BISPHENOL A ALTERNATIVES IN THERMAL PAPER
DRAFT FOR PUBLIC COMMENT
July 2012
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Table of Contents
1 Introduction 1-1
1.1 Purpose of the BP A in Thermal Paper Alternatives Assessment 1-2
1.2 Scope of the BPA in Thermal Paper Alternatives Assessment 1-3
1.3 Chemical Alternatives Assessment as a Risk Management Tool 1-3
2 Products and Materials: BPA in Thermal Paper 2-1
2.1 BPA as a Developer in Thermal Paper 2-1
2.2 Thermal Paper Uses 2-2
3 Background on Thermal Printing Technology 3-1
3.1 Components of Thermal Paper 3-1
3.1.1 Paper 3-1
3.1.2 Printing Chemistry 3-2
3.2 Thermal Printing Equipment and Process 3-5
3.3 Advantages and Disadvantages of Thermal Printing Technology 3-6
3.4 Alternatives Included in this Assessment 3-7
3.5 Alternatives Not Included in this Assessment 3-11
4 Hazard Evaluation of Bisphenol A (BPA) and Alternatives 4-1
4.1 Toxicological and Environmental Endpoints 4-1
4.1.1 Definitions of Each Endpoint Evaluated Against Criteria 4-1
4.1.2 Criteria 4-4
4.1.3 Endpoints Characterized but Not Evaluated 4-7
4.2 Data Sources and Assessment Methodology 4-8
4.2.1 Identifying and Reviewing Measured Data 4-8
4.2.2 Hierarchy of Data Adequacy 4-10
4.2.3 Assessment of Oligomeric Mixtures 4-11
4.3 Importance of Physical and Chemical Properties, Environmental Transport, and
Biodegradation 4-11
4.4 Evaluating Human Health Endpoints 4-18
4.4.1 Endpoints Characterized and Evaluated Against Criteria Based on Measured Data. 4-
18
4.4.2 SAR - Application of SAR and Expert Judgment to Endpoint Criteria 4-19
4.5 Evaluating Environmental Endpoints 4-20
4.5.1 Ecotoxicity 4-20
4.5.2 Bioaccumulation 4-22
4.5.3 Environmental Persistence 4-23
4.6 Endocrine Activity 4-25
4.7 Hazard Summary Table 4-28
4.8 Hazard Profiles 4-32
Bisphenol A 4-32
Bisphenol F 4-85
Bisphenol C 4-116
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MBHA 4-141
BisOPP-A 4-162
Bisphenol AP 4-183
Substituted Phenolic Compound #1 4-205
Substituted Phenolic Compound #2 4-224
PI IBB 4-246
Bisphenol S 4-268
2,4-BPS 4-292
TGSA 4-305
BPS-MAE 4-321
BPS-MPE 4-333
D-8 4-348
D-90 4-361
DD-70 4-374
Pergafast 201 4-384
BUM 4-399
11 4-409
5 General Exposure and Lifecycle Information 5-1
5.1 Potential Exposure Pathways and Routes (General) 5-2
5.1.1 Inhalation Exposures 5-2
5.1.2 Dermal Exposures 5-3
5.1.3 Ingestion Exposures 5-3
5.1.4 Environmental and General Population Exposures 5-3
5.1.5 Exposures to Susceptible Populations 5-4
5.1.6 Physical-Chemical Properties for the Alternatives to BPA included in this
Assessment that May Impact Exposure 5-6
5.2 Potential Sources of Exposure in the Life-cycle of Thermal Paper 5-8
5.2.1 Manufacture of Developers 5-8
5.2.2 Manufacture of Thermal Paper 5-9
5.2.3 Conversion of Thermal Paper 5-11
5.2.4 Use of Thermal Paper 5-11
5.2.5 End-of-Life 5-12
5.2.6 Manufacture of Recycled Paper Products 5-13
5.3 Available Data on Occupational, Consumer, and Environmental Exposures to BPA,
Thermal Paper Lifecycle 5-13
5.3.1 BPA in Receipts 5-13
5.3.2 BPS in Receipts 5-14
5.3.3 BPA Transfer to Skin and Potential for Dermal Absorption 5-14
5.3.4 Occupational Exposure 5-14
5.3.5 Consumer and General Population Exposure 5-15
5.3.6 Environmental Exposure 5-17
6 Considerations for Selecting Thermal Paper Developers 6-1
6.1 Human Health and Environmental Considerations 6-1
6.1.1 Human Health Hazard 6-1
6.1.2 Ecotoxicity 6-2
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6.1.3 Persi stence 6-2
6.1.4 Bioaccumulation Potential 6-2
6.1.5 Exposure Considerations 6-3
6.3 Performance Considerations 6-4
6.4 Economic Considerations 6-5
6.5 Social Considerations 6-6
6.7 Innovation and Design Challenges 6-10
6.8 Relevant Resources 6-11
6.8.1 Resources for State and Local Authorities 6-11
6.8.2 Federal Agency Resources 6-12
6.8.3 Resources for Global Regulations 6-12
6.9 Related Assessments 6-13
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List of Acronyms and Abbreviations
AIM
Analog Identification Methodology
ACR
Acute to Chronic Ratio
ADME
Absorption, Distribution, Metabolism, and Excretion
AIST
Advanced Industrial Science and Technology
ASTM
American Society for Testing and Materials
BAF
Bioaccumulation Factor
BCF
Bioconcentration Factor
BPA
Bisphenol A
CASRN
Chemical Abstracts Service Registry Number
CDC
Centers for Disease Control and Prevention
CHO
Chinese Hamster Ovary Cells
ChV
Chronic Value
CPSC
Consumer Product Safety Commission
CVL
Crystal Violet Lactone
DfE
Design for the Environment
dpi
Dots per inch
EC50
Half Maximal Effective Concentration
ECHA
European Chemicals Agency
ECOSAR
Ecological Structure Activity Relationships
EDSP
Endocrine Disruptor Screening Program
EEC
European Economic Community
EKG
El ectrocardi ogram
EPA
U. S. Environmental Protection Agency
EPCRA
Community Right-to-Know Act
EPI
Estimations Program Interface
ERMA
Environmental Risk Management Authority
EU
European Union
FDA
U.S. Food and Drug Administration
GHS
Globally Harmonized System of Classification and Labeling of Chemicals
GLP
Good Laboratory Practice
HGPRT
Hypoxanthine-Guanine Phosphoribosyl-Transferase
HPLC
High Performance Liquid Chromatography
HPV
High Production Volume
HSDB
Hazardous Substances Data Bank
IARC
International Agency for Research on Cancer
IR
Infrared
IRIS
Integrated Risk Information System
IUCLID
International Uniform Chemical Information Database
Koc
Organic carbon/water partition coefficient (a.k.a. soil adsorption coefficient)
Kow
Octanol/water partition coefficient
LC50
Median Lethal Concentration
LCA
Life cycle assessment
LD50
Median Lethal Dose
LD
Lactation Day
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LFL
LOAEL
LOEC
MF
MITI
MW
MSDS
NAICS
NES
NGO
NHANES
NICNAS
NIOSH
NIR
NOAEL
NOEC
NOEL
NTP
OECD
OPPT
P2
PBB
PBDE
PBT Profiler
PMN
PNEC
POS
ppb
ppm
PVC
REACH
RoHS
SAR
SF
SIDS
SMILES
SPARC
TDI
TRI
TSCA
QSAR
UFL
USGS
WHO
WWTP
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Lower limit of flammability
Lowest Observed Adverse Effect Level
Lowest Observed Effective Concentration
Molecular Formula
Japanese Ministry of International Trade and Industry
Molecular Weight
Material Safety Datasheet
North American Industry Classification System
No Effects at Saturation
Non-Governmental Organization
National Health and Nutrition Examination Survey
National Industrial Chemicals Notification and Assessment Scheme
National Institute for Occupational Safety and Health
Near infrared
No Observed Adverse Effect Level
No Observed Effect Concentration
No Observed Effect Level
National Toxicology Program
Organisation for Economic Cooperation and Development
Office of Pollution Prevention and Toxics
Pollution Prevention
Poly-Brominated Biphenyls
Polybrominated diphenyl Ether
Persistent, Bioaccumulative, and Toxic (PBT) Chemical Profiler
Premanufacture Notice
Predicted No Effect Concentration
Point-of-sale
parts per billion
parts per million
Polyvinyl Chloride
Registration, Evaluation, Authorisation and Restriction of Chemical substances
Restriction of Hazardous Substances
Structure Activity Relationship
Sustainable Futures
Screening Information Data Set
Simplified Molecular-Input Line-Entry System
Sparc Performs Automated Reasoning in Chemistry
Total Daily Intake
Toxics Release Inventory
Toxic Substances Control Act
Quantitative Structure Activity Relationships
Upper Limit of Flammability
U.S. Geological Survey
World Health Organization
Wastewater Treatment Plant
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1 Introduction
As part of its effort to enhance the Agency"s current chemicals management program, the U.S.
Environmental Protection Agency (EPA) has taken steps to identify chemicals that may pose
environmental and health concerns; in 2009-2011 EPA developed action plans to investigate
potential regulatory and voluntary actions. In March 2010, EPA released a chemical action plan
that summarizes hazard, exposure, and use information on bisphenol A (BPA) and identifies
actions EPA is considering.1 Under this Action Plan, EPA"s Design for the Environment (DfE)
Program initiated this alternatives assessment: BP A Alternatives in Thermal Paper. DfE"s
Alternatives Assessment Program helps industries choose safer chemicals and provides a basis
for informed decision-making by developing an in-depth comparison of potential human health
and environmental impacts of chemical alternatives. Representatives from industrial, academic,
governmental, and non-governmental organizations (NGOs) engaged with DfE to select and
evaluate alternatives to BPA in thermal paper2 and develop this report. Although this report is
intended to provide information that will enable selection of safer alternatives to BPA in thermal
paper, it also contains helpful risk management information for thermal paper companies who
are not currently using BPA.
BPA is a high production volume (HPV) chemical with a U.S. volume estimated at 2.4 billion
pounds in 2007 and an estimated value of almost $2 billion (U.S. EPA 2010a). It is a monomer
used in manufacturing most polycarbonate plastics, the majority of epoxy resins, and other
chemical products such as flame retardants. Recently, there has been heightened public attention
around exposures to BPA and its potential effects as an environmental pollutant. Because BPA is
a reproductive, developmental, and systemic toxicant in animal studies and interacts with
estrogen receptors, there are questions about its potential impact, particularly on children"s health
and ecosystems. Several government entities have published reports examining potential human
health and environmental hazards associated with BPA exposure. Such entities include a number
of regulatory agencies in the European Union (EU), Health Canada and Environment Canada,
Japan"s National Institute of Advanced Industrial Science and Technology (AIST), the U.S. Food
and Drug Administration (FDA), and the U.S. National Institute of Environmental Health
Sciences National Toxicology Program (NTP). Additional research is underway, particularly
concerning whether BPA may cause effects at low concentrations (U.S. EPA 2010a).
Approximately 94% of BPA is used as a monomer to make polycarbonate plastic and epoxy
resins (U.S. EPA 2010a). Although most human exposure to BPA is believed to come from food
and beverage packaging made from these materials, less than 5% of the BPA produced is used in
food contact applications (U.S. EPA 2010a). Apart from food-related uses, BPA-based materials
are used in automotive and other transportation equipment, optical media such as DVDs,
electrical/electronics equipment, construction, linings inside drinking water pipes, thermal paper
coatings, foundry casting, and elsewhere.
1 The BPA Action Plan is available online at
http://www.epa.gov/opptintr/existingchemicals/pubs/actionplans/bpa action planpdf
2 The term "thermal paper" used in this report refers to paper used in direct thermal transfer machines.
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BPA is a commonly used developer in a number of thermal paper applications, such as point of
sale receipts, but may also be used in other thermal paper applications, such as airline tickets,
event and cinema tickets, and labels. When used in thermal paper, BPA is present as "free" (i.e.,
discrete, non-polymerized) BPA, which is likely to be more available for exposure than BPA
polymerized into a resin or plastic (U.S. EPA 2010a). Upon handling, BPA in thermal paper can
be transferred to skin, and there is some concern that residues on hands could be ingested
through incidental hand-to-mouth contact (Zalko, Jacques et al. 2011). Furthermore, some
studies suggest that dermal absorption may contribute some small fraction to the overall human
exposure (Biedermann, Tschudin et al. 2010; Zalko, Jacques et al. 2011). European data indicate
that the use of BPA in paper may also contribute to the presence of BPA in the stream of
recycled paper and in landfills (JRC-IHCP 2010). Although there are currently no estimates for
the amount of BPA used in thermal paper in the United States, in Western Europe, the volume of
BPA reported to be used in thermal paper in 2005/2006 was 1,890 tonnes per year, while total
production was estimate at 1,150,000 tonnes per year (JRC-IHCP 2010), which accounts for
roughly 0.2% of the annual use of BPA.
As described in the Action Plan, EPA"s DIE Program initiated this multi-stakeholder partnership
alternatives assessment: Alternatives to BPA in Thermal Paper. DfE"s Alternatives Assessment
Program provides a basis for informed decision-making by developing an in-depth comparison
of potential human health and environmental impacts of chemical alternatives. The BPA
Alternatives in Thermal Paper Partnership was formed in July 2010 and includes a diverse array
of stakeholders, such as thermal paper manufacturers, thermal paper converters, chemical
manufacturers, point-of-sale equipment manufacturers, retailers, trade associations, non-
governmental organizations, green chemistry and technical experts, and international
governmental organizations. Partners engaged with DfE to identify and evaluate potential
alternatives to BPA in thermal paper and develop this report. This report is intended to provide
information that will enable selection of safer alternatives to BPA in thermal paper.
This alternatives assessment evaluated the available alternatives that were judged as most likely
to be used in thermal printing applications. Selection of a chemical for evaluation in the report
does not denote environmental preferability. Rather, the report provides information that will
help decision-makers consider environmental and human health profiles for all evaluated
chemicals, so that they can choose the safest possible functional alternative. This report also
presents general information on exposures to thermal paper, life-cycle considerations, and some
considerations for weighing human health and environmental considerations with other factors,
such as cost and performance.
1.1 Purpose of the BPA in Thermal Paper Alternatives Assessment
The purpose of the BPA in Thermal Paper Alternatives Assessment is to inform substitution to
safer alternatives for BPA by evaluating the hazard associated with functional alternatives to
BPA and making that information available to decision-makers and the public. Information
generated from this partnership will contribute to more informed decisions concerning the
3 For more information on the DfE Program's alternatives assessments,
seewww.epa.gov/dfe/alternative assessments.html.
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selection and use of developers in thermal paper technologies and the disposal and recycling of
thermal paper.
1.2 Scope of the BPA in Thermal Paper Alternatives Assessment
The BPA in Thermal Paper Alternatives Assessment is an evaluation of potential hazards
associated with thermal paper developers that are likely to be functional alternatives to BPA.
Thermal paper systems include a developer and other components such as dyes and sensitizers.
EPA recognizes that a change in the developer may require additional adjustments to the system.
This report summarizes the outcomes of the alternatives assessment, and aims to improve
understanding of the potential environmental and human health impacts of BPA and alternative
developers in thermal paper throughout their life cycles. It is intended to provide information that
will inform industry and other stakeholders on the selection of potentially safer alternative
developers for use in thermal paper.
This report is organized as follows:
• Chapter 1 (Introduction): This chapter provides background to the BPA Alternatives in
Thermal Paper Partnership, including the purpose and scope of the assessment.
• Chapter 2 (Products and Materials: BPA in Thermal Paper): This chapter provides
information on BPA and its use in thermal paper as a developer.
• Chapter 3 (Background on Thermal Printing Technology): This chapter describes the
thermal paper printing system and how developers interact with other components in the
system to create a printed product.
• Chapter 4 (BPA Alternatives Evaluations): This chapter provides the results of the hazard
assessment of BPA and the 19 alternatives that the partnership identified. This chapter
also discusses how the alternatives were identified.
• Chapter 5 (GeneralExposure andLifecycle Information): This chapter details the human
health and environmental exposure pathways of developers from thermal paper.
• Chapter 6 (Considerations for Selecting a Replacement for BPA): This chapter describes
considerations involved with selecting an alternative developer to BPA in thermal paper.
This chapter also discusses green chemistry options and alternative technologies that
could be used in place of thermal paper applications.
1.3 Chemical Alternatives Assessment as a Risk Management Tool
Among other actions, the Agency included an alternatives assessment for BPA in thermal paper
as a suitable risk management tool in the Action Plan for BPA. The Agency chose this tool to
inform the chemical substitution that may occur as an outcome of other activities described in the
Action Plan. Alternatives assessment provides information on the environmental and human
health profiles of chemicals that may be used as substitutes so that industry and other
stakeholders can use this information, in combination with analysis of cost, performance, and
other factors to choose alternatives.
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Chemical alternatives assessment, life cycle assessment (LCA) and risk assessment are all tools
that can be used to improve the sustainability profiles of chemicals and products. These tools,
which can be complementary, should be selected according to the risk management need and
other regulatory and policy considerations. DfE Alternatives Assessments establish a foundation
that other tools, such as risk assessment and LCA, can build upon.
The focus of this DfE alternatives assessment report is a comparative hazard assessment of the
chemical alternatives that may be substituted for BPA in thermal paper. Comparative chemical
hazard assessment is a comparison of chemicals within the same functional use group (e.g.,
solvent, surfactant, flame retardant, ink developer) that evaluates alternatives across a consistent
and comprehensive set of hazard endpoints. Information about chemical hazards derived from
this type of comparative chemical hazard assessment can be used by decision-makers to help
them select safer alternative chemicals.
Risk assessment and alternatives assessment are both based on the premise that risk is a function
of hazard and exposure. Risk assessment characterizes the nature and magnitude of hazard and
exposure from chemical contaminants and other stressors. The DfE alternatives assessment
evaluates and compares the nature of the chemical hazards and reflects a view that when
exposure is comparable, risk is reduced through the use of less hazardous chemicals. Alternatives
assessment strives to decrease the reliance on exposure controls thus reducing risk even when
these controls fail.
Chemical alternatives assessment differs substantially from LCA. An LCA can present a robust
picture of many environmental impacts associated with the material and energy inputs and
outputs throughout the life cycle of a product, and by doing so can identify opportunities for
reducing those impacts. However, unlike chemical alternatives assessment, LCA typically
provides a limited (if any) review of inherent toxicity.
DfE"s „functional use" approach to alternatives assessment orients chemical evaluations within a
given product type and functionality. Under this approach, factors related to exposure scenarios,
such as physical form and route of exposure, can be constant within a given functional use
analysis and would fall out of the comparison so that a reduction in hazard is a reduction of risk.
When less hazardous alternatives have different physical-chemical profiles or require different
use levels, it may be appropriate to also conduct an exposure assessment. DfE alternatives
assessments consider intrinsic properties of chemical substitutes that affect exposure potential,
including absorption potential, persistence, and bioaccumulation. Under this approach, the health
and environmental profiles in the alternatives assessments become the key variable and source of
distinguishing characteristics. The potential impact of exposure attributes, including significant
differences in environmental fate and transport based on persistence, bioaccumulation, and
physical properties, are discussed in Chapters 4 and 5.
Alternatives assessment is most useful in identifying safer substitutes when available alternatives
meet performance requirements and are expected to present lower hazards for human health and
the environment. During decision-making, risk assessment or LCA could be applied to the
lower-hazard or potentially preferable alternatives to complement the alternatives assessment
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findings. Alternatives assessments can also identify the characteristics of a safer alternative and
guide innovation and product development, especially when clearly preferable alternatives are
not available.
Chemical Alternatives Assessment Furthers the Goals of Green Chemistry
The DfE alternatives assessment approach is aligned with green chemistry principles.4 The
relationship to two of those principles is especially noteworthy:
• Principle 4: Design of safer chemicals — "Chemical products should be designed to
effect their desired function while minimizing their toxicity," and
• Principle 10: Design for degradability — "Chemical products should be designed so that
at the end of their function they break down into innocuous degradation products and do
not persist in the environment."
DfE incorporates these two green chemistry principles in its criteria and applies them in its
assessment of chemical hazard and fate in the environment. This approach enables identification
of safer substitutes that emphasize greener chemistry and points the way to innovation in safer
chemical design where hazard becomes a part of a performance evaluation.
Aspects beyond the Scope of this Assessment and Report
An assessment of process chemicals (i.e., those used in manufacturing of BPA) and other
chemicals used in the manufacture of thermal paper is beyond the scope of this assessment.
Similarly, assessments of technologies that could replace thermal paper applications altogether,
such as alternative printing technologies or electronic receipts, are also outside the scope of this
assessment. Selected alternative technologies are briefly discussed in Chapter 6.
4 http://www.epa. gov/sciencematters/iune2011/principles.htm
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References
Biedermann, S., P. Tschudin, et al. (2010). "Transfer of bisphenol A from thermal printer paper
to the skin." Anal Bioanal Chem 398: 571-576.
Joint Research Centre-Institute for Health and Consumer Protection (JRC-IHCP) (2010).
European Union Risk Assessment Report, 4,4'-Isopropylidenediphenol (Bisphenol-A).
U.S. Environmental Protection Agency (U.S. EPA) (2010a). Bisphenol A Action Plan.
Zalko, D., C. Jacques, et al. (2011). "Viable skin efficiently absorbs and metabolizes bisphenol
A." Chemosphere 82(3): 424-430.
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2 Products and Materials: BPA in Thermal Paper
Bisphenol A (BPA) is one of the highest production volume chemicals in the world. Global
production capacity of BPA was about 5,160 kilotons in 2008 (Chemical Weekly 2009). The
U.S. alone had a production capacity of 1,226 kilotons of BPA in 2008. In 2008, Europe"s
estimated annual production capacity was 1,438 kilotons (Chemical Weekly 2009), up from 1150
kilotons/year in 2005/2006 (JRC-IHCP 2010).
BPA is found in a diverse array of products in addition to thermal paper. For example, one of the
main sources of BPA is in polycarbonate plastics and in epoxy resins. Applications of
polycarbonates include reusable food and drink containers such as plastic bottles, optical media
such as CDs and DVDs, automotive and other transport equipment, sports safety equipment,
glazing, and polycarbonate blends in the electronics industry (OECD 2002; Polycarbonate/BPA
Global Group 2011). Applications of epoxy resins containing BPA include lacquers in protective
coatings in food cans and water pipes, structural composites, electrical laminates such as for
printed circuit boards, composites, electrical applications, as well as paints, adhesives and other
protective coatings such as dental sealants (OECD 2002; Polycarbonate/BPA Global Group
2011). BPA is used in the production of polyester resins, polysulfone resins, polyacrylate resins,
and flame retardants (NTP-CERHR 2008). It is also contained in polyvinyl chloride (PVC)
plastics and foundry castings (U.S. EPA 2010a).
BPA is synthesized by the condensation of phenol and acetone in the presence of an acid catalyst
(e.g., hydrogen chloride) and a promoter (e.g., methyl mercaptan). This condensation reaction
yields two grades of BPA, both of which may be used in the manufacture of thermal paper (ICIS
2011; S. MacNeil, personal communication, November 28, 2011).
This chapter describes BPA"s use as a developer, as well as the thermal paper applications in
which BPA is often used. Thermal printing technology is described in Chapter 3.
2.1 BPA as a Developer in Thermal Paper
BPA is widely used as a developer in thermal paper because it is efficacious, available, and
affordable (Mendum, Stoler et al. 2011). In a sample of ten twelve-inch blank cash register
receipts from businesses in suburban Boston, Mendum et al. found that eight receipts had
quantifiable concentrations of BPA (level of quantification 26 |ig/g). Detectable BPA varied
from 3 to 19 mg per 12-inch receipt (2011). Mendum et al. identified three categories for the
amount of BPA in thermal paper: full BPA content (9-19mg/12 inches), low BPA content (1-3
mg/12 inches), and BPA-free paper (below the detection limit) (2011).
In a larger study, 103 thermal receipt papers from 58 locations in the U.S., Japan, Korea, and
Vietnam were tested (Liao and Kannan 201 lb). BPA was found in 94 percent of the receipts,
ranging from below the level of quantification (1 ng/g in this study) to 13.9 mg/g (geometric
mean: 0.211 mg/g). Some receipt papers claimed to be "BPA-free," as specifically printed on the
receipt paper, but all of these receipt papers contained hundreds of |ig/g levels of BPA
(geometric mean: 217|ig/g). Of the receipt papers collected in the U.S., 100 percent of them
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contained BPA. BPA was not detected in any of the six samples from Japan, likely due to the
2001 Japanese phase-out of BPA in thermal paper.
Although there are currently no estimates for the amount of BPA used in thermal paper in the
U.S., in Europe, the amount of BPA used in 2005/2006 in thermal paper amounted to 1.89
kilotons (JRC-IHCP 2010). This accounts for roughly 0.2 percent of total European BPA
consumption (JRC-IHCP 2010).
2.2 Thermal Paper Uses
Thermal paper has extensive applications with the most common uses including: point-of-sale
(POS) receipts, labels, tickets, and print-outs from recording devices Point-of-sale receipts
include sales receipts from cash registers, ATMs, and banks. Labels printed on thermal paper
include labels on prescriptions, industrial barcodes, packaged items such as supermarket foods
(e.g. deli meats, cheese, bulk items), and retail shelf labels. Tickets for transportation (e.g.
airlines, trains), entertainment (e.g., cinema, theatre, gaming, sporting events, amusement parks,
arenas, and museums), parking tickets, and tickets from kiosks are all common applications of
thermal paper (Nashua Corporation 2008). Ultrasound, electrocardiogram, and printouts from
other laboratory recorders are also common examples of thermal printing (JPI Healthcare n.d.).
Testing of thermal paper used in medical applications, such as electrocardiogram (EKG)
printouts, indicates that it is made with bisphenol S (J. Warner, personal communication, March
1,2011).
According to European estimates, point-of-sale receipts account for only half of thermal paper
sold. Nearly one-third of thermal paper is used in self-adhesive labels in applications such as deli
trays, shipping labels, luggage tags, etc. Lottery tickets account for ten percent of thermal paper
applications and another ten percent for fax paper (JRC-IHCP 2010).
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References
Chemical Weekly (2009). Bisphenol-A: A Techno-Commercial Profile. September 1, 2009:
205-211.
ICIS (2011). Bisphenol A (BPA) Production and Manufacturing Information.
Joint Research Centre-Institute for Health and Consumer Protection (JRC-IHCP) (2010).
European Union Risk Assessment Report, 4,4'-Isopropylidenediphenol (Bisphenol-A).
JPI Healthcare, (n.d.). "Ultrasound Paper." from http://www.ipihealthcare.com/ultrasound-paper.
Liao, C. and K. Kannan (201 lb). "Widespread Occurence of Bisphenol A in Paper and Paper
Products: Implications for Human Exposure." Environ. Sci. Technol. 45: 9372-9379.
Mendum, T., E. Stoler, et al. (2011). "Concentration of bisphenol A in thermal paper." Green
Chemistry Letters and Reviews 4(1): 81-86.
Nashua Corporation. (2008). "Label Products." from
http://nashua.com/prodandservices/labelproducts.aspx?selected=labeltrans.
National Toxicology Program-Center for the Evaluation of Risks to Human Reproduction (NTP-
CERHR) (2008). NTP-CERHR Monograph on the Potential Human Reproductive and
Developmental Effects of Bisphenol A. U.S. Department of Health and Human Services.
Organisation for Economic Co-operation and Development (OECD) (2002). "SIDS Initial
Assessment Profile." Existing Chemicals Database SIAM 14: 26-28.
Polycarbonate/BPA Global Group. (2011). "Bisphenol A." from http://bisphenol-a.org/.
U.S. Environmental Protection Agency (U.S. EPA) (2010a). Bisphenol A Action Plan.
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3 Background on Thermal Printing Technology
Thermal printing is a rapid and inexpensive printing technology widely used in commercial
applications such as point-of-sale receipts, luggage tags, faxes, and labels (Mendum, Stoler et al.
2011). Direct thermal printing produces an image when specific chemicals within the coating of
thermal paper are heated.5 Thermal printing technology was first developed in the late 1960s, and
its popularity grew in the 1980s and 1990s as it became more cost effective and versatile. This
chapter describes the components of the thermal paper system, its associated equipment, process,
and applications, as well as the alternative chemicals analyzed and considered in the alternatives
assessment.
3.1 Components of Thermal Paper
Thermal paper is a highly engineered product that is coated with a thermal sensitive layer that
reacts in the presence of heat to create the printed image. The following sections describe the key
components of thermal paper development, including chemistry and manufacture. This
information was useful in evaluating potential alternatives in this application.
3.1.1 Paper
Thermal paper is a standard paper grade that has been coated with a thermal sensitive layer, also
known as a thermal reactive layer (see Figure 3-1). A pre-coat, or base coat, is applied to the
base paper and allows for high resolution by preventing the heat transfer through all of the
paper"s layers, and for smoothness. Applied to the pre-coat is a thermal layer that contains the
necessary reactive components (see Section 3.1.2). Additionally, thermal paper may contain a
protective top coat and/or back coat. Top coats may be used for some applications to protect
thermal paper from mechanical stress or chemical reactions. Similarly, back coats may be used to
provide additional protection during lamination, printing, or other mechanical processes (Koehler
Thermal Papers n.d.). Thermal paper used for receipts typically lack the top and back coats.
Figure 3-1: Cross-Section of Thermal Paper
Top Coat
Thermal Reactive Layer
Pre-Coat
Base Paper
Back Coat
Thermal paper manufacturers produce the thermal paper in "jumbo rolls," which is considered a
semi-finished product. Paper converters print, cut the product to the appropriate size for use,
rewind the paper onto a specific core (called "slit rolls"), and package the paper for sale to
distributors. There are three major categories of thermal paper depending on basis weight, or
density (typically g/m or pounds per ream): (1) fax and point-of-sale (POS) grades, with an
average basis weight of 58 grams, (2) label and ticket grades, with an average basis weight of 80
5 Note: Other types of thermal printing include thermal transfer printing or dye sublimation. Direct thermal printing
is the focus of the DfE alternatives assessment and thus, of this report.
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grams, and (3) heavy ticket grades, with an average basis weight of 120 grams (USITC 2007).
Thermal paper is generally not made from recycled material, as post-consumer content can lack
the consistency required for this highly engineered product. Limited quantities of recycled
thermal paper are available, often including up to 50 percent post-consumer content. Thermal
paper can be printed in both single-sided and double-sided formats.
3.1.2 Printing Chemistry
The thermal layer includes three key compounds (see Figure 3-2): a dye (also referred to as a
colorformer), a developer (also referred to as a coreactant), and in some systems, a sensitizer
(also referred to as a modifier). A binder, such as polyvinyl alcohol or latex, helps these coatings
adhere to the paper. The materials are slurried and applied as an aqueous emulsion to the paper.
The combination of these materials and their properties determines the image color, scanning
characteristics and durability.
The colorant typically used in thermal paper is a leuco dye, which is colorless at room
temperature (Biedermann, Tschudin et al. 2010). Leuco dyes used in thermal paper undergo a
structural change when protonated in the presence of heat and a proton donor (i.e., developer).
The structural change results in the production of color. During printing, the thermal head of the
printing unit pulses heat to the paper, which causes the components to melt, triggering the
transfer of the proton from the developer to the dye, causing the leuco dye molecule to change
structure to form a visible color (Biedermann, Tschudin et al. 2010). When used, the sensitizer
has a lower melting point, thus acting as a solvent, promoting the interaction of the developer
with the dye.
The dyes are often spirolactone compounds, with Black 305 and ODB2 among the most
common. Some dyes extend the wavelength resulting in direct transfer systems that can scan in
the near infrared (NIR) and infrared (IR) wavelengths (ETAC and NIR Black 78, respectively).
Based on discussions with stakeholders, Design for the Environment (DfE) has compiled a list
that illustrates a variety of dyes that can be used in direct thermal printing (see Table 3-1). Each
of these dyes shares the property that they are colorless until developed following heat
Figure 3-2: Elements of the Thermal Reactive Layer
¦ Binder
Dye
activation.
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Table 3-1: Example of Dyes Used in Thermal Paper
Name
Synonyms
CASRN
Color
Spiro[isobenzofuran-l(3H),9'-
[9H]xanthen]-3-one, 6'-
(dibutylamino)-3 '-methyl-2'-
(phenylamino)-
2-Anilino-6-dibutylamino-3-
methylfluoran; ODB-2,
Black 400
89331-94-2
black
Spiro[isobenzofuran-l(3H),9'-
[9H]xanthen]-3-one, 6'-
(dipentylamino)-3'-methyl-2'-
(phenylamino)-
Black 305
129473-78-5
black
, Furo[3,4-b]pyridin-5(7H)-one,
7,7-bis[4-(diethylamino)-2-
ethoxyphenyl]-
3,3-Bis (4-diethylamino-2-
ethoxyphenyl)-4-
azaphthalide
GN-2
132467-74-4
green
7 - Anilino-3 -di ethyl amino-6-
methyl fluoran
N-102 (ODB)
29513-49-0
black
Spiro[isobenzofuran-l(3H),9'-
[9H]xanthen] -3 -one, 6'- [ethyl(4-
methylphenyl)amino] -3 '-methyl-
2'-(phenylamino)-
ODB-250, ETAC
59129-79-2
black
Spiro[isobenzofuran-l(3H),9'-
[9H]xanthen] -3 -one, 6'-
(diethylamino)-3'-methyl-2'-[(3-
methylphenyl)amino] -
ODB-7
151019-95-3
black
Spiro[12H-benzo[a]xanthene-
12, l'(3'H)-i sobenzofuran] -3 '-
one,9-[ethyl(3-
methylbutyl)amino]-
Red 500
115392-27-3
red
Spiro[isobenzofuran-l(3H),9'-
[9H]xanthen] -3 -one, 6'- [ethyl(4-
methylphenyl)amino]-2'-methyl-
Red 520
42228-32-0
red
l(3H)-Isobenzofuranone,6-
(dimethylamino)-3,3-bis[4-
(dimethylamino)phenyl]-
CVL, crystal violet lactone
1552-42-7
blue
Spiro[isobenzofuran-l(3H),9'-
[9H]xanthen]-3-one,6'-[ethyl(3-
methylbutyl)amino]-3'-methyl-
2'-(phenylamino)-
S-205
70516-41-5
black
3,3-Bis[2-[4-
(dimethylamino)phenyl]-2-(4-
methoxyphenyl)vinyl] -4,5,6,7-
tetrachl orophthali de
NIR Black 78
113915-68-7
black
3-(4-Diethylamino-2-
methylphenyl)-3-(l-ethyl-2-
Blue 220
114090-18-5
blue
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Name
Synonyms
CASRN
Color
methyl-lH-indol-3-yl)-4-
azaphthalide
7-[4-(diethylamino)-2-
hexoxyphenyl]-7-(l-ethyl-2-
methylindol-3-yl)furo[3,4-
b]pyridin-5-one
Blue 203
98660-18-5
blue
Spiro[isobenzofuran-l(3H),9'-
[9H]xanthen] -3 -one, 6'- [ethyl(4-
methylphenyl)amino]-2'-
(methylphenylamino)-
ATP
42530-35-8
green
Spiro[isobenzofuran-l(3H),9'-
[9H]xanthen] -3 -one, 6'- [(3 -
ethoxypropyl )ethyl amino] -3' -
methyl-2'-(phenylamino)-
(93071-94-4)
Black 500
93071-94-4
black
Developer
The purpose of the developer, also referred to as a coreactant, which are weakly acidic, is to
transfer protons to the dye, triggering color formation. In selecting a developer, its solubility,
pKa, melting point, color, odor, purity, and vapor pressure are key properties. Performance
characteristics of effective developers include:
• Acidity such that it produces no background imaging
• Ability to fully react with the colorformer when heated
• Reaction at the temperature of the specific printer
• Stable at end use temperatures
• Appropriate permanence for the application
• Appropriate performance vs. cost balance
• Feasible in large-scale production.
See Section 3.4 for a list of alternative developers considered in this alternatives assessment.
Sensitizer
Sensitizers, also referred to as modifiers, can facilitate the dye coloration process by lowering the
melting point of the dye/developer, and/or by acting as a type of solvent in which a dye and
developer dissolve below their melting point. Sensitizers typically have a melting point between
45-65°C (Mendum, Stoler et al. 2011). The sensitizer helps to provide the optimal conditions for
the developer to transfer protons upon heating, which enables color formation and can increase
printing speed, or make a product suitable for low-energy printers. A variety of sensitizers are
used in direct thermal printing (see Table 3-2).
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Table 3-2: Examples of Sensitizers Used in Thermal Printing
Name
Synonyms
CASRN
Di-(P-Chlorobenzyl)
oxalate
Ethanedioic acid,l,2-bis[(4-
chlorophenyl)methyl] ester
19829-42-6
Di-(P-Menthylbenzyl)
oxalate
Ethanedioic acid,l,2-bis[(4-
methylphenyl)methyl] ester
18241-31-1
Dibenzyl oxalate
Ethanedioic acid,l,2-bis(phenylmethyl)
ester
7579-36-4
2-B enzyl oxynapthal ene
Naphthalene, 2-(phenylmethoxy)-
613-62-7
1,4-Diphenoxybutanes
1,4-diphenylbutane-1,4-dione
495-71-6
4-Benzylbiphenyl
1 -phenyl -4-(phenylmethyl)benzene
613-42-3
Dimethyl terephthalate
1,4-B enzenedi carb oxyli caci d,
dimethylester
120-61-6
1,2-Diphenoxy ethane
(2-Phenoxyethoxy)benzene
104-66-5
1,2-Bis(3-
methoxyphenoxy) ethane
Benzene, 1,1'-[1,2-
ethanediylbis(oxy)]bis[3-methyl-
54914-85-1
Diphenyl sulfone
1,1'- Sulfonylbi sbenzene
127-63-9
Stearamide (waxy)
Octadecanamide
124-26-5
Kemamide S (waxy)
Oligoethylene butylene glycol adipate,
Hexanedioic acid
26570-73-0
Ethylene bis stearamide
Octadecanamide,N,N'-ethylenebis-
(6CI,7CI,8CI)
110-30-5
Octadecanamide, N-
phenyl
N-phenyl stearami de
637-54-7
o-Acetoacetotolui di de
N-(2-methylphenyl)-3-oxobutanamide
93-68-5
3.2 Thermal Printing Equipment and Process
Direct thermal printing produces an image by selectively heating specific areas of thermal paper
(Mendum, Stoler et al. 2011). At room temperature, the dye is in its neutral, unprotenated state,
which is colorless. When the dye/developer/ sensitizer system is heated above the melting point
of the sensitizer, the developer (commonly bisphenol A (BP A)) donates a proton. In the case of
the CVL dye (Table 3-1), this causes the lactone ring to open and increases the conjugation of
the system, resulting in color formation (Mendum, Stoler et al. 2011). The chemicals then
solidify to create a relatively stable image.
As Figure 3-3 illustrates, a thermal printing system consists of three basic components: a printer
head, thermal paper, and a platen (i.e., backing roll). The printer head contains miniature heating
units along the length of the printer head that electronically transfers the required amount of heat
to the paper. As the thermal paper is driven by the platen, it is heated by the unit"s thermal head
causing the dye and the developer in the coating of the paper to melt and react, which
subsequently produces an image on the paper (Koehler Thermal Papers n.d.).
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Figure 3-3: Overview of Thermal Printing Process
(based on Koehler Thermal Paper n.d. and Charters Paper Pty Ltd 2006)
Thermal paper
Platen feed roller
To ensure optimal printing results, it is important to consider the characteristics of the type of
thermal paper and printer used. Different grades of thermal paper have certain characteristics that
render them more applicable to certain uses. One important characteristic is dynamic sensitivity,
which pertains to the length of time the paper is exposed to heat. The faster a printer operates, the
less time the paper is exposed to the unit"s heating element. Thermal paper with a higher
dynamic sensitivity is most appropriate for higher-speed or lower-energy printing. If thermal
paper with low dynamic sensitivity is instead used, insufficient heat will be applied to the paper
resulting in a reduced long-term stability of the finished product (Koehler Thermal Papers n.d.).
Static sensitivity is another important characteristic of thermal paper. Static sensitivity defines
the temperature at which the dye and the developer begin to melt. The static sensitivity value is
important for thermally-sensitive applications, such as for parking tickets or environments with
high temperatures (e.g., pizza boxes, coffee cup labels) (Koehler Thermal Papers n.d.). Different
grades of thermal paper exhibiting varying degrees of thicknesses and sensitivities affect the
lifespan of the print job. If the appropriate paper and printer combination is used, and proper
storage conditions are met, an image printed on thermal paper typically lasts between five to ten
years (Koehler Thermal Papers 2011).
3.3 Advantages and Disadvantages of Thermal Printing Technology
Direct thermal printing offers several advantages in commercial environments, including not
requiring any additional inks or chemicals to form the printer image. The only consumable item
needed for direct thermal paper printing is the paper. Unlike thermal transfer printing, the direct
thermal paper technology obviates the need for ink or ribbon maintenance and replacement.6
Thermal printing systems also have few moving parts, making them reliable and relatively
durable. In addition, direct thermal printing systems are quiet, have appropriate edge definition
(up to 400 dpi, or dots per inch), can be manufactured to be small and lightweight, and can print
quickly (up to 406 mm per second) (Charters Paper Pty Ltd 2006). Such advantages make direct
thermal printing systems a useful tool for market segments like retailers, laboratories with
6 The use of ribbons, which contain a mirror image of anything printed, raise privacy and security concerns; ribbons
used in the printing of medical information must be destroyed in accordance with the Health Insurance Portability
and Accountability Act of 1996 (HIPAA).
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recorders, transportation, and hospitality, which tend to value an economical and fast printing
system. Stakeholders noted that direct transfer print systems can be made portable, which is a
highly valued attribute.
Thermal paper rolls exposed to heat may turn black, necessitating appropriate storage conditions.
Point-of-sale (POS) thermal paper is generally very thin and may be damaged by prolonged
exposure to sunlight, water, or chemicals (e.g., solvents, plasticizers) and to friction. In general,
POS thermal printing is best suited for short-term printing needs more so than longer term data
storage. However, some thermal printing is estimated to last five to twelve years (Koehler
Thermal Papers n.d.).
3.4 Alternatives Included in this Assessment
With the assistance of the partnership, EPA identified 19 alternatives to BPA in thermal paper
(see Table 3-3 below). These alternatives were selected because have the potential to be
functional substitutes to BPA based on their physical and chemical properties and/or because
they are already in commercial use. A hazard assessment was conducted on these 19 alternatives
and the findings are discussed in Chapter 4.
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Table 3-3: The Alternatives Selected for Analysis in the Hazard Assessment
CASRN
Chemical Name
Common
Name
Molecular
Formula
Structure
Known to Be
Used in
Thermal Paper
80-05-7
2,2-bis(p-
hydroxyphenyl)propane
Bisphenol A,
BPA
C'isH 1602
HP —^ ^—
-0~°h
yes
620-92-8
Bis(4-
hydroxyphenyl)methane
Bisphenol F,
BPF
C13H12O2
O H
yes
79-97-0
2,2"-Bis(4-hydroxy-3-
methylphenyl)propane
Bisphenol C,
BPC
C17H20O2
»-bn
unknown
5129-00-0
Methyl bis(4-
hydroxyphenyl)acetate
MBHA
C15H14O4
c
JO
unknown
24038-68-4
4,4"-Isopropyllidenebis(2-
phenylpheno)
BisOPP-A
C27H24O2
°X)
unknown
1571-75-1
4,4"-(l-
Phenylethylidene)bisphenol
Bisphenol AP,
BPAP
C20H18O2
C
0~oh
)
yes
PROPRIETARY
Substituted
phenolic
compound #1
N/A
N/A
unknown
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CASRN
Chemical Name
Common
Name
Molecular
Formula
Structure
Known to Be
Used in
Thermal Paper
PROPRIETARY
Substituted
phenolic
compound #2
N/A
N/A
proprietary
94-18-8
Benzyl 4-hydroxybenzoate
PHBB
C14H12O3
0
yes
80-09-1
4-Hydroxyphenyl sulfone
Bisphenol S
C12H10O4S
^—' 0
yes
5397-34-2
2,4"-
Bis(hydroxyphenyl)sulfone
2,4-BPS
C12H10O4S
0 0 OH
yes
41481-66-7
bis-(3-allyl-4-
hydroxyphenyl) sulfone
TGSA
C18H18O4S
O /=.
™^Lyi-\yoH
yes
97042-18-7
Phenol,4-[[4-(2-propen-l-
yloxy)phenyl] sulfonyl] -
BPS-MAE
C15H14O4S
/—^ 0,—,
HO—^ %—S—/ %—0
° H
yes
63134-33-8
4-Hydroxy-4"-
benzyloxydiphenylsulfone
BPS-MPE
c19h1604s
yes
95235-30-6
4-hydroxyphenyl 4-
isoprooxyphenylsulfone
D-8
c15h1604s
yes
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CASRN
Chemical Name
Common
Name
Molecular
Formula
Structure
Known to Be
Used in
Thermal Paper
191680-83-8
4 - [4' - [(1' -methy lethy loxy)
phenyl] sulfonyljphenol
D-90
C28H26O9S2 (n= 1);
C44H42O14S3 (n = 2)
-,° °o 'P
yes
93589-69-6
1,7-bis(4-
Hydroxypheny ltliio) -3,5 -
dioxaheptane
DD-70
C17H20O4S2
unknown
232938-43-1
N-(p-Toluenesulfonyl)-N'-
(3-p-
toluenesulfonyloxyphenyl)u
rea
Pergafast 201
C21H20N2O6S2
w-O+l
w 0 0H
yes
151882-81-4
4.4'-bis(\-carbamoyl-4-
methylbenzenesulfonamide)
diphenylmetliane
BTUM
C29H28N4O6S2
yes
321860-75-7
Urea Uretliane Compound
UU
C42H36N608S
h3c °s° ch3
0 0 rT^r ° ° r^n
Yes
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3.5 Alternatives Not Included in this Assessment
The chemicals listed in this section were identified as possible alternatives to BP A, but were not
included in the alternatives assessment. Chemicals were excluded, based on feedback from the
partnership, because their physical or chemical properties would likely render them incompatible
as a functional replacement developer to BPA. Required physical properties of developers
include acidity, water solubility, and melting point. A summary of the chemicals that were
discussed but not included in this assessment are listed in Table 3-4.
Table 3-4: Alternatives Considered but Not Included in the Hazard Assessment
CASRN
Chemical or
Common Name
Molecular
Formula
Structure
98-54-4
p-tert-butylphenol
Ci0H14O
92-69-3
p-phenylphenol
Ci2H10O
OOh
2664-63-3
4,4' -thiodiphenol
c12h10o2s
jf
hO^-
V
s
I
19715-19-6
3,5-di-tert-
butylsalicylic acid
C15H22O3
>
\
120-47-8
ethyl-p-
hydroxybenzoate,
ethyl paraben
C9H10O3
J
z
0
3-^
22479-95-4
dimethyl-4-
hydroxyphthalate,
DMP-OH
C10H10O5
ho"
c
\ /
0 0
1694-06-0
N-(p-
toluenesulphonyl)-N"-
(3-p-
toluenesulphonyloxyp
henyl)urea
C8H10N2O3S
0
jC
n 0
4724-47-4
octadecylphosphonic
acid
Ci8H3903P
H> O H
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CASRN
Chemical or
Common Name
Molecular
Formula
Structure
O
[J
65-85-0
benzoic acid
c7h6o2
u OH
57-11-4
stearic acid
C18H30O2
0
II
144-62-7
oxalic acid
c2h2o4
»V
0
11113-50-1
boric acid
H3B03
ho„ ,oh
B
1
OH
O
149-91-7
gallic acid
c7h6o5
I*/"
OH
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References
Biedermann, S., P. Tschudin, et al. (2010). "Transfer of bisphenol A from thermal printer paper
to the skin." Anal Bioanal Chem 398: 571-576.
Charters Paper Pty Ltd (2006). Leaders in the field of Thermal Paper Technology.
Koehler Thermal Papers (2011). Koehler Thermal Papers: Product Range.
Koehler Thermal Papers (n.d.). Thermal Papers: Product Information.
Mendum, T., E. Stoler, et al. (2011). "Concentration of bisphenol A in thermal paper." Green
Chemistry Letters and Reviews 4(1): 81-86.
U.S. International Trade Commission (2007). Certain Lightweight Thermal Paper From China,
Germany, and Korea.
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4 Hazard Evaluation of Bisphenol A (BPA) and Alternatives
This chapter summarizes the toxicological and environmental hazards of bisphenol A (BPA) and
each of the 20 alternative chemicals that were identified as potential functional substitutes for
BPA. In general, the hazard profiles include the assessment of unchanged starting materials,
byproducts, and impurities. Evaluations of chemical formulations may also require the
consideration of associated substances (e.g. starting materials, byproducts, and impurities) if
their presence is specifically required to allow that alternative to fully function in the assigned
role. In general, associated substances were assumed to remain unchanged in this assessment,
but may need to be considered in the selection of an alternative. This report is a hazard
assessment, not a full risk assessment. Hazard assessment as a risk management tool is discussed
in more detail in Section 1.3.
Toxicological and environmental endpoints included in the hazard profiles are discussed in
Section 4.1 along with the criteria used to evaluate each hazard endpoint. Data sources and the
review methodology are described in Section 4.2. The report then offers a detailed description of
the utility of physical/chemical properties in understanding hazard in Section 4.3. Next, the
process of evaluating human health and environmental endpoints are described in Sections 4.4
and 4.5, respectively and a discussion of the evaluation of endocrine activity is included in
Section 4.6. The characteristics of each chemical included in the alternatives assessment are
summarized in the comparative hazard summary table in Section 4.7. Lastly, the collected data
and hazard profile of each chemical are presented in Section 4.8.
4.1 Toxicological and Environmental Endpoints
The assessment of endpoints with the intent to create hazard profiles for a Design for the
Environment (DfE) alternatives assessment follows the guidance of the "Alternatives
Assessment Criteria for Hazard Evaluation" (U.S. EPA 201 lc). The definitions for each
endpoint evaluated following these criteria are outlined in Section 4.1.1 and the criteria by which
these endpoints are evaluated are outlined in Section 4.1.2. Lastly, there are endpoints which
DfE characterizes but does not assign criteria to and these are summarized in Section 4.1.3.
4.1.1 Definitions of Each Endpoint Evaluated Against Criteria
Hazard designations for each chemical discussed in this report were made by direct comparison
of the experimental or estimated data to the DfE "Alternatives Assessment Criteria for Hazard
Evaluation" (U.S EPA 201 lc). Table 4-1 provides brief definitions of human health toxicity,
environmental toxicity and environmental fate endpoints.
Table 4-1: Definitions of Toxicological and Environmental Endpoints for Hazard
Assessment
Endpoint
Category
Endpoint
Definition
Human Health
Effects
Acute mammalian toxicity
Adverse effects occurring following oral or dermal
administration of a single dose of a substance, or multiple
doses given within 24 hours, or an inhalation exposure of
4 hours.
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Endpoint
Category
Endpoint
Definition
Carcinogenicity
Capability of a substance to increase the incidence of
malignant neoplasms, reducing their latency, or increasing
their severity or multiplicity.
Mutagenicity/Genotoxicity
Mutagenicity - the ability of an agent to induce
permanent, transmissible changes in the amount, chemical
properties or structure of the genetic material. These
changes may involve a single gene or gene segment, a
block of genes, parts of chromosomes, or whole
chromosomes. Mutagenicity differs from genotoxicity in
that the change in the former case is transmissible to
subsequent cell generations.
Genotoxicity - the ability of an agent or processes to alter
the structure, information content, or segregation of DNA,
including those which cause DNA damage by interfering
with normal replication process, or which in a non-
physiological manner (temporarily) alter its replication.
Reproductive toxicity
The occurrence of biologically adverse effects on the
reproductive systems of females or males that may result
from exposure to enviromnental agents. The toxicity may
be expressed as alterations to the female or male
reproductive organs, the related endocrine system or
pregnancy outcomes. The manifestation of such toxicity
may include, but is not limited to, adverse effects on onset
of puberty, gamete production and transport, reproductive
cycle normality, sexual behavior, fertility, gestation,
parturition, lactation developmental toxicity, premature
reproductive senescence, or modifications in other
functions that were dependent on the integrity of the
reproductive systems.
Developmental toxicity
Adverse effects in the developing organism that may
result from exposure prior to conception (either parent),
during prenatal development, or postnatally to the time of
sexual maturation. Adverse developmental effects may be
detected at any point in the lifespan of the organism. The
major manifestations of developmental toxicity include:
(1) death of the developing organism, (2) structural
abnormality, (3) altered growth, and (4) functional
deficiency.
Neurotoxicity
An adverse change in the structure or function of the
central and/or peripheral nervous system following
exposure to a chemical, physical, or biological agent.
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Endpoint
Category
Endpoint
Definition
Repeated dose toxicity
Adverse effects (immediate or delayed) that impair
normal physiological function (reversible and irreversible)
to specific target organs or biological systems following
repeated exposure to a chemical substance by any route
relevant to humans. Adverse effects include biologically
significant changes in body and organ weights, changes
that affect the function or morphology of tissues and
organs (gross and microscopic), mortality, and changes in
biochemistry, urinalysis, and hematology parameters that
are relevant for human health; may also include
immunological and neurological effects.
Respiratory sensitization
Result of a substance that will lead to hypersensitivity of
the airways following inhalation of the substance.
Skin sensitization
A chemical that elicits a cell-mediated or antibody-
mediated allergic response characterized by the presence
of inflammation that may result in cell death, following an
initial induction exposure to the same chemical substance,
i.e., skin allergy.
Eye irritation/corrosivity
Irritation or corrosion to the eye following the application
of a test substance.
Skin irritation/corrosion
Skin irritation - Reversible damage to the skin following
the application of a test substance for up to 4 hours.
Skin corrosion - Irreversible damage to the skin namely,
visible necrosis through the epidermis and into the dermis
following the application of a test substance for up to 4
hours.
Environmental
Toxicity
Adverse effects observed in living organisms that typically inhabit the wild; this assessment is
focused on effects in three groups of surrogate aquatic organisms (freshwater fish, invertebrates,
algae).
Aquatic toxicity (Acute)
The property of a substance to be injurious to an organism
in a short-term, aquatic exposure to that substance.
Aquatic toxicity (Chronic)
The property of a substance to cause adverse effects to
aquatic organisms during aquatic exposures which were
determined in relation to the life-cycle of the organism.
Environmental
Fate
Enviromnental Persistence
The length of time the chemical exists in the environment,
expressed as a half-life, before it is destroyed (i.e.,
transformed) by natural or chemical processes. For
alternatives assessments, the amount of time for complete
assimilation (ultimate removal) is preferred over the initial
step in the transformation (primary removal).
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Endpoint
Category
Endpoint
Definition
Bioaccumulation
The process in which a chemical substance is absorbed in
an organism by all routes of exposure as occurs in the
natural environment e.g., dietary and ambient
enviromnent sources. Bioaccumulation is the net result of
competing processes of chemical uptake into the organism
at the respiratory surface and from the diet and chemical
elimination from the organism including respiratory
exchange, fecal egestion, metabolic biotransformation of
the parent compound and growth dilution.
The hazard profile for each chemical contains endpoint-specific summary statements (Section
4.8). For each of the endpoints in Table 4-1, these summary statements give the hazard
designation, the type of data (experimental or estimated), and the rationale. The endpoint
summaries may also include explanatory comments, a discussion of confounding factors, or an
indication of the confidence in the data to help put the results in perspective.
4.1.2 Criteria
Table 4-2 summarizes the criteria that were used by the U.S. Environmental Protection Agency
(EPA) DfE Program to interpret the data presented in the hazard evaluations. The DfE
Alternatives Assessment Criteria for Hazard Evaluation underwent internal and public comment,
and were finalized in 2011 (U.S. EPA 201 lc). A hazard designation for each human health
endpoint was not given for each route of exposure but rather was based on the exposure route
with the highest hazard designation. Data may have been available for some or all relevant
routes of exposure.
The details as to how each endpoint was evaluated are described below and in the DfE full
criteria document, DfE Alternatives Assessment Criteria for Hazard Evaluation, available at:
http://www.epa.gov/dfe/alternatives assessment criteria for hazard eval.pdf.
Table 4-2: Criteria Used to Assign Hazard Designations
Endpoint
Very High
High
Moderate
Low
Very Low
Human Health Effects
Acute mammalian toxicity
Oral median lethal dose
(LD50) (mg/kg)
<50
>50-300
>300-2000
>2000
-
Dermal LD50 (mg/kg)
<200
>200-1000
>1000-2000
>2000
-
Inhalation median lethal
concentration (LC50) -
vapor/gas
(mg/L)
<2
>2-10
>10-20
>20
Inhalation LC50 - dust/mist/
fume (mg/L)
<0.5
>0.5-1.0
>1-5
>5
-
Carcinogenicity
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Endpoint
Very High
High
Moderate
Low
Very Low
Known or
-
presumed
human
carcinogen
(equivalent to
Globally
Harmonized
System of
Classification
and Labeling of
Chemicals
Suspected
human
Limited or
marginal
evidence of
Negative studies
or robust
mechanism-
carcinogen
(equivalent to
GHS Category
2)
carcinogenicity
in animals (and
inadequate
evidence in
humans)
based structure
activity
relationships
(SAR) (as
described above)
(GHS) Category
1A and IB)7'
Mutagenicity/Genotoxicity
GHS Category
1A or IB:
Substances
known to
induce heritable
GHS Category
2: Substances
which cause
concern for
humans owing
to the
possibility that
they may
induce heritable
mutations in the
germ cells of
humans
OR
Germ cell mutagenicity
mutations or to
be regarded as
if they induce
heritable
mutations in the
germ cells of
humans
Evidence of
mutagenicity
supported by
positive results
in in vitro OR in
vivo somatic
Negative for
chromosomal
aberrations and
gene mutations,
or no structural
Evidence of
cells of humans
alerts.
Mutagenicity and
genotoxicity in somatic
cells
mutagenicity
supported by
positive results
in in vitro AND
in vivo somatic
or animals
cells and/or
germ cells of
humans or
animals
Reproductive toxicity
Oral (mg/kg/day)
-
<50
50-250
>250-1000
>1000
Dermal (mg/kg/day)
-
<100
100-500
>500-2000
>2000
Inhalation - vapor, gas
(mg/L/day)
-
<1
1-2.5
>2.5-20
>20
Inhalation - dust/mist/fume
—
<0.1
0.1-0.5
>0.5-5
>5
(mg/L/day)
Developmental toxicity
Oral (mg/kg/day)
-
<50
50-250
>250-1000
>1000
Dermal (mg/kg/day)
-
<100
100-500
>500-2000
>2000
7 The United Nations" GHS document can be found at
http://www.unece.org/fileadmin/DAM/trans/danger/publi/ghs/glis rev04/English/ST-SG-AC10-30-Rev4e.pdf.
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Endpoint
Very High
High
Moderate
Low
Very Low
Inhalation - vapor, gas
(mg/L/day)
-
<1
1-2.5
>2.5-20
>20
Inhalation - dust/mist/fume
(mg/L/day)
-
<0.1
0.1-0.5
>0.5-5
>5
Neurotoxicity
Oral (mg/kg/day)
-
<10
10-100
>100
-
Dermal (mg/kg/day)
-
<20
20-200
>200
-
Inhalation - vapor, gas
(mg/L/day)
-
<0.2
0.2-1.0
>1.0
-
Inhalation - dust/mist/fume
(mg/L/day)
-
<0.02
0.02-0.2
>0.2
-
Repeated-dose toxicity
Oral (mg/kg/day)
-
<10
10-100
>100
-
Dermal (mg/kg/day)
-
<20
20-200
>200
-
Inhalation - vapor, gas
(mg/L/day)
-
<0.2
0.2-1.0
>1.0
-
Inhalation - dust/mist/fume
(mg/L/day)
-
<0.02
0.02-0.2
>0.2
-
Sensitization
Skin sensitization
High frequency
of sensitization
in humans
and/or high
potency in
animals (GHS
Category 1A)
Low to moderate
frequency of
sensitization in
human and/or
low to moderate
potency in
animals (GHS
Category IB)
Adequate data
available and not
GHS Category
1A or IB
Respiratory sensitization
Occurrence in
humans or
evidence of
sensitization in
humans based
on animal or
other tests
(equivalent to
GHS Category
1Aand IB)'
Limited
evidence
including the
presence of
structural alerts
Adequate data
available
indicating lack
of respiratory
sensitization
Irritation/corrosivity
Eye irritation/corrosivity
Irritation
persists for
>21 days or
corrosive
Clearing in 8-
21 days,
severely
irritating
Clearing in
<7 days,
moderately
irritating
Clearing in
<24 hours,
mildly irritating
Not irritating
Skin irritation/corrosivity
Corrosive
Severe
irritation at
72 hours
Moderate
irritation at
72 hours
Mild or slight
irritation at
72 hours
Not irritating
Endocrine activity
For this endpoint, High/Moderate/Low etc. characterizations will not apply. A
qualitative assessment of available data will be prepared.
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Endpoint
Very High
High
Moderate
Low
Very Low
Environmental Toxicity and Fate
Aquatic toxicity
Acute aquatic toxicity -
LC50 or Half Maximal
Effective Concentration
(ECS0) (mg/L)
<1.0
1-10
>10-100
>100 or No
Effects at
Saturation
(NES)
Chronic aquatic toxicity -
lowest-observed-effect
concentration (LOEC) or
ChV (mg/L)
<0.1
0.1-1
>1-10
>10 or NES
Environmental persistence
Persistence in water, soil,
or sediment
Half-life
>180 days or
recalcitrant
Half-life of 60-
180 days
Half-life <60
but >16 days
Half-life
<16 days OR
passes Ready
Biodegradability
test not
including the
10-day window.
No degradation
products of
concern.
Passes Ready
Biodegradability
test with 10-day
window. No
degradation
products of
concern.
Persistence in air (half-life
days)
For this endpoint, High/Moderate/Low etc. characterizations will not apply. A
qualitative assessment of available data will be prepared.
Bioaccumulation
Bioconcentration Factor
(BCF)/Bioaccumulation
Factor (BAF)
>5000
5000-1000
<1000-100
<100
Log BCF/BAF
>3.7
3.7-3
<3-2
<2
-
Very High or Very Low designations (if an option for a given endpoint in Table 4-2) were assigned only when there
were experimental data available for the chemical under evaluation. In addition, the experimental data must have
been collected from a well conducted study specifically designed to evaluate the endpoint under review. If the
endpoint was estimated using experimental data from a close structural analog, professional judgment, or a
computerized model, then the next-level designation was assigned (i.e.. High or Low).
4.1.3 Endpoints Characterized but Not Evaluated
Several additional endpoints were characterized, but not evaluated against hazard criteria. This is
because the endpoints lacked a clear consensus concerning the evaluation criteria (endocrine
activity), data and expert judgment were limited for industrial chemicals (persistence in air,
terrestrial ecotoxicology), or the information was valuable for interpretation of other toxicity and
fate endpoints (including toxicokinetics and transport in the environment).
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Table 4-3: Definitions of Endpoints and Information Characterized but Not Evaluated
Against Hazard Criteria
Toxicological Endpoint
Definition
Toxicokinetics
The determination and quantification of the time course of absorption, distribution,
metabolism, and excretion (ADME) of chemicals (sometimes referred to as
pharmacokinetics).
Biomonitoring Information
The measured concentration of a chemical in biological tissues where the analysis
samples were obtained from a natural or non-experimental setting.
Enviromnental Transport
The potential movement of a chemical, after it is released to the enviromnent,
within and between each of the enviromnental compartments, air, water, soil, and
sediment. Presented as a qualitative summary in the alternatives assessment based
on physical/chemical properties, environmental fate parameters, and simple
volatilization models. Also includes distribution in the enviromnent as estimated
from a fugacity model.8
Persistence in Air
The half-life for destructive removal of a chemical substance in the atmosphere.
The primary chemical reactions considered for atmospheric persistence include
hydrolysis, direct photolysis, and the gas phase reaction with hydroxyl radicals,
ozone, or nitrate radicals. Results are used as input into the enviromnental
transport models.
Immunotoxicology
Adverse effects on the normal structure or function of the immune system caused
by chemical substances (e.g., gross and microscopic changes to immune system
organs, suppression of immunological response, autoimmunity, hypersensitivity,
inflammation, and disruption of immunological mechanistic pathways).
Terrestrial Ecotoxicology
Reported experimental values effects from guideline and non-guideline studies on
adverse effects on the terrestrial enviromnent. Studies on soil, plants, birds,
mammals, invertebrates were also included.
Endocrine Activity
A change in endocrine homeostasis caused by a chemical and/or other stressor.
4.2 Data Sources and Assessment Methodology
This section explains how data were collected (Section 4.2.1), prioritized and reviewed (Section
4.2.2) for use in the development of hazard profiles. High-quality experimental studies lead to a
thorough understanding of behavior and effects of the chemical in environment and in living
organisms. Analog approaches and SAR-based estimation methods are also useful tools and are
discussed throughout this Section. Information on how polymers differ from discrete chemicals
in terms of how they are evaluated is presented in Section 4.2.3.
4.2.1 Identifying and Reviewing Measured Data
For each chemical assessed, data were collected in a manner consistent with the High Production
Volume (HPV) Chemical Challenge Program guidance on searching for existing chemical
information (U.S. EPA 1999b). This process resulted in a comprehensive search of the literature
for available experimental data. For well characterized chemicals this usually resulted in the
collection of recent high-quality reviews or peer-reviewed risk assessments. These were
8 A fugacity model predicts partitioning of chemicals among air, soil, sediment, and water under steady state
conditions for a default model "environment" (U.S. EPA, 201 le).
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supplemented by primary searches of scientific literature published after these secondary sources
were released, this explained in greater detail below. For chemicals that are not as well
characterized, that is, where these secondary sources were not available or lacked relevant or
adequate data, a comprehensive search of the primary scientific literature was done.
Subsequently, these searches led to the collection and review of articles from the scientific
literature, industrial submissions, encyclopedic sources, and government reports. In addition,
data presented in U.S. EPA public and confidential databases (e.g., integrated risk information
system (IRIS)) were obtained for this project. Generally, foreign language (non-English) reports
were not used unless they provided information that was not available from other sources.
Chemical assessments were performed by first searching for experimental data for all endpoints
in Table 4-1. For most chemicals assessed, high quality secondary sources were not available to
assess all endpoints, and a comprehensive search of the primary literature was performed to
identify experimental data. In some cases, confidential studies submitted to EPA by chemical
manufacturers were also available to support hazard designations. For those chemicals that were
expected to form stable metabolites, searches were performed to identify relevant fate and
toxicity information for the metabolite or degradate.
Well-Studied Chemicals - Literature Search Strategy
As mentioned above, for chemicals that have been well studied, limited to BPA in this
Alternatives Assessment, the literature review focused primarily on the use of secondary sources,
such as in the case of BPA, the 2008 National Toxicology Program (NTP) expert panel review
(National Toxicology Program-Center for the Evaluation of Risks to Human Reproduction
(NTP-CERHR) 2008) and the 2011 Food and Agricultural Organization of the United
Nations/World Health Organization expert panel review (FAO/WHO 2011). Using high-quality
secondary sources maximized available resources and eliminated potential duplication of effort.
However, more than one secondary source was typically used to verify reported values, which
also reduced the potential for presenting a value that was transcribed incorrectly from the
scientific literature. Although other sources might also contain the same experimental value for
an endpoint, effort was not focused on building a comprehensive list of these references, as it
would not have enhanced the ability to reach a conclusion in the assessment. When data for a
selected endpoint could not be located in a secondary source for an otherwise well-studied
chemical, the primary literature was searched by endpoint and experimental studies were
assessed for relevant information.
Making Predictions in the Absence of Measured Data
In the absence of primary or secondary data, hazard designations were based on (1) Quantitative
Structure Activity Relationships (QSAR)-based estimations from the EPA New Chemical
Program"s predictive methods; (2) analog data (3) category-based assignments from the EPA
Chemical Categories document; and (4) expert judgment by EPA subject matter experts.
For chemicals that lacked experimental information, QSAR assessments were made using either
EPA"s Estimation Programs Interface (EPISuite™) for physical-chemical property and
environmental fate endpoints or EPA"s Ecological Structure Activity Relationships
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(ECOSAR™) QSARs for ecotoxicity. For the cancer endpoint, estimates were also obtained
from EPA"s OncoLogic expert system. These estimation methods have been automated, and are
available for free (http://www.epa.gov/oppt/sf/tools/methods.htm). Often analog data were used
to support predictions from models. These approaches were described in the EPA Pollution
Prevention (P2) Framework (U.S. EPA 2005b) and Sustainable Futures (SF) program (U.S. EPA
201 If).
For some physical-chemical properties that could not be estimated using EPISuite™, such as
acid/base dissociation constants, other available methods (e.g., the Sparc Performs Automated
Reasoning in Chemistry (SPARC) website for dissociation constants) were used. All estimation
methods employed were limited to those freely available in the public domain.
The methodology and procedures used to assess polymers are described in Section 4.2.3. In
addition, the endpoints for impurities or oligomers with a molecular weight (MW) >1,000 were
estimated using professional judgment and the results assessed for inclusion in the overall hazard
designation. This process is described, as appropriate, under the corresponding endpoints
appearing in Section 4.3.
When QSAR models were not available, professional judgment was used to identify hazards for
similar chemicals using the guidance from EPA"s New Chemicals Categories (U.S. EPA 2010c).
This document groups substances that have similar chemical structure and toxicological
properties into categories based on EPA"s experience evaluating thousands of chemicals under
the Toxic Substances Control Act (TSCA) New Chemicals Program. The categories identify
substances that share chemical and toxicological properties and possess potential health or
environmental concerns. In the absence of an identified category, analogs for which
experimental data are available were identified using EPA"s Analog Identification Methodology
(AIM) or by substructure searches of confidential EPA databases (U.S. EPA 2012a). If a hazard
designation was still not available, the expert judgment of scientists from EPA"s New Chemical
Program would provide an assessment of the physical-chemical properties, environmental fate,
aquatic toxicity, and human health endpoints to fill remaining data gaps.
4.2.2 Hierarchy of Data Adequacy
Once the studies were obtained they were then evaluated to establish whether the hazard data
were of sufficient quality to meet the needs of the assessment process. The adequacy and quality
of the studies identified in the literature review are described in the Data Quality field of the
chemical assessments presented in Section 4.8. The tiered approach described below represents
a general preferred data hierarchy, but the evaluation of toxicological data also requires
flexibility based on expert judgment.
1. One or more studies conducted in a manner consistent with established testing guidelines
2. Experimentally valid but non-guideline studies (i.e., do not follow established testing
guidelines)
3. Reported data do not have supporting experimental details
4. Estimated data using SAR methods or professional judgment based on an analog
approach
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5. Expert judgment based on mechanistic and structural considerations
In general, data were considered adequate to characterize an endpoint if they were obtained using
the techniques identified in the HPV data adequacy guidelines (U.S. EPA 1999b). Studies
performed according to Harmonized EPA or Organisation for Economic Cooperation and
Development guidelines were reviewed to confirm that the studies followed all required steps.
Experimental studies published in the open literature were reviewed for their scientific rigor and
were also compared and contrasted to guideline studies to identify potential problems arising
from differences in the experimental design. Data from adequate, well-performed, experimental
studies were used to assign hazard designations in preference to those lacking in sufficient
experimental detail. When multiple adequate studies were available for a given endpoint, any
conflicts that were identified were addressed using a weight-of-evidence approach to
characterize the endpoint whenever possible.
When available, experimental data from guideline or well-performed experimental studies were
preferred (items 1 and 2 in the hierarchy list). Information from secondary sources such as
Material Safety Data Sheets (MSDS), or online databases (such as the National Library of
Medicine"s Hazardous Substances Data Bank (HSDB)) (item 3 in the hierarchy list) was
considered appropriate for some endpoints when it included numerical values for effect levels
that could be compared to the evaluation criteria.
4.2.3 Assessment of Oligomeric Mixtures
In the BPA Alternatives Assessment, there are two chemicals that are mixtures of low MW
oligomers comprised of 2 or 3 repeating units. For these materials, all of the oligomers
anticipated to be present in the mixture have MW of less than 1,000 daltons. The hazard
assessment evaluated all oligomers present. From all the oligomers, the higher concern material
was used to assign the hazard designation. This process is essentially identical to the evaluation
of the hazards associated with impurities or byproducts present in discrete chemical products.
As a result, the alternatives assessment process determined the amount of oligomers and
unchanged monomers (starting materials) present and considered their potential hazards in the
alternatives designation.
4.3 Importance of Physical and Chemical Properties, Environmental Transport, and
Biodegradation
Physical-chemical properties provide basic information on the characteristics of a chemical
substance and were used throughout the alternatives assessment process to inform expert
judgment and as inputs into predictive models. These endpoints provide information required to
assess potential environmental release, exposure, and partitioning as well as insight into the
potential for adverse toxicological effects. The physical-chemical properties are given in the
individual chemical hazard profiles presented in Section 4.8. For information on how key
physical-chemical properties of alternatives can be used to address the potential for human and
environmental exposure, please refer to Section 5.1.6. Descriptions of relevant physical-
chemical properties and how they contribute to the hazard assessments are presented below.
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Molecular Weight (MW)
MW informs how a chemical behaves in a physical or biological system including bioavailability
and environmental fate. In general, but not strictly, larger compounds tend to be less mobile in
biological and environmental systems. Their large size restricts their transport through
biological membranes and lowers their vapor pressure. Oligomers evaluated in this alternatives
assessment are mixtures that contain a distribution of components and they may not have a
unique MW (see also Section 4.2.3). To account for variation in these mixtures, the MW of a
representative structure for each oligomer or mixture component was evaluated for this
alternatives assessment. Selection of this representative structure is based on expert judgment on
how the oligomer is produced.
Melting Point and Boiling Point
These two properties provide an indication of the physical state of the material at ambient
temperature. Chemicals with a melting point more than 25 °C were assessed as a solid. Those
with a melting point less than 25 °C and a boiling point more than 25 °C were assessed as a
liquid and those with a boiling point less than 25 °C were assessed as a gas. The physical state
was used throughout the assessment, such as in the determination of potential routes of human
and environmental exposure, as described in Section 5.1. The melting and boiling points were
also useful in determining the potential environmental fate, ecotoxicity, and human health
hazards of a chemical. For example, organic compounds with high melting points generally have
low water solubility and low rates of dissolution. These properties influence a materials
bioavailability and were therefore taken into account in both the assessment process and the
evaluation of experimental studies. Similarly, chemicals with a low melting point also have a
higher potential to be absorbed through the skin, gastrointestinal tract, and lungs.
In the absence of experimental data, the melting point value was not reported and no estimations
were performed. If a chemical decomposes before it melts, this information was included in the
assessment. For boiling point, the maximum value reported in the assessment was 300 °C for
high boiling materials (U.S. EPA 1999b). Melting points for polymers and/or oligomers were not
reported as these materials typically reach a softening point and do not undergo the phase change
associated with melting (i.e., solid to liquid).
Vapor Pressure
Vapor pressure is useful in determining the potential for a chemical substance to volatilize to the
atmosphere from dry surfaces, from storage containers, or during mixing, transfer, or
loading/unloading operations (see Section 5.2). In the assessment process, chemicals with a
vapor pressure less than 1 x 10"6 mm Hg have a low potential for inhalation exposure resulting
from gases or vapors. Vapor pressure is also useful for determining the potential environmental
fate of a substance. Substances with a vapor pressure more than 1 x 10"4 mm Hg generally exist
in the gas phase in the atmosphere. Substances with a vapor pressure between 1 x 10"4 and 1 x
10" mm Hg exist as a gas/particulate mixture. Substances with a vapor pressure less than 1x10"
mm Hg exist as a particulate. The potential atmospheric degradation processes described
below in the reactivity section generally occur when a chemical exists in the gas phase. Gases in
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the atmosphere also have the potential to travel long distances from their original point of
release. Materials in the liquid or solid (particulate) phases in the atmosphere generally undergo
deposition onto the Earth"s surface.
A maximum vapor pressure of 1 x 10" mm Hg was assigned for chemicals without experimental
data or for those substances that were anticipated by professional judgment to be non-volatile
(U S EPA 201 If).
Water Solubility
The water solubility of a chemical provides an indication of its distribution between
environmental media, potential for environmental exposure through release to aquatic
compartments, and potential for human exposure through ingestion of drinking water; water
solubility was also used extensively to determine potential human health and ecotoxicity hazards.
In general, chemicals with water solubility less than 1 x 10"5 g/L indicate a lower concern for
both the expression of adverse effects, and potential aquatic and general population exposure due
to their low bioavailability. However, chemicals with a low bioavailability also tend to be more
environmentally persistent. Low bioavailability is different than no bioavailability, and the two
should not be used interchangeably.
Within the context of this alternatives assessment, the following descriptors were used according
to ranges of water solubility values: more than 10,000 mg/L was considered very soluble; 1,000-
10,000 mg/L represents soluble; 100-1,000 mg/L represents moderately soluble, 1-100 mg/L
represents slightly soluble, and less than 1 mg/L represents insoluble, noting that these guidelines
were not followed consistently within the scientific literature (U.S. EPA 201 If). Chemicals with
higher water solubility were more likely to be transported into groundwater with runoff during
storm events, be absorbed through the gastrointestinal tract or lungs, partition to aquatic
compartments, undergo atmospheric removal by rain washout, and possess a greater potential for
human exposure through the ingestion of contaminated drinking water. Chemicals with lower
water solubility are generally more persistent and have a greater potential to bioconcentrate.
The water solubility of a substance was also used to evaluate the quality of experimental aquatic
toxicity and oral exposure human health studies as well as the reliability of aquatic toxicity
estimates. If the water solubility of a substance was lower than the reported exposure level in
these experiments, then the study was likely to be regarded as inadequate due to potentially
confounding factors arising from the presence of undissolved material. For aquatic toxicity
estimates obtained using SARs, when the estimated toxicity was higher than a chemical"s water
solubility (i.e., the estimated concentration in water at which adverse effects appear cannot be
reached because it was above the materials water solubility), the chemical was described as
having NES. When NES occured, a low ecotoxicity hazard designation was assigned.
While assessing the water solubility of a chemical substance, its potential to form a dispersion in
an aqueous solution was also considered. Ideally, a chemical"s potential to disperse would be
obtained from the scientific literature. In the absence of experimental data, dispersibility can be
determined from chemical structure and/or comparison to closely related analogs. There are two
general structural characteristics that lead to the formation of dispersions in water: (1) chemicals
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that have both a hydrophilic (polar) head and a hydrophobic (non-polar) tail (e.g., surfactants),
and (2) molecules that have a large number of repeating polar functional groups (e.g.,
polyethylene oxide).
The potential for a chemical to form a dispersion influences potential exposure, environmental
fate, and toxicity. Dispersible chemicals have greater potential for human and environmental
exposure, leachability, and aquatic toxicity than what might be anticipated based on the
materials water solubility alone.
Chemicals without experimental data or chemicals that were anticipated by professional
judgment to be sufficiently insoluble and thus were not bioavailable were assigned a water
solubility maximum value of 1 x 10"6 g/L (U.S. EPA 201 If). A water solubility of 1 x 10"3 mg/L
is the default value used for discrete organics as well as non-ionic polymers with a MW > 1,000
daltons according to the SF Polymer Assessment guidance assignment is consistent with an
analysis of the chemicals used in the development of the water solubility estimation program in
EPA"s EPISuite™ software (U.S. EPA 2010b). The training set for this model included 1,450
chemicals with a MW range 27-628 daltons and experimental water solubilities ranging from
miscible to 4 x 10"7 mg/L (Meylan, Howard et al. 1996; U.S. EPA 201 lh). Given that water
solubility decreases with MW, a default value of 1 x 10"3 mg/L is consistent with the limited
bioavailability expected for materials with a MW >1,000 daltons. Although no BPA alternatives
had a MW >1,000, there are two compounds that may contain small amounts of higher MW
oligomeric materials or impurities that were evaluated using a water solubility suggestive of
limited bioavailability.
Octanol/Water Partition Coefficient (K<,w)
The octanol/water partition coefficient, commonly expressed as its log value (i.e., log Kow) is one
of the most useful properties for performing a hazard assessment. The log Kow provides the
partitioning between octanol and water, where octanol is used to mimic fat and other
hydrophobic components of biological systems. Chemicals with a log Kow less than 1 are highly
soluble in water (hydrophilic), while those with a log Kow more than 4 are not very soluble in
water (hydrophobic). A log Kow more than 8 indicates that the chemical is not readily
bioavailable and is essentially insoluble in water. In addition, log Kow greater than
approximately 8 may be difficult to obtain experimentally.
The log Kow can be used as a surrogate for the water solubility in a hazard assessment and is
frequently used to estimate the water solubility if an experimental value is not available. It can
also be used to estimate other properties important to the assessment, including bioconcentration
and soil adsorption, and is a required input for SAR models used to estimate ecotoxicity values.
For chemicals, that are not within the domain of EPISuite™ or that were expected to be
insoluble in water (WS <-1 x 10"6 g/L), a minimum value of 10 was assigned for the log Kow
(U.S. EPA 201 If). Insoluble chemicals that could be run through EPISuite™ software used a
log Kow >10 if the result appeared to be valid based on expert review. This assignment is
consistent with an analysis of the chemicals used in the development of the octanol/water
partition coefficient estimation program in the EPISuite™ software. The training set (chemicals
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used for calibration) for this model included 10,946 chemicals with a MW range 18-720 daltons
and experimental log Kow ranging from -3.89 to 8.70 (Meylan and Howard 1995; U.S. EPA
201 li). Given that log Kowincreases with MW, a default value of 10 is consistent with the
limited bioavailability expected for materials with a MW >1,000 daltons. Although no BPA
alternatives had a MW >1,000, there are two compounds that may contain small amounts of
higher MW oligomeric materials or other impurities that were evaluated using a log Kow
suggestive of limited bioavailability. A maximum log Kow of -2 was used for water soluble
materials. For most polymers and other materials that are anticipated to be insoluble in both
water and octanol, the log Kow cannot be measured and was therefore not listed.
Flammability (Flash Point)
The flash point of a substance is defined as the minimum temperature at which the substance
emits sufficient vapor to form an ignitable mixture with air. Flash point can be used to identify
hazards associated with the handling of volatile chemicals. Substances with a flash point above
37.8 °C (100 °F) were commonly referred to as non-flammable, as this is the flammability
definition used in the shipping industry. There are exceptions to this definition such as
chemicals that may form explosive mixtures in the presence of air.
Explosivity
Explosivity refers to the potential for a chemical to form explosive mixtures in air and can be
defined using the limits of flammability. The lower limit of flammability (LFL) is defined as the
minimum concentration of a combustible substance that is capable of propagating a flame
through a homogenous mixture in the presence of an ignition source. The upper limit of
flammability (UFL) is similarly defined as the highest concentration that can propagate a flame.
LFLs and UFLs are commonly reported as the volume percent or volume fraction of the
flammable component in air at 25°C. If the ambient air concentration of the gas (or vapor) is
between the upper and lower explosion limit, then the material has the potential to explode if it
comes in contact with an ignition source. Knowledge regarding the explosivity of a given
material in air is also useful in identifying potential hazards associated with the manufacture and
use of that material.
pH
The pH scale measures how acidic or basic a substance is on a range from 0 to 14. A pH of 7 is
neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. This scale is used primarily
to identify potential hazards associated with skin or eye contact with a chemical or its aqueous
solutions. The corrosive nature of chemicals that form either strongly basic (high pH) or
strongly acidic (low pH) solutions are generally likely to result in harm to skin and other
biological membranes. For corrosive chemicals, some experimental studies, such as
biodegradation tests, require additional analysis to determine if the tests were performed at
concentrations that cause harm to microbes in the test (and, therefore, may result in incorrectly
identifying a chemical as persistent in the environment). For chemicals that form moderately
basic or acidic solutions in water, the pH of the resulting solution can be used in lieu of a
measured dissociation constant.
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Dissociation Constant in Water (pKa)
The dissociation constant determines if a chemical will ionize under environmental conditions.
The dissociation constant in water provides the amount of the dissociated and undissociated
forms of an acid, base, or organic salt in water. Knowledge of the dissociation constant is
required to assess the importance of the other physical/-chemical properties used in the hazard
assessment. As the percentage of ionization increases, the water solubility increases while the
vapor pressure, Henry"sLaw constant, and octanol/water partition coefficient decrease. For
acids and bases, the dissociation constant was expressed as the pKa and pKe. respectively.
Henry's Law Constant
Henry"sLaw constant is the ratio of a chemical"s concentration in the gas phase to that in the
liquid phase (at equilibrium). In environmental assessments, the Henry"sLaw constant is
typically measured in water at 25 °C. The Henry"s Law constant provides an indication of a
chemical"s volatility from water, which can be used to derive partitioning within environmental
compartments and the amount of material removed by stripping in a sewage treatment plant.
Henry"sLaw constants less than 1 x 10"7 atm-m3/mole indicate slow volatilization from water to
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air (the Henry"sLaw constant for the volatilization of water from water is 1 x 10" atm-m /mole)
and values more than 1 x 10"3 atm-m3/mole indicate rapid volatilization from water to air. To aid
in determining the importance of volatilization, the assessment uses two models based on the
Henry"sLaw constant. These models determine the half-life for volatilization from a model
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river and a model lake. A maximum value of 1 x 10" atm-m /mole for the Henry"sLaw
Constant was assigned for chemicals without experimental data or for those that were anticipated
by professional judgment to be non-volatile.
Sediment/Soil Adsorption/Desorption Coefficient (KoC)
The soil adsorption coefficient provides a measure of a chemical"s ability to adsorb to the
organic portion of soil and sediment. This provides an indication of the potential for the
chemical to leach through soil and be introduced into groundwater, which may lead to
environmental exposures to wildlife or humans through the ingestion of drinking water drawn
from underground sources. Chemicals with high soil adsorption coefficients are expected to be
strongly adsorbed to soil and are unlikely to leach into ground water. The soil adsorption
coefficient also describes the potential for a chemical to partition from environmental waters to
suspended solids and sediment. The higher the Koc the more strongly a chemical is adsorbed to
soil. Strong adsorption may impact other fate processes, such as the rate of biodegradation, by
making the chemical less bioavailable.
The soil adsorption coefficient, Koc, is normalized with respect to the organic carbon content of
the soil to account for geographic differences. The assignments for the degree that a chemical is
adsorbed to soil within the context of the assessment were described qualitatively as very strong
(above 30,000), strong (above 3,000), moderate (above 300), low (above 30), and negligible
(above 3) when determining the potential for a chemical to adsorb to soil and suspended organic
matter, the potential for a chemical to form chemical bonds with humic acids and attach to soil
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also needs to be considered, although this process is generally limited to a small number of
chemical classes.
A maximum value of 30,000 for the Koc was assigned for chemicals without experimental data or
for those that were anticipated by professional judgment to be strongly absorbed to soil (U.S.
EPA 201 If).
Reactivity
The potential for a substance to undergo irreversible chemical reactions in the environment can
be used in the assessment of persistence. The primary chemical reactions considered in an
environmental fate assessment are hydrolysis, photolysis, and the gas phase reaction with
hydroxyl radicals, ozone, or nitrate radicals. The most important reaction considered in the
hazard assessment of organic compounds is hydrolysis, or the reaction of a chemical substance
with water. Because the rate of hydrolysis reactions can change substantially as a function of
pH, studies performed in the pH range typically found in the environment (pH 5-9) were
considered. The second reaction considered in the assessment is photolysis, the reaction of a
chemical with sunlight. Both hydrolysis and photolysis occur in air, water, and soil, while only
hydrolysis was considered in sediment. The half-lives for reactive processes, if faster than
removal via biodegradation, were used to assign the hazard designation by direct comparison to
the DfE persistence criteria.
For the atmospheric compartment, persistence also includes the evaluation of oxidative gas-
phase processes. These processes include the reaction with ozone, hydroxyl radicals, and nitrate
radicals. Since the average concentration of these oxidative species in the atmosphere has been
measured, the experimental or estimated rate constants were converted to, and reported as, a
half-life in the assessment using standard pseudo first-order kinetics (U.S. EPA 201 lg; U.S. EPA
201 le).
For inorganic compounds, an additional chemical process was considered, the potential to be
reduced or oxidized (undergo a redox reaction) under environmental conditions. Redox
reactions change the oxidation state of the species through the transfer of electrons to form
another compound (such as the reduction of Cr(VI) to Cr(III). A change in the oxidation state of
a metal or inorganic species can result in significant change in the materials hazard designation,
in this example going from Cr(VI) to Cr(III) makes the compound less toxic.
Transport
The persistence of a chemical substance is based on determining the importance of removal
processes that may occur once a chemical enters the environment. As noted in Section 4.1.2,
chemicals with a half-life of less than 60 days are expected to be at most a moderate hazard
designation for persistence. Persistence does not directly address the pathways in which a
chemical substance might enter the environment (e.g., volatilization or disposal in a landfill) and
focuses instead on the removal processes that are expected to occur once it is released into air,
water, soil, or sediment. Similarly, the persistence assessment does not address what might
happen to a chemical substance throughout its life cycle, such as disposal during incineration of
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consumer or commercial products. Understanding the environmental transport of a chemical
substance can help identify processes relevant to environmental assessment. For example, if a
chemical is toxic to benthic organisms and partitions primarily to sediment, its potential release
to water should be carefully considered in the selection of alternatives.
Biodegradation
In the absence of rapid hydrolysis or other chemical reactions, biodegradation is typically the
primary environmental degradation process for organic compounds. Determining the importance
of biodegradation is, therefore, an important component of the assessment. Biodegradation
processes are divided into two types. The first is primary biodegradation, in which a chemical
substance is converted to another substance. The second is ultimate biodegradation, in which a
chemical is completely mineralized to small building-block components (e.g., CO2 and water).
DfE persistence criteria use data that are reported as a percent removal in the guideline Ready
Biodegradability test or as a half-life in other experimental studies; both of these measurements
can be compared directly to the DfE criteria in 4.1.2. When considering primary degradation,
the assessment process includes an evaluation of the potential for the formation of metabolites
that were more persistent than the parent materials. Chemical substances that undergo rapid
primary degradation but only slow ultimate biodegradation were considered to have stable
metabolites. In the absence of measured data on the substance of interest, DfE evaluated the
potential for biodegradation for chemicals with a MW <1,000 daltons using the EPA EPISuite™
models. EPISuite™ estimates the probability for ready biodegradation as well as the potential
for primary and ultimate removal, as described in Section 4.5.
4.4 Evaluating Human Health Endpoints
After data collection and analysis of the physical-chemical properties for the chemicals being
assessed the comparison of the data against the hazard criteria can begin. Section 4.4.1 discusses
how measured data are used to make hazard designations for human health endpoints and
Section 4.4.2 presents the approach for filling in data gaps to make these hazard designations.
4.4.1 Endpoints Characterized and Evaluated Against Criteria Based on
Measured Data
This section provides a short description of how measured data were used to designate the level
of hazard for each endpoint. As a reminder, the criteria for the hazard designations are in
Section 4.1.2.
For acute mammalian toxicity the median lethal doses or concentrations were used to assign the
hazard designation. Four levels of hazard designation have been defined ranging from Low to
Very High.
For cancer the hazard designation was contingent on the level of evidence for increased
incidence of cancer, and not potency. The definitions applied in DfE criteria are based on
International Agency for Research Cancer (IARC) levels of evidence (International Agency for
Research on Cancer 2006). For example, a designation of Very High concern requires that the
substance be characterized as a "known or presumed human carcinogen", whereas a designation
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of Low concern requires either negative studies or robust SAR conclusions. A designation of
Moderate was applied as a default value when there was an absence of data suggesting High
carcinogenicity, and an absence of data supporting Low carcinogenicity (i.e., a lack of negative
studies or weak SAR conclusion).
Similarly, the hazard designation for mutagenicity/genotoxicity was also based on the level of
evidence rather than potency. Complete data requirements for this endpoint were both gene
mutation and chromosomal aberration assays. For instances of incomplete or inadequate
mutagenicity/genotoxicity data, a Low hazard designation cannot be given.
For chronic endpoints, such as reproductive, developmental, neurological and repeated dose
toxicity, the hazard designation was based on potency. The evaluation considers both lowest
observed adverse effect levels (LOAELs) and identification of no observed adverse effect levels
(NOAELs) when available. The LOAEL and the NOAEL are experimental dose levels, and their
reliability is dictated by the study design. In studies for which the lowest dose tested resulted in
an adverse effect (and therefore a NOAEL was not established), and in studies for which the
highest dose tested was a NOAEL, a conservative approach using professional judgment was
used to address uncertainty regarding the lowest dose or exposure level that might be expected to
cause a particular adverse effect. For example, in the absence of an established a NOAEL, an
identified LOAEL might fall within the range of a Moderate hazard; however, it is uncertain if a
lower dose, such as one that falls within the range of high hazard exists because no lower doses
were tested. In such cases, professional judgment was applied to assign a hazard designation
when possible. Some degree of uncertainty was evident in results from studies in which a
NOAEL may fall within one hazard range (e.g., moderate hazard) and the identified LOAEL
falls within a different hazard range (e.g., low hazard) because the true LOAEL may fall in either
category, but there were not enough experimental data points to determine the true LOAEL.
Professional judgment was also applied to these cases to assign a hazard descriptor when
possible and the rationale used was described in the assessment.
Developmental neurotoxicity, for which data were only available for BP A, was considered and
was evaluated using the developmental toxicity criteria, which are more stringent than the
criteria for neurotoxicity, and thus more protective (U.S. EPA 201 lc).
The criteria for skin and respiratory sensitization, which are immune-based responses, consider
the frequency and potency of the reactions. For skin sensitization, categories were based on the
weight of evidence from traditional animal bioassays, but in vitro alternative studies were also
considered. At this time, there are no standard test methods for respiratory sensitization; as a
result there was often no designation for this endpoint.
The evaluation of skin and eye irritation and corrosivity were based on the time to recovery.
4.4.2 SAR - Application of SAR and Expert Judgment to Endpoint Criteria
If measured data pertaining to human health criteria were not available, potential adverse effects
were estimated with SAR analysis. To make these estimates, DfE relied on the expertise of
scientists in EPA"s New Chemicals Program who have reviewed thousands of chemicals and
associated data using these methods. SAR uses the molecular structure of a chemical to infer a
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physicochemical property that can be related to specific effects on human health. These
correlations may be qualitative (simple SAR) or quantitative (QSAR). Information on EPA"s use
of SAR analysis has been published by U.S. EPA (1994). Public access to free validated
quantitative SAR models for human health endpoints is far more limited than physical/-chemical
properties, environmental fate parameters, or ecotoxicology.
Carcinogenicity
Carcinogenicity was assessed using the OncoLogic expert system that provides a qualitative
result directly applicable to the DfE criteria. For other endpoints that required SAR approaches,
an analog approach using expert judgment was used as discussed in Section 4.2.
The potential for a chemical to cause cancer in humans was estimated using OncoLogic expert
system. This program uses a decision tree based on the known carcinogenicity of chemicals with
similar chemical structures, information on mechanisms of action, short-term predictive tests,
epidemiological studies, and expert judgment. All estimates obtained in this project were
reviewed by EPA scientists having appropriate expertise. Estimates for the other human health
endpoints were based on expert judgment using an analog approach and not through the use of
computerized SAR methodologies.
Oligomeric Mixtures
Oligomers with MW<1,000 were assessed using a representative structure for all the MW
species anticipated to be present in the mixture. The procedures were essentially identical to
those employed for the evaluation of impurities or byproducts in discrete chemicals although in
this case the oligomer with the highest concern was used to drive the hazard designation.
Unreacted monomers, if present, were also assessed and considered in the hazard evaluation. In
this alternatives assessment, two chemicals are mixtures of low MW oligomers comprised of 2 or
3 repeating units.
4.5 Evaluating Environmental Endpoints
As with endpoints previously mentioned, the preferred method for the evaluation of
environmental endpoints is the use of experimental data. In their absence, the alternatives
assessment uses computerized QSAR models developed by EPA for the evaluation of
environmental endpoints that can be directly compared to the DfE criteria. When measured data
were unavailable, the hazard designation for aquatic toxicity was estimated using EPA"s
ECOSAR™ software and the persistence designation was estimated using models in EPA"s
EPISuite™ software. As a direct result of the design of these models and their direct application
to DfE criteria, the evaluation of environmental endpoints using experimental or estimated data
was discussed together in the following subsections.
4.5.1 Ecotoxicity
For ecological toxicity, the alternatives assessment focused on the hazard designations for acute
and chronic studies on freshwater species of algae, invertebrates, and fish, often referred to as the
„thiee surrogate species'). Aquatic toxicity values were reported in the assessment as follows:
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• Acute (estimated or experimental) - LC50 in mg/L
• Chronic (experimental) - No observed effect concentration (NOEC) in mg/L ; and
• Chronic (estimated) - ChV, or the geometric mean between the NOEC and the LOEC, in
mg/L
Experimental data reported in the alternatives assessment also included information on the
species tested. Test data on other organisms (e.g., worms) were included in the assessment if
data were readily available. These data would be evaluated using professional judgment to
support hazard designations assigned using the three surrogate species; however they were not
used by themselves to assign a hazard designation as DfE criteria are not available.
If an experimental or estimated effect level exceeded the known water solubility of a chemical
substance, or if the log Kow exceeded the estimated ECOSAR™ cut-off values for acute and
chronic endpoints (which are class specific), NES were predicted for the aquatic toxicity
endpoints. NES indicates that at the highest concentration achievable, the limit of a chemical"s
water solubility, no adverse effects were observed (or would be expected). In these cases, a Low
hazard designation was assigned. In the cases where both an estimated water solubility and
ECOSAR™ estimate were used, then an additional factor of ten was applied to the water
solubility before a NES designation was assigned to account for the combined uncertainty in the
model estimates.
In the case where an experimental aquatic toxicity value was significantly higher than the
chemical"s water solubility, it was likely the result of a poorly conducted study. In this
circumstance, which is generally more frequent for formulated products or mixtures, additional
details were provided in the data quality section to describe why the reported values could not be
used to assign a hazard designation.
EPA"s ECOSAR™ estimation program uses chemical structure to estimate toxicity of a chemical
substance using class-specific QSARs. ECOSAR™ automatically determines all of the classes
that a chemical substance may belong to and, therefore, may provide a number of different
ecotoxicity estimates for some or all of the species and durations estimated. Modeled results are
dependent on the functional groups present on the molecule as well as the diversity of chemicals
with experimental data that were used to build the models. The hazard profiles report every
estimated value returned from ECOSAR™. However, the hazard designation was based on the
most conservative ECOSAR™ estimate, unless expert judgment suggested that an individual
substance was better represented by a specific class based on analysis of the operative
mechanism of action. Experimental log Kow values were used preferentially as input into
ECOSAR™. In their absence, estimated log Kowvalues from EPISuite™ were used.
The QSARs for ECOSAR™ were built using experimental data for several chemical classes.
For a chemical class to be defined within ECOSAR™, sufficient acute experimental data were
required to build a QSAR for all three species included in the model. There were instances,
however, where sufficient experimental data are not available to build a chronic QSAR for some
of the three surrogate species. When ECOSAR™ did not provide chronic estimates, the acute
value (experimental or estimated) was divided by an acute to chronic ratio (ACR) to arrive at the
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chronic value. ACRs of 10 were used for fish and daphnid and an ACR of 4 was used for algae
(Mayo-Bean, Nabholz et al. 2011).
An estimate of NES is the default value used for organics, oligomers, or non-ionic polymers with
a MW >1,000 daltons in the assignment of aquatic toxicity hazard. In EPA"s New Chemcial
program, aquatic toxicity is not predicted for chemicals with a MW >1,000 daltons as uptake has
been found to decrease exponentially with MWs >600 daltons (Nabholz, Clements et al. 1993)
due to a decrease in passive absorption through respiratory membranes (Mayo-Bean, Nabholz et
al. 2011). Although no BPA alternatives had a MW <1,000, there are two oligomeric materials
that may contain small amounts of higher MW components. The aquatic toxicity hazard
potential for these materials was would be assigned a low designation as discussed above and, as
a direct result, their presence did not influence the hazard designation for this endpoint.
4.5.2 Bioaccumulation
Bioaccumulation is a process in which a chemical substance is absorbed in an organism by all
routes of exposure as occurs in the natural environment, e.g., from dietary and ambient
environment sources. Bioaccumulation is the net result of the competing processes; this includes
uptake, metabolism and elimination of a chemical in an organism. Bioaccumulation can be
evaluated using the BAF, the steady state ratio of a chemical in an organism relative to its
concentration in the ambient environment, where the organism is exposed through ingestion and
direct contact. Experimental BAFs have not been widely available in the scientific literature and,
as a result, experimental BCFs are more commonly used to evaluate the bioaccumulation hazard.
BCFs are defined as the ratio of the concentration of a chemical in an organism to the
concentration of the chemical in theorganism"s surroundings; BCFs are typically measured for
fish (in water) using guideline studies.
Experimental BAF or BCF values can be compared directly to the DfE criteria for this endpoint
to assign a hazard designation. The BCF/BAF designations range from <100 for a Low
designation to >5,000 for a Very High Designation (see Table 4-2). If experimental values were
available for both of these endpoints, and the BCF and BAF were >100 (i.e., above the Low
designation), the largest factor was used to assign hazard designation. If experimental BCFs
<100 were available, the estimated upper trophic BAF from EPISuite™ was used preferentially
if its use resulted in a more conservative hazard designation and the potential for metabolism was
accurately accounted for within the model estimates.
In the absence of experimental data, evaluation of bioaccumulation potential can be done using
the log Kow and the log octanol/air partition coefficient Koa as estimated by EPISuite™.
However, analysis using Koa requires the use of metabolism data for higher trophic, air breathing
organisms, which can be difficult to obtain from the scientific literature and cannot be readily
estimated. BAFs and BCFs from EPISuite™ were, therefore, typically used for the
bioaccumulation hazard designation when experimental data were lacking. These values can be
compared directly to DfE criteria and the most conservative result was used for the hazard
designation. For chemicals that had estimated bioaccumulation data, available experimental
monitoring data were used to provide insight into the reliability of the model results. For
example, an estimated Low bioaccumulation potential may be increased to a Moderate
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designation if a chemical was routinely identified in samples from higher trophic levels, or a
High designation if the chemical was routinely measured in animals at the top of the food chain.
An estimate of Low is the default value used for organics with a MW >1,000 daltons in the
assignment of bioaccumulation hazard. This assignment is consistent with an analysis of the
chemicals used in the development the bioconcentration and bioaccumulation estimation
programs in the EPISuite™ software (U.S. EPA 201 lh). The training sets for these models
included 527 and 421 chemicals, respectively, with a MW range 68-992 (959 for BAF) daltons.
Given that BCF and BAF reach a maximum and then decrease with increasing log Kow, a default
value of Low is in general consistent with the limited bioavailability expected for materials with
a MW >1,000 daltons. DfE will use all available well-conducted studies when evaluating
bioaccumulation potential for materials with a MW >1,000, including environmental
biomonitoring data on higher trophic levels. Although no BPA alternatives had a MW <1,000,
there are two compounds that may contain small amounts of higher MW oligomeric impurities;
the bioaccumulation hazard potential for these materials was would be assigned a low
designation as discussed above and, as a direct result, their presence did not influence the hazard
designation for this endpoint.
4.5.3 Environmental Persistence
A chemical"s persistence in the environment is evaluated by determining the type and rate of
potential removal processes. These removal processes were generally divided into two
categories: chemical and biological. Of the chemical degradation processes, an evaluation of
environmental persistence includes the reaction of a chemical with water, also known as
hydrolysis, because water is ubiquitous in the environment.Hydrolysis rate constants can be
obtained from the literature or estimated, and the resulting half-lives can be compared directly to
DfE criteria. For commercial chemicals, hydrolysis tends to be a slower environmental removal
process than biodegradation. Direct and indirect photolysis also represent other potential
chemical degradation processes that are considered in the alternatives assessment, and they are
discussed later in this section.
Biodegradation, the most prevalent biological removal processes, were divided into two types.
The first is primary biodegradation, in which a chemical substance is converted to another
substance through a single transformation. The second is ultimate biodegradation, in which a
chemical is completely mineralized to small building-block components (e.g., CO2 and water).
DfE criteria utilize ultimate biodegradation preferentially for the persistence hazard designation,
although primary removal rates were informative in assigning hazard designations particularly
for materials that were transformed slowly, and to a lesser extent for those that are transformed
rapidly.
If ultimate biodegradation data were not available, primary removal data were used in some
cases. For primary removal processes, the potential for the formation of degradation products
that are more persistent than the parent compounds must be considered in the hazard designation.
When present, the persistent degradation products should be evaluated for fate and toxicity.
Half-life data on the persistent degradation products, if available, were used to determine the
assignment for the persistence designation. In the absence of persistent degradation products,
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primary biodegradation half-life data were compared directly to the DfE criteria to assign a
hazard designation.
Biodegradation processes can be classified as either aerobic or anaerobic. Aerobic
biodegradation is an oxidative process that occurs in the presence of oxygen. Anaerobic
biodegradation is a reductive process that occurs only in the absence of oxygen. Aerobic
biodegradation is typically assessed for soil and water, while anaerobic biodegradation is
generally assessed in sediment. For determining the persistence hazard, the importance of both
aerobic and anaerobic biodegradation as well as partitioning and transport in the environment
were considered to determine what removal processes were most likely to occur.
One aspect of the assessment is to determine the potential for biodegradation of a chemical
substance within a sewage treatment plant and other environments. In this assessment, the term
"ready biodegradability" refers to a chemical"s potential to undergo removal in guideline
laboratory studies. A positive result in a test for ready biodegradability can be considered as
indicative of rapid and ultimate degradation in most environments including biological sewage
treatment plants. Ready tests typically include a 10-window, beginning when the biodegradation
parameter (e.g., dissolved organic carbon, theoretical oxygen demand) reaches 10%. The
window must occur within the 28-day length of the test. If the pass level of the test (typically
60%) is met in the 10-day window, the chemical received a Very Low hazard designation. Those
that did not pass the 10-day window criterion but met the pass level in 28 days received a Low
hazard designation. -If ready biodegradability test data were available but the chemical did not
meet the pass level, the chemical was evaluated based on measured data using the DfE half-life
criteria (Table 4-1). These half-life criteria were also used to assign a hazard designation for
nonguideline ultimate biodegradation studies reported in the scientific literature.
In the absence of a reported half-life, experimental data were also used to approximate half-life
as appropriate. For example, a chemical that undergoes <5% removal in 30 days would be
expected to have a half-life >60 days and would be assigned a High persistence concern.
When experimental data on the biodegradation of a chemical substance were not available, the
potential of that substance to undergo this removal process was assessed from the results of the
EPISuite™ models. These models fall into one of four classes: Rapid biodegradation models
based on linear and non-linear regressions that estimate the probability that a chemical substance
will degrade fast; Expert survey models that determine the rate of ultimate and primary
biodegradation using semi-quantitative methods; Probability of ready biodegradability; and
Probability of rapid biodegradation under anaerobic conditions. Each of these is discussed in the
following paragraphs.
The first models (Biowin 5 and 6) used in the assessment estimated ready biodegradability (also
known as Japanese Ministry of International Trade and Industry (MITI) models), and provided
the probability that a material passes this standardized test. Those chemicals that were estimated
to pass the ready biodegradability test received a Low persistence designation. If a chemical was
not estimated to pass the MITI test, the results of the other EPISuite™ biodegradation models
were used.
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The rapid biodegradation potential models within EPISuite™ (Biowin 1 and 2) were useful for
determining if a chemical substance was expected to biodegrade quickly in the environment. If a
chemical was likely to biodegrade quickly, it was generally assigned a Low hazard designation
for persistence. The results of the estimates from these models may be used in concert with the
semi-quantitative output from a second set of models, which include an ultimate and primary
survey models (Biowin 3 and 4) for evaluating persistence. These models provided a numeric
result, ranging from 1 to 5, as an indication of the amount of time required for complete
mineralization (ultimate degradation) and removal of the parent substance (primary degradation)
of the test compound. The numeric result was converted to an estimated half-life for removal
that can be compared directly to DfE criteria. If results from different models (other than the
MITI models) led to a different hazard designation, then the ultimate biodegradation model
results were used preferentially. If the transport properties indicate the potential for the material
to partition to sediment, an anoxic compartment, then the results of the anaerobic probability
model (Biowin 7) will also be evaluated.
Half-lives for hydrolysis from experimental studies or EPISuite™ estimates, were used in
preference to biodegradation data when they suggested that hydrolysis is a more rapid removal
process. Hydrolysis half-lives were compared directly to DfE criteria to assign the persistence
designation. Similar to primary biodegradation, breakdown products resulting from hydrolysis
were evaluated for fate and toxicity when they were expected to be more persistent than the
parent compound.
Photolysis may also be an important environmental removal process. In general, environmental
removal rates from photolysis do not compete with biodegradation or hydrolysis although there
are exceptions such as iodides. Photolysis may be an important removal process for chemicals
that were not bioavailable because of their limited water solubility. Estimation methods for
photolysis rates were not available using computerized SAR tools. If experimental or suitable
analog data were available, the rate of photolysis was evaluated relative to other removal
processes.
When evaluating the environmental persistence designation, it should be noted that chemicals
with a High or Very High designation can degrade over time, although this process may occur at
a very slow rate. As a result, a Very High designation may have been assigned if persistent
degradates were expected to be produced, even at a very slow rate, in the absence of
experimental biodegradation data for the parent substance.
4.6 Endocrine Activity
Chemicals included in this DfE alternatives assessment were screened for potential endocrine
activity, consistent with the DfE Alternatives Assessment Criteria (U.S. EPA 201 lc). Endocrine
activity refers to a change in endocrine homeostasis caused by a chemical or other stressor. An
endocrine disruptor is an external agent that interferes in some way with the role of natural
hormones in the body, in a manner causing adverse effects. Relevant data are summarized in the
hazard assessments for each chemical, located in Section 4.8. Data on endocrine activity were
available for BPA and 10 of the 20 alternatives included in this report. For chemicals without
available data on endocrine activity, this was acknowledged with a "no data available" statement.
When endocrine activity data were available, the data were summarized as a narrative. A unique
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hazard designation of Low, Moderate or High is not provided for this endpoint in Table 4-3, for
reasons discussed below.
The document Special Report on Environmental Endocrine Disruption: An Effects Assessment
and Analysis describes EPA"s activities regarding the evaluation of endocrine disruption (U.S.
EPA 1997). This report was requested by the Science Policy Council and prepared by EPA"s
Risk Assessment Forum. This report states that "Based on the current state of the science, the
Agency does not consider endocrine disruption to be an adverse endpoint per se, but rather to be
a mode or mechanism of action potentially leading to other outcomes, for example, carcinogenic,
reproductive or developmental effects, routinely considered in reaching regulatory decisions"
(U.S. EPA 1997). The report also states that "Evidence of endocrine disruption alone can
influence priority setting for further testing and the assessment of results of this testing could
lead to regulatory action if adverse effects are shown to occur" (U.S. EPA 1997).
The 1996 Food Quality Protection Act directed EPA to develop a scientifically-validated
screening program to determine whether certain substances may cause hormonal effects in
humans. In response, EPA established the Endocrine Disruptor Screening Program (EDSP)
(U.S. EPA 2012b). The EDSP is developing requirements for the screening and testing of
thousands of chemicals for their potential to affect the endocrine system. When complete, EPA
will use these screening and testing approaches to set priorities and conduct further testing when
warranted. The science related to measuring and demonstrating endocrine disruption is
relatively new, and validated testing methods at EPA are still being developed.
The EDSP proposes a two-tiered approach that includes initial screening followed by more in-
depth testing when warranted (U.S. EPA 201 lb). The Tier 1 screening battery is intended to
identify chemicals with the potential to interact with the estrogen, androgen, or thyroid hormone
systems through any of several recognized modes of action. Positive findings for Tier 1 tests
identify the potential for an interaction with endocrine systems, but do not fully characterize the
nature of possible effects in whole animals. Tier 2 testing is intended to confirm, characterize,
and quantify the effects for chemicals that interact with estrogen, androgen, and thyroid hormone
systems. These test methods must undergo a four-stage validation process (protocol
development, optimization/prevalidation, validation, and peer-review) prior to regulatory
acceptance and implementation. Validation is ongoing for Tier 1 and Tier 2 methods.9 Once
validated test methods have been established for screening and testing of potential endocrine
disruptors, guidance must be developed for interpretation of these test results using an overall
weight-of-evidence characterization.
To assess the data on endocrine activity, DfE applies the weight of evidence approach developed
by the EDSP (U.S. EPA 201 Id). Generally, weight of evidence is defined as the process for
characterizing the extent to which the available data support a hypothesis that an agent causes a
particular effect (U.S. EPA 1999a; U.S. EPA 2002; U.S. EPA 2005a). This process integrates
and evaluates data, and always relies on professional judgment (U.S. EPA 201 Id). To evaluate
endocrine activity with this weight of evidence approach, DfE examined multiple lines of
evidence (when available) and considered the nature of the effects within and across studies,
9 Information on the status of assay development and validation efforts for each assay in EPA's EDSP can be found
at: http://www.epa.gov/oscpmont/oscpendo/pubs/assaYvalidation/status.htm
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including number, type, and severity/magnitude of effects, conditions under which effects
occurred (e.g., dose, route, duration), consistency, pattern, range, and interrelationships of effects
observed within and among studies, species, strains, and sexes, strengths and limitations of the in
vitro and in vivo information, and biological plausibility of the potential for an interaction with
the endocrine, androgen, or thyroid hormonal pathways.
Most test data for chemicals in this report consist of in vitro assays, but results of in vitro assays
alone were not generally expected to provide a sufficient basis to support a hazard designation
for endocrine disruption. EPA expects that in vivo evidence would typically be given greater
overall influence in the weight of evidence evaluation than in vitro findings because of the
inherent limitations of such assays. Although in vitro assays can provide insight into the mode of
action, they have limited ability to account for normal metabolic activation and clearance of the
compound, as well as normal intact physiological conditions (e.g., the ability of an animal to
compensate for endocrine alterations).
As described in the DfE Alternatives Assessment Criteria, endocrine activity was summarized in
a narrative, rather than by High, Moderate or Low hazard designation. The endocrine activity
summaries can be found in the hazard profiles. This is an appropriate approach because there is
no consensus on what constitutes high, moderate or low concern for this endpoint. The summary
of endocrine activity largely relies on representative studies and expert review summaries.
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4.7 Hazard Summary Table
Table 4-4 Screening Level Hazard Summary
This table only contains information regarding the inherent hazards of the chemicals evaluated. Evaluation of risk considers both the hazard and exposure.
The caveats listed in the legend and footnote sections must be taken into account when interpreting the hazard information in the table below.
VL = Very Low hazard L = Low hazard = Moderate hazard H = High hazard VH = Very High hazard — Endpoints in colored text (VL, L, , H, and VH)
were assigned based on empirical data. Endpoints in black italics (VL, L, M, H, and VH) were assigned using values from estimation software and professional judgment.
0 The highest hazard designation of a representative component of the oligomeric mixture with MWs <1,000.
{ The highest hazard designation of any of the oligomers with MW <1,000§ Based on analogy to experimental data for a structurally similar compound.
Chemical
CASRN
Human Health Effects
Aquatic Toxicity
Environmental
Fate
Acute Toxicity
Carcinogenicity
Muta genicity/Genotoxicity
Reproductive
Developmental
Neurological
Repeated Dose
Skin Sensitizer
Respiratory Sensitization
Eye Irritation
Dermal Irritation
3
u
<
Chronic
Persistence
Bioaccumulation
Hi: up)—\-cy™
Bisphenol A 2,2-bis(p-hydroxyphenyl)propane
80-05-7
L
M
L
H
H
M
M
M
M
H
H
VL
L
kXAJ
Bisphenol F Bis(4-hydroxyphenyl)methane
620-92-8
L
M
L
H*
M
H
L
VH
A/'
M
H
L
L
Bisphenol C 2,2"-Bis(4-hydroxy-3-methylphenyl)propane
79-97-0
L*
M
M
A/5
M*
IP
A/'
H
H
M
M
MB HA Methyl bis(4-hydroxyphenyl)acetate
5129-00-0
L*
M
M
A/5
L
A/'
H
H
M
L
cVcco
BisOPP-A 4,4"-I sopropyllidenebis(2 -phenylphenol)
24038-68-4
L''
M
M
A/5
A/'
L
H
H
M
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Bisphenol AP 4,4"-( 1 - Phenylethylidene)bisphenol
1571-75-1
Z®
M
Z®
i?®
i?®
M
A/5
A/'
A/'
A/'
H
H
H
M
Substituted phenolic compound, PROPRIETARY #1
Z®
M
L
H*
®
M
A/5
A/'
A/'
A/
§
H
M
M
L
Substituted phenolic compound, PROPRIETARY #2
Z®
M
Z®
i?®
i?®
M
A/5
A/'
A/'
A/®
H
H
H
H
PHBB Benzyl 4-hydroxybenzoate
94-18-8
L
M
M
Z
M
M
L
A/'
VL
V
L
H
H
Z®
L
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Chemical
CASRN
Human Health Effects
Aquatic Toxicity
Environmental
Fate
Acute Toxicity
Carcinogenicity
Mutagenicity/Genotoxicity
Reproductive
Developmental
Neurological
Repeated Dose
Skin Sensitizer
Respiratory Sensitization
Eye Irritation
Dermal Irritation
Acute
Chronic
Persistence
Bioaccumulation
ho_ch~o~3h
Bisphenol S 4-Hydroxyphenyl sulfone
80-09-1
L
M
M
£
M
M
H
L
L
L
M
M
M
L
o o 9H
2,4-BPS 2,4"-Bis(hydroxyphenyl)sulfone
5397-34-2
£®
M
M
if
if
M
i?®
£®
Z®
Z®
M
H
M
Z
ho—s—m
TGSA bis-(3-allyl-4-hydroxyphenyl) sulfone
41481-66-7
L
M
L
if
M
M
H
M
L
VL
H
H
H
L
-OjO^
B P S-MAE Phenol,4- [ [4-(2-propen-1 -yloxy)phenyl] sulfonyl] -
97042-18-7
L
A/®
if
if
M
L
L
M
L
VL
H
H
H
L
°^c+Q~
B P S-MPE 4-Hydroxy-4"-benzyloxydiphenylsulfone
63134-33-8
L
M
if
if
M
i?®
L
L
L
VH
H
H
M
D-8 4-hydroxyphenyl 4-isoprooxyphenylsulfone
95235-30-6
L®
M
M
if
if
M
i?®
£®
Z®
Z®
H
H
A/®
L
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Chemical
CASRN
Human Health Effects
Aquatic Toxicity
Environmental
Fate
Acute Toxicity
Carcinogenicity
Mutagenicity/Genotoxicity
Reproductive
Developmental
Neurological
Repeated Dose
Skin Sensitizer
Respiratory Sensitization
Eye Irritation
Dermal Irritation
Acute
Chronic
Persistence
Bioaccumulation
-O+O-pw-OfO-^
D-90 Phenol, 4,4"-sulfonylbis-, polymer with l,l"-oxybis[2-
chloroethane]
191680-83-8
L
M
L
L
L
M
L
L
M
VL
L*
VH1
Hi
DD-70
1,7 -bis(4-Hydroxyphenylthio) -3,5- dioxaheptane
93589-69-6
L
M
L
M
A/®
M
A/®
A/®
H
H
H
L
Pergafast 201
N- (p-T oluenesulfonyl) -N'- (3 -p-toluenesulfonyloxyphenyl)urea
232938-43-1
L
M
L
M
L
M
L
L
VL
VH
H
VH
L
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Bisphenol A
4.8 Hazard Profiles
Use: Developer for thermal papers
MW: 228.29
MF: C15H160;
CASRN: 80-05-7
Physical Forms: Solid
Neat: Solid
• *-15-n-16^2
SMILES: Oc 1 ccc(cc 1 )C(c 1 ccc(0)cc 1 )(C)C
Synonyms: Phenol,4,4'-(l-methylethylidene)bis- (TSCA Inventory); BPA; 2,2-(4,4"-dihydroxydiphenyl)propane; 2,2-bis(4"-hydroxyphenyl)propane; 2,2-bis(4-
hydroxyphenyl)propane; 2,2-bis-(4-hydroxy-phenyl)-propane; 2,2-bis(p-hydroxyphenyl)propane; 2,2-bis-4"-hydroxyfenylpropan; 2,2-di(4-hydroxyphenyl)propane;
2,2-di(4-phenylol)propane; 4,4"-( 1 -Methylethylidene)bisphenol; 4,4"-Dihydroxy-2,2"-diphenylpropane; 4,4"-Dihydroxydiphenyl-2,2"-propane; 4,4"-bisphenol A;
4,4"-dihydroxydiphenyl-2,2-propane; 4,4"-dihydroxydiphenyldimethylmethane; 4,4"-dihydroxydiphenylpropane; 4,4"-dihydroxyphenyl-2,2-propane; 4,4"-
isopropylidenebisphenol; 4,4"-isopropylidenediphenol; 4,4-isopropylidenediphenyl; beta, beta"-bis(p-hydroxylphenyl)propane; beta-di-p-hydroxyphenylpropane;
bis(4-hydroxyphenyl)dimethylmethane; bis(4-hydroxyphenyl)propane; bis[phenol],4,4"-(l-methylethylidene)-; Bisferol A; bisphenol; Bisphenol,4,4"-( 1 -
methylethylidene)-; Bisphenol-a; Dian; Diano; dimethylbis(p-hydroxyphenyl)methane; dimethylmethylene-p,p"-di-phenol; dimethylmethylene-p,p"-diphenol;
Diphenolmethylethylidene; diphenylolpropane; Ipognox88; Isopropylidenebis(4-hydroxybenzene); p,p"-Isopropylidene-bisphenol; p,p"-Isopropylidene-di-phenol;
p,p"-bisphenolA; p,p"-dihydroxydiphenyldimethylmethane; p,p"-dihydroxydiphenylpropane; p,p"-isopropylidenebisphenol; p,p"-isopropylidenediphenol; Parabis;
ParabisA; Phenol,(1 -methylethylidene)bis-; Phenol,4,4"-Isopropylidene-di; Phenol,4,4"-dimethylmethylenedi-; Phenol,4,4"-isopropylidenedi-; Pluracol 245;
propane,2,2-bis(p-hydroxyphenyl)-; Rikabanol; B-Di-p-Hydroxyphenylpropane; Ucarbisphenol A; Ucarbisphenol HP
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Polymeric: No
Oligomers: Not applicable
Metabolites, Degradates and Transformation Products: BPA glucuronide, BPA sulfate conjugate, BPA diglucuronide, 5-hydroxy BPA and the corresponding
sulfate conjugate, isopropyl-hydroxyphenol, BPA glutathione conjugate, glutathionyl-phenol, glutathionyl 4-isopropylphenol, BPA dimmers, monohydroxybisphenol
A, beta-glucoside, BPA mono-O-B-D-gentiobioside and the trisaccharide BPA, (3>-D -glucopyranoside, mono- and di- O-B-D-glucopyranosides, phenol,
4-isopropenylphenol, 4-isopropylphenol, hexestrol, 5,5"-bis-[ 1 -(4-hydroxy-phenyl)-1 -methylethyl]-bisphenyl-2,2"-diol, 4-hydroxyacetephenone, 4-hydroxybenzoic
acid, 2,2-bis(4-hydrozyphenyl)-l-propanol, 2, 3- bis(4-hydroxyphenyl)-l, 2-propanediol (Kang, Katayama et al., 2006)
Analog: None
Endpoint(s) using analog values: Not applicable
Analog Structure: Not applicable
Structural Alerts: Phenols, neurotoxicity (U.S. EPA, 2010)
Risk Phrases: 37 - Irritating to respiratory system; 41 - Risk of serious damage to eyes; 43 - May cause sensitization by skin contact; 52 - Harmful to aquatic
organisms; 62 - Possible risk of impaired fertility (ESIS, 2011).
Risk Assessments: Risk assessment completed for Bisphenol A by Canada in 2008, the European Union in 2010 and lapan in 2007 (Canada, 2008; EINECS, 2010;
Nakanishi and Miyamoto, 2007).
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Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
155 (Measured)
EINECS, 2010
Adequate; consistent values reported in
secondary sources.
150-157 (Measured)
EINECS, 2010; Canada, 2008
150-155 (Measured)
O'Neil, 2006
Boiling Point (°C)
360.5 at 760 mmHg (Measured)
EINECS, 2010; IUCLID, 2000
Adequate.
250-252 at 13 mmHg (decomposes)
(Measured)
EINECS, 2010
Reduced boiling point consistent with
values reported in secondary sources.
220-398 (Measured)
Canada, 2008
Range of values not entirely consistent
with other located sources.
220 at 4 mm Hg (Measured); decomposes
when heated above 220°C
O'Neil, 2006
Data indicate that BPA will decompose
at elevated temperatures.
Vapor Pressure (mm Hg)
3.99xl0"8 (Measured)
EINECS, 2010; Canada, 2008
Adequate; consistent with values
reported in other secondary sources.
3.08xl0"9 - 3.99x10 s (Measured)^
EINECS, 2010
Water Solubility (mg/L)
300 (Measured)
EINECS, 2010
Adequate; selected value for
assessment.
120-301 (Measured)
Canada, 2008
Adequate; consistent values which span
a narrow range have been reported in
secondary sources.
120 (Measured)
Dorn, Chou et al., 1987
Adequate; well conducted nonguideline
study.
Log Kow
3.32 (Measured)
Hansch, Leo et al., 1995;
Canada, 2008
Adequate; consistent values that span a
relatively narrow range have been
reported in secondary sources; selected
value for assessment.
2.2 (Measured)
EINECS, 2010
Adequate; reported in a secondary
source.
Flammability (Flash Point)
79.4-227°C (Measured)
EINECS, 2010
Lower temperatures in this range are
inconsistent with values reported in
other secondary sources.
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Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
213°C (Measured)
Reported as 415°F
CHRIS, 1985
Adequate; reported in a secondary
source.
Auto flammability = approximately 532 °C
(Measured)
EINECS, 2010
Substantial degradation is anticipated
to occur before this temperature is
reached.
Explosivity
Minimum explosive concentration (in air)
0.012 g/L with oxygen >5% (Measured)
EINECS, 2010
Adequate; reported in a secondary
source.
Dust is flammable if ignited (Measured)
IUCLID, 2000
Adequate; reported in a secondary
source.
pH
No data located.
pKa
9.59-11.30 (Measured)
Canada, 2008
Adequate; initial value in range is for
first ionization; higher values likely for
second ionization step.
HUMAN HEALTH EFFECTS
Toxicokinetics
In rats, BPA was rapidly absorbed following oral administration and extensively metabolized, predominantly
via first-pass metabolism. BPA and its metabolites did not appear to accumulate. In rats, excretion following
oral exposure occurred mainly in the feces (50-83% of the administered dose) and urine (13-42% of the
administered dose, mainly as the glucuronide conjugate). Maternal transfer to the rat fetus was demonstrated
and excretion may also occur via the mother's milk. In humans, essentially 100% of a relatively small oral dose
of BPA was rapidly absorbed, readily metabolized, and excreted in the urine as BPA-glucuronide (essentially
100% of the administered dose). Information was not located regarding the toxicokinetics of BPA following in
vivo inhalation or dermal exposure.
Dermal Absorption in vitro
Human skin, 10% of applied millimolar
dose was absorbed
EINECS, 2010
Adequate.
Pig skin, 10 |ig/mL radiolabeled BPA.
2, 5, and 10 hours of exposure; the total
BPA skin content was 3%, 6.9%, and
11.4% of the applied dose, respectively.
BPA remained in the skin surface and
accumulated primarily in the dermis.
NIOSH, 2010
Adequate.
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Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal or
Inhaled
Data located for rats, mice, monkeys, and
humans indicate that ingested BPA is
rapidly and extensively absorbed from the
gastrointestinal tract (up to 85-86% in rats
and monkeys and essentially 100% of a
relatively small dose in humans). Orally-
absorbed BPA undergoes extensive first-
pass metabolism. In all species studied, the
major metabolic pathway involved the
conjugation of BPA to BPA-glucuronide.
There does not appear to be a selective
affinity of yolk sac/placenta or embryo/
fetus for BPA or BPA metabolites.
Enterohepatic recirculation of BPA-
glucuronide readily occurs in rats, resulting
in availability of some free BPA to tissues.
Enterohepatic recirculation does not appear
to occur in humans. Approximately
13-42% of an administered BPA dose was
recovered in the urine of rats as the
glucuronide metabolite; 50-83% was
eliminated in the feces, mostly as free BPA.
Limited excretion in the milk was observed.
In monkeys, 82-85% of an orally-
administered BPA dose was recovered in
the urine; only 2-3% was detected in the
feces. In volunteers given relatively low
doses of BPA, the dose was completely
recovered as BPA-glucuronide in the urine.
No animal data were located regarding the
toxicokinetics of BPA following in vivo
exposure via inhalation or dermal routes.
EINECS, 2010
Summary of multiple studies reported
in secondary source.
Acute Mammalian Toxicity
LOW: The acute oral and dermal toxicity hazard of BPA is low based on experimental data in animals. Data
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Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
for exposure via inhalation were inconclusive, as only a single concentration was tested and an LCS0 was not
provided.
Acute Lethality
Oral
Rat LD50 = 3,200 to >5,000 mg/kg bw
EINECS, 2010; European
Commission, 2000; NTP, 1982
Adequate; multiple studies, some
guideline studies.
Mouse LD50 = 4,000-5,200 mg/kg bw
EINECS, 2010; European
Commission, 2000; NTP, 1982
Adequate; multiple studies, some
guideline studies.
Mouse LD50 = 1,600 mg/kg bw
EINECS, 2010; European
Commission, 2000
Inadequate; insufficient study details,
relatively old study, results not
supported by other studies.
Rabbit LD50 = 2,230 mg/kg bw
EINECS, 2010; European
Commission, 2000
Inadequate; insufficient study details,
old study.
Dermal
Rabbit LD50 = 3,000-6,400 mg/kg bw
EINECS, 2010; European
Commission, 2000
Adequate; limited study details for
multiple studies reported in secondary
sources.
Inhalation
No deaths among male and female F344
rats (10/sex) exposed to BPA dust at
0.17 mg/L (highest attainable
concentration) for 6 hours; transient slight
nasal tract epithelial damage was evident
EINECS, 2010; European
Commission, 2000
Adequate, although test guidelines
were not reported in secondary sources.
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Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Carcinogenicity
MODERATE: Two standard 2-year guideline carcinogenicity studies found no increased incidence of cancer
associated with adult exposures. There is concern for carcinogenicity associated with endocrine related
mechanisms due to its estrogenic properties. Several nonguideline studies indicate proliferation of mammary
ductal epithelium and squamous metaplasia of prostatic epithelium in offspring, conditions thought by many to
predispose to neoplasia (FAO/WHO 2011). In response to the uncertainty, NTP and FDA are conducting a new
GLP study that is designed to include a wide oral dosing range, to include pre-and perinatal exposures
(FAO/WHO 2011). Since data from guideline studies suggest low concern for cancer, but there are
nonguideline studies that demonstrate evidence of proliferative lesions, carcinogenicity cannot be ruled out at
this time, DfE criteria calls for an assignment of MODERATE hazard concern.
OncoLogic Results
Moderate (Estimate)
OncoLogic class: phenols and phenolic
compounds: However, several types of
phenolic compounds are of concern based
on structural similarities to estrogenic and
androgenic compounds known to be
potential carcinogens or tumor promoters
via endocrine-related mechanisms.
OncoLogic
OncoLogic SAR analysis using the
phenols and phenolic compounds class.
Carcinogenicity
Based on existing carcinogenicity study
data,
It is confident that exposure to BPA:
• Exhibits endocrine activity and has
estrogenic properties
• Estradiol-17|3 is classified as
carcinogenic (IARC);
It is likely that exposure to BPA:
• may be associated with increased
cancers of the hematopoietic system
and increased interstitial-cell
tumors in the testes
• Alters function of microbules
• Induces aneuploidy in cells and
tissues
Keri, Ho et al., 2007
2007 consensus statement for NIEHS-
funded cancer researchers evaluating
evidence of carcinogenicity in human
and animal models following exposure
to BPA.
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• Exposure early in life may cause a
predisposition for pre-neoplastic
lesions in adult mammary gland
and prostate gland tissues
• Prenatal exposure alters mammary
gland development in mice and
increases effects relevant to
markers of breast cancer risk in
humans;
It is possible that exposure to BPA:
• Induces in vitro cellular
transformation
• Promote tumor progression and
reduces time to recurrence in
advanced prostate cancers with
androgen receptor mutations.
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Combined Chronic
Toxicity/
Carcinogenicity
2-Year dietary study in male and female
F344 rats (50/sex/group)
Dietary concentrations: 0, 1,000, and
2,000 ppm (estimated doses 0, 84, and
167 mg/kg-day for males and females
combined).
Chronic toxicity: Lower mean body weight
of low- and high-dose females and high-
dose males likely the result of decreased
food consumption.
Carcinogenicity: Marginally significant
increase in leukemia in male rats, non-
significant increase in female rats,
significant increase in interstitial-cell
tumors of testes (known to occur at high
incidence in aging F344 rats) not considered
by NTP to be convincing evidence of a
carcinogenic effect for BPA.
NTP, 1982
Adequate.
2-Year dietary study in male and female
B6C3F1 mice (50/sex/group)
Dietary concentrations: 0, 1,000, and
5,000 ppm (males); 0, 5,000, and 10,000
ppm (females) (estimated doses 0, 172, and
858 mg/kg-day for males and 0, 864, and
1,728 mg/kg-day for females).
Chronic toxicity: Increased incidence of
multinucleated giant hepatocytes in males
(incidences of 41/49 and 41/50 versus
1/49 in controls)
Carcinogenicity: Non-significantly
increased incidences of leukemia or
lymphomas in low- and high-dose male
mice (9/50, 5/50 versus 2/50 in controls) not
NTP, 1982
Adequate.
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considered by NTP to be convincing
evidence of carcinogenic effect for BPA.
Studies that included perinatal (gestational
and/or lactational) exposures to BPA (oral
doses to the dam from -10 to 250 u g/kg
bw per day) have reported, among other
lesions, proliferation of mammary ductal
epithelium and squamous metaplasia of
prostatic epithelium in offspring, conditions
thought by many to predispose to neoplasia
(Timms et al., 2005; Moral et al., 2008).
Additional treatments with initiating or
promoting agents have led to earlier onset
of mammary tumors (Jenkins et al., 2009)
or prostatic intraepithelial neoplasia (Prins
et al., 2011). However, the studies that
included exposures to BPA during the
appropriate periods all suffered from one or
more deficiencies in design or execution
that prevent a definitive evaluation of its
potential as a carcinogen. These include 1)
lack of consideration of litter effects, 2)
small numbers of animals, 3) insufficient
study duration to determine whether
developmental conditions thought to
enhance cancer susceptibility actually did
so and 4) additional treatment with a strong
initiating or additional promoting agent(s).
In the absence of additional studies
addressing these deficiencies, there is
currently insufficient evidence on which to
judge the carcinogenic potential of BPA.
FAO/WHO, 2011
Summary of data, data quality, and
conclusions from the expert panel.
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Genotoxicity
LOW: Based on determination by FAO/WHO (2011) that: (1) BPA is not a mutagen in in vitro test systems,
(2) BPA does not induce cell transformation, (3) in vivo evidence for BPA-induced clastogenic effects is
inconsistent and inconclusive, although some in vitro studies have shown BPA to affect chromosomal structure
in dividing cells. The conclusion of FAO/WHO (2011) is that BPA is not likely to pose a genotoxic hazard to
humans.
Largely negative results in a variety of in
vitro test systems, including studies with
Salmonella typhimurium, Chinese hamster
V79 cells, Syrian hamster embryo cells, and
mouse lymphoma cells. However, DNA
damage was induced in MCF-7 and MDA-
MB-231 cells, DNA adduct formation in
Syrian hamster ovary cells, and a number of
positive findings have been reported for the
potential for BPA to inhibit purified
microtubule polymerization, affect the
spindle apparatus and produce aneuploidy
in in vitro studies with Chinese hamster
V79 cells or oocytes from Balb/c or MF1
mice.
FAO/WHO, 2011
Summary of data, data quality, and
conclusions from the expert panel.
FAO/WHO Expert Panel concludes:
BPA is not a mutagen in in vitro test
systems, nor does it induce cell
transformation. BPA has been shown to
affect chromosomal structure in dividing
cells in in vitro studies, but evidence for this
effect in in vivo studies is inconsistent and
inconclusive. BPA is not likely to pose a
genotoxic hazard to humans.
Reproductive Effects
HIGH: Based on NOAELs of 4.75 mg/kg bw-day and 47.5 mg/kg bw-day for reproductive toxicity in male and
female rats, respectively. Conclusions of NTP-CERHR (2008) include sufficient evidence in rats and mice that
subchronic or chronic oral exposures to bisphenol A causes female reproductive toxicity at doses >475 mg/kg
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bw-day (highest NOAEL = 47.5 mg/kg-day) and male reproductive toxicity at doses >47.5mg/kg bw-day
(highest NOAEL = 4.75 mg/kg bw-day). There is considerable uncertainty regarding the results of recent
studies that reported reproductive and/or developmental effects in laboratory animals administered BPA at
oral doses <5 mg/kg bw-day.
Reproduction/
Developmental
Toxicity Screen
No data located.
Combined Repeated
Dose with
Reproduction/
Developmental
Toxicity Screen
No data located.
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Reproduction and
Fertility Effects
Multigenerational dietary study on fertility
and reproductive performance in Sprague-
Dawley rats (30/sex/group)
BPA concentrations: 0, 0.015, 0.3, 4.5, 75,
750, and 7,500 ppm (estimated doses 0,
0.0095, 0.019, 0.285, 4.75, 47.5, and
475 mg/kg bw-day)
Exposure period: 10 weeks premating,
2 weeks mating, gestation (parental males
and females), lactation (parental females);
similar exposure regimen for Fi and F2
parental males and females; F3 weanlings
exposed for 10 weeks
Parental systemic toxicity:
NOAEL = 4.75 mg/kg bw-day
LOAEL = 47.5 mg/kg bw-day for 12%
decreased terminal body weight in Fi
parental males
Reproductive toxicity:
Females: NOAEL = 47.5 mg/kg bw-day
LOAEL = 475 mg/kg bw-day for decreases
in number of implantation sites, delayed
vaginal opening in F,. F2, F3 offspring
Males: NOAEL = 4.75 mg/kg bw-day,
LOAEL = 47.5 mg/kg-day for delayed
preputial separation in F, males
NTP-CERHR, 2008
Adequate, guideline study as reported
in the secondary source.
Classified by NTP-CERHR as having
as High Utility.
Two-generation dietary study of fertility
and reproductive performance in CD-I mice
(28/sex/group)
Dietary concentrations: 0, 0.018, 0.18, 1.8,
30, 300, and 3,500 ppm (approximate doses
of 0.003, 0.03, 0.3, 5, 50, and 600 mg/kg
bw-day based on target doses of 0, 0.003,
NTP-CERHR, 2008
Adequate; guideline study as reported
in the secondary source.
Classified by NTP-CERHR as having
as High Utility.
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0.03, 0.3, 5, 50, and 600 mg/kg bw-day)
Exposure period: 8 weeks premating,
2 weeks mating, gestation, and lactation for
F0 and Fi parental mice
Parental systemic toxicity:
NOAEL = 5 mg/kg bw-day
LOAEL = 50 mg/kg bw-day for increased
incidences of centrilobular hepatocellular
hypertrophy in males and females
Reproductive toxicity:
NOAEL = 50 mg/kg bw-day
LOAEL = 600 mg/kg bw-day for increased
gestation length, decreased epididymal
sperm concentration in Fi males, increased
incidence of gross ovarian cysts in F, and F2
females
Summary of
Reproductive Effects
A large experimental animal literature was
reviewed by the NTP-CERHR Expert
Panel, assessed for its utility, and weighted
based on the criteria established by this
expert panel, including an evaluation of
experimental design and statistical
procedures. These animal data are assumed
relevant for the assessment of human
hazard. The NTP-CERHR Expert Panel
concluded the following:
Female effects: There is sufficient evidence
in rats and mice that bisphenol A causes
female reproductive toxicity with
subchronic or chronic oral exposures with a
NOAEL of 47.7 mg/kg bw-day and a
LOAEL of 475 mg/kg bw-day.
Chapin et al. 2008; NTP-
CERHR 2008
Classified by NTP-CERHR as having
High Utility.
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Male effects: There is sufficient evidence in
rats and mice that bisphenol A causes male
reproductive toxicity with subchronic or
chronic oral exposures with a NOAEL of
4.75 mg/kg bw-day and a LOAEL of 47.5
mg/kg bw/day.
The joint FAO/WHO Expert Panel
reviewed located reproductive and
developmental toxicity data for BPA as of
November, 2010 and noted that most
regulatory bodies reviewing the numerous
studies on BPA have indicated an oral
reproductive and developmental NOAEL of
50 mg/kg bw-day.
Regarding the potential for low oral doses
(<1 mg/kg bw-day) of BPA to alter
reproduction and development in rodents,
the FAO/WHO noted that:
(1) There is sufficient evidence that BPA
does not:
* induce gross morphological reproductive
abnormalities in F1 offspring;
* reduce F1 pup survival or body weight;
* alter F1 growth or survival during
lactation;
* alter F1 anogenital distance in males or
females; or
* cause undermasculinization of male
morphology or masculinization of female
morphology.
(2) There is evidence (with some
FAO/WHO, 2011
Summary of data, data quality, and
conclusions from the expert panel.
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uncertainty) that BPA does not:
* reduce P0 implantation, infertility, or
fecundity.
(3) There is conflicting evidence (with
higher uncertainty) that BPA:
* alters F1 pubertal landmarks;
* alters PO male or female reproductive
tract organ weights or histopathology; and
* alters F1 male reproductive tract organ
weights or histopathology and semen
parameters.
Furthermore, changes in brain biochemical
signaling, morphometric, and cellular
endpoints within sexually dimorphic
anatomical structures and neuroendocrine
endpoints were reported at dietary
exposures below 5 mg/kg bw-day.
Methodological limitations introduce
uncertainty in interpretation of the findings.
Developmental Effects
HIGH: The NTP-CERHR (2008) Expert Panel concluded that there is suggestive evidence that BPA causes
neural and behavioral alterations related to disruptions in normal sex differences in rats and mice (0.01-
0.2 mg/kg bw-day). The FAO/WHO Expert Panel concluded that while there was broad agreement in a
NOAEL of 50 mg/kg bw-day for developmental toxicity, low-level (<1 mg/kg bw-day) effects were uncertain.
These conclusions support a hazard designation of High concern, with lower confidence.
Reproduction/
Developmental
Toxicity Screen
No data located.
Combined Repeated
Dose with
Reproduction/
Developmental
Toxicity Screen
No data located.
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Summary of
Developmental Effects
The NTP-CERHR Expert Panel concluded
that bisphenol A:
* does not cause malformations or birth
defects in rats or mice at levels up to the
highest doses evaluated: 640 mg/kg/day
(rats) and 1,250 mg/kg bw-day (mice).
* does not alter male or female fertility after
gestational exposure up to doses of
450 mg/kg bw/day in the rat and 600 mg/kg
bw-day in the mouse (highest dose levels
evaluated).
* does not permanently affect prostate
weight at doses up to 475 mg/kg bw-day in
adult rats or 600 mg/kg bw-day in mice.
* does not cause prostate cancer in rats or
mice after adult exposure at up to 148 or
600 mg/kg bw-day, respectively.
* does change the age of puberty in male or
female rats at high doses (ca. 475 mg/kg
bw-day).
And that rodent studies suggest that
bisphenol A:
* causes neural and behavioral alterations
related to disruptions in normal sex
differences in rats and mice (0.01-0.2 mg/kg
bw-day).
Chapin et al., 2008; NTP-
CERHR 2008
Summary of data, data quality, and
conclusions from the expert panel.
The joint FAO/WHO Expert Panel
reviewed located reproductive and
developmental toxicity data for BPA as of
November, 2010 and noted that most
regulatory bodies reviewing the numerous
studies on BPA have indicated an oral
FAO/WHO, 2011
Summary of data, data quality, and
conclusions from the expert panel.
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reproductive and developmental NOAEL of
50 mg/kg bw-day.
Regarding the potential for low oral doses
(<1 mg/kg bw-day) of BPA to alter
reproduction and development in rodents,
the FAO/WHO noted that:
(1) There is sufficient evidence that BPA
does not:
* induce gross morphological reproductive
abnormalities in F1 offspring;
* reduce F1 pup survival or body weight;
* alter F1 growth or survival during
lactation;
* alter F1 anogenital distance in males or
females; or
* cause undermasculinization of male
morphology or masculinization of female
morphology.
(2) There is evidence (with some
uncertainty) that BPA does not:
* reduce P0 implantation, infertility or
fecundity.
(3) There is conflicting evidence (with
higher uncertainty) that BPA:
* alters F1 pubertal landmarks;
* alters P0 male or female reproductive tract
organ weights or histopathology; and
* alters F1 male reproductive tract organ
weights or histopathology and semen
parameters.
Furthermore, changes in brain biochemical
signaling, morphometric and cellular end-
points within sexually dimorphic
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anatomical structures and neuroendocrine
end-points were reported at dietary
exposures below 5 mg/kg bw-day.
Methodological limitations introduce
uncertainty in interpretation of the findings.
Neurotoxicity
MODERATE: Estimated to have potential for neurotoxicity based on the presence of the phenol structural
alert.
Neurotoxicity
Screening Battery
(Adult)
There is potential for neurotoxicity effects
based on the presence of the phenol
structural alert
(Estimated)
U.S. EPA, 2010; Professional
judgment
Estimated based on structural alert.
Repeated Dose Effects
MODERATE: BPA produced histopathologic changes in the liver (centrilobular hepatocyte hypertrophy)
from oral dosing at 50 mg/kg bw-day (NOAEL = 5 mg/kg bw-day) and there is uncertainty regarding the
potential for BPA doses between the NOAEL of 5 mg/kg bw-day and the LOAEL of 50 mg/kg-day to cause
adverse systemic effects. Furthermore, lesions in the nasal cavity of rats were reported following repeated
inhalation exposure to BPA dust at 0.05 mg/L. These findings indicate a Moderate hazard concern for the oral
and inhalation exposure routes.
The FAO/WHO Expert Panel reviewed the
located information regarding repeated-dose
oral toxicity of BPA and concluded that
results demonstrated effects on the liver,
kidney, and body weight at doses of 50
mg/kg bw-day and higher and that the
lowest NOAEL was 5 mg/kg-day, as
identified in several studies.
FAO/WHO, 2011
Summary of data, data quality, and
conclusions from the expert panel.
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Multigenerational dietary study on fertility
and reproductive performance in Sprague-
Dawley rats (30/sex/group)
BPA concentrations: 0, 0.015, 0.3, 4.5, 75,
750, and 7,500 ppm (estimated doses 0,
0.0095, 0.019, 0.285, 4.75, 47.5, and
475 mg/kg bw-day)
Exposure period: 10 weeks premating,
2 weeks mating, gestation (parental males
and females), lactation (parental females);
similar exposure regimen for Fi and F2
parental males and females; F3 weanlings
exposed for 10 weeks
Parental systemic toxicity:
NOAEL = 4.75 mg/kg bw-day
LOAEL = 47.5 mg/kg bw-day for 12%
decreased terminal body weight in Fi
parental males
NTP-CERHR, 2008
Adequate; guideline study as reported
in the secondary source.
Classified by NTP-CERHR as having
High Utility.
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Two-generation dietary study of fertility
and reproductive performance in CD-I mice
(28/sex/group)
Dietary concentrations: 0, 0.018, 0.18, 1.8,
30, 300, and 3,500 ppm (approximate doses
of 0.003, 0.03, 0.3, 5, 50, and 600 mg/kg
bw-day based on target doses of 0, 0.003,
0.03, 0.3, 5, 50, and 600 mg/kg bw-day)
Exposure period: 8 weeks premating,
2 weeks mating, gestation, lactation for F0
and Fi parental mice
Parental systemic toxicity:
NOAEL = 5 mg/kg bw-day
LOAEL = 50 mg/kg bw-day for increased
incidences of centrilobular hepatocellular
hypertrophy in males and females
NTP-CERHR, 2008
Adequate; guideline study as reported
in the secondary source.
Classified by NTP-CERHR as having
High Utility.
Inhalation study (whole body, dust) in
Fischer 344 rats
Exposure concentrations: 0, 10, 50, 150
mg/m3 (0, 0.01, 0.05, 0.15 mg/L)
Exposure period: 6 hours/day, 5 days/week
for 13 weeks
NOAEL = 0.01 mg/L
LOAEL = 0.05 mg/L based on microscopic
changes in the anterior portion of the nasal
cavity
EINECS, 2010; European
Commission, 2000
Adequate.
Nasal epithelium changes were
reversible (not apparent after 4-week
recovery period)
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Inhalation study in rats (species not defined)
Exposure concentrations: 0, 15-86 mg/irf:
mean = 47 mg/irf (0.047 mg/L)
Exposure period: 4 hours/day for 4 months.
NOAEL = None established
LOAEL = 0.047 mg/L for decreased body
weight gain, increased liver and kidney
weight, unspecified "morphological
changes" in liver, kidney, and lungs
European Commission, 2000;
EINECS, 2010
Inadequate; single exposure level,
insufficient study details in secondary
sources.
Inhalation study in male Alderley Park rats
Exposure concentrations: Saturated
atmosphere
Exposure period: 6 hours/day for five
exposures
Results: No signs of toxicity, no gross
macroscopic changes
EINECS, 2010
Inadequate; single exposure level,
insufficient study duration, lack of
study details in secondary sources.
Skin Sensitization
MODERATE: Recent data from three BPA manufacturing facilities indicate that BPA does not elicit skin
sensitization; however, results of some human studies suggest the possibility of a dermal sensitization response,
although cross-sensitization was not ruled out. Most animal studies were negative for dermal sensitization,
although assays may not have been maximized. There is evidence of ear swelling in a photoallergy test in mice
and moderate redness and swelling following repeated dermal exposure in rabbits. Based on suggestive
evidence of skin sensitization in humans and mice, a MODERATE hazard designation is warranted.
Skin Sensitization
Negative in a modified local lymph node
assay of mice administered BPA
epicutaneously on the ears at concentrations
up to 30% on 3 consecutive days.
EINECS, 2010
Adequate, although the assay did not
include concentrations >30%.
Negative in a local lymph node assay
modified to test for photoreactivity in mice
administered BPA epicutaneously on the
ears at concentrations up to 30% on
3 consecutive days and irradiated with UV
light immediately following application.
EINECS, 2010
Adequate, although the assay did not
include concentrations >30%.
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Negative in several sensitization tests using
guinea pigs.
European Commission, 2000;
EINECS, 2010
Inadequate; study details lacking and
induction and challenge concentrations
may not have been maximized.
Negative, mouse; BPA applied as 1%
solution in acetone and corn oil for 2 days;
induced UV-photosensitization on flank and
ears.
European Commission, 2000
Inadequate; insufficient experimental
details.
Positive in 2/16 guinea pigs receiving BPA
(50% in dimethyl phthalate) for 4 hours
(occluded) once per week for 3 weeks and
single challenge (4 hours occluded) 2 weeks
later.
European Commission, 2000;
EINECS, 2010
Inadequate; insufficient experimental
details.
Positive, mouse ear swelling photoallergy
test.
European Commission, 2000
Inadequate; no data on concentrations,
methods or GLP.
Negative in comprehensive medical
surveillance data obtained from three BPA
manufacturing plants for 875 employees
examined for several years where workers
were potentially exposed to other chemicals
(phenol, acetone) that are not considered to
be skin sensitizers.
EINECS, 2010
Adequate.
Positive, rabbits; repeated dermal
application (30 times over 37 days) of BPA
(pure powder) produced moderate swelling
and redness; skin turned yellow followed by
dark pigmentation after day 15.
NIOSH, 2010
Adequate.
Limited human data provide suggestive
evidence that BPA may potentially act as a
dermal sensitizer, although concomitant
exposure to other potential dermal
sensitizers may reflect a cross-sensitization
EINECS, 2010
Inadequate; possible cross-sensitization
responses.
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response.
The Joint FAO/WHO Expert Meeting to
review toxicological aspects of BPA
concurs with previous reviews that BPA is
capable of producing a skin sensitization
response in humans.
FAO/WHO, 2011
Summary of data, data quality, and
conclusions from the expert panel.
Respiratory Sensitization
No data located.
Respiratory
Sensitization
No data located.
Eye Irritation
MODERATE: BPA was slightly to highly irritating to rabbit eyes.
Eye Irritation
Rabbit, slightly to highly irritating
EINECS, 2010; European
Commission, 2000
Adequate; study details provided for
multiple studies indicate potential for
BPA to cause eye irritation.
Dermal Irritation
MODERATE: BPA was slightly irritating to moderately irritating to rabbit skin. NIOSH has assigned BPA as
a skin irritant.
Dermal Irritation
Rabbit, nonirritating to slightly irritating
when applied as undiluted or 10% aqueous
suspension to intact or abraded skin.
European Commission, 2000;
EINECS, 2010; NIOSH, 2010
Adequate; study details provided for
multiple studies indicate potential for
BPA to cause dermal irritation.
Rabbit, moderately irritating when applied
as 40% solution in dimethyl sulfoxide under
non-occlusive conditions.
European Commission, 2000
Adequate.
Guinea pig, not irritating when applied as
5% solution in acetone for 24-hours under
occlusive conditions.
European Commission, 2000
Adequate.
Although a limited number of studies were
identified that contained data on the direct
hazard of skin exposures to BPA, located
evidence indicates that mild skin irritation
following prolonged dermal exposure may
occur. Therefore, on the basis of the data for
this assessment, BPA is assigned the SK:
NIOSH, 2010
Adequate; summary of conclusions
provided by NIOSH.
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DIR (IRR) notation.
Endocrine Activity
Bisphenol A displays endocrine activity in in vitro assays, but yields mixed results in in vivo studies. In vitro
assays demonstrate that bisphenol A can bind to estrogen receptors, elicit estrogen-induced gene transcription,
induce progesterone receptors, and induce cell proliferation in MCF7 cancer cells. The data located indicate
that the in vitro endocrine activity of bisphenol A is approximately 3-5 orders of magnitude less than that of
17p-estradiol, although the results are influenced by cell-type. In vitro assays suggest that, bisphenol A did not
elicit an androgenic but there is some evidence of anti-androgenic activity. Limited comparative in vitro data
suggest that the estrogenicity of bisphenol A is similar in magnitude to that of bisphenol AP, bisphenol C, and
bisphenol F and somewhat more potent than bisphenol S. Based on in vitro data there is also evidence of
biological interactions involving rapid signaling networks. Data from in vivo studies exhibit a more complex
picture; oral bisphenol A does not consistently produce robust estrogenic responses. EINECS provides
summary data to suggest that bisphenol A has been shown to act as an estrogen or xenoestrogen in ecological
systems.
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Reviews
The estrogenicity of bisphenol A has since
been evaluated using several different kinds
of in vitro assays, including binding assays,
recombinant reporter systems, MCF-7 cells,
rat pituitary cells, rat uterine
adenocarcinoma cells, human
adenocarcinoma cells, fish hepatocytes
(vitellogenin production) and frog
hepatocytes (vitellogenin production).
According to the NTP-CERHR Expert
Panel, there is considerable variability in
the results of these studies with the
estrogenic potency of bisphenol A ranging
over about 8 orders of magnitude.
NTP-CERHR, 2008
Summary of data, data quality, and
conclusions from NTP-CERHR.
A number of in vivo tests have been
conducted with most of the focus on effects
on uterine weight in immature or
ovariectomized animals. These studies
indicate that the potency of bisphenol A in
increasing uterine weight varies over ~4
orders of magnitude. According to the NTP-
CERHR Expert Panel, oral bisphenol A
does not consistently produce robust
estrogenic responses and, when seen,
estrogenic effects after oral treatment occur
at high-dose levels.
NTP-CERHR, 2008
Summary of data, data quality, and
conclusions from NTP-CERHR.
A limited number of studies have evaluated
androgen activity of bisphenol A. These
studies provide little evidence of androgenic
effects, but there is limited evidence of
antiandrogenicity.
NTP-CERHR, 2008
Summary of data, data quality, and
conclusions from NTP-CERHR.
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Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Positive estrous response; subcutaneous
injections of BPA to ovariectomised rats
(strain not specified) (positive response
measured by cornification in vaginal
smears)
European Commission, 2000
Adequate.
Numerous studies were locatedregarding
the behavior of bisphenol A as an estrogen
or xenoestrogen in ecological organisms.
Important results include findings that
bisphenol A increases plasma vitellogenin
concentration in freshwater and saltwater
fish at a potency in the range of 10"4 that of
17|3-estradiol and that bisphenol A can bind
to the estrogen receptor of fish, albeit at a
lower affinity than that of 17|3-estradiol.
EINECS, 2010
Adequate.
BPA can interact with non-classic estrogen
receptor systems at similar or lower
concentrations than interactions with ERa
and ER|3. BPA has a high binding affinity to
estrogen-related receptor-y (ERRy), an
orphan receptor that shares a sequence
homology with ERa and ER|3 but is not
activated by estradiol.
NTP, 2010
Adequate.
BPA also impacts cellular physiology
through rapid signaling mechanisms,
independent of nuclear hormone receptor
activity, to modify the activities of various
intracellular signaling networks. Maximal
rapid signaling effects for BPA and 17|3-
estradiol are often observed at similar
concentrations.
NTP, 2010
Adequate.
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Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Representative in vitro studies
Receptor Binding Assays
In a human ER binding assay, the relative
binding affinity (RBA) of bisphenol A was
0.195% compared to 126% for 17|3-
estradiol. RBAs for other bisphenol
compounds included 0.129% for bisphenol
C, 0.0803% for bisphenol AP, 0.0719% for
bisphenol F, and 0.0055% for bisphenol S.
An RBA of 0.00473% was reported for
PHBB.
METI, 2002
Adequate.
In a competitive ER binding assay using
human ERa, the RBA for bisphenol A was
0.32% that of 17|3-estradiol. RBAs for
other bisphenol compounds included 1.68%
for bisphenol C, 1.66% for bisphenol AP,
and 0.09% for bisphenol F.
Coleman, Toscano et al., 2003
Adequate.
In a rat uterine cytosol assay that evaluated
ER binding affinity, ER binding affinities
for bisphenol A and bisphenol F were
approximately 3 orders of magnitude less
than that for 17|3-estradiol
Perez, Pulgar et al., 1998
Adequate.
In a rat uterine cytosolic ER-competitive
binding assay, results for bisphenol A,
bisphenol S, and PHBB indicated a weak
affinity for ER.
Laws, Yavanhxay et al., 2006
Adequate.
Bisphenol A exhibited weak ER binding
activity in preparations from uteri of
ovariectomized Sprague-Dawley rats as
evidenced by a relative binding affinity
(RBA) that was 0.008% of the binding
affinity of 17|3-estradiol. RBAs for other
Blair, Branham et al., 2000
Adequate.
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Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
tested chemicals included 0.003% for
PHBB, 0.0009% for bisphenol F, and
0.0007% for the proprietary substituted
phenolic compound.
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Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Representative in vitro studies
Gene Transcription Assays
Bisphenol A exhibited evidence of
estrogenic activity in a yeast
(Scicchciromyces cerevisicte) two-hybrid
assay using ERa and the coactivator TIF2.
Based on estrogenic activity that was 5
orders of magnitude lower than that of 17|3-
estradiol, bisphenol A was considered
weakly estrogenic. Assessment of other
bisphenols resulted in a ranking of relative
potency as follows: bisphenol C > bisphenol
A > bisphenol F > bisphenol S.
Chen, Michihiko et al., 2002
Adequate.
Bisphenol A exhibited estrogenic activity
approximately 10,000-fold less than that of
17|3-estradiol) in an in vitro recombinant
yeast estrogen assay; the estrogenic
activities of bisphenol F and PHBB were
9,000-fold and 4,000-fold less than that of
17|3-estradiol
Miller, Wheals et al., 2001
Adequate.
Bisphenol A exhibited evidence of
estrogenic activity in a yeast
(Scicchciromyces cerevisicte) two-hybrid
assay using ERa and the coactivator TIF2.
Nishihara, Nishikawa et al.,
2000
Adequate.
In a yeast two-hybrid system (reporter gene
assay) using |3-galactosidase activity as a
measure of estrogenic activity, an
estrogenic response was elicited by
bisphenol A and bisphenol F but not by
bisphenol S.
Hashimoto and Nakamura, 2000
Adequate.
In a yeast two-hybrid assay (reporter gene
assay) using |3-galactosidase activity as a
Ogawa, Kawamura et al. 2006
Adequate.
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Bisphenol A CASRN 80-05-7
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DATA QUALITY
measure of estrogenic activity, an
estrogenic response was elicited by
bisphenol A and bisphenol F.
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Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In a reporter gene assay of estrogen-induced
transcriptional activity, relative activity
(RA) for bisphenol A was 0.00278%
compared to 81.7% for 17|3-estradiol. RAs
for other bisphenol compounds included
0.00189% for bisphenol C, 0.000639% for
bisphenol F, 0.000254% for bisphenol S,
and 0.000184% for bisphenol AP. An RA
of 0.000592% was reported for PHBB.
METI, 2002
Adequate.
In an ER-mediated reporter gene expression
assay, bisphenol A induced reporter gene
expression at a relative activity (RA) of
2.75 x 10° that of 17|3-estradiol. RAs for
other bisphenol compounds included 5.3 x
10"4 for bisphenol F, 4.9 x 10"4 for
bisphenol C, and 9.0 x 10"5 for bisphenol
AP.
Coleman, Toscano et al., 2003
Adequate.
In an ERE-luciferase reporter assay using
MCF-7 cells, an EC50 was 0.63 (iM for
bisphenol A compared to an EC50 of 8.6 x
10"6 for 17|3-estradiol (i.e., bisphenol A was
approximately 5 orders of magnitude less
potent than 17|3-estradiol at inducing
estrogenic activity). EC50 values for other
bisphenol compounds included 0.42 (.iM for
bisphenol C, 1.0 (.iM for bisphenol F, and
1.1 (iM for bisphenol S.
Kitamura, Suzuki et al., 2005
Adequate.
In an ERE-luciferase reporter assay using
MCF-7 cells in the presence of 17|3-
estradiol, neither bisphenol A, bisphenol C,
bisphenol F, bisphenol S, nor bisphenol M
appeared to exert an anti-estrogenic effect
Kitamura, Suzuki et al., 2005
Adequate.
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Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Representative in vitro studies
Progesterone Receptor Induction
Bisphenol A induced progesterone receptors
in cultured human mammary cancer cells
(MCF-7) cells, but the magnitude of the
induction was not specified
EINECS, 2010; European
Commission, 2000
Adequate.
In an assay designed to evaluate estrogenic
effects on the number of progesterone
receptors (PgR) in MCF7 cells, 17|3-
estradiol, bisphenol A, and bisphenol F each
increased the concentration of PgR by
approximately 10-to 15-fold
Perez, Pulgar et al., 1998
Adequate.
Representative in vitro studies
Cell Proliferation Assays
In an E-SCREEN test of MCF7 cell
proliferation (an indicator of estrogenic
activity), the proliferative potency of
bisphenol A was approximately 10"5 that of
17|3-estradiol, suggestive of a weakly
estrogenic effect for bisphenol A. The
potency of bisphenol F was somewhat less
than that of bisphenol A.
Perez, Pulgar et al., 1998
Adequate.
In a proliferation assay of MCF-7 human
breast cancer cells that contain ERa and
ER|3 and are known to proliferate in
response to estrogens, bisphenol A induced
a proliferative response that was 2.0 xl0°
that of 17|3-estradiol. Proliferative values
for other bisphenol compounds included 1.6
x 10° for bisphenol C, 1.0 x 10° for
bisphenol F, and 6.0 x 10"4 for bisphenol
AP.
Coleman, Toscano et al., 2003
Adequate.
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Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In an E-screen test for estrogenicity,
bisphenol A and bisphenol F increased
proliferation of MCF-7 cells with EC50
values of 410 nM and 84.8 nM,
respectively, compared to an EC50 of 0.0045
nM for 17|3-estradiol. The results indicate a
weak estrogenic effect with bisphenol F
exerting a more potent effect than bisphenol
A.
Stroheker, Picard et al., 2004
Adequate.
In an E-screen test for estrogenicity,
bisphenol A bisphenol F, and bisphenol S
increased proliferation of MCF-7 cells at
concentrations in the range of 10"4 to 10"7
M. Bisphenol A appeared to be more
effective than bisphenol S or bisphenol F.
Hashimoto, Moriguchi et al.,
2001
Adequate.
Bisphenol A increased the rate of
proliferation of MCF-7 cells at 3-5 orders of
magnitude less than that of 17|3-estradiol
EINECS, 2010; European
Commission, 2000
Adequate.
In an assay that measured induction and
secretion of pS2 in cultured MCF7 cells
(ELSA-pS2 immunoradiometric assay),
induction of pS2 by bisphenol A and
bisphenol F was approximately 1,000-fold
less than that of 17|3-estradiol
Perez, Pulgar et al., 1998
Adequate.
Representative in vivo studies
Exposure of immature female rats to
bisphenol A (gavage dosing once daily for 4
days) resulted in no apparent effects on
uterine weight. Bisphenol F-treated rats
exhibited significantly increased uterine
weight. There were no effects on uterine
Stroheker, Picard et al., 2003
Adequate.
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Bisphenol A CASRN 80-05-7
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DATA QUALITY
weight of bisphenol F- or bisphenol A-
treated ovariectromized rats.
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DATA QUALITY
In uterotrophic assays using ovariectomized
mice, bisphenol A treatment at doses in the
range of 20 to 500 mg/kg/day for 3 days
resulted in dose-related increased relative
uterus weights of 147-185% that of controls
compared to nearly 500% increased uterus
weight in mice administered 17|3-estradiol
at 50 (ig/kg/day. This result is indicative of
an estrogenic effect in vivo.
Kitamura, Suzuki et al., 2005
Adequate.
In a uterotrophic assay in which immature
female rats were injected with bisphenol F,
bisphenol S, or bisphenol M subcutaneously
for three consecutive days, observed
changes in uterine weight indicated that
bisphenol F, bis phenol S, and bisphenol M
exerted both estrogenic and anti-estrogenic
responses.
Akahori, Makai et al., 2008
Adequate.
Representative Androgen Assays
In an ARE-luciferase reporter assay using a
mouse fibroblast cell line (NIH3T3 cells),
neither bisphenol A, bisphenol C, bisphenol
F, nor bisphenol S exerted an androgenic
effect
Kitamura, Suzuki et al., 2005
Adequate.
In an ARE-luciferase reporter assay using a
mouse fibroblast cell line (NIH3T3 cells),
bisphenol A inhibited the androgenic
activity of dihydrotestosterone. Anti-
androgenic responses were elicited by
bisphenol C, bisphenol F, and bisphenol S
as well.
Kitamura, Suzuki et al., 2005
Adequate.
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Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
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REFERENCE
DATA QUALITY
Bisphenol A and bisphenol F induced
androgenic effects in MDA-MB453 cells
transfected with an AR responsive
luciferase reporter gene; anti-androgenic
effects were elicited in the presence of
dihydrotestosterone. Relative potency of
the androgenic and anti-androgenic effects
elicited by bisphenol A was similar to that
of bisphenol F.
Stroheker, Picard et al., 2004
Adequate.
Representative Thyroid Assays
In an assay of thyroid hormonal activity
whereby induction of growth hormone
production is assessed in GH3 cells, neither
bisphenol A nor bisphenol C inhibited
growth hormone production
Kitamura, Suzuki et al., 2005
Adequate.
Bisphenol A did not exhibit thyroid
hormone receptor binding in a yeast two-
hybrid assay system with TRa and
coactivator TIF-2.
Kitagawa, Takatori et al., 2003
Adequate.
Immunotoxicity
No data located.
Immune System
Effects (Included
under Repeated Dose)
Rodent studies (direct or in utero exposure)
suggest that BPA may modulate immune
homeostasis, but due to study variations and
deficiencies, there is no clear evidence that
BPA interferes with immune function.
Willhite, Ball et al., 2008;
FAO/WHO, 2011
Inadequate; few of the studies followed
regulatory protocols (U.S. EPA, 1999)
or GLP requirements.
ECOTOXICITY
ECOSAR Class
Phenols
Acute Toxicity
HIGH: Based on experimental data indicating a High hazard concern for fish, Daphnid, and green algae.
Fish LC50
Freshwater
Oryzias latipes (Medaka fish) 96-hour LC50
= 13 mg/L
(Experimental)
EINECS, 2010; Wright-Walters,
Volz et al., 2010
Adequate; guideline study (OECD
204).
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Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Oryzias latipes (Medaka fish, early life
stage) 96-hour LC50 =13.9 mg/L
(Experimental)
Wright-Walters, Volz et al.,
2010
Adequate; secondary source considered
the study valid. Test concentrations
were not analytically measured.
Oryzias latipes (Medaka fish)
72-hour LC50 = 5.1 mg/L (embryo)
72-hour LC50 = 6.8 mg/L ( adult male)
72-hour LC50 = 8.3 mg/L (adult female)
(Nominal, daily renewal)
EINECS, 2010; Wright-Walters,
Volz et al., 2010
Adequate; secondary sources
considered the study valid. Measured
test concentrations.
Pimephales promelas (fathead minnow)
96-hour LC50 = 4.7 mg/L (static)
96-hour LC50 = 4.6 mg/L (flow-through)
(Experimental)
No toxicity at levels <2.29 mg/L
Alexander, Dill et al., 1988;
EINECS, 2010; European
Commission, 2000
Adequate; ASTM guideline study.
Similar LC50 values for static and flow-
through measurements indicated
stability of BPA in water during the 96-
hour test period.
Multiple additional studies of freshwater
fish species reported 48-96-hour LC50
values in the range of 3-15 mg/L
European Commission, 2000;
Wright-Walters, Volz et al.,
2010
Although individual studies were
inadequate based on lack of provided
study details or insufficient exposure
duration, the LC50 range supports the
results of studies considered adequate.
Fish LC50
Saltwater
Menidia menidia (silverside fish)
96-hour LC50 = 9.4 mg/L (flow-through)
(Experimental)
No discernible effect concentration >4.8
mg/L
EINECS, 2010; Wright-Walters,
Volz et al., 2010; European
Commission, 2000
Adequate; U.S. EPA guideline study.
Cyprinodon variegates (sheepshead
minnow)
96-hour LC50 = 7.5 mg/L
(Experimental)
EINECS, 2010
Adequate; EINECS considered the
study "apparently valid", but noted
missing data such as pH, temperature,
dissolved oxygen.
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Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
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REFERENCE
DATA QUALITY
Daphnid LCS0
Daphnia magna (water flea)
48-hour EC50 = 10.2 mg/L
(Experimental)
EINECS, 2010; European
Commission, 2000; Alexander,
Dill etal., 1988
Adequate; ASTM guideline study.
Daphnia magna (water flea)
48-hour EC50 = 3.9 mg/L
(Nominal)
EINECS, 2010; European
Commission, 2000
Adequate; European Commission,
2000 indicates that analytical
monitoring was used.
Saltwater Invertebrate LCS0
Mysidopsis bahia (mysid shrimp)
96-hour LC50 (flow-through) =1.1 mg/L
(Experimental)
EINECS, 2010; European
Commission, 2000; Alexander,
Dill etal., 1988
Adequate; OPPT 830.1035 guideline
study.
Acartia tonsa (copepod)
48-hour LC50 (static) = 3.4-5.0 mg/L
(Nominal)
EINECS, 2010
Inadequate; nominal concentrations
only, organisms 10-12 days old at start
of test.
Green Algae ECS0
Freshwater
Pseiidokirchneriella subcapitata
96-hour EC50 = 2.7 mg/L (biomass)
96-hour EC50 = 3.1 mg/L (cell volume)
(Experimental)
EINECS, 2010; European
Commission, 2000; Alexander,
Dill etal., 1988
Adequate; ASTM guideline study.
Pseiidokirchneriella subcapitata
96-hour EC50 (biomass) = 2.5 mg/L
(Experimental)
European Commission, 2000
Inadequate; test conditions not
specified in secondary source.
Green Algae ECS0
Saltwater
Skeletonema costatum
96-hour EC50 =1.0 mg/L (biomass)
96-hour EC50 =1.8 mg/L (chlorophyll a
content)
(Experimental)
European Commission, 2000;
Wright-Walters, Volz et al.,
2010; Alexander, Dill et al.,
1988
Adequate; ASTM guideline study. Cell
count and chlorophyll a content are
both measures of biomass.
Chronic Aquatic Toxicity
HIGH: Based on experimental data from multiple studies indicating a High hazard concern for fish.
Fish ChV
Branchvdanio rerio (Zebraflsh) 14-day
survival
NOEC = 3.2 mg/L
LOEC = 10.15 mg/L
(Experimental)
EINECS, 2010; Wright-Walters,
Volz et al., 2010
Adequate; guideline study (OECD
204).
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Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Branchydctnio rerio (Zebrafish) growth and
reproduction:
NOEC = 0.75 mg/L
LOEC = 1.5 mg/L
(Experimental)
EINECS, 2010; Wright-Walters,
Volz et al., 2010
Inadequate; lack of experimental
design details.
Oryzias latipes (Medaka fish)
60-day survival:
NOEC = 1.82 mg/L
Growth:
NOEC = 0.355 mg/L
LOEC =1.82 mg/L
(Experimental)
EINECS, 2010; Wright-Walters,
Volz et al., 2010
Adequate; modified OECD 210 early
life stage study.
Oryzias latipes (Medaka fish) 14-day
hatchability
NOEC = 625 mg/L
LOEC = 12.5 mg/L
(Nominal)
EINECS, 2010; Wright-Walters,
Volz et al., 2010
Adequate; early life stage toxicity
study, although test concentrations
apparently not measured analytically.
Oryzias latipes (Medaka fish) 21-day
reproductive capacity test
NOEC = 3.1 mg/L
(Experimental)
EINECS, 2010
Adequate; reproductive toxicity study
of adult fish. Test methods
subsequently recommended by OECD
for elucidation of effects on survival,
growth, and reproduction of potential
endocrine disrupting compounds.
Oryzias latipes (Medaka fish) 14-day
hatchability:
NOEC = 0^68 mg/L
LOEC = 2.3 mg/L
(Experimental)
EINECS, 2010; Wright-Walters,
Volz et al., 2010
Inadequate; early life stage toxicity
study, insufficient study details in
secondary sources. Test concentrations
not measured analytically.
Pimephcdes promelas (Fathead minnow)
multigenerational toxicity study
Survival, growth:
NOEC = 0.16 mg/L
EINECS, 2010; Wright-Walters,
Volz et al., 2010
Adequate, although secondary sources
did not mention guidelines followed.
Test concentrations were analytically
measured.
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LOEC: = 0.64 mg/L
Hatchability:
NOEC = 0.016 mg
LOEC = 0.16 mg/L
(Experimental)
Pimephcdes promelas (Fathead minnow)
32-day post-hatch survival and growth:
NOEC = 0.64 mg/L
(Experimental)
Wright-Walters, Volz et al.,
2010
Adequate; considered valid GLP study
by secondary source. Chemical
exposures measured analytically.
Pimephcdes promelas (Fathead minnow)
29-30 day survival, growth, and
development study
Survival, growth:
NOEC = 1.0 mg/L
Development:
NOEC = 0.1 mg/L
(Experimental)
Wright-Walters, Volz et al.,
2010
Adequate; considered valid GLP study
by secondary source. Chemical
exposures measured analytically.
Oncorhvnchiis mvkiss (Rainbow trout)
2 8-day growth
NOEC = 3.64 mg/L
LOEC = 11 mg/L
(Experimental)
EINECS, 2010; Wright-Walters,
Volz et al., 2010
Adequate; guideline study (OECD 215)
of juvenile growth rate.
Cyrimis carpio (carp) 28- and 49-day
growth
28-day NOEC = 0.6 mg/L
49-day NOEC = 0.1 mg/L
(Experimental)
EINECS, 2010
Adequate; guideline study (not
specified).
Cyrimis carpio (carp) 28-day survival/
growth
NOEC: 0.74 mg/L
(Experimental)
Wright-Walters, Volz et al.,
2010
Inadequate; non-GLP and abstract
only.
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Bisphenol A CASRN 80-05-7
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REFERENCE
DATA QUALITY
Poecilia reticulata (guppy)
21-day sperm count
LOEC = 0.274 mg/L
(Experimental)
Wright-Walters, Volz et al.,
2010
Inadequate; insufficient study details in
secondary source.
Poe cilia reticulata (guppy) 30-day survival
NOEC = 0.5 mg/L
LOEC = 5.0 mg/L
(Experimental)
EINECS, 2010; Wright-Walters,
Volz et al., 2010
Inadequate; insufficient study details in
secondary source.
Daphnid ChV
Daphnia magna 21- day survival, molting
success, growth, reproduction
NOEC = 3.16 mg/L
(Experimental)
Caspers, 1998; EINECS, 2010;
European Commission, 2000
Adequate; guideline study (OECD
202).
Green Algae ChV
Green algae ChV = 0.278 mg/L
(ECOSAR: poly phenols)
ECOSAR; EPI
Teratogenicity in Frog Embryos
Rana temporaria (common frog) 20-day
embryo survival
NOEC = 0.1 mg/L
LOEC = 1 mg/L
(Experimental)
EINECS, 2010; Wright-Walters,
Volz et al., 2010
Inadequate; embryos used, no chemical
analysis of exposure concentrations.
Xenopus laevis (African clawed frog)
90-day survival, growth, development
NOEC = 0.5 mg/L
(Experimental)
EINECS, 2010; Wright-Walters,
Volz et al., 2010
Adequate GLP study, although study
guidelines were not mentioned in the
secondary source. Test concentrations
were analytically measured.
Xenopus laevis (African clawed frog)
12-week survival, growth
NOEC = 0.23 mg/L
(Experimental)
EINECS, 2010; Wright-Walters,
Volz et al., 2010
Inadequate; study report lacks
information regarding test conditions
(e.g., temperature, water quality). Test
concentrations were not analytically
measured. Non-GLP study.
ENVIRONMENTAL FATE
Transport
Based on the Level III fugacity models incorporating the located experimental property data, bisphenol A is
expected to partition primarily to soil. Bisphenol A is expected to be moderately mobile in soil based on
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experimental Koc studies. Leaching of bisphenol A through soil to groundwater is not expected to be an
important transport mechanism. Estimated volatilization half-lives indicate that it will be nonvolatile from
surface water. Volatilization from dry surfaces is also not expected based on its measured vapor pressure. In
the atmosphere, bisphenol A is expected to exist in the particulate phase, based on its measured vapor pressure.
Particulates will be removed from air by wet or dry deposition.
Henry's Law
Constant(atm-
m3/mole)
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Persistence
VERY LOW: Bisphenol A has passed Ready Biodegradability tests, OECD 301 F and OECD 301C within the
10 day window. Experimental data using a wide variety of innocula have demonstrated that rapid primary and
ultimate biodegradation of BPA occurs under aerobic condition in water and soil. The biodegradation of BPA
does not result in the formation of stable metabolites. Aerobic biodegradation processes are anticipated to be
the predominant environmental removal process. Experimental data indicate that BPA does not biodegrade
under anaerobic conditions. Although models suggest that BPA may display limited partitioning to sediment, it
has been detected in sediment samples. BPA may also undergo removal by both direct and indirect photolysis
in environmental waters, although this process is anticipated to be far slower than aerobic biodegradation
processes.
Water
Aerobic
Biodegradation
OECD301B: No biodegradation of
bisphenol A was observed with modified
Sturm test (Measured)
EINECS, 2010
Adequate, data from a guideline study
as reported in secondary source.
OECD301C: Reported biodegradation
half-lives of <3.5 days in river surface water
samples (Measured)
Mm, 1992; Canada, 2008
Adequate, data from a guideline study
as reported in secondary source.
OECD301D: No biodegradation of
bisphenol A was observed with OECD
30ID closed bottle test (Measured)
EINECS, 2010
Adequate, data from a guideline study
as reported in secondary source.
OECD 30IF: Average percent removal by
BOD was 89%; 10-day window met and no
bisphenol A detected by HPLC after 28
days (Measured)
CERI, 2004; EINECS, 2010
Adequate, data from a guideline study.
OECD 30IF: Rapid biodegradation by
standard aerobic 28-day ready
biodegradability test (Measured)
West, 1997; Canada, 2008;
EINECS, 2010
Adequate, data from a guideline study.
Bisphenol A met the criteria for inherently
biodegradable substances; using a modified
SCAS procedure (Measured)
Turner and Watkinson, 1986;
EINECS, 2010
Adequate, data from a valid
nonguideline study.
Degradation was noted in 40 of 44 river
water systems; 6 river water systems were
able to mineralize the substance completely,
and 34 showed TOC removal of 40-90%
Ike, Chen et al, 2000; EINECS,
2010
Adequate, data from a valid
nonguideline study.
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
(Measured)
Bisphenol A biodegradation half-life of <4
days was measured in natural waters
following a 1- to 4-day adaptation period -
acclimation (Measured)
Dorn, Chou et al., 1987; Canada,
2008J
Adequate, data from a valid
nonguideline study.
Biodegradation half-lives of 0.5-3.5 days in
river surface water samples after a lag phase
of 2-8 days (Measured)
Klecka, Gonsior et al., 2001;
Canada, 2008
Adequate, data from a valid
nonguideline study.
River water samples had Bisphenol A
biodegradation half-lives of 2, 3 and 6 days;
bisphenol A was completely degraded after
10-15 days (Measured)
Kang and Kondo, 2002; Canada,
2008; EINECS, 2010
Adequate, data from a valid
nonguideline study.
River water degradation of Bisphenol A
half-life of 3-4 days; some seawater
degradation of bisphenol A after lag period
of 30-40 days (Measured)
Kang and Kondo, 2005;
EINECS, 2010
Adequate, data from a valid
nonguideline study.
>90% degradation after 56 days in
seawater; or bisphenol A degradation half-
life of 14.4 after lag period of
35 days.(Measured)
Ying and Kookana, 2003;
EINECS, 2010
Adequate, data from a valid
nonguideline study.
Volatilization Half-life
for Model River
>1 year (Estimated)
EPI
Volatilization Half-life
for Model Lake
>1 year (Estimated)
EPI
Soil
Aerobic
Biodegradation
Biodegradation half-life of 7 days
(Measured)
EINECS, 2010; Canada, 2008;
Ying and Kookana, 2005
Adequate, data from a valid
nonguideline study.
Biodegradation half-life of 3 days 14C-BPA
was transiently converted to up to five
metabolites. The parent 14C-BPA and
14C-BPA metabolites were not detected
after 3 days (Measured)
Fent, Hein et al., 2003; Canada,
2008
Adequate, data from a valid
nonguideline study.
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Anaerobic
Biodegradation
No biodegradation after 70 days (Measured)
Ying and Kookana, 2005;
EINECS, 2010
Adequate, data from a valid
nonguideline study.
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
Biodegradation
No biodegradation after 70 days; anaerobic
conditions with Aquifer water and sediment
(Measured)
Ying and Kookana, 2003;
Canada, 2008; EINECS, 2010
Adequate, data from a valid
nonguideline study.
50% dissipation times in days
Aerobic conditions:
river water-sediment test system: 0.57
groundwater-aquifer te st system: 1.212
Anaerobic conditions:
river water-sediment test system: 1.38
groundwater-aquifer te st system: 2.75
(Measured)
Canada, 2008
Invalid; losses of up to 40% of the
initial amount applied occurred in the
sterile (control) treatments.
Bisphenol A was not biodegraded under
anaerobic conditions using estuarine
sediments (Measured)
Voordeckers, Fennell et al.,
2002
Adequate, data from a valid
nonguideline study.
Air
Atmospheric Half-life
1.6 hours (Estimated)
EPI
Reactivity
Photolysis
Direct and indirect photochemical
transformation of bisphenol A in aquatic
media has been described (Measured)
Chin, Miller et al., 2004;
Canada, 2008; EINECS, 2010
Adequate; the located secondary
sources do not quantify the importance
of this process, although it is not
anticipated to compete with
biodegradation in natural waters.
Hydrolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain functional
groups that would be expected to
hydrolyze readily under environmental
conditions.
Pyrolysis
No data located.
Environmental Half-life
75 days (Estimated)
EPI; PBT Profiler
Half-life estimated for the predominant
compartment, as determined by EPI
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Bisphenol A CASRN 80-05-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
and the PBT Profiler methodology.
Bioconcentration
LOW: The measured fish BCF values reported for a number of experimental studies are <100.
Fish BCF
3.5-68 (Measured)
Canada, 2008
As reported in secondary source.
67 (Measured)
EINECS, 2010
As reported in secondary source.
38 ± 21 L/kg in halibut {Varaspar
variegates) (Measured)
EINECS, 2010; Lee, Soyano et
al., 2004
As reported in secondary source.
73.4 Killifish (Oryzias latipes) (Measured)
Takino, Tsuda et al., 1999;
EINECS, 2010
Adequate.
5.1-13.8 (Measured)
<20-67.7 (Measured)
Canada, 2008; MITI, 1992
Adequate.
3.5-5.5 (Measured)
Lindholst, Pedersen et al., 2001;
Canada, 2008; ^
Adequate.
Green Algae BCF
From the Tama River, Japan
Periphytons: 18-650
Benthos: 8-170 (Measured)
Adequate.
Earthworms BCF
7.9 kg/kg (Estimated)
EINECS, 2010
Adequate.
Metabolism in fish
Metabolites identified 7 days after exposure
in fish (Danio rerio) (Measured)
Kang, Katayama et al., 2006;
Canada, 2008,
Adequate.
Fish plasma half- life of Bisphenol A was
calculated to be 3.75 hours following
injection of the compound (Measured)
Lindholst, Pedersen et al., 2001;
Canada, 2008
Adequate.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
Bisphenol A was detected in environmental samples, including those from groundwater, wastewater treatment plume
water, landfill lagoon water, drinking water, streams and rivers, and sediments.
Ecological Biomonitoring
Bisphenol A was found in ecological samples; detectable levels were found in snails, mussels, fish, clams, and
zooplankton.
Human Biomonitoring
Bisphenol A was detected in a variety of human biological samples including serum, breast milk, urine, fetal blood,
and umbilical cord blood. This chemical was included in the NHANES biomonitoring report (CDC, 2011).
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Akahori, Y.; Makai, M.; Yamasaki, K.; et al. Relationship between the results of in vitro receptor binding assay to human estrogen
receptor a and in vivo uterotrophic assay: Comparative study with 65 selected chemicals. Toxicol. In vitro 2008, 22:225-231.
Alexander, H., Dill, D., Smith, L., et al. Bisphenol-A: Acute aquatic toxicity. Environ. Toxicol. Chem., 1988. 7:19-26.
Blair, R., Branham, W., Hass, B., et al. The estrogen receptor relative binding affinities of 188 natural and xenochemicals: Structural
diversity of ligands. Toxicol. Sci., 2000. 54:138-153.
Boethling, R., Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences. Boca Raton:
Lewis Publishers. 2000.
Canada. Environment Canada, Health Canada. Screening Assessment for the Challenge Phenol, 4,4' (1-methyl ethylidene)bis-
(Bisphenol A) CAS 80-05-7. October 2008.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
Chapin, R.E., Adams, J., Boekelheide, K., et al. NTP-CERHR Expert Panet report on the reproductive and developmental toxicity of
bisphenol A. Birth Defects Research. Part B. Developmental and Reproductive Toxicology. 2008. 83:157-395.
Chemicals Evaluation and Research Institute (CERI, Japan), 2004. Biodegradation study of BP A by microorganisms. Study number
14293, Final Report.
Chen, M.-Y., Michihiko, I., Fujita, M. Acute toxicity, mutagenicity, and estrogenicity of bisphenol-A and other bisphenols. Environ.
Toxicol., 2002. 17:80-86.
Chin, Y-P.; Miller, P.; Zeng, L.; Cawley, k.; Weavers, L. Photosensitized Degradation of Bisphenol A by Dissolved Organic Matter.
Environ. Sci. Technol. 2004, 38, 5888-5894.
Coleman, K.P., Toscano, W.A., Wiese, T.E. QSAR Models of the in vitro estrogen activity of bisphenol A analogs. QSAR &
Combinatorial Science 2003. 22:78-88.
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Dorn, P.; Chou, C.; Gentempo, J. Degradation of bisphenol-A in natural waters. Chemosphere, 1987, 16(7), 1501-1507.
ECOSAR/EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 3.20. U.S. Environmental Protection
Agency: Washington D.C. http://www.epa.gov/opptintr/exposure/.
EINECS. 4,4"-Isopropylidenediphenol (bisphenol A). European Union Risk Assessment Report. 2010.
EPI (EPIWIN/EPISUITE) Estimations Programs Interface for Windows, Version 4.00. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
European Commission. IUCLID Dataset for 4,4-isopropylidenediphenol (CAS No. 80-05-7). European Chemicals Bureau, February
19, 2000. 2000.
FAO/WHO. Toxicological and health aspects of bisphenol A. Report of Joint FAO/WHO expert meeting 2-5 November 2010 and
report of stakeholder meeting on bisphenol A 1 November 2010. Food and Agriculture Organization of the United Nations; World
Health Organization. Ottawa, Canada. 2011.
Fent, G.; Hein, W.; Moendel, M.; Kubiak, R. Fate of 14C-bisphenol A in soils. Chemosphere, 2003, 51; 735-746.
Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American
Chemical Society., 1995., p. 131
Hashimoto, Y.; Nakamura, M. Estrogenic activity of dental materials and bisphenol-A related chemicals in vitro. Dent. Mater. J.
2000, 19(3):245-262.
Hashimoto, Y.; Moriguchi, Y.; Oshima, H.; et al. Measurement of estrogenic activity of chemicals for the development of new dental
polymers. Toxicol. In vitro 2001, 15:421-425.
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Hollrigl-Rosta, A.; Vinken, R.; Lenz, M.; Schaffer, A. Sorption and dialysis experiments to assess the binding of phenolic xenobiotics
to dissolved organic matter in soil. Environ. Toxicol. Chem., 2003, 22(4), 746-752.
Ike, M.; Chen, M.Y.; Danzl, E.; et al. Biodegradation of a variety of bisphenols under aerobic and anaerobic conditions. Water Sci.
Technol. 2006, 53:153-159.
Kang, J-H.; Kondo, F. Bisphenol A degradation by bacteria isolated from river water. Arch. Environ. Contam. Toxicol., 2002, 43,
265-269.
Kang, J-H.; Kondo, F. Bisphenol A degradation in seawater is different from that in river water. Chemosphere, 2005, 60, 1288-1292.
Kang, J-H.; Katayama, Y.; Kondo, F. Biodegradation or metabolism of bisphenol A: from microorganisms to mammals. Toxicology,
2006, 217, 81-90.
Kitagawa, Y., Takatori, S., Oda, H., et al. Detection of thyroid hormone receptor-binding activities of chemicals using a yeast two-
hybrid assay. J. Health Sci. 2003, 49(2):99-104.
Keri R.A., Ho S-M, Hunt, P., et al. An evaluation of evidence for the carcinogenic activity of bisphenol A. Reprod Toxicol. 2007.
24(2):240-252.
Kitamura, S, Suzuki, T., Sanoh, S., et al. Comparative study of the endocrine-disrupting activity of bisphenol A and 19 related
compounds. Toxicol. Sci., 2005. 84:249-259.
Klecka, G.; Gonsior, S.; West, R.; Goodwin, P.; Markham, D.; Biodegradation of bisphenol A in aquatic environments: river die-
away. Environ. Toxicol., Chem. 2001, 20(12): 2725-2735.
Laws, S., Yavanhxay, S, Cooper, R., et al. Nature of the binding interaction for 50 structurally diverse chemicals with rat estrogen
receptors. Toxicol. Sci. 2006, 94(l):46-56.
Lee, H.; Soyano, K; Ishimatsu, A.; Nagae, M.; Kohra, S.; Ishibashi, Y.; Arizono, K; Takao, Y. Bisphenol A and nonylphenol
bioconcentration in spotted halibut Varaspar variegates. Fisheries Science, 2004, 70, 192-194.
4-81
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Lindholst, C.; Pedersen, S.; Bjerregaard, P. Uptake, metabolism and excretion of bisphenol A in the rainbow trout (Oncorhynchus
mykiss). Aquat. Toxicol., 2001, 55:75-84.
Loffredo, E.; Senesi, N. Fate of anthropogenic organic pollutants in soils with emphasis on adsorption/desorption processes of
endocrine disruptor compounds. Pure Appl. Chem., 2006, 78(5), 947-961.
METI. Current status of testing methods development for endocrine disruptors. Ministry of Economy, Trade and Industry, Japan. 6th
meeting of the task force on Endocrine Disruptors Testing and Assessments (EDTA). 24-25 June, 2002. Tokyo. 2002.
Miller, D.; Wheals, B.B.; Beresford, N.; et al. Estrogenic activity of phenolic additives determined by an in vitro yeast bioassay.
Environ. Health Perspect. 2001, 109(2): 13 3 -13 8.
MITI. Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. 1998, Compiled under the
supervision of Chemical Products Safety Division, Basic Industries Bureau, Ministry of International Trade & Industry, Japan;
Chemicals Inspection & Testing Institute, Japan. Ed.; Japan Chemical Industry Ecology- Toxicology & Information Center: 1998.
Nakanishi, J.; Miyamoto, K.; AIST Risk Assessment Document Series No. 4 - Bisphenol A. 2007 Available at:
http://unit.aist.go.jp/crm/index_e.html as of February 09, 2010.
NIOSH. Skin Notation (SK) Profile, Bisphenol A (BP A) [CAS No. 80-05-7], Department of Health and Human Services; Centers for
Disease Control and Prevention; National Institute for Occupational Safety and Health. 2010.
Nishihara, T.; Nishikawa, J.; Kanayama, T.; et al. Estrogenic activities of 517 chemicals by yeast two-hybrid assay. J. Health Sci.
2000, 46(4) 282-298.
NTP-CERHR. Monograph on the potential human reproductive and developmental effects of biphenol A. National Toxicology
Program; U.S. Department of Health and Human Service. Center for the Evaluation of Risks to Human Reproduction. NIH
Publication No. 08-5994. September 2008.
NTP. Carcinogenesis bioassay of bisphenol-A (CAS No. 80-05-7) in F344 rats and B6C3F1 mice (feed study). National Toxicology
Program. Technical Report No. 215, Order No. PB82-184060. 1982.
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NTP. Bisphenol A. National Toxicology Program, Department of Health and Human Services. http://ntp-
apps.niehs.nih.gov/ntp tox/index.cfm?searchterm=80-05-7&fuseaction=ntpsearch.searchresults. 2010.
Ogawa, Y.; Kawamura, Y.; Wakui, C.; et al. Estrogenic activities of chemicals related to food contact plastics and rubbers tested by
the yeast two-hybrid assay. FoodAddit. Contain. 2006, 23(4):422-430.
O'TSTeil, M., et al. eds. e-Merck Index. 14th ed. Basic Search. Whitehouse Station, NJ: Merck & Co., Inc. 2010.
https://themerckindex.cambridgesoft.com/TheMerckIndex/index.asp as of December 10, 2010.
Patrolecco, L.; Capri, S.; De Angelis, S.; Pagnotta, R.; Polesello, S.; Valsecchi, S. Partition of nonylphenol and related compounds
among different aquatic compartments in Tiber River (central Italy). Water, Air and Soil Pollution, 2006, 172, 151-166.
PBT Profiler Persistent (P),Bioaccumulative (B), and Toxic (T) Chemical (PBT)Profiler, U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
Perez, P., Pulgar, R., Olea-Serrano, F., et al. 1998. The estrogenicity of bisphenol A-related diphenylalkanes with various
substituents at the central carbon and the hydroxyl groups. Environ. Health Perspect., 1998. 106(3): 167-174.
Stroheker, T., Picard, K., Lhuguenot, J., et al. Steroid activities comparison of natural and food wrap compounds in human breast
cancer cell lines. Food Chem. Toxicol. 2004,42:887-897.
Takino, A.; Tsuda, T.; Kojima, M.; Harada, H.; Muraki, K.; Wada, M. Bioconcentration factor of bisphenol A for killifish (Oryzias
latipes) Rep Shiga Prefecture. Public Health & Environ Sci, 1999, 34, 65-67.
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U.S. EPA Sustainable Futures. Using Non Cancer Screening within the SF Initiative. Environmental Protection Agency: Washington
D.C. 2010. http://www.epa.gOv/opptintr/sf/pubs/noncan-screen.htm#systemic as of February 09, 2011.
U.S. EPA (Environmental Protection Agency). High Production Volume (HPV) Challenge. Determining the Adequacy of Existing
Data. U.S. Environmental Protection Agency: Washington D.C. 1999. http://www.epa.gov/hpv/pubs/general/datadfin.htm
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Voordeckers, J.; Fennell, D.; Jones, K.; Haggblom, M. Anaerobic biotransformation of tetrabromobisphenol A, tetrachlorobisphenol A
and bisphenol A in estuarine sediments. Environ. Sci. Technol. 2002. 36, 696-701.
Willhite C.C.; Ball G.L.; McLellan C.J. Derivation of a bisphenol a oral Reference Dose (RfD) and drinking-water equivalent
concentration. J Toxicol Environ Health, Part B., 2008, 11: 69-146.
West, R.; Goodwin, P. Evaluation of Ready Biodegradability of Bisphenol-A Using the OECD 301F: Manometric Respirometry Test.
Dow Company Report. Study ID 971108A, 1997.
Wright-Walters, M.; Volz, C.; Talbott, E.; et al. An updated weight of evidence approach to the aquatic hazard assessment of
Bisphenol A and the derivation a new predicted no effect concentration (Pnec) using a non-parametric methodology. Sci. Total
Environ., 2011 409(4):676-685.
Ying, G.; Kookana, R. Degradation of five selected endocrine-disrupting chemicals in seawater and marine sediment. Environ Sci.
Technol., 2003, 37, 1256-1260.
Ying, G.; Kookana, R. Sorption and degradation of estrogen-like endocrine disrupting chemicals in soil. Environ. Toxicol. Chem.,
2005, 24(10), 2640-2645.
Zeng, G.; Zhang, C.; Huang, G.; Yu, J.; Wang, Q.; Li, J.; Xi, B.; Liu, H. Adsorption behaviour of bisphenol A on sediments in
Xiangjiang River, south-central China. Chemosphere, 2006, 65, 1490-1499.
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Bisphenol F
CASRN: 620-92-8
MW: 200.24
MF: C13H1202
Physical Forms:
Neat: Solid
Use: Developer for thermal paper
SMILES: 0C(CCC(C1)CC(CCC(0)C2)C2)C1
Synonyms: Phenol, 4,4'-methylenebis- (TSCA Inventory); Bis(4-hydroxyphenyl)methane; 4,4'-Methylenebis(phenol); 4,4'-Dihydroxydiphenylmethane;
4,4'-Methylene diphenol; Bis(4-hydroxyphenyl)methane; Bis(p-hydroxyphenyl)methane; Phenol, 4,4'-methylenedi-; p,p'-Bis(hydroxyphenyl)methane;
p-(p-Hydroxybenzyl)phenol
Polymeric: No
Oligomers: Not applicable
Metabolites, Degradates and Transformation Products: 4,4"-dihydroxybenzophenone, bis(4-hydroxyphenyl)methanol, 4-hydroxyphenyl-4-hydroxybenzoate,
4-hydroxybenzoate and 1,4-hydroquinine, sulfate conjugate of bisphenol F
Analog: Bisphenol A (80-05-7)
Endpoint(s) using analog values: Reproductive and developmental
toxicity, dermal irritation
Analog Structure:
HO-
// W
// \
¦OH
Structural Alerts: Phenols, neurotoxicity (U.S. EPA, 2010)
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 2011).
Risk Assessments: None identified
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Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
162.5 (Measured)
Lide, 2008
Adequate.
Boiling Point (°C)
Sublimes
Lide, 2008
Adequate.
Vapor Pressure (mm Hg)
3.7xl0"7 (Estimated)
EPI
Water Solubility (mg/L)
190 (Estimated)
EPI
Log Kow
2.91 (Measured)
Hansch, 1995
Adequate.
Flammability (Flash Point)
No data located.
Explosivity
No data located.
pH
No data located.
pKa
7.55 (Measured)
Seijeant and Dempsey, 1979
Adequate.
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Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
HUMAN HEALTH EFFECTS
Toxicokinetics
Bisphenol F is readily absorbed following oral exposure and is widely distributed, metabolized to multiple
metabolites, and excreted primarily in the urine and to a lesser extent in the feces.
Dermal Absorption in vitro
No data located.
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal or Inhaled
Single gavage doses of 7 or 100 mg/kg
[3H] bisphenol F to pregnant or
nonpregnant Sprague-Dawley rats.
Approximately 15-20% of the
administered radioactivity was recovered
in the urine during the first 24 hours
postdosing, indicating that bisphenol F
was readily absorbed. By 96 hours
postdosing, nearly 50% of the dose had
been recovered in the urine; fecal
excretion accounted for <20% of the
dose. Parent compound accounted for
<25% of the radioactivity in the urine and
at least six urinary metabolites were
detected; the major urinary metabolite
(>50%) appeared to be a sulfate
conjugate of bisphenol F. At 96 hours
postdosing, <1% of the administered
radioactivity was detected in selected
organs and tissues; the highest levels
were found in the liver (0.5% of dose).
Radioactivity was detected in placenta,
amniotic fluid, and fetuses of pregnant
rats. In bile-cannulated rats, nearly 50%
of an administered dose of |'H|bisphenol
F was collected in the bile between 2 and
8 hours postdosing, indicating the
involvement of enterohepatic cycling of
bisphenol F and/or its metabolites.
Cabaton, Chagnon et al., 2006
Adequate.
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Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Acute Mammalian Toxicity
LOW: Based on an experimental rat LDS0 of 4,950 mg/kg. No data were located to assess acute inhalation
or dermal toxicity.
Acute Lethality
Oral
Rat oral LD50 = 4,950 mg/kg
Smyth, Carpenter et al., 1962
Adequate.
Dermal
No data located.
Inhalation
No data located.
Carcinogenicity
MODERATE: Estimated using OncoLogic expert system which describes a concern for this compound as a
potential carcinogen or tumorigenesis promoter arising from its structural similarity to
estrogenic/androgenic compounds, using the phenols and phenolic compounds structural alert.
OncoLogic Results
Moderate (Estimate)
OncoLogic class: Phenols and phenolic
compounds
OncoLogic
OncoLogic SAR analysis using the
phenols and phenolic compounds
class.
Carcinogenicity (Rat and
Mouse)
No data located.
Combined Chronic
Toxicity/Carcinogenicity
No data located.
Genotoxicity
LOW: Bisphenol F did not cause gene mutations or chromosomal aberrations in located in vitro assays in
multiple test strains and cell types. Bisphenol F did cause DNA damage in a Comet assay; however,
assessment guidance indicates a low concern given the negative results for gene mutations and chromosomal
aberrations assays.
Gene Mutation in vitro
Negative; Ames assay in Salmonella
Typhimiiriiim strains TA98, TA100,
TA1535, TA1537, and Escherichia coli
W2 uvrA pKMlOl with and without
metabolic activation
Cabaton, Dumont et al., 2009
Adequate.
Negative, umu test in S. typhimiiriiim
strain TA1335 with and without
metabolic activation
Chen, Michihiko et al., 2002
Adequate.
Negative, gene mutation tests at the
Na+/K+ ATPase locus and hprt locus of
Syrian hamster embryo (SHE) cells
Tsutsui, Tamura et al., 2000
Adequate.
4-88
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Gene Mutation in vivo
No data located.
Chromosomal Aberrations
in vitro
Negative, chromosomal aberrations in
SHE cells
Tsutsui, Tamura et al., 2000
Adequate.
Negative, micronucleus test in HepG2
cells
Cabaton, Dumont et al., 2009
Adequate.
Chromosomal Aberrations
in vivo
No data located.
DNA Damage and Repair
Positive; DNA damage (single and
double strand breaks); Comet assay
HepG2 cells
Cabaton, Dumont et al., 2009
Adequate.
Other
No data located.
Reproductive Effects
HIGH: Estimated based on male and female NOAELs of 4.75 mg/kg bw-day and 47.5 mg/kg bw-day,
respectively, for reproductive toxicity following exposure to the analog bisphenol A. Conclusions of NTP-
CERHR (2008) included sufficient evidence in rats and mice that subchronic or chronic oral exposures to
bisphenol A causes female reproductive toxicity at doses >475 mg/kg bw-day (highest NOAEL = 47.5 mg/kg
bw-day) and male reproductive toxicity at doses >47.5 mg/kg bw-day (highest NOAEL = 4.75 mg/kg bw-
day). There is considerable uncertainty regarding the results of recent studies that reported reproductive
and/or developmental effects in laboratory animals administered the analog bisphenol A at oral doses
<5 mg/kg bw-day. Adequate data were not located to assess reproductive toxicity following exposure to
bisphenol F. Changes in uterine weight were reported following in vivo exposure in rats. However, a 28-day
gavage study reported no effects on reproductive organ weights, estrous cycles, or spermatocytes at doses up
to 500 mg/kg-day. These studies were not guideline reproductive toxicity studies, and are therefore not
adequate to evaluate the potential reproductive hazard.
Reproduction/
Developmental Toxicity
Screen
Bisphenol F increased absolute and
relative uterine weight in a rat
uterotrophic assay.
Yamasaki, Noda et al., 2004
Adequate.
4-89
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
28-Day study with Cij:CD Sprague-
Dawley rats (10/sex/dose), gavaged with
0, 20, 100, or 500 mg/kg-day:
NOAEL = 500 mg/kg-day
(endocrine/reproductive parameters).
No changes in spermatological findings,
estrous cycles, reproductive organ
weight, or thyroid weight.
Higashihara, Shiraishi et al., 2007
Adequate.
Exposure to bisphenol F in immature rats
resulted in a dose-dependent increase in
relative wet and dry uterine weight and
increased vaginal cornification in
immature female Wistar rats.
LOAEL =100 mg/kg-day (based on
increased relative wet uterine weight
NOAEL = 50 mg/kg-day
Stroheker, Chagnon et al., 2003
Adequate.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
4-90
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproduction and Fertility
Effects
Parental systemic toxicity:
NOAEL = 4.75 mg/kg bw-day
LOAEL = 47.5 mg/kg bw-day for 12%
decreased terminal body weight in Fi
parental males
Reproductive toxicity:
Females: NOAEL = 47.5 mg/kg bw-day
LOAEL = 475 mg/kg bw-day for
decreases in number of implantation sites,
delayed vaginal opening in Fi, F2, F3
offspring
Males: NOAEL = 4.75 mg/kg bw-day,
LOAEL = 47.5 mg/kg-day for delayed
preputial separation in F, males
(Estimated by analogy)
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
adequate, guideline study as
reported in the secondary source.
Classified by NTP-CERHR as
having High Utility.
Parental systemic toxicity:
NOAEL = 5 mg/kg bw-day
LOAEL = 50 mg/kg bw-day for increased
incidences of centrilobular hepatocellular
hypertrophy in males and females
Reproductive toxicity:
NOAEL = 50 mg/kg bw-day
LOAEL = 600 mg/kg bw-day for
increased gestation length, decreased
epididymal sperm concentration in F,
males, increased incidence of gross
ovarian cysts in Fi and F2 females
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
adequate, guideline study as
reported in the secondary source.
Classified by NTP-CERHR as
having High Utility.
(Estimated by analogy)
4-91
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Female effects: There is sufficient
evidence in rats and mice that bisphenol
A causes female reproductive toxicity
with subchronic or chronic oral exposures
NOAEL of 47.5mg/kg bw-day
LOAEL of 475 mg/kg bw-day.
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
Classified by NTP-CERHR as
having High Utility.
Male effects: There is sufficient evidence
in rats and mice that bisphenol A causes
male reproductive toxicity with
subchronic or chronic oral exposures
NOAEL of 4.75mg/kg bw-day
LOAEL of 47.5mg/kg bw/day.
(Estimated by analogy)
The joint FAO/WHO Expert Panel
reviewed located reproductive and
developmental toxicity data for bisphenol
A as of November, 2010 and noted that
most regulatory bodies reviewing the
numerous studies on bisphenol A have
indicated an oral reproductive and
developmental NOAEL of 50 mg/kg bw-
day.
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
Classified by NTP-CERHR as
having High Utility.
(Estimated by analogy)
Developmental Effects
HIGH: Estimated based on analogy to bisphenol A. The NTP-CERHR (2008) Expert Panel concluded that
there is suggestive evidence that bisphenol A causes neural and behavioral alterations related to disruptions
in normal sex differences in rats and mice (0.01-0.2 mg/kg bw-day). The FAO/WHO (2011) Expert Panel
concluded that while there was broad agreement in a NOAEL of 50 mg/kg bw-day for developmental
toxicity, low-level (<1 mg/kg bw-day) effects were uncertain. These conclusions support a High hazard
designation, with lower confidence.
4-92
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproduction/
Developmental Toxicity
Screen
No data located.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
4-93
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Summary of
Developmental effects
The NTP-CERHR Expert Panel
concluded that bisphenol A:
*does not cause malformations or birth
defects in rats or mice at levels up to the
highest doses evaluated: 640 mg/kg/day
(rats) and 1,250 mg/kg bw-day (mice).
*does not alter male or female fertility
after gestational exposure up to doses of
450 mg/kg bw-day in the rat and
600 mg/kg bw-day in the mouse (highest
dose levels evaluated).
*does not permanently affect prostate
weight at doses up to 475 mg/kg bw-day
in adult rats or 600 mg/kg bw-day in
mice.
*does not cause prostate cancer in rats or
mice after adult exposure at up to 148 or
600 mg/kg bw-day, respectively.
*does change the age of puberty in male
or female rats at high doses (ca.
475 mg/kg/day).
And that rodent studies suggest that
bisphenol A:
* causes neural and behavioral alterations
related to disruptions in normal sex
differences in rats and mice (0.01-
0.2 mg/kg/day).
(Estimated by analogy)
NTP-CERHR, 2008; Professional
judgment
Based on the analog bisphenol A.
4-94
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
The joint FAO/WHO Expert Panel
reviewed located reproductive and
developmental toxicity data for bisphenol
A as of November, 2010 and noted that
most regulatory bodies reviewing the
numerous studies on bisphenol A have
indicated an oral reproductive and
developmental NOAEL of 50 mg/kg bw-
day.
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
Neurotoxicity
MODERATE: Estimated to have potential for neurotoxicity based on the presence of the phenol structural
alert.
Neurotoxicity Screening
Battery (Adult)
There is potential for neurotoxicity
effects based on the presence of the
phenol structural alert
(Estimated)
U.S. EPA, 2010; Professional
judgment
Estimated based on structural alert.
Repeated Dose Effects
HIGH: Based on adverse effects (12% lower body weight than controls; decreased total cholesterol, glucose,
and albumin in the serum) in female rats administered bisphenol F by gavage for 28 days at 20 mg/kg-day
(the lowest dose tested). Because the standard criteria thresholds are for 90-day studies, this study was
evaluated using modified criteria at 3 times the threshold values.
28-day oral study of Cij:CD Sprague-
Dawley rats (10/sex/dose), gavaged with
0, 20, 100, or 500 mg/kg-day.
LOAEL = 20 mg/kg-day (based on
significant decreases in final mean body
weight [12% less than controls], serum
total cholesterol, glucose, and albumin in
female rats).
Higashihara, Shiraishi et al., 2007
Adequate 28-day repeated dose
toxicity study; this study will be
evaluated using modified criteria at
3 times the thresholds because the
standard thresholds are based on
90-day studies.
Skin Sensitization
LOW: One study in guinea pigs suggested bisphenol F is not a skin sensitizer.
Skin Sensitization
Negative for skin sensitizing capacity in
guinea pig maximization test
Bruze, 1986
Adequate.
Respiratory Sensitization
No data located.
4-95
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Respiratory Sensitization
No data located.
Eye Irritation
VERY HIGH: One study of rabbits indicated that bisphenol F caused severe eye injury.
Eye Irritation
Severe corneal injury in rabbits
Smyth, Carpenter et al., 1962
Adequate.
Dermal Irritation
MODERATE: Based on analogy to bisphenol A; bisphenol F is estimated to be slightly irritating to
moderately irritating to rabbit skin based on test data for the analog bisphenol A. NIOSH has assigned the
analog bisphenol A as a skin irritant.
Dermal Irritation
Rabbit, nonirritating to slightly irritating
when applied as undiluted or 10%
aqueous suspension to intact or abraded
skin
(Estimated by analogy)
EINECS, 2010; European
Commission, 2000; NIOSH, 2010;
Professional judgment
Based on the analog bisphenol A;
the details provided for multiple
studies indicate potential for
bisphenol A to cause dermal
irritation.
Rabbit, moderately irritating when
applied as 40% solution in dimethyl
sulfoxide under non-occlusive conditions.
(Estimated by analogy)
European Commission, 2000;
Professional judgment
Based on the analog bisphenol A;
adequate.
Guinea pig, not irritating when applied as
5% solution in acetone for 24 hours under
occlusive conditions.
(Estimated by analogy)
European Commission, 2000;
Professional judgment
Based on the analog bisphenol A;
adequate.
Endocrine Activity
Based on in vitro and in vivo data. Bisphenol F exhibited estrogenic and anti-estrogenic activity in some in
vivo studies of female rats. In vitro assays indicate that bisphenol A can bind to estrogen receptors (ERs),
elicit estrogen-induced gene transcription, induce progesterone receptors (PgR), and induce cell
proliferation in MCF7 cancer cells. Bisphenol F has been shown to exhibit androgenic and anti-androgenic
properties in vitro. Bisphenol F appears to exhibit estrogenic potency similar to or somewhat less than the
potency of bisphenol A.
Receptor Binding Assays
4-96
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Bisphenol F exhibited weak ER binding
activity in preparations from uteri of
ovariectomized Sprague-Dawley rats as
evidenced by a relative binding affinity
(RBA) that was 0.0009% of the binding
affinity of 17|3-estradiol. RBAs for other
tested chemicals included 0.008% for
bisphenol A, 0.003% for PHBB, and
0.0007% for the proprietary substituted
phenolic compound.
Blair, Branham et al., 2000
Adequate.
In a human ER binding assay, the RBA of
bisphenol F was 0.0719% compared to
126% for 17|3-estradiol. RBAs for other
bisphenol compounds included 0.195%
for bisphenol A, 0.129% for bisphenol C,
0.0803% for bisphenol AP, and 0.0055%
for bisphenol S. An RBA of 0.00473%
was reported for PHBB.
METI, 2002
Adequate.
In a competitive ER binding assay using
human ERa, the RBA for bisphenol A
was 0.32% that of 17|3-estradiol. RBAs
for other bisphenol compounds included
1.68% for bisphenol C, 1.66% for
bisphenol AP, and 0.09% for bisphenol F.
Coleman, Toscano et al., 2003
Adequate.
In a human ER binding assay, the RBA of
bisphenol F was 0.0719% relative to 17|3-
estradiol (set at 100%). RBAs for other
bisphenol compounds included 0.175%
for bisphenol M and 0.0055% for
bisphenol A.
Yamasaki, Noda et al., 2004
Adequate.
4-97
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In a rat uterine cytosol assay that
evaluated ER binding affinity, ER
binding affinities for bisphenol A and
bisphenol F were approximately 3 orders
of magnitude less than that for 17|3-
estradiol
Perez, Pulgar et al., 1998
Adequate.
Gene Transcription and Reporter
Gene Assays
Bisphenol F exhibited evidence of
estrogenic activity in a yeast
(Scicchciromyces cerevisicte) two-hybrid
assay using ERa and the coactivator
TIF2. Based on estrogenic activity that
was 5 orders of magnitude lower than that
of 17|3-estradiol, bisphenol A was
considered weakly estrogenic.
Assessment of other bisphenols resulted
in a ranking of relative potency as
follows: bisphenol C > bisphenol A >
bisphenol F > bisphenol S.
Chen, Michihiko et al., 2002
Adequate.
Bisphenol F exhibited estrogenic activity
approximately 9,000-fold less than that of
17|3-estradiol) in an in vitro recombinant
yeast estrogen assay; the estrogenic
activities of bisphenol A and PHBB were
10,000-fold and 4,000-fold less than that
of 17|3-estradiol
Miller, Wheals et al., 2001
Adequate.
In a yeast two-hybrid system (reporter
gene assay) using |3-galactosidase activity
as a measure of estrogenic activity, an
estrogenic response was elicited by
bisphenol F and bisphenol A but not by
bisphenol S.
Hashimoto and Nakamura, 2000
Adequate.
4-98
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In yeast two-hybrid systems (reporter
gene assay) using |3-galactosidase activity
as a measure of estrogenic activity, an
estrogenic response was elicited by
bisphenol F and bisphenol A both in the
absence and presence of exogenous
metabolic activation; bisphenol S elicited
a similar response only in the presence of
exogenous metabolic activation
Hashimoto and Nakamura, 2000;
Hashimoto et al. 2001
Adequate.
In a yeast two-hybrid assay (reporter gene
assay) using |3-galactosidase activity as a
measure of estrogenic activity, an
estrogenic response was elicited by
bisphenol F and bisphenol A
Ogawa, Kawamura et al. 2006
Adequate.
In a reporter gene assay of estrogen-
induced transcriptional activity, relative
activity (RA) for bisphenol F was
0.000639% compared to 81.7% for 17|3-
estradiol. RAs for other bisphenol
compounds included 0.00278% for
bisphenol A, 0.00189% for bisphenol C,
0.000254% for bisphenol S, and
0.000184% for bisphenol AP. An RA of
0.000592% was reported for PHBB.
METI, 2002
Adequate.
In an ER-mediated reporter gene
expression assay, bisphenol F induced
reporter gene expression at a RA of 5.3 x
10"4 that of 17|3-estradiol. RAs for other
bisphenol compounds included 2.75 x 10"
3 for bisphenol A, 4.9 x 10"4 for bisphenol
C, and 9.0 x 10"5 for bisphenol AP.
Coleman, Toscano et al., 2003
Adequate.
4-99
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In an ERE-luciferase reporter assay using
MCF-7 cells, an EC50 was 1.0 pM for
bisphenol F compared to an EC50 of 8.6 x
10"6 for 17|3-estradiol (i.e., bisphenol A
was approximately 5 orders of magnitude
less potent than 17|3-estradiol at inducing
estrogenic activity). EC50 values for
other bisphenol compounds included
0.63% for bisphenol A, 0.42 (iM for
bisphenol C, and 1.1 (iM for bisphenol S.
Kitamura, Suzuki et al., 2005
Adequate.
In an ERE-luciferase reporter assay using
MCF-7 cells in the presence of 17|3-
estradiol, neither bisphenol F, bisphenol
A, bisphenol C, nor bisphenol S appeared
to exert an anti-estrogenic effect
Kitamura, Suzuki et al., 2005
Adequate.
Weakly estrogenic in a transcriptional
activation assay using human ER and
HepG2 cells
Cabaton, Dumont et al., 2009
Adequate.
Progesterone Receptor Induction
In an ERE-luciferase reporter assay using
MCF-7 cells, an EC50 was 1.0 (iM for
bisphenol F compared to an EC50 of 8.6 x
10"6 for 17|3-estradiol (i.e., bisphenol A
was approximately 5 orders of magnitude
less potent than 17|3-estradiol at inducing
estrogenic activity). EC50 values for
other bisphenol compounds included
0.63% for bisphenol A, 0.42 (iM for
bisphenol C, and 1.1 pM for bisphenol S.
Kitamura, Suzuki et al., 2005
Adequate.
4-100
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In an assay designed to evaluate
estrogenic effects on the number of
progesterone receptors (PgR) in MCF7
cells, 17|3-estradiol, bisphenol F, and
bisphenol A each increased the
concentration of PgR by approximately
10-to 15-fold
Perez, Pulgar et al., 1998
Adequate.
Cell Proliferation Assays
Weakly estrogenic in a transcriptional
activation assay using human ER and
HepG2 cells
Cabaton, Dumont et al., 2009
Adequate.
In an E-screen test for estrogenicity,
bisphenol F, bisphenol A, and bisphenol
S increased proliferation of MCF-7 cells
at concentrations in the range of 10"4 to
10"7 M. Bisphenol A appeared to be more
effective than bisphenol S or bisphenol F.
Hashimoto et al., 2001
Adequate.
In an E-SCREEN test of MCF7 cell
proliferation (an indicator of estrogenic
activity), the proliferative potency of
bisphenol A was approximately 10"5 that
of 17|3-estradiol, suggestive of a weakly
estrogenic effect for bisphenol A. The
potency of bisphenol F was somewhat
less than that of bisphenol A.
Perez, Pulgar et al., 1998
Adequate.
4-101
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In an E-screen test for estrogenicity,
bisphenol F and bisphenol A increased
proliferation of MCF-7 cells with EC50
values of 84.8 nM and 410 nM,
respectively, compared to an EC50 of
0.0045 nM for 17|3-estradiol. The results
indicate a weak estrogenic effect with
bisphenol F exerting a more potent effect
than bisphenol A.
Stroheker, Picard et al., 2004
Adequate.
In a proliferation assay of MCF-7 human
breast cancer cells that contain ERa and
ER|3 and are known to proliferate in
response to estrogens, bisphenol A
induced a proliferative response that was
1.0 xlO"3 that of 17|3-estradiol.
Proliferative values for other bisphenol
compounds included 2.0 x 10~3 for
bisphenol A, 1.6 x 10"3 for bisphenol C,
and 6.0 x 10"4 for bisphenol AP.
Coleman, Toscano et al., 2003
Adequate.
In an assay that measured induction and
secretion of pS2 in cultured MCF7 cells
(ELSA-pS2 immunoradiometric assay),
induction of pS2 by bisphenol F and
bisphenol A was approximately 1,000-
fold less than that of 17|3-estradiol
Perez, Pulgar et al., 1998
Adequate.
Androgen Assays
4-102
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Bisphenol F and bisphenol A induced
androgenic effects in MDA-MB453 cells
transfected with an AR responsive
luciferase reporter gene; anti-androgenic
effects were elicited in the presence of
dihydrotestosterone. Relative potency of
the androgenic and anti-androgenic
effects elicited by bisphenol F was
similar to that of bisphenol A.
Stroheker, Picard et al., 2004
Adequate.
In an ARE-luciferase reporter assay using
a mouse fibroblast cell line (NIH3T3
cells), neither bisphenol F, bisphenol A,
bisphenol C, nor bisphenol S exerted an
androgenic effect
Kitamura, Suzuki et al., 2005
Adequate.
In an ARE-luciferase reporter assay using
a mouse fibroblast cell line (NIH3T3
cells), bisphenol F inhibited the
androgenic activity of
dihydrotestosterone. Anti-androgenic
responses were elicited by bisphenol A,
bisphenol C, and bisphenol S as well.
Kitamura, Suzuki et al., 2005
Adequate.
Bisphenol F induced an anti-androgenic
response in a transcriptional activation
assay at a concentration of 10"5M
Cabaton, Dumont et al., 2009
Adequate.
In Vivo Studies
4-103
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
28-Day study with Cij:CD Sprague-
Dawley rats (10/sex/dose), gavaged with
0, 20, 100, or 500 mg/kg-day:
NOAEL = 500 mg/kg-day
(endocrine/reproductive parameters).
No changes in spermatological findings,
estrous cycles, reproductive organ
weight, or thyroid weight.
Higashihara, Shiraishi et al., 2007
Adequate.
Exposure of immature female rats to
bisphenol F (gavage dosing once daily for
4 days) resulted in a dose-dependent
increase in uterine weight in immature
female rats.
LOAEL =100 mg/kg-day (based on
increased relative wet uterine weight
NOAEL = 50 mg/kg-day
There were no significant effects on
uterine weight in bisphenol A-treated
immature female rats and no effects on
uterine weight in bisphenol F- or
bisphenol A-treated ovariectromized rats.
Stroheker, Chagnon et al., 2003
Adequate.
In a uterotrophic assay of rats
subcutaneously injected with bisphenol F
once daily for 3 days, an apparent
estrogenic effect was evidenced by
increased absolute and relative uterine
weight. Similar effects were elicited by
bisphenol S and bisphenol M.
Yamasaki, Noda et al., 2004
Adequate.
4-104
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In a uterotrophic assay in which
immature female rats were injected with
bisphenol F, bisphenol S, or bisphenol M
subcutaneously for three consecutive
days, observed changes in uterine weight
indicated that bisphenol F, bisphenol S,
and bisphenol M exerted both estrogenic
and anti-estrogenic responses.
Akahori, Makai et al., 2008
Adequate.
Immunotoxicity
No data located.
Immune System Effects
No data located.
ECOTOXICITY
ECOSAR Class
Polyphenols
Acute Toxicity
MODERATE: Based on an experimental 48-hour ECS0 of 56 mg/L in Daphnia magna.
Fish LC50
Fish 96-hour LC50 = 4.55 mg/L
(Estimated)
ECOSAR: polyphenols
EPI
Fish 96-hour LC50 = 19.74 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid LCS0
Daphnia magna 48-hour EC50 = 56 mg/L
24-hour EC50 = 80 mg/L
(Experimental)
Chen, Michihiko et al., 2002
Adequate.
Daphnid 48-hour LC50 = 12.94 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid 48-hour LC50 = 13.0 mg/L
(Estimated)
ECOSAR: polyphenols
EPI
Green Algae ECS0
Green algae 96-hour EC50 = 1.37 mg/L
(Estimated)
ECOSAR: polyphenols
EPI
4-105
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Green algae 96-hour EC50 = 8.6 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Chronic Aquatic Toxicity
HIGH: Based on an estimated ChV of 0.29 mg/L for green algae that is within the range of 0.1-1.0 mg/L.
Fish ChV
Fish 30-day ChV =1.18 mg/L
(Estimated)
ECOSAR: polyphenols
EPI
Fish 30-day ChV = 1.83 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid ChV
Daphnid ChV = 1.44 mg/L (Estimated)
ECOSAR: neutral organics
EPI
Daphnid ChV = 4.56 mg/L
(Estimated)
ECOSAR: polyphenols
EPI
Green Algae ChV
Green algae ChV = 0.29 mg/L
(Estimated)
ECOSAR: polyphenols
EPI
Green algae ChV = 3.78 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
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Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
ENVIRONMENTAL FATE
Transport
Based on the Level III fugacity models incorporating the located experimental property data, bisphenol F is
expected to partition primarily to soil. Bisphenol F is expected to exist in both neutral and anionic forms at
environmentally-relevant pH, based on its measured pKa. The neutral form of bisphenol F is expected to
have low mobility in soil based on its estimated Koc. The anionic form may be more mobile, as anions do not
bind as strongly to organic carbon and clay due to their enhanced water solubility. However, leaching of
bisphenol F through soil to groundwater is not expected to be an important transport mechanism.
Estimated volatilization half-lives indicate that it will be nonvolatile from surface water. Volatilization from
dry surfaces is also not expected based on its estimated vapor pressure. In the atmosphere, bisphenol F is
expected to exist in both vapor and particulate phases, based on its estimated vapor pressure. Particulates
will be removed from air by wet or dry deposition. Vapor-phase bisphenol F will be susceptible to
atmospheric degradation processes.
Henry's Law Constant
(atm-m3/mole)
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Persistence
LOW: Bisphenol F degraded 100% after 2 weeks in a modified river die-away test (TOC-Handai Method).
Complete mineralization was reported. Based on these data, the aerobic biodegradation half-life is expected
to be <16 days. An anaerobic biodegradation test assessing primary degradation in concentrated pond
sediment reported >80% after ca. 80 days with no lag period. A pure culture study evaluating the ability of
a Sphingobium yanoikuyae strain to degrade bisphenol F suggested that the mechanism for biodegradation
started at the bridging carbon between the two phenols via hydroxylation and subsequent oxidation to
4,4'-dihydroxybenzophenone. This degradation mechanism can occur for this BPA alternative because of
the presence of labile benzylic hydrogens. Bisphenol F did not pass a ready biodegradability test (Japanese
MITI), which reported only 1% degradation after 4 weeks, indicating that it may be resistant to
biodegradation under more stringent conditions. Bisphenol F is not expected to undergo hydrolysis since it
does not contain hydrolysable functional groups. Absorption of light at environmentally relevant
wavelengths indicates that it may be susceptible to direct photolysis by sunlight. The atmospheric half-life
for the hydroxyl radical reaction of vapor phase bisphenol F is estimated to be 1.6 hours, although it is
expected to exist in both the vapor and particulate phases in air. Based on these findings, biodegradation of
bisphenol F is expected to be the main fate process in aquatic and terrestrial environments.
Water
Aerobic Biodegradation
100% after 2 weeks (Measured; TOC-
Handai Method). Method similar to
aerobic river die-away test. Used
concentrated (10 times) river water
microcosms diluted in "artificial water".
Reported complete mineralization at TOC
concentration of 10 mg/L.
Ike, Chen et al., 2006
Valid, nonguideline study
demonstrating river water
microcosms have the potential to
biodegrade bisphenol F.
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Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Biodegradation efficiencies varied from 8
to 58% after 30 days, depending on the
sampling site. A modified TOC-Handai
Method was used, which is similar to
aerobic river die-away test. Used
concentrated seawater microcosms
diluted in "artificial water". Resistance to
seasonal variation was noted.
Efficiencies varied from 75 to 100% after
30 days, depending on the sampling site
using a sea-die away method. Purified
seawater inoculums were used.
Danzl, Sei et al., 2009
Valid, nonguideline study
demonstrating seawater
microcosms have the potential to
biodegrade bisphenol F.
Sphingobiam yanoikiivae strain FM-2
(isolated from river water) biodegraded
bisphenol F. Reported mechanism
suggested hydroxylation and subsequent
oxidation at the bridging carbon to form
the following metabolites:
bis(4-hydroxyphenyl)methanol to
4,4"-dihydroxybenzophenone to
4-hydroxyphenyl-4-hydroxybenzoate to
4-hydroxybenzoate and 1,4-hydro-
quinone, all of which are mineralized.
Inoue, Hara et al., 2008
Valid, pure culture study
demonstrating biodegradation
potential and mechanism.
Volatilization Half-life
for Model River
>1 year (Estimated)
EPI
Volatilization Half-life
for Model Lake
>1 year (Estimated)
EPI
Soil
Aerobic Biodegradation
1% after 4 weeks (Measured in activated
sludge). Japanese MITI test (OECD
301C) measuring BOD with test
concentration of 100 mg/L and
concentration of activated sludge
inoculum = 30 mg/L
MITI, 1998
Adequate, guideline study.
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Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Anaerobic
Biodegradation
>80% after ca. 80 days (Measured; no lag
period). Anaerobic pond sediment
condensed to twice its original
concentration. TOC = 10 mg/L.
Measured primary degradation only. No
discussion of metabolites.
Ike, Chen et al., 2006
Valid nonguideline study,
demonstrating anaerobic seawater
sediments have potential to
biodegrade bisphenol F.
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
Biodegradation
No data located.
Air
Atmospheric Half-life
1.6 hours (Estimated for hydroxyl radical
reaction assuming a 12-hour day and a
hydroxyl radical concentration of
L5xl0® OH/cm3)
EPI
Reactivity
Photolysis
Susceptible to direct photolysis, with a
reported UV absorption at 279 nm.
Partial absorption at environmental
wavelengths expected.
Lide and Milne, 1994; Professional
judgment
Qualitative assessment based on
functional groups.
Hydrolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain
functional groups that would be
expected to hydrolyze readily under
environmental conditions.
Pyrolysis
No data located.
Environmental Half-life
30 days
EPI, PBT Profiler
Half-life estimated for the
predominant compartment, as
determined by EPI and the PBT
Profiler methodology.
Bioaccumulation
LOW: The measured fish BCFs are <100.
Fish BCF
6.6 (25 (ig/L) (Measured);
11 (2.5 (ig/L) (Measured)
MITI, 1998
Adequate, guideline study.
BAF
28 (Estimated)
EPI
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Bisphenol F CASRN 620-92-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Metabolism in Fish
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
Detected in landfill leachates (Oman and Hynning, 1993).
Ecological Biomonitoring
No data located.
Human Biomonitoring
This chemical was not included in the NHANES biomonitoring report (CDC, 2011).
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Akahori, Y.; Makai, M.; Yamasaki, K.; et al. Relationship between the results of in vitro receptor binding assay to human estrogen
receptor a and in vivo uterotrophic assay: Comparative study with 65 selected chemicals. Toxicol. In vitro 2008, 22:225-231.
Blair, R.; Branham, W.; Hass, B.; et al. The estrogen receptor relative binding affinities of 188 natural and xenochemicals: Structural
diversity of ligands. Toxicol. Sci. 2000, 54:138-153.
Boethling, R.; Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences, Boca Raton:
Lewis Publishers. 2000.
Bruze, M. Sensitizing capacity of dihydroxydiphenyl methane (bisphenol F) in the guinea pig. Contact Dermatitis 1986, 14:228-232.
Cabaton, N.; Chagnon, M-C.; Lhuguenot, J-C.; et al. Disposition and metabolic profiling of bisphenol F in pregnant and nonpregnant
rats. J. Agj'ic. Food Chem. 2006, 54:10307-10314.
Cabaton, N.; Dumont, C.; Severin, I.; et al. Genotoxic and endocrine activities of bis(hydroxyphenyl)methane (bisphenol F) and its
derivatives in the HepG2 cell line. Toxicology 2009, 255:15-24.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
Chen, M-Y.; Michihiko, I.; Fujita, M. Acute toxicity, mutagenicity, and estrogenicity of bisphenol-A and other bisphenols. Environ.
Toxicol. 2002, 17:80-86.
Coleman, K.P., Toscano, W.A., Wiese, T.E. QSAR Models of the in vitro estrogen activity of bisphenol A analogs. QSAR &
Combinatorial Science 2003. 22:78-88.
Danzl, E.; Sei, K.; Soda, S., et al. Biodegradation of Bisphenol A, Bisphenol F and Bisphenol S in Seawater. Int. J. Environ. Res.
Public Health 2009, 6:1472-1484.
EINECS. 4,4"-Isopropylidenediphenol (bisphenol A). European Union Risk Assessment Report. 2010.
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EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 4.0. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
European Commission. IUCLID Dataset for 4,4-isopropylidenediphenol (CAS No. 80-05-7). European Chemicals Bureau, February
19, 2000. 2000.
FAO/WHO. Toxicological and health aspects of bisphenol A. Report of Joint FAO/WHO expert meeting 2-5 November 2010 and
report of stakeholder meeting on bisphenol A 1 November 2010. Food and Agriculture Organization of the United Nations; World
Health Organization. Ottawa, Canada. 2011.
Hansch, C.; Leo, A.; Hoekman, D. Exploring OSAR: Hydrophobic, electronic, andsteric constants. Washington, D.C.: American
Chemical Society. 1995.
Hashimoto, Y.; Nakamura, M. Estrogenic activity of dental materials and bisphenol-A related chemicals in vitro. Dent. Mater. J.
2000, 19(3):245-262.
Hashimoto, Y.; Moriguchi, Y.; Oshima, H.; et al. Measurement of estrogenic activity of chemicals for the development of new dental
polymers. Toxicol. In vitro 2001, 15:421-425.
Higashihara, N; Shiraishi, K.; Miyata, K.; et al. Subacute oral toxicity study of bisphenol F based on the draft protocol for the
"Enhanced OECD Test Guideline No. 407". Arch. Toxicol. 2007, 81:825-832.
Ike, M.; Chen, MY.; Danzl, E.; et al. Biodegradation of a variety of bisphenols under aerobic and anaerobic conditions. Water Sci.
Technol. 2006, 53:153-159.
Inoue, D.; Hara, S.; Kashihara, M.; et al. Degradation of Bis(4-Hydroxyphenyl)Methane (Bisphenol F) by Sphingobiumyanoikuyae
Strain FM-2 isolated from river water. Appl. Environ. Microbiol. 2008, 74(2):352-358.
Kitamura, S.; Suzuki, T.; Sanoh, S.; et al. Comparative study of the endocrine-disrupting activity of bisphenol A and 19 related
compounds. Toxicol. Sci. 2005, 84:249-259.
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Lide, D.R.; Milne, G.W.A. Handbook of data on organic compounds. Boca Raton: CRC Press. 1994.
Lide, D. R., ed. CRC Handbook of Chemistry and Physics, 88th edition, CRC Press: Boca Raton. 2008.
METI. Current status of testing methods development for endocrine disruptors. Ministry of Economy, Trade and Industry, Japan. 6th
meeting of the task force on Endocrine Disruptors Testing and Assessments (EDTA). 24-25 June, 2002. Tokyo. 2002.
Miller, D.; Wheals, B. B.; Beresford, N.; et al. Estrogenic activity of phenolic additives determined by an in vitro yeast bioassay.
Environ. Health Perspect. 2001, 109(2): 13 3 -13 8.
MITI. Bi ode gradation and bioaccumidation data of existing chemicals based on the CSCL Japan. Compiled under the supervision of
Chemical Products Safety Division, Basic Industries Bureau, Ministry of International Trade & Industry, Japan; Chemicals Inspection
& Testing Institute, Japan. Ed.; Japan Chemical Industry Ecology- Toxicology & Information Center: 1998. 1998.
NIOSH (National Institute for Occupational Safety and Health). Skin Notation (SK) Profile, bisphenol A (BPA) [CAS No. 80-05-7],
Department of Health and Human Services; Centers for Disease Control and Prevention, 2010.
NTP-CERHR. Monograph on the potential human reproductive and developmental effects ofbiphenolA. National Toxicology
Program; U.S. Department of Health and Human Service. Center for the Evaluation of Risks to Human Reproduction. NIH
Publication No. 08-5994. 2008.
Ogawa, Y.; Kawamura, Y.; Wakui, C.; et al. Estrogenic activities of chemicals related to food contact plastics and rubbers tested by
the yeast two-hybrid assay. FoodAddit. Contam. 2006, 23(4):422-430.
Oman, C. and Hynning, P-A.; Identification of organic compounds in municipal landfill leachates. Environ Pollut. 1993, 80: 265-271.
OncoLogic. U.S. EPA and LogiChem, Inc. 2005, Version 7.0. 2008.
PBT Profi 1 er Persistent (P),Bioaccumulative (B), and Toxic (T) Chemical (PBT)Profiler. U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
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Perez, P.; Pulgar, R.; Olea-Serrano, F.; et al. The estrogenicity of bisphenol A-related diphenylalkanes with various substituents at the
central carbon and the hydroxyl groups. Environ. Health Perspect. 1998, 106(3): 167-174.
Serjeant, E.; Dempsey, B. Ionisation constants of organic acids in aqueous solution. 1979, New York: Pergamon Press.
Smyth, H.F. Jr.; Carpenter, C.P.; Weil, C.S. Range-finding toxicity data: List VI. Am. Ind. Hyg. Assoc. J. 1962, 23:95-107.
Stroheker, T., Chagnon, M-C., Pinnert, M-F., et al. Estrogenic effects of food wrap packaging xenoestrogens and flavonoids in female
Wistarrats: a comparative study. Reprod. Toxicol. 2003, 17:421-432.
Stroheker, T., Picard, K., Lhuguenot, J., et al. Steroid activities comparison of natural and food wrap compounds in human breast
cancer cell lines. Food Chem. Toxicol. 2004,42:887-897.
Tsutsui, T.; Tamura, Y.; Suzuki, A.; et al. Mammalian cell transformation and aneuploidy induced by five bisphenols. Int. J. Cancer
2000, 86:151-154.
U.S. EPA Sustainable Futures Using NonCancer Screening within the Sustainable Futures Initiative Environmental Protection
Agency: Washington D.C. 2010. http://www.epa.gOv/opptintr/sf/pubs/noncan-screen.htm#svstemic (accessed on February 09, 2011).
Yamasaki, K.; Noda, S.; Imatanaka, N; et al. Comparative study of the uterotrophic potency of 14 chemicals in a uterotrophic assay
and their receptor-binding affinity. Toxicol. Lett. 2004, 146:111-120.
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Bisphenol C
CASRN: 79-97-0
MW: 256.35
MF: C17H20O2
Physical Forms:
Neat: Solid
Use: Developer for thermal paper
SMILES: Cclcc(cccl0)C(C)(C)c2ccc(c(c2)C)0
Synonyms: Phenol, 4,4'-(l-methylethylidene) bis[2-methyl- (TSCA Inventory); Bisphenol C; 2,2-Bis(3-methyl-4-hydroxyphenyl)propane; 2,2-Bis(3-methyl-
4-hydroxyphenyl)propane; 2,2-Bis(4-hydroxy-3-methylphenyl)propane; 2,2-Bis-(4-hydroxy-3-methylphenyl)propane; 3,3'-Dimethylbisphenol A; 3,3'-Dimethyldian;
4,4'-( 1 -Methylethylidene)bis(2-methylphenol); 4,4'-Isopropylidenebis(2-methylphenol); 4,4'-Isopropylidenebis[2-methylphenol]; 4,4'-isopropylidenedi-o-cresol
Polymeric: No
Oligomers: Not applicable
Metabolites, Degradates and Transformation Products: 4-hydroxy-3-methyl acetophenone, 4-hydroxy-3-methyl benzoic acid, and 2,2-bis[4-hydroxy-
3 -methylphenyl] -1 -propanol
Analog: Bisphenol A (80-05-7)
Endpoint(s) using analog values: Acute toxicity, reproductive,
developmental, repeated dose, skin sensitization, dermal irritation
Analog: Confidential analog (structure not available)
Endpoint(s) using analog values: eye irritation
Analog Structure:
Structural Alerts: Phenols, neurotoxicity (U.S. EPA, 2010)
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 2011).
Risk Assessments: None identified
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
138-140 (Measured)
Aldrich, 2009
Adequate; reported values that span a
relatively narrow range and are
consistent with those provided in
other sources.
140 (Measured)
Lide, 2008
Adequate.
Boiling Point (°C)
368 (Extrapolated from the reduced
boiling point reported by Aldrich, 2009)
Professional judgment
The boiling point at 760 mm Hg was
extrapolated from the measured
boiling point at reduced pressure
using a computerized nomograph.
238-240 at 12 mm Hg (Measured)
Aldrich, 2009
Inadequate; value obtained at a
reduced pressure.
Vapor Pressure (mm Hg)
2.3xl0"6 (Estimated from the reduced
boiling point reported by Aldrich, 2009)
Professional judgment
The vapor pressure was extrapolated
from the measured boiling point at
reduced pressure using a
computerized nomograph.
Water Solubility (mg/L)
4.7 (Estimated)
EPI
Log Kow
4.7 (Estimated)
EPI
Flammability (Flash Point)
No data located.
Explosivity
No data located.
pH
No data located.
pKa
10.5 (Estimated)
SPARC
HUMAN HEALTH EFFECTS
Toxicokinetics
Bisphenol C as a neat material is estimated to not be absorbed through the skin and have poor skin
absorption when in solution. Bisphenol C is expected to be absorbed via the lungs and gastrointestinal
tract.
Dermal Absorption in vitro
No data located.
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal or Inhaled
Not absorbed through the skin as neat
material and has poor absorption in
solution; can be absorbed through the
lung and gastrointestinal tract
(Estimated by analogy)
Professional judgment
Based on closely related analog with
similar structure, functional groups,
and physical/chemical properties.
Acute Mammalian Toxicity
LOW: Based on analogy to bisphenol A, the acute oral and dermal toxicity hazard of bisphenol C is
estimated to be low based on experimental data in animals for the analog. Data for exposure to the analog
bisphenol A via inhalation were inconclusive, as only a single concentration was tested and an LCS0 was not
provided.
Acute Lethality
Oral
Rat LD50 = 3,200->5,000 mg/kg bw
(Estimated by analogy)
NTP, 1982; European
Commission, 2000; EINECS,
2010; Professional judgment
Based on the analog bisphenol A;
multiple studies, some guideline
studies.
Mouse LD50 = 4,000-5,200 mg/kg bw
(Estimated by analogy)
NTP, 1982; European
Commission, 2000; EINECS,
2010; Professional judgment
Based on the analog bisphenol A;
multiple studies, some guideline
studies.
Dermal
Rabbit LD50 = 3,000-6,400 mg/kg bw
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
limited study details provided for
multiple studies reported in secondary
sources.
Inhalation
No deaths among male and female F344
rats (10/sex) exposed to bisphenol A dust
at 0.17 mg/L (highest attainable
concentration) for 6 hours; transient
slight nasal tract epithelial damage was
evident
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A; test
guidelines were not reported in
secondary sources.
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Carcinogenicity
MODERATE: Estimated using OncoLogic expert system which describes a concern for this compound as a
potential carcinogen or tumorigenesis promoter arising from its structural similarity to
estrogenic/androgenic compounds, using the Phenols and phenolic compounds structural alert.
OncoLogic Results
Moderate (Estimate)
OncoLogic class: Phenols and phenolic
compounds
OncoLogic
OncoLogic SAR analysis using the
phenols and phenolic compounds
class.
Carcinogenicity (Rat and
Mouse)
No data located.
Combined Chronic
T oxi city/Car cinogenicity
No data located.
Genotoxicity
MODERATE: Bisphenol C induced micronuclei in Chinese hamster V79 cells and human AG1522C
fibroblasts, but was not mutagenic in one assay of Salmonella typhimurium strain TA1335 either with or
without exogenous metabolic activity and did not induce chromosomal aberrations in Syrian hamster ovary
cells.
Gene Mutation in vitro
Negative, umu test in S. typhimurium
TA1335 with and without metabolic
activation
Chen et al., 2002
Adequate.
Negative, gene mutation tests at the
Na+/K+ ATPase locus and hprt locus of
Syrian hamster embryo (SHE) cells
Tsutsui et al., 2000
Adequate.
Gene Mutation in vivo
No data located.
Chromosomal Aberrations
in vitro
Negative, chromosomal aberrations in
SHE cells
Tsutsui et al., 2000
Adequate.
Positive; induction of micronuclei in
Chinese hamster V79 cells
Pfeiffer et al., 1997
Adequate.
Positive; induction of micronuclei in
human AG1522C fibroblasts
Lehmann and Metzler, 2004
Adequate.
Chromosomal Aberrations
in vivo
No data located.
DNA Damage and Repair
No data located.
Other
No data located.
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproductive Effects
HIGH: Estimated based on analogy to bisphenol A. Based on NOAELs of 4.75 mg/kg bw-day and 47.5
mg/kg bw-day for reproductive toxicity in male and female rats, respectively following oral exposure to the
analog bisphenol A. Conclusions of NTP-CERHR (2008) include sufficient evidence in rats and mice that
subchronic or chronic oral exposures to the analog bisphenol A causes female reproductive toxicity at doses
>475 mg/kg bw-day (highest NOAEL = 47.5 mg/kg-day) and male reproductive toxicity at doses >47.5mg/kg
bw-day (highest NOAEL = 4.75 mg/kg bw-day). There is considerable uncertainty regarding the results of
recent studies that reported reproductive and/or developmental effects in laboratory animals administered
the analog bisphenol A at oral doses <5 mg/kg bw-day.
Reproduction/
Developmental Toxicity
Screen
No data located.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Reproduction and Fertility
Effects
Potential for toxic effects to testes and
ovaries
(Estimated by analogy)
Professional judgment
Estimated based on located test data
for a confidential analog.
Potential for reproductive toxicity
(Estimated by analogy)
Professional judgment
Estimated based on reported
experimental data for the analog
bisphenol A.
Parental systemic toxicity:
NOAEL = 4.75 mg/kg bw-day
LOAEL = 47.5 mg/kg bw-day for 12%
decreased terminal body weight in Fi
parental males
Reproductive toxicity:
Females: NOAEL = 47.5 mg/kg bw-day
LOAEL = 475 mg/kg bw-day for
decreases in number of implantation
sites, delayed vaginal opening in Fi, F2,
F3 offspring
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
adequate, guideline study as reported
in the secondary source.
Classified by NTP-CERHR as having
High Utility.
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Males: NOAEL = 4.75 mg/kg bw-day,
LOAEL = 47.5 mg/kg-day for delayed
preputial separation in Fi males
(Estimated by analogy)
Parental systemic toxicity:
NOAEL = 5 mg/kg bw-day
LOAEL = 50 mg/kg bw-day for
increased incidences of centrilobular
hepatocellular hypertrophy in males and
females
NTP-CERHR, 2008; Professional
judgment
Based on the analog bisphenol A;
adequate, guideline study as reported
in the secondary source.
Classified by NTP-CERHR as having
High Utility.
Reproductive toxicity:
NOAEL = 50 mg/kg bw-day
LOAEL = 600 mg/kg bw-day for
increased gestation length, decreased
epididymal sperm concentration in Fi
males, increased incidence of gross
ovarian cysts in F, and F2 females
(Estimated by analogy)
Summary of Reproductive
effects
Female effects: There is sufficient
evidence in rats and mice that bisphenol
A causes female reproductive toxicity
with subchronic or chronic oral
exposures
NOAEL of 47.5mg/kg bw-day
LOAEL of 475 mg/kg bw-day.
Male effects: There is sufficient evidence
in rats and mice that bisphenol A causes
male reproductive toxicity with
subchronic or chronic oral exposures
NTP-CERHR, 2008; Professional
judgment
Based on the analog bisphenol A;
Classified by NTP-CERHR as having
High Utility.
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
NOAEL of 4.75mg/kg bw-day
LOAEL of 47.5mg/kg bw-day.
(Estimated by analogy)
The joint FAO/WHO Expert Panel
(2010) reviewed located reproductive
and developmental toxicity data for
bisphenol A as of November, 2010 and
noted that most regulatory bodies
reviewing the numerous studies on
bisphenol A have indicated an oral
reproductive and developmental NOAEL
of 50 mg/kg bw-day.
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
Classified by NTP-CERHR as having
High Utility.
(Estimated by analogy)
Developmental Effects
HIGH: Estimated based on analogy to bisphenol A. The NTP-CERHR (2008) Expert Panel concluded that
there is suggestive evidence that the analog bisphenol A causes neural and behavioral alterations related to
disruptions in normal sex differences in rats and mice (0.01-0.2 mg/kg bw-day). The FAO/WHO (2011)
Expert Panel concluded that while there was broad agreement in a NOAEL of 50 mg/kg bw-day for
developmental toxicity, low-level (<1 mg/kg bw-day) effects were uncertain. These conclusions support a
hazard designation of High concern of the analog, with lower confidence.
Reproduction/
Developmental Toxicity
Screen
No data located.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Summary of Developmental
Effects
Potential for developmental
neurotoxicity due to effects of thyroid
toxicity
(Estimated by analogy)
Professional judgment
Estimated based on located test data
for a confidential analog.
Potential for developmental toxicity
Professional judgment
Estimated based on reported
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
(Estimated by analogy)
experimental data for the analog
bisphenol A.
The NTP-CERHR (2008) Expert Panel
concluded that bisphenol A:
*Does not cause malformations or birth
defects in rats or mice at levels up to the
highest doses evaluated: 640 mg/kg-day
(rats) and 1,250 mg/kg bw-day (mice).
*Does not alter male or female fertility
after gestational exposure up to doses of
450 mg/kg bw-day in the rat and
600mg/kg bw-day in the mouse (highest
dose levels evaluated).
*Does not permanently affect prostate
weight at doses up to 475 mg/kg-day in
adult rats or 600 mg/kg-day in mice.
*Does not cause prostate cancer in rats or
mice after adult exposure at up to 148 or
600 mg/kg-day, respectively.
*Does change the age of puberty in male
or female rats at high doses (ca.
475 mg/kg-day).
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A.
And that rodent studies suggest that
bisphenol A:
* Causes neural and behavioral alterations
related to disruptions in normal sex
differences in rats and mice.
(0.01-0.2 mg/kg/day).
(Estimated by analogy)
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
The joint FAO/WHO Expert Panel
reviewed located reproductive and
developmental toxicity data for bisphenol
A as of November, 2010 and noted that
most regulatory bodies reviewing the
numerous studies on bisphenol A have
indicated an oral reproductive and
developmental NOAEL of 50 mg/kg bw-
day.
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
Neurotoxicity
MODERATE: Estimated to have potential for neurotoxicity based on the presence of the phenol structural
alert.
Neurotoxicity Screening
Battery (Adult)
There is potential for neurotoxicity
effects based on the presence of the
phenol structural alert
(Estimated)
U.S. EPA, 2010; Professional
judgment
Estimated based on structural alert.
Repeated Dose Effects
MODERATE: Estimated based on analogy to bisphenol A, which produced histopathologic changes in the
liver (centrilobular hepatocyte hypertrophy) from oral dosing at 50 mg/kg bw-day (NOAEL = 5 mg/kg bw-
day) and there is uncertainty regarding the potential for bisphenol A doses between the NOAEL of 5 mg/kg
bw-day and the LOAEL of 50 mg/kg bw-day to cause adverse systemic effects. Furthermore, lesions in the
nasal cavity of rats were reported following repeated inhalation exposure to bisphenol A dust at 0.05 mg/L.
These findings indicate a Moderate hazard potential for the oral and inhalation exposure routes.
Potential for liver toxicity
(Estimated by analogy)
Professional judgment
Estimated based on reported
experimental data for the analog
bisphenol A.
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
The FAO/WHO Expert Panel reviewed
the located information regarding
repeated-dose oral toxicity of bisphenol
A and concluded that results
demonstrated effects on the liver, kidney,
and body weight at doses of 50 mg/kg
bw-day and higher and that the lowest
NOAEL was 5 mg/kg-day, as identified
in several studies.
(Estimated by analogy)
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
Parental systemic toxicity:
NOAEL = 4.75 mg/kg bw-day
LOAEL = 47.5 mg/kg bw-day for 12%
decreased terminal body weight in F,
parental males
(Estimated by analogy)
NTP-CERHR, 2008; Professional
judgment
Based on the analog bisphenol A;
guideline study as reported in the
secondary source.
Classified by NTP-CERHR as having
High Utility.
Parental systemic toxicity:
NOAEL = 5 mg/kg bw-day
LOAEL = 50 mg/kg bw-day for
increased incidences of centrilobular
hepatocellular hypertrophy in males and
females
(Estimated by analogy)
NTP-CERHR, 2008; Professional
judgment
Based on the analog bisphenol A;
guideline study as reported in the
secondary source.
Classified by NTP-CERHR as having
High Utility.
NOAEL = 0.01 mg/L
LOAEL = 0.05 mg/L based on
microscopic changes in the anterior
portion of the nasal cavity
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A.
NOAEL = None established
European Commission, 2000;
Based on the analog bisphenol A;
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
LOAEL = 0.047 mg/L for decreased
body weight gain, increased liver and
kidney weight, unspecified
"morphological changes" in liver,
kidney, and lungs
EINECS, 2010; Professional
judgment
single exposure level, insufficient
study details in secondary sources.
(Estimated by analogy)
Skin Sensitization
MODERATE: Based on analogy to bisphenol A, bisphenol C is estimated to be a skin sensitizer. Recent
data from three bisphenol A manufacturing facilities indicate that it does not elicit skin sensitization;
however, results of some human studies suggest the possibility of a dermal sensitization response, although
cross-sensitization was not ruled out. Most animal studies conducted on the analog were negative for
dermal sensitization, although assays may not have been maximized. There is evidence of ear swelling in a
photoallergy test in mice and moderate redness and swelling following repeated dermal exposure in rabbits.
Based on suggestive evidence of skin sensitization in humans and mice for the analog, MODERATE hazard
designation is warranted.
Skin Sensitization
Potential for dermal sensitization
(Estimated by analogy)
Professional judgment
Estimated based on reported
experimental data for the analog
bisphenol A.
Negative in a modified local lymph node
assay of mice administered bisphenol A
epicutaneously on the ears at
concentrations up to 30% on three
consecutive days.
(Estimated by analogy)
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate, although the assay did not
include concentrations >30%.
Negative in a local lymph node assay
modified to test for photoreactivity in
mice administered bisphenol A
epicutaneously on the ears at
concentrations up to 30% on three
consecutive days and irradiated with UV
light immediately following application.
(Estimated by analogy)
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate, although the assay did not
include concentrations >30%.
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Negative in comprehensive medical
surveillance data obtained from three
bisphenol A manufacturing plants for
875 employees examined for several
years where workers were potentially
exposed to other chemicals (phenol,
acetone) that are not considered to be
skin sensitizers.
(Estimated by analogy)
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate.
Positive, rabbits; repeated dermal
application (30 times over 37 days) of
bisphenol A (pure powder) produced
moderate swelling and redness. Skin
turned yellow followed by dark
pigmentation after day 15.
(Estimated by analogy)
NIOSH, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate.
The Joint FAO/WHO Expert Meeting to
review toxicological aspects of bisphenol
A concurs with previous reviews that
bisphenol A is capable of producing a
skin sensitization response in humans.
(Estimated by analogy)
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A;
adequate.
Respiratory Sensitization
No data located.
Respiratory Sensitization
No data located.
Eye Irritation
HIGH: Based on analogy to a confidential analog, bisphenol C is estimated to potentially cause severe
irritation and corrosion to eyes.
Eye Irritation
Potential for severe irritation and
corrosion to eyes
(Estimated by analogy)
Professional judgment
Estimated based on located test data
for a confidential analog.
Dermal Irritation
MODERATE: Based on analogy to bisphenol A; bisphenol C is estimated to be slightly irritating to
moderately irritating to rabbit skin based on test data for the analog bisphenol A. NIOSH has assigned the
analog, bisphenol A, as a skin irritant.
Dermal Irritation
Rabbit, nonirritating to slightly irritating
European Commission, 2000;
Based on the analog bisphenol A;
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
when applied as undiluted or 10%
aqueous suspension to intact or abraded
skin
(Estimated by analogy)
EINECS, 2010; NIOSH, 2010;
Professional judgment
Adequate, study details provided for
multiple studies indicate potential for
bisphenol A to cause dermal irritation.
Rabbit, moderately irritating when
applied as 40% solution in dimethyl
sulfoxide under non-occlusive
conditions.
(Estimated by analogy)
European Commission, 2000;
Professional judgment
Based on the analog bisphenol A;
adequate.
Guinea pig, not irritating when applied as
5% solution in acetone for 24 hours
under occlusive conditions.
(Estimated by analogy)
European Commission, 2000;
Professional judgment
Based on the analog bisphenol A;
adequate.
Endocrine Activity
Based on limited in vitro data it appears that Bisphenol C exhibits endocrine activity. In vitro assays
demonstrate that bisphenol C can bind to estrogen receptors, elicit estrogen-induced gene transcription,
and induce cell proliferation in MCF7 cancer cells. In an ARE-luciferase reporter assay using a mouse
fibroblast cell line, bisphenol C did not elicit an androgenic response, but did inhibit the androgenic activity
of dihydrotestosterone. Data located indicate that the in vitro endocrine activity of bisphenol C is
approximately 3-5 orders of magnitude less than that of 17p-estradiol, suggesting that bisphenol C acts as a
weak estrogen. Limited comparative in vitro data suggest that the endocrine activity of bisphenol C is
similar in magnitude to that of bisphenol A, bisphenol AP, and bisphenol F and somewhat more potent than
bisphenol S. Bisphenol C elicited estrogenic and anti-estrogenic responses in a CARP-HEP/vitellogenin
assay.
Binding Assays
In a human ER binding assay, the
relative binding affinity (RBA) of
bisphenol C, was 0.129% compared to
126% for 17|3-estradiol. RBAs for other
bisphenol compounds included 0.195%
for bisphenol A, 0.0803% for bisphenol
AP, 0.0719% for bisphenol F, and
0.0055% for bisphenol S. An RBA of
0.00473% was reported for PHBB.
METI, 2002
Adequate.
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In a competitive ER binding assay using
human ERa, the RBA for bisphenol C
was 1.68% that of 17|3-estradiol. RBAs
for other bisphenol compounds included
0.32% for bisphenol A, 1.66% for
bisphenol AP, and 0.09% for bisphenol
F.
Coleman et al., 2003
Adequate.
Gene Transcription and Reporter
Gene Assays
Bisphenol C exhibited evidence of
estrogenic activity in a yeast
(Scicchciromyces cerevisicte) two-hybrid
assay using ERa and the coactivator
TIF2. Based on estrogenic activity that
was 5 orders of magnitude lower than
that of 17|3-estradiol, bisphenol C was
considered weakly estrogenic.
Assessment of other bisphenols resulted
in a ranking of relative potency as
follows: bisphenol C > bisphenol A >
bisphenol F > bisphenol S.
Chen et al., 2002
Adequate.
Bisphenol C did not exhibit evidence of
estrogenic activity in a yeast
0Scicchciromyces cerevisicte) two-hybrid
assay using ERa and the coactivator
TIF2.
Nishihara et al., 2000
Adequate.
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In a reporter gene assay of estrogen-
induced transcriptional activity, relative
activity (RA) for bisphenol C was
0.00189% compared to 81.7% for 17(3-
estradiol. RAs for other bisphenol
compounds included 0.00278% for
bisphenol A, 0.000639% for bisphenol F,
0.000254% for bisphenol S, and
0.000184% for bisphenol AP. An RA of
0.000592% was reported for PHBB.
METI, 2002
Adequate.
In an ERE-luciferase reporter assay
using MCF-7 cells, an EC50 was 0.42 (.iM
for bisphenol C compared to an EC50 of
8.6 x 10"6 for 17|3-estradiol (i.e.,
bisphenol A was approximately 5 orders
of magnitude less potent than 17|3-
estradiol at inducing estrogenic activity).
EC50 values for other bisphenol
compounds included 0.63 (.iM for
bisphenol A, 1.0 (.iM for bisphenol F,
and 1.1 (.iM for bisphenol S
Kitamura et al., 2005
Adequate.
In an ER-mediated reporter gene
expression assay, bisphenol C induced
reporter gene expression at a relative
activity (RA) of 4.9 x 10"4that of 17|3-
estradiol. RAs for other bisphenol
compounds included 5.3 x 10"4 for
bisphenol F, 9.0 x 10"5 for bisphenol AP,
and 2.75 x 10° for bisphenol A.
Coleman et al., 2003
Adequate.
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In an ERE-luciferase reporter assay
using MCF-7 cells in the presence of
17|3-estradiol, neither bisphenol C,
bisphenol A, bisphenol F, nor bisphenol
S appeared to exert an anti-estrogenic
effect
Kitamura et al., 2005
Adequate.
In a proliferation assay of MCF-7 human
breast cancer cells that contain ERa and
ER|3 and are known to proliferate in
response to estrogens, bisphenol C
induced a proliferative response that was
1.6xl0"3 that of 17|3-estradiol.
Respective proliferative responses for
other bisphenol compounds were
2.0xl0"3 for bisphenol A, 1.0x10° for
bisphenol F, and 6.0xl0"4 for bisphenol
AP.
Coleman et al., 2003
Adequate.
In an ERE-luciferase reporter assay
using MCF-7 cells in the presence of
17|3-estradiol, neither bisphenol C,
bisphenol A, bisphenol F, nor bisphenol
S appeared to exert an anti-estrogenic
effect
Kitamura et al., 2005
Adequate.
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Cell Proliferation Assays
In a proliferation assay of MCF-7 human
breast cancer cells that contain ERa and
ER|3 and are known to proliferate in
response to estrogens, bisphenol C
induced a proliferative response that was
1.6 x 10"3 that of 17|3-estradiol.
Respective proliferative responses for
other bisphenol compounds were 2.0
xl0° for bisphenol A, 1.0 x 10° for
bisphenol F, and 6.0 x 10"4 for bisphenol
AP.
Coleman et al., 2003
Adequate.
Androgen Assays
In an ARE-luciferase reporter assay
using a mouse fibroblast cell line
(NIH3T3 cells), neither bisphenol C,
bisphenol A, bisphenol F, nor bisphenol
S exerted an androgenic effect
Kitamura et al., 2005
Adequate.
In an ARE-luciferase reporter assay
using a mouse fibroblast cell line
(NIH3T3 cells), bisphenol C inhibited
the androgenic activity of
dihydrotestosterone. Anti-androgenic
responses were elicited by bisphenol A,
bisphenol F, and bisphenol S as well.
Kitamura et al., 2005
Adequate.
Thyroid Assays
In an assay of thyroid hormonal activity
whereby induction of growth hormone
production is assessed in GH3 cells,
neither bisphenol C nor bisphenol A
inhibited growth hormone production
Kitamura et al., 2005
Adequate.
Vitellogenin Assays
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In a CARP-HEP/vitellogenin assay,
bisphenol C and bisphenol A induced
vitellogenin production by up to 5 and
3%, respectively, of the vitellogenin
production elicited by 17|3-estradiol,
indicating an estrogenic effect. In 17|3-
estradiol-induced preparations, bisphenol
C inhibited vitellogenin production with
a potency approximately one-hundredth
that of the known estrogen antagonist
tamoxifen, indicating an anti-estrogenic
effect for bisphenol C.
Letcher et al., 2005
Adequate.
Immunotoxicity
No data located.
Immune System Effects
No data located.
ECOTOXICITY
ECOSAR Class
Polyphenols
Acute Toxicity
HIGH: Based on an experimental LCS0 value for Daphnid (1.6 mg/L) and estimated acute toxicity values.
Fish LC50
Fish 96-hour LC50 = 0.60 mg/L
(Estimated)
ECOSAR: polyphenols
EPI
Fish 96-hour LC50 = 0.95 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Daphnid LCS0
Daphnia magna 48-hour EC50 =
1.6 mg/L; 24-hour EC50 = 4 mg/L
(Experimental)
Chen et al., 2002
Adequate.
Daphnid 48-hour LC50 = 0.77 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid 48-hour LC50 = 0.85 mg/L
(Estimated)
ECOSAR: polyphenols
EPI
Green Algae ECS0
Green algae 96-hour EC50 = 1.02 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Green algae 96-hour EC50 = 1.25 mg/L
(Estimated)
ECOSAR: polyphenols
EPI
Chronic Aquatic Toxicity
HIGH: Estimated LCS0 values for fish (neutral organics) <0.1 mg/L. All other estimated LCS0 and ECS0
values for neutral organics and polyphenol classes fall within 0.1 and 1.0.
Fish ChV
Fish ChV = 0.09 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Fish ChV = 0.12 mg/L
(Estimated)
ECOSAR: polyphenols
EPI
Daphnid ChV
Daphnid ChV = 0.12 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid ChV = 0.27 mg/L
(Estimated)
ECOSAR: polyphenols
EPI
Green Algae ChV
Green algae ChV = 0.13 mg/L
(Estimated)
ECOSAR: polyphenols
EPI
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Green algae ChV = 0.61 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
ENVIRONMENTAL FATE
Transport
If released to air, a vapor pressure of 2.3xl0~6 mmHg at 25°C indicates that bisphenol C will exist in both
the vapor and particulate phases in the atmosphere. Particulate-phase bisphenol C will be removed from
the atmosphere by wet or dry deposition. If released to soil, bisphenol C is expected to have low mobility
based upon an estimated Koc of 100,000. Volatilization from water surfaces is not expected to be an
important fate process based upon this compound's estimated Henry's Law constant. Level III fugacity
model results, which utilized estimated values as the input parameters, indicate that bisphenol C will
partition primarily to soil and sediment.
Henry's Law Constant
(atm-m3/mole)
30,000 (Estimated)
EPI; U.S. EPA, 2011
Cutoff value for nonmobile
compounds according to SF
assessment guidance.
Level III Fugacity Model
Air = <1% (Estimated)
Water = 6%
Soil = 63%
Sediment = 31%
EPI
Persistence
MODERATE: Experimental studies indicate that bisphenol C may be removed from the environment by
aerobic biodegradation. Bisphenol C has a measured primary biodegradation half-life in water of less than
2 weeks in a TOC Handai river die away method. Ultimate biodegradation will take longer based on
experimental studies demonstrating 17% mineralization after 2 weeks (Ike, 2006). Although three
bisphenol C degradation intermediates have been identified (Sakai, 2007), the ultimate biodegradation data
indicate that they do not persist in the environment. Bisphenol C lacks functional groups susceptible to
hydrolysis and so hydrolysis is not an expected removal process. In addition, photolysis and anaerobic
biodegradation have not been reported for bisphenol C.
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Water
Aerobic Biodegradation
17% in 2 weeks (complete degradation)
(Measured)
Ike, 2006
Adequate; valid nonguideline study
demonstrating river water
microcosms have the potential to
biodegrade bisphenol C.
58% in 2 weeks; % removal in a
microcosm study (partial degradation)
(Measured)
Ike, 2006
Supporting information presented;
nonguideline study.
94% in four days by Sphingomoncts sp.
Strain BP-7 (degradation intermediates
detected)
(Measured)
Sakai, 2007
Adequate; valid nonguideline study
using a pure culture innoculum
supporting the potential for aerobic
biodegradation.
Degradation products 4-hydroxy-
3-methyl acetophenone, 4-hydroxy-
3-methyl benzoic acid, and
2,2-bis[4-hydroxy-3-methylphenyl]-
1-propanol identified; no biodegradation
rate information included
(Measured)
Lobos, 1992
Adequate, nonguideline study that
provides supporting information on
environmental persistence.
Volatilization Half-life for
Model River
>1 year (Estimated)
EPI
Volatilization Half-life for
Model Lake
>1 year (Estimated)
EPI
Soil
Aerobic Biodegradation
No data located.
Anaerobic
Biodegradation
Not probable (anaerobic-methanogenic
biodegradation probability model)
EPI
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
Biodegradation
No data located.
Air
Atmospheric Half-life
1.3 hours (Estimated)
EPI
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Bisphenol C CASRN 79-97-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reactivity
Photolysis
Not a significant fate process
(Estimated)
Boethling and Mackay, 2000;
Professional judgment
The substance does not contain
functional groups that would be
expected to absorb light at
environmentally significant
wavelengths.
Hydrolysis
Not a significant fate process
(Estimated)
Boethling and Mackay, 2000;
Professional judgment
The substance does not contain
functional groups that would be
expected to hydrolyze readily under
environmental conditions.
Pyrolysis
No data located.
Environmental Half-life
75 days (Estimated)
EPI; PBT Profiler
Half-life estimated for the
predominant compartment, as
determined by EPI and the PBT
Profiler methodology.
Bioaccumulation
MODERATE: The estimated fish BCF is <1,000.
Fish BCF
620 (Estimated)
EPI
BAF
110 (Estimated)
EPI
Metabolism in Fish
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
Ecological Biomonitoring
No data located.
Human Biomonitoring
This chemical was not included in the NHANES biomonitoring report (CDC, 2011).
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Aldrich. Handbook of Fine Chemicals and Laboratory Equipment. 2009-2010. Milwaukee, WI: Aldrich Chem Co. 2009, p.344.
Boethling, R., Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences. Boca Raton:
Lewis Publishers. 2000.
Chen, M-Y.; Michihiko, I.; Fujita, M. Acute toxicity, mutagenicity, and estrogenicity of bisphenol-A and other bisphenols. Environ.
Toxicol. 2002, 17:80-86.
Coleman, K.P., Toscano, W.A., Wiese, T.E. QSAR Models of the in vitro estrogen activity of bisphenol A analogs. QSAR &
Combinatorial Science 2003. 22:78-88.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
EINECS. 4,4"-Isopropylidenediphenol (bisphenol A). European Union Risk Assessment Report. 2010.
EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 4.00. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
European Commission. IUCLID Dataset for 4,4-isopropylidenediphenol (CAS No. 80-05-7). European Chemicals Bureau, February
19, 2000. 2000.
FAO/WHO. Toxicological and health aspects of bisphenol A. Report of Joint FAO/WHO expert meeting 2-5 November 2010 and
report of stakeholder meeting on bisphenol A 1 November 2010. Food and Agriculture Organization of the United Nations; World
Health Organization. Ottawa, Canada. 2011.
Ike, M.; Chen, M.Y.; Danzl, E.; et al. Biodegradation of a variety of bisphenols under aerobic and anaerobic conditions. Water Sci.
Technol. 2006, 53:153-159.
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Kitamura, S.; Suzuki, T.; Sanoh, S.; et al. Comparative study of the endocrine-disrupting activity of bisphenol A and 19 related
compounds. Toxicol. Sci. 2005, 84:249-259.
Lehmann L., Metzler M. Bisphenol A and its methylated congeners inhibit growth and interfere with microtubules in human
fibroblasts in vitro. Chem. Biol. Interact. 2004, 147:273-285.
Letcher, R. J., Sanderson, J.T., Bokkers, A., et al. Effects of bisphenol A-related diphenylalkanes on vitellogenin production in male
carp (Cyprinus carpio) hepatocytes and aromatase (CYP19) activity in human H295R adrenocortical carcinoma cells. Toxicol. Appl.
Pharmacol. 2005, 209:95-104.
Lide, D. R, ed. CRC Handbook of Chemistry and Physics, 88th edition; CRC Press Taylor Francis: Boca Raton, FL. 2008.
Lobos, J., Leib, T., Su, T. Biodegradation of Bisphenol A and Other Bisphenols by a Gram-Negative Aerobic Bacterium. Appl.
Environ. Microbiol. 1992, 58(6): 1823-1831.
METI. Current status of testing methods development for endocrine disruptors. 2002, Ministry of Economy, Trade and Industry,
Japan. 6th meeting of the task force on Endocrine Disruptors Testing and Assessments (EDTA). 24-25 June, 2002. Tokyo.
NIOSH (National Institute for Occupational Safety and Health). Skin notation (SK) profile, bisphenol A (BPA) [CAS No. 80-05-7],
Department of Health and Human Services; Centers for Disease Control and Prevention, 2010.
Nishihara, T.; Nishikawa, J.; Kanayama, T.; et al. Estrogenic activities of 517 chemicals by yeast two-hybrid assay. J. Health Sci.
2000, 46(4) 282-298.
NTP (National Toxicology Program). Carcinogenesis bioassay of bisphenol-A (CAS No. 80-05-7) in F344 rats and B6C3F1 mice
(feed study). Technical Report No. 215, PB82-184060. 1982.
NTP-CERHR. Monograph on the potential human reproductive and developmental effects of biphenol A. National Toxicology
Program; U.S. Department of Health and Human Service. Center for the Evaluation of Risks to Human Reproduction. NIH
Publication No. 08-5994. September 2008.
Oncologic. U.S. EPA and LogiChem, Inc. 2005, Version 7.0. 2008.
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PBT Profiler Persistent (P),Bioaccumulative (B), and Toxic (T) Chemical (PBT)Profiler, U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
Perez, P., Pulgar, R., Olea-Serrano, F., et al. The estrogenicity of bisphenol A-related diphenylalkanes with various substituents at the
central carbon and the hydroxyl groups. Environ. Health Perspect. 1998, 106(3): 167-174.
Pfeiffer, E., Rosenberg, B., Deuschel, S., et al. Interference with microtubules and induction of micronuclei in vitro by various
bisphenols. Mutat. Res. 1997, 390:21-31.
Sakai, K., Yamanaka, H., Moriyoshi, K, et al. Biodegradation of bisphenol A and related compounds by Sphingomonas sp. strain BP-7
isolated from seawater. Biosci. Biotechnol. Biochem. 2007, 71(1):51-57.
SPARC On Line Calculator pKaproperty server. Ver 4.5 September, 2009. Available from, http://ibmlc2.chem.uga.edu/sparc/
(accessed on August 12, 2010).
Tsutsui, T., Tamura, Y., Suzuki, A., et al. Mammalian cell transformation and aneuploidy induced by five bisphenols. Int. J. Cane.
2000, 86:151-154.
U.S. EPA Sustainable Futures Using NonCancer Screening within the Sustainable Futures Initiative Environmental Protection
Agency: Washington D.C. 2010. http://www.epa.gOv/opptintr/sf/pubs/noncan-screen.htm#svstemic (accessed on February 09, 2011).
U.S. EPA (Environmental Protection Agency). Sustainable Futures Summary Assessment. Assessment of Discrete Organic
Chemicals. U.S. Environmental Protection Agency: Washington D.C. 2011.
http://www.epa.gov/oppt/sf/pubs/iad_discretes_092011 .pdf
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MBHA
Cu „0.
HO'
CASRN 5129-00-0
MW: 258.28
MF: C15H1404
Physical Forms:
Neat: Solid
Use: Developer for thermal paper
SMILES: 0=C(0C)C(c(ccc(0)c 1 )c 1 )c(ccc(0)c2)c2
Synonyms: Benzeneacetic acid, 4-hydroxy-.alpha.-(4-hydroxyphenyl)-, methyl ester (TSCA Inventory); Methyl bis(4-hydroxyphenyl)acetate
Polymeric: No
Oligomers: Not applicable
Metabolites, Degradates and Transformation Products: None identified
Analog: Bisphenol A (80-05-7)
Endpoint(s) using analog values: Acute toxicity, reproductive,
developmental, repeated dose, skin and eye irritation, genotoxicity
Analog Structure:
Structural Alerts: Phenols, neurotoxicity (U.S. EPA, 2010)
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 2011).
Risk Assessments: None identified
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MBHA CASRN 5129-00-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
No data located.
Boiling Point (°C)
>300 (Estimated)
EPI; U.S. EPA, 1999
Cutoff value for high boiling point
compounds according to HPV
assessment guidance.
Vapor Pressure (mm Hg)
3.3x10 s (Estimated)
EPI
Water Solubility (mg/L)
360 (Estimated)
EPI
Log Kow
2.8 (Estimated)
EPI
Flammability (Flash Point)
No data located.
Explosivity
No data located.
pH
No data located.
pKa
9.7-9.9 (Estimated)
SPARC
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MBHA CASRN 5129-00-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
HUMAN HEALTH EFFECTS
Toxicokinetics
MBHA as a neat material is estimated to not be absorbed through the skin and will have poor skin
absorption when in solution. MBHA is expected to be absorbed via the lungs and gastrointestinal tract. It is
expected that MBHA will undergo ester hydrolysis by esterases in the body.
Dermal Absorption in vitro
No data located.
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal or Inhaled
Not absorbed through the skin as neat
material and has poor absorption in
solution; can be absorbed through the lung
and gastrointestinal tract
(Estimated by analogy)
Professional judgment
Based on closely related analog with
similar structure, functional groups,
and physical/chemical properties.
Acute Mammalian Toxicity
LOW: Based on analogy to bisphenol A. The acute oral and dermal toxicity hazard of MBHA is estimated
to be low based on experimental data in animals for a closely related substance. Data for exposure to the
analog bisphenol A via inhalation were inconclusive, as only a single concentration was tested and an LCS0
was not provided.
Acute Lethality
Oral
Rat LD50 = 3,200->5,000 mg/kg bw
(Estimated by analogy)
NTP, 1982; European
Commission, 2000; EINECS,
2010; Professional judgment
Based on the analog bisphenol A;
multiple studies, some guideline
studies.
Mouse LD50 = 4,000-5,200 mg/kg bw
(Estimated by analogy)
NTP, 1982; European
Commission, 2000; EINECS,
2010; Professional judgment
Based on the analog bisphenol A;
multiple studies, some guideline
studies.
Dermal
Rabbit LD50 = 3,000-6,400 mg/kg bw
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate by weight of evidence,
multiple studies, although study
details were not reported in
secondary sources.
Inhalation
No deaths among male and female F344
rats (10/sex) exposed to bisphenol A dust
at 0.17 mg/L (highest attainable
concentration) for 6 hours; transient slight
nasal tract epithelial damage was evident
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A; test
guidelines were not reported in
secondary sources.
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MBHA CASRN 5129-00-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Carcinogenicity
MODERATE: Estimated using OncoLogic expert system which describes a concern for this compound as a
potential carcinogen or tumorigenesis promoter arising from its structural similarity to
estrogenic/androgenic compounds, using the 'phenols and phenolic compounds' structural alert.
OncoLogic Results
Moderate (Estimate)
OncoLogic class: phenols and phenolic
compounds
OncoLogic
OncoLogic SAR analysis using the
phenols and phenolic compounds
class.
Carcinogenicity (Rat and
Mouse)
No data located.
Combined Chronic
T oxi city/Car cinogenicity
No data located.
Genotoxicity
LOW: Based on analogy to bisphenol A. FAO/WHO (2011) determined that: (1) the analog bisphenol A is
not a mutagen in in vitro test systems, (2) the analog bisphenol A does not induce cell transformation, and (3)
in vivo evidence for clastogenic effects induced by the analog bisphenol A is inconsistent and inconclusive,
although some in vitro studies have shown bisphenol A to affect chromosomal structure in dividing cells. The
conclusion of FAO/WHO (2011) is that the analog bisphenol A is not likely to pose a genotoxic hazard to
humans.
Potential for mutagenicity
(Estimated by analogy)
Professional judgment
Estimated based on reported
experimental data for the analog
bisphenol A.
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MBHA CASRN 5129-00-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Largely negative results in a variety of in
vitro test systems, including studies with
Salmonella typhimurium, Chinese hamster
V79 cells, Syrian hamster embryo cells
and mouse lymphoma cells. However,
DNA damage was induced in MCF-7 and
MDA-MB-231 cells, DNA adduct
formation in Syrian hamster ovary cells
and a number of positive findings have
been reported for the potential for
bisphenol A to inhibit purified microtubule
polymerization, affect the spindle
apparatus and produce aneuploidy in in
vitro studies with Chinese hamster V79
cells or oocytes from Balb/c or MF1 mice.
FAO/WHO, 2011
Based on the analog bisphenol A.
FAO/WHO Expert Panel concludes:
bisphenol A is not a mutagen in in vitro
test systems, nor does it induce cell
transformation. Bisphenol A has been
shown to affect chromosomal structure in
dividing cells in in vitro studies, but
evidence for this effect in in vivo studies is
inconsistent and inconclusive. Bisphenol
A is not likely to pose a genotoxic hazard
to humans.
(Estimated by analogy)
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MBHA CASRN 5129-00-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproductive Effects
HIGH: Based on analogy to bisphenol A. Based on NOAELs of 4.75 mg/kg bw-day and 47.5 mg/kg bw-day
for reproductive toxicity in male and female rats, respectively, following oral exposure to the analog
bisphenol A. Conclusions of NTP-CERHR (2008) include sufficient evidence in rats and mice that
subchronic or chronic oral exposures to the analog bisphenol A causes female reproductive toxicity at doses
>475 mg/kg bw-day (highest NOAEL = 47.5 mg/kg-day) and male reproductive toxicity at doses >47.5mg/kg
bw-day (highest NOAEL = 4.75 mg/kg bw-day). There is considerable uncertainty regarding the results of
recent studies that reported reproductive and/or developmental effects in laboratory animals administered
the analog BPA at oral doses <5 mg/kg bw-day.
Reproduction/
Developmental Toxicity
Screen
No data located.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
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MBHA CASRN 5129-00-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproduction and Fertility
Effects
Potential for reproductive toxicity
(Estimated by analogy)
Professional judgment
Estimated based on reported
experimental data for the analog
bisphenol A.
Parental systemic toxicity:
NOAEL = 4.75 mg/kg bw-day
LOAEL = 47.5 mg/kg bw-day for 12%
decreased terminal body weight in F,
parental males
Reproductive toxicity:
Females: NOAEL = 47.5 mg/kg bw-day
LOAEL = 475 mg/kg bw-day for
decreases in number of implantation sites,
delayed vaginal opening in Fi, F2, and F3
offspring
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
adequate, guideline study as reported
in the secondary source.
Classified by NTP-CERHR as having
High Utility.
Males: NOAEL = 4.75 mg/kg bw-day,
LOAEL = 47.5 mg/kg bw-day for delayed
preputial separation in F, males
(Estimated by analogy)
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MBHA CASRN 5129-00-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Parental systemic toxicity:
NOAEL = 5 mg/kg bw-day
LOAEL = 50 mg/kg bw-day for increased
incidences of centrilobular hepatocellular
hypertrophy in males and females
Reproductive toxicity:
NOAEL = 50 mg/kg bw-day
LOAEL = 600 mg/kg bw-day for
increased gestation length, decreased
epididymal sperm concentration in Fi
males, increased incidence of gross
ovarian cysts in F, and F2 females
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
adequate, guideline study as reported
in the secondary source.
Classified by NTP-CERHR as having
High Utility.
(Estimated by analogy)
Summary of Reproductive
Effects
Female effects: There is sufficient
evidence in rats and mice that bisphenol A
causes female reproductive toxicity with
subchronic or chronic oral exposures
NOAEL of 47.5 mg/kg bw-day
LOAEL of 475 mg/kg bw-day
Male effects: There is sufficient evidence
in rats and mice that bisphenol A causes
male reproductive toxicity with subchronic
or chronic oral exposures
NOAEL of 4.75mg/kg bw-day
LOAEL of 47.5mg/kg bw/day
(Estimated by analogy)
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A.
Classified by NTP-CERHR as having
High Utility.
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MBHA CASRN 5129-00-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
The joint FAO/WHO Expert Panel (2011)
reviewed available reproductive and
developmental toxicity data for bisphenol
A as of November, 2010 and noted that
most regulatory bodies reviewing the
numerous studies on bisphenol A have
indicated an oral reproductive and
developmental NOAEL of 50 mg/kg bw-
day.
FAO/WHO, 2011; NTP-CERHR
2008; Professional judgment
Based on the analog bisphenol A.
Classified by NTP-CERHR as having
High Utility.
(Estimated by analogy)
Developmental Effects
HIGH: Based on analogy to bisphenol A. The NTP-CERHR (2008) Expert Panel concluded that there is
suggestive evidence that the analog bisphenol A causes neural and behavioral alterations related to
disruptions in normal sex differences in rats and mice (0.01-0.2 mg/kg bw-day). The FAO/WHO (2011)
Expert Panel concluded that while there was broad agreement in a NOAEL of 50 mg/kg bw-day for
developmental toxicity, low level (<1 mg/kg bw-day) effects were uncertain. These conclusions support a call
of High concern of the analog, with lower confidence.
Reproduction/
Developmental Toxicity
Screen
No data located.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Summary of
Developmental Effects
Potential for developmental toxicity
(Estimated by analogy)
Professional judgment
Estimated based on reported
experimental data for the analog
bisphenol A.
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MBHA CASRN 5129-00-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
The NTP-CERHR (2008) Expert Panel
concluded that bisphenol A:
*does not cause malformations or birth
defects in rats or mice at levels up to the
highest doses evaluated: 640 mg/kg bw-
day (rats) and 1,250 mg/kg bw-day (mice).
*does not alter male or female fertility
after gestational exposure up to doses of
450 mg/kg bw-day in the rat and
600mg/kg bw-day in the mouse (highest
dose levels evaluated).
*does not permanently affect prostate
weight at doses up to 475 mg/kg bw-day in
adult rats or 600 mg/kg bw-day in mice.
*does not cause prostate cancer in rats or
mice after adult exposure at up to 148 or
600 mg/kg bw-day, respectively.
*does change the age of puberty in male or
female rats at high doses (ca. 475 mg/kg
bw-day).
And that rodent studies suggest that
bisphenol A:
* causes neural and behavioral alterations
related to disruptions in normal sex
differences in rats and mice. (0.01-
0.2 mg/kg bw-day).
(Estimated by analogy)
NTP-CERHR, 2008; Professional
judgment
Based on the analog bisphenol A.
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MBHA CASRN 5129-00-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
The joint FAO/WHO (2011) Expert Panel
reviewed available reproductive and
developmental toxicity data for bisphenol
A as of November, 2010 and noted that
most regulatory bodies reviewing the
numerous studies on bisphenol A have
indicated an oral reproductive and
developmental NOAEL of 50 mg/kg bw-
day.
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
(Estimated by analogy)
Neurotoxicity
MODERATE: Estimated to have potential for neurotoxicity based on the presence of the phenol structural
alert.
Neurotoxicity Screening
Battery (Adult)
There is potential for neurotoxicity effects
based on the presence of the phenol
structural alert
(Estimated)
U.S. EPA, 2010; Professional
judgment
Estimated based on structural alert.
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MBHA CASRN 5129-00-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Repeated Dose Effects
MODERATE: Estimated based on analogy to bisphenol A, which produced histopathologic changes in the
liver (centrilobular hepatocyte hypertrophy) from oral dosing at 50 mg/kg bw-day (NOAEL = 5 mg/kg bw-
day) and there is uncertainty regarding the potential for bisphenol A doses between the NOAEL of 5 mg/kg
bw-day and the LOAEL of 50 mg/kg bw-day to cause adverse systemic effects. Furthermore, lesions in the
nasal cavity of rats were reported following repeated inhalation exposure to bisphenol A dust at 0.05 mg/L.
These findings indicate a Moderate hazard concern for the oral and inhalation exposure routes.
Potential for liver toxicity
(Estimated by analogy)
Professional judgment
Estimated based on reported
experimental data for the analog
bisphenol A.
The FAO/WHO (2011) Expert Panel
reviewed the available information
regarding repeated-dose oral toxicity of
bisphenol A and concluded that results
demonstrated effects on the liver, kidney,
and body weight at doses of 50 mg/kg bw-
day and higher and that the lowest
NOAEL was 5 mg/kg-day, as identified in
several studies.
(Estimated by analogy)
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
Parental systemic toxicity:
NOAEL = 4.75 mg/kg bw-day
LOAEL = 47.5 mg/kg bw-day for 12%
decreased terminal body weight in F,
parental males
(Estimated by analogy)
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
guideline study as reported in the
secondary source.
Classified by NTP-CERHR as having
High Utility.
Parental systemic toxicity:
NOAEL = 5 mg/kg bw-day
LOAEL = 50 mg/kg bw-day for increased
incidences of centrilobular hepatocellular
hypertrophy in males and females
(Estimated by analogy)
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
guideline study as reported in the
secondary source.
Classified by NTP-CERHR as having
High Utility.
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MBHA CASRN 5129-00-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
NOAEL = 0.01 mg/L
LOAEL = 0.05 mg/L based on
microscopic changes in the anterior
portion of the nasal cavity
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A.
(Estimated by analogy)
NOAEL = None established
LOAEL = 0.047 mg/L for decreased body
weight gain, increased liver and kidney
weight, unspecified "morphological
changes" in liver, kidney, and lungs
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
single exposure level, insufficient
study details in secondary sources.
(Estimated by analogy)
Skin Sensitization
LOW: Based on experimental data, MBHA is not a skin sensitizer in guinea pigs.
Skin Sensitization
Not a skin sensitizer in maximization
assay in guinea pigs
Kawaguchi Chemical Co., 2011
Conducted according to OECD
guideline 406.
Respiratory Sensitization
No data located.
Respiratory Sensitization
No data located.
Eye Irritation
MODERATE: Based on analogy to bisphenol A. The analog bisphenol A was slightly to highly irritating to
rabbit eyes.
Eye Irritation
Rabbit, slightly to highly irritating
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A.
Adequate; multiple studies, weight of
evidence indicates potential for
bisphenol A to cause eye irritation.
Dermal Irritation
MODERATE: Based on analogy to bisphenol A. The analog bisphenol A was slightly irritating to
moderately irritating to rabbit skin. NIOSH has assigned the analog, bisphenol A as a skin irritant.
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MBHA CASRN 5129-00-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Dermal Irritation
Rabbit, nonirritating to slightly irritating
when applied as undiluted or 10% aqueous
suspension to intact or abraded skin
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; NIOSH 2010;
Professional judgment
Based on the analog bisphenol A.
Adequate; multiple studies, weight of
evidence indicates potential for
bisphenol A to cause dermal irritation.
Rabbit, moderately irritating when applied
as 40% solution in dimethyl sulfoxide
under non-occlusive conditions
(Estimated by analogy)
European Commission, 2000;
Professional judgment
Based on the analog bisphenol A;
adequate.
Guinea pig, not irritating when applied as
5% solution in acetone for 24 hours under
occlusive conditions
(Estimated by analogy)
European Commission, 2000;
Professional judgment
Based on the analog bisphenol A;
adequate.
Endocrine Activity
No data located.
No data located.
Immunotoxicity
No data located.
Immune System Effects
No data located.
ECOTOXICITY
ECOSAR Class
Polyphenols, esters
Acute Toxicity
HIGH: Estimated 96-hour LCS0 for fish and 96-hour ECS0 for algae are in the range of 1-10 mg/L.
Fish LC50
Fish 96-hour LC50 = 8.80 mg/L
(Estimated)
ECOSAR: polyphenols
EPI
Fish 96-hour LC50 =13.0 mg/L
(Estimated)
ECOSAR: esters
EPI
Fish 96-hour LC50 = 45.72 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
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MBHA CASRN 5129-00-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Daphnid LCS0
Daphnid 48-hour LC50 = 24.24 mg/L
(Estimated)
ECOSAR: esters
EPI
Daphnid 48-hour LC50 = 28.52 mg/L
(Estimated)
ECOSAR: polyphenols
EPI
Daphnid 48-hour LC50 = 28.9 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Saltwater Invertebrate LCS0
Mysid shrimp 96-hour LC50 = 12.60 mg/L
(Estimated)
ECOSAR: esters
EPI
Green Algae ECS0
Green algae 96-hour EC50 = 1.88 mg/L
(Estimated)
ECOSAR: polyphenols
EPI
Green algae 96-hour EC50 = 9.53 mg/L
(Estimated)
ECOSAR: esters
EPI
Green algae 96-hour EC50 = 16.98 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Chronic Aquatic Toxicity
HIGH: Estimated ChV for fish and ChV for algae are in the range of 0.1-1.0 mg/L.
Fish ChV
Fish 32/33-day ChV = 0.97 mg/L
(Estimated)
ECOSAR: esters
EPI
Fish 30-day ChV = 2.41 mg/L
(Estimated)
ECOSAR: polyphenols
EPI
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MBHA CASRN 5129-00-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Fish ChV = 4.27 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid ChV
Daphnid ChV = 3.050 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid 21-day ChV = 12.60 mg/L
(Estimated)
ECOSAR: esters
EPI
Daphnid 21-day ChV = 10.19 mg/L
(Estimated)
ECOSAR: polyphenols
EPI
Saltwater Invertebrate ChV
Mysid shrimp ChV = 194.76 mg/L
(Estimated)
ECOSAR: esters
EPI
Green Algae ChV
Green algae ChV = 0.450 mg/L
(Estimated)
ECOSAR: polyphenols
EPI
Green algae ChV = 3.07 mg/L
(Estimated)
ECOSAR: esters
EPI
Green algae ChV = 7.05 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Earthworm Subchronic Toxicity
Earthworm 14-day LC50 = 1,922.81 mg/L
(Estimated)
ECOSAR: esters
(MBHA may not be soluble enough to
measure this predicted effect)
EPI
ENVIRONMENTAL FATE
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MBHA CASRN 5129-00-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Transport
MBHA is expected to partition primarily to soil based on results from a level III fugacity model
incorporating estimated property data. Based on its estimated pKa, it is expected to exist primarily in the
neutral form at environmentally-relevant pH, but anionic forms may be present at the upper-range of
environmental pH. The neutral form of MBHA is expected to be moderately mobile in soil based on its
estimated Koc. The anionic form may have higher mobility, as anions do not bind as strongly to organic
carbon and clay. However, leaching of MBHA through soil to groundwater is not expected to be an
important transport mechanism. In the atmosphere, MBHA is expected to exist in the particulate phase,
based on its estimated vapor pressure. Particulates will be removed from air by wet or dry deposition. If
released to soil, MBHA is expected to bind strongly to soils with minimal migration to subsurface depths. It
is not expected to migrate from water or soil surfaces to air. Release of particulates to the atmosphere will
result in deposition to soil and water surfaces.
Henry's Law Constant
(atm-m3/mole)
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MBHA CASRN 5129-00-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Water
Aerobic
Biodegradation
Days-weeks (primary survey model)
Weeks (ultimate survey model)
EPI
Volatilization Half-life
for Model River
>1 year (Estimated)
EPI
Volatilization Half-life
for Model Lake
>1 year (Estimated)
EPI
Soil
Aerobic
Biodegradation
No data located.
Anaerobic
Biodegradation
Not probable (anaerobic-methanogenic
biodegradation probability model)
EPI
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
Biodegradation
No data located.
Air
Atmospheric Half-life
1.6 hours (Estimated)
EPI
Reactivity
Photolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
The substance does not contain
functional groups that would be
expected to absorb light at
wavelengths >290 nm.
Hydrolysis
Half-life at pH 8 = 200 days (Estimated)
Half-life at pH 7 >1 year (Estimated)
EPI
Pyrolysis
No data located.
Environmental Half-life
30 days
EPI, PBT Profiler
Half-life estimated for the
predominant compartment, as
determined by EPI and the PBT
Profiler methodology.
Bioaccumulation
LOW: The estimated BCF is <100.
Fish BCF
31 (Estimated)
EPI
BAF
6 (Estimated)
EPI
Metabolism in Fish
No data located.
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MBHA CASRN 5129-00-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
Ecological Biomonitoring
No data located.
Human Biomonitoring
This chemical was not included in the NHANES biomonitoring report (CDC, 2011).
4-159
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Boethling, R., Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences. Boca Raton:
Lewis Publishers. 2000.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
EINECS (European Inventory of Existing Commercial Chemical Substances). 4,4"-Isopropylidenediphenol (bisphenol A). European
Union Risk Assessment Report. 2010.
EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 4.00. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
European Commission. IUCLID Dataset for 4,4-isopropylidenediphenol (CAS No. 80-05-7). European Chemicals Bureau, February
19, 2000. 2000.
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
FAO/WHO. Toxicological and health aspects of bisphenol A. Report of Joint FAO/WHO expert meeting 2-5 November 2010 and
report of stakeholder meeting on bisphenol A 1 November 2010. Food and Agriculture Organization of the United Nations; World
Health Organization. Ottawa, Canada. 2011.
Kawaguchi Chemical Co. Skin sensitization test of MBHA in guinea pigs (maximization test). Study No. STG045. Sumika
Technoservice corporation, Osaka, Japan. 2011.
NIOSH (National Institute for Occupational Safety and Health). Skin Notation (SK) Profile, Bisphenol A (BPA) [CAS No. 80-05-7],
Department of Health and Human Services; Centers for Disease Control and Prevention. 2010.
NTP-CERHR. Monograph on the potential human reproductive and developmental effects of biphenol A. National Toxicology
Program; U.S. Department of Health and Human Service. Center for the Evaluation of Risks to Human Reproduction. NIH
Publication No. 08-5994. September 2008.
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NTP (National Toxicology Program). Carcinogenesis bioassay of bisphenol-A (CAS No. 80-05-7) in F344 rats and B6C3F1 mice
(feed study). Technical Report No. 215, PB82-184060. 1982.
Oncologic. U.S. EPA and LogiChem, Inc. 2005, Version 7.0. 2008.
PBT Profi 1 er Persistent (P),Bioaccumulative (B), and Toxic (T) Chemical (PBT)Profiler. U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
SPARC On Line Calculator pKaproperty server. Ver 4.5 September, 2009. Available from, http://ibmlc2.chem.uga.edu/sparc/
(accessed on August 12, 2010).
U.S. EPA (Environmental Protection Agency). High Production Volume (HPV) Challenge. Determining the Adequacy of Existing
Data. U.S. Environmental Protection Agency: Washington D.C. 1999. http://www.epa.gov/hpv/pubs/general/datadfin.htm
U.S. EPA Sustainable Futures Using NonCancer Screening within the Sustainable Futures Initiative Environmental Protection
Agency: Washington D.C. 2010. http://www.epa.gOv/opptintr/sf/pubs/noncan-screen.htm#svstemic (accessed on February 09, 2011).
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BisOPP-A
CASRN: 24038-68-4
MW: 380.49
MF: C27H2402
Physical Forms:
Neat: Solid
Use: Developer for thermal paper
SMILES: CC(C1=CC(C2=CC=CC=C2)=C(0)C=C1)(C)C3=CC(C4=CC=CC=C4)=C(0)C=C3
Synonyms: 5,5'-Propane-2,2-diyldibiphenyl-2-ol; 4,4"-Isopropyllidenebis(2-phenylphenol)
Polymeric: No
Oligomers: Not applicable
Metabolites, Degradates and Transformation Products: None
Analog: Bisphenol A (80-05-7)
Endpoint(s) using analog values: Acute toxicity, eye and dermal
irritation, skin sensitization, reproductive and developmental toxicity,
genotoxicity, repeated dose effects
Analog Structure:
Structural Alerts: Phenols, neurotoxicity (U.S. EPA, 2010)
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 2011).
Risk Assessments: None identified
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BisOPP-A CASRN 24038-68-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
118 (Measured)
ChemSpider, 2010
Secondary source; study details and
test conditions were not provided.
Boiling Point (°C)
>300 (Estimated)
EPI; U.S. EPA, 1999
Cutoff value for high boiling point
compounds according to HPV
assessment guidance.
Vapor Pressure (mm Hg)
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DRAFT REPORT - DO NOT CITE OR QUOTE
BisOPP-A CASRN 24038-68-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
HUMAN HEALTH EFFECTS
Toxicokinetics
BisOPP-A is estimated not to be absorbed through the skin and poorly absorbed via the lungs and
gastrointestinal tract based on data for structurally similar compounds.
Dermal Absorption in vitro
No data located.
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal or Inhaled
Not absorbed through the and has poor
through the lung and gastrointestinal tract
(Estimated by analogy)
Professional judgment
Based on closely related analog with
similar structure, functional groups,
and physical/chemical properties.
Acute Toxicity
LOW: Based on analogy to bisphenol A. Potential for acute oral and dermal toxicity of bisOPP-A is estimated
to be low based on experimental data in animals for the analog bisphenol A. Data for exposure to the analog
bisphenol A via inhalation were inconclusive, as only a single concentration was tested and an LCS0 was not
provided.
Acute Lethality
Oral
Rat LD50 = 3,200>5,000 mg/kg bw
(Estimated by analogy)
NTP, 1982; European
Commission, 2000; EINECS,
2010; Professional judgment
Based on the analog bisphenol A;
multiple studies, some guideline
studies.
Mouse LD50 = 4,000-5,200 mg/kg bw
(Estimated by analogy)
NTP, 1982; European
Commission, 2000; EINECS,
2010; Professional judgment
Based on the analog bisphenol A;
multiple studies, some guideline
studies.
Dermal
Rabbit LD50 = 3,000-6,400 mg/kg bw
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A.
Adequate; limited study details for
multiple studies reported in secondary
sources.
Inhalation
No deaths among male and female F344
rats (10/sex) exposed to bisphenol A dust
at 0.17 mg/L (highest attainable
concentration) for 6 hours; transient slight
nasal tract epithelial damage was evident
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A; test
guidelines were not reported in
secondary sources.
Carcinogenicity
MODERATE: Estimated using OncoLogic expert system, which describes a potential for this compound as a
potential carcinogen or tumorigenesis promoter arising from its structural similarity to estrogenic/androgenic
compounds.The 'Phenols and phenolic compounds' structural alert was used.
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BisOPP-A CASRN 24038-68-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
OncoLogic Results
Moderate (Estimate)
OncoLogic class: Phenols and phenolic
compounds
OncoLogic
OncoLogic SAR analysis using the
phenols and phenolic compounds
class.
Carcinogenicity (Rat and
Mouse)
No data located.
Combined Chronic
T oxi city/Car cinogenicity
No data located.
Genotoxicity
LOW: Based on analogy to bisphenol A. FAO/WHO (2011) determined that: (1) the analog bisphenol A is
not a mutagen in in vitro test systems, (2) does not induce cell transformation, and (3) in vivo evidence for
clastogenic effects induced by the analog bisphenol A is inconsistent and inconclusive, although some in vitro
studies have shown bisphenol A to affect chromosomal structure in dividing cells. FAO/WHO (2011)
concluded that the analog bisphenol A is not likely to pose a genotoxic hazard to humans.
Potential for mutagenicity
(Estimated by analogy)
Professional judgment
Estimated based on reported
experimental data for the analog
bisphenol A.
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BisOPP-A CASRN 24038-68-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Largely negative results in a variety of in
vitro test systems, including studies with
Salmonella typhimurium, Chinese hamster
V79 cells, Syrian hamster embryo cells and
mouse lymphoma cells. However, DNA
damage was induced in MCF-7 and MDA-
MB-231 cells, DNA adduct formation in
Syrian hamster ovary cells and a number of
positive findings have been reported for
the potential for bisphenol A to inhibit
purified microtubule polymerization, affect
the spindle apparatus and produce
aneuploidy in in vitro studies with Chinese
hamster V79 cells or oocytes from Balb/c
or MF1 mice.
FAO/WHO, 2011
Based on the analog bisphenol A.
FAO/WHO Expert Panel concludes:
bisphenol A is not a mutagen in in vitro
test systems, nor does it induce cell
transformation. Bisphenol A has been
shown to affect chromosomal structure in
dividing cells in in vitro studies, but
evidence for this effect in in vivo studies is
inconsistent and inconclusive. Bisphenol
A is not likely to pose a genotoxic hazard
to humans.
(Estimated by analogy)
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BisOPP-A CASRN 24038-68-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproductive Effects
HIGH: Estimated based on analogy to bisphenol A. Based on NOAELs of 4.75 mg/kg bw-day and 47.5 mg/kg
bw-day for reproductive toxicity in male and female rats, respectively, following oral exposure to the analog
bisphenol A. Conclusions of NTP-CERHR (2008) included sufficient evidence in rats and mice that
subchronic or chronic oral exposures to the analog bisphenol A caused female reproductive toxicity at doses
>475 mg/kg bw-day (highest NOAEL = 47.5 mg/kg bw-day) and male reproductive toxicity at doses
>47.5mg/kg bw-day (highest NOAEL = 4.75 mg/kg bw-day). There is considerable uncertainty regarding the
results of recent studies that reported reproductive and/or developmental effects in laboratory animals
administered the analog bisphenol A at oral doses <5 mg/kg bw-day.
Reproduction/
Developmental Toxicity
Screen
No data located.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Reproduction and Fertility
Effects
Potential for reproductive toxicity
(Estimated by analogy)
Professional judgment
Estimated based on test data located
for a confidential analog.
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BisOPP-A CASRN 24038-68-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Parental systemic toxicity:
NOAEL = 4.75 mg/kg bw-day
LOAEL = 47.5 mg/kg bw-day for 12%
decreased terminal body weight in Fi
parental males
Reproductive toxicity:
Females: NOAEL = 47.5 mg/kg bw-day
LOAEL = 475 mg/kg bw-day for decreases
in number of implantation sites, delayed
vaginal opening in Fi, F2, and F3 offspring
NTP-CERHR, 2008; Professional
judgment
Based on the analog bisphenol A;
adequate, guideline study as reported
in the secondary source.
Classified by NTP-CERHR as having
High Utility.
Males: NOAEL = 4.75 mg/kg bw-day,
LOAEL = 47.5 mg/kg bw-day for delayed
preputial separation in F, males
(Estimated by analogy)
Parental systemic toxicity:
NOAEL = 5 mg/kg bw-day
LOAEL = 50 mg/kg bw-day for increased
incidences of centrilobular hepatocellular
hypertrophy in males and females
Reproductive toxicity:
NOAEL = 50 mg/kg bw-day
LOAEL = 600 mg/kg bw-day for increased
gestation length, decreased epididymal
sperm concentration in Fi males, increased
incidence of gross ovarian cysts in F, and
F2 females
NTP-CERHR, 2008; Professional
judgment
Based on the analog bisphenol A;
adequate, guideline study as reported
in the secondary source.
Classified by NTP-CERHR as having
High Utility.
(Estimated by analogy)
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BisOPP-A CASRN 24038-68-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Summary of Reproductive
Effects
Female effects: There is sufficient
evidence in rats and mice that bisphenol A
causes female reproductive toxicity with
subchronic or chronic oral exposures
NOAEL of 47.5mg/kg bw-day
LOAEL of 475 mg/kg bw-day
Male effects: There is sufficient evidence
in rats and mice that bisphenol A causes
male reproductive toxicity with subchronic
or chronic oral exposures
NOAEL of 4.75mg/kg bw-day
LOAEL of 47.5mg/kg bw/day
(Estimated by analogy)
NTP-CERHR, 2008; Professional
judgment
Based on the analog bisphenol A;
Classified by NTP-CERHR as having
High Utility..
The FAO/WHO Expert Panel reviewed
located reproductive and developmental
toxicity data for bisphenol A as of
November, 2010 and noted that most
regulatory bodies reviewing the numerous
studies on bisphenol A have indicated an
oral reproductive and developmental
NOAEL of 50 mg/kg bw-day.
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
(Estimated by analogy)
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BisOPP-A CASRN 24038-68-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Developmental Effects
HIGH: Estimated based on analogy to bisphenol A. The NTP-CERHR (2008) Expert Panel concluded that
there is suggestive evidence that the analog bisphenol A causes neural and behavioral alterations related to
disruptions in normal sex differences in rats and mice (0.01-0.2 mg/kg bw-day). The FAO/WHO (2011)
Expert Panel concluded that while there was broad agreement in a NOAEL of 50 mg/kg bw-day for
developmental toxicity, low-level (<1 mg/kg bw-day) effects were uncertain. These conclusions support a call
of High hazard potential for the analog, with lower confidence.
Reproduction/
Developmental Toxicity
Screen
No data located.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Summary of
Developmental Effects
Potential for developmental toxicity
(Estimated by analogy)
Professional judgment
Estimated based on test data located
for a confidential analog.
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BisOPP-A CASRN 24038-68-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
The NTP-CERHR Expert Panel concluded
that bisphenol A:
*does not cause malformations or birth
defects in rats or mice at levels up to the
highest doses evaluated: 640 mg/kg bw-
day (rats) and 1,250 mg/kg bw-day (mice).
*does not alter male or female fertility
after gestational exposure up to doses of
450 mg/kg bw-day in the rat and 600mg/kg
bw-day in the mouse (highest dose levels
evaluated).
*does not permanently affect prostate
weight at doses up to 475 mg/kg bw-day in
adult rats or 600 mg/kg bw-day in mice.
*does not cause prostate cancer in rats or
mice after adult exposure at up to 148 or
600 mg/kg bw-day, respectively.
*does change the age of puberty in male or
female rats at high doses (ca. 475 mg/kg
bw-day).
And that rodent studies suggest that
bisphenol A:
* causes neural and behavioral alterations
related to disruptions in normal sex
differences in rats and mice. (0.01-
0.2 mg/kg bw-day).
(Estimated by analogy)
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A.
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BisOPP-A CASRN 24038-68-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
The FAO/WHO Expert Panel reviewed
located reproductive and developmental
toxicity data for bisphenol A as of
November, 2010 and noted that most
regulatory bodies reviewing the numerous
studies on bisphenol A have indicated an
oral reproductive and developmental
NOAEL of 50 mg/kg bw-day.
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
Neurotoxicity
MODERATE: Estimated to have potential for neurotoxicity based on the presence of the phenol structural
alert.
Neurotoxicity Screening
Battery (Adult)
There is potential for neurotoxicity effects
based on the presence of the phenol
structural alert
(Estimated)
U.S. EPA, 2010; Professional
judgment
Estimated based on structural alert.
Repeated Dose Effects
MODERATE: Estimated based on analogy to bisphenol A which produced histopathologic changes in the
liver (centrilobular hepatocyte hypertrophy) from oral dosing at 50 mg/kg bw-day (NOAEL = 5 mg/kg bw-
day) and there is uncertainty regarding the potential for bisphenol A doses between the NOAEL of 5 mg/kg
bw-day and the LOAEL of 50 mg/kg bw-day to cause adverse systemic effects. Furthermore, lesions in the
nasal cavity of rats were reported following repeated inhalation exposure to bisphenol A dust at 0.05 mg/L.
These findings indicate a moderate hazard potential for the oral and inhalation exposure routes.
The FAO/WHO Expert Panel reviewed
located information regarding repeated-
dose oral toxicity of bisphenol A and
concluded that results demonstrated effects
on the liver, kidney, and body weight at
doses of 50 mg/kg bw-day and higher and
that the lowest NOAEL was 5 mg/kg bw-
day, as identified in several studies.
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
(Estimated by analogy)
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BisOPP-A CASRN 24038-68-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Parental systemic toxicity:
NOAEL = 4.75 mg/kg bw-day
LOAEL = 47.5 mg/kg bw-day for 12%
decreased terminal body weight in Fi
parental males
(Estimated by analogy)
NTP-CERHR, 2008; Professional
judgment
Based on the analog bisphenol A;
guideline study as reported in the
secondary source.
Classified by NTP-CERHR as having
High Utility.
Parental systemic toxicity:
NOAEL = 5 mg/kg bw-day
LOAEL = 50 mg/kg bw-day for increased
incidences of centrilobular hepatocellular
hypertrophy in males and females
(Estimated by analogy)
NTP-CERHR, 2008; Professional
judgment
Based on the analog bisphenol A;
guideline study as reported in the
secondary source.
Classified by NTP-CERHR as having
High Utility.
NOAEL = 0.01 mg/L
LOAEL = 0.05 mg/L based on microscopic
changes in the anterior portion of the nasal
cavity
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A.
NOAEL = None established
LOAEL = 0.047 mg/L for decreased body
weight gain, increased liver and kidney
weight, unspecified "morphological
changes" in liver, kidney, and lungs
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
single exposure level, insufficient
study details in secondary sources.
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BisOPP-A CASRN 24038-68-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Skin Sensitization
MODERATE: Based on analogy to bisphenol A, bisOPP-A is estimated to be a skin sensitizer. Recent data
from three bisphenol A manufacturing facilities indicated that the chemical does not elicit skin sensitization;
however, results of some human studies suggested the possibility of a dermal sensitization response, although
cross-sensitization was not ruled out. Most animal studies conducted on the analog were negative for dermal
sensitization, although assays may not have been maximized. There is evidence of ear swelling in a
photoallergy test in mice and moderate redness and swelling following repeated dermal exposure in rabbits.
The MODERATE hazard designation is based on suggestive evidence of skin sensitization in humans and mice
for the analog.
Skin Sensitization
Negative in a modified local lymph node
assay of mice administered bisphenol A
epicutaneously on the ears at
concentrations up to 30% on 3 consecutive
days
(Estimated by analogy)
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate, although the assay did not
include concentrations >30%.
Negative in a local lymph node assay
modified to test for photoreactivity in mice
administered bisphenol A epicutaneously
on the ears at concentrations up to 30% on
3 consecutive days and irradiated with UV
light immediately following application
(Estimated by analogy)
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate, although the assay did not
include concentrations >30%.
Negative in comprehensive medical
surveillance data obtained from three
bisphenol A manufacturing plants for 875
employees examined for several years
where workers were potentially exposed to
other chemicals (phenol, acetone) that are
not considered to be skin sensitizers
(Estimated by analogy)
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate.
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BisOPP-A CASRN 24038-68-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Positive, rabbits; repeated dermal
application (30 times over 37 days) of
bisphenol A (pure powder) produced
moderate swelling and redness. Skin
turned yellow followed by dark
pigmentation after day 15
(Estimated by analogy)
NIOSH, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate.
The Joint FAO/WHO Expert Meeting to
review toxicological aspects of bisphenol
A concurs with previous reviews that
bisphenol A is capable of producing a skin
sensitization response in humans
(Estimated by analogy)
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
Respiratory Sensitization
No data located.
Respiratory Sensitization
No data located.
Eye Irritation
MODERATE: Based on analogy to bisp
rabbit eyes based on test data for the ana
lenol A. BisOPP-A is estimated to be slightly to highly irritating to
log bisphenol A.
Eye Irritation
Rabbit, slightly to highly irritating
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A.
Adequate; study details provided for
multiple studies indicate potential for
bisphenol A to cause eye irritation.
Dermal Irritation
MODERATE: Based on analogy to bisp
to rabbit and guinea pig skin based on te
irritant.
lenol A. BisOPP-A is estimated to be slightly to moderately irritating
st data for the analog and NIOSH identifying bisphenol A as a skin
Dermal Irritation
Rabbit, nonirritating to slightly irritating
when applied as undiluted or 10% aqueous
suspension to intact or abraded skin
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; NIOSH, 2010;
Professional judgment
Based on the analog bisphenol A.
Adequate, study details provided for
multiple studies indicate potential for
bisphenol A to cause dermal
irritation.
Rabbit, moderately irritating when applied
as 40% solution in dimethyl sulfoxide
under nonocclusive conditions
(Estimated by analogy)
European Commission, 2000;
Professional judgment
Based on the analog bisphenol A;
adequate.
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BisOPP-A CASRN 24038-68-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Guinea pig, not irritating when applied as
5% solution in acetone for 24 hours under
occlusive conditions
(Estimated by analogy)
European Commission, 2000;
Professional judgment
Based on the analog bisphenol A;
adequate.
Endocrine Activity
No data located.
Mo data located.
Immunotoxicity
No data located.
Immune System Effects
No data located.
ECOTOXICITY
ECOSAR Class
Polyphenols
Acute Toxicity
LOW: The log Kow of 7.17 for this compound exceeds the SAR limitations to predict acute aquatic toxicity. No
effects at saturation are predicted for these endpoints.
Fish LC50
Fish 96-hour LC50 = 0.012 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
NES: The chemical may not be
soluble enough to measure this
predicted effect; the log K0„ of 7.17
for this chemical exceeds the SAR
limitation for log Kow of 7.0; NES are
predicted for these endpoints.
Fish 96-hour LC50 = 0.034 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
NES: The chemical may not be
soluble enough to measure this
predicted effect; the log Kow of 7.17
for this chemical exceeds the SAR
limitation for log K0„ of 7.0; NES are
predicted for these endpoints.
Daphnid LCS0
Daphnid 48-hour LC50 = 0.013 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
NES: The chemical may not be
soluble enough to measure this
predicted effect; the log Kow of 7.17
for this chemical exceeds the SAR
limitation for log K0„ of 5.5; NES are
predicted for these endpoints.
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BisOPP-A CASRN 24038-68-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Daphnid 48-hour LC50 = 0.017 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
NES: The chemical may not be
soluble enough to measure this
predicted effect; the log Kow of 7.17
for this chemical exceeds the SAR
limitation for log Kow of 5.5; NES are
predicted for these endpoints.
Green Algae ECS0
Green algae 96-hour LC50 = 0.048 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
NES: The chemical may not be
soluble enough to measure this
predicted effect; the log Kow of 7.17
for this chemical exceeds the SAR
limitation for log K0„ of 6.4; NES are
predicted for these endpoints.
Green algae 96-hour LC50 =1.13 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
NES: The chemical may not be
soluble enough to measure this
predicted effect; the log K0„ of 7.17
for this chemical exceeds the SAR
limitation for log Kow of 6.4; NES are
predicted for these endpoints.
Chronic Aquatic Toxicity
HIGH: Based on estimated ChV values <0.1 mg/L for fish, Daphnid, and green algae.
Fish ChV
Fish ChV = 0.0010 mg/L (Estimated)
ECOSAR: neutral organics
EPI
Fish 30-day ChV = 0.004 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Daphnid ChV
Daphnid ChV = 0.003 mg/L (Estimated)
ECOSAR: neutral organics
EPI
Daphnid 21-day ChV = 0.005 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
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BisOPP-A CASRN 24038-68-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Green Algae ChV
Green algae ChV = 0.041 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Green algae ChV = 0.045 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
ENVIRONMENTAL FATE
Transport
Evaluation of BisOPP-A transport is based entirely on QSAR estimations for fugacity (level III),
disassociation constant (pKa), Koc, volatilization, and vapor pressure. It is expected to exist in neutral form at
environmentally-relevant pH. BisOPP-A is expected to partition primarily to soil; therefore, leaching through
soil to groundwater is not expected to be an important transport mechanism. In the atmosphere, BisOPP-A is
expected to exist in the particulate phase, which will be deposited back to the soil and water surfaces through
wet or dry deposition.
Henry's Law Constant
(atm-m3/mole)
30,000 (Estimated)
EPI; U.S. EPA, 2011
Cutoff value for nonmobile
compounds according to SF
assessment guidance.
Level III Fugacity
Model
Air = <1%
Water = 2%
Soil = 36%
Sediment = 62% (Estimated)
EPI
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BisOPP-A CASRN 24038-68-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Persistence
HIGH: The persistence of bisOPP-A is based on an estimated half-life of 340 days in soil. BisOPP-A is
expected to partition primarily to soil. Experimental biodegradation data for bisOPP-A were not located. The
biodegradation assessment for bisOPP-A is based entirely on QSARs of aerobic and anaerobic
biodegradation. Results from these models estimate primary biodegradation in weeks and ultimate
degradation in weeks-months. Biodegradation under anaerobic methanogenic conditions is estimated to be
not probable. BisOPP-A does not contain functional groups that absorb light at environmentally-relevant
wavelengths. Therefore, it is not expected to be susceptible to direct photolysis. It is not expected to undergo
hydrolysis as it does not contain hydrolysable functional groups. The atmospheric half-life of bisOPP-A is
estimated to be 1.8 hours, although it is expected to exist primarily as a particulate in air. Based on the
estimated data and qualitative assessments based on functional groups, biodegradation of bisOPP-A is
expected to be the major removal process in the environment.
Water
Aerobic
Biodegradation
Weeks (primary survey model)
Weeks-months (ultimate survey model)
EPI
Volatilization Half-life
for Model River
>1 year (Estimated)
EPI
Volatilization Half-life
for Model Lake
>1 year (Estimated)
EPI
Soil
Aerobic
Biodegradation
No data located.
Anaerobic
Biodegradation
Not probable (anaerobic-methanogenic
biodegradation probability model)
EPI
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
Biodegradation
No data located.
Air
Atmospheric Half-life
2 hours (Estimated assuming 12-hour day
and hydroxyl radical concentration of
1.5xl06 molecules/cm3)
EPI
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BisOPP-A CASRN 24038-68-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reactivity
Photolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
The substance does not contain
functional groups that would be
expected to absorb light at
wavelengths >290 nm.
Hydrolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
The substance does not contain
functional groups that would be
expected to hydrolyze readily under
environmental conditions.
Pyrolysis
No data located.
Environmental Half-life
340 days (Estimated)
EPI; PBT Profiler
Half-life estimated for the
predominant compartment, as
determined by EPI and the PBT
Profiler methodology.
Bioaccumulation
MODERATE: The estimated fish BAF is <1,000. Although the BCF suggests a High potential hazard, the
BAF model is anticipated to better account for metabolism of this substance.
Fish BCF
11,000 (Estimated)
EPI
BAF
590 (Estimated)
EPI
Metabolism in Fish
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
Ecological Biomonitoring
No data located.
Human Biomonitoring
This chemical was not included in the NHANES biomonitoring report (CDC, 2011).
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Boethling, R., Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences. Boca Raton:
Lewis Publishers. 2000.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
Chemspider. ChemSpider; Structure-based Chemistry Information. Royal Society of Chemistry:London. 2010.
http://www.chemspider.com (accessed on December 11, 2010).
EINECS. 4,4"-Isopropylidenediphenol (bisphenol A). European Union Risk Assessment Report. 2010.
EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 4.0. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
European Commission. IUCLID Dataset for 4,4-isopropylidenediphenol (CAS No. 80-05-7). European Chemicals Bureau, February
19, 2000. 2000.
FAO/WHO. Toxicological and health aspects of bisphenol A. Report of Joint FAO/WHO expert meeting 2-5 November 2010 and
report of stakeholder meeting on bisphenol A 1 November 2010. Food and Agriculture Organization of the United Nations; World
Health Organization. Ottawa, Canada. 2011.
NIOSH (National Institute for Occupational Safety and Health). Skin Notation (SK) profile, bisphenol A (BPA) [CAS No. 80-05-7],
Department of Health and Human Services; Centers for Disease Control and Prevention. 2010.
NTP (National Toxicology Program). Carcinogenesis bioassay of bisphenol-A (CAS No. 80-05-7) in F344 rats and B6C3F1 mice
(feed study). Technical Report No. 215, PB82-184060. 1982.
NTP-CERHR. Monograph on the potential human reproductive and developmental effects of biphenol A. National Toxicology
Program; U.S. Department of Health and Human Service. Center for the Evaluation of Risks to Human Reproduction. NIH
Publication No. 08-5994. September 2008.
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OncoLogic. U.S. EPA and LogiChem, Inc. 2005, Version 7.0. 2008.
PBT Profi 1 er Persistent (P),Bioaccumulative (B), and Toxic (T) Chemical (PBT)Profiler. U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
SPARC On Line Calculator pKaproperty server. Ver 4.5 September, 2009. Available from, http://ibmlc2.chem.uga.edu/sparc/
(accessed on August 12, 2010).
U.S. EPA Sustainable Futures Using NonCancer Screening within the Sustainable Futures Initiative Environmental Protection
Agency: Washington D.C. http://www.epa.gOv/opptintr/sf/pubs/noncan-screen.htm#svstemic (accessed on February 09, 2011).
U.S. EPA (Environmental Protection Agency). High Production Volume (HPV) Challenge. Determining the Adequacy of Existing
Data. U.S. Environmental Protection Agency: Washington D.C. 1999. http://www.epa.gov/hpv/pubs/general/datadfin.htm
U.S. EPA (Environmental Protection Agency). Sustainable Futures Summary Assessment. Assessment of Discrete Organic
Chemicals. U.S. Environmental Protection Agency: Washington D.C. 2011.
http://www.epa.gov/oppt/sf/pubs/iad_discretes_092011 .pdf
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Bisphenol AP
H-O—O~0H
MW: 290.36
MF: C20H18O2
CASRN: 1571-75-1
Physical Forms:
Neat: Solid
Use: Developer for thermal paper
SMILES: OC 1=CC=C(C(C)(C2=CC=CC=C2)C3=CC=C(0)C=C3)C=C 1
Synonyms: 4,4'-(g-methylbenzylidene)diphenol; 4,4'-(l-Phenylethylidene)bisphenol; phenol, 4,4'-( 1 -phenylethylidene)bis-
Polymeric: No
Oligomers: Not applicable
Metabolites, Degradates and Transformation Products: None
Analog: Bisphenol A (80-05-7)
Endpoint(s) using analog values: Acute toxicity, dermal irritation, skin
sensitization, reproductive and developmental toxicity, genotoxicity,
repeated dose effects
Analog: Confidential analog (structure not available)
Endpoint(s) using analog values: Eye irritation, immunotoxicity
Analog Structure:
Structural Alerts: Phenols, neurotoxicity (U.S. EPA, 2010)
Risk Phrases: 50/53 - Very toxic to aquatic organisms may cause long-term adverse effects in the aquatic environment (ESIS, 2011).
Risk Assessments: None identified
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Bisphenol AP CASRN 1571-75-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
189
ChemSpider, 2010
Secondary source, consistent with
other reported values.
188-191 (Measured)
Aldrich, 2009
Adequate; measured by chemical
supplier. Consistent with other
reported values.
Boiling Point (°C)
>300 (Estimated)
EPI; U.S. EPA, 1999
Cutoff value for high boiling
compounds according to HPV
assessment guidance.
Vapor Pressure (mm Hg)
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bisphenol AP CASRN 1571-75-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
HUMAN HEALTH EFFECTS
Toxicokinetics
Bisphenol AP, as a neat material, is estimated to not be absorbed through the skin and have poor skin
absorption when in solution. Bisphenol AP is expected to have poor absorption via the lungs and
gastrointestinal tract.
Dermal Absorption in vitro
No data located.
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal or Inhaled
Not absorbed through the skin and has
poor absorption to skin when in a solution;
poor absorption through the lung and
gastrointestinal tract
(Estimated by analogy)
Professional judgment
Based on closely related confidential
analog with similar structure,
functional groups, and
physical/chemical properties.
Acute Mammalian Toxicity
LOW: The acute oral and dermal toxicity hazard of bisphenol AP is estimated to be low based on analogy
to bisphenol A. Data for exposure to the analog bisphenol A via inhalation were inconclusive, as only a
single concentration was tested and an LCS0 was not provided.
Acute Lethality
Oral
Rat LD50 = 3,200->5,000 mg/kg bw
(Estimated by analogy)
NTP, 1982; European
Commission, 2000; EINECS,
2010; Professional judgment
Based on the analog bisphenol A;
multiple studies, some guideline
studies.
Mouse LD50 = 4,000-5,200 mg/kg bw
(Estimated by analogy)
NTP, 1982; European
Commission, 2000; EINECS,
2010; Professional judgment
Based on the analog bisphenol A;
multiple studies, some guideline
studies.
Dermal
Rabbit LD50 = 3,000-6,400 mg/kg bw
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
limited study details for multiple
studies reported in secondary
sources.
Inhalation
No deaths among male and female F344
rats (10/sex) exposed to bisphenol A dust
at 0.17 mg/L (highest attainable
concentration) for 6 hours; transient slight
nasal tract epithelial damage was evident
(Estimated by analogy)
EINECS, 2010; European
Commission, 2000; Professional
judgment
Based on the analog bisphenol A;
test guidelines were not reported in
secondary sources.
Carcinogenicity
MODERATE: Estimated using OncoLogic expert system, which describes potential for this compound as a
potential carcinogen or tumorigenesis promoter arising from its structural similarity to
estrogenic/androgenic compounds, using the 'phenols and phenolic compounds' structural alert.
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Bisphenol AP CASRN 157]
L-75-1
PROPE]
RTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
OncoLogic Results
Moderate (Estimate)
OncoLogic class: phenols and phenolic
compounds
OncoLogic
OncoLogic SAR analysis using the
phenols and phenolic compounds
class.
Carcinogenicity (Rat and
Mouse)
No data located.
Combined Chronic Toxicity/
Carcinogenicity
No data located.
Genotoxicity
LOW: Based on analogy to bisphenol A. FAO/WHO (2011) determined that: (1) the analog bisphenol A is
not a mutagen in in vitro test systems, (2) does not induce cell transformation, and (3) in vivo evidence for
clastogenic effects induced by the analog bisphenol A is inconsistent and inconclusive although some in vitro
studies have shown bisphenol A to affect chromosomal structure in dividing cells. The conclusion of
FAO/WHO (2011) is that the analog bisphenol A is not likely to pose a genotoxic hazard to humans.
Gene Mutation in vitro
Potential for mutagenicity
(Estimated by analogy)
Professional judgment
Estimated based on located test data
for a confidential analog with
additional substituents.
Gene Mutation in vivo
No data located.
Chromosomal Aberrations
in vitro
Potential for mutagenicity;
Positive for chromosomal aberrations in
Chinese hamster ovary (CHO) cells with
metabolic activation
(Estimated by analogy)
Professional judgment
Estimated based on located test data
for a confidential analog with
additional substituents.
Chromosomal Aberrations
in vivo
No data located.
DNA Damage and Repair
No data located.
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Bisphenol AP CASRN 1571
[-75-1
PROPE]
RTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Other
Largely negative results in a variety of in
vitro test systems, including studies with
Salmonella typhimurium, Chinese hamster
V79 cells, Syrian hamster embryo cells,
and mouse lymphoma cells. However,
DNA damage was induced in MCF-7 and
MDA-MB-231 cells, DNA adduct
formation in Syrian hamster ovary cells
and a number of positive findings have
been reported for the potential for
bisphenol A to inhibit purified
microtubule polymerization, affect the
spindle apparatus and produce aneuploidy
in in vitro studies with Chinese hamster
V79 cells or oocytes from Balb/c or MF1
mice.
FAO/WHO Expert Panel concludes:
bisphenol A is not a mutagen in in vitro
test systems, nor does it induce cell
transformation. Bisphenol A has been
shown to affect chromosomal structure in
dividing cells in in vitro studies, but
evidence for this effect in in vivo studies is
inconsistent and inconclusive. Bisphenol
A is not likely to pose a genotoxic hazard
to humans.
(Estimated by analogy)
Need reference
Based on the analog bisphenol A.
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Bisphenol AP CASRN 1571-75-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproductive Effects
HIGH: Estimated based on analogy to bisphenol A. Based on NOAELs of 4.75 mg/kg bw-day and 47.5
mg/kg bw-day for reproductive toxicity in male and female rats, respectively, following oral exposure to the
analog bisphenol A. Conclusions of NTP-CERHR (2008) include sufficient evidence in rats and mice that
subchronic or chronic oral exposures to the analog bisphenol A causes female reproductive toxicity at doses
>475 mg/kg bw-day (highest NOAEL = 47.5 mg/kg bw-day) and male reproductive toxicity at doses
>47.5mg/kg bw-day (highest NOAEL = 4.75 mg/kg bw-day). There is considerable uncertainty regarding
the results of recent studies that reported reproductive and/or developmental effects in laboratory animals
administered the analog BAP at oral doses <5 mg/kg bw-day. Data based on a confidential analog also
indicates that there is potential for reproductive effects due to effects to the prostate, testes, and ovaries. A
NOAEL for reproductive effects is identified as 5 mg/kg bw-day, while a LOAEL for these effects was not
identified. There is uncertainty for at what dose these effects occur, so the data based on the analog
bisphenol A was used to make this hazard designation.
Reproduction/
Developmental Toxicity
Screen
No data located.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Reproduction and Fertility
Effects
Potential for toxic effects to prostate,
testes and ovaries.
Rat, 2 8-day oral study
NOAEL = 5 mg/kg-day
(Estimated by analogy)
Professional judgment
Estimated based on located test data
for a confidential analog with
additional substituents; a LOAEL for
these effects was not identified.
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Bisphenol AP CASRN 1571
[-75-1
PROPE]
RTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Parental systemic toxicity:
NOAEL = 4.75 mg/kg bw-day
LOAEL = 47.5 mg/kg bw-day for 12%
decreased terminal body weight in F,
parental males
Reproductive toxicity:
Females: NOAEL = 47.5 mg/kg bw-day
LOAEL = 475 mg/kg bw-day for
decreases in number of implantation sites,
delayed vaginal opening in F,. F2. and F3
offspring
Males: NOAEL = 4.75 mg/kg bw-day,
LOAEL = 47.5 mg/kg bw-day for delayed
preputial separation in Fi males
(Estimated by analogy)
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
adequate, guideline study as reported
in the secondary source.
Classified by NTP-CERHR as
having High Utility.
Parental systemic toxicity:
NOAEL = 5 mg/kg bw-day
LOAEL = 50 mg/kg bw-day for increased
incidences of centrilobular hepatocellular
hypertrophy in males and females
Reproductive toxicity:
NOAEL = 50 mg/kg bw-day
LOAEL = 600 mg/kg bw-day for
increased gestation length, decreased
epididymal sperm concentration in Fi
males, increased incidence of gross
ovarian cysts in F, and F2 females
(Estimated by analogy)
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
adequate, guideline study as reported
in the secondary source.
Classified by NTP-CERHR as
having High Utility.
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Bisphenol AP CASRN 1571
[-75-1
PROPE]
RTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Summary of Reproductive
Effects
Female effects: There is sufficient
evidence in rats and mice that bisphenol A
causes female reproductive toxicity with
subchronic or chronic oral exposures
NOAEL of 47.5mg/kg bw-day
LOAEL of 475 mg/kg bw-day.
Male effects: There is sufficient evidence
in rats and mice that bisphenol A causes
male reproductive toxicity with
subchronic or chronic oral exposures
NOAEL of 4.75mg/kg bw-day
LOAEL of 47.5mg/kg bw/day.
(Estimated by analogy)
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
Classified by NTP-CERHR as
having High Utility.
The joint FAO/WHO Expert Panel
reviewed located reproductive and
developmental toxicity data for bisphenol
A as of November, 2010 and noted that
most regulatory bodies reviewing the
numerous studies on bisphenol A have
indicated an oral reproductive and
developmental NOAEL of 50 mg/kg bw-
day.
(Estimated by analogy)
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
Classified by NTP-CERHR as
having High Utility.
Developmental Effects
HIGH: Estimated based on analogy to bisphenol A. The NTP-CERHR (2008) Expert Panel concluded that
there is suggestive evidence that the analog bisphenol A causes neural and behavioral alterations related to
disruptions in normal sex differences in rats and mice (0.01-0.2 mg/kg bw-day). The FAO/WHO (2011)
Expert Panel concluded that while there was broad agreement in a NOAEL of 50 mg/kg bw/day for
developmental toxicity, low-level (<1 mg/kg bw-day) effects were uncertain. These conclusions support a
High hazard designation for the analog, with lower confidence.
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Bisphenol AP CASRN 1571
[-75-1
PROPE]
RTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproduction/
Developmental Toxicity
Screen
No data located.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
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Bisphenol AP CASRN 1571
[-75-1
PROPE]
RTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Summary of Developmental
Effects
The NTP-CERHR Expert Panel concluded
that bisphenol A:
*does not cause malformations or birth
defects in rats or mice at levels up to the
highest doses evaluated: 640 mg/kg bw-
day (rats) and 1,250 mg/kg bw-day (mice).
*does not alter male or female fertility
after gestational exposure up to doses of
450 mg/kg bw-day in the rat and
600mg/kg bw-day in the mouse (highest
dose levels evaluated).
*does not permanently affect prostate
weight at doses up to 475 mg/kg bw-day
in adult rats or 600 mg/kg bw-day in mice.
*does not cause prostate cancer in rats or
mice after adult exposure at up to 148 or
600 mg/kg bw-day, respectively.
*does change the age of puberty in male
or female rats at high doses (ca.
475 mg/kg bw-day).
And that rodent studies suggest that
bisphenol A:
* causes neural and behavioral alterations
related to disruptions in normal sex
differences in rats and mice.
(0.01-0.2 mg/kg bw-day).
(Estimated by analogy)
NTP-CERHR, 2008; Professional
judgment
Based on the analog bisphenol A.
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Bisphenol AP CASRN 1571
[-75-1
PROPE]
RTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
The joint FAO/WHO Expert Panel
reviewed located reproductive and
developmental toxicity data for bisphenol
A as of November, 2010 and noted that
most regulatory bodies reviewing the
numerous studies on bisphenol A have
indicated an oral reproductive and
developmental NOAEL of 50 mg/kg bw-
day.
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
Neurotoxicity
MODERATE: Estimated to have potential for neurotoxicity based on the presence of the phenol structural
alert.
Neurotoxicity Screening
Battery (Adult)
There is potential for neurotoxicity effects
based on the presence of the phenol
structural alert
(Estimated)
U.S. EPA, 2010, Professional
judgment
Estimated based on structural alert.
Repeated Dose Effects
MODERATE: Estimated based on analogy to bisphenol A, which produced histopathologic changes in the
liver (centrilobular hepatocyte hypertrophy) from oral dosing at 50 mg/kg bw-day (NOAEL = 5 mg/kg bw-
day) and there is uncertainty regarding the potential for bisphenol A doses between the NOAEL of 5 mg/kg
bw-day and the LOAEL of 50 mg/kg-day to cause adverse systemic effects. Furthermore, lesions in the
nasal cavity of rats were reported following repeated inhalation exposure to bisphenol A dust at 0.05 mg/L.
These findings indicate a Moderate hazard potential for the oral and inhalation exposure routes. In
addition, while no LOAEL was identified, data located for a confidential analog indicates the potential that
bisphenol AP may cause toxic effects to the blood, liver, and kidney.
Potential for toxic effects to blood, liver
and kidney
Rat, 2 8-day oral study
NOAEL = 5 mg/kg-day
(Estimated by analogy)
Professional judgment
Estimated based on located test data
for a confidential analog with
additional substituents; a LOAEL for
these effects was not identified.
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Bisphenol AP CASRN 1571
[-75-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
The FAO/WHO Expert Panel reviewed
the located information regarding
repeated-dose oral toxicity of bisphenol A
and concluded that results demonstrated
effects on the liver, kidney, and body
weight at doses of 50 mg/kg bw-day and
higher and that the lowest NOAEL was 5
mg/kg bw-day, as identified in several
studies.
(Estimated by analogy)
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
Parental systemic toxicity:
NOAEL = 4.75 mg/kg bw-day
LOAEL = 47.5 mg/kg bw-day for 12%
decreased terminal body weight in Fi
parental males
(Estimated by analogy)
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
guideline study as reported in the
secondary source.
Classified by NTP-CERHR as
having High Utility.
Parental systemic toxicity:
NOAEL = 5 mg/kg bw-day
LOAEL = 50 mg/kg bw-day for increased
incidences of centrilobular hepatocellular
hypertrophy in males and females
(Estimated by analogy)
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
guideline study as reported in the
secondary source.
Classified by NTP-CERHR as
having High Utility.
NOAEL = 0.01 mg/L
LOAEL = 0.05 mg/L based on
microscopic changes in the anterior
portion of the nasal cavity
(Estimated by analogy)
European Commission, 2000 ;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A.
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Bisphenol AP CASRN 157]
L-75-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
NOAEL = None established
LOAEL = 0.047 mg/L for decreased body
weight gain, increased liver and kidney
weight, unspecified "morphological
changes" in liver, kidney, and lungs
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
single exposure level, insufficient
study details in secondary sources.
Skin Sensitization
MODERATE: Based on analogy to bisphenol A, bisphenol AP is estimated to be a skin sensitizer. Recent
data from three bisphenol A manufacturing facilities indicate that it does not elicit skin sensitization;
however, results of some human studies suggest the possibility of a dermal sensitization response, although
cross-sensitization was not ruled out. Most animal studies conducted on the analog, bisphenol A, were
negative for dermal sensitization, although assays may not have been maximized. There is evidence of ear
swelling in a photoallergy test in mice and moderate redness and swelling following repeated dermal
exposure in rabbits. Based on suggestive evidence of skin sensitization in humans and mice for the analog,
MODERATE hazard call is warranted.
Skin Sensitization
Negative in a modified local lymph node
assay of mice administered bisphenol A
epicutaneously on the ears at
concentrations up to 30% on 3 consecutive
days.
(Estimated by analogy)
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate, although the assay did not
include concentrations >30%.
Negative in a local lymph node assay
modified to test for photoreactivity in
mice administered bisphenol A
epicutaneously on the ears at
concentrations up to 30% on 3 consecutive
days and irradiated with UV light
immediately following application
(Estimated by analogy)
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate, although the assay did not
include concentrations >30%.
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Bisphenol AP CASRN 1571
[-75-1
PROPE]
RTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Negative in comprehensive medical
surveillance data obtained from three
bisphenol A manufacturing plants for 875
employees examined for several years
where workers were potentially exposed
to other chemicals (phenol, acetone) that
are not considered to be skin sensitizers
(Estimated by analogy)
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate.
Positive, rabbits; repeated dermal
application (30 times over 37 days) of
bisphenol A (pure powder) produced
moderate swelling and redness. Skin
turned yellow followed by dark
pigmentation after day 15
(Estimated by analogy)
NIOSH, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate.
The Joint FAO/WHO Expert Meeting to
review toxicological aspects of bisphenol
A concurs with previous reviews that
bisphenol A is capable of producing a skin
sensitization response in humans.
(Estimated by analogy)
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
Respiratory Sensitization
No data located.
Respiratory Sensitization
No data located.
Eye Irritation
MODERATE: Based on confidential analog, bisphenol AP was moderately irritating to rabbit eyes.
Bisphenol AP may potentially be irritating to eyes.
Eye Irritation
Potential for irritation to eyes; caused
moderate eye irritation in rabbits
(Estimated by analogy)
Professional judgment
Estimated based on located test data
for a confidential analog.
Dermal Irritation
MODERATE: Based on analogy to bisphenol A. Bisphenol AP is estimated to be slightly to moderately
irritating to rabbit skin based on test data for the analog and NIOSH identifying bisphenol A as a skin
irritant.
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Bisphenol AP CASRN 1571
[-75-1
PROPE]
RTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Dermal Irritation
Rabbit, nonirritating to slightly irritating
when applied as undiluted or 10% aqueous
suspension to intact or abraded skin
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; NIOSH, 2010;
Professional judgment
Based on the analog bisphenol A;
the details provided for multiple
studies indicate potential for
bisphenol A to cause dermal
irritation.
Rabbit, moderately irritating when applied
as 40% solution in dimethyl sulfoxide
under non-occlusive conditions
(Estimated by analogy)
European Commission, 2000;
Professional judgment
Based on the analog bisphenol A;
adequate.
Guinea pig, not irritating when applied as
5% solution in acetone for 24 hours under
occlusive conditions
(Estimated by analogy)
European Commission, 2000;
Professional judgment
Based on the analog bisphenol A;
adequate.
Endocrine Activity
Based on in vitro data, Bisphenol AP exhibits endocrine activity. In vitro assays indicate that bisphenol AP
can bind to estrogen receptors, elicit estrogen-induced gene transcription, and induce cell proliferation in
MCF7 cancer cells. Bisphenol AP appears to be similar to or somewhat less potent than bisphenol A in its
estrogenic responses in vitro.
In a human ER binding assay, the relative
binding affinity (RBA) of bisphenol AP
was 0.0803% compared to 126% for 17|3-
estradiol. RBAs for other bisphenol
compounds included 0.195% for
bisphenol A, 0.129% for bisphenol C,
0.0719% for bisphenol F, and 0.0055% for
bisphenol S. An RBA of 0.00473% was
reported for PHBB.
METI, 2002
Adequate.
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Bisphenol AP CASRN 1571
[-75-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In a reporter gene assay of estrogen-
induced transcriptional activity, relative
activity (RA) for bisphenol AP was
0.000184% compared to 81.7% for 17|3-
estradiol. RAs for other bisphenol
compounds included 0.00278% for
bisphenol A, 0.00189% for bisphenol C,
0.000639% for bisphenol F, and
0.000254% for bisphenol S. An RA of
0.000592% was reported for PHBB.
METI, 2002
Adequate.
In a competitive ER binding assay using
human ERa, the RBA for bisphenol AP
was 1.66% that of 17|3-estradiol. RBAs
for other bisphenol compounds included
1.68% for bisphenol C, 0.32% for
bisphenol A, and 0.09% for bisphenol F.
Coleman, Toscano et al., 2003
Adequate.
In an ER-mediated reporter gene
expression assay, bisphenol AP induced
reporter gene expression at a relative
activity (RA) of 9.0 x 10"5 that of 17|3-
estradiol. RAs for other bisphenol
compounds included 2.75 x 10° for
bisphenol A, 5.3 x 10"4 for bisphenol F,
and 4.9 x 10"4 for bisphenol C.
Coleman, Toscano et al., 2003
Adequate.
In a proliferation assay of MCF-7 human
breast cancer cells that contain ERa and
ER|3 and are known to proliferate in
response to estrogens, bisphenol AP
induced a proliferative response that was
6.0 x 10"4 that of 17|3-estradiol.
Proliferative values for other bisphenol
compounds included 2.0 xlO"3 for
bisphenol A, 1.6 x 10° for bisphenol C,
and 1.0 x 10° for bisphenol F.
Coleman, Toscano et al., 2003
Adequate.
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Bisphenol AP CASRN 1571-75-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Immunotoxicity
Estimated based on analogy to confidential analog. There is uncertain potential for immunotoxicity based
on effects to the spleen.
Immune System Effects
Uncertain potential for toxic effects to
adrenal glands and spleen
Rat, 2 8-day oral study
NOAEL = 5 mg/kg-day
(Estimated by analogy)
Professional judgment
Estimated based on located test data
for a confidential analog with
additional substituents; a LOAEL for
these effects was not identified.
ECOTOXICITY
ECOSAR Class
Phenols, poly
Acute Toxicity
HIGH: Based on estimated LCS0 values for fish and Daphnid and ECS0 value for algae, which are all <1.0
mg/L.
Fish LC50
Fish 96-hour LC50 = 0.580 mg/L
(Estimated)
ECOSAR: phenols, poly^
EPI
Fish 96-hour LC50 = 0.851mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid LCS0
Daphnid 48-hour LC50 = 0.694 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid 48-hour LC50 = 0.774 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Green Algae ECS0
Green algae 96-hour EC50 = 0.967 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Green algae 96-hour EC50 =1.38 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Chronic Aquatic Toxicity
HIGH: Based on an estimated fish ChV of 0.076 mg/L.
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Bisphenol AP CASRN 1571
[-75-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Fish ChV
Fish ChV = 0.076 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Fish 30-day ChV = 0.110 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Daphnid ChV
Daphnid ChV = 0.106 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid 21-day ChV = 0.243 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Green Algae ChV
Green algae ChV = 0.134 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Green algae ChV = 0.590 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
ENVIRONMENTAL FATE
Transport
Evaluation of bisphenol AP transport is based entirely on QSAR estimations for fugacity (level III),
disassociation constant (pKa), Koc, volatilization, and vapor pressure. Bisphenol AP is expected to exist in
neutral form at environmentally-relevant pH. Bisphenol AP is expected to partition primarily to soil;
therefore, leaching through soil to groundwater is not expected to be an important transport mechanism. In
the atmosphere, bisphenol AP is expected to exist in the particulate phase which will be deposited back to
the soil and water surfaces through wet or dry deposition.
Henry's Law Constant
(atm-m3/mole)
30,000 (Estimated)
EPI; U.S. EPA, 2011
Cutoff value for nonmobile
compounds according to SF
assessment guidance.
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Bisphenol AP CASRN 157]
L-75-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Level III Fugacity Model
Air = <1%
Water = 2.4%
Soil = 44%
Sediment = 53% (Estimated)
EPI
Persistence
HIGH: The persistence of bisphenol AP is based on an estimated half-life of 75 days in soil. Bisphenol AP is
expected to partition primarily to soil based on results from a Level III fugacity model. Evaluation of the
persistence of bisphenol AP is based entirely on QSARs of aerobic and anaerobic biodegradation. Results
from these models estimate primary biodegradation in days-weeks and ultimate degradation in weeks-
months. Biodegradation under anaerobic methanogenic conditions is not probable. Bisphenol AP does not
contain chromophores that absorb light at environmentally-relevant wavelengths. Therefore, it is not
expected to be susceptible to direct photolysis. It is not expected to undergo hydrolysis as it does not contain
hydrolysable functional groups. The atmospheric half-life of bisphenol AP is estimated at 1.5 hours,
although it is expected to exist primarily as a particulate in air. Based on the estimated data and qualitative
assessments based on functional groups, biodegradation of bisphenol AP is expected to be the major
removal process in the environment.
Water
Aerobic Biodegradation
Days-weeks (primary survey model)
Weeks-months (ultimate survey model)
EPI
Volatilization Half-life
for Model River
>1 year (Estimated)
EPI
Volatilization Half-life
for Model Lake
>1 year (Estimated)
EPI
Soil
Aerobic Biodegradation
No data located.
Anaerobic
Biodegradation
Not probable (anaerobic-methanogenic
biodegradation probability model)
EPI
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
Biodegradation
No data located.
Air
Atmospheric Half-life
1.5 hours
EPI
Reactivity
Photolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain
functional groups that would be
expected to absorb light at
wavelengths >290 nm.
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Bisphenol AP CASRN 1571
[-75-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Hydrolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain
functional groups that would be
expected to hydrolyze readily under
environmental conditions.
Pyrolysis
No data located.
Environmental Half-life
75 days
EPI
Half-life estimated for the
predominant compartment, as
determined by EPI and the PBT
Profiler methodology.
Bioaccumulation
MODERATE: The estimated BCF is <1,000.
Fish BCF
750 (Estimated)
EPI
BAF
250 (Estimated)
EPI
Metabolism in Fish
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
Ecological Biomonitoring
No data located.
Human Biomonitoring
This chemical was not included in the NHANES biomonitoring report (CDC, 2011).
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Aldrich. Handbook of Fine Chemicals and Laboratory Equipment. 2009-2010. Milwaukee, WI: Aldrich Chem Co. 2009, p.344.
Boethling, R., Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences. Boca Raton:
Lewis Publishers. 2000.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
ChemSpider. ChemSpider; Structure-based Chemistry Information. Royal Society of Chemistry: London. 2010.
http://www.chemspider.com. accessed on December 11, 2010.
Coleman, K.P., Toscano, W.A., Wiese, T.E. QSAR Models of the in vitro estrogen activity of bisphenol A analogs. OSAR &
Combinatorial Science. 2003, 22:78-88.
EINECS. 4,4"-Isopropylidenediphenol (bisphenol A). European Union Risk Assessment Report. 2010.
EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 4.0. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
European Commission. IUCLID Dataset for 4,4-isopropylidenediphenol (CAS No. 80-05-7). European Chemicals Bureau, February
19, 2000. 2000.
FAO/WHO. Toxicological and health aspects of bisphenol A. Report of Joint FAO/WHO expert meeting 2-5 November 2010 and
report of stakeholder meeting on bisphenol A 1 November 2010. Food and Agriculture Organization of the United Nations; World
Health Organization. Ottawa, Canada. 2011.
METI. Current status of testing methods development for endocrine disruptors. Ministry of Economy, Trade and Industry, Japan. 6th
meeting of the task force on Endocrine Disruptors Testing and Assessments (EDTA). Tokyo. 2002.
4-203
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NIOSH (National Institute for Occupational Safety and Health). Skin Notation (SK) Profile, bisphenol A (BPA) [CAS No. 80-05-7],
Department of Health and Human Services; Centers for Disease Control and Prevention, 2010.
NTP. Carcinogenesis bioassay of bisphenol-A (CAS No. 80-05-7) in F344 rats and B6C3F1 mice (feed study). National Toxicology
Program. Technical Report No. 215, Order No. PB82-184060. 1982.
NTP-CERHR. Monograph on the potential human reproductive and developmental effects ofbiphenolA. National Toxicology
Program; U.S. Department of Health and Human Service. Center for the Evaluation of Risks to Human Reproduction. NIH
Publication No. 08-5994. September 2008.
Oncologic. U.S. EPA and LogiChem, Inc. 2005, Version 7.0. 2008.
PBT Profi 1 er Persistent (P),Bioaccumulative (B), and Toxic (T) Chemical (PBT)Profiler. U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
SPARC On Line Calculator pKa property server. Ver 4.5 September, 2009. Available from, http://ibmlc2.chem.uga.edu/spare/
(accessed on August 12, 2010).
U.S. EPA (Environmental Protection Agency). High Production Volume (HPV) Challenge. Determining the Adequacy of Existing
Data. U.S. Environmental Protection Agency: Washington D.C. 1999. http://www.epa.gov/hpv/pubs/general/datadfin.htm
U.S. EPA (Environmental Protection Agency). Sustainable Futures Summary Assessment. Assessment of Discrete Organic
Chemicals. U.S. Environmental Protection Agency: Washington D.C. 2011.
http://www.epa.gov/oppt/sf/pubs/iad discretes 092011.pdf
U.S. EPA Sustainable Futures Using NonCancer Screening within the Sustainable Futures Initiative Environmental Protection
Agency: Washington D.C. 2010. http://www.epa.gOv/opptintr/sf/pubs/noncan-screen.htm#svstemic as of February 09, 2011.
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Substituted Phenolic Compound #1
CASRN: Confidential CASRN
MW: Confidential MW
MF: Confidential MF
Physical Forms:
Neat: Solid
Use: Developer for thermal paper
SMILES: This mixture containing confidential material is not amenable to the generation of a single SMILES notation.
Synonyms:
Polymeric: No
Oligomers: Not applicable
Metabolites, Degradates and Transformation Products: None identified
Analog: Bisphenol A (80-05-7)
Endpoint(s) using analog values: Acute toxicity, eye and skin irritation, skin
sensitization, reproductive and developmental toxicity, repeated dose effects
Analog Structure:
Structural Alerts: Phenols, neurotoxicity (U.S. EPA, 2010)
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 2011).
Risk Assessments: None identified
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
171.5 (Measured)
Lide, 2008
Adequate; selected value for
assessment.
171-172 (Measured)
O'Neil etal.,2010
Adequate; reported values, which
span a relatively narrow range, are
consistent with those provided in
other sources.
Boiling Point (°C)
>300 (Estimated)
EPI; U.S. EPA, 1999
Cutoff value for high boiling point
compounds according to HPV
assessment guidance.
Vapor Pressure (mm Hg)
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal or Inhaled
Not absorbed through the skin as neat
material and has poor absorption in
solution; can be moderately absorbed
through the lung and gastrointestinal tract
(Estimated by analogy)
Professional judgment
Based on closely related analog with
similar structure, functional groups,
and physical/chemical properties.
Acute Mammalian Toxicity
LOW: Based on analogy to bisphenol A. The acute oral and dermal toxicity hazard of this substituted
phenolic compound is estimated to be low based on experimental data in animals for a closely related
substance. Data for exposure to the analog bisphenol A via inhalation were inconclusive, as only a single
concentration was tested and an LCS0 was not provided.
Acute Lethality
Oral
Rat LD50 = 3,200->5,000 mg/kg bw
(Estimated by analogy)
NTP, 1982; European
Commission, 2000; EINECS,
2010; Professional judgment
Based on the analog bisphenol A;
multiple studies, some guideline
studies.
Mouse LD50 = 4,000-5,200 mg/kg bw
(Estimated by analogy)
NTP, 1982; European
Commission, 2000; EINECS,
2010; Professional judgment
Based on the analog bisphenol A;
multiple studies, some guideline
studies.
Dermal
Rabbit LD50 = 3,000-6,400 mg/kg bw
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate by weight of evidence,
multiple studies, although study
details were not reported in
secondary sources.
Inhalation
No deaths among male and female F344
rats (10/sex) exposed to bisphenol A dust at
0.17 mg/L (highest attainable
concentration) for 6 hours; transient slight
nasal tract epithelial damage was evident
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A; test
guidelines were not reported in
secondary sources.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Carcinogenicity
MODERATE: Estimated using OncoLogic expert system, which describes a concern for this compound as
a potential carcinogen or tumorigenesis promoter arising from its structural similarity to
estrogenic/androgenic compounds, using the 'phenols and phenolic compounds' structural alert.
OncoLogic Results
Moderate (Estimate)
OncoLogic class: phenols and phenolic
compounds
Carcinogenicity (Rat and
Mouse)
Combined Chronic
Toxicity/ Carcinogenicity
OncoLogic
OncoLogic SAR analysis using the
phenols and phenolic compounds
class.
No data located.
No data located.
Genotoxicity
LOW: This compound was not mutagenic in one assay that included several strains of Salmonella
typhimurium and did not induce micronuclei in peripheral bone marrow of male B6C3F1 mice in vivo.
Gene Mutation in vitro
Negative, Ames assay (standard plate) in
S. typhimurium strains TA97, TA98,
TA100, and TA1535 with and without
metabolic activation
NTP, 2010
Gene Mutation in vivo
Chromosomal Aberrations
in vitro
Chromosomal Aberrations
in vivo
Negative, micronucleus assay of peripheral
bone marrow and blood in B6C3F1 mice
(males only)
DNA Damage and Repair
Other
Adequate.
No data located.
No data located.
Mutat. Res., 2008 (Sanitized)
Adequate.
No data located.
No data located.
Reproductive Effects
HIGH: Based on analogy to bisphenol A. Based on a NOAEL of 4.75 mg/kg bw-day and LOAEL of 47.5
mg/kg bw-day for reproductive toxicity in male rats following oral exposure to the analog bisphenol A.
Conclusions of NTP-CERHR (2008) include sufficient evidence in rats and mice that subchronic or chronic
oral exposures to the analog bisphenol A causes female reproductive toxicity at doses >475 mg/kg bw-day
(highest NOAEL = 47.5 mg/kg bw-day) and male reproductive toxicity at doses >47.5mg/kg bw-day (highest
NOAEL = 4.75 mg/kg bw-day). There is considerable uncertainty regarding the results of recent studies that
reported reproductive and/or developmental effects in laboratory animals administered the analog bisphenol
A at oral doses <5 mg/kg bw-day.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproduction/
Developmental Toxicity
Screen
No data located.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Reproduction and Fertility
Effects
Parental systemic toxicity:
NOAEL = 4.75 mg/kg bw-day
LOAEL = 47.5 mg/kg bw-day for 12%
decreased terminal body weight in Fi
parental males
Reproductive toxicity:
Females: NOAEL = 47.5 mg/kg bw-day
LOAEL = 475 mg/kg bw-day for decreases
in number of implantation sites, delayed
vaginal opening in Fi, F2, and F3 offspring
Males: NOAEL = 4.75 mg/kg bw-day,
LOAEL = 47.5 mg/kg-day for delayed
preputial separation in Fi males
(Estimated by analogy)
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
adequate, guideline study as reported
in the secondary source.
Classified by NTP-CERHR as having
High Utility.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Parental systemic toxicity:
NOAEL = 5 mg/kg bw-day
LOAEL = 50 mg/kg bw-day for increased
incidences of centrilobular hepatocellular
hypertrophy in males and females
Reproductive toxicity:
NOAEL = 50 mg/kg bw-day
LOAEL = 600 mg/kg bw-day for increased
gestation length, decreased epididymal
sperm concentration in Fi males, increased
incidence of gross ovarian cysts in F, and
F2 females
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
adequate, guideline study as reported
in the secondary source.
Classified by NTP-CERHR as having
High Utility.
(Estimated by analogy)
Summary of Reproductive
Effects
Female effects: There is sufficient evidence
in rats and mice that bisphenol A causes
female reproductive toxicity with
subchronic or chronic oral exposures
NOAEL of 47.5 mg/kg bw-day
LOAEL of 475 mg/kg bw-day.
Male effects: There is sufficient evidence in
rats and mice that bisphenol A causes male
reproductive toxicity with subchronic or
chronic oral exposures
NOAEL of 4.75 mg/kg bw-day
LOAEL of 47.5 mg/kg bw/day.
(Estimated by analogy)
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A.
Classified by NTP-CERHR as having
High Utility.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
The joint FAO/WHO Expert Panel (2010)
reviewed available reproductive and
developmental toxicity data for bisphenol
A as of November, 2010 and noted that
most regulatory bodies reviewing the
numerous studies on bisphenol A have
indicated an oral reproductive and
developmental NOAEL of 50 mg/kg bw-
day.
FAO/WHO, 2011; NTP-CERHR
2008; Professional judgment
Based on the analog bisphenol A.
Classified by NTP-CERHR as having
High Utility.
(Estimated by analogy)
Developmental Effects
HIGH: Estimated based on analogy to bisphenol A. The NTP-CERHR (2008) Expert Panel concluded that
there is suggestive evidence that the analog bisphenol A causes neural and behavioral alterations related to
disruptions in normal sex differences in rats and mice (0.01-0.2 mg/kg bw-day). The FAO/WHO (2011)
Expert Panel concluded that while there was broad agreement in a NOAEL of 50 mg/kg bw-day for
developmental toxicity, low level (<1 mg/kg bw-day) effects were uncertain. These conclusions support a call
of High concern of the analog, with lower confidence.
Reproduction/
Developmental Toxicity
Screen
No data located.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Summary of
Developmental Effects
The NTP-CERHR (2008) Expert Panel
concluded that bisphenol A:
*does not cause malformations or birth
defects in rats or mice at levels up to the
highest doses evaluated: 640 mg/kg bw-day
(rats) and 1,250 mg/kg bw-day (mice).
*does not alter male or female fertility after
gestational exposure up to doses of 450
mg/kg bw-day in the rat and 600 mg/kg
bw-day in the mouse (highest dose levels
evaluated).
*does not permanently affect prostate
weight at doses up to 475 mg/kg bw-day in
adult rats or 600 mg/kg bw-day in mice.
*does not cause prostate cancer in rats or
mice after adult exposure at up to 148 or
600 mg/kg bw-day, respectively.
*does change the age of puberty in male or
female rats at high doses (ca. 475 mg/kg
bw-day).
And that rodent studies suggest that
bisphenol A:
* causes neural and behavioral alterations
related to disruptions in normal sex
differences in rats and mice (0.01-
0.2 mg/kg bw-day).
(Estimated by analogy)
NTP-CERHR, 2008; Professional
judgment
Based on the analog bisphenol A.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
The joint FAO/WHO (2011) Expert Panel
reviewed available reproductive and
developmental toxicity data for bisphenol
A as of November, 2010 and noted that
most regulatory bodies reviewing the
numerous studies on bisphenol A have
indicated an oral reproductive and
developmental NOAEL of 50 mg/kg bw-
day.
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
(Estimated by analogy)
Neurotoxicity
MODERATE: Estimated to have potential for neurotoxicity based on the presence of the phenol structural
alert.
Neurotoxicity Screening
Battery (Adult)
There is potential for neurotoxicity effects
based on the presence of the phenol
structural alert
(Estimated)
U.S. EPA 2010, Professional
judgment
Estimated based on structural alert.
Repeated Dose Effects
MODERATE: Estimated based on analogy to bisphenol A, which produced histopathologic changes in the
liver (centrilobular hepatocyte hypertrophy) from oral dosing at 50 mg/kg bw-day (NOAEL = 5 mg/kg bw-
day) and there is uncertainty regarding the potential for bisphenol A doses between the NOAEL of 5 mg/kg
bw-day and the LOAEL of 50 mg/kg bw-day to cause adverse systemic effects. Furthermore lesions in the
nasal cavity of rats were reported following repeated inhalation exposure to bisphenol A dust at 0.05 mg/L.
These findings indicate a Moderate hazard concern for the oral and inhalation exposure routes.
The FAO/WHO (2011) Expert Panel
reviewed the available information
regarding repeated-dose oral toxicity of
bisphenol A and concluded that results
demonstrated effects on the liver, kidney,
and body weight at doses of 50 mg/kg bw-
day and higher and that the lowest NOAEL
was 5 mg/kg-day, as identified in several
studies.
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
(Estimated by analogy)
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Parental systemic toxicity:
NOAEL = 4.75 mg/kg bw-day
LOAEL = 47.5 mg/kg bw-day for 12%
decreased terminal body weight in Fi
parental males
(Estimated by analogy)
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
guideline study as reported in the
secondary source.
Classified by NTP-CERHR as having
High Utility.
Parental systemic toxicity:
NOAEL = 5 mg/kg bw-day
LOAEL = 50 mg/kg bw-day for increased
incidences of centrilobular hepatocellular
hypertrophy in males and females
(Estimated by analogy)
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
guideline study as reported in the
secondary source.
Classified by NTP-CERHR as having
High Utility.
NOAEL = 0.01 mg/L
LOAEL = 0.05 mg/L based on microscopic
changes in the anterior portion of the nasal
cavity
(Estimated by analogy)
EINECS, 2010; European
Commission, 2000; Professional
judgment
Based on the analog bisphenol A.
NOAEL = None established
LOAEL = 0.047 mg/L for decreased body
weight gain, increased liver and kidney
weight, unspecified "morphological
changes" in liver, kidney, and lungs
(Estimated by analogy)
EINECS, 2010; European
Commission, 2000; Professional
judgment
Based on the analog bisphenol A;
single exposure level, insufficient
study details in secondary sources.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Skin Sensitization
MODERATE: Based on analogy to bisphenol A, this substituted phenolic compound is estimated to be a skin
sensitizer. Recent data from three bisphenol A manufacturing facilities indicate that it does not elicit skin
sensitization; however, results of some human studies suggest the possibility of a dermal sensitization
response, although cross-sensitization was not ruled out. Most animal studies conducted on the analog were
negative for dermal sensitization, although assays may not have been maximized. There is evidence of ear
swelling in a photoallergy test in mice and moderate redness and swelling following repeated dermal exposure
in rabbits. Based on suggestive evidence of skin sensitization in humans and mice for the analog,
MODERATE hazard call is warranted.
Skin Sensitization
Negative in a modified local lymph node
assay of mice administered bisphenol A
epicutaneously on the ears at
concentrations up to 30% on 3 consecutive
days
(Estimated by analogy)
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate, although the assay did not
include concentrations >30%.
Negative in a local lymph node assay
modified to test for photoreactivity in mice
administered bisphenol A epicutaneously
on the ears at concentrations up to 30% on
three consecutive days and irradiated with
UV light immediately following application
(Estimated by analogy)
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate, although the assay did not
include concentrations >30%.
Negative in comprehensive medical
surveillance data obtained from three
bisphenol A manufacturing plants for
875 employees examined for several years
where workers were potentially exposed to
other chemicals (phenol, acetone) that are
not considered to be skin sensitizers
(Estimated by analogy)
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Positive, rabbits; repeated dermal
application (30 times over 37 days) of
bisphenol A (pure powder) produced
moderate swelling and redness; skin turned
yellow followed by dark pigmentation after
day 15
(Estimated by analogy)
NIOSH, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate.
The Joint FAO/WHO Expert Meeting to
review toxicological aspects of bisphenol A
concurs with previous reviews that
bisphenol A is capable of producing a skin
sensitization response in humans
(Estimated by analogy)
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
Respiratory Sensitization
No data located.
Respiratory Sensitization
No data located.
Eye Irritation
MODERATE: Based on analogy to bisphenol A. The analog bisphenol A was slightly to highly irritating to
rabbit eyes.
Eye Irritation
Rabbit, slightly to highly irritating
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A.
Adequate; multiple studies, weight of
evidence indicates potential for
bisphenol A to cause eye irritation.
Dermal Irritation
MODERATE: Based on analogy to bisphenol A; bisphenol C is estimated to be slightly irritating to
moderately irritating based on test data for the analog bisphenol A.
Dermal Irritation
Rabbit, nonirritating to slightly irritating
when applied as undiluted or 10% aqueous
suspension to intact or abraded skin
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; NIOSH, 2010;
Professional judgment
Based on the analog bisphenol A.
Adequate; multiple studies, weight of
evidence indicates potential for
bisphenol A to cause dermal
irritation.
Rabbit, moderately irritating when applied
as 40% solution in dimethyl sulfoxide
under non-occlusive conditions
(Estimated by analogy)
European Commission, 2000;
Professional judgment
Based on the analog bisphenol A;
adequate.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Guinea pig, not irritating when applied as
5% solution in acetone for 24-hours under
occlusive conditions
(Estimated by analogy)
European Commission, 2000;
Professional judgment
Based on the analog bisphenol A;
adequate.
Endocrine Activity
This compound exhibited a weakly positive ER binding affinity in one in vitro assay.
The proprietary phenolic compound
exhibited weak ER binding activity in
preparations from uteri of ovariectomized
Sprague-Dawley rats as evidenced by a
relative binding affinity (RBA) that was
0.0007% of the binding affinity of 17|3-
estradiol. RBAs for other tested chemicals
included 0.008% for bisphenol A, 0.003%
for PHBB and 0.0009% for bisphenol F.
Blair et al., 2000
Adequate.
Immunotoxicity
No data located.
Immune System Effects
No data located.
ECOTOXICITY
ECOSAR Class
Phenols, poly - acid
Acute Toxicity
HIGH: Based on an estimated 96-hour ECS0 of 7.67 (ECOSAR class: neutral organics) for green algae.
Fish LC50
Fish 96-hour LC50 = 14.75 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Fish 96-hour LC50 = 41.53 mg/L
(Estimated)
ECOSAR: phenols, poly - acid
EPI
Daphnid LCS0
Daphnid 48-hour LC50 = 10.07 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid 48-hour LC50 = 103.05 mg/L
(Estimated)
ECOSAR: phenols, poly - acid
EPI
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Green Algae ECS0
Green algae 96-hour EC50 = 7.67 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Green algae 96-hour EC50 = 18.35 mg/L
(Estimated)
ECOSAR: phenols, poly - acid
EPI
Chronic Aquatic Toxicity
MODERATE: Based on ECOSAR-estimated data for fish, Daphnid, and green algae.
Fish ChV
Fish ChV = 1.36 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Fish 30-day ChV = 10.16 mg/L
(Estimated)
ECOSAR: phenols, poly - acid
EPI
Daphnid ChV
Daphnid ChV =1.19 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid 21-day ChV =35.44 mg/L
(Estimated)
ECOSAR: phenols, poly - acid
EPI
Green Algae ChV
Green algae ChV = 3.34 mg/L
(Estimated)
ECOSAR: phenols, poly - acid
EPI
Green algae ChV = 3.58 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
ENVIRONMENTAL FATE
Transport
Based on the Level III fugacity models incorporating the available experimental property data, this
substituted phenolic compound is expected to partition primarily to soil where it is expected to be immobile in
based on its estimated Koc. Estimated volatilization half-lives indicate it will be non-volatile from surface
water. Volatilization from dry surface is also not expected based on its estimated vapor pressure. In the
atmosphere, this substituted phenolic compound is expected to exist solely in the particulate phase, based on
its estimated vapor pressure. Particulates may be removed from air by wet or dry deposition.
Henry's Law Constant
(atm-m3/mole)
1 year (Estimated)
EPI
Volatilization Half-life
for Model Lake
>1 year (Estimated)
EPI
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Soil
Aerobic
Biodegradation
No data located.
Anaerobic
Biodegradation
Not probable (anaerobic-methanogenic
biodegradation probability model)
EPI
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
Biodegradation
No data located.
Air
Atmospheric Half-life
1.5 hours (Estimated)
EPI
Reactivity
Photolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain
functional groups that would be
expected to absorb light at
environmentally significant
wavelengths.
Hydrolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain
functional groups that would be
expected to absorb light at
environmentally significant
wavelengths.
Pyrolysis
No data located.
Environmental Half-life
30 days (Estimated)
EPI; PBT Profiler
Half-life estimated for the
predominant compartment, as
determined by EPI and the PBT
Profiler methodology.
Bioaccumulation
LOW: The fish BCF and BAF estimates are <100.
Fish BCF
3.2 (Estimated)
EPI
BAF
84 (Estimated)
EPI
Metabolism in Fish
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Ecological Biomonitoring
No data located.
Human Biomonitoring
This chemical was not included in the NHANES biomonitoring report (CDC, 2011).
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Alfa Aesar - A Johnson Matthey Company. Material Safety Data Sheet (MSDS). Available at http://www.alfa.com. Accessed on November,
19,2010.
Blair R.M., Fang H., Branham, W.S., et al. The estrogen receptor relative binding affinities of 188 natural and xenochemicals:
structural diversity of ligands. Toxicol. Sci. 2000, 54:138-153.
Boethling, R., Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences. Boca Raton:
Lewis Publishers. 2000.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
EINECS (European Inventory of Existing Commercial chemical Substances). 4,4"-Isopropylidenediphenol (bisphenol A). European
Union Risk Assessment Report. 2010.
EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 4.00. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
European Commission. IUCLID Dataset for 4,4-isopropylidenediphenol (CAS No. 80-05-7). European Chemicals Bureau, February
19, 2000.
FAO/WHO (Food and Agriculture Organization/World Health Organization). 2010. Joint FAO/WHO expert meeting to review
toxicological and health aspects of bisphenol A. Summary report including report of stakeholder meeting on bisphenol A. Food and
Agriculture Organization of the United Nations; World Health Organization. Ottawa, Canada. November 1-5, 2010.
Lide, D. R, ed. CRC Handbook of Chemistry and Physics, 88th edition; CRC Press Taylor & Francis: Boca Raton, FL. 2008.
Mutat Res. 2008 (Sanitized - article title and author)
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NIOSH (National Institute for Occupational Safety and Health). Skin Notation (SK) Profile, bisphenol A (BPA) [CAS No. 80-05-7],
Department of Health and Human Services; Centers for Disease Control and Prevention, 2010.
NTP (National Toxicology Program). Carcinogenesis bioassay of bisphenol-A (CAS No. 80-05-7) in F344 rats and B6C3F1 mice
(feed study). Technical Report No. 215, PB82-184060. 1982.
NTP (National Toxicology Program). Department of Health and Human Services. 2010. http://ntp-apps.niehs.nih.gov/ntp_tox/
NTP-CERHR. Monograph on the potential human reproductive and developmental effects of biphenol A. National Toxicology
Program; U.S. Department of Health and Human Service. Center for the Evaluation of Risks to Human Reproduction. NIH
Publication No. 08-5994. September 2008.
Oncologic. U.S. EPA and LogiChem, Inc. 2005, Version 7.0. 2008.
O'TSTeil, M., et al. eds. e-Merck Index. 14th ed. Basic Search. Whitehouse Station, NJ: Merck & Co., Inc. 2010.
https://themerckindex.cambridgesoft.com/TheMerckIndex/index.asp (accessed on December 10, 2010).
PBT Profi 1 er Persistent (P), Bioaccumulative (B), and Toxic (T) Chemical (PBT) Profiler, U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
SPARC On Line Calculator pKaproperty server. Ver 4.5 September, 2009. Available from, http://ibmlc2.chem.uga.edu/spare/
(accessed on August 12, 2010).
U.S. EPA Sustainable Futures Using NonCancer Screening within the Sustainable Futures Initiative Environmental Protection
Agency: Washington D.C. 2010. http://www.epa.gOv/opptintr/sf/pubs/noncan-screen.htm#svstemic (accessed on February 09, 2011).
U.S. EPA (Environmental Protection Agency). High Production Volume (HPV) Challenge. Determining the Adequacy of Existing
Data. U.S. Environmental Protection Agency: Washington D.C. 1999. http://www.epa.gov/hpv/pubs/general/datadfin.htm
U.S. EPA (Environmental Protection Agency). Sustainable Futures Summary Assessment. Assessment of Discrete Organic
Chemicals. U.S. Environmental Protection Agency: Washington D.C. 2011.
http://www.epa.gov/oppt/sf/pubs/iad_discretes_092011 .pdf
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Substituted Phenolic Compound #2
CASRN: Confidential CASRN
MW: Confidential MW
MF: Confidential MF
Physical Forms:
Neat: Solid
Use: Developer for thermal paper
SMILES: This confidential material is not amenable to the generation of a single SMILES notation.
Synonyms: None
Polymeric: No
Oligomers: Not applicable
Metabolites, Degradates and Transformation Products: None identified
Analog: Bisphenol A (80-05-7)
Endpoint(s) using analog values: Acute toxicity, eye and skin irritation, skin
sensitization, reproductive and developmental toxicity, genotoxicity, repeated dose
effects
Analog Structure:
Structural Alerts: Phenols, neurotoxicity (U.S. EPA, 2010)
Risk Phrases: R43 - May cause sensitization by skin contact; 62 Possible risk of impaired fertility; 51/53 - Toxic to aquatic organisms, may cause long-term adverse
effects in the aquatic environment (ESIS, 2011).
Risk Assessments: None identified
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
138 (Measured)
Chemspider, 2010
Adequate; secondary source, study
details and test conditions were not
provided; selected value for
assessment.
135-139 (Measured)
Aldrich, 2009
Adequate; measured by chemical
supplier, consistent with other
reported values.
Boiling Point (°C)
>300 (Estimated)
EPI; U.S. EPA, 1999
Cutoff value for high boiling point
compounds according to HPV
assessment guidance.
Vapor Pressure (mm Hg)
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DRAFT REPORT - DO NOT CITE OR QUOTE
PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
HUMAN HEALTH EFFECTS
Toxicokinetics
Substituted phenolic compound #2 is estimated to not be absorbed through the skin and have poor
absorption when in solution via the lungs and gastrointestinal tract.
Dermal Absorption in vitro
No data located.
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal or Inhaled
Not absorbed through the skin and has
poor absorption through the lung and
gastrointestinal tract
(Estimated by analogy)
Professional judgment
Based on closely related analog with
similar structure, functional groups,
and physical/chemical properties.
Acute Mammalian Toxicity
LOW: Based on analogy to bisphenol A. The acute oral and dermal toxicity hazard of substituted phenolic
compound #2 is estimated to be low based on experimental data in animals for a closely related substance.
Data for exposure to the analog bisphenol A via inhalation were inconclusive, as only a single concentration
was tested and an LCS0 was not provided.
Acute Lethality
Oral
Rat LD50 = 3,200-5,000 mg/kg bw
(Estimated by analogy)
NTP, 1982; European
Commission, 2000; EINECS,
2010; Professional judgment
Based on the analog bisphenol A;
multiple studies, some guideline
studies.
Mouse LD50 = 4,000-5,200 mg/kg bw
(Estimated by analogy)
NTP, 1982; European
Commission, 2000; EINECS,
2010; Professional judgment
Based on the analog bisphenol A;
multiple studies, some guideline
studies.
Dermal
Rabbit LD50 = 3,000-6,400 mg/kg bw
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate by weight of evidence,
multiple studies, although study
details were not reported in
secondary sources.
Inhalation
No deaths among male and female F344
rats (10/sex) exposed to bisphenol A
dust at 0.17 mg/L (highest attainable
concentration) for 6 hours; transient
slight nasal tract epithelial damage was
evident
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A; test
guidelines were not reported in
secondary sources.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Carcinogenicity
MODERATE: Estimated using OncoLogic expert system, which describes a concern for this compound as a
potential carcinogen or tumorigenesis promoter arising from its structural similarity to
estrogenic/androgenic compounds, using the 'phenols and phenolic compounds' structural alert.
OncoLogic Results
Moderate (Estimate)
OncoLogic class: phenols and phenolic
compounds
OncoLogic
OncoLogic SAR analysis using the
phenols and phenolic compounds
class.
Carcinogenicity (Rat and
Mouse)
No data located.
Combined Chronic
Toxicity/ Carcinogenicity
No data located.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Genotoxicity
LOW: Based on analogy to bisphenol A. FAO/WHO (2011) determined that: (1) the analog bisphenol A is
not a mutagen in in vitro test systems, (2) the analog bisphenol Adoes not induce cell transformation, and (3)
in vivo evidence for clastogenic effects induced by the analog bisphenol A is inconsistent and inconclusive
although some in vitro studies have shown bisphenol A to affect chromosomal structure in dividing cells.
The conclusion of FAO/WHO (2011) is that the analog bisphenol A is not likely to pose a genotoxic hazard to
humans.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Largely negative results in a variety of in
vitro test systems, including studies with
Salmonella typhimurium, Chinese
hamster V79 cells, Syrian hamster
embryo cells, and mouse lymphoma
cells. However, DNA damage was
induced in MCF-7 and MDA-MB-231
cells, DNA adduct formation in Syrian
hamster ovary cells and a number of
positive findings have been reported for
the potential for bisphenol A to inhibit
purified microtubule polymerization,
affect the spindle apparatus and produce
aneuploidy in in vitro studies with
Chinese hamster V79 cells or oocytes
from Balb/c or MF1 mice.
FAO/WHO Expert Panel concludes:
BPA is not a mutagen in in vitro test
systems, nor does it induce cell
transformation. Bisphenol A has been
shown to affect chromosomal structure
in dividing cells in in vitro studies, but
evidence for this effect in in vivo studies
is inconsistent and inconclusive.
Bisphenol A is not likely to pose a
genotoxic hazard to humans.
(Estimated by analogy)
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproductive Effects
HIGH: Based on analogy to bisphenol A. Based on NOAELs of 4.75 mg/kg bw-day and 47.5 mg/kg bw-day
for reproductive toxicity in male and female rats, respectively, following oral exposure to the analog
bisphenol A. Conclusions of NTP (2008) include sufficient evidence in rats and mice that subchronic or
chronic oral exposures to the analog bisphenol A causes female reproductive toxicity at doses >475 mg/kg
bw-day (highest NOAEL = 47.5 mg/kg bw-day) and male reproductive toxicity at doses >47.5mg/kg bw-day
(highest NOAEL = 4.75 mg/kg bw-day). There is considerable uncertainty regarding the results of recent
studies that reported reproductive and/or developmental effects in laboratory animals administered the
analog bisphenol A at oral doses <5 mg/kg bw-day.
Reproduction/
Developmental Toxicity
Screen
No data located.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Reproduction and Fertility
Effects
Parental systemic toxicity:
NOAEL = 4.75 mg/kg bw-day
LOAEL = 47.5 mg/kg bw-day for 12%
decreased terminal body weight in Fi
parental males
Reproductive toxicity:
Females: NOAEL = 47.5 mg/kg bw-day
LOAEL = 475 mg/kg bw-day for
decreases in number of implantation
sites, delayed vaginal opening in Fi, F2,
and F3 offspring
Males: NOAEL = 4.75 mg/kg bw-day,
LOAEL = 47.5 mg/kg-day for delayed
preputial separation in F, males
(Estimated by analogy)
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
adequate, guideline study as reported
in the secondary source.
Classified by NTP-CERHR as having
High Utility.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Parental systemic toxicity:
NOAEL = 5 mg/kg bw-day
LOAEL = 50 mg/kg bw-day for
increased incidences of centrilobular
hepatocellular hypertrophy in males and
females
FAO/WHI, 2011; NTP-CERHR,
2008; Professional judgment
Based on the analog bisphenol A;
adequate, guideline study as reported
in the secondary source.
Classified by NTP-CERHR as having
High Utility.
Reproductive toxicity:
NOAEL = 50 mg/kg bw-day
LOAEL = 600 mg/kg bw-day for
increased gestation length, decreased
epididymal sperm concentration in F,
males, increased incidence of gross
ovarian cysts in Fi and F2 females
(Estimated by analogy)
Summary of Reproductive
Effects
Female effects: There is sufficient
evidence in rats and mice that bisphenol
A causes female reproductive toxicity
with subchronic or chronic oral
exposures
NOAEL of 47.5 mg/kg bw-day
LOAEL of 475 mg/kg bw-day
Male effects: There is sufficient
evidence in rats and mice that bisphenol
A causes male reproductive toxicity with
subchronic or chronic oral exposures
NOAEL of 4.75 mg/kg bw-day
LOAEL of 47.5 mg/kg bw/day
(Estimated by analogy)
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A.
Classified by NTP-CERHR as having
High Utility.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
The joint FAO/WHO Expert Panel
(2010) reviewed available reproductive
and developmental toxicity data for
bisphenol A as of November, 2010 and
noted that most regulatory bodies
reviewing the numerous studies on
bisphenol A have indicated an oral
reproductive and developmental
NOAEL of 50 mg/kg bw-day.
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A.
Classified by NTP-CERHR as having
High Utility.
(Estimated by analogy)
Developmental Effects
HIGH: Based on analogy to bisphenol A. The NTP-CERHR (2008) Expert Panel concluded that there is
suggestive evidence that the analog bisphenol A causes neural and behavioral alterations related to
disruptions in normal sex differences in rats and mice (0.01-0.2 mg/kg bw-day). The FAO/WHO (2011)
Expert Panel concluded that while there was broad agreement in a NOAEL of 50 mg/kg bw/day for
developmental toxicity, low-level (<1 mg/kg bw-day) effects were uncertain. These conclusions support a
call of High concern of the analog, with lower confidence.
Reproduction/
Developmental Toxicity
Screen
No data located.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Summary of
Developmental Effects
The NTP-CERHR (2008) Expert Panel
concluded that bisphenol A:
*does not cause malformations or birth
defects in rats or mice at levels up to the
highest doses evaluated: 640 mg/kg bw-
day (rats) and 1,250 mg/kg bw-day
(mice).
*does not alter male or female fertility
after gestational exposure up to doses of
450 mg/kg bw-day in the rat and
600mg/kg bw-day in the mouse (highest
dose levels evaluated).
*does not permanently affect prostate
weight at doses up to 475 mg/kg bw-day
in adult rats or 600 mg/kg bw-day in
mice.
*does not cause prostate cancer in rats or
mice after adult exposure at up to 148 or
600 mg/kg bw-day, respectively.
*does change the age of puberty in male
or female rats at high doses (ca.
475 mg/kg bw-day).
And that rodent studies suggest that
bisphenol A:
* causes neural and behavioral alterations
related to disruptions in normal sex
differences in rats and mice
(0.01-0.2 mg/kg bw-day).
(Estimated by analogy)
NTP-CERHR, 2008; Professional
judgment
Based on the analog bisphenol A.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
The joint FAO/WHO (2011) Expert
Panel reviewed available reproductive
and developmental toxicity data for
bisphenol A as of November, 2010 and
noted that most regulatory bodies
reviewing the numerous studies on
bisphenol A have indicated an oral
reproductive and developmental
NOAEL of 50 mg/kg bw-day.
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
(Estimated by analogy)
Neurotoxicity
MODERATE: Estimated to have potential for neurotoxicity based on the presence of the phenol structural
alert.
Neurotoxicity Screening
Battery (Adult)
There is potential for neurotoxicity
effects based on the presence of the
phenol structural alert
(Estimated)
U.S. EPA 2010, Professional
judgment
Estimated based on structural alert.
Repeated Dose Effects
MODERATE: Estimated based on analogy to bisphenol A, which produced histopathologic changes in the
liver (centrilobular hepatocyte hypertrophy) from oral dosing at 50 mg/kg bw-day (NOAEL = 5 mg/kg bw-
day) and there is uncertainty regarding the potential for bisphenol A doses between the NOAEL of 5 mg/kg
bw-day and the LOAEL of 50 mg/kg bw-day to cause adverse systemic effects. Furthermore, lesions in the
nasal cavity of rats were reported following repeated inhalation exposure to bisphenol A dust at 0.05 mg/L.
These findings indicate a Moderate hazard concern for the oral and inhalation exposure routes.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
The FAO/WHO (2011) Expert Panel
reviewed the available information
regarding repeated-dose oral toxicity of
bisphenol A and concluded that results
demonstrated effects on the liver,
kidney, and body weight at doses of
50 mg/kg bw-day and higher and that the
lowest NOAEL was 5 mg/kg bw-day, as
identified in several studies.
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
(Estimated by analogy)
Parental systemic toxicity:
NOAEL = 4.75 mg/kg bw-day
LOAEL = 47.5 mg/kg bw-day for 12%
decreased terminal body weight in Fi
parental males
(Estimated by analogy)
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
guideline study as reported in the
secondary source.
Classified by NTP-CERHR as having
High Utility.
Parental systemic toxicity:
NOAEL = 5 mg/kg bw-day
LOAEL = 50 mg/kg bw-day for
increased incidences of centrilobular
hepatocellular hypertrophy in males and
females
NTP-CERHR 2008; Professional
judgment
Based on the analog bisphenol A;
guideline study as reported in the
secondary source.
Classified by NTP-CERHR as having
High Utility.
(Estimated by analogy)
NOAEL = 0.01 mg/L
LOAEL = 0.05 mg/L based on
microscopic changes in the anterior
portion of the nasal cavity
EINECS, 2010; European
Commission, 2000; Professional
judgment
Based on the analog bisphenol A.
(Estimated by analogy)
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
NOAEL = None established
LOAEL = 0.047 mg/L for decreased
body weight gain, increased liver and
kidney weight, unspecified
"morphological changes" in liver,
kidney, and lungs
EINECS, 2010; European
Commission, 2000; Professional
judgment
Based on the analog bisphenol A;
single exposure level, insufficient
study details in secondary sources.
(Estimated by analogy)
Skin Sensitization
MODERATE: Based on analogy to bisphenol A, substituted phenolic compound #2 is estimated to be a skin
sensitizer. Recent data from three bisphenol A manufacturing facilities indicate that it does not elicit skin
sensitization; however, results of some human studies suggest the possibility of a dermal sensitization
response, although cross-sensitization was not ruled out. Most animal studies conducted on the analog were
negative for dermal sensitization, although assays may not have been maximized. There is evidence of ear
swelling in a photoallergy test in mice and moderate redness and swelling following repeated dermal
exposure in rabbits. Based on suggestive evidence of skin sensitization in humans and mice for the analog,
MODERATE hazard call is warranted.
Skin Sensitization
Negative in a modified local lymph node
assay of mice administered bisphenol A
epicutaneously on the ears at
concentrations up to 30% on
3 consecutive days
(Estimated by analogy)
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate, although the assay did not
include concentrations >30%.
Negative in a local lymph node assay
modified to test for photoreactivity in
mice administered bisphenol A
epicutaneously on the ears at
concentrations up to 30% on
3 consecutive days and irradiated with
UV light immediately following
application
(Estimated by analogy)
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate, although the assay did not
include concentrations >30%.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Negative in comprehensive medical
surveillance data obtained from three
bisphenol A manufacturing plants for
875 employees examined for several
years where workers were potentially
exposed to other chemicals (phenol,
acetone) that are not considered to be
skin sensitizers
(Estimated by analogy)
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate.
Positive, rabbits; repeated dermal
application (30 times over 37 days) of
bisphenol A (pure powder) produced
moderate swelling and redness. Skin
turned yellow followed by dark
pigmentation after day 15
(Estimated by analogy)
NIOSH, 2010; Professional
judgment
Based on the analog bisphenol A;
adequate.
The Joint FAO/WHO Expert Meeting to
review toxicological aspects of
bisphenol A concurs with previous
reviews that BPA is capable of
producing a skin sensitization response
in humans
(Estimated by analogy)
FAO/WHO, 2011; Professional
judgment
Based on the analog bisphenol A.
Respiratory Sensitization
No data located.
Respiratory Sensitization
No data located.
Eye Irritation
MODERATE: Based on analogy to bisphenol A. Substituted phenolic compound #2 is estimated to be
slightly to highly irritating to rabbit eyes based on test data for the analog bisphenol A.
Eye Irritation
Rabbit, slightly to highly irritating
European Commission, 2000;
EINECS, 2010; Professional
judgment
Based on the analog bisphenol A.
Adequate; multiple studies, weight of
evidence indicates potential for
bisphenol A to cause eye irritation.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Dermal Irritation
MODERATE: Based on analogy to bisphenol A; substituted phenolic compound #2 is estimated to be
slightly irritating to moderately irritating to rabbit skin based on test data for the analog bisphenol A.
NIOSH has assigned the analog bisphenol A as a skin irritant.
Dermal Irritation
Rabbit, nonirritating to slightly irritating
when applied as undiluted or 10%
aqueous suspension to intact or abraded
skin
(Estimated by analogy)
European Commission, 2000;
EINECS, 2010; NIOSH, 2010;
Professional judgment
Based on the analog bisphenol A.
Adequate; multiple studies, weight of
evidence indicates potential for BPA
to cause dermal irritation.
Rabbit, moderately irritating when
applied as 40% solution in dimethyl
sulfoxide under non-occlusive
conditions.
(Estimated by analogy)
European Commission, 2000;
Professional judgment
Based on the analog bisphenol A;
adequate.
Guinea pig, not irritating when applied
as 5% solution in acetone for 24 hours
under occlusive conditions
(Estimated by analogy)
European Commission, 2000;
Professional judgment
Based on the analog bisphenol A;
adequate.
Endocrine Activity
Substituted phenolic compound #2 is capable of eliciting an estrogenic response in rats injected with
substituted phenolic compound #2 subcutaneously, as evidenced by increased uterine weight. Substituted
phenolic compound #2 did not bind to estrogen receptors in one in vitro assay and did not elicit androgenic
or anti-androgenic responses in another in vitro assay.
In a uterotrophic assay in which
immature female rats were injected with
bisphenol F, bisphenol S, or substituted
phenolic compound #2 subcutaneously
for 3 consecutive days, observed
changes in uterine weight indicated that
bisphenol F, bisphenol S, and substituted
phenolic compound #2 exerted both
estrogenic and anti-estrogenic responses.
Akahori et al., 2008
Adequate.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In a uterotrophic assay of rats
subcutaneously injected with bisphenol
F once daily for 3 days, an apparent
estrogenic effect was evidenced by
increased absolute and relative uterine
weight. Similar effects were elicited by
bisphenol S and substituted phenolic
compound #2.
Toxicol. Lett. 2004 (Sanitized)
Adequate.
In a human ER binding assay, the
relative binding affinity (RBA) of
substituted phenolic compound #2 was
0.175% relative to 17|3-estradiol (set at
100%). RBAs for other bisphenol
compounds included 0.0719% for
bisphenol F and 0.0055% for bisphenol
A.
Toxicol. Lett. 2004 (Sanitized)
Adequate.
In an ERE-luciferase reporter assay
using MCF-7 cells, substituted phenolic
compound #2 did not appear to elicit an
estrogenic response (EC50 >1,000 (iM).
EC50 values for other bisphenol
compounds included 0.63% for
bisphenol A, 0.42 (.iM for bisphenol C,
1.0 (.iM for bisphenol F, and 1.1 (.iM for
bisphenol S.
Toxicol. Sci., 2005 (Sanitized)
Adequate.
In an ERE-luciferase reporter assay
using MCF-7 cells in the presence of
17|3-estradiol, neither substituted
phenolic compound #2, bisphenol A,
bisphenol C, bisphenol F, nor bisphenol
S, appeared to exert an anti-estrogenic
effect.
Toxicol. Sci., 2005 (Sanitized)
Adequate.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In an ARE-luciferase reporter assay
using NIH3T3 cells without expressing
AR, substituted phenolic compound #2
did not elicit an androgenic response or
an anti-androgenic response in the
presence of dihydrotestosterone.
Toxicol. Sci., 2005 (Sanitized)
Adequate although actual data were
not shown in study report.
Immunotoxicity
No data located.
Immune System Effects
No data located.
ECOTOXICITY
ECOSAR Class
Phenols, Poly
Acute Toxicity
HIGH: Based on estimated 96-hour LCS0 for fish, 48-hour LCS0 for Daphnid, and 96-hour ECS0 for green
algae (neutral organics).
Fish LC50
Fish 96-hour LC50 = 0.067 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Fish 96-hour LC50 = 0.106 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Daphnid LCS0
Daphnid 48-hour LC50 = 0.065 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid 48-hour LC50 = 0.078 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Green Algae ECS0
Green algae 96-hour EC50 = 0.16 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Chemical may not be sufficiently
soluble to measure this predicted
effect.
Green algae 96-hour EC50 = 1.24 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Chemical may not be sufficiently
soluble to measure this predicted
effect.
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Chronic Aquatic Toxicity
HIGH: Based on estimated ChVs for fish, Daphnid, and green algae.
Fish ChV
Fish ChV = 0.006 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Fish 30-day ChV = 0.016 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Daphnid ChV
Daphnid ChV = 0.013 mg/L (Estimated)
ECOSAR: neutral organics
EPI
Daphnid ChV = 0.023 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Green Algae ChV
Green algae ChV = 0.066 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Green algae ChV = 0.126 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Chemical may not be sufficiently
soluble to measure this predicted
effect.
ENVIRONMENTAL FATE
Transport
The transport evaluation for substituted phenolic compound #2 is based on available experimental and
estimated physical and chemical properties. Based on the Level III fugacity models incorporating the
available experimental property data, substituted phenolic compound #2 is expected to partition to sediment
and soil. Additionally, substituted phenolic compound #2 is expected to have low mobility in soil based on
its estimated Koc therefore, leaching of substituted phenolic compound #2 through soil to groundwater is not
expected to be an important transport mechanism. Estimated volatilization half-lives indicate that it will be
non-volatile from surface water. In the atmosphere, substituted phenolic compound #2 is expected to exist
in the particulate phase, based on its estimated vapor pressure. Particulates will be removed from air by
wet or dry deposition.
Henry's Law Constant
(atm-m3/mole)
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Sediment/Soil
Adsorption/Desorption
Coefficient - Koc
>30,000 (Estimated)
EPI; U.S. EPA, 2011
Cutoff value for non mobile
compounds according to SF
assessment guidance.
Level III Fugacity
Model
Air = <1% (Estimated)
Water =1%
Soil = 42%
Sediment = 57%
EPI
Persistence
HIGH: Evaluation of the persistence of substituted phenolic compound #2 is based entirely on QSARs of
aerobic and anaerobic biodegradation. Results from these models estimate ultimate biodegradation in
months and primary degradation in weeks. Biodegradation under anaerobic methanogenic conditions is not
probable based on results from estimation models, substituted phenolic compound #2 does not contain
chromophores that absorb light at wavelengths >290 nm. Therefore, it is not expected to be susceptible to
direct photolysis. It is not expected to undergo hydrolysis as it does not contain hydrolysable functional
groups. The atmospheric half-life of substituted phenolic compound #2 is estimated at 1.4 hours, although it
is expected to exist primarily as a particulate in air. Therefore, biodegradation is expected to be the main
degradation pathway for substituted phenolic compound #2.
Water
Aerobic Biodegradation
Weeks (primary survey model)
Months (ultimate survey model)
EPI
Volatilization Half-life
for Model River
>1 year (Estimated)
EPI
Volatilization Half-life
for Model Lake
>1 year (Estimated)
EPI
Soil
Aerobic Biodegradation
No data located.
Anaerobic
Biodegradation
Not probable (Anaerobic-methanogenic
biodegradation probability model)
EPI
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
Biodegradation
No data located.
Air
Atmospheric Half-life
1.4 hours (Estimated)
EPI
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PROPRIETARY SUBSTITUTED PHENOLIC COMPOUND #2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reactivity
Photolysis
Not a significant fate process
(Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain functional
groups that would be expected to
absorb light at environmentally
significant wavelengths.
Hydrolysis
Not a significant fate process
(Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain functional
groups that would be expected to
hydrolyze readily under
environmental conditions.
Pyrolysis
No data located.
Environmental Half-life
>180 days (Estimated)
EPI; PBT Profiler
Half-life estimated for the
predominant compartment, as
determined by EPI and the PBT
Profiler methodology.
Bioaccumulation
HIGH: The estimated BAF and fish BCF values are >5,000.
Fish BCF
6,200 (Estimated)
EPI
BAF
9,100 (Estimated)
EPI
Metabolism in fish
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
Ecological Biomonitoring
No data located.
Human Biomonitoring
This chemical was not included in the NHANES biomonitoring report (CDC, 2011).
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Aldrich. Material Safety Data Sheet (MSDS). Available at: http://www.sigmaaldrich.com/ Accessed on December 21, 2010.
Akahori, Y., Makai, M., Yamasaki, K., et al. Relationship between the results of in vitro receptor binding assay to human estrogen
receptor a and in vivo uterotrophic assay: Comparative study with 65 selected chemicals. Toxicology In Vitro 2008, 22:225-231.
Boethling, R., Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences. Boca Raton:
Lewis Publishers. 2000.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http ://www. cdc. gov/exposurereport/ (accessed on May 10, 2011).
ChemSpider. ChemSpider; Stractare-based Chemistry Information. Royal Society of Chemistry:London. 2010.
http://www.chemspider.com (accessed on December 11, 2010).
EINECS (European Inventory of Existing Commercial chemical Substances). 4,4"-Isopropylidenediphenol (bisphenol A). European
Union Risk Assessment Report. 2010.
EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 4.0. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
European Commission. IUCLID Dataset for 4,4-isopropylidenediphenol (CAS No. 80-05-7). European Chemicals Bureau, February
19, 2000. 2000.
FAO/WHO (Food and Agriculutre Organization/World Health Organization). Joint FAO/WHO expert meeting to review toxicological
and health aspects of bisphenol A. Summary report including report of stakeholder meeting on bisphenol A. Food and Agriculture
Organization of the United Nations; World Health Organization. Ottawa, Canada. November 1-5, 2010.
NIOSH (National Institute for Occupational Safety and Health). Skin Notation (SK) Profile, Bisphenol A (BPA) [CAS No. 80-05-7],
Department of Health and Human Services; Centers for Disease Control and Prevention. 2010.
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NTP (National Toxicology Program). Carcinogenesis bioassay of bisphenol-A (CAS No. 80-05-7) in F344 rats and B6C3F1 mice
(feed study). Technical Report No. 215, PB82-184060. 1982.
NTP-CERHR. Monograph on the potential human reproductive and developmental effects of biphenol A. National Toxicology
Program; U.S. Department of Health and Human Service. Center for the Evaluation of Risks to Human Reproduction. NIH
Publication No. 08-5994. September 2008.
Oncologic. U.S. EPA and LogiChem, Inc. 2005, Version 7.0. 2008.
PBT Profi 1 er Persistent (P),Bioaccumulative (B), and Toxic (T) Chemical (PBT)Profiler, U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
SPARC On Line Calculator pKaproperty server. Ver 4.5 September, 2009. Available from, http://ibmlc2.chem.uga.edu/spare/
(accessed on August 12, 2010).
Toxicol. Lett. 2004 (Sanitized - article title and author).
Toxicol. Sci., 2005 (Sanitized - article title and author).
U.S. EPA (Environmental Protection Agency). High Production Volume (HPV) Challenge. Determining the Adequacy of Existing
Data. U.S. Environmental Protection Agency: Washington D.C. 1999. http://www.epa.gov/hpv/pubs/general/datadfin.htm
U.S. EPA Sustainable Futures. Using Non Cancer Screening within the SF Initiative. Environmental Protection Agency: Washington
D.C. 2010. http://www.epa.gOv/opptintr/sf/pubs/noncan-screen.htm#systemic as of February 09, 2011.
U.S. EPA (Environmental Protection Agency). Sustainable Futures Summary Assessment. Assessment of Discrete Organic
Chemicals. U.S. Environmental Protection Agency: Washington D.C. 2011.
http://www.epa.gov/oppt/sf/pubs/iad_discretes_092011 .pdf
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PHBB
CASRN: 94-18-8
MW: 228.25
MF: C14H1203
Physical Forms:
Neat: Solid
Use: Developer for thermal paper
SMILES: c 1 (C(0Cc2ccccc2)=0)ccc(0)cc 1
Synonyms: Benzoic acid, 4-hydroxy-, phenylmethyl ester (TSCA Inventory); Benzyl 4-hydroxybenzoate; Benzyl p-hydroxybenzoate; Benzyl parahydroxybenzoate;
Benzylparaben; Phenylmethyl 4-hydroxybenzoate; AI3-02955; Benzyl Parasept; Benzyl Tegosept; Nipabenzyl; Parosept; Solbrol Z; p-Hydroxybenzoic acid benzyl
ester
Polymeric: No
Oligomers: Not applicable
Metabolites, Degradates and Transformation Products: Hydrolysis products - 4-hydroxybenzoic acid (99-96-7) and benzyl alcohol (100-51-6)
Analog: Benzyl-2-hydroxybenzoate (118-58-1)
Endpoint(s) using analog values: Aerobic biodegradation
and genotoxicity
Analog Structure:
Structural Alerts: Phenols, neurotoxicity (U.S. EPA, 2010)
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 2011).
Risk Assessments: None identified
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PHBB CASRN 94-18-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROP
ERTIES
Melting Point (°C)
111 (Measured)
PhysProp
Adequate; consistent values
reported in secondary source.
110-112 (Measured)
CIR, 1986
Adequate; valid, nonguideline
study.
Boiling Point (°C)
>300 (Estimated)
EPI; U.S. EPA, 1999
Cutoff value for high boiling point
compounds according to HPV
assessment guidance.
Vapor Pressure (mm Hg)
3. 8x 10"6 (Estimated)
EPI
Water Solubility (mg/L)
60 at 25 °C (Measured)
Thomas, 2006
Nonguideline study reported in
secondary source. Although the
value is consistent with other
reported properties, the pH of the
measurement was not reported, and
was interpreted as pH 7.
Log Kow
3.56 (Measured)
PhysProp
Adequate; nonguideline study
reported in secondary source.
Value is consistent with other
reported properties.
Flammability (Flash Point)
No data located.
Explosivity
No data located.
pH
No data located.
pKa
7.8 (Estimated)
SPARC
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DATA QUALITY
HUMAN HEALTH EFFECTS
Toxicokinetics
PHBB is estimated to not be absorbed through the skin as neat material and has moderate absorption
through skin when in solution. PHBB can be absorbed through the lung and gastrointestinal tract.
Although not readily hydrolyzed, PHBB is expected to undergo ester hydrolysis by esterases in the body
and produce the metabolites benzyl alcohol and p-hydroxybenzoic acid.
Dermal Absorption in vitro
At 24 hours following application of
PHBB to human skin (in vitro), recoveries
in the receptor medium as parent
compound and its hydrolysis product
(4-hydroxybenzoic acid) were 17 and
24%, respectively. Hydrolysis of PHBB
to 4-hydroxybenzoic acid in the human
skin was catalyzed by carboxylesterases,
particularly human carboxylesterase 2.
Jewell, Prusakiewicz et al., 2007
Adequate.
20% dermal absorption in vitro (Estimated
by analogy).
Professional judgment
Based on a confidential study on a
closely related analog.
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal, Inhaled
Trace amounts of PHBB (in conjugated
form) were detected in the urine of
39/100 demographically-diverse adult
volunteers with no known occupational
exposure to PHBB.
Ye, Bishop et al., 2006
Adequate.
Following ingestion of PHBB (2 g/day for
5 days) by two volunteers, analysis of the
urine revealed that 6% of the administered
dose was eliminated unchanged; 87% was
eliminated as the sulfate conjugate of the
ester. Only small quantities of PHBB
metabolites (4-hydroxybenzoic acid,
benzyl alcohol, benzoic acid,
4-hydroxyhippuric acid, and hippuric acid)
were detected.
Sabalitschka and Neufeld-
Crzellitzer, 1954 (as cited in
CIR 1986, 2008)
Adequate.
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DATA QUALITY
Not absorbed through the skin as neat
material and has moderate absorption
through skin when in solution. Can be
absorbed through the lung and
gastrointestinal tract. PHBB is expected to
undergo ester hydrolysis by esterases in
the body and produce benzyl alcohol and
p-hydroxybenzoic acid.
(Estimated by analogy)
Professional judgment
Based on closely related analog
with similar structure, functional
groups, and physical/chemical
properties.
93% absorbed in gastrointestinal tract
(Estimated by analogy)
Professional judgment
Based on a confidential study on a
closely related analog.
Acute Mammalian Toxicity
LOW: Based on experimental data in w
of acute oral exposure of laboratory anin
was limited to summary statements in se
data were located regarding the hazard (
lich no overt clinical signs of toxicity or death occurred as result
lals to doses 2,000-10,000 mg/kg, although the information located
condary sources that did not include important study details. No
)f acute inhalation or dermal exposure.
Acute Lethality
Oral
No deaths or clinical signs of toxicity were
observed in slc-ddy mice administered
10,000 mg/kg PHBB via gavage.
Sabalitschka, 1933 (as cited in
CIR, 1986)
Inadequate; details are missing as
this is a review on various animal
toxicity studies.
No deaths occurred when Charles River
CD rats were given 5,000 mg/kg PHBB.
CTFA, 1985 (as cited in CIR,
1986, 2008)
Adequate.
No signs of toxicity were evident in guinea
pigs fed 2,000 mg PHBB/day for an
unspecified period.
Sabalitschka and Neufeld-
Crzellitzer, 1954 (as cited in CIR,
1986, 2008)
Adequate.
Dermal
No data located.
Inhalation
No data located.
Carcinogenicity
MODERATE: Estimated to have potential for carcinogenicity based on the benzyl alcohol hydrolysis
product; potential is dependent on the rate of hydrolysis and oxidation of the alcohol to an aldehyde. Also,
there is uncertainty due to the lack of data located for this substance. Carcinogenic effects cannot be ruled
out.
OncoLogic Results
No data located.
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Carcinogenicity (Rat and
Mouse)
Potential for carcinogenicity
(Estimated)
Professional judgment
Estimated based on professional
judgment and concern for the
benzyl alcohol hydrolysis product;
concern is dependent on the rate of
hydrolysis and oxidation of the
alcohol to an aldehyde.
Combined Chronic
Toxicity/Carcinogenicity
No data located.
Genotoxicity
MODERATE: Estimated to have potential for genotoxicity based on the benzyl alcohol hydrolysis
product; potential is dependent on the rate of hydrolysis and oxidation of the alcohol to an aldehyde. This
endpoint was also evaluated by analogy to measured data for the closely related compound benzyl-
2 hydroxybenzoate. These chemicals differ only by the position of the hydroxyl grouped (ortho vs. para),
which is not anticipated to result in significant differences in the mechanistic interpretation of this end
point. In addition, there is uncertainty due to the lack of data for this substance. Carcinogenic effects
cannot be ruled out.
Gene Mutation in vitro
No data for PHBB. An analog (benzyl
2-hydroxybenzoate) did not induce
mutations in Salmonella typhimiirium
strains TA 98, TA100, TA1535, or
TA1537 with and without metabolic
activation.
Zeiger, Anderson et al., 1987
Adequate.
Uncertain concern for mutagenicity based
on the benzyl alcohol hydrolysis product
(Estimated by analogy)
Professional judgment
Estimated based on test data
located for a hydrolysis product
benzyl alcohol and is dependent on
the rate of hydrolysis and oxidation
of the alcohol to an aldehyde.
Gene Mutation in vivo
No data located.
Chromosomal Aberrations
in vitro
No data located.
Chromosomal Aberrations
in vivo
No data located.
DNA Damage and Repair
No data located.
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Other (Mitotic Gene
Conversion)
No data located.
Reproductive Effects
LOW: Estimated to have low potential for reproductive effects based on no identified structural alerts and
expert judgment.
Reproduction/
Developmental Toxicity
Screen
No data located.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No potential for reproductive effects
(Estimated)
Expert judgment
Estimated based on expert
judgment and because no structural
alerts were identified.
Reproduction and Fertility
Effects
No data located.
Developmental Effects
MODERATE: Estimated to have potential for developmental effects based on the 4-hydroxybenzoic acid
hydrolysis product and professional judgment.
Reproduction/
Developmental Toxicity
Screen
Potential for developmental effects
(Estimated)
Professional judgment
Estimated based on the 4-
hydroxybenzoic acid hydrolysis
product.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Prenatal Development
No data located.
Postnatal Development
No data located.
Neurotoxicity
MODERATE: Estimated to have potential for neurotoxicity based on the presence of the phenol
structural alert.
Neurotoxicity Screening
Battery (Adult)
There is potential for neurotoxicity effects
based on the presence of the phenol
structural alert
(Estimated)
U.S. EPA, 2010; Professional
judgment
Estimated based on the phenol
structural alert.
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Repeated Dose Effects
LOW: Estimated to have low potential for repeated dose effects based on no identified structural alerts
and expert judgment.
No signs of toxicity were evident in guinea
pigs fed 1,000 mg PHBB/day for 19 days.
Ishizeki, Ayoama et al., 1955 (as
cited in CIR 1986)
Inadequate; details are missing as
this is a review on various animal
toxicity studies. Test methodology
appears not to be standard with
only a 19-day exposure duration
period.
Low potential for repeated dose effects
(Estimated)
Expert judgment
Estimated to have low potential for
repeated dose effects based on
expert judgment and because no
structural alerts were identified.
Skin Sensitization
MODERATE: Potential for skin sensitization based on close structural analog and based on concerns for
the 4-hydroxybenzoic acid hydrolysis product.
Skin Sensitization
Contact dermatitis has been observed in
several studies of large numbers of
eczematous patients or single case reports
of patients with dermal disorders topically
administered products containing mixed
4-hydroxybenzoates that typically
included PHBB. The overall rate of
allergic reactions is in the range of 1%.
Among patients sensitized to mixed 4-
hydroxybenzoate substances, patch testing
for sensitivity to individual 4-hydroxy
benzoate substances reveal significant
cross-sensitization potential and the lowest
frequency of sensitization to PHBB
compared to the other
4-hydroxybenzoates.
Bandmann, Calnan et al., 1972(as
cited in CIR 1986, 2008);
Meynadier, Meynadier et al.,
1982 (as cited in CIR 1986,
2008); Romaguera and Grimalt,
1980 (as cited in CIR 1986,
2008); Rudner, 1978 (as cited in
CIR, 1986, 2008);
Menne and Hjorth, 1988;
Wurbach, Schubert et al., 1993;
Tosi, Fanti et al., 1989
Inadequate; patients were
sensitized to mixed
4-hydroxybenzoates prior to patch
testing of individual
4-hydroxybenzoates and cross-
sensitization was apparent.
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Potential for dermal sensitization
(Estimated by analogy)
Professional judgment
Estimated based on reported
experimental data for a confidential
analog and for the 4-
hydroxybenzoic acid hydrolysis
product.
Respiratory Sensitization
No data located.
Respiratory Sensitization
No data located.
Eye Irritation
VERY LOW: PHBB is not an eye irritant.
Eye Irritation
Negative for ocular irritation in New
Zealand rabbits (n = 3) 1, 24, 48 and
72 hours after instillation of 100 mg into
the conjunctival sac.
CTFA, 1985 (as cited in CIR,
1986)
Adequate.
Dermal Irritation
VERY LOW: PHBB is not a skin irritant.
Dermal Irritation
Negative for skin irritation in New
Zealand rabbits when applied under
occlusive conditions to intact and abraded
skin at 500 mg.
European Economic
Commission, 1984 (as cited in
CIR, 1986)
Inadequate; details are missing as
this is a review on various animal
toxicity studies.
Negative for skin irritation/corrosion in
rabbits when 500 mg PHBB was applied
under semi-occlusive conditions.
CTFA, 1985 (as cited in CIR
1986, 2008)
Adequate.
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Endocrine Activity
Based on primarily in vitro test data PHBB exhibits endocrine activity. PHBB exhibited estrogenic and
anti-estrogenic activity in various test systems.
PHBB demonstrated estrogen agonistic
properties both in vitro and in vivo by
displacing 17|3-estradiol from cytosolic ER
of MCF-7 human breast cancer cells,
increasing expression of a stably
transfected estrogen-responsive reporter
gene in MCF-7 cells, increasing the
growth of estrogen-dependent MCF-7 cells
(which could be inhibited by pure anti-
estrogen ICI182 780 indicating that the
growth effects were ER mediated),
increasing the growth of a second
estrogen-dependent human breast cancer
cell line ZR-75-1 but not the estrogen
insensitive MDA-MB-231 line, and by
inducing increased uterine weight in
immature mice receiving three daily
dermal applications of PHBB to unshaven
dorsal skin (NOAEL = lOmg , LOAEL =
33 mg)^
Darbre, Byford et al., 2003
Adequate.
Receptor Binding Assays
PHBB exhibited weak ER binding activity
in preparations from uteri of
ovariectomized Sprague-Dawley rats.
Relative binding affinity (RBA) = 0.003%
of the binding affinity of 17|3-estradiol.
An RBA of 0.008% was observed for
bisphenol A.
Blair, Fang et al., 2000
Adequate.
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In a rat uterine cytosolic ER-competitive
binding assay, results for PHBB, bisphenol
S, and bisphenol A indicated a weak
affinity for ER.
Laws, Yavanhxay et al., 2006
Adequate.
In a human ER binding assay, the relative
binding affinity (RBA) of PHBB was
0.00473% compared to 126% for 17|3-
estradiol. RBAs for bisphenol compounds
included 0.195% for bisphenol A, 0.129%
for bisphenol C, 0.0803% for bisphenol
AP, 0.0719% for bisphenol F, and
0.0055% for bisphenol S.
METI, 2002
Adequate.
PHBB did not elicit an estrogenic response
in a receptor binding assay with human
ERa or ER(3.
Schultis and Metzger, 2004
Adequate.
Gene Transcription and Reporter Gene
Assays
PHBB exhibited estrogenic activity
approximately 4,000-fold less than that of
17|3-estradiol) in an in vitro recombinant
yeast estrogen assay; the estrogenic
activities of bisphenol A and bisphenol F
were 10,000-fold and 9,000-fold less than
that of 17|3-estradiol
Miller, Wheals et al., 2001
Adequate.
PHBB exhibited estrogenic activity in
multiple in vitro assays. Compared to the
activity of 17|3-estradiol, the relative
activity (RA) values were E-Screen RA
(relative to = 1.0 x 10"4 for the E-screen
assay, 6.0 x 10"5 for the LYES-assay, and
3.7 x 10"4 for the YES-assay.
Schultis and Metzger, 2004
Adequate.
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In a reporter gene assay of estrogen-
induced transcriptional activity, relative
activity (RA) for PHBB was 0.000592%
compared to 81.7% for 17|3-estradiol. RAs
for bisphenol compounds included
0.00278% for bisphenol A, 0.00189% for
bisphenol C, 0.000639% for bisphenol F,
0.000254% for bisphenol S, and
0.000184% for bisphenol AP.
METI, 2002
Adequate.
PHBB exhibited estrogenic activity in in
vitro yeast two-hybrid assays
incorporating human or medaka ERa.
hER a assay: RA (relative to 17|3-
estradiol)= 1.1 x 10"4
MedER a assay: RA = 3.3xl0"3
Terasaki, Kamata et al., 2009b
Adequate.
PHBB exhibited estrogenic activity in a
hERa competitive enzyme-linked
immunosorbent assay (ER-ELISA).
RBA (relative to DES) = 8.1 x 10"4
Terasaki, Kamata et al., 2009b
Adequate.
PHBB showed relatively high estrogenic
activity in an ER yeast reporter assay.
Ozaki, Shinohara et al., 2007
Adequate.
Cell Proliferation Assays
PHBB was estrogenic in an E-screen
(MCF-7 proliferation assay) and inhibited
aromatase activity in microsomes derived
from a human placenta. Inhibition of
aromatase activity results in decreased
conversion of testosterone into estrogens
suggestive of an anti-estrogenic effect.
van Meeuwen, van Son et al.,
2008
Adequate.
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Thyroid Assays
PHBB did not exhibit thyroid hormone
receptor binding in a yeast two-hybrid
assay system with TRa and coactivator
TIF-2.'
Kitagawa, Takatori et al., 2003
Adequate.
Immunotoxicity
No data located.
Immune System Effects
No data located.
ECOTOXICITY
ECOSAR Class
Phenols, esters
Acute Toxicity
HIGH: Based on experimental data for fis
1 and Daphnid with LC50 values between 1.0 and 10 mg/L.
Fish LC50
Fathead minnow, static conditions
48-hour LC50 = 3.3 mg/L (Experimental)
Dobbins, Usenko et al., 2009
Adequate; follows standardized
acute and subchronic tests for
freshwater fish.
Fish 96-hour LC50 = 2452 mg/L
(Estimated)
ECOSAR: phenols
EPI
Fish 96-hour LC50 = 3.98 mg/L
(Estimated)
ECOSAR: esters
EPI
Fish 96-hour LC50 = 8.42 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
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Daphnid LCS0
Daphnict magna, static conditions
48-hour LC50 = 4.0 mg/L (Experimental)
Dobbins, Usenko et al., 2009
Adequate; follows standardized
acute and subchronic tests for
daphnia.
Daphnia magna, acute immobilization
test.
48-hour EC50 = 6.6 mg/L (Experimental)
Terasaki, Makino et al., 2009a
Adequate.
Daphnid 48-hour LC50 = 1.5 5 9 mg/L
(Estimated)
ECOSAR: phenols
EPI
Daphnid 48-hour LC50 = 6.69 mg/L
(Estimated)
ECOSAR: esters
EPI
Daphnid 48-hour LC50 = 5.86 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Saltwater Invertebrate LCS0
Mysid shrimp 96-hour LC50 = 2.526 mg/L
(Estimated)
ECOSAR: esters
EPI
Green Algae ECS0
Green algae 96-hour EC50 = 2.411 mg/L
(Estimated)
ECOSAR: esters
EPI
Green algae 96-hour EC50 = 6.16 mg/L
(Estimated)
ECOSAR: phenols
EPI
Green algae 96-hour EC50 = 4.79 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
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Chronic Aquatic Toxicity
HIGH: Based on an estimated fish 30-day ChV of 0.029 mg/L (ECOSAR class: phenol). The ECOSAR
phenol class resulted in the lowest estimated chronic toxicity value. Experimental studies located for fish
and daphnia were of insufficient exposure duration to be utilized to assign the hazard concern.
Fish ChV
Fathead minnow, static-renewal
conditions, 7-day LOEC-growth =
1.7 mg/L
(Experimental)
Dobbins, Usenko et al., 2009
Inadequate; exposure duration only
7 days.
Fish 30-day ChV = 0.293 mg/L
(Estimated)
ECOSAR: phenol
EPI
Fish 60-day ChV = 0.007 mg/L
(Estimated)
ECOSAR: phenol
EPI
Fish 32/33-d-day ChV = 0.246 mg/L
(Estimated)
ECOSAR: esters
EPI
Fish ChV = 0.772 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid ChV
Daphnia magna, static-renewal conditions,
10-day LOEC (growth) = 0.1 mg/L
10-day LOEC (reproduction) = 2.0 mg/L
(Experimental)
Dobbins, Usenko et al., 2009
Inadequate; exposure duration only
10 days.
Daphnid 21-day ChV = 0.296 mg/L
(Estimated)
ECOSAR: phenols
EPI
Daphnid 21-day ChV = 2.825 mg/L
(Estimated)
ECOSAR: esters
EPI
Daphnid ChV = 0.714 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
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Saltwater Invertebrate ChV
Mysid shrimp ChV = 7.231 mg/L
(Estimated)
ECOSAR: esters
EPI
Green Algae ChV
Green algae ChV = 1.010 mg/L
(Estimated)
ECOSAR: esters
EPI
Green algae ChV = 2.84 mg/L
(Estimated)
ECOSAR: phenols
EPI
Green algae ChV = 2.31 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Earthworm Subchronic Toxicity
Earthworm 14-day LC50 = 48.812 mg/L
(Estimated)
ECOSAR: phenols
EPI
Earthworm 14-day LC50 = 934.7 mg/L
(Estimated)
ECOSAR: esters
EPI
ENVIRONMENTAL FATE
Transport
The transport evaluation for PHBB is based on located experimental data and estimated physical/chemical
properties. Based on the Level III fugacity models incorporating the located experimental property data,
PHBB is expected to partition primarily to soil. It is expected to exist in both neutral and anionic forms at
environmentally-relevant pH, based on its estimated pKa. The neutral form of PHBB is expected to have
moderate mobility in soil based on its estimated Koc. The anionic form may have more mobility, as anions
do not bind as strongly to organic carbon and clay due to their enhanced water solubility. However,
leaching of PHBB through soil to groundwater is not expected to be an important transport mechanism.
Estimated volatilization half-lives indicate that it will be nonvolatile from surface water. In the
atmosphere, PHBB is expected to exist in both vapor and particulate phases, based on its estimated vapor
pressure. Particulates will be removed from air by wet or dry deposition. Vapor-phase PHBB will be
susceptible to atmospheric degradation processes.
Henry's Law Constant
(atm-m3/mole)
2.9xl0"lu (Estimated)
EPI
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Sediment/Soil
Adsorption/Desorption
Coefficient - Koc
3,200 (Estimated)
EPI
Level III Fugacity Model
Air = <1%
Water = 16%
Soil = 83%
Sediment = 1.6% (Estimated)
EPI
Persistence
VERY LOW: No experimental data were located regarding the persistence of PHBB and it was evaluated
using measured biodegradation data for the analog benzyl-2-hydroxybenzoate. These chemicals differ
only by the position of the hydroxyl group (ortho vs. para) and this is not anticipated to result in a
different mechanistic interpretation of this endpoint. Estimates based on this analog are expected to be
superior to those based solely on modeling. The analog benzyl-2-hydroxybenzoate passed two ready
biodegradability tests, one that met the 10-day window in an activated sludge inoculum and one that did
not meet the 10-day window in a secondary effluent inoculum. Based on these data, the environmental
persistence of PHBB is estimated to be Very Low. PHBB is not expected to undergo hydrolysis based on
estimated half-lives of >1 year at pH 7 and 8. PHBB does not absorb light at environmentally significant
wavelengths, and is not expected to be susceptible to direct photolysis. The atmospheric half-life for the
vapor-phase hydroxyl radical reaction of PHBB is estimated at 7.5 hours. This is an important removal
process for vapor-phase PHBB in the atmosphere. However, it is also expected to exist in the particulate
form in the atmosphere. Biodegradation of PHBB is expected to be the primary removal process in
aquatic and terrestrial environments.
Water
Aerobic Biodegradation
Days (primary survey model);
Weeks (ultimate survey model)
EPI
Volatilization Half-life for
Model River
>1 year (Estimated)
EPI
Volatilization Half-life for
Model Lake
>1 year (Estimated)
EPI
Soil
Aerobic Biodegradation
87% after 28 days; readily biodegradable,
10-day window met (Estimated by analogy
to benzyl-2-hydroxybenzoate in activated
sludge inoculum)
HPV Robust Summary, 2003
Adequate; PHBB and benzyl-
2-hydroxybenzoate are closely
related structures that differ only
by position of the hydroxyl group.
Benzyl-2-hydroxybenzoate data are
for a guideline study.
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62% after 28 days; 10-day window not
met. (Estimated by analogy to benzyl-2-
hydroxybenzoate in secondary effluent
inoculum during an ISO 14593 Carbon
Dioxide Evolution Test)
HPV Robust Summary, 2003
Adequate; PHBB and benzyl-
2-hydroxybenzoate are closely
related structures that differ only
by position of the hydroxyl group.
Benzyl-2-hydroxybenzoate data are
for a guideline study.
Anaerobic
No data located.
Biodegradation
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
No data located.
Biodegradation
Air
Atmospheric Half-life
7.5 hours (Estimated)
EPI
Reactivity
Photolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
The substance does not contain
functional groups that would be
expected to absorb light at
wavelengths >290 nm.
Hydrolysis
Half-life >1 year (Estimated at pH = 8 and
pH =7)
EPI
Hydrolysis products expected:
4-hydroxybenzoic acid (99-96-7)
and benzyl alcohol (100-51-6).
Pyrolysis
No data located.
Environmental Half-life
30 days
EPI; PBT Profiler
Half-life estimated for the
predominant compartment, as
determined by EPI and the PBT
Profiler methodology.
Bioaccumulation
LOW: The estimated fish BAF is <100. Although the BCF is estimated to be 100, the BAF model is
anticipated to better account for metabo
ism for this substance.
Fish BCF
100 (Estimated)
EPI
BAF (upper trophic)
9.8 (Estimated)
EPI
Metabolism in Fish
No data located.
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DRAFT REPORT - DO NOT CITE OR QUOTE
PHBB CASRN 94-18-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
Ecological Biomonitoring
No data located.
Human Biomonitoring
PHBB and its metabolites have been detected in human urine biological samples (CIR, 1986; Ye, 2006). This
chemical was not included in the NHANES biomonitoring report (CDC, 2011).
4-263
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DRAFT REPORT - DO NOT CITE OR QUOTE
Bandmann, H.J., Calnan C.D., Cronin, E., et al. Dermatitis from applied medicaments. Arch. Dermatol. 1972, 106:335-337 (as cited
in CIR 1986, 2008).
Blair, R. M., Fang, H., Branham, W. S., et al. The estrogen receptor relative binding affinities of 188 natural and xenochemicals:
structural diversity of ligands. Toxicol. Sci. 2000, 54:138-153.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
CIR. Final report on the safety assessment of benzylparaben. J. Am. Coll. Toxicol. 1986, 5(5):301-307.
CIR. Final amended report on the safety assessment of methylparaben, ethylparaben, propylparaben, isopropylparaben, butylparaben,
isobutylparaben, and benzylparaben as used in cosmetics products. Int. J. Toxicol. 2008, 27(Suppl. 4): 1-82.
CTFA. Acute oral toxicity, acute dermal irritation corrosion, acute eye irritation corrosion, and COLIPA summary. Submission of
unpublished data by CFTA.1985. (as cited in CIR 1986; Golden et al., 2005).
Darbre, P.D., Byford, J.R., Shaw, L.E., et al. Oestrogenic activity of benzylparaben. J. Appl. Toxicol. 2003, 23:43-51.
Dobbins, L., Usenko, S., Brain, R., et al. Probabilistic ecological hazard assessment of parabens using Daphnia magna and
Pimephalespromelas. Environ. Toxicol. Chem. 2009, 28(12):2744-2753.
EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 4.0. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
European Economic Commission. Colipa number 7. 1984. (as cited in CIR, 1986).
4-264
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DRAFT REPORT - DO NOT CITE OR QUOTE
FAO/WHO. Toxicological and health aspects of bisphenol A. Report of Joint FAO/WHO expert meeting 2-5 November 2010 and
report of stakeholder meeting on bisphenol A 1 November 2010. Food and Agriculture Organization of the United Nations; World
Health Organization. Ottawa, Canada. 2011.
HPV Robust Summary from The Flavor and Fragrance High Production Volume Consortia. HPV Robust Summary for Benzyl
Derivatives. 2003. Available at: http://www.epa.gov/chemrtk/pubs/summaries/benzylde/cl3450rs.pdf.
Ishizeki, Ch., Aoyama, S., Hatta, Y., et al. 1955. Studies on food antiseptic. I. Bull. Natl. Hyg. Lab. Tokyo No. 73, 237-243 (as cited
in CIR, 1986)
Jewell, C., Prusakiewicz, J. J., Ackerman, C., et al. Hydrolysis of a series of parabens by skin microsomes and cytosol from human and
minipigs and in whole skin short-term culture. Toxicol. Appl. Pharmacol. 2007, 225:221-228.
Kitagawa, Y., Takatori, S., Oda, H., et al. Detection of thyroid hormone receptor-binding activities of chemicals using a yeast two-
hybrid assay. J. Health Sci. 2003, 49(2):99-104.
Laws, S.C., Yavanhxay, S., Cooper, R.L., et al. Nature of the binding interaction from 50 structurally diverse chemicals with rat
estrogen receptors. Toxicol. Sci. 2006, 94(l):45-56.
Menne, T., Hjorth, N. Routine patch testing with paraben esters. Contact Derm. 1988, 19:189-191.
METI. Current status of testing methods development for endocrine disruptors. Ministry of Economy, Trade and Industry, Japan. 6th
meeting of the task force on Endocrine Disruptors Testing and Assessments (EDTA). 24-25 June, 2002. Tokyo. 2002.
Meynadier, J. M., Meynadier, J., Colmas, A., et al. Allergie aux conservateurs (translated from the original French). Ann. Dermatol.
Venereol. 1982, 109:1017-1023 (as cited in CIR, 1986).
Miller, D., Wheals, B.B., Beresford, N. et al. Estrogenic activity of phenolic additives determined by an in vitro yeast bioassay.
Environ. Health Perspect. 2001, 109(2): 13 3 -13 8.
Ozaki, H., Shinohara, S., Tange, S., et al. Parabens and phthalates: Their metabolism, AHR ligand activity, estrogenic activity, and
P450-inhibitory activity. Organohalogen Compounds 2007, 69: 2991-2994.
4-265
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PhysProp. Physical Properties Database SRC, Inc.
PBT Profi 1 er Persistent (P),Bioaccumulative (B), and Toxic (T) Chemical (PBT)Profiler. U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
Romaguera, C., Grimalt. F. Statistical and comparative study of 4,600 patients tested in Barcelona. Contact Derm. 1980, 6:309-315
(as cited in CIR, 1986; Golden et al., 2005).
Rudner, E. J. Patch test results of the North American Contact Dermatitis Group. Cosmet. Toilet. 1978, 93:53-54 (as cited in CIR,
1986, 2008).
Sabalitschka, T. Arztl. Apotheker. Krankenhaus. Nr. 10. 1933. (as cited in CIR, 1986).
Sabalitschka, T., Neufeld-Crzellitzer, R. Zum Verhalten der poxybenzoesaureester im menschlichen Korper (translated from the
original German). Arzneimittelforschnng 1954, 4:575-579 (as cited in CIR, 1986, 2008).
Schultis, T., Metzger, J.W. Determination of estrogenic activity by LYES-assay (yeast estrogen screen-assay assisted by enzymatic
digestion with lyticase). Chemosphere 2004, 57:1649-1655.
SPARC On Line Calculator pKaproperty server. Ver 4.5 September, 2009. Available from, http://ibmlc2.chem.uga.edu/spare/
(accessed on August 12, 2010).
Terasaki M., Makino, M., Tatarazako, N. Acute toxicity of parabens and their chlorinated by-products with Dapnia magna and Vibrio
fischeri bioassays. J. Appl. Toxicol. 2009, 29:242-247.
Terasaki M., Kamata, R., Shiraishi, F., et al. Evaluation of estrogenic activity of parabens and their chlorinated derivatives by using
the yeast two-hybrid assay and the enzyme-linked immunosorbent assay. Environ. Toxicol. Chem. 2009, 28(l):204-208.
Thomas, M.R. Salicylic Acid and Related Compounds. Kirk-Othmer Encyclopedia of Chemical Technology. Wiley-Interscience.
Posted online: January 27, 2006.
Tosi A., Fanti, F.A., Pileri, S. Short communications. Dermal contact dermatitis from benzylparaben. Contact Derm. 1989, 21:49-63.
4-266
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U.S. EPA (Environmental Protection Agency). High Production Volume (HPV) Challenge. Determining the Adequacy of Existing
Data. U.S. Environmental Protection Agency: Washington D.C. 1999. http://www.epa.gov/hpv/pubs/general/datadfin.htm
U.S. EPA Sustainable Futures Using NonCcmcer Screening within the Sustainable Futures Initiative Environmental Protection
Agency: Washington D.C. 2010. http://www.epa.gOv/opptintr/sf/pubs/noncan-screen.htm#svstemic as of February 09, 2011.
van Meeuwen, J.A., van Son, O., Piersma, A.FL, et al. Aromatase inhibiting and combined estrogenic effects of parabens and
estrogenic effects of other additives in cosmetics. Toxicol. Appl. Pharmacol. 2008, 230:372-382.
Wiirbach, G., Schubert H., Phillipp, I. Contact allergy to benzyl alcohol and benzyl paraben. Contact Derm. 1993, 28:187-188.
Ye, X., Bishop, A.M., Reidy, J. A., et al. Parabens as urinary biomarkers of exposure in humans. Environ. Health Perspect. 2006,
114(12): 1843-1846.
Zeiger, E., Anderson, B., Haworth, S., et al. Salmonella mutagenicity tests: III. Results from the testing of 255 chemicals. Environ.
Mutagen. 1987, 9(Suppl. 9), 1-110.
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Bisphenol S
MW: 250.27
MF: C12H10O4S
CASRN: 80-09-1
Physical Forms:
Neat: Solid
Use: Developer for thermal paper
SMILES: 0=S(=0)(clccc(0)cc 1 )c2ccc(0)cc2
Synonyms: Phenol, 4,4'-sulfonylbis- (TSCA Inventory); bis(4-hydroxyphenyl)sulfone; l,l'-Sulfonylbis(4-hydroxybenzene); 2,4'-Sulfonyldiphenol; 4,4'-Bisphenol S;
4,4'-Dihydroxydiphenyl sulfone; 4,4'-Sulfonylbisphenol; 4,4'-Sulfonyldiphenol; 4-Hydroxyphenyl sulfone; Bis(4-hydroxyphenyl) sulfone; Bis(p-hydroxyphenyl)
sulfone; Diphone C; p,p'-Dihydroxydiphenyl sulfone
Polymeric: No
Oligomers: Not applicable
Metabolites, Degradates and Transformation Products: None
Analog: None
Endpoint(s) using analog values: Not applicable
Analog Structure: Not applicable
Structural Alerts: Phenols, neurotoxicity (U.S. EPA, 2010)
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 2011).
Risk Assessments: None identified
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Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
240.5 (Measured)
Lide, 2008
Adequate.
245-248 (Measured)
ECHA, 2011
Adequate; reported values, which
span a relatively narrow range, are
consistent with other sources.
242-247 (Measured)
ECHA, 2011
Adequate; reported values, which
span a relatively narrow range, are
consistent with other sources.
Boiling Point (°C)
>300 (Estimated)
EPI; U.S. EPA, 1999
Cutoff value for high boiling point
compounds according to HPV
assessment guidance; decomposition
is anticipated to occur before the
melting point is reached.
315 decomposition temperature
Boiling point of the test item could not be
determined, OECD 103 (Measured)
ECHA, 2011
Inadequate; nonspecific value.
Vapor Pressure (mm Hg)
400°C
auto-flammability/self-ignition
temperature DIN 51 794 (Measured)
ECHA, 2011
Adequate guideline study.
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Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Not highly flammable
ECHA, 2011
EU Method A. 10 (Measured)
Explosivity
No data located.
pH
No data located.
pKa
8
OECD Method 112 (Measured)
ECHA, 2011
Adequate, guideline study.
HUMAN HEALTH EFFECTS
Toxicokinetics
No toxicokinetic data located.
Dermal Absorption in vitro
No data located.
Absorption,
Oral, Dermal or Inhaled
No data located.
Distribution,
Metabolism &
Excretion
Acute Mammalian Toxicity
LOW: The weight of evidence indicates that the acute oral toxicity of bisphenol S is low. A reported acute
oral LDS0 of 1,600 mg/kg for the mouse could not be verified because no study details were available.
Located data suggest a low hazard concern for acute dermal exposure. No data were located regarding the
acute inhalation hazard.
Acute Lethality
Oral
Rat oral LD50 >5,000 mg/kg
ECHA, 2011
Adequate guideline study (OECD
401); no deaths at limit dose of
5,000 mg/kg.
Wistar rat (male)
LD50 = 2,830 mg/kg
ECHA, 2011
Adequate guideline comparable to
OECD guideline 401; the LD50
value supports other reported
results.
Rat oral LD50 = 4,556 mg/kg
BIOFAX Industrial Bio-Test
Laboratories, Inc., 1974, cited in
CHEMID
Although no study details were
provided in the secondary source,
the LD50 value supports other
reported results.
Rat (male, female; strain unspecified)
LD50 = 2,540 mg/kg (females)
LD50 = >3,200 mg/kg (males)
Eastman Kodak, 1991
Although study details were lacking
in the study summary, the LD50
value supports other reported
results.
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Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Sprague-Dawley rat (male, female)
LD50 >2,000 mg/kg
ECHA, 2011
Although the secondary source
indicated that the study followed
OECD guideline 401, it was noted
that only an abstract of the study
was located.
Wistar rat (gender unspecified)
A single dosed rat died following a single
oral dose of 10,000 mg/kg; a single rat
given 7,000 mg/kg survived
Monsanto Company, 1945
(OTS0555048)
Although insufficient numbers of
animals were assessed, the results
support study results for rats.
Mouse (gender, strain unspecified)
LD50 = 1,600 mg/kg
Eastman Kodak, 1991
This value could not be verified
because the study summary provides
only the LD50 value for the mouse.
Albino rabbit (gender unspecified)
One of two rabbits died following a single
oral dose of 7,000 mg/kg; a single rabbit
given 4,700 mg/kg survived
Monsanto Company, 1945
(OTS0555048)
Although insufficient numbers of
animals were assessed, the results
support study results for rats.
Dermal
Rabbit dermal LD50 >10,250 mg/kg
BIOFAX Industrial Bio-Test
Laboratories, Inc., 1974, cited in
CHEMID
Although limited study information
was located, the high dose suggests
a low hazard concern for the dermal
exposure route.
Guinea pig (strain and gender
unspecified) dermal LD50 >1,000 mg/kg
Eastman Kodak, 1991
Inadequate, limited study
information located.
Inhalation
No data located.
Carcinogenicity
MODERATE: Estimated using OncoLogic expert system which describes a concern for this compound as a
potential carcinogen or tumorigenesis promoter arising from its structural similarity to
estrogenic/androgenic compounds, using the 'Phenols and phenolic compounds' structural alert.
OncoLogic Results
Moderate (Estimate)
OncoLogic class: Phenols and phenolic
compounds
OncoLogic
OncoLogic SAR analysis using the
Phenols and phenolic compounds
class.
Carcinogenicity (Rat and
Mouse)
No data located.
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Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Combined Chronic
Toxicity/ Carcinogenicity
No data located.
Genotoxicity
MODERATE: Bisphenol S did not induce gene mutations in several in vitro assays and did not induce
chromosomal aberrations in vivo in a mammalian erythrocyte micronucleus assay in NMRI mice or in
Chinese hamster ovary (CHO) cells in vitro in the presence of exogenous metabolic activation. However,
bisphenol S did induce chromosomal aberrations in CHO cells in vitro in the absence of exogenous
metabolic activation (at a noncytotoxic concentration). The positive result in the in vitro assay and negative
result in the in vivo test suggest an equivocal response and therefore a Moderate hazard concern.
Gene Mutation in vitro
Negative, mouse lymphoma L5178Y
(TK+/TK-) cells, with and without
metabolic activation
CCRIS, 2010
Adequate.
Negative, Ames assay (standard plate) in
Salmonella typhimiirium strains TA98,
TA100, TA1537, TA1535, and TA1538
with and without metabolic activation
CCRIS, 2010
Adequate.
Negative, Salmonella/microsome test, S.
typhimiirium strains TA1535, TA100,
TA1537, and TA98 with and without
metabolic activation
Miles Inc., 1992; ECHA, 2011
Adequate guideline study (OECD
471).
Negative, Ames assay (preincubation) in
S. typhimiirium strains TA98, TA100,
TA1537, and TA1535, sad Escherichia
coli WP2UVRA with and without
metabolic activation
CCRIS, 2010; ECHA, 2011
Adequate guideline study (OECD
471).
Negative, umu test in S. typhimiirium
strain TA1335
Chen, Michihiko et al., 2002
Adequate.
Negative, CHO HGPRT mutation assay,
with and without metabolic activation
Amoco Corp., 1991a; ECHA,
2011
Adequate.
Gene Mutation in vivo
No data located.
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Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Chromosomal Aberrations
in vitro
Positive, chromosomal aberrations in
CHO cytogenetics assay, without
metabolic activation, negative with
metabolic activation. Results were
obtained in the absence of cytotoxicity.
Amoco Corp., 1991b; ECHA,
2011
Adequate guideline study (similar to
OECD 473).
Chromosomal Aberrations
in vivo
Negative, did not produce chromosomal
aberrations in vivo in a mammalian
erythrocyte micronucleus assay in male
NMRI mice (5/group) administered
bisphenol S via single gavage dose at dose
levels up to 2,000 mg/kg.
ECHA, 2011
Adequate guideline study (OECD
474).
DNA Damage and Repair
No data located.
Other (Mitotic Gene
Conversion)
No data located.
Reproductive Effects
MODERATE: In a reproduction/developmental toxicity screening test, oral exposure of parental rats to
bisphenol S resulted in marked systemic effects and the NOAEL for reproductive effects is 60 mg/kg-day
(prolonged estrous cycle, decreased fertility index and decreased number of live offspring). Based on the
NOAEL for reproductive effects a Moderate hazard designation is selected.
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Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproduction/
Developmental Toxicity
Screen
In a reproduction/developmental toxicity
screening test, groups of Sprague-Dawley
rats (12/sex/group) were administered
bisphenol S by gavage at 0, 10, 60, or
300 mg/kg bw-day (males for 45 days and
females from 14 days before mating to
LD 3). The mid dose caused parental
gross- and histo-pathological changes in
cecum of both sexes. The high dose
caused decreased body weight gain and
food consumption in females, increased
relative liver weight in males, hypertrophy
of hepatocytes in both sexes, prolonged
estrous cycle, decreased fertility index,
and decreased number of live offspring on
LD 4.
Parental toxicity:
NOAEL =10 mg/kg bw-day
LOAEL = 60 mg/kg bw-day for effects on
cecum (distension, diffuse hyperplasia of
mucosal epithelium)
Reproductive toxicity:
NOAEL = 60 mg/kg bw-day
LOAEL = 300 mg/kg bw-day for
prolonged estrous cycle, decreased
fertility index, and decreased number of
live offspring on LD 4.
ECHA, 2011
Adequate guideline study (OECD
421) reported in a secondary source.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Reproduction and Fertility
Effects
No data located.
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Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Developmental Effects
MODERATE: In a reproduction/developmental toxicity screening test, oral exposure of parental rats to
bisphenol S resulted in marked systemic effects and decreased number of live offspring (PND 4) at the
highest dose level (300 mg/kg-day), with a NOAEL of 60 mg/kg-day. Based on the NOAEL a Moderate
hazard designation is selected.
Reproduction/
Developmental Toxicity
Screen
In a reproduction/developmental toxicity
screening test, groups of Sprague-Dawley
rats (12/sex/group) were administered
bisphenol S by gavage at 0, 10, 60, or
300 mg/kg bw-day (males for 45 days and
females from 14 days before mating to
LD 3). The mid dose caused parental
gross- and histo-pathological changes in
cecum of both sexes. The high dose
caused decreased body weight gain and
food consumption in females, increased
relative liver weight in males, hypertrophy
of hepatocytes in both sexes, prolonged
estrous cycle, decreased fertility index,
and decreased number of live offspring on
LD 4. No changes attributable to the
compound were observed in parameters
including the sex ratio, the live birth
index, body weight, viability index on day
4, anogenital distance, external or
necropsy findings.
Parental toxicity:
NOAEL =10 mg/kg bw-day
LOAEL = 60 mg/kg bw-day for effects on
cecum (distension, diffuse hyperplasia of
mucosal epithelium)
Reproductive toxicity:
NOAEL = 60 mg/kg bw-day
LOAEL = 300 mg/kg bw-day for
prolonged estrous cycle, decreased
ECHA, 2011
Adequate guideline study (OECD
421) reported in a secondary source.
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Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
fertility index, and decreased number of
live offspring on LD 4.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Prenatal Development
No data located.
Postnatal Development
No data located.
Neurotoxicity
MODERATE: Estimated to have potential for neurotoxicity based on the presence of the phenol structural
alert.
Neurotoxicity Screening
Battery (Adult)
There is potential for neurotoxicity effects
based on the presence of the phenol
structural alert
(Estimated)
U.S. EPA, 2010; Professional
judgment
Estimated based on structural alert.
Repeated Dose Effects
HIGH: Among two adequately-designed, repeated-dose oral studies in rats, one study identified a NOAEL
of 10 mg/kg-day and a LOAEL of 60 mg/kg-day for systemic effects and the other study identified a
NOAEL of 40 mg/kg-day and a LOAEL of 200 mg/kg-day for systemic effects. Based on uncertainty as to
the potential systemic toxicity in the range of 40 to 60 mg/kg-day, a High hazard designation is selected. It
should be noted that because the standard criteria thresholds are for 90-day studies, the 28-day study was
evaluated using modified criteria at 3 times the threshold values.
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Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In a repeated-dose oral study, Sprague-
Dawley rats (6/sex/dose group) were
administered bisphenol S by gavage at 0,
40, 200, or 1,000 mg/kg bw-day. No
treatment-related effects were seen at low
dose. Effects at the 200 mg/kg bw-day
dose level included decreased body
weight gain in females, increased
incidences of proteinuria in males and
females and urobilinogen in males,
increased kidney weight in males, and
increased incidences of hyperplasia and
necrosis in cecal mucosal epithelium of
males and females.
NOAEL = 40 mg/kg bw-day
LOAEL = 200 mg/kg-bw-day
ECHA, 2011
Adequate 28-day repeat dose
toxicity guideline study; this study
will be evaluated using modified
criteria at 3 times the thresholds
because the standard thresholds are
based on 90-day studies.
4-277
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Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In a reproduction/developmental toxicity
screening test, groups of Sprague-Dawley
rats (12/sex/group) were administered
bisphenol S by gavage at 0, 10, 60, or
300 mg/kg bw-day (males for 45 days and
females from 14 days before mating to
LD 3). The mid dose caused parental
gross- and histo-pathological changes in
cecum of both sexes. The high dose
caused decreased body weight gain and
food consumption in females, increased
relative liver weight in males, and
hypertrophy of hepatocytes in both sexes.
NOAEL =10 mg/kg bw-day
LOAEL = 60 mg/kg bw-day for effects on
cecum (distension, diffuse hyperplasia of
mucosal epithelium)
ECHA, 2011
Adequate guideline study (OECD
421).
In a 13-day oral (dietary) study in rats,
increases in red blood cell count,
hemoglobin concentrations, and
hematocrit were observed; histopathologic
examinations revealed cytoplasmic
basophilia of the renal distal convoluted
tubule epithelium. Decreased weight
gain, decreased absolute liver and kidney
weight, and atrophy in adipose tissue may
have been secondary effects of decreased
food consumption.
NOAEL = 97 mg/kg-day
LOAEL = 810 mg/kg-day
Eastman Kodak, 1991
Inadequate; exposure duration only
13 days.
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Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Skin Sensitization
LOW: Studies on guinea pigs and mice indicate that bisphenol S not a likely skin sensitizer.
Skin Sensitization
Negative for skin sensitization, guinea
Pig
Eastman Kodak, 1991
Limited study details.
Negative for skin sensitization, mouse
local lymph node assay
ECHA, 2011
Adequate guideline study (OECD
429).
Respiratory Sensitization
No data located.
Respiratory Sensitization
No data located.
Eye Irritation
LOW: Bisphenol S was non-irritating to mildly irritating to rabbit eyes.
Eye Irritation
Slightly irritating, rabbit
Eastman Kodak, 1991
Limited study details.
Mildly irritating, rabbit
Monsanto, 1991
Limited study details.
Nonirritating, rabbit
ECHA, 2011
Adequate guideline study (OECD
405).
Dermal Irritation
LOW: Bisphenol S was slightly irritating to guinea pig skin and not irritating to rabbit skin.
Dermal Irritation
Slight skin irritant, guinea pig
Eastman Kodak, 1991
Limited study details.
Non-irritant, rabbit
Monsanto, 1991
Adequate.
Non-irritant, rabbit
ECHA, 2011
Adequate guideline study (OECD
404).
Endocrine Activity
Based on limited data it appears that bisphenol S exhibits endocrine activity. In vitro assays demonstrate
that bisphenol S can bind to estrogen receptors (ER), elicit estrogen-induced gene transcription, and induce
cell proliferation in MCF7 cancer cells, and inhibit the androgenic activity of dihydrotestosterone. In an
ARE-luciferase reporter assay using a mouse fibroblast cell line, bisphenol S did not elicit an androgenic
response, but did inhibit the androgenic activity of dihydrotestosterone. Located data indicate that the in
vitro endocrine activity of bisphenol S is approximately 5-7 orders of magnitude less than that of 170-
estradiol, suggesting that bisphenol S acts as a weak estrogen. Comparative in vitro data suggest that the
endocrine activity of bisphenol S is somewhat less than that of bisphenol A, bisphenol AP, bisphenol C, and
bisphenol F. Limited in vivo data suggest the potential for estrogenic activity.
Receptor Binding Assays
4-279
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Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In a human ER binding assay, the relative
binding affinity (RBA) of bisphenol S was
0.0055% relative to 17|3-estradiol (set at
100%). RBAs for other bisphenol
compounds included 0.175% for
bisphenol M and 0.0719% for bisphenol
F.
Yamasaki, Noda et al., 2004
Adequate.
In a human ER binding assay, the RBA of
bisphenol S was 0.0055% compared to
126% for 17|3-estradiol. RBAs for other
bisphenol compounds included 0.195%
for bisphenol A, 0.129% for bisphenol C,
0.0803% for bisphenol AP, and 0.0719%
for bisphenol F. A RBA of 0.00473% was
reported for PHBB.
METI, 2002
Adequate.
In a rat uterine cytosolic ER-competitive
binding assay, results for bisphenol S,
bisphenol A, and PHBB indicated a weak
affinity for ER.
Laws, Yavanhxay et al., 2006
Adequate.
Gene Transcription and Reporter Gene
Assays
4-280
-------
Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Bisphenol S exhibited evidence of
estrogenic activity in a yeast
(Scicchciromyces cerevisicte) two-hybrid
assay using ERa and the coactivator TIF2.
Based on estrogenic activity that was
approximately 7 orders of magnitude
lower than that of 17|3-estradiol, bisphenol
S was considered less estrogenic than
bisphenol A which was considered
weakly estrogenic (5 orders of magnitude
less active than 17|3-estradiol).
Assessment of other bisphenols resulted
in a ranking of relative potency as
follows: bisphenol C > bisphenol A >
bisphenol F > bisphenol S.
Chen, Michihiko et al., 2002
Adequate.
In a yeast two-hybrid assay using
P-galactosidase activity as a measure of
estrogenic activity, bisphenol S did not
appear to elicit an estrogenic response but
a weakly estrogenic response was elicited
by bisphenol A.
Nishihara, Nishikawa et al., 2000
Adequate.
In yeast two-hybrid systems (reporter
gene assay) using p-galactosidase activity
as a measure of estrogenic activity, an
estrogenic response was elicited by
bisphenol S only in the presence of
exogenous metabolic activation;
estrogenic responses were elicited by
bisphenol A and bisphenol F both in the
absence and presence of exogenous
metabolic activation.
Hashimoto and Nakamura, 2000;
Hashimoto, Moriguchi et al., 2001
Adequate.
4-281
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Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In a reporter gene assay of estrogen-
induced transcriptional activity, relative
activity (RA) for bisphenol S was
0.000254% compared to 81.7% for 17(3-
estradiol. RAs for other bisphenol
compounds included 0.00278% for
bisphenol A, 0.00189% for bisphenol C,
0.000639% for bisphenol F, and
0.000184% for bisphenol AP. An RA of
0.000592% was reported for PHBB
METI, 2002
Adequate.
In an ERE-luciferase reporter assay using
MCF-7 cells, an EC50 was 1.1 (iM for
bisphenol S compared to an EC50 of 8.6 x
10"6 for 17|3-estradiol (i.e., bisphenol A
was approximately 5 orders of magnitude
less potent than 17|3-estradiol at inducing
estrogenic activity). EC50 values for other
bisphenol compounds included 0.63 (.iM
for bisphenol A, 0.42 (.iM for bisphenol C,
and 1.0 (.iM for bisphenol F.
Kitamura, Suzuki et al., 2005
Adequate.
In an E-screen test for estrogenicity,
bisphenol S, bisphenol A, and bisphenol F
increased proliferation of MCF-7 cells at
concentrations in the range of 10"4 to 10"7
M. Bisphenol A appeared to be more
effective than bisphenol S or bisphenol F.
Hashimoto, Moriguchi et al., 2001
Adequate.
In an ERE-luciferase reporter assay using
MCF-7 cells in the presence of 17|3-
estradiol, neither bisphenol S, bisphenol
A, bisphenol C, nor bisphenol F appeared
to exert an anti-estrogenic effect
Kitamura, Suzuki et al., 2005
Adequate.
Cell Proliferation Assays
4-282
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Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
In a cell proliferation assay using human
breast cancer MCF-7 cells, bisphenol S
elicited a proliferative response
comparable to that of bisphenol A.
Kuruto-Niwa, Nowaza et al., 2005
Adequate.
Androgen Activity
In an ARE-luciferase reporter assay using
a mouse fibroblast cell line (NIH3T3
cells), bisphenol S inhibited the
androgenic activity of
dihydrotestosterone. Anti-androgenic
responses were elicited by bisphenol A,
bisphenol C, and bisphenol F as well.
Kitamura, Suzuki et al., 2005
Adequate.
In an ARE-luciferase reporter assay using
a mouse fibroblast cell line (NIH3T3
cells), neither bisphenol S, bisphenol A,
bisphenol C, nor bisphenol F exerted an
androgenic effect
Kitamura, Suzuki et al., 2005
Adequate.
In Vivo Studies
In a uterotrophic assay of rats
subcutaneously injected with bisphenol S
once daily for 3 days, an apparent
estrogenic effect was evidenced by
increased absolute and relative uterine
weight. Similar effects were elicited by
bisphenol F and bisphenol M.
Yamasaki, Noda et al., 2004
Adequate.
Immunotoxicity
No data located.
Immune System Effects
No data located.
ECOTOXICITY
ECOSAR Class
Phenols, poly
Acute Toxicity
MODERATE: Based on an experimental 48-hour LCS0 value of 55 mg/L for Daphnid.
4-283
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Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Fish LC50
Fish (species unspecified)
96-hour LC50 >100 mg/L
(Experimental, nominal)
ECHA, 2011
Adequate guideline study (OECD
203), although information
regarding measured test substance
concentrations was not located.
Oryzias latipes (orange-red killifish)
96-hour LC50 > 500 mg/L (semi-static)
(Experimental, nominal)
ECHA, 2011
Adequate guideline study (Japanese
Industrial Standard JIS K 0102-
1986-71), although information
regarding measured test substance
concentrations was not located.
Fish 96-hour LC50 = 37.75 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Daphnid LCS0
Daphnict magna (water flea)
48-hour EC50 = 55 mg/L
24-hour EC50 = 76 mg/L
(Experimental)
Chen, Michihiko et al., 2002;
ECHA, 2011
Adequate guideline study (OECD
202), although information
regarding measured test substance
concentrations was not located.
Daphnid (water flea)
96-hour LC50 = 45 mg/L
NOEC = 10 mg/L
(Experimental)
Eastman Kodak, 1991
Adequate, non guideline study,
although information regarding
measured test substance
concentrations was not located.
Daphnia sp. (water flea)
48-hour EC50 = 100 mg/L
(Experimental)
ECHA, 2011
Adequate guideline study (OECD
202), although information
regarding measured test substance
concentrations was not located.
Daphnid
48-hour LC50 = 195.08 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Green Algae ECS0
Desmodesmas siibspicatus (green algae)
72-hour EC50 =106 mg/L (growth)
72-hour NOEC = 10.2 mg/L
(Measured; static conditions)
ECHA, 2011
Adequate guideline study (OECD
201).
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Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Green algae
72-hour EC50 = 65 mg/L (growth)
72-hour NOEC = 4.6 mg/L
(Experimental)
ECHA, 2011
Adequate guideline study (OECD
201); secondary source noted that
test substance concentrations were
measured, but did not indicate
whether nominal or measured
concentrations were used for effect
levels.
Green algae
96-hour EC50 = 2.29 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Chronic Aquatic Toxicity
MODERATE: The measured ECS0 value for Daphnid is 14 mg/L while the measured NOEC is 2.7mg/L.
Using a conservative approach, the unidentified LOEC for chronic toxicity in Daphnid is assumed to fall
between 2.7 and 14 mg/L, which partly spans across the range of values that indicate a Moderate hazard
concern (1-10 mg/L).
Fish ChV
Fish
30-day ChV = 12.58 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Daphnid ChV
Daphnia sp. (water flea)
21-day EC50 =14 mg/L (reproduction)
21-day NOEC = 2.7 mg/L (Experimental)
ECHA, 2011
Adequate guideline study (OECD
211), although information
regarding measured test substance
concentrations was not located.
Daphnid ChV = 18.31 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Green Algae ChV
Green algae
ChV = 0.88 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
ENVIRONMENTAL FATE
4-285
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Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Transport
The transport evaluation for bisphenol S is based on located experimental and estimated physical and
chemical properties. Based on the Level III fugacity models incorporating the located experimental
jroperty data, bisphenol S is expected to partition primarily to soil. It is expected to exist in both neutral
and anionic forms at environmentally-relevant pH, based on its measured pKa. The neutral form of
jisphenol S is expected to have slight mobility in soil based on its estimated Koc. The anionic form may be
more mobile, as anions do not bind as strongly to organic carbon and clay due to their enhanced water
solubility. However, leaching of bisphenol S through soil to groundwater is not expected to be an important
transport mechanism. Estimated volatilization half-lives indicate that it will be non-volatile from surface
water. In the atmosphere, bisphenol S is expected to exist in the particulate phase, based on its estimated
vapor pressure. Particulates will be removed from air by wet or dry deposition.
Henry's Law Constant
(atm-m3/mole)
-------
Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Water
Aerobic Biodegradation
Bisphenol S aerobic degradation was not
detected after 2 weeks; degradation based
on TOC decrease in river water and
measured with HPLC (Measured)
Ike, Chen et al., 2006
Adequate nonguideline study.
This study measured the degradation of
bisphenol A, F, and S in seawater.
Degradation of bisphenol S was not
detected in seawater. This study used
TOC Handai and river die-away methods.
(Measured)
Danzl, Sei et al., 2009
Adequate nonguideline study.
Volatilization Half-life
for Model River
>1 year (Estimated)
EPI
Volatilization Half-life
for Model Lake
>1 year (Estimated)
EPI
Soil
Aerobic Biodegradation
Ready Test: MITI-I (OECD 301C) No
biodegradation detected; Bisphenol S for
4 weeks with 100 mg/L in 30 mg/L
activated sludge BOD 0%; TOC 0%
(Measured)
MITI, 1998
Adequate guideline study.
Anaerobic
Biodegradation
Not probable (anaerobic-methanogenic
biodegradation probability model)
EPI
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
Biodegradation
Anaerobic degradation of bisphenol S was
detected by HPLC analysis.
Approximately 60% of bisphenol S was
removed after 70 days in anoxic bottles
with pond sediment (Measured)
Ike, Chen et al., 2006
Adequate, nonguideline study.
Air
Atmospheric Half-life
8.8 hours (Estimated)
EPI
Reactivity
Photolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain
functional groups that would be
expected to absorb light at
wavelengths >290 nm
4-287
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Bisphenol S CASRN 80-09-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Hydrolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain
functional groups that would be
expected to hydrolyze readily under
environmental conditions.
Pyrolysis
No data located.
Environmental Half-life
30 days (Estimated)
EPI; PBT Profiler
Half-life estimated for the
predominant compartment, as
determined by EPI and the PBT
Profiler methodology.
Bioaccumulation
LOW: The low concern for bioaccumulation was based on two experimental BCF values. Both values are
well below the low criteria cutoff of 100.
Fish BCF
A BCF of <2.2 at a concentration of
50 |a,g/L after 6 weeks in carp (Cyprinus
carpio); OECD 305C
(Measured)
MITI, 1998
Adequate guideline study.
A BCF of <02 at a concentration of
MITI, 1998
Adequate guideline study.
500 |a,g/L after 6 weeks in carp (Cyprinus
carpio); OECD 305C
(Measured)
BAF
1.8 (Estimated)
EPI
Metabolism in Fish
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
Ecological Biomonitoring
No data located.
Human Biomonitoring
BPS was detected in human urine samples from general populations of the United States, China, India, Japan,
Korea, Kuwait, Malaysia and Vietnam (Liao, Liu, et al., 2012). This chemical was not included in the NHANES
biomonitoring report (CDC, 2011).
4-288
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Amoco Corp. CHO HGPRTmutation assay (final report) with attachment and cover letter dated 111491. TSCATS submission
OTS0534324. 1991a.
Amoco Corp. Chromosome aberrations in Chinese hamster ovary (CHO) cells (final report) with attachment and cover letter dated
111491. TSCATS submission OTS0534325. 1991b.
BIOFAX Industrial Bio-Test Laboratories, Inc. Data sheets. Vol. 601-05501, 1974, as cited in ChemlD.
http://chem.sis.nlm.nih.gov/chemidplus/.
Boethling, R., Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences. Boca Raton:
Lewis Publishers. 2000.
CCRIS. Chemical Carcinogenesis Research Information System. Bisphenol S. 2010. http://toxnet.nlm.nih.gov/cgi-
bin/si s/html gen? CCRIS. (accessed on August, 2010).
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
Chen, M-Y.; Michihiko, I.; Fujita, M. Acute toxicity, mutagenicity, and estrogenicity of bisphenol-A and other bisphenols. Environ.
Toxicol. 2002, 17:80-86.
Danzl, E.; Sei, K.; Soda, S., et al. Biodegradation of Bisphenol A, Bisphenol F and Bisphenol S in Seawater. Int. J. Environ. Res.
Public Health. 2009, 6:1472-1484.
Eastman Kodak. Letter concerning enclosed information on bisphenol S with attachments. Eastman Kodak Company, Rochester NY.
TSCATS submission OTS0534330. 1991.
ECHA. European Chemicals Agency. Information on registered substances, http://apps.echa.europa.eu/registered/registered-sub.aspx
(accessed February 18, 2011).
EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 4.00. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
4-289
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ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
Hashimoto, Y.; Nakamura, M. Estrogenic activity of dental materials and bisphenol-A related chemicals in vitro. Dent. Mater. J.
2000, 19(3):245-262.
Hashimoto, Y.; Moriguchi, Y.; Oshima, H.; et al. Measurement of estrogenic activity of chemicals for the development of new dental
polymers. Toxicol. In Vitro 2001, 15:421-425.
HSNO. New Zealand Hazardous Substances and New Organisms Chemical Classification Information Database. 2010.
Environmental Risk Management Authority (ERMA) - New Zealand. August 5, 2010.
Ike, M.; Chen, MY.; Danzl, E.; et al. Biodegradation of a variety of bisphenols under aerobic and anaerobic conditions. Water Sci.
Technol. 2006, 53:153-159.
Kitamura, S.; Suzuki, T.; Sanoh, S.; et al. Comparative study of the endocrine-disrupting activity of bisphenol A and 19 related
compounds. Toxicol. Sci. 2005, 84:249-259.
Kuruto-Niwa, R.; Nozawa, R.; Miyakoshi, T.; et al. Estrogenic activity of alkylphenols, bisphenol S, and their chlorinated derivatives
using a GFP expression system. Environ. Toxicol. Pharmacol. 2005, 19:121-130.
Laws, S., Yavanhxay, S, Cooper, R., et al. Nature of the binding interaction for 50 structurally diverse chemicals with rat estrogen
receptors. Toxicol. Sci. 2006, 94(l):46-56.
Liao, C.; Liu, F.; Alomirah, H.; Loi, V.D.; Mohd, M.A.; Moon, H-B.; Nakata, H.; and Kannan, K. Bisphenol S in Urine from the
United States and Seven Asian Countries: Occurrence and Human Exposures. Environ. Sci. Technol. Just Accepted version: May 23,
2012.
METI. Current status of testing methods development for endocrine disruptors. Ministry of Economy, Trade and Industry, Japan. 6th
meeting of the task force on Endocrine Disruptors Testing and Assessments (EDTA). 24-25 June, 2002. Tokyo. 2002.
Monsanto, 1945. National Technical Information Service. Col. OTS0555048, as cited in ChemlD.
http://chem.sis.nlm.nih.gov/chemidplus/.
4-290
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Monsanto. Toxicological investigation of dihydroxydiphenyl sulfone (final report) with cover letter datedl 12190. TSC ATS
submission OTS0534356. 1991.
Miles Inc. Salmonella microsome test (final report) with cover letter dated 04392. TSCATS submission OTS0435648. 1992.
MITI. Bi ode gradation and bioaccumidation data of existing chemicals based on the CSCL Japan. Compiled under the supervision of
Chemical Products Safety Division, Basic Industries Bureau, Ministry of International Trade & Industry, Japan; Chemicals Inspection
& Testing Institute, Japan. Ed.; Japan Chemical Industry Ecology- Toxicology & Information Center: 1998.
Nishihara, T.; Nishikawa, J.; Kanayama, T.; et al. Estrogenic activities of 517 chemicals by yeast two-hybrid assay. J. Health Sci.
2000, 46(4) 282-298.
OncoLogic. U.S. EPA and LogiChem, Inc. 2005, Version 7.0. 2008.
PBT Profi 1 er Persistent (P),Bioaccumulative (B), and Toxic (T) Chemical (PBT)Profiler, U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
SPARC On Line Calculator pKaproperty server. Ver 4.5 September, 2009. Available from, http://ibmlc2.chem.uga.edu/spare/
(accessed on August 12, 2010).
U.S. EPA (Environmental Protection Agency). High Production Volume (HPV) Challenge. Determining the Adequacy of Existing
Data. U.S. Environmental Protection Agency: Washington D.C. 1999. http://www.epa.gov/hpv/pubs/general/datadfin.htm
U.S. EPA (Environmental Protection Agency). Sustainable Futures Summary Assessment. Assessment of Discrete Organic
Chemicals. U.S. Environmental Protection Agency: Washington D.C. 2011.
http://www.epa.gov/oppt/sf/pubs/iad_discretes_092011 .pdf
U.S. EPA Sustainable Futures. UsingNonCancer Screening within the SFInitiative. Environmental Protection Agency: Washington
D.C. available at: http://www.epa.gOv/opptintr/sf/pubs/noncan-screen.htm#svstemic as of February 09, 2011.
Yamasaki, K.; Noda, S.; Imatanaka, N.; et al. Comparative study of the uterotrophic potency of 14 chemicals in a uterotrophic assay
and their receptor-binding affinity. Toxicol. Lett. 2004, 146:111-120.
4-291
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DRAFT REPORT - DO NOT CITE OR QUOTE
2,4-BPS
MW: 250.3
MF: C12H10O4S
CASRN: 5397-34-2
Physical Forms:
Neat: Solid
Use: Developer for thermal paper
SMILES: 0=S(=0)(clccc(0)cc 1 )clc(0)cccc 1
Synonyms: Phenol, 2-[(4-hydroxyphenyl)sulfonyl]- (TSCA Inventory); 2,4'-Dihydroxydiphenyl sulfone; 2,4'-Sulfonyldiphenol; 2-((4-
Hydroxyphenyl)sulfonyl)phenol; 4,2'-Dihydroxydiphenyl sulfone; 0,P-Dihydroxydiphenyl sulfone; Phenol, 2,4'-sulfonyldi-; o-((4-Hydroxyphenyl)sulphonyl)phenol
Polymeric: No
Oligomers: Not applicable
Metabolites, Degradates and Transformation Products: None
Analog: Bisphenol S (80-09-1)
Endpoint(s) using analog values: Boiling point, Acute lethality (oral
and dermal); Irritation (eye, dermal); dermal sensitization, repeated dose
effects, reproductive and developmental toxicity
Analog Structure:
HO
Structural Alerts: Phenols, neurotoxicity (U.S. EPA, 2010)
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 2011).
Risk Assessments: None identified
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DRAFT REPORT - DO NOT CITE OR QUOTE
2,4-BPS CASRN 5397-34-2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
184
ChemSpider, 2010
Secondary source; study details and test
conditions were not provided.
Boiling Point (°C)
>300 (Estimated)
EPI; U.S. EPA, 1999
Decomposition may occur before the
boiling point is reached based on the
experimental decomposition
temperature of 315°C for the analog
bisphenol S. Cutoff value for high
boiling point compounds according to
HPV assessment guidance.
Vapor Pressure (mm Hg)
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DRAFT REPORT - DO NOT CITE OR QUOTE
2,4-BPS CASRN 5397-34-2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Acute Lethality
Oral
Rat oral LD50 >5,000 mg/kg
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; using the analog bisphenol S.
Data are for an adequate guideline study
(OECD 401). No deaths at limit dose of
5,000 mg/kg.
Wistar rat (male)
LD50 = 2,830 mg/kg
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; using the analog bisphenol S.
Data are for an adequate guideline
comparable to OECD guideline 401.
The LD50 value supports other reported
results.
Rat oral LD50 = 4,556 mg/kg
(Estimated by analogy)
BIOFAX Industrial Bio-Test
Laboratories, Inc., Data Sheets.
Vol. 601-05501, 1974, cited in
CHEMID, 2010; Professional
judgment
Adequate; using the analog bisphenol S.
Although no study details were
provided in the secondary source, the
LD50 value supports other reported
results.
Rat oral LD50 = 2,540 mg/kg (females) and
>3,200 mg/kg (males)
(Estimated by analogy)
Eastman Kodak, 1991;
Professional judgment
Adequate; using the analog bisphenol S.
Although study details were lacking in
the study summary, the LD50 value
supports other reported results.
Sprague-Dawley rat (male, female)
LD50 >2,000 mg/kg
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; using the analog bisphenol S.
Although the secondary source
indicated that the study followed OECD
guideline 401, it was noted that only an
abstract of the study was located.
Dermal
Guinea pig dermal LD50 >1,000 mg/kg
(Estimated by analogy)
Eastman Kodak, 1991;
Professional judgment
Adequate; using the analog bisphenol S.
Data are for an adequate, nonguideline
study.
Inhalation
No data located.
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DRAFT REPORT - DO NOT CITE OR QUOTE
2,4-BPS CASRN 5397-34-2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Carcinogenicity
MODERATE: Estimated using OncoLogic expert system, which describes a potential for this compound as a
potential carcinogen or tumorigenesis promoter arising from its structural similarity to estrogenic/androgenic
compounds. The phenols and phenolic compounds structural alert was used.
OncoLogic Results
Moderate (Estimate)
OncoLogic class: phenols and phenolic
compounds
OncoLogic
OncoLogic SAR analysis using the
phenols and phenolic compounds class.
Carcinogenicity (Rat and
Mouse)
No data located.
Combined Chronic
Toxicity/Carcinogenicity
No data located.
Genotoxicity
MODERATE: 2,4-BPS did not cause genetic mutations in Salmonella typhimurium, but did cause
chromosomal aberrations in Chinese hamster ovary (CHO) cells in vitro. Based on evidence of mutagenicity
in animal cells, Moderate hazard is designated.
Gene Mutation in vitro
Negative for gene mutations in S.
typhimurium strains TA98, TA100, TA1535,
and TA1538 with and without metabolic
activation, and TA1537 with exogenous
metabolic activation; positive in TA1537
without exogenous metabolic activation, but
only at cytotoxic concentration.
NICCA USA Inc., 1996
Adequate; guideline (OECD 473).
Gene Mutation in vivo
No data located.
Chromosomal
Aberrations in vitro
Positive for chromosomal aberrations in
CHO cells with and without metabolic
activation.
NICCA USA Inc., 1996
Adequate; guideline (OECD 473).
Chromosomal
Aberrations in vivo
DNA Damage and Repair
No data located.
Other (Mitotic Gene
Conversion)
No data located.
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DRAFT REPORT - DO NOT CITE OR QUOTE
2,4-BPS CASRN 5397-34-2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproductive Effects
MODERATE: Estimated based on analogy to bisphenol S. In a reproductive/developmental toxicity
screening test, oral exposure of parental rats to the analog bisphenol S resulted in marked systemic and the
NOAEL for reproductive effects is 60 mg/kg-day (prolonged estrous cycle, decreased fertility index and
decreased number of live offspring). Based on the NOAEL for reproductive effects a Moderate hazard
designation is selected.
Reproduction/
Developmental Toxicity
Screen
Parental toxicity:
NOAEL =10 mg/kg bw-day
LOAEL = 60 mg/kg bw-day
Reproductive toxicity:
NOAEL = 60 mg/kg bw-day
LOAEL = 300 mg/kg bw-day
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; using the analog bisphenol S.
Data are for an adequate guideline study
(OECD 421) reported in a secondary
source.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Reproduction and
Fertility Effects
Potential for reproductive toxicity
(Estimated by analogy)
Professional judgment
Estimated based on reported
experimental data for the analog
bisphenol S.
Developmental Effects
MODERATE: Estimated based on analogy to bisphenol S. In a reproductive/developmental toxicity
screening test, oral exposure of parental rats to the analog bisphenol S resulted in marked systemic effects and
decreased number of live offspring (PND 4) at the highest dose level (300 mg/kg-day) with a NOAEL of 60
mg/kg-day. Based on the NOAEL a Moderate hazard designation is selected.
Reproduction/
Developmental Toxicity
Screen
Parental toxicity:
NOAEL =10 mg/kg bw-day
LOAEL = 60 mg/kg bw-day
Reproductive toxicity:
NOAEL = 60 mg/kg bw-day
LOAEL = 300 mg/kg bw-day
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; using the analog bisphenol S.
Data are for an adequate guideline study
(OECD 421) reported in a secondary
source.
Potential for developmental toxicity
(Estimated by analogy)
Professional judgment
Estimated based on reported
experimental data for the analog
bisphenol S.
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2,4-BPS CASRN 5397-34-2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Prenatal Development
No data located.
Postnatal Development
No data located.
Neurotoxicity
MODERATE: Estimated to have potential for neurotoxicity based on the presence of the phenol structural
alert.
Neurotoxicity Screening
Battery (Adult)
There is potential for neurotoxicity effects
based on the presence of the phenol
structural alert
(Estimated)
U.S. EPA, 2010; Professional
judgment
Estimated based on structural alert.
Repeated Dose Effects
HIGH: Based on analogy to bisphenol S. Among two adequately-designed repeated-dose oral studies in rats,
one study identified a NOAEL of 10 mg/kg-day and a LOAEL of 60 mg/kg-day for systemic effects and the
other study identified a NOAEL of 40 mg/kg-day and a LOAEL of 200 mg/kg-day for systemic effects
following exposure to the analog bisphenol S. Based on uncertainty as to the potential systemic toxicity in the
range of 40-60 mg/kg-day, a High hazard designation is selected.
In a repeated-dose oral study, Sprague-
Dawley rats, NOAEL = 40 mg/kg bw-day
LOAEL = 200 mg/kg-bw-day
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; using the analog bisphenol S.
Data are for an adequate 28-day repeat
dose toxicity guideline study.
In a reproduction/developmental toxicity
screening test, Sprague-Dawley rats,
NOAEL =10 mg/kg bw-day
LOAEL = 60 mg/kg bw-day
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; using the analog bisphenol S.
Data are for an adequate guideline study
(OECD421).
Skin Sensitization
LOW: Not considered a skin sensitizer in the guinea pig based on analog data for bisphenol S.
skin Sensitization
Negative for skin sensitization, guinea pig
(Estimated by analogy)
Eastman Kodak, 1991;
Professional judgment
Adequate; using the analog bisphenol
S. Data are for an adequate study with
limited details.
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2,4-BPS CASRN 5397-34-2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Negative for skin sensitization, mouse local
lymph node assay
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; using the analog bisphenol
S. Data are for an adequate guideline
study (OECD 429).
Respiratory Sensitization
No data located.
Respiratory Sensitization
No data located.
Eye Irritation
LOW: Estimated based on analogy to bisphenol S. The analog bisphenol S was nonirritating to mildly
irritating to rabbit eyes.
Eye Irritation
Slight eye irritant, rabbit
(Estimated by analogy)
Eastman Kodak, 1991;
Professional judgment
Adequate; using the analog bisphenol
S. Data are for an adequate,
nonguideline study.
Mild eye irritant, rabbit
(Estimated by analogy)
Monsanto, 1991; Professional
judgment
Adequate; using the analog bisphenol
S. Data are for an adequate,
nonguideline study.
Nonirritating, rabbit
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; using the analog bisphenol
S. Data are for an adequate guideline
study (OECD 405).
Dermal Irritation
LOW: Estimated based on analogy to bisphenol S. The analog bisphenol S was slightly irritating to guinea pig
skin, and not irritating to rabbit skin.
Dermal Irritation
Slight skin irritant, guinea pig
(Estimated by analogy)
Eastman Kodak, 1991;
Professional judgment
Adequate; using the analog bisphenol
S. Data are for an adequate,
nonguideline study.
Non-irritant, rabbit
(Estimated by analogy)
Monsanto, 1991; Professional
judgment
Adequate; using the analog bisphenol
S, data are for an adequate,
nonguideline study.
Non-irritant, rabbit
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; using the analog bisphenol
S. Data are for an adequate guideline
study (OECD 404).
Endocrine Activity
No data located.
No data located.
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2,4-BPS CASRN 5397-34-2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Immunotoxicity
No data located.
Immune System Effects
No data located.
ECOTOXICITY
ECOSAR Class
Phenols, Poly
Acute Toxicity
MODERATE: Based on estimated 96-hour ECS0 of 2.3 mg/L for green algae.
Fish LC50
Fish 96-hour LC50 = 37.91 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Fish 96-hour LC50 = 383.85 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid LCS0
Daphnid 48-hour LC50 = 196.26 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Daphnid 48-hour LC50 = 212.23 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Green Algae ECS0
Green algae 96-hour EC50 = 2.29 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Green algae 96-hour EC50 = 79.15 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Chronic Aquatic Toxicity
HIGH: Based on estimated a ChV value of 0.88 mg/L for green algae.
Fish ChV
Fish 30-day ChV = 12.64 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Fish ChV = 36.72 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
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2,4-BPS CASRN 5397-34-2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Daphnid ChV
Daphnia sp. (water flea)
21-day EC50 = 14 mg/L (reproduction)
21-day NOEC = 2.7 mg/L (Estimated by
analogy)
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; using the analog bisphenol S.
Data are for an adequte guideline study
(OECD211).
Daphnid ChV = 18.42 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid 21-day ChV = 74.99 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Green Algae ChV
Green algae ChV = 0.88 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Green algae ChV = 26.85 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
ENVIRONMENTAL FATE
Transport
2,4-BPS is expected to exist in both neutral and anionic forms at environmentally-relevant pH, based on its
estimated pKa. The neutral form of 2,4-BPS is expected to have moderate mobility in soil based on its
estimated Koc. The anionic form may be more mobile although leaching of 2,4-BPS through soil to
groundwater is not expected to be an important transport mechanism. Estimated volatilization half-lives
indicate that it will be nonvolatile from surface water. Volatilization from dry surface is also not expected
based on its estimated vapor pressure. In the atmosphere, 2,4-BPS is expected to exist solely in the particulate
phase, based on its estimated vapor pressure. Particulates may be removed from air by wet or dry deposition.
Level III fugacity models incorporating the located experimental property data, indicate that the unionized
form of 2,4-BPS is expected to partition primarily to soil.
Henry's Law Constant
(atm-m3/mole)
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DRAFT REPORT - DO NOT CITE OR QUOTE
2,4-BPS CASRN 5397-34-2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Level III Fugacity
Model
Air = <1% (Estimated)
Water = 16%
Soil = 83%
Sediment = <1%
EPI
Persistence
MODERATE: Evaluation of the persistence of 2,4-BPS is based entirely on QSARs for aerobic and anaerobic
biodegradation. Results from these models estimate primary biodegradation in days-weeks and ultimate
degradation in weeks. The persistence of 2,4-BPS is supported by an estimated half-life of 30 days in soil. 2,4-
BPS is expected to partition primarily to soil. 2,4-BPS is not expected to partition to sediment and removal
under anaerobic conditions is not anticipated to be a significant fate process. 2,4-BPS is not expected to
undergo hydrolysis since it does not contain hydrolysable functional groups. 2,4-BPS does not absorb UV
light at environmentally significant wavelengths. The vapor phase reaction of 2,4-BPS with atmospheric
hydroxyl radicals is estimated at 8.8 hours, although it is expected to exist primarily in the particulate phase in
air. Consideration of all of these factors indicates that the persistence concern is Moderate for 2,4-BPS.
Water
Aerobic Biodegradation
Days-weeks (primary survey model)
Weeks (ultimate survey model)
EPI
Volatilization Half-life
for Model River
>1 year (Estimated)
EPI
Volatilization Half-life
for Model Lake
>1 year (Estimated)
EPI
Soil
Aerobic Biodegradation
No data located.
Anaerobic
Biodegradation
Not probable (anaerobic-methanogenic
biodegradation probability model)
EPI
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
Biodegradation
No data located.
Air
Atmospheric Half-life
8.8 hours (Estimated)
EPI
Reactivity
Photolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain functional
groups that would be expected to absorb
light at wavelengths >290 nm.
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2,4-BPS CASRN 5397-34-2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Hydrolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain functional
groups that would be expected to
hydrolyze readily under environmental
conditions.
Pyrolysis
No data located.
Environmental Half-Life
30 days (Estimated)
EPI; PBT Profiler
Half-life estimated for the predominant
compartment, as determined by EPI and
the PBT Profiler methodology.
Bioaccumulation
LOW: The low potential for bioaccumulation is based on an estimated BCF for fish that is less than the low
criteria cutoff of 100. In addition, the estimated BAF of 3.5, which accounts for metabolism, suggests that
2,4-BPS will not bioaccumulate in higher trophic levels.
Fish BCF
5.7 (Estimated)
EPI
BAF
3.5 (Estimated)
EPI
Metabolism in Fish
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
Ecological Biomonitoring
No data located.
Human Biomonitoring
This chemical was not included in the NHANES biomonitoring report (CDC, 2011).
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DRAFT REPORT - DO NOT CITE OR QUOTE
BIOFAX Industrial Bio-Test Laboratories, Inc. Data sheets. Vol. 601-05501, 1974, as cited in ChemlD.
http://chem.sis.nlm.nih.gov/chemidplus/.
Boethling, R., Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences. Boca Raton:
Lewis Publishers. 2000.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
ChemlD. ChemlDplus. National Library of Medicine. 2010: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen7CHEM (accessed on December
10, 2010).
ChemSpider. ChemSpider; Stractare-based Chemistry Information. Royal Society of Chemistry:London. 2010.
http://www.chemspider.com (accessed on December 11, 2010).
Eastman Kodak. Letter concerning enclosed information on bisphenol S with attachments. Eastman Kodak Company, Rochester NY.
TSCATS submission OTS0534330. 1991.
ECHA. European Chemicals Agency. Information on registered substances. 2011. http://apps.echa.europa.eu/registered/registered-
sub.aspx (accessed February 18, 2011).
EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 4.00. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
Monsanto. Toxicological investigation of dihydroxydiphenyl sulfone (final report) with cover letter datedl 12190. TSCATS
submission OTS0534356. 1991.
NICCAUSA Inc. Letter from NICCA U.S.A. Inc to USEPA regarding genotoxicity testing of phenol, 2-[(4-hydroxyphenyl)-sidfonyl],
with attachments and dated 3/5/96. Nicca Chemical Company Limited. OTS0558479. 1996.
4-303
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DRAFT REPORT - DO NOT CITE OR QUOTE
Oncologic. U.S. EPA and LogiChem, Inc. 2005, Version 7.0. 2008.
PBT Profi 1 er Persistent (P),Bioaccumulative (B), and Toxic (T) Chemical (PBT)Profiler. U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
SPARC On Line Calculator pKaproperty server. Ver 4.5 September, 2009. Available from, http://ibmlc2.chem.uga.edu/spare/
(accessed on August 12, 2010).
U.S. EPA (Environmental Protection Agency). High Production Volume (HPV) Challenge. Determining the Adequacy of Existing
Data. U.S. Environmental Protection Agency: Washington D.C. 1999. http://www.epa.gov/hpv/pubs/general/datadfin.htm.
U.S. EPA Sustainable Futures. Using Non-Cancer Screening within the SF Initiative. Environmental Protection Agency: Washington
D.C. 2010. http://www.epa.gOv/opptintr/sf/pubs/noncan-screen.htm#svstemic (accessed on February 09, 2011).
U.S. EPA (Environmental Protection Agency). Sustainable Futures Summary Assessment. Assessment of Discrete Organic
Chemicals. U.S. Environmental Protection Agency: Washington D.C. 2011.
http://www.epa.gov/oppt/sf/pubs/iad_discretes_092011 .pdf.
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TGSA
/ O /=v
ho—P y— s—
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DRAFT REPORT - DO NOT CITE OR QUOTE
TGSA CASRN 41481-66-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
151-155 ±1 (Measured)
Nippon Kayaku Co., 1992b
Adequate; guideline study.
144 (Measured)
Submitted confidential study
Adequate.
Boiling Point (°C)
Decomposed prior to boiling (Measured)
Nippon Kayaku Co., 1992b
Adequate; decomposition occurs
before the boiling point is reached.
Vapor Pressure (mm Hg)
9.5xl0"lu (Measured)
Nippon Kayaku Co., 1992b
Adequate; guideline study.
Water Solubility (mg/L)
4.79 at 20.3°C ±0.5 (Measured)
Nippon Kayaku Co., 1992b
Adequate; guideline study.
Log Kow
3.22 (Measured)
Nippon Kayaku Co., 1992b
Adequate; guideline study.
Flammability (Flash Point)
Not highly flammable (Measured)
Nippon Kayaku Co., 1992b
Adequate; guideline study.
Explosivity
Not explosive (Measured)
Nippon Kayaku Co., 1992b
Adequate; guideline study.
pH
No data located.
pKa
8.3-8.5 (Estimated)
SPARC
HUMAN HEALTH EFFECTS
Toxicokinetics
TGSA as a neat material is not estimated to be absorbed through the skin and is expected to have poor skin
absorption when in solution. It is estimated to be absorbed via the lungs and gastrointestinal tract based on
data for bisphenol A. TSGA is a potential cross-linking agent because it has two terminal double bonds that
are expected to be oxidized in the body via an epoxide intermediate.
Dermal Absorption in vitro
No data located.
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal or Inhaled
Not absorbed through the skin as neat
material and has poor absorption in solution.
Can be absorbed through the lung and
gastrointestinal tract.
(Estimated by analogy)
Oxidation of the terminal double bonds in
the body via an epoxide intermediate is
expected. TGSA is a potential cross-linking
agent because it has two terminal double
bonds.
(Estimated by analogy)
Professional judgment
Estimate based on reported
experimental data for the analog
bisphenol A; the potential for
crosslinking is based on a
mechanistic analysis.
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TGSA CASRN 41481-66-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Acute Mammalian Toxicity
LOW: Based on experimental values for oral and dermal exposure. Experimental data indicated that the
acute oral and dermal toxicity of TGSA is low. No data were located regarding the acute inhalation hazard.
Acute Lethality
Oral
Sprague-Dawley rat LD50 >2,000 mg/kg
Nippon Kayaku Co., 199If
Adequate guideline study (OECD
401).
Dermal
Rat dermal LD50 >2,000 mg/kg
Nippon Kayaku Co., 199Id
Adequate guideline study (OECD
402).
Inhalation
No data located.
Carcinogenicity
MODERATE: Estimated to be a concern for carcinogenicity based on data reported for the epoxide
oxidation product. In addition, there is uncertainty due to the lack of data located for this substance.
Carcinogenic effects cannot be ruled out.
OncoLogic Results
No data located; not amenable to
available estimation method.
Carcinogenicity (Rat and
Mouse)
Concern for carcinogenicity
(Estimated)
Professional judgment
Estimated based on potential for
the epoxide oxidation product.
Combined Chronic
T oxi city/Car cinogenicity
No data located.
Genotoxicity
LOW: Based on experimental data showing that TGSA did not induce gene mutations or chromosomal
aberrations in vitro, and was negative in a mammalian erythrocyte micronucleus assay in mice.
Gene Mutation in vitro
Negative, Ames assay (standard plate) in S.
typhimiiriiim strains TA98, TA100, TA1537,
TA1535, and E. coli WP2«vrA~ with and
without metabolic activation
Nippon Kayaku Co., 199 Ig
Test conducted in accordance with
OECD 471; test substance purity:
96.2%.
Gene Mutation in vivo
No data located.
Chromosomal
Aberrations in vitro
Negative for chromosome aberrations in
human lymphocytes
Nippon Kayaku Co., 2000c
Test conducted in accordance with
OECD 473.
Negative for sister chromatid exchanges
Submitted confidential study
Adequate.
Chromosomal
Aberrations in vivo
No data located.
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TGSA CASRN 41481-66-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
DNA Damage and Repair
No data located.
Other (Mitotic Gene
Conversion)
Negative, mammalian erythrocyte
micronucleus test in mice (gavage)
Nippon Kayaku Co., 199li
Test conducted in accordance with
OECD 474; test substance purity:
96.2%.
Reproductive Effects
MODERATE: Estimated based on analogy to bisphenol S. In a reproductive/developmental toxicity
screening test, oral exposure of parental rats to the analog bisphenol S resulted in marked systemic effects
and the NOAEL for reproductive effects is 60 mg/kg-day (prolonged estrous cycle, decreased fertility index
and decreased number of live offspring). Based on the NOAEL for reproductive effects a Moderate hazard
designation is selected.
Reproduction/
Developmental Toxicity
Screen
Parental toxicity:
NOAEL =10 mg/kg bw-day
LOAEL = 60 mg/kg bw-day Reproductive
toxicity:
NOAEL = 60 mg/kg bw-day
LOAEL = 300 mg/kg bw-day
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Using the analog bisphenol S, data
are for an adequate guideline study
(OECD 421) reported in a
secondary source.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Reproduction and
Fertility Effects
Concern for male reproductive toxicity
(Estimated)
Professional judgment
Estimated based on reported data
for the epoxide oxidation product
and on reported experimental data
for the analog bisphenol S.
Developmental Effects
MODERATE: Estimated based on analogy to bisphenol S. In a reproductive/developmental toxicity
screening test, oral exposure of parental rats to the analog bisphenol S resulted in marked systemic effects
and decreased number of live offspring (PND 4) at the highest dose level (300 mg/kg-day) with a NOAEL of
60 mg/kg-day. Based on the NOAEL a Moderate hazard designation is selected.
Reproduction/
Developmental Toxicity
Screen
Concern for developmental toxicity
(Estimated)
Professional judgment
Estimated based on reported data
for the epoxide oxidation product
and on reported experimental data
for the analog bisphenol S.
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TGSA CASRN 41481-66-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Parental toxicity:
NOAEL =10 mg/kg bw-day
LOAEL = 60 mg/kg bw-day Reproductive
toxicity:
NOAEL = 60 mg/kg bw-day
LOAEL = 300 mg/kg bw-day
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Using the analog bisphenol S, data
are for an adequate guideline study
(OECD 421) reported in a
secondary source.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Prenatal Development
No data located.
Postnatal Development
No data located.
Neurotoxicity
MODERATE: Estimated to have potential for neurotoxicity based on the presence of the phenol structural
alert.
Neurotoxicity Screening
Battery (Adult)
There is potential for neurotoxicity effects
based on the presence of the phenol
structural alert
(Estimated)
U.S. EPA, 2010; Professional
judgment
Estimated based on structural alert.
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TGSA CASRN 41481-66-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Repeated Dose Effects
MODERATE: Based on experimental data for a 28-day oral exposure to TGSA in rats. A NOAEL of 15
mg/kg-day and a LOAEL of 150 mg/kg-day was identified for repeated dose effects that would indicate a
MODERATE hazard designation; however, there is concern for liver and kidney toxicity based on data for
the epoxide oxidation product.
28-day repeated-dose oral exposure study,
Sprague-Dawley rats;
There was no mortality and no clinical signs
of toxicity; increased salivation with wet fur
and red/brown staining of body surface at
doses of 150 mg/kg-day and higher;
Decreased body weight gain in females
administered 1,000 mg/kg-day; no treatment
related effects on hematology, serum
chemistry, necropsy, or organ weights;
increased incidence of basophilic tubules
and interstitial mononuclear cell infiltrates in
kidneys of males in the 1,000 mg/kg-day
group; similar but less pronounce effect
occurred at 150 mg/kg-day in males.
Nippon Kayaku Co., 199 Ij
Test conducted in accordance with
OECD 474; test substance purity:
96.2%.
NOAEL =15 mg/kg-day
LOAEL =150 mg/kg-day (microscopic
renal changes)
Skin Sensitization
HIGH: There is concern that TGSA is a skin sensitizer based on experimental data indicating a potential for
sensitization in guinea pigs.
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TGSA CASRN 41481-66-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Skin Sensitization
Strong skin sensitizer in guinea pigs;
produced a 70% (14/20) sensitization rate in
guinea pigs.
Nippon Kayaku Co., 199 Ih
Test conducted in accordance with
OECD 406 skin sensitization
Magnusson and Kligman
maximization test; test substance
purity: 96.2%; intradermal
induction: 25% in arachis oil B.P,
topical induction: 50% in arachis
oil B.P., topical challenge: 50% in
arachis oil B.P.
Did not produce skin sensitization in guinea
pigs
Nippon Kayaku Co., 1992b
Test conducted in accordance with
EEC methodology 84/449/EEC
(OJ No. L251, 19.9.84), Part B,
test substance purity: 97.9 %;
Method B.6; Induction: 60%
Alembicol D; challenge: 60% in
Alembicol D.
Classified as non-sensitizer in local lymph
node assay in female CBA/JN mice; applied
to dorsum of ears for 3 days; all stimulation
indexes were below 3.
Nippon Kayaku Co., 2010
Test conducted in accordance with
OECD TG429; test substance
purity: 97.8%.
Respiratory Sensitization
MODERATE: There is concern that TGSA is a respiratory sensitizer based on the epoxide oxidation
product.
Respiratory Sensitization
Concern for respiratory sensitization
Professional judgment
Estimated based on reported data
for the epoxide oxidation product.
Eye Irritation
LOW: Based on experimental data suggesting that TGSA is a minimal irritant to rabbit eyes.
Eye Irritation
Minimal irritant, rabbit
Nippon Kayaku Co., 1991e
Test conducted in accordance with
OECD 405; test substance purity:
96.2%.
Dermal Irritation
VERY LOW: Based on experimental data indicating that TGSA is not an irritant to rabbit skin.
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TGSA CASRN 41481-66-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Dermal Irritation
Non-irritant, rabbit
Nippon Kayaku Co., 1991c
Test conducted in accordance with
OECD 404; test substance purity:
96.2%.
Endocrine Activity
There was no evidence that TGSA elicits estrogenic activity. TGSA did not bind to estrogen receptors in
yeast, and did not have estrogenic effects on uterus of immature rats in vivo.
Did not cause significant estrogenic activity
in a recombinant yeast screen assay in
Sacchctromyces cerevisicte; did not bind to
estrogen receptor in recombinant yeast; there
was an estrogenic response that was 4 orders
of magnitude less than 17B-estradiol and 1
order of magnitude less than bisphenol A
Nippon Kayaku Co., 1999a
Adequate study details provided.
Uterotrophic assay in immature rat; No
evidence of estrogenic effects on uterus of
immature rats at oral doses up to 100 mg/kg
bd. Wt.
Nippon Kayaku Co., 1999b
Adequate study details provided;
TGSA also did not provide a
synergistic effect when
administered in combination with
diethylstilbestrol (positive control).
Immunotoxicity
No data located.
Immune System Effects
No data located.
ECOTOXICITY
ECOSAR Class
Phenols, poly
Acute Toxicity
HIGH: Based on experimental acute aquatic toxicity values for fish and Daphnia which are in the range of 1-
10 mg/L.
Fish LC50
Oncorhvnchiis mykiss (rainbow trout) 96
hour LC50 = 4.0 mg/L;
NOEC - 96 hour =1.8 mg/L
(Experimental)
Nippon Kayaku Co., 1991b
Test conducted in accordance with
OECD 203.
Oryzias latipes (medaka) 96 hour LC50 >9.8
mg/L
(Experimental)
Nippon Kayaku Co., 201 lb
Test conducted in accordance with
OECD 203; test substance purity:
98%.
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TGSA CASRN 41481-66-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Fish 96-hour LC50 =1.17 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Fish 96-hour LC50 = 2.22 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid LCS0
Daphnia (Daphnia magna) 48-hour EC50 =
5.5 mg/L (immobilization);
24-hour EC50 = 7.8 mg/L (immobilization);
NOEC - 48-hour = 3.2 mg/L
(Experimental)
Nippon Kayaku Co., 1991a
Test conducted in accordance with
OECD 202.
Daphnia (Daphnia magna) 48-hour EC50 >
12 mg/L (immobilization);
24-hour EC50 >12 mg/L (immobilization);
(Experimental)
Nippon Kayaku Co., 201 la
Test conducted in accordance with
OECD 202; test substance purity:
98%.
Daphnid 48-hour LC50 = 1.72 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid 48-hour LC50 = 1.87 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Green Algae ECS0
Green algae (Scenedesmus subspicatus)
72-hour EC50 = > 100 mg/L
(Experimental)
Nippon Kayaku Co., 2000b
Test conducted in accordance with
OECD 201; test substance purity:
50% TGSA, 4%PVA, 46% water.
Green algae 96-hour EC50 =1.71 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Green algae 96-hour EC50 = 2.01 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
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TGSA CASRN 41481-66-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Chronic Aquatic Toxicity
HIGH: Based on estimated ChV values for fish and algae that are in the range of 0.1-1.0 mg/L. Experimental
chronic toxicity values were located for daphnia, but not for fish or algae. Experimental values for daphnia
are in the Moderate hazard range of 1-10 mg/L. Without experimental values for fish or algae, a conservative
approach using estimated values will be the basis for the hazard designation.
Fish ChV
Fish ChV = 0.20 mg/L (Estimated)
ECOSAR: neutral organics
EPI
Fish ChV = 0.24 mg/L (Estimated)
ECOSAR: phenols, poly
EPI
Daphnid ChV
Daphnia (Daphnia magna) 14-day EC50 =
4.1 mg/L (immobilization)
(Experimental)
Nippon Kayaku Co., 2000a
Test conducted in accordance with
OECD 211; 14-day value
determined during 21-day
reproduction test in parental
daphnia generation; based on time-
weighted mean measured test
concentrations of the filtered test
substance.
Daphnia (Daphnia magna) 21-day EC50 =
2.8 mg/L (immobilization)
(Experimental)
Nippon Kayaku Co., 2000a
Test conducted in accordance with
OECD 211; 21-day reproduction
test in parental daphnia generation;
Based on time-weighted mean
measured test concentrations of the
filtered test substance.
Daphnia {Daphnia magna) 21-day EC50 =
2.0 mg/L (reproduction)
(Experimental)
Nippon Kayaku Co., 2000a
Test conducted in accordance with
OECD 211; 21-day reproduction
test; Based on time-weighted mean
measured test concentrations of the
filtered test substance.
Daphnia (Daphnia magna)
LOEC =1.6 mg/L (reproduction)
NOEC = 0.50 mg/L
(Experimental)
Nippon Kayaku Co., 2000a
Test conducted in accordance with
OECD 211; 21-day reproduction
test; based on time-weighted mean
measured test concentrations of the
filtered test substance.
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TGSA CASRN 41481-66-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Daphnid ChV = 0.25 mg/L (Estimated)
ECOSAR: neutral organics
EPI
Daphnid ChV = 0.61 mg/L (Estimated)
ECOSAR: phenols, poly
EPI
Green Algae ChV
Green algae ChV = 0.20 mg/L (Estimated)
ECOSAR: phenols, poly
EPI
Green algae ChV =1.14 mg/L (Estimated)
ECOSAR: neutral organics
EPI
ENVIRONMENTAL FATE
Transport
TGSA is expected to exist in both the neutral and anionic forms at environmentally-relevant pH. TGSA is
expected to have moderate mobility in soil. Anionic TGSA may have higher mobility due to enhanced water
solubility. However, leaching through soil to groundwater is not expected to be an important transport
mechanism. In the atmosphere, TGSA is expected to exist in the particulate phase, which will be deposited
back to the soil and water surfaces through wet or dry deposition. The Level III fugacity model indicates
that TGSA will partition primarily to soil.
Henry's Law Constant
(atm-m3/mole)
8.6x10 s (Estimated)
EPI
Sediment/Soil
Adsorption/Desorption
Coefficient - Koc
996 (Measured)
HPLC screening method using cyanopropyl
packed column; GLP compliance
TSCATS
Adequate, nonguideline study yet
established method considered to
have higher reliability than QSAR-
based estimations.
>30,000 (Estimated)
EPI; U.S. EPA, 2011
Cutoff value for nonmobile
compounds according to SF
assessment guidance.
Level III Fugacity
Estimations
Air = <1% (Estimated)
Water = 9.8%
Soil = 58.2%
Sediment = 31.9%
EPI
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TGSA CASRN 41481-66-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Persistence
HIGH: The persistence of TGSA is based on an estimated half-life of 75 days in soil. TGSA is expected to
partition primarily to soil. Experimental biodegradation data for TGSA were not located. Evaluation of the
biodegradation potential for TGSA is based entirely on QSARs of aerobic and anaerobic biodegradation.
Results from these models estimate ultimate biodegradation in weeks-months and primary degradation in
days-week. Biodegradation under anaerobic methanogenic conditions is not probable based on results from
estimation models. TGSA does not contain functional groups that absorb light at environmentally-relevant
wavelengths. Therefore, it is not expected to be susceptible to direct photolysis. It is not expected to undergo
hydrolysis as it does not contain hydrolysable functional groups. The atmospheric half-life of TGSA is
estimated at 1.8 hours, although it is expected to exist primarily as a particulate in air. Therefore,
biodegradation is expected to be the main degradation pathway for TGSA.
Water
Aerobic Biodegradation
Days-weeks (primary survey model)
Weeks-months (ultimate survey model)
EPI
Volatilization Half-life
for Model River
>1 year (Estimated)
EPI
Volatilization Half-life
for Model Lake
>1 year (Estimated)
EPI
Soil
Aerobic Biodegradation
No data located.
Anaerobic
Biodegradation
Not probable (anaerobic-methanogenic
biodegradation probability model)
EPI
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
Biodegradation
No data located.
Air
Atmospheric Half-life
1.8 hours (Estimated)
EPI
Reactivity
Photolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain
functional groups that would be
expected to absorb light at
wavelengths >290 nm.
Hydrolysis
<10% in 5 days at 50°C, pH 4
Nippon Kayaku Co., 1992b
Adequate; guideline study.
Pyrolysis
No data located.
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TGSA CASRN 41481-66-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Environmental Half-life
75 days
EPI; PBT Profiler
Half-life estimated for the
predominant compartment, as
determined by EPI and the PBT
Profiler methodology.
Bioaccumulation
LOW: The estimated fish BAF and BCF is <100.
Fish BCF
62 (Estimated)
EPI
Estimate performed using
experimental log Kow.
BAF
18 (Estimated)
EPI
Estimate performed using
experimental log K0„.
Metabolism in Fish
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
Ecological Biomonitoring
No data located.
Human Biomonitoring
This chemical was not included in the NHANES biomonitoring report (CDC, 2011).
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DRAFT REPORT - DO NOT CITE OR QUOTE
Boethling, R.; Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences, Boca Raton:
Lewis Publishers. 2000.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
ECHA (European Chemicals Agency). Information on registered substances, http://apps.echa.europa.eu/registered/registered-sub.aspx
(accessed February 18, 2011)
EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 4.00. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
U.S. EPA (Environmental Protection Agency). Sustainable Futures Summary Assessment. Assessment of Discrete Organic
Chemicals. U.S. Environmental Protection Agency: Washington D.C. 2011.
http://www.epa.gov/oppt/sf/pubs/iad_discretes_092011 .pdf
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
Nippon Kayaku Co. The acute toxicity ofTG-SA to dctphnia magna. Nippon Kayaku Co. Limited, Tokyo Japan. Project Number: 189-320. 1991a.
Nippon Kayaku Co. The acute toxicity ofTG-SA to rainbow trout (Oncorhvnchus mykiss). Nippon Kayaku Co. Limited, Tokyo Japan. Project
Number: 189/321. 1991b.
Nippon Kayaku Co. TG-SA: Acute dermal irritation test in the rabbit. Nippon Kayaku Co. Limited, Tokyo Japan. Project number: 189/316.
1991c.
Nippon Kayaku Co. TG-SA: Acute dermal toxicity (limit test) in the rat. Nippon Kayaku Co. Limited, Tokyo Japan. Project number: 189/315.
1991d.
Nippon Kayaku Co. TG-SA: Acute eye irritation test in the rabbit. Nippon Kayaku Co. Limited, Tokyo Japan. Project number 189/317. 1991e.
Nippon Kayaku Co. TG-SA: Acute oral toxicity (limit test) in the rat. Nippon Kayaku Co. Limited, Tokyo Japan. Project number: 189/314. 1991f.
4-318
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DRAFT REPORT - DO NOT CITE OR QUOTE
Nippon Kayaku Co. TG-SA: Determination of Physico-Chemical Properties. Nippon Kayaku Co. Limited, Tokyo Japan. Project number: 189/324.
1992a.
Nippon Kayaku Co. TG-SA: Reverse mutation assay 'Ames test" using Salmonella typhimurium and Escherichia coli. Nippon Kayaku Co.
Limited, Tokyo Japan. Project number 189/322. 1991g.
Nippon Kayaku Co. TG-SA: Magnusson & Kligman maximization. Study in the guinea pig. Nippon Kayaku Co. Limited, Tokyo Japan. Project
number: 189/318. 1991h.
Nippon Kayaku Co. TG-SA: Micromicleiis test. Nippon Kayaku Co. Limited, Tokyo Japan. Project number: 189/323. 1991i.
Nippon Kayaku Co. TG-SA: Twenty-eight day sub-acute oral toxicity study in the rat. Nippon Kayaku Co. Limited, Tokyo Japan. Project number
189/325. 1991j.
Nippon Kayaku Co. TG-SA: Skin sensitisation in the guinea-pig. Nippon Kayaku Co. Limited, Tokyo Japan. 920596D/NKU 268/SS. 1992b.
Nippon Kayaku Co. TG-SA (Lot No. 710427): Assessment of oestrogenic activity using a recombinant yeast screen assay. Nippon Kayaku Co.
Limited, Tokyo Japan.SPL project number: 189/1663. 1999a.
Nippon Kayaku Co. TG-SA: Uterotrophic assay in the immature rat. Nippon Kayaku Co. Limited, Tokyo Japan. SPL project number: 189/1659.
1999b.
Nippon Kayaku Co. TG-SA: Daphnia magna reproduction test. Nippon Kayaku Co. Limited, Tokyo Japan. SPL project number: 189/1717.
2000a.
Nippon Kayaku Co. TG-SA 50% liquid: Algal inhibition test. Nippon Kayaku Co. Limited, Tokyo Japan. SPL project number: 189/1743. 2000b.
Nippon Kayaku Co. TG-SA: Chromosome aberration test in human Ivmphocvtes in vitro. Nippon Kayaku Co. Limited, Tokyo Japan. SPL project
number: 189/1716. 2000c.
Nippon Kayaku Co. Evaluation of skin sensitization potency ofTG-SH based on EC 3 value derived from local lymph node assay (LLNA). Nippon
Kayaku Co. Limited, Tokyo Japan. Study code 937-10-V-0069. 2010.
4-319
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DRAFT REPORT - DO NOT CITE OR QUOTE
Nippon Kayaku Co. A 48-hour acute immobilization study ofTG-SH(H) in daphnia magna. Nippon Kayaku Co. Limited, Tokyo Japan. Receipt
number 662-10-E-5538. Study number 95538. 2011a.
Nippon Kayaku Co. A 96-hour acute toxicity study ofTG-SH(H) in Medaka. Nippon Kayaku Co. Limited, Tokyo Japan. Receipt number 662-10-
E-5540. Study number 95540. 2011b.
SPARC On Line Calculator pKa property server. Ver 4.5 September, 2009. Available from, http://ibmlc2.chem.uga.edu/sparc/
(accessed on August 12, 2010).
TSCATS. Marubeni. PMN # P-85-67 2, 2 '-diallyl-4,4'-sulfonyl diphenol (or commonly known as TGSA). Marubeni Specialty
Chemicals Inc., White Plains NY. Submitted March 22, 2005 to TSCATS submission FYI.
U.S. EPA Sustainable Futures Using NonCancer Screening within the Sustainable Futures Initiative Environmental Protection
Agency: Washington D.C. 2010. http://www.epa.gOv/opptintr/sf/pubs/noncan-screen.htm#svstemic (accessed on February 09, 2011).
4-320
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DRAFT REPORT - DO NOT CITE OR QUOTE
BPS-MAE
HO—^ S—^ ^—0
CASRN 97042-18-7
MW: 290.34
MF: C15H1404S
0 ^
Physical Forms:
Neat: Solid
Use: Developer for thermal paper
SMILES: C=CC0c2ccc(cc2)S(=0)(=0)clccc(0)ccl
Synonyms: BPS-MAE; bis(4-Hydroxyphenyl) sulfone monoallyl ether; 4-[[4-(2-Propenyloxy)phenyl]sulfonyl]phenol; 4-{[4-(allyloxy)phenyl]sulfonyl}phenol
Polymeric: No
Oligomers: Not applicable
Metabolites, Degradates and Transformation Products: Potential for e
joxide formation on terminal double bond.
Analog: Bisphenol S (80-09-1)
Endpoint(s) using analog values: Boiling point, carcinogenicity,
reproductive and developmental toxicity.
Analog Structure:
/ \ 0 /=\
H0~\ Z-°H
\=/ 0 /
Structural Alerts: Phenols, neurotoxicity (U.S. EPA, 2010)
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 2011).
Risk Assessments: None identified
<3
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BPS-MAE CASRN 97042-18-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
172 (Measured)
Submitted confidential study
Adequate.
Boiling Point (°C)
>300 (Estimated)
EPI; U.S. EPA, 1999
Decomposition may occur before the
boiling point is reached based on the
experimental decomposition
temperature of 315 degrees C for an
analogous structure, bisphenol S.
Cutoff value for high boiling point
compounds according to HPV
assessment guidance.
Vapor Pressure (mm Hg)
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DRAFT REPORT - DO NOT CITE OR QUOTE
BPS-MAE CASRN 97042-18-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
HUMAN HEALTH EFFECTS
Toxicokinetics
BPS-MAE is estimated not to be absorbed through the skin as the neat material and have poor skin
absorption when in solution. BPS-MAE is estimated to have good absorption via the lungs and
gastrointestinal tract based on data for the analog bisphenol A. BPS-MAE is a potential cross-linking agent
because it has two terminal double bonds that are expected to be oxidized in the body via an epoxide
intermediate.
Dermal Absorption in vitro
No data located.
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal or Inhaled
Estimated to be poorly absorbed as neat
material and in solution through the
skin. Absorption through lungs and
gastrointestinal tract is expected to be
good. The terminal double bonds have
the potential be oxidized metabolically
to the epoxide.
(Estimated by analogy)
Professional judgment
Estimated based on reported
experimental data for the analog
bisphenol A; the potential for epoxide
formation is based on a mechanistic
analysis.
Acute Mammalian Toxicity
LOW: BPS-MAE was not toxic following acute oral exposure based on the acute oral LCS0 value of >2,000
mg/kg-bw in rats.
Acute Lethality
Oral
Rat (Sprague-Dawley CD) oral LD50 >
2,000 mg/kg-bw, no mortalities or signs
of systemic toxicity at the highest dose
tested (2,000 mg/kg-bw).
Submitted Confidential Study
Adequate; guideline study (OECD
423).
Dermal
No data located.
Inhalation
No data located.
Carcinogenicity
MODERATE: Estimated to have potential for carcinogenicity based on data reported for the epoxide
oxidation product and structural analogy to bisphenol S. In addition, there is uncertainty due to the lack of
data for this substance. Carcinogenic effects cannot be ruled out.
OncoLogic Results
Not amenable to available estimation
method.
Carcinogenicity (Rat and
Mouse)
Potential for carcinogenicity
(Estimated)
Professional judgment
Estimated based on potential for the
epoxide oxidation product and based
on analogy to bisphenol S.
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BPS-MAE CASRN 97042-18-7
PROPE1
RTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Combined Chronic
Toxicity/Carcinogenicity
No data located.
Genotoxicity
MODERATE: BPS-MAE was clastogenic in CHL/IU cells with metabolic activation, but did not cause
mutations in bacterial cells nor cause an increase in the induction of micronucleated immature erythrocytes
or bone marrow cells in CD-I mice.
Gene Mutation in vitro
Negative, Reverse Mutation assay in
Salmonella typhimurium strains TA98,
TA100, TA1535, and TA1537 and
Escherichia coli WP2 uvrA/pKMlOl
with and without metabolic activation.
Cytotoxicity was observed in
Salmonella typhimurium strains TA98,
TA1535, and TA1537 in the presence of
activation at 5000 pg/plate.
Submitted Confidential Study
Adequate; guideline study (OECD
471).
Gene Mutation in vivo
No data located.
Chromosomal Aberrations
in vitro
Positive for chromosome aberrations
with activation in the CHL/IU cell line;
the incidences of cells with structural
chromosome aberrations was 6.0%
(1250 pg/mL), 7.5% (2500 pg/mL) and
11% (5000 pg/ml) with metabolic
activation.
Submitted Confidential Study
Adequate; guideline study (lapanese
Guidelines on Industrial Chemicals
(1997) and OECD Guideline (1997)).
Chromosomal Aberrations
in vivo
BPS-MAE did not cause an increase in
the induction of micronucleated
immature erythrocytes or bone marrow
cells following oral gavage exposure to
CD-I mice.
Submitted Confidential Study
Adequate; guideline study (OECD
474).
DNA Damage and Repair
No data located.
Other (Mitotic Gene
Conversion)
No data located.
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BPS-MAE CASRN 97042-18-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproductive Effects
MODERATE: Estimated based on analogy to bisphenol S. In a reproduction/developmental toxicity
screening test, oral exposure of parental rats to the analog bisphenol S resulted in marked systemic effects
and the NOAEL for reproductive effects is 60 mg/kg-day (prolonged estrous cycle, decreased fertility index
and decreased number of live offspring). Based on the NOAEL for reproductive effects a Moderate hazard
designation is selected.
Reproduction/
Developmental Toxicity
Screen
Parental toxicity:
NOAEL =10 mg/kg bw-day
LOAEL = 60 mg/kg bw-day
Reproductive toxicity:
NOAEL = 60 mg/kg bw-day
LOAEL = 300 mg/kg bw-day
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Using the analog bisphenol S, data are
for an adequate guideline study
(OECD 421) reported in a secondary
source.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Reproduction and Fertility
Effects
Potential for male reproductive toxicity
(Estimated)
Professional judgment
Estimated based on reported data for
the epoxide oxidation product and on
reported experimental data for the
analog bisphenol S.
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BPS-MAE CASRN 97042-18-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Developmental Effects
MODERATE: Estimated based on analogy to bisphenol S. In a reproduction/developmental toxicity
screening test, oral exposure of parental rats to the analog bisphenol S resulted in marked systemic effects
and decreased number of live offspring (PND 4) at the highest dose level (300 mg/kg-day with a NOAEL of 60
mg/kg-day. Based on the NOAEL a Moderate hazard designation is selected.
Reproduction/
Developmental Toxicity
Screen
Parental toxicity:
NOAEL =10 mg/kg bw-day
LOAEL = 60 mg/kg bw-day
Reproductive toxicity:
NOAEL = 60 mg/kg bw-day
LOAEL = 300 mg/kg bw-day
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Using the analog bisphenol S, data are
for an adequate guideline study
(OECD 421) reported in a secondary
source.
Potential for developmental toxicity
(Estimated)
Professional judgment
Estimated based on reported data for
the epoxide oxidation product and on
reported experimental data for the
analog bisphenol S.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Prenatal Development
No data located.
Postnatal Development
No data located.
Neurotoxicity
MODERATE: Estimated to have potential for neurotoxicity based on the presence of the phenol structural
alert.
Neurotoxicity Screening
Battery (Adult)
There is potential for neurotoxicity
effects based on the presence of the
phenol structural alert
(Estimated)
U.S. EPA 2010, Professional
judgment
Estimated based on structural alert.
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BPS-MAE CASRN 97042-18-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Repeated Dose Effects
LOW: Effects from BPS-MAE were limited to increased kidney weights at 1,000 mg/kg/day in a 28-day
repeated-dose toxicity study in rats.
Adverse effects were limited to higher
absolute and relative kidney weights in
female Cij :CD (SD) IGS rats at 1,000
mg/kg-bw; NOEL = 1,000 mg/kg-
bw/day (males) and 200 mg/kg-bw/day
(females).
Submitted Confidential Study
Adequate; guideline study (OECD
407).
Skin Sensitization
LOW: BPS-MAE was not a skin sensitizer in one study of Guinea pigs.
Skin Sensitization
Negative for skin sensitization in
Dunkin Hartley guinea pigs.
Submitted Confidential Study
Adequate; guideline study (OECD
406).
Respiratory Sensitization
MODERATE: BPS-MAE is estimatec
oxidation product.
to have potential to be a respiratory sensitizer based on the epoxide
Respiratory Sensitization
Potential for respiratory sensitization
Professional judgment
Estimated based on reported data for
the epoxide oxidation product.
Eye Irritation
LOW: Minimal conjunctival irritation was observed that cleared by the 24-hour observation.
Eye Irritation
Slight irritant (maximum group mean
score: 2.7) in New Zealand White
rabbits, minimal conjunctival irritation,
treated eyes appeared normal at the 24-
hour observation.
Submitted Confidential Study
Adequate; guideline study (OECD
405).
Dermal Irritation
VERY LOW: BPS-MAE was not a dermal irritant in one study of rabbits.
Dermal Irritation
Non-irritant (primary irritation index: 0)
in New Zealand White rabbits.
Submitted Confidential Study
Adequate; guideline study (OECD
404).
Endocrine Activity
No data located.
No data located.
Immunotoxicity
No data located.
Immune System Effects
No data located.
ECOTOXICITY
ECOSAR Class
Phenols; Vinyl/allyl ethers
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BPS-MAE CASRN 97042-18-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Acute Toxicity
HIGH: Based on measured ECS0 values for fish, daphnia, and algae of 4.5,13.5, and 4.5 mg/L, respectively.
Fish LC50
Rainbow trout (Oncorhvnchus mykiss)
96-hour LC50 = 4.5 mg/L; mean
measured concentrations; static-renewal
test system; solvent: dimethylformamide
(DMF); sub-lethal effects included loss
of equilibrium, hyperventilation,
lying on base of tank, increased
pigmentation, and erratic swimming.
Submitted Confidential Study
Adequate; guideline study (OECD
203).
Daphnid LCS0
Daphnia magna 48-hour EC50 =
13.5 mg/L; mean measured
concentrations; static test system;
solvent: DMF.
Submitted Confidential Study
Adequate; guideline study (OECD
202).
Green Algae ECS0
Pseiidokirchneriella subcapitata 72-
hour EC50 = 4.5 mg/L (biomass), 7.8
mg/L (growth rate); mean measured
concentrations; solvent: DMF.
Submitted Confidential Study
Adequate; guideline study (OECD
201).
Chronic Aquatic Toxicity
HIGH: Based on measured fish and daphnd ChV values of 0.162 mg/L and 0.102 mg/L, respectively.
Fish ChV
Fathead minnow (Pimephales promelas)
32-day NOEC= 0.0939 mg/L, LOEC=
0.28 mg/L, ChV (MATC)= 0.162 mg/L;
mean measured concentrations; flow-
through test system; solvent:
tetrahydrofuran (THF); basis of effect
level: survival.
Submitted Confidential Study
Adequate; guideline study (OECD
210).
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BPS-MAE CASRN 97042-18-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Daphnid ChV
Daphnia magna 21-day NOEC= 0.0664
mg/L, LOEC= 0.157 mg/L, ChV =
0.102 mg/L; mean measured
concentrations; static-renewal test
system; solvent: DMF; basis of effect
level: parental survival and
reproduction.
Submitted Confidential Study
Adequate; guideline study (OECD
211).
Green Algae ChV
Pseiidokirchneriella subcapitata 72-
hour NOEC =1.8 mg/L , LOEC = 3.7
mg/L, ChV = 2.6 mg/L; mean measured
concentrations; solvent: DMF.
Submitted Confidential Study
Adequate; guideline study (OECD
201).
Earthworm Subchronic Toxicity
Earthworm 14-day LC5n =
100.029 mg/L
(Estimated)
ECOSAR: phenols
EPI
ENVIRONMENTAL FATE
Transport
BPS-MAE is expected to exist in both neutral and anionic forms at environmentally-relevant pH, based on its
estimated pKa. The neutral form of BPS-MAE is expected to be immobile in soil based on its estimated Koc.
The anionic form may be more mobile although leaching of BPS-MAE through soil to groundwater is not
expected to be an important transport mechanism. Estimated volatilization half-lives indicate that it will be
non-volatile from surface water. Volatilization from dry surface is also not expected based on its estimated
vapor pressure. In the atmosphere, BPS-MAE is expected to exist solely in the particulate phase, based on its
estimated vapor pressure. Particulates may be removed from air by wet or dry deposition. Level III fugacity
models incorporating the available experimental property data indicate that the unionized form of BPS-MAE
is expected to partition primarily to soil.
Henry's Law Constant
(atm-m3/mole)
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BPS-MAE CASRN 97042-18-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Level III Fugacity Model
Air = <1% (Estimated)
Water = 11%
Soil = 87%
Sediment = 2%
EPI
Persistence
HIGH: High persistence concern for BPS-MAE results from an estimated half-life of 75 days in soil, the
compartment where according to fugacity models; it is expected to primarily partition. Evaluation of QSARs
models estimate ultimate biodegradation in weeks to months, which suggest a biodegradation half-life of
<60 days with no persistent metabolites in aquatic environments. Biodegradation under anaerobic
methanogenic conditions is not probable based on results from estimation models. BPS-MAE is not expected
to undergo hydrolysis since it does not contain hydrolysable functional groups. The atmospheric half-life of
BPS-MAE is estimated at 3 hours, although it is expected to exist primarily in the particulate phase in air.
Water
Aerobic Biodegradation
Days-weeks (primary survey model)
Weeks-months (ultimate survey model)
EPI
Volatilization Half-life
for Model River
>1 year (Estimated)
EPI
Volatilization Half-life
for Model Lake
>1 year (Estimated)
EPI
Soil
Aerobic Biodegradation
No data located.
Anaerobic
Biodegradation
Not probable (anaerobic-methanogenic
biodegradation probability model)
EPI
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
Biodegradation
No data located.
Air
Atmospheric Half-life
3.0 hours (Estimated)
EPI
Reactivity
Photolysis
Not a significant fate process
(Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain functional
groups that would be expected to
absorb light at wavelengths >290 nm.
Hydrolysis
Not a significant fate process
(Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain functional
groups that would be expected to
hydrolyze readily under environmental
conditions.
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BPS-MAE CASRN 97042-18-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Pyrolysis
No data located.
Environmental Half-life
75 days (Estimated)
EPI; PBT Profiler
Half-life estimated for the
predominant compartment, as
determined by EPI and the PBT
Profiler methodology.
Bioaccumulation
LOW: The estimated BCF and BAF are both <100.
Fish BCF
48 (Estimated)
EPI
BAF
76 (Estimated)
EPI
Metabolism in Fish
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
Ecological Biomonitoring
No data located.
Human Biomonitoring
This chemical was not included in the NHANES biomonitoring report (CDC, 2011).
4-331
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Boethling, R., Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences. Boca Raton:
Lewis Publishers. 2000.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
ECHA (European Chemicals Agency). Information on registered substances, http://apps.echa.europa.eu/registered/registered-sub.aspx
(accessed February 18, 2011).
EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 4.00. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
PBT Profi 1 er Persistent (P), Bioaccumulative (B), and Toxic (T) Chemical (PBT) Profiler, U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
SPARC, 2010. SPARC On Line CalculatorpKaproperty server. Ver 4.5 September, 2009. Available from,
http://ibmlc2.chem.uga.edu/spare/ (accessed on August 12, 2010).
U.S. EPA Sustainable Futures UsingNonCancer Screening within the Sustainable Futures Initiative Environmental Protection
Agency: Washington D.C. 2010. http://www.epa.gOv/opptintr/sf/pubs/noncan-screen.htm#svstemic (accessed on February 09, 2011).
U.S. EPA (Environmental Protection Agency). High Production Volume (HPV) Challenge. Determining the Adequacy of Existing
Data. U.S. Environmental Protection Agency: Washington D.C. 1999. http://www.epa.gov/hpv/pubs/general/datadfin.htm
U.S. EPA (Environmental Protection Agency). Sustainable Futures Summary Assessment. Assessment of Discrete Organic
Chemicals. U.S. Environmental Protection Agency: Washington D.C. 2011.
http://www.epa.gov/oppt/sf/pubs/iad_discretes_092011 .pdf
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BPS-MPE
CASRN: 63134-33-8
MW: 340.4
MF: C19H1604S
Physical Forms:
Neat: Solid
Use: Developer for thermal paper
SMILES: 0=S(=0)(c(ccc(0Cc(ccccl)cl)c2)c2)c(ccc(0)c3)c3
Synonyms: Phenol, 4-[[4-(phenylmethoxy)phenyl]sulfonyl]- (TSCA Inventory); 4-Benzyloxy-4'-hydroxydiphenyl sulfone; 4-Hydroxy-4"-benzyloxydiphenylsulfone
Polymeric: No
Oligomers: Not applicable
Metabolites, Degradates and Transformation Products: None
Analog: Bisphenol S (80-09-1)
Endpoint(s) using analog values: Boiling point, reproductive and
developmental toxicity, repeated dose toxicity, genotoxicity
Analog Structure:
"~0-K>
OH
Structural Alerts: Phenols, neurotoxicity (U.S. EPA, 2010)
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 2011).
Risk Assessments: None identified
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BPS-MPE CASRN 63134-33-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
170
ChemSpider, 2010
Secondary source; study details and
test conditions were not provided.
Boiling Point (°C)
>300 (Estimated)
EPI; U.S. EPA, 1999
Cutoff value for high boiling point
compounds according to the HPV
assessment guidance; decomposition
may occur before the boiling point is
reached based on the experimental
decomposition temperature of 315°C
for the analog bisphenol S (80-09-1).
Vapor Pressure (mm Hg)
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BPS-MPE CASRN 63134-33-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
HUMAN HEALTH EFFECTS
Toxicokinetics
One experimental study indicated that BPS-MPE was not absorbed through the skin in guinea pigs. BPS-
MPE is estimated not to be absorbed through the skin as a neat material and to have poor skin absorption
when in solution. BPS-MPE is estimated to have good absorption via the lungs and gastrointestinal tract
based on data for the analog bisphenol A.
Dermal Absorption in vitro
No data located.
Absorption,
Distribution,
Metabolism &
Excretion
Oral
Not absorbed through the skin as a neat
material and has poor absorption in
solution; can be absorbed through the lung
and gastrointestinal tract
(Estimated by analogy)
Professional judgment
Estimated based on experimental data
for the analog bisphenol A.
Dermal
No evidence of skin absorption at
1,000 mg/kg; three guinea pigs, solid-
moist with water
Eastman Kodak, 1991
Adequate.
Acute Mammalian Toxicity
LOW: Based on acute oral LDS0 values >2,000 mg/kg in rats and mice. The acute dermal lethality study in
guinea pigs failed to identify an LDS0, although the results indicated that the LDS0 was >1,000 mg/kg, the
highest dose tested.
Acute Lethality
Oral
Rat LD50 >3,200 mg/kg; 10 male rats,
moderate weakness and diarrhea
Eastman Kodak, 1991
Adequate.
Mouse LD50 = 3,200 mg/kg; 10 male mice,
moderate weakness, rough hair coats
Eastman Kodak, 1991
Adequate.
Dermal
Guinea pig LD50 >1,000 mg/kg; slight
edema, desquamation, slight to moderate
alopecia
Eastman Kodak, 1991
Adequate.
Inhalation
No data located.
Carcinogenicity
MODERATE: There is uncertain potential for carcinogenicity due to the lack of data located for this
substance. Carcinogenic effects cannot be ruled out.
OncoLogic Results
No data located.
Carcinogenicity (Rat and
Mouse)
No data located.
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BPS-MPE CASRN 63134-33-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Combined Chronic
Toxicity/Carcinogenicity
No data located.
Genotoxicity
MODERATE: Estimated based on analogy to bisphenol S. Bisphenol S did not induce gene mutations in
several in vitro assays and did not induce chromosomal aberrations in vivo in a mammalian erythrocyte
micronucleus assay in NMRI mice or in Chinese hamster ovary (CHO) cells in vitro in the presence of
exogenous metabolic activation. However, the analog bisphenol S did induce chromosomal aberrations in
CHO cells in vitro in the absence of exogenous metabolic activation (at a noncytotoxic concentration). The
positive result in the in vitro assay and negative result in the in vivo test suggest an equivocal response and
therefore a Moderate hazard potential.
Gene Mutation in vitro
Negative, mouse lymphoma L5178Y
(TK+/TK-) cells, with and without
metabolic activation
(Estimated by analogy)
CCRIS database; Professional
judgment
Adequate; based on experimental data
measured for the analog bisphenol S.
Negative, Ames assay (standard plate) in
Salmonella typhimurium strains TA98,
TA100, TA1537, TA1535, and TA1538
with and without metabolic activation
(Estimated by analogy)
CCRIS database; Professional
judgment
Adequate; based on experimental data
measured for the analog bisphenol S.
Negative, Salmonella/microsome test, S.
typhimurium strains TA1535, TA100,
TA1537, and TA98 with and without
metabolic activation
(Estimated by analogy)
Miles Inc., 1992; ECHA, 2011;
Professional judgment
Adequate; based on experimental data
measured for the analog bisphenol S
in an adequate guideline study
(OECD471).
Negative, Ames assay (preincubation) in S.
typhimurium strains TA98, TA100,
TA1537, TA1535 and Escherichia coli
WP2UVRA with and without metabolic
activation
(Estimated by analogy)
CCRIS database, 2010; ECHA,
2011; Professional judgment
Adequate; based on experimental data
measured for the analog bisphenol S
in an adequate guideline study
(OECD471).
Negative, umu test in S.typhimurium strain
TA1335
(Estimated by analogy)
Chen, Michihiko et al., 2002;
Professional judgment
Adequate; based on experimental data
measured for the analog bisphenol S.
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BPS-MPE CASRN 63134-33-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Negative, CHO HGPRT mutation assay,
with and without metabolic activation
(Estimated by analogy)
Amoco Corp., 1991a; Professional
judgment
Adequate; based on experimental data
measured for the analog bisphenol S.
Potential for mutagenicity
(Estimated by analogy)
Professional judgment
Estimated based on experimental data
for the analog bisphenol S.
Gene Mutation in vivo
No data located.
Chromosomal
Aberrations in vitro
Positive, without metabolic activation;
negative, with metabolic activation
(Estimated by analogy)
Amoco Corp., 1991b; ECHA,
2011; Professional judgment
Adequate; based on experimental data
measured for the analog bisphenol S
in an adequate guideline study
(similar to OECD 473).
Chromosomal
Aberrations in vivo
Negative, mammalian erythrocyte
micronucleus assay in male NMRI mice
(gavage)
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; based on experimental data
measured for the analog bisphenol S
in an adequate guideline study
(OECD 474).
DNA Damage and Repair
No data located.
Other (Mitotic Gene
Conversion)
No data located.
Reproductive Effects
MODERATE: Estimated based on analogy to bisphenol S. In a reproductive/developmental toxicity
screening test, oral exposure of parental rats to the analog bisphenol S resulted in marked systemic effects
and the NOAEL for reproductive effects is 60 mg/kg-day (prolonged estrous cycle, decreased fertility index
and decreased number of live offspring). Based on the NOAEL for reproductive effects a Moderate hazard
designation is selected.
Reproduction/
Developmental Toxicity
Screen
Parental toxicity:
NOAEL =10 mg/kg bw-day
LOAEL = 60 mg/kg bw-day
Reproductive toxicity:
NOAEL = 60 mg/kg bw-day
LOAEL = 300 mg/kg bw-day
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; based on experimental data
measured for the analog bisphenol S
in an adequate guideline study
(OECD 421) reported in a secondary
source.
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BPS-MPE CASRN 63134-33-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Reproduction and
Fertility Effects
Potential for reproductive toxicity
(Estimated by analogy)
Professional judgment
Estimated based on experimental data
for the analog bisphenol S.
Developmental Effects
MODERATE: Estimated based on analogy to bisphenol S. In a reproductive/developmental toxicity
screening test, oral exposure of parental rats to the analog bisphenol S resulted in marked systemic effects
and a decreased number of live offspring (PND 4) at the highest dose level (300 mg/kg-day) with a NOAEL of
60 mg/kg-day. Based on the NOAEL a Moderate hazard designation is selected.
Reproduction/
Developmental Toxicity
Screen
Parental toxicity:
NOAEL =10 mg/kg bw-day
LOAEL = 60 mg/kg bw-day
Reproductive toxicity:
NOAEL = 60 mg/kg bw-day
LOAEL = 300 mg/kg bw-day
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; based on experimental data
measured for the analog bisphenol S
in an adequate guideline study
(OECD 421) reported in a secondary
source.
Potential for developmental toxicity
(Estimated by analogy)
Professional judgment
Estimated based on experimental data
for the analog bisphenol S.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Prenatal Development
No data located.
Postnatal Development
No data located.
Neurotoxicity
MODERATE: Estimated to have potential for neurotoxicity based on the presence of the phenol structural
alert.
Neurotoxicity Screening
Battery (Adult)
There is potential for neurotoxicity effects
based on the presence of the phenol
structural alert
(Estimated)
U.S. EPA, 2010; Professional
judgment
Estimated based on structural alert.
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BPS-MPE CASRN 63134-33-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Repeated Dose Effects
HIGH: Based on analogy to bisphenol S. In two adequately-designed repeated dose oral studies in rats, one
study identified a NOAEL of 10 mg/kg-day and a LOAEL of 60 mg/kg-day for systemic effects and the other
study identified a NOAEL of 40 mg/kg-day and a LOAEL of 200 mg/kg-day for systemic effects following
exposure to the analog bisphenol S. The High hazard designation is based on uncertainty as to the potential
systemic toxicity in the range of 40-60 mg/kg-day. Data located for BPS-MPE are inadequate to assess the
hazard for repeated dose effects.
Oral
12-Day repeated dose oral (dietary) study,
5 male rats/group, test compound
concentrations of 0, 0.1, and 1.0% in corn
oil (~0, 100, and 980 mg/kg-day,
respectively), slightly increased absolute
(high dose) and relative (high and low
dose) liver weights, no abnormalities or
changes in body weight, clinical
chemistry, gross pathology, or
histopathology
NOAEL =100 mg/kg-day
LOAEL = 980 mg/kg-day
Eastman Kodak, 1991
Inadequate; exposure duration only
12 days, and only one species tested.
In a repeated-dose oral study, Sprague-
Dawley rats, NOAEL = 40 mg/kg bw-day
LOAEL = 200 mg/kg-bw-day
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; based on experimental data
measured for the analog bisphenol S
in an adequate 28-day repeat dose
toxicity guideline study.
In a reproduction/developmental toxicity
screening test, Sprague-Dawley rats,
NOAEL =10 mg/kg bw-day
LOAEL = 60 mg/kg bw-day
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; based on experimental data
measured for the analog bisphenol S
in an adequate guideline study
(OECD421).
Potential for liver and kidney toxicity
(Estimated by analogy)
Professional judgment
Estimated based on experimental data
for the analog bisphenol S.
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BPS-MPE CASRN 63134-33-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Dermal
10-Day repeated-dose dermal study,
5 guinea pigs; repeated dosing slightly
exacerbated skin reaction; by day 10,
severe erythema and minute eschar
formation in 2/5 guinea pigs
Eastman Kodak, 1991
Inadequate; treatment period only
10 days, no dose level.
Skin Sensitization
LOW: Not an apparent skin sensitizer in guinea pigs.
Skin Sensitization
Negative for skin sensitization; 10 guinea
pigs
Eastman Kodak, 1991
Adequate.
Respiratory Sensitization
No data located.
Respiratory Sensitization
No data located.
Eye Irritation
LOW: Slightly irritating to rabbit eyes with clearing within 24 hours.
Eye Irritation
Slight irritant, rabbits, clearing within
24 hours
Eastman Kodak, 1991
Adequate.
Dermal Irritation
LOW: Slightly irritating to the skin of guinea pigs.
Dermal Irritation
Slight irritant at 24 hours recovering within
2 weeks, guinea pigs
Eastman Kodak, 1991
Adequate.
Endocrine Activity
No data located.
No data located.
Immunotoxicity
No data located.
Immune System Effects
No data located.
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BPS-MPE CASRN 63134-33-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
ECOTOXICITY
ECOSAR Class
Phenols
Acute Toxicity
VERY HIGH: Based on measured 96-hour LCS0 values for fish and Daphnid in the range of 0.34-3.4 mg/L,
although detailed study results were not provided.
Fish LC50
Fathead minnow 96-hour LC50 = 0.34-
3 4 mg/L (Experimental)
Eastman Kodak, 1991
Although experimental details were
not provided, the study demonstrates
the potential for adverse effects at
concentrations corresponding to a
Very High hazard concern.
Fish 96-hour LC50 = 2.01 mg/L
(Estimated)
ECOSAR: phenols
EPI
Fish 96-hour LC50 = 6.28 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid LCS0
Daphnid 96-hour LC50 = 0.34-3.4 mg/L
(Experimental)
Eastman Kodak, 1991
Although experimental details were
not provided, the study demonstrates
the potential for adverse effects at
concentrations corresponding to a
Very High hazard concern.
Daphnid 48-hour LC50 = 1.46 mg/L
(Estimated)
ECOSAR: phenols
EPI
Daphnid 48-hour LC50 = 4.57 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
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BPS-MPE CASRN 63134-33-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Green Algae ECS0
Green algae 96-hour EC50 = 4.32 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Green algae 96-hour EC50 = 5.58 mg/L
(Estimated)
ECOSAR: phenols
EPI
Chronic Aquatic Toxicity
HIGH: Based on an estimated fish 30-day ChV of 0.27 mg/L.
Fish ChV
Fish 30-day ChV = 0.27 mg/L
(Estimated)
ECOSAR: phenols
EPI
Fish ChV = 0.57 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid ChV
Daphnid 21-day ChV = 0.28 mg/L
(Estimated)
ECOSAR: phenols
EPI
Daphnid ChV = 0.59 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Green Algae ChV
Green algae ChV = 2.22 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Green algae ChV = 2.56 mg/L
(Estimated)
ECOSAR: phenols
EPI
Earthworm Subchronic Toxicity
Earthworm 14-day LC50 = 52.09 mg/L
(Estimated)
ECOSAR: phenols
(chemical may not be soluble enough to
measure this predicted effect)
EPI
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BPS-MPE CASRN 63134-33-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
ENVIRONMENTAL FATE
Transport
Based on the Level III fugacity models incorporating the located experimental property data, BPS-MPE is
expected to partition primarily to soil. BPS-MPE is expected to exist in both neutral and anionic forms at
environmentally-relevant pH, based on its estimated pKa. The neutral form of BPS-MPE is expected to be
immobile in soil based on its estimated Koc. The anionic form may be more mobile, as anions do not bind as
strongly to organic carbon and clay as their neutral counterparts. However, leaching of BPS-MPE through
soil to groundwater is not expected to be an important transport mechanism. Estimated volatilization half-
lives indicate that it will be nonvolatile from surface water. Volatilization from dry surface is also not
expected based on its estimated vapor pressure. In the atmosphere, BPE-MPE is expected to exist solely in
the particulate phase, based on its estimated vapor pressure. Particulates may be removed from air by wet
or dry deposition.
Henry's Law Constant
(atm-m3/mole)
30,000 (Estimated)
EPI; U.S. EPA, 2011
Cutoff value for nonmobile
compounds according to SF
assessment guidance.
Level III Fugacity
Model
Air = <1% (Estimated)
Water = 8.5%
Soil = 75%
Sediment = 16%
EPI
Persistence
HIGH: Evaluation of the persistence of BPS-MPE is based entirely on QSARs for aerobic and anaerobic
biodegradation. Results from these models estimate primary biodegradation in days-weeks and ultimate
degradation in weeks-months. BPS-MPE is expected to partition primarily to soil. Based on these data, the
biodegradation half-life is expected to be 75 days in soil. Biodegradation under anaerobic methanogenic
conditions is not probable. BPS-MPE is not expected to undergo hydrolysis since it does not contain
hydrolysable functional groups. BPS-MPS does not absorb UV light at environmentally significant
wavelengths. The vapor phase reaction of BPS-MPE with atmospheric hydroxyl radicals is estimated at 5.7
hours, although it is expected to exist primarily in the particulate phase in air. Considerations of all these
factors indicate that the persistence concern is High for BPS-MPE.
Water
Aerobic
Biodegradation
Days-weeks (Primary survey model)
Weeks-months (Ultimate survey model)
EPI
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BPS-MPE CASRN 63134-33-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Volatilization Half-life
for Model River
>1 year (Estimated)
EPI
Volatilization Half-life
for Model Lake
>1 year (Estimated)
EPI
Soil
Aerobic
Biodegradation
No data located.
Anaerobic
Biodegradation
Not probable (anaerobic-methanogenic
biodegradation probability model)
EPI
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
Biodegradation
No data located.
Air
Atmospheric Half-life
5.7 hours (Estimated)
EPI
Reactivity
Photolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
The substance does not contain
functional groups that would be
expected to absorb light at
wavelengths >290 nm.
Hydrolysis
Not a significant fate process
(Estimated)
Boethling and Mackay, 2000;
Professional judgment
The substance does not contain
functional groups that would be
expected to hydrolyze readily under
environmental conditions.
Pyrolysis
No data located.
Environmental Half-life
75 days (Estimated)
EPI, PBT Profiler
Half-life estimated for the
predominant compartment, as
determined by EPI and the PBT
Profiler methodology.
Bioaccumulation
MODERATE: Both the estimated BCF for fish and the BAF are in the range from 100 to 1,000.
Fish BCF
180 (Estimated)
EPI
BAF
110 (Estimated)
EPI
Metabolism in Fish
No data located.
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BPS-MPE CASRN 63134-33-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
Ecological Biomonitoring
No data located.
Human Biomonitoring
This chemical was not included in the NHANES biomonitoring report (CDC, 2011).
4-345
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Amoco Corp. CHO HGPRTmutation assay (final report) with attachment and cover letter dated 111491. TSCATS submission
OTS0534324. 1991a.
Amoco Corp. Chromosome aberrations in Chinese hamster ovary (CHO) cells (final report) with attachment and cover letter dated
111491. TSCATS submission OTS0534325. 1991b.
Boethling, R., Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences. Boca Raton:
Lewis Publishers. 2000.
CCRIS. Chemical Carcinogenesis Research Information System. Bisphenol S. 2010. http://toxnet.nlm.nih.gov/cgi-
bin/sis/htmlgen?CCRIS (accessed on August, 2010).
Chemspider. ChemSpider; Structure-based Chemistry Information. Royal Society of Chemistry: London. 2010.
http://www.chemspider.com (accessed on December 11, 2010).
Chen, M-Y.; Michihiko, I.; Fujita, M. Acute toxicity, mutagenicity, and estrogenicity of bisphenol-A and other bisphenols. Environ.
Toxicol. 2002, 17:80-86.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
Eastman Kodak. Letter concerning enclosed information on bisphenol S with attachments. Eastman Kodak Company, Rochester NY.
TSCATS submission OTS0534330. 1991.
ECHA. European Chemicals Agency. Information on registered substances, http://apps.echa.europa.eu/registered/registered-sub.aspx
(accessed February 18, 2011).
EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 4.00. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
4-346
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DRAFT REPORT - DO NOT CITE OR QUOTE
Miles Inc. Salmonella microsome test (final report) with cover letter dated 04392. TSCATS submission OTS0435648. 1992.
PBT Profi 1 er Persistent (P), Bioaccumulative (B), and Toxic (T) Chemical (PBT) Profiler. U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
SPARC On Line Calculator pKaproperty server. Ver 4.5 September, 2009. Available from, http://ibmlc2.chem.uga.edu/spare/
(accessed on August 12, 2010).
U.S. EPA (Environmental Protection Agency). High Production Volume (HPV) Challenge. Determining the Adequacy of Existing
Data. U.S. Environmental Protection Agency: Washington D.C. 1999. http://www.epa.gov/hpv/pubs/general/datadfin.htm
U.S. EPA (Environmental Protection Agency). Sustainable Futures UsingNonCancer Screening within the Sustainable Futures
Initiative Environmental Protection Agency: Washington D.C. 2010. http://www.epa.gov/opptintr/sf/pubs/noncan-
screen.htm#svstemic (accessed on February 09, 2011).
U.S. EPA (Environmental Protection Agency). Sustainable Futures Summary Assessment. Assessment of Discrete Organic
Chemicals. U.S. Environmental Protection Agency: Washington D.C. 2011.
http://www.epa.gov/oppt/sf/pubs/iad_discretes_092011 .pdf
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D-8
CASRN 95235-30-6
MW: 292.35
MF: C15H1604S
Physical Forms:
Neat: Solid
Use: Developer for thermal paper
SMILES: Q=S(=0)(clccc(0)ccl)c2ccc(0C(C)C)cc2
Name: 4-hydroxyphenyl 4-isoprooxyphenylsulfone
Synonyms: Phenol, 4-[[4-(l-methylethoxy)phenyl]sulfonyl]- (TSCA Inventory); 4-(4-isopropoxyphenylsulfonyl)phenol; Phenol, 4-[[4-(l-
methylethoxy)phenyl]sulfonyl]-; 4-Hydroxy-4-isopropoxydiphenylsulfone; D-8; DD-8; ALD-2000
Polymeric: No
Oligomers: Not applicable
Metabolites, Degradates and Transformation Products: None identified
Analog: Bisphenol S (80-09-1)
Endpoint(s) using analog values: Boiling point, persistence, reproductive effects,
developmental effects, and repeated dose effects
Analog: BPS-MPE (63134-33-8)
Endpoint(s) using analog values: Acute mammalian toxicity; eye irritation; dermal irritation;
skin sensitization
Structural Alerts: Phenols, neurotoxicity (U.S. EPA, 2010)
Risk Phrases: 51/53 - Toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment (ESIS, 2011).
Risk Assessments: None identified
Analog Structures:
Structure:
S-(\ /)-OH
Name: Bisphenol S (80-09-1) BPS-MPE (63134-33-8)
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D-8 CASRN 95235-30-6
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
129 (Measured)
Submitted confidential study
Adequate.
Boiling Point (°C)
>300 (Estimated)
EPI; U.S. EPA, 1999
Decomposition may occur before the
boiling point is reached based on the
experimental decomposition
temperature of 315 degrees C for an
analogous structure, bisphenol S.
Cutoff value for high boiling point
compounds according to HPV
assessment guidance.
Vapor Pressure (mm Hg)
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DRAFT REPORT - DO NOT CITE OR QUOTE
D-8 CASRN 95235-30-6
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Acute Lethality
Oral
Rat LD50 >3,200 mg/kg; 10 male rats,
moderate weakness and diarrhea
Eastman Kodak, 1991
Adequate.
Mouse LD50 = 3,200 mg/kg; 10 male
Eastman Kodak, 1991
Adequate.
mice, moderate weakness, rough hair
coats
Dermal
Guinea pig LD50 >1,000 mg/kg; slight
edema, desquamation, slight to moderate
alopecia
Eastman Kodak, 1991
Adequate.
Inhalation
No data located.
Carcinogenicity
MODERATE: There is uncertain potential for carcinogenicity due to the lack of data for this substance.
Carcinogenic effects cannot be ruled out.
OncoLogic Results
No data located.
Carcinogenicity (Rat and
Mouse)
No data located.
Combined Chronic
No data located.
Toxicity/Carcinogenicity
Genotoxicity
MODERATE: There is uncertain potential for genotoxicity due to the lack of data for this substance.
Genotoxic effects cannot be ruled out.
Gene Mutation in vitro
Potential for mutagenicity
(Estimated)
Professional judgment
Estimated by analogy to confidential
analog and professional judgment.
Gene Mutation in vivo
No data located.
Chromosomal Aberrations
Negative, chromosomal aberrations in
Submitted confidential study
Adequate.
in vitro
Chinese hamster lung cells
(Measured)
Chromosomal Aberrations
in vivo
DNA Damage and Repair
No data located.
Other (Mitotic Gene
No data located.
Conversion)
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D-8 CASRN 95235-30-6
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproductive Effects
MODERATE: Estimated based on analogy to bisphenol S. In a reproduction/developmental toxicity
screening test, oral exposure of parental rats to the analog bisphenol S resulted in marked systemic effects
and the NOAEL for reproductive effects is 60 mg/kg-day (prolonged estrous cycle, decreased fertility index
and decreased number of live offspring). Based on the NOAEL for reproductive effects a Moderate hazard
designation is selected.
Reproduction/
Developmental Toxicity
Screen
Parental toxicity:
NOAEL =10 mg/kg bw-day
LOAEL = 60 mg/kg bw-day
Reproductive toxicity:
NOAEL = 60 mg/kg bw-day
LOAEL = 300 mg/kg bw-day
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; using the analog bisphenol
S, data are for an adequate guideline
study (OECD 421) reported in a
secondary source.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Reproduction and Fertility
Effects
Potential for reproductive toxicity
(Estimated by analogy)
Professional judgment
Estimated based on reported
experimental data for the analog
bisphenol S.
Developmental Effects
MODERATE: Estimated based on analogy to bisphenol S. In a reproduction/developmental toxicity
screening test, oral exposure of parental rats to the analog bisphenol S resulted in marked systemic effects
and decreased number of live offspring (PND 4) at the highest dose level (300 mg/kg-day with a NOAEL of
60 mg/kg-day. Based on the NOAEL a Moderate hazard designation is selected.
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D-8 CASRN 95235-30-6
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproduction/
Developmental Toxicity
Screen
Parental toxicity:
NOAEL =10 mg/kg bw-day
LOAEL = 60 mg/kg bw-day
Reproductive toxicity:
NOAEL = 60 mg/kg bw-day
LOAEL = 300 mg/kg bw-day
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; using the analog bisphenol
S, data are for an adequate guideline
study (OECD 421) reported in a
secondary source.
Potential for developmental toxicity
(Estimated by analogy)
Professional judgment
Estimated based on reported
experimental data for the analog
bisphenol S.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Prenatal Development
No data located.
Postnatal Development
No data located.
Neurotoxicity
MODERATE: Estimated to have potential for neurotoxicity based on the presence of the phenol structural
alert.
Neurotoxicity Screening
Battery (Adult)
There is potential for neurotoxicity
effects based on the presence of the
phenol structural alert
(Estimated)
U.S. EPA 2010, Professional
judgment
Estimated based on structural alert.
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D-8 CASRN 95235-30-6
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Repeated Dose Effects
HIGH: Based on analogy to bisphenol S. Among two adequately-designed repeated-dose oral studies in
rats, one study identified a NOAEL of 10 mg/kg-day and a LOAEL of 60 mg/kg-day for systemic effects and
the other study identified a NOAEL of 40 mg/kg-day and a LOAEL of 200 mg/kg-day for systemic effects
following exposure to the analog bisphenol S. Based on uncertainty as to the potential systemic toxicity in
the range of 40 to 60 mg/kg-day, a High hazard concern is selected.
In a repeated-dose oral study, Sprague-
Dawley rats,
NOAEL = 40 mg/kg bw-day
LOAEL = 200 mg/kg-bw-day
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; using the analog bisphenol
S, data are for an adequate 28-day
repeated dose toxicity guideline study
(lapan).
In a reproduction/developmental toxicity
screening test, Sprague-Dawley rats,
NOAEL =10 mg/kg bw-day
LOAEL = 60 mg/kg bw-day
(Estimated by analogy)
ECHA, 2011; Professional
judgment
Adequate; using the analog bisphenol
S, data are for an adequate guideline
study (OECD guideline 421).
Potential for liver and kidney toxicity
(Estimated by analogy)
Professional judgment
Estimated based on reported
experimental data for the analog
bisphenol S.
Skin Sensitization
LOW: Estimated based on analogy to BPS-MPE. Not considered a skin sensitizer in the guinea pig based
on analog data for BPS-MPE.
Skin Sensitization
Negative for skin sensitization;
10 guinea pigs
Eastman Kodak, 1991
Adequate.
Respiratory Sensitization
No data located.
Respiratory Sensitization
No data located.
Eye Irritation
LOW: Estimated based on analogy to BPS-MPE. The analog bisphenol BPS-MPE was non-irritating to
slightly irritating to rabbit eyes.
Eye Irritation
Slight irritant, rabbits, clearing within
24 hours
Eastman Kodak, 1991
Adequate.
Dermal Irritation
LOW: Estimated based on analogy to BPS-MPE. The analog bisphenol BPS-MPE was slightly irritating to
guinea pig skin.
Dermal Irritation
Slight irritant at 24 hours recovering
within 2 weeks, guinea pigs
Eastman Kodak, 1991
Adequate.
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D-8 CASRN 95235-30-6
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Endocrine Activity
Based on several in vitro studies there is limited evidence of endocrine activity. Negative for estrogenicity in
two ER binding assays and one competitive ER binding assay, positive for anti-estrogenicity in a
competitive binding assay in the presence of 17p-estradiol.
Negative for ER binding in yeast two-
hybrid assay using human and medaka
fish estrogen receptor (hERa and
medERa, respectively) and coactivator
TIF2 in Sacchctromyces cerevisicte with
or without exogenous metabolic
activation
Terasaki et al., 2007
Adequate.
Negative for competitive ER-binding
affinity in ER-ELISA assay with or
without exogenous metabolic activation
Terasaki et al., 2007
Adequate.
Positive for anti-estrogenic activity in
cell proliferation assay of ERE-GFP-
MCF7 cells treated with 17|3-estradiol
Kuruto-Niwa et al., 2005
Adequate.
Negative for estrogenic activity in cell
proliferation assay of ERE-GFP-MCF7
cells in the absence of 17|3-estradiol
Kuruto-Niwa et al., 2005
Adequate.
Immunotoxicity
No data located.
Immune System Effects
No data located.
ECOTOXICITY
ECOSAR Class
Phenols
Acute Toxicity
HIGH: Based on estimated LCS0 for fish and Daphnid, which are in the range of 1-10 mg/L.
Fish LC50
Fish 96-hour LC50 = 6.64 mg/L
(Estimated)
ECOSAR: phenols
EPI
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D-8 CASRN 95235-30-6
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Fish 96-hour LC50 = 25.58 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid LCS0
Daphnid 48-hour LC50 = 3.56 mg/L
(Estimated)
ECOSAR: phenols
EPI
Daphnid 48-hour LC50 = 16.89 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Green Algae ECS0
Green algae 96-hour EC50 = 11.52 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Green algae 96-hour EC50 = 14.70 mg/L
(Estimated)
ECOSAR: phenols
EPI
Chronic Aquatic Toxicity
HIGH: Based on estimated ChVs0 for
ish and Daphnid, which are in the range of 0.1-1 mg/L.
Fish ChV
Fish 30-day ChV = 0.69 mg/L
(Estimated)
ECOSAR: phenols
EPI
Fish 60-day ChV = 2.37 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid ChV
Daphnid 21-day ChV = 0.68 mg/L
(Estimated)
ECOSAR: phenols
EPI
Daphnid 21-day ChV = 1.90 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
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DRAFT REPORT - DO NOT CITE OR QUOTE
D-8 CASRN 95235-30-6
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Green Algae ChV
Green algae ChV = 5.11 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Green algae ChV = 5.11 mg/L
(Estimated)
ECOSAR: phenols
EPI
Earthworm Subchronic Toxicity
Earthworm 14-day LC50 = 6.81 mg/L
(Estimated)
ECOSAR: phenols
EPI
ENVIRONMENTAL FATE
Transport
Evaluation of D-8 transport is based entirely on estimations on QSARs for fugacity (level III),
disassociation constant (pKa), adsorption coefficient (Koc), volatilization, and vapor pressure. If released to
air, an estimated vapor pressure of
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DRAFT REPORT - DO NOT CITE OR QUOTE
D-8 CASRN 95235-30-6
PROPER!
rY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Bisphenol S aerobic degradation was not
detected after 2 weeks; degradation
based on total organic carbon (TOC)
decrease in river water and measured
with high performance liquid
chromatography (HPLC).
(Estimated by analogy)
Ike et al., 2006
Estimated based on reported
experimental data for the analog
bisphenol S.
Volatilization Half-life for
Model River
>1 year (Estimated)
EPI
Volatilization Half-life for
Model Lake
>1 year (Estimated)
EPI
Soil
Aerobic Biodegradation
Ready Test: MITI-I (OECD 301C) No
biodegradation detected; Bisphenol S for
4 weeks with 100 mg/L in 30 mg/L
activated sludge biological oxygen
demand 0%; TOC 0%. (Estimated by
analogy)
MITI, 1998
Estimated based on reported
experimental data for the analog
bisphenol S.
Anaerobic
Biodegradation
Not probable (anaerobic-methanogenic
biodegradation probability model)
EPI
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
Biodegradation
Anaerobic degradation of bisphenol S
was detected by HPLC analysis.
Approximately 60% of bisphenol S was
removed after 70 days in anoxic bottles
with pond sediment (Estimated by
analogy)
Ike et al., 2006
Estimated based on reported
experimental data for the analog
bisphenol S.
Air
Atmospheric Half-life
5.3 hours (Estimated)
EPI
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DRAFT REPORT - DO NOT CITE OR QUOTE
D-8 CASRN 95235-30-6
PROPER!
rY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reactivity
Photolysis
Not a significant fate process
(Estimated)
Boethling and Mackay, 2000;
Professional judgment
The substance does not contain
functional groups that would be
expected to absorb light at
environmentally significant
wavelengths.
Hydrolysis
Not a significant fate process
(Estimated)
Boethling and Mackay, 2000;
Professional judgment
The substance does not contain
functional groups that would be
expected to hydrolyze readily under
environmental conditions.
Pyrolysis
No data located.
Environmental Half-life
75 days
EPI; PBT Profiler
Half-life estimated for the
predominant compartment, as
determined by EPI and the PBT
Profiler methodology.
Bioaccumulation
LOW: The estimated fish BCF and BAF values are both <100.
Fish BCF
53 (Estimated)
EPI
BAF
83 (Estimated)
EPI
Metabolism in Fish
No data located.
EP
mRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
Ecological Biomonitoring
No data located.
Human Biomonitoring
This chemical was not included in the NHANES biomonitoring report (CDC, 2011).
4-358
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DRAFT REPORT - DO NOT CITE OR QUOTE
Boethling, R., Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences. Boca Raton:
Lewis Publishers. 2000.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
Eastman Kodak. Letter concerning enclosed information on bisphenol S with attachments. Eastman Kodak Company, Rochester NY.
TSCATS submission OTS0534330. 1991.
ECHA (European Chemicals Agency). Information on registered substances, http://apps.echa.europa.eu/registered/registered-sub.aspx
(accessed February 18, 2011)
EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 4.00. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
Ike, M.; Chen, M.Y.; Danzl, E.; et al. Biodegradation of a variety of bisphenols under aerobic and anaerobic conditions. Water Sci.
Technol. 2006, 53:153-159.
Kuruto-Niwa, R., Nozawa, R., Miyakoshi, T., et al. Estrogenic activity of alkylphenols, bisphenol S, and their chlorinated derivatives
using a GFP expression system. Environ. Toxicol. Pharmacol. 2005, 19:121-130.
MITI (Ministry of International Trade & Industry). Biodegradation and bioaccamidation data of existing chemicals based on the
CSCL Japan. Compiled under the supervision of Chemical Products Safety Division, Basic Industries Bureau, Ministry of
International Trade & Industry, Japan; Chemicals Inspection & Testing Institute, Japan. Ed.; Japan Chemical Industry Ecology-
Toxicology & Information Center: 1998.
PBT Profi 1 er Persistent (P),Bioaccumulative (B), and Toxic (T) Chemical (PBT)Profiler, U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
4-359
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DRAFT REPORT - DO NOT CITE OR QUOTE
SPARC On Line Calculator pKaproperty server. Ver 4.5 September, 2009. Available from, http://ibmlc2.chem.uga.edu/sparc/
(accessed on August 12, 2010).
Terasaki, M., Shiraishi, F., Fukazawa, H., et al. Occurrence and estrogenicity of phenolics in paper-recycling process water:
Pollutants originating from thermal paper in waste paper. Environ. Toxicol. Chem. 2007, 26(11):2356-2366.
U.S. EPA (Environmental Protection Agency). High Production Volume (HPV) Challenge. Determining the Adequacy of Existing
Data. U.S. Environmental Protection Agency: Washington D.C. 1999. http://www.epa.gov/hpv/pubs/general/datadfin.htm
U.S. EPA Sustainable Futures. Using Noncancerous Screening within the SF Initiative. Environmental Protection Agency:
Washington D.C. 2010. available at: http://www.epa.gOv/opptintr/sf/pubs/noncan-screen.htm#svstemic (accessed on February 09,
2011).
U.S. EPA Sustainable Futures Summary Assessment. Assessment of Discrete Organic Chemicals. U.S. Environmental Protection
Agency: Washington D.C. 2011. http://www.epa.gov/oppt/sf/pubs/iad_discretes_092011.pdf
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D-90
-H
CASRN 191680-83-8
MW: 570.63 (n = 1)
891.00 (n = 2)
MF: C28H26O9S2 (n = 1)
C44H42O14S3 (n = 2)
Physical Forms:
Neat: Solid
Use: Developer for thermal paper
SMILES:
(n = 1): 0=S(C1=CC=C(0CC0CC0C2=CC=C(S(=0)(C3=CC=C(0)C=C3)=0)C=C2)C=C1)(C4=CC=C(0)C=C4)=0
(n = 2):
0=S(C1=CC=C(0CC0CC0C2=CC=C(S(=0)(C3=CC=C(0CC0CC0C4=CC=C(S(=0)(C5=CC=C(0)C=C5)=0)C=C4)C=C3)=0)C=C2)C=C1)(C6=CC=C(0)C=C
6)=0
Synonyms: Bis(2-chloroethyl)ether-4,4'-dihydroxydiphenyl sulfone copolymer; Ethane, l,l'-oxybis(2-chloro-, polymer with 4,4'-sulfonylbis(phenol); Phenol, 4,4'-
sulfonylbis-, polymer with l,l'-oxybis(2-chloroethane); 4,4'-Dihydroxydiphenyl sulfone- 2,2'-dichlorodiethyl ether copolymer; 4,4'-Dihydroxydiphenyl sulfone-
bis(2-chloroethyl) ether copolymer
Polymeric: Yes
Oligomers: Two representative structures for the low MW oligomers evaluated in this assessment are indicated above (n = 1 or 2). These representative structures
are anticipated to be the predominant components of the polymeric mixture.
Metabolites, Degradates and Transformation Products: None identified
Analog: No analogs
Endpoint(s) using analog values: Not applicable
Analog Structure: Not applicable
Structural Alerts: Phenols, neurotoxicity (U.S. EPA, 2010)
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 2011).
Risk Assessments: None identified
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D-90 CASRN 191680-83-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
No data located.
Boiling Point (°C)
>300 (Estimated for n = 1 and n = 2)
EPI; U.S. EPA, 1999
Estimates were performed on
representative components of the
polymer that have a MW <1,000;
those with n = 1 or 2. Higher
oligomers are expected to have a
similar value. Cutoff value for high
boiling point compounds according
to HPV assessment guidance.
Vapor Pressure (mm Hg)
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DRAFT REPORT - DO NOT CITE OR QUOTE
D-90 CASRN 191680-83-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Flammability (Flash Point)
No data located.
Explosivity
No data located.
pH
No data located.
pKa
6.9-7.5 (Estimated, identical values
obtained for both n = 1 and n = 2)
ACD/Labs, 2010
SMILES notation was too long for
SPARC estimations, which were
used for the other chemicals
assessed, and an alternative
estimation method was used.
HUMAN HEALTH EFFECTS
Toxicokinetics
No data located.
Dermal Absorption in vitro
No data located.
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal or Inhaled
No data located.
Acute Mammalian Toxicity
LOW: D-90 was not toxic following acute exposure, based on the acute oral and dermal LCS0 values of
>2,000 mg/kg-bw in rats.
Acute Lethality
Oral
Rat (Sprague-Dawley CD) oral LD50
>2,000 mg/kg bw; no mortalities or signs
of systemic toxicity at the highest dose
tested (2,000 mg/kg bw).
Submitted confidential study
Adequate; guideline study (OECD
401).
Dermal
Rat (Sprague-Dawley CD) dermal LD50
>2,000 mg/kg bw; no mortalities or signs
of systemic toxicity at the highest dose
tested (2,000 mg/kg bw).
Submitted confidential study
Adequate; guideline study (OECD
402).
Inhalation
No data located.
Carcinogenicity
MODERATE: There is uncertainty due to the lack of data for this substance. Carcinogenic effects cannot
be ruled out.
OncoLogic Results
No data located.
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D-90 CASRN 191680-83-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Carcinogenicity (Rat and
Mouse)
No data located.
Combined Chronic
Toxicity/Carcinogenicity
No data located.
Genotoxicity
LOW: D-90 does not cause mutations in bacterial cells in vitro and is not clastogenic in human lymphocytes
in vitro.
Gene Mutation in vitro
Negative, reverse mutation assay in
Salmonella typhimurium strains TA98,
TA100, TA1535, and TA1537 and
Escherichia coli WP2 uvrA with and
without metabolic activation.
Submitted confidential study
Adequate; non-standard guideline
study (Japanese guideline for
mutagenicity tests using
microorganisms).
Gene Mutation in vivo
No data located.
Chromosomal Aberrations
in vitro
Non-clastogenic, chromosome
aberrations test in human lymphocytes
with and without activation.
Submitted confidential study
Adequate; guideline study (OECD
473).
Chromosomal Aberrations
in vivo
No data located.
DNA Damage and Repair
No data located.
Other (Mitotic Gene
Conversion)
No data located.
Reproductive Toxicity
LOW: A combination of limited predicted absorption, low predicted metabolism, and lack of significant
toxicological concerns from repeated dose testing suggests low potential for reproductive effects, with lower
confidence. (Professional judgment)
Reproduction/
Developmental Toxicity
Screen
Low potential for reproductive toxicity
(Estimated)
Professional judgment
Estimated based on predicted limited
absorption, low metabolism, lack of
evidence from repeated dose studies.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
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D-90 CASRN 191680-83-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproduction and Fertility
Effects
No data located.
Developmental Toxicity
LOW: A combination of limited predicted absorption, low predicted metabolism, and lack of significant
toxicological concerns from repeated dose testing suggests low potential for developmental effects, with
lower confidence. (Professional judgment)
Reproduction/
Developmental Toxicity
Screen
Low potential for developmental toxicity
(Estimated)
Professional judgment
Estimated based on predicted limited
absorption, low metabolism, lack of
evidence from repeated dose studies.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Prenatal Development
No data located.
Postnatal Development
No data located.
Neurotoxicity
MODERATE: Estimated to have potential for neurotoxicity based on the presence of the phenol structural
alert.
Neurotoxicity Screening
Battery (Adult)
There is potential for neurotoxicity
effects based on the presence of the
phenol structural alert
(Estimated)
U.S. EPA, 2010, Professional
judgment
Estimated based on structural alert.
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D-90 CASRN 191680-83-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Repeated Dose Effects
LOW: D-90 did not cause mortality or systemic effects at oral doses as high as 1,000 mg/kg-day in a 28-day
repeated-dose toxicity study in rats.
No adverse effects (e.g., mortality;
clinical signs; and changes in body
weights, food consumption, urinalysis
data, hematology data, gross pathology,
organ weights, organ-to-body weight
ratios or histopathology) were observed
in a 28-day oral (gavage) study in male
and female Fischer 344 rats; increases in
y-glutamyl transpeptidase was observed
in females exposed to 300 and
1,000 mg/kg-bw-day, which did not
correspond to histopathological effects.
NOEL = 1,000 mg/kg-bw-day (highest
dose tested)
Submitted confidential study
Adequate; not specified as a
guideline study, but follows general
OECD guidelines.
Skin Sensitization
LOW: D-90 was not a skin sensitizer in one study of guinea pigs.
Skin Sensitization
Negative for skin sensitization, Dunkin
Hartley guinea pigs
Submitted confidential study
Adequate; guideline study (OECD
406).
Respiratory Sensitization
No data located.
Respiratory Sensitization
No data located.
Eye Irritation
MODERATE: Iridial inflammation and moderate conjunctival irritation were observed up to the 48- or
72-hour observation in on study of rabbits.
Eye Irritation
Irritant (maximum group mean score:
13), iridial inflammation and moderate
conjunctival irritation, treated eyes
appeared normal at the 48- or 72-hour
observation, New Zealand White rabbits
Submitted confidential study
Adequate; guideline study (OECD
405).
Dermal Irritation
VERY LOW: D-90 was not a dermal irritant in one study of rabbits.
Dermal Irritation
Non-irritant (primary irritation index: 0),
New Zealand White rabbits
Submitted confidential study
Adequate; guideline study (OECD
404).
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D-90 CASRN 191680-83-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Endocrine Activity
No data located.
Mo data located.
Immunotoxicity
No data located.
Immune System Effects
Mo data located.
ECOTOXICITY
ECOSAR Class
Phenols, poly
Acute Toxicity
LOW: Based on estimated 96-hour LCS0 for fish, 48-hour LCS0 for Daphnid, and 96-hour ECS0 for green
algae that result in no effects at saturation, as obtained for representative components of the polymer that
have a MW <1,000. Higher MW components of the polymer are expected to have similar behavior.
Fish LC50
Fish 96-hour LC50 = 4.76 mg/L (n = 1)
(Estimated)
ECOSAR: phenols, poly
EPI
NES for representative component
of the polymer with a MW <1,000.
Fish 96-hour LC50 = 0.31 mg/L (n = 2)
(Estimated)
ECOSAR: neutral organics
EPI
NES for representative component
of the polymer with a MW <1,000.
Daphnid LCS0
Daphnid 48-hour LC50 = 9.46 mg/L
(n = 1) (Estimated)
ECOSAR: neutral organics
EPI
NES for representative component
of the polymer with a MW <1,000.
Daphnid 48-hour LC50 = 0.29 mg/L
(n = 2) (Estimated)
ECOSAR: neutral organics
EPI
NES for representative component
of the polymer with a MW <1,000.
Green Algae ECS0
Green algae 96-hour EC50 = 3.36 mg/L
(n = 1) (Estimated)
ECOSAR: phenols, poly
EPI
NES for representative component
of the polymer with a MW <1,000.
Green algae 96-hour EC50 = 0.63 mg/L
(n = 2) (Estimated)
ECOSAR: phenols, poly
EPI
NES for representative component
of the polymer with a MW <1,000.
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D-90 CASRN 191680-83-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Chronic Aquatic Toxicity
LOW: Based on ChV values for fish, Daphnid, and green algae that result in no effects at saturation, as
obtained for representative components of the polymer that have a MW < 1,000. Higher MW components
of the polymer are expected to have similar behavior.
Fish ChV
Fish 30-day ChV = 1.08 mg/L (n = 1)
(Estimated)
ECOSAR: phenols, poly
EPI
NES for representative component
of the polymer with a MW <1,000.
Fish 30-day ChV = 0.027 mg/L (n = 2)
(Estimated)
ECOSAR: neutral organics
EPI
NES for representative component
of the polymer with a MW <1,000.
Daphnid ChV
Daphnid ChV = 1.20 mg/L (n = 1)
(Estimated)
ECOSAR: neutral organics
EPI
NES for representative component
of the polymer with a MW <1,000.
Daphnid ChV = 0.054 mg/L (n = 2)
(Estimated)
ECOSAR: neutral organics
EPI
NES for representative component
of the polymer with a MW <1,000.
Green Algae ChV
Green algae ChV = 0.51 mg/L (n = 1)
(Estimated)
ECOSAR: phenols, poly
EPI
NES for representative component
of the polymer with a MW <1,000.
Green algae ChV = 0.206 mg/L (n = 2)
(Estimated)
ECOSAR: phenols, poly
EPI
NES for representative component
of the polymer with a MW <1,000.
ENVIRONMENTAL FATE
Transport
Evaluation of D-90 transport is based entirely on estimations on QSARs that were performed on two
representative components of the polymer (n = 1 and n = 2) that are a MW <1,000, although the higher
MW oligomers are anticipated to behave similarly. These representative structures are anticipated to be
the predominate components of the polymeric mixture. D-90 is expected to have low mobility in soil based
on its expected strong absorption to soil. If released to the atmosphere, D-90 is likely to exist solely as
particulate. As a particulate, atmospheric oxidation is not expected to be a significant route of
environmental removal. Level III fugacity models indicate that D-90 will partition predominantly to the
soil and sediment.
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D-90 CASRN 191680-83-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Henry's Law Constant
(atm-m3/mole)
30,000 (Estimated for n = 1 and n = 2)
EPI; U.S. EPA, 2011
Estimates were performed on
representative components of the
polymer that have a MW <1,000;
those with n = 1 or 2. Higher
oligomers are expected to have a
similar value. Cutoff value for non-
mobile compounds according to SF
assessment guidance.
Level III Fugacity
Estimations
Estimated for n = 1:
Air = 0%
Water = 3%
Soil = 57%
Sediment = 40%
EPI
Estimates performed on
representative components of the
polymer indicated.
Estimated for n = 2:
Air = 0%
Water =1%
Soil = 52%
Sediment = 48%
EPI
Estimates performed on
representative components of the
polymer indicated.
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D-90 CASRN 191680-83-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Persistence
VERY HIGH: Evaluation of D-90 persistence is based entirely on estimations that were performed on two
representative components of the polymer (n = 1 and n = 2) that have a MW <1,000 and are anticipated to
be the predominant component of the polymeric mixture. Primary aerobic degradation was estimated to
be in the order of weeks for both representative structures. Ultimate biodegradation was estimated to be in
the order of months for the n = 1 polymer, and the n = 2 polymer was estimated to be recalcitrant.
Estimated volatilization half-lives of >1 year for both representative structures indicate that volatilization is
not expected to occur. D-90 does not contain functional groups that absorb light at environmentally-
relevant wavelengths, and is not expected to be susceptible to direct photolysis. Atmospheric hydroxyl-
radical photooxidation half-lives were estimated to be 2.5 and 1.4 hours, respectively. However, this is not
expected to be an important removal process since D-90 is expected to exist in the particulate phase in the
atmosphere. Higher MW components of the polymer are expected to have similar persistence behavior.
Water
Aerobic Biodegradation
Weeks (primary survey model; n = 1 )
Months (ultimate survey model; n = 1)
Weeks (primary survey model; n = 2)
Recalcitrant (ultimate survey model;
n = 2)
EPI
Estimates performed on
representative components of the
polymer indicated.
Volatilization Half-life
for Model River
>1 year (Estimated for n = 1 and n = 2)
EPI
Estimates performed on
representative components of the
polymer indicated.
Volatilization Half-life
for Model Lake
>1 year (Estimated for n = 1 and n = 2)
EPI
Estimates performed on
representative components of the
polymer indicated.
Soil
Aerobic Biodegradation
No data located.
Anaerobic
Biodegradation
Not probable (anaerobic-methanogenic
biodegradation probability model; for
n = 1 and n = 2)
EPI
Estimates performed on
representative components of the
polymer that have a MW <1,000;
those with n = 1 or 2; higher
oligomers are expected to have a
similar value.
Soil Biodegradation w/
Product Identification
No data located.
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D-90 CASRN 191680-83-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Sediment/Water
Biodegradation
No data located.
Air
Atmospheric Half-life
2.5 hours (Estimated for n = 1 for
hydroxyl radical reaction assuming a 12-
hour day and a hydroxyl radical
concentration of 1.5x106 OH/cirf):
1.4 hours (Estimated for n = 2 for
hydroxyl radical reaction assuming a
12-hour day and a hydroxyl radical
concentration of 1.5xl06 OH/cirf)
EPI
Estimates performed on
representative components of the
polymer that have a MW <1,000;
those with n = 1 or 2; higher
oligomers are expected to have a
similar value.
Reactivity
Photolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain
functional groups that would be
expected to absorb light at
wavelengths >290 nm.
Hydrolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain
functional groups that would be
expected to hydrolyze readily under
environmental conditions.
Pyrolysis
No data located.
Environmental Half-life
120 days in soil (Estimated for n = 1);
540 days in sediment (Estimated for
n = 2)
360 days in soil (Estimated for n = 1);
1,600 days in sediment (Estimated for n =
2)
EPI; PBT Profiler
Half-life estimated for the
predominant compartment, as
determined by EPI and the PBT
Profiler methodology; estimates
were performed on representative
components of the polymer
indicated.
Bioaccumulation
HIGH: The estimated BAF value for the low MW oligomers with n = 2 is >1,000, indicating that this
component has the potential to bioaccumulate.
Fish BCF
149 (n = 1) (Estimated)
EPI
Estimates performed on
representative components of the
polymer indicated.
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D-90 CASRN 191680-83-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
166 (n = 2) (Estimated)
EPI
Estimates performed on
representative components of the
polymer indicated.
BAF
163 (n = 1) (Estimated)
EPI
Estimates performed on
representative components of the
polymer indicated.
4,270 (n = 2) (Estimated)
EPI
Estimates performed on
representative components of the
polymer indicated.
Metabolism in Fish
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
Ecological Biomonitoring
No data located.
Human Biomonitoring
This chemical was not included in the NHANES biomonitoring report (CDC, 2011).
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DRAFT REPORT - DO NOT CITE OR QUOTE
ACD/Labs, 2010. ACD/LogP, version 5.0, Advanced Chemistry Development, Inc., Toronto, ON, Canada, www.acdlabs.com, 2010.
Boethling, R., Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences. Boca Raton:
Lewis Publishers. 2000.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 4.00. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
PBT Profi 1 er Persistent (P),Bioaccumulative (B), and Toxic (T) Chemical (PBT)Profiler. U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
U.S. EPA (Environmental Protection Agency). High Production Volume (HPV) Challenge. Determining the Adequacy of Existing
Data. U.S. Environmental Protection Agency: Washington D.C. 1999. http://www.epa.gov/hpv/pubs/general/datadfin.htm
U.S. EPA Sustainable Futures. Using Noncancerous Screening within the SF Initiative. Environmental Protection Agency:
Washington D.C. 2010. available at: http://www.epa.gOv/opptintr/sf/pubs/noncan-screen.htm#svstemic (accessed on February 09,
2011).
U.S. EPA (Environmental Protection Agency). Sustainable Futures Summary Assessment. Assessment of Discrete Organic
Chemicals. U.S. Environmental Protection Agency: Washington D.C. 2011.
http://www.epa.gov/oppt/sf/pubs/iad_discretes_092011 .pdf
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DRAFT REPORT - DO NOT CITE OR QUOTE
DD-70
ja tx ^
CASRN 93589-69-6
MW: 352.5
MF: C17H20O4S2
Physical Forms:
Neat: Solid
Use: Developer for thermal paper
SMILES: 0clccc(ccl)SCC0C0CCSc2ccc(cc2)0
Synonyms: Phenol, 4,4'-(methylenebis(oxy-2,l-ethanediylthio))bis- (TSCA Inventory)
Polymeric: No
Oligomers: Not applicable
Metabolites, Degradates and Transformation Products: None identified
Analog: No
Endpoint(s) using analog values: Not applicable
Analog Structure: Not applicable
Structural Alerts: Phenols, neurotoxicity (U.S. EPA, 2010)
Risk Phrases: 51/53 - Toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment (ESIS, 2011).
Risk Assessments: None identified
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DD-70 CASRN 93589-69-6
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
108 (Measured)
Submitted
confidential study
Adequate.
Boiling Point (°C)
>350 (Estimated)
EPI; U.S. EPA, 1999
Cutoff value for high boiling
compounds according to HPV
assessment guidance.
Vapor Pressure (mm Hg)
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DRAFT REPORT - DO NOT CITE OR QUOTE
DD-70 CASRN 93589-69-6
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Inhalation
No data located.
Carcinogenicity
MODERATE: Estimated using OncoLogic expert system, which describes a concern for this compound as
a potential carcinogen or tumorigenesis promoter arising from its structural similarity to
estrogenic/androgenic compounds, using the 'phenols and phenolic compounds' structural alert.
OncoLogic Results
Moderate (Estimate)
OncoLogic class: phenols and phenolic
compounds
OncoLogic
OncoLogic SAR analysis using the
phenols and phenolic compounds class.
Carcinogenicity (Rat and
Mouse)
No data located.
Combined Chronic
Toxicity/Carcinogenicity
No data
Genotoxicity
LOW: Based on professional judgment, the absence of structural alerts suggests lower concern.
Gene Mutation in vitro
Low potential for genotoxicity toxicity
(Estimated)
Professional judgment
Estimated based on professional
judgment.
Gene Mutation in vivo
No data located.
Chromosomal Aberrations
in vitro
No data located.
Chromosomal Aberrations
in vivo
No data located.
DNA Damage and Repair
No data located.
Other (Mitotic Gene
Conversion)
No data located.
Reproductive Effects
MODERATE: There are no data and no appropriate analog for this endpoint, however an analog for DD-70
is toxicologically active in repeated dose and developmental toxicity studies, such that potential reproductive
toxicity cannot be ruled out. (Professional judgment)
Reproduction/
Developmental Toxicity
Screen
No data located.
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DD-70 CASRN 93589-69-6
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Reproduction and Fertility
Effects
No data located.
Developmental Effects
MODERATE: Based on confidential analog. Unspecified effects occurred at a dose of 100 mg/kg-day in a
developmental study in rats.
Developmental Toxicity
Screen
Rabbit, oral, developmental study
NOAEL = 300 mg/kg-day
(Estimated by analogy)
Professional judgment
Estimated based on available test data
for a confidential analog.
Rat, oral, developmental study
LOAEL =100 mg/kg-day (NOAEL not
established)
(Estimated by analogy)
Professional judgment
Estimated based on available test data
for a confidential analog.
Neurotoxicity
MODERATE: Estimated to have potential for neurotoxicity based on the presence of the phenol structural
alert.
Neurotoxicity Screening
Battery (Adult)
There is potential for neurotoxicity effects
based on the presence of the phenol
structural alert
(Estimated)
U.S. EPA, 2010; Professional
judgment
Estimated based on structural alert.
Repeated Dose Effects
MODERATE: Based on a confidential analog. Repeated dose effects including blood toxicity, severe
gastrointestinal irritation and histopathological changes to the glandular stomach occurred at doses
>50 mg/kg-day. Because the LOAEL is not specified, there is uncertainty as to the dose at which these effects
occur. Using a conservative approach in the absence of a specified LOAEL, a Moderate hazard concern is
selected because it is possible that effects can occur at doses between 50 and 100 mg/kg-day.
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DD-70 CASRN 93589-69-6
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Rat, 13-week oral exposure
Blood toxicity, severe gastrointestinal
irritation, histopathogical changes in the
glandular stomach
NOAEL = 50 mg/kg-day
LOAEL - not identified
(Estimated by analogy)
Professional judgment
Estimated based on available test data
for a confidential analog.
Skin Sensitization
MODERATE: Based on confidential analog. DD-70 may potentially cause dermal sensitization.
Skin Sensitization
Positive for dermal sensitization in guinea
pigs
(Estimated by analogy)
Professional judgment
Estimated based on available test data
for a confidential analog.
Respiratory Sensitization
No data located.
Respiratory Sensitization
No data located.
Eye Irritation
HIGH: Based on confidential analog. DD-70 may potentially cause corrosion to eyes.
Eye Irritation
Concern for potential corrosion to mucous
membranes and eyes
(Estimated by analogy)
Professional judgment
Estimated based on available test data
for a confidential analog.
Dermal Irritation
MODERATE: Based on confidential analog. DD-70 may have the potential to cause dermal irritation.
Dermal Irritation
Concern for dermal irritation
(Estimated by analogy)
Professional judgment
Estimated based on available test data
for a confidential analog.
Endocrine Activity
No data located.
No data located.
Immunotoxicity
No data located.
Immune System Effects
No data located.
ECOTOXICITY
ECOSAR Class
Phenols, poly
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DD-70 CASRN 93589-69-6
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Acute Toxicity
HIGH: Based on estimated 96-hour LCS0 value for fish and 96-hour ECS0 value for green algae that are in
the range of 1-10 mg/L.
Fish LC50
Fish 96-hour LC50 = 5.39 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Fish 96-hour LC50 = 19.6 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid LCS0
Daphnia 48-hour LC50 = 13.30 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnia 48-hour LC50 =13.6 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Green Algae ECS0
Green algae 96-hour EC50 = 2.28 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Green algae 96-hour EC50 = 9.98 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Chronic Aquatic Toxicity
HIGH: Based on an estimated ChV of 0.42 mg/L for green algae.
Fish ChV
Fish 30-day ChV = 1.33 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Fish ChV = 1.80 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
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DD-70 CASRN 93589-69-6
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Daphnid ChV
Daphnid ChV = 1.56 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnid ChV = 4.68 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Green Algae ChV
Green algae ChV = 0.422 mg/L
(Estimated)
ECOSAR: phenols, poly
EPI
Green algae ChV = 4.62 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
ENVIRONMENTAL FATE
Transport
Based on the Level III fugacity models incorporating the available experimental property data, DD-70 is
expected to partition primarily to soil. DD-70 is expected to exist in both neutral and anionic forms at
environmentally-relevant pH, based on its estimated pKa. The neutral form of DD-70 is expected to be
immobile in soil based on its estimated Koc. The anionic form may be more mobile, as anions do not bind as
strongly to organic carbon and clay as their neutral counterparts. However, leaching of DD-70 through soil
to groundwater is not expected to be an important transport mechanism. Estimated volatilization half-lives
indicate that it will be non-volatile from surface water. Volatilization from dry surface is also not expected
based on its estimated vapor pressure. In the atmosphere, DD-70 is expected to exist solely in the particulate
phase, based on its estimated vapor pressure. Particulates may be removed from air by wet or dry
deposition.
Henry's Law Constant
(atm-m3/mole)
<1x10"ui (Estimated)
EPI; U.S. EPA, 1999
Cutoff value for non-volatile
compounds according to HPV
assessment guidance.
Sediment/Soil
Adsorption/Desorption
Coefficient - Koc
3. 3x 104 (Estimated)
EPI
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DD-70 CASRN 93589-69-6
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Level III Fugacity Model
Air = <1% (Estimated)
Water = 8.6%
Soil = 75%
Sediment = 16%
EPI
Persistence
HIGH: Evaluation of the persistence of DD-70 is based entirely on QSARs for aerobic and anaerobic
biodegradation. Results from these models estimate primary biodegradation in days-weeks and ultimate
degradation in weeks-months. DD-70 is expected to partition primarily to soil; the half-life is estimated as 75
days. Biodegradation under anaerobic methanogenic conditions is not probable. DD-70 is not expected to
undergo hydrolysis since it does not contain hydrolysable functional groups. DD-70 does not contain
chromophores that absorb at wavelengths >290 nm, and therefore, it is not expected to be susceptible to
direct photolysis by sunlight. The vapor phase reaction of DD-70 with atmospheric hydroxyl radicals is
estimated at 1.2 hours, although it is expected to exist primarily in the particulate phase in air.
Considerations of all these factors indicate that the persistence concern is High for DD-70.
Water
Aerobic Biodegradation
Days-weeks (primary survey model)
Weeks-months (ultimate survey model)
EPI
Volatilization Half-life
for Model River
>1 year (Estimated)
EPI
Volatilization Half-life
for Model Lake
>1 year (Estimated)
EPI
Soil
Aerobic Biodegradation
No data located.
Anaerobic
Biodegradation
Not probable (anaerobic-methanogenic
biodegradation probability model)
EPI
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
Biodegradation
No data located.
Air
Atmospheric Half-life
1.2 hours (Estimated)
EPI
Reactivity
Photolysis
Not a significant fate process
(Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain functional
groups that would be expected to
absorb light at environmentally
significant wavelengths.
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DRAFT REPORT - DO NOT CITE OR QUOTE
DD-70 CASRN 93589-69-6
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Hydrolysis
Not a significant fate process
(Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain functional
groups that would be expected to
hydrolyze readily under environmental
conditions.
Pyrolysis
No data located.
Environmental Half-life
75 days (Estimated)
EPI, PBT Profiler
Half-life estimated for the predominant
compartment, as determined by EPI
and the PBT Profiler methodology.
Bioaccumulation
LOW: The estimated BCF for fish is less than the low criteria cutoff of 100. In addition, the estimated BAF
of 35, which accounts for metabolism, suggests that DD-70 will not bioaccumulate in higher trophic levels.
Fish BCF
75 (Estimated)
EPI
BAF
35 (Estimated)
EPI
Metabolism in Fish
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
Ecological Biomonitoring
No data located.
Human Biomonitoring
This chemical was not included in the NHANES biomonitoring report (CDC, 2011).
4-382
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DRAFT REPORT - DO NOT CITE OR QUOTE
Boethling, R., Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences. Boca Raton:
Lewis Publishers. 2000.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 4.00. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
Oncologic. U.S. EPA and LogiChem, Inc. 2005, Version 7.0. 2008.
PBT Profi 1 er Persistent (P),Bioaccumulative (B), and Toxic (T) Chemical (PBT)Profiler. U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
SPARC On Line Calculator pKaproperty server. Ver 4.5 September, 2009. Available from, http://ibmlc2.chem.uga.edu/sparc/
(accessed on August 12, 2010).
U.S. EPA (Environmental Protection Agency). High Production Volume (HPV) Challenge. Determining the Adequacy of Existing
Data. U.S. Environmental Protection Agency: Washington D.C. 1999. http://www.epa.gov/hpv/pubs/general/datadfin.htm
U.S. EPA Sustainable Futures Using NonCancer Screening within the Sustainable Futures Initiative Environmental Protection
Agency: Washington D.C. 2010. http://www.epa.gOv/opptintr/sf/pubs/noncan-screen.htm#svstemic as of February 09, 2011.
4-383
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Pergafast 201
CASRN: 232938-43-1
MW: 460.5
MF: C21H20N2O6S2
Physical Forms:
Neat: Solid
Use: Developer for thermal paper
SMILES: 0=S(=0)(0clcccc(cl)NC(=0)NS(=0)(=0)c2ccc(C)cc2)c3ccc(C)cc3
Synonyms: Benzenesulfonamide, 4-Methyl-N-(((3-(((4-Methylphenyl)Sulfonyl)Oxy)Phenyl)Amino)Carbonyl)-;
N-(P-Toluenesulfonyl)-N'-(3-P-Toluenesulfonyloxyphenyl)Urea;
N-(4-Methylphenylsulfonyl)-N'-(3-(4-Methylphenylsulfonyloxy)Phenyl)Urea; N-P-Tolylsulfonyl-N'-3-(P-Tolylsulfonyloxy)Phenylurea;
Pergafast 201; PF 201
Polymeric: No
Oligomers: Not applicable
Metabolites, Degradates and Transformation Products: None identified
Analog: No
Endpoint(s) using analog values: Not applicable
Analog Structure: Not applicable
Structural Alerts: Sulfonamides, photoreactions; Alkyl esters of sulfonic acids, toxicity caused by electrophiles (U.S. EPA, 2011)
Risk Phrases: 51/53 - Toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment (ESIS, 2011).
Risk Assessments: Risk assessment completed for Pergafast 201 by the Australian Department of Health and Ageing in 2004 (NICNAS, 2004).
4-384
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Pergafast 201 CASRN 232938-43-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
157.7 (Measured)
NICNAS, 2004
Adequate; selected value.
>155 (Measured)
BASF, 2010
Adequate; measured by chemical
supplier.
Boiling Point (°C)
Decomposes at 250 (Measured)
NICNAS, 2004
Adequate.
Vapor Pressure (mm Hg)
2,000 mg/kg. No data were located regarding the acute
inhalation hazard.
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Pergafast 201 CASRN 232938-43-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Acute Lethality
Oral
Rat oral LD50 >2,000 mg/kg
NICNAS, 2004
Adequate.
Dermal
Rat dermal LD50 >2,000 mg/kg
NICNAS, 2004
Adequate.
Inhalation
No data located.
Carcinogenicity
MODERATE: There is uncertainty due to the lack of data for this substance. Carcinogenic effects cannot be
ruled out.
OncoLogic Results
No data located.
Carcinogenicity (Rat and
Mouse)
No data located.
Combined Chronic
No data located.
T oxi city/Car cinogenicity
Genotoxicity
LOW: Pergafast 201 did not cause gene mutations in vitro or chromosomal aberrations in vivo. Pergafast
201 did induce chromosomal aberrations in Chinese hamster V79 cells in vitro, but only at cytotoxic
concentrations.
Gene Mutation in vitro
Negative, Ames assay of Salmonella
typhimiirium strains TA98, TA100,
TA1535, TA1537 and Escherichia coli
WP2 uvrA both with and without
metabolic activation
NICNAS, 2004
Adequate.
Gene Mutation in vivo
No data located.
Chromosomal Aberrations
Positive, chromosomal aberrations in
NICNAS, 2004
Adequate.
in vitro
Chinese hamster V79 cells at cytotoxic
concentrations
Chromosomal Aberrations
Negative, in vivo micronucleus test in
NICNAS, 2004
Adequate.
in vivo
mouse, gavage exposure
DNA Damage and Repair
No data located.
Other
No data located.
Reproductive Effects
MODERATE: There were no reproductive effects observed at any dose tested in a
reproduction/developmental toxicity screening test in rats. The highest dose tested (200 mg/kg bw-day) is
considered the NOAEL. This NOAEL value falls in the "Moderate" hazard range (50-250 mg/kg bw-day),
but because it was the highest dose tested there is uncertainty if there would be reproductive effects occurring
between 200 and 250 mg/kg bw-day.
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DRAFT REPORT - DO NOT CITE OR QUOTE
Pergafast 201 CASRN 232938-43-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproduction/
Developmental Toxicity
Screen
Rat, oral gavage;
Males exposed for 29 days pre-mating,
during mating, and up to sacrifice;
Females exposed 42-46 days (2 weeks
pre-mating, during mating, during post-
coitum, up to LD 4.
No reproductive toxicity was observed at
any dose.
NOAEL (maternal toxicity): 50 mg/kg
bw-day
LOAEL (maternal toxicity): 100 mg/kg
bw-day (accentuated lobular pattern of
the liver, increased liver to body weight
ratio)
NOAEL (F1 pups): >200 mg/kg bw-day
Submitted confidential study
Adequate; according to OECD
guideline 421.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Reproduction and Fertility
Effects
No data located.
Developmental Effects
MODERATE: Decreased body weight (LDs 1 and 4) were observed in pups from dams exposed to 200 mg/kg
bw-day. It should be noted that developmental effects occurred in the presence of maternal toxicity, although
toxicity to dams (liver and kidney toxicity) does not appear to be the cause of developmental effects.
4-387
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DRAFT REPORT - DO NOT CITE OR QUOTE
Pergafast 201 CASRN 232938-43-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproduction/
Developmental Toxicity
Screen
Rat, oral gavage;
Males exposed for 29 days pre-mating,
during mating, and up to sacrifice;
Females exposed 42-46 days (2 weeks
pre-mating, during mating, during post-
coitum, up to LD 4.
There were no relevant adverse effects to
the offspring, changes in litter size, or
mortality of newborns compared to
controls; there was decreased body
weight in pups (LDs 1 and 4) of dams
exposed to the highest dose.
NOAEL (maternal toxicity): 50 mg/kg
bw-day
LOAEL (maternal toxicity): 100 mg/kg
bw-day (accentuated lobular pattern of
the liver, increased liver to body weight
ratio)
NOAEL (F1 pups): 100 mg/kg bw-day
LOAEL (F1 pups): 200 mg/kg bw-day
(decreased pup body weight on LDs 1
and 4)
Submitted confidential study
Adequate; according to OECD
guideline 421.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Prenatal Development
No data located.
Postnatal Development
No data located.
Neurotoxicity
LOW: No structural alerts or mechanistic pathways associated with neurotoxic effect identified.
4-388
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DRAFT REPORT - DO NOT CITE OR QUOTE
Pergafast 201 CASRN 232938-43-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Neurotoxicity Screening
Battery (Adult)
Low potential for neurotoxicity effects.
(Estimated)
Professional judgment
Estimated based on no identified
structural alerts or mechanistic
pathways associated with neurotoxicity.
Repeated Dose Effects
MODERATE: A 28-day oral toxicity study in rats identified a NOAEL of 30 mg/kg-day and a LOAEL of
150 mg/kg-day for clinical signs, organ weight changes, and histopathologic liver and kidney lesions.
According to DfE guidance, the guidance values are tripled for chemicals evaluated in a 28-day study to
estimate effect levels from 90 days of treatment in order to assess the hazard of repeated-dose toxicity.
Therefore, Moderate hazard is indicated in a 28-day study when oral toxicity is observed at doses between 30
and 300 mg/kg bw-day. A 90-day study identified a LOAEL of 150 mg/kg bw-day and a NOAEL of 25 mg/kg
bw-day; while the LOAEL value is >100 mg/kg bw-day (suggestive of a low hazard concern), the NOAEL is
25 mg/kg bw-day. Based on uncertainty in the dose range of 25-100 mg/kg bw-day, and data from the 28-day
study indicating effects occurring in the Moderate hazard range, a Moderate hazard designation is selected.
28-Day repeated-dose study, rat, oral
gavage, salivation, indications of
hemolytic anemia, increased liver and
kidney weights, microscopic changes
including minimal hypertrophy of
ventrilobular hepatocytes in liver of
males and females and extramedullary
haemopoiesis in spleen of females.
NOAEL = 30 mg/kg bw-day,
LOAEL =150 mg/kg bw-day
NICNAS, 2004
90-Day repeated-dose study, rat, oral
gavage; Changes in hematology
parameters and increased extramedullary
hematopoiesis, increased absolute and
relative organ weights with
histopathological correlation in the liver;
histopathological changes in spleen and
adrenal glands.
NOAEL = 25 mg/kg bw-day
LOAEL =150 mg/kg bw-day
Adequate.
Submitted confidential study
Adequate; according to OECD
guideline 408.
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DRAFT REPORT - DO NOT CITE OR QUOTE
Pergafast 201 CASRN 232938-43-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
5-Day range finding study, rat, oral
gavage; decreased mean daily food
consumption (male and female),
decreased body weight gain (females),
decreased absolute and relative thymus
weights (males), increased absolute and
relative liver weight (male and female).
Submitted confidential study
Adequate.
LOAEL = 200 mg/kg bw-day (lowest
dose tested)
Skin Sensitization
LOW: Pergafast 201 did not appear to be a skin sensitizer in guinea pigs.
Skin Sensitization
Skin irritation was observed in 1/10
guinea pigs at 24 hours (but not at
48 hours) following induction and
subsequent challenge. The severity of
the response was not described in the
available source.
NICNAS, 2004
Inadequate; limited study details.
Non-sensitizing, Guinea pig
BASF, 2010
Valid.
Respiratory Sensitization
No data located.
Respiratory Sensitization
No located.
Eye Irritation
LOW: Pergafast 201 was slightly irritating to rabbit eyes.
Eye Irritation
Slightly irritating, rabbits
NICNAS, 2004
Adequate.
Non-irritating, rabbits
BASF, 2010
Valid.
Dermal Irritation
VERY LOW: Pergafast 201 was not irritating to rabbit skin.
Dermal Irritation
Non-irritating, rabbits
NICNAS, 2004
Adequate.
Endocrine Activity
A single study showed Pergafast 201 to be non-estrogenic with a relative potency substantially low compared
to 17-beta-estradiol.
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DRAFT REPORT - DO NOT CITE OR QUOTE
Pergafast 201 CASRN 232938-43-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Negative for estrogenic activity;
Increased luciferase activity in a human
estrogen recetpro-a transcriptional
activation assay. Relative potency was
estimated to be about 107 times less than
estrogen.
Submitted confidential study
Adequate; similar to OECD guideline
455.
Immunotoxicity
There is uncertain concern for immunotoxicity based on effects to the spleen and adrenal glands.
Immune System Effects
90-day repeated-dose study, rat, oral
gavage; changes in spleen and adrenal
glands.
NOAEL = 25 mg/kg bw-day
LOAEL =150 mg/kg bw-day
Submitted confidential study
Adequate; according to OECD
guideline 408.
ECOTOXICITY
ECOSAR Class
Esters, Amides, Sulfonyl ureas
Acute Toxicity
VERY HIGH: Based on a measured 72-hour ECS0 of 0.77 mg/L for biomass in Scenedesmus subspicatus.
Fish LCso
Zebra fish 96-hour LC5n >63 mg/L,
NOEC = 63 mg/L
(Experimental)
NICNAS, 2004
Chemical may not be soluble enough to
measure this effect; LC50 value exceeds
water solubility.
Fish 96-hour LC50 = 19.88 mg/L
(Estimated)
ECOSAR: amides
EPI
Fish 96-hour LC50 = 28.42 mg/L
(Estimated)
ECOSAR: esters
EPI
Fish 96-hour LC50 = 110.21 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Chemical may not be soluble enough to
measure this predicted effect; LC50
value exceeds water solubility.
Brctchydanio rerio 96-hour LC50 >100
mg/L (Experimental)
BASF, 2010
Chemical may not be soluble enough to
measure this effect; LC50 value exceeds
water solubility.
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DRAFT REPORT - DO NOT CITE OR QUOTE
Pergafast 201 CASRN 232938-43-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Daphnid LCS0
Daphnict magna 48-hour EC50 = 57 mg/L
(Experimental)
NICNAS, 2004
Inadequate (OECD 202). Chemical may
not be soluble enough to measure this
effect; EC50 value exceeds water
solubility.
Daphnid 48-hour LC50 = 13.78 mg/L
(Estimated)
ECOSAR: amides
EPI
Daphnid 48-hour LC50 = 54.07 mg/L
(Estimated)
ECOSAR: esters
EPI
Chemical may not be soluble enough to
measure this predicted effect; LC50
value exceeds water solubility.
Daphnid 48-hour LC50 = 40.69 mg/L
(Estimated)
ECOSAR: Sulfonyl ureas
EPI
Chemical may not be soluble enough to
measure this predicted effect; LC50
value exceeds water solubility.
Daphnid 48-hour LC50 = 68.38 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Chemical may not be soluble enough to
measure this predicted effect; LC50
value exceeds water solubility.
Saltwater Invertebrate LCS0
Mysid shrimp 96-hour LC50 =
29.89 mg/L
(Estimated)
ECOSAR: esters
EPI
Green Algae ECS0
Scenedesmus subspicatus 72-hour EC50 =
0.77 mg/L (nominal) based on biomass
inhibition;
72-hour EC50 = 3 mg/L (nominal) based
on growth rate
(Experimental)
NICNAS, 2004;
Submitted confidential study
Adequate; OECD 201.
Scenedesmus subspicatus 96-hour EC50 =
6.3 mg/L (nominal) based on biomass;
96-hour EC50 >10 mg/L (nominal) based
on growth rate
Static conditions
(Experimental)
Submitted confidential study
Adequate; OECD 201.
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DRAFT REPORT - DO NOT CITE OR QUOTE
Pergafast 201 CASRN 232938-43-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Scenedesmus subspicatus 72-hour EC50 =
1.3 mg/L (nominal) based on biomass;
72-hour EC50 = 3.2 mg/L (nominal)
based on growth rate
Static conditions
(Experimental)
Submitted confidential study
Adequate; OECD 201.
Green algae 96-hour EC50 = 21.60 mg/L
(Estimated)
ECOSAR: esters
EPI
Green algae 96-hour EC50 = 0.69 mg/L
(Estimated)
ECOSAR: amides
EPI
Green algae 96-hour EC50 = 0.05 mg/L
(Estimated)
ECOSAR: sulfonyl ureas
EPI
Green algae 96-hour EC50 = 37.71 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Chemical may not be soluble enough to
measure this predicted effect; EC50
value exceeds water solubility.
Chronic Aquatic Toxicity
HIGH: Based on an estimated ChV of 0.013 mg/L for green algae.
Fish ChV
Fish ChV = 0.12 mg/L
(Estimated)
ECOSAR: amides
EPI
Fish 32/33-day ChV = 2.21 mg/L
(Estimated)
ECOSAR: esters
EPI
Fish ChV = 10.32 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Pimephcdes promelas, flow through
conditions.
32-day NOEC = 0.89 mg/L
(Experimental)
Submitted confidential study
Adequate; EPA OPPTS 850.1400
guidelines; LOEC not identified.
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Pergafast 201 CASRN 232938-43-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Daphnid ChV
Daphnict magna 21-day EC50 = 21 mg/L
(Experimental)
NICNAS, 2004
Adequate; LOEC not identified.
Daphnid ChV = 0.18 mg/L
(Estimated)
ECOSAR: amides
EPI
Daphnid 21-day ChV = 29.23 mg/L
(Estimated)
ECOSAR: esters
EPI
Daphnid ChV = 4.11 mg/L
(Estimated)
ECOSAR: sulfonyl ureas
EPI
Daphnid ChV = 7.02 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Daphnia magna 21-day NOEC =
10.2 mg/L
(Experimental)
BASF, 2010
Valid; LOEC not identified.
Daphnia Magna; semi-static conditions;
21-day NOEC = 10.2 mg/L
21-day LOEC = 34.5 mg/L (for
immobilization)
(Experimental)
Submitted confidential study
Adequate; OECD 211; Chemical may
not be soluble enough to measure this
predicted effect; LOEC value is at the
level of water solubility.
Saltwater Invertebrate ChV
Mysid shrimp ChV = 640 mg/L
(Estimated)
ECOSAR: esters
EPI
Chemical may not be soluble enough to
measure this predicted effect.
Green Algae ChV
Green algae ChV = 0.013 mg/L
(Estimated)
ECOSAR: sulfonyl ureas
EPI
Green algae ChV = 6.62 mg/L
(Estimated)
ECOSAR: esters
EPI
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Pergafast 201 CASRN 232938-43-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Green algae ChV = 0.77 mg/L
(Estimated)
ECOSAR: amides
EPI
Green algae ChV = 15.23 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
Earthworm Subchronic Toxicity
Earthworm 14-day LC50 = 3,500 mg/L
(Estimated)
ECOSAR: esters
EPI
NES for measured water solubility of
35 mg/L.
ENVIRONMENTAL FATE
Transport
The transport evaluation for Pergafast 201 is based on available experimental and estimated physical and
chemical properties. Based on the Level III fugacity models incorporating the available experimental
property data, Pergafast 201 is expected to partition primarily to soil. Pergafast 201 is expected to have
slight mobility in soil based on its estimated Koc. However, leaching of Pergafast 201 through soil to
groundwater is not expected to be an important transport mechanism. Estimated volatilization half-lives
indicate that it will be non-volatile from surface water. In the atmosphere, Pergafast 201 is expected to exist
in the particulate phase, based on its estimated vapor pressure. Particulates will be removed from air by wet
or dry deposition.
Henry's Law Constant
(atm-m3/mole)
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DRAFT REPORT - DO NOT CITE OR QUOTE
Pergafast 201 CASRN 232938-43-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Water
Aerobic Biodegradation
OECD TG 301 F Ready
Biodegradability: Manometric
Respirometry Test. Pergafast 201 is not
readily biodegradable; 1.5% degradation
of the test substance occurred after 28
days (Measured)
NICNAS, 2004
Adequate; guideline study described in
secondary source.
OECD 302B: Not readily
biodegradable; >99% after 28 days
(Measured)
BASF, 2010
Adequate, guideline study.
No biodegradation occurred after 28
days in. Ready biodegradability test
with non-adapted, activated sludge.
(Measured)
Submitted confidential study
Adequate; non-guideline study reported
in secondary source.
Volatilization Half-life
>1 year (Estimated)
EPI
for Model River
Volatilization Half-life
>1 year (Estimated)
EPI
for Model Lake
Soil
Aerobic Biodegradation
Half-life of 4.9 days according to OECD
307; decreased to 14% of applied amount
in 30 days (Measured)
Submitted confidential study
Inadequate as reported in a secondary
source. The cited source indicated that
the material did not mineralize over the
course of the study, although no mass
balance information was provided.
These are results are not consistent with
other biodegradation results.
Anaerobic
Biodegradation
Not probable (anaerobic-methanogenic
biodegradation probability model)
EPI
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
No data located.
Biodegradation
Air
Atmospheric Half-life
0.64 hours (Estimated)
EPI
Reactivity
Photolysis
Not a significant fate process
Professional judgment
Qualitative assessment based on
functional groups.
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DRAFT REPORT - DO NOT CITE OR QUOTE
Pergafast 201 CASRN 232938-43-1
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Hydrolysis
Half-life >1 year at pH 4, 7, and 9
OECD 111; <10%hydrolysis after 5
days (Measured)
NICNAS, 2004
Adequate; guideline study described in
secondary source.
Pyrolysis
No data located.
Environmental Half-life
120 days (Estimated)
EPI; PBT Profiler
Half-life estimated for the predominant
compartment, as determined by EPI and
the PBT Profiler methodology.
Bioaccumulation
LOW: The measured BCF in fish is <100.
Fish BCF
<1 (0.2 mg/L) (Measured);
<8 (0.02 mg/L) (Measured)
according to guideline study OECD 305
Submitted confidential study
Adequate; guideline study described in
a secondary source.
30 (Measured)
NICNAS, 2004
Reported in a secondary source,
although the resulting hazard is
consistent with other studies.
BAF
18 (Estimated)
EPI
Metabolism in Fish
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
Ecological Biomonitoring
No data located.
Human Biomonitoring
This chemical was not included in the NHANES biomonitoring report (CDC, 2011).
4-397
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DRAFT REPORT - DO NOT CITE OR QUOTE
BASF. BASF The Chemical Company. Material Safety Data Sheet. 2010.
Boethling, R., Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences. Boca Raton:
Lewis Publishers. 2000.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
EPI. (EPIWIN EP1SUITE) Estimations Programs Interface for Windows, Version 4.00. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
NICNAS (National Industrial Chemicals Notification and Assessment Scheme). Full public report. Pergafast 201. National Industrial
Chemicals Notification and Assessment Scheme. National Occupational Health and Safety Commission, Australia. 2004.
PBT Profi 1 er Persistent (P), Bioaccumulative (B), and Toxic (T) Chemical (PBT) Profiler, U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
SPARC On Line Calculator pKaproperty server. Ver 4.5 September, 2009. Available from, http://ibmlc2.chem.uga.edu/spare/
(accessed on August 12, 2010).
U.S. EPA Sustainable Futures Using NonCancer Screening within the Sustainable Futures Initiative Environmental Protection
Agency: Washington D.C. 2010. http://www.epa.gOv/opptintr/sf/pubs/noncan-screen.htm#svstemic (accessed on February 09, 2011).
U.S. EPA (Environmental Protection Agency). Sustainable Futures Summary Assessment. Assessment of Discrete Organic
Chemicals. U.S. Environmental Protection Agency: Washington D.C. 2011.
http://www.epa.gov/oppt/sf/pubs/iad_discretes_092011 .pdf
4-398
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BTUM
o ° o 9 ° °
s 1 I J I J I ^ ^
CASRN 151882-81-4
MW: 592.70
MF: C29H28N406S2
Physical Forms:
Neat: Solid
Use: Developer for thermal paper
SMILES: 0=C(NS(C1=CC=C(C)C=C1)(=0)=0)NC(C=C2)=CC=C2CC3=CC=C(NC(NS(C4=CC=C(C)C=C4)(=0)=0)=0)C=C3
Synonyms: 4/l'-bis(/V-carbamoyl-4-methylbenzenesulfonamide)di phenyl methane
Polymeric: No
Oligomers: Not applicable
Metabolites, Degradates and Transformation Products: None identified
Analog: None
Endpoint(s) using analog values: Not applicable
Analog Structure: Not applicable
Structural Alerts: None identified
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 2011).
Risk Assessments: None identified
4-399
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BTUM CASRN 151882-81-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
154-156 (Measured)
Non-confidential PMN
submission
Adequate.
Boiling Point (°C)
>300 (Estimated)
EPI; U.S. EPA, 1999
Cutoff value for high boiling
compounds according to HPV
assessment guidance.
Vapor Pressure (mm Hg)
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BTUM CASRN 151882-81-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Acute Mammalian Toxicity
LOW: The acute oral and dermal toxicity concern of BTUM is low based on experimental data in animals.
Data indicate no mortality or signs of toxicity at doses up to 2,000 mg/kg.
Acute Lethality
Oral
Rat, LD0 = 2,000 mg/kg
No signs of toxicity
Non-confidential PMN
submission
Adequate.
Dermal
Rat, LD0 = 2,000 mg/kg
No signs of toxicity
Non-confidential PMN
submission
Adequate.
Inhalation
No data located.
Carcinogenicity
MODERATE: There is uncertainty due to the lack of data for this substance. Carcinogenic effects cannot be
ruled out.
OncoLogic Results
No data located.
Carcinogenicity (Rat and
Mouse)
No data located.
Combined Chronic
T oxi city/Car cinogenicity
No data located.
Genotoxicity
LOW: BTUM did not cause mutations in bacteria or chromosomal aberrations in human lymphocytes.
Gene Mutation in vitro
Negative for mutations in Salmonella
typhi murium and Escherichia coli with
and without activation
Non-confidential PMN
submission
Adequate.
Gene Mutation in vivo
No data located.
Chromosomal Aberrations
in vitro
Negative for chromosomal aberrations in
human lymphocytes
Non-confidential PMN
submission
Adequate.
Chromosomal Aberrations
in vivo
No data located.
DNA Damage and Repair
No data located.
Other (Mitotic Gene
Conversion)
No data located.
4-401
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BTUM CASRN 151882-81-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Reproductive Effects
LOW: A combination of poor predicted absorption through all routes, low predicted metabolism, and lack of
significant toxicological concerns from repeated dose testing suggests low potential hazard, with lower
confidence. (Professional judgment)
Reproduction/
Developmental Toxicity
Screen
Low potential for reproductive effects
(Estimated)
Professional judgment
Estimated based on professional
judgment.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Reproduction and Fertility
Effects
No data located.
Developmental Effects
LOW: A combination of poor predicted absorption through all routes, low predicted metabolism, and lack of
significant toxicological concerns from repeated dose testing suggests low potential hazard, with lower
confidence. (Professional judgment)
Reproduction/
Developmental Toxicity
Screen
Low potential for reproductive effects
(Estimated)
Professional judgment
Estimated based on professional
judgment.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Prenatal Development
No data located.
Postnatal Development
No data located.
Neurotoxicity
LOW: No structural alerts or mechanistic pathways associated with neurotoxic effect identified.
Neurotoxicity Screening
Battery (Adult)
Low potential for neurotoxicity effects
(Estimated)
U.S. EPA, 2010; Professional
judgment
Estimated based on no identified
structural alerts or mechanistic
pathways associated with
neurotoxicity.
4-402
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BTUM CASRN 151882-81-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Repeated Dose Effects
MODERATE: Blood toxicity and liver changes resulted in rats at a dose of 1,000 mg/kg-day following a 28-
day exposure to BTUM. While the LOAEL identified in the study indicates a Low hazard concern (>300
mg/kg-day), the NOAEL is within the Moderate hazard concern range for a 28-day study duration (30-300
mg/kg-day). The uncertainty of where effects might occur warrants a Moderate hazard concern.
Rat, 2 8-day oral (gavage)
blood toxicity and liver changes.
NOAEL = 200 mg/kg-day
LOAEL = 1,000 mg/kg-day
Non-confidential PMN
submission
Adequate.
Skin Sensitization
LOW: BTUM did not cause dermal sensitization in one study of guinea pigs.
Skin Sensitization
No skin sensitization in guinea pigs using
the Magnusson Kligman assay
Non-confidential PMN
submission
Adequate.
Respiratory Sensitization
No data located.
Respiratory Sensitization
No data located.
Eye Irritation
LOW: BTUM was slightly irritating to eyes in one study of rabbits.
Eye Irritation
Mild eye irritation in rabbits
Non-confidential PMN
submission
Adequate.
Dermal Irritation
LOW: BTUM did not cause dermal irritation in one study of rabbits.
Dermal Irritation
No skin irritation in rabbits
Non-confidential PMN
submission
Adequate.
Endocrine Activity
No data located.
No data located.
Immunotoxicity
No data located.
Immune System Effects
No data located.
ECOTOXICITY
ECOSAR Class
Sulfonyl ureas
Acute Toxicity
HIGH: Based on an estimated acute toxicity value of <1.0 mg/L for algae, although there is a high degree of
uncertainty and limited confidence in the estimation.
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BTUM CASRN 151882-81-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Fish LC50
Fish 96-hour LC50 = 37 mg/L
(Estimated)
EPI
NES; estimated LC50 is greater than
the measured water solubility (0.77
mg/L).
Fish 96-hour LC50 =137 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
NES; estimated LC50 is greater than
the measured water solubility (0.77
mg/L).
Daphnid 48-hour LC50 = 34 mg/L
(Estimated)
ECOSAR: sulfonyl ureas
EPI
NES; estimated LC50 is greater than
the measured water solubility (0.77
mg/L).
Daphnid 48-hour LC50 = 82 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
NES; estimated LC50 is greater than
the measured water solubility (0.77
mg/L).
Green Algae ECS0
Green algae 96-hour EC50 = 0.188 mg/L
(Estimated)
ECOSAR: sulfonyl ureas
EPI
There is some uncertainty to the
estimated value for this compound
since all chemicals in the training set
for the sulfonyl urea class equation
consists solely of triazine herbicides.
Green algae 96-hour EC50 = 76. mg/L
(Estimated)
ECOSAR: neutral organics
EPI
NES; estimated EC50 is greater than
the measured water solubility (0.77
mg/L).
Chronic Aquatic Toxicity
HIGH: Based on an estimated ChV of 0.73 mg/L for daphnid and 0.035 for algae, although there is a high
degree of uncertainty and limited confidence in the estimations.
Fish ChV
Fish ChV = 2.5 mg/L
(Estimated)
ECOSAR: sulfonyl ureas
EPI
NES; estimated ChV is greater than
the measured water solubility (0.77
mg/L).
Fish ChV =14 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
NES; estimated ChV is greater than
the measured water solubility (0.77
mg/L).
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BTUM CASRN 151882-81-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Daphnid ChV
Daphnid ChV = 0.73 mg/L
(Estimated)
ECOSAR: sulfonyl ureas
EPI
There is a high degree of uncertainty
for this estimate since the chemical
may not be soluble enough to measure
this predicted effect; ChV value is
near the water solubility.
Daphnid ChV = 94 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
NES; estimated ChV is greater than
the measured water solubility (0.77
mg/L).
Green Algae ChV
Green algae ChV = 0.035 mg/L
(Estimated)
ECOSAR: sulfonyl ureas
EPI
There is some uncertainty to the
estimated value for this compound
since all chemicals in the training set
for the sulfonyl urea class equation
consists solely of triazine herbicides.
Green algae ChV = 76 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
NES; estimated ChV is greater than
the measured water solubility (0.77
mg/L).
ENVIRONMENTAL FATE
Transport
Evaluation of BTUM transport is based entirely on estimations based on QSARs for fugacity (level III),
disassociation constant (pKa), adsorption coefficient (Koc), volatilization, and vapor pressure. It is expected to
exist in both the neutral and anionic form at environmentally-relevant pH. BTUM is expected to have low
mobility in soil. Anionic BTUM may have higher mobility due to enhanced water solubility. However,
leaching through soil to groundwater is not expected to be an important transport mechanism. In the
atmosphere, BTUM is expected to exist in the particulate phase, which will be deposited back to the soil and
water surfaces through wet or dry deposition.
Henry's Law Constant
(atm-m3/mole)
30,000 (Estimated)
EPI; U.S. EPA, 2011
Cutoff value for non mobile
compounds according to SF
assessment guidance.
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BTUM CASRN 151882-81-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Level III Fugacity
Model
Air = <1%
Water = 2 %
Soil = 72%
Sediment = 26% (Estimated)
EPI
Persistence
HIGH: Evaluation of the persistence of BTUM is based entirely on QSARs of aerobic and anaerobic
biodegradation. Results from these models estimate ultimate biodegradation in months and primary
degradation in weeks. Biodegradation under anaerobic methanogenic conditions is not probable based on
results from estimation models. BTUM does not contain chromophores that absorb light at wavelengths >290
nm. Therefore, it is not expected to be susceptible to direct photolysis. It is not expected to undergo
hydrolysis as it does not contain hydrolysable functional groups. The atmospheric half-life of BTUM is
estimated at 1.2 hours, although it is expected to exist primarily as a particulate in air. Therefore,
biodegradation is expected to be the main degradation pathway for BTUM.
Water
Aerobic
Biodegradation
Weeks (primary survey model);
Recalcitrant (ultimate survey model)
EPI
Volatilization Half-life
for Model River
>1 year (Estimated)
EPI
Volatilization Half-life
for Model Lake
>1 year (Estimated)
EPI
Soil
Aerobic
Biodegradation
No data located.
Anaerobic
Biodegradation
Not probable (anaerobic-methanogenic
biodegradation probability model)
EPI
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
Biodegradation
No data located.
Air
Atmospheric Half-life
1.2 hours (Estimated)
EPI
Reactivity
Photolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain functional
groups that would be expected to
absorb light at environmentally
significant wavelengths.
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BTUM CASRN 151882-81-4
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Hydrolysis
Not a significant fate process (Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain functional
groups that would be expected to
hydrolyze readily under
environmental conditions.
Pyrolysis
No data located.
Environmental Half-life
120 days (Estimated)
EPI; PBT Profiler
Half-life estimated for the
predominant compartment, as
determined by EPI and the PBT
Profiler methodology.
Bioaccumulation
LOW: Based on both the estimated BCF and BAF that are <100.
Fish BCF
25 (Estimated)
EPI
BAF
4 (Estimated)
EPI
Metabolism in Fish
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
Ecological Biomonitoring
No data located.
Human Biomonitoring
This chemical was not included in the NHANES biomonitoring report (CDC, 2011).
4-407
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DRAFT REPORT - DO NOT CITE OR QUOTE
Boethling, R., Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences. Boca Raton:
Lewis Publishers. 2000.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 4.0. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
PBT Profi 1 er Persistent (P),Bioaccumulative (B), and Toxic (T) Chemical (PBT)Profiler, U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
SPARC On Line Calculator pKa property server. Ver 4.5 September, 2009. Available from, http://ibmlc2.chem.uga.edu/spare/
(accessed on August 12, 2010.
U.S. EPA (Environmental Protection Agency). High Production Volume (HPV) Challenge. Determining the Adequacy of Existing
Data. U.S. Environmental Protection Agency: Washington D.C. 1999. http://www.epa.gov/hpv/pubs/general/datadfin.htm
U.S. EPA (Environmental Protection Agency). Sustainable Futures Summary Assessment. Assessment of Discrete Organic
Chemicals. U.S. Environmental Protection Agency: Washington D.C. 2011.
http://www.epa.gov/oppt/sf/pubs/iad_discretes_092011 .pdf
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UU
O N
O
CASRN: 321860-75-7
MW: 784.9
(for representative structure)
MF: C42H36N608S
(for representative structure)
Physical Forms:
Neat: Solid
Use: Developer for thermal paper
SMILES: cl(NC(=0)0c6ccccc6)c(C)cc(NC(=0)Nc2ccc(S(=0)(=0)c3ccc(NC(=0)Nc4c(C)cc(NC(=0)0c5ccccc5)cc4)cc3)cc2)ccl (for representative structure)
Synonyms: Urea Urethane Compound
Polymeric: Yes
Oligomers: A representative structure for the low molecular weight oligomer evaluated in this assessment is drawn above.
Metabolites, Degradates and Transformation Products: None
Analog: Confidential analog
Endpoint(s) using analog values: Eye and skin irritation, respiratory
and skin sensitization, immunotoxicity, neurotoxicity, genotoxicity,
repeated dose
Analog Structure: Not applicable
Structural Alerts: None identified
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 2011).
Risk Assessments: None identified
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UU CASRN 321860-75-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
No data located.
Boiling Point (°C)
>300 (Estimated)
EPI; U.S. EPA, 1999
Estimates were performed on a
representative component of the
polymer shown above. This
representative structure is anticipated
to be the predominant component of
the polymeric mixture. Cutoff value
for high boiling point compounds
according to HPV assessment
guidance.
Vapor Pressure (mm Hg)
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UU CASRN 321860-75-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Log K0„
6.5 (Estimated)
EPI
Estimates were performed on a
representative component of the
polymer shown above. This
representative structure is anticipated
to be the predominant component of
the polymeric mixture.
Flammability (Flash Point)
No data located.
Explosivity
No data located.
pH
No data located.
pKa
10.3 (Estimated)
SPARC
Estimates were performed on a
representative component of the
polymer shown above. This
representative structure is anticipated
to be the predominant component of
the polymeric mixture.
HUMAN HEALTH EFFECTS
Toxicokinetics
UU is not absorbed by skin, poorly absorbed by the lung, and can be absorbed in the gastrointestinal tract.
Dermal Absorption in vitro
No data located.
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal, or Inhaled
No absorption through skin, poor
absorption by lung, and can be absorbed
by the gastrointestinal tract.
Professional judgment
Based on closely related analog with
similar structure, functional groups,
and physical/chemical properties.
Acute Mammalian Toxicity
LOW: No acute mammalian toxicity observed at oral and dermal exposure doses of less than or equal to
2,000 mg/kg.
Acute Lethality
Oral
Rat oral LD0=2,000 mg/kg
(Measured)
Submitted Confidential Study
Adequate.
Dermal
Rat dermal LC0=3161 mg/kg (Measured)
Submitted Confidential Study
Adequate.
Inhalation
No data located.
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UU CASRN 321860-75-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Carcinogenicity
MODERATE: There is uncertainty due to the lack of data located for this substance. Carcinogenic effects
cannot be ruled out.
OncoLogic Results
No data located.
Carcinogenicity (Rat and
Mouse)
No data located.
Combined Chronic
Toxicity/Carcinogenicity
No data located.
Genotoxicity
LOW: UU was negative in bacterial mutagenicity assays and negative for chromosomal aberration in
mammalian cells.
Gene Mutation in vitro
Negative, Ames Assay, with and without
activation (Measured)
Submitted Confidential Study
Adequate.
Negative, E. coli reverse mutation assay,
with and without activation (Measured)
Submitted Confidential Study
Adequate.
Gene Mutation in vivo
No data located.
Chromosomal Aberrations
in vitro
No data located.
Chromosomal Aberrations
in vivo
Negative, chromosomal aberration in
CHL cells, with and without activation
(Measured)
Submitted Confidential Study
Adequate.
DNA Damage and Repair
No data located.
Other (Mitotic Gene
Conversion)
No data located.
Reproductive Effects
LOW: Based on professional judgment. A combination of limited predicted absorption, low predicted
metabolism, and lack of significant toxicological concerns from repeated dose testing on a close analog
suggests low potential hazard, with lower confidence.
Reproduction/
Developmental Toxicity
Screen
Low potential for reproductive effects
(Estimated)
Professional judgment
Estimated based on professional
judgment.
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UU CASRN 321860-75-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Reproduction and Fertility
Effects
No data located.
Developmental Effects
LOW: Based on professional judgment. A combination of limited predicted absorption, low predicted
metabolism, and lack of significant toxicological concerns from repeated dose testing on a close analog
suggests low potential hazard, with lower confidence.
Reproduction/
Developmental Toxicity
Screen
Low potential for developmental effects
(Estimated)
Professional judgment
Estimated based on professional
judgment.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Prenatal Development
No data located.
Postnatal Development
No data located.
Neurotoxicity
LOW: No structural alerts or mechanistic pathways associated with neurotoxic effect identified.
Neurotoxicity Screening
Battery (Adult)
Low potential for neurotoxicity effects
(Estimated)
U.S. EPA, 2010; Professional
judgment
Estimated based on no identified
structural alerts or mechanistic
pathways associated with
neurotoxicity.
Repeated Dose Effects
LOW: There were no repeated dose effects at oral doses <1,000 mg/kg-day.
28-Day repeated-dose study, rat, oral,
gavage, no clinical signs, no macroscopic
or histopathological abnormalities,
NOAEL = 1000 mg/kg-day. (Measured)
Submitted Confidential Study
Adequate.
Skin Sensitization
LOW: Based on closely related confidential analog with similar structure, functional groups, and
physical/chemical properties.
Skin Sensitization
Non-sensitizing, Guinea pigs (Measured)
Submitted Confidential Study
Adequate.
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UU CASRN 321860-75-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Respiratory Sensitization
No data located.
Respiratory Sensitization
No data located.
Eye Irritation
LOW: UU is not an eye irritant.
Eye Irritation
Slight irritation, rabbits (Measured)
Submitted Confidential Study
Adequate.
Dermal Irritation
LOW: UU is not a dermal irritant.
Dermal Irritation
Non-irritating, rabbits (Measured)
Submitted Confidential Study
Adequate.
Endocrine Activity
No data located.
No data located.
Immunotoxicity
No data located.
Immune System Effects
No data located.
ECOTOXICITY
ECOSAR Class
Substituted ureas; Amides; Carbamate esters
Acute Toxicity
LOW: Based on measured 96-hour LCS0for fish and on estimated 96-hour LCS0 for fish, 48-hour LCS0 for
Daphnid, and 96-hour ECS0 for green algae that result in no effects at saturation (NES), as obtained for a
representative component of the polymer that has a MW <1,000.
Fish LC50
Fish 96-hour LC50>250 mg/L (Measured)
Submitted Confidential Study
Adequate
Fish 96-hour LC50 = 0.028 mg/L
(Estimated)
ECOSAR: amides
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
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UU CASRN 321860-75-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Fish 96-hour LC50 = 0.118 mg/L
(Estimated)
ECOSAR: substituted ureas
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Fish 96-hour LC50 = 0.061 mg/L
(Estimated)
ECOSAR: carbamate esters
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Fish 96-hour LC50 = 0.094 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Daphnid LCS0
Daphnid 48-hour LC50 = 0.074 mg/L
(Estimated)
ECOSAR: amides
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Daphnid 48-hour LC50 = 0.088 mg/L
(Estimated)
ECOSAR: substituted ureas
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Daphnid 48-hour LC50 = 0.958 mg/L
(Estimated)
ECOSAR: carbamate esters
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Daphnid 48-hour LC50 = 0.093 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Green Algae ECS0
Green algae 96-hour EC50 = 0.096 mg/L
(Estimated)
ECOSAR: amides
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Green algae 96-hour EC50 = 0.288 mg/L
(Estimated)
ECOSAR: substituted ureas
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Green algae 96-hour EC50 = 0.223
(Estimated)
ECOSAR: carbamate esters
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
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UU CASRN 321860-75-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Green algae 96-hour EC50 = 0.255
(Estimated)
ECOSAR: neutral organics
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Chronic Aquatic Toxicity
LOW: Based on ChV values for fish, Daphnid, and green algae that result in no effects at saturation (NES),
as obtained for a representative component of the polymer that has a MW <1,000.
Fish ChV
Fish ChV = 0.00016 mg/L
(Estimated)
ECOSAR: amides
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Fish ChV = 0.003 mg/L
(Estimated)
ECOSAR: substituted ureas
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Fish ChV = 0.005 mg/L
(Estimated)
ECOSAR: carbamate esters
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Fish ChV = 0.008 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Daphnid ChV
Daphnid ChV = 0.00098 mg/L
(Estimated)
ECOSAR: amides
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Daphnid ChV = 0.019 mg/L
(Estimated)
ECOSAR: substituted ureas
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Daphnid ChV = 0.006 mg/L
(Estimated)
ECOSAR: carbamate esters
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Daphnid ChV = 0.019 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
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UU CASRN 321860-75-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Green Algae ChV
Green algae ChV = 0.046 mg/L
(Estimated)
ECOSAR: substituted ureas
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Green algae ChV =1.31 lmg/L
(Estimated)
ECOSAR: amides
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Green algae ChV = 0.488 mg/L
(Estimated)
ECOSAR: carbamate esters
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
Green algae ChV = 0.210 mg/L
(Estimated)
ECOSAR: neutral organics
EPI
NES; estimates were performed for
the representative component of the
polymer shown above.
ENVIRONMENTAL FATE
Transport
Evaluation of UU transport is based entirely on QSAR estimations that were performed on a representative
component of the polymer that has a MW <1,000. This representative structure is anticipated to be the
predominant component of the polymeric mixture. UU is expected to have low mobility in soil based on its
expected strong absorption to soil. If released to the atmosphere, UU is likely to exist solely as particulate.
As a particulate, atmospheric oxidation is not expected to be a significant route of environmental removal.
Based on the Henry's Law constant, volatilization from water or moist soil is not expected to occur at an
appreciable rate. Level III fugacity models indicate that UU will partition predominantly to the soil and
sediment.
Henry's Law Constant
(atm-m3/mole)
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UU CASRN 321860-75-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Sediment/Soil
Adsorption/Desorption
Coefficient - Koc
>30,000 (Estimated)
EPI
Estimates were performed on a
representative component of the
polymer shown above. This
representative structure is anticipated
to be the predominant component of
the polymeric mixture. Cutoff value
for nonmobile compounds according
to SF assessment guidance.
Level III Fugacity
Model
Air = <1% (Estimated)
Water =1%
Soil = 52%
Sediment = 47%
EPI
Estimates were performed on a
representative component of the
polymer shown above. This
representative structure is anticipated
to be the predominant component of
the polymeric mixture.
Persistence
VERY HIGH: UU is not ready biodegradable based on a Japanese MITI test. Further evaluation of the
persistence of UU is based on predictive QSAR models for the representative component estimates UU to be
recalcitrant to ultimate biodegradation, and suggest a biodegradation half-life of >180 days. In addition, the
larger oligomers in the polymeric mixture with a MW>1,000 are expected to have Very High persistence
potential based on DfE assessment guidance as they are likely too large and too water insoluble to be
bioavailable.
Water
Ready Biodegradability
Not ready biodegradable in Japanese
MITI test (OECD 301C). 1% (by BOD)
and 2% (by HPLC) biodegradation in 28
days. (Measured)
Submitted Confidential Study
Adequate.
Aerobic Biodegradation
Weeks (primary survey model)
Recalcitrant (ultimate survey model))
EPI
Estimates were performed on a
representative component of the
polymer shown above. This
representative structure is anticipated
to be the predominant component of
the polymeric mixture.
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UU CASRN 321860-75-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Volatilization Half-life
for Model River
>1 year (Estimated)
EPI
Estimates were performed on a
representative component of the
polymer shown above. This
representative structure is anticipated
to be the predominant component of
the polymeric mixture.
Volatilization Half-life
for Model Lake
>1 year (Estimated)
EPI
Estimates were performed on a
representative component of the
polymer shown above. This
representative structure is anticipated
to be the predominant component of
the polymeric mixture.
Soil
Aerobic Biodegradation
No data located.
Anaerobic
Biodegradation
No data located.
Soil Biodegradation w/
Product Identification
No data located.
Sediment/Water
Biodegradation
No data located.
Air
Atmospheric Half-life
0.64 hours (Estimated)
EPI
The estimated half-life is for a gas-
phase reaction; UU is expected to
exist as a particulate in the
atmosphere and the rate of this
process will be highly attenuated.
Reactivity
Photolysis
Not a significant fate process
(Estimated)
Boethling and Mackay, 2000;
Professional judgment
Substance does not contain functional
groups that would be expected to
absorb light at environmentally
significant wavelengths.
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UU CASRN 321860-75-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Hydrolysis
42 minutes at pH 8;
7 hours at pH 7 (Estimated)
EPI
Limited confidence in the estimated
half-lives given the limited solubility
anticipated for this material.
Hydrolysis is not expected to occur to
an appreciable extent and UU is
anticipated to lie outside the domain
of this model.
Pyrolysis
No data located.
Environmental Half-life
360 days (Estimated)
EPI; PBT Profiler
Half-life estimated for the
predominant compartment, as
determined by EPI and the PBT
Profiler methodology for the
representative component of the
polymer shown above.
Bioaccumulation
LOW: The measured BCF for UU is <100 (4.6). The estimated BAF for the representative component of the
polymer is <100 (7.9). Although the BCF model results in a higher hazard concern, the BAF model is
anticipated to better account for metabolism for this class of compounds. In addition, the polymeric
components of the mixture that have a MW >1,000 are not expected to be bioaccumulative because, in
general, substances with a MW >1,000 are not bioaccumulative due to their large size.
Fish BCF
0.46-4.6 (Measured)
Submitted Confidential Study
Adequate.
Fish BCF
9,100 (Estimated)
EPI
Estimates were performed on a
representative component of the
polymer shown above. This
representative structure is anticipated
to be the predominant component of
the polymeric mixture.
BAF
7.9 (Estimated)
EPI
Estimates were performed on a
representative component of the
polymer shown above. This
representative structure is anticipated
to be the predominant component of
the polymeric mixture.
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UU CASRN 321860-75-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Metabolism in Fish
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
Ecological Biomonitoring
No data located.
Human Biomonitoring
This chemical was not included in the NHANES biomonitoring report (CDC, 2011).
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Boethling, R., Mackay, D. Handbook of Property Estimation Methods for Chemicals, Environmental Health Sciences. Boca Raton:
Lewis Publishers. 2000.
CDC (Centers for Disease Control and Prevention). Fourth national report on human exposure to environmental chemicals, updated
tables. Department of Health and Human Services. 2011. http://www.cdc.gov/exposurereport/ (accessed on May 10, 2011).
EPI (EPIWIN EPISUITE) Estimations Programs Interface for Windows, Version 4.00. U.S. Environmental Protection Agency:
Washington D.C. http://www.epa.gov/opptintr/exposure/.
ESIS (European chemical Substances Information System) Classification, labeling and Packaging of dangerous substances annex VI
to regulation (EC) No 1272/2008 [Online] http://esis.jrc.ec.europa.eu/ (accessed on June 10, 2011).
PBT Profi 1 er Persistent (P), Bioaccumulative (B), and Toxic (T) Chemical (PBT) Profiler, U.S. Environmental Protection Agency:
Washington D.C. www.pbtprofiler.net.
SPARC On Line Calculator pKaproperty server. Ver 4.5 September, 2009. Available from, http://ibmlc2.chem.uga.edu/sparc/
(accessed on August 12, 2010).
U.S. EPA (Environmental Protection Agency). High Production Volume (HPV) Challenge. Determining the Adequacy of Existing
Data. U.S. Environmental Protection Agency: Washington D.C. 1999. http://www.epa.gov/hpv/pubs/general/datadfin.htm
U.S. EPA Sustainable Futures UsingNonCancer Screening within the Sustainable Futures Initiative Environmental Protection
Agency: Washington D.C. 2010. http://www.epa.gOv/opptintr/sf/pubs/noncan-screen.htm#svstemic (accessed on February 09, 2011).
U.S. EPA (Environmental Protection Agency). Sustainable Futures Summary Assessment. Assessment of Discrete Organic
Chemicals. U.S. Environmental Protection Agency: Washington D.C. 2011.
http://www.epa.gov/oppt/sf/pubs/iad_discretes_092011 .pdf.
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References
FAO/WHO (2011). Toxicological and Health Aspects of Bisphenol A: Report of Joint
F AO/WHO Expert Meeting 2-5 November 2010 and Report of Stakeholder Meeting on
Bisphenol A 1 November 2010. Ottawa.
International Agency for Research on Cancer. (2006). "Preamble to the IARC Monographs."
Retrieved April 17, 2012, from
http://monographs.iarc.fr/ENG/Preamble/currentb6evalrationale0706.php.
Mayo-Bean, K., K. V. Nabholz, et al. (2011). Methodology Document for the Ecological
Structure-Activity Relationship Model (ECOSAR) Class Program. Office of Pollution
Prevention and Toxics. Washington, DC.
Meylan, W. M. and P. H. Howard (1995). "Atom/fragment contribution method for estimating
octanol-water partition coefficients." J Pharm Sci 84(1): 83-92.
Meylan, W. M., P. H. Howard, et al. (1996). "Improved method for estimating water solubility
from octanol/water partition coefficient." Environ Toxicol Chem 15(2): 100-106.
Nabholz, J. V., R. G. Clements, et al. (1993). Validation of Structure Activity Relationships
Used by the USEPA"s Office of Pollution Prevention and Toxics for the Environmental
Hazard Assessment of Industrial Chemcials. Environmental Toxicology and Risk
Assessment. J. W. Gorsuch, F. J. Dwyer, C. G. Ingersoll and T. W. La Point.
Philadelphia, American Society for Testing and Materials. 2: 571-590.
National Toxicology Program-Center for the Evaluation of Risks to Human Reproduction (NTP-
CERHR) (2008). NTP-CERHR Monograph on the Potential Human Reproductive and
Developmental Effects of Bisphenol A. U.S. Department of Health and Human Services.
U.S. Environmental Protection Agency (U.S. EPA) (1994). Joint Project on the Evaluation of
(Quantitative Structure Activity Relationships. Office of Prevention Pesticides and Toxic
Substances. Washington DC, EPA 743R-94-001. .
U.S. Environmental Protection Agency (U.S. EPA) (1997). Special Report on Environmental
Endocrine Disruption: An Effects Assessment and Analysis. R. A. Forum. Washington,
DC.
U.S. Environmental Protection Agency (U.S. EPA) (1999a). Guidelines for Carcinogen Risk
Assessment, Review Draft. Office of Research and Development. CEA-F-0644.
U.S. Environmental Protection Agency (U.S. EPA) (1999b). High Production Volume (HPV)
Challenge: Determining the Adequacy of Existing Data. Office of Pollution Prevention &
Toxics. Washington, DC.
U.S. Environmental Protection Agency (U.S. EPA) (2002). A Review of the Reference Dose and
Reference Concentration Processes. Risk Assessment Forum. December 2002 Final
Report. Washington, DC, EPA. EPA/630/P-02/002F.
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U.S. Environmental Protection Agency (U.S. EPA) (2005a). Guidelines for Carcinogen Risk
Asessment. Risk Assessment Forum. Washington, DC, EPA. EPA/630/P-03/001F.
U.S. Environmental Protection Agency (U.S. EPA) (2005b). Pollution Prevention (P2)
Framework. Office of Pollution Prevention and Toxics. Washington D.C.
U.S. Environmental Protection Agency (U.S. EPA) (2010b). Interpretive Assistance Document
for Assessment of Polymers. Sustainable Futures Summary Assessment. Office of
Pollution Prevention and Toxics. Washington D.C.
U.S. Environmental Protection Agency (U.S. EPA) (2010c). TSCANew Chemicals Program
(NCP) Chemical Categories. Office of Pollution Prevention and Toxics. Washington, DC.
U.S. Environmental Protection Agency (U.S. EPA). (201 lb). "Assay Development." Retrieved
April 17, 2012, from
http://www.epa.gov/oscpmont/oscpendo/pubs/assavvalidation/index.htm.
U.S. Environmental Protection Agency (U.S. EPA) (201 lc). Design for the Environment
Program Alternatives Assessment Criteria for Hazard Evaluation, Version 2.0. Office of
Pollution Prevention & Toxics. Washington D.C.
U.S. Environmental Protection Agency (U.S. EPA) (201 Id). Endocrine Disruptor Screening
Program, Weight-of-Evdence: Evaluating Results of EDSP Tier 1 Screening to Identify
the Need for Tier 2 Testing. Office of Chemical Safety and Pollution Prevention.
Washington, DC.
U.S. Environmental Protection Agency (U.S. EPA). (201 le). "Estimation Program Interface
(EPI) Suite." Retrieved April 18, 2012, from
http://www.epa. gov/oppt/exposure/pub s/epi suite, htm.
U.S. Environmental Protection Agency (U.S. EPA) (201 If). Interpretive Assistance Document
for Assessment of Discrete Organic Chemicals. Sustainable Futures Summary
Assessment. Office of pollution Prevention and Toxics. Washington, DC.
U.S. Environmental Protection Agency (U.S. EPA) (201 lg). On-line AOPWIN™ User's Guide.
U.S. Environmental Protection Agency (U.S. EPA) (201 lh). On-line BCFBAF™ User's Guide.
U.S. Environmental Protection Agency (U.S. EPA) (201 li). On-line KOWWIN™ User's Guide.
U.S. Environmental Protection Agency (U.S. EPA). (2012a). "Analog Identification
Methodology (AIM)." Retrieved April 17, 2012, from
http://www.epa.gov/oppt/sf/tools/aim.htm.
U.S. Environmental Protection Agency (U.S. EPA). (2012b). "Endocrine Disruptor Screening
Program (EDSP)." Retrieved April 17, 2012, from
http ://www. epa. gov/scipol v/oscpendo/index .htm.
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5 General Exposure and Lifecycle Information
The purpose of this chapter is to provide general information on exposure and life-cycle
considerations of thermal paper developers. This discussion will be framed in the context of six
life-cycle stages: manufacture of developers (Section 5.2.1), manufacture of thermal paper
(Section 5.2.2), conversion of thermal paper (Section 5.2.3), use of thermal paper (Section 5.2.4),
end-of-life (Section 5.2.5), and manufacture of recycled paper products (Section 5.2.6), as shown
in Figure 5-1. A quantitative exposure assessment is outside the scope of this project and not
necessary for comparative hazard assessment. Rather, this chapter represents a qualitative review
of potential environmental releases and exposures based on limited information from the
published literature and publicly available sources (Section 5.3). Understanding the factors that
affect exposure to bisphenol A (BPA) and alternative developers across the life-cycle provides
additional context to the alternative selection process. This chapter includes information on the
presence of BPA in people and the environment, which is generally not available for other
chemicals in the assessment. The information on BPA can be considered as a surrogate for the
other developers that have similar physical-chemical properties and behaviors and use patterns.
Manufacture of
Developers
Section 5.2.1
Manufacture of
Thermal Paper
(coat)
Section 5.2.2
Conversion of
Thermal Paper
(add adhesives,
resize, and package)
Use of
Thermal Paper
(receipts, labels,
tickets, etc.)
Section 5.2.4
Manufacture of
Recycled Paper
Products
Section 5.2.6
Figure 5-1: Summary of Life Cycle of Developers in Thermal Paper
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5.1 Potential Exposure Pathways and Routes (General)
Exposure to developers can occur at many points in the life cycle of a thermal paper. There is a
potential for occupational exposures during chemical and product manufacturing and product
end-of-life (i.e., recycling, landfilling, or incineration). Additionally, there may be exposures to
workers and consumers while thermal paper is being used and to the general population and the
environment from releases during product manufacturing, use, and end-of-life.
The risk associated with a given chemical or substance is influenced by how exposure occurs.
For example, exposure associated with inhaling the chemical can be different from exposure via
ingestion, in turn influencing the toxic outcome. As a result, exposure is typically characterized
by different pathways and routes. An exposure pathway is the physical course a chemical takes
from the source of release to the organism that is exposed, whereas the exposure route is how the
chemical gets inside the organism. The three primary routes of exposure are inhalation, dermal
absorption, and ingestion. The physical-chemical properties of the chemical influence the
pathways and routes of exposure.
5.1.1 Inhalation Exposures
The physical state of the chemical during chemical manufacturing, downstream processing,
incorporation into consumer use products, and after release to the environment significantly
influences the potential for inhalation exposure. In particular, there are three types of inhalation
exposures to consider.
Dust: Chemicals that are manufactured, processed, and used as solids have the potential to result
in occupational and consumer exposures to fugitive dusts. The potential for fugitive dust
formation depends on whether the solid chemical is handled in the crystalline form, as an
amorphous solid, or as a fine powder, as well as the particle size distribution and solids handling
techniques. It is important to note the physical state of the chemical at the potential point of
release and contact. The pure chemical may be manufactured as a solid powder, indicating a
potential occupational exposure to dust. However, it may be formulated into solution before
anyone comes in contact with it, thereby eliminating inhalation exposure to dust as a potential
route. If there is exposure to dust, particle size influences the degree to which the chemical enters
the body. Particles less than 10 microns in diameter are "respirable" with potential to reach and
attach to tissues in the respiratory tract and deep lung where they may irritate lung tissue or be
absorbed into the body. Once released into air or other media, the chemical can associate with
particulate material through sorption onto particles or as particulates. For example, vapor phase
chemicals can partition onto house dust and contribute to ingestion and dermal exposure
pathways as well as inhalation.
Vapor: Exposure to vapors can occur when chemicals volatilize during manufacturing,
processing, and use, or are associated with particulates in air. Most chemical manufacturing
operations occur in closed systems. However, fugitive emissions are expected during
manufacturing processes if there are open mixing operations, transfer operations, and
loading/unloading of raw materials. The more volatile the chemical, the greater the fugitive
releases and higher the potential occupational and consumer exposures. Therefore, vapor
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pressure (a measure of volatility) is a key indicator of potential exposures to vapors. Particulate
exposures can result in physical breakdown of products, erosion of materials from surfaces etc.
Mist: Both volatile and non-volatile liquids can result in inhalation exposure if manufacturing
operations or use results in the formation of mist. Droplet size is an important consideration in
determining exposure to chemicals released as a mist; as with dust, mist particles less than 10
microns in diameter are "respirable" with potential to be absorbed in the respiratory tract.
5.1.2 Dermal Exposures
Dermal exposure is also affected by the physical state of the chemical at the point of release and
contact. For example, the likelihood of liquids being splashed or spilled during sampling and
drumming operations is different than for similar operations involving polymerized solids,
powders, or pellets. Dermal exposure is also generally assumed to be proportional to the
concentration of chemical in the formulation. For example, in general the dermal exposure from
contacting a pure chemical is greater than the exposure from contacting a solution that contains
only 10 percent of the chemical (unless the formulation contains penetration enhancers).
Screening-level evaluations of dermal exposure can be based on the worker activities involving
the chemical, and consumer uses and contact. For example, there may be significant exposure
when workers handle bags of solid materials during loading and transfer operations.
Maintenance and cleanup activities during shutdown procedures, connecting transfer lines, and
sampling activities also result in potential for dermal exposures. In the case of thermal paper,
workers may be exposed to high concentrations of developer while changing cash register receipt
rolls or cleaning machines. Consumer exposure from dermal contact will be dependent upon the
amount and availability of the chemical in the product.
5.1.3 Ingestion Exposures
Exposures via ingestion typically occur when individuals eat food or drink water that has become
contaminated with chemicals. Dust particles may spread throughout the facility and settle (or
deposit) on tables, on lunchroom surfaces, or even on food itself. Vapors may similarly spread
throughout the facility and may be adsorbed onto food or particles in drinking water or dissolved
in the drinking water. Another potential pathway for ingestion occurs from dust particles that are
too large to be absorbed through the lungs. These "non-respirable particles" are often swallowed,
resulting in exposures from this route. Children and others can be exposed by transfer from dust
or other media to hands to mouth. Compared to inhalation and dermal exposures, ingestion is
typically considered a less significant exposure pathway from an occupational and consumer
health standpoint. However, ingestion is often an equally or more significant exposure route for
the general population, and especially for children that ingest house dust, than inhalation and
dermal exposure, as described in the next section.
5.1.4 Environmental and General Population Exposures
Releases to the environment can result in contamination of environmental media, leading to
exposures in the general population and environmental organisms. In general, exposure
concentrations may be lower, but they may be most widespread and may occur over a lifetime.
Wildlife may be impacted by direct contact with contaminated media. If the chemical is
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bioaccumulative, it may concentrate in the animal and reach higher trophic levels and people
through the food chain. Food contamination can also come from contaminants in biosolids
derived from wastewater treatment plants (WWTP) that are applied to agricultural fields, or the
ingestion of contaminated feed by livestock.
Direct human contact with contaminated environmental media, such as soil, sediment, house
dust, and surface water, can lead to dermal exposure and incidental ingestion. Contact with
contaminated drinking water can result in dermal and inhalation exposures, via washing and
showering, as well as ingestion through consumption.
Products used in the home can lead to exposures in the general population. Chemicals can
volatilize from products and become incorporated into indoor air, or dust in the home, office, car,
or other locations where products are used. Inhalation of contaminants in air, dermal contact with
contaminated surfaces and dust, and incidental ingestion of dust or hand-to-mouth contact are all
viable exposure pathways in the home. The physical properties of the chemical, along with how
the chemical is incorporated into the product, influence how much of a chemical will enter the
dust in a consumer's environment. A person who does not have direct contact with products
containing a particular chemical still has the potential to be exposed to them once the chemical is
released.
5.1.5 Exposures to Susceptible Populations
Individuals within a population can vary with respect to susceptibility and exposure. Variability
can be characterized but not reduced, and therefore it can be helpful to consider potentially
exposed susceptible populations when considering chemical alternatives. Genetics, gender,
lifestage, pregnancy status, lifestyle, predisposition to diseases and other medical conditions, and
other chemical exposures are examples of factors that lead to differential susceptibility (National
Academy of Sciences 2008).
For example, children may be more susceptible to environmental exposures than adults because:
Their bodily systems are still developing;
They eat more, drink more, and breathe more in proportion to their body size;
Their behavior can expose them more to chemicals and organisms, for example, hand-to-
mouth and object-to-mouth behaviors (Xue, Zartarian et al. 2007); and
They may be exposed to chemicals, including BP A, in human milk (Landrigan,
Sonawane et al. 2002) and infant formula (Cao, Dufresne et al. 2008).
Prenatal development represents a potential window of susceptibility whereby exposures to
chemicals in the environment can contribute to adverse pregnancy and developmental outcomes
(Stillerman 2008). During prenatal development, biological systems are forming, and disruption
of these processes can have consequences later in life. While the placenta is designed to protect
the fetus from stressors, including chemical exposures, chemicals (including BP A) have been
shown to pass through this organ resulting in prenatal exposures (Perera, Rauh et al. 2003;
Myren, Mose et al. 2006).
Potential perinatal and childhood exposures to thermal paper chemicals can occur via exposure
pathways that are unique to, or more common during early life, including:
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• Maternal consumer and occupational exposures resulting in exposures to the fetus;
• Maternal consumer and occupational exposures resulting in ingestion via human milk;
• Transfer of thermal paper chemicals on hands to mouth; and
• Mouthing of thermal paper (chew and/or swallow).
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5.1.6 Physical-Chemical Properties for the Alternatives to BPA included in this Assessment that May Impact Exposure
CASRN
Chemical Name
Common
Name
Molecular
Formula
Structure
MW
&
p
p
ffl
•¦Ti
r-i
(§)
I ^
Ph
>
0
S5 ^
J |
& ?
ai £
ffi s
|
CJ)
O
i—1
80-05-7
2,2-bis(p-
hy d r oxy p henyl)pr op a ne
Bisphenol A
C15H16O2
rO~OH
228.29
9.59-11.30
55
60.5
3.99 10"8
120-300
<1 10"8a
3.32
620-92-8
Bis(4-
hydroxyphenyl)methane
Bisphenol F
C13H12O2
OH
200.24
7.55
162.5
sub
3.73 10"7 a
190a
<1 10 s a
2.91
79-97-0
2,2'-Bis(4-hydroxy-3-
methyIphenyl)propane
Bisphenol C
C17H20O2
HO—^ —
256.35
10.5a
138-140
368b
2.3 10"6 b
4.7a
<1 10 s a
4.7
5129-00-0
Methyl bis(4-
hy d r o xy pheny l)a cetate
MBHA
C15H14O4
JC
°v,°N
nX
258.28
9.7-9.9
ND
>300a
3.3 10"8a
360a
<1 10 s a
2.8a
24038-68-4
4,4'-Isopropyllidenebis(2-
phenylpheno)
BisOPP-A
C27H24O2
380.49
10.8-10.9a
118
>300a
<1 10"8 a
0.01 la
<1 l(TSa
7.2a
1571-75-1
4,4' (1-
Phe nylethy lide ne) b is p he nol
Bisphenol AP
C20H18O2
C
O0H
)
290.36
9.91-10.1
189
>300a
<1 10"8 a
l.la
<1 l(TSa
4.9a
PROPRIETARY
PROPRIETARY
Substituted
phenolic
compound #1
4.7, 10a
171-172
>300a
<1 10"8a
180a
<1 10"8a
3.4a
PROPRIETARY
PROPRIETARY
Substituted
phenolic
compound #2
10a
135-139
>300a
<1 10"8a
0.12a
<1 10"8a
6.3a
94-18-8
Benzyl 4-hydroxybenzoate
PHBB
Ci4H1203
J
0
228.25
7.8a
111-112
>300a
3.8 10-6
60
2.9 10"10a
3.56
80-09-1
4-Hydr oxy phenyl sulfone
Bisphenol S
Ci2H10O4S
250.27
8
240.5
>300a
<1 10"8a
l.lxlO'3
<1 10"8a
1.2
5397.34.2
2,4'-
Bis (hydr oxy p he nyl)s ulfo ne
2,4-BPS
c12h10o4s
f
0 0 PH
\\//
250.3
7.6, 8.2a
184
>300a
<1 10"8a
1.7xl03a
<1 10"8a
1.7a
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CASRN
Chemical Name
Common
Name
Molecular
Formula
Structure
MW
&
p
p
ffl
•¦Ti
r-i
®
CJ) ^
I ^
>
^CJ)
0
iT
J |
& £
aj £
ffi s
|
CJ)
0
1—1
41481-66-7
bis-(3-aIIyl-4-hydroxyphenyl)
sulfone
TGSA
c18h18o4s
O
ho—P y— s—^ ff~OH
330.40
8.3-8.5a
151-155
dec
9 2 iir10
4.79
8 10"8"
3.22
/—\ 0 /—<.
97042-18-7
Phenol,4-[[4-(2-propen-l-
y lo xy)p heny 1] s u 1 fo nyl ]-
BPS-MAE
C15H14O4S
HO—^ \— S—O
° " H
290.34
8.20a
172
>300a
<1 1IT8"
83a
<1 1IT8"
3.1
63134-33-8
4-Hydroxy-4'-
be nzy lo xy dip heny Is ul fone
BPS-MPE
c19h16o4s
340.40
8.2
170°
>300a
<1 10"8"
10a
<1 10"8"
3.9
95235-30-6
4-hydroxyphenyl 4-
isoprooxyphenylsulfone
D-8
c15h16o4s
292.35
8.2a
129
>300a
<1 10"8"
21
<1 10"8"
3.1a
191680-83-8
4-[4,-[(l,-methylethyloxy)
phenyljsulfo nyl] phenol
D-90
C28H2609S2
(n=l);
C44H42014S3
(n = 2)
.
570.6;
891.00
6.9-7.5a
ND
>300a
<1 10"8"
0.54a;
<1 xlO'3 a
<1 10"8"
3.8a;
5.9a
93589-69-6
l,7-bis(4-
Hydroxyphenylthio)-3,5-
dioxaheptane
DD-70
C17H20O4S2
352.5
9.6a
108
>300a
<1 10"8"
130a
<1 10"8"
3.4a
232938-43-1
N-(p-T oluenesulfonyl)-N'-(3-
P-
toIuenesulfonyloxyphenyl)ure
a
Pergafast 201
C2iH2oN206S
2
w ° hl\
460.5
12.5; 5.3;
-3.8;
-13.6a
157.7
250
(dec)
<1 10"8"
35
<1 10"8"
2.6
151882-81-4
4,4' -bis(iV-car ba moy 1 -4-
methylbenzenesulfonamide)d
iphenylmethane
BTUM
C29H28N406S
2
0 0 0 0 0 0
--V' n jy j u a x^
592.70
4.8-5.4a
154-156
>300a
<1 1IT8"
0.77
<1 1IT8"
2.61
321860-75-7
Urea Urethane Compound
UU
C42H36N608S
u p _ 00 CH,
0.1 fx ° x y ijx ° 0,i f)
784.9d
10.3
ND
>300a
<1 1IT8"
<1 xlO'3
<1 1IT8"
6.5a
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5.2 Potential Sources of Exposure in the Life-cycle of Thermal Paper
This section addresses potential releases and exposures throughout the life-cycle of thermal
paper. Exposure pathways can be extremely complex. For example, the release of a chemical to
the environment during manufacture and use could potentially lead to environmental
contamination. The entry of chemicals into the environment may then lead to exposure of the
general population to substances through the consumption of contaminated drinking water,
contact with contaminated environmental media (e.g., soil, house dust, sediment, water), and/or
the consumption of contaminated food. This section is not intended to be a comprehensive
exposure assessment but instead is designed to offer readers a general overview of potential
sources of exposure throughout the life-cycle of thermal paper.
5.2.1 Manufacture of Developers
This section addresses potential exposure scenarios associated with the manufacture of BP A and
alternative developers. Unit operations, operating conditions, transfer procedures, and packaging
operations vary with the manufacture of different developers. Potential releases and occupational
exposures will depend on each of these parameters. While it is outside the scope of this report to
identify and quantify the releases and exposures associated with individual chemicals, this
section presents a general description of typical chemical manufacturing processes and identifies
potential releases.
Throughout the chemical manufacturing process, there are several release points that may pose
an exposure risk to workers including packaging operations, leaks from pumps and tanks,
fugitive emissions from equipment, cleaning of process equipment, and product sampling
activities. Additionally, crude or finished products are often stored on-site in drums, day-tanks,
or more permanent storage vessels until the chemical is packaged and shipped to next user.
Transfer and packaging operations, as well as any routine and unplanned maintenance activities,
and spills or accidents may result in releases of chemicals to environmental media leading to
general population exposures.
Potential release points from manufacturing and formulating can include:
• Transfer and packaging operations involving handling a chemical product;
• Routine and unplanned maintenance activities;
• Leaks from pumps and pipelines;
• Fugitive emissions from equipment;
• Product sampling;
• Transport and cleaning or equipment and storage vessels; and
• Accidental releases.
BPA is present in the environment as a result of direct releases from manufacturing or processing
facilities (U.S. EPA 2010a). BPA may also be present in the environment as a result of fugitive
emissions during processing and handling, or a release of unreacted monomer from products
(NTP-CERHR 2008). Workers may be exposed to BPA by inhalation or skin contact during the
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manufacture of BP A and BPA-containing products. A worst-case potential inhalation exposure
to BPA during manufacturing is estimated at 100 (J,g/kg body weight/day (NTP-CERHR 2008).
The general population may be exposed to BPA through the contamination of drinking water, or
contact with contaminated environmental media. Alternative chemicals with similar physical-
chemical properties are likely to result in similar exposure and release pathways.
5.2.2 Manufacture of Thermal Paper
A general manufacturing process for paper, in six major steps, is depicted in Figure 5-2 below
(Evergreen Packaging 2011).
Figure 5-2 The Overall Paper Production Process
1
2
3
4
5
6
Pulp Manufacturing
—~
Oxygen
Delignification
—~
Paper
Manufacturing
—*
Paper Pressing
—~
Paper Drv>ng
—~
Paper Winding
• The first step of the paper manufacturing process involves the generation of pulp. To
accomplish this, wood chips and cooking liquor are mixed in a digester and heated. The
wood chips are then expelled through the high-pressure digester, which breaks them up
into individual fibers, or pulp.
• The oxygen delignification step next removes 40 to 50 percent of the lignin that remains
in the pulp. The pulp is washed and bleached, which aids in the removal of the pulp"s raw
brown color.
• A large volume of water is then added in order to manufacture the paper. A slurry is
created, with a pulp to water ratio of about 1 to 99. The slurry is moved on a moving wire
mesh to form a uniform sheet. As the wet sheet travels along the wire, water drains
through the wire mesh.
• This wet sheet is then moved onto a moving belt of felt where the sheet is pressed and
squeezed in sections to compact the fibers.
• Once the fibers have been pressed, the sheet is moved onto dryer felts that pass over a
series of heating rollers. Nine-five percent of the water is removed, leaving a small
percentage of moisture to prevent cracking.
• Lastly, in the paper winding process, the paper is wound onto large reels, which are then
cut into smaller rolls for convenient shipping and packaging.
The manufacture of thermal paper follows the same general manufacturing process as for non-
specialty paper, with a few extra steps to incorporate additives in the formulation. The
manufacturing process for thermal paper is shown below in Figure 5-3.
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A release liner is added to the pulp prior to the coalescing of the thermal paper"s multiple layers.
This liner contains a release agent that provides a release effect against any type of sticky
material. The various formulated layers (see Section 3.1), which contain the key additives in
thermal paper (see Section 3.1.2), are pressed or calendered together between metal cylinders
called calendars; this renders the paper"s surface smooth. This step also defines the paper"s
texture: matte or glossy. The paper is then wound, bound, and shipped to product stores (see
Section 5.2.3 for further details on the conversion process) (Torraspapel 2008).
Figure 5-3: The Production Process for Thermal Paper
Reference: (Torraspapel 2008)
Potential release points from paper manufacturing can include:
• Addition and handling of chemicals,
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• Fugitive emissions from equipment, and
• Wastewater discharges.
The amount of thermal paper manufactured in Europe in 2005 - 2006 was approximately 370
million pounds of paper or an area of approximately 2.9 billion square yards (JRC-IHCP 2010).
This accounts for 4.2 million pounds of BPA. Similar statistics are not available for manufacture
of thermal paper in the United States or for the amounts of alternatives used in thermal paper.
Very little information exists regarding releases of BPA, or alternative developers, by paper
manufacturers in the United States. BPA is listed under section 313 of the Emergency Planning
and Community Right-to-Know Act (EPCRA) of 1986. Under EPCRA, facilities with more than
10 employees, subject to Toxics Release Inventory (TRI) reporting requirements, that are
manufacturing or processing more than 25,000 pounds of a listed chemical within a calendar
year, or are using more than 10,000 pounds of a listed chemical within a calendar year, must
report releases and transfers to the U.S. Environmental Protection Agency (EPA). None of the
alternatives are TRI-listed chemicals. A review of TRI reporting for 2009 for BPA by paper
companies (North America Industry Classification System (NAICS) Code 322) indicates two
companies reporting: one that reported releases of 60 pounds for fugitive emissions, and another
that reported total off-site transfers of 14,796 pounds (4,829 pounds transferred to treatment;
9,967 pounds transferred to a wastewater treatment facility) (U.S. EPA 201 lj).
5.2.3 Conversion of Thermal Paper
Once thermal paper is manufactured, it is then sent to a facility where it is converted into a
specific paper application. During this conversion process, thermal paper is wound onto large
rolls. If the paper is to be used for label applications, such as shipping labels or labels for deli
food packaging, adhesives may be applied to the paper. (See Section 2.2 for additional
applications of thermal paper.) The thermal paper is then cut into smaller rolls, packaged, and
sent to product stores (Torraspapel 2008).
Potential release points from converting thermal paper can include:
• Addition or handling of chemicals, such as adhesives applied to labels,
• Cutting and packaging operations, and
• Fugitive emissions from equipment.
Up to ten percent of thermal paper from European manufacturers, which manufacture an
estimated three millions pounds of thermal paper annually (JRC-IHCP 2010), is removed during
manufacturing as trimmings. This waste material, known as "broke," is immediately sent to a
recycling facility. Similar statistics are not available for U.S. thermal paper conversion industry.
5.2.4 Use of Thermal Paper
Thermal paper is used in a variety of applications. Most commonly this includes point-of-sale
receipts, but it may also include tickets, labels, and medical applications. In its finished form,
thermal paper may release chemicals, including developers such as BPA, via dermal contact.
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While thermal paper does not account for a large percentage of the production volume of BP A,
unlike most applications, BPA in thermal paper is a free monomer and is not chemically bound;
thus, it is expected that the free BPA in this use would be more readily available to humans and
the environment (Zalko, Jacques et al. 2011). Studies show that BPA is transferred from thermal
receipt paper to currency when they come in contact, suggesting thermal receipt paper is an
important source of BPA in paper currency (Schreder 2010; Liao and Kannan 201 la). Braun,
Kalkbrenner et al. (2011) found that, by occupation, cashiers had the highest relative BPA
concentrations in their blood.
5.2.5 End-of-Life
After use, thermal paper has several end-of-life possibilities, including recycling, landfilling, and
incineration, as well as abandonment. Limited information is available on the fate of BPA in
thermal paper during end-of-life processes. No information is available on the other thermal
paper developers. The European Union Risk Assessment Report for BPA included an analysis of
thermal paper recycling and disposal practices that estimated that approximately 4 million
pounds of BPA was used to produce thermal paper in 2005-2006, with 1.5 million pounds of
BPA reaching paper recycling sites each year (JRC-IHCP 2010). In the EU, about 10 percent of
thermal paper is sent for recycling when trimmed with an additional 30 percent from commercial
uses and consumer uses eventually ending up in the paper recycling stream (JRC-IHCP 2010).
According to the European Union (EU) report, BPA releases from paper recycling plants can
vary greatly based on capacity and process differences, such as the de-inking and pulping
processes, and the level of wastewater treatment. There is also some evidence from Europe that
BPA is entering recycled paper streams, including consumer paper products such as towels and
tissue paper (Vinggaard, Korner et al. 2000). It is expected that disposal practices in the EU
differ from the United States because recycling and incineration are much more common in the
EU. Information on U.S. practices is not available but it is likely that recycled paper in the U.S.
also contains BPA.
The concentration of BPA in paper processing wastewater effluent depends on the recycled
paper treated. The concentration of BPA in the final effluent of 20 recycling facilities in Japan
ranged from 0.2 to 370 [j,g/L (average of 59 (J,g/L) (Fukazawa, Watanabe et al. 2002). Effluents
from facilities where only pulp was processed contained lower BPA concentrations.
Chlorinated BPA byproducts may be formed in secondary paper mills that use recycled paper
feedstock containing thermal paper with BPA. BPA contaminants from recycled thermal paper
can react with low concentrations of chlorine and sodium hypochlorite, which is added as a
bleaching agent, yielding poly-chlorinated derivatives of BPA (Fukazawa, Watanabe et al.
2002). Chlorinated derivatives of BPA were detected at concentrations ranging from trace to 2.0
[j,g/L. Estrogenic activities of chlorinated derivatives of BPA were found to be relatively more
potent than BPA, based on the yeast two-hybrid system assay (Fukazawa, Watanabe et al. 2002).
Post-use thermal paper that is sent to a landfill can contribute to leachate (i.e., the mixture of
rainwater and contaminants within the waste). This leachate has the potential to seep into the
ground or drain into nearby surface water, transporting chemicals where humans and wildlife
might be exposed to them. For example, there is concern that free monomeric BPA can leach out
of thermal paper and contaminate landfill leachate. Gehring et al. (2004) concluded that
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continuous emissions of BP A from leachate from landfills receiving significant amounts of
wastepaper can occur under anaerobic conditions. Although no data are available, the same
concern would exist for alternatives to BPA depending on their suitability to anaerobic
degradation and transport processes.
5.2.6 Manufacture of Recycled Paper Products
Several researchers have analyzed the BPA content in recycled paper products. Gehring et al.
examined various sources of recycled paper collected in the city of Dresden, Germany (2004).
Samples included toilet paper, imported cellulose, and various types of post-use paper stock
including brown/grey corrugated board, advertising supplements, magazines, catalogues,
newspapers, free advertising papers, and chromo board. Of the types of recycled products
analyzed, Gehring et al. found the most significant levels of BPA in toilet paper. The amount of
BPA in toilet paper derived from recycled paper varied greatly, ranging from 3.2 to 41.1 mg/kg
dry matter (2004). Gehring et al. also demonstrated that BPA in toilet paper also results in
significant emission of the chemical into domestic wastewater, contributing about 36,000 pounds
of BPA to wastewater annually (2004).
Other sources of BPA in recycled paper products include paper and paperboard commonly used
for food packaging. These products are often adapted to directly contact foodstuff. According to
a study conducted by Ozaki et al. (2004), 67 percent of the recycled paper analyzed contained
BPA (0.19-26 (J,g/g) (2004). BPA was also detected in virgin paper products however, its
concentrations were ten-fold higher in recycled paper products (Ozaki, Yamaguchi et al. 2004).
Similarly, Vinggaard et al. (2000) analyzed BPA levels in 20 different brands of paper towels
sold in retail shops in Denmark. Results indicated that paper towels manufactured from recycled
paper contained 0.6 to 24 mg/kg of BPA whereas extracts from virgin paper contained negligible
levels. Although no data are available, it is likely that alternatives to BPA would also be present
in recycled paper products.
5.3 Available Data on Occupational, Consumer, and Environmental Exposures to BPA,
Thermal Paper Lifecycle
A quantitative exposure assessment is outside the scope of this project and not necessary for
comparative hazard assessment. However, this section presents information on the levels of
human and environmental exposures to developers in thermal paper that have already been
published in the literature. Most published studies pertain to BPA but chemicals with similar
physical-chemical and environmental properties can be expected to behave similarly.
5.3.1 BPA in Receipts
As discussed in Chapter 2, BPA is widely used as a developer in thermal paper, including
receipts. Several studies evaluated the presence of BPA in thermal paper, noting that alternatives
to BPA are currently on the market. In one study, BPA was detected at levels up to 2.2 percent of
the total weight in 11 of the 22 point-of-sale receipts sampled, but half of the receipts were BPA-
free (Biedermann, Tschudin et al. 2010). Mendum et al. (2011) likewise found BPA in 8 of 10
receipts tested with levels ranging from 0.3-1.54 percent of the total weight.
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The Environmental Working Group (EWG) conducted a similar study to determine BPA levels
in cash register receipts. Of the 36 receipts tested, 16 contained BPA in levels from 0.8 percent to
2.8 percent (Lunder, Andrews et al. 2010). The Washington Toxics Coalition found BPA in 11
of the 22 receipts it tested (Schreder 2010). The study also found BPA in 21 of the 22 dollar bills
it tested, concluding that BPA travels from receipts to other objects.
Liao and Kannan studied levels of BPA in paper currency from 21 countries (201 la). BPA was
found in all paper currencies analyzed at concentrations ranging from 0.001 to 82.7 |ig/g (equal
to 0.000001 to 0.0827 mg/g). They also found that concentrations of BPA increased after 24
hours of contact with thermal paper, which suggests that thermal paper is a major source of BPA
in paper currency bills. Liao and Kannan conducted a similar study that found BPA in 94 percent
of receipts tested at a geometric mean level of 0.211 mg/g (Liao and Kannan 201 lb). Other paper
products tested, such as napkins and toilet paper made from recycled paper, contained BPA at
microgram-per-gram concentrations, and the authors concluded that contamination during the
paper recycling process is a source of BPA in paper products.
5.3.2 BPS in Receipts
Liao, Liu et al. (2012b) also evaluated levels of BPS in 16 types of paper and paper products and
paper currency from 21 countries. BPS was found in all thermal receipt paper samples at
concentrations ranging from 0.0000138 to 22.0 mg/g. BPS was detected in 14 other types of
paper products, such as napkins and toilet paper, at concentrations ranging from the level of
quantitation to 0.00838 mg/g. BPS was found in 87% paper currencies analyzed at
concentrations ranging from the limit of quantitation to 0.00626 mg/g.
5.3.3 BPA Transfer to Skin and Potential for Dermal Absorption
Releases of free BPA monomers in thermal paper can occur upon contact with the paper and can
be subsequently absorbed into the skin, leading to exposure during handling and use. Several
studies have analyzed such releases of BPA, particularly in point-of-sale receipts. Biedermann et
al. (2010) demonstrated that BPA can be extracted from the receipts and has the potential to be
absorbed in the skin upon contact; 2 hours after contact, about 0.17 [j,g (equal to 0.00017 mg)
BPA migrated into the skin, such that it could not be recovered by washing with water.
Zalko, Jacques et al. (2011) demonstrated that BPA can penetrate the skin under experimental
conditions. Applying BPA to pig and human explants demonstrated that only two percent of the
BPA remained on the skin surface; nearly half of the chemical passed completely through the
skin and the rest persisted in the skin after 72 hours. There is also evidence that enzymes located
in the skin glucuronidate BPA (Zalko, Jacques et al. 2011), a mechanism that facilitates
elimination.
5.3.4 Occupational Exposure
Occupational exposures may occur during the manufacture of developers, the manufacture of
thermal paper, or the handling of thermal paper. There is limited information on worker
exposures to BPA during chemical manufacture. A series of studies conducted by Li and
colleagues suggests a relationship between exposure to BPA and reproductive and
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developmental effects in Chinese workers in the BPA and epoxy manufacturing industry (Li,
Zhou et al. 2010; Li, Zhou et al. 2011; Miao, Yuan et al. 2011); however, similar studies are not
available for U.S. manufacturers of BPA. To our knowledge, there are no studies examining
BPA exposures in thermal paper manufacturing.
Occupational exposure to BPA may come from handling receipts. Biedermann et al. (2010)
estimated that repeated handling of thermal paper containing BPA could result in transfer of up
to 71[j,g/day (equal to 0.071 mg/day), which is well below 3000 (j,g/day (equal to 3 mg/day), a
value derived by Biederman et al from the present total daily intake (TDI) 0 of 0.050 mg/kg
bw/day, assuming 60 kg body weight. Liao and Kannan estimated that mean daily intake of BPA
through dermal absorption in adults handling thermal paper was 921 ng/day (equal to 0.000921
mg/day) for occupationally exposed individuals (201 lb), significantly lower than the estimates
of Biederman et al. The cumulative occupational exposure from handling a variety of thermal
paper products was estimated to be 1303 ng/day (equal to 0.001303 mg/day) (Liao and Kannan
201 lb). Liao and Kannan (201 la) also estimated that the mean daily intake of BPA from
handling U.S. paper currency to be 1.02 ng/day (equal to 0.00000102 mg/day) for occupationally
exposed individuals in the United States.
In one U.S. study pregnant women who worked as cashiers, who presumably had frequent
contact with thermal paper used in cash register receipts, had the highest urinary BPA
concentrations at 2.8 |ig/g (equal to 0.0028 mg/g) compared with pregnant women in other
occupations, including 1.8 |ig/g (equal to 0.0018 mg/g) in teachers and 1.2 |ig/g (equal to 0.0012
mg/g) in industrial workers (Braun, Kalkbrenner et al. 2011).
To date, one study has estimated the mean daily intake of BPS from handling paper products and
currency. Liao, Liu et al. (2012b) estimated that mean daily intake of BPS through dermal
absorption in adults handling paper products and paper currency was 789 ng/day (equal to
0.000789 mg/day) for occupationally exposed individuals.
5.3.5 Consumer and General Population Exposure
Several studies have estimated consumer and/or general population exposures. This section
provides an overview of this research. Based on BPA concentrations in thermal paper, the
Washington Toxics Coalition estimated that an average shopper would transfer approximately 30
jag (equal to 0.030 mg) of BPA to the skin by rubbing a receipt (five times between two fingers
and a thumb) (Schreder 2010). Liao and Kannan (201 lb) estimated that the mean daily intake of
BPA, via handling of thermal paper to be 12.3 ng/day (equal to 0.0000123 mg/day) for the
general population (201 lb). Liao and Kannan (201 la) also estimated that the mean daily intake
of BPA from handling paper currency to be 0.102 ng/day (equal to 0.000000102 mg/day) for the
general population in the United States.
111 TDI is a protective estimate of the amount of a chemical substance humans can be exposed to daily basis over the
course of a lifetime without experiencing significant health risk. The TDI value set by the European Food Safety
Authority (EFS A) for BPA is 0.05 mg/kg bw. More information about EFS A and BPA can be found at:
http://www.efsa.europa.eu/en/topics/topic/bisphenol.htm.
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Although BPA exposure from dietary sources is estimated to be much greater, thermal paper
accounted for more than 98 percent of the exposure from paper products, mainly because thermal
receipt papers contain relatively high concentrations of BPA (Liao and Kannan 201 lb). BPA is
also used in numerous other applications with which consumers and the general public come into
contact on a regular basis contributing to exposure. Measured levels of urinary BPA reflect these
complex exposure patterns.
The Centers for Disease Control (CDC) reported that 95 percent of a sample size of 294
Americans had detectable levels of BPA in their urine (Calafat, Ye et al. 2008). The median
concentration of BPA in urine across all ages was found to be 2.7 ng/mL (equal to 0.0000027
mg/mL) (uncorrected for creatinine) (Calafat, Ye et al. 2008). Based on currently available
exposure data, BPA exposures appear to be higher in infants and children (NTP-CERHR 2008).
Two studies evaluating exposure in children based on the National Health and Nutrition
Examination Survey indicate that children ages 6-11 have higher exposures relative to adults
(LaKind and Naiman 2008; LaKind and Naiman 2011).
Subsequent studies have sought to clarify sources of BPA exposures in children. In one recent
study, Morgan, Jones et al. (2011) quantified urinary total BPA in 81 Ohio preschool children
ages 23-64 months over 48-hours. This study found the BPA intake through diet correlated with
urinary excretion, suggesting that diet is the predominant source. The study authors estimated
mean intake of 156. 5 ng/kg/day (equal to 0.0001565 mg/kg/day) through dietary ingestion, and
0.11 ng/kg/day (equal to 0.00000011 mg/kg/day) through non-dietary ingestion. The data were in
agreement with an earlier study in which dietary ingestion through the consumption of both solid
and liquid foods was shown to be the major route of exposure for 257 preschool children to BPA
at their homes and daycare centers in North Carolina and Ohio (Wilson, Chuang et al. 2007).
BPA is also found in breast milk; in a study of 23 healthy women, all breast milk samples
registered positive for BPA (Sun, Irie et al. 2004). Additionally, the presence of BPA has been
documented in human amniotic fluid (Ikezuki, Tsutsumi et al. 2002), although there is
controversy regarding the ability of the fetus to metabolize BPA (Nishikawa, Iwano et al. 2010;
Doerge, Twaddle et al. 2011), which would influence the concentration of free and
glucuronidated BPA in this compartment.
To date, one study has estimated the mean daily intake of BPS from handling paper products and
currency. Liao, Liu et al. (2012b) estimated that mean daily intake of BPS through dermal
absorption in adults handling paper products and paper currency was 12.0 ng/day (equal to
0.000012 mg/day) for the general population. The results of this study suggest that other
alternatives with similar physical-chemical properties and behavior would also transfer from the
surface of thermal paper at least to the surface of skin, and potentially be absorbed through the
skin or ingested.
Another study reported exposure to bisphenol S based on urinary measurements (Liao, Liu et al.
2012a). BPS was detected in 81% of the urine samples collected from 315 individuals in eight
countries. The mean value in the US was reported as 0.299 ng/ml (equal to 0.000000299
mg/day). Using a pharmokinetic model, the authors estimated that the median estimated daily
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intake of BPS associated with these urinary values is 0.316 |ig/person (equal to 0.000316
mg/person).
5.3.6 Environmental Exposure
As noted above, there are releases and transfers of BP A from the paper sector that are reportable
to TRI. The relationship between these releases and transfers and environmental concentrations
is not known. There are several studies on concentrations of BP A in the environment (Klecka,
Staples et al. 2009). BPA is present in the environment as a result of direct releases and fugitive
emissions from manufacturing or processing facilities (U.S. EPA 201 la). In addition, based on
information from European and Japanese studies, the use of monomelic BPA in thermal paper
also may contribute to environmental releases of BPA from paper manufacturing and recycling
plants and to the presence of BPA in the stream of recycled paper used in toilet paper, paper
tableware, and other products, and may contribute to the presence of BPA in landfills because
paper products are a major contributor to the U.S. solid waste stream (JRC-IHCP 2010;
Vinggaard, Korner et al. 2000; Fukazawa, Hoshino et al. 2001; Gehring, Vogel et al. 2004;
Ozaki, Yamaguchi et al. 2004; Terasaki, Shiraishi et al. 2007). Liao and Kannan estimated that
between 33.5 tons (based on the median concentration of BPA in thermal paper) and 1040 tons
(based on the 95th percentile) are released into the environment in the United States and Canada
through the disposal of thermal receipt papers (201 lb). The following paragraphs provide a brief
overview of some of the available studies of BPA in environmental media.
Surface Water: Most environmental monitoring results show that the concentrations of BPA in
surface water bodies are lower than 1 |ig/L (ppb), mainly due to its partitioning and
biodegradability (Tsai 2006). Current Predicted No Effect Concentrations (PNEC) for ecological
organisms are 1.5 |ig/L (European Union), 1.6 |ig/L (Japan), and 0.175 |ig/L (Canada) (U.S.
EPA 2010a). BPA was detected at a median concentration of 0.14 |ig/L (ppb) and a maximum
concentration of 12 |ig/L (ppb) in 41.2 percent of 85 samples collected from U.S. streams in
1999 and 2000, although the authors suggest that the maximum concentration of 12 |ig/L (ppb)
may be an outlier as it was much higher than any of the other samples (Kolpin, Furlong et al.
2002). A recent review of BPA monitoring studies found that out of 26 studies in North America
(2 in Canada and 24 in the United States), 80 percent (852 of 1,068) of surface water samples
reported BPA concentrations below the detection limit. The median concentration reported was
0.081 |ig/L (ppb) and the 95th percentile concentration was 0.47 |ig/L (ppb) (Klecka, Staples et
al. 2009).
Wastewater: Two studies have addressed individual WWTPs; BPA was not detected above the
detection limit of 0.0001 |ig/L (ppb) in Louisiana in effluent from a WWTP, in samples collected
from surface waters in Louisiana, or in drinking water at various stages of treatment at plants in
Louisiana (Boyd, Reemtsma et al. 2003). A California study detected BPA in two of three treated
wastewater samples at 0.38 and 0.31 |ig/L (ppb) (limit of detection = 0.25 |ig/L (ppb)) (Jackson
and Sutton 2008). It also reported detecting BPA in wastewater generated by a pharmaceutical
manufacturer (0.295 |ig/L (ppb)), an industrial laundry (21.5 |ig/L (ppb)), and a paper products
manufacturer (0.753 |ig/L (ppb)).
A Canadian study reported BPA concentrations ranging from 0.031 to 49.9 |ig/L (ppb) in sewage
influent and effluent (generally < 1 |ig/L (ppb) in the influent and < 0.3 |ig/ L (ppb) in the
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effluent) and from 0.104 to 36.7 |ig/g (ppm) in raw and digested sewage sludge from multiple
WWTPs in Canada (Lee and Peart 2000b). The same authors reported that BPA was detected in
100 percent of sewage samples from 31 WWTPs across Canada with concentrations ranging
from 0.080 to 4.98 |ig/L (ppb) (median 0.329 |ig/L (ppb)) for the influent and from 0.010 to 1.08
|ig/L (ppb)(median 0.136 |ig/L (ppb)) for the effluent (Lee and Peart 2000a). Based on
comparison of influent and effluent levels, they estimated that BPA in the influent was removed
by the sewage treatment process with a median reduction rate of 68 percent. BPA was detected
in sludge samples at concentrations ranging from 0.033 to 36.7 |ig/g (ppm), on a dry weight
basis. A wide range of BPA was detected in wastewater discharges from industrial facilities with
concentrations ranging from 0.23 to 149.2 |ig/L (ppb). Higher BPA levels in wastewater were
associated with facilities producing chemicals and chemical products and packaging and paper
products, and with commercial dry cleaning establishments. BPA concentrations in pulp and
paper mill sludge ranged from < 0.02 (below detection limit) to 3.33 |ig/g (ppm), with a median
value of 0.076 |ig/g (ppm), on a dry weight basis (Lee and Peart 2000a; Melcer and Klecka
2011).
WWTP Biosolids: One recent study measured BPA in biosolids (treated municipal waste
sewage sludge) products from WWTPs in seven states and found concentrations between 1,090
and 14,400 |ig/kg (ppb) BPA (median 4,690 |ig/kg (ppb)) (Kinney, Furlong et al. 2006). Another
study reported BPA in treated biosolids from a single municipal U.S. WWTP at 4,600 |ig/kg
(ppb) and reported 81|ig/ kg (ppb) in soil that received the land applied biosolids, and
concentrations of 147|j.g/ kg (ppb) in a nearby ,„,control""soil that did not receive treatment with
biosolids (Kinney, Furlong et al. 2008). That study also detected BPA at 81 |ig/kg (ppb) in
earthworms living in treated soil. A separate study conducted by Staples, Friederich et al. (2010)
investigated the risk of BPA in sludge-amended soil to invertebrates and plants at the bottom of
the terrestrial food chain. The risks for adverse effects to potworms, springtails, and six plant
species were found to be low based on hazard quotient values that were <0.04 (Staples,
Friederich et al. 2010)
Groundwater: The U.S. Geological Survey (USGS) collected samples from 47 ambient ground
water sites (not drinking water wells) in 18 States and analyzed them for 65 organic wastewater
contaminants. BPA was detected in 29.8 percent of the sampled ground water sites, with a mean
detected concentration of 1.78 |ig/L (ppb) and a range of 1.06 to 2.55 |ig/L (ppb). BPA was
among the top 5 most frequently detected organic compounds in this study (Barnes, Kolpin et al.
2008a; Barnes, Kolpin et al. 2008b). The analysis of BPA concentrations in areas that were
known or suspected to have at least some human and/or animal wastewater sources in upstream
or upgradient areas detected BPA in 9.5 percent of the samples at a reporting level of 1 |ig/L
(ppb). The maximum concentration measured in these samples was 1.9 |ig/ L (ppb) (Barnes,
Kolpin et al. 2008a; Focazio, Kolpin et al. 2008).
Landfill Leachate: BPA has been detected in landfill leachate with maximum concentrations of
1.7 |ig/L (ppb) and 1.4 |ig/L (ppb) in the receiving ground water plume at a landfill that was
known to be leaking (Rudel, Melly et al. 1998). Data for other landfill sites in the United States
were not available, and this single point is not likely to be representative of the country. Landfill
leachate measured in other countries contained more than 500 |ig/L (ppb) of BPA (Tsai 2006).
Studies conducted at Japanese landfills resulted in maximum untreated leachate concentrations
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of 17,200 |ig/L (ppb) and treated leachate concentrations of 5.1 |ig/L (ppb) (Crain, Eriksen et al.
2007).
Soil: Wilson et al. reported that BPA concentrations in soil samples taken from outdoor play
areas of homes and daycare centers ranged from 4-14 ppb dry weight, with means of 6-7 ppb
dry weight (2003). Klecka et al. reported a median concentration of 0.6 ppb BPA in North
American freshwater sediments, including samples with measurements below the detection limit;
BPA concentrations in samples from the United States ranged from 1.4 to 140 ppb dry weight
(2009). Levels in U.S. marine sediments were reported to have a median of 3.5 ppb of BPA and
to range from 1.5 to 5 ppb dry weight (Stuart, Capulong et al. 2005).
No data have been reported on releases to the environment for any of the alternative developers.
However, it is possible that alternatives will be released to the environment during the thermal
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References
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Fukazawa, H., K. Hoshino, et al. (2001). "Identification and quantification of chlorinated
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Gehring, M., D. Vogel, et al. (2004). Bisphenol A contamination of wastepaper, cellulose and
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Anthropogenic Waste Indicators in Earthworms from Agricultural Soil Amended With
Biosolid or Swine Manure." Environ. Sci. Technol. 42: 1863-1870.
Kinney, C. A., E. T. Furlong, et al. (2006). "Survey of Organic Wastewater Contaminants in
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Klecka, G. M., C. A. Staples, et al. (2009). "Exposure Analysis of Bisphenol A in Surface Water
Systems in North America and Europe." Environ. Sci. Technol. 43: 6145-6150.
Kolpin, D. W., E. T. Furlong, et al. (2002). "Pharmaceuticals, Hormones, and Other Organic
Wastewater Contaminants in U.S. Streams, 1999-2000: A National Reconnaissance."
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LaKind, J. S. and D. Q. Naiman (2008). " Bisphenol A (BPA) Daily intakes in the United States:
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LaKind, J. S. and D. Q. Naiman (2011). "Daily intake of bisphenol A and potential sources of
exposure: 2005-2006 National Health and Nutrition Examination Survey." Journal of
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Landrigan, P. J., B. Sonawane, et al. (2002). "Chemical contaminants in breast milk and their
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Lee, H.-B. and T. E. Peart (2000a). "Bisphenol A Contamination in Canadian Municipal and
Industrial Wastewater and Sludge Samples." Water Oual. Red. J. Canada 35(2): 283-298.
Lee, H.-B. and T. E. Peart (2000b). "Determination of Bisphenol A in Sewage Effluent and
Sludge by Solid-Phase and Supercritical Fluid Extraction and Gas Chromatography/Mass
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Li, D.-K., Z. Zhou, et al. (2010). "Relationship Between Urine Bisphenol-A Level and Declining
Male Sexual Function." Journal of Andrology 31(5): 500-506.
Li, D.-K., Z. Zhou, et al. (2011). "Urine bisphenol-A (BPA) level in relation to semen quality."
Fertility and Sterility 95(2): 625-630.
Liao, C. and K. Kannan (201 la). "High Levels of Bisphenol A in Paper Currencies from Several
Countries, and Implications for Dermal Exposure." Environ. Sci. Technol. 45: 6761-
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Liao, C. and K. Kannan (201 lb). "Widespread Occurence of Bisphenol A in Paper and Paper
Products: Implications for Human Exposure." Environ. Sci. Technol. 45: 9372-9379.
Liao, C., F. Liu, et al. (2012a). "Bisphenol S in Urine from the United States and Seven Asian
Countries: Occurrence and Human Exposures." Environ Sci Technol. Epub May 23,
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Liao, C., F. Liu, et al. (2012b). "Bisphenol S, a New Bisphenol Analogue, in Paper Products and
Currency Bills and Its Association with Bisphenol A Residues." Environ Sci Technol.
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Lunder, S., D. Andrews, et al. (2010). "Synthetic estrogen BPA coats cash register receipts."
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Melcer, H. and G. Klecka (2011). "Treatment of wastewaters containing bisphenol A: State of
the science review." Water Environ Res 83(7): 650-666.
Mendum, T., E. Stoler, et al. (2011). "Concentration of bisphenol A in thermal paper." Green
Chemistry Letters and Reviews 4(1): 81-86.
Miao, M., W. Yuan, et al. (2011). "In utero exposure to bisphenol-A and its effect on birth
weight." Reproductive Toxicology 32: 64-68.
Morgan, M. K, P. A. Jones, et al. (2011). "Assessing the quantitative relationships between
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Environ. Sci. Technol. 45(1): 5309-5316.
Myren, M., T. Mose, et al. (2006). "The human placenta - an alternative for studying foetal
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Nishikawa, M., H. Iwano, et al. (2010). "Placental Transfer of Conjugated Bisphenol A and
Subsequent Reactivation in the Rat Fetus." Environmental Health Perspectives 118(9):
1196-1203.
Ozaki, A., Y. Yamaguchi, et al. (2004). "Chemical analysis and genotoxicological safety
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Rudel, R. A., S. J. Melly, et al. (1998). "Identification of Alkylphenols and Other Estrogenic
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U.S. Environmental Protection Agency (U.S. EPA) (201 lj). Toxics Release Inventory.
Vinggaard, A. M., W. Korner, et al. (2000). "Identification and Quantification of Estroggenic
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6 Considerations for Selecting Thermal Paper Developers
Selecting an appropriate developer for use in the manufacture of thermal paper involves
consideration of a range of factors. Design for the Environment (DfE) alternatives assessments
provide information on chemical hazards and discuss other factors relevant to substitution
decisions, such as use information, exposure considerations, and performance. Decision makers
will likely supplement the human health and environmental information in this report with
information on cost and performance.
This chapter begins by describing five general attributes evaluated in this assessment that can
inform decision-making about chemical hazards: human health hazard, ecotoxicity, persistence,
bioaccumulation, and exposure potential. This chapter provides a discussion of data gaps in the
full characterization of chemicals included in this assessment. Performance, economic, and social
considerations are also briefly addressed. This chapter concludes by discussing interim risk
management measures that may be relevant for instances in which alternatives are associated
with tradeoffs, and by providing additional resources related to state, federal, and international
regulations, and available life cycle assessment (LCA) information.
6.1 Human Health and Environmental Considerations
This section identifies a set of attributes for consideration when formulating or selecting
alternative thermal paper developers. In general, a safer chemical has low human health hazard,
low exposure potential, low ecotoxicity, rapid degradability, and low potential for
bioaccumulation.
6.1.1 Human Health Hazard
The DfE alternatives assessment criteria address a consistent and comprehensive list of hazard
endpoints (U.S. EPA 201 lc). Chemical hazards to human health include acute lethality,
carcinogenicity, genotoxicity, reproductive and developmental toxicity, neurotoxicity, repeated
dose toxicity, skin and respiratory sensitization, irritation/corrosivity, and endocrine activity. DfE
criteria for most of these endpoints involve thresholds establishing levels of concern. Where data
for certain endpoints were not available, hazard values were assigned using structure-activity
modeling and professional judgment.
Several of the chemicals evaluated in this assessment are structurally similar to either bisphenol
A (BPA) or bisphenol S, resulting in similar human health hazard profiles. Some general trends
based on the information provided in Chapter 4 include: all chemicals exhibit low concern for
acute toxicity; and most chemicals exhibit low to moderate concern for carcinogenicity,
genotoxicity, repeated dose toxicity, irritation, and sensitization, however an important caveat is
that most hazard calls are based on modeled data and expert judgment. There are some
opportunities for distinction based on reproductive and developmental toxicity. With lower
absorption, systemic effects are not as likely.
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6.1.2 Ecotoxicity
Ecotoxicity includes adverse effects observed in wildlife, discussed in detail in Section 4.5.1.
Aquatic organisms have historically been the focus of this endpoint.11 Industry and government
chemical reviews have traditionally focused on fish, aquatic invertebrates, and algae. Both acute
and chronic aquatic toxicity should be considered in choosing a developer for use in thermal
paper. Where data or expert knowledge is available, ecotoxic effects on other classes of animals
and plants should be included in the hazard evaluation. Data from standard laboratory animals
presented in respect to human health attributes can also be relevant to wildlife. To prevent
concerns for higher trophic level organisms, bioaccumulation potential (Section 6.1.4) is an
important consideration for substitution decisions.
For the thermal paper developers evaluated in this report, acute and chronic aquatic toxicity are
variable and thus may present an opportunity for distinction among the alternatives.
6.1.3 Persistence
Persistence describes the tendency of a chemical to resist degradation and removal from
environmental media, such as air, water, soil, and sediment. This is an important characteristic
for chemicals used in thermal paper, as the paper may be recycled with potential releases to the
environment. Chemical degradation in the environment either occurs through chemical
reactivity with its surroundings or through biodegradation by microorganisms. Chemical
reactivity is most commonly a result of hydrolysis (reactions with water) and photolysis
(reactions with sunlight). Oxidative gas-phase processes may also play a role. In the absence of
rapid chemical reactivity, biodegradation is the primary process that causes degradation. The
destruction of a chemical by biodegradation is accomplished by the action of a living organism.
Depending on the organism and chemical substrate combination, chemicals may degrade into
other chemical substances (primary degradation) or may be completely mineralized into carbon
dioxide and water (ultimate degradation). Depending on the organism and chemical substrate
combination, chemicals may degrade into other chemical substances (primary degradation) or
may be completely broken down into carbon dioxide and water (ultimate degradation).
The rate of degradation is important, but equally important are the byproducts formed through
the degradation process. In some cases, the products of biodegradation might be more toxic and
persistent than the parent compound.
For the thermal paper developers evaluated in this report, persistence is variable and may be an
opportunity for distinction among the alternatives (see Chapter 4).
6.1.4 Bioaccumulation Potential
The ability of a chemical to accumulate in living organisms is described by the bioconcentration,
bioaccumulation, biomagnification, and/or trophic magnification factors. Most of the
11 Aquatic organisms became the focus of ecotoxicology assessments for several reasons: releases to water were a
prominent concern, data were more abundant, and hence computer models were developed based on aquatic
organisms.
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alternatives assessed in this report have been assessed as having low-moderate potential for
bioaccumulation but nearly all of the assessments are based on computer models. Based on
structure activity relationships, the potential for a molecule to be absorbed by an organism tends
to be lower when the molecule is larger than 1,000 daltons. None of the chemicals in this
assessment meet this threshold. Note that care should be taken not to consider the 1,000 daltons
size to be an absolute threshold for absorption - biological systems are dynamic and even
relatively large chemicals may be absorbed under certain conditions.
The test guidelines available to predict potential for bioaccumulation have some limitations.
Bioconcentration tests tend to be limited for chemicals that have low water solubility
(hydrophobic. Even if performed properly, a bioconcentration test may not adequately measure
bioaccumulation potential because bioaccumulation is a measure of all uptake while most
bioconcentration tests do not currently measure dietary uptake (i.e., uptake by fish via food
versus via their gills respectively). Under review in the Organisation for Economic Cooperation
and Development (OECD) program and close to finalization is a major upgrade to the fish
bioconcentration test, in which dietary uptake is included for the first time. Dietary uptake is of
critical importance and is probably the dominant route of exposure for hydrophobic chemicals.
For the thermal paper developers evaluated in this report, bioaccumulation concerns generally
fall within the low-moderate range (see Chapter 4).
6.1.5 Exposure Considerations
For humans, chemical exposures may occur at different points throughout the chemical and
product lifecycle, through skin contact, by inhalation, and by ingestion, and exposures are
affected by multiple physicochemical factors, as discussed in Chapter 5. The DfE alternatives
assessment begins with the assumption that exposure scenarios for chemicals and their
alternatives within a functional use class are roughly equivalent. The assessment also recognizes
that in some instances chemical properties or use patterns may affect exposure scenarios. For
example, some BPA alternatives may require different amounts to achieve the same technical
specifications. Stakeholders should evaluate whether manufacturing changes, lifecycle
considerations, and physicochemical properties will result in different patterns of exposure as a
result of informed chemical substitution. In general, the chemicals included in this assessment
have similar physicochemical parameters and their use as developers is roughly equivalent.
Therefore, exposure patterns are expected to be similar.
6.2 Considerations for Poorly or Incompletely Characterized Chemicals and Variable
Amounts of Data
For most industrial chemicals, experimental data for hazard characterization are limited. For
chemicals in this report without full data sets, analogs, structure activity relationship (SAR)
modeling, and expert judgment were used. More information on predicted hazard levels can be
found in Chapter 4. Estimated values in the report can be used to prioritize testing needs.
Several chemicals included in this analysis appear to have more preferable profiles, with low
human health and ecotoxicity endpoints (see Chapter 4). However, because no chemical-specific
empirical data were available, their hazard evaluations were entirely predicted based on
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structure-activity relationships, analogs, and expert judgment. Empirical data will allow for a
more robust assessment that will support expert judgments, therefore we strongly encourage
additional studies to fill these data gaps.
In the absence of measured data, users of this alternatives assessment should be cautious in the
interpretation of hazard profiles. For chemicals without data, developing data would prevent
unexpected consequences if a prediction did not hold true. If chemicals are used at higher
volumes, or are likely to be in the future, this fact should also be given weight when considering
data needs. Decision-makers should proceed with caution and are advised to read the full hazard
assessments for each chemical (see Chapter 4) which may inform whether additional testing is
needed.
Where hazard characterizations are based on measured data, there are often cases where the
amount of test data supporting the hazard rating varies considerably between alternative
chemicals. In Table 4-4, the hazard characterizations based on SAR or expert judgment are listed
in black italics, while those with hazard characterizations based on measured test data are listed
in color. The amount of measured test data available to inform the evaluation of endpoints can
vary from only one study to many studies in many species with different routes of exposure and
exposure duration. In some instances, testing may go beyond basic guideline studies, and it can
be difficult to compare data for such chemicals against those with only a single guideline study,
even though hazard calls for both chemicals are "based on empirical data" and thus come with a
higher level of confidence. Comparisons between a chemical with only one study and a second
chemical with many studies are complex and merit careful consideration. For hazard screening
assessments, such as the DfE approach, a single adequate study can be sufficient to provide a
hazard rating. Therefore some ratings reflect assessment based on one study while others reflect
assessment based on multiple studies of different design. The hazard rating does not convey
these differences - the full hazard profile should be consulted to understand the limitations of the
available data.
6.3 Performance Considerations
This section identifies general performance attributes that companies can consider when
formulating or selecting alternative chemicals. These attributes are critical to the overall function
and marketability of the chemicals and can be considered jointly with economic considerations
and the human health and environmental attributes described above.
Known thermal paper developers are typically organic or organometallic-compounds that have
the following physical properties: low water solubility, substantially colorless, odorless, and
chemically inert towards water and oxygen over a pH range from 6 to 10 (D. Keller, personal
communication, December 1, 2011).
As discussed in Chapter 3, performance characteristics of effective developers in thermal paper
include:
• Appropriate acidity, such that it produces no background imaging;
• Ability to fully react with the colorformer when heated;
• Reaction at the temperature of the specific printer;
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• Stable at end use temperatures;
• Appropriate level of permanence for the application;
• Appropriate performance vs. cost balance; and
• Feasibility for large-scale production.
In considering alternative formulations or chemical substitutions, decision makers will need to
consider the pH, temperature, and water solubility of the developer, as well as the stability and
durability of the resulting image. The following conditions may limit the durability of thermal
images: exposure to temperatures greater than 40°C, wet environments, direct sunlight, and
certain chemicals such as alcohol, fuels, and oils (Koehler Thermal Papers 2011). However,
depending on the grade, thermal papers can retain their image integrity even in conditions of
bright lights, moisture, scuffing, and high temperatures up to 180°F (Appleton 2003).
In addition to considering the hazard information provided in Chapter 4 and the performance
characteristics described above, other considerations include:
• Printer Compatibility: Modifications to thermal paper manufacture, either to developers
or more broadly to other chemistry or process, should require consideration of how these
changes may affect compatibility with existing thermal printers or what changes to
printer technology or re-design may be required as a result.
• Compatibility with End Use: Specific developers and types of thermal paper are used
for specific applications, depending on performance, design, and economic
considerations. Direct thermal paper can be used in a wide range of applications,
including amusement park tickets, produce labels, retail hang tags, ski lift tickets,
baggage tags, mass transit tickets, parking receipts, and lottery tickets (Appleton 2011).
Modifications to thermal paper design would require consideration of appropriateness for
specific end uses.
• Appropriate Image Quality: Alternatives should ensure appropriate image quality at the
time of printing and stability for the required time period. Thermal images have sufficient
resolutions for printing of text, graphics, and barcodes. Depending on grade, image
integrity can last up to ten years (Appleton 2003; Koehler Thermal Papers 2011).
6.4 Economic Considerations
This section identifies economic attributes that companies can consider when formulating or
selecting alternative chemicals. Full consideration of economic factors is often more fully
addressed by decision-makers within the context of their companies or organizations. Accurate
cost estimations are company-specific; the impact of substituting chemicals on complex product
formulations can only be analyzed using in-house data that is likely to be business confidential;
and a company should determine for itself how changes will impact market share or other
business factors. Cost considerations may be relevant across the chemical and/or product
lifecycle. These attributes are critical to the overall function and marketability of alternatives and
can be considered jointly with performance attributes and human health and environmental
attributes.
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To ensure economic viability, alternatives should be easy to process and cost-effective to
integrate into products. The most desirable alternatives are compatible with existing process
equipment and can be integrated in existing products. If this compatibility is not available,
manufacturers will need to modify their processes and potentially purchase new equipment.
From an economic standpoint, the ideal alternative would be a drop-in replacement that has
similar physical and chemical properties such that existing storage and transfer equipment as
well as manufacturing technologies could be used without significant modification. However,
chemicals with similar physical and chemical properties may have similar hazard and exposure
profiles.
Substituting chemicals can involve significant costs, as industries may need to adapt their
production processes and have products re-tested for all required performance and product
standards. Decision-makers are advised to see informed chemical substitution decisions as long-
term investments, and to replace the use of BP A with a chemical they anticipate using for many
years to come. This includes attention to potential future regulatory actions as well as market
trends.
Alternatives that are either more expensive per pound or require more chemical per unit area to
be functional will increase costs. In this situation, the cost of a chemical that must be used at a
higher application rate may be passed on to customers, who will subsequently pass the cost on to
consumers. In some cases, the price premium may diminish over the different stages of the value
chain.
Some of the alternative chemicals assessed in this report are currently manufactured in high
volume. Others are not currently available in quantities that would allow for immediate
widespread use. Prices and availability are likely to change with an increase in demand.
Handling, disposal, and treatment costs may be important considerations when evaluating
alternatives. Inherently high-hazard chemicals may require special engineering controls and
worker protections that are not required of less hazardous alternatives. Disposal costs for high
hazard chemicals may also be greater than for low hazard alternatives. High hazard chemicals
may be more likely to result in unanticipated clean-up requirements should risk management
protections fail or unanticipated exposures or spills occur. Also, some chemicals may require
specific treatment technologies prior to discharge through wastewater treatment systems. These
costs can be balanced against the up-front costs for the purchase of the alternative chemical, new
equipment, etc. Finally, initial chemical substitution expenses may reduce future costs of
mitigating consumer concerns and perceptions related to hazardous chemicals.
6.5 Social Considerations
Decision-makers should be mindful of a number of social considerations when choosing
alternative chemicals. This section highlights occupational, consumer, and environmental justice
considerations. Stakeholders may identify additional social considerationsfor application to their
own decision-making processes.
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Awareness of social considerations related to informed substitutions includes attention to
participation in decision-making processes, the impacts of human behaviors on the
implementation or on outcomes of interventions, and the distributions of impacts across
populations. Social considerations are one of the three pillars of sustainability (National
Academy of Sciences 2011), and a focus on sustainability recognizes that human and
environmental systems are coupled and interdependent (Clark 2007). Decisions should be made
to maximize social, environmental, and economic benefits and to minimize the adverse effects of
conflicts between these areas. According to the National Academy of Sciences report on
"Sustainability and the U.S. EPA" (2011), the U.S. Environmental Protection Agency (EPA)
would benefit from working with stakeholders to develop robust indicators for these attributes.
Occupational considerations: Some stakeholders have raised concerns for differential exposure
to BPA based on occupation. In particular, some partners noted that cashier jobs are often held
by young women of childbearing age, who may experience greater exposures to BPA due to
frequent handling of thermal paper receipts. Existing research reinforces these concerns (see
Section 5.3.4). Braun et al. (2011) found that prenatal urinary BPA exposures were highest
among cashiers, although this finding was attenuated after adjustment for socioeconomic factors.
Prenatal exposures are of particular concern due to the increased susceptibility of early life
stages, discussed in Section 5.3.4. Liao and Kannan (2011b) compared occupational exposure,
based on handling 150 pieces of thermal paper/day, to exposure in the general population, based
on handling two pieces of thermal paper/day. They estimated occupational exposure to thermal
paper at 1303 ng/day of BPA, compared to BPA exposure in the general population of only 17.5
ng/day.
Consumer considerations: Consumers are potentially exposed to any chemicals found on
thermal paper. As detailed in Section 5.3.5, exposure research documents that Americans carry
body burdens of BPA (Calafat, Ye et al. 2008), although thermal paper is not considered to be
the primary source of exposure (Rudel, Gray et al. 2011). Nonetheless, consumer reactions to
exposure concerns can impact markets by creating pressure for substitution. DfE alternatives
assessments can assist companies navigating these substitution pressures. There is greater
emphasis on "green" products, and some consumers and non-governmental organizations
(NGOs) advocate for informed substitution of chemicals, moving away from certain classes of
chemicals entirely, with product re-design.
In recent years there has been a greater emphasis on „gieen" products. In addition to substituting
in alternative chemicals, some organizations advocate for moving away from certain classes of
chemicals entirely, with product re-design, to avoid future substitutions altogether. Product
manufacturers should be mindful of the role of these organizations in creating market pressure
for alternative chemicals and strategies, and should choose replacement chemicals - or re-
designs - that meet the demands of their customers.
Environmental justice considerations: At EPA, environmental justice concerns refer to the
disproportionate impacts on minority, low-income, or indigenous populations that exist prior to
or that may be created by the proposed action. These disproportionate impacts arise because
these population groups experience higher exposures, are more susceptible in response to
exposure, or experience both conditions. Factors that are likely to influence resilience/ability to
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withstand harm from a toxic insult can vary with sociodemographics (e.g. co-morbidities, diet,
metabolic enzyme polymorphisms, etc) and are therefore important considerations. Adverse
outcomes associated with exposure to chemicals may be disproportionately borne by minority
and low income populations. Insights into EPA"s environmental justice policy can be accessed
at: www.epa.gov/compliance/ei/resources/policv/considering-ei-in-rulemaking-suide-07-
2010.pdf.
Some populations have higher exposures to certain chemicals in comparison to the average
member of the general population. Minority and low-income populations are over-represented in
the manufacturing sector, increasing their occupational exposure to chemicals. Higher exposures
to environmental chemicals may also be attributable to atypical product use patterns and
exposure pathways. This may be due to a myriad of factors such as cultural practices, language
and communication barriers, and economic conditions. The higher exposures may also be a
result of the proximity of these populations to sources that emit the environmental chemical (e.g.
manufacturing industries, industries that use the chemical as production input, hazardous waste
sites, etc), access to and use of consumer products that may result in additional exposures to the
chemical, or higher employment of these groups in occupations associated with exposure to the
chemical.
Considering environmental justice in the assessment of an alternative chemical may include
exploring product use patterns, pathways and other sources of exposure to the substitute,
recognizing how upstream factors such as socio-economic position, linguistic and
communication barriers, may alter typical exposure considerations. One tool available to these
populations is the Toxics Release Inventory (TRI), which was established under the Emergency
Planning and Community Right-to-Know Act (EPCRA) to provide information about the
presence, releases, and waste management of toxic chemicals. Communities can use information
reported to TRI to learn about facilities in their area that release toxic chemicals and to enter into
constructive dialogue with those facilities. This information can empower impacted populations
by providing an understanding about chemical releases and the associated environmental impacts
in their community. Biomonitoring data for the alternative chemical, if available, can also signal
the potential for disproportionate exposure among populations with environmental justice issues.
6.6 Trade-offs and Interim Risk Mitigation
In the absence of clearly-preferable low hazard functional alternatives, risk mitigation may be
necessary in the interim. The hazard evaluations in Chapter 4 of this alternatives assessment
include an analysis of the intrinsic properties that influence exposure, fate and transport. Further
information on exposure pathways and life cycle considerations is presented in Chapter 5. A
chemical alternative that poses a significantly greater opportunity for exposure should be further
evaluated, and decision-makers should supplement the comparative chemical hazard assessment
described in this report with other assessments, such as risk assessments, for potentially
preferable alternatives.
In many instances it is apparent that alternative chemicals come with trade-offs. For any
chemical identified as a potential alternative, some endpoints may appear preferable while others
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indicate increased concern relative to the original chemical. For example, a chemical may have a
lower concern for human health but a higher concern for aquatic toxicity or persistence.
These types of trade-offs can be difficult to evaluate, and such decisions should take into account
relevant information about the chemical"s hazard profile, expected product use, the potential for
worker and consumer exposure, and the opportunity for the chemical to enter various waste
streams, among other life-cycle and mitigation considerations. For example, chemicals expected
to have high levels of developmental or reproductive toxicity should not be used in products
intended for use by children or women of child-bearing age. Chemicals with high aquatic
toxicity concerns should not be used if releases to water cannot be mitigated in the
manufacturing, use, and disposal process.
Risk mitigation actions provide the opportunity to limit human health and environmental
exposure. These actions provide immediate opportunities to address exposure concerns and may
be considered alone or in conjunction with selection of an alternative, if appropriate. Examples
of actions that may be appropriate are presented below.
The traditional hierarchy of exposure control practices begins with elimination and substitution
(NIOSH 2011). When chemicals cannot be eliminated or substituted with safer alternatives, there
are a variety of modifications and engineering controls that should be considered. For example,
in the manufacture and use of chemicals in industrial processes, exposure can be limited through
innovative engineering controls such as containment, improvements to local ventilation, and the
use of negative-pressure systems for feeding materials (Fie, Miao et al. 2009). Personal
protective equipment can also be used, and is considered to be the last line of protection in the
exposure control hierarchy.
Figure 6-1: Traditional Hierarchy of Exposure Control Practices
Traditional Hierarchy
of Exposure Control Prac
llces
Elimination
Modification
Containment
Ventilation
Wort Practices
Source: (NIOSH 2011)
In consumer and occupational settings, risk mitigation measures may help reduce or avoid
exposure to BPA in thermal paper. For example, after handling receipts consumers and retail
workers can limit their exposure to BPA by washing their hands prior to preparing or eating
food, storing receipts separately in a wallet or purse, and avoiding the use of alcohol-based hand
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cleaners, which have the potential to increase dermal BPA absorption (Lunder, Andrews et al.
2010).
Risk mitigation measures may also limit human and environmental exposures to BPA and other
chemicals during recycling or disposal. For example, recycling of thermal paper can lead to
release of BPA into the environment through sludge and wastewater (JRC-IHCP 2010), and BPA
contamination of recycled paper products, which are often used to store food (Ozaki, Yamaguchi
et al. 2004). As an alternative to recycling, thermal paper can be disposed of in a landfill. While
the anaerobic conditions associated with many landfills do not favor the degradation of BPA
(Ying and Kookana 2005), the collection and treatment of landfill leachate can decrease the
likelihood of BPA entering the environment.
A recent study suggests that the burning of plastics in waste disposal is a significant source of
atmospheric BPA, but further research is needed to confirm the results and determine if
prolonged exposure to low level atmospheric BPA could be associated with negative health
effects (Fu and Kawamura 2010). Incineration produces negligible waste to soil and aquatic
environments (JRC-IHCP 2010).
6.7 Innovation and Design Challenges
A DfE alternatives assessment can suggest directions for innovation and product development,
especially when clearly preferable alternatives are not available. This can spur innovation by
identifying design challenges and by highlighting the hazard endpoints and measures of exposure
potential that delineate safer chemicals. Green chemistry tools and expertise are growing. The
DfE approach enables identification of safer substitutes that emphasize greener chemistry and
points the way to innovation in safer chemical design where hazard becomes a part of a
performance evaluation. EPA encourages collaboration to identify safer solutions to complex
chemical hazards. For more information on green chemistry, please refer to the EPA Green
Chemistry Program (http://www.epa.gov/greenchemistry/) or the American Chemical Society
Green Chemistry Institute (www.acs.org/greenchmistry).
Options to be considered include the development of new chemicals that have a preferable
hazard profile, while still meeting the performance considerations required by particular
applications. Another option would be to redesign thermal paper. This would include
consideration of a variety of sustainability considerations, including use of recycled materials
and low concern chemicals as developers, colorformers, and sensitizers. Other approaches could
include additional research to determine if the application of a top coat (currently an optional
design characteristic depending on a particular application) helps to limit exposure to consumers
or workers. It is important to note that these approaches are not mutually exclusive; a
combination of techniques may be appropriate.
In addition to reconfiguring thermal printing systems, decision makers may wish to consider
alternative printing systems. These systems should be evaluated and compared to thermal
printing to better understand relative performance, cost, and hazard. To make an informed
substitution, chemicals used in alternative printing systems must not be assumed to be low
hazard. Thermal transfer printing, impact printing, and laser printing are all alternatives to direct
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thermal printing (Seiko Instruments U.S.A. Inc. n.d.). However, thermal paper printers are
unique because they require no ribbons, inks, or toner cartridges. Thermal paper printers
typically have fewer moving parts and low maintenance costs compared to similar technology
(Appleton 2003).
A significant use of thermal paper is for point-of-sale receipts. Every year, an estimated 9.6
million trees are cut down in the United States for receipts (Clifford 2011), although many
companies strive for sustainability through stewardship and management programs. Electronic
receipts (e-receipts) are becoming increasingly common in the retail industry, being offered by
Apple, Nordstrom, Whole Foods, and other major retailers. They are either emailed directly to
consumers or uploaded to a password-protected website. E-receipts allow consumers to keep
searchable records of purchases on their computer. E-receipts could reduce paper waste and also
limit exposure to BPA and other chemicals, making them an approach to be considered in
alternatives discussions. A full examination of the relative merits of thermal paper versus e-
receipts requires the consideration of lifecycle attributes, which is beyond the scope of this
project.
6.8 Relevant Resources
In addition to the information provided in this report there are a variety of resources which
provide information on chemical regulations at the state, national and global levels, some of
which are cited in this section. Tools, including GreenScreen™ are also available to assist in
using the information in this report to make a substitution decision.
6.8.1 Resources for State and Local Authorities
The University of Massachusetts at Lowell created an online database that contains a collection
of state and local legislative and executive branch policies from all 50 states from 1990 to the
present that regulate or ban specific chemicals, provide comprehensive state policy reform,
establish biomonitoring programs, or foster "green" chemistry. (National Caucus of
Environmental Legislators 2008).
http://www.chemicalspolicv.org/chemicalspolicv.us.state.database.php
The Washington Department of Ecology concluded that averting toxic exposures and avoiding
future health and cleanup costs is the smartest, cheapest and healthiest approach to preventing
the harm associated with toxic chemicals, and created the Reducing Toxic Threats initiative to
coordinate activities to achieve this goal (see: http://www.ecv.wa.gov/toxics/index.htm).
Although the Department has conducted alternatives assessments as part of this effort, they are
now focused on developing tools and guidance documents to allow businesses to conduct their
own alternatives assessments to facilitate the movement to safer substitutes for chemicals of
concern. The Department of Ecology has developed the Quick Chemical Assessment Tool, based
on the Green Screen (see 6.7.4 below), to rapidly assess chemical options and remove from
consideration those that are likely to be most toxic, so that in-depth assessments can focus on
those chemicals that are likely to be safer. This is particularly important for businesses with
limited resources. At the time of the writing of this report, the Department is in the process of
developing an alternatives assessment guidance document.
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6.8.2 Federal Agency Resources
EPA"s website contains information on how the Agency develops regulations, the regulations
that are in place, and information to assist companies in maintaining compliance with
regulations. The website also provides information on EPA"s partnership programs, such as DfE
Some EPA resources are listed below.
EPA Laws and Regulations
http ://www. epa. gov/1 awsregs/
EPA Office of Pollution Prevention and Toxics (OPPT)
http ://www. epa. gov/oppt/
EPA Design for the Environment (DfE) Program
http ://www. epa. gov/oppt/dfe/
Websites from other federal agencies that may be relevant to this alternatives assessment are
provided below.
Consumer Product Safety Commission (CPSC)
http://www.cpsc.gov/
U.S. Food and Drug Administration (FDA)
http://www.fda.gov/
National Institute for Occupational Safety and Health (NIOSH) (part of the Centers for Disease
Control and Prevention (CDC))
http://www.cdc.gov/niosh/
6.8.3 Resources for Global Regulations
The European Union (EU)"s REACH (Registration, Evaluation, Authorisation and Restriction of
Chemical substances) legislation was enacted in 2007 and aims "to improve the protection of
human health and the environment through the better and earlier identification of the intrinsic
properties of chemical substances" (European Commission 2011a). Their website contains
information on legislation, publications and enforcement.
http://ec.europa.eu/environment/chemicals/reach/enforcement en.htm
The EU"s Restriction of Hazardous Substances (RoHS) legislation ensures that new electrical
and electronic equipment put on the market does not contain any of the six banned substances:
lead, mercury, cadmium, hexavalent chromium, poly-brominated biphenyls (PBB) or
polybrominated diphenyl ethers (PBDE) above specified levels (European Commission 2011b).
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http://www.rohs.eu/english/index.html
6.8.4 GreenScreen™ for Safer Chemicals
The GreenScreen™ for Safer Chemicals was developed by the non-profit group Clean
Production Action. It is a method for chemical hazard assessment to help move society toward
the use of greener and safer chemicals. At the foundation of the GreenScreen™ method are the
Principles of Green Chemistry and the work of the EPA DfE program. The GreenScreen™
addresses many of the principles of green chemistry and design for the environment through its
focus on hazard reduction and informed substitution.
http://www.cleanproduction.org/Greenscreen.php
6.9 Related Assessments
In 2008, the European Commission published an environmental and human health addenda to its
risk assessment of BP A.
European Union Risk Assessment Report, Human Health Addendum of April 2008, 4,4'-
ISOPROPYLIDENEDIPHENOL (Bisphenol-A), Part 1 Environment
http://publications.irc.ec. europa.eu/repository/bitstream/11111111 l/15063/l/lbna24588enn.pdf
European Union Risk Assessment Report, Human Health Addendum of April 2008, 4,4'-
ISOPROPYLIDENEDIPHENOL (Bisphenol-A), Part 2 Human Health
http://publications.irc.ec. europa.eu/repository/bitstream/11111111 l/15069/l/lbna24589enn.pdf
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Appleton (2011). End Use Applications. Appleton.
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Calafat, A. M., X. Ye, et al. (2008). "Exposure of the U.S. Population to Bisphenol A and 4-
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