model for Industrial and Commercial Activities and Uses: Potential Exposures and Hazards 37 2.5.2 Conceptual Model for Consumer Activities and Uses: Potential Exposures and Hazards.... 41 2.5.3 Conceptual Model for Environmental Releases and Wastes: Potential Exposures and Hazards 41 2.5.3.1 Pathways That EPA Plans to Include and Further Analyze in the Risk Evaluation 41 2.5.3.2 Pathways that EPA Plans to Include in the Risk Evaluation But Not Further Analyze. 41 2.5.3.3 Pathways That EPA Does Not Plan to Include in the Risk Evaluation 42 2.6 Analysis Plan 47 Page 2 of 90 ------- 2.6.1 Exposure 47 2.6.1.1 Environmental Releases, Fate and Exposures 47 2.6.1.2 Occupational Exposures 48 2.6.1.3 General Population 49 2.6.2 Hazard 50 2.6.2.1 Environmental Hazards 50 2.6.2.2 Human Health Hazards 50 2.6.3 Risk Characterization 52 REFERENCES 53 APPENDICES 59 Appendix A REGULATORY HISTORY 59 A.l Federal Laws and Regulations . 59 A.2 State Laws and Regulations .............65 A.3 International Laws and Regulations 65 Appendix B PROCESS, RELEASE AND OCCUPATIONAL EXPOSURE INFORMATION .. 67 B.l Process Information.. .67 B. 1.1 Manufacture (Including Import) 67 B. 1.2 Processing and Distribution 67 B. 1.2.1 Processing as a Reactant/Intermediate 67 B. 1.2.2 Processing - Non-Incorporative 68 B.1.2.3 Repackaging 68 B. 1.2.4 Recycling 68 B.1.3 Uses 68 B. 1.3.1 Processing Aids, Not Otherwise Listed 68 B. 1.3.1 Functional Fluids (Open and Closed Systems) 68 B.1.3.2 Laboratory Chemicals 68 B. 1.3.3 Adhesives and Sealants 69 B. 1.3.4 Other Uses 69 B.1.4 Disposal 69 B.2 Occupational Exposure Data[[[ ...................69 Appendix C ANALYSIS: ENVIRONMENTAL CONCENTRATION OF CONCERN (COC).. 70 Appendix D SUPPORTING TABLE FOR INDUSTRIAL AND COMMERCIAL ACTIVITIES AND USES CONCEPTUAL MODEL 71 Appendix E SUPPORTING TABLE FOR ENVIRONMENTAL RELEASES AND WASTES CONCEPTUAL MODEL 81 Appendix F INCLUSION AND EXCLUSION CRITERIA FOR FULL TEXT SCREENING... 83 F. 1 Inclusion Criteria for the Data Sources Reporting Environmental Fate Data. .......83 F.2 Inclusion Criteria for Data Sources Reporting Engineering and Occupational Exposure Data..84 F.3 Inclusion Criteria for Data Sources Reporting Environmental and General Population Exposure ..87 ------- LIST OF TABLES Table 1-1. Assessment History of 1,4-Dioxane 13 Table 2-1. Physical and Chemical Properties of 1,4-Dioxane 16 Table 2-2. Categories and Subcategories Determined Not to Be Conditions of Use During Problem Formulation 18 Table 2-3. Categories and Subcategories of Conditions of Use Included in the Scope of the Risk Evaluation 19 Table 2-4. Production Volume of 1,4-Dioxane in Chemical Data Reporting (CDR) Reporting Period (2012 to 2015) a 22 Table 2-5. Environmental Fate Characteristics of 1,4-Dioxane 25 Table 2-6. Summary of 1,4-Dioxane TRI Production-Related Waste Managed in 2015 (lbs) 26 Table 2-7. Summary of 1,4-Dioxane TRI Releases to the Environment in 2015 (lbs) 26 Table 2-8. Ecological Hazard Characterization of 1,4-Dioxane 33 Table 2-9. 1,4-Dioxane Conditions of Use that May Produce a Mist 38 Table 2-10. Potential Sources of 1,4-Dioxane Occupational Exposure Data 48 LIST OF FIGURES Figure 2-1. 1,4-Dioxane Life Cycle Diagram 23 Figure 2-2. 1,4-Dioxane Conceptual Model for Industrial and Commercial Activities and Uses: Potential Exposures and Hazards 40 Figure 2-3. 1,4-Dioxane Conceptual Model for Environmental Releases and Wastes: Potential Exposures and Hazards 46 LIST OF APPENDIX TABLES Table_Apx A-l. Federal Laws and Regulations 59 Table_Apx A-2. State Laws and Regulations 65 Table_Apx A-3. Regulatory Actions by other Governments and Tribes 65 TableApx B-l. Summary of Industry Sectors with 1,4-Dioxane Personal Monitoring Air Samples Obtained from OSHA Inspections Conducted Between 2002 and 2016 69 Table Apx D-l: Industrial and Commercial Occupational Exposure Scenarios for 1,4-Dioxane 71 Table Apx E-l: Environmental Releases and Wastes Exposure Scenarios for 1,4-Dioxane 81 Table Apx F-l: Inclusion Criteria for Data Sources Reporting Engineering and Occupational Exposure Data 85 Table Apx F-2: Engineering, Environmental Release and Occupational Data Necessary to Develop the Environmental Release and Occupational Exposure Assessments 86 Table Apx F-3: Inclusion and Exclusion Criteria for Data Sources Reporting Human Health Hazards Related to 1,4-Dioxane Exposure21 88 LIST OF APPENDIX FIGURES Figure Apx B-l: General Process Flow Diagram for 1,4-Dioxane Manufacturing 67 Page 4 of 90 ------- 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). 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) and SRC (Contract No. EP-W-12-003). Docket Supporting information can be found in public docket: T--201.6-0723. 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. Page 5 of 90 ------- ABBREVIATIONS °c Degrees Celsius AAL Allowable Ambient Level ACGIH American Conference of Government Industrial Hygienists AEGL Acute Exposure Guideline Level AES Alkyl Ethyl Sulphates AMA Ambient Monitoring Archive AQS Air Quality System atm Atmosphere(s) AT SDR Agency for Toxic Substances and Disease Registries BAF Bioaccumulation Factor BCF Bioconcentration Factor BSER Best System of Emission Reduction CAA Clean Air Act CASRN Chemical Abstracts Service Registry Number CBI Confidential Business Information CCL Candidate Contaminant List CDR Chemical Data Reporting CERCLA Comprehensive Environmental Response, Compensation and Liability Act cm3 Cubic Centimeter(s) coc Concentration of Concern cou Conditions of Use CP Centipoise CPCat Chemical and Product Categories CSCL Chemical Substances Control Law EC European Commission EPA Environmental Protection Agency EPCRA Emergency Planning and Community Right-to-Know Act EU European Union FDA Food and Drug Administration FFDCA Federal Food, Drug and Cosmetic Act g Gram(s) GACT Generally Available Control Technology HAP Hazardous Air Pollutant HHE Health Hazard Evaluation HPV High Production Volume IARC International Agency for Research on Cancer IRIS Integrated Risk Information System ISHA Industrial Safety and Health Act kg Kilogram(s) kPa Kilopascal(s) L Liter(s) lb Pound Log Koc Logarithmic Soil Organic Carbon:Water Partitioning Coefficient Log Kow Logarithmic Octanol:Water Partition Coefficient 3 m Cubic Meter(s) MACT Maximum Achievable Control Technology mg Milligram(s) Page 6 of 90 ------- ng Microgram(s) mmHg Millimeter(s) of Mercury MSDS Material Safety Data Sheet NAC National Advisory Committee NAICS North American Industry Classification System NATA National Air Toxics Assessment NCEA National Center for Environmental Assessment NEI National Emissions Inventory NESHAP National Emission Standards for Hazardous Air Pollutants NICNAS National Industrial Chemicals Notification and Assessment Scheme NIH National Institute of Health NIOSH National Institute of Occupational Safety and Health NOAEL No-Observed-Adverse-Effect Level NPRI National Pollutant Release Inventory NSPS New Source Performance Standards NTP National Toxicology Program OCSPP Office of Chemical Safety and Pollution Prevention OECD Organisation for Economic Co-operation and Development ONU Occupational Non-User OPPT Office of Pollution Prevention and Toxics OSHA Occupational Safety and Health Administration PBPK Physiologically Based Pharmacokinetic PEL Permissible Exposure Limit PESS Potentially Exposed or Susceptible Subpopulations PET Polyethylene Terephthalate POD Point of Departure POTW Publicly Owned Treatment Works ppm Part(s) per Million PWS Public Water System RCRA Resource Conservation and Recovery Act REL Recommended Exposure Level SDS Safety Data Sheet SDWA Safe Drinking Water Act SIDS Screening Information Data Set TCA 1,1,1 -Trichloroethane TCCR Transparent, Clear, Consistent and Reasonable TLV Threshold Limit Value TRI Toxics Release Inventory TSCA Toxic Substances Control Act TWA Time-Weighted Average UCMR Unregulated Contaminant Monitoring Rule U.S. United States UV Ultraviolet VCCEP Voluntary Children's Chemical Evaluation Program VOC Volatile Organic Compound WHO World Health Organisation Page 7 of 90 ------- EXECUTIVE SUMMARY TSCA § 6(b)(4) requires the United States Environmental Protection Agency (U.S. EPA) to establish a risk evaluation process. In performing risk evaluations for existing chemicals, EPA is directed to "determine whether a chemical substance presents an unreasonable risk of injury to health or the environment, without consideration of costs 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." In December of 2016, EPA published a list of 10 chemical substances that are the subject of the Agency's initial chemical risk evaluations ( ), as required by TSCA § 6(b)(2)(A). 1,4-Dioxane was one of these chemicals. TSCA § 6(b)(4)(D) requires that EPA publish the scope of the risk evaluation to be conducted, including the hazards, exposures, conditions of use and potentially exposed or susceptible subpopulations that the Administrator expects to consider. In June 2017, EPA published the Scope of the Risk Evaluation for 1,4-Dioxane. As explained in the scope document, because there was insufficient time for EPA to provide an opportunity for comment on a draft of the scope, as EPA intends to do for future scope documents, EPA is publishing and taking public comment on a problem formulation document to refine the current scope, as an additional interim step prior to publication of the draft risk evaluation for 1,4- dioxane. Comments received on this problem formulation document will inform development of the draft risk evaluation. This problem formulation document refines the conditions of use, exposures and hazards presented in the scope of the risk evaluation for 1,4-dioxane and presents refined conceptual models and analysis plans that describe how EPA expects to evaluate the risk for 1,4-dioxane. 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 a reportable 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 listed as a waste 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). Information on domestic manufacture, processing and use of 1,4-dioxane is available to EPA through its Chemical Data Reporting (CDR) Rule, issued under TSCA. In 2016, approximately 1 million pounds per year was reported to be manufactured in the U.S. ( 1116c). 1,4-Dioxane is currently used in industrial processes and for industrial and commercial uses. Industrial processing uses include use as a processing aid and in functional fluids in open and closed systems. 1,4-Dioxane has uses as a laboratory chemical reagent, in adhesives and sealants and several other identified uses. Historically, 90% of 1,4-dioxane produced was used as a stabilizer in chlorinated solvents such as 1,1,1- trichloroethane (TCA). Use of 1,4-dioxane has decreased since TCA was phased out by the Montreal Protocol in 1996. The most recent data on environmental releases, according to the Toxics Release Inventory (TRI), indicate that approximately 675,000 pounds of 1,4-dioxane were released to the environment in 2015 G . !"-J h.\ /_<')• Releases are reported to all types of environmental media: air, water and land. The environmental fate of 1,4-dioxane is characterized by partitioning to the atmosphere, surface water and Page 8 of 90 ------- groundwater, and degradation by atmospheric oxidation or biodegradation. It is expected to be moderately persistent in the environment and has a low bioaccumulation potential. This document presents the potential exposures that may result from the conditions of use of 1,4- dioxane. Workers and occupational non-users may be exposed to 1,4-dioxane during industrial and commercial conditions of use such as manufacturing, processing, distribution, use and disposal. EPA plans to further analyze inhalation exposures to vapors and mists for workers and occupational non-users and dermal exposures for skin contact with liquids in occluded situations for workers in the risk evaluation. For environmental release pathways, EPA plans to include surface water exposure to aquatic vertebrates, invertebrates and aquatic plants, exposure to sediment organisms and exposure to 1,4- dioxane in land-applied biosolids in the risk evaluation. 1,4-Dioxane has been the subject of numerous human health reviews including EPA's Integrated Risk Information System (IRIS) Toxicological Review, Agency for Toxic Substances and Disease Registry's (ATSDR's) Toxicological Profile, Health Canada Screening Assessment, and Interim Acute Exposure Guideline Levels (AEGL). Many targets of toxicity from exposures to 1,4-dioxane have been identified in animal and human studies for both oral and inhalation exposures. EPA plans to evaluate all potential hazards for 1,4-dioxane, including any found in recent literature. Hazard endpoints identified in previous assessments include acute toxicity, non-cancer effects and cancer. Non-cancer effects include irritation of the eyes and respiratory tract, liver toxicity and kidney toxicity. Animals exposed to 1,4-dioxane by inhalation and oral exposure have also developed multiple types of cancer. If additional hazard concerns are identified during the systematic review of the literature, these will also be considered. These hazards will be evaluated based on the specific exposure scenarios identified. The revised conceptual models presented in this problem formulation identify conditions of use; exposure pathways (e.g., media); exposure routes (e.g., inhalation, dermal, oral); potentially exposed or susceptible subpopulations; and hazards EPA expects to further analyze in the risk evaluation. The initial conceptual models provided in the scope document (U.S. EPA. ) were revised during problem formulation based on evaluation of reasonably available information for physical and chemical properties, fate, exposures and hazards to indicate conditions of use, exposure pathways, exposure routes, and hazards, conditions of use and consideration of other statutory and regulatory authorities. In each problem formulation document for the first 10 chemical substances, EPA also refined the activities, hazards and exposure pathways that will be included in and excluded from the risk evaluation. EPA's overall objectives in the risk evaluation process are to conduct timely, relevant, high-quality, and scientifically credible risk evaluations within the statutory deadlines, and to evaluate the conditions of use that raise greatest potential for risk 82 FR 33726, 33728 (July 20, 2017). Page 9 of 90 ------- 1 INTRODUCTION This document presents for comment the problem formulation of the risk evaluation to be conducted 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 (TSCA), the Nation's primary chemicals management law, on June 22, 2016. The new law includes statutory requirements and deadlines for actions related to conducting risk evaluations of existing chemicals. In December of 2016, EPA published a list of 10 chemical substances that are the subject of the Agency's initial chemical risk evaluations (81 FR 91927), as required by TSCA § 6(b)(2)(A). These 10 chemical substances were drawn from the 2014 update of EPA's TSCA Work Plan for Chemical Assessments, a list of chemicals that EPA identified in 2012 and updated in 2014 (currently totaling 90 chemicals) for further assessment under TSCA. EPA's designation of the first 10 chemical substances constituted the initiation of the risk evaluation process for each of these chemical substances, pursuant to the requirements of TSCA § 6(b)(4). TSCA § 6(b)(4)(D) requires that EPA publish the scope of the risk evaluation to be conducted, including the hazards, exposures, conditions of use and potentially exposed or susceptible subpopulations that the Administrator expects to consider, within 6 months after the initiation of a risk evaluation. The scope documents for all first 10 chemical substances were issued on June 22, 2017. The first 10 problem formulation documents are a refinement of what was presented in the first 10 scope documents. TSCA § 6(b)(4)(D) does not distinguish between scoping and problem formulation, and requires EPA to issue scope documents that include information about the chemical substance, such as the hazards, exposures, conditions of use, and the potentially exposed or susceptible subpopulations that the Administrator expects to consider in the risk evaluation. In the future, EPA expects scoping and problem formulation to be completed prior to the issuance of scope documents and intends to issue scope documents that include problem formulation. As explained in the scope document, because there was insufficient time for EPA to provide an opportunity for comment on a draft of the scope, as EPA intends to do for future scope documents, EPA is publishing and taking public comment on a problem formulation document to refine the current scope, as an additional interim step prior to publication of the draft risk evaluation for 1,4-dioxane. Comments received on this problem formulation document will inform development of the draft risk evaluation. The Agency defines problem formulation as the analytical phase of the risk assessment in which "the purpose for the assessment is articulated, the problem is defined, and a plan for analyzing and characterizing risk is determined" (see section 2.2 of the Framework for Human Health Risk Assessment to Inform Decision Making, (\ J I \ 20J-V). The outcome of problem formulation is a conceptual model(s) and an analysis plan. The conceptual model describes the linkages between stressors and adverse human health effects, including the stressor(s), exposure pathway(s), exposed life stage(s) and population(s), and endpoint(s) that will be addressed in the risk evaluation (I; ^ \ IP 2014c). The analysis plan follows the development of the conceptual model(s) and is intended to describe the approach for conducting the risk evaluation, including its design, methods and key inputs and intended outputs as described in the EPA Human Health Risk Assessment Framework (U.S. EPA. 2014c). The problem formulation documents refine the initial conceptual models and analysis plans that were provided in the scope documents. Page 10 of 90 ------- First, EPA has removed from the risk evaluation any activities and exposure pathways that EPA has concluded do not warrant inclusion in the risk evaluation. For example, for some activities that were listed as "conditions of use" in the scope document, EPA has insufficient information following the further investigations during problem formulation to find they are circumstances under which the chemical is actually "intended, known, or reasonably foreseen to be manufactured, processed, distributed in commerce, used, or disposed of." Second, EPA also identified certain exposure pathways that are under the jurisdiction of regulatory programs and associated analytical processes carried out under other EPA-administered environmental statutes - namely, the Clean Air Act (CAA), the Safe Drinking Water Act (SDWA), the Clean Water Act (CWA), and the Resource Conservation and Recovery Act (RCRA) - and which EPA does not expect to include in the risk evaluation. As a general matter, EPA believes that certain programs under other Federal environmental laws adequately assess and effectively manage the risks for the covered exposure pathways. To use Agency resources efficiently under the TSCA program, to avoid duplicating efforts taken pursuant to other Agency programs, to maximize scientific and analytical efforts, and to meet the three-year statutory deadline, EPA is planning to exercise its discretion under TSCA 6(b)(4)(D) to focus its analytical efforts on exposures that are likely to 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.1 EPA does not expect to include any such excluded pathways in the risk evaluation as further explained below. The provisions of various EPA-administered environmental statutes and their implementing regulations represent the judgment of Congress and the Administrator, respectively, as to the degree of health and environmental risk reduction that is sufficient under the various environmental statutes. Third, EPA identified any conditions of use, hazards, or exposure pathways which were included in the scope document and that EPA expects to include in the risk evaluation but which EPA does not expect to further analyze in the risk evaluation. EPA expects to be able to reach conclusions about particular conditions of use, hazards or exposure pathways without further analysis and therefore plans to conduct no further analysis on those conditions of use, hazards or exposure pathways in order to focus the Agency's resources on more extensive or quantitative analyses. Each risk evaluation will be "fit-for- purpose," meaning not all conditions of use will warrant the same level of evaluation and the Agency may be able to reach some conclusions without comprehensive or quantitative risk evaluations. 82 FR 33726, 33734, 33739 (July 20, 2017). EPA received comments on the published scope document for 1,4-dioxane and has considered the comments specific to 1,4-dioxane in this problem formulation document. EPA is soliciting public comments on this problem formulation document and when the draft risk evaluation is issued the Agency intends to respond to comments that are submitted. In its draft risk evaluation, EPA may revise the conclusions and approaches contained in this problem formulation, including the conditions of use and pathways covered and the conceptual models and analysis plans, based on comments received. 1 As explained in the final rule for chemical risk evaluation procedures, "EPA may, on a case-by case basis, exclude certain activities that EPA has determined to be conditions of use in order to focus its analytical efforts on those exposures that are likely to present the greatest concern, and consequently merit an unreasonable risk determination." [82 FR 33726, 33729 (July 20, 2017)]. Page 11 of 90 ------- 1.1 Regulatory 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. As noted in public comments to the scope document, the NESHAP for Rubber Manufacturing does not apply to 1,4-dioxane and has been removed from Table Apx A-l. EPA evaluated and considered the impact of existing laws and regulations in the problem formulation step to determine what, if any further analysis might be necessary as part of the risk evaluation. Consideration of the nexus between these existing regulations and TSCA uses may additionally be made as detailed/specific conditions of use and exposure scenarios are developed in conducting the analysis phase of the risk evaluation. 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 implemented by state agencies or departments. 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. 1.2 Assessment History EPA has identified assessments conducted by other EPA Programs and other organizations (see Table 1-1). Depending on the source, these assessments may include information on conditions of use, hazards, exposures and potentially exposed or susceptible subpopulations. Table 1-1 shows the assessments that have been conducted. EPA found no additional assessments beyond those listed in the Scope document. In addition to using this information, EPA intends to conduct a full review of the relevant data/information collected in the initial comprehensive search (see 1,4-Dioxane (CASRN123-91-1) Bibliography: Supplemental File for the TSCA Scope Document, EPA-HQ-0 ) 1.6-0723) following the literature search and screening strategies documented in the Strategy for Conducting Literature Searches for 1,4-Dioxane: Supplemental File for the TSCA Scope Document, EPA-H.Q-OPPT-: 0723. This will ensure that EPA considers data/information that has been made available since these assessments were conducted. Page 12 of 90 ------- Table 1-1. 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 (2015c") EPA, National Center for Environmental Assessment (NCEA) lexicological Review of 1,4-Dioxane (With Inhalation Uod* (2013c) EPA, NCEA lexicological review of 1.4-Dioxane (CAS No. i'M iu2010} 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) Agency for Toxic Substances and Disease Registry (AT SDR) Toxicological 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 rL) fc-i 1 4 Dioxane (CAS Reg. No 123-'"> 1-1) (2005b) International International Cooperation on Cosmetics Regulation Report of the ICCR Working Group: Considerations on. Acceptable Trace Level o Dioxane in Cosmetic Products (2017) International Agency for Research on Cancer (IARC) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Volut ( 9) Government of Canada, Environment Canada, Health Canada Screening Assessment for the Challenge. 1.4- Dioxane. CASRN 123- ( ) Research Center for Chemical Risk Management, National Institute of Advanced Industrial Science and Technology, Japan Estimating Health Risk from Exposure to 1.4- World Health Organisation (WHO) tane in Drinking-water (2005) Employment, Social Affairs, and Inclusion, European Commission (EC) Recommendation from the Scientific Committee on Occupational Exposure Limits for 1.4-dioxane (2004) European Chemicals Bureau, Institute for Health and Consumer Protection European Union Risk Assessment Report. 1.4- dioxane. No: 204- 661-8. (2002) Page 13 of 90 ------- Authoring Organization Assessment National Industrial Chemicals Notification and Assessment Scheme (NICNAS), Australian Government 1 l-Oioxane "rn n ttv Existing Chemical No. 7. Full Public Ret) ( 98) Organisation for Economic Co-operation and Development (OECD), Screening Information Data Set (SIDS) Dioxane. SIDS initial assessment profile ( ) 1.3 Data and Information Collection EPA/OPPT generally applies a systematic review process and workflow that includes: (1) data collection, (2) data evaluation and (3) data integration of the scientific data used in risk evaluations developed under TSCA. Scientific analysis is often iterative in nature as new knowledge is obtained. Hence, EPA/OPPT expects that multiple refinements regarding data collection may occur during the process of risk evaluation. Data Collection: Data Search EPA/OPPT conducted chemical-specific searches for data and information on: physical and chemical properties; environmental fate and transport; conditions of use information; environmental exposures, human exposures, including potentially exposed or susceptible subpopulations; ecological hazard, human health hazard, including potentially exposed or susceptible subpopulations. EPA/OPPT designed its initial data search to be broad enough to capture a comprehensive set of sources containing data and/or information potentially relevant to the risk evaluation. Generally, the search was not limited by date and was conducted on a wide range of data sources, including but not limited to: peer-reviewed literature and gray literature (e.g., publicly-available industry reports, trade association resources, government reports). For human health hazard, EPA/OPPT relied on the search strategies from recent assessments, such as EPA Integrated Risk Information System (IRIS) assessments and the NTP Report on Carcinogens, to identify relevant information published after the end date of the previous search to capture more recent literature. The Strategy for Conducting Literature Searches for 1,4-Dioxane: Supplemental File for the TSCA Scope Document (EPA-HQ-OIT I '¦11 ^ 111" 3) provides details about the data and information sources and search terms that were used in the literature search. Data Collection: Data Screening Following the data search, references were screened and categorized using selection criteria outlined in the Strategy for Conducting Literature Searches for 1,4-Dioxane: Supplemental File for the TSCA Scope Document (EPA-HQ-QPPT-2016-0723). Titles and abstracts were screened against the criteria as a first step with the goal of identifying a smaller subset of the relevant data to move into the subsequent data extraction and data evaluation steps. Prior to full-text review, EPA/OPPT anticipates refinements to the search and screening strategies, as informed by an evaluation of the performance of the initial title/abstract screening and categorization process. The categorization scheme (or tagging structure) used for data screening varies by scientific discipline (i.e., physical and chemical properties; environmental fate and transport; chemical use/conditions of use information; environmental exposures, human exposures, including potentially exposed or susceptible subpopulations identified by virtue of greater exposure; human health hazard, including potentially exposed or susceptible subpopulations identified by virtue of greater susceptibility; and ecological Page 14 of 90 ------- hazard). However, within each data set, there are two broad categories or data tags: (1) on-topic references or (2) off-topic references. On-topic references are those that may contain data and/or information relevant to the risk evaluation. Off-topic references are those that do not appear to contain data or information relevant to the risk evaluation. The supplemental document, Strategy for Conducting Literature Searches for 1,4-Dioxane: Supplemental File for the TSCA Scope Document (EPA-H.Q- QPPT-2016-0723) discusses the inclusion and exclusion criteria that EPA/OPPT used to categorize references as on-topic or off-topic. Additional data screening using sub-categories (or sub-tags) was also performed to facilitate further sorting of data/information. For example, identifying references by source type (e.g., published peer- reviewed journal article, government report); data type (e.g., primary data, review article); human health hazard (e.g., liver toxicity, cancer, reproductive toxicity); or chemical-specific and use-specific data or information. These sub-categories are described in the supplemental document, Strategy for Conducting Literature Searches for 1,4-Dioxane: Supplemental File for the TSCA Scope Document (EPA-H.O- QPPT-2016-0723) and will be used to organize the different streams of data during the stages of data evaluation and data integration steps of systematic review. Results of the initial search and categorization can be found in the 1,4-Dioxane (CASRN123-91-1) Bibliography: Supplemental File for the TSCA Scope Document (EP A-HQ-QPP'T-2016-0723). This document provides a comprehensive list (bibliography) of the sources of data identified by the initial search and the initial categorization for on-topic and off-topic references. Because systematic review is an iterative process, EPA/OPPT expects that some references may move from the on-topic to the off- topic categories, and vice versa. Moreover, targeted supplemental searches may also be conducted to address specific needs for the analysis phase (e.g., to locate specific data needed for modeling); hence, additional on-topic references not initially identified in the initial search may be identified as the systematic review process proceeds. 1.4 Data Screening During Problem Formulation EPA/OPPT is in the process of completing the full text screening of the on-topic references identified in the 1,4-Dioxane (CASRN 123-91-1) Bibliography: Supplemental File for the TSCA Scope Document (EPA-H.O-QPP'T-21 23). The screening process at the full-text level is described in the Application of Systematic Review in TSCA Risk Evaluations (U.S. EPA. 2018a). Appendix F provides the inclusion and exclusion criteria applied at the full text screening. The eligibility criteria are guided by the analytical considerations in the revised conceptual models and analysis plan, as discussed in the problem formulation document. Thus, it is expected that the number of data/information sources entering evaluation is reduced to those that are relevant to address the technical approach and issues described in the analysis plan of this document. Following the screening process, the quality of the included data/information sources will be assessed using the evaluation strategies that are described in the Application of Systematic Review in TSCA Risk Evaluations ( 1018a). Page 15 of 90 ------- 2 PROBLEM FORMULATION As required by TSCA, the scope of the risk evaluation identifies the conditions of use, hazards, exposures and potentially exposed or susceptible subpopulations that the Administrator expects to consider. To communicate and visually convey the relationships between these components, EPA included in the scope document a life cycle diagram and conceptual models that describe the actual or potential relationships between 1,4-dioxane and human and ecological receptors. During the problem formulation, EPA revised the conceptual models based on further data gathering and analysis as presented in this Problem Formulation document. An updated analysis plan is also included which identifies, to the extent feasible, the approaches and methods that EPA may use to assess exposures, effects (hazards) and risks under the conditions of use of 1,4-dioxane. 2.1 Physical and Chemical Properties Physical-chemical properties influence the environmental behavior and the toxic properties of a chemical, thereby informing the potential conditions of use, exposure pathways and routes and hazards that EPA intends to consider. For scope development, EPA considered the measured or estimated physical-chemical properties set forth in Table 2-1 and EPA found no additional information during problem formulation that would change these values. Table 2-1. Physical and Chemical Properties of 1,4-Dioxane Property Value a References Molecular formula C4H8O2 Molecular weight 88.1 g/mole (Howard. 1990) Physical form Clear liquid (O'Neil et al.„ 2001) Melting point 11.75°C (Havmes. 2.014) Boiling point 101.1°C (O'Neil et aL 2.006) Density 1.0329 g/cm3 (O'Neil et aL 2006) Vapor pressure 40 mm Hg at 25°C (Lewis. 2.000) Vapor density Not readily available Water solubility >8.00 x 102 g/L (Yalkowskv et al. 20 i 0) Octanol:water partition -0.27 (estimated) (Hansch et al.. 1995) Henry's Law constant 4.8 x 10"6 atm-m3/mole at 25°C (Sander. 2017); (Howard. 1990); (Atkins. 1986) Flash point 18.3°C (open cup) (Lewis.: ) Autoflammability Not readily available Viscosity 0.0120 cP at 25°C (O'Neil. 2013) Refractive index 1.4224 at 20°C CHavnes. 2.014) Dielectric constant 2.209 (Bruno and Svoronos. 2006) a Measured unless otherwise noted Page 16 of 90 ------- 2.2 Conditions of Use TSCA § 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." 2.2.1 Data and Information Sources In the scope documents, EPA identified, based on reasonably available information, the conditions of use for the subject chemicals. As further described in this document, EPA searched a number of available data sources (e.g. Use and Market Profile for 1,4-Dioxane, (I V x 1 i1 » 1 il1lT~2QI6 0723). Based on this search, EPA published a preliminary list of information and sources related to chemical conditions of use (sqq Preliminary Information on Manufacturing, Processing, Distribution, Use, and Disposal: 1,4-Dioxane, EPA-HQ-OPPT- 723-0003) prior to a February 2017 public meeting on scoping efforts for risk evaluations convened to solicit comment and input from the public. EPA also convened meetings with companies, industry groups, chemical users and other stakeholders to aid in identifying conditions of use and verifying conditions of use identified by EPA. The information and input received from the public and stakeholder meetings has been incorporated into this problem formulation document to the extent appropriate. Thus, EPA believes the identified manufacture, processing, distribution, use and disposal activities constitute the intended, known, and reasonably foreseeable activities associated with the subject chemical, based on reasonably available information. 2.2.2 Identification of Conditions of Use To determine the current conditions of use of 1,4-dioxane and inversely, conditions of use that are no longer ongoing, EPA conducted extensive research and outreach. This included EPA's review of published literature and online databases including the most recent data available from EPA's Chemical Data Reporting program (CDR) and Safety Data Sheets (SDSs). EPA also conducted online research by reviewing company websites of potential manufacturers, importers, distributors, retailers, or other users of 1,4-dioxane and queried government and commercial trade databases. EPA also received comments on the Scope of the Risk Evaluation for 1,4-Dioxane (EPA.~H.0~QI 3) that were used to determine the current conditions of use. In addition, EPA convened meetings with companies, industry groups, chemical users, states, environmental groups, and other stakeholders to aid in identifying conditions of use and verifying conditions of use identified by EPA. Those meetings included a February 14, 2017 public meeting with such entities and a September 15, 2017 meeting with several representatives from trade associations. EPA has removed from the risk evaluation activities that EPA concluded do not constitute conditions of use - for example because EPA has insufficient information to find certain activities are circumstances under which the chemical is actually "intended, known, or reasonably foreseen to be manufactured, processed, distributed in commerce, used or disposed of." EPA has also identified any conditions of use that EPA does not plan to include in the risk evaluation. As explained in the final rule for Procedures for Chemical Risk Evaluation Under the Amended Toxic Substances Control Act, TSCA section 6(b)(4)(D) requires EPA to identify "the hazards, exposures, conditions of use and the potentially exposed or susceptible subpopulations that the Agency expects to consider in a risk evaluation," suggesting that EPA may exclude certain activities that EPA has determined to be conditions of use on a case-by-case basis (82 FR 33736, 33729; July 20, 2017). For example, EPA may exclude conditions of use that the Agency has sufficient basis to conclude would present only de minimis exposures or otherwise insignificant risks (such as use in a closed system that effectively precludes exposure or as an intermediate). Page 17 of 90 ------- The activities that EPA no longer believes are conditions of use or were otherwise excluded during problem formulation are described in Section 2.2.2.1. The conditions of use included in the scope of the risk evaluation are summarized in Section 2.2.2.2. 2.2.2.1 Categories and Subcategories Determined Not to be Conditions of Use During Problem Formulation For 1,4-dioxane, EPA has reviewed reasonably available information about 1,4-dioxane conditions of use. EPA did not find evidence of any current consumer uses ( 2016c) for 1,4-dioxane and is excluding consumer uses from the scope of the risk evaluation as explained in the Scope document ( EPA, 2017c). As described in the Scope, contamination of industrial, commercial and consumer products are not intended conditions of use for 1,4-dioxane and will not be evaluated. For fuels and fuel additives (Other uses category), EPA contacted several racing authorities that indicated that their organizations banned the use of dioxane in competitions. The organizations also could not provide credible information on whether or how often dioxane was used prior to their bans nor whether it is currently used at all. Based on the lack of information confirming that 1,4-dioxane is currently used as a fuel or fuel additive and the fact that racing authorities have prohibited this use, use in fuels and fuel additives is not a condition of use under which EPA will evaluate 1,4-dioxane. Table 2-2. Categories and Subcategories Determined Not to Be Conditions of Use During Problem Formulation l.il'e Cycle Stage Category Subcategory References Industrial use, potential commercial use Other Uses Fuels and fuel additives Use document, EPA- HO-OPI '23- 0003 2.2.2.2 Categories and Subcategories of Conditions of Use Included in the Scope of the Risk Evaluation For 1,4-dioxane, EPA has conducted public outreach and literature searches to collect information about conditions of use and has reviewed reasonably available information obtained or possessed by EPA concerning activities associated with 1,4-dioxane. 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-QPPT-2016-0723-0012; BASF (2017). Industrial processing uses included in the scope include processing as a reactant or intermediate, non-incorporative processing, repackaging and recycling. Uses include processing aids (not otherwise listed), functional fluids in open and closed systems, laboratory chemicals, adhesives and sealants, other uses (spray polyurethane foam, printing and printing compositions) and disposal. Note that during problem formulation, EPA determined that some subcategories, such as cutting and tapping fluid, may also be used in open systems and is including these uses. Activities related to distribution (e.g., loading, unloading) will be considered throughout the 1,4-dioxane life cycle, rather than as a single distribution scenario. Also included in the scope are 1,4-dioxane use as a laboratory chemical reagent and use in adhesives and sealants in industrial and/or commercial settings and use in laboratory reference materials or standards containing 1,4-dioxane. Searches identified two products with greater than 5% of 1,4- dioxane that are included: a professional film cement and a chemiluminescent laboratory reagent. Other uses included are spray polyurethane foam; and printing and printing compositions. Page 18 of 90 ------- Table 2-3 summarizes each life cycle stage and the corresponding categories and subcategories of conditions of use for 1,4-dioxane that EPA is including in the scope of the risk evaluation. Using the 2016 CDR (U.S. EPA. 2016c). EPA identified industrial processing or use activities, industrial function categories and commercial use product categories. EPA identified the subcategories by supplementing CDR data with other published literature and information obtained through stakeholder consultations. For this risk evaluation, EPA intends to consider each life cycle stage (and corresponding use categories and subcategories) and assess certain relevant potential sources of release and human exposure associated with that life cycle stage. Beyond the uses identified in the Scope of the Risk Evaluation for 1,4-Dioxane ( ), EPA has received no additional information identifying additional current conditions of use for 1,4-dioxane from public comment and stakeholder meetings. Table 2-3. Categories and Subcategories of Conditions of Use Included in the Scope of the Risk Evaluation l.il'e Cycle Stage Category " Subcategory h References Manufacture Domestic manufacture Domestic manufacture Use document 0- OPPT-2016-0723-0003: Public Comment, EPA-HO- OPPT-2016-0723-( Import Import Use document, (V OPPT-2016-0723 -0003 Processing Processing as a reactant Pharmaceutical intermediate Use document, .0- OPPT-2016-0723-0003 Polymerization catalyst Use document. O- OPPT-2016-0723-0003 Non-incorporative Pharmaceutical and medicine manufacturing (process solvent) Public Comment, EPA-HO- OPPT-2016-0723-0012 Basic organic chemical manufacturing (process solvent) Public Comment, EPA-HO- OPPT-2016-07: Repackaging Bulk to packages, then distribute Public Comment, EPA-HO- OPPT-2016-07: Recycling Recycling 0 n«\ >0 Distribution in commerce Distribution Distribution Use document, EPA-HO- OPPT-2016-0723-0003 Industrial use Intermediate use Agricultural chemical intermediate Use document, .0- OPPT-2016-0723-0003 Plasticizer intermediate Use document, (V OPPT-2016-0723-0003 Catalysts and reagents for anhydrous acid reactions, Use document, .0- OPPT-2016-0723-0003 Page 19 of 90 ------- l.il'e ( vole Slsige Csilegorv 11 Siihe:iU'«or\ h UeforoiKTs brominations and sulfonations Processing aids, not otherwise listed Wood pulping Use document, Q- OPPT-2016-0723 -0003 Extraction of animal and vegetable oils Use document, ()~ OPPT-2016-0723-0003 Wetting and dispersing agent in textile processing Use document, 1 ^ \ S Q- OPPT-2016-0723-0003 Polymerization catalyst Use document, EPA-HO- OPPT -2016-0723-0003 Purification of pharmaceuticals Use document. EPA-HO- OPPT -2016-0723-0003 Etching of fluoropolymers Public Comment. EPA-HO- OPPT-2016-0723-( Functional fluids (open and closed system); refer to section 2.5.1 below for details Polyalkylene glycol lubricant Use document, I 'P \ i 10- OPPT-2016-0723-0003 Synthetic metalworking fluid Use document, ()~ OPPT-2016-0723-0003 Cutting and tapping fluid Use document, 1 ^ \ S Q- OPPT-2016-0723-0003 Hydraulic fluid Use document, O- OPPT-2016-0723-0003 Industrial use, potential commercial use Laboratory chemicals Chemical reagent Use document, ^ O- OPPT-2016-0723-0003: Public Comment, EPA-HO- OPPT-2016-0723-0009 Reference material Use document, 1 ^ \ S Q- OPPT-2016-0723-0003 Spectroscopic and photometric measurement Use document, O- OPPT-2016-0723-0003: Public Comment, EPA-HO- OPPT-2016-0723-0009 Liquid scintillation counting medium Use document, ()~ OPPT-2016-0723-0003 Stable reaction medium Use document, 1 \ S Q- OPPT-2016-0723-0003 Cryoscopic solvent for molecular mass determinations Use document, O- OPPT-2016-0723-0003 Page 20 of 90 ------- l.il'e Cycle Slagc Category 11 Subcategory h References Preparation of histological sections for microscopic examination I sc document. OPPT-2016-0723 -0003 Adhesives and sealants Film cement Use document. O- OPPT-2016-0723-0003: Public Comment, EPA-HO- OPPT-2016-0723-0021 Other uses Spray polyurethane foam Printing and printing compositions Use document O- OPPT-2016-0723-0003: Public Comment, EPA-HO- OPPT-2016-072 3 -0012 Disposal Disposal Industrial pre-treatment ( 2017d") Industrial wastewater 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 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. 2.2.2.3 Overview of Conditions of Use and Lifecycle Diagram The life cycle diagram provided in Figure 2-1 depicts the conditions of use that are considered within the scope of the risk evaluation during various life cycle stages including manufacturing, processing, distribution, use (industrial, commercial; when distinguishable) and disposal. Additions or changes to conditions of use based on additional information gathered or analyzed during problem formulation were described in Section 2.2.2.1 and 2.2.2.2. The activities that EPA determined are out of scope during problem formulation are not included in the life cycle diagram. The information is grouped according to Chemical Data Reporting (CDR) processing codes and use categories (including functional use codes for industrial uses and product categories for commercial and consumer uses), in combination with other data sources (e.g., published literature and consultation with stakeholders), to provide an overview of conditions of use. EPA notes that some subcategories may be grouped under multiple CDR categories. Page 21 of 90 ------- Use categories include the following: "industrial use" means use at a site at which one or more chemicals or mixtures are manufactured (including imported) or processed. "Commercial use" means the use of a chemical or a mixture containing a chemical (including as part of an article) in a commercial enterprise providing saleable goods or services (U.S. EPA. ). To understand conditions of use relative to one another and associated potential exposures under those conditions of use, the life cycle diagram includes the production volume associated with each stage of the life cycle, as reported in the 2016 CDR reporting ( 016c). when the volume was not claimed confidential business information (CBI). The 2016 CDR reporting data for 1,4-dioxane are provided in Table 2-4 for 1,4-dioxane from EPA's CDR database (U.S. EPA. 2016c). This information has not changed from that provided in the scope document. Table 2-4. 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 " The CDR data for the 2016 rcportinu period is available via ChemView (httDs://iava.eDa.eov/chemview) (U.S. EPA. 2014a). Because of an onsoins CBI substantiation process reauired bv amended TSCA. the CDR data available in the scope document is more specific than currently in ChemView. According to data collected in EPA's JO I * Chemical Data Reporting ' >Rj Rule, over one million pounds of 1,4-dioxane were produced or imported in the U.S. in 2015 ( :). Data reported indicate that there was one manufacturer of 1,4-dioxane in the U.S. in 2015. The total volume (in lbs) of 1,4-dioxane manufactured (including imported) in the U.S. from 2012 to 2015 indicates that production has varied over that time period. Historically, the main use (90%) of 1,4-dioxane was as a stabilizer of chlorinated solvents such as 1,1,1 trichloroethane (TCA) ( DR. 2012). Use of TCA was phased out under the 1995 Montreal Protocol and the use of 1,4-dioxane as a solvent stabilizer was terminated (NTP. 2011; ECJRC. 2002). Lack of recent reports for other previously reported uses (Sapphire Group. 2007) suggest that many other industrial, commercial and consumer uses were also stopped. Descriptions of the industrial, commercial and consumer use categories identified from the 2016 CDR (U.S. EPA. 2016a) and included in the life cycle diagram . Descriptions in Appendix B contain detailed descriptions (e.g., process descriptions, worker activities, process flow diagrams, equipment illustrations) for each manufacture, processing, distribution, use and disposal category. The descriptions are primarily based on the corresponding industrial function category and/or commercial and consumer product category descriptions from the 2016 CDR and can be found in EPA's Instructions for Reporting 2016 TSCA Chemical Data Reporting ( 016b). Figure 2-1 depicts the life cycle diagram of 1,4-dioxane from manufacture to the point of disposal. Activities related to distribution (e.g., loading, unloading) will be considered throughout the 1,4-dioxane life cycle, rather than using a single distribution scenario. Page 22 of 90 ------- MFG/IMPORT PROCESSING INDUSTRIAL and COMMERCIAL USES3 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-lncorporative Activities (270,000 lbs.) Recycling Processing Aids, Not Otherwise Listed (270,000 lbs.) e.g., wood pulping, pharmaceutical manufacture, etching of fluoropolymers Functional Fluids (Open and Closed Systems) (<150,000 lbs.) e.g., hydraulicfluid Disposal Laboratory Chemicals (<150,000 lbs.) e.g., laboratory reagent Adhesives and Sealants e.g., film cement Other Uses Spray Polyurethane Foam; Printing and Printing Compositions See Figure 2-3 for Environmental Releases and Wastes l l Manufacture (Includes Import) I I Processing ~ Industrial uses of 1,4-dioxane. ~ Industrial and/or commercial uses of 1,4-dioxane Figure 2-1. 1,4-Dioxane Life Cycle Diagram The life cycle di agram depicts the condi tions 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). Activities related to distribution (e.g., loading, unloading) will be considered throughout the 1,4-dioxane life cycle, rather than using a single distribution scenario. a See Table 2-3 for additional uses not mentioned specifically in this diagram. Page 23 of 90 ------- 2.3 Exposures For TSCA exposure assessments, EPA expects to evaluate exposures and releases to the environment resulting from the conditions of use applicable to 1,4-dioxane. Post-release pathways and routes will be described to characterize the relationship between the conditions of use of 1,4-dioxane and the exposure to human receptors, including potentially exposed or susceptible subpopulations, and ecological receptors. EPA will take into account, where relevant, the duration, intensity (concentration), frequency and number of exposures in characterizing exposures to 1,4-dioxane. 2.3.1 Fate and Transport Environmental fate includes both transport and transformation processes. Environmental transport is the movement of the chemical within and between environmental media. Transformation occurs through the degradation or reaction of the chemical with other species in the environment. Hence, knowledge of the environmental fate of the chemical informs the determination of the specific exposure pathways and potential human and environmental receptors EPA expects to consider in the risk evaluation. Table 2-5 provides environmental fate data that EPA identified and considered in developing the scope for 1,4- dioxane. This information has not changed from that provided in the scope document. Fate data including volatilization during wastewater treatment, volatilization from lakes and rivers, biodegradation rates, and organic carbon:water partition coefficient (log Koc) were used when considering changes to the conceptual models. Systematic literature review is currently underway, so model results and basic principles were used to support the fate data used in problem formulation. EPI Suite™ (U.S. EPA. 2012c) modules were used to predict volatilization of 1,4-dioxane from wastewater treatment plants, lakes, and rivers and to confirm the data showing slow biodegradation. The EPI Suite™ module that estimates chemical removal in sewage treatment plants ("STP" module) was run using default settings to evaluate the potential for 1,4-dioxane to volatilize to air or adsorb to sludge during wastewater treatment. The STP module estimates that 0.27% of 1,4-dioxane in wastewater will be removed by volatilization while 1.75% of 1,4-dioxane will be removed by adsorption. The EPI Suite™ module that estimates volatilization from lakes and rivers ("Volatilization" module) was run using default settings to evaluate the volatilization half-life of 1,4-dioxane in surface water. The volatilization module estimates that the half-life of 1,4-dioxane in a model river will be 4.8 days and the half-life in a model lake will be 56 days. The EPI Suite™ module that predicts biodegradation rates ("BIOWIN" module) was run using default settings to estimate biodegradation rates of 1,4-dioxane in soil and sediment. Three of the models built into the BIOWIN module (BIOWIN 1, 2, and 5) estimate that 1,4-dioxane will not rapidly biodegrade in aerobic environments, while a fourth (BIOWIN 6) estimates that 1,4-dioxane will rapidly biodegrade in aerobic environments. These results support the biodegradation data presented in the 1,4-dioxane scope document, which demonstrate slow biodegradation under aerobic conditions. The model that estimates anaerobic biodegradation (BIOWIN 7) predicts that 1,4-dioxane will not rapidly biodegrade under anaerobic conditions. Further, previous assessments of 1,4-dioxane found that biodegradation was slow or negligible ( J>K. 2012; NTP. 2011: Health Canada. 2010; ECJRC. 2002; NICNAS. 1998V The log Koc reported in the 1,4-dioxane scoping document was predicted using EPI Suite™. That value (0.4) is supported by the basic principles of environmental chemistry which states that the Koc is typically within one order of magnitude (one log unit) of the octanol: water partition coefficient (Kow). Page 24 of 90 ------- Indeed, the log Kow reported for 1,4-dioxane in the scoping document was -0.27, which is within the expected range. Further, the Koc could be approximately one order of magnitude larger than predicted by EPI Suite™ before sorption would be expected to significantly impact the mobility of 1,4-dioxane in groundwater. The log Koc reported in previous assessments of 1,4-dioxane were in the range of 0.4 - 1.23 (U.S. EPA. 2013b: AT SDR. 2012; U.S. EPA. 2010; ECJRC. 2002; NICNAS. 1998) and all values within that range would be associated with low sorption to soil and sediment (ECJRC. 2002; NICNAS. 1998). and all values within that range would be associated with low sorption to soil and sediment. Table 2-5. Environmental Fate Characteristics of 1,4-Dioxane Property or Endpoint Value a References Direct photodegradation Not expected to undergo direct photolysis (U.S. EPA. 2015c) Indirect photodegradation 4.6 hours (estimated for atmospheric degradation) (U.S. EPA. 2015c) Hydrolysis half-life Does not undergo hydrolysis (U.S. EPA. 2015c) Biodegradation <10% in 29 days (aerobic in water, OECD 301F) <5% in 60 days (aerobic in water, OECD 310) 0% in 120 days, 60% in 300 days (aerobic in soil microcosm) (U.S. EPA. 2015c) Bioconcentration factor (BCF) 0.2-0.7 (OECD 305C) (U.S. EPA. 2015c) Bioaccumulation factor (BAF) 0.93 (estimated) (U.S. EPA. 2015c) Organic carbon:water partition coefficient (log Koc) 0.4 (estimated) (U.S. EPA. 2015c) a Measured unless otherwise noted. 1,4-Dioxane is expected to volatilize from dry surfaces and dry soil due to its vapor pressure of 40 mm Hg at 25°C (Table 2-1). It reacts with hydroxyl radicals (OH*) in the atmosphere with an estimated indirect photolysis half-life on the order of hours. 1,4-Dioxane is not expected to be susceptible to direct photolysis under environmental conditions since this compound lacks functional groups that absorb light at visible-ultraviolet (UV) light wavelengths. Due to its water solubility (>800 g/L; Table 2-1) and Henry's Law constant (4.8 x 10"6 atm-m3/mole at 25°C; Table 2-1), 1,4-dioxane is expected to demonstrate limited volatility from water surfaces and moist soil. Once it enters the environment, 1,4-dioxane is expected to be mobile in soil based on its organic carbon partition coefficient (estimated log Koc = 0.4) and may therefore migrate to surface waters and groundwater. 1,4-Dioxane will not hydrolyze in water because it does not have functional hydrolyzable groups. In experimental studies, 1,4-dioxane has been demonstrated to be not readily biodegradable but was subject to biodegradation after acclimation in a soil microcosm. Measured bioconcentration factors for 1,4-dioxane are 0.7 or below and the estimated bioaccumulation factor is 0.93. Therefore, 1,4-dioxane has low bioaccumulation potential. Page 25 of 90 ------- 2.3.2 Releases to the Environment Releases to the environment from conditions of use (e.g., industrial and commercial processes, commercial or consumer uses resulting in down-the-drain releases) 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 rule, 1,4- dioxane is a TRI-reportable substance effective January 1, 1987. During problem formulation EPA further analyzed the TRI data and examined the definitions of elements in the TRI data to determine the level of confidence that a release would result from certain types of disposal to land (i.e. RCRA Subtitle C hazardous landfill and Class I underground Injection wells) and incineration. EPA also examined how many facilities recycle 1,4 dioxane, and how it is treated at industrial facilities. Table 2-6 provides production-related waste managed data (also referred to as waste managed) for 1,4- dioxane reported by industrial facilities to the TRI program for 2015. Table 2-7 provides more detailed information on the quantities released to air or water or disposed of on land. Table 2-6. Summary of 1,4-Dioxane TRI Production-Related Waste Managed in 2015 (lbs) Number of Facilities Recycling Energy Recovery Treatment Releases a'b'c Total Production Related Waste 49 4,292 1,591,064 1,923,623 705,691 4,224,670 Data source: 2015 TRI Data (undated March 2017) (U.S. EPA. 2017d). a 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 Does not include releases due to one-time event not associated with production such as remedial actions or earthquakes. 0 Counts all releases including release quantities transferred and release quantities disposed of by a receiving facility reporting to TRI. Table 2-7. Summary of 1,4-Dioxane TRI Releases to the Environment in 2015 ( bs) Air Releases Number of Facilities Stack Air Releases Fugitive Air Releases Water Releases Land Disposal Class I Under- ground Injection RCRA Subtitle C Landfills All other Land Disposala Other Releases ! Subtotal 46,219 16,377 563,976 13,376 49 Totals 49 62,596 35,402 577,400 Data source: 2015 TRI Data (updated March 2017) (U.S. EPA. 2017dY a 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. 0 Counts release quantities once at final disposition, accounting for transfers to other TRI reporting facilities that ultimately dispose of the chemical waste. Facilities are required to report if they manufacture (including import) or process more than 25,000 pounds of 1,4-dioxane, or if they otherwise use more than 10,000 pounds of 1,4-dioxane. In 2015, 49 facilities reported a total of 4.2 million pounds of 1,4-dioxane waste managed. Of this total, over 4 thousand pounds were recycled, 1.6 million pounds were recovered for energy, 1.9 million pounds were treated and 700 thousand pounds were released to the environment. No TRI facilities reported recycling Page 26 of 90 ------- 1,4-dioxane on-site, but one reported transferring it off-site for recycling, specifically for solvents/organics recovery. Of the almost 700 thousand pounds of total releases, there were stack and fugitive air releases, water releases, Class I underground injection, release to Resource Conservation and Recovery Act (RCRA) Subtitle C landfills and other land disposal (Table 2-7). For stack releases, multiple types of facilities report on incineration destruction, including hazardous waste facilities, and facilities that perform other industrial activities and may be privately or publically (i.e., federal, state or municipality) owned or operated. Approximately 46,000 lbs of 1,4-dioxane releases were reported to TRI as on-site stack releases, and account for any incineration destruction. Stack releases reported to TRI represent the total amount of 1,4 dioxane being released to the air at the facility from stacks, confined vents, ducts, pipes or other confined air streams. In 2015, 205,725 pounds of 1,4-dioxane were released on-site, and 469,674 pounds were released off- site. Of the on-site releases, 52% (107,726 pounds) went to land disposal, 30% (62,596 pounds) went to air, including stack and fugitive releases, and 17% (35,402 pounds) was discharged to water. Of the on- site land disposal, most went to Class I underground injection wells or RCRA Subtitle C Landfills. Just 47 pounds went to on-site landfills other than RCRA Subtitle C Landfills, and none was disposed of in on-site Class II-V underground injection wells, on-site land treatment, or on-site surface impoundments. Of the off-site releases, the vast majority (469,672 lb) went to Class I underground injection wells. Very small amounts were transferred off-site to RCRA Subtitle C Landfills (0.31 lb), landfills other than RCRA Subtitle C Landfills (0.1 lb), and other types of land disposal (1.65 lb) and are considered of negligible concern for exposure. While most 1, 4-dioxane going to land disposal went to highly regulated land disposal units in 2015, in past years, the TRI data show 1,4-dioxane going to other types of land disposal as well. From 1989 to 2002 the data show thousands of pounds of 1,4-dioxane disposed of via on-site land treatment. From 2009 to 2011, hundreds of pounds were disposed of in on-site landfills other than RCRA Subtitle C Landfills. There was also off-site disposal, with thousands of pounds disposed of off-site in landfills other than RCRA Subtitle C from 2002 to 2005. The volumes then decreased from hundreds, to tens, to almost no pounds disposed of off-site in landfills other than RCRA Subtitle C from 2006 to 2015. While the volume of production-related waste managed shown in Table 2-6 excludes any quantities reported as catastrophic or one-time releases (TRI section 8 data), release quantities shown in Table 2-7 includes both production-related and non-routine quantities (TRI section 5 and 6 data). As a result, release quantities may differ slightly and may reflect differences in TRI calculation methods for reported release range estimates (U.S. EPA. 2017d). EPA's Compilation of Air Pollutant Emission Factors, AP-42 section 6.13 on pharmaceuticals production provides general process and emissions information and the ultimate disposition of 1,4- dioxane (air, sewer, incineration, solid waste, product) by pharmaceutical manufacturers. Other sources of information provide evidence of releases of 1,4-dioxane, including National Emission Standards for Hazardous Air Pollutants (NESHAPs) promulgated under the Clean Air Act (CAA) or other EPA standards and regulations that set legal limits on the amount of 1,4-dioxane that can be emitted to a particular media. Page 27 of 90 ------- 2.3.3 Presence in the Environment and Biota Monitoring studies or a collection of relevant and reliable monitoring studies provide(s) information that can be used in an exposure assessment. Monitoring studies that measure environmental concentrations or concentrations of chemical substances in biota provide evidence of exposure. Monitoring data were identified in EPA's data search for 1,4-dioxane. Monitoring data (measured) from EPA's Air Quality System (AQS) and the open literature, as well as modeled estimates based on the National Air Toxics Assessment (NATA) and TRI emissions data suggest that 1,4-dioxane is present in ambient air. Monitored and modeled air concentrations from these sources suggest that many air concentrations may be low (i.e., <1 |ig/m3) and appear to have been higher in the past, possibly reflecting past uses Q H' \ 2015a. JO I Ui). Recent (2015) air monitoring data). Recent (2015) air monitoring data were extracted from the Ambient Monitoring Archive (AMA). Of a total of 1397 collected samples, there were 948 non-detects (68%) and 449 detections (32%), which ranged from 0.005 to 0.96 ppb. All non-detects and detections for this chemical were sampled in four states: MI, OH, NC, and IN. Indoor air monitoring data are available. One recent study reported annual average concentrations of 1,4-dioxane ranging from 0.01 to 0.1 1 [j,g/m3 in several hundred homes in Germany (Wissenbach et at. 2016). Older indoor air monitoring studies are summarized in the U.S. EPA Voluntary Children's Chemical Evaluation Program (VCCEP) submission and report slightly higher concentrations, possibly reflecting past uses (Sapphire Group. 2007). EPA's third Unregulated Contaminant Monitoring Rule (UCMR 3), published in 2012, required monitoring for 1,4-dioxane, along with 29 other contaminants. Over 28,000 drinking water samples were collected for chemicals suspected to be present in drinking water that lack health-based standards under the Safe Drinking Water Act. Reported levels of 1,4-dioxane in groundwater range from 3 to 31,000 |ig/L (ATSDR. 2012; LISGS. 2002). Such instances of ground water contamination with 1,4-dioxane are documented in the states of California and Michigan. These data provide a basis for including groundwater in the scope of the l,4dioxane risk evaluation from manufacturing, processing, distribution and use unless otherwise regulated or managed. There are relatively fewer data available on 1,4-dioxane levels in surface water, though some studies of groundwater contamination also reported levels in nearby surface water. 1,4-Dioxane is released into surface water and some studies have examined 1,4-dioxane levels in sewage treatment or chemical plant effluent, combined collection treatments from apartment homes, and in river basin systems (ATSDR. 2012). 1,4-Dioxane has also been detected in landfill leachate (ATSDR. 2012). 1,4-Dioxane has not been measured and is unlikely to be present at elevated levels in sediment, sludge, soil or dust, based on its physical and chemical properties. Note, 1,4 dioxane is expected to be present in the water within the biosolids and the porewater within the soil. 1,4-Dioxane has a low bioaccumulation potential for accumulation in aquatic organisms and is short-lived in humans and few biomonitoring data are available. 2.3.4 Environmental Exposures The manufacturing, processing, use and disposal of 1,4-dioxane can result in releases to the environment. In this section, EPA presents exposures to aquatic and terrestrial organisms. Page 28 of 90 ------- Aquatic Environmental Exposures EPA identified and reviewed national scale monitoring data to support this problem formulation. Based on national-scale monitoring data from EPA's STOrage and RETreival (STORET) and National Water Information System (NWIS) for the past ten years, 1,4-dioxoane is detected in surface water. The data points showed a detection rate of approximately 6% for this media, with detections ranging from 0.568 to 100 |ig/L. While recent monitoring data on ambient surface water levels indicate relatively low levels, EPA has used release estimates and measured effluent concentrations from EPA's Toxic Release Inventory (TRI) and Discharge Monitoring Report (DMR) Pollutant Loading Tool, respectively, to predict surface water concentrations near such discharging facilities for this problem formulation. To examine whether near- facility surface water concentrations could approach 1,4-dioxane's concentrations of concern, EPA employed a conservative approach, using readily-available modeling tools and data, as well as conservative assumptions. EPA's Exposure and Fate Assessment Screening Tool (U.S. EPA. 2.014b) was used to estimate site-specific surface water concentrations based on estimated loadings of 1,4- Dioxane into receiving water bodies or reported on-site releases to surface waters for DMR and TRI facilities. The estimated loadings for the DMR facilities are calculated by the DMR Tool by combining the reported effluent concentrations with facility effluent flows. For TRI, the reported releases are based on monitoring, emission factors, mass balance and/or other engineering calculations. E-FAST 2014 incorporates stream dilution using stream flow information contained within the model. E-FAST also incorporates wastewater treatment removal efficiencies. Wastewater treatment removal is assumed to be 0% for this exercise, as reported loadings/releases are assumed to account for any treatment. To ensure this effort was likely to capture high-end surface water concentrations, loading data from the top ten dischargers from each data source were modeled for the last two years of complete datasets (2014-2015 for TRI sites and 2015-2016 for DMR facilities). Furthermore, as days of release and operation are not reported in these sources, EPA assumed a range of possible release days (i.e., 1, 20, and 250 days/year for facilities and 250 days/year for wastewater treatment plants or POTWs). Refer to the E-FAST 2014 Documentation Manual for equations used in the model to estimate surface water concentrations (U.S. EPA. 2007). Based on availability of site-specific flow data within E-FAST 2014 and scenario results, refinements were made to clarify or confirm the receiving water body and/or likely days of release. High-end surface water concentrations (i.e., those obtained assuming low receiving water body stream flows) from all E-FAST 2014 runs ranged from 0.006 |ig/L to 11,500 |ig/L, with the minimum of 0.006 |ig/L associated with a chronic release scenario (i.e., more than 20 days of release per year assumed) and the maximum of 11,500 |ig/L associated with an acute release scenario (i.e., fewer than 20 days of release per year assumed). The maximum acute scenario high-end concentration was 11,500 |ig/L and the maximum chronic scenario high-end concentration was 5,762 |ig/. Results based on TRI release estimates were within the same range as those based on DMR annual loading values for the top ten dischargers and the reporting years covered. For a full table of results, see Appendix E. Terrestrial Environmental Exposures Based on its fate properties, 1,4-dioxane is not expected to reside in soil because it will either volatilize from dry surfaces and dry soil or move through the soil column with pore water. Page 29 of 90 ------- 2.3.5 Human Exposures In this section, EPA presents occupational and general population exposures. Subpopulations, including potentially exposed and susceptible subpopulations, within these exposure categories are also presented. 2.3.5.1 Occupational Exposures Exposure pathways and exposure routes are listed below for worker activities under the various conditions of use described in Section 2.2. In addition, exposures to occupational non-users who do not directly handle the chemical but perform work in an area where the chemical is present are listed. Engineering controls and/or personal protective equipment may impact the occupational exposure levels. Workers and occupational non-users may be exposed to 1,4-dioxane when performing activities associated with the conditions of use described in Section 2.2, including, but not limited to: • Unloading and transferring 1,4-dioxane to and from storage containers to process vessels. • Using 1,4-dioxane in process equipment. • Cleaning and maintaining equipment. • Sampling chemical, formulations or products containing 1,4-dioxane for quality control. • Repackaging chemicals, formulations or products containing 1,4-dioxane. • Handling, transporting and disposing waste containing 1,4-dioxane. • Performing other work activities in or near areas where 1,4-dioxane is used. Key Data Key data that inform occupational exposure assessment include: the OSHA Chemical Exposure Health Data (CEHD) and NIOSH Health Hazard Evaluation (HHE) program data. OSHA data are workplace monitoring data from OSHA inspections. The inspections can be random or targeted, or can be the result of a worker complaint. OSHA data can be obtained through the OSHA Integrated Management Information System (IMIS) at https://www.osha.gov/oshstats/index.html. Table Apx B-l in Appendix B.1.3 provides a summary of industry sectors with 1,4-dioxane personal monitoring air samples obtained from OSHA inspections conducted between 2002 and 2016. NIOSH HHEs are conducted at the request of employees, union officials, or employers and help inform potential hazards at the workplace. HHEs can be downloaded at https://www.cdc. gov/niosh/hhe/. Inhalation Based on these activities, inhalation exposure to vapors and mists are expected for workers and occupational non-users. There is potential for spray application of some products containing 1,4-dioxane so exposures to mists are also expected for workers and will be incorporated into the worker inhalation exposure. See section 2.5.1 for additional details on the pathways EPA expects to analyze for occupational exposures. The United States has several regulatory and non-regulatory exposure limits for 1,4-dioxane: An Occupational Safety and Health Administration (OSHA) Permissible Exposure Limit (PEL) of 100 ppm 8-hour time-weighted average (TWA) (360 mg/m3) with a skin notation, a National Institute of Occupational Safety and Health (NIOSH) Recommended Exposure Limit (REL) of 1 ppm (3.6 mg/m3) as a 30-minute ceiling and an American Conference of Government Industrial Hygienists (ACGIH) Threshold Limit Value (TLV) of 20 ppm TWA (72 mg/m3) (OSHA. 2005). The influence of these exposure limits on occupation exposures will be considered in the occupational exposure assessment. Dermal Page 30 of 90 ------- Based on the conditions of use, EPA expects dermal exposure for workers and occupational non-users, including skin contact with vapors, liquids and mists. Occupational non-users do not handle the chemical directly, so dermal exposure from liquids containing 1,4-dioxane are not expected. Oral Worker exposure via the oral route is not expected. For some uses (described in Section 2.5.1), there are potential worker exposures through mists that deposit in the upper respiratory tract. Based on physical chemical properties, mists of 1,4-dioxane will likely be rapidly absorbed in the respiratory tract and will be considered as an inhalation exposure. 2.3.5.2 Consumer Exposures As stated in the Scope document (U.S. EPA. 2017c) and Section 2.2.2.1, there are no current consumer uses for 1,4-dioxane in the U.S. 2.3.5.3 General Population Exposures Wastewater/liquid wastes, solid wastes or air emissions of 1,4-dioxane could result in potential pathways for oral, dermal or inhalation exposure to the general population. Inhalation The general population may be exposed to 1,4-dioxane through inhalation of ambient air and indoor air. Ambient air exposures may occur from releases from industrial/commercial sources. Indoor air exposures may occur from infiltration from ambient air or emissions from tap water during activities such as showering and bathing. Based on the relatively high water solubility and relatively low Henry's law constant for 1,4-dioxane, EPA expects that volatilization would be low for many indoor uses. However, increased water temperature during bathing and showering can increase volatilization. The Henry's Law constant for 1,4-dioxane is appreciably higher at 40°C (4.9 x 10"4 atm-m3/mole) than 25°C (4.8 x 10"6 atm-m3/mole). Furthermore, smaller droplets of water created by some indoor uses (e.g., showering) have a larger surface area from which 1,4-dioxane may volatize. Vapor intrusion and volatilization from wastewater treatment are not considered significant sources of exposure to the general population because the Henry's Law constant (4.8 x 10"6 atm-m3/mole) and high water solubility of 1,4-dioxane (>800 g/L) indicate that 1,4-dioxane will primarily remain in the aqueous phase (wastewater or groundwater) and that volatilization from water to air will be limited. Estimated volatilization from the sewage treatment plant (STP) module in EPI Suite™ found that 0.27% of 1,4- dioxane in wastewater would be removed by volatilization during wastewater treatment. Oral The general population may ingest 1,4-dioxane via contaminated drinking water. Based on reported uses, down-the-drain sources may contribute to surface water and drinking water levels. Therefore, there is potential oral exposure to 1,4-dioxane by ingestion of drinking water from surface water and ground water sources to municipal drinking water. Dermal Dermal exposure via water may occur through extended contact with tap water containing 1,4-dioxane during washing and bathing. The source of the contaminated water may be either contaminated surface or ground waters used as a source of municipal drinking water. Page 31 of 90 ------- 2.3.5.4 Potentially Exposed or Susceptible Subpopulations TSCA requires that the determination of whether a chemical substance presents an unreasonable risk to "a potentially exposed or susceptible subpopulation identified as relevant to the risk evaluation" by EPA. 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 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." General population is "the total of individuals inhabiting an area or making up a whole group" and refers here to the U.S. general population ( ). As part of the Problem Formulation, EPA identified potentially exposed and susceptible subpopulations for further analysis during the development and refinement of the life cycle, conceptual models, exposure scenarios and analysis plan. In this section, EPA addresses the potentially exposed or susceptible subpopulations identified as relevant based on greater exposure. EPA will address the subpopulations identified as relevant based on greater susceptibility in the hazard section. EPA identifies the following as potentially exposed or susceptible subpopulations due to their greater exposure: • Workers and occupational non-users. • Other groups of individuals within the general population who may experience greater exposures due to their proximity to conditions of use identified in Section 2.2 that result in releases to the environment and subsequent exposures (e.g., individuals who live or work near manufacturing, processing, distribution, use or disposal sites). In developing exposure scenarios, EPA will analyze available data to ascertain whether some human receptor groups may be exposed via exposure pathways that may be distinct to a particular subpopulation or lifestage and whether some human receptor groups may have higher exposure via identified pathways of exposure due to unique characteristics (e.g., activities, duration or location of exposure) when compared with the general population (U.S. EPA. 2006). In summary, in the risk evaluation for 1,4-dioxane, EPA plans to analyze the following potentially exposed groups of human receptors: workers, occupational non-users and the general population. EPA may also identify additional potentially exposed or susceptible subpopulations that will be considered based on greater exposure. 2.4 Hazards (Effects) For scoping, EPA conducted comprehensive searches for data on hazards of 1,4-dioxane, as described in Strategy for Conducting Literature Searches for 1,4-Dioxane: Supplemental File for the TSCA Scope Document (If IP -I iQ-OPPT -2016-0723). Based on initial screening, EPA plans to analyze the hazards of 1,4-dioxane identified in this problem formulation document. However, when conducting the risk evaluation, the relevance of each hazard within the context of a specific exposure scenario will be judged for appropriateness. For example, hazards that occur only as a result of chronic exposures may not be applicable for acute exposure scenarios. This means that it is unlikely that every identified hazard will be analyzed for every exposure scenario. 2.4.1 Environmental Hazards During problem formulation, EPA analyzed potential environmental health hazards associated with 1,4- dioxane. EPA identified the following sources of environmental hazard data for 1,4-dioxane: (Health Page 32 of 90 ------- Canada. 2010; ECJRC. 2002; OECD. 1999; NICNAS. 1998); and the European Chemicals Agency (ECHA) Database. Studies published since 2003 were identified in the literature search for 1,4-dioxane (1,4-Dioxane (CASRN123-91-1) Bibliography: Supplemental File for the TSCA Scope Document, EPA- HQ-QPPT-2016-0723) and were reviewed as described in Application of Systematic Review in TSCA Risk Evaluations (U.S. EPA. 2018a) and Strategy for Assessing Data Quality in TSCA Risk Evaluations (U.S. EPA. 2018b). Only the on-topic references listed in the Ecological Hazard Literature Search Results were considered as potentially relevant data/information sources for the risk evaluation. Inclusion criteria were used to screen the results of the ECOTOX literature search (as explained in the Strategy for Conducting Literature Searches for 1-4-Dioxane: Supplemental Document to the TSCA Scope Document, CASRN: 123-91-1). Data from the screened literature are summarized below (Table 2-8) as ranges (min-max). EPA plans to complete review of these 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 (U.S. EPA. 2018a). Toxicity to Aquatic Organisms EPA identified 1,4-dioxane environmental hazard data for fish, aquatic invertebrates and aquatic plants exposed under acute and chronic exposure conditions. Aquatic toxicity studies are summarized in Table 2-8. Table 2-J i. Ecological Hazard Characterization of 1,4-Dioxane Duration Test organism Endpoint Hazard valuc(s) Units Effect(s) Citation(s) Aquatic Organisms Acute Fish LCso >100- 67,000 mg/L Mortality (Geieer et al.. 1990) Aquatic invertebrates ECso >299 - >1,000 mg/L Immobilization (Dow Chemical Comoanv. 1989) as cited in (ECJRC. 2002) Algae ECso 575 - 5600 mg/L Inhibition (Brineman and Kulin. 1977) 580 mg/L Biomass (ECHA. 2014b) >1,000 mg/L Biomass (ECHA. 2014b) Acute COC = 60 mg/L Chronic Fish NOECb 565 mg/L Carcinogenicity (Johnson et al.. 1993) MATC° >145 Development, Hatching, Survival (TSCATS. 1989) as cited in (ECJRC. 2002) Aquatic invertebrates NOEC 1,000 mg/L Reproduction (ECHA. 2014a) Chronic COC = 15 mg/L Terrestrial Organisms Chronic Terrestrial Plant ECso 1,450 mg/L Germination/Root Elongation (Reynolds. 1989) aValues in the tables are presented as reported by the study authors. bNOEC: No Observable Effect Concentration, °MATC, Maximum Acceptable Toxicant Concentration; Calculated using the geometric mean of LOEC and NOEC values (as described in (U.S. EPA. 2013a) Page 33 of 90 ------- The acute 96-hour LCso values for fish range from >100 mg/L (highest concentration tested) for fathead minnow {Pimephalespromelas) to 67,000 mg/L for inland silversides (Menidia beryllina). Two studies on the acute ecotoxicity to aquatic invertebrates (Daphnia magna and Ceridodaphnia dubia) indicate that the 48-hour EC.mi is >1,000 mg/L (highest concentration tested) (ECJRC. 2002) and >299 mg/L (highest concentration tested; (Dow Chemical Company. 1989)). In a chronic study, Medaka (Oryzias latipes) were exposed to measured concentrations of 1,4-dioxane ranging from 565 to 6,933 mg/L for 28 days under flow-through conditions. There were effects on growth and survival (Johnson etai. 1993). A no observed effect concentration (NOEC) 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 27.6, 40.3, 65.3, 99.7 and 145 mg/L to observe the effects on embroyonic development (i.e., hatching, larval development, and larval survival) under flow-through conditions. No effects were observed. A NOEC of >103 mg/L based on larval survival and a maximum acceptable toxicant concentration (MATC) of 145 mg/L was calculated (NOEC=M ATC/V2) (ECJRC. 2002). In a study on the chronic toxicity of 1,4-dioxane to aquatic invertebrates, water fleas (D. magna) were exposed to unspecified concentrations of 1,4-dioxane in a 21-day reproduction test. The exposure conditions were not reported. The highest exposure concentration tested was 1,000 mg/L. No effects on reproduction, survival, or growth were reported. A 21 -day NOEC of > 1,000 mg/L was reported (ECH.A. 2014a). Three studies have characterized the toxicity of 1,4-dioxane to aquatic plants. In one study, green algae (Pseudokirchnerella subcapitata) were exposed to unspecified concentrations of 1,4-dioxane for 72- hours under static conditions. No effects were observed on growth rate or biomass at 1,000 mg/L, the highest concentration tested. A 72-hour EC so (growth rate and biomass) of > 1,000 mg/L was reported. A NOEC (biomass) of 580 mg/L and a NOEC (growth rate) of 1,000 mg/L was reported (ECHA. 2014b). Also, two short-term toxicity studies in Microcystis aeruginosa and Scenedesmus quadricauda reported EC so cell inhibition of 575 and 5,600 mg/L after eight days of exposure to 1,4-dioxane (Bringman and Kuhn. 1977). Toxicity to Sediment and Terrestrial Organisms In one study, lettuce (Actuca sativa) were exposed to 1,4-dioxane in a germination/root elongation toxicity test for 3-days. An EC50 of 1,450 mg/L was reported for germination (Reynolds. 1989). There are no available acute or chronic toxicity studies that characterize the hazard of 1,4-dioxane to sediment organisms. However, available hazard, fate and exposure characteristics (Sections 2.3.1 and 2.3.3) suggest that sediment organisms are not at risk from 1,4-dioxane exposures. Concentrations of Concern (COC) The concentrations of concern (COCs) for aquatic species were calculated based on the summarized environmental hazard data for 1,4-dioxane. The analysis of the environmental COCs are described in Appendix C and are based on EPA/OPPT methods (U.S. EPA. 2013a. 2012d). The acute and chronic COC for 1,4-dioxane are based on the lowest toxicity value in the dataset. For a particular environment (e.g., aquatic environment), the COC is based on the most sensitive species or the species with the lowest toxicity value reported in that environment. Page 34 of 90 ------- The acute concentration of concern for 1,4-dioxane is based on a 96-hour fish toxicity study where the LC.mi is >100 mg/L (ECH.A. 2.014a; Geigeretal.. 1990) and the chronic COC is based on a 32-day MATC fish toxicity value of 145 mg/L (Brooke. 1987). The acute and chronic COCs for 1,4-dioxane are 59,800 ppb and 14,500 ppb, respectively. 2.4,2 Human Health Hazards 1,4-Dioxane has an existing EPA IRIS Assessment ( ), an ATSDR Toxicological Profile (ATSDR. 2012), a Canadian Screening Assessment (Health Canada. 2010). a European Union (EU) Risk Assessment Report (ECJRC. 2002) and an Interim AEGL (U.S. EPA. 2005b); hence, many of the hazards of 1,4-dioxane have been previously compiled and reviewed. EPA expects to use these previous analyses as a starting point for identifying key and supporting studies to inform the human health hazard assessment, including dose-response analysis. The relevant studies will be evaluated using the data quality criteria in the Application of Systematic Review in TSCA Risk Evaluations (U.S. EPA. 2.018a). EPA also plans to analyze other studies (e.g., more recently published, alternative test data) that have been published since these reviews, as identified in the literature search conducted by the Agency for 1,4-dioxane (1,4-Dioxane (CASRN123-91-1) Bibliography: Supplemental File for the TSCA Scope Document, EPA-HQ-QPPT-2016-0723). Based on reasonably available information, the following sections describe the potential hazards associated with 1,4-dioxane. 2.4.2.1 Non-Cancer Hazards Acute Toxicity Effects following acute exposures were evaluated (U.S. EPA. 2005b). The Interim AEGLs ( 2005b) evaluated the data on acute toxicity and irritation and concluded that, in animals, acute toxic effects of 1,4-dioxane include central nervous system depression, kidney and liver damage and irritation. Humans acutely exposed to 1,4-dioxane experienced irritation of the eyes, nose and throat, nausea and vomiting, coma and death. Also, 1,4-dioxane can cause narcosis in animals inhaling very high concentrations (U.S. EPA. 2005b). Irritation Acute inhalation studies in human volunteers noted irritation of the eyes, nose and throat (U.S. EPA. 2005b). In rats, 2 years of inhalation exposure to 1,4-dioxane, resulted in metaplasia, hyperplasia, atrophy, hydropic change, vacuolic change and preneoplastic cell proliferation in the nasal cavity (U.S. EPA. 2013c). Liver Toxicity In subchronic and chronic repeated exposure studies conducted in rats and mice by the oral (via drinking water) and inhalation routes, evidence shows that 1,4-dioxane is toxic to the liver ( 013c). Chronic administration of 1,4-dioxane via the drinking water resulted in hepatocellular degeneration and preneoplastic changes. Inhalation exposure to 1,4-dioxane resulted in necrosis of the centrilobular region and preneoplastic changes in the liver. Kidney Toxicity In subchronic and chronic repeated exposure studies conducted in rats and mice by the oral (via drinking water) and inhalation routes, evidence shows that 1,4-dioxane is toxic to the kidney (U.S. EPA. 2013c). Kidney damage following drinking water exposure to 1,4-dioxane includes degeneration of cortical tubule cells, necrosis with hemorrhage and glomerulonephritis. Page 35 of 90 ------- 2.4.2.2 Genotoxicity and Cancer Hazards ;013c) concluded that overall, the available literature indicates that 1,4-dioxane is nongenotoxic or weakly genotoxic. Per EPA's Cancer Guidelines ( 05a). EPA concluded "there is insufficient biological support for potential key events and to have reasonable confidence in the sequence of events and how they relate to the development of nasal tumors following exposure to 1,4- dioxane". No single mode of action (MO A) accounts for the formation of liver, nasal, peritoneal (mesotheliomas), and mammary gland tumors seen in laboratory animals exposed to 1,4-dioxane. Some data support a non-linear MOA for liver tumorigenesis, but currently available data do not support non- linearity for the remaining tumor types. EPA evaluated the weight of the evidence for cancer in humans and animals and concluded that 1,4-dioxane is "likely to be carcinogenic to humans" based on evidence of carcinogenicity in several 2-year bioassays (oral and inhalation) conducted in four strains of rats, two strains of mice and in guinea pigs (U.S. EPA. 2013c). The National Toxicology Program classified 1,4-dioxane as "reasonably anticipated to be a human carcinogen" (NTP. 2016). and NIOSH has classified it as a "potential occupational carcinogen" (ATSDR. 2012). Human occupational studies into 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. 2.4.2.3 Potentially Exposed or Susceptible Subpopulations TSCA requires that the determination of whether a chemical substance presents an unreasonable risk include consideration of unreasonable risk to "a potentially exposed or susceptible subpopulation identified as relevant to the risk evaluation" by EPA. 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 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 hazard assessment, EPA will analyze available data to ascertain whether some human receptor groups may have greater susceptibility than the general population to the chemical's hazard(s). 2.5 Conceptual Models EPA risk assessment guidance (( , ?)), defines Problem Formulation as the part of the risk assessment framework that identifies the factors to be considered in the assessment. It draws from the regulatory, decision-making and policy context of the assessment and informs the assessment's technical approach. A conceptual model describes the actual or predicted relationships between the chemical substance and receptors, either human or environmental. These conceptual models are integrated depictions of the conditions of use, exposures (pathways and routes), hazards and receptors. The initial conceptual models describing the scope of the assessment for 1,4-dioxane, have been refined during problem formulation. The changes to the conceptual models in this problem formulation are described along with the rationales. In this section EPA outlines those pathways that will be included and further analyzed in the risk evaluation; will be included but will not be further analyzed in risk evaluation; and will not be included in the TSCA risk evaluation and the underlying rationale for these decisions. Page 36 of 90 ------- EPA determined as part of problem formulation that it is not necessary to conduct further analysis on certain exposure pathways that were identified in the 1,4-dioxane scope document and that remain in the risk evaluation. Each risk evaluation will be "fit-for-purpose," meaning not all conditions of use will warrant the same level of evaluation and the Agency may be able to reach some conclusions without comprehensive risk evaluations. 82 FR 33726, 33734, 33739 (July 20, 2017). As part of this problem formulation, EPA also identified t exposure pathways under other environmental statutes, administered by EPA, which adequately assess and effectively manage exposures and for which long-standing regulatory and analytical processes already exist, i.e., the Clean Air Act (CAA), the Safe Drinking Water Act (SDWA), the Clean Water Act (CWA) and the Resource Conservation and Recovery Act (RCRA). OPPT worked closely with the offices within EPA that administer and implement the regulatory programs under these statutes. In some cases, EPA has determined that chemicals present in various media pathways (i.e., air, water, land) fall under the jurisdiction of existing regulatory programs and associated analytical processes carried out under other EPA-administered statutes and have been assessed and effectively managed under those programs. EPA believes that the TSCA risk evaluation should focus on those exposure pathways associated with TSCA uses that are not subject to the regulatory regimes discuss above because these pathways are likely to represent the greatest areas of concern to EPA. As a result, EPA does not plan to include in the risk evaluation certain exposure pathways identified in the 1,4-dioxane scope document. 2.5.1 Conceptual Model for Industrial and Commercial Activities and Uses: Potential Exposures and Hazards The revised conceptual model (Figure 2-2) describes the pathways of exposure from industrial and commercial activities and uses of 1,4-dioxane that EPA plans to include in the risk evaluation. There are exposures to workers and occupational non-users via dermal and inhalation routes during manufacturing, processing, use and disposal of 1,4-dioxane for all uses identified in the scope, except for distribution in commerce. During distribution, 1,4-dioxane is contained in closed systems (e.g. drums, pails, bottles) so releases and exposures are not expected. Any associated open system loading and unloading activities into these containers will be analyzed for the condition of use. The description for uses of 1,4-dioxane as Functional Fluids has been refined to include both open and closed systems. When the scope of the risk evaluation was determined, the information available to EPA suggested that 1,4-dioxane was used as Functional Fluids only in closed systems. However, during problem formulation, EPA determined that some of the subcategories of uses, such as cutting and tapping fluid, may also include uses in open systems. This change is reflected in the conceptual model ( Figure 2-2). Inhalation EPA expects that for workers and occupational non-users, exposure via inhalation will be the most significant route of exposure for most exposure scenarios. EPA plans to further analyze inhalation exposures to vapors and mists for workers and occupational non-users in the risk evaluation. EPA reviewed the potential for occupational exposures associated with subcategories of conditions of use where a mist may be generated. EPA determined that most subcategories will not produce a mist during their typical use and, for these, EPA concludes that exposure to 1,4-dioxane would be negligible and does not plan further analysis. For subcategories of uses where either a spray application or rotary equipment is likely, EPA determined that these conditions of use may produce a mist that could result in exposures for workers when the mist is inhaled and subsequently swallowed and EPA plans to analyze Page 37 of 90 ------- exposures associated with these uses. EPA will also evaluate subcategories of uses where EPA is uncertain whether a mist is likely to be produced during use. EPA expects to further evaluate exposure via a mist for the uses listed in Table 2-9. Table 2-9.1,4-Dioxane Conditions of Use that May Produce a Mist Life Cycle S(a«e Category Subcategory Processing Recycling Recycling Industrial use Processing aids, not otherwise listed Wood pulping Extraction of animal and vegetable oils Wetting and dispersing agent in textile processing Etching of fluoropolymers Industrial use Functional fluids (open and closed system) Polyalkylene glycol lubricant Synthetic metalworking fluid Cutting and tapping fluid Hydraulic fluid Industrial use, potential commercial use Other uses Spray polyurethane foam Printing and printing compositions Dermal There is the potential for dermal exposures to 1,4-dioxane in many worker scenarios. Dermal exposure from contact with liquids containing 1,4-dioxane are expected primarily for workers, such as operators, directly involved in working with these liquids. Where workers may be exposed to 1,4-dioxane, the OSHA standard requires that workers are protected from contact (e.g. gloves) (29 CFR 1910.1052). Occupational non-users are not directly handling 1,4-dioxane; therefore, skin contact with liquid 1,4- dioxane is not expected for occupational non-users and will not be further analyzed in the risk evaluation. EPA plans to further analyze dermal exposures for skin contact with liquids in occluded situations for workers. Workers and occupational non-users can have skin contact with 1,4-dioxane vapor concurrently with inhalation exposures. The parameters determining the absorption of 1,4-dioxane vapor are based on the concentration of the vapor, the duration of exposure and absorption. The concentration of the vapor and the duration of exposure are the same for concurrent dermal and inhalation exposures. Therefore, the differences between dermal and inhalation exposures depend on the absorption. The dermal absorption can be estimated from the skin permeation coefficient (0.00043 cm/hr from a water solution; (Bronaugh. 1982)) and exposed skin surface area (on the order of 0.2 nr, (U.S. EPA. 201 la)). The absorption of inhaled vapors can be estimated from the volumetric inhalation rate (approximately 1.25 m3/hr for a person performing light activity, (U.S. EPA. JO LI 3)) adjusted by a retention factor such as 0.75. Based on these parameters the absorption of 1,4-dioxane vapor via skin will be orders of magnitude lower than via inhalation and will not be further analyzed. Oral There are potential worker exposures through mists that deposit in the upper respiratory tract. Based on physical chemical properties, mists of 1,4-dioxane will likely be rapidly absorbed in the respiratory tract Page 38 of 90 ------- or evaporate and contribute to the amount of 1,4-dioxane vapor in the air. Furthermore, if 1,4-dioxane mists were ingested orally the available toxicological data do not suggest significantly different toxicity from considering the mists as an inhalation exposure. Waste Handling, Treatment and Disposal Figure 2-2 shows that waste handling, treatment and disposal is expected to lead to the same pathways as other industrial and commercial activities and uses. The path leading from the "Waste Handling, Treatment and Disposal" box to the "Hazards Potentially Associated with Acute and/or Chronic Exposures See Section 2.4.2" box was re-routed to accurately reflect the expected exposure pathways, routes, and receptors associated with these conditions of use of 1,4-dioxane. For each condition of use identified in Table 2-3, a determination was made as to whether each unique combination of exposure pathway, route, and receptor will be evaluated further in the risk evaluation. The results of that analysis along with the supporting rationale are presented in Appendix D and Appendix E. Page 39 of 90 ------- INDUSTRIAL AND COMMERCIAL EXPOSURE PATHWAY EXPOSURE ROUTE RECEPTORSd HAZARDS ACTIVITES / USES a Manufacture (Including Import) Hazards Potentially Associated with Acute and/or Chronic Exposures See Section 2.4.2 Liquid Contact Dermal Workerse Processing: • Processing as a reactant/intermediate • Repackaging • Non-incorporative activities Occupational Non-Users Vapor/ Mist Inhalationc Fugitive Emissionsb Recycling Processing Aids, Not Otherwise Listed Functional Fluids (Open and Closed Systems) Laboratory Chemicals Other Industrial or Commercial Uses Waste Handling, Treatment and Disposal KEY: ^ Pathway that will be further analyzed —^ Pathway that will not be further analyzed Black txt: In scope; will be further analyzed Wastewater, Liquid Wastes, Solid Wastes (See Figure 2-3) Figure 2-2.1,4-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 plans to analyze. a Additional uses of 1,4-dioxane are included in Table 2-3. 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 may be considered an inhalation exposure. d Receptors include potentially exposed or susceptible subpopulations. e When data and information are available to support the analysis, EPA also considers the effect that engineering controls and/or personnel protective equipment have on occupational exposure levels. Page 40 of 90 ------- 2.5.2 Conceptual Model for Consumer Activities and Uses: Potential Exposures and Hazards The 1,4-dioxane life cycle diagram (Figure 2-1) indicates that no uses of 1,4-dioxane were identified in consumer products. EPA did not receive data, information or comments that informed a change was necessary to the scope. Therefore, EPA does not plan to evaluate use of 1,4-dioxane in consumer products and there is no conceptual model provided for consumer activities and uses. 2.5.3 Conceptual Model for Environmental Releases and Wastes: Potential Exposures and Hazards The revised conceptual model (Figure 2-2) illustrates the expected exposure pathways to human and ecological receptors from environmental releases and waste stream associated with industrial and commercial activities for 1,4-dioxane. The pathways that EPA plans to include but not analyze further in risk evaluation are described in Section 2.5.3.2 and shown in the conceptual model. The pathways that EPA does not plan to include in the risk evaluation are described in Section 2.5.3.2. 2.5.3.1 Pathways That EPA Plans to Include and Further Analyze in the Risk Evaluation There are no environmental release and waste pathways for the environment or general populations that EPA plans to include and further analyze in the risk evaluation (see Figure 2-3). 2.5.3.2 Pathways that EPA Plans to Include in the Risk Evaluation But Not Further Analyze The pathways that EPA plans to include in the risk evaluation but not further analyze are ambient water exposure to aquatic vertebrates, invertebrates and aquatic plants, sediment and land-applied biosolids. Aquatic Pathways EPA analyzed risks to aquatic organisms exposed to 1,4-dioxane in surface water based on the relatively high potential for release, fate properties, and the availability of environmental monitoring data and hazard data. Based on 2015 TRI reporting, an estimated 35,402 lb of 1,4-dioxane was released to water from industrial sources. 1,4-Dioxane has high water solubility and slow removal from surface water due lack of hydrolysis (no hydrolyzable groups) and slow biodegradation (< 10% degradation in 29 days). Monitored concentrations in surface water from STORET/NWIS are as high as 100 |ig/L and predicted concentrations in surface water for acute and chronic scenarios are up to 11,500 |ig/L and 5,762 |ig/L, respectively (Section 2.3.4). Measured and estimated levels of 1,4-dioxane in the environment are sufficiently below the acute and chronic aquatic COCs of 20,000 |ig/L and 14,500 |ig/L (See Environmental Hazards, Section 2.4.1 and Analysis of the Environmental Concentrations of Concern, Appendix C). EPA is including the analysis of risks to aquatic invertebrates and aquatic plants from exposures to 1,4-dioxane in surface waters in the evaluation, but will not further analyze the data. Sediment Pathways EPA does not plan to further analyze 1,4-dioxane pathways to sediment. 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 (ECHA, 1996)], 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 Page 41 of 90 ------- pore water and not 1,4-dioxane that was sorbed to the sediment solids. While no ecotoxicity studies were available for sediment organisms, the toxicity of 1,4-dioxane to sediment invertebrates is expected to be similar to the toxicity to aquatic invertebrates. Land-Applied Biosolids Pathway EPA does not plan to further analyze other releases to land during risk evaluation, including biosolids application to soil. EPA expects releases of 1,4-dioxane to wastewater treatment plants (WWTP), resulting in biosolids that can be land-applied. Species in the environment including aquatic organisms, amphibians and terrestrial organisms may come into contact with 1,4-dioxane-contaminated biosolids and soil pore water when the biosolids are land applied. However, the release of 1,4-dioxane from land- applied biosolids represents a negligible fraction of its overall environmental release, due to its physical- chemical properties. 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. 1996). 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 approximately 2% will be removed via adsorption to sludge or volatilization to air, < 2% will be removed with biosolids-associated water, and > 95% will be present in the effluent (see Section 2.3.1, 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, and therefore exposures of aquatic organisms from surface water due to land-applied biosolids will not be further analyzed. 2.5.3.3 Pathways That EPA Does Not Plan to Include in the Risk Evaluation Exposures to receptors (i.e. general population) may occur from industrial and/or commercial uses; industrial releases to air, water or land; and other conditions of use. As described in section 2.5, pathways under other environmental statutes, administered by EPA, which adequately assess and effectively manage exposures and for which long-standing regulatory and analytical processes already exist will not be included in the risk evaluation. These pathways are described below. Ambient Air Pathway The Clean Air Act (CAA) contains a list of hazardous air pollutants (HAP), including 1,4-dioxane, 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 Page 42 of 90 ------- adequately protect public health and the environment. The CAA thereby provides EPA with comprehensive authority to regulate emissions to ambient air of any HAP. 1,4-Dioxane is a HAP. EPA has issued a number of technology-based standards for source categories that emit 1,4-dioxane to ambient air and, as appropriate, has reviewed, or is in the process of reviewing remaining risks. Because stationary source releases of 1,4-dioxane to ambient air are adequately assessed and any risks effectively managed when under the jurisdiction of the CAA, EPA does not plan to evaluate emission pathways to ambient air from commercial and industrial stationary sources or associated inhalation exposure of the general population or terrestrial species in this TSCA evaluation. Drinking Water Pathway EPA has regular analytical processes to identify and evaluate drinking water contaminants of potential regulatory concern for public water systems under the Safe Drinking Water Act (SDWA). Under SDWA, EPA must also review and revise "as appropriate" existing drinking water regulations every 6 years. The Contaminant Candidate List (CCL) is a list of unregulated contaminants that are known or anticipated to occur in public water systems and that may require regulation. EPA must publish a CCL every 5 years and make Regulatory Determinations (RegDet) to regulate (or not) at least five CCL contaminants every 5 years. To regulate a contaminant EPA must conclude 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. Currently, there is no National Primary Drinking Water regulation for 1,4-Dioxane under SDWA. 1,4- dioxane released to surface water can contribute to levels of the chemical in drinking water. EPA's Office of Water has established a Health Advisory level of 35 |ig/L (which corresponds to a 1 in ten thousand lifetime cancer risk) for 1,4-Dioxane. 1,4-Dioxane is also currently listed on EPA's Fourth Contaminant Candidate List (CCL 4) and was subject to occurrence monitoring in public water systems under the third Unregulated Contaminants Monitoring Rule (UMCR 3). Under UMCR 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. None of the systems measured levels greater than the Health Advisory level, however, 341 systems (6.9%) had results at or above 0.35 |ig/L (which corresponds to a 1 in a million-lifetime cancer risk). In accordance with EPA-OW's process, 1,4- dioxane is currently being evaluated under the fourth Regulatory Determination process under SDWA. Hence, because the drinking water exposure pathway for 1,4-dioxane is being addressed under the regular analytical processes to identify and evaluate drinking water contaminants of potential regulatory concern for public water systems under SDWA, EPA does not plan to include this pathway in the risk evaluation for 1,4-dioxane under TSCA. EPA's Office of Water and Office of Pollution Prevention and Toxics will continue to work together providing understanding and analysis of the SDWA regulatory analytical processes for public water systems and to exchange information related to toxicity and occurrence data on chemicals undergoing risk evaluation under TSCA. Ambient Water Pathways 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 Page 43 of 90 ------- EPA approves as part of 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. EPA has not developed CWA section 304(a) recommended water quality criteria for the protection of aquatic life for 1,4-dioxane, so there are no national recommended criteria for this use available for adoption into state water quality standards and available for use in NPDES permits. Currently, only one state (Colorado) includes human health criteria for 1,4-dioxane in their water quality standards and none include aquatic life criteria for 1,4-dioxane. As a result, this pathway will undergo aquatic life risk evaluation under TSCA (see Section 2.5.3.2). EPA may publish CWA section 304(a) aquatic life criteria for 1,4-dioxane in the future if it is identified as a priority under the CWA. Disposal Pathways 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 RCRA standard in section 3004(a) for the technical (regulatory) criteria that govern the management (treatment, storage, and disposal) of hazardous waste (i.e., Subtitle C) 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 Clean Air Act (CAA) hazardous waste combustion MACT) or injected into UIC Class I hazardous waste wells (subject to joint control under Subtitle C and the Safe Drinking Water Act (SDWA)). Emissions to ambient air from municipal and industrial waste incineration and energy recovery units will not be included in the risk evaluation, as they are regulated under section 129 of the Clean Air Act. CAA section 129 also requires EPA to review and, if necessary, add provisions to ensure the standards adequately protect public health and the environment. Thus, combustion by-products from incineration treatment of 1,4 dioxane wastes (the majority of the 46,000 lbs identified as treated in Table 2-6) would be subject to these regulations, as would 1,4 dioxane burned for energy recovery (1.6 million lbs). EPA does not plan to include on-site releases to land that go to underground injection in its risk evaluation. TRI data ( 1015b) indicate that 94,304 lb of 1,4-dioxane was disposed of on-site to Class I underground injection wells and no releases to underground injection wells of Classes II-VI. Environmental disposal of 1,4-dioxane injected into Class I well types are managed and prevented from further environmental release by RCRA and SDWA regulations. Therefore, disposal of 1,4-dioxane via underground injection is not likely to result in environmental and general population exposures. EPA does not plan to include on-site releases to land that go to RCRA Subtitle C hazardous waste landfills or RCRA Subtitle D municipal solid waste (MSW) landfills in its risk evaluation. TRI data (U.S. EPA. 2015b) indicate that RCRA Subtitle C Landfills received 13,375 lb of 1,4-dioxane, with a small amount of 1,4-dioxane (47 lb) reported to on-site landfills other than RCRA Subtitle C Landfills. Design standards for Subtitle C landfills require double liner, double leachate collection and removal Page 44 of 90 ------- 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 must also meet RCRA waste treatment standards before disposal. Given these controls, general population exposure to 1,4-dioxane in groundwater from Subtitle C landfill leachate is not expected to be a significant pathway. EPA does not plan to include on-site releases to land from RCRA Subtitle C hazardous waste landfills or RCRA Subtitle D municipal solid waste landfills or exposures of the general population (including susceptible populations) or terrestrial species from such releases in the TSCA evaluation. While permitted and managed by the individual states, municipal solid waste (MSW) 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. EPA does not expect to include on-site releases to land from industrial non-hazardous and construction/demolition waste landfills. Industrial non-hazardous and construction/demolition waste landfills are primarily regulated under 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 requirement such as for liners, post-closure and financial assurance, but are not required to do so. Therefore, EPA does not expect to include this pathway in the risk evaluation. Page 45 of 90 ------- RELEASES AND WASTES FROM INDUSTRIAL / COMMERCIAL USES EXPOSURE PATHWAY Direct Discharge Water/ Sediment Indirect Discharge Biosolids POTW Wastewater or Liquid Wastes a Industrial Pre- Treatment or Industrial WWT Land D|sposal I Soil RECEPTORS HAZARDS Aquatic Species Hazards Potentially Associated with Acute and/or Chronic Exposures: See Section 2.4.1 KEY: Gray text: Receptor that will not be further analyzed - -k Pathway that will not be further analyzed Figure 2-3.1,4-Dioxane Conceptual Model for Environmental Releases and Wastes: Potential Exposures and Hazards The conceptual model presents the exposure pathways, exposure routes and hazards to human and environmental receptors from environmental releases and wastes of 1,4-dioxane that EPA plans to analyze. a Industrial wastewater or liquid wastes may be treated on-site and then released to surface water (direct discharge), or pre-treated and released to POTW (indirect discharge). Drinking water will undergo further treatment in drinking water treatment plants. Ground water may also be a source of drinking water. Page 46 of 90 ------- 2.6 Analysis Plan The analysis plan presented in the problem formulation elaborates on the initial analysis plan that was published in the Scope of the Risk Evaluation for 1,4-Dioxane ( 17c). The analysis plan is based on the conditions of use of 1,4-dioxane, as described in Section 2.2 of this problem formulation. EPA is implementing systematic review approaches and/or methods to identify, select, assess, integrate and summarize the findings of studies supporting the TSCA risk evaluation. The analytical approaches and considerations in the analysis plan are used to frame the scope of the systematic review activities for this assessment. The supplemental document, Application of Systematic Review in TSCA Risk Evaluations (U.S. EPA. 2018a), provides additional information about the criteria, approaches and/or methods that have been and will be applied to the first ten chemical risk evaluations. This supplemental document will be published in early 2018. While EPA has conducted a search for reasonably available information as described in the Scope of the Risk Evaluation for 1,4-Dioxane ( ), EPA encourages submission of additional existing data, such as full study reports or workplace monitoring from industry sources, that may be relevant for refining conditions of use, exposures, hazards and potentially exposed or susceptible subpopulations during the risk evaluation. EPA will continue to consider new information submitted by the public until the end of the public comment period in 2018. During the risk evaluation, EPA will rely on the search results [/, 4-Dioxane (CASRN123-91-1) Bibliography: Supplemental File for the TSCA Scope Document., (U.S. EPA. 2017a) 1 or perform supplemental searches to address specific questions. Further, EPA may consider any relevant CBI information in the risk evaluation in a manner that protects the confidentiality of the information from public disclosure. The analysis plan is based on EPA's knowledge of 1,4-dioxane to date which includes partial, but not complete review of identified information. Should additional data or approaches become available, EPA may refine its analysis plan based on this information. 2.6.1 Exposure For 1,4-dioxane, EPA does not plan to further analyze background levels for ambient air, indoor air, groundwater, and drinking water. 2.6.1.1 Environmental Releases, Fate and Exposures EPA does not plan to further analyze environmental releases to environmental media based on information described in Section 2.5. For the purposes of developing estimates of occupational exposure, EPA may use release related data collected under selected data sources such as the Toxics Release Inventory (TRI) and National Emissions Inventory (NEI) programs. Analyses conducted using physical and chemical properties, fate information and TRI/DMR show that TSCA-related environmental releases for 1,4-dioxane do not result in significant exposure to aquatic species through water and sediment exposure pathways (see Section 2.5.3.3). For the pathways of exposures for the general population and terrestrial species, EPA has determined that the existing regulatory programs and associated analytical processes have addressed or are in the process of addressing potential risks of chemicals that may be present in other media pathways. For these cases, EPA believes that the TSCA Page 47 of 90 ------- risk evaluation should focus not on those exposure pathways, but rather on exposure pathways associated with TSCA uses that are not subject to those regulatory processes. EPA does not plan to further analyze the environmental fate of 1,4-dioxane based on the conceptual models described in Section 2.5.2 and Section 2.5.3. EPA does not plan to further analyze environmental exposures to 1,4-dioxane based on the exposure assessment presented in Section 2.3.4. 2.6.1.2 Occupational Exposures EPA expects to evaluate both worker and occupational non-user exposures as follows: 1) Review reasonably available exposure monitoring data for specific condition(s) of use. Exposure data to be reviewed may include workplace monitoring data collected by government agencies such as OSHA and the NIOSH, and monitoring data found in published literature [e.g., personal exposure monitoring data (direct measurements) and area monitoring data (indirect measurements)]. Studies will be evaluated using the evaluation strategies laid out in the Application of Systematic Review in TSCA Risk Evaluations ( ,). EPA will evaluate applicable regulatory and non-regulatory exposure limits. Available data sources that may contain relevant monitoring data for the various conditions of use are listed in Table 2-10. Table 2-10. Potential Sources of 1,4-Dioxane Occupational Exposure Data The 2002 ECJRC Summary Risk Assessment Report: 1,4-Dioxane (ECJRC. 2002) Health Canada Screening Assessment for the Challenge: 1,4-Dioxane (Health Canada. 2010) U.S. NIOSH Health Hazard Evaluation (HHE) Program reports (NIOSH H c . 1 82. 1980) U.S. OSHA Chemical Exposure Health Data (CEHD) program data (OS ) Industry workplace exposure monitoring data submitted to EPA by BASF Corporation and the American Chemistry Council (ACC) (BASF. 2017: ACC. 2.015) U.S. EPA Generic Scenarios (https://www.epa.gov/tsca-screening-tools/using-predictive- methods-assess-exposure-and-fate-under-tsca#fate) OECD Emission Scenario Documents (OEl II >. ^ > l l) Buffler, P. A., Wood, S. M., Suarez, L., Kilian, D. J. Mortality follow-up of workers exposed to 1,4-dioxane. Journal of Occupational and Environmental Medicine. 1978. 20:255-259. Jezewska, A., Szewczynska, M., Woznica, A. Occupational exposure to airborne chemical substances in paintings conservators. Medycyna Pracy. 2014. 65:33-41. Kupczewska-Dobecka, M., Czerczak, S., Jakubowski, M., Maciaszek, P., Janasik, B. Application of predictive model to estimate concentrations of chemical substances in the work environment. Medycyna Pracy. 2010. 61:307-314. 2) For conditions of use where data are limited or not available, review existing exposure models that may be applicable in estimating exposure levels. EPA has identified potentially relevant OECD ESDs and EPA GS corresponding to some conditions of use. For example, the GS for Synthetic Fiber Manufacture, the GS on Lubricant Additives, the ESD on the Use of Metalworking Fluid, and the ESD on the Use of Adhesives are some of the ESDs and GS's that EPA may use to estimate occupational exposures for conditions of use such as use as a Page 48 of 90 ------- wetting and dispersing agent in textile manufacturing, use in hydraulic fluids, and use in film cement. EPA will need to critically review these generic scenarios and ESDs to determine their applicability to the conditions of use assessed. EPA was not able to identify ESDs or GS's corresponding to several conditions of use, including solvent recycling, distribution, wood pulping, animal and vegetable oil extraction, fluoropolymer etching, and use as a fuel additive. EPA will perform additional targeted research, such as consulting Kirk-Othmer, in order to better understand those conditions of use, which may inform the identification of exposure scenarios. EPA may also need to perform targeted research to identify applicable models that may be used to estimate exposures for certain conditions of use. 3) Review reasonably available data that may be used in developing, adapting or applying exposure models to the particular risk evaluation. If necessary, EPA will evaluate relevant data to determine whether the data can be used to develop, adapt, or apply models for specific conditions of use and corresponding exposure scenarios. 4) Consider and incorporate applicable engineering controls and/or personal protective equipment into exposure scenarios. EPA will review potential data sources on engineering controls and personal protective equipment as identified in Table 2-10 to determine their applicability and incorporation into exposure scenarios during risk evaluation. Studies will be evaluated using the evaluation strategies laid out in the Application of Systematic Review in TSCA Risk Evaluations (tj S K j> \ 2018a). 5) Evaluate the weight of the evidence of occupational exposure data. EPA will rely on the weight of the scientific evidence when evaluating and integrating occupational exposure data. The data integration strategy will be designed to be fit-for-purpose in which EPA will use systematic review methods to assemble the relevant data, evaluate the data for quality and relevance, including strengths and limitations, followed by synthesis and integration of the evidence. 6) Map or group each condition of use to occupational exposure assessment scenario(s). EPA has identified release/occupational exposure scenarios and mapped them to relevant conditions of use in Appendix D. As presented in the fourth column of the table in this appendix, EPA has grouped the uses into 23 representative release/exposure scenarios each with 5-6 unique combinations of exposure pathway, route, and receptor that will be further evaluated. EPA may further refine the mapping/grouping of 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. Consumer Exposures EPA does not expect to consider and analyze consumer exposures in the risk evaluation as described in the Scope of the Risk Evaluation for 1,4-Dioxane (X \ < i* \ J 1 \ ,). 2.6.1.3 General Population EPA does not expect to consider and analyze general population exposures in the risk evaluation for 1,4- dioxane based on Section 2.5.3.3. EPA has determined that the existing regulatory programs and associated analytical processes have addressed or are in the process of addressing potential risks of 1,4- dioxane that may be present in various media pathways (e.g., air, water, land) for the general population. Page 49 of 90 ------- For these cases, EPA believes that the TSCA risk evaluation should focus not on those exposure pathways, but rather on exposure pathways associated with TSCA uses that are not subject to those regulatory processes. 2.6.2 Hazard 2.6.2.1 Environmental Hazards EPA does not plan to further analyze environmental hazards to 1,4-dioxane based on the hazard assessment presented in Section 2.4.1. 2.6.2.2 Human Health Hazards EPA expects to evaluate human health hazards as follows: 1) Review reasonably available human health hazard data, including data from alternative test methods (e.g., computational toxicology and bioinformatics; high-throughput screening methods; data on categories and read-across; in vitro studies; systems biology). For the 1,4 dioxane risk evaluation, EPA will evaluate information in the IRIS assessment and human health studies using OPPT's structured process described in the document, Application of Systematic Review in TSCA Risk Evaluations ( 018a). Human, animal and mechanistic data will be identified and included as described in Appendix F.3. EPA plans to prioritize the evaluation of mechanistic evidence. Specifically, EPA does not plan to evaluate mechanistic studies unless needed to clarify questions about associations between 1,4-dioxane and health effects and its relevance to humans. The protocol describes how studies will be evaluated using specific data evaluation criteria and a predetermined systematic approach. Study results will be extracted and presented in evidence tables by hazard endpoint. EPA plans to evaluate key studies used in the Integrated Risk Information System (IRIS) Toxicological Review of 1,4-Dioxane ( ,013c. 2010). the TSCA Work Plan Problem Formulation and Initial Assessment ( ) and studies published after 2010 (oral) and 2013 (inhalation) that were captured in the comprehensive literature search conducted by the Agency for 1,4 Dioxane (/, 4-Dioxane (CASRN123-91-1) Bibliography: Supplemental File for the TSCA Scope Document, (U.S. EPA. )). EPA intends to review studies published after the IRIS assessment to ensure that EPA is considering information that has been made available since these assessments were conducted. 2) In evaluating reasonably available data, determine whether particular human receptor groups may have greater susceptibility to the chemical's hazard(s) than the general population. Reasonably available human health hazard data will be evaluated to ascertain whether some human receptor groups may have greater susceptibility than the general population to 1,4-dioxane hazard(s). Susceptibility of particular human receptor groups to 1,4-dioxane will be determined by evaluating information on factors that influence susceptibility. 3) Conduct hazard identification (the qualitative process of identifying non-cancer and cancer endpoints) and dose-response assessment (the quantitative relationship between hazard and exposure) for all identified human health hazard endpoints. Page 50 of 90 ------- Human health hazards from acute and chronic exposures will be identified by evaluating the human and animal data that meet the systematic review data quality criteria described in the Application of Systematic Review in TSCA Risk Evaluations document (U.S. EPA. 2.018a). Data quality evaluation will be performed on key studies identified from the IRIS assessments (U.S. EPA. 2013b. 2010). the TSCA Work Plan Problem Formulation and Initial Assessment (\_ S f P \ 201 >c) and studies published after 2010 (oral) and 2013 (inhalation) that were captured in the comprehensive literature search. Hazards identified by studies meeting data quality criteria will be grouped by routes of exposure relevant to humans (oral, dermal, inhalation) and by cancer and noncancer endpoints. Dose-response assessment will be performed in accordance with EPA guidance ( 2011 h, r ^ [). Dose-response analyses performed for the IRIS oral and inhalation reference dose determinations ( 13c, 2010) may be used if the data meet data quality criteria and if additional information on the identified hazard endpoints are not available or would not alter the analysis. The cancer mode of action (MOA) determines how cancer risks can be quantitatively evaluated. EPA will evaluate information on genotoxicity and the mode of action for all tumor types to determine the appropriate approach for quantitative cancer assessment in accordance with the U.S. EPA Guidelines for Carcinogen Risk Assessment ( .005a). 4) Derive points of departure (PODs) where appropriate; conduct benchmark dose modeling depending on the available data. Adjust the PODs as appropriate to conform (e.g., adjust for duration of exposure) to the specific exposure scenarios evaluated. Hazard data will be evaluated to determine the type of dose-response modeling that is applicable. Where modeling is feasible, a set of dose-response models that are consistent with a variety of potentially underlying biological processes will be applied to empirically model the dose-response relationships in the range of the observed data consistent with the EPA Benchmark Dose Technical Guidance Document (U. S. EPA. 2012b). Where dose-response modeling is not feasible, NOAELs or LOAELs will be identified. EPA will evaluate whether the available PBPK and empirical kinetic models are adequate for route- to-route and interspecies extrapolation of the POD, or for extrapolation of the POD to standard exposure durations (e.g., lifetime continuous exposure). If application of the PBPK model is not possible, oral PODs may be adjusted by BW3'4 scaling in accordance with (I r \ .011 h), and inhalation PODs may be adjusted by exposure duration and chemical properties in accordance with ( 4). 5) Consider the route(s) of exposure (oral, inhalation, dermal), available route-to-route extrapolation approaches, available biomonitoring data and available approaches to correlate internal and external exposures to integrate exposure and hazard assessment. EPA believes there are sufficient data to conduct dose-response analysis and/or benchmark dose modeling for both inhalation and oral routes of exposure. If sufficient dermal toxicity studies are not identified in the literature search to assess risks from dermal exposures, then a route-to-route extrapolation from the inhalation and oral toxicity studies would be needed to assess systemic risks from dermal exposures. Without an adequate PBPK model, Page 51 of 90 ------- the approaches described in the EPA guidance document Risk Assessment Guidance for Superfund Volume I: Human Health Evaluation Manual (Part E, Supplemental Guidance for Dermal Risk Assessment) could be applied. These approaches may be able to further inform the relative importance of dermal exposures compared with other routes of exposure. 6) Evaluate the weight of the evidence of human health hazard data. EPA will rely on the weight of the scientific evidence when evaluating and integrating human health hazard data. The data integration strategy will be designed to be fit-for-purpose in which EPA will use systematic review methods to assemble the relevant data, evaluate the data for quality and relevance, including strengths and limitations, followed by synthesis and integration of the evidence. 2.6.3 Risk Characterization Risk characterization is an integral component of the risk assessment process for both ecological and human health risks. EPA will derive the risk characterization in accordance with EPA's Risk Characterization Handbook (U.S. EPA. 2000). As defined in EPA's Risk Characterization Policy, "the risk characterization integrates information from the preceding components of the risk evaluation and synthesizes an overall conclusion about risk that is complete, informative and useful for decision makers." Risk characterization is considered to be a conscious and deliberate process to bring all important considerations about risk, not only the likelihood of the risk but also the strengths and limitations of the assessment, and a description of how others have assessed the risk into an integrated picture. Risk characterization at EPA assumes different levels of complexity depending on the nature of the risk assessment being characterized. The level of information contained in each risk characterization varies according to the type of assessment for which the characterization is written. Regardless of the level of complexity or information, the risk characterization for TSCA risk evaluations will be prepared in a manner that is transparent, clear, consistent and reasonable (TCCR) ( 2000). EPA will also present information in this section consistent with approaches described in the Procedures for Chemical Risk Evaluation Under the Amended Toxic Substances Control Act (8! 5). For instance, in the risk characterization summary, EPA will further carry out the obligations under TSCA section 26; for example, by identifying and assessing uncertainty and variability in each step of the risk evaluation, discussing considerations of data quality such as the reliability, relevance and whether the methods utilized were reasonable and consistent, explaining any assumptions used, and discussing information generated from independent peer review. EPA will also be guided by EPA's Information Quality Guidelines (U.S. EPA. 2002) as it provides guidance for presenting risk information. Consistent with those guidelines, in the risk characterization, EPA will also identify: (1) Each population addressed by an estimate of applicable risk effects; (2) the expected risk or central estimate of risk for the potentially exposed or susceptible subpopulations affected; (3) each appropriate upper-bound or lower bound estimate of risk; (4) each significant uncertainty identified in the process of the assessment of risk effects and the studies that would assist in resolving the uncertainty; and (5) peer reviewed studies known to the Agency that support, are directly relevant to, or fail to support any estimate of risk effects and the methodology used to reconcile inconsistencies in the scientific information. Page 52 of 90 ------- REFERENCES ACC (American Chemistry Council). (2015). ARASP recommendations for the work plan chemical problem formulation and initial assessment for 1,4-dioxane. 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Toxicological review of 1,4-Dioxane (with inhalation update) (CAS No. 123-91-1) in support of summary information on the Integrated Risk Information System (IRIS) [EPA Report], (EPA-635/R-11/003-F). Washington, DC. U.S. EPA (U.S. Environmental Protection Agency). (2014a). ChemView. In Pollution Prevention and Toxics Program. Environmental Protection Agency. http://iava.epa.eov/chemview U.S. EPA (U.S. Environmental Protection Agency). (2014b). Exposure and Fate Assessment Screening Tool version 2014 (E-FAST 2014). Available online at https://www.epa. eov/tsca-screenine- tools/e-fast-exposure-and-fate-assessment-screening-tool-version- U.S. EPA (U.S. Environmental Protection Agency). (2014c). Framework for Human Health Risk Assessment to Inform Decision Making. (EPA/100/R-14/001). Washington, DC: Environmental Protection Agency, Office of the Science Advisor. https://www.epa.gov/sites/production/files/2<' i 4 t»'ouments/hhra-framework-final-2^M t ^ df U.S. EPA (U.S. Environmental Protection Agency). (2015a). Air Quality System (AQS). Available online at http://www.epa.gov/aqs U.S. EPA (U.S. Environmental Protection Agency). (2015b). EPA Risk-Screening Environmental Indicators (RSEI) Model-Toxics Release Inventory (TRI) data. Available online at http ://www. epa. eov/rsei U.S. EPA (U.S. Environmental Protection Agency). (2015c). TSCA Work Plan Chemical Problem Formulation and Initial Assessment. 1,4-Dioxane. (740-R1-5003). Washington, DC: Environmental Protection Agency, Office of Chemical Safety and Pollution Prevention. http ://nepis. epa. eov/Exe/ZyPURL.cei?Dockev=P 1OOMDC1. TXT U.S. EPA (U.S. Environmental Protection Agency). (2016a). Instructions for reporting 2016 TSCA chemical data reporting, https://www.epa.eov/chemical-data-report.ine/instaictions-report.ine- 2016-tsca-chemieal-data-reportine Page 57 of 90 ------- U.S. EPA (U.S. Environmental Protection Agency). (2016b). Instructions for the 2016 TSCA Chemical Data Reporting. Washington, DC: Office of Pollution Prevention and Toxics. https://www. epa. gov/ sites/producti on/fil e s/2016- 05/documents/instructions for reporting 2016 tsca crfi L»iuav2QI6 ndf U.S. EPA (U.S. Environmental Protection Agency). (2016c). Public database 2016 chemical data reporting (May 2017 release). Washington, DC: US Environmental Protection Agency, Office of Pollution Prevention and Toxics. Retrieved from https://www.epa.gov/chemical-data-reporting U.S. EPA (U.S. Environmental Protection Agency). (2017a). 1,4-dioxane (CASRN: 123-91-1) bibliography: Supplemental file for the TSCA Scope Document [EPA Report], https://www.epa.gOv/sites/prodiiction/files/2 / docum ents/14di oxan e comp bib.pdf U.S. EPA (U.S. Environmental Protection Agency). (2017b). Preliminary information on manufacturing, processing, distribution, use, and disposal: 1,4 Dioxane. (EPA-HQ-OPPT-2016-0723). Office of Pollution Prevention and Toxics (OPPT), Office of Chemical Safety and Pollution Prevention (OCSPP). file -JIIC:/Users/2616 l/Saved%20Games/Downloads/EPA-HQ-OPPT-2016-0723 - 0003.pdf U.S. EPA (U.S. Environmental Protection Agency). (2017c). Scope of the risk evaluation for 1,4- dioxane. CASRN: 123-91-1 [EPA Report], (EPA-740-R1-7003). https://www.epa.gov/sites/prodiiction/files/201 -Ov'/documents/dioxane scope 06-22-201pdf U.S. EPA (U.S. Environmental Protection Agency). (2017d). Toxics Release Inventory (TRI). Retrieved from https://www.epa.gov/toxics-release-inventorY4ri-program/tri-data-and-tools U.S. EPA (U.S. Environmental Protection Agency). (2018a). Application of systematic review in TSCA risk evaluations: Version 1.0. (740P18001). Washington, D.C.: U.S. Environmental Protection Agency, Office of Chemical Safety and Pollution Prevention. U.S. EPA (U.S. Environmental Protection Agency). (2018b). Strategy for assessing data quality in TSCA risk evaluations. Washington DC: U.S. Environmental Protection Agency, Office of Pollution Prevention and Toxics. USGS (U.S. Geological Survey). (2002). Geohydrology, Water Quality, and Simulation of Ground- Water Flow in the Vicinity of a Former Waste-Oil Refinery near Westville, Indiana, 1997-2000. (Water-Resources Investigations Report 01-4221). Indianapolis, Indiana: U.S. Department of the Interior, https://in.water.iisgs.gov/newreports/camor.pdf WHO (World Health Organization). (2005). 1,4-Dioxane in drinking water. (WHO/SDE/WSH/05.08/120). Geneva, Switzerland. Wissenbach, DK; Winkler, B; Otto, W; Kohajda, T; Roeder, S; Mueller, A; Hoeke, H; Matysik, S; Schlink, U; Borte, M; Herbarth, O; Lehmann, I; Von-Bergen, M. (2016). Long-term indoor VOC concentrations assessment a trend analysis of distribution, disposition, and personal exposure in cohort study samples. Air Qual Atmos Health 9: 941-950. http://dx.doi.org/10.1007/sl 1869-01 o- 0396-1 Yalkowsky, SH; He, Y; Jain, P. (2010). Handbook of aqueous solubility data (2nd ed.). Boca Raton, FL: CRC Press, faftp://dx.doi.org/10.1201 /EBK1439802.458 Page 58 of 90 ------- APPENDICES Appendix A REGULATORY HISTORY A.l Federal Laws and Regulations Table Apx A-l. Federal Laws and Regulations Malulcs/Uegulalions 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 ? p (iO 1 1,11 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 1,4-Dioxane is a listed substance subject to reporting requirements under 40 CFR 372.65 effective as of January 01, 1987. Page 59 of 90 ------- Stiiliitcs/Ucgiihllions Description of Aiilhorily/Ucgiihilion Description of Requisition and that manufacture, process or otherwise use a TRI-listed chemical in quantities above threshold levels. Federal Food, Drug, and Cosmetic Act (FFDCA) - Section 408 FFDCA governs the allowable residues of pesticides in food. Section 408 of the FFDCA provides EPA with the authority to set tolerances (rules that establish 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. In 1998, 1,4-dioxane was removed from the list of pesticide product inert ingredients because it 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 CFRPart 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 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, Page 60 of 90 ------- Stiiliitcs/Ucgiihllions Description of Aiilhorily/Ucgiihilion Description of Requisition 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 (taking into account the cost of achieving reductions and environmental impacts and energy requirements) EPA determines has been adequately demonstrated. 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 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. 1,4-Dioxane is listed as a HAP under section 112 (42 U.S.C. § 7412) of the CAA. 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 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) Page 61 of 90 ------- Stiiliitcs/Ucgiihllions Description of Aiilhorily/Ucgiihilion Description of Requisition control technology (GAC I ) standards, are allowed at the Administrator's discretion for area sources. Off-Site Waste and Reco\ cry Operations (40 CFRPart 63, Subpart DD), Wood Furniture Manufacturing Operations (40 CFRPart 63, Subpart JJ), Pharmaceuticals Production (40 CFR Part 63, Subpart GGG), Group IV Polymers and Resins (thermoplastic product manufacturing) (40 CFRPart 63, Subpart JJJ), Organic Liquids Distribution (Non- gasoline) (40 CFRPart 63, Subpart EEEE), Miscellaneous Organic Chemical Manufacturing (40 CFR Part 63, Subpart FFFF), Site Remediation (40 CFR Part 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). Page 62 of 90 ------- Staliitcs/Ucgulalions Description of Aiilhorily/Ucgulalion Description of Regulation 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, taking 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. 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). 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 l,4dioxane 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 In 1989, 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 Page 63 of 90 ------- Stiiliitcs/Ucgiihllions Description of Aiilhorily/Ucgiihilion Description of Requisition levels, mechanical dangers, heal 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. that many of its PN.s are ouldaled 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 ACGIH 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 Secretary determines that 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. 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 171, 40 CFR 173.202 and 40 CFR 173.242). Page 64 of 90 ------- A.2 State Laws and Regulations Table Apx A-2. State Laws and Regulations State Actions Description of Action State 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 Apx A-3. Regulatory Actions by 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 bv facilities across the country [Government of Canada £. 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 0.4-Dioxane. Priority Existing Chemical No. 7. Full Public Reotn < (i )8Y). 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 Page 65 of 90 ------- Country/Organization Requirements and Restrictions • 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 (CHIRPHMTE. 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.. 2.014). 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 (In si tut fur Asheitsschutz d------- Appendix B PROCESS, RELEASE AND OCCUPATIONAL EXPOSURE INFORMATION This appendix provides information and data found in preliminary data gathering for 1,4-dioxane. B.l Process Information Process-related information potentially relevant to the risk evaluation may include process diagrams, descriptions and equipment. Such information may inform potential release sources and worker exposure activities for consideration. B.l.l Manufacture (Including Import) The primary method for industrial production of 1,4-dioxane involves an acid-catalyzed conversion of ethylene glycol (mono-, di-, tri- and polyethylene glycol may be used) by ring closure in a closed system. The process is carried out at a temperature between 266 and 392°F (130 and 200°C) and a pressure between 0.25 and 1.1 atm (25 and 110 kPa). The synthesis step is performed in a heated vessel. The raw 1,4-dioxane product is then moved to a distillation column to start the purification process. Multiple steps are used to purify the 1,4-dioxane, including separation from water and volatile by- products by extractive distillation, heating with acids, salting out withNaCl, CaCh orNaOH, and fine subsequent distillation (ECJRC. 2002). FigureApx B-l (BASF. 2017). Components Reaction ~isolation NeuVa Nation D'stillalcn F rial PioJuct Feed Tank Disfilltfi en Colimr Figure Apx B-l: General Process Flow Diagram for 1,4-Dioxane Manufacturing Source: EPA-HQ-QPPT-2016-0723-0012 (BASF. 2017). Two other reactions can be used to make 1,4-dioxane, but they are primarily used to make substituted dioxanes and not known to be used for industrial 1,4-dioxane production (ECJRC. 2002). B.1.2 Processing and Distribution B.l.2.1 Processing as a Reactant/Intermediate 1,4-Dioxane can be used as a chemical reactant in the production of pharmaceuticals, polyethylene terephthalate (PET) plastics, rubber, insecticides and pesticides, cement, deodorant fumigant, magnetic Page 67 of 90 ------- tape and adhesives [EPA-HO-OPPT-lOl / 0723-000 » (I ? U- \ 2017b)1. Exact process operations involved in the use of 1,4-dioxane as a chemical reactant are dependent on the final product that is being synthesized. For the use of 1,4-dioxane as a chemical reactant, operations would typically involve unloading 1,4-dioxane from transport containers and feeding the 1,4-dioxane into a reaction vessel(s), where the 1,4-dioxane would react either fully or to a lesser extent. Following completion of the reaction, the produced substance may or may not be purified further, thus removing unreacted 1,4- dioxane (if any exists). Reacted 1,4-dioxane is assumed to be destroyed and is thus not expected to be released or cause potential worker exposures. B.l.2.2 Processing - Non-Incorporative 1,4-Dioxane is used as a process solvent during the manufacturing of cellulose acetate, resins, waxes and fats [ ; H *-QPPT-201' -0 /23-0003 (U.S. EPA. 2017bn. B. 1.2.3 Repackaging Typical repackaging operations involve transferring of chemicals into appropriately sized containers to meet customer demands/needs. B.l.2.4 Recycling 1,4-Dioxane is used as a solvent in several applications. In this capacity, 1,4-dioxane can be regenerated and recycled for reuse. B.1.3 Uses B.l.3.1 Processing Aids, Not Otherwise Listed Processing aids are chemical substances used to improve the processing characteristics or the operation of process equipment or to alter or buffer the pH of the substance or mixture, when added to a process or to a substance or mixture to be processed. Processing agents do not become a part of the reaction product and are not intended to affect the function of a substance or article created (U.S. EPA. 2016c). 1,4-Dioxane is used in a number of industrial processes as a processing aid. These processes include wood pulping, extraction of animal and vegetable oils, textile processing, polymerization, pharmaceutical purification and etching of fluoropolymers fEPA-HQ-OPPT~ 723-0003; (U.S. 17b): EPA-HO-QPPT-2016-0723-0012 (BASF. 2017)1. Exact process operations involved in the use of 1,4-dioxane as a processing aid are dependent on the final product that is being synthesized. B.l.3.1 Functional Fluids (Open and Closed Systems) Functional fluids are liquid or gaseous chemical substances used for one or more operational properties (U.S. EPA. 2016c). 1,4-Dioxane is used in polyalkylene glycol lubricants, synthetic metalworking fluids, cutting and tapping fluids and hydraulic fluids [EPA-HQ-QPPT-2017-072.3-0003 ( 2017b)]. Exact operations involved in the use of 1,4-dioxane as a functional fluid are dependent on the final product. B. 1.3.2 Laboratory Chemicals 1,4-Dioxane is used in laboratories as a chemical reagent, reference material, stable reaction medium, liquid scintillation counting medium, spectroscopic and photometric measurement, cryoscopic solvent and histological preparation [EPA-HO-OPPT-2Q17-0723-0003 ( )]. Laboratory procedures are generally done within a fume hood, on a bench with local exhaust ventilation or under general ventilation. Page 68 of 90 ------- B.l.3.3 Adhesives and Sealants 1,4-Dioxane is found in film cement and as a residual contaminant in two-component glues and adhesives [EPA-HQ-QPPT-2017-0723-0003 ( )]. The application procedure depends on the type of adhesive and the type of substrate. After the adhesive is received by the user, it may be diluted or mixed prior to application. The formulation is then loaded into the application reservoir or apparatus and applied to the substrate via spray, roll, curtain or syringe or bead application. Application may be manual or automated. After application, the adhesive or sealant is allowed to dry, usually at ambient temperature, such that the solvent completely evaporates and a bond is formed between the substrates (OECD. 2015). B.l.3.4 Other Uses Other conditions of use where 1,4-dioxane may be formulated into a product or used as part of another process may include use in fuels and fuel additives [EPA-HQ-OPPT-1 r23~0012 (BASF. 2017)1. spray polyurethane foam and in printing and printing compositions rEPA-HQ-OPIH'-AM I 0723-0003 (U.S. EPA. 2017b)1. B.1.4 Disposal 1,4-Dioxane is disposed of to a variety of environmental media: land, water and air. Land disposals include Class I underground injection, RCRA Subtitle C landfills and to other uncategorized land points. 1,4-Dioxane is sometimes discharged to water. Wastewater treatment may or may not precede these water releases. Additionally, 1,4-dioxane is also commonly incinerated (U.S. EPA. 2015c). B.2 Occupational Exposure Data EPA presents below an example of occupational exposure-related information from the preliminary data gathering. EPA will consider this information and data in combination with other data and methods for use in the risk evaluation. TableApx B 1 summarizes OSHA CEHD data by North American Industry Classification System (NAICS) code (OS] ). Table Apx B-l. Summary of Industry Sectors with 1,4-Dioxane Personal Monitoring Air Samples Obtained from OSHA Inspections Conducted Between 2002 and 2016 NAICS NAICS IK'siripliiiii 315225 Men's and Boys' Cut and Sew Work Clothing Manufacturing 325199 All Other Basic Organic Chemical Manufacturing 334418 Printed Circuit Assembly (Electronic Assembly) Manufacturing 336399 All Other Motor Vehicle Parts Manufacturing 926150 Regulation, Licensing, and Inspection of Miscellaneous Commercial Sectors Page 69 of 90 ------- Appendix C ANALYSIS: ENVIRONMENTAL CONCENTRATION OF CONCERN (COC) The concentrations of concern (COC) for aquatic species were calculated based on the environmental hazard data for 1,4-dioxane summarized in Section 2.4.1. The methods for calculating the COCs are are based on published EPA/OPPT methods ( ., 2012d). The acute and chronic COC for 1,4- dioxane for each endpoint are determined based on the lowest toxicity value in the dataset. For a particular environment (e.g., aquatic environment), the COC is based and on the most sensitive species in that environment. After selecting the lowest toxicity value, an assessment factor (AF) is applied according to EPA/OPPT methods (U.S. EPA. 2013a. 2012d). 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. AFs are also account for differences in inter- and intra-species variability, as well as laboratory-to-field variability. These assessment factors are dependent upon the availability of datasets that can be used to characterize relative sensitivities across multiple species within a given taxa or species group, but are often standardized in risk assessments conducted under TSCA, since the data available for most industrial chemicals is limited. The acute COC for the aquatic plant endpoint is determined based on the lowest value in the dataset divided by an assessment factor (AF) of 4. 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. Acute COC calculations The lowest acute toxicity value for aquatic organisms (i.e., most sensitive species) for 1,4-dioxane is from a 96-hour fish toxicity study where the LC.mi is >100 mg/L (Geiger et at... 1990). The lowest value was then divided by the assessment factor (AF) of 5 for aquatic invertebrates. Lowest value for the 96-hour fish toxicity LCso (>100 mg/L) / AF of 5 = 20,000 |ig/L or ppb. Chronic COC Calculations 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. Lowest value for 32-day fish MATC = 145 mg/L / 10 = 14.5 x 1000 = 14,500 |ig/L or ppb. Summary The acute concentration of concern for 1,4-dioxane is based on the 96-hour toxicity value for fish of >100 mg/L (Geiger et at.. 1990) and the chronic COC is based on a 32-day MATC fish toxicity value of 145 mg/L (Brooke. 1987). The acute and chronic COCs for 1,4-dioxane are 20,000 ppb and 14,500 ppb, respectively. Page 70 of 90 ------- Appendix D SUPPORTING TABLE FOR INDUSTRIAL AND COMMERCIAL ACTIVITIES AND USES CONCEPTUAL MODEL 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. All possible exposure scenarios for each condition of use were identified according to the COU in Table 2-3 and the conceptual model in Figure 2-2 and are presented in Table Apx D-l. EPA used readily available fate, engineering, exposure and/or toxicity information to determine whether to conduct further analysis on each exposure scenario. EPA has identified release/occupational exposure scenarios and mapped them to relevant conditions of use in the table 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 may further refine 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 Apx E >-1: Industrial and Commercial Occupational Exposure Scenarios for 1,4- Jioxane l.il'e Cjck' S(;i»e Siihciileiion Kck'sisi'/ l'l\pOMIIV SiTii.irio Kxposiir 0 l\i(h\\;i\ l'l\|)OMIIV Route Rm-plor I'm ri her l.\;ilu;ilion? Kiilioiiiilo lor l-'iirlhcr 1'\ ;i In ;i I ion / no lurllur l.\;ilu;ilion 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 vapor should be further evaluated. Manufacture Domestic Manufacture or Import Domestic Manufacture or Import Liquid ( oiiiael Dermal <>\l (()eeiipali nual \mi- l sen \n Dermal e\pnsure is e\peeled In he primariK in worker direelh in\nl\edin haiidliim I lie chemical Manufacture Domestic Manufacture or Import Domestic Manufacture or Import Vapor Dermal ONU No The absnrpunii nf 14-din vine \ apnr \ la skin is expected to be orders of magnitude lower than via inhalation and will not be further analyzed. Page 71 of 90 ------- 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 ueneralion is uoi e\pecled Processing Processing as a Reactant 1. iquid 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 Pharmaceutical Pharmaceutical 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 Intermediate product manufacture Liquid ( oniacl Dermal <>\l \o Dermal e\posure is e\peeled lo he primariK lo workeis direelK iii\ol\edni haiidlinu llie chemical. Processing Processing as a Reactant Polymerization catalyst Polymer 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. 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 catalvst Processing Processing as a Reactant \llsl Dermal In halation () nil Workers. <>\l \o Misi izeiieralioii is noi e\peeled. Processing Liquid Contact Dermal Workers Yes Workers are expected to routinely handle liquids containing 1,4-dioxane. Processing Non- Pharmaceutical and medicine Pharmaceutical product Vapor Dermal Workers No The absorption of 1,4-dioxane vapor via skin is expected to be orders of Page 72 of 90 ------- incorporativ e Repackaging manufacturing (process solvent) Basic organic chemical manufacturing (process solvent) Bulk to packages, then distribute manufacture Basic organic chemical manufacture Repackaging to large and small containers magnitude lower than via inhalation and will not be further analyzed. Processing Vapor Inhalation Workers Yes Due to high volatility at room temperature, inhalation exposure from vapor should be further evaluated. Processing Liquid ( ouiacl Dermal <>\l \o Dermal e\posure is e\pecled in he primarily in worker direct l\ uiuil\ediu haiidliuu 11 ic chemical Processing 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. Processing Vapor Inhalation ONU Yes Due to high volatility at room temperature, inhalation exposure from vapor should be further evaluated. Processing \lls| Dermal In halation () nil Workers. <>\l No Misi ueiieralKiu is uoi e\pecled Processing Recycling Recycling Recycling of process solvents containing 1,4- dioxane Liquid Contact Dermal Workers Yes Workers are expected to routinely handle liquids containing 1,4-dioxane. Processing Recycling Recycling 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 e\posure is e\pecled In he primarily lo worker direclK iu\ol\cdiii haudliiiu I lie chemical. Processing Recycling Recycling 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. 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 Page 73 of 90 ------- 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 Liquid Contact Dermal Workers Yes Workers are expected to routinely handle liquids containing 1,4-dioxane. Industrial use Agricultural chemical Agricultural product manufacture Plasticizer manufacture Anhydrous acid, bromination and sulfonation reaction chemical manufacture Polymer Manufacture 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 Intermediate Use intermediate Plasticizer intermediate Catalysts and 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. Industrial use reagents for anhydrous acid reactions, Liquid ( ouiacl Dermal <>\l \n Dermal e\pnMiie is e\pecled In he piiuiaiiK lii workeiN direct l\ uiuil\ediu haudliim I lie chemical. Industrial use Processing aids, not otherwise brominations and sulfonations 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 listed Polymerization catalyst 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 74 of 90 ------- Industrial use \lisi Dermal In halation () nil Willie is. ()\l \n Misi ueiicialinii is urn e\pecled 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 Wood pulping Extraction of Wood pulping 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 animal and vegetable oils Wetting and Extraction of animal and vegetable oils l.k|iiid ( niilacl Dermal <>\l Yes Dermal e\pnsiiie is e\pecled In he piimaiiK lo woikeis direclh in\ i»l\ ed in handliiiu I lie chemical Industrial use Processing aids, not otherwise listed dispersing agent in textile processing Textile processing 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 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 Purification of pharmaceuticals Pharmaceutical product manufacture 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 Vapor Inhalation Workers Yes Due to high volatility at room temperature, inhalation exposure from vapor should be further evaluated. Page 75 of 90 ------- otherwise listed Industrial use Processing aids, not otherwise listed l.k|iiid (nulacl Dermal <>\l \o Dermal c\pnsiiic is e\peeled in he pi'imai'iK lo workeiN direelK in\ ol\ ed in 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. Industrial use Processing aids, not otherwise listed \lls| Dermal In halation () nil Workers. <>\l \n Misi uciicralinii is imi e\peeled 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 Etching of Etching of 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 fluoropolymers fluoropolymers Liquid (nulacl Dermal ()\l \n Dermal c\pnsiiic is c\pecled In he pi'imai'iK lo wDikeiN direelK in\ ol\ ed in handlnm 11 ic chemical. Industrial use Processing aids, not otherwise listed Vapor Dermal ONU No The absorption of l,4-dio\ane \ apor \ la 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. Page 76 of 90 ------- 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 Tapping Fluid Synthetic metalworking fluid Hydraulic fluid Use of lubricants Use of metalworking fluids Servicing hydraulic equipment and charging hydraulic fluids in original equipment manufacture Liquid Contact Dermal Workers Yes Workers are expected to routinely handle liquids containing 1,4-dioxane. Industrial use Functional fluids (closed/open system) 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 Functional fluids (closed/open system) Vapor Inhalation Workers Yes Due to high volatility at room temperature, inhalation exposure from \ ;i|x>r should be liii'llicr e\ alualed Industrial use Functional fluids (closed/open system) liquid ( niilael Dermal <>\l \n Dermal e\pi»siire is e\peeled In he piimai'iK lo woikeis direelh in\ i»l\ ed in haiidlum I lie chemical Industrial use Functional fluids (closed/open system) 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 material Spectroscopic and photometric Laboratory chemical use Liquid Contact Dermal Workers Yes Workers are expected to routinely handle liquids containing 1,4-dioxane. Industrial use, potential commercial use Laboratory chemicals 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 77 of 90 ------- Industrial use, potential commercial use Laboratory chemicals measurement Liquid scintillation and 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 ( nuiacl Dermal ()\l \n Dermal censure is e\pccleil in he primarily in woikeiN direelK iu\iil\ediu hauilliuu 11 ic 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. 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 \ apnr should be fuilhei' c\ alualed Industrial use, potential commercial use Laboratory chemicals histological sections for microscopic examination \llsl Dermal In halalinu () nil Workers. <>\l \n Misi ucucralinii is uni e\peeled 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 Industrial and commercial small brush application 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 Adhesives and sealants Other Uses Film cement 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 (nuiacl Dermal ()\l \n Dermal e\pnsiii'e is e\pecled In he primarily in workers direelK iu\ nl\ ed m haiiilliuu 11 ic 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. Page 78 of 90 ------- 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 \n Misi ueiieralmii is urn 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 Spray polyurethane foam Printing and printing compounds Application of spray Vapor Inhalation Workers Yes Due to high volatility at room temperature, inhalation exposure from vapor should be further evaluated. Industrial use, potential commercial use Other Uses polyurethane foam through a nozzle Liquid ( nulacl Dermal ()\l \n Dermal e\pnsiiie is e\peeled in he primai'iK in woikeiN direelK in\ ol\ ed in hamllnm 11 ic chemical. Industrial use, potential commercial use Use of Printing Inks Vapor Dermal ONU No The absorption of l,4-dio\ane \ 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- Worker Handling of wastes Liquid Contact Dermal Workers Yes Workers are expected to routinely handle liquids containing 1,4-dioxane. Manufacture, processing, use, Disposal Wastewater treatment Industrial Vapor Dermal Workers No The absorption of 1,4-dioxane vapor via skin is expected to be orders of Page 79 of 90 ------- Solid wastes and liquid wastes wastewater treatment Publicly owned treatment works (POTW) Underground Injection Municipal landfill Hazardous landfill magnitude lower than via inhalation and will not be further analyzed. Manufacture, processing, use, Disposal Vapor Inhalation Workers Yes Due to high volatility at room temperature, inhalation exposure from vapor should be further evaluated. Manufacture, processing, use, Disposal Liquid ( milacl Dermal <>\l \n Dermal e\pnMiie is e\peeled In he primariK lo uoikei's diieelK iiiuil\edni haiidlniu 11 ic chemical Manufacture, processing, use, Disposal 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, 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 Willie is. ()\l \n Misi ueiieialKin is uni c\pecled Page 80 of 90 ------- Appendix E SUPPORTING TABLE FOR ENVIRONMENTAL RELEASES AND WASTES CONCEPTUAL MODEL All possible exposure scenarios for each condition of use were identified according to the COU in Table 2-3 and the environmental releases conceptual model in Figure 2-3 and are presented in Table Apx E-l. 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. EPA may further refine the mapping/grouping of exposure scenarios based on factors corresponding to conditions of use as additional information is identified during risk evaluation. Table Apx E-l: Environmental Releases and Wastes Exposure Scenarios for 1,4-Dioxane l.ilVock' Si;i»e I so Release l'l\|)OMIIV Pill h \\ ;¦> l'l\|)OMIIV Roule Reeeplor l-'urfher l.\;ilii;i(ion? R;iliun;ile for I'll rl her r.\;ilu;ilion / no lull lie i- l.\;ilu;ilion 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. 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 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). Page 81 of 90 ------- Owned Treatment Works (POTW) 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 82 of 90 ------- Appendix F INCLUSION AND EXCLUSION CRITERIA FOR FULL TEXT SCREENING Appendix F contains the eligibility criteria for various data streams informing the TSCA risk evaluation: environmental fate; engineering and occupational exposure; exposure to the general population and consumers; and human health hazard. The criteria are applied to the on-topic references that were identified following title and abstract screening of the comprehensive search results published on June 22, 2017. Systematic reviews typically describe the study eligibility criteria in the form of PECO statements or a modified framework. PECO stands for Population, Exposure, Comparator and Outcome and the approach is used to formulate explicit and detailed criteria about those characteristics in the publication that should be present in order to be eligible for inclusion in the review. EPA/OPPT adopted the PECO approach to guide the inclusion/exclusion decisions during full text screening. Inclusion and exclusion criteria were also used during the title and abstract screening, and documentation about the criteria can be found in the Strategy for Conducting Literature Searches document published in June 2017 along with each of the TSCA Scope documents. The list of on-topic references resulting from the title and abstract screening is undergoing full text screening using the criteria in the PECO statements. The overall objective of the screening process is to select the most relevant evidence for the TSCA risk evaluation. As a general rule, EPA is excluding non-English data/information sources and will translate on a case by case basis. The inclusion and exclusion criteria for ecotoxicological data have been documented in the ECOTOX SOPs. The criteria can be found at https://cfpub.epa.gov/ecotox/h.elp.cfm.?h.elptabs=tab4) and in the Strategy for Conducting Literature Searches document published along with each of the TSCA Scope documents. Since full text screening commenced right after the publication of the TSCA Scope document, the criteria were set to be broad to capture relevant information that would support the initial scope. Thus, the inclusion and exclusion criteria for full text screening do not reflect the refinements to the conceptual model and analysis plan resulting from problem formulation. As part of the iterative process, EPA is in the process of refining the results of the full text screening to incorporate the changes in information/data needs to support the revised scope. These refinements will include changes to the inclusion and exclusion criteria discussed in this appendix to better reflect the revised scope of the risk evaluation and will likely reduce the number of data/information sources that will undergo evaluation. F.l Inclusion Criteria for the Data Sources Reporting Environmental Fate Data EPA/OPPT developed a generic PESO statement to guide the full text screening of environmental fate data sources. PESO stands for Pathways and Processes, Exposure, Setting or Scenario, and Outcomes. Subsequent versions of the PESO statement may be produced throughout the process of screening and evaluating data for the chemicals undergoing TSCA risk evaluation. Studies that comply with the inclusion criteria in the PESO statement are eligible for inclusion, considered for evaluation, and Page 83 of 90 ------- possibly included in the environmental fate assessment. On the other hand, data sources are excluded if they do not meet the criteria in the PESO statement. During the development of conceptual models and consideration of the nexus between TSCA and other EPA regulations for 1,4-dioxane it was determined that no pathways for consumer or environmental exposure requiring environmental fate information would be further analyzed. As described in Section 2.5.2, EPA does not plan to evaluate exposure pathways to human receptors from consumer uses of 1,4- dioxane. As described in Section 2.5.3, there are no exposure pathways for general population or ecological receptors from environmental releases and waste streams associated with industrial and commercial activities for 1,4-dioxane that EPA plans to include and further analyze in the risk assessment. For 1,4-dioxane no exposure pathways to human and ecological receptors from consumer products, environmental releases, or waste streams associated with industrial and commercial activities will be further analyzed in risk evaluation. In the absence of exposure pathways for further analysis, environmental fate data will not be evaluated further. Therefore, no PESO statement or fate data needs and associated processes, media and exposure pathways considered in the development of the environmental fate assessment for 1,4-dioxane will be presented. F.2 Inclusion Criteria for Data Sources Reporting Engineering and Occupational Exposure Data EPA/OPPT developed a generic RESO statement to guide the full text screening of engineering and occupational exposure literature (TableApx F-l). RESO stands for Receptors, Exposure, Setting or Scenario, and Outcomes. Subsequent versions of the RESO statement may be produced throughout the process of screening and evaluating data for the chemicals undergoing TSCA risk evaluation. Studies that comply with the inclusion criteria specified in the RESO statement will be eligible for inclusion, considered for evaluation, and possibly included in the environmental release and occupational exposure assessments, while those that do not meet these criteria will be excluded. The RESO statement should be used along with the engineering and occupational exposure data needs table (Table Apx F-2) when screening the literature. Since full text screening commenced right after the publication of the TSCA Scope document, the criteria for engineering and occupational exposure data were set to be broad to capture relevant information that would support the risk evaluation. Thus, the inclusion and exclusion criteria for full text screening do not reflect the refinements to the conceptual model and analysis plan resulting from problem formulation. As part of the iterative process, EPA is in the process of refining the results of the full text screening to incorporate the changes in information/data needs to support the risk evaluation. Page 84 of 90 ------- TableApx F-l: Inclusion Criteria for Data Sources Reporting Engineering and Occupational Exposure Data KI-'.SO l.lemcnl 11 \ iriencc Receptors • Humans: Workers, including occupational non-users Please refer to the conceptual models for more information about the human receptors included in the TSCA risk evaluation. Exposure • Worker exposure and relevant environmental releases of the chemical substance of interest o Dermal and inhalation exposure routes (as indicated in the conceptual model) o Surface water (as indicated in the conceptual model) Please refer to the conceptual models for more information about the routes and media/pathways included in the TSCA risk evaluation. Setting or Scenario • Any occupational setting or scenario resulting in worker exposure and relevant environmental releases (includes all manufacturing, processing, use, disposal indicated in Table Apx F-2 below. Outcomes • Quantitative estimates* of worker exposures and of relevant environmental releases from occupational settings • General information and data related and relevant to the occupational estimates* * Metrics (e.g., mg/kg/day or mg/m3 for worker exposures, kg/site/day for releases) are determined by toxicologists for worker exposures and by exposure assessors for releases; also, the Engineering Data Needs (Table Apx F-2) provides a list of related and relevant general information. TSCA=Toxic Substances Control Act Page 85 of 90 ------- TableApx F-2: Engineering, Environmental Release and Occupational Data Necessary to Develop the Environmental Release and Occupational Exposure Assessments Ohjiiiitc Dckriniiiod (In rin vi Scoping l \|)o ol' l);K;i General Engineering Assessment (may apply for either or both Occupational Exposures and / or Environmental Releases) 2. 3. 4. 5. Description of the life cycle of the chemical(s) of interest, from manufacture to end-of-life (e.g., each manufacturing, processing, or use step), and material flow between the industrial and commercial life cycle stages. {Tags: Life cycle description, Life cycle diagram}3 The total annual U.S. volume (lb/yr or kg/yr) of the chemical(s) of interest manufactured, imported, processed, and used; and the share of total annual manufacturing and import volume that is processed or used in each life cycle step. {Tags: Production volume, Import volume, Use volume, Percent PV}a Description of processes, equipment, unit operations, and material flows and frequencies (lb/site-day or kg/site-day and days/yr; lb/site-batch and batches/yr) of the chemical(s) of interest during each industrial/ commercial life cycle step. Note: if available, include weight fractions of the chemicals (s) of interest and material flows of all associated primary chemicals (especially water). {Tags: Process description, Process material flow rate, Annual operating days, Annual batches, Weight fractions (for each of above, manufacture, import, processing, use)}11 Basic chemical properties relevant for assessing exposures and releases, e.g., molecular weight, normal boiling point, melting point, physical forms, and room temperature vapor pressure. {Tags: Molecular weight, Boiling point, Melting point, Physical form, Vapor pressure, Water solubility}a Number of sites that manufacture, process, or use the chemical(s) of interest for each industrial/ commercial life cycle step and site locations. {Tags: Numbers of sites (manufacture, import, processing, use), Site locations}a Occupational Exposures 6. 7. 9. Description of worker activities with exposure potential during the manufacture, processing, or use of the chemical(s) of interest in each industrial/commercial life cycle stage. {Tags: Worker activities (manufacture, import, processing, use)}a Potential routes of exposure (e.g., inhalation, dermal). {Tags: Routes of exposure (manufacture, import, processing, use)}a Physical form of the chemical(s) of interest for each exposure route (e.g., liquid, vapor, mist) and activity. {Tags: Physical form during worker activities (manufacture, import, processing, use)}a Breathing zone (personal sample) measurements of occupational exposures to the chemical(s) of interest, measured as time-weighted averages (TWAs), short-term exposures, or peak exposures in each occupational life cycle stage (or in a workplace scenario similar to an occupational life cycle stage). {Tags: PBZ measurements (manufacture, import, processing, use)}a 10. Area or stationary measurements of airborne concentrations of the chemical(s) of interest in each occupational setting and life cycle stage (or in a workplace scenario similar to the life cycle stage of interest). {Tags: Area measurements (manufacture, import, processing, use)}a 11. For solids, bulk and dust particle size characterization data. {Tags: PSD measurements (manufacture, import, processing, use)}a 12. Dermal exposure data. {Tags: Dermal measurements (manufacture, import, processing, use)} 13. Data needs associated with mathematical modeling (will be determined on a case-by-case basis). {Tags: Worker exposure modeling data needs (manufacture, import, processing, use)}a 14. Exposure duration (hr/day). {Tags: Worker exposure durations (manufacture, import, processing, use)}a 15. Exposure frequency (days/yr). {Tags: Worker exposure frequencies (manufacture, import, processing, use)}a 16. Number of workers who potentially handle or have exposure to the chemical(s) of interest in each occupational life cycle stage. {Tags: Numbers of workers exposed (manufacture, import, processing, use)} a 17. Personal protective equipment (PPE) types employed by the industries within scope. {Tags: Worker PPE (manufacture, import, processing, use)}a 18. Engineering controls employed to reduce occupational exposures in each occupational life cycle stage (or in a workplace scenario similar to the life cycle stage of interest), and associated data or estimates of exposure reductions. {Tags: Engineering controls (manufacture, import, processing, use), Engineering control effectiveness data}a Page 86 of 90 ------- Objec(i\e Delermineri (Inrinvi Scopiii" l \|H' of Dala Environmental Releases 1Dcbci'ipuon of iclc\ anl s>ouiv.vs> of poleiiual en\ iioimieiiial reload, including cleaning of residues from process equipment and transport containers, involved during the manufacture, processing, or use of the chemical(s) of interest in each life cycle stage. {Tags: Release sources (manufacture, import, processing, use)}a 20. Estimated mass (lb or kg) of the chemical(s) of interest released from industrial and commercial sites to relevant environmental media (water) and treatment and disposal methods (POTW), including releases per site and aggregated over all sites (annual release rates, daily release rates) {Tags: Release rates (manufacture, import, processing, use)}" 21. Relevant release or emission factors. {Tags: Emission factors (manufacture, import, processing, use)}a 22. Number of release days per year. {Tags: Release frequencies (manufacture, import, processing, use)}11 23. Data needs associated with mathematical modeling (will be determined on a case-by-case basis). {Tags: Release modeling data needs (manufacture, import, processing, use)}a 24. Waste treatment methods and pollution control devices employed by the industries within scope and associated data on release/emission reductions. {Tags: Treatment/ emission controls (manufacture, import, processing, use), Treatment/ emission controls removal/ effectiveness data}a Notes: a These are the tags included in the full text screening form. The screener makes a selection from these specific tags, which describe more specific types of data or information. Abbreviations: hr=Hour kg=Kilogram(s) lb=Pound(s) yr=Year PV=Particle volume PBZ= POTW=Publicly owned treatment works PPE=Personal projection equipment PSD=Particle size distribution TWA=Time-weighted average F.3 Inclusion Criteria for Data Sources Reporting Environmental and General Population Exposure EPA/OPPT developed a generic PECO statement to guide the full text screening of environmental and general population exposure data sources. PECO stands for Population, Exposure, Comparator and Outcome and the approach is used to formulate explicit and detailed criteria about those characteristics in the publication that should be present to be eligible for inclusion in the review. Subsequent versions of the PECO statement may be produced throughout the process of screening and evaluating data for the chemicals undergoing TSCA risk evaluation. Exposure pathways to human and ecological receptors from environmental releases associated with industrial and commercial activities will not be further analyzed in risk evaluation (see Section 2.5.3.2 and Section 2.5.3.3). In the absence of exposure pathways for further analysis, data related to environmental and general population exposure will not be further analyzed. Page 87 of 90 ------- F.4 Inclusion Criteria for Data Sources Reporting Human Health Hazards TableApx F-3: Inclusion and Exclusion Criteria for Data Sources Reporting Human Health Hazards Related to 1,4-Dioxane Exposure" PECO Element Evidence Stream Papers/Features Included Papcrs/Fcatu res Excluded Population Human • Any population • All lifestages • Study designs: o Controlled exposure, cohort, case-control, cross- sectional, case-crossover, case studies, and case series for all endpoints Animal • All non-human whole-organism mammalian species • All lifestages • Non-mammalian species Mechanistic • Human or animal cells, tissues, or biochemical reactions (e.g., ligand binding assays) with in vitro exposure regimens; bioinformatics pathways of disease analysis; or high throughput screening data. Exposure Human • Exposure based on administered dose or concentration of 1,4-dioxane, biomonitoring data (e.g., urine, blood or other specimens), environmental or occupational-setting monitoring data (e.g., air, water levels), job title or residence • Primary metabolites of interest (e.g., HTTA) as identified in biomonitoring studies • All routes of exposure • Any number of exposure groups • Quantitative, semi-quantitative or qualitative estimates of exposure • Exposures to multiple chemicals/mixtures only if 1,4- dioxane or related metabolites were independently measured and analyzed • Multiple chemical/mixture exposures with no independent measurement of or exposure to 1,4-dioxane (or related metabolite) Animal • A minimum of 2 quantitative dose or concentration levels of 1,4-dioxane plus a negative control group a • Acute, subchronic, chronic exposure from oral, dermal, inhalation routes • Exposure to 1,4-dioxane only (no chemical mixtures) • Only 1 quantitative dose or concentration level in addition to the controla • Route of exposure not by inhalation, oral or dermal type (e.g., intraperitoneal, injection) • No duration of exposure stated • Exposure to 1,4-dioxane in a chemical mixture Mechanistic • Exposure based on concentrations of the neat material of 1,4-dioxane • A minimum of 2 dose or concentration levels tested plus a control group a • Only 1 quantitative dose or concentration level in addition to the controla • Exposure to 1,4-dioxane in a chemical mixture Comparator Human • A comparison population [not exposed, exposed to lower levels, exposed below detection] for all endpoints • No comparison population for all endpoints Animal • Negative controls that are vehicle-only treatment and/or no treatment • Negative controls other than vehicle-only treatment or no treatment Mechanistic • Exposed to vehicle-only treatment and/or no treatment • For genotoxicity studies only, studies using positive controls • Negative controls other than vehicle-only treatment or no treatment • For genotoxicity studies only, a lack of positive controls Outcome Human and Animal • Endpoints described in the 1,4-dioxane scope documentb: o Cancer o Liver toxicity Page 88 of 90 ------- PI'.CO I! lemon 1 l.\ idcncc Siiviim P;i|)crs/l"V;ilures Included Pii|K'rs/l-Vii(uivs l.xcliidcd o Kidney toxicity o Neurotoxicity o Irritation o Acute Toxicity/Poisoning • Other endpointsc Mechanistic • All mechanistic data that may inform the following health outcomes: o Cancer o Genotoxicity o Neurological/Behavior o Renal o Hepatic o Irritation o Acute Toxicity/Poisoning o ADME/PBPK • Data related to other mechanisms of toxicity a General Considerations Papers/Features Included Pa pe rs/Featu res Excluded • Written in English11 • Reports a primary source or meta-analysis a • Full-text available • Reports both 1,4-dioxane exposure and a health outcome (or mechanism of action) • Not written in Englishd • Reports a secondary source (e.g., review papers)" • No full-text available (e.g., only a study description/abstract, out-of-print text) • Reports a 1,4-dioxane-related exposure or a health outcome, but not both (e.g. incidence, prevalence report) a Some of the studies that are excluded based on the PECO statement may be considered later during the systematic review process. For 1,4-dioxane, EPA will evaluate studies related to susceptibility after other data are reviewed. Finally, EPA may also review other data as needed (e.g., animal studies using one concentration, review papers). b EPA will review key and supporting studies in the IRIS assessment that were considered in the dose-response assessment for non-cancer and cancer endpoints as well as studies published after the IRIS assessment. c EPA may screen for hazards other than those listed in the scope document if they were identified in the updated literature search that accompanied the scope document. d EPA may translate studies as needed. Page 89 of 90 ------- F.5 List Of Retracted Papers The following reference was retracted by the journal: HERO ID: 3538089 (1,4-dioxane; HBCD) Kreipke, CW; Rafols, JA; Reynolds, CA; Schafer, S; Marinica, A; Bedford, C; Fronczak, M; Kuhn, D; Armstead, WM. (2011). Clazosentan, a novel endothelin A antagonist, improves cerebral blood flow and behavior after traumatic brain injury. Neurol Res 33: 208-213. http://dx.doi.org/10.! 179/016164111X12881719352570 Page 90 of 90 -------