SEPA
United States
Environmental Protection Agency
EPA DocumentW 740-R1-5003
April 2015
Office of Chemical Safety and
Pollution Prevention
TSCA Work Plan Chemical
Problem Formulation and Initial Assessment
1,4-Dioxane
CASRN: 123-91-1
O
O
April 2015
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TABLE OF CONTENTS
TABLE OF CONTENTS 2
AUTHORS / CONTRIBUTORS / ACKNOWLEDGEMENTS 4
ABBREVIATIONS 5
EXECUTIVE SUMMARY 7
1 INTRODUCTION 10
1.1 SCOPE OF THE ASSESSMENT 11
1.2 REGULATORY AND ASSESSMENT HISTORY 12
2 PROBLEM FORMULATION 14
2.1 PHYSICAL AND CHEMICAL PROPERTIES 14
2.2 PRODUCTION AND USES 15
2.3 FATE AND TRANSPORT 19
2.4 EXPOSURES 21
2.4.1 Releases to the Environment 21
2.4.2 Presence in the Environment 21
2.4.3 Occupational Exposure 23
2.4.4 General Population Exposure 25
2.4.5 Consumer Exposure 27
2.5 HAZARD ENDPOINTS 28
2.5.1 Environmental Hazard 28
2.5.2 Human Health Hazard 28
2.6 RESULTS OF PROBLEM FORMULATION 30
2.6.1 Conceptual Model 30
2.6.2 Analysis Plan 33
2.6.3 Uncertainties and Data Gaps 34
REFERENCES 35
APPENDICES 40
Appendix A Regulatory and Assessment History 40
Appendix B Summary of Uses and End Products 43
Appendix C Occupational Exposure Data 44
Appendix D Ecological Hazard Studies 46
D-l ACUTE TOXICITY TO AQUATIC ORGANISMS 46
D-2 CHRONIC TOXICITY TO AQUATIC ORGANISMS 48
D-3 TERRESTRIAL PLANTS TOXICITY 49
D-4 SOIL INVERTEBRATE AND AVIAN TOXICITY 49
Appendix E Human Health Hazard Studies 50
E-l ACUTE TOXICITY STUDIES 50
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E-2 REPEATED-DOSE TOXICITY STUDIES 50
E-3 REPRODUCTIVE AND DEVELOPMENTAL TOXICITY STUDIES 51
E-4 SKIN IRRITATION AND SENSITIZATION STUDIES 51
E-5 GENOTOXICITY AND CANCER STUDIES 51
LIST OF TABLES
Table 2-1: Physical and Chemical Properties of 1,4-Dioxane 15
Table 2-2: 1986-2012 National Production Volume Data for 1,4-Dioxane (Millions of Pounds) 15
Table 2-3: CDR Industrial and Consumer Use Data 18
Table 2-4: Environmental Fate End points for 1,4-Dioxane 20
Table 2-5: Exposure Concentrations for Occupational Scenarios in European Industrial and Laboratory
Facilities 24
Table 2-6: Preliminary Data from the EPA UCMR 3 (January 2015) 26
Table A 1: History of Regulatory and Assessment Actions in the U.S. and Internationally 39
Table B-l: Summary of All Uses of 1,4-Dioxane and End Products 43
Table C-l: Summary of 1,4 Dioxane Occupational Monitoring Data for Process Operators in the
Synthesis Area from an ACC Member Company where 1,4-Dioxane is Produced as a Byproduct in its
Manufacturing Process 43
Table C-2: 1,4-Dioxane - OSHA Chemical Exposure Health Data, 1997 - 2011 45
Table D-l: Aquatic Toxicity Data for 1,4-Dioxane - Acute Toxicity 47
Table D-2: Aquatic Toxicity Data for 1,4-Dioxane - Chronic Toxicity 48
Table E-l: Human Health Endpointsfor 1,4-Dioxane 53
LIST OF FIGURES
Figure 2-1: Chemical structure of 1,4-dioxane 14
Figure 2-2: Conceptual Model of Potential Exposure Pathways for 1,4-Dioxane 31
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AUTHORS / CONTRIBUTORS / ACKNOWLEDGEMENTS
This report was developed by the United States Environmental Protection Agency (US EPA),
Office of Chemical Safety and Pollution Prevention (OCSPP), Office of Pollution Prevention and
Toxics (OPPT). The Work Plan Chemical Problem Formulation for 1,4-dioxane was prepared based on
currently available data. Mention of trade names does not constitute endorsement by EPA.
EPA Assessment Team
Leads:
Katherine Anitole, OPPT/Risk Assessment Division (RAD)
Susan A. Laessig, OPPT/RAD
Team Members:
Nishkam Agarwal, OPPT/ Chemistry, Economics and Sustainable Strategies Division (CESSD)
Christina Cinalli (retired), OPPT/RAD
Ana Corado, OPPT/Environmental Assistance Division (EAD)
Joe Ford, OPPT/RAD
Amuel Kennedy, OPPT/RAD
Scott Prothero, OPPT/RAD
Teresa Washington, OPPT/RAD
Management Leads:
Yvette Selby-Mohamadu, OPPT/RAD
Todd Stedeford, OPPT/RAD
Contract Support
Technical support for portions of this document was provided by Abt Associates, Inc. under EPA
Contract No. EP-W-08-010.
Docket
Please visit the public docket (www.regulations.gov; Docket: EPA-HQ-OPPT-2015-0078) to view
supporting information.
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ABBREVIATIONS
ACC American Chemistry Council
ACGIH American Conference of Government Industrial Hygienists
AEGL Acute Exposure Guideline Level
AES Alkyl ethoxy sulphates
ATSDR Agency for Toxic Substances and Disease Registries
BCF Bioconcentration factor
CAA Clean Air Act
CASRN Chemical Abstract Service Registry Number
CBI Confidential Business Information
CCL Candidate Contaminant List
CDR Chemical Data Reporting
CPSC Consumer Product Safety Commission
CSF Cancer Slope Factor
EC European Commission
ECHA European Chemicals Agency
EPA Environmental Protection Agency
EU European Union
EUSES European System for the Evaluation of Substances
FDA Food and Drug Administration
HEAA p-hydroxyethoxy acetic acid
Hg Mercury
HHS Department of Health and Human Services
HPV High Production Volume
IARC International Agency for Research on Cancer
IRIS Integrated Risk Information System
IUR Inventory Update Reporting Rule; Inhalation Unit Risk
kg Kilogram(s)
Kow OctanohWater partition coefficient
Ib Pound
LOEC Lowest Observed Effect Concentration
LOEL Lowest Observed Effect Level
Log KOW Logarithmic Octanol:Water partition coefficient
MATC Maximum Acceptable Toxicant Concentration
mg Milligram(s)
MOE Margin of Exposure
MRL Minimal Risk Level
NIOSH National Institute of Occupational Safety and Health
NOEC No Observed Effect Concentration
NOAEL No Observed Adverse Effect Level
NPL National Priorities List
NTP National Toxicology Program
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OAR Office of Air and Radiation
OCSPP Office of Chemical Safety and Pollution Prevention
OECD Organisation for Economic Co-operation and Development
OPPT Office of Pollution Prevention and Toxics
OSHA Occupational Safety and Health Administration
OSWER Office of Solid Waste and Emergency Response
OW Office of Water
PBPK Physiologically Based Pharmacokinetic
PBT Persistent, Bioaccumulative, Toxic
PDE Permitted Daily Exposure
PEC Predicted Environmental Concentration
PEL Permissible Exposure Level
ppb Parts per billion
ppm Parts per million
PV Production Volume
PWS Public Water System
RA Risk Assessment
RAR Risk Assessment Report
REACH Registration, Evaluation, Authorisation and Restriction of Chemicals
REL Recommended Exposure Level
RfC Reference Concentration
RfD Reference Dose
TCA 1,1,1-trichloroethane
TLV Threshold Limit Value
TRI Toxic Release Inventory
TSCA Toxic Substances Control Act
UCMR Unregulated Contaminant Monitoring Rule
US United States
WHO World Health Organisation
WWTP Wastewater Treatment Plant
Yr Year
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EXECUTIVE SUMMARY
As part of EPA's comprehensive approach to enhance the Agency's management of existing
chemicals, in March 2012 EPA/OPPT identified a work plan of chemicals for further assessment
under the Toxic Substances Control Act (TSCA)1. Chemical risk assessments will be conducted if,
as a result of scoping and problem formulation, there are exposures of concern, identified
hazards and sufficient data for quantitative analysis. If an assessment identifies unreasonable
risks to humans or the environment, EPA will pursue risk management. This document presents
the problem formulation and initial assessment for 1,4-dioxane as part of the TSCA Work Plan
program.
The conclusions from this problem formulation and initial assessment are that:
EPA/OPPT will further assess potential risks to workers exposed during product
formulation and use as a cleaning agent.
EPA/OPPT will further assess potential risks to workers and consumers exposed during
the use of TSCA-use products that contain 1,4-dioxane as a contaminant, such as paints,
varnishes, adhesives, cleaners and detergents.
Risk to the general population through inhalation exposure to ambient air emissions is
estimated to be low.
An assessment of risk from exposure through drinking water is not needed at this time
because 1,4-dioxane is currently being monitored and EPA will determine whether or
not regulatory action is needed as part of EPA's Regulatory Determination process.
Based on the low hazard profile for 1,4-dioxane to aquatic organisms, risks to these
organisms are expected to be low. Lack of hazard data for sediment and soil organisms
precludes determination of risk to these environmental compartments. Therefore,
further analysis of environmental risk is not planned.
1,4-Dioxane is an industrial solvent used in the production of a wide variety of products, as a
laboratory reagent, a chemical intermediate, an extraction medium for fats and oils, and as part
of a polymerization catalyst. Other uses of 1,4-dioxane are in commercial and consumer
products such as lacquers, varnishes, paint strippers, dyes, greases, cleaners and detergents,
adhesives, cosmetics and deodorants. 1,4-Dioxane is also present as an unintended byproduct
in cosmetics, detergents, and shampoos. Historically, 90% of all 1,4-dioxane was used as a
stabilizer in chlorinated solvents such as 1,1,1-trichloroethane (TCA). Use of 1,4-dioxane has
decreased since 1,1,1-trichloroethane was phased out by the Montreal Protocol in 1996 for all
uses except a few select applications. In the 1980's and early 1990's, 10 to 50 million pounds
were manufactured yearly and from 1994 to 2006, the yearly U.S. production volume of 1,4-
1 http://www.epa.gov/oppt/existingchemicals/
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dioxane has been 1 to 10 million pounds. Recent data show that 1.1 million pounds is released
to the environment.
During scoping and problem formulation, EPA/OPPT reviewed previous risk assessments and
additional published studies on the fate, exposure and hazard of 1,4-dioxane. EPA/OPPT
examined likely exposure and hazard scenarios based on current production, use, and fate
information to identify scenarios amenable to risk analysis. The scenarios considered were:
Workers potentially exposed during manufacturing and formulation of 1,4-dioxane or in
industrial or laboratory facilities where 1,4-dioxane is used.
Workers and consumers potentially exposed during the use of products that contain
1,4-dioxane as a contaminant.
The general population potentially exposed via inhalation of ambient air receiving
emissions from manufacturing/formulating facilities, as well as incineration of waste
streams/products.
The general population potentially exposed to 1,4-dioxane through contaminated
drinking water.
The routes of potential human exposure to 1,4-dioxane are inhalation, ingestion and dermal
contact. Dermal exposures are not addressed due to high volatilization, low absorption and lack
of dermal toxicity studies. Potential human health effects from inhalation and ingestion include
cancer and noncancer outcomes (liver, kidney and nasal effects) in workers, consumers and the
general population.
EPA/OPPT reviewed the ecological hazards of 1,4-dioxane and determined that acute and
chronic hazard is low for aquatic species. There are no sediment or soil toxicity data to assess
the hazard to organisms in these environmental compartments. A conceptual model was not
developed for environmental health and further analysis of environmental risk is not planned.
The results of problem formulation as illustrated in the conceptual model for human health and
described under the assessment questions indicate that:
A 2002 European assessment found potential risk to workers for occupational exposures via
the dermal and inhalation routes during product formulation and the use of 1,4-dioxane as
a cleaning agent. Availability of EPA's recently updated benchmarks for human health
suggest that human health risks should be reassessed. While US data on occupational
exposures are limited, EPA/OPPT will further assess the risk to workers from inhalation of
1,4-dioxane during manufacture, formulation and use of products using available data or
modeled exposures in the absence of data.
Workers and consumers may be exposed to 1,4-dioxane present as a contaminant in
products such as personal care products, paints, adhesives, varnishes, cleaners and
detergents. Risk assessments in Canada and Europe concluded that levels of contamination
do not pose concerns for human health. While personal care products are regulated by the
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FDA, uses in paints, adhesives, varnishes, cleaners and detergents fall under TSCA authority.
Availability of EPA's recently updated benchmarks for human health suggest that human
health risks should be reassessed. Therefore, EPA/OPPT plans to further assess potential
risks posed to consumers by 1,4-dioxane in products covered under TSCA.
The general population may be exposed from inhalation to ambient levels of 1,4-dioxane in
air. Regulations for air pollution are in place through the Clean Air Act (CAA). 1,4-Dioxane is
short lived in the environment and historical ambient air levels of 1,4-dioxane are
considered low. Risk assessments in Canada and Europe concluded that there are no risks of
concern from exposure to 1,4-dioxane in ambient air. Given that 1,4-dioxane is regulated
under the CAA as a hazardous air pollutant (US EPA, 2000) and EPA/OPPT's comparison of
historical air concentrations of 1,4-dioxine against the recent EPA IRIS benchmarks (RfC and
IUR) indicate these concentrations are below levels of concern, assessment of general
population exposure to 1,4-dioxane in ambient air will not be further analyzed by EPA/OPPT
underTSCA.
The general population may be exposed to 1,4-dioxane in contaminated drinking water.
EPA's Office of Water is currently monitoring public drinking water systems in order to
evaluate the risk to defined populations. Potential source contributions to drinking water
are uncertain. Since 1,4-dioxane is being monitored through December 2015, decisions as to
whether or not to regulate the contaminant in drinking water will be considered as part of
the EPA's Regulatory Determination process.
In summary, as a result of problem formulation, EPA/OPPT plans to conduct additional risk
analysis on potential worker and consumer exposures under the TSCA Existing Chemicals
Program using existing data and methods. EPA/OPPT plans to carefully review and evaluate the
results of previous exposure assessments and health benchmarks. EPA will develop margins of
exposure and cancer risk estimates to evaluate the potential risks from worker and consumer
exposure to 1,4-dioxane. EPA does not have risk concerns for the general population through
inhalation exposure to ambient air emissions.
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1 INTRODUCTION
As a part of EPA's comprehensive approach to enhance the Agency's management of existing
chemicals, in March 2012 EPA/OPPT identified a work plan of chemicals for further assessment
under the Toxic Substances Control Act (TSCA)2. After gathering input from stakeholders,
EPA/OPPT developed criteria used for identifying chemicals for further assessment3. The
criteria focused on chemicals that meet one or more of the following factors: (1) potentially of
concern to children's health (for example, because of reproductive or developmental effects);
(2) neurotoxic effects; (3) persistent, bioaccumulative and toxic (PBT); (3) probable or known
carcinogens; (4) used in children's products; or (5) detected in biomonitoring programs. Using
this methodology, EPA/OPPT identified a TSCA Work Plan of chemicals as candidates for risk
assessment in the next several years. In the prioritization process, 1,4-dioxane was identified
for assessment based on classification as a probable human carcinogen, wide use in consumer
products, high reported releases to the environment, and presence in groundwater, ambient air
and indoor environments.
EPA/OPPT is performing risk assessments on chemicals in the work plan. If an assessment
identifies unacceptable risks to humans or the environment, EPA will pursue risk management.
The target audience for the final risk assessment is primarily EPA risk managers; however, it
may also be of interest to the broader risk assessment community as well as US stakeholders
interested in 1,4-dioxane. The information presented in the risk assessment may be of
assistance to other federal, state and local agencies as well as to members of the general public
who are interested in understanding whether there are risks from exposure to 1,4-dioxane.
The initial step in the EPA/OPPT risk assessment development process, which is distinct from
the initial prioritization exercise, includes planning, scoping and problem formulation. During
these steps EPA/OPPT may review currently available data and information, including but not
limited to, assessments conducted by others (e.g., authorities in other countries), published or
readily available reports and published scientific literature. The problem formulation data
review could result in refinement of pathways of interest previously identified in the initial
prioritization.
This document includes the results of scoping, problem formulation, and initial assessment for
1,4-dioxane. In the scoping stage, EPA/OPPT determined which chemical(s) to include and what
uses to consider in the assessment. During problem formulation, EPA/OPPT identified available
fate, exposure and hazard data, and characterized potential exposures, receptors and effects.
EPA/OPPT developed a conceptual model and an analysis plan as a result of problem
formulation.
2 http://www.epa.gov/oppt/existingchemicals/pubs/workplans.html
3 http://www.epa.gov/oppt/existingchemicals/pubs/wpmethods.pdf
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1.1 Scope of the Assessment
The TCSA Work Plan chemical 1,4-dioxane is a high production volume chemical (up to 10
million Ibs/yr, based on publicly available information), has a variety of industrial uses and may
be present in both consumer and commercial products. 1,4-Dioxane is used as an industrial
solvent in the production of a wide variety of products, as a laboratory reagent, a chemical
intermediate, an extraction medium for fats and oils and as part of a polymerization catalyst
(ATSDR, 2012). 1,4-dioxane is also used in commercial and consumer products such as lacquers,
varnishes, paint strippers, dyes, greases, cleaners and detergents, adhesives, cosmetics and
deodorants (European Chemicals Bureau, 2002; US EPA, 2014d). In addition, 1,4-dioxane is
present as a contaminant in consumer cosmetics/toiletries, household detergents,
Pharmaceuticals, foods, agricultural and veterinary products and ethylene glycol-based
antifreeze coolants, because it is a byproduct of certain ethoxylated substances (ATSDR, 2012).
Workers, consumers and the general population may be exposed to 1,4-dioxane by inhalation,
ingestion and dermal routes. Because 1,4-dioxane is not intentionally added to consumer
products, only workers are exposed to products which intentionally contain 1,4-dioxane.
Inhalation is expected to be the predominant route of exposure due to the high vapor pressure
and volatility of 1,4-dioxane. Workers and consumers may be exposed to products that contain
1,4-dioxane as an unwanted byproduct or an intermediate that is not fully reacted and the
concentrations of 1,4-dioxane in these cases are lower, usually measured in parts per million or
less. The general population may be exposed environmentally from air or water containing 1,4-
dioxane.
Absorption of 1,4-dioxane occurs readily through the lungs and gastrointestinal system and
poorly through the skin. After absorption, 1,4-dioxane is rapidly eliminated from the body and
does not accumulate. EPA classifies 1,4-dioxane as "likely to be carcinogenic to humans" by all
routes of exposure based on liver tumors in rats and mice following chronic drinking water
exposure (US EPA, 2013b). Nasal tumors were observed in rats following chronic inhalation or
drinking water exposure. Short-term exposure may result in irritation of the eyes and throat
(ATSDR, 2012) and chronic exposure may result in dermatitis, eczema, drying and cracking of
skin, and liver and kidney damage (ATSDR, 2012).
In the environment, 1,4-dioxane partitions to water and is highly mobile in soil. 1,4-Dioxane is
highly volatile, has a short residence time in air and does not readily biodegrade in water.
Toxicity to aquatic organisms is not expected based on low hazard values.
Given the common use, widespread exposure and potential human health hazards of 1,4-
dioxane, EPA/OPPT conducted a problem formulation and evaluation of readily available data
and information to determine the exposures and hazards of interest for risk assessment.
Available data were used including chemical structure, physical chemistry, production volume,
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reported uses and toxicological information from existing assessments to develop a conceptual
model and an analysis plan.
1.2 Regulatory and Assessment History
EPA/OPPT reviewed and considered the regulatory and assessment history of 1,4-dioxane
(Appendix A: Regulatory and Assessment History).
National (U.S.)
1,4-Dioxane is a known animal carcinogen according to the National Toxicology Program (NTP)
(NTP, 2014). The US Department of Health and Human Services (DHHS) considers 1,4-dioxane
as reasonably anticipated to be a human carcinogen (US DHHS, 1993). EPA has determined that
1,4-dioxane is likely to be carcinogenic to humans (US EPA, 1999).
Occupational exposure limits have been set by federal agencies and organizations in the US
(OSHA, NIOSH, ACGIH) and are summarized in Appendix A. A recent Toxicological Profile for 1,4-
dioxane (ATSDR, 2012) provided a detailed analyses of available hazard data. The data were
used to derive minimal risk levels (MRLs), exposure levels posing minimal risk to humans, for
inhalation and oral exposures. The EPA Integrated Risk Information System (IRIS) Program
recently updated the assessment of 1,4-dioxane, including the results of a two-year inhalation
bioassay (US EPA, 2013b). IRIS developed cancer and non-cancer reference values for inhalation
and drinking water exposure. Acute Exposure Guideline Levels (AEGLs) for 1,4-dioxane have
been established (NAS/COT Subcommittee for AEGLs, 2005). The MRLs, IRIS benchmarks and
AEGLs are provided in Appendix A.
The Food and Drug Administration (FDA) does not require 1,4-dioxane to be listed on labels of
personal care products and considers it a contaminant. FDA has indicated that the levels of 1,4-
dioxane found in their monitoring of cosmetics do not present a hazard to consumers and
recommended a level of 3.8 mg/day (380 ppm) as the "permitted daily exposure (PDE)" for 1,4-
dioxane that is an acceptable intake of residual solvents in drugs and dietary supplements (US
FDA, 2011). FDA limits 1,4-dioxane levels in glycerides and polyglycerides of hydrogenated
vegetable oils used as a food additive to 10 mg/kg.
Industries manufacturing, processing or using 1,4-dioxane are legally required to report
releases to EPA's Toxic Release Inventory (TRI) if they manufacture or process more than
25,000 pounds of a TRI-listed chemical or otherwise use more than 10,000 pounds of a listed
chemical in a given year.
The EPA Office of Water (OW) has included 1,4-dioxane on the third Candidate Contaminant
List (CCL3). No federal drinking water standards have been established for 1,4-dioxane and it is
being monitored in public water systems as part of the Unregulated Contaminant Monitoring
Rule 3 (UCMR3) list. OW is conducting a three-year (2013-2015) monitoring program of public
water systems to collect data for contaminants suspected to be present in finished drinking
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water including 1,4-dioxane (USEPA, 2013). Information about UCMR3 and 1,4-dioxane
monitoring in Public Water Systems (PWS) can be found at:
http://water.epa.gov/lawsregs/rulesregs/sdwa/ucmr/data.cfm.
EPA's Office of Air and Radiation (OAR) regulates 1,4-dioxane as a Hazardous Air Pollutant
(http://www.epa.gov/ttn/uatw/hlthef/dioxane.html). EPA's Office of Solid Waste and
Emergency Response (OSWER) regulates the Superfund sites that are historically a source of
1,4-dioxane in ground water around those sites. 1,4-Dioxane has been reported at 32 National
Priorities List (NPL) sites (http://www.atsdr.cdc.gov/SPL/index.html). Examples include sites in
New Hampshire (http://www.epa.gov/regionl/removal-sites/NH14DioxaneSite.html) and
Massachusetts (http://www.epa.gov/regionl/superfund/sites/graceacton/507061.pdf).
States
1,4-Dioxane is listed on California's Proposition 65 list because it is known to cause cancer (CA
EPA OEHHA, 2007, 2014). The action level under California Proposition 65 for 1,4-dioxane in
personal care products is above 10 ppm. California also lists 1,4-dioxane on the Informational
"Initial" Candidate Chemicals List and the Informational Candidate Chemicals List under
California's Safer Consumer Products regulations (State of California, 2010). Further, Minnesota
and Washington classify 1,4 dioxane as a chemical of high concern (Minnesota Department of
Health (MDH), 2013; Washington State, 2013).
International
The International Agency for Research on Cancer (IARC) has determined that 1,4-dioxane is
possibly carcinogenic to humans (IARC, 1976) based on inadequate evidence in humans and
sufficient evidence in experimental animals.
A Canadian screening assessment (Environment Canada and Health Canada, 2010) evaluated
the risk of 1,4-dioxane to human health. Ecological risks were not assessed since 1,4-dioxane
did not meet the criteria for bioaccumulation and inherent toxicity to aquatic organisms.
Exposures to the general population from intake from air, water, soil, diet, use of personal care
products and household products were estimated. The report concluded that 1,4-dioxane is not
entering the environment in a quantity or concentration or under conditions that constitute or
may constitute a danger in Canada to human life or health.
The European Union Risk Assessment Report (EU RAR, 2002) concluded that there is no concern
for human safety with regard to repeated-dose toxicity, carcinogenicity and reproductive
toxicity. The assessed risk concern was low for the general population (inhalation and drinking
water), direct and indirect consumer exposures in cosmetic/toiletries and household
detergents, Pharmaceuticals, foods, agricultural and veterinary products, and ethylene glycol-
based antifreeze coolants and ecological exposures. A potential risk concern for workers was
found for occupational exposures via the dermal and inhalation routes during product
formulation and the use of cleaning agents containing 1,4-dioxane.
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2 PROBLEM FORMULATION
Problem formulation aims to determine the major factors to be considered in an assessment,
including exposure pathways, receptors and health endpoints (US EPA, 1998, 2014b).
Accordingly, this problem formulation summarizes the exposure pathways, receptors and
health endpoints that EPA/OPPT considered to determine whether to conduct further risk
analysis and what exposure/hazard scenarios to include in a potential risk assessment. To make
this determination, EPA/OPPT conducted a preliminary data review to identify available fate,
exposure and hazard data and determine its likely suitability for quantitative analysis and to
identify exposure pathways, receptors and health endpoints for quantitative analysis.
The outcome of this evaluation is summarized in a conceptual model (Figure 2-2) that illustrates
the exposure pathways, receptors and effects that were considered for potential risk
assessment. An analysis plan is developed if the results of problem formulation indicate the
need for further analysis.
2.1 Physical and Chemical Properties
1,4-Dioxane is a clear liquid at room temperature. The cyclic structure (Figure 2-1) has oxygen
molecules attached at the first and fourth bonds, each with free electrons (US EPA, 2006b). 1,4-
Dioxane is expected to volatilize from dry soil surfaces based on its high vapor pressure (40 mm
Hg at 25 °C) (US EPA, 2009). 1,4-Dioxane has a Log Kow value of -0.27, which indicates that this
chemical is hydrophilic, readily miscible in water (US EPA, 2009). A summary of the physical and
chemical properties of 1,4-dioxane are listed in Figure 2-1.
O
O
Figure 2-1: Chemical structure of 1,4-dioxane.
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Table 2-1: Physical and Chemical Properties of 1,4-Dioxane.
Property
Molecular Weight
Melting Point
Boiling Point
Vapor Pressure
Water Solubility
Log KOW
Henry's Law Constant
Value
88.1g/mol
11.85 °C (measured)
101.1 °C (measured)
40 mm Hg at 25 °C
> 8.00 x 102 g/L
-0.27
4.8 x 10"6 atm-m3/mol at 25 °C
References
(Howard, 1990)
(Lide, 2008-2009)
(O'Neiletal., 2006)
(Lewis, 2000)
(Yalkowskyand He, 2003)
(Hanschetal., 1995)
(Howard, 1990)
2.2
Production and Uses
The EPA's Inventory Update Reporting (IUR) and 2012 Chemical Data Reporting (CDR) databases
were searched to identify the uses and associated production volumes of 1,4-dioxane. Some
information was claimed as Confidential Business Information (CBI) and is not included in this
report. Additional information on uses and specific end products that may contain 1,4-dioxane
can be found in Appendix B: Summary of Uses and End Products.
Production
In 2006, the U.S. production volume of 1,4-dioxane was between 1 million and 10 million
pounds, including both imports and domestic manufacture (US EPA, 2010). Data from the 2012
CDR for reporting years 2010 and 2011 were claimed as CBI and indicate only domestic
manufacture of 1,4-dioxane (US EPA, 2014c). The non-confidential U.S. production volumes of
1,4-dioxane, as submitted by companies under the IUR or CDR for 1986 to 2012, are given in
Table 2-2.
Table 2-2:1986-2012 National Production Volume Data for 1,4-Dioxane (Millions of Pounds).
1986 IUR
10-50
1990 IUR
10-50
1994 IUR
1-10
1998 IUR
1-10
2002 IUR
1-10
2006 IUR
1-10
2012 CDR
Withheld
Source: (US EPA, 2006a, 2010, 2012b)
Uses
1,4-Dioxane is currently used as both an industrial and a commercial solvent. As a result of
chemical ethoxylation of surfactants, 1,4-dioxane can be formed as a byproduct and may be
present as a contaminant in commercial and consumer products. Historically, the main use of
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1,4-dioxane (90 percent) was as a stabilizer in chlorinated solvents such as 1,1,1-
trichloroethane (TCA). Use of TCA was phased out under the 1995 Montreal Protocol and the
use of 1,4-dioxane as a stabilizer is no longer significant (European Chemicals Bureau, 2002;
NTP, 2014).
Industrial Uses. At present, 1,4-dioxane is used as an industrial solvent in the manufacture of
chemicals because it is capable of solubilizing most organic and many inorganic compounds
(ATSDR, 2012; Ullman's, 2012). As an industrial solvent, 1,4-dioxane is used as:
a processing solvent
a reaction medium solvent
an industrial solvent with an unspecified function in the production of various end
products (ATSDR, 2012; US EPA, 2006a)
Other industrial uses include:
as an extraction medium
an inert (chemically inactive) ingredient in pesticides and fumigants
a chemical intermediate
a polymerization catalyst
a dehydrating agent
a wetting and dispersing agent
a degreasing agent (ATSDR, 2012; US EPA, 2006a)
Appendix B lists examples of end products for each of these industrial uses. Table 2-3 provides
the industrial use data as reported in the 2012 CDR database4.
Commercial and Consumer Uses. As an industrial processing solvent or chemical intermediate,
1,4-dioxane has previously been reported to be used in the production of products that may
have commercial or consumer applications such as paints, adhesives, detergents, and pesticides
(ATSDR, 2012; US EPA, 2006a, 2014c). In the most recent CDR database, no consumer uses were
reported for 1,4-dioxane in the US (Table 2-3). Additional US sources do not differentiate
between consumer and commercial products (ATSDR, 2012; US EPA, 2006a). EPA was unable to
identify any US sources that definitively stated the chemical is used in the production of
consumer products. A European risk assessment stated that the chemical is used as a solvent in
the production of several products that may be used by consumers (European Chemicals
Bureau, 2002).
Contaminant in Consumer Products. 1,4-dioxane may be present as a contaminant in
consumer cosmetics/toiletries, household detergents, Pharmaceuticals, foods, agricultural and
veterinary products and ethylene glycol-based antifreeze coolants. It is formed as a byproduct
The manufacturer submitted a correction to EPA to revise the 2012 CDR to reflect that 1,4-dioxane is not used for
the categories 'Paints and Coatings' and 'Laundry and Dishwashing Products'. The correction was received and is
not yet indicated in the CDR public database.
Page 16 of 54
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during the manufacture of ethoxylated surfactants. Manufacturers can remove most of the 1,4-
dioxane in consumer products through a vacuum stripping process (ATSDR, 2012), although the
extent that this occurs is unknown.
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Table 2-3: CDR Industrial and Consumer Use Data.
Manufacturing
Site
Novolyte
Performance
Materials
111 West Irene
Road
Zachary, LA
70791
Parent
Company
BASF
Industrial Use Data
Sector
All Other Basic
Organic Chemical
Manufacturing
Function
Category
Processing
aids, not
otherwise
listed
Industrial Use
Use-non-
incorporative
activities*
Percent of
Production
Volume
CBI
Consumer and Commercial Use Data
Product
Category*
Paints and
Coatings
Laundry and
Dishwashing
Products
Commercial or
Consumer Use
Commercial
Commercial
Percent of
Production
Volume
CBI
CBI
Note: Use in non-incorporative activities would include uses such as chemical processing aids or chemical manufacturing aids, where the chemical is not intended to remain in or
become part of the final product, or ancillary activities where a chemical is used at a facility for purposes other than aiding chemical processing or manufacturing (e.g.
degreasers or cleaners).
Source: The public 2012 CDR Database; updated June 11, 2014 (US EPA, 2012b).
*A correction was received that is not yet indicated in the CDR public database.
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2.3 Fate and Transport
Environmental fate properties are summarized in Table 2-4.
Based on available environmental fate data, 1,4-dioxane is expected to volatilize readily from
dry surfaces, reside in water and soil compartments if released to the environment, and have
high persistence and low bioaccumulation potential in the environment. 1,4-Dioxane is not
readily biodegradable under normal environmental conditions.
1,4-Dioxane is expected to volatilize from dry surfaces and dry soil due to its high vapor
pressure. It reacts with hydroxyl radicals (OH») in the atmosphere where the estimated
atmospheric photooxidation half-life of 1,4-dioxane is 4.6 hours (US EPA, 2013a). 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-UV light wavelengths (Lyman et
al., 1982; NIH, 2006). 1,4-dioxane will not hydrolyze in water because it does not have
functional hydrolyzable groups (ATSDR, 2012).
Due to a high water solubility of > 8.00 x 102 g/L (Yalkowsky and He, 2003) and a low Henry's
Law constant of 4.8 x 10"6 atm-m3/mol at 25 °C (Howard, 1990; US EPA, 2009), 1,4-dioxane is
expected to be only slightly volatile from water surfaces and moist soil. Once it enters the
environment, 1,4-dioxane is expected to have high mobility in soil based on its negligible Koc
value of 0.4 (US EPA, 2013a). 1,4-dioxane is not expected to significantly sorb to suspended
solids and sediment and, therefore, may migrate rapidly to surface waters and groundwater.
In a ready biodegradation test, following OECD Guideline 301 F (Manometric Respirometry
Test), reported by the European Chemicals Agency (ECHA), 1,4-dioxane was degraded less than
10 percent in 29 days (ECHA, 2014a). In another ready biodegradation test following OECD
Guideline 310 (Headspace Test) 1,4-dioxane was degraded less than 5 percent in 60 days
(ECHA, 2014b). 1,4-dioxane is considered to be not readily biodegradable.
In a soil microcosm study which analyzed the potential for bacteria to degrade 1,4-dioxane,
1,4-dioxane was not biodegraded during a 120 day period by indigenous bacteria. During the
next 6 months, the bacteria removed about 60% of the added 1,4-dioxane. The reason for the
delayed biodegradation was not clear (Kelley et al., 2001).
In a bioaccumulation test using the common carp (Cyprinus carpio) following OECD Test
Guideline 305, measured bioconcentration factor (BCF) values of 0.3-0.7 at a concentration of
10 mg/L, and 0.2-0.6 at a concentration of 1 mg/L were reported (ECHA, 2014c). These values
indicate that bioaccumulation 1,4-dioxane is low.
Using the environmental fate estimation model EPISuite (Estimation Program Interface Suite
for Microsoft Windows) v 4.11, a level III fugacity model with equal releases of 1,4-dioxane to
Page 19 of 54
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air, water, soil, and sediment, estimates that 1,4-dioxane will tend to partition mostly to soil
(52.6%), and water (44.7%) (US EPA, 2013a) (Table 2-4).
Table 2-4: Environmental Fate Endpoints for 1,4-Dioxane.
Endpoint
Photodegradation
Half-life
Hydrolysis Half-life
Biodegradation
Bioconcentration
Log Koc
Fugacity
(Level III Model)
Air (%)
Water (%)
Soil (%)
Sediment (%)
Environmental Fate Data
4. 579 hours
(estimated rate constant of 2.8 x 10"11 cm3/molec-sec
1.5 x 106hydroxyl radicals per cm3
12-hour day)
Does not undergo hydrolysis
<10% in 29 days (OECD 301F)
<5%in60days(OECD310)
0% after 120 days in soil microcosms; 60% after 300 days
BCF = 0.2 - 0.6 (measured in carp at
BCF = 0.3 - 0.7 (measured in carp at
1 mg/L)
10 mg/L)
0.4 (estimated)
2.65
44.7
52.6
0.0868
(The input values for this estimation are the melting
point, boiling point, vapor pressure, water solubility, Log
KQW and Henry's Law constant values provided in Table
2.1 above, and the following SMILES notation:
O(CCOCl)Cl)
References
(US EPA, 2013a)
(ATSDR, 2012)
(ECHA, 2014a)
(ECHA, 2014b)
(Kelleyetal., 2001)
(ECHA, 2014c)
(US EPA, 2013a)
(US EPA, 2013a)
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2.4 Exposures
The exposure data identified and considered during problem formulation and used to construct
the conceptual model and pose assessment questions is summarized. Use and exposure
scenarios were selected for inclusion in the conceptual model by the identification of high
volume uses that are known or likely to be associated with significant exposures.
Releases to the environment were assessed to determine potential pathways of exposure for
both human and ecological receptors. Exposures to workers, consumers and the general
population were evaluated to determine the potential exposure to 1,4-dioxane during
manufacturing, formulation and use of products. Environmental exposure of the general
population to 1,4-dioxane in air or water was also considered.
2.4.1 Releases to the Environment
Environmental releases of 1,4-dioxane to air and water may contribute to ecological and
general population exposures. The potential for release of 1,4-dioxane to air is high due to the
high vapor pressure of 1,4-dioxane and disposal through incineration. Industrial and
commercial use of 1,4-dioxane and presence in consumer products suggest releases to water
are possible. Readily available sources of information for environmental releases that may lead
to exposures were reviewed including the EPA Toxic Release Inventory (TRI) database (US EPA,
2012c).
An analysis of TRI data from 1988 to 2007 indicates that total on-site releases of 1,4-dioxane
are generally decreasing. During this period, the high was 1,234,968 pounds in 1993 and the
low was 182,338 pounds in 2007; 69% of the 2007 total releases from 45 facilities were to air
(ATSDR, 2012). Data from the most recent TRI indicate that 82% of the total on- and off-site
releases of 106,300 pounds from 39 sites (including the manufacturing site) were to air (on-site
fugitive and point sources) and 18% were to surface water. An additional 1,035,300 pounds
were reported released from two additional sites that primarily inject 1,4-dioxane in
underground wells (on-site and off-site) or send to waste brokers (US EPA, 2012c). Releases to
these wells and to waste brokers are not usually a concern for human exposures. Facilities that
release less than 25,000 pounds are not required to report data to the TRI.
The EPISuite model (Table 2-4) indicates that following release, 1,4-dioxane will partition
predominantly to water and moist soil. Likely exposure pathways are by atmospheric
deposition and runoff into surface water and leaching into groundwater.
2.4.2 Presence in the Environment
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EPA/OPPT reviewed available information on the presence of 1,4-dioxane in the environment
from the 2002 EU Risk Assessment Report (RAR), a leachate study from two landfills, a
groundwater plume study and two WWTP studies.
The EU RAR included predicted environmental concentrations (PECs) for wastewater effluent
and surface water and a limited number of measured data of 1,4-dioxane in surface water,
drinking water, wastewater effluent and leachate from the vicinity of landfills (European
Chemicals Bureau, 2002). Site-specific and generic location emission data were used to
generate estimated regional release values to surface water and WWTPs and develop the PECs.
The PECs in surface water were based on estimated regional releases to water of 434 kg/d and
the estimated regional release via WWTP was 304 kg/d (European Chemicals Bureau, 2002).
PECs of 1,4-dioxane in wastewater effluent ranged from 0.002 - 183 mg/L based on life cycle
stages or scenarios. PECs in surface water during an emission episode ranged from 0.001 mg/L
(contaminated alkyl ethoxy sulphates) to 18.3 mg/L (processing Pharmaceuticals and pesticides)
(European Chemicals Bureau, 2002).
In the EU RAR, surface water data in a Dutch study were compared to the predicted regional
environmental concentration of 1.3 u,g/L and was within the study values of 1-10 u,g/L. The
measured data for the WWTP effluent from unintentional release from a PET plant was much
higher (100 mg/L) than the PEC of 0.01 - 6.9 mg/L for site-specific emission data for various
unintentional 1,4-dioxane releases. However, the EU RAR noted that the source of the
measured 100 mg/L value used may be unreliable (European Chemicals Bureau, 2002).
The primary method of disposal of 1,4-dioxane is by incineration (ATSDR, 2012). In a study, that
investigated 1,4-dioxane in landfill leachate, extremely high levels of 1,4-dioxane (89 and 340
mg/L) were detected in the leachate from two landfill sites. Analysis of leachate and
measurement of 1,4-dioxane in incineration residues suggest that the most likely source of 1,4-
dioxane in the leachate is the fly ash produced by municipal solid waste incinerators (Fujiwara
etal.,2008).
Groundwater beneath the city of Ann Arbor, Michigan is currently contaminated with 1,4-
dioxane after it was used as an industrial solvent and the contaminated waste water was stored
in unlined wastewater lagoons between 1976 and 1986 (City of Ann Arbor, 2015). Since then,
the chemical has seeped through the soil and entered the groundwater in the Ann Arbor area.
Concentrations up to 7,000 ppb have been detected in the plume at the source. The maximum
concentration of 1,4-dioxane detected at an off-site monitoring well near the center of the
plume was 3,788 ppb (Pall Corporation, 2004). In 2004, concentrations of 1,4-dioxane in
influent and effluent were measured in a WWTP in Ann Arbor, Ml. In February, April and June,
raw wastewater influent concentrations were 3, 2 and 3 u,g/L, respectively. Treated effluent
concentrations were 3,1 and 3 for those same months (Skadsen, 2004). The similar influent and
effluent values suggest that 1,4-dioxane is not readily removed and passes through a municipal
WWTP.
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Samples of waste water effluent were collected from 40 municipal WWTPs that receive
predominantly domestic wastewater from households. Sampling took place in 2010 and
included WWTPs at select sites in 15 states. Of the WWTPs effluents samples, two had 1,4-
dioxane concentrations below the LOQ (<0.30 u,g/L) and 38 samples had concentrations
between 0.30 and 3.30 u,g/L (Simonich et al., 2013).
2.4.3 Occupational Exposure
Occupational exposure data from three sources were reviewed: the 2002 EU RAR, the OSHA
Chemical Exposure Health Data database, and a data set provided by an American Chemistry
Council (ACC) member company.
Manufacturing sites produce 1,4-dioxane in liquid form at 90 percent concentration or higher.
Workers may be exposed by inhalation and skin contact when they work with 1,4-dioxane. The
high vapor pressure of 1,4-dioxane causes a high potential for air releases and associated
worker inhalation exposure. Dermal exposure may occur, but due to a low rate of absorption
through the skin and rapid volatilization, inhalation is considered the predominant route of
exposure.
Occupational exposure limits can affect the handling and processing of chemicals, thereby
reducing the potential for exposures. The US has several regulatory and non-regulatory
exposure limits for 1,4-dioxane (ACGIH, 2009): 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).
Public CDR information (US EPA, 2012c) indicates there is one domestic manufacturing site, 25
to 99 industrial processing sites and two commercial/ consumer product categories (Paints and
Coatings and Laundry and Dishwashing Products) for this chemical5. Information on current
domestic processing and use of 1,4-dioxane that may result in exposures is limited. 1,4-dioxane
has been potentially formulated into specialized products for industries in Europe with no
expected consumer uses. Also, some processes to make other chemicals produce 1,4-dioxane
as a reaction byproduct (e.g., ethoxylation reactions), and these chemicals have a variety of
uses that may result in worker and consumer exposures.
5 The manufacturer submitted a correction to EPA to revise the 2012 CDR to reflect that 1,4-dioxane is not used for
the categories 'Paints and Coatings' and 'Laundry and Dishwashing Products'. The correction was received and is
not yet indicated in public database.
Page 23 of 54
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In the US, limited worker inhalation monitoring data for this chemical were found in the OSHA
Chemical Exposure Health Data database (OSHA, 2014). During the most recent 15 year period
(1997 - 2011), 21 samples were taken from 6 sites, with 2 detects of 0.21 and 0.22 ppm and 19
non-detects. Worker monitoring data specific to an American Chemistry Council (ACC) member
company facility where 1,4-dioxane is produced as a byproduct in its manufacturing process
were collected from 2001 to 2003 (Franz, 2014). All of the 21 samples taken at this facility were
below analytical detection limits, which ranged from 0.044 to 0.9 ppm (0.16 to 3.24 mg/m3).
The two sets of data are too limited to consider representative of potential exposures that may
occur throughout the US (Appendix C: Occupational Exposure Data).
Estimates of worker exposure in Europe are provided in the EU RAR (European Chemicals
Bureau, 2002) for 1,4-dioxane. Inhalation concentrations and dermal doses for worker
exposures in five "Worker Use Activity" scenarios (Table 2-5) were estimated: production,
formulation and three end uses (cleaning agents in industries such as metal fabrication; paints
and varnishes in the production of precision and optical instruments, watches and clocks; and
lab solvents). All of these scenarios were relevant primarily to industrial and laboratory
facilities.
Table 2-5: Exposure Concentrations for Occupational Scenarios in European Industrial and Laboratory
Facilities.
Worker Use Activity
Manufacturing
Processing/ formulating
Use of cleaning agent
Use of paint
Use of solvent in lab
Reasonable Worst-case
inhalation concentration
(mg/m3, TWA)
10 (measured)
180 (modeled)
50 (measured)
11 (modeled)
25 (calc. from measured values)
Typical inhalation
concentration
(mg/m3, TWA)
0.2 (measured)
40 (modeled)
15 (measured)
2 (modeled)
5 (measured)
Table Note: "It is not clear whether the chemical is still used in cleaning agents." Source: Table 4-4 in
(European Chemicals Bureau, 2002).
Comparing the concentrations of 1,4-dioxane estimated for worker inhalation in Europe (Table
2-5) to US limits and recommended action levels, exposures did not exceed the OSHA
Permissible Exposure Limit (PEL), but typically exceeded the NIOSH Recommended Exposure
Limit (REL). EPA/OPPT could not determine whether the worker exposures estimated in the EU
assessment are similar to those in the US.
The European report did not estimate worker exposures for processes that produce 1,4-dioxane
as a reaction byproduct (e.g., ethoxylation reactions). Concentrations of 1,4-dioxane as a
contaminant in detergents and paints are expected to be lower than the estimated
concentrations of 1,4-dioxane in processed formulations. Formulations typically contain 10
weight percent or higher handled by workers in the assessed European scenarios. Worker
exposures to commercial products (such as detergents and paints) containing 1,4-dioxane as a
Page 24 of 54
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contaminant could therefore be orders of magnitude below the EU RAR estimated exposure
concentrations.
No information was found regarding the current total number of workers exposed to 1,4-
dioxane. Historical estimates from the 1970s and 1980s indicate that the number of workers
potentially exposed to 1,4-dioxane could have been up to 466,000 individuals (ATSDR, 2012). Of
those workers, significant numbers were estimated to have been exposed as a result of the use
of 1,4-dioxane as a stabilizer in TCA. While there is no data on current worker populations, the
numbers are expected to be much lower assuming production of 1,4-dioxane has been
reduced, particularly for use as a stabilizer in 1,1,1-trichloroethane (TCA).
In conclusion, workers in the US may be exposed to 1,4-dioxane. Several very limited worker
monitoring data sets for US workers showed exposures to be below both the OSHA PEL and the
NIOSH REL, but these data are very limited and may not be representative of exposures in the
US. Worker exposure estimates in the EU could be a reasonable starting point for assessing
exposures in the US. In order to better characterize worker exposures to 1,4-dioxane in the US,
information on current uses and volumes, processes used during production/formulation,
worker activities and measurements of exposure levels are needed.
2.4.4 General Population Exposure
General population exposures were identified and considered during problem formulation. A
review of available data and assessments for 1,4-dioxane revealed that potential general
population exposure can occur from ingesting contaminated drinking water and inhaling 1,4-
dioxane in the air. Exposures to 1,4-dioxane in food and cosmetics are outside the scope of
TSCA, have been addressed by other organizations such as FDA and are not addressed in this
assessment.
Exposure in Air
Air releases of 1,4-dioxane have decreased notably due to the ban of TCA according to historical
data. The TRI data indicate that air is the media with the greatest releases (ATSDR, 2012; US
EPA, 2012c). TRI data is summarized in Section 2.4.1 Releases to the Environment.
Exposure in Drinking Water
Recent actions from the State of California (CSWRCB, 2014) have labeled 1,4-dioxane as an
emerging contaminant because of its increased presence in drinking water. The California
Department of Public Health's Drinking Water Program measured 1,4-dioxane levels in drinking
water systems from 2000 to 2013. The program reported a mean concentration of 0.0042
mg/L; a median of 0.003 mg/L; and maximum concentration of 0.053 mg/L in the 2,592 samples
taken.
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High concentrations of 1,4-dioxane have been found in runoff ditches around Superfund sites
and nearby drinking water wells have been contaminated at levels above concern for health
effects (ATSDR, 2012).
EPA/OW's three year monitoring program (i.e. UCMR) of public water systems (PWS) tests for
1,4-dioxane and other chemicals in finished drinking water (US EPA, 2014e). Samples are
collected at entry points to the distribution system (i.e., the point at which water is discharged
into the distribution system from a well, storage tank, pressure tank or water treatment plant).
Source water (i.e., ambient surface or ground water) is not measured as part of the UCMR.
Monitoring data from PWSs during the first two years of the UCMR program as of January 2015
are summarized in Table 2-6. The results include 243 PWSs representing 708 samples with
results greater than the 10"6 cancer reference concentration (0.35 u.g/1) and no PWSs with
detections above the 10"4 cancer reference concentration level (35 ppb). It is unknown whether
additional monitoring data will result in higher occurrence or detection levels of 1,4-dioxane in
PWSs. Since 1,4-dioxane is being monitored through December 2015, decisions as to whether
or not to regulate the contaminant in drinking water will be considered as part of the EPA's
Regulatory Determination process (US EPA, 2014e). The reference concentrations used for 1, 4-
dioxane are based on publically-available health information found in the 2012 Drinking Water
Standards and Health Advisory (US EPA, 2012a) and range from 0.35 to 35 u.g/1, based on
cancer risk of 10"6 to 10"4, respectively. The draft reference concentration does not represent an
"action level"; EPA requires no particular action based simply on the fact that UCMR monitoring
results exceed draft reference concentrations, nor should the draft reference concentration be
interpreted as any indication of EPA's intent to establish a future drinking water regulation for
the contaminant at this or any other level (US EPA, 2014e).
Table 2-6: Preliminary Data from the EPA UCMR 3 (January 2015).
Contaminant
1,4-dioxane
MRL1
0.07
Reference
Cone. 1 2
0.35/35
Total #
of results
22,611
#of
results
>MRL
6132
#of
results
>Ref.
Cone.2
708/0
% of total
results
>Ref.
Cone.2
3.1%/0%
Total
number
of PWSs
with
results
5873
#of
PWSs
with
results
>MRL
727
# of PWSs
with
results
>Rof
^___ 2
Cone.
243/0
% of PWSs
with results
>Ref.
Cone. 2
6.8% / 0%
(http://water.epa.gov/lawsregs/rulesregs/sdwa/ucmr/upload/epa815sl5001.pdf
Measured in u.g/L (ppb)
2Where two reference concentrations are listed, the first number is associated with a 10"6 cancer risk; the
second number a 10 cancer risk. Where two results are presented the first number is associated with the first
reference concentration; the second number is associated with the second reference concentration.
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2.4.5 Consumer Exposure
The primary route of consumer exposure to 1,4-dioxane is by inhalation and dermal contact
with contaminated consumer products containing ethoxylated surfactants such as personal
care products, soaps and detergents. Limited data on concentrations in consumer products
exist. Currently, manufacturers may voluntarily 1) minimize the formation of the 1,4-dioxane as
by-product during manufacture of alkyl ethoxy sulfates (AES), or 2) remove 1,4-dioxane by
stripping the AES paste before formulation of ethoxylated surfactants into consumer cosmetics
and household products. The extent to which manufacturers use these practices is uncertain.
Cosmetics and personal care products are regulated by FDA. FDA has estimated consumer
exposure to 1,4-dioxane to be low (US FDA, 2007). FDA reported that levels of 1,4-dioxane
present in products such as shampoo and body wash do not pose a significant risk to consumers
since products do not remain in contact with the skin for a long period of time (US FDA, 2007).
FDA does not consider concentrations of 1,4-dioxane measured in cosmetics and toiletries to be
a risk of concern (ATSDR, 2012). These uses are outside the jurisdiction of TSCA regulatory
authority.
EPA/OPPT reviewed limited data on measured concentrations of 1,4-dioxane in products. Levels
of 1,4-dioxane in cosmetics are reported from two sources as 6-34 ppm (Black, 2001) and non-
detectable to 487 ppm (European Chemicals Bureau, 2002). When used as a chemical
intermediate, 1,4-dioxane concentrations are 100-380 ppm in Pharmaceuticals and 1.0 to 2.8%
w/w% in household adhesives (ATSDR, 2012). Unintentional contamination levels of 1,4-
dioxane in products are < 10 ppm in food (European Chemicals Bureau, 2002), 6-160 ppm in
household detergents (ATSDR, 2012) and 0.1 - 22 ppm in antifreeze and deicing products
(European Chemicals Bureau, 2002). An analysis of consumer products by the Campaign for
Safe Cosmetics found 1,4-dioxane in 32 out of 48 personal care products and cosmetics tested
(67%) at levels ranging from 0.27 to 35 ppm. The Organic Consumers Association tested 100
organic and natural consumer products and found detectable levels of 1,4-dioxane in 47
products. In a study of household products (soaps, shampoos, cleaners and detergents) in
Japan, 1,4-dioxane was detected in 40 out of 51 products at concentrations from 0.05 to 33
mg/kg with a mean of 2.7 mg/kg (Tanabe and Kawata, 2008).
The European risk assessment evaluated risk of exposure to several consumer products:
shampoos, baby lotion and hand dishwashing liquid via dermal and inhalation routes using
ConsExpo, a well-documented exposure model for substances from consumer products
(European Chemicals Bureau, 2002). The worst case scenario yielded a combined total internal
dose of 3.3 u.g/kg-bw/day and the "very worst case" combined total internal dose was 10
u.g/kg-bw/day (European Chemicals Bureau, 2002). The margins of safety for consumer
inhalation and dermal exposure scenarios for the three product categories ranged from greater
than 1000 to greater than 10,000 using health benchmarks available at the time.
The Canadian risk assessment presented aggregate exposure estimates for various age groups
including infants, children and adults (Environment Canada and Health Canada, 2010). Adult
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women were considered the highest exposed demographic group due to the use of cosmetics
and well as other consumer products. The estimated aggregate intake of 1,4-dioxane for daily
use of hair conditioner, hair shampoo, skin moisturizer (body cream) and body wash was 1.2
u.g/kg-bw per day. The margins of safety for daily intake (dermal and inhalation) for aggregate
exposure of the general population and consumers ranged from 7620 to 50,000 using the same
point of departure (Kociba et al., 1974) as used to derive the oral IRIS RfD.
EPA/OPPT concludes that exposure to consumers can result from the use of soaps and
detergents and other products that contain 1,4-dioxane as a contaminant. Adult women who
use multiple cosmetics and cleaning products are likely the most exposed population as
determined in the Canada assessment. The EU RAR and Canada separately assessed aggregate
risks from exposure to several consumer products and found no risk of concern. However, the
assumptions used in those assessments may differ from EPA risk assessment guidelines, and
EPA IRIS recently published an updated review of health benchmarks for non-cancer and cancer
endpoints that includes new studies not considered in the previous assessments.
2.5 Hazard Endpoints
2.5.1 Environmental Hazard
The available ecotoxicity studies for 1,4-dioxane on fish, aquatic invertebrates and aquatic
plants are summarized in Appendix D. There are no studies for 1,4-dioxane on sediment, soil or
terrestrial organisms.
The hazard of 1,4-dioxane to aquatic organisms is low. The hazard of 1,4-dioxane is expected to
be low for soil organisms due to its high potential to volatilize from soil surfaces and low for
sediment-dwelling organisms due to its low adsorption potential to sediment.
2.5.2 Human Health Hazard
A detailed summary of human health studies is in Appendix E-l and additional information can
be found in the EPA IRIS Toxicological Review of 1,4-Dioxane (with Inhalation Update) available
at: http://www.epa.gov/IRIS/toxreviews/0326tr.pdf.
Several national and international organizations have evaluated the human health hazard of
1,4-dioxane. Previous assessments were reviewed to identify potential hazard concerns of 1,4-
dioxane including a 2013 IRIS review (US EPA, 2013b), a 2012 ATSDR Toxicological Profile
(ATSDR, 2012), a Canadian screening assessment (Environment Canada and Health Canada,
2010) and the EU RAR (European Chemicals Bureau, 2002).
Moderate to high hazard concerns for repeated exposures are based on subchronic and chronic
oral and inhalation studies. In subchronic studies, the primary target organs are the liver,
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kidney and nasal/respiratory epithelium. Chronic studies have reported an apparent
progression to tumor formation at these sites that appears to be independent of genotoxicity.
Physiologically based pharmacokinetic models (PBPK) models have been developed for 1,4-
dioxane in rats, mice, humans and lactating women (US EPA, 2013b). Animal studies indicate
1,4-dioxane is readily absorbed via oral and inhalation exposures, with less absorption through
the skin (ATSDR, 2012). No data are available on the distribution of 1,4 dioxane in humans, and
no data on distribution are available in animals via oral or inhalation routes. Metabolism of 1,4-
dioxane in humans and experimental animals is extensive. Rats were shown to metabolize
inhaled 1,4-dioxane to 3-hydroxyethoxy acetic acid (HEAA). Elimination of 1,4-dioxane in
humans and rats is via the urine in the form of HEAA.
Mortality was observed in multiple acute high-dose studies in rats, mice and rabbits. The acute
oral, dermal and inhalation toxicity of 1,4-dioxane is low in rats, mice and rabbits. Repeated-
dose toxicity studies in rats via oral administration with 1,4-dioxane at mid- and high-dose,
showed variable degrees of kidney and liver changes and mortality. Liver and nasal carcinomas
were observed in rats via the inhalation route.
Delayed ossification of the sternebrae and reduced fetal body weights were observed in a
prenatal developmental toxicity study with 1,4-dioxane. No reproductive toxicity studies have
been performed with 1,4-dioxane; however, no histopathological changes were reported in the
reproductive organs of male and female rats/mice exposed in subchronic and chronic studies.
The high dose at which developmental effects occurred suggests a low hazard for
developmental and reproductive toxicity.
The genotoxic potential of 1,4-dioxane has been evaluated using in vitro and in vivo assay
systems. The majority of in vitro assays with 1,4-dioxane were nongenotoxic. Fifty-percent of in
vivo studies with 1,4-dioxane were positive. EPA (US EPA, 2013b) concluded that 1,4-dioxane is
nongenotoxic or weakly genotoxic based on the IRIS review.
No treatment-related effects were observed in a single dose dermal irritation assay in rats. In a
90-day inhalation study, no gross or microscopic alterations were reported in the skin of rats.
However, this study was conducted via inhalation and does not provide an adequate
representation of dermal toxicity.
Evidence of carcinogenicity in animals (liver and nasal tumors, mesotheliomas of the
peritoneum in male rats and an increase in mammary gland adenomas in female rats) indicates
that 1,4-dioxane is "likely to be carcinogenic to humans" (US EPA, 2013b). A cancer slope factor
(CSF) of 0.1 (mg/kg/day)"1 was derived from the tumor incidence data for nasal squamous cell
carcinomas in mice and gall bladder carcinomas in guinea pigs. A new two-year inhalation
bioassay in rats was used to calculate an inhalation unit risk (IUR) of 5 x 10"6 (jag/m3)"1 (US EPA,
2013b).
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2.6 Results of Problem Formulation
The results of problem formulation are a conceptual model, key assessment questions and an
analysis plan for human health (US EPA, 2014b). A conceptual model was not developed for
environmental health due to the low ecotoxicity hazard values reported from standard acute
and chronic ecological toxicity tests.
2.6.1 Conceptual Model
The following conceptual model (Figure 2-2) illustrates the sources and potential pathways
(arrows) of 1,4-dioxane from chemical manufacture and formulation, releases to the
environment and potential exposure pathways for human (workers, consumer and general
population) receptors. The blue solid and dotted blue lines in the conceptual model represent
pathways from potential sources, and the red solid and dotted lines represent potential
exposure pathways via inhalation or ingestion for human receptors. Dermal exposures are not
addressed due to a low rate of absorption, high volatilization and lack of dermal toxicity studies.
Potential human health effects include cancer (progression of tumor formation) and noncancer
outcomes (liver, kidney and nasal effects) in workers, consumers and the general population.
The source-exposure-receptor pathways, labeled numerically in the conceptual model, are
described as follows:
1. Workers may be potentially exposed from inhalation exposures during manufacturing
and formulation of 1,4-dioxane or in industrial or laboratory facilities where 1,4-dioxane
is used.
2. Workers and consumers may be potentially exposed by inhalation during the use of
products that contain 1,4-dioxane as a contaminant.
3. Inhalation exposures may occur to the general population as a result of emissions
from manufacturing/formulating/use facilities, as well as incineration of waste
streams/products.
4. Oral exposures to the general population may occur from drinking contaminated
water. 1,4-Dioxane in surface water or ground water may travel through public drinking
water treatment plants (DWTPs) and private wells to the "tap". The source
contributions to drinking water are uncertain and may originate from wastewater
effluent, leaching from landfills and disposal sites to groundwater and surface water.
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-» Air
Incineration
General
population
Ground
Water/Wells
Figure 2-2: Conceptual Model of Potential Exposure Pathways for 1,4-Dioxane.
Solid blue lines represent potential source pathways; solid red lines represent exposure pathways to
receptors; dotted blue lines indicate pathways with limited data to assess.
Four key assessment questions were developed from the Conceptual Model:
1. Are there risks to workers exposed during manufacturing and formulation of 1,4-
dioxane or in industrial or laboratory facilities where 1,4-dioxane is used?
A 2002 European assessment found potential risk to workers for occupational exposures via the
dermal and inhalation routes during product formulation and the use of 1,4-dioxane as a
cleaning agent. Comparing the estimates of worker inhalation in Europe to US limits and
recommended action levels, exposures did not exceed the OSHA Permissible Exposure Limit
(PEL), but typically exceeded the NIOSH Recommended Exposure Limit (REL). Exceeding the
NIOSH REL may indicate potential exposure concerns. The few US data on worker exposure
were below the NIOSH REL. However, EPA's recently updated IRIS cancer and non-cancer
benchmarks for human health suggest that human health risks should be reassessed.
2. Are there risks to workers and consumers potentially exposed by inhalation during the
use of products that contain 1,4-dioxane as a contaminant?
Workers and consumers may be exposed to 1,4-dioxane present as a contaminant in products
such as personal care products, paints, adhesives, varnishes, cleaners and detergents. Previous
risk assessments in Canada and Europe concluded that levels of contamination do not pose
concerns for human health. However, the assumptions used in those assessments may differ
from EPA risk assessment guidelines. EPA's recently updated IRIS benchmarks for non-cancer
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and cancer human health endpoints, including new studies, were not considered in the
previous assessments. EPA/OPPT should reassess risks to workers and consumers from
products. While personal care products are regulated by the FDA, uses in paints, adhesives,
varnishes, cleaners and detergents fall under TSCA authority.
3. Are air emissions of 1,4-dioxane a potential risk to the general population from
inhalation exposure?
EPA/OPPT considered the exposure of the general population to ambient air levels of 1,4-
dioxane. Minimal data on 1,4-dioxane uses and releases to the environment exist for estimating
the ambient levels of 1,4-dioxane in air and recent monitoring data is unavailable. TRI data (US
EPA, 2012c) indicate that there are 39 sites reporting the release of 106,300 pounds of 1,4-
dioxane to on- and off-site releases with 82% of these air releases to onsite fugitive and point
sources and 18% to surface water. There was an additional 1,035,300 pounds from two sites
with almost all going to underground injection wells (on-site and off-site) and waste brokers.
Since phasing out of the use of 1,4-dioxane as a stabilizer in chlorinated solvents except for
select uses, air releases of 1,4-dioxane have decreased as can be seen in the TRI data (Section
2.4.1). Air monitoring data from urban areas in the 1980s and 1990s showed significant
decreases in 1,4-dioxane over the period covering the phase out. Since the 1990's, the
reduction seems to have leveled off. The latest TRI data indicate that air releases continue to
occur.
During problem formulation, EPA/OPPT considered that 1,4-dioxane is: 1) regulated under the
CAA as a hazardous air pollutant (US EPA, 2000); 2) photooxidized in the environment with a ti/2
of 1-3 days; and, 3) historical levels of 1,4-dioxane range from 0.0001 to 0.0004 mg/m3 (i.e., 0.1
u.g/m3 to 0.4 u.g/m3) (ATSDR, 2012). Canada assessed the exposure of the general population to
1,4-dioxane in air and concluded that there is no risk of concern (Environment Canada and
Health Canada, 2010). Compared to the IRIS Reference Concentration (RfC) (US EPA, 2013b) for
noncancer effects (0.03 mg/m3), the historical levels are 75 to 300 times lower than the RfC.
Calculation of lifetime cancer risk using the IRIS IUR (5 x 10"6 (ug/m3)"1) (US EPA, 2013b)
indicates that risks associated with historical 1,4-dioxane levels range from 5 x 10"7 to 2 x 10"6,
which are below EPA's target risk range of 1 x 10"6 to 1 x 10"4.
4. Are there risks to the general population from drinking water contaminated with 1,4-
dioxane?
Data being generated by EPA's OW show that the general population may be exposed to 1,4-
dioxane from contamination of finished drinking water. Groundwater may also be a source of
general population exposures especially around Superfund sites. However, based on the limited
data, it may be premature for EPA/OPPT to conduct a TSCA risk assessment of the drinking
water pathway because there is too much uncertainty to adequately characterize source
contributions of 1,4-dioxane in drinking water from TSCA uses. EPA's OW is currently
monitoring for 1,4-dioxane as part of the UCMR 3 monitoring program until December 2015.
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EPA will determine whether or not regulatory action is needed as part of the EPA's Regulatory
Determination process.
2.6.2 Analysis Plan
Based on Problem Formulation, EPA/OPPT plans to use available data to evaluate:
1. Potential occupational risks of exposure to 1,4-dioxane during manufacturing and
formulation of 1,4-dioxane or in industrial or laboratory facilities where 1,4-dioxane is
used.
2. Potential risks to workers and consumers exposed by inhalation during the use of
products that contain 1,4-dioxane as a contaminant.
For the exposure assessment, EPA/OPPT plans to use the following data and information to
estimate worker exposures:
Physico-chemical data on 1,4-dioxane
Production volume and use information (non-confidential)
Data on concentrations of 1,4-dioxane in commercial products from published literature
or provided by industry or consumer groups
Data and information on production, formulation and use processes
Data from the OSHA Chemical Exposure Health Data database or provided by industry
Measured and modeled data and information from exposure scenarios considered in
the Canadian and European assessments.
For the hazard assessment, EPA/OPPT plans to carefully review the existing human health
benchmarks established by OSHA, NIOSH, ATSDR and EPA IRIS (Appendix B). EPA/OPPT will
select the relevant benchmarks according to the relevant route of exposure. The exposure
estimates will be corrected for expected duration and frequency in agreement with the hazard
assessment.
For the risk characterization, EPA/OPPT will compare measured or estimated exposures to the
selected hazard benchmarks and calculate cancer risk estimates and non-cancer margins of
exposure for workers and consumers exposed to 1,4-dioxane through inhalation.
Given the limited amount of exposure data identified during problem formulation, EPA/OPPT
will search for additional data and information on current uses and production volumes,
processes used during production/formulation, worker activities, concentrations in products
and measurements of exposure levels.
Following review of comments and consideration of any additional data or information
EPA/OPPT may receive, EPA/OPPT plans to publish a final assessment for 1,4-dioxane.
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2.6.3 Uncertainties and Data Gaps
The industrial and commercial use data as reported in the 2012 CDR database indicate no
current consumer uses (US EPA, 2012b). The 2012 CDR does not give a complete picture of all
uses because only manufacturers of more than 25,000 pounds of a chemical at a single site are
required to report. Downstream industrial, consumer and commercial use data are reported
only if they manufactured more than 100,000 pounds of a chemical during a particular year.
Processing and use is often not under the control of the manufacturers and they may have
incomplete knowledge of these activities (US EPA, 2014a). As a result of these factors, the
processing and use information in the CDR public database presents only a limited picture of
the actual processing and use situation in the United States (US EPA, 2014a). Recent production
volume and use data are claimed confidential by the manufacturer. EPA was unable to identify
any US sources that definitively stated the chemical is used in the production of consumer
products, and therefore assumes there are no current consumer uses. As a contaminant, data
on the concentrations of 1,4-dioxane in consumer products are limited.
Data to understand the sources and pathways by which 1,4-dioxane enters the environment
are limited. The total actual releases from facilities that formulate or use 1,4-dioxane have
some uncertainties. For example, these releases may be higher than the total reported since
facilities that release less than 25,000 pounds are not required to report data to the TRI. Legacy
contamination, wastewater effluent and non-point sources may also contribute to releases of
1,4-dioxane into the environment. Recent ambient air data are needed to better understand
current worker exposures.
EPA/OPPT is uncertain whether worker exposures to 1,4-dioxane in the US may be similar to
those estimated in the EU RAR (European Chemicals Bureau, 2002). EPA/ OPPT is also uncertain
whether the limited 1,4-dioxane inhalation monitoring data for US workers are representative
of occupational exposures in the US. Also, the historical total numbers of workers exposed to
1,4-dioxane is expected to be much higher than the current total, which is unknown.
Information on current uses and volumes, processes used during production/formulation,
worker activities and measurements of exposure levels are not available. The extent to which
manufacturers use processes to reduce the contamination of 1,4-dioxane in products is
unknown.
In the human health hazard assessment, EPA IRIS noted uncertainties in the development of
the cancer risk values including the use of low-dose extrapolation, dose metric, cross-species
scaling, alternative bioassays, species/gender combination, human relevance to mouse tumor
data and human population variability in metabolism and response/sensitive subpopulations.
There is a data gap in human health hazard since no multigeneration reproductive toxicity
studies are available for 1,4-dioxane.
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APPENDICES
Appendix A Regulatory and Assessment History
Table A-l: History of Regulatory and Assessment Actions in the U.S. and Internationally.
COUNTRY
REGULATORY/ASSESSMENT ACTION
UNITED STATES
Occupational Exposure
Limits
Occupational exposure limits are established:
1989 OSHA PEL: 25 ppm (90 mg/m3) TWA
1994 NIOSH REL: 1 ppm (3.6 mg/m3) 30-minute ceiling, [skin]
1993-1994 ACGIH TLV: 25 ppm (90 mg/m3) TWA
UNITED STATES
ATSDR Minimal Risk Levels
(MRLs) 2013
Inhalation MRLs:
Acute-duration inhalation exposure (14 days or less) = 7.2 mg/m3 (2 ppm) was
derived from a NOAEL of 72 mg/m3 (20 ppm) for eye and respiratory irritation
and pulmonary function effects in humans.
Intermediate-duration inhalation exposure (15 to 364 days) = 0.72 mg/m3 (0.2
ppm) was derived from a BMCL10 of 101 mg/m3 (27.99 ppm) (subsequently
adjusted for duration) for increased incidence of nasal lesions in rats.
Chronic-duration inhalation exposure (365 days or more) = 0.11 mg/m3 (0.03
ppm) was derived from a LOAEL of 180 mg/m3 (50 ppm) (subsequently
adjusted for duration) for increased incidence of nasal lesions in rats (Kasai et
a I, 2009).
Oral MRLs:
Acute-duration oral exposure (14 days or less) = 5 mg/kg-bw/day was derived
from a NOAEL of 516 mg/kg-bw/day for developmental and maternal effects
in rats.
Intermediate-duration oral exposure (15 to 364 days) = 0.5 mg/kg-bw/day was
derived from a NOAEL of 52 mg/kg-day for liver effects in rats.
Chronic-duration oral exposure (365 days or more) = 0.1 mg/kg-bw/day was
derived from a NOAEL of 9.6 mg/kg-day for liver effects in rats (Kociba et a I,
1974).
UNITED STATES
IRIS Cancer and Non-
cancer Benchmarks 2013
Cancer Slope Factor: 0.1 (mg/kg/day)" (based on Kano et al, 2009)
Drinking Water Unit Risk: 2.9 x 10"6 u.g/L
Inhalation Unit Risk: 5 x 10"6 (ng/m3)"1
RfD = 0.03 mg/kg-day based on degenerative liver effects as the most
sensitive endpoint observed in a chronic bioassay; point of departure = 9.6
mg/kg-day (Kociba et al, 1974)
RfC = 3.0 x 10"2 mg/m3 (0.0083 ppm) based on co-critical effects of olfactory
Page 40 of 54
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COUNTRY
REGULATORY/ASSESSMENT ACTION
epithelium atrophy and respiratory metaplasia in rats exposed for 2 years via
inhalation; point of departure = 32.2 mg/m3 (Kasai et a I, 2009).
http://www.epa.gov/iris/subst/0326.htm
UNITED STATES
Drinking Water Limits
2012
Health advisory levels for 1,4-dioxane in drinking water: 4 mg/L (one-day, 10-
kg child), 0.4 mg/L (ten-day, 10-kg child), 1 mg/L (DWEL), 0.2 mg/L (Life-time),
and 0.035 mg/L at 10"4 cancer risk. (USEPA, 2012)
On the EPA Unregulated Contaminant Monitoring Rule 3 (UCMR3) list.
UNITED STATES
Cancer Classification
EPA - classified as B2- Probable human carcinogen (EPA 2003) - "1,4-dioxane is
'likely to be carcinogenic to humans' based on evidence of carcinogenicity in
several 2-year bioassays conducted in four strains of rats, two strains of mice,
and guinea pigs.
The National Toxicology Program concluded that 1,4-dioxane is 'reasonably
anticipated to be a human carcinogen' (NTP 2005).
IARC classifies 1,4-dioxane as 'possibly carcinogenic to humans' (IARC 1999
UNITED STATES
Hazardous Air Pollutant
Listed as a hazardous air pollutant under the Clean Air Act (CAA)
UNITED STATES
Wastes, Releases, and
Remediation
May be regulated as hazardous waste when used as a solvent stabilizer
Reportable quantity of 100 pounds has been established under CERCLA
Facilities manufacturing, processing, or otherwise using 1,4-dioxane are
required to report releases to EPA's Toxic Release Inventory (TRI).
UNITED STATES
Food and Drugs
FDA set limits of 10 ppm in approving glycerides and polyglycerides for use in
dietary supplements, and for spermicides.
EUROPEAN UNION
2002
The European Union Risk Assessment Report (EU RAR) concluded that:
Environmental risk, risk to consumers, and risk to general populations are not
expected.
Risks are expected to workers due to: (i) skin effects during production,
formulation and use of the substance or the product containing the
substance, and (ii) systemic toxicity and carcinogenicity due to dermal
exposure from the use of the substance as cleaning agent, and due to
inhalation during formulation of the substance.
CANADA
2010
Environment Canada (2010) assessed risks to human health based on
potential exposure and carcinogenicity and concluded that 1,4-dioxane is not
entering the environment in a quantity or concentration or under conditions
that constitute or may constitute a danger in Canada to human life or health.
Australia
1998
Priority existing chemical, report published in 1998.
The occupational risk assessment concluded that, for known Australian work
situations, 1,4-dioxane is unlikely to cause acute or chronic adverse effects,
including inhalation and dermal exposure. However, estimated exposure
based on modeled data to workers involved in optical lens manufacture
indicate a potential risk.
The public health risk assessment concluded there are no significant health
risks to the general public from the only source of potential exposure
Page 41 of 54
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COUNTRY
REGULATORY/ASSESSMENT ACTION
(consumer products containing 1,4-dioxane as impurity).
The environmental risk assessment indicated that the majority of 1,4-dioxane
will be released to wastewater, and that the chemical does not present a
significant risk of adverse effects to the Australian aquatic environment.
Japan
Priority Assessment Chemical Substance (PACS). PACS are substances whose
long-term toxicity to humans or to flora and fauna in the human living
environment is unclear, that have been found, or are expected to be found,
inconsiderable amounts over a substantially extensive area of the
environment. These substances are designated as chemicals that require a
priority assessment to assess the risk they may pose.)
Page 42 of 54
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Appendix B Summary of Uses and End Products
Table B-l: Summary of All Uses of 1,4-Dioxane and End Products.
Use
Processing solvent
Reaction medium solvent
Industrial solvent with an unspecified
function
Extraction medium
Inert ingredient
Chemical intermediate
Polymerization catalyst
Dehydrating agent
Wetting and dispersing agent
Degreasing agent
Unintentional Impurity
End Product(s)
Waxes
Fats
Lacquers and varnishes
Cleaning and detergent preparations
Adhesives
Cosmetics*
Deodorant fumigants
Emulsions and polishing compositions
Wood pulp
Organic chemicals
Fluid for scintillation counter (radiation detector) samples
Specific applications in biological procedures (histology)
Cellulose acetate membranes used as filters
Dye baths
Lacquers and paints
Waxes
Varnishes and stains
Printing compositions
Paint and varnish removers
Laboratory reagent (e.g., mobile phase in chromatography)
Animal and vegetable oils
Pesticides and fumigants
Pharmaceuticals
PET plastic
Rubber
Insecticides and herbicides
Cements
Deodorant fumigants
Magnetic tape
Adhesives
Plastics (unspecified plastic type)
Unknown
Textiles
Unknown
Food (as a result of food additives or pesticides)
Cosmetics
Agricultural/veterinary products
Industrial detergents
Household detergents
Pharmaceuticals
Antifreeze and deicing products
*As listed in ECHA, 2002 and not confirmed by US sources.
Sources: EPA, 2006; ASTDR, 2012; ECHA, 2002; FDA, 2007; Environment Canada, 2010
Page 43 of 54
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Appendix C Occupational Exposure Data
Appendix C contains US occupational exposure inhalation data from two sources.
Table C-l: Summary of 1,4 Dioxane Occupational Monitoring Data for Process Operators in the
Synthesis Area from an ACC Member Company where 1,4-Dioxane is Produced as a Byproduct in its
Manufacturing Process.
Sample Date
10/29/01
10/29/01
10/29/01
10/29/01
10/29/01
10/29/01
10/29/01
07/11/02
05/29/03
06/03/03
06/09/03
06/09/03
06/11/03
06/13/03
06/16/03
06/19/03
06/23/03
07/02/03
07/06/03
07/09/03
07/14/03
Activity
Emptying & Boiling out Vessel
Emptying & Boiling out Vessel
Emptying & Boiling out Vessel
Emptying & Boiling out Vessel
Emptying & Boiling out Vessel
Emptying & Boiling out Vessel
Emptying & Boiling out Vessel
Running PO and EO into
[Product] batch
Drumming [Product]
Drumming [Product]
Sampling and Drumming
[Product]
Adding [Raw Material] to
[Product]
Drumming [Product]
Drumming [Product]
Sampling and Drumming
[Product]
Drumming [Product]
Sampling [Product]
Sampling and Drumming
[Product]
Dumping P2O5 into [Product]
Drumming [Product]
Drumming [Product]
Results (ppm, 8-hour TWA)
LT 0.044
LT 0.054
LT 0.045
LT 0.045
LT 0.046
LT 0.043
LT 0.046
LTO.l
LT0.9
LT0.3
LT0.3
LT0.3
LT0.3
LT0.3
LT0.3
LT0.4
LT0.3
LT0.3
LT0.3
LT0.3
LT0.3
Source: Franz, 2014.
Key: LT = Less than (the value provided is the limit of detection (LOD)).
TWA = time weighted average over an 8-hour period
Page 44 of 54
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Table C-2:1,4-Dioxane - OSHA Chemical Exposure Health Data, 1997 - 2011.
Establishment
Peter Cremer North
America, Lp
Peter Cremer North
America, Lp
Peter Cremer North
America, Lp
Crystal, Inc. - Pmc
Crystal, Inc. - Pmc
Crystal, Inc. - Pmc
Crystal, Inc. - Pmc
Crystal, Inc. - Pmc
Crystal, Inc. - Pmc
Crystal, Inc. - Pmc
Tex-Tube, Inc.
Raytheon Aircraft
Company
Raytheon Aircraft
Company
Raytheon Aircraft
Company
Raytheon Aircraft
Company
Raytheon Aircraft
Company
Raytheon Aircraft
Company
Yellow Freight
Systems, Inc.
Yellow Freight
Systems, Inc.
Yellow Freight
Systems, Inc.
Baker Petrolite
City
Cincinnati
Cincinnati
Cincinnati
Lansdale
Lansdale
Lansdale
Lansdale
Lansdale
Lansdale
Lansdale
Houston
Wichita
Wichita
Wichita
Wichita
Wichita
Wichita
Columbus
Columbus
Columbus
Sand
Springs
State
OH
OH
OH
PA
PA
PA
PA
PA
PA
PA
TX
KS
KS
KS
KS
KS
KS
OH
OH
OH
OK
Zip
45204
45204
45204
19446
19446
19446
19446
19446
19446
19446
77024
67206
67206
67206
67206
67206
67206
43228
43228
43228
74063
Date
15-
May-08
15-
May-08
15-
May-08
16-Jun-
00
16-Jun-
00
16-Jun-
00
16-Jun-
00
16-Jun-
00
16-Jun-
00
16-Jun-
00
13-Jul-
98
2-Apr-
98
2-Apr-
98
2-Apr-
98
2-Apr-
98
2-Apr-
98
2-Apr-
98
9-Mar-
98
9-Mar-
98
9-Mar-
98
17-Feb-
98
SIC
2869
2869
2869
2841
2841
2841
2841
2841
2841
2841
3498
3721
3721
3721
3721
3721
3721
4231
4231
4231
2869
NAICS
325199
D46774
325199
D46775
325199
D46773
0 E77374
0 E77370
0 E77372
0 E77368
0 E77369
0 E77371
0 E77373
0 E65998
0 E63443
0 E63444
0 E63441
0 E63440
0 E63442
0 E63439
OJ61640
OJ61642
OJ61639
0
Type
P
P
P
P
P
P
P
P
P
P
P
A
A
A
A
A
A
P
B
P
P
Time
(minutes)
15
19
15
32
65
30
60
84
50
60
18
75
40
75
75
75
75
17
0
25
225
Result
(ppm)
ND
ND
ND
ND
ND
ND
ND
0.2117
0.2242
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
Source: https://www.osha.gov/opengov/healthsamples.html accessed 3/7/14
Key: SIC = Standard Industrial Classification; NAICS = North American industrial Classification System; ND = Not
Detected; Types: P = Personal, A = Area, B = Bulk
The detection limits for samples labeled as ND are not given.
Page 45 of 54
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Appendix D Ecological Hazard Studies
The ecological hazard summary of 1,4-dioxane is based on available hazard data. In addition, an
updated literature survey was conducted to identify articles on ecological toxicity published
between 2003 and 2014. The search terms included freshwater and saltwater fish, aquatic
invertebrates, and aquatic plants; pelagic and benthic organisms; acute and chronic sediment
toxicity in freshwater and saltwater and terrestrial toxicity to soil organisms, birds, and
mammals. The test species, test conditions, toxicity endpoints, statistical significance, and
strengths/limitations of the study were evaluated for data quality.
1,4-dioxane has been tested for acute and chronic aquatic toxicity. In order to characterize the
effects of 1,4-dioxane to the environment, a hazard rating was assigned based on EPA
methodology for existing chemical classification (US EPA, 2009). Included in this assessment are
eight acute aquatic toxicity studies and three chronic aquatic toxicity studies. There is one study
that characterizes the toxicity of 1,4-dioxane for aquatic plants. Acute and chronic toxicity data
for 1,4-dioxane exist for freshwater and saltwater fish, daphnia, and green algae. There are no
available sediment, soil, or avian toxicity studies found in literature for 1,4-dioxane. Also,
EPA/OPPT agrees with the classification of studies previously reviewed in the EU RAR (European
Chemicals Bureau, 2002). The European Chemicals Agency (ECHA) database on 1,4-dioxane
contains updated hazard studies that were used to supplement the EU RAR.
A summary of the available ecotoxicity data for 1,4-dioxane is provided below. The data show
that there is a low acute and chronic ecotoxicity for fish, aquatic invertebrates and aquatic
plants Hazard to soil and sediment organisms are expected to be low based on the lack of
partitioning to and persistence in these environmental compartments. The EU RAR (European
Chemicals Bureau, 2002) also concluded low hazard for soil and sediment organisms.
D-l Acute Toxicity to Aquatic Organisms
Acute aquatic toxicity studies considered for this assessment are summarized in Table D-l.
Based on the available studies, fish, invertebrates and algae, 1,4-dioxane exhibits low acute
toxicity for aquatic species.
Page 46 of 54
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Table D-l: Aquatic Toxicity Data for 1,4-Dioxane - Acute Toxicity.
Test Species
Fresh/ Salt
Water
Duration
End-
point
Cone.
(mg/L)
Test
Analysis
Effect References
Fish
Bluegill sunfish (Lepomis
macrochirus)
Fathead minnow
(Pimphales promelas)
Fathead minnow
(Pimphales promelas)
Fathead minnow
(Pimphales promelas)
Fathead minnow
(Pimphales promelas)
Inland Silversides
(Menidia beryllina)
Fresh
Fresh
Fresh
Fresh
Fresh
Salt
96-hour
96-hour
96-hour
96-hour
96-hour
96-hour
LC50
LC50
LC50
LC50
LC50
LC50
>1,000
1,080 to
9,850
9,872
12,326
>100
67,000
Nominal
Measured
Measured
Nominal
Nominal
Nominal
Mortality
Mortality
Mortality
Mortality
Mortality
Mortality
Dawson et al.
(1977) as cited
in Verschueren,
(2010)
Geiger, et al.
(1990)
Brooke (1987)
Brooke (1987)
Dow (1991) as
cited in the EU
RAR (2002)
Dawson et al.
(1977)
Aquatic Invertebrates
Water flea
(Daphnia magna)
Water flea
(Ceridodaphnia dubia)
Fresh
Fresh
48-hour
48-hour
EC50
EC50
>1,000
>299
Nominal
Nominal
Immobilization
Immobilization
ECHA
Assessment
Report (2014)
Dow (1989) as
cited in the
2002 EU RAR
Acute Toxicity to Aquatic Invertebrates
For this assessment, there are two studies on the acute ecotoxicity to aquatic invertebrates.
The water flea (Daphnia magna) were exposed to unspecified concentrations of 1,4-dioxane for
48-hours under semi-static conditions. The highest concentration tested was 1,000 mg/L. No
effects were seen at the highest concentration of 1,000 mg/L. A 48-hour EC50 of >1,000 mg/L
was reported (European Chemicals Bureau, 2002). In the other study, Ceridodaphnia dubia was
tested under the same conditions. A 48-hour EC50 of >299 mg/L was reported (Dow Chemical,
1989). These values show that the acute toxicity of 1,4-dioxane to aquatic invertebrates is low.
Acute Toxicity to Fish
The acute 96-hour LC50 values ranges from >100 mg/L for fathead minnows (Pimephales
promelas) to 67,000 mg/L for the Inland Silversides (Menidia beryllina). Overall, the acute
toxicity of 1,4-dioxane to fish is low (European Chemicals Bureau, 2002).
Page 47 of 54
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D-2 Chronic Toxicity to Aquatic Organisms
Table D-2: Aquatic Toxicity Data for 1,4-Dioxane - Chronic Toxicity.
Test Species
Fresh/
Salt
Water
Duration
End-
point
Cone.
(mg/L)
Test Analysis
Effect
References
Aquatic Plants
Green algae
(Pseudokirchnerella
subcapitata)
Fresh
72-hour
EC50
580
1,000
unspecified
growth
biomass
ECHA
Assessment
Report, 2014
Aquatic Invertebrates
Water flea
(Daphnia magna)
Fresh
21-day
NOEC
>1,000
Unspecified
Reproduction
ECHA
Assessment
Report, 2014
Fish
Medaka (Oryzias latipes)
Fathead minnow (Pimphales
promelas)
Fresh
Fresh
28-day
32-day
NOEC
MATC
565
145
Measured
Measured
Not Reported
Development,
Hatching,
Survival
Johnson et al.
(1993) as cited
in EPA's
Ecotox
Database,
2014
TSCATS, (1989)
as cited in the
EU RAR (2002)
Toxicity to Aquatic Plants
Only one adequate study is available to characterize the toxicity of 1,4-dioxane to aquatic
plants. 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 EC50
(growth rate and biomass) of > 1,000 mg/L (growth rate) was reported. A NOEC of 580 mg/L
(biomass) and a NOEC of 1,000 mg/L were reported (ECHA Assessment Report, 2014). This
study indicates the toxicity of 1,4-dioxane to aquatic plants is low.
Chronic Toxicity to Aquatic Invertebrates
One study is available that characterizes 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 (ECHA Assessment Report, 2014).
The reported NOEC indicates the chronic effects of 1,4-dioxane to aquatic invertebrates is low.
There are no available studies on the toxicity of 1,4-dioxane to sediment-dwelling organisms. EPA/OPPT
agrees with the EU RAR (European Chemicals Bureau, 2002) that there is low potential of 1,4-dioxane to
adsorb to sediment and elevated levels are not expected in sediments.
Page 48 of 54
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Chronic Toxicity to Fish
There are three available studies that characterize the chronic toxicity of 1,4-dioxane to
freshwater fish. 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. The effects
on growth and survival were reported (Johnson et al., 1993). No effects were seen. A no
observed effect concentration (NOEC) of 565 mg/L was reported. In another study, fathead
minnows (P. promelas) were exposed to mean measured concentrations of 27.6, 40.3, 65.3,
99.7, and 145 mg/L of 1,4-dioxane to observe the effects of the chemical on hatching,
development and survival for 32 days underflow-through conditions. 1,4-dioxane had no
significant effects on embryo development, hatching, larvae survival or larvae weight. A NOEC
of >103 and a maximum acceptable toxicant concentration (MATC) of >145 mg/L were reported
(European Chemicals Bureau, 2002).
D-3 Terrestrial Plants Toxicity
One study was found that characterizes the hazard of 1,4-dioxane to terrestrial plants. Lettuce
(Actuca sativa) was 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). This is a non-
guideline study. Currently, EPA has no available hazard criteria that applies to this endpoint.
D-4 Soil Invertebrate and Avian Toxicity
There are no available acute or chronic toxicity studies that characterize the hazard of 1,4-
dioxane to soil or terrestrial organisms. However, the toxicity of 1,4-dioxane is expected to be
low in these environments based on the chemical's high vapor pressure and it's propensity to
volatilize from soil. 1,4-dioxane is slightly volatile from water surfaces and moist soil due to its
high water solubility. No toxicity data are available for 1,4-dioxane to birds.
Page 49 of 54
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Appendix E Human Health Hazard Studies
The human health studies summarized here and in Table E- are referenced in the EPA IRIS
Toxicological Review of 1,4-Dioxane (with Inhalation Update) available at:
http://www.epa.gov/IRIS/toxreviews/0326tr.pdf.
E-l Acute Toxicity Studies
Mortality was observed in multiple acute high-dose studies in rats, rabbits, and mice via the
oral, dermal, or inhalation route. The oral LD50 values calculated for rats ranged from 5,170 -
7,339 mg/kg-bw; the dermal LD50 in rabbits is equal to 7,885 mg/kg-bw, and the inhalation LC50
in mice is equal to 36,700 mg/m3 and ranged from 46,000 - 52,000 mg/m3 in rats.
E-2 Repeated-Dose Toxicity Studies
Oral Toxicity
A 90-day oral repeated-dose toxicity study in male and female F344 rats and BDFl-mice with
1,4-dioxane in drinking water (Kano et a I, 2008) showed a dose-depended increase in the
relative weights of the kidney and lung in rats and mice with a relative liver weight increase
only in rats. A no-observed-adverse-effect level (NOAEL) was determined at 170 mg/kg-bw/day
in mice and 52 mg/kg-bw/day in rat.
Kociba et al (1974), conducted a study in which Sherman rats were administered 1,4-dioxane in
drinking water for up to 716 days. No treatment-related effects were observed at the lowest
dose tested for either sex. Both sexes that were treated at the mid-dose, showed variable
degrees of renal and hepatic degenerative changes with no occurances of tumors.
Hepatocellular and renal degenerative changes, and hepatocellular and nasal carcinomas
observed at the highest dose were considered equivalent to previous reported study results. A
LOAEL of 94 mg/kg-bw/day and a NOAEL of 9.6 mg/kg-bw/day were determined.
Dermal Toxicity
The 90-day study conducted by Kasai et al (2008) via inhalation does not provided appropriated
details of the dermal toxicity of 1,4-dioxane.
Inhalation Toxicity
A 90-day repeated-dose toxicity study with F344 with vaporized 1,4-dioxane for 6 hours/day
and 5/days/week as reported by Kasai (2008), showed mortality at the highest dose tested.
Histopathological changes in the liver, kidney, nasal epithelium, and lung were observed at 360
mg/m3. A LOAEC of 360 mg/m3 is based on histopathological changes in the liver, kidney, nasal
epithelium, and lung.
Page 50 of 54
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E-3 Reproductive and Developmental Toxicity Studies
No reproductive toxicity studies have been performed; however, no histopathological changes
were reported in the reproductive organs of male and female rats/mice exposed to 1,4-dioxane
in subchronic and chronic studies, which suggests a low concern for reproductive toxicity.
Pregnant female Sprague Dawley rats given 1,4-dioxane by oral gavage in water on gestation
days 6-15, showed decreases in maternal body weight gain at 1000 mg/kg-bw/day (Giavini et.
al., 1985). A slight decrease in fetal weight and ossification of the sternebrae was also observed
at 1000 mg/kg-bw/day.
E-4 Skin Irritation and Sensitization Studies
Clark et al (1994) conducted a dermal irritation assay where male (COBS/Wister rats (number
not stated) were shaved on specific areas of the back and flank then exposed to a single dose of
1,4-dioxane at 8,300 mg/kg and observed for 14 days. No treatment-related effects were
observed.
The 90-day study conducted by Kasai et al (2008) via inhalation does not provide appropriate
details of the dermal toxicity of 1,4-dioxane.
E-5 Genotoxicity and Cancer Studies
The genotoxic potential of 1,4-dioxane has been evaluated using in vitro and in vivo assay
systems. The majority of in vitro assays with 1,4-dioxane were nongenotoxic. Fifty-percent of in
vivo studies with 1,4-dioxane were positive. EPA's IRIS program concluded that 1,4-dioxane is
nongenotoxic or weakly genotoxic based on reviewed gene mutation and chromosome
aberration studies.
In the Kociba et al (1974) repeated-dose oral drinking water study in rats previously mentioned,
1,4-dioxane increased tumor progression in the liver via the oral route.
Kasai et al (2009) conducted a two-year bioassay in male F344 rats exposed to 1,4-dioxane via
vapor inhalation at various concentrations for 6 hours/day, 5/days/week. Mortality was
observed at the mid- and high dose. A statistically significant dose-dependent increase in nasal
squamous cell carcinomas, hepatocellular adenomas, and peritoneal mesotheliomas were
observed predominantly at the high dose. Renal cell carcinomas, mammary gland
fibroadenomas, and adenomas were observed in a dose-dependent manner. Nasal cavity and
liver preneoplastic lesions were observed at all doses. At 50 ppm, nonneoplastic lesions,
nuclear enlargement, atrophy, and respiratory metaplasia in the nasal cavity were significantly
increased. 1,4-Dioxane increased the incidence of tumors in rats.
Page 51 of 54
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The IRIS cancer slope factor (CSF) was based on the development of liver tumors in female mice
(Kano et al, 2009). In this study, male and female F344/DuCrj rats and Crj:BDF(l) mice were
exposed up to 5000 ppm (rats) and 8000 ppm in mice of 1,4-dioxane in the drinking water for 2
years. A significant induction of nasal squamous cell carcinomas (females), hepatocellular
adenomas and carcinomas (males and females), peritoneal mesotheliomas (males), and
mammary gland adenomas (females) were observed. Mice showed a significant induction of
hepatocellular tumors in males and females.
In a supporting study (NCI, 1978), Osborne-Mendel rats (0, 240, and 530 mg/kg-bw/day- males;
0, 350 and 640 mg/kg-bw/day-females) and B6C3F1 mice (0, 720, and 830 mg/kg-bw/day-
males; 0, 380, and 860 mg/kg-bw/day-females) were exposed to 1,4-dioxane (v/v) via drinking
water for 2-years. 1,4-Dioxane induced squamous-cell carcinomas of the nasal turbinates in
treated rats and hepatocellular carcinomas in treated mice.
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Table E-l: Human Health Endpoints for 1,4-Dioxane.
Endpoint
Acute Oral Toxicity
LD50(mg/kg-bw)
Acute Dermal Toxicity
LD50(mg/kg-bw)
Acute Inhalation Toxicity
LC50 (mg/L)
Repeated-Dose Toxicity
Oral (mg/kg-bw/day)
Inhalation (mg/L/day)
Developmental Toxicity
Reproductive Toxicity
Genetic Toxicity, gene
mutation
In vitro
Hazard Determination
5,170 -7,339 (rat)
7,885 (rabbit)
36,700 (mouse)
46,00 -52,000 (rat)
NOAEL = 170 mg/kg-bw/day (mice); NOAEL = 52 mg/kg-bw/day
(rat)
Moderate hazard via the oral route based on histopathological
changes in the liver, kidney and bronchial epithelium
LOAEL = 94 mg/kg-bw/day; NOAEL = 9.6 mg/kg-bw/day (rat)
High hazard based on degeneration and necrosis of renal cells and
hepatocytes (non-cancer)
NOAEC = 360 mg/m3 (rat)
Moderate hazard via the inhalation route based on
histopathological changes in the liver, kidney, nasal epithelium,
and lung
NOAEL = 500; LOAEL = 1,000 mg/kg-bw/day
Low hazard based on delayed ossification of the sternebrae and
reduced body weights in rats
No specific reproductive studies have been performed
Low hazard based on no histopathological changes in reproductive
organs of male and female mice in subchronic and chronic studies.
Nongenotoxic
Low hazard based on available in vitro studies
References
(all are as cited in (US EPA, 2013b))
Laug et al. (1939); Smyth et al. (1941);
Nelson (1951); Pozzani et al. (1959); JBRC
(1998)
Clark etal. (1984)
Fairley et al. (1934); Wirth and Klimmer
(1936)
Failey et al. (1934); Nelson (1951);
Pozzani etal. (1959)
Kano etal. (2008 and 2009)
Kociba et al (1974).
Endpoint used as the point of departure
(POD) for the IRIS Reference Dose (RfD).
Kasai et al. (2008)
Giavinietal. (1985)
Giavinietal. (1985)
Morita and Hayashi (1998); Stott et al.
(1981); Hellmerand Bolcsfoldi (1992);
Zimmerman et al. (1985)
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Endpoint
In vivo
Genetic Toxicity,
chromosomal aberrations
In vitro
In vivo
Chronic (Non-Cancer)
Oral
Inhalation
Carcinogenicity
Oral
Inhalation
Dermal Irritation
Skin Sensitization
Respiratory Sensitization
Hazard Determination
Nongenotoxic or weakly genotoxic
Low hazard based on available in vitro and in vivo studies
Nongenotoxic
Low hazard based on available in vitro studies
Nongenotoxic or weakly genotoxic
Low hazard based on available in vitro and in vivo studies
NOAEL = 9.6; LOAEL = 94 mg/kg-bw/day
NOAEL = 170; LOAEL = 387 mg/kg-bw/day
NOAEC = 360 mg/m3
"Likely to be carcinogenic to humans based on evidence of
carcinogenicity in several 2-year bioassays"
High hazard base on tumor progression in the liver via the oral
route
"Likely to be carcinogenic to humans based on evidence of
carcinogenicity in several 2-year bioassays"
High hazard base on tumor progression tumor progression at
multiple sites via
inhalation
Not irritating
No Data
Positive for Sensitization
References
(all are as cited in (US EPA, 2013b))
Roy et al. (2005); Morita and Hayashi
(1998); Stott et al. (1981)
Galloway et al. (1987); Morita and
Hayashi (1998)
Miyagawa et al. (1999); Goldsworthy et
al. (1991); Stott etal. (1981)
Kociba et al. (1974); Giavini et al. (1985);
Kano et al. (2008)
Kasai et al. (2008)
Endpoint used as the POD for IRIS
Reference Concentration (RfC)
Kociba et al (1974); Kano et al (2009); NCI
(1978)
Kasai et al. (2009)
Clark etal (1994)
Kasai et al. (2008)
Kasai et al. (2009)
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