Bisphenol A Alternatives in Thermal Paper Final Report January 2014


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FINAL REPORT - January 2014

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United States
Environmental Protection
Agency

BISPHENOL A ALTERNATIVES IN THERMAL PAPER

FINAL REPORT

January 2014

1

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FINAL REPORT - January 2014

Executive Summary

This report provides information on bisphenol A (BPA), its use in thermal paper, and possible
substitutes for this use. The report was developed by the U.S. Environmental Protection Agency
(EPA) with input from stakeholders from business, government, academia, and environmental
organizations. Based on conversations with technical experts, including stakeholders, we
identified nineteen alternatives that are potential functional substitutes for inclusion and
assessment. In addition to information on potential hazards of BP A and possible substitutes,
information on the trade-offs associated with each alternative is presented for consideration in
substitution decision-making.

Background

In March 2010, EPA released a chemical action plan for BPA. BPA is a high production volume
(HPV) chemical that is used in manufacturing most polycarbonate plastics, the majority of epoxy
resins, and other uses subject to regulation under the Toxic Substances Control Act. The action
plan summarizes hazard, exposure, and use information, and identifies actions to address BPA
in the environment based on concerns for potential effects on aquatic species. 1 BPA is also a
commonly used developer in a number of thermal paper applications, such as point-of-sale
(POS) receipts. The developer is a component of a chemically reactive layer of thermal paper,
which reacts in the presence of heat to create the printed image. 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 2010).

One component of the action plan tasked the EPA Design for the Environment (DfE) Branch to
conduct an alternatives assessment for BPA in thermal paper. Thermal paper was selected for
evaluation based on concern for potential exposures to consumers and workers, releases to the
environment, and stakeholder interest. DfE's Alternatives Assessment Program provides a basis
for informed decision-making by developing a semi-quantitative, screening-level comparison of
the potential human health and environmental impacts of chemical alternatives. DfE Alternatives
Assessments provide information on functional use class, intrinsic hazard, exposure properties,
and environmental fate for chemical alternatives. Information from DfE Alternatives
Assessments can support the selection of safer alternatives when combined with other
information not addressed in DfE Alternatives Assessments, such as performance, cost, and
life-cycle impacts.

Goal of the Alternatives Assessment and Report Overview

In July 2010, DfE convened a multi-stakeholder effort to assess the human health and
environmental effects of BPA and its alternatives as developers in thermal paper. This informal
partnership includes a diverse array of stakeholders, such as thermal paper manufacturers,
thermal paper converters, chemical manufacturers, POS equipment manufacturers, retailers,
trade associations, non-governmental organizations (NGOs), green chemistry and technical
experts, and international governmental organizations. The outcome of this effort is presented in
this report. The report provides information that will help decision-makers consider

1 The U.S. Food and Drug Administration (FDA) is expected to take the lead on assessing potential human health
impacts associated with exposure to BPA. See www.fda.gov/ForConsumers/ConsumerUpdates/ucm297954.htm.

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FINAL REPORT - January 2014

environmental and human health profiles for all evaluated chemicals so that they can choose
safer functional alternatives and take into account potential hazard trade-offs that may exist.

Chapter lof this report provides background information on BPA and defines the report's
purpose and scope. Chapter 2 discusses information on BPA and its use in thermal paper as a
developer. Chapter 3 offers background information on the thermal paper printing system and
how developers interact with other components in the system to create a printed product. Chapter
4 explains the hazard evaluation methodology and includes the hazard profiles for BPA and the
alternatives. Chapter 5 provides exposure information and life-cycle considerations for BPA.
Chapter 6 discusses considerations for selecting thermal paper developers and provides relevant
resources for moving towards a substitution decision.

Hazard Evaluation of BPA and Alternatives

Given that the project scope is limited to BPA's use as a developer in thermal paper, this
alternatives assessment does not consider alternatives to BPA for other uses. In addition to
BPA, 19 potential chemical alternatives were identified for evaluation, which were considered
by stakeholders likely to be functional in thermal paper. The assessment evaluated three
general attributes to inform decision-making on chemical alternatives: (1) human health
effects, (2) ecotoxicity, and (3) environmental fate. The evaluation was conducted according to
the DfE Alternatives Assessment Criteria for Hazard Evaluation, which is a transparent tool for
evaluating and differentiating among chemicals based on their human health and environmental
hazards. For most endpoints, the criteria define "High," "Moderate," and "Low" concern. Very
few chemicals had measured data for all endpoints; therefore, estimation methods were applied
to fill data gaps. Since estimation methods come with a lower degree of confidence, this
circumstance may be an important consideration for decision-making. No clearly safer
alternatives to BPA were identified in this report - most alternatives have Moderate or High
hazard designations for human health or aquatic toxicity endpoints. Persistence and
bioaccumulation potential were not distinguishing for this group of alternatives.

The human health effects endpoints evaluated in DfE Alternatives Assessments include acute
toxicity, carcinogenicity, genotoxicity, reproductive toxicity, developmental toxicity,
neurotoxicity, repeated dose toxicity, skin sensitization, respiratory sensitization, eye irritation,
and dermal irritation. Qualitative discussions on available endocrine activity and immunotoxicity
data were included, where relevant. All chemicals (including BPA) had Low designations for
acute mammalian toxicity. Nine chemicals had High designations for developmental toxicity.
For repeated dose toxicity, five chemicals had a High designation. Thirteen chemicals had
Moderate, High, or Very High designations for at least one of the irritation and sensitization
endpoints. All chemicals were assigned Moderate concern for carcinogenicity. Six chemicals
were assigned Moderate concern for genotoxicity, with the remaining chemicals being of Low
concern for this endpoint.

The ecotoxicity endpoints evaluated in DfE Alternatives Assessments include acute and chronic
aquatic toxicity. Ecotoxicity data for terrestrial species is limited. Most of the alternatives had
High designations for aquatic toxicity (acute and chronic).

Environmental fate of BPA and the 19 alternatives were also evaluated. Three of the
20 chemicals had Low or Very Low persistence values; 11 had High or Very High persistence
values. Only two chemicals had a High bioaccumulation potential.

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FINAL REPORT - January 2014

For a screening-level summary of the hazard evaluations for alternatives (including BP A), see
Table ES-1 below.

General Exposure and Life-Cycle Factors

Environmental exposure to BPA or alternatives may occur during manufacture, conversion, or
use of thermal paper, at its end-of-life (i.e., recycling, landfilling, or incineration), or during
manufacture of recycled paper products. Understanding the factors that affect exposure to BPA
and alternative developers across their life-cycles provides additional context to the alternative
selection process. There is a potential for occupational exposure during chemical and product
manufacturing and product end-of-life. 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.

Considerations for Selecting Thermal Paper Developers

Along with presenting information on hazard to inform substitution decisions, the report
discusses considerations for selecting thermal paper developers, including opportunities for
innovation and design challenges. Options that may be considered for substitution 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
re-design thermal paper to eliminate the need for chemical developers. 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. Finally, another option would be the use of e-
receipts. A full examination of the relative merits of thermal paper versus e-receipts would
require the consideration of life-cycle impacts, which is beyond the scope of this study.

How to Use This Report

The intended audience for the report includes, but is not limited to, chemical manufacturers,
product manufacturers, retailers, consumers, NGOs, consultants, and state and federal regulators.
Four possible uses of this report include: (1) identification of potential substitutes, (2) selection
of alternative chemicals based on comparative hazard assessment, (3) incorporation of hazard
information for further analysis and decision-making, and (4) as a baseline for the development
of new and safer chemical substitutes.

This report allows stakeholders interested in chemical substitution to identify functional
substitutes for BPA in thermal paper. The list of potential alternatives introduced in Chapter 3
includes chemicals identified by stakeholders as likely to be viable, functional alternatives as
well as chemicals that are not considered functional alternatives, which were subsequently
removed from consideration. The inclusion of a chemical in this assessment does not indicate
environmental- or health-based preferability. By identifying potential functional alternatives, this
report assists manufacturers in selecting chemicals for additional performance testing.

Chapter 4 contains human health and environmental profiles for each chemical. Decision-makers
can use this information to understand and compare the hazard concerns associated with
potential alternatives, and it may help businesses avoid the cost of repeated substitution. Some
alternatives may be associated with hazard concerns similar to those of BPA, while others may

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FINAL REPORT - January 2014

be associated with different hazard concerns. The profiles in Chapter 4 can help decision-makers
understand which potential alternatives may come under scrutiny in the future.

In addition to reading the hazard summary table (ES-1), decision-makers should review the full
hazard assessments for each chemical available in Section 4.2 of the report. The hazard
assessments provide more information on hazard criteria, data interpretation, and information
used to assign hazard values in each category. Decision-makers should consider this information
to ensure a complete understanding of the hazard profiles of each alternative.

The information in this report can be used to inform further analyses on preferred alternative
chemicals, such as risk assessments or life-cycle assessments. For example, a decision-maker
could identify several preferred functional alternatives and conduct product-specific risk
assessments based on exposure expectations along the product's life-cycle. This type of
supplementary information may be helpful in guiding product-specific decision-making. The
criteria used to develop the hazard assessments in this report can also be used to inform green
chemistry design, if availability of safer alternatives is limited.

Many of the chemicals have significant data gaps; while estimation methods can be used to
address these data gaps, access to high quality, relevant toxicological and environmental fate
data is preferred as it provides more robust assessments. Chemicals used at high volumes, or
likely to be used at high volumes in the future, should be of high priority for further testing. The
full hazard assessments for each chemical, available in Chapter 4, may inform whether additional
assessment or testing is needed.

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FINAL REPORT - January 2014

ES-1 Screening Level Toxicology Hazard Summary for BPA and Alternatives

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, , , 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.

§ Based on analogy to experimental data for a structurally similar compound.

Structure

Chemical

(for TSCA inventory name and
relevant trade names see the
individual profiles in Section 4.8)

CASRN

Human Health Effects

Aquatic
Toxicity

Environmental
Fate

Acute Toxicity

Carcinogenicity

Genotoxicity

Reproductive

Developmental

Neurological

Repeated Dose

Skin Sensitization

Respiratory
Sensitization

Eye Irritation

Dermal Irritation

Acute

Chronic

Persistence

Bioaccumulation



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Bisphenol A

2,2-bis(p-hydroxyphenyl)propane

80-05-7

L

M

L

M

H

M

M

M



M

M

H

H

VL

L

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Bisphenol F

Bis(4-hydroxyphenyl)methane

620-92-8

L

M

L

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M

H

L



VH

M*

M

H

L

L



Bisphenol C

2,2'-Bis(4-hydroxy-3-

methylphenyl)propane

79-97-0

L§

M

M
L§

M§

H§

M

M*

M*



H§

M5

H

H

M

M

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Methyl bis(4-hydroxyphenyl)acetate

5129-00-0

L§

M

M§

H§

M

M*

L



M*

M*

H

H

M

L



BisOPP-A

4,4'-Isopropyllidenebis(2-
phenylphenol)

24038-68-
4

L§

M

L§

M§

H§

M

M*

M*



M*

M*

L

H

H

M



Bisphenol AP

4,4'-(1 -Phenylethylidene)bisphenol

1571-75-1

L§

M

L§

M§

H§

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M*



M*

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Substituted phenolic compound,
PROPRIETARY #1



L§

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Substituted phenolic compound,
PROPRIETARY #2



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M*

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PHBB

Benzyl 4-hydroxybenzoate

94-18-8

L

M

M

L

M

M

L

M*



VL

VL

H

H

L§

L

vi

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FINAL REPORT - January 2014

ES-1 Screening Level Toxicology Hazard Summary for BPA and Alternatives (Continued)

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 E = High hazard VH = Very High hazard — Endpoints in colored text (VL, L, , , 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.

§ Based on analogy to experimental data for a structurally similar compound.







Human Health Effects

Aquatic
Toxicity

Environmental
Fate

Structure

Chemical

(for TSCA inventory name and
relevant trade names see the
individual profiles in Section 4.8)

CASRN

Acute Toxicity

Carcinogenicity

Genotoxicity

Reproductive

Developmental

Neurological

Repeated Dose

Skin Sensitization

Respiratory
Sensitization

Eye Irritation

Dermal Irritation

Acute

Chronic

Persistence

Bioaccumulation

Hydroxyphenyl Sulfone Alternatives

h°^Ch~O-3"

Bisphenol S

4-Hydroxyphenyl sulfone

80-09-1

L

M

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

L*

M

M

M*

M*

M

H§

L§



L§

L§

M

H

M

L







ho

TGSA

Bis-(3 -allyl-4-hydroxyphenyl)
sulfone

41481-66-7

L

M

L

M5

M*

M

H

M

M

L

VL

H

M

H

L











BPS-MAE

Phenol,4-[[4-(2-propen-l-
yloxy )phenyl] sulfonyl] -

97042-18-7

L

M*

M



M*

M

L

L

M

L

VL

H

H

H

L









W:+>-

BPS-MPE

4-Hydroxy-4'-

benzyloxydiphenylsulfone

63134-33-8

L

M

M*

M*

M*

M

H§

L



L

L

VH

H

H

M



D-8

4-Hydroxyphenyl
4-isoprooxyphenylsulfone

95235-30-6

L

M

L

M5

M*

M

M

L§



L§

L§

H

H

M

M

Vll

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FINAL REPORT - January 2014

ES-1 Screening Level Toxicology Hazard Summary for BPA and Alternatives (Continued)

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 E = High hazard VH = Very High hazard — Endpoints in colored text (VL, L, , , 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.	

Structure

Chemical

(for TSCA inventory name and
relevant trade names see the
individual profiles in Section 4.8)

CASRN

Human Health Effects

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l,7-bis(4-Hydroxyphenylthio)-3,5-
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93589-69-6

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M

M*

M*



H§

M*

H

H

H

L



Pergafast 201

N-(p-Toluenesulfonyl)-N'-(3-p-
toluenesulfonyloxyphenyl)urea

232938-43-1

L

M

L

M

H

L

M

L



L

VL

H

H

VH

L

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BTUM

4.4'-bis(\-carbamovl-4-

methylbenzenesulfomide)diphenylme

tliane

151882-81-4

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M

L

L

L

L

M

L



L

L

H

H

H

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UU

Urea Urethane Compound

321860-75-7

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M

L

L

L

L

L

L



L

L

L

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viii

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FINAL REPORT - January 2014

Table of Contents

Executive Summary	ii

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	DfE 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

4.3	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	4-21

4.5.3	Environmental Persi stence	4-22

4.6	Endocrine Activity	4-25

4.7	Hazard Summary Table	4-1

4.8	Hazard Profiles	4-4

Bisphenol A	4-4

Bisphenol F	4-54

Bisphenol C	4-87

MBHA	4-114

BisOPP-A	4-136

IX

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FINAL REPORT - January 2014

Bisphenol AP	4-158

Substituted Phenolic Compound #1	4-182

Substituted Phenolic Compound #2	4-202

PI IBB	4-227

Bisphenol S	4-250

2,4-BPS	4-275

TGSA	4-289

BPS-MAE	4-307

BPS-MPE	4-321

D-8	4-337

D-90	4-353

DD-70	4-367

Pergafast 201 	4-378

BUM	4-395

11 	4-406

5.	General Exposure and Life-cycle 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 that May Impact Exposure to

BP A and Alternatives	5-5

5.2	Potential Sources of Exposure in the Life-cycle of Thermal Paper	5-7

5.2.1	Manufacture of Developers	5-7

5.2.2	Manufacture of Thermal Paper	5-8

5.2.3	Conversion of Thermal Paper	5-10

5.2.4	Use of Thermal Paper	5-10

5.2.5	End-of-Life	5-11

5.2.6	Manufacture of Recycled Paper Products	5-11

5.3	Available Data on Occupational, Consumer, and Environmental Exposures

to BP A, Thermal Paper Life-cycle	5-12

5.3.1	BPA in Receipts	5-12

5.3.2	Bisphenol S (BPS) in Receipts	5-13

5.3.3	BPA Transfer to Skin and Potential for Dermal Absorption	5-13

5.3.4	Occupational Exposure	5-13

5.3.5	Consumer and General Population Exposure	5-14

5.3.6	Environmental Exposure	5-15

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

6.1.3	Persistence	6-2

6.1.4	Bioaccumulation Potential	6-2

x

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FINAL REPORT - January 2014

6.1.5 Exposure Considerations	6-3

6.2	Considerations for Poorly or Incompletely Characterized Chemicals and

Variable Amounts of Data	6-3

6.3	Performance Considerations	6-4

6.4	Economic Considerations	6-5

6.5	Social Considerations	6-6

6.6	Trade-offs and Interim Risk Mitigation	6-8

6.7	Innovation and Design Challenges	6-9

6.8	Relevant Resources	6-10

6.8.1	Resources for State and Local Authorities	6-10

6.8.2	Federal Agency Resources	6-11

6.8.3	Resources for Global Regulations	6-11

6.8.4	GreenScreen™ for Safer Chemicals	6-12

6.9	Related Assessments	6-12

xi

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FINAL REPORT - January 2014

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

BMD

Benchmark Dose

BMDL

Benchmark Dose Lower-confidence Limit

BPA

Bisphenol A

BPS

Bisphenol S

BOD

Biochemical Oxygen Demand

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

DOC

Dissolved Organic Carbon

dpi

Dots per inch

EC 50

Half Maximal Effective Concentration

ECHA

European Chemicals Agency

ECOSAR

Ecological Structure Activity Relationships

EDSP

Endocrine Disruptor Screening Program

EEC

European Economic Community

Eh

Redox potential

EKG

El ectrocardi ogram

EPA

U.S. Environmental Protection Agency

EPCRA

Emergency Planning and Community Right-to-Know Act

EPI

Estimations Program Interface

ERMA

Environmental Risk Management Authority

EU

European Union

EWG

Environmental Working Group

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

HIPAA

Health Insurance Portability and Accountability Act of 1996

HPLC

High Performance Liquid Chromatography

HPV

High Production Volume

HSDB

Hazardous Substances Data Bank

IARC

International Agency for Research on Cancer

IR

Infrared

11

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FINAL REPORT - January 2014

IRIS

Integrated Risk Information System

IUC LID

International Uniform Chemical Information Database

Koc

Soil adsorption coefficient

Kow

Octanol/water partition coefficient

LC50

Median Lethal Concentration

LCA

Life-cycle Assessment

LD50

Median Lethal Dose

LD

Lactation Day

LFL

Lower Limit of Flammability

LOAEL

Lowest Observed Adverse Effect Level

LOEC

Lowest Observed Effective Concentration

MDI

Mean Daily Intake

MF

Molecular Formula

MITI

Japanese Ministry of International Trade and Industry

MW

Molecular Weight

MSDS

Material Safety Data Sheet

NAICS

North American Industry Classification System

NES

No Effects at Saturation

NGO

Non-Governmental Organization

NHANES

National Health and Nutrition Examination Survey

NICNAS

National Industrial Chemicals Notification and Assessment Scheme

NIOSH

National Institute for Occupational Safety and Health

NIR

Near Infrared

NOAEL

No Observed Adverse Effect Level

NOEC

No Observed Effect Concentration

NOEL

No Observed Effect Level

NTP

National Toxicology Program

OECD

Organisation for Economic Cooperation and Development

OPPT

Office of Pollution Prevention and Toxics

P2

Pollution Prevention

PBB

Poly-Brominated Biphenyls

PBDE

Polybrominated Diphenyl Ether

PBT Profiler

Persistent, Bioaccumulative, and Toxic (PBT) Chemical Profiler

PMN

Premanufacture Notice

PNEC

Predicted No Effect Concentration

POS

Point-of-sale

ppb

parts per billion

ppm

parts per million

PVC

Polyvinyl Chloride

REACH

Registration, Evaluation, Authorisation and Restriction of Chemical substances

RoHS

Restriction of Hazardous Substances

SAR

Structure Activity Relationship

SCAS

Semi-Continuous Activated Sludge

SF

Sustainable Futures

SMILES

Simplified Molecular-Input Line-Entry System

SPARC

Sparc Performs Automated Reasoning in Chemistry

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TDI

Total Daily Intake

TOC

Total Organic Carbon

TRI

Toxics Release Inventory

TSCA

Toxic Substances Control Act

QSAR

Quantitative Structure Activity Relationships

UFL

Upper Limit of Flammability

USGS

U.S. Geological Survey

WHO

World Health Organization

WWTP

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) Branch initiated this alternatives assessment: BPA Alternatives in Thermal
Paper. Thermal paper was selected for evaluation based on concern for potential exposures to
consumers and workers, releases to the environment, and stakeholder interest. DfE's Alternatives
Assessment Program helps industries choose safer chemicals and provides a basis for informed
decision-making by developing a screening-level comparison of potential human health and
environmental impacts of chemical alternatives. Representatives from industry, academia,
government, and non-governmental organizations (NGOs) provided input which DfE considered
to select and evaluate alternatives to BPA in thermal paper and develop this report. Although
the purpose of DfE Alternatives Assessments is to provide information that will enable selection
of safer alternatives, in some projects, clearly safer alternatives are not available. Hazard trade-
offs complicate the interpretation of results. Nonetheless, the report contains helpful risk
management information for thermal paper companies who are considering alternative
chemicals.

BPA is a high production volume (HPV) chemical with U.S. production volume estimated at
2.4 billion pounds in 2007, with an estimated value of almost $2 billion (U.S. EPA 2010). 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 doses
(U.S. EPA 2010).

Approximately 94% of BPA is used as a monomer to make polycarbonate plastic and epoxy
resins (U.S. EPA 2010). 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 2010). Apart from food-related uses, BPA-based materials
are used in automotive and other transportation equipment, optical media such as DVDs,

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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electrical/electronics equipment, construction, linings inside drinking water pipes, thermal paper
coatings, foundry casting, and elsewhere.

BPA is a commonly used developer in a number of thermal paper applications, such as
point-of-sale (POS) 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 2010). 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 estimated 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 DfE Branch initiated this multi-stakeholder effort
alternatives assessment: BPA Alternatives in Thermal Paper. DfE's Alternatives Assessment
Program provides a basis for informed decision-making by developing a screening-level
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, POS equipment manufacturers, retailers, trade associations, NGOs, 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 alternatives assessment evaluated the alternatives that were judged by stakeholders as most
likely to be functional 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 information 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 by
evaluating the hazards associated with likely functional alternatives to BPA, and make this
information available to decision-makers and the public. Information generated from this effort
will contribute to more informed decisions concerning the selection and use of developers in
thermal paper technologies and the disposal and recycling of thermal paper.

3 For more information on the DfE Program's Alternatives Assessments, see
www.epa. eov/dfe/alternative assessments.html.

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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.

An assessment of process chemicals (i.e., those used in the manufacture 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.

This report summarizes the outcomes of the alternatives assessment, and aims to improve
understanding of the potential environmental and human health hazards 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 alternative developers for use
in thermal paper. This report does not provide a ranking of alternatives or provide guidance on
the appropriate use of BPA or other alternatives; rather the information provided in this
alternatives assessment is meant to assist decision makers in better understanding BPA and its
potential chemical alternatives in thermal paper.

This report is organized as follows:

• Chapter 1 (Introduction): provides background on the BPA Alternatives in Thermal Paper
Partnership, including the purpose and scope of the assessment.

• Chapter 2 (Products and Materials: BPA in Thermal Paper): provides information on BPA
and its use in thermal paper as a developer.

• Chapter 3 (Background on Thermal Printing Technology): describes the thermal paper
printing system and how developers interact with other components in the system to create a
printed product.

• Chapter 4 (Hazard Evaluation of Bisphenol A (BPA) and Alternatives): provides the results
of the hazard assessment of BPA and the 19 alternatives identified for inclusion. This chapter
also discusses how the alternatives were identified.

• Chapter 5 (General Exposure and Life-cycle Information): details the human health and
environmental exposure pathways of developers from thermal paper and other life-cycle
considerations.

• Chapter 6 (Considerations for Selecting Thermal Paper Developers): 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 DfE 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 BPA action plan. The Agency chose this tool to inform
the chemical substitution that may occur as an outcome of other activities described in the action

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plan. The intent was to compare the intrinsic properties of chemical alternatives that may be
substituted for BPA in thermal paper, based on a consistent and comprehensive set of endpoints.
DfE Alternatives Assessments provide an opportunity to learn more about chemicals used in
specific applications. This approach often complements other EPA activities, such as research or
regulatory programs.

Alternatives assessments may include a comparison of the chemical of interest with design or
process changes, alternative materials, or chemical substitutes. DfE Alternatives Assessments
focus on the hazard characteristics of chemical alternatives, providing information on the
environmental and human health profiles of each chemical included. In addition, DfE
Alternatives Assessments describe intrinsic properties that inform our understanding of the
potential for exposure and hazard. These properties include concerns associated with chemical
structure, absorption potential, persistence and bioaccumulation. Industry and other stakeholders
can use this information, in combination with an analysis of cost, performance, and other factors,
to choose alternatives. DfE Alternatives Assessments can also identify the characteristics of safer
alternatives and guide innovation and product development, especially when clearly preferable
alternatives are not available.

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 assessments, life-cycle assessments (LCAs), and risk assessments 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 upon
which other tools, such as risk assessments and LCAs, can build.

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. 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 the amount
used, physical form, and route of exposure, can be quite similar within a given functional use,
allowing for a focus on hazard reduction. When less hazardous alternatives have different
physical/chemical profiles or require different use levels, it may be appropriate to also conduct
an exposure assessment.

The substitutes evaluated in some DfE alternatives assessments include chemical alternatives
that are of low concern for human health and environmental health hazards, while in other
alternatives assessments, the chemical alternatives exhibit significant hazard trade-offs. When
trade-offs are a concern, other approaches may be needed. For example, it may be necessary to
gather additional information on exposure scenarios and the potential for control or mitigation of
risks, such as design changes, alternative materials, or, when necessary, exposure controls. The
National Institute for Occupational Safety and Health (NIOSH) Hierarchy of Controls illustrates
the order of preference of potential control solutions (NIOSH 2011).

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DfE 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: Designing safer chemicals — "Design chemical products to affect their desired
function while minimizing their toxicity," and

•	Principle 10: Design for degradation — "Design chemical products so they break down into
innocuous products that 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 can enable
identification of safer substitutes that emphasize greener chemistry and point the way to
innovation in safer chemical design, where hazard becomes a part of a performance evaluation.

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).

NIOSH. (2011). "Workplace Safety & Health Topics." from

http://www.cdc.gov/niosh/topics/ctrlbandins/ctrlbandingfaq.html.

U.S. Environmental Protection Agency (U.S. EPA) (2010). 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
1,150 kilotons/year in 2005/2006 (JRC-IHCP 2010).

BPA is found in a diverse array of products in addition to thermal paper. One of the main uses 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 2010).

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). Although there are currently no estimates for the
amount of BPA used in thermal paper in the U.S., the amount of BPA used in Europe 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).

In a sample of ten twelve-inch blank cash register receipts from businesses in suburban Boston,
Mendum et al. (2011) 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. 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 2011). 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

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(geometric mean: 217|ig/g). Of the receipt papers collected in the U.S., 100 percent of them
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.

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. POS 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 (EKG), 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 EKG printouts, indicates that it is
made with bisphenol S (J. Warner, personal communication, March 1, 2011).

According to European estimates, POS 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 10 percent of thermal paper
applications and another 10 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 (2011). "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) (2010). 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 (POS) 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.1 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, in which paper 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 lacks 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 the paper, 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/m2 or pounds per ream): (1) fax and POS grades, with an average basis
weight of 58 grams, (2) label and ticket grades, with an average basis weight of 80 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

1 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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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.

Figure 3-2: Elements of the Thermal Reactive Layer

O °Ve

0 Developer

~ Sensitizer

¦ Binder

Dye

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) 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 activation.

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Table 3-1: Example of Dyes Used in Thermal Paper

Chemical Names and 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

Spiro[isobenzofuran-l(3H),9'-
[9H]xanthen]-3-one, 6'-
(diethylamino)-3'-methyl-2'-
(phenylamino)-; N-102 (ODB)

29512-49-0

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-12,1 '(3'H)-
isobenzofuran]-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]-; Crystal violet lactone; CVL

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

1 (3H)-Isobenzofuranone,
4,5,6,7-tetrachloro-3,3-bis[2-[4-
(dimethylamino)phenyl]-2-(4-
methoxyphenyl)ethenyl]-; NIR Black 78

113915-68-7

black

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Chemical Names and Synonyms

CASRN

Color

3-(4-Diethylamino-2-methylphenyl)-3-(l-ethyl-2-
methyl-lH-indol-3-yl)-4-azaphthalide; Blue 220

114090-18-5

blue

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 is 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, and

•	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

Chemical Names and Synonyms

CASRN

Ethanedioic acid,l,2-bis[(4-chlorophenyl)methyl] ester; Di-
(P-Chlorobenzyl) oxalate

19829-42-6

Ethanedioic acid,l,2-bis[(4-methylphenyl)methyl] ester; Di-
(P-Menthylbenzyl) oxalate

18241-31-1

Ethanedioic acid,l,2-bis(phenylmethyl) ester; Dibenzyl
oxalate

7579-36-4

Naphthalene, 2-(phenylmethoxyl)-; 2-Benzyloxynapthalene

613-62-7

1,4-diphenylbutane-1,4-dione; 1,4-Diphenoxybutanes

495-71-6

1 -phenyl -4-(phenylmethyl )benzene; 4-B enzylbiphenyl

613-42-3

1,4-Benzenedicarboxylicacid, 1,4-dimethylester; Dimethyl
terephthalate

120-61-6

Benzene, l,l'-[l,2-ethanediylbis(oxy)]bis-; (2-
Phenoxyethoxy)benzene; 1,2-Diphenoxy ethane

104-66-5

Benzene, 1,1'-[ 1,2-ethanediylbis(oxy)]bis[3 -methyl-; 1,2-
Bis(3-methoxyphenoxy) ethane

54914-85-1

l,l'-Sulfonylbisbenzene; Diphenyl sulfone

127-63-9

Octadecanamide; Stearamide (waxy)

124-26-5

Hexanedioic acid, polymer with 1,4-butanediol and 1,2-
ethanediol; Oligoethylene butylene glycol adipate,
Hexanedioic acid; Kemamide S (waxy)

26570-73-0

Octadecanamide,N,N'-l,2-ethylenebis-; Ethylene bis
stearamide

110-30-5

Octadecanamide, N-phenyl; N-phenylstearamide;

637-54-7

N-(2-methylphenyl)-3-oxobutanamide; o-
Acetoacetotolui di de

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)

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 used instead, 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.2
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

2 The use of ribbons, which contain a mirror image of any tiling 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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thermal printing systems a useful tool for market segments like retailers, laboratories with
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.
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 12 years (Koehler Thermal
Papers n.d.).

3.4 Alternatives Included in this Assessment

Potential alternatives to BPA for use in thermal paper were initially identified through internet
searches, and focused on chemicals of similar structure and physical/chemical properties.
Stakeholders also suggested specific chemicals for inclusion. With the assistance of stakeholders,
the U.S. Environmental Protection Agency (EPA) identified 19 alternatives to BPA in thermal
paper (see Table 3 3 below). These alternatives were selected because they 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. Current commercial use was not a requirement for inclusion.
A hazard assessment was conducted on BPA and these 19 alternatives; the findings are discussed
in Chapter 4.

Chemical Alternatives and the Toxic Substances Control Act

EPA's Design for the Environment (DfE) program is administered by the Office of Pollution Prevention and
Toxics (OPPT), which is charged with the implementation of the Toxic Substances Control Act (TSCA) and the
Pollution Prevention Act (PPA).

Central to the administration of TSCA is the management of the TSCA Inventory. Section 8 (b) of TSCA
requires EPA to compile, keep current, and publish a list of each chemical substance that is manufactured or
processed in the United States. Companies are required to verify the TSCA status of any substance they wish to
manufacture or import for a TSCA-related purpose. For more information please refer to the TSCA Chemical
Substance Inventory website: http://www.epa.gov/opptintr/existingchemicals/pubs/tscainventorv/basic.html.

TSCA and DfE Alternatives Assessments

Substances selected for evaluation in a DfE Alternatives Assessment generally fall under the TSCA regulations
and therefore must be listed on the TSCA inventory, or be exempt or excluded from reporting before being
manufactured in or imported to, or otherwise introduced in commerce in, the United States. For more
information see http://www.epa.gov/oppt/newchems/pubs/whofiles.htm

To be as inclusive as possible, DfE Alternatives Assessments may consider substances that may not have
been reviewed under TSCA, and therefore may not be listed on the TSCA inventory. DfE lias worked with
stakeholders to identify and include chemicals that are of interest and likely to be functional alternatives,
regardless of their TSCA status. Chemical identities are gathered from the scientific literature and from
stakeholders and, for non-confidential substances, appropriate TSCA identities are provided.

Persons are advised that substances, including DfE-identified functional alternatives, may not be introduced into
U.S. commerce unless they are in compliance with TSCA. Introducing such substances without adhering to the
TSCA provisions may be a violation of applicable law. Those who are considering using a substance discussed
in this report should check with the manufacturer or importer about the substance's TSCA status. If you have
questions about reportability of substances under TSCA, please contact the OPPT Industrial Chemistry Branch
at 202-564-8740.

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FINAL REPORT - January 2014

Table 3-3: The Alternatives Selected for Analysis in the Hazard Assessment

The chemicals included in this assessment are identified based on information provided to us by stakeholders, supplemented with publicly available information
obtained through internet information searches.

CASRN

Chemical Name(s)

Common

Name(s)

Molecular
Formula

Structure

80-05-7

Phenol, 4,4'-
(methylethylidene)bis-;

2,2-bis(p-
hydroxyphenyl)propane

Bisphenol A,
BPA

c15h1602

HO——

O0H

620-92-8

Phenol, 4,4'-methylenebis-;
Bis(4-'
hydro xyphenyl)methane

Bisphenol F,
BPF

CbHjoOt

ho"

a



79-97-0

Phenol, 4,4'-(l-
methylethylidene)bis[2-
methyl; ,2'-Bis(4-hydroxy-
3 -methylpheny l)propane

Bisphenol C,
BPC

C17H20O2

HO—	

C^~°H

5129-00-0

Benzeneacetic acid, 4-

hy droxy-. alpha. -(4 -
hydroxyphenyl)-, methyl

ester; Methyl bis(4-
hydroxyphenyl)acetate

MBHA

Ci5H1404

ho"

cx

or

TX

24038-68-4

[1,1 '-Biphenyl]-2-ol, 5,5"-
(1 -methylethylidene)bis-;
4,4'-Isopropyllidenebis(2-
phenylpheno)

BisOPP-A

C27H24O2

cx

ho"

&



1571-75-1

4,4'-(l-
Phenylethylidene)bisphenol

Bisphenol AP,
BPAP

C20H18O2

HO—^ ^—

Ooh

)

PROPRIETARY

Substituted
phenolic
compound #1

N/A

N/A

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FINAL REPORT - January 2014

CASRN

Chemical Name(s)

Common

Name(s)

Molecular
Formula

Structure

PROPRIETARY

Substituted
phenolic
compound #2

N/A

94-18-8

Benzoic acid, 4-hydroxy-,
phenylmethyl ester; Benzyl
4-hydroxybenzoate

PHBB

Ci4H1203

HO ^

80-09-1

Phenol, 4,4'-sulfonylbis-;
4-Hydroxyphenyl sulfone

Bisphenol S

C12H10O4S

ho—$ y— s—
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FINAL REPORT - January 2014

CASRN

Chemical Name(s)

Common

Name(s)

Molecular
Formula

Structure

93589-69-6

Phenol, 4,4'-
[methylenebis(oxy-2,1 -
ethanediylthio)]bis-; 1,7-
bis(4-Hydroxyphenylthio)-
3,5-dioxaheptane

DD-70

C17H20O4S2

232938-43-1

N-(p-Toluenesulfonyl)-N'-
(3-p-

toluenesulfonyloxyphenyl)u
rea

Pergafast 201

C21H20N2O6S2

,_Ofj p-i-O"

w 0 f~W

151882-81-4

Benzenesulfonamide, N,N'-

[methylenebis(4,1 -
phenyleneiminocarbonyl)]bi
s[4-methyl-; 4.4'-bis( \ -
carbamoyl-4-
methylbenzenesulfonamide)
diphenylmetliane

BTUM

C29H28N4O6S2

Y X X V

321860-75-7

UU, Urea
Urethane
Compound

C42H36N608S

H3C °s° ch3

U.A,J^A0iJ

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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 this alternatives assessment. Chemicals were excluded based on feedback from the
stakeholders, because their physical and/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 this DfE Alternatives Assessment

CASRN

Chemical and
Common Name(s)

Molecular
Formula

Structure

98-54-4

p-tert-butylphenol:
Phenol," 4-( 1,1-
dime thy lethy 1)-

Ci0H14O

\ f~S ON

/ w

92-69-3

p-Phenylphenol; [1,1-
Biphenyl] -4-ol

Ci2H10O

^ ^—OH

2664-63-3

4,4' -Thiodiphenol;
Phenol, 4,4'-thiobis-

c12h10o2s

19715-19-6

Benzoic acid, 3,5-

bis(l,l-
dimethyl ethyl) -2 -
hydroxy-; 3,5-di-tert-
butylsalicylic acid

C15H2203

3 O

120-47-8

Benzoic acid, 4-
hydroxy-, ethyl
ester; ethyl-p-
hydroxybenzoate,
ethyl paraben

C9H10O3

22479-95-4

Dimethyl-4-
hydroxyphthalate;
DMP-OH

C10H10O5

\ /

0 0

1694-06-0

N-(p-

toluenesulphonyl)-N' -

(3-p-

toluenesulphonyloxyp
henyl)urea

C8H10N2O3S

°, ,0 j

4724-47-4

octadecylphosphonic
acid; Phosphonic acid,
P-octadecyl-

Ci8H3903P

ho' oh

65-85-0

Benzoic acid

c7h6o2

aoh

57-11-4

Octadecanoic acid;
stearic acid

Ci8H30O2

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CASRN

Chemical and
Common Name(s)

Molecular
Formula

Structure

144-62-7

Ethanedioic acid;
oxalic acid

c2h2o4

A .OH

H°J

11113-50-1

Boric acid

h3bo3

HO^ xOH
B
1

149-91-7

Benzoic acid, 3,4,5-
trihydroxy-; gallic acid

c7h6o5

y/-

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FINAL REPORT - January 2014

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 19 alternative chemicals that were identified as potential functional substitutes for
BPA. 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. Otherwise, pure substances were analyzed in this assessment.
Users of the hazard information in this alternatives assessment should be aware of the purity of
the trade product they purchase, as the presence of impurities may alter the assessment of the
alternative. 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, and the process
of evaluating human health and environmental endpoints in Sections 4.4 and 4.5, respectively. 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 4.1. Lastly, the collected data and hazard profile of each
chemical are presented in Section 4.2.

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 DfE Alternatives
Assessment Criteria for Hazard Evaluation (U.S. EPA 201 lb). 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 that DfE
characterizes but does not assign criteria, which 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 lb). Table 4 1 provides brief definitions of human health toxicity,
environmental toxicity, and environmental fate endpoints

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Table 4-1: Definitions of Toxicological and Environmental Endpoints for Hazard Assessment

Endpoint

Category

Endpoint

Definition

Repeated Dose Toxicity

Adverse effects (immediate or delayed) that impair normal
physiological function (reversible and irreversible) of
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

Hypersensitivity of the airways following inhalation of a
substance.

Skin Sensitization

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

Enviromnental toxicity refers to 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 enviromnent,
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).

Bioaccumulation

The process in which a chemical substance is absorbed in
an organism by all routes of exposure as occurs in the
natural enviromnent (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.

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The hazard profile for each chemical contains endpoint-specific summary statements (see
Section 4.2). For each of the endpoints listed in Table 4 1, these summary statements provide 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 review
and comment, and were finalized in 2011 (U.S. EPA 201 lb). 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)

>2-10

>10-20

>20

Inhalation LC50 - dust/mist/
fume (mg/L)

<0.5

>0.5-1.0

>1-5

Carcinogenicity

Known or
presumed

human
carcinogen
(equivalent to

Globally
Harmonized
System of
Classification
and Labeling of
Chemicals
(GHS)

Suspected
human
carcinogen
(equivalent to
GHS Category
2)

Limited or
marginal
evidence of
carcinogenicity
in animals (and
inadequate
evidence in
humans)

Negative studies
or robust
mechanism-
based structure
activity
relationships
(SAR) (as
described above)

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Endpoint

Very High

High

Moderate

Low

Very Low

Categories 1A
and IB)1

Mutagenicity/Genotoxicity

GHS Category
1A or IB: '
Substances
known to
induce heritable

GHS Category
2: Substances
which cause
concern for
humans owing
to the

Germ cell mutagenicity

mutations or to
be regarded as
if they induce

possibility that

they may
induce heritable

Evidence of

heritable
mutations in the
germ cells of
humans

mutations in the
germ cells of
humans

mutagenicity
supported by
positive results

in in vitro OR in

Negative for
chromosomal
aberrations and
gene mutations.

vivo somatic

or no structural

Evidence of

cells of humans

alerts

mutagenicity
supported by

or animals

Mutagenicity and
genotoxicity in somatic
cells

positive results

in in vitro AND
in vivo somatic

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

1-2.5

>2.5-20

>20

(mg/L/day)

Inhalation - dust/mist/fume

<0.1

0.1-0.5

>0.5-5

(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

Inhalation - vapor, gas

1-2.5

>2.5-20

>20

(mg/L/day)

Inhalation - dust/mist/fume

<0.1

0.1-0.5

>0.5-5

(mg/L/day)

Neurotoxicity

Oral (mg/kg/day)

<10

10-100

>100

Dermal (mg/kg/day)

<20

20-200

>200

Inhalation - vapor, gas

<0.2

0.2-1.0

>1.0

(mg/L/day)

1 The United Nations' GHS document can be found at

http://www.unece.org/fileadmin/DAM/trans/danger/publi/ghs/ghs rev04/English/ST-SG-AC 10-30-Rev4e.pdf.

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Endpoint

Very High

High

Moderate

Low

Very Low

Inhalation - dust/mist/fume
(mg/L/day)

<0.02

0.02-0.2

>0.2

Repeated-dose toxicity1

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
1A and 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

Fortius 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
(EC50) (mg/L)

<1.0

1-10

>10-100

>100 or No
Effects at
Saturation
(NES)

Chronic aquatic toxicity -
Lowest Observed Effect
Concentration (LOEC) or
Chronic Value (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)

Fortius 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

in 28-day studies or similarly modified for studies of other durations.

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, enviromnental fate parameters, and simple
volatilization models. Also includes distribution in the enviromnent as estimated

from a fugacity model.

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 from guideline and nonguideline 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
0) 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 the environment and in living
organisms. Analog approaches and SAR-based estimation methods are also useful tools and are
discussed throughout Section 0. Information on how the evaluation of polymers differs from the
evaluation of discrete chemicals is presented in Section 0.

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 chemicals well characterized by experimental studies, this
usually resulted in the collection of recent high-quality reviews or peer-reviewed risk
assessments. In some cases, these reviews and risk assessments were supplemented by primary

2 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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searches of scientific literature published after these secondary sources were released, which is
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 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 alternatives assessed, high-quality secondary sources were not available;
therefore, 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 degradation product.

Well-Studied Chemicals - Literature Search Strategy

As mentioned above, for chemicals that have been well characterized (limited to BPA in this DfE
Alternatives Assessment), the literature review began with recent, high-quality, authoritative
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. In some cases,
primary studies were also evaluated to supplement the secondary sources. 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
(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

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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 le).

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 0. In addition,
the endpoints for impurities or oligomers with a molecular weight (MW) >1,000 daltons 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 2010).
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.

Hierarchy of Data Adequacy

Once the studies were obtained, they were 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 4.2. 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 nonguideline 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

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

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performed according to Harmonized EPA or Organisation for Economic Cooperation and
Development (OECD) 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
discrepancies that were identified within the set of data were examined further and addressed
using a weight-of-evidence approach that was described in the data entry to characterize the
endpoint whenever possible.

When available, experimental data from guideline or well-performed experimental studies were
generally 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.

Assessment of Oligomeric Mixtures

In this alternatives assessment, there are two chemicals that were mixtures of low molecular
weight (MW) oligomers comprised of two or three 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 provided in the
individual chemical hazard profiles presented in Section 4.2. 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.

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

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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 Section 0). 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 material's 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 1x10" 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 lxlO"4 mm Hg generally exist in

4 8

the gas phase in the atmosphere. Substances with a vapor pressure between 1x10" and 1x10"

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 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 1x10" mm Hg was assigned for chemicals without experimental
data or for those substances that were anticipated by professional judgment to be nonvolatile
(U.S. EPA 1999b).

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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 lxlO"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: >10,000 mg/L represents 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 <1 mg/L represents insoluble, noting that these guidelines were not
followed consistently within the scientific literature (U.S. EPA 201 le). 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 material's water solubility), the chemical was described as
having no effects at saturation (NES). An NES designation is equivalent to a low ecotoxicity
hazard designation for that endpoint.

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, dispersability 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
that have both a hydrophilic (polar) head and a hydrophobic (nonpolar) 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
material's water solubility alone.

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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 lxlO"6 g/L (U.S. EPA 201 le). A water solubility of lxlO"3 mg/L is
the default value used for discrete organics as well as nonionic polymers with a MW >1,000
daltons. According to information contained in the literature concerning polymer assessment and
the SF Polymer Assessment guidance assignment this is consistent with an analysis of the
chemicals used in the development of the water solubility estimation program in EPA's
EPISuite™ software (Boethling and Nabholz 1997; U.S. EPA 2010). The training set for this
model included 1,450 chemicals with a MW range 27-628 daltons, and experimental water
solubility values ranging from miscible to 4x10" mg/L (Meylan, Howard et al. 1996; U.S. EPA

201 lg). Given that water solubility decreases with MW, a default value of 1x10" mg/L is
consistent with the limited bioavailability expected for materials with a MW >1,000 daltons.
Although no BP A 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 (Kow)

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 indicates the
partitioning of a chemical 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, a log Kow value 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. The log
Kow 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 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 used for
calibration) for this model included 10,946 chemicals with a MW range of 18-720 daltons and
experimental log Kow ranging from -3.89 to 8.70 (Meylan and Howard 1995; U.S. EPA 201 lh).
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.

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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 nonflammable, 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.

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.

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's Law constant, and octanol/water partition coefficient decrease. For acids
and bases, the dissociation constant is expressed as the pKA and pKB, respectively.

Henry's Law Constant

Henry's Law 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's Law constant is

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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 information about the chemical's
tendency to partition within environmental compartments and the amount of material removed
by stripping in a sewage treatment plant. Henry's Law constant values less than lxlO"7 atm-

m /mole indicate slow volatilization from water to air (the Henry's Law constant for the

7 3 3

volatilization of water from water is 1x10" atm-m /mole) and values more than 1x10" atm-

m /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's Law constant. These models
determine the half-life for volatilization from a model river and a model lake. A maximum value

8 3

of 1x10" atm-m /mole for the Henry's Law constant was assigned for chemicals without
experimental data or for those that were anticipated by professional judgment to be nonvolatile.

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 less likely to leach into groundwater. 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
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 2004).

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

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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 If; U.S. EPA
201 Id).

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 changes in the material's hazard designation. In this
example, going from Cr(VI) to Cr(III) makes the compound less toxic.

Environmental 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
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 biodegradation
processes 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 of theoretical ultimate degradation 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 Section 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

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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 LD50s or LC50S 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 rather than 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
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). Information suggestive of pre-cancerous lesions also merits
the designation of Moderate concern.

Similarly, the hazard designation for mutagenicity/genotoxicity was also based on the level of
evidence rather than potency. Complete data requirements for this endpoint include 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

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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 lb).

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 evidence3 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
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 EPA (1994). Public access to free validated QSAR
models for human health endpoints is far more limited than physical/chemical properties,
environmental fate parameters, or ecotoxicology.

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. 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.

Carcinogenicity

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.

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

3 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).

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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 two
or three 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 not available, the aquatic toxicity was estimated using EPA's ECOSAR™ software, and the
persistence designation was estimated using models in EPA's EPISuite™ software. The hazard
designation was determined by applying the criteria to these estimates.

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 "three surrogate species"). Aquatic toxicity values were reported in the assessment as
follows:

• Acute (estimated or experimental) - LC50 in mg/L or EC50 in mg/L

• Chronic (experimental) - No observed effect concentration (NOEC) in mg/L

• Chronic (estimated) - ChV, or the geometric mean between the NOEC and the LOEC, in
mg/L

Experimental data and estimates reported in the alternatives assessment includes information on
the species tested and typically focus on freshwater aquatic organisms. Test data on other
organisms (e.g., worms) were included in the assessment if data or models were readily
available. These data would be evaluated using professional judgment in support of the hazard
designations assigned using the three surrogate freshwater species; however, they were not used
exclusively to assign a hazard designation as DfE criteria are not available. For the estimated
results from ECOSAR, the equations are derived from surrogate species of fish, zooplankton,
and phytoplankton. While these surrogate species can comprise several genera as well as
families, the equations are not intended to be species specific, but rather estimate toxicity to the
general trophic levels they represent (Mayo-Bean, Nabholz et al. 2011).

If an experimental or estimated effect level exceeded the known water solubility of a chemical
substance, or if the log Kow exceeded the ECOSAR™ cut-off values for acute and chronic
endpoints (which are class specific), No Effects at Saturation (NES) were determined for the
aquatic toxicity endpoints. NES indicates that at the highest concentration achievable, which is
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

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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. No effects at saturation are also expected in most cases for
insoluble organics, oligomers, or non-ionic polymers with a MW >1,000 daltons resulting in an
overall low hazard concern for aquatic toxicity (Nabholz, Clements et al. 1993).

EPA's ECOSAR™ estimation program uses chemical structure to estimate toxicity of a
substance using class-specific QSARs. ECOSAR™ automatically determines all classes that a
chemical may be related to based on the molecular features of the substance and, therefore, may
provide multiple class-specific estimates for some or all of the species and durations estimated
(Mayo-Bean, Nabholz et al. 2011). Modeled results are dependent on the functional groups
present on the molecule as well as the diversity of chemicals with experimental data used to
build the models (the training set). The hazard profiles report estimates for every class identified
by ECOSAR™. However, the hazard designation was based on the most conservative
ECOSAR™ estimate (highest hazard value). If professional judgement indicate that certain
class-specific estimates were not appropriate for a particular substance, the narcosis (baseline
toxicity) associated with the neutral organic class will be used. Experimental log Kow values were
used preferentially as input into ECOSAR™. In their absence, estimated log Kowvalues from
EPISuite™ were used. ECOSAR™ is maintained and developed as a stand-alone program
(http://www.epa.gov/oppt/newchems/tools/21ecosar.htm). but is also accessible through the EPA
EPISuite™ program after it is installed; therefore the Estimations Program Interface (EPI)
program was may also be used as a citation for the ECOSAR™ values in this report.

There were instances where sufficient experimental data were 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 ChV. ACRs of 10 were used for fish and daphnid, and an ACR of 4 was
used for algae (Rand, Wells et al. 1995).

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 bioaccumulation factor (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 bioconcentration factors (BCFs) are more

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commonly used to evaluate the bioaccumulation hazard. BCFs are defined as the ratio of the
concentration of a dissolved chemical in an aquatic organism to the concentration of the
chemical in the exposure medium (surrounding water); 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 and 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
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 of the bioconcentration and bioaccumulation estimation
programs in the EPISuite™ software (U.S. EPA 201 lg). The training sets for these models
included 527 and 421 chemicals, respectively, with a MW range 68-992 daltons (959 daltons for
BAF). 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 used 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 assigned a Low designation as
discussed above and, as a 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

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hydrolysis, because water is ubiquitous in the environment. Hydrolysis rate constants can be
obtained from the literature or can be estimated, and the resulting half-lives can be compared
directly to DfE criteria. For chemicals without hydrolyzable groups, biodegradation tends to be
the faster degradation process in water, soil, and sediments; however, numerous commercial
chemicals possess labile groups, and these may hydrolyze in the environment at significant or
even rapid rates. Direct and indirect photolysis also represents other potential chemical
degradation processes that are considered in the alternatives assessment, and they are discussed
later in this section. Oxidation by hydroxyl radicals and ozone is the dominant degradation
process for organic chemicals in air.

Biodegradation, the most prevalent biological removal process, was 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 degraded to CO2, water, mineral oxides of certain other elements in the molecule,
and low-MW compounds that can directly enter microbial metabolism. 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,
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 most
relevant for sediments, landfills and sludge digesters in sewage treatment plants; although anoxic
conditions can also occur in soil and the water column. For determining the persistence hazard
designation, 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. Anaerobic degradation may use any of several electron acceptors,
depending on their availability in a given environment and the prevailing redox potential (Eh).
The biodegradative populations that are dominant in a given environment vary with the
conditions, and so do their biodegradative capabilities.

One aspect of the assessment is to determine the potential for removal of a chemical substance,
and especially removal attributable to biodegradation, within a sewage treatment plant and other
environments. In this assessment, the term "ready biodegradability" refers to a chemical's
potential to undergo ultimate degradation in guideline laboratory studies. A positive result in a
test for ready biodegradability can be considered indicative of rapid and ultimate degradation in
most environments, including biological sewage treatment plants. Ready tests typically include a
10-day window, beginning when the biodegradation parameter (e.g., disappearance of dissolved

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organic carbon from test substance, or theoretical oxygen demand) reaches 10%. If the pass level
of the test (60% for oxygen demand and CO2 production; 70% for dissolved organic carbon
disappearance) was 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 hazard
designation.

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 estimate the rate of ultimate and primary
biodegradation using semi-quantitative methods; probability of ready biodegradability in the
OECD 301C test; and probability of rapid biodegradation under methanogenic anaerobic
conditions (specifically under conditions of the OECD 311 test). Each of these is discussed in the
following paragraphs.

The first models (Biowin 5 and 6) used in the screening assessment estimated ready
biodegradability in the OECD 301C test and are also known as the Japanese Ministry of
International Trade and Industry (MITI) models. These models 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.

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 ultimate and primary
biodegradation survey models (Biowin 3 and 4) for evaluating persistence. These models
provided a numeric result, ranging from 1 to 5, that relates to the amount of time required for
complete ultimate degradation (Biowin 3) and removal of the parent substance by primary
degradation (Biowin 4) of the test compound. The numeric result from Biowin 3 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
indicated the potential for the material to partition to sediment, an anoxic compartment, then the
results of the anaerobic probability model (Biowin 7) were also evaluated.

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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 the predominant 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 lb). 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 4.2. Data on endocrine activity were
available for BPA and 10 of the 19 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
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 (FQPA) 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

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(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 la). 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.4 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 lc). 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 2011c). 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,
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 estrogen, 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

4 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/assavvalidation/status.htm.

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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.

Chemical Alternatives and the Toxic Substances Control Act

EPA's Design for the Environment (DfE) program is administered by the Office of Pollution Prevention and Toxics
(OPPT), which is charged with the implementation of the Toxic Substances Control Act (TSCA) and the Pollution
Prevention Act (PPA).

Central to the administration of TSCA is the management of the TSCA Inventory. Section 8 (b) of TSCA requires
EPA to compile, keep current, and publish a list of each chemical substance that is manufactured or processed in the
United States. Companies are required to verify the TSCA status of any substance they wish to manufacture or
import for a TSCA-related purpose. For more information please refer to the TSCA Chemical Substance Inventory
website: http://www.epa.gov/opptintr/existingchemicals/pubs/tscainventorv/basic.html.

TSCA and DfE Alternatives Assessments

Substances selected for evaluation in a DfE Alternatives Assessment generally fall under the TSCA regulations and
therefore must be listed on the TSCA inventory, or be exempt or excluded from reporting before being
manufactured in or imported to, or otherwise introduced in commerce in, the United States. For more information
see http://www.epa.gov/oppt/newchems/pubs/whofiles.htm.

To be as inclusive as possible, DfE Alternatives Assessments may consider substances that may not have been
reviewed under TSCA, and therefore may not be listed on the TSCA inventory. DfE lias worked with
stakeholders to identify and include chemicals that are of interest and likely to be functional alternatives, regardless
of their TSCA status. Chemical identities are gathered from the scientific literature and from stakeholders and, for
non-confidential substances, appropriate TSCA identities are provided.

Persons are advised that substances, including DfE-identified functional alternatives, may not be introduced into US
commerce unless they are in compliance with TSCA. Introducing such substances without adhering to the TSCA
provisions may be a violation of applicable law. Those who are considering using a substance discussed in this
report should check with the manufacturer or importer about the substance's TSCA status. If you have questions
about reportability of substances under TSCA, please contact the OPPT Industrial Chemistry Branch at 202-564-
8740.

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FINAL REPORT - January 2014

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.

; Based on analogy to experimental data for a structurally similar compound.

Structure

Chemical

(for TSCA inventory name and
relevant trade names see the
individual profiles in Section 4.8)

CASRN

Human Health Effects

Aquatic
Toxicity

Environmental
Fate

Acute Toxicity

Carcinogenicity

Genotoxicity

Reproductive

Developmental

Neurological

Repeated Dose

Skin Sensitization

Respiratory
Sensitization

Eye Irritation

Dermal Irritation

Acute

Chronic

Persistence

Bioaccumulation

—C3- OH

Bisphenol A

2,2-bis(p-hydroxyphenyl)propane

80-05-7

xur

Bisphenol F

Bis(4-hydroxyphenyl)methane

620-92-8

M§

IIs

»-b+Q-H

Bisphenol C

2,2'-Bis(4-hydroxy-3-

methylphenyl)propane

79-97-0

L§

M§

H§

H
H

°^V°-x

MBHA

Methyl bis(4-

hydroxyphenyl)acetate

5129-00-0

L§

M§

H§

BisOPP-A

4,4'-Isopropyllidenebis(2-
phenylphenol)

24038-68-4

L§

M§

H§

Bisphenol AP

4,4'-(1 -Phenylethylidene)bisphenol

1571-75-1

L§

M§

H§

Substituted phenolic compound,
PROPRIETARY #1

L§

M§

H§

Substituted phenolic compound,
PROPRIETARY #2

L§

M§

H§

PHBB

Benzyl 4-hydroxybenzoate

94-18-8

L§

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FINAL REPORT - January 2014

Table 4-5: Screening Level Hazard Summary (Continued)

§ Based on analogy to experimental data for a structurally similar compound.

Human Health Effects

Aquatic
Toxicity

Environmental
Fate

Structure

Chemical

(for TSCA inventory name and
relevant trade names see the
individual profiles in Section 4.8)

CASRN

Acute Toxicity

Carcinogenicity

Genotoxicity

Reproductive

Developmental

Neurological

Repeated Dose

Skin Sensitization

Respiratory
Sensitization

Eye Irritation

Dermal Irritation

Acute

Chronic

Persistence

Bioaccumulation

Hydroxyphenyl Sulfone Alternatives

"-Oi-O*

Bisphenol S

4-Hydroxyphenyl sulfone

80-09-1

o o 9H

2,4-BPS

2,4'-Bis(hydroxyphenyl)sulfone

5397-34-2

H§

L§

TGSA

Bis-(3 -allyl-4-hydroxyphenyl)
sulfone

41481-66-7

-OrCK^

BPS-MAE

Phenol,4-[[4-(2-propen-l-
yloxy )phenyl] sulfonyl] -

97042-18-7

•>-c+n-

BPS-MPE

4-Hydroxy-4'-

benzyloxydiphenylsulfone

63134-33-8

H§

<
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FINAL REPORT - January 2014

Table 4-6: Screening Level Hazard Summary (Continued)

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.

Structure

Chemical

(for TSCA inventory name and
relevant trade names see the
individual profiles in Section 4.8)

CASRN

Human Health Effects

Aquatic
Toxicity

Environmental
Fate

Acute Toxicity

Carcinogenicity

Genotoxicity

Reproductive

Developmental

Neurological

Repeated Dose

Skin Sensitization

Respiratory
Sensitization

Eye Irritation

Dermal Irritation

Acute

Chronic

Persistence

Bioaccumulation

Oligomeric and Polymeric Alternatives

-ofo^jw-o+o]-

D-90

Phenol, 4,4'-sulfonylbis-, polymer
with 1,1' -oxybis[2-chloroethane]

191680-83-8

DD-70

l,7-bis(4-Hydroxyphenylthio)-3,5-
dioxaheptane

93589-69-6

H§

Pergafast 201

N-(p-Toluenesulfonyl)-N'-(3-p-
toluenesulfonyloxyphenyl)urea

232938-43-1

xjl-xjy

BTUM

4.4'-bis(\-carbamoyl-4-

methylbenzenesulfomide)diphenylme

thane

151882-81-4

Urea Urethane Compound

321860-75-7

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4.8 Hazard Profiles
Bisphenol A

CASRN: 80-05-7

MW: 228.29

MF: C15H16Q2

Physical Forms:

Neat: Solid

Use: Developer for thermal papers
SMILES: Oc lccc(cc 1 )C(c 1 ccc(0)cc 1 )(C)C

Synonyms: Phenol,4,4'-(l-methylethylidene)bis-; 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'-(l-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'-(l-
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,(l-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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FINAL REPORT - January 2014

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, B-D -glucopyranoside, mono- and di- O-B-D-glucopyranosides, phenol,
4-isopropenylphenol, 4-isopropylphenol, hexestrol, 5,5'-bis-[l-(4-hydroxy-phenyl)-l-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 Japan 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, 2010

Boiling Point (°C)

360.5 at 760 mm Hg (Measured)

EINECS, 2010; IUCLID, 2000

Adequate.

250-252 at 13 mm Hg (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, 2010

Data indicate that BPA will decompose
at elevated temperatures.

Vapor Pressure (mm Hg)

3.99x10 s (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, 1999

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.

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.

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Bisphenol A CASRN 80-05-7

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

Acute Mammalian Toxicity

LOW: The acute oral and dermal toxicity hazard of BPA is low based on experimental data in animals. Data
for exposure via inhalation were inconclusive, as only a single concentration was tested and a 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 the assignment of a Moderate hazard designation.

OncoLogic Results

Moderate (Estimated)

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,

There is confidence 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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Bisphenol A CASRN 80-05-7

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

• 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

• Promotes tumor progression and
reduces time to recurrence in
advanced prostate cancers with
androgen receptor mutations.

Combined Chronic
T oxicity/Car cinogenicity

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.

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Bisphenol A CASRN 80-05-7

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

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-significant increased
incidences of leukemia or lymphomas in
low- and high-dose male mice (9/50, 5/50
versus 2/50 in controls) not considered by
NTP to be convincing evidence of
carcinogenic effect for BPA.

NTP, 1982

Adequate.

Studies that included perinatal (gestational
and/or lactational) exposures to BPA (oral
doses to the dam from -10 to 250 |ig/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

FAO/WHO, 2011

Summary of data, data quality, and
conclusions from the expert panel.

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Bisphenol A CASRN 80-05-7

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

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.

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, and (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

FAO/WHO, 2011

Summary of data, data quality, and
conclusions from the expert panel.

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Bisphenol A CASRN 80-05-7

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

mice.

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

MODERATE: Key studies identified by NTP indicate there are multiple distinct endpoints with NOAELs in
the range of Moderate hazard concern with LOAELs in the range of Low hazard concern. At the target dose of
50 mg/kg-day, the NOAELs are on the margin of High and Moderate hazard, according to DfE criteria.
Benchmark Dose (BMD) Modeling conducted by NTP, which interpolates between NOAEL and LOAEL
values, yields values that further support a Moderate hazard designation.

Reproduction/
Developmental Toxicity
Screen

No data located.

Combined Repeated
Dose with Reproduction/
Developmental Toxicity
Screen

No data located.

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Bisphenol A CASRN 80-05-7

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

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 (Tyl, et al., 2002
estimated target doses of 0, 0.0095, 0.019,
0.285, 5, 50, and 500 mg/kg bw-day)
Exposure period: 10 weeks premating,
2 weeks mating, gestation (parental males
and females), lactation (parental females);
similar exposure regimen for F, and F2
parental males and females; F3 weanlings
exposed for 10 weeks
Parental systemic toxicity:

NOAEL = 5 mg/kg bw-day
LOAEL = 50 mg/kg bw-day for 12%
decreased terminal body weight in F,
parental males
Reproductive toxicity:

Females: NOAEL = 50 mg/kg bw-day
LOAEL = 500 mg/kg bw-day for decreases
in number of implantation sites, delayed
vaginal opening in Fi, F2, F3 offspring
BMDLs (change of 1 standard deviation
from control) reported for delayed vaginal
opening (female s)-
Fa = 176 mg/kg-day
F2 = 228 mg/kg-day
F3 = 203 mg/kg-day
Males: NOAEL = 50 mg/kg bw-day,
LOAEL = 500 mg/kg-day for delayed
preputial separation in Fi males
BMDLs (change of 1 standard deviation
from control) reported for delayed preputial
separation (males)-
Fi = 163 mg/kg-day
F2 = 203 mg/kg-day 4-42
F3 = 189 mg/kg-day

Chapin et al. 2008; 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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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 (Tyl, et al., 2002

estimated target doses of 0.003, 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 F, 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 F, males, increased

incidence of gross ovarian cysts in F, and F2

females

BMDi (change of 1 standard deviation from
control) reported for increased gestation
length

F0 = 1144 mg/kg-day (BMDL = 599 mg/kg -
day)

F, = 772 mg/kg-day (BMDL = 531 mg/kg-
day)

BMDios (10% extra risk) reported for
increased incidence of gross ovarian cysts
F0 = 225 mg/kg-day (BMDL =141 mg/kg-
day)

F, = 202 mg/kg-day (BMDL =120 mg/kg-
day)

Chapin et al. 2008; 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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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 BPA causes female
reproductive toxicity with subchronic or
chronic oral exposures with a NOAEL of 50
mg/kg bw-day and a LOAEL of 500 mg/kg
bw-day.

Male effects: There is sufficient evidence
in rats and mice that BPA causes male
reproductive toxicity with subchronic or
chronic oral exposures with a NOAEL of 50
mg/kg bw-day and a LOAEL of 500 mg/kg
bw/day.

Chapin et al. 2008; NTP-
CERHR, 2008

Classified by NTP-CERHR as having
High Utility.

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

FAO/WHO, 2011

Summary of data, data quality, and
conclusions from the expert panel.

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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 Fi offspring;

* reduce Fj pup survival or body weight;

* alter F, growth or survival during
lactation;

* alter F, anogenital distance in males or
females; or

* cause under masculinization 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 F, pubertal landmarks;

* alters P0 male or female reproductive
tract organ weights or histopathology; and

* alters F, 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.

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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) following developmental exposures. The FAO/WHO (2011) Expert Panel also concluded
that while there was broad agreement in a NOAEL of 50 mg/kg bw-day for developmental toxicity based on
standard bioassays, specific targeted studies identified neurodevelopmental effects at low doses (<1 mg/kg bw-
day), but the human relevance is less certain. There is great variation in results with different types of studies
measuring different endpoints; developmental effects at lower doses cannot be ruled out. Taken together these
findings support a hazard designation of High concern.

Reproduction/
Developmental Toxicity
Screen

No data located.

Combined Repeated
Dose with Reproduction/
Developmental Toxicity
Screen

No data located.

Summary of
Developmental Effects

The NTP-CERHR Expert Panel concluded
that BPA:

* 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 500 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

Chapin et al., 2008; NTP-
CERHR, 2008

Summary of data, data quality, and
conclusions from the expert panel.

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female rats at high doses (ca. 500 mg/kg
bw-day).

And that rodent studies suggest that BP 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 joint FAO/WHO Expert Panel
reviewed reproductive and developmental
toxicity data for BPA located 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 Fi offspring;

* reduce Fj pup survival or body weight;

* alter F, growth or survival during
lactation;

* alter Fi anogenital distance in males or
females; or

* cause under masculinization 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 Fi pubertal landmarks;

* alters P0 male or female reproductive tract
organ weights or histopathology; and

* alters Fi male reproductive tract organ
weights or histopathology and semen
parameters.

Furthermore, changes in brain biochemical
signaling, morphometric and cellular end-
points within sexually dimorphic
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.

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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.

NOAEL = 4.75 mg/kg bw-day
LOAEL = 47.5 mg/kg bw-day for 12%
decreased terminal body weight in Fi
parental males

Chapin et al. 2008; 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 (Tyl, et al., 2002
estimated target doses of 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 F, 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

Chapin et al. 2008; 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.

response.

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The Joint FAO/WHO Expert Meeting
review of the toxicological aspects of BPA
concludes 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:
DIR (IRR) notation; (potential to be a skin
irritant following exposure to the skin).

NIOSH, 2010

Adequate; summary of conclusions
provided by NIOSH.

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Endocrine Activity

BPA displays endocrine activity in in vitro assays, but yields mixed results in in vivo studies. In vitro assays
demonstrate that BPA 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 BPA 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 BPA did not elicit an androgenic
response but there is some evidence of anti-androgenic activity. Limited comparative in vitro data suggest that
the estrogenicity of BPA 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 BPA does
not consistently produce robust estrogenic responses. EINECS provides summary data to suggest that BPA has
been shown to act as an estrogen or xenoestrogen in ecological systems.

Reviews

The estrogenicity of BPA 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 BPA 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 BPA in
increasing uterine weight varies over ~4
orders of magnitude. According to the NTP-

NTP-CERHR, 2008

Summary of data, data quality, and
conclusions from NTP-CERHR.

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CERHR Expert Panel, oral BPA does not
consistently produce robust estrogenic
responses and, when seen, estrogenic
effects after oral treatment occur at high-
dose levels.

A limited number of studies have evaluated
androgen activity of BPA. 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.

Positive estrous response; subcutaneous
injections of BPA to ovariectomized rats
(strain not specified) (positive response
measured by cornification in vaginal
smears).

European Commission, 2000

Adequate.

Numerous studies were located regarding
the behavior of BPA as an estrogen or
xenoestrogen in ecological organisms.
Important results include findings that BPA
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 BPA 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.

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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.

Representative in vitro studies
Receptor Binding Assays

In a human ER binding assay, the relative
binding affinity (RBA) of BPA 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 BPA 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 BPA 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 BPA, bisphenol S,
and PHBB indicated a weak affinity for ER.

Laws, Yavanhxay et al., 2006

Adequate.

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BPA 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 tested chemicals
included 0.003% for PHBB, 0.0009% for
bisphenol F, and 0.0007% for the
proprietary substituted phenolic compound.

Blair, Branham et al., 2000

Adequate.

Representative in vitro studies
Gene Transcription Assays

BPA exhibited evidence of estrogenic
activity in a yeast (Saccharomyces
cerevisiae) 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, BPA was
considered weakly estrogenic. Assessment
of other bisphenols resulted in a ranking of
relative potency as follows: bisphenol C >
BPA > bisphenol F > bisphenol S.

Chen, Michihiko et al., 2002

Adequate.

BPA 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.

BPA exhibited evidence of estrogenic
activity in a yeast (Saccharomyces
cerevisiae) two-hybrid assay using ERa and
the coactivator TIF2.

Nishihara, Nishikawa et al.,
2000

Adequate.

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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 BPA
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
measure of estrogenic activity, an
estrogenic response was elicited by BPA
and bisphenol F.

Ogawa, Kawamura et al. 2006

Adequate.

In a reporter gene assay of estrogen-induced
transcriptional activity, relative activity
(RA) for BPA 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, BPA induced reporter gene
expression at a relative activity (RA) of
2.75xl0"3 that of 17|3-estradiol. RAs for
other bisphenol compounds included
5.3xl0"4 for bisphenol F, 4.9xl0"4 for
bisphenol C, and 9.0xl0"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 BPA
compared to an EC50 of 8.6xl0"6 for 17|3-
estradiol (i.e., BPA was approximately 5
orders of magnitude less potent than 17|3-
estradiol at inducing estrogenic activity).
EC50 values for other bisphenol compounds

Kitamura, Suzuki et al., 2005

Adequate.

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DATA

REFERENCE

DATA QUALITY

included 0.42 pM for bisphenol C, 1.0 pM
for bisphenol F, and 1.1 pM for bisphenol
S.

In an ERE-luciferase reporter assay using
MCF-7 cells in the presence of 17|3-
estradiol, neither BPA, bisphenol C,
bisphenol F, bisphenol S, nor bisphenol M
appeared to exert an anti-estrogenic effect.

Kitamura, Suzuki et al., 2005

Adequate.

Representative in vitro studies
Progesterone Receptor Induction

BPA 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, BPA, 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 BPA
was approximately 10"5 that of 17|3-
estradiol, suggestive of a weakly estrogenic
effect for BPA. The potency of bisphenol F
was somewhat less than that of BPA.

Perez, Pulgar et al., 1998

Adequate.

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DATA QUALITY

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, BPA induced a
proliferative response that was 2.Ox 10" that
of 17|3-estradiol. Proliferative values for
other bisphenol compounds included
1.6xl0"3 for bisphenol C, 1.0x10° for
bisphenol F, and 6.0xl0"4 for bisphenol AP.

Coleman, Toscano et al., 2003

Adequate.

In an E-screen test for estrogenicity, BPA
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 BPA.

Stroheker, Picard et al., 2004

Adequate.

In an E-screen test for estrogenicity, BPA,
bisphenol F, and bisphenol S increased
proliferation of MCF-7 cells at
concentrations in the range of 10"4 to 10"7
M. BPA appeared to be more effective than
bisphenol S or bisphenol F.

Hashimoto, Moriguchi et al.,
2001

Adequate.

BPA 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 BPA and bisphenol F
was approximately 1,000-fold less than that
of 17|3-estradiol.

Perez, Pulgar et al., 1998

Adequate.

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DATA QUALITY

Representative in vivo studies

Exposure of immature female rats to BPA
(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 weight of
bisphenol F- or BPA-treated
ovariectromized rats.

Stroheker, Picard et al., 2004

Adequate.

In uterotrophic assays using ovariectomized
mice, BPA 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 pg/kg/day. This result is indicative of
an estrogenic effect in vivo.

Kitamura, Suzuki et al., 2005

Adequate.

In an 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.

Representative Androgen Assays

In an ARE-luciferase reporter assay using a
mouse fibroblast cell line (NIH3T3 cells),
neither BPA, bisphenol C, bisphenol F, nor
bisphenol S exerted an androgenic effect

Kitamura, Suzuki et al., 2005

Adequate.

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DATA

REFERENCE

DATA QUALITY

In an ARE-luciferase reporter assay using a
mouse fibroblast cell line (NIH3T3 cells),
BPA 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.

BPA 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 BPA 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
BPA nor bisphenol C inhibited growth
hormone production.

Kitamura, Suzuki et al., 2005

Adequate.

BPA 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

Sufficient data was not located to determine a hazard designation for the immunotoxicity endpoint.

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

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Acute Toxicity

HIGH: Based on experimental data indicating a High hazard concern for fish, Daphnid, and green algae.

Fish LCso
Freshwater

Oryzias latipes (Medaka fish) 96-hour LC50

= 13 mg/L

(Experimental)

EINECS, 2010; Wright-Walters
et al., 2011

Adequate; guideline study (OECD
204).

Oryzias latipes (Medaka fish, early life
stage) 96-hour LC50 =13.9 mg/L
(Experimental)

Wright-Walters et al., 2011

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,
et al., 2011

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 et al., 2011

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 96-hour LC50 =12 mg/L
(Estimated)

ECOSAR: Neutral organics

ECOSAR version 1.11

Narcosis classes (neutral organics) are
provided for comparative purposes;
DfE assessment methodology will use
the lowest estimated toxicity value
provided by ECOSAR classes that have
a more specific mode of action relative
to narcosis.

Fish 96-hour LC50 = 2 mg/L
(Estimated)

ECOSAR: polyphenols

ECOSAR version 1.11

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Fish LC50
Saltwater

Menidict 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
et al., 2011; 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.

Daphnid LCS0

Daphnia magna (water flea)
48-hour EC50 = 10.2 mg/L
(Experimental)

EINECS, 2010; European
Commission, 2000; Alexander,
Dill et al.,

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.

Daphnid 48-hour LC50 = 7.9 mg/L
(Estimated)

ECOSAR: Neutral organics

ECOSAR version 1.11

Daphnid 48-hour LC50 = 9.3 mg/L
(Estimated)

ECOSAR: polyphenols

ECOSAR version 1.11

Saltwater Invertebrate LCS0

Mysidopsis bahia (mysid shrimp)
96-hour LC50 (flow-through) =1.1 mg/L
(Experimental)

EINECS, 2010; European
Commission, 2000; Alexander,
Dill et al.,

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.

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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 96-hour EC50 =9.7 mg/L
(Estimated)

ECOSAR: Neutral organics

ECOSAR version 1.11

Green algae 96-hour EC50= 1.7 mg/L
(Estimated)

ECOSAR: polyphenols

ECOSAR version 1.11

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.,
2011; 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

Branchydanio rerio (Zebrafish) 14-day
survival

NOEC = 3.2 mg/L
LOEC = 10.15 mg/L
(Experimental)

EINECS, 2010; Wright-Walters,
Volz etal., 2011

Adequate; guideline study (OECD
204).

Branchydanio rerio (Zebrafish) growth and

reproduction

NOEC = 0.75 mg/L

LOEC = 1.5 mg/L

EINECS, 2010; Wright-Walters,
Volz etal., 2011

Inadequate; lack of experimental
design details.

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(Experimental)

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,
Volzetal., 2011

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,
Volzetal., 2011

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,
Volzetal., 2011

Inadequate; early life stage toxicity
study, insufficient study details in
secondary sources. Test concentrations
not measured analytically.

Pimephales promelas (Fathead minnow)

multigenerational toxicity study

Survival, growth:

NOEC = 0.16 mg/L

LOEC: = 0.64 mg/L

Hatchability:

NOEC = 0.016 mg

LOEC = 0.16 mg/L

EINECS, 2010; Wright-Walters,
Volzetal., 2011

Adequate, although secondary sources
did not mention guidelines followed.
Test concentrations were analytically
measured.

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(Experimental)

Pimephcdes promelas (Fathead minnow)
32-day post-hatch survival and growth
NOEC = 0.64 mg/L
(Experimental)

Wright-Walters, Volz et al.,
2011

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.,
2011

Adequate; considered valid GLP study
by secondary source. Chemical
exposures measured analytically.

Oncorhvnchiis mykiss (Rainbow trout)

2 8-day growth

NOEC = 3.64 mg/L

LOEC = 11 mg/L

(Experimental)

EINECS, 2010; Wright-Walters,
Volz et al., 2011

Adequate; guideline study (OECD 215)
of juvenile growth rate.

Cyrimis cctrpio (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 cctrpio (carp) 28-day survival/
growth

NOEC = 0.74 mg/L
(Experimental)

Wright-Walters, Volz et al.,
2011

Inadequate; non-GLP and abstract
only.

Poecilia reticulata (guppy)
21-day sperm count
LOEC = 0.274 mg/L
(Experimental)

Wright-Walters, Volz et al.,
2011

Inadequate; insufficient study details in
secondary source.

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DATA QUALITY

Poecilia reticulata (guppy) 30-day survival
NOEC = 0.5 mg/L
LOEC = 5.0 mg/L
(Experimental)

EINECS, 2010; Wright-Walters,
Volzetal., 2011

Inadequate; insufficient study details in
secondary source.

Fish ChV =1.4 mg/L
(Estimated)

ECOSAR: Neutral organics

ECOSAR version 1.11

Fish ChV = 0.9 mg/L
(Estimated)

ECOSAR: polyphenols

ECOSAR version 1.11

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).

Daphnid ChV =1.1 mg/L
(Estimated)

ECOSAR: Neutral organics

ECOSAR version 1.11

Daphnid ChV = 3.2 mg/L
(Estimated)

ECOSAR: polyphenols

ECOSAR version 1.11

Green Algae ChV

Green algae ChV = 3.3 mg/L
(ECOSAR: Neutral organics)

ECOSAR version 1.11

Narcosis classes (neutral organics) are
provided for comparative purposes;
DfE assessment methodology will use
the lowest estimated toxicity value

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provided by ECOSAR classes that have
a more specific mode of action relative
to narcosis.

Green algae ChV = 0.278 mg/L
(ECOSAR: polyphenols)

ECOSAR version 1.11

Teratogenicity in Frog Embryos

Rcma temporaria (common frog) 20-day

embryo survival

NOEC = 0.1 mg/L

LOEC = 1 mg/L

(Experimental)

EINECS, 2010; Wright-Walters,
Volzetal., 2011

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,
Volzetal., 2011

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,
Volzetal., 2011

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, BPA is expected
to partition primarily to soil. BPA is expected to be moderately mobile in soil based on experimental Koc
studies. Leaching of BPA 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, BPA 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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DATA QUALITY

Adsorption/Desorption
Coefficient - Koc

OECD Test Guideline 106 (Measured)

2003; EINECS, 2010

reported in secondary source.

795.9

OECD Test Guideline 106 (Measured)

Fent, Hein et al., 2003; EINECS,
2010

Adequate, data from guideline study as
reported in secondary source.

251-1507, mean value of 962 (Measured)

Ying and Kookana, 2005;
EINECS, 2010

Adequate, data from guideline study as
reported in secondary source.

335-703, mean value of 375 (Measured)

Loffredo and Senesi, 2006;
EINECS, 2010

Adequate, data from guideline study as
reported in secondary source.

778 (Measured)

Ying and Kookana, 2003;
EINECS, 2010

Adequate, valid nonguideline study as
reported in secondary source.

115 (Measured)

Zeng, Zhang et al., 2006;
EINECS, 2010

Adequate, valid nonguideline study as
reported in secondary source.

335-703; reported as Log Koc = 2.53-2.85 at
pH 4.5-5.9 (Measured)

Canada, 2008

Adequate, data from guideline study as
reported in secondary source.

The levels of BPA measured in water and
bed sediments were used to calculate Koc
values. The range of results was 11,220-
17,000 (log Koc 4.04-4.23). (Measured)

Patrolecco, Capri et al., 2006;
EINECS, 2010

Adequate, data are from a valid
nonguideline study; Koc values are
likely for the unionized species.

Level III Fugacity Model

Air = <1% (Estimated)
Water = 8.4%

Soil = 74%

Sediment = 18%

EPI

Experimental water solubility
(0.12 g/L) and vapor pressure
(3.99x10 s mm Hg) used in model
calculations.

Persistence

VERY LOW: BPA 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.

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Water

Aerobic Biodegradation

OECD 30IB: No biodegradation of BPA
was observed with modified Sturm test
(Measured)

EINECS, 2010

Adequate, data from a guideline study
as reported in secondary source.

OECD 301C: Reported biodegradation
half-lives of <3.5 days in river surface
water samples (Measured)

MITI, 1992; Canada, 2008

Adequate, data from a guideline study
as reported in secondary source.

OECD301D: No biodegradation of BPA
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
biochemical oxygen demand (BOD) was
89%; 10-day window met and no BPA
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 and Goodwin, 1997;
Canada, 2008; EINECS, 2010

Adequate, data from a guideline study.

BPA met the criteria for inherently
biodegradable substances; using a modified
semi-continuous activated sludge (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 total organic carbon (TOC)
removal of 40-90% (Measured)

Ike, Chen et al., 2006; EINECS,
2010

Adequate, data from a valid
nonguideline study.

BPA 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,
2008

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.

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DATA QUALITY

River water samples had BPA
biodegradation half-lives of 2, 3 and 6 days;
BPA 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 BPA half-life of
3-4 days; some seawater degradation of
BPA 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 BPA degradation half-life of
144 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.

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:

Canada, 2008

Invalid; losses of up to 40% of the
initial amount applied occurred in the

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FINAL REPORT - January 2014

Bisphenol A CASRN 80-05-7

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

river water-sediment test system: 0.57
groundwater-aquifer test system: 1.212
Anaerobic conditions:
river water-sediment test system: 1.38
groundwater-aquifer test system: 2.75
(Measured)

sterile (control) treatments.

BPA 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 BPA 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)

Wolfe and Jeffers, 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.

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.

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FINAL REPORT - January 2014

Bisphenol A CASRN 80-05-7

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

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 BPA 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

BPA 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

BPA was found in ecological samples; detectable levels were found in snails, mussels, fish, clams, and zooplankton.

Human Biomonitoring

BPA 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.

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.

CHRIS, Chemical Hazards Response Information System. Cautionary Response Information. Bisphenol A.
http://cameochemicals.noaa.gov/chris/BPA.pdf. 1999.

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.

Dorn, P.; Chou, C.; Gentempo, J. Degradation of bisphenol-A in natural waters. Chemosphere, 1987, 16(7), 1501-1507.

ECOSAR (2012) Ecological Structure Activity Relationship (ECOSAR) Version 1.11. Washington, DC: U.S. Environmental
Protection Agency, http://www.epa.gov/oppt/newchems/tools/21ecosar.htm.

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 4.00. 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.

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.

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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.

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.

MET! 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): 133-138.

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.

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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 bisphenol 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.

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'Neil, 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. FoodChem. 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.

Turner, S.; Watkinson, R. Diphenylol Propane: An Assessment of Inherent Biodegradability. Shell Company Report. 1986.

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Tyl, R.W.; Myers, C.B.; Marr, M.C.; Thomas, B.F.; Keimowitz, A.R.; Brine, D.R.; Veselica, M.M.; Fail, P.A.; Chang, T.Y.; Seely,
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reproductive toxicity study of dietary bisphenol A in CD Sprague-Dawley rats. Toxicol Sci. 2002. 68:121-146. As cited in
NTP-CERHR, 2008 and Chapin et al., 2008.

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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.

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Willhite C.C.; Ball G.L.; McLellan C.J. Derivation of a Bisphenol A oral Reference Dose (RfD) and drinking-water equivalent
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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
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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: OC(CCC(C 1)CC(CCC(0)C2)C2)C 1

Synonyms: Phenol, 4,4'-methylenebis-; 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-

// \

/ \

¦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, Leo et al., 1995

Adequate.

Flamm ability (Flash Point)

No data located.

Explosivity

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
|TI|bisphcnol F were administered 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|bisphcnol
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 (Estimated)

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 oxicity/Car cinogenicity

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
Typhi murium 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. typhimurium
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 cells

Tsutsui, Tamura et al., 2000

Adequate.

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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
Syrian hamster embryo 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

MODERATE: Estimated based on analogy to BP A. Key studies identified by NTP for the analog BPA
indicate there are multiple distinct endpoints with NOAELs in the range of Moderate hazard concern with
LOAELs in the range of Low hazard concern. At the target dose of 50 mg/kg-day (BPA), the NOAELs are
on the margin of High and Moderate hazard, according to DfE criteria. Benchmark Dose (BMD) Modeling
conducted by NTP, which interpolates between NOAEL and LOAEL values, yields values that further
support a Moderate hazard designation. The limited test data on bisphenol F were inadequate for the
evaluation of hazard using DfE criteria. 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.

Reproduction/
Developmental Toxicity
Screen

Bisphenol F increased absolute and
relative uterine weight in a rat
uterotrophic assay.

Yamasaki, Noda et al., 2004

Adequate.

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.

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Bisphenol F CASRN 620-92-8

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

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.

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Bisphenol F CASRN 620-92-8

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

Reproduction and Fertility
Effects

Parental systemic toxicity:

NOAEL = 5 mg/kg bw-day

LOAEL = 50 mg/kg bw-day for 12%

decreased terminal body weight in F,

parental males

Reproductive toxicity:

Females: NOAEL = 50 mg/kg bw-day

LOAEL = 500 mg/kg bw-day for

decreases in number of implantation sites,

delayed vaginal opening in Fu F2, F3

offspring

BMDLs (change of 1 standard deviation
from control) reported for delayed
vaginal opening (females)-
Fi = 176 mg/kg-day
F2 = 228 mg/kg-day
F3 = 203 mg/kg-day
Males: NOAEL = 50 mg/kg bw-day,
LOAEL = 500 mg/kg-day for delayed
preputial separation in F, males

BMDLs (change of 1 standard deviation
from control) reported for delayed
preputial separation (males)-
F i = 163 mg/kg-day
F2 = 203 mg/kg-day

Estimated by analogy)

NTP-CERHR 2008; Professional
judgment

Based on the analog BPA;
adequate, guideline study as
reported in the secondary source.

Classified by NTP-CERHR as
having High Utility.

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Bisphenol F CASRN 620-92-8

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 F,
males, increased incidence of gross
ovarian cysts in Fi and F2 females
BMDi (change of 1 standard deviation
from control) reported for increased
gestation length

F0 = 1144 mg/kg-day (BMDL = 599
mg/kg-day)

Fj = 772 mg/kg-day (BMDL = 531
mg/kg-day)

BMD10s (10% extra risk) reported for
increased incidence of gross ovarian cysts
F0 = 225 mg/kg-day (BMDL =141
mg/kg-day)

Fj = 202 mg/kg-day (BMDL = 120
mg/kg-day)

(Estimated by analogy)

NTP-CERHR 2008; Professional
judgment

Based on the analog BPA;
adequate, guideline study as
reported in the secondary source.

Classified by NTP-CERHR as
having High Utility.

4-87

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Bisphenol F CASRN 620-92-8

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

Female effects: There is sufficient
evidence in rats and mice that BPA
caused female reproductive toxicity with
subchronic or chronic oral exposures with
a NOAEL of 50 mg/kg bw-day and a
LOAEL of 500 mg/kg bw-day.

NTP-CERHR 2008; Professional
judgment

Based on the analog BPA;
Classified by NTP-CERHR as
having High Utility.

(Estimated by analogy)

The joint FAO/WHO Expert Panel
reviewed reproductive and developmental
toxicity data for BPA located 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.

FAO/WHO, 2011; Professional
judgment

Based on the analog BPA.

(Estimated by analogy)

4-88

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Bisphenol F CASRN 620-92-8

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

Developmental Effects

HIGH: Estimated based on analogy to BP A. 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) following developmental exposures. The FAO/WHO
(2011) Expert Panel also concluded that while there was broad agreement in a NOAEL of 50 mg/kg bw-day
for developmental toxicity based on standard bioassays, specific targeted studies identified
neurodevelopmental effects at low doses (<1 mg/kg bw-day), but the human relevance is less certain. There
is great variation in results with different types of studies measuring different endpoints; developmental
effects at lower doses cannot be ruled out. Taken together these findings support a hazard designation of
High concern.

Reproduction/
Developmental Toxicity
Screen

No data located.

Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen

No data located.

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Bisphenol F CASRN 620-92-8

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

Summary of
Developmental effects

The NTP-CERHR Expert Panel

concluded that BPA:

*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 BPA:
* 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 BPA.

4-90

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FINAL REPORT - January 2014

Bisphenol F CASRN 620-92-8

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

The joint FAO/WHO Expert Panel
reviewed reproductive and developmental
toxicity data for BPA located 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.

FAO/WHO, 2011; Professional
judgment

Based on the analog BPA.

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.

Respiratory Sensitization

No data located.

4-91

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Bisphenol F CASRN 620-92-8

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

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 etal., 1962

Adequate.

Dermal Irritation

MODERATE: Bisphenol F is estimated to be slightly irritating to moderately irritating to rabbit skin based
on test data for the analog BPA. NIOSH has assigned the analog 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.

(Estimated by analogy)

EINECS, 2010; European
Commission, 2000; NIOSH, 2010;
Professional judgment

Based on the analog BPA; the
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.
(Estimated by analogy)

European Commission, 2000;
Professional judgment

Based on the analog BPA;
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 BPA;
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 BPA 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 BPA.

4-92

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Bisphenol F CASRN 620-92-8

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

Receptor Binding Assays

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
BPA, 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 BPA, 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 BPA 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 BPA.

Yamasaki, Noda et al., 2004

Adequate.

4-93

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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 BPA 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, BPA was considered
weakly estrogenic. Assessment of other
bisphenols resulted in a ranking of
relative potency as follows: bisphenol C
> BPA > 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 BPA 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 BPA but not by
bisphenol S.

Hashimoto and Nakamura, 2000

Adequate.

4-94

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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 BPA 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, Moriguchi 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 BPA.

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 BPA,
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
5.3xl0"4 that of 17|3-estradiol. RAs for
other bisphenol compounds included
2.75xl0"3 for BPA, 4.9x10^ for
bisphenol C, and 9.0xl0"5 for bisphenol
AP.

Coleman, Toscano et al., 2003

Adequate.

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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
8.6xl0"6 for 17|3-estradiol (i.e., BPA 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
BPA, 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, BPA,
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
8.6xl0"6 for 17|3-estradiol (i.e., BPA 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
BPA, 0.42 (iM for bisphenol C, and 1.1
pM for bisphenol S.

Kitamura, Suzuki et al., 2005

Adequate.

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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
BPA 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, BPA, and bisphenol S
increased proliferation of MCF-7 cells at
concentrations in the range of 10"4 to 10"7
M. BPA appeared to be more effective
than bisphenol S or bisphenol F.

Hashimoto, Moriguchi et al., 2001

Adequate.

In an E-SCREEN test of MCF7 cell
proliferation (an indicator of estrogenic
activity), the proliferative potency of
BPA was approximately 10"5 that of 17|3-
estradiol, suggestive of a weakly
estrogenic effect for BPA. The potency of
bisphenol F was somewhat less than that
of BPA.

Perez, Pulgar et al., 1998

Adequate.

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Bisphenol F CASRN 620-92-8

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

In an E-screen test for estrogenicity,
bisphenol F and BPA 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 BPA.

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, BPA induced a
proliferative response that was 1.0x10°
that of 17|3-estradiol. Proliferative values
for other bisphenol compounds included
2.0x10° for BPA, 1.6x10° for bisphenol
C, and 6.0xl0"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 BPA
was approximately 1,000-fold less than
that of 17|3-estradiol.

Perez, Pulgar et al., 1998

Adequate.

Androgen Assays

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Bisphenol F CASRN 620-92-8

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

Bisphenol F and BP 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 BPA.

Stroheker, Picard et al., 2004

Adequate.

In an ARE-luciferase reporter assay using
a mouse fibroblast cell line (NIH3T3
cells), neither bisphenol F, BPA,
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 BPA,
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.

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Bisphenol F CASRN 620-92-8

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

In Vivo Studies

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 BPA-treated immature
female rats and no effects on uterine
weight in bisphenol F- or BPA-treated
ovariectromized rats.

Stroheker, Chagnon et al., 2003

Adequate.

In an 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.

4-100

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Bisphenol F CASRN 620-92-8

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

In an 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

ECOSAR version 1.00

Fish 96-hour LC50 = 19.74 mg/L
(Estimated)

ECOSAR: neutral organics

ECOSAR version 1.00

Narcosis classes (neutral organics)
are provided for comparative
purposes; DfE assessment
methodology will use the lowest
estimated toxicity value provided
by ECOSAR classes that have a
more specific mode of action
relative to narcosis.

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Bisphenol F CASRN 620-92-8

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

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

ECOSAR version 1.00

Narcosis classes (neutral organics)
are provided for comparative
purposes; DfE assessment
methodology will use the lowest
estimated toxicity value provided
by ECOSAR classes that have a
more specific mode of action
relative to narcosis.

Daphnid 48-hour LC50 = 13.0 mg/L
(Estimated)

ECOSAR: polyphenols

ECOSAR version 1.00

Green Algae ECS0

Green algae 96-hour EC50 = 1.37 mg/L
(Estimated)

ECOSAR: polyphenols

ECOSAR version 1.00

Green algae 96-hour EC50 = 8.6 mg/L
(Estimated)

ECOSAR: neutral organics

ECOSAR version 1.00

Narcosis classes (neutral organics)
are provided for comparative
purposes; DfE assessment
methodology will use the lowest
estimated toxicity value provided
by ECOSAR classes that have a
more specific mode of action
relative to narcosis.

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

ECOSAR version 1.00

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Bisphenol F CASRN 620-92-8

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

Fish 30-day ChV = 1.83 mg/L
(Estimated)

ECOSAR: neutral organics

ECOSAR version 1.00

Narcosis classes (neutral organics)
are provided for comparative
purposes; DfE assessment
methodology will use the lowest
estimated toxicity value provided
by ECOSAR classes that have a
more specific mode of action
relative to narcosis.

Daphnid ChV

Daphnid ChV = 1.44 mg/L
(Estimated)

ECOSAR: neutral organics

ECOSAR version 1.00

Narcosis classes (neutral organics)
are provided for comparative
purposes; DfE assessment
methodology will use the lowest
estimated toxicity value provided
by ECOSAR classes that have a
more specific mode of action
relative to narcosis.

Daphnid ChV = 4.56 mg/L
(Estimated)

ECOSAR: polyphenols

ECOSAR version 1.00

Green Algae ChV

Green algae ChV = 0.29 mg/L
(Estimated)

ECOSAR: polyphenols

ECOSAR version 1.00

Green algae ChV = 3.78 mg/L
(Estimated)

ECOSAR: neutral organics

ECOSAR version 1.00

Narcosis classes (neutral organics)
are provided for comparative
purposes; DfE assessment
methodology will use the lowest
estimated toxicity value provided
by ECOSAR classes that have a
more specific mode of action
relative to narcosis.

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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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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 hydrolyzable 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'-dihydroxybcnzophcnone 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 hydroxy 1 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)

Wolfe and Jeffers, 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.

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. Agric. FoodChem. 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.

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.

ECOSAR (2010) Ecological Structure Activity Relationship (ECOSAR) Version 1.00. Washington, DC: U.S. Environmental
Protection Agency, http://www.epa.gov/oppt/newchems/tools/21ecosar.htm.

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/.

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European Commission. IUCLID Dataset for 4,4-isopropylidenediphenol (CAS No. 80-05-7). European Chemicals Bureau, February
19, 2000. 2000.

Hansch, C.; Leo, A.; Hoekman, D. Exploring QSAR: 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, M.Y.; 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 Sphingobium yanoikuyae
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.

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): 133-138.

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MITI. Biodegradation and bioaccumulation 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 ofbiphenol 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. 2008.

Oman, C. andHynning, P-A.; Identification of organic compounds in municipal landfill leachates. Environ Polhtt. 1993, 80: 265-271.

OncoLogic. U.S. EPA and LogiChem, Inc. 2005, Version 7.0. 2008.

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.

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. FoodChem. 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.

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Wolfe, N.; Jeffers, P. 2000. Hydrolysis. In Boethling, R.; Mackay, D., Handbook of Property Estimation Methods for Chemicals,
Environmental Health Sciences (311-334). Boca Raton: Lewis Publishers.

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: C,7H,nO,

Physical Forms:
Neat: Solid

Use: Developer for thermal paper

SMILES: Cc 1 cc(ccc 10)C(C)(C)c2ccc(c(c2)C)0

Synonyms: Phenol, 4,4'-(l-methylethylidene) bis[2-methyl-; 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'-(l-
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.

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 confidential
analog with similar structure,
functional groups, and
physical/chemical properties.

Acute Mammalian Toxicity

LOW: Based on analogy to BPA, 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 BPA via
inhalation were inconclusive, as only a single concentration was tested and a 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 BPA; 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 BPA; 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 BPA; limited
study details provided 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.

(Estimated by analogy)

European Commission, 2000;
EINECS, 2010; Professional
judgment

Based on the analog BPA; test
guidelines were not reported in
secondary sources.

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PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

Carcinogenicity

OncoLogic Results

Moderate (Estimated)

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: 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, Michihiko et al., 2002

Adequate.

Negative; gene mutation tests at the
Na+/K+ ATPase locus and hprt locus of
Syrian hamster embryo cells

Tsutsui, Tamura et al., 2000

Adequate.

Gene Mutation in vivo

No data located.

Chromosomal Aberrations

in vitro

Negative; chromosomal aberrations in
Syrian hamster embryo cells

Tsutsui, Tamura et al., 2000

Adequate.

Positive; induction of micronuclei in
Chinese hamster V79 cells

Pfeiffer, Rosenberg 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

MODERATE: Estimated based on analogy to BPA. Key studies identified by NTP for the analog BPA
indicate that there are multiple distinct endpoints with NOAELs in the range of Moderate hazard concern
and LOAELs in the range of Low hazard concern. At the target dose of 50 mg/kg-day (BPA), the NOAELs
are on the margin of High and Moderate hazard, according to DfE criteria. Benchmark Dose (BMD)
Modeling conducted by NTP, which interpolates between NOAEL and LOAEL values, yields values that
further support a Moderate 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 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 BPA.

Parental systemic toxicity:

NOAEL = 5 mg/kg bw-day
LOAEL = 50 mg/kg bw-day for 12%
decreased terminal body weight in F,
parental males
Reproductive toxicity:

Females: NOAEL = 50 mg/kg bw-day
LOAEL = 500 mg/kg bw-day for
decreases in number of implantation
sites, delayed vaginal opening in Fi, F2,
F3 offspring

BMDLs (change of 1 standard deviation
from control) reported for delayed
vaginal opening (females)-
Fx = 176 mg/kg-day

NTP-CERHR, 2008; Professional
judgment

Based on the analog BPA; 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

F2 = 228 mg/kg-day
F3 = 203 mg/kg-day
Males: NOAEL = 50 mg/kg bw-day,
LOAEL = 500 mg/kg-day for delayed
preputial separation in Fi males

BMDLs (change of 1 standard deviation
from control) reported for delayed
preputial separation (males)-
Fj = 163 mg/kg-day
F2 = 203 mg/kg-day
F3 = 189 mg/kg-day

(Estimated by analogy)

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Bisphenol C CASRN 79-97-0

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 F,
males, increased incidence of gross
ovarian cysts in F, and F2 females
BMD, (change of 1 standard deviation
from control) reported for increased
gestation length

F0 = 1144 mg/kg-day (BMDL = 599
mg/kg-day)

Fj = 772 mg/kg-day (BMDL = 531
mg/kg-day)

BMD10s (10% extra risk) reported for
increased incidence of gross ovarian
cysts

Fo = 225 mg/kg-day (BMDL = 141
mg/kg-day)

Fj = 202 mg/kg-day (BMDL = 120
mg/kg-day)

NTP-CERHR, 2008; Professional
judgment

Based on the analog BPA; 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 BPA
caused female reproductive toxicity with
subchronic or chronic oral exposures
with a NOAEL of 50 mg/kg bw-day and

NTP-CERHR, 2008; Professional
judgment

Based on the analog BPA; Classified
by NTP-CERHR as having High
Utility.

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PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

a LOAEL of 500 mg/kg bw-day.

Male effects: There is sufficient
evidence in rats and mice that BPA
causes male reproductive toxicity with
subchronic or chronic oral exposures
with a NOAEL of 50 mg/kg bw-day and
a LOAEL of 500 mg/kg bw/day.

(Estimated by analogy)

The joint FAO/WHO Expert Panel
reviewed reproductive and
developmental toxicity data for BPA
located 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.

FAO/WHO, 2011

Based on the analog BPA.

(Estimated by analogy)

Developmental Effects

HIGH: Estimated based on analogy to BPA. 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) following developmental exposures. The FAO/WHO
(2011) Expert Panel also concluded that while there was broad agreement in a NOAEL of 50 mg/kg bw-day
for developmental toxicity based on standard bioassays, specific targeted studies identified
neurodevelopmental effects at low doses (<1 mg/kg bw-day), but the human relevance is less certain. There
is great variation in results with different types of studies measuring different endpoints; developmental
effects at lower doses cannot be ruled out. Taken together these findings support a hazard designation of
High concern.

Reproduction/
Developmental Toxicity
Screen

No data located.

Combined Repeated Dose

No data located.

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Bisphenol C CASRN 79-97-0

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

with Reproduction/
Developmental Toxicity
Screen

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
(Estimated by analogy)

Professional judgment

Estimated based on reported
experimental data for the analog BPA.

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Bisphenol C CASRN 79-97-0

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

The NTP-CERHR (2008) Expert Panel
concluded that BPA:

*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).

And that rodent studies suggest that
BPA:

* 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 BPA.

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Bisphenol C CASRN 79-97-0

PROPERTY/ENDPOINT

DATA

REFERENCE

DATA QUALITY

The joint FAO/WHO Expert Panel
reviewed reproductive and
developmental toxicity data for BPA
located 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.

FAO/WHO, 2011; Professional
judgment

Based on the analog BPA.

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 BPA, 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 BPA 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 BPA 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 BPA.

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; Professional
judgment

Based on the analog BPA.

(Estimated by analogy)

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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

(Estimated by analogy)

NTP-CERHR, 2008; Professional
judgment

Based on the analog BPA; 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 BPA; 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 BPA.

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 BPA; single
exposure level, insufficient study
details in secondary sources.

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DATA

REFERENCE

DATA QUALITY

Skin Sensitization

MODERATE: Based on analogy to BPA, bisphenol C is estimated to be a skin sensitizer. Recent data from
three BPA 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, a 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 BPA.

Negative in a modified local lymph node
assay of mice administered BPA
epicutaneously on the ears at
concentrations up to 30% on three
consecutive days.

(Estimated by analogy)

EINECS, 2010; Professional
judgment

Based on the analog BPA; 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 three consecutive days and irradiated
with UV light immediately following
application.

(Estimated by analogy)

EINECS, 2010; Professional
judgment

Based on the analog BPA; adequate,
although the assay did not include
concentrations >30%.

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.
(Estimated by analogy)

EINECS, 2010; Professional
judgment

Based on the analog BPA; adequate.

Positive, rabbits; repeated dermal

NIOSH, 2010; Professional

Based on the analog BPA; adequate.

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DATA QUALITY

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.

(Estimated by analogy)

judgment

The Joint FAO/WHO Expert Meeting
review of the toxicological aspects of
BPA concludes that BPA is capable of
producing a skin sensitization response
in humans.

(Estimated by analogy)

FAO/WHO, 2011; Professional
judgment

Based on the analog BPA; 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: Bisphenol C is estimate
based on test data for the analog BPA.

d to be slightly irritating to moderately irritating to rabbit skin
VIOSH has assigned the analog, 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.

(Estimated by analogy)

European Commission, 2000;
EINECS, 2010; NIOSH, 2010;
Professional judgment

Based on the analog BPA; 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.

(Estimated by analogy)

European Commission, 2000;
Professional judgment

Based on the analog BPA; adequate.

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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 BPA; 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 BP 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 BPA, 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 C
was 1.68% that of 17|3-estradiol. RBAs
for other bisphenol compounds included
0.32% for BPA, 1.66% for bisphenol
AP, and 0.09% for bisphenol F.

Coleman, Toscano et al., 2003

Adequate.

Gene Transcription and Reporter
Gene Assays

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DATA QUALITY

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 > BPA > bisphenol
F > bisphenol S.

Chen, Michihiko 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, Nishikawa et al., 2000

Adequate.

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 BPA,
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
8.6xl0"6 for 17|3-estradiol (i.e., BPA was
approximately 5 orders of magnitude less
potent than 17|3-estradiol at inducing

Kitamura, Suzuki et al., 2005

Adequate.

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estrogenic activity). EC50 values for
other bisphenol compounds included
0.63 pM for BPA, 1.0 pM for bisphenol
F, and 1.1 pM for bisphenol S

In an ER-mediated reporter gene
expression assay, bisphenol C induced
reporter gene expression at a relative
activity (RA) of 4.9xl0"4that of 17|3-
estradiol. RAs for other bisphenol
compounds included 5.3xl0~4 for
bisphenol F, 9.0xl0"5 for bisphenol AP,
and 2.75xl0~3 for BPA.

Coleman, Toscano et al., 2003

Adequate.

In an ERE-luciferase reporter assay
using MCF-7 cells in the presence of
17|3-estradiol, neither bisphenol C, BPA,
bisphenol F, nor bisphenol S appeared to
exert an anti-estrogenic effect

Kitamura, Suzuki 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.Ox 10"' for
BPA, 1.0x10° for bisphenol F, and
6.0xl0"4 for bisphenol AP.

Coleman, Toscano et al., 2003

Adequate.

In an ERE-luciferase reporter assay
using MCF-7 cells in the presence of
17|3-estradiol, neither bisphenol C, BPA,
bisphenol F, nor bisphenol S appeared to
exert an anti-estrogenic effect

Kitamura, Suzuki et al., 2005

Adequate.

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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
1.6xl0"3 that of 17|3-estradiol. Respective
proliferative responses for other
bisphenol compounds were 2.Ox 10"' for
BP A, 1.0x10° for bisphenol F, and
6.0xl0"4 for bisphenol AP.

Coleman, Toscano et al., 2003

Adequate.

Androgen Assays

In an ARE-luciferase reporter assay
using a mouse fibroblast cell line
(NIH3T3 cells), neither bisphenol C,
BPA, 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 C inhibited
the androgenic activity of
dihydrotestosterone. Anti-androgenic
responses were elicited by BPA,
bisphenol F, and bisphenol S as well.

Kitamura, Suzuki 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 BPA inhibited
growth hormone production.

Kitamura, Suzuki et al., 2005

Adequate.

Vitellogenin Assays

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DATA QUALITY

In a CARP-HEP/vitellogenin assay,
bisphenol C and BPA 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, Sanderson 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

ECOSAR version 1.00

Fish 96-hour LC50 = 0.95 mg/L
(Estimated)

ECOSAR: neutral organics

ECOSAR version 1.00

Narcosis classes (neutral organics) are
provided for comparative purposes;
DfE assessment methodology will use
the lowest estimated toxicity value
provided by ECOSAR classes that
have a more specific mode of action
relative to narcosis.

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DATA QUALITY

Daphnid LCS0

Daphnict magna 48-hour EC50 =
1.6 mg/L; 24-hour EC50 = 4 mg/L
(Experimental)

Chen, Michihiko et al., 2002

Adequate.

Daphnid 48-hour LC50 = 0.77 mg/L
(Estimated)

ECOSAR: neutral organics

ECOSAR version 1.00

Narcosis classes (neutral organics) are
provided for comparative purposes;
DfE assessment methodology will use
the lowest estimated toxicity value
provided by ECOSAR classes that
have a more specific mode of action
relative to narcosis.

Daphnid 48-hour LC50 = 0.85 mg/L
(Estimated)

ECOSAR: polyphenols

ECOSAR version 1.00

Green Algae ECS0

Green algae 96-hour EC50 = 1.02 mg/L
(Estimated)

ECOSAR: neutral organics

ECOSAR version 1.00

Narcosis classes (neutral organics) are
provided for comparative purposes;
DfE assessment methodology will use
the lowest estimated toxicity value
provided by ECOSAR classes that
have a more specific mode of action
relative to narcosis.

Green algae 96-hour EC50 = 1.25 mg/L
(Estimated)

ECOSAR: polyphenols

ECOSAR version 1.00

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: neu
tral organics

ECOSAR version 1.00

Narcosis classes (neutral organics) are
provided for comparative purposes;
DfE assessment methodology will use
the lowest estimated toxicity value
provided by ECOSAR classes that
have a more specific mode of action
relative to narcosis.

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DATA QUALITY

Fish ChV = 0.12 mg/L
(Estimated)

ECOSAR: polyphenols

ECOSAR version 1.00

Daphnid ChV

Daphnid ChV = 0.12 mg/L
(Estimated)

ECOSAR: neutral organics

ECOSAR version 1.00

Narcosis classes (neutral organics) are
provided for comparative purposes;
DfE assessment methodology will use
the lowest estimated toxicity value
provided by ECOSAR classes that
have a more specific mode of action
relative to narcosis.

Daphnid ChV = 0.27 mg/L
(Estimated)

ECOSAR: polyphenols

ECOSAR version 1.00

Green Algae ChV

Green algae ChV = 0.13 mg/L
(Estimated)

ECOSAR: polyphenols

ECOSAR version 1.00

Green algae ChV = 0.61 mg/L
(Estimated)

ECOSAR: neutral organics

ECOSAR version. 1.00

Narcosis classes (neutral organics) are
provided for comparative purposes;
DfE assessment methodology will use
the lowest estimated toxicity value
provided by ECOSAR classes that
have a more specific mode of action
relative to narcosis.

ENVIRONMENTAL FATE

Transport

If released to air, a vapor pressure of 2.3xl0~6 mm Hg 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 >30,000. 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

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PROPERTY/ENDPOINT

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DATA QUALITY

(atm-m3/mole)

compounds based on professional
judgment.

Sediment/Soil
Adsorption/Desorption
Coefficient - Koc

>30,000 (Estimated)

EPI; U.S. EPA 2004;
Professional judgment

Cutoff value for nonmobile
compounds.

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, Chen et al, 2006). Although
three bisphenol C degradation intermediates have been identified (Sakai, Yamanaka et al., 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.

Water

Aerobic Biodegradation

17% in 2 weeks (complete degradation)
(Measured)

Ike, Chen et al., 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, Chen et al., 2006

Supporting information presented;
nonguideline study.

94% in four days by Sphingomoncts sp.
Strain BP-7 (degradation intermediates
detected)

(Measured)

Sakai, Yamanaka et al., 2007

Adequate; valid nonguideline study
using a pure culture inoculum
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]-

Lobos, Leib et al., 1992

Adequate, nonguideline study that
provides supporting information on
environmental persistence.

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DATA QUALITY

1-propanol identified; no biodegradation
rate information included
(Measured)

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

Reactivity

Photolysis

Not a significant fate process
(Estimated)

Mill, 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)

Wolfe and Jeffers, 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.

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DATA QUALITY

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.