United States
Environmental Protection
Agency
FLAME RETARDANTS IN PRINTED CIRCUIT BOARDS
^3100
9012B
FINAL REPORT
August 2015
EPA Publication 744-R-15-001
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Disclaimer
This document has not been through a formal external peer review process and does not
necessarily reflect all of the most recent policies of the U.S. Environmental Protection Agency
(EPA), in particular those now under development. The use of specific trade names or the
identification of specific products or processes in this document is not intended to represent an
endorsement by EPA or the U.S. government. Discussion of environmental statutes is intended
for information purposes only; this is not an official guidance document and should not be relied
upon to determine applicable regulatory requirements.
This document addresses environmental and human health issues associated with the production,
use, and disposal of Flame Resistant 4 (FR-4) printed circuit boards using current and emerging
flame retardant technologies. The report provides an evaluation of the environmental and human
health hazards associated with flame-retardant chemicals during manufacturing and use of the
FR-4 boards and a discussion and identification of end of life issues. The report also presents
experimental data from the investigation of the thermal breakdown of boards and the by-products
formed under different combustion and pyrolysis conditions. These data may provide further
insight into any issues that may arise, including possible end of life disposal issues.
For More Information
To learn more about the Design for the Environment (DfE) Flame Retardant in Printed Circuit
Board Partnership or the DfE Program, please visit the DfE Program website at:
www.epa.gov/dfe.
To obtain copies of DfE Program technical reports, pollution prevention case studies, and project
summaries, please contact:
National Service Center for Environmental Publications
U.S. Environmental Protection Agency
P.O. Box 42419
Cincinnati, OH 45242
Phone: (513)489-8190
(800)490-9198
Fax: (513)489-8695
E-mail: ncepimal@one.net
11
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Acknowledgements
This report was prepared by Abt Associates Inc. and Syracuse Research Corporation under
contract to the U.S. Environmental Protection Agency (EPA)'s Design for the Environment
(DfE) Program in the Economics, Exposure, and Technology Division of the Office of Pollution
Prevention and Toxics.
This document was produced as part of the DfE Flame Retardants in Printed Circuit Boards
Partnership under the direction of the partnership's steering committee, including: Ray Dawson,
BSEF; Lauren Heine, Clean Production Action; Art Fong, IBM; Steve Tisdale, Intel; Fern
Abrams, IPC; Mark Buczek, Supresta; Adrian Beard, Clariant and HFFREC; and Clive Davies,
Kathleen Yokes, and Melanie Adams, U.S. EPA DfE. The partnership's technical committee
also provided technical input, research, and other support. This project could not have been
completed without their participation.
The Flame Retardants in Printed Circuit Boards Partnership includes representatives from the
following organizations:
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IV
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Executive Summary
Background
In 2006, U.S. Environmental Protection Agency (EPA)'s Design for the Environment (DfE)
Program and the electronics industry convened a multi-stakeholder partnership to identify and
evaluate commercially available flame retardants in Flame Resistant 4 (FR-4) printed circuit
boards (PCBs). The majority of PCBs are classified as FR-4, indicating that they meet certain
performance criteria, as well as the VO requirements of the UL (Underwriters Laboratories) 94
flammability testing standard. Over 90 percent of FR-4 PCBs used epoxy resins containing the
reactive flame retardant tetrabromobisphenol A (TBBPA) to meet flammability standards when
the partnership was convened. Because little information existed concerning the potential
environmental and human health impacts of the materials being developed as alternatives to the
brominated epoxy resins being used in PCBs, the partnership developed information to improve
understanding of new and current materials that can be used to meet the flammability
requirements. This information was published in a 2008 draft report titled Partnership to
Evaluate Flame Retardants in Printed Circuit Boards. In addition to this written draft report,
experimental testing was conducted as part of this project to learn more about the combustion
by-products released during end-of-life disposal processes of PCBs.
In this version of the report, the hazard profiles in Chapter 4 and the accompanying methodology
were updated to ensure that most recent information was used for hazard assessment. Each
human health and environmental endpoint was evaluated using the 2011 DfE Criteria for Hazard
Assessment. The information on the physical-chemical and fate properties of the alternatives in
Table 5-2 of Chapter 5 and text in Chapter 7 were also updated. Chapter 6 was revised to
describe the results of the combustion testing experiments. Additional edits have been made
throughout the report as appropriate in response to public comments received on the 2008 draft
report.
Goal of the Partnership and This Report
The partnership, which includes members of the electronics industry, flame retardants industry,
environmental groups, academia, and others, developed the information in the report Partnership
to Evaluate Flame Retardants in Printed Circuit Boards to advance understanding of the human
health and environmental impacts of conventional and new flame-retardant materials that can
provide fire safety for PCBs. Participation of a diverse group of stakeholders has been critical to
developing the information for this partnership. The multi-stakeholder nature of the partnership
led to a report that takes into consideration many diverse viewpoints, making the project richer
both in approach and outcome.
This partnership report provides objective information that will help members of the electronics
industry more efficiently factor human health and environmental considerations into decision-
making when selecting flame retardants for PCB applications. This report can also serve as a step
toward developing a more comprehensive understanding of the human health and environmental
implications of flame-retardant chemicals by noting gaps in the existing human health and
environmental literature. For example, future studies could be directed at key human health and
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environmental toxicological endpoints that are not yet adequately characterized. Additional
testing could also be directed at improving understanding of fate and transport of flame-retardant
chemicals during the most relevant life-cycle phases.
The objective of the partnership is not to recommend a single best flame retardant for PCB
applications or to rank the evaluated flame retardants. In addition to information on
environmental and human health impacts, performance, and cost are critical in the final decision.
The information in this report could be used in decision-making frameworks that address these
critical elements. When using these flame-retardant chemical profiles, it is important to consider
other life-cycle impacts, including exposure considerations.
Fire Safety for Fainted Circuit Boards (PCBs) and Flame Retardants Evaluated
PCBs are commonly found in consumer and industrial electronic products, including computers
and mobile phones. Manufacturers commonly produce PCBs with flame-retardant chemicals to
help ensure fire safety. In 2008, the majority of PCBs produced worldwide met the VO
requirements of the UL 94 fire safety standard. This standard was usually achieved through the
use of brominated epoxy resins in which the reactive flame retardant TBBPA forms part of the
polymeric backbone of the resin. These UL 94 VO compliant boards are referred to as FR-4
boards, which must meet performance specifications as well as the fire safety standard. While
alternative flame-retardant materials are used in only a small percentage of FR-4 boards, in 2008,
the use of alternatives was increasing and additional flame-retardant chemicals and laminate
materials were under development. In 2008, TBBPA was used to make the epoxy resin base
material in more than 90 percent of FR-4 boards while alternative flame-retardant materials were
used in only 3 to 5 percent of FR-4 boards.
The partnership originally evaluated nine commercially available flame retardants or resins for
FR-4 laminate materials for PCBs: TBBPA, DOPO, Fyrol PMP, aluminum hydroxide, Exolit
OP 930, Melapur 200, silicon dioxide (amorphous and crystalline), and magnesium hydroxide.
Three reaction products of epoxy resin with flame retardants (TBBPA, DOPO, and Fyrol PMP)
were also evaluated for a total of 12 hazard profiles. These chemicals were identified through
market research and consultation with industry and iNEMI (the International Electronics
Manufacturing Initiative) as potentially viable options for PCBs. The reaction products of
TBBPA, DOPO, Fyrol PMP, and other reactive flame retardants are present during the
manufacturing process, and trace quantities may be locked in the PCB polymer matrix. Chemical
components making up less than 1 percent by weight of the flame-retardant formulation were not
considered in this assessment.
For this updated report, ten flame-retardant chemicals and resins for FR-4 laminate materials for
PCBs were evaluated. One of the alternatives from the 2008 draft report - "reaction product of
Fyrol PMP with bisphenol A, polymer with epichlorohydrin" - was not reassessed in the updated
Chapter 4 because the product is not known to be on the market. In the 2008 draft report, there
were two profiles for silicon dioxide - amorphous and crystalline; for this update, the two were
combined into one profile that accounts for the differences between the two forms. The ten
revised hazard profiles and their accompanying methodology are located in the updated Chapter
4 of the alternatives assessment report. A summary of the hazard assessment results by chemical
group are summarized in this updated executive summary.
VI
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Hazard Assessment Results
The level of available human health and environmental information varies widely by flame-
retardant chemical. Little information exists concerning many of the alternative flame-retardant
materials included in this report. TBBPA and silicon dioxide are more fully characterized. To
help address this discrepancy, and to increase the usefulness of this report, EPA used the tools
and expertise developed for the New Chemicals Program to estimate the potential impacts of
flame retardants when no experimental data were available.
Hazard profiles for the reactive flame retardant alternatives TBBPA, DOPO, and Fyrol PMP
vary; all three have High to Very High persistence. TBBPA is relatively well characterized with
empirical data while DOPO and Fyrol PMP have a limited data set and therefore many hazard
designations based on analogs, structural alerts, or estimation models. The primary hazard for
TBBPA is aquatic toxicity (High to Very High). TBBPA has Moderate potential for
bioaccumulation based on measured bioconcentration and estimated bioaccumulation factors.
Human health hazard designations for TBBPA are Low to Moderate; Moderate designations
were determined for carcinogenicity, developmental toxicity, and eye irritation. Comparatively,
DOPO has Low hazard for acute
aquatic toxicity and bioaccumulation potential but similar estimated hazards for carcinogenicity,
developmental toxicity, neurotoxicity, and eye irritation. DOPO is estimated to have Low
bioaccumulation potential due to hydrolysis in aqueous conditions. Fyrol PMP, with the least
amount of empirical data, has potential for Low to Moderate human health effects and High
aquatic toxicity. Fyrol PMP also has High potential for bioaccumulation based on presence of
low molecular weight oligomers.
The reactive flame retardant resins D.E.R. 500 Series (TBBPA-based resin) and Dow XZ-
92547 (DOPO-based resin) are poorly characterized. The hazard profiles for these alternatives
identify Low acute mammalian toxicity. A High skin sensitization designation was assigned
based on empirical data and Moderate respiratory sensitization was estimated for Dow XZ-
92547. Moderate hazard was estimated for carcinogenicity, genotoxicity, reproductive toxicity,
developmental effects, neurotoxicity, and repeated dose toxicity. Acute and chronic aquatic
toxicity are estimated to be Low for D.E.R. 500 Series; chronic aquatic toxicity is estimated to be
High for Dow XZ-92547. Bioaccumulation potential is estimated High and persistence estimated
to be Very High for both reactive flame retardant resins.
The additive flame retardant alternatives aluminum diethylphosphinate, aluminum hydroxide,
magnesium hydroxide, melamine polyphosphate, and silicon dioxide have varied hazard
designations for human health effects. The majority of the endpoints range from Very Low to
Moderate hazard with the exception of High repeated dose toxicity for silicon dioxide, which is
based upon inhalation of particles less than 10 jim in size. Aluminum diethylphosphinate has
Moderate aquatic toxicity hazard while the other four additive flame retardants have Low
designations for these endpoints. Persistence is expected to be High for all five of the additive
flame retardant alternatives and bioaccumulation potential is expected to be Low. The four
additive flame retardant alternatives that contain a metal (aluminum diethylphosphinate,
aluminum hydroxide, magnesium hydroxide, and silicon dioxide) were assigned High
persistence designations because these inorganic moieties are recalcitrant.
vn
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A hazard comparison summary table (presented below as Table ES-1 and Table ES-2) is also
presented in Chapter 4. The tables show relative hazard levels for eleven human health
endpoints, two aquatic toxicity endpoints, and two environmental fate endpoints. The tables also
highlight exposure considerations through the chemical life cycle. Selected flame retardants are
presented according to their reactive or additive nature. An explanation of EPA's chemical
assessment methodology and more detailed characteristics of the chemicals in each formulation
are presented in Chapter 4.
Life-Cycle Thinking and Exposure Considerations
In addition to evaluating chemical hazards, this partnership agreed it was important to apply life-
cycle thinking to more fully understand the potential human health and environmental impacts of
evaluated flame retardants. Human health and environmental impacts can occur throughout the
life cycle: from raw material extraction and chemical manufacturing, to laminate, PCB, and
electronic product manufacturing, to product use, and finally to the end of life of the material or
product. Factors such as occupational best practices and raw material extraction and subsequent
flame-retardant and laminate manufacturing, together with the physical and chemical properties
of the flame retardants, can serve as indicators of a chemical's likelihood to pose human health
and environmental exposure concerns. During later stages of the life cycle, from PCB
manufacturing to end-of-life, human health and environmental exposure potential is highly
dependent upon whether the flame retardant was incorporated additively or reactively into the
resin system. Chapter 5 explores the exposure considerations of these flame retardants and other
life-cycle considerations. The detailed chemical assessments in this report are focused only on
the flame-retardant chemicals. Other chemicals, such as feedstocks used to make the flame
retardants; chemicals used in manufacturing resins, laminate materials, and PCBs; and
degradation products and combustion by-products are only mentioned in the process
descriptions.
Combustion Testing Results
As part of this life-cycle thinking, the partnership decided that experimental testing of FR-4
laminates and PCB materials was necessary to better understand the potential by-products during
thermal end-of-life processes. The combustion by-products of four epoxy laminates alone and
with PCB components added were identified and compared. The four laminates tested were: a
brominated flame retardant epoxy laminate (BFR), an additive phosphorus-based flame retardant
epoxy laminate (PFR1), a reactive phosphorus-based flame retardant epoxy laminate (PFR2),
and a non-flame retardant epoxy laminate (NFR). PCB components designed for conventional
boards were provided by Seagate and combined with the laminates as homogeneous powders to
simulate a circuit board. A standard halogenated component (SH) blend and a low-halogen
component (LH) blend were created and combusted with the various laminates. The two end-of-
life processes simulated by a cone calorimeter in this testing were open burning (50 kW/m2 heat
flux) and incineration (100 kW/m2 heat flux). Halogenated dioxins and furans as well as
polyaromatic hydrocarbons (PAHs) emitted during combustion were measured using gas
chromatography-mass spectrometry. Cone calorimetry data on CO, CO2, particulate matter,
smoke, and heat release were also recorded. The results of the combustion testing, completed in
2012, are summarized here. A more detailed description of the testing methods, results, and
conclusions can be found in Chapter 6 with full study reports in the Appendices.
Vlll
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Analysis of halogenated dioxins and furans was conducted only for the BFRs because initial
testing indicated that PFR1 and PFR2 contained low levels of bromine and therefore would not
generate detectable levels of polybrominated dibenzo-p-dioxins/furans (PBDD/Fs). Detectable
levels of PBDD/Fs were emitted for all BFRs combusted. For the BFRs without components,
nearly 40 percent more PBDD/F emissions were generated in open burn conditions compared to
incineration conditions. PBDD/Fs were detected in the BFRs containing low-halogen
components but could not be quantitated in the samples containing standard halogen components
due to significant interference with the standard. Polychlorinated dibenzo-p-dioxins/furans
(PCDD/Fs) were quantified in the initial testing but could not be quantified in the final studies
due to an ineffective quality control standard.
PAH emissions were measured and detected in all laminate types. Of the laminates without
components, BFR emitted over three times the amount of PAHs of PFR1 in incineration
conditions; BFRs emitted almost three times more PAHs than PFR1 and almost two times more
PAHs than PFR2 in open burn conditions. BFR emitted over eight times more PAHs than NFR
in open burn conditions, while PFR1 and PFR2 emitted nearly three times and five times the
PAHs of the NFR, respectively. In incineration conditions, BFR1 emitted over three times the
PAHs of PFR1. Of the samples with standard halogen components in open burn conditions, BFR
generated nearly twice the amount of PAHs compared to PFR2 and PFR1; a similar emissions
trend was observed for the samples containing low-halogen components.
Data on smoke, particulate matter, CO and CO2 releases, and heat release were collected for all
laminate types. Smoke release was nearly twice as high for BFRs compared to PFR1 and PFR2
for laminates without components in both combustion scenarios. A similar trend was observed
for smoke release from laminates with standard halogen components. Particulate matter
emissions for PFR1 without components were nearly twice that of NFR in open burn conditions.
Of the samples containing standard halogen components, BFRs emitted over 25 percent more
particulate matter than PFR2; BFRs emitted over 50 percent more particulate matter than PFR2
in samples containing low-halogen components. However, particulate matter trends did not
always align with smoke release emissions. While differences in CO release between samples
were negligible, CO2 emissions varied depending on laminate type. Heat release results showed
flame retardant laminates to have lower peak heat releases compared to the non-flame retardant
laminates in open burn scenarios. In incineration conditions, the BFRs lowered heat release
compared to the NFRs. PFR1 emitted heat at levels about equal or slightly higher than the NFRs;
heat release was not measured for PFR2 in incineration conditions.
Selecting Flame Retardants for PCBs
The partnership recognizes that the human health and environmental impacts are important
factors in selecting a flame-retardant chemical or formulation to provide fire safety in a PCB.
However, the partnership also believes other factors are important, such as flame retardant
effectiveness, electrical and mechanical performance, reliability, cost, and impacts on end-of-life
emissions. These factors are discussed as considerations for selecting flame retardants in Chapter
7. While the report focuses on human health and environmental attributes of each flame-retardant
chemical, it is important to note that many of these flame-retardant chemicals must be used
together in different combinations to meet the performance specifications. It is also important to
note that performance requirements will vary depending on the use of the PCB.
IX
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In parallel with this draft assessment, industry trade groups tested alternative non-halogenated
flame retardants and found that they function equally as well as TBBPA-based circuit boards for
certain products. Performance testing for commercially available halogen-free flame-retardant
materials to determine their key electrical and mechanical properties has been the focus of
several separate but complementary projects conducted by iNEMI. This partnership worked
closely with iNEMI to develop this alternatives assessment, as well as the High Density
Packaging User Group (HDPUG). iNEMI recently conducted performance testing of halogen-
free alternatives to traditional flame-retardant PCB used in the high-reliability market segment
(e.g., servers, telecommunications, military) as well as those used by desktop and laptop
computer manufacturers. The HFR-Free High-Reliability PCB Project found that the eight
halogen-free flame-retardant laminates tested generally outperformed the traditional FR-4
laminate control. The HFR-Free Leadership Program, which assessed the feasibility of a broad
conversion to HFR-free PCB materials used by desktop and laptop computer manufacturers,
found the halogen-free flame-retardant laminates tested have electrical and thermo-mechanical
properties that meet or exceed those of brominated laminates and that laminate suppliers can
meet the demand for halogen-free flame-retardant PCB materials. HDPUG completed a project
in 2011 to build a database of existing information on halogen-free materials, including halogen-
free flame retardants - both commercially available and in research and development.l
http://hdpug.org/content/completed-projects#HalogenFree
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ES-1. Screening Level Hazard Summary for Reactive Flame-Retardant Chemicals & Resins
This table contains hazard information for each chemical; evaluation of risk considers both hazard and exposure. Variations in end-of-life processes or degradation and combustion by-
products are discussed in the report but not addressed directly in the hazard profiles. The caveats listed below must be taken into account when interpreting the information in the table.
VL = Very Low hazard L = Low hazard = Moderate hazard = 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 predictive models and/or professional judgment.
* TBBPA has been shown to degrade under anaerobic conditions to form bisphenol A (BPA; CASRN 80-05-7). BPA has hazard designations different than TBBPA, as follows:
MODEPxATE (experimental) for reproductive, skin Sensitization and dermal irritation. § Based on analogy to experimental data for a structurally similar compound. ^The highest hazard
designation of any of the oligomers with MW < 1,000. ¥ Aquatic toxicity : EPA/DfE criteria are based in large part upon water column exposures which may not be adequate for poorly
soluble substances such as many flame retardants that may partition to sediment and particulates.
Chemical
(for full chemical name
and relevant trade
names see the
individual profiles in
Section 4.9)
CASRN
Human Health Effects
Acute Toxicity
Carcinogenicity
Genotoxicity
Reproductive
Developmental
Neurological
Repeated Dose
Skin Sensitization
Respiratory
Sensitization
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Chronic
Environ-
mental
Fate
Persistence
Bioaccumulation
Exposure Considerations
Availability of flame retardants
throughout the life cycle for reactive and
additive flame-retardant chemicals and
resins
Reactive Flame-Retardant Chemicals
Tetrabromobisphenol A
79-94-7
L
L
L*
L
L
L*
L*
VH
H
H
DOPO
35948-25-5
L
M
L
tf
M
M
L
VL
L
M
H
L
Fyrol PMP
63747-58-0
L
L^
L§
M§
M§
M§
M§
L
L
L
fl*
H*
VH
H*
Manufacture
End-of-Life of of FR ~>(
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Safe and ^
Use of ~
Electronics Manufacture
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Jk Manufacture of PCB ,
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Reactive Flame-Retardant Resins
D.E.R. 500 Series*
26265-08-7
L
M
M
M
M
M
M
H
MJ
MJ
L
L
VH
rf
Dow XZ-92547*
Confidential
L
M%
M§
M*
M*
M*
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H
MJ
VL
L
L
H
VH
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Manufacture of
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End-of-Life of ~
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XI
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ES-2. Screening Level Hazard Summary for Additive Flame-Retardant Chemicals
This table contains hazard information for each chemical; evaluation of risk considers both hazard and exposure. Variations in end-of-life processes or degradation and combustion by-
products are discussed in the report but not addressed directly in the hazard profiles. The caveats listed below must be taken into account when interpreting the information in the table.
VL = Very Low hazard L = Low hazard = Moderate hazard = 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 predictive models and/or professional judgment.
R Recalcitrant: Substance is comprised of metallic species (or metalloids) that will not degrade, but may change oxidation state or undergo complexation processes under environmental
conditions. § Based on analogy to experimental data for a structurally similar compound. QConcern linked to direct lung effects associated with the inhalation of poorly soluble particles
less than 10 microns in diameter. A Depending on the grade or purity of amorphous silicon dioxide commercial products, the crystalline form of silicon dioxide may be present. The
hazard designations for crystalline silicon dioxide differ from those of amorphous silicon dioxide, as follows: VERY HIGH (experimental) for carcinogenicity; HIGH (experimental)
genotoxicity; MODERATE (experimental) for acute toxicity and eye irritation. ¥ Aquatic toxicity : EPA/DfE criteria are based in large part upon water column exposures which may not
be adequate for poorly soluble substances such as many flame retardants that may partition to sediment and particulates.
Chemical
(for full chemical name
and relevant trade
names see the
individual profiles in
Section 4.9)
CASRN
Human Health Effects
Acute Toxicity
Carcinogenicity
Genotoxicity
Reproductive
Developmental
Neurological
Repeated Dose
Skin Sensitization
Respiratory
Sensitization
Eye Irritation
Dermal Irritation
Aquatic
Toxicity
1
u
<
Chronic
Environ-
mental
Fate
Persistence
Bioaccumulation
Exposure Considerations
Availability of flame retardants throughout
the life cycle for reactive and additive
flame-retardant chemicals and resins
Additive Flame-Retardant Chemicals
Aluminum
Diethylphosphinate*
225789-38-8
L
L§
L
L
M§
M§
M§
L
L
VL
M
M
//*
L
Aluminum Hydroxide*
21645-51-2
L
L§
L
L§
L
M
M§
L
VL
VL
L
L
//*
L
Magnesium
Hydroxide*
1309-42-8
L
L
L
L
L
L
//*
L
Melamine
Polyphosphate1*
15541-60-3
L
M
M
H
M
M
M
L
L
VL
L
L
H
L
Silicon Dioxide
(amorphous)
7631-86-9
L§
HD
L
LA
VL
L
L
//*
L
Mar
ot
Manufacture
ofFR V.
End-of-Life of
Electronics *
Jt (Recycle, Manufa
/ Disposal) Lam
1
Sale and Use
of Electronics /
V Manufacture of PCS and 1
^- Incorporation into ••
Electronics
ufacture
Resin
i
cture of
nate
Hazard designations are based upon the component of the salt with the highest hazard designation, including the corresponding free acid or base.
xn
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Table of Contents
Executive Summary v
1 Introduction 1-1
1.1 Purpose of the Flame Retardant Alternatives Assessment 1-1
1.2 Scope of the Flame Retardant Alternatives Assessment 1-2
1.2.1 Life-Cycle Stages Considered 1-3
1.2.2 Aspects Beyond the Scope of This Assessment 1-4
2 FR-4 Laminates 2-1
2.1 Overview of FR-4 Laminates Market (Prismark, 2006) 2-2
2.2 Halogen-Free Laminate Market 2-4
2.3 Past Research Efforts 2-5
2.4 Process for Manufacturing FR-4 Laminates 2-7
2.4.1 Epoxy Resin Manufacturing 2-7
2.4.2 Laminate Manufacturing 2-9
2.5 Next Generation Research and Development 2-10
2.6 References 2-10
3 Chemical Flame Retardants for FR-4 Laminates 3-1
3.1 General Characteristics of Flame-Retardant Chemicals 3-1
3.1.1 Flame Retardant Classification 3-1
3.1.2 Flame Retardant Modes of Action 3-3
Flaming Combustion 3-3
Smoldering (Non-Flaming) Combustion 3-5
3.2 Flame-Retardant Chemicals Currently Used in FR-4 Laminates 3-5
Reactive Flame-Retardant Chemicals 3-5
Flame-Retardant Fillers 3-7
Other Chemicals 3-9
3.3 Next Generation Research and Development of Flame-Retardant Chemicals 3-9
3.4 References 3-10
4 Hazard Evaluation of Flame Retardants for Printed Circuit Boards 4-1
4.1 Toxicological and Environmental Endpoints 4-1
4.1.1 Definitions of Each Endpoint Evaluated Against Criteria 4-1
4.1.2 Criteria 4-4
4.1.3 Endpoints Characterized but Not Evaluated 4-7
4.2 Data Sources and Assessment Methodology 4-8
4.2.1 Identifying and Reviewing Measured Data 4-8
4.2.2 Hierarchy of Data Adequacy 4-10
4.2.3 Assessment of Polymers and Oligomers 4-11
4.3 Importance of Physical and Chemical Properties, Environmental Transport, and
Biodegradation 4-11
4.4 Evaluating Human Health Endpoints 4-18
4.4.1 Endpoints Characterized and Evaluated Against Criteria Based on Measured Data....
4-18
4.4.2 SAR - Application of SAR and Expert Judgment to Endpoint Criteria 4-20
4.5 Evaluating Environmental Toxicity and Fate Endpoints 4-21
4.5.1 Aquatic Toxicity 4-21
Xlll
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4.5.2 Bioaccumulation 4-23
4.5.3 Environmental Persistence 4-24
4.6 Endocrine Activity 4-26
4.7 References 4-30
4.8 Hazard Summary Table 4-32
4.9 Hazard Profiles 4-34
Tetrabromobisphenol A 4-34
DOPO 4-107
FyrolPMP 4-128
D.E.R. 500 Series 4-156
DowXZ-92547 4-187
Aluminum Diethylphosphinate 4-215
Aluminum Hydroxide 4-235
Magnesium Hydroxide 4-253
Melamine Polyphosphate 4-274
Silicon Dioxide (amorphous) 4-316
Potential Exposure to Flame Retardants and Other Life-Cycle Considerations 5-1
5.1 Potential Exposure Pathways and Routes (General) 5-4
5.2 Potential Occupational Releases and Exposures 5-8
5.2.1 Flame Retardant andEpoxy Resin Manufacturing 5-9
5.2.2 Laminate and Printed Circuit Board Manufacturing 5-12
5.2.3 Best Practices 5-15
5.3 Potential Consumer and General Population Exposures 5-15
5.3.1 Physical and Chemical Properties Affecting Exposures 5-15
5.3.2 Consumer Use and End-of-Life Analysis 5-16
5.4 Methods for Assessing Exposure 5-20
5.5 Chemical Life-Cycle Considerations 5-22
5.5.1 TBBPA 5-22
5.5.2 DOPO 5-25
5.5.3 FyrolPMP 5-27
5.5.4 Aluminum Diethylphosphinate 5-28
5.5.5 Aluminum Hydroxide 5-28
5.5.6 Magnesium Hydroxide 5-29
5.5.7 Melamine Polyphosphate 5-31
5.5.8 Silicon Dioxide 5-31
5.6 References 5-32
Combustion and Pyrolysis Testing of FR-4 Laminates 6-1
6.1 Background and Objectives 6-1
6.2 Phase 1 Methods and Results 6-3
6.3 Phase 2 6-6
6.3.1 Phase 2 Conclusions 6-7
6.3.2 Phase 2 Methods 6-9
6.3.3 Phase 2 Results 6-11
Considerations for Selecting Flame Retardants 7-1
7.1 Preferable Human Health and Environmental Attributes 7-1
7.1.1 Low Human Health Hazard 7-2
xiv
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7.1.2 Low Ecotoxi city 7-2
7.1.3 Readily Degradable: Low Persistence 7-2
7.1.4 Low Bioaccumulation Potential 7-3
7.1.5 Low Exposure Potential 7-4
7.2 Considerations for Poorly or Incompletely Characterized Chemicals 7-5
7.3 Social Considerations 7-6
7.4 Other Considerations 7-7
7.4.1 Flame Retardant Effectiveness and Reliability 7-7
7.4.2 Epoxy/Laminate Properties 7-8
7.4.3 Economic Viability 7-9
7.4.4 Smelting Practices 7-10
7.5 Moving Towards a Substitution Decision 7-11
7.6 Relevant Resources 7-12
7.6.1 Resources for State and Local Government Activities 7-12
7.6.2 Resources for EPA Regulations and Activities 7-12
7.6.3 Resources for Global Regulations 7-13
7.6.4 Resources from Industry Consortia 7-13
7.7 References 7-15
Appendix A Open-burning, Smelting, Incineration, Off-gassing of Printed Circuit Board
Materials Phase I Flow Reactor Experimental Results Final Report
Appendix B Use of Cone Calorimeter to Estimate PCDD/Fs and PBDD/Fs Emissions From
Combustion of Circuit Board Laminates
Appendix C Analysis of Circuit Board Samples by XRF
Appendix D Flame Retardant in Printed Circuit Boards Partnership: Short Summary of
Elemental Analyses
JR 22 - Br and Cl Analysis in Copper Clad Laminates - part II
ICL-IP Analysis of Laminate Boards
Analysis of Chlorine and Bromine
Appendix E Use of Cone Calorimeter to Identify Selected Polyhalogenated Dibenzo-P-
Dioxins/Furans and Polyaromatic Hydrocarbon Emissions from the Combustion
of Circuit Board Laminates
xv
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List of Acronyms and Abbreviations
ACR Acute to chronic ratio
AIM Analog Identification Methodology
ATH Aluminum trihydroxide (a.k.a. Alumina trihydrate)
BAF Bioaccumulation Factor
BAN Basel Action Network
BCF Bioconcentration factor
BFR Brominated flame retardant epoxy laminate
BPA Bisphenol A
BSEF Bromine Science and Environmental Forum
CCL Copper clad laminate
ChV Chronic value
DfE Design for the Environment
Dicy Dicyandiamide
EASE Estimation and Assessment of Substance Exposure
ECOSAR EPA's Ecological Structure Activity Relationships estimation program
EDSP Endocrine Disrupter Screening Program
EETD Economics, Exposure, and Technology Division
EHS Environmental, health, and safety
EMT Environmental Monitoring Technologies, Inc.
EPA U.S Environmental Protection Agency
EPIWIN Estimations Program Interface for Windows
EU European Union
E-waste Electronic waste
FR-4 Flame Resistant 4
GHS Globally Harmonized System of Classification and Labeling of Chemicals
GS-MS Gas chromatography-mass spectrometry
HDPUG High Density Packaging User Group
HPV High Production Volume
HSDB Hazardous Substances Data Bank
HSE Health and Safety Executive
IC2 Interstate Chemicals Clearinghouse
iNEMI International Electronics Manufacturing Initiative
IRIS Integrated Risk Information System
ISO International Organization for Standardization
Koc Sediment/soil adsorption/desorption coefficient
Kow Octanol/water partition coefficient
LER Liquid epoxy resin
LFL Lower limit of flammability
LH Low-halogen components
LOAEL Lowest observed adverse effect level
LOEC Lowest observed effect concentration
MITI Japanese Ministry of International Trade and Industry
MW Molecular weight
NES No effects at saturation
xvi
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NFR Non-flame retardant laminate
NOAEL No observed adverse effect level
NOEC No observed effect concentration
OECD Organisation for Economic Cooperation and Development
OPPT Office of Pollution Prevention and Toxics
ORD Office of Research and Development
P2 Pollution prevention
PAH Polycyclic aromatic hydrocarbon
PBDD/Fs Polybrominated dibenzo-p-dioxins/furans
PCB Printed circuit board
PCDD/Fs Polychlorinated dibenzo-p-dioxins/furans
PEC Predicted environmental concentration
PFR1 Additive phosphorus-based flame retardant epoxy laminate
PFR2 Reactive phosphorus-based flame retardant epoxy laminate
Prepreg Pre-impregnated material
PTFE Polytetrafluoroethylene
QSAR Quantitative structure activity relationship
SAR Structure activity relationship
SF Sustainable Futures
SH Standard halogen components
SMILES Simplified molecular input line entry specification
SVTC Silicon Valley Toxics Coalition
TBBPA Tetrabromobisphenol A
Td Decomposition temperature
Tg Transition temperature
TSCA Toxic Substances Control Act
UDRI University of Dayton Research Institute
UFL Upper limit of flammability
UK United Kingdom
UL Underwriters Laboratories
VECAP Voluntary Emissions Control Action Programme
XRF X-ray fluorescence
xvn
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1 Introduction
The electronics industry engaged in a multi-stakeholder partnership with the U.S. Environmental
Protection Agency (EPA)'s Design for the Environment (DfE) Program to identify and evaluate
commercially available flame retardants and their environmental, human health and safety, and
environmental fate aspects in Flame Resistant 4 (FR-4) printed circuit boards (PCBs). The
majority of PCBs are classified as FR-4, indicating that they meet certain performance criteria, as
well as the VO requirements of the UL (Underwriters Laboratories) 94 flammability testing
standard.2 For more than 90 percent of FR-4 PCBs, the UL 94 VO requirement is met by the use
of epoxy resins in which the reactive flame retardant tetrabromobisphenol A (TBBPA) forms
part of the polymeric backbone of the resin.
As of 2008, alternative flame-retardant materials were used in only 3 to 5 percent of FR-4
boards, but additional alternative flame-retardant materials are under development. Little
information existed at the time the partnership was convened concerning the potential
environmental and human health impacts of the materials that are being developed as alternatives
to the brominated epoxy resins. Environmental and human health impacts can occur throughout
the life cycle of a material, from development and manufacture, through product use, and finally
at the end of life of the material or product. In addition to understanding the potential
environmental and human health hazards associated with the reasonably anticipated use and
disposal of flame-retardant chemicals, stakeholders have expressed a particular interest in
understanding the combustion products that could be formed during certain end-of-life scenarios.
A risk assessment conducted in 2006 by the European Union did not find significant human
health risk associated with reacted TBBPA in PCBs.3 However, the potential environmental and
health impacts of exported electronic waste (e-waste) are not fully understood. A large
percentage of e-waste is sent to landfills or recycled through smelting to recover metals. An
unknown portion of the waste is recycled under unregulated conditions in certain developing
countries, and the health implications of such practices are of concern.
This report aims to increase understanding of the potential environmental and human health
impacts of PCBs throughout their life cycle. Information generated from this partnership will
contribute to more informed decisions concerning the selection and use of flame-retardant
materials and technologies and the disposal and recycling of e-waste.
1.1 Purpose of the Flame Retardant Alternatives Assessment
The partnership committee identified the overall purpose of this assessment as follows:
FR-4 refers to the base material of the printed circuit board; namely, a composite of an epoxy resin reinforced with
a woven fiberglass mat. UL 94 is an Underwriters Laboratories standard for flammability of plastic materials.
Within UL 94, VO classification entails one of the highest requirements.
3 The EU results, while noteworthy, will not form the basis of this assessment, but rather should be viewed in
conjunction with the independent conclusions drawn in this assessment.
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• To identify and evaluate current and alternative flame retardants and their environmental,
human health and safety, and environmental fate aspects in FR-4 PCBs.
• To allow industry and other stakeholders to consider environmental and human health
impacts along with cost and performance of circuit boards as they evaluate alternative
materials and technologies.
1.2 Scope of the Flame Retardant Alternatives Assessment
The partnership will incorporate life-cycle thinking into the project as it explores the potential
hazards associated with flame retardants and potential exposures throughout the life cycle of
flame retardants used in FR-4 PCBs. While the report focuses on flame retardants used in FR-4
PCBs, these flame retardants may also be applicable in a wide range of PCBs constructed of
woven fiberglass reinforced with thermoset resin.
As appropriate, the scope will include aspects of the life cycle where public and occupational
exposures could occur. For example, consideration of exposures from open burning or
incineration at the end of life will be included, as will exposures from manufacturing and use.
The following investigations were considered within the scope of the project:
• An environmental, health, and safety (EHS) assessment of commercially available flame-
retardant chemicals and fillers for FR-4 laminate materials;
• An assessment of environmental and human health endpoints (environmental endpoints
include ecotoxicity, fate, and transport);
• A review of potential life-cycle concerns; and
• Combustion testing to compare the potential by-products of concern from commercially
available FR-4 laminates and PCB materials during thermal end-of-life processes,
including open burning and incineration.
The project's scope will be limited to flame-retardant chemicals used in bare (i.e., unpopulated)
FR-4 PCBs. Other elements of PCBs (such as solder and casings) and chemicals in components
often attached to PCBs to make an electronic assembly (such as cables, capacitors, connectors,
and integrated circuits) will not be assessed.
The report is intended to provide information that will allow industry and other stakeholders to
evaluate alternatives for flame retardants in PCBs. The report is organized as follows:
• Chapter 1 (Introduction): This chapter provides background to the Flame Retardants in
Printed Circuit Boards partnership project including the purpose and scope of the
partnership and of this report.
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• Chapter 2 (FR-4 Laminates): This chapter describes the characteristics, market for, and
manufacturing process of FR-4 laminates and investigates possible next generation
developments.
• Chapter 3 (Chemical Flame Retardants for FR-4 Laminates): This chapter describes
chemical flame retardants generally, as well as those specific flame retardants used in
FR-4 laminates. The next generation of flame-retardant chemicals is also discussed.
• Chapter 4 (Hazard Evaluation of Flame Retardants for Printed Circuit Boards): This
chapter explains the chemical assessment methodology used in this report and
summarizes the assessment of hazards associated with individual chemicals.
• Chapter 5 (Potential Exposure to Flame Retardants and Other Life-cycle
Considerations): This chapter discusses reasonably anticipated exposure concerns and
identifies potential exposure pathways and routes associated with flame-retardant
chemicals during each stage of their life cycle.
• Chapter 6 (Combustion andPyrolysis Testing of FR-4 Laminates): This chapter describes
the rationale and methods for combustion and pyrolysis testing of PCB materials.
• Chapter 7 (Considerations for Selecting Flame Retardants): This chapter addresses
considerations for selecting alternative flame retardants based on environmental,
technical, and economic feasibility.
1.2.1 Life-Cycle Stages Considered
Figure 1-1 shows the life-cycle stages of a PCB and the associated potential exposure pathways
that will be examined in this report. In brief, the flame-retardant chemical is manufactured and
then incorporated, either reactively or additively, into the epoxy resin. The epoxy resin is then
applied to a woven fiberglass mat and hardened. Layers of copper foil are attached to both sides
of the reinforced resin sheet to form a laminate. Next, a PCB is manufactured by combining
several laminate layers that have had conductive pathways (i.e., circuits) etched into the copper
foil. The layers are then laminated together, and holes are drilled to connect circuits between
layers and hold certain electronic components (e.g., connectors or resistors). Once assembled,
PCBs are incorporated into various products by original equipment manufacturers. When the
product is no longer in use, there are several end-of-life pathways that the product may take:
landfilling, regulated incineration, unregulated incineration (or open burning), and recycling. All
of these life-cycle stages will be discussed in further detail in the subsequent chapters of this
report.
1-3
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Figure 1-1. Exposure Pathways Considered During the Life Cycle of a PCB
/A.
FR
building
blocks
Resin
building
blocks
_£//
Potential Routes of Exposure
— • — > Air Emissions
Solid/ Hazardous Waste
•" •" —^ Water Emissions
Combustion
Byproducts
Degradation
Byproducts
Transport occurs between (and sometimes [ rwi ' t /
within) each of these life-cycle processes.
1.2.2 Aspects Beyond the Scope of This Assessment
Although the assessment will explore hazard data associated with potential exposure scenarios,
the partnership does not intend to conduct a full risk assessment, which would require a full
exposure assessment along with the hazard assessment. Likewise, the project will not be a
complete life-cycle analysis, which inventories inputs and outputs from processes throughout the
life cycle and evaluates the environmental impacts associated with those inputs and outputs.
Process chemicals (i.e., etching or washing solutions used in manufacturing PCBs) are not
included in the scope of this assessment. Although PCBs come in many varieties, the scope of
this assessment is limited to FR-4 boards which meet the VO requirements of the UL 94 standard.
Boards of this type are used in consumer products such as computers and cell phones and make
up a large portion of the PCBs used in consumer products. The assessment may be useful beyond
FR-4 boards to the extent that the same flame retardants are used in other laminates constructed
of woven fiberglass reinforced with other thermoset resins such as phenolics.
Finally, this assessment is not a technical evaluation of key electrical and mechanical properties
of halogenated and halogen-free materials. These properties have been explored in parallel
assessments conducted by iNEMI (International Electronics Manufacturing Initiative) that are
described in greater detail in Section 2.3 and Section 7.6.4 of this report. Together, these
resources will provide information on both the performance and environmental properties of the
various materials being evaluated.
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2 FR-4 Laminates
Flame Resistant 4 (FR-4) laminates are flame-retardant systems of woven glass reinforced with
epoxy-like resin, notable for their resistance to heat, mechanical shock, solvents, and chemicals.
Unlike lower grade laminates, a finished FR-4 laminate can obtain a VO rating in the UL
(Underwriters Laboratories) 94 test, a vertical burning test for flammability. The UL 94 VO test
is typically conducted using a 5-inch by 0.5-inch test specimen (thickness may vary) (RTF
Company, 2014). The specimen is fastened vertically with a holding clamp at the top so that the
5-inch side is perpendicular to the ground (Figure 2-1). A cotton indicator is located 12 inches
below the bottom of the specimen to capture any flaming dripped particles from the specimen
(Figure 2-1). A burner flame is applied at a 45° angle to the bottom of the specimen in two
intervals. The burner is first applied for 10 seconds and is removed until all flaming stops (UL,
2014). The burner is then reapplied for an additional 10 seconds (UL, 2014). Two sets of five
specimens are tested (UL, 2014). In order to meet the UL 94 VO flammability standard: (1) the
specimens must not burn with flaming combustion for more than 10 seconds after the burner is
removed; (2) the total flaming combustion time for each set of five specimens must not be
greater than 50 seconds; (3) any flaming or glowing combustion must not burn up to the holding
clamp; (4) flaming dripped particles from the specimens must not ignite the cotton indicator; and
(5) glowing combustion must not exceed 30 seconds after the second burner flame is removed
from the specimen (UL, 2014).
Figure 2-1. UL 94 VO Experimental Setup
Cotton
Source: UL, 2014
FR-4 laminates can be categorized as (1) high glass transition temperature (Tg) FR-4 laminates,4
(2) middle Tg FR-4 laminates,5 and (3) low Tg FR-4 laminates.6 Within each of those
categories, individual FR-4 laminates are differentiated through reference to their physical
properties (e.g., rate of water absorption, flexural strength, dielectric constant, and resistance to
4 High glass transition temperature laminates have a Tg above 170°C.
5 Middle glass transition temperature laminates are usually considered to have a Tg of approximately 150°C.
6 Low glass transition temperature laminates are usually considered to have a Tg of 130°C and below.
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heat). With the introduction of halogen-free FR-4 materials,7 a similar segmentation is emerging
(e.g., high Tg halogen-free, low Tg halogen-free), leading to a multiplication of the number of
FR-4 materials available (Beard et al., 2006; Bergum, 2007). As different formulations (different
flame-retardant systems and different resin chemistries) result in different laminate properties,
there can be different materials within one class (e.g., low Tg) having different performance
(e.g., dielectrics, mechanics), thus addressing the different market needs. Such differences in
performance are not specific to halogen-free materials and may also exist among brominated
grades of the same Tg class.
2.1 Overview of FR-4 Laminates Market (Prismark, 2006)
In 2006, global printed circuit board (PCB) production exceeded $45 billion. PCBs are fabricated
using a variety of laminate materials, including laminate, pre-impregnated material, and resin-
coated copper. In 2006, $7.66 billion of laminate materials were consumed globally. Laminate
materials can be sub-segmented according to their composition, and include paper, composite,
FR-4, high Tg FR-4, and specialty products (polytetrafluoroethylene (PTFE) and high-
performance materials).
• Paper and composite laminates represent 17.1 percent of the global laminate market in
value (Figure 2-2). These materials are used as the basic interconnecting material for
consumer applications. The materials are low in cost, and their material characteristics
are adequate for use in mainly low-end consumer products.
• The workhorse laminate for the PCB industry is FR-4. In terms of value, approximately
70.4 percent of the material used in the industry is FR-4 glass-based laminate (including
high Tg and halogen-free) (Figure 2-2). This material provides a reliable and cost-
effective solution for the vast majority of designs.
• Many laminators offer halogen-free FR-4 laminate materials. These materials are
typically designed to be drop-in replacements for current halogenated materials, but they
carry a price premium. Halogen-free materials have been slowly gaining acceptance on a
regional basis.
• There are special applications that call for laminate materials with characteristics beyond
the capability of FR-4. These materials consist of special integrated circuit packaging
substrates and materials for use in wireless or high-speed digital applications, including
laminate containing bismaleimide-triazine resins, poly(p-phenylene oxide), high-
performance PTFE, and polyimide.
7 In accordance with IEC-61249-2-21, this report defines "halogen-free materials" ~~ materials that are <900ppm by
weight chlorine; <900ppm by weight bromine; and
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Figure 2-2. 2006 Global PCB Laminate Market by Supplier
Other Wngboard
23.8%
11.1%
Chang Chun /
2.0%\ §
Taiwan Union Tech \
2.7%^\^
Sumitomo Bakelite
2.6%
Park Nelco
3.3%
Mitsubishi
4.2% /
\ Nan Ya Plastics
70.8%
Isola
10.5%
/ Matsushita Electric
9.4%
\ Doosan
6.4%
/ Dongguan ShengYi
Hitachi Chemical 5.4%
4.7%
TOTAL: $7.66Bn
Wote: This market includes prepieg and RCC values.
Figure 2-3. 2006 Global PCB Laminate Market by Material Type
Special and Others
72.5%
Composite
4.
Paper
72.2%
FR-4 Halogen-Free
4.0%
FR-4
51.1%
FR-4 High Tg
75.3%
TOTAL:$7.66Bn
Note: Includ es prepreg
Global sales of laminate materials in 2006 were estimated at $7.66 billion. In terms of area
production, it is estimated that more than 420.2 million square meters of laminate was
manufactured to support the PCB industry in 2006. The distribution of laminate sales
geographically and the leading suppliers to each region are shown in Figure 2-4 and Figure 2-5.
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Figure 2-4. 2006 Regional Laminate Sales
America
6.7
Other
7.1%
Europe
6.5%
torea
11.9%
Taiwan
23.4%
TOTAL: $7.66Bn
TOTAL: $5.77Bn
Figure 2-5. 2006 Laminate Sales by Region
Other
27%
Other
31%
Isola, Park Nelco,
Rogers
73%
Isola, Matsushita,
Park Nelco
69%
Total: $0.51 Bn
Total: $0.50Bn
Japan
Asia
Other
18%
Other
36%
Hitachi Chemical,
Matsushita,
Mitsubishi
82%
Doosan, Chang Chun,
Isola, ITEQ, Kingboard,
Matsushita, Mitsubishi
NanYa Plastics, ShengYi
64%
Total: $0.88Bn
Total: $5.77Bn
2.2 Halogen-Free Laminate Market
There has been a continuous increase in the demand for halogen-free material over the past few
years. In 2003, the global halogen-free laminate market was approximately $60 million. In 2004
this market grew to $161 million, in 2005 it reached $239 million, and it is estimated at $307
million for 2006.
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Most laminate suppliers now include halogen-free materials in their portfolio. Pricing for
halogen-free laminate is still higher than conventional material by at least 10 percent, and often
by much more. Tallying the production volumes of such leading laminate manufacturers as
Hitachi Chemical, NanYa, Matsushita, ITEQ, Isola, Park Nelco, and others, Prismark has
constructed a market segmentation, shown in Figure 2-6.
Figure 2-6. 2006 Global Halogen-Free Laminate Market
Others
Doosan 5.1%
5.7%
ITEQ /-
6.4% /\ _ _
\ Matsushita
L 35.0%
/ ^^
/ \\\
Hitachi Chemical
20.7%
NanYa
27.7%
Total Market: 11.5M
2.3 Past Research Efforts
While demand for halogen-free laminates is increasing, there was a lack of information regarding
their performance and environmental impact when this partnership was convened. The
International Electronics Manufacturing Initiative (iNEMI) and the High Density Packaging User
Group (HDPUG) have taken on separate but complementary roles in helping to fill information
gaps.
iNEMI has carried out a series of projects to determine the key performance properties and the
reliability of halogen-free flame-retardant PCB materials. Each project has observed different
outcomes, with the latest findings indicating that the halogen-free flame-retardant laminates
tested have properties that meet or exceed those of traditional brominated laminates. Technology
improvements, especially those that optimize the polymer/fire retardant combinations used in
PCBs, have helped shift the baseline in regards to the performance of halogen-free flame-
retardant laminates.
In 2009, iNEMI completed a project focused on performance testing of commercially available
halogen-free materials to determine their electrical and mechanical properties. In 2008 when this
alternative assessment was first published, the list of laminate materials identified by iNEMI for
further study include nine laminate materials from seven different suppliers:
• NanYa NPG-TL and NPG-170TL
• Hitachi BE-67G(R)
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• TUC TU-742
• Panasonic R1566W
• ITEQIT140GandIT155G
• ShengyiS1155
• Supresta FR Laminate
While not in the final list for further study, the following laminates were also identified as
promising candidates by iNEMI:
• IsolaDE156andIS500
• TUC TU-862
• ITEQIT170G
• Nelco 4000-7EF
The results of the testing and evaluation of these laminate materials were made public in 2009.8
The overall conclusions from the investigation were (1) that the electrical, mechanical, and
reliability attributes of the halogen-free laminate materials tested were not equivalent to FR-4
laminates and (2) that the attributes of the halogen-free laminates tested were not equivalent
among each other (Fu et al., 2009). Due to the differences in performance and material properties
among laminates, iNEMI suggested that decision-makers conduct testing of materials in their
intended applications prior to mass product production (Fu et al., 2009).
iNEMI also conducted two follow-on projects to its HFR-free Program Report: (1) the HFR-Free
High-Reliability PCB Project and (2) the HFR-Free Leadership Program. The focus of the HFR-
Free High-Reliability PCB Project was to identify technology readiness, supply capability, and
reliability characteristics for halogen-free alternatives to traditional flame-retardant PCB
materials based on the requirements of the high-reliability market segment (e.g., servers,
telecommunications, military) (iNEMI, 2014). In general, the eight halogen-free flame-retardant
laminates tested outperformed the traditional FR-4 laminate control (Tisdale, 2013). The other
project, the HFR-Free Leadership Program, assessed the feasibility of a broad conversion to
HFR-free PCB materials by desktop and laptop computer manufacturers (Davignon, 2012). Key
electrical and thermo-mechanical properties were tested for six halogen-free flamed-retardant
laminates and three traditional FR-4 laminates. The results of the testing demonstrated that the
computer industry is ready for a transition to halogen-free flame-retardant laminates. It was
concluded that the halogen-free flame-retardant laminates tested have properties that meet or
exceed those of brominated laminates and that laminate suppliers can meet the demand for
halogen-free flame-retardant PCB materials (Davignon, 2012). A "Test Suite Methodology" was
also developed under this project that can inform flame retardant substitution by enabling
manufacturers to compare the electrical and thermo-mechanical properties of different laminates
based on testing (Davignon, 2012).
In contrast to the iNEMI project, HDPUG collected existing data on halogen-free flame-retardant
materials; no performance testing was conducted. HDPUG created a database of information on
the physical and mechanical properties of halogen-free flame-retardant materials, as well as the
environmental properties of those materials. The HDPUG project, completed in 2011, broadly
8 http://thor.inemi.org/webdownload/newsroom/Presentations/SMTA South China Aug09/HFR-
Free Report Aug09.pdf
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examined flame-retardant materials, both ones that are commercially viable and in research and
development (R&D). For more information about the database and other HDPUG halogen-free
projects, visit: http://hdpug.org/content/completed-projects#HalogenFree.
Even though they are taking on different roles, FIDPUG and iNEMI have been in contact with
each other, as well as this DfE partnership project, to ensure minimal duplication in scope. The
results of their efforts help inform companies that want to select halogen-free laminate materials.
2.4 Process for Manufacturing FR-4 Laminates
This section describes general processes for manufacturing epoxy resins and laminates. Specific
chemicals and process steps can differ between manufacturers and intended use of the product.
2.4.1 Epoxy Resin Manufacturing
The process for making brominated epoxy resins that are used to make FR-4 laminates is shown
below. Two different classes of oligomers (low molecular weight (MW) linear polymers) are in
common use. The simplest are prepared by reacting TBBPA with a "liquid epoxy resin" ("X" is
hydrogen in this case). The products (for example D.E.R. 500 Series) have an Mn (number
average MW) of 800-1,000 g/mole and contain about 20 percent bromine by weight After the
oligomers are prepared, they are dissolved in a variety of solvents such as acetone or methyl
ethyl ketone (2-butanone) to reduce the viscosity. The Mw (average MW) is typically about
2,000 g/mole. An excess of the epoxy resin is used, and therefore essentially all of the TBBPA is
converted.
Br,
X
In cases where it is desired to have an oligomer with a higher concentration of bromine, the
liquid epoxy resin (LER) is replaced with a brominated epoxy resin ("X" = Br in the above
structure). The products (D.E.R.™ 560 is a typical example) have similar MWs, but the content
of bromine is higher (about 50 percent bromine by weight). These "high-brominated" resins are
typically used when other non-brominated materials must be added to the formulation (or
"varnish").
In the past a large majority of laminate varnishes would be prepared by simply combining the 20
weight percent brominated resin with 3 percent weight "dicy" (dicyandiamide) as a curing agent,
along with additional solvent. After the solvent was removed and the laminate pressed, the
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thermoset matrix would contain about 20 percent bromine by weight. This is sufficient bromine
to allow the thermoset matrix to pass the VO performance requirements in the standard UL 94
test. The cure chemistry of dicy is very complex and poorly understood. However, it is known to
be capable of reacting with 4, 5, or even 6 epoxy groups.
"Catalysts" such as 2-methylimidazole are used to increase the cure rate. Imidazoles are not true
catalysts: they initiate polymer chains, and become covalently bound to the matrix.
A simplified representation of the final thermoset is shown below. In a properly cured laminate
all of the resin has become one molecule, meaning every atom is covalently linked into one
three-dimensional structure. This is desirable because it means that there are no teachable (or
volatile) materials that can be released during the various procedures used to make a final PCB.
Br Br polymer ^
polymer | O
OH
Br
.
OH/ \
polymer polymer
With the advent of lead-free solders that melt at higher temperatures, phenolic hardeners (in
place of dicy) are becoming more common. Such formulations typically have higher
decomposition temperatures. A common phenolic hardener is an oligomer prepared from phenol
and formaldehyde that has the structure shown below. These "novolaks" typically have 2.5 to 5.5
phenolic groups per molecule, which translates to Mns of 450 to 780 g/mole. Bisphenol A
novolak is also becoming increasingly common to boost the glass Tg.
OH OH OH
The cross-linked matrix formed in this case is represented below. The use of phenolic hardeners
in the formulation has the effect of reducing the bromine concentration in the final cured resin. In
some cases additional flame retardant is needed to meet the UL 94 VO classification. This is
typically a solid additive such as alumina trihydrate or other fillers. Other methods are to mix in
a fraction of the fully brominated resin that contains 50 percent bromine by weight. Finally,
additional TBBPA and LER can be mixed into the crosslinked matrix to increase the bromine
concentration of the final cured resin, although it is unclear how common this practice is among
epoxy resin manufacturers (Mullins, 2008).
Br
polymer
polymet polyme^
O O
This description does not cover all of the formulations used by laminate producers to meet their
product specifications. Various epoxy novolaks can be added.
The process of making epoxy resins containing alternative flame retardants is similar to the
process used for making brominated epoxy resins. In the case of phosphorus-based flame
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retardants, the epoxy resin is produced by reacting diglycidyl ether of bisphenol A or an epoxy
novolak with a stoichiometric deficiency of phosphorus flame retardant. This produces a new
resin containing both an epoxy group and covalently bound phosphorus. Alternatively, a
phosphorus-containing hardener can be prepared by condensing a phenolic compound with a
phosphorus-containing flame retardant. For example, hydroquinone can condense with
phosphorus-containing flame retardants in the presence of an oxidizing agent to give a
hydroquinone-phosphorus compound. The laminator uses this hardener in conjunction with an
epoxy resin (such as an epoxy novolak) and catalysts. A laminate can also be made halogen-free
by using solid inorganic flame retardants (or fillers) to achieve the VO requirement of the UL 94
fire safety standard. A phosphorus content of about 4 to 5 percent by weight in the laminate is
generally sufficient to achieve the VO requirement of the UL 94 fire safety standard.
2.4.2 Laminate Manufacturing
Most PCBs are composed of 1 to 16 conductive layers separated and supported by layers
(substrates) of insulating material. In a typical four-layer board design, internal layers are used to
provide power and ground connections with all other circuit and component connections made
on the top and bottom layers of the board. The more complex board designs have a large number
of layers necessary for different voltage levels, ground connections, and circuit package formats.
The basic layer of the PCB is a woven fiberglass mat embedded with a flame-resistant epoxy
resin. A layer of copper is often placed over this fiberglass/epoxy layer, using methods such as
silk screen printing, photoengraving, or PCB milling to remove excess copper. Various
conductive copper and insulating dielectric layers are then bonded into a single board structure
under heat and pressure. The layers are connected together through drilled holes called vias,
typically made with laser ablation or with tiny drill bits made of solid tungsten carbide. The
drilled holes can then be plated with copper to provide conductive circuits from one side of the
board to the other (How Products Are Made, 2006).
Next, the outer surfaces of a PCB may be printed with line art and text using silk screening. The
silk screen, or "red print," can indicate component designators, switch setting requirements, test
points, and other features helpful in assembling, testing, and servicing the circuit board. PCBs
intended for extreme environments may also be given a conformal coat made up of dilute
solutions of silicone rubber, polyurethane, acrylic, or epoxy, which is applied by dipping or
spraying after the components have been soldered. This coat will prevent corrosion and leakage
currents or shorting due to condensation.
Once printed, components can be added in one of two ways. In through-hole construction,
component leads are electrically and mechanically fixed to the board with a molten metal solder,
while in surface-mount construction, the components are soldered to pads or lands on the outer
surfaces of the PCB. The parts of the circuit board to which components will be mounted are
typically "masked" with solder in order to protect the board against environmental damage and
solder shorts. The solder itself was traditionally a tin-lead alloy, but new solder compounds are
now used to achieve compliance with the Restriction of Hazardous Substances directive in the
European Union, which restricts the use of lead. These new solder compounds include organic
surface protectant, immersion silver, and electroless nickel with immersion gold coating (Oresjo
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and Jacobsen, 2005). Tin-silver-copper alloys have also been developed, some containing small
amounts of an additional fourth element (IPC, 2005; Lasky, 2005).
After construction, the PCB's circuit connections are verified by sending a small amount of
current through test points throughout the board. The PCB is then ready to be packaged and
shipped for use (Electronic Interconnect, 2007).
2.5 Next Generation Research and Development
Most R&D is oriented around improving the performance of FR-4 laminates. For example,
manufacturers are seeking to improve the glass Tg of FR-4 laminates in order to produce
laminates better able to withstand heat. A higher Tg is generally compatible with the use of lead-
free solder, which often requires a higher soldering temperature (Thomas et al., 2005).
Manufacturers often consider Tg together with the decomposition temperature (Td) when
assembling lead-free assemblies. Td is the temperature at which material weight changes by 5
percent. Due to marketplace concerns over potential environmental impacts of TBBPA, such as
the generation of halogenated dioxins and furans during combustion, as supported by this
project's combustion testing (Chapter 6), the development of non-halogen flame retardants
(discussed in Section 3.2) has also been a priority of manufacturers. However, concerns over the
human health and environmental impact, as well as the expense and performance of laminates
containing these non-halogen flame retardants, are still an issue.
There are many types of FR-4 laminates under development that have a resin design different
from the epoxy-based construction described above. These typically include more thermally
stable inflexible structures (such as biphenyl or naphthalene groups) and/or nitrogen heterocyclic
structures (such as reacted-in triazine, oxazoline, or oxazine rings). Another alternative to epoxy
resin, polyimide resin, can be produced through condensation reactions between aromatic
dianhydrides and aromatic diamines (Morose, 2006). IF Technologies has manufactured an
aliphatic LER system produced from epoxidized plant oils and anhydrides that reduces
emissions, decreases toxicity, and replaces bisphenol A and epichlorohydrin. Other technologies
in development use substances such as keratin, soybean oil, or lignin in the manufacturing
process.
Improvements in the lamination process are also being developed. Technologies may soon
enable the formation and multi-layering at room temperature of ceramic film on resin circuit
boards, allowing for further multi-functionality, miniaturization, and cost reduction of electronic
devices (PhysOrg, 2004). Laser drilling techniques will allow for the production of smaller
microvias, which may allow for the creation of smaller circuit boards (Barclay, 2004). Lasers can
also be used for direct copper ablation, as they can quickly vaporize copper without damaging
the epoxy and glass substrate (Lange, 2005).
2.6 References
Barclay, Brewster. What Designers Should Know about LDI. Printed Circuit Design and
Manufacture [Online] 2004,
http://pcdandf.com/cms/images/stories/mag/0401/0401barclay.pdf (accessed 2007).
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Beard, A.; De Boysere, J. (Clariant). Halogen-Free Laminates: Worldwide Trends,
Driving Forces and Current Status. Circuit World 2006, 32 (2).
Bergum, E. (Isola). FR-4 Proliferation. CircuiTree 2007, (Apr).
Davignon, J. 2012. iNEMI HFR-Free PCB Materials Team Project: An Investigation to Identify
Technology Limitations Involved in Transitioning to HFR-Free PCB Materials.
http://thor.inemi.org/webdownload/Pres/APEX2012/Halogen-Free Forum/HFR-
Free PCB Materials Paper 022912.pdf (accessed July 30, 2014).
Electronic Interconnect. Manufacturer of Printed Circuit Boards (PCB).
http://www.eiconnect.com/eipcbres.aspx?type=howpcb (accessed 2007).
Fu, H.; Tisdale, S.; Pfahl, R. C. 2009. iNEMI HFR-free Program Report.
http://thor.inemi.org/webdownload/newsroom/Presentati ons/SMTA_South_China_AugO
9/HFR-Free Report Aug09.pdf (accessed July 30, 2014).
Fujitsu: World's First Technologies to Form and Multi-layer High Dielectric Constant Ceramic
Film on Resin Circuit Board. PhysOrg [Online] August 6, 2004,
http://www.physorg.com/news717.html (accessed 2007).
How Products Are Made. Printed Circuit Boards. http://www.madehow.com/Volume-2/Printed-
Circuit-Board.html (accessed 2007).
iNEMI. HFR-Free High-Reliability PCB. http://www.inemi.org/project-page/hfr-free-high-
reliability-pcb (accessed July 30, 2014).
IPC. SnAgCu. 2005. http://leadfree.ipc.org/RoHS 3-2-l-3.asp (accessed Feb 14, 2008).
Lange, Bernd. PCB Machining and Repair via Laser. OnBoard Technology 2005, (Feb), 14.
Lasky, Ron. "SAC Alloy for RoHS Compliant Solder Paste: Still on Target." Oct 7, 2005.
http://blogs.indium.com/blog/an-interview-with-the-professor/sac-alloy-for-rohs-
compliant-solder-paste-still-on-target (accessed Feb 14, 2008).
Morose, G. An Investigation of Alternatives to Tetrabromobisphenol A (TBBPA) and
Hexabromocyclododecane (HBCD). Lowell Center for Sustainable Production:
University of Massachusetts Lowell, 2006. Prepared for: The Jennifer Altman
Foundation.
Mullins, Michael. Personal communication by phone with Melanie Vrabel, April 2008.
Oresjo, S.; Jacobsen, C. Pb-Free PCB Finishes for ICT. Circuits Assembly. [Online] 2005,
http://circuitsassembly.com/cms/content/view/2278/95 (accessed 2007).
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Prismark Partners LLC. Halogen-Free PCB Laminate Materials Current Commercial Status and
Short-Term Forecast; Report No. 3371; Abt Associates: Prepared under subcontract
August 2006.
RTF Company. UL94 V-0, V-l, V-2 Flammability Standard.
http://web.rtpcompany.com/info/ul/ul94v012.htm (accessed June 30, 2014).
Tisdale, S. 2013. "BFR-Free High Reliability PCB Project Summary." Presented at the iNEMI
Sustainability Forum, APEX 2013. February 21, 2013. San Diego, CA.
http://thor.inemi.org/webdownload/Pres/APEX2013/Sustainabilitv Forum 022113.pdf
(accessed July 30, 2014).
Thomas, Samuel G. Jr. et al. Tetrabromobisphenol-A Versus Alternatives in PWBs. OnBoard
Technology 2005, (June).
UL. UL 94 Flame Rating, http://www.ides.com/property descriptions/UL94.asp (accessed June
30, 2014).
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3 Chemical Flame Retardants for FR-4 Laminates
This chapter summarizes the general characteristics of flame retardants and associated
mechanisms of flame retardancy. The flame-retardant chemicals currently used in printed circuit
boards (PCBs) are also briefly introduced, with more detailed information about their potential
exposure pathways, toxicity, and life-cycle considerations presented in later chapters.
3.1 General Characteristics of Flame-Retardant Chemicals
Fire occurs in three stages: (a) thermal decomposition, where the solid, or condensed phase,
breaks down into gaseous decomposition products as a result of heat, (b) combustion chain
reactions in the gas phase, where thermal decomposition products react with an oxidant (usually
air) and generate more combustion products, which can then propagate the fire and release heat,
and (c) transfer of the heat generated from the combustion process back to the condensed phase
to continue the thermal decomposition process (Hirschler, 1992; Beyler and Hirschler, 2002).
In general, flame retardants decrease the likelihood of a fire occurring and/or decrease the
undesirable consequences of a fire (Lyons, 1970; Cullis and Hirschler, 1981). The simplest way,
in theory, of preventing polymer combustion is to design the polymer so that it is thermally very
stable. Thermally stable polymers are less likely to thermally degrade, which prevents
combustion from initiating. However, thermally stable polymers are not typically used due to
cost and/or other performance issues such as mechanical and electrical properties incompatible
with end-use needs for the finished part/item. As a result, manufacturers use other methods, such
as using flame-retardant chemicals, to impart flame-retardant properties to polymers.
Flame retardants typically function by decreasing the release rate of heat (Hirschler, 1994), thus
reducing the burning rate or flame spread of a fire, or by reducing smoke generation (Morose,
2006). In the gas phase, flame retardants can interfere with free radical chain reactions, thereby
reducing the tendency of the fire to propagate and spread. Flame retardants can also act in the gas
phase by cooling reactants and thereby decrease the rate of combustion. In the condensed phase,
flame retardants can act by forming a solid char (or a glassy layer), which interferes with the
transfer of heat back from the gas phase to the condensed phase. This inhibits or prevents further
thermal decomposition.
Typically, flame retardants contain one of the following seven elements: chlorine, bromine,
aluminum, boron, nitrogen, phosphorus, or antimony (Lyons, 1970; Cullis and Hirschler, 1981;
Hirschler, 1982). There are, however, a number of replacements and synergists that are also
effective. For example, aluminum (which is most often used as an oxide or hydroxide) can be
replaced with magnesium hydroxide or by a magnesium salt. In addition, some elements, such as
zinc (often used as zinc borate or zinc stannate) and molybdenum (often used as ammonium
molybdates), are effective primarily as smoke suppressants in mixtures of flame retardants.
3.1.1 Flame Retardant Classification
Flame retardants are generally incorporated throughout the polymeric material, although they can
also be coated on the external surface of the polymer to form a suitable protective barrier. Flame
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retardants can be classified, broadly speaking, into two types according to the method of
incorporation:
• Reactive: Reactive flame retardants are incorporated into polymers via chemical
reactions. The production of existing polymers is modified so that one or more
unsubstituted reactant monomers is replaced with a substituted monomer containing
flame-retardant heteroelements. The substituted monomers and their heteroelement
components become an integral part of the resulting polymer structure. Reactive flame
retardants must be incorporated at an early stage of manufacturing, but once introduced
they become a permanent part of the polymer structure. Once they are chemically bound,
reactive flame-retardant chemicals cease to exist as separate chemical entities. Reactive
flame retardants have a greater effect than additive flame retardants on the chemical and
physical properties of the polymer into which they are incorporated.
• Additive: Additive flame retardants are incorporated into the compounds via physical
mixing. Compounds containing flame-retardant elements are mixed with existing
polymers without undergoing any chemical reactions. As a result, the polymer/additive
mixture is less susceptible to combustion than the polymer alone. Since additive flame
retardants can be incorporated into the product up until the final stages of manufacturing,
it is typically simpler for manufacturers to use additive flame retardants than reactive
flame retardants.
Due to the differing physical and chemical properties of flame-retardant chemicals, most are
used exclusively as either reactive or additive flame retardants. Both reactive and additive flame
retardants can significantly change the properties of the polymers into which they are
incorporated. For example, they may change the viscosity, flexibility, density, and electrical
properties, and may also increase the susceptibility of the polymers to photochemical and
thermal degradation.
Flame retardants can also be classified into four main categories according to chemical
composition (TPC, 2003; and Morose, 2006):
• Inorganic: This category includes silicon dioxide, metal hydroxides (e.g., aluminum
hydroxide and magnesium hydroxide), antimony compounds (e.g., antimony trioxide),
boron compounds (e.g., zinc borate), and other metal compounds (molybdenum trioxide).
As a group, these flame retardants represent the largest fraction of total flame retardants
in use.
• Halogenated. These flame retardants are primarily based on chlorine and bromine.
Typical halogenated flame retardants are halogenated paraffins, halogenated alicyclic and
aromatic compounds, and halogenated polymeric materials. Some halogenated flame
retardants also contain other heteroelements, such as phosphorus or nitrogen. When
antimony oxide is used, it is almost invariably used as a synergist for halogenated flame
retardants. The effectiveness of halogenated additives, as discussed below, is due to their
interference with the radical chain mechanism in the combustion process of the gas
phase. Brominated compounds represent approximately 25 percent by volume of the
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global flame retardant production (Morose, 2006). Chemically, they can be further
divided into three classes:
o Aromatic, including tetrabromobisphenol A (TBBPA), polybrominated diphenyl
ethers, and polybrominated biphenyls;
o Aliphatic; and
o Cycloaliphatic, including hexabromocyclododecane.
• Phosphorus-based: When this partnership was convened, the current information
showed that this category represented about 20 percent by volume of the global
production of flame retardants and includes organic and inorganic phosphates,
phosphonates, and phosphinates as well as red phosphorus, thus covering a wide range of
phosphorus compounds with different oxidation states. There are also halogenated
phosphate esters, often used as flame retardants for polyurethane foams or as flame-
retardant plasticizers but not commonly used in electronics applications (Hirschler, 1998;
Green, 2000; Weil, 2004).
• Nitrogen-based: These flame retardants include melamine and melamine derivatives
(e.g., melamine cyanurate, melamine polyphosphate). It is rare for flame retardants to
contain no heteroatom other than nitrogen and to be used on their own. Nitrogen-
containing flame retardants are often used in combination with phosphorus-based flame
retardants, often with both elements in the same molecule.
3.1.2 Flame Retardant Modes of Action
The burning of polymers is a complex process involving a number of interrelated and
interdependent stages. It is possible to decrease the overall rate of polymer combustion by
interfering with one or more of these stages. The basic mechanisms of flame retardancy will vary
depending on the flame retardant and polymer system.
Flaming Combustion
Chemical Inhibitors — Some flame retardants interfere with the first stage of burning, in which
the polymer undergoes thermal decomposition and releases combustible gases. Interference
during this stage alters polymer breakdown in such a way as to change either the nature of
released gases or the rate at which they are released. The resulting gas/oxidant mixture may no
longer be flammable.
Fillers - A completely different mode of action is that exerted by inert solids incorporated into
polymers. Such materials, known as fillers, absorb heat and conduct heat away by virtue of their
heat capacity and thermal conductivity, respectively. As a result, fillers keep polymers cool and
prevent them from thermally decomposing. The temperature is kept down even more effectively
if the fillers decompose endothermically. Since fillers act predominantly via a physical rather
than a chemical process, large levels of fillers are needed.
Protective Barriers - Some flame retardants cover the flammable polymer surface with a non-
flammable protective coating. The coating helps insulate the flammable polymer from the source
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of heat, thus preventing the formation of combustible breakdown products and their escape into
the gas phase. The non-flammable coating may also prevent gaseous oxidants (normally air or
oxygen) from contacting the polymer surface. Intumescent compounds, which swell as a result of
heat exposure, lead to the formation of a protective barrier in which the gaseous products of
polymer decomposition are trapped. Alternatively, a non-flammable layer can be directly applied
to the surface of the polymer to form a non-intumescent barrier coating. Many phosphorus-
containing compounds form such non-intumescent surface chars.
Gaseous Phase Mechanisms - Flame-retardant chemicals can also inhibit combustion of the
gaseous products of polymer decomposition. These reactions are known as the gaseous flame
reactions. As for condensed phase inhibition, there are several rather distinct possible modes of
action.
In some cases, flame retardants lead to the release of reactive gaseous compounds into the
combustion zone, which can replace highly active free radicals with less reactive free radicals.
The less reactive free radicals slow the combustion process and reduce flame speed. In other
cases, flame retardants can cause the evolution of a small particle "mist" during combustion.
These small particles act as "third bodies" that catalyze free-radical recombination and hence
chain termination. This mode of action is typical of halogenated flame retardants, which usually
act by decomposing at high temperature to generate hydrogen chloride or hydrogen bromide.
These compounds react with oxygenated radicals and inhibit gas phase combustion reactions
(Cullis and Hirschler, 1981; Hirschler, 1982; Georlette et al., 2000).
Flame-retardant chemicals can also operate by releasing relatively large quantities of inert gas
during decomposition, which can change the composition and temperature of gaseous polymer
decomposition products. The resulting mixture of gaseous products and surrounding gaseous
oxidants are no longer capable of propagating flame. In some systems, when the polymer burns
the flame-retardant chemical is released chemically unchanged as a heavy vapor, which
effectively "smothers" the flame by interfering with the normal interchange of combustible
gaseous polymer decomposition products and combustion air or oxygen. This mode of action is
typical of metal hydroxides, such as aluminum or magnesium hydroxide (Horn, 2000).
Melting and Dripping - Some flame-retardant chemicals inhibit combustion by interfering with
the transfer of heat from combustion back to the polymer. Certain chemicals may promote
depolymerization, which lowers the molecular weight of the polymer and facilitates melting. As
the burning melt drips away from the bulk of the polymer it carries with it a proportion of the
heat that would otherwise contribute to polymer decomposition and volatilization. By reducing
the release of volatile decomposition products into the gas phase, these flame retardants reduce
the amount of gaseous decomposition products available to feed the flame. While enhanced
melting should decrease flammability in theory, in practice droplets of burning molten polymer
may help spread a fire to other combustible materials.
Ablation — Combustion can also be retarded by coating or constructing the polymer in such a
way that, when it burns, incandescent sections disintegrate from the original polymer and remove
with them heat from the combustion zone. This mechanism of action, known as ablation, is in a
sense the solid phase parallel of liquid phase melting and dripping. A surface char layer is
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frequently formed, which isolates the bulk of the polymer material from the high temperature
environment. This charry layer remains attached to the substrate for at least a short period while
a degradation zone is formed underneath it. In this zone, the organic polymer undergoes melting,
vaporization, oxidation, or pyrolysis. The ablative performance of polymeric materials is
influenced by polymeric composition and structure, as well as environmental factors, such as
atmospheric oxygen content. Higher hydrogen, nitrogen, and oxygen content of the polymer
increases the char oxidation rate; higher carbon content decreases the char oxidation rate
(Levchik and Wilkie, 2000).
Smoldering (Non-Flaming) Combustion
Smoldering (non-flaming) combustion and the closely related phenomenon of glowing
combustion occur primarily with high-surface area polymeric materials that break down during
combustion to form a residual carbonaceous char (typically cellulosic materials). In general, it is
possible to inhibit non-flaming combustion either by retarding or preventing the initial
breakdown of the polymer to form a char, or by interfering with the further combustion of this
char. Boric acid and phosphates are the primary flame retardants used for preventing non-
flaming combustion of organic polymers.
3.2 Flame-Retardant Chemicals Currently Used in FR-4 Laminates
Over the last several years, the electronics industry has been increasingly focused on researching
and developing halogen-free alternatives to TBBPA, due in large part to environmental concerns
and the anticipation of possible regulatory actions in the European Union. Several flame-
retardant chemicals are commercially available to meet fire safety standards for Flame Resistant
4 (FR-4) laminates. As of 2008, the halogenated flame retardant TBBPA is used in
approximately 90 percent of FR-4 PCBs. The majority of halogen-free alternatives to TBBPA
are based on phosphorus compounds that are directly reacted into the epoxy resin or combined
with aluminum trioxide or other fillers (De Boysere and Dietz, 2005). This section briefly
discusses TBBPA, dihydrooxaphosphaphenanthrene (DOPO), Fyrol PMP, and four commonly
used halogen-free fillers: aluminum hydroxide, melamine polyphosphate, metal phosphinate,
and silica. In this report, these four fillers are also referred to as additive flame retardants.
Reactive Flame-Retardant Chemicals
TBBPA
Br\ /-, >< /-\ /Br
HO y y OH
Br Br
TBBPA is a crystalline solid with the chemical formula CisH^B^C^. TBBPA increases the
glass transition temperature (Tg) of the epoxy resins and enables the resin to achieve a UL
(Underwriters Laboratories) 94 VO flammability rating. TBBPA is most commonly reacted into
the epoxy resin through "chain extension," meaning TBBPA is reacted with a molar excess of
diglycidyl ether of bisphenol A, or other similar epoxy. Once the TBBPA is chemically bound,
5-5
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the finished epoxy resin typically contains about 18 to 21 percent bromine (Weil and Levchik,
2004).
TBBPA is produced by several flame retardant manufacturers. According to High Density
Packaging User Group International (2004) and Morose (2006), TBBPA's market dominance is
due primarily to its moisture resistance, thermal stability, cost-effectiveness, compatibility with
the other components of PCBs, and ability to preserve the board's physical properties. Aside
from PCBs, another primary application of TBBPA is its use as an additive flame retardant in the
acrylonitrile-butadiene-styrene resins found in electronic enclosures of televisions and other
products.
DOPO
DOPO is a hydrogenphosphinate made from o-phenyphenol and phosphorus trichloride. Similar
to TBBPA, it can be chemically reacted to become part of the epoxy resin backbone. DOPO was
originally developed as a flame retardant for polyester textile fibers and also has applications as
an antioxidant-type stabilizer (Weil and Levchik, 2004). Due to DOPO's higher cost (nearly four
times as much as TBBPA at the time this partnership was convened), its use has been limited by
laminate manufacturers. To decrease the cost of their formulations, some laminate manufacturers
are using DOPO in combination with less expensive materials such as alumina trihydrate (ATH)
and/or silica (Thomas et al., 2005) or along with more cost-effective compounds like metal
phosphinates (De Boysere and Dietz, 2005).
FyrolPMP
Fyrol PMP is an aromatic phosphonate oligomer with high phosphorus content (17 to 18
percent). Similar to TBBPA and DOPO, Fyrol PMP can be chemically reacted to become part of
the epoxy resin backbone. When reacted into a phenol-formaldehyde novolak epoxy, Fyrol PMP
provides good flame retardancy at loadings as low as 20 percent (Weil, 2004).
-------
Flame-Retardant Fillers
Aluminum Hydroxide
HCL JDH
/M
OH
While the use of aluminum hydroxide (A1(OH)3) in FR-4 PCBs was relatively low several years
ago, it was the largest volume flame retardant used worldwide, with an estimated 42 percent
volume market share in 2006 (BCC, 2006). Aluminum hydroxide is commonly referred to as
ATH and has been used to impart flame retardancy and smoke suppression in carpet backing,
rubber products, fiberglass-reinforced polyesters, cables, and other products. It is also used in the
manufacture of a variety of items - antiperspirants, toothpaste, detergents, paper, and printing
inks - and is used as an antacid.
ATH is difficult to use alone to achieve the FR-4 rating of laminates, and as a result, high
loadings relative to the epoxy resin, typically up to 60 to 70 percent by weight, are needed
(Morose, 2006). ATH is most commonly used in FR-4 PCBs as a flame-retardant filler, in
combination with DOPO or other phosphorus-based compounds. When heated to 200-220°C,
ATH begins to undergo an endothermic decomposition to 66 percent alumina and 34 percent
water (Morose, 2006). It retards the combustion of polymers by acting as a "heat sink" - i.e., by
absorbing a large portion of the heat of combustion (HDPUG, 2004).
Melamine Polyphosphate
O O
l^P^ J^P^
HO^L 0-ft| OH
O OH
H
NH2
Melamine polyphosphate, an additive-type flame retardant based on a combination of
phosphorus and nitrogen chemistries, is typically used as crystalline powder and in combination
with phosphorus-based compounds. Its volume market share in 2006 was slightly more than 1
percent (BCC, 2006) but is expected to increase as the demand for halogen-free alternatives
increases. Similar to ATH, melamine polyphosphate undergoes endothermic decomposition but
at a higher temperature (350°C). It retards combustion when the released phosphoric acid coats
and therefore forms a char around the polymer, thus reducing the amount of oxygen present at
the combustion source (Special Chem, 2007). Melamine polyphosphate does not negatively
impact the performance characteristics of standard epoxy laminates, and functions best when
blended with other non-halogen flame retardants (Kaprinidis, 2008). Melamine polyphosphate
dissociates in water to form melamine cations and phosphate anions.
5-7
-------
Metal Phosphinates
R1-
•O"
Mn4
R2'
R jn
Flame retardants based on phosphinate chemistry were a relatively new class of halogen-free
flame retardants on the market at the time this partnership was convened. One such phosphinate-
based flame retardant - aluminum diethylphosphinate - is a fine-grained powder with high
phosphorus content (23 to 24 percent) used as a filler in FR-4 laminates (De Boysere and Dietz,
2005). It is designed primarily for use in FR-4 laminate materials with Tg greater than 150°C
(mid-range and high Tg applications). Like most phosphorus-based compounds, metal
phosphinates achieve flame retardancy by forming a char barrier upon heating, thereby cutting
off access to the oxygen needed for the combustion process. Due to its low density and high
surface area, aluminum diethylphosphinate cannot be used alone. It is typically used as a
powerful synergist in combination with modified resins and sometimes other filler-type flame
retardants.
Silica
o-
0-
:sf
Also known as silicon dioxide (SiC^), silica is characterized by its abrasion resistance, electrical
insulation, and high thermal stability. Silica is not a flame retardant in the traditional sense. It
dilutes the mass of combustible components, thus reducing the amount of flame retardant
necessary to pass the flammability test. Silica is most commonly used in combination with
novolak-type epoxy resins. For example, silica clusters can be reacted with phenolic novolak
resins (the resin bonds to hydroxyl groups on the silica cluster) to form a silica-novolak hybrid
resin (Patent Storm, 2002). It can be used as an inert, low expansion material in both the epoxy
resin and electronic circuit. One drawback is its abrasiveness, which affects drilling operation
during the PCB manufacturing process.
Magnesium Hydroxide
HO-Mg-OH
Magnesium hydroxide is functionally similar to ATH, in that it endothermically decomposes at
high temperatures to produce an oxide (MgO) and water. The absorption of heat retards the
combustion of polymers, and the release of water may create a barrier that prevents oxygen from
supporting the flame (Huber, 2007). However, whereas ATH undergoes thermal decomposition
at 200-220°C, magnesium hydroxide decomposes at approximately 330°C. This allows
manufacturers to use magnesium hydroxide when processing temperatures are too high for ATH
(Morose, 2006). Similar to ATH, high loadings of magnesium hydroxide are required to achieve
-------
the FR-4 rating. In many polymer systems, in order to reduce loadings, magnesium hydroxide is
sometimes combined with more effective flame retardants, such as phosphorus (Morose, 2006).
Other Chemicals
Following is a brief description of other chemicals that can be used as flame retardants in FR-4
PCBs but are not evaluated in this paper.
Ammonium Polyphosphate
Ammonium polyphosphate is an intumescent flame retardant, meaning that it swells when
exposed to heat, and can be used in epoxies. However, it is not commonly used in electronic
applications. At high temperatures (>250°C), ammonium polyphosphate decomposes into
ammonia and polyphosphoric acid. When exposed to water, polyphosphate reacts to form
monoammonium phosphate, a fertilizer (Chemische Fabrik Budenheim, 2007).
Red Phosphorus
Red phosphorus is produced from white phosphorus by heating white phosphorus in its own
vapor to 250°C in an inert atmosphere. It is fairly stable and is used in the manufacture of several
products, such as matches, pesticides, and flame retardants (Lide, 1993; Diskowski and
Hofmann, 2005). Its main use as a flame retardant is in fiberglass-reinforced polyamides.
Although it does function in epoxy resins, it is not recommended for electronic applications,
because red phosphorus can form phosphine (PH3) and acidic oxides under hot and humid
conditions (Clariant, 2002). The oxides can lead to metal corrosion, and hence electric defects
can occur (Clariant, personal communication 2007).
Antimony Oxide
Antimony oxide, typically antimony trioxide (Sb2O3), can be used as a flame retardant in a wide
range of plastics, rubbers, paper, and textiles. Antimony trioxide does not usually act directly as
a flame retardant, but as a synergist for halogenated flame retardants. Antimony trioxide
enhances the activity of halogenated flame retardants by releasing the halogenated radicals in a
stepwise manner. This retards gas phase chain reactions associated with combustion, which
slows fire spread (Hastie and McBee, 1975; Hirschler, 1982; Chemical Land 21, 2007).
Melamine Cyanurate
Melamine cyanurate is relatively cheap and highly available. However, it is a poor flame
retardant and requires high dosage (>40 percent weight) (Albemarle, 2007).
3.3 Next Generation Research and Development of Flame-Retardant Chemicals
Some companies are already offering halogen-free alternatives to TBBPA. In 2008, JJI
Technologies, for example, is developing new activated, non-halogen flame-retardant
formulations for PCBs - both additive and reactive. An activated flame retardant is one that
provides enhanced flame retardancy through the incorporation of an activator, which may consist
of either a char-forming catalyst or phase-transfer catalyst or both. Activated flame retardants
may improve flame-retardant features, including faster generation of char, higher char yield,
5-9
-------
denser char, self-extinguishing performance, thermal insulation, and lower smoke emissions (JJI
Technologies, 2007).
In addition to halogen-free alternatives to TBBPA, flame retardant manufacturers have
beenexploring ways to achieve a VO rating in the UL 94 fire test result through the redesign of
flame-retardant chemicals and epoxy resin systems. One of the largest areas of research and
development involves the use of nanotechnology to impart flame retardancy and increased
functionality to PCBs and other electronics products. However, their technical and commercial
viability is still limited, and their future use in commercial settings remains unknown. So far,
only combinations of nano flame retardants with traditional flame retardants have met
performance requirements. In addition, these new nano-traditional flame-retardant combinations
are only usable in certain polymer systems.
One type of halogen-free nano flame retardant is being developed through the synthesis of
ethylene-vinyl acetate copolymers with nanofillers (or nanocomposites) made of modified
layered silicates (Beyer, 2005). Nanofillers are incorporated into the olefin polymer during the
polymerization process by treating the surface of the nanofiller to induce hydrophobic
tendencies. The hydrophobic nanofiller disperses in the olefin monomers, which then undergo
polymerization and trap the nanofillers (Nanocor, 2007). Nanocomposites can also incorporate
aluminum into their structures, and can be combined with additive flame retardants, such as
ATH, leading to a reduction of the total ATH content and a corresponding improvement in
mechanical properties (Beyer, 2005).
3.4 References
Albemarle. The Future Regulatory Landscape of Flame Retardants from an Industry Perspective.
In Environmentally Friendly Flame Retardants., Proceedings of the Intertech Pira
Conference, Baltimore, MD, July 19, 2007.
BCC Research. Flame Retardancy News 2006,16 (3).
Beyer, Gunter. Flame Retardancy of Nanocomposites - from Research to Technical Products. J.
Fire Sci. 2005, 23 (Jan).
Beyler, C. L.; Hirschler, M. M. Thermal Decomposition of Polymers. In SFPE Handbook of Fire
Protection Engineering, 3rd ed; DiNenno, P.J., Ed.; NFPA: Quincy, MA, 2002, 1/110-
1/131.
Chemical Land 21. Antimony Oxide.
http://www.chemicalland21.com/industrialchem/inorganic/ANTIMONY%20TRIOXIDE.
htm (accessed 2007).
Chemische Fabrik Budenheim. Halogen Free Flame Retardants and their Applications. In
Environmentally Friendly Flame Retardants, Proceedings of the Intertech Pira
Conference, Baltimore, MD, July 19, 2007.
Clariant. Exolit RP for Thermoplastics: Technical Product Information, May 2002.
3-10
-------
Clariant. New Phosphorus Flame Retardants to Meet Industry Needs. In Environmentally
Friendly Flame Retardants, Proceedings of the Intertech Pira Conference, Baltimore,
MD, July 20, 2007.
Clariant. Personal communication by email between Kathleen Yokes and Adrian Beard,
December 2007.
Cullis, C. F.; Hirschler, M. M. The Combustion of Organic Polymers; Oxford University Press:
Oxford, 1981.
De Boysere, J.; Dietz, M. Clariant. Halogen-Free Flame Retardants For Electronic Applications.
OnBoard Technology. [Online] 2005, February, http://www.onboard-
technology.com/pdf febbraio2005/020505.pdf (accessed 2007).
Diskowski H, Hofmann T (2005): Phosphorus. Wiley-VCH, Weinheim, 10.1002/14356007.al9
505. Ullmann's Encyclopedia of Industrial Chemistry, pp. 1-22.
Georlette, P.; Simons, J.; Costa, L. Chapter 8: Halogen-containing fire retardant compounds. In
Fire Retardancy of Polymeric Materials; Grand, A.F., Wilkie, C.A., Eds.; Marcel
Dekker: New York, 2000, p 245.
Green, J. Chapter 5: Phosphorus-containing flame retardants. In Fire Retardancy of Polymeric
Materials; Grand, A.F., Wilkie, C.A., Eds.; Marcel Dekker: New York, 2000, p 147.
Hastie, J. W.; McBee, C. L. In Halogenated Fire Suppressants, Proceedings of the ACS
Symposium Series 16; Gann, R.G., Ed; American Chemical Society: Washington, DC,
1975, p 118.
High Density Packaging User Group International, Inc. (HDPUG). Environmental Assessment of
Halogen-free Printed Circuit Boards. DfE Phase II; Revised Final: January 15, 2004.
Hirschler, M. M. Recent developments in flame-retardant mechanisms. In Developments in
Polymer Stabilisation; Scott, G., Ed.; Applied Science Publ: London, 1982, 5, 107-152.
Hirschler, M. M., Ed.; Fire hazard and fire risk assessment; ASTM STP 1150; Amer. Soc.
Testing and Materials: Philadelphia, PA, 1992.
Hirschler, M. M. Fire Retardance, Smoke Toxicity and Fire Hazard. Proceedings of Flame
Retardants '94, London, UK, Jan. 26-27, 1994; British Plastics Federation, Ed.;
Interscience Communications: London, UK, 1994, 225-237.
Hirschler, M. M. Fire Performance of Poly(Vinyl Chloride) - Update and Recent Developments.
Proceedings of Flame Retardants '98, London, UK, February 3-4, 1998; Interscience
Communications: London, UK, 1998, 103-123.
3-11
-------
Horn Jr., W. E. Chapter 9: Inorganic hydroxides and hydroxycarbonates: their function and use
as flame-retardant additives. In Fire Retardancy of Polymeric Materials; Grand, A.F.,
Wilkie, C.A., Eds.; Marcel Dekker: New York, 2000, p 285.
Huber Engineered Materials (2007). Magnesium hydroxide functions in the same manner as
alumina trihydrate. http://www.hubermaterials.com/magnesiumHydroxide.htm (accessed
July 2008).
JJI Technologies. Personal communication by email between Kathleen Yokes, EPA and Jose
Reyes, JJI Technologies, Nov. 28, 2007.
IPC. IPC White Paper and Technical Report on Halogen-Free Materials Used for Printed
Circuit Boards and Assemblies; IPC-WP/TR-584, April, 2003.
Kaprinidis, N.; Fuchs S. Halogen-Free Flame Retardant Systems For PCBs. OnBoard
Technology 2008, (July).
Levchik, S.; Wilkie, C. A. Chapter 6: Char formation. In Fire Retardancy of Polymeric
Materials; Grand, A.F., Wilkie, C.A., Eds.; Marcel Dekker: New York, 2000, p 171.
Lide, D. R., ed. CRC Handbook of Chemistry and Physics, 74th edition, 1993/94; CRC Press:
Boca Raton.
Lyons, J.W. The Chemistry and Use of Fire Retardants; Wiley, New York, 1970.
Morose, G. An Investigation of Alternatives to Tetrabromobisphenol A (TBBPA) and
Hexabromocyclododecane (HBCD). Lowell Center for Sustainable Production:
University of Massachusetts Lowell, March 2006. Prepared for: The Jennifer Altman
Foundation.
Nanocor. Nanomer nanoclay as flame retardation additives. In Environmentally Friendly Flame
Retardants., Proceedings of the Intertech Pira Conference, Baltimore, MD July 20, 2007.
Special Chem. Flame Retardants Center: Melamine Compounds.
http://www.specialchem4polymers.com/tc/Melamine-Flame-
Retardants/index.aspx?id=4004 (accessed 2007).
Thomas, S. G., Jr.; Hardy, M. L.; Maxwell, K. A.; Ranken, P. F. Tetrabromobisphenol-A Versus
Alternatives in PWBs. OnBoard Technology 2005, (June).
Weil, E. D. In Flame Retardancy of Polymeric Materials; Kuryla, W.C., Papa, A.J., Eds.; Marcel
Dekker: New York, 1975, 3, 185.
Weil, E. D. Chapter 4: Synergists, adjuvants and antagonists in flame-retardant systems. In Fire
Retardancy of Polymeric Materials; Grand, A.F., Wilkie, C.A., Eds.; Marcel Dekker:
New York, 2000, 115.
3-12
-------
Weil, E. D. Flame Retardants - Phosphorus Compounds. In Kirk-Othmer Encyclopedia of
Chemical Technology; John Wiley & Sons, Inc.: NY, 1994; 2004 Revision.
Weil, E. D. and Levchik, S. A Review of Current Flame Retardant Systems for Epoxy Resins. J.
Fire Sci. 2004, 22 (Jan).
3-13
-------
4 Hazard Evaluation of Flame Retardants for Printed Circuit
Boards
This chapter summarizes the toxicological and environmental hazards of each flame-retardant
chemical that was identified for potential functional use in printed circuit boards (PCBs)
laminates. Evaluations of chemical formulations may also include associated substances (e.g.,
starting materials, by-products, and impurities) if their presence is specifically required to allow
that alternative to fully function in the assigned role. Otherwise, pure substances were analyzed
in this assessment. Users of the alternative assessments should be aware of the purity of the
trade product they purchase, as the presence of impurities may alter the hazard of the
alternative.
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 Section 4.4 and Section 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 4.8. Lastly, the collected data and hazard profile of
each chemical are presented in Section 4.9.
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 Program
Alternatives Assessment Criteria for Hazard Evaluation (U.S. EPA, 2011b). The definitions for
each endpoint evaluated following these criteria are outlined in Section 4.1.1 and the criteria by
which these endpoints are evaluated are outlined in Section 4.1.2. Lastly, there are endpoints
which DfE characterizes but does not assign criteria to and these are summarized in Section
4.1.3.
4.1.1 Definitions of Each Endpoint Evaluated Against Criteria
Hazard designations for each chemical discussed in this report were made by direct comparison
of the experimental or estimated data to the DfE Program Alternatives Assessment Criteria for
Hazard Evaluation (U.S. EPA, 20 lib). Table 4-1 provides brief definitions of human health
toxicity, environmental toxicity and environmental fate endpoints.
Table 4-1. Definitions of Toxicological and Environmental Endpoints for Hazard Assessment
Endpoint
Category
Endpoint
Definition
Human Health
Effects
Acute Mammalian Toxicity
Adverse effects occurring following oral or dermal
administration of a single dose of a substance, or multiple
doses given within 24 hours, or an inhalation exposure of
4 hours.
4-1
-------
Endpoint
Category
Endpoint
Definition
Carcinogenicity
Mutagenicity/Genotoxicity
Reproductive Toxicity
Developmental Toxicity
Neurotoxicity
Capability of a substance to increase the incidence of
malignant neoplasms, reduce their latency, or increase
their severity or multiplicity.
Mutagenicity - The ability of an agent to induce
permanent, transmissible changes in the amount, chemical
properties or structure of the genetic material. These
changes may involve a single gene or gene segment, a
block of genes, parts of chromosomes, or whole
chromosomes. Mutagenicity differs from genotoxicity in
that the change in the former case is transmissible to
subsequent cell generations.
Genotoxicity - The ability of an agent or process to alter
the structure, information content, or segregation of DNA,
including those which cause DNA damage by interfering
with normal replication process, or which in a non-
physiological manner (temporarily) alter its replication.
The occurrence of biologically adverse effects on the
reproductive systems of females or males that may result
from exposure to environmental agents. The toxicity may
be expressed as alterations to the female or male
reproductive organs, the related endocrine system, or
pregnancy outcomes. The manifestation of such toxicity
may include, but is not limited to: adverse effects on onset
of puberty, gamete production and transport, reproductive
cycle normality, sexual behavior, fertility, gestation,
parturition, lactation, developmental toxicity, premature
reproductive senescence or modifications in other
functions that were dependent on the integrity of the
reproductive systems.
Adverse effects in the developing organism that may
result from exposure prior to conception (either parent),
during prenatal development, or postnatally to the time of
sexual maturation. Adverse developmental effects may be
detected at any point in the lifespan of the organism. The
major manifestations of developmental toxicity include:
(1) death of the developing organism, (2) structural
abnormality, (3) altered growth, and (4) functional
deficiency.
An adverse change in the structure or function of the
central and/or peripheral nervous system following
exposure to a chemical, physical or biological agent.
4-2
-------
Endpoint
Category
Environmental
Toxicity
Environmental
Fate
Endpoint
Repeated Dose Toxicity
Respiratory Sensitization
Skin Sensitization
Eye Irritation/Corrosivity
Skin Irritation/Corrosion
Definition
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.
Hypersensitivity of the airways following inhalation of a
substance.
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.
Irritation or corrosion to the eye following the application
of a test substance.
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 refers to adverse effects observed in living organisms that typically
inhabit the wild; the assessment is focused on effects in three groups of surrogate aquatic
organisms (freshwater fish, invertebrates, and algae).
Aquatic Toxicity (Acute)
Aquatic Toxicity (Chronic)
Environmental Persistence
Bioaccumulation
The property of a substance to be injurious to an organism
in a short-term, aquatic exposure to that substance.
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.
The length of time the chemical exists in the environment,
expressed as a half-life, before it is destroyed (i.e.,
transformed) by natural or chemical processes. For
alternative assessments, the amount of time for complete
assimilation (ultimate removal) is preferred over the initial
step in the transformation (primary removal).
The process in which a chemical substance is absorbed in
an organism by all routes of exposure as occurs in the
natural environment, e.g., dietary and ambient
environment 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.
4-3
-------
The hazard profile for each chemical contains endpoint specific summary statements (see Section
4.9). 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 Program
Alternatives Assessment Criteria for Hazard Evaluation underwent internal and public comment,
and were finalized in 2011 (U.S. EPA, 201 Ib). 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 Program 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
Very Low
Human Health Effects
Acute mammalian toxicity
Oral median lethal dose
(LD5o) (mg/kg)
Dermal LD50 (mg/kg)
Inhalation median lethal
concentration (LC50) -
vapor/gas
(mg/L)
Inhalation LC50 - dust/mist/
fume (mg/L)
<50
<200
<2
<0.5
>50-300
>200-1000
>2-10
>0.5-1.0
>300-2000
>1000-2000
>10-20
>l-5
>2000
>2000
>20
>5
—
-
—
—
Carcinogenicity
Carcinogenicity
Known or
presumed
human
carcinogen
(equivalent to
Globally
Harmonized
System of
Classification
and Labeling of
Chemicals
(GHS)
Categories 1A
and IB)
Suspected
human
carcinogen
(equivalent to
GHS Category
2)
Limited or
marginal
evidence of
Carcinogenicity
(And inadequate
evidence in
humans)
Negative studies
or robust
mechanism-
based Structure
Relationship
(SAR)
(As described
above)
4-4
-------
Endpoint
Very High
High
Moderate
Very Low
Mutagenicity/Genotoxicity
Germ cell mutagenicity
Mutagenicity and
genotoxicity in somatic
cells
GHS Category
lAorlB:
Substances
known to
induce heritable
mutations or to
be regarded as
if they induce
heritable
mutations in the
germ cells of
humans
GHS Category
2: Substances
which cause
concern for
humans owing
to the
possibility that
they may
induce heritable
mutations in the
germ cells of
humans
OR
Evidence of
mutagenicity
supported by
positive results
in in vitro AND
in vivo somatic
cells and/or
germ cells of
humans or
animals
Evidence of
mutagenicity
supported by
positive results
in in vitro OR in
vivo somatic
cells of humans
or animals
Negative for
chromosomal
aberrations and
gene mutations,
or no structural
alerts.
-
Reproductive toxicity
Oral (mg/kg/day)
Dermal (mg/kg/day)
Inhalation - vapor, gas
(mg/L/day)
Inhalation - dust/mist/fume
(mg/L/day)
-
-
-
-
<50
<100
<1
<0.1
50-250
100-500
1-2.5
0.1-0.5
>250-1000
>500-2000
>2.5-20
>0.5-5
>1000
>2000
>20
>5
Developmental toxicity
Oral (mg/kg/day)
Dermal (mg/kg/day)
Inhalation - vapor, gas
(mg/L/day)
Inhalation - dust/mist/fume
(mg/L/day)
-
-
-
-
<50
<100
<1
<0.1
50-250
100-500
1-2.5
0.1-0.5
>250-1000
>500-2000
>2.5-20
>0.5-5
>1000
>2000
>20
>5
Neurotoxicity
Oral (mg/kg/day)
Dermal (mg/kg/day)
Inhalation - vapor, gas
(mg/L/day)
Inhalation - dust/mist/fume
(mg/L/day)
-
-
-
-
<10
<20
<0.2
0.02
10-100
20-200
0.2-1.0
0.02-0.2
>100
>200
>1.0
>0.2
-
-
-
-
Repeated-dose toxicity
Oral (mg/kg/day)
-
<10
10-100
>100
-
4-5
-------
Endpoint
Dermal (mg/kg/day)
Inhalation - vapor, gas
(mg/L/day)
Inhalation - dust/mist/fume
(mg/L/day)
Very High
-
-
-
High
<20
O.2
O.02
20-200
0.2-1.0
0.02-0.2
>200
>1.0
>0.2
Very Low
-
-
-
Sensitization
Skin sensitization
Respiratory sensitization
High frequency
of sensitization
in humans
and/or high
potency in
animals (GHS
Category 1A)
Occurrence in
humans or
evidence of
sensitization in
humans based
on animal or
other tests
(equivalent to
GHS Category
1A and IB)
Low to moderate
frequency of
sensitization in
human and/or
low to moderate
potency in
animals (GHS
Category IB)
Limited
evidence
including the
presence of
structural alerts
Adequate data
available and not
GHS Category
lAorlB
Adequate data
available
indicating lack
of respiratory
sensitization
Irritation/corrosivity
Eye irritation/corrosivity
Skin irritation/corrosivity
Irritation
persists for
>21 days or
corrosive
Corrosive
Clearing in 8-
21 days,
severely
irritating
Severe
irritation at
72 hours
Clearing in
<7 days,
moderately
irritating
Moderate
irritation at
72 hours
Clearing in
<24 hours,
mildly irritating
Mild or slight
irritation at
72 hours
Not irritating
Not irritating
Endocrine activity
Endocrine Activity
For this endpoint, High/Moderate/Low etc. characterizations will not apply. A
qualitative assessment of available data will be prepared.
Environmental Toxicity and Fate
Aquatic toxicity
Acute aquatic toxicity -
LC50 or half maximal
effective concentration
(EC50) (mg/L)
Chronic aquatic toxicity -
lowest observed effect
concentration (LOEC) or
chronic value (ChV)
(mg/L)
<1.0
0.1
1-10
0.1-1
>10-100
>1-10
>100orNo
Effects at
Saturation
(NES)
>10orNES
Environmental persistence
4-6
-------
Endpoint
Persistence in water, soil,
or sediment
Persistence in air (half -life
days)
Very High
Half-life
>180 days or
recalcitrant
High
Moderate
Half-life of 60-
180 days
Half-life <60
but>16 days
Low
Half-life
<16 days OR
passes Ready
Biodegradability
test not
including the
10-day window.
No degradation
products of
concern.
Very Low
Passes Ready
Biodegradability
test with 10-day
window. No
degradation
products of
concern.
For this endpoint, High/Moderate/Low etc. characterizations will not apply. A
qualitative assessment of available data will be prepared.
Bioaccumulation
Bioconcentration Factor
(BCF)/Bioaccumulation
Factor (BAF)
Log BCF/BAF
>5000
>3.7
5000-1000
3.7-3
<1000-100
<3-2
<100
<2
"
-
Very High or Very Low designations (if an option for a given endpoint in Table 4-2) were assigned only when there were experimental data
located 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, by
professional judgment, or from a computerized model, then the next-level designation was assigned (e.g., use of data from a structural analog
that would yield a designation of Very High would result in a designation of high for the chemical in review). One exception is for the estimated
persistence of polymers with an average molecular weight (MW) > 1,000 daltons, which may result in a Very High designation.
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 the interpretation of other toxicity
and fate endpoints (including toxicokinetics and transport in the environment).
Table 4-3. Definitions of Endpoints and Information Characterized but Not Evaluated Against Hazard
Criteria
Toxicological Endpoint
Toxicokinetics
Biomonitoring
Information
Environmental Transport
Persistence in Air
Definition
The determination and quantification of the time course of absorption, distribution,
biotransformation, and excretion of chemicals (sometimes referred to as
pharmacokinetics).
The measured concentration of a chemical in biological tissues where the analysis
samples were obtained from a natural or non-experimental setting.
The potential movement of a chemical, after it is released to the environment, within
and between each of the environmental compartments, air, water, soil, and sediment.
Presented as a qualitative summary in the alternative assessment based on physical-
chemical properties, environmental fate parameters, and simple volatilization models.
Also includes distribution in the environment as estimated from a fugacity model1 .
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 environmental transport models.
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Toxicological Endpoint
Immunotoxicology
Terrestrial Ecotoxicology
Endocrine Activity
Definition
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).
Reported experimental values from guideline and nonguideline studies on adverse
effects on the terrestrial environment. Studies on soil, plants, birds, mammals,
invertebrates were also included.
A change in endocrine homeostasis caused by a chemical or other stressor from
human activities (e.g., application of pesticides, the discharge of industrial chemicals
to air, land, or water, or the use of synthetic chemicals in consumer products.)
1A 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).
4.2 Data Sources and Assessment Methodology
This section explains how data were collected (Section 4.2.1), prioritized and reviewed (Section
4.2.2) for use in the development of hazard profiles. High-quality experimental studies lead to a
thorough understanding of behavior and effects of the chemical in the environment and in living
organisms. Analog approaches and SAR-based estimation methods are also useful tools and are
discussed throughout this section. Information on how polymers differ from discrete chemicals
in terms of how they are evaluated is presented in Section 4.2.3.
4.2.1 Identifying and Reviewing Measured Data
For each chemical assessed, data were collected in a manner consistent with the High Production
Volume (HPV) Chemical Challenge Program Guidance (U.S. EPA, 1999b) on searching for
existing chemical information. 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. These were supplemented by primary searches of scientific literature published
after these secondary sources were released; this 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 U.S. Environmental Protection Agency (EPA) public databases (e.g.,
integrated risk information system (IRIS); the High Production Volume Information System) and
confidential databases 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 4-2. For most alternatives assessed, high-quality secondary sources were not available;
therefore a comprehensive search of the 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
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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, the literature review
focused primarily on the use of secondary sources, such as Agency for Toxic Substances and
Disease Registry Toxicological Profiles or IRIS assessments. Using high-quality secondary
sources maximized available resources and eliminated potential duplication of effort. However,
more than one secondary source was typically used to verify reported values, which also reduced
the potential for presenting a value that was transcribed incorrectly from the scientific literature.
Although other sources might also contain the same experimental value for an endpoint, effort
was not focused on building a comprehensive list of these references, as it would not have
enhanced the ability to reach a conclusion in the assessment. When data for a selected endpoint
could not be located in a secondary source for an otherwise well-studied chemical, the primary
literature was searched by endpoint and experimental studies were assessed for relevant
information.
Making Predictions in the Absence of Measured Data
In the absence of primary or secondary data, hazard designations were based on (1) Quantitative
Structure Activity Relationship (QSAR)-based estimations from the EPA New Chemical
Program's predictive methods; (2) analog data; (3) class-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 Program 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
available for free (U.S. EPA, 2012c). Often analog data were used to support predictions from
models. These approaches were described in the EPA Pollution Prevention (P2) Framework and
Sustainable Futures (SF) program (U.S. EPA, 2005; 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 ACE acidity and basicity
calculator website for dissociation constants) were used (ACE Organic 2013). All estimation
methods employed were limited to those freely available in the public domain.
The methodology and procedures used to assess polymers are described in Section 4.2.3. In
addition, the endpoints for impurities or oligomers with a 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.
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When QSAR models were not available, professional judgment was used to identify hazards for
similar chemicals using the guidance from EPA's New Chemicals Categories (U.S. EPA, 2010c).
The categories identify substances that share chemical and toxicological properties and possess
potential health or environmental concerns (U.S. EPA, 2010a). In the absence of an identified
category, analogs for which experimental data are available were identified using EPA's Analog
Identification Methodology (AIM) or by substructure searches of confidential EPA databases
(U.S. EPA, 2012a). If a hazard designation was still not available, the expert judgment of
scientists from EPA's New Chemical Program would provide an assessment of the physical-
chemical properties, environmental fate, aquatic toxicity and human health endpoints to fill
remaining data gaps.
4.2.2 Hierarchy of Data Adequacy
Once the studies were obtained, they were evaluated to establish whether the hazard data were of
sufficient quality to meet the requirements 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 4.9. 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 without 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
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
preferred (Items 1 and 2 in the hierarchy list). Information from secondary sources such as
Material Safety Data Sheets, or online databases (such as the National Library of Medicine's
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Hazardous Substances Data Bank, Item 3 in the hierarchy list) was considered appropriate for
some endpoints when it included numerical values for effect levels that could be compared to the
evaluation criteria.
4.2.3 Assessment of Polymers and Oligomers
The methodology and procedures used to assess polymers were slightly different than those used
for oligomers, discrete compounds and simple mixtures. Although experimental data for
polymers were identified using the literature search techniques discussed above in Section 4.2.1,
in the absence of experimental data, estimates were performed using professional judgment as
presented in the literature (U.S. EPA, 201 Ob). The polymers are a mixture of molecules with a
distribution of components (e.g., different chain lengths) that depend on the monomers used,
their molar ratios, the total number of monomeric units in the polymer chain, and the
manufacturing conditions. To account for this variation, the average MW profile (also referred to
as the number average molecular weight MWn) was used in their assessment as the individual
chains rarely have the same degree of polymerization and weight yet their physical, chemical,
and environmental properties are essentially identical for the purposes of this assessment. The
polymers evaluated as alternatives typically have average MWs ranging from > 1,000 to
<100,000 daltons.
For polymers with relatively low average MWs (i.e., those with average MWs generally less than
2,000), the alternative assessment also determined the amount of oligomers and unchanged
monomers (starting materials) in the MW profile with MWs < 1,000 daltons. Special attention
was paid to materials that have a MW <1,000 daltons as these materials often have the highest
hazard (potentially bioavailable substances) in the mixture. This type of assessment was similar
to the evaluation of the hazards of impurities present in discrete chemical products.
Methodological differences between the evaluation of discrete products and polymers are
discussed in Section 4.3.
For the Alternatives Assessment, there were chemicals that are mixtures of low MW oligomers
comprised of 2 or 3 repeating units. 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
by-products 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. 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
4.9. 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 Table 5-2.
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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 less mobile in
biological and environmental systems. Their large size restricts their transport through biological
membranes and lowers their vapor pressure. Polymers and oligomers evaluated in this
alternatives assessment were mixtures that contain a distribution of components and they may
not have a unique MW (see also Section 4.2.3). To account for variation in these mixtures, the
average MW or MWn, determined experimentally (typically using high pressure liquid
chromatography, viscosity, or light-scattering), was used in the assessment of polymers. The
assessment of polymers also includes oligomers and unchanged monomers (starting materials)
that have MW of <1,000 daltons as these were often the highest concern materials (bioavailable
substances) in the mixture.
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 Chapter 5. 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 including polymers (U.S. EPA, 1999b). Melting points for polymers
and/or oligomers were not reported as these materials typically reach a softening point and do
not undergo the phase change associated with melting (i.e., solid to liquid).
Vapor Pressure
Vapor pressure is useful in determining the potential for a chemical substance to volatilize to the
atmosphere from dry surfaces, from storage containers, or during mixing, transfer, or
loading/unloading operations (see Section 5.2). In the assessment process, chemicals with a
vapor pressure less than 1 x 10"6 mm Hg have a low potential for inhalation exposure resulting
from gases or vapors. Vapor pressure is also useful for determining the potential environmental
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fate of a substance. Substances with a vapor pressure more than 1 x 10"4 mm Hg generally exist
in the gas phase in the atmosphere. Substances with a vapor pressure between 1 x 10"4 and 1 x
10"8 mm Hg exist as a gas/particulate mixture. Substances with a vapor pressure less than 1 x 10"8
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 Earth's surface.
A maximum vapor pressure of 1 x 10"8 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, 201 le). The maximum vapor pressure of 1 x 10"8 mm Hg was also the default value
reported for the vapor pressure of and other materials polymers with a MW >1,000 daltons (U.S.
EPA, 201 Ob).
Water Solubility
The water solubility of a chemical provides an indication of its distribution between
environmental media, potential for environmental exposure through release to aquatic
compartments, and potential for human exposure through ingestion of drinking water. Water
solubility was also used extensively to determine potential human health and ecotoxicity hazards.
In general, chemicals with water solubility less than 1 x 10"5 g/L indicate a lower concern for
both the expression of adverse effects, and potential aquatic and general population exposure due
to their low bioavailability. However, chemicals with a low bioavailability also tend to be more
environmentally persistent. Low bioavailability is different than no bioavailability, and the two
should not be used interchangeably.
Within the context of this alternatives assessment, the following descriptors were used according
to ranges of water solubility values: more than 10,000 mg/L was considered very soluble; 1,000-
10,000 mg/L represents soluble; 100-1,000 mg/L represents moderately soluble, 1-100 mg/L
represents slightly soluble, and less than 1 mg/L represents insoluble, noting that these guidelines
might not match what is used elsewhere within the scientific literature for other disciplines.
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 un-dissolved 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
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reached because it was above the material's water solubility), the chemical was described as
having NES. An NES designation is equivalent to a low aquatic toxicity hazard designation for
that endpoint.
While assessing the water solubility of a chemical substance, its potential to disperse in an
aqueous solution was also considered. Ideally, a chemicals potential to disperse would be
obtained from the scientific literature. In the absence of experimental data, the potential for
dispersion 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 disperse influences potential exposure, environmental fate, and
toxicity. Dispersible chemicals have greater potential for human and environmental exposure,
teachability, and aquatic toxicity than what might be anticipated based on the material's water
solubility alone.
Chemicals without experimental data or chemicals that were anticipated by professional
judgment to be sufficiently insoluble and thus were not bioavailable were assigned a water
solubility maximum value of 1 x 10"3 mg/L (U.S. EPA, 201 le). A water solubility of 1 x 10"3
mg/L is the default value used for discrete organics as well as non-ionic polymers with a MW
>1,000 daltons according to information contained in the literature concerning polymer
assessment (U.S. EPA, 2010b). This assignment is consistent with an analysis of the chemicals
used in the development of the water solubility estimation program in EPA's EPISuite™
software. 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 4 x 10"7 mg/L
(Meylan, Howard et al., 1996; U.S. EPA, 201 li). Given that water solubility decreases with MW,
a default value of 1 x 10"3 mg/L is consistent with the limited bioavailability expected for
materials with a MW >1,000 daltons.
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 greater than
approximately 8 may be difficult to obtain experimentally.
The log Kow can be used as a surrogate for the water solubility in a hazard assessment and is
frequently used to estimate the water solubility if an experimental value is not available. It can
also be used to estimate other properties important to the assessment, including bioconcentration
and soil adsorption, and is a required input for SAR models used to estimate ecotoxicity values.
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For chemicals without data, that are not within the domain of EPISuite™ or that were expected
to be insoluble in water (WS <1 x 10"3 mg/L), a minimum value of 10 was assigned for the log
Kow (U.S. EPA, 201 le). Insoluble chemicals that could be run through EPISuite™ software may
use a log Kow >10 if the result appeared to be valid based on expert review. This assignment is
consistent with an analysis of the chemicals ("training set") used in the development of the
octanol/water partition coefficient estimation program in the EPISuite™ software. The training
set for this model included 10,946 chemicals with a MW range 18-720 daltons and experimental
log Kow values ranging from -3.89 to 8.70 (Meylan and Howard, 1995; U.S. EPA, 201 Ih). Given
that log Kow increases with MW, a default value of 10 is consistent with the limited
bioavailability expected for materials with a MW > 1,000 daltons. A maximum log Kow of-2 was
used for water soluble materials. For most polymers and other materials that are anticipated to be
insoluble in both water and octanol, the log Kow cannot be measured and was therefore not listed.
Flammability (Flash Point)
The flash point of a substance is defined as the minimum temperature at which the substance
emits sufficient vapor to form an ignitable mixture with air. Flash point can be used to identify
hazards associated with the handling of volatile chemicals. Substances with a flash point above
37.8°C (100°F) were commonly referred to as non-flammable, as this is the flammability
definition used in the shipping industry. There are exceptions to this definition such as chemicals
that may form explosive mixtures in the presence of air.
Explosivity
Explosivity refers to the potential for a chemical to form explosive mixtures in air and can be
defined using the limits of flammability. The lower limit of flammability (LFL) is defined as the
minimum concentration of a combustible substance that is capable of propagating a flame
through a homogenous mixture in the presence of an ignition source. The upper limit of
flammability (UFL) is similarly defined as the highest concentration that can propagate a flame.
LFLs and UFLs are commonly reported as the volume percent or volume fraction of the
flammable component in air at 25°C. If the ambient air concentration of the gas (or vapor) is
between the upper and lower explosion limit, then the material has the potential to explode if it
comes in contact with an ignition source. Knowledge regarding the explosivity of a given
material in air is also useful in identifying potential hazards associated with the manufacture and
use of that material.
pH
The pH scale measures how acidic or basic a substance is on a range from 0 to 14. A pH of 7 is
neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. This scale is used primarily
to identify potential hazards associated with skin or eye contact with a chemical or its aqueous
solutions. The corrosive nature of chemicals that form either strongly basic (high pH) or strongly
acidic (low pH) solutions are generally likely to result in harm to skin and other biological
membranes. For corrosive chemicals, some experimental studies, such as biodegradation tests,
require additional analysis to determine if the tests were performed at concentrations that cause
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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
typically measured in water at 25°C. The Henry's Law constant provides an indication of a
chemical's volatility from water, which can be used to derive partitioning within environmental
compartments and the amount of material removed by stripping in a sewage treatment plant.
Henry's Law constant values less than 1 x 10"7 atm-m3/mole indicate slow volatilization from
water to air (the Henry's Law constant for the volatilization of water from water is 1 x 10"7 atm-
m3/mole) and values more than 1 x 10"3 atm-m3/mole indicate rapid volatilization from water to
air. To aid in determining the importance of volatilization, the assessment uses two models based
on the Henry's Law constant. These models determine the half-life for volatilization from a
model river and a model lake. A maximum value of 1 x 10"8 atm-m3/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 unlikely to leach into ground water. The soil adsorption
coefficient also describes the potential for a chemical to partition from environmental waters to
suspended solids and sediment. The higher the Koc, the more strongly a chemical is adsorbed to
soil. Strong adsorption may impact other fate processes, such as the rate of biodegradation, by
making the chemical less bioavailable.
The soil adsorption coefficient, Koc, is normalized with respect to the organic carbon content of
the soil to account for geographic differences. The assignments for the degree that a chemical is
adsorbed to soil within the context of the assessment were described qualitatively as very strong
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(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, 201 le). A default Koc of 30,000 was used for polymers and other materials with a MW
> 1,000 daltons.
Reactivity
The potential for a substance to undergo irreversible chemical reactions in the environment can
be used in the assessment of persistence. The primary chemical reactions considered in an
environmental fate assessment are: hydrolysis, photolysis, and the gas phase reaction with
hydroxyl radicals, ozone or nitrate radicals. The most important reaction considered in the hazard
assessment of organic compounds is hydrolysis, or the reaction of a chemical substance with
water. Because the rate of hydrolysis reactions can change substantially as a function of pH,
studies performed in the pH range typically found in the environment (pH 5-9) were considered.
The second reaction considered in the assessment is photolysis, the reaction of a chemical with
sunlight. Both hydrolysis and photolysis occur in air, water, and soil, while only hydrolysis was
considered in sediment. The half-lives for reactive processes, if faster than removal via
biodegradation, were used to assign the hazard designation by direct comparison to the DfE
persistence criteria.
For the atmospheric compartment, persistence also includes the evaluation of oxidative gas-
phase processes. These processes include the reaction with ozone, hydroxyl radicals, and nitrate
radicals. Since the average concentration of these oxidative species in the atmosphere has been
measured, the experimental or estimated rate constants were converted to, and reported as, a
half-life in the assessment using standard pseudo first-order kinetics (U.S. EPA, 201 If; U.S.
EPA, 20lid).
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 4.3,
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
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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 the importance
of biodegradation is, therefore, an important component of the assessment. Biodegradation
processes are divided into two types. The first is primary biodegradation, in which a chemical
substance is converted to another substance. The second is ultimate biodegradation, in which a
chemical is completely mineralized to small building-block components (e.g., CC>2 and water).
DfE persistence criteria use data that are reported as 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
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 4.3. A default
Very High persistence hazard designation was assigned for polymers and other materials with a
MW >1,000 daltons according to information contained in the literature concerning polymer
assessment (U.S. EPA, 2010b).
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 Table
4-2.
For acute mammalian toxicity the median lethal doses or concentrations were used to assign the
hazard designation. Four levels of hazard designation have been defined ranging from Low to
Very High.
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For cancer the hazard designation was contingent on the level of evidence for increased
incidence of cancer, and not potency. The definitions applied in DfE criteria are based on
International Agency for Research on Cancer 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 conclusions).
Similarly, the hazard designation for mutagenicity/genotoxicity was also based on the level of
evidence rather than potency. Complete data requirements for this endpoint were both gene
mutation and chromosomal aberration assays. For instances of incomplete or inadequate
mutagenicity/genotoxicity data, a Low hazard designation cannot be given.
For chronic endpoints, such as reproductive, developmental, neurological and repeated dose
toxicity, the hazard designation was based on potency. The evaluation considers both lowest
observed adverse effect levels (LOAELs) and identification of no observed adverse effect levels
(NOAELs) when available. The LOAEL and the NOAEL are experimental dose levels, and their
reliability is dictated by the study design. In studies for which the lowest dose tested resulted in
an adverse effect (and therefore a NOAEL was not established), and in studies for which the
highest dose tested was a NOAEL, a conservative approach using professional judgment was
used to address uncertainty regarding the lowest dose or exposure level that might be expected to
cause a particular adverse effect. For example, in the absence of an established a NOAEL, an
identified LOAEL might fall within the range of a Moderate hazard; however, it is uncertain if a
lower dose, such as one that falls within the range of High hazard exists because no lower doses
were tested. In such cases, professional judgment was applied to assign a hazard designation
when possible. Some degree of uncertainty was evident in results from studies in which a
NOAEL may fall within one hazard range (e.g., Moderate hazard) and the identified LOAEL
falls within a different hazard range (e.g., Low hazard) because the true LOAEL may fall in
either category, but there were not enough experimental data points to determine the true
LOAEL. Professional judgment was also applied to these cases to assign a hazard descriptor
when possible and the rationale used was described in the assessment. Developmental
neurotoxicity was considered and was evaluated using the developmental toxicity criteria, which
are more stringent than the criteria for neurotoxicity, and thus designed to be more protective
(U.S. EPA, 201 Ib).
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 evidence9 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.
9 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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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 U.S. EPA (1994). Public access to free validated
quantitative SAR models for human health endpoints is far more limited than physical-chemical
properties, environmental fate parameters, or ecotoxicology. Carcinogenicity 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 subject matter 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.
Polymer Assessment
Estimates for polymers were obtained using information contained in the literature concerning
polymer assessment based on the MW profile (U.S. EPA, 201 Ob). Those polymers with MW
>1,000 were assessed using an appropriate representative structure that has a MW less than or
equal to the average MW. For polymers with an average MW > 1,000 daltons and a significant
amount of low MW material <1,000 daltons, the low MW components were also assessed for
their environmental fate and potential toxicity in order to identify any possible hazards for the
most bioavailable fraction. Similarly, the presence of unreacted monomers requires that the
assessment consider these components for polymers of any MW range. The properties for
polymers with an average MW > 1,000 with no low MW components were generally evaluated as
a single high MW material for each of the properties described below. In general, polymers with
an average MW > 1,000 were not amenable to the available SAR estimation methods and based
on the literature are assumed to have low to no bioavailability. Polymers with MW >1,000 that
were not degradable or reactive are also typically not bioavailable. Polymers with an average
MW >10,000 have potential for adverse effects due to lung overloading when respirable particles
are present (less than ten microns). The potential for fibrosis or cancer are not assumed with high
MW compounds. There may be exceptions to the rules of thumb outlined above and as such this
guidance should not be held as absolute thresholds.
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Polymers and oligomers with MWs < 1,000 were assessed using a representative structure for all
the MW species anticipated to be present in the mixture. The procedures were essentially
identical to those employed for the evaluation of impurities or by-products 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.
4.5 Evaluating Environmental Toxicity and Fate 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 Aquatic Toxicity
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) - LCso 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 reported in the alternatives assessment also included information on the
species tested. Test data on other organisms (e.g., worms) were included in the assessment if data
were readily available. These data would be evaluated using professional judgment to support
hazard designations assigned using the three surrogate species; however, they were not used by
themselves to assign a hazard designation as DfE criteria are not available. Poorly soluble
substances where the water column exposures may not be adequate to describe sediment and
particulate exposures will be identified by a footnote.
If an experimental or estimated effect level exceeded the known water solubility of a chemical
substance, or if the log Kow exceeded the estimated ECOSAR™ cut-off values for acute and
chronic endpoints (which are class specific), NES were predicted for the aquatic toxicity
endpoints. NES indicates that at the highest concentration achievable, the limit of a chemical's
water solubility, no adverse effects were observed (or would be expected). In these cases, a Low
hazard designation was assigned. In the cases where both an estimated water solubility and
ECOSAR™ estimate were used, then an additional factor often was applied to the water
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solubility before a NES designation was assigned to account for the combined uncertainty in the
model estimates.
In the case where an experimental aquatic toxicity value was significantly higher than the
chemical's water solubility, it was likely the result of a poorly conducted study. In this
circumstance, which is generally more frequent for formulated products or mixtures, additional
details were provided in the data quality section to describe why the reported values could not be
used to assign a hazard designation.
EPA's ECOSAR™ estimation program uses chemical structure to estimate toxicity of a chemical
substance using class-specific QSARs. ECOSAR™ automatically determines all of the classes
that a chemical substance may belong to and, therefore, may provide a number of different
ecotoxicity estimates for some or all of the species and durations estimated. Modeled results are
dependent on the functional groups present on the molecule as well as the diversity of chemicals
with experimental data that were used to build the models (their training set). The hazard profiles
report every estimated value returned from ECOSAR™. Narcosis classes (neutral organics) are
only provided for comparative purposes if class-specific QSARs are available; the latter will be
used preferentially. If multiple class-specific QSARs are available, the hazard designation was
based on the most conservative ECOSAR™ estimate, unless expert judgment suggested that an
individual substance was better represented by a specific class based on analysis of the operative
mode of action. However, if the chemical substance is not anticipated to lie within the domain of
the class-specific estimates provided by ECOSAR or to undergo the same mode of action of the
chemicals that appear in their training sets, then 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 Kow values from EPISuite™ were used.
ECOSAR™ is maintained and developed as a stand-alone program but is also accessible through
the EPA EPISuite™ program after it is installed; therefore the Estimations Program Interface
(EPI) program was cited for the ECOSAR™ values in this report.
The QSARs for ECOSAR™ were built using experimental data for several chemical classes. For
a chemical class to be defined within ECOSAR™, sufficient acute experimental data were
required to build a QSAR for all three species included in the model. The equations in ECOSAR
are derived from surrogate species offish, 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 estimates of toxicity to the general trophic levels they represent
(fish, aquatic invertebrates, and aquatic plants). There were instances, however, where sufficient
experimental data are not available to build a chronic QSAR for some of the three surrogate
species. When ECOSAR™ did not provide chronic estimates, the acute value (experimental or
estimated) was divided by an acute to chronic ratio (ACR) to arrive at the ChV. ACRs of 10
were used for fish and daphnid and an ACR of 4 was used for algae (Mayo-Bean, Nabholz et al.,
2011).
An estimate of NES is the default value used for organics, oligomers, or non-ionic polymers with
a MW >1,000 daltons in the assignment of aquatic toxicity hazard. In EPA's New Chemical
program, aquatic toxicity is not predicted for chemicals with a MW > 1,000 daltons as uptake has
been found to decrease exponentially with MWs >600 daltons (Nabholz, Clements et al., 1993)
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due to a decrease in passive absorption through respiratory membranes (Mayo-Bean, Nabholz et
al., 2011).
4.5.2 Bioaccumulation
Bioaccumulation is a process in which a chemical substance is absorbed in an organism by all
routes of exposure as occurs in the natural environment, e.g., from dietary and ambient
environment sources. Bioaccumulation is the net result of the competing processes; this includes
uptake, metabolism and elimination of a chemical in an organism. Bioaccumulation can be
evaluated using the BAF, the steady state ratio of a chemical in an organism relative to its
concentration in the ambient environment, where the organism is exposed through ingestion and
direct contact. Experimental BAFs have not been widely available in the scientific literature and,
as a result, experimental BCFs are more commonly used to evaluate the bioaccumulation hazard.
BCFs are defined as the ratio of the concentration of a chemical in an organism to the
concentration of the chemical in the organism's surroundings; BCFs are typically measured for
fish (in water) using guideline studies.
Experimental BAF or BCF values can be compared directly to the DfE criteria for this endpoint
to assign a hazard designation. The BCF/BAF designations range from <100 for a Low
designation to >5,000 for a Very High designation (see 4.1.2). 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 if 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 discrete 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 Ig). 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 will use all available well-conducted studies when
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evaluating bioaccumulation potential for materials with a MW > 1,000, including environmental
biomonitoring data on higher trophic levels.
In general, for polymers and other materials with a MW > 1,000 daltons, the default
bioaccumulation designation of Low was assigned, arising from their predicted limited
bioavailability (U.S. EPA, 2010b). A more detailed analysis was performed for compounds at or
near this bright line cutoff as well as for polymers with components where residuals <1,000 had
the potential to be present.
4.5.3 Environmental Persistence
A chemical's persistence in the environment is evaluated by determining the type and rate of
potential removal processes. These removal processes were generally divided into two
categories: chemical and biological. Of the chemical degradation processes, an evaluation of
environmental persistence includes the reaction of a chemical with water, also known as
hydrolysis, because water is ubiquitous in the environment. Hydrolysis rate constants can be
obtained from the literature or estimated, and the resulting half-lives can be compared directly to
DfE criteria. For commercial chemicals, hydrolysis tends to be a slower environmental removal
process than biodegradation. Direct and indirect photolysis also represents other potential
chemical degradation processes that are considered in the alternative assessment, and they are
discussed later in this section.
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 CC>2, water, and mineral oxides (such as phosphates for chemicals
containing phosphorus). 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
generally assessed in sediment. For determining the persistence hazard, the importance of both
aerobic and anaerobic biodegradation as well as partitioning and transport in the environment
were considered to determine what removal processes were most likely to occur. Anaerobic
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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 as 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 organic carbon from test substance, or theoretical oxygen demand) reaches 10 percent.
The 10-day window must occur within the 28-day length of the test. If the pass level of the test
(60 percent for oxygen demand and CC>2 production; 70 percent for dissolved organic carbon
disappearance) is met in the 10-day window, the chemical received a Very Low hazard
designation. Those that did not pass the 10-day window criterion but met the pass level in 28
days received a Low hazard designation. If ready biodegradability test data were available but
the chemical did not meet the pass level, the chemical was evaluated based on measured data
using the DfE half-life criteria (Table 4-1). These half-life criteria were also used to assign a
hazard designation for nonguideline ultimate biodegradation studies reported in the scientific
literature.
In the absence of a reported half-life, experimental data were also used to approximate half-life
as appropriate. For example, a chemical that undergoes <5 percent removal in 30 days would be
expected to have a half-life >60 days and would be assigned a High persistence concern.
When experimental data on the biodegradation of a chemical substance were not available, the
potential of that substance to undergo this removal process was assessed from the results of the
EPISuite™ models. These models fall into one of four classes: Rapid biodegradation models
based on linear and non-linear regressions that estimate the probability that a chemical substance
will degrade fast; expert survey models that estimated 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. 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 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
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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, which 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
indicate the potential for the material to partition to sediment, an anoxic compartment, then the
results of the anaerobic probability model (Biowin 7) will also be evaluated.
Half-lives for hydrolysis from experimental studies or EPISuite™ estimates were used in
preference to biodegradation data when they suggested that hydrolysis is a more rapid removal
process. Hydrolysis half-lives were compared directly to DfE criteria to assign the persistence
designation. Similar to primary biodegradation, breakdown products resulting from hydrolysis
were evaluated for fate and toxicity when they were expected to be more persistent than the
parent compound.
Photolysis may also be an important environmental removal process. In general, environmental
removal rates from photolysis do not compete with biodegradation or hydrolysis although there
are exceptions such as iodides. Photolysis may be an important removal process for chemicals
that were not bioavailable because of their limited water solubility. Estimation methods for
photolysis rates were not available using computerized SAR tools. If experimental or suitable
analog data were available, the rate of photolysis was evaluated relative to other removal
processes.
When evaluating the environmental persistence designation, it should be noted that chemicals
with a High or Very High designation can degrade over time, although this process may occur at
a very slow rate. As a result, a Very High designation may have been assigned if persistent
degradates were expected to be produced, even at a very slow rate, in the absence of
experimental biodegradation data for the parent substance.
Chemicals that contain a metal were assigned a High persistence designation in the assessment,
as these inorganic moieties are recalcitrant. In this instance, an 'R' footnote was added to the
hazard summary table to indicate that the persistence potential was based on the presence of a
recalcitrant inorganic moiety. The assessment process also included the evaluation of the
potential chemical reactions of metal-containing and inorganic moieties to determine if they were
potentially transformed to more or less hazardous forms.
Polymers with a MW >1,000 generally received a Very High persistence designation due to their
lack of bioavailability.
4.6 Endocrine Activity
Chemicals included in DfE alternatives assessments were screened for potential endocrine
activity, consistent with the DfE Program Alternatives Assessment Criteria for Hazard
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Evaluation. Endocrine activity refers to a change in endocrine homeostasis caused by a
chemical or other stressor. An endocrine disrupter 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 4.9. Data on
endocrine activity were available for two of the alternatives included in this report. For
chemicals without available data on endocrine activity, this was acknowledged with a "no data
located" statement. When endocrine activity data were available, the data are summarized as a
narrative. A unique hazard designation of Low, Moderate or High is not provided for this
endpoint in Table 4-2, for reasons discussed below.
The document Special Report on Environmental Endocrine Disruption: An Effects Assessment
and Analysis describes EPA's activities regarding the evaluation of endocrine disruption (U.S.
EPA, 1997). This report was requested by the Science Policy Council and prepared by EPA's
Risk Assessment Forum. This report states that "Based on the current state of the science, the
Agency does not consider endocrine disruption to be an adverse endpoint per se, but rather to be
a mode or mechanism of action potentially leading to other outcomes, for example, carcinogenic,
reproductive or developmental effects, routinely considered in reaching regulatory decisions"
(U.S. EPA, 1997). The report also states that "Evidence of endocrine disruption alone can
influence priority setting for further testing and the assessment of results of this testing could
lead to regulatory action if adverse effects are shown to occur" (U.S. EPA, 1997).
The 1996 Food Quality Protection Act directed EPA to develop a scientifically validated
screening program to determine whether certain substances may cause hormonal effects in
humans. In response, EPA established the Endocrine Disrupter Screening Program (EDSP) (U.S.
EPA, 2012b). The EDSP is developing requirements for the screening and testing of thousands
of chemicals for their potential to affect the endocrine system. When complete, EPA will use
these screening and testing approaches to set priorities and conduct further testing when
warranted. The science related to measuring and demonstrating endocrine disruption is relatively
new, and validated testing methods at EPA are still being developed.
The EDSP proposes a two-tiered approach that includes initial screening followed by more in-
depth testing when warranted (U.S. EPA, 201 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 methods10. Once
validated test methods have been established for screening and testing of potential endocrine
disrupters, guidance must be developed for interpretation of these test results using an overall
weight-of-evidence characterization.
10 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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To assess the data on endocrine activity, DfE applies the weight-of-evidence approach developed
by the EDSP (U.S. EPA, 201 Ic). This process integrates and evaluates data, and always relies on
professional judgment (U.S. EPA, 201 Ic). 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 endocrine,
androgen, or thyroid hormonal pathways.
Most test data for chemicals in this report consist of in vitro assays, but results of in vitro assays
alone were not generally expected to provide a sufficient basis to support a hazard designation
for endocrine disruption. EPA expects that in vivo evidence would typically be given greater
overall influence in the weight-of-evidence evaluation than in vitro findings because of the
inherent limitations of such assays. Although in vitro assays can provide insight into the mode of
action, they have limited ability to account for normal metabolic activation and clearance of the
compound, as well as normal intact physiological conditions (e.g., the ability of an animal to
compensate for endocrine alterations).
As described in the DfE Program Alternatives Assessment Criteria for Hazard Evaluation,
endocrine activity was summarized in a narrative, rather than by High, Moderate or Low hazard
designation. The endocrine activity summaries can be found in the hazard profiles. This is an
appropriate approach because there is no consensus on what constitutes high, moderate or low
concern for this endpoint. The summary of endocrine activity largely relies on representative
studies and expert review summaries.
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Chemical Alternatives and the Toxic Substances Control Act
EPA's 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 U. S. 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 U.S. 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 has 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.
4-29
-------
4.7 References
ACE Organic. (2013). "ACE Acidity and Basicity Calculator." Retrieved December 13, 2013,
from http://aceorganic.pearsoncmg.com/epoch-plugin/public/pKa.jsp.
International Agency for Research on Cancer. (2006). "Preamble to the IARC Monographs."
Retrieved April 17, 2012, from
http://monographs.iarc.fr/ENG/Preamble/currentb6evalrationale0706.php.
Mayo-Bean, K., K. V. Nabholz, et al. (2011). Methodology Document for the Ecological
Structure-Activity Relationship Model (ECOSAR) Class Program. Office of Pollution
Prevention and Toxics. Washington, DC.
Meylan, W. M. and P. H. Howard (1995). "Atom/fragment contribution method for estimating
octanol-water partition coefficients." J Pharm Sci 84(1): 83-92.
Meylan, W. M., P. H. Howard, et al. (1996). "Improved method for estimating water solubility
from octanol/water partition coefficient." Environ Toxicol Chem 15(2): 100-106.
Nabholz, J. V., R. G. Clements, et al. (1993). Validation of Structure Activity Relationships
Used by the USEPA's Office of Pollution Prevention and Toxics for the Environmental
Hazard Assessment of Industrial Chemcials. Environmental Toxicology and Risk
Assessment. J. W. Gorsuch, F. J. Dwyer, C. G. Ingersoll and T. W. La Point.
Philadelphia, American Society for Testing and Materials. 2: 571-590.
U.S. EPA. (1994). "Joint Project on the Evaluation of (Quantitative) Structure Activity
Relationships." Retrieved November 18, 2013, from
http://www.epa.gov/oppt/newchems/pubs/ene4147.pdf.
U.S. EPA. (1997). "Special Report on Environmental Endocrine Disruption: An Effects
Assessment and Analysis." Retrieved November 18, 2013, from
http://www.epa. gov/raf/publications/pdfs/ENDOCRINE.PDF.
U.S. EPA. (1999a). "Guidelines for Carcinogen Risk Assessment, Review Draft." Retrieved
November 18, 2013, from
http://www.epa.gov/raf/publications/pdfs/CANCER GLS.PDF.
U.S. EPA. (1999b). "High Production Volume (HPV) Challenge: Determining the Adequacy of
Existing Data." Retrieved November 18, 2013, from
http://www.epa.gov/hpv/pubs/general/datadfm.htm.
U.S. EPA. (2005). "Pollution Prevention (P2) Framework." Retrieved November 18, 2013,
from http ://www.epa.gov/oppt/sf/pubs/p2frame-juneOSa2.pdf.
U.S. EPA. (2010a). "Chemical Categories Report." Retrieved April 17, 2012, from
http://www.epa.gov/opptintr/newchems/pubs/chemcat.htm.
4-30
-------
U.S. EPA. (201 Ob). "Interpretive Assistance Document for Assessment of Polymers. Sustainable
Futures Summary Assessment." Retrieved November 18, 2013, from
http://www.epa.gov/oppt/sf/pubs/iad_polymers_092011 .pdf
U.S. EPA. (2010c). "TSCA New Chemicals Program (NCP) Chemical Categories." Retrieved
November 18, 2013, from
http://www.epa.gov/oppt/newchems/pubs/npcchemicalcategories.pdf.
U.S. EPA. (201 la). "Assay Development." Retrieved April 17, 2012, from
http://www.epa.gov/oscpmont/oscpendo/pubs/assayvalidation/index.htm.
U.S. EPA. (201 Ib). "Design for the Environment Program Alternatives Assessment Criteria for
Hazard Evaluation (version 2.0)." Retrieved November 18, 2013, from
http://www.epa.gov/dfe/alternatives_assessment_criteria_for_hazard_eval.pdf.
U.S. EPA. (201 Ic). "Endocrine Disrupter Screening Program. Weight of the Evidence:
Evaluating Results of EDSP Tier 1 Screening to Identify the Need for Tier 2 Testing."
Retrieved November 18, 2013, from
http://www.regulations.gov/#!documentDetail:D=EPA-HQ-OPPT-2010-0877-0021.
U.S. EPA. (201 Id). "Estimation Program Interface (EPI) Suite." Retrieved April 18, 2012, from
http://www.epa.gov/oppt/exposure/pub s/epi suite, htm.
U.S. EPA. (201 le). "Interpretive Assistance Document for Assessment of Discrete Organic
Chemicals. Sustainable Futures Summary Assessment." Retrieved November 18, 2013,
from http://www.epa.gov/oppt/sf/pubs/iad discretes 092011 .pdf
U.S. EPA. (201 If). "On-line AOPWIN™ User's Guide." Retrieved November 18, 2013, from
http://www.epa.gov/oppt/exposure/pub s/epi suite, htm.
U.S. EPA. (201 Ig). "On-line BCFBAF™ User's Guide." Retrieved November 18, 2013, from
http://www.epa.gov/oppt/exposure/pub s/epi suite, htm.
U.S. EPA. (201 Ih). "On-line KOWWIN™ User's Guide." from
http://www.epa.gov/oppt/exposure/pub s/epi suite, htm.
U.S. EPA. (201 li). "On-line WSKOWWIN™ User's Guide." from
http://www.epa.gov/oppt/exposure/pub s/epi suite, htm.
U.S. EPA. (2012a). "Analog Identification Methodology (AIM)." Retrieved April 17, 2012,
from http ://www.epa.gov/oppt/sf/tools/aim.htm.
U.S. EPA. (2012b). "Endocrine Disrupter Screening Program (EDSP)." Retrieved April 17,
2012, from http://www.epa.gov/scipoly/oscpendo/index.htm.
U.S. EPA. (2012c). "Models & Methods." Retrieved April 17, 2012, from
http ://www. epa. gov/oppt/sf/tool s/methods .htm.
4-31
-------
4.8 Hazard Summary Table
Table 4-4. Screening Level Hazard Summary for Reactive-Flame Retardant Chemicals & Resins
VL = Very Low hazard L = Low hazard = Moderate hazard = High hazard VH = Very High hazard — Endpoints in colored text (VL, L, M, H, and VH) were
assigned based on empirical data. Endpoints in black italics (VL, L, M, H, and VH) were assigned using values from predictive models and/or professional judgment.
This table contains hazard information for each chemical; evaluation of risk considers both hazard and exposure. Variations in end-of-life processes or degradation and combustion by-
products are discussed in the report but not addressed directly in the hazard profiles. The caveats listed below must be taken into account when interpreting the information in the table.
* TBBPA has been shown to degrade under anaerobic conditions to form bisphenol A (BPA; CASRN 80-05-7). BPA has hazard designations different than TBBPA, as follows:
MODERATE (experimental) for reproductive, skin Sensitization and dermal irritation. § Based on analogy to experimental data for a structurally similar compound. ^The highest hazard
designation of any of the oligomers with MW < 1,000. ¥ Aquatic toxicity: EPA/DfE criteria are based in large part upon water column exposures which may not be adequate for poorly
soluble substances such as many flame retardants that may partition to sediment and particulates.
Chemical
(for full chemical name
and relevant trade
names see the
individual profiles in
Section 4.9)
CASRN
Human Health Effects
Acute Toxicity
Carcinogenicity
Genotoxicity
Reproductive
Developmental
Neurological
Repeated Dose
Skin Sensitization
Respiratory
Sensitization
Eye Irritation
Dermal Irritation
Aquatic
Toxicity
•S*
u
Chronic
Environ-
mental
Fate
o
Bioaccumulation
Exposure Considerations
Availability of flame retardants
throughout the life cycle for reactive and
additive flame-retardant chemicals and
resins
Reactive Flame-Retardant Chemicals
Tetrabromobisphenol A
79-94-7
L
L
L*
L
L
L*
L*
VH
H
H
M
DOPO
35948-25-5
L
M
L
tf
M
M
L
VL
L
M
H
L
Fyrol PMP
63747-58-0
L
L^
L*
AfS
AfS
AfS
AfS
L
L
L
H*
rf
VH
rf
Manufacture
End-of-Life of of FR """^
» Electronics Manufacture
/ (Recycle, Disposal) of FR Resin
Sate and Use ^
of Electronics Manufacture of
k. Manufacture of PCB Laminate
^«-— and Incorporation into ^ "*
Electronics
Reactive Flame-Retardant Resins
D.E.R. 500 Series*
26265-08-7
L
M
M
M
M
M
M
H
M%
M%
L
L
VH
rf
Dow XZ-92547*
Confidential
L
M*
M*
M1
M1
M*
M*
H
M1
VL
L
L
H
VH
rf
Manufacture of
FR *"^M
End-of-Life of ^
jp Electronics Manufacture
f (Recycle, Disposal) of FR Resin
Sate and Use i
of Electronics •
V Manufacture
Manufacture of PCB of Laminate
and Incorporation ^ "^
4-32
-------
Table 4-5. Screening Level Hazard Summary for Additive Flame-Retardant Chemicals
VL = Very Low hazard L = Low hazard = Moderate hazard = 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 predictive models and/or professional judgment.
This table contains hazard information for each chemical; evaluation of risk considers both hazard and exposure. Variations in end-of-life processes or degradation and combustion by-
products are discussed in the report but not addressed directly in the hazard profiles. The caveats listed below must be taken into account when interpreting the information in the table.
R Recalcitrant: Substance is comprised of metallic species (or metalloids) that will not degrade, but may change oxidation state or undergo complexation processes under environmental
conditions. § Based on analogy to experimental data for a structurally similar compound. °Concern linked to direct lung effects associated with the inhalation of poorly soluble particles
less than 10 microns in diameter. A Depending on the grade or purity of amorphous silicon dioxide commercial products, the crystalline form of silicon dioxide may be present. The
hazard designations for crystalline silicon dioxide differ from those of amorphous silicon dioxide, as follows: VERY HIGH (experimental) for carcinogenicity; HIGH (experimental)
genotoxicity; MODERATE (experimental) for acute toxicity and eye irritation. ¥ Aquatic toxicity: EPA/DfE criteria are based in large part upon water column exposures which may not
be adequate for poorly soluble substances such as many flame retardants that may partition to sediment and particulates.
Chemical
(for full chemical name
and relevant trade
names see the
individual profiles in
Section 4.9)
CASRN
Human Health Effects
Acute Toxicity
Carcinogenicity
Genotoxicity
Reproductive
Developmental
Neurological
Repeated Dose
Skin Sensitization
Respiratory
Sensitization
Eye Irritation
Dermal Irritation
Aquatic
Toxicity
3
u
•<
Chronic
Environ-
mental
Fate
Persistence
Bioaccumulation
Exposure Considerations
Availability of flame retardants throughout
the life cycle for reactive and additive
flame-retardant chemicals and resins
Additive Flame-Retardant Chemicals
Aluminum
Diethylphosphinate*
225789-38-8
L
L§
L
L
M^
M§
M§
L
L
VL
M
M
HR
L
Aluminum Hydroxide*
21645-51-2
L
L§
L
L§
L
M§
L
VL
VL
L
L
//*
L
Magnesium
Hydroxide*
1309-42-8
L
L
L
L
L
L
//*
L
Melamine
Polyphosphate1*
15541-60-3
L
M
M
H
M
M
M
L
L
VL
L
L
H
L
Silicon Dioxide
(amorphous)
7631-86-9
A
A
A
L§
Hn
L
LA
VL
L
L
//*
L
Manufacture of Manufacture of
FR ~"N. Resin
End-of-Life of \ /
^^ Electronics \l
^"^ (Recycle, ip
Sale and Disposal) Manufacture of
Use of Laminate
Electronics 1
^v^ Manufacture of PCS ^/
^— and Incorporation 4f
into Electronics
1 Hazard designations are based upon the component of the salt with the highest hazard designation, including the corresponding free acid or base.
4-33
-------
4.9 Hazard Profiles
Tetrabromobisphenol A
VL = Very Low hazard L = Low hazard = Moderate hazard H = High hazard VH = Very High hazard — Endpoints in colored text (VL, L, M, H, and VH) were
assigned based on empirical data. Endpoints in black italics (VL, L, M, H, and VH) were assigned using values from predictive models and/or professional judgment.
This table contains hazard information for each chemical; evaluation of risk considers both hazard and exposure. Variations in end-of-life processes or degradation and combustion
by-products are discussed in the report but not addressed directly in the hazard profiles. The caveats listed below must be taken into account when interpreting the information in the
table.
» TBBPA has been shown to degrade under anaerobic conditions to form bisphenol A (BPA; CASRN 80-05-7). BPA has hazard designations different than TBBPA, as follows:
MODERATE (experimental) for reproductive, skin sensitization and dermal irritation.
Chemical
CASRN
Human Health Effects
cute Toxicity
<
>>
arcinogenicit
U
enotoxicity
0
eproductive
C£
evelopmental
Q
eurological
Z
%
o
P
•a
%
0)
g"
C£
=
o
kin Sensitizat
C/5
espiratory
msitization
C4 vi
ye Irritation
W
0
ermal Irritat
P
Aquatic
Toxicity
1
u
<
_u
1
JS
U
Environmental
Fate
srsistence
a.
a
o
loaccumulati
CO
Tetrabromobisphenol A
79-94-7
L* VH
H
4-34
-------
Tetrabromobisphenol A
CASRN: 79-94-7
MW: 543.*
MF: C,,H12Br4O2
Physical Forms: Solid
Neat: Solid
Use: Flame retardant
SMILES: Oc(c(cc(cl)C(c(cc(c(O)c2Br)Br)c2)(C)C)Br)clBr
Synonyms: Tetrabromobisphenol A; TBBPA; TBBP-A; 4,4'-Isopropylidenebis(2,6-dibromophenol); 2,2-bis(3,5-dibromo-4-hydroxyphenyl) propane; 3,3',5,5'-
tetrabromobisphenol-A; phenol, 4,4'-isopropylidinebis, (dibromo-); 4,4'-(l-methylethylidene)bis(2,6-dibromophenol); 2,2',6,6'-Tetrabromobisphenol A; 2,2-Bis(3,5-
dibromo-4-hydroxyphenyl)propane; 2,2-Bis(4-hydroxy-3,5-dibromophenyl)propane
Trade names:BA-59P; F-2016; F-2400; F-2400E; FR-1524; Fire Guard FG2000; Firemaster BP 4A; Saytex RB-100; Saytex RB 100PC; Tetrabrom; Tetrabromodian;
Bromdian
Chemical Considerations: This is a discrete organic chemical with a MW below 1,000. EPI v 4.11 was used to estimate physical/chemical and environmental fate
values in the absence of experimental data. Measured values from experimental studies were incorporated into the estimations. TBBPA is produced by bromination of
bisphenol A (BPA). (HSDB, 2013).
Polymeric: No
Oligomeric: Not applicable
Metabolites, Degradates and Transformation Products: TBBPA-glucuronic acid conjugates (mono, di and a mixed glucuronide-sulfate conjugate); TBBPA-sulfate
ester conjugates; tribromobisphenol A and glucuronide of tribromobisphenol A were identified as metabolites in experimental studies.
4-isopropyl-2,6-dibromophenol, 4-isopropylene-2,6-dibromophenol and 4-(2-hydroxyisopropyl)-2,6-dibromophenol were identified as major degradation products by
UV light photolysis; other reported products include di- and tribromobisphenol A, dibromophenol, 2,6-dibromo-4-(bromoisopropylene)phenol, 2,6-dibromo-4-
(dibromoisopropylene)phenol and 2,6-dibromo-l,4-hydroxybenzene. Polybrominated dibenzofurans (PBDF) and dibenzodioxins (PBDD) were identified by pyrolytic
degradation. Debromination of TBBPA to tribrominated-BPA, dibrominated-BPA and BPA has been demonstrated in experimental anaerobic biodegradation studies.
(Eriksson and Jakobsson, 1998; Eriksson et al., 2004; Ravit et al, 2005; EU, 2006; ACC, 2006b; Roper et al., 2007; Environment Canada, 2013; NTP, 2013)
Analog: None Analog Structure: Not applicable
Structural Alerts: Phenols, neurotoxicity (EPA, 2010).
Risk Phrases: 50/53 - Very toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment (ESIS, 2012).
Hazard and Risk Assessments: Risk assessments were completed for TBBPA by the European Union in 2006 and Canada in 2013. (EU, 2006; Environment Canada,
2013).
4-35
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
Boiling Point (°C)
Vapor Pressure (mm Hg)
179 (Measured)
181
Reported as a range 181-182°C
(Measured)
178 (Measured)
181 (Measured)
178.35
Reported as 45 1 .5 ± 0.5 K using
differential scanning calorimeter
(Measured)
316
Decomposes (Measured)
>300
(Estimated)
4.7xlO-8at25°C
Reported as 6.24xlO~6 Pa (Measured)
<8.9xl(r8at200C
Organisation for Economic Co-operation
and Development (OECD) Guideline 104
"Vapor Pressure Curve" Spinning rotor
gauge method; reported as < 1.1 9x1 0"5 Pa
(Measured)
3.54x10-"
Reported as 4.72xlO'9 Pa at 298K using
Knudsen effusion method (Measured)
<1
Ashford, 1994; HSDB, 2013
EU, 2006
EU, 2006
WHO, 1995; ACC, 2006b
Kuramochi et al., 2008
Stenger, 1978; WHO, 1995
EPIv4.11;EPA, 1999
BRE, 2009
Lezotte and Nixon, 200 1 (as
cited in EU, 2006; ACC, 2006b)
Kuramochi et al., 2008
WHO, 1995; Hardy and Smith,
Reported in a secondary source.
Study details and test conditions
were not stated.
Reported in a secondary source.
Details and test method were not
stated.
The measurement was performed on
a commercial product which was
not 100% pure.
Adequate study details provided.
Consistent with other reported
values.
TBBPA will decompose before
boiling based on measurements on a
commercial product, which may not
have been 100% pure.
Cutoff value for high boiling
materials according to HPV
assessment guidance.
Valid study with limited details
reported.
Value reported is based on the limit
of quantification of the method. The
vapor pressure was below the limit
of quantification of the method.
Adequate study details provided.
Sufficient study details were not
4-36
-------
Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
Water Solubility (mg/L)
Log Kow
DATA
(Measured)
4.16
(Measured)
0.171 ±0.004 at pH 3.05
4. 15 ±0.36 at pH 7.56
30.5 ±1.8 at pH 7.99
228 ±6 at pH 8. 48
1,5 10 ±60 at pH 8.91
27,900 ±400 at pH 9.50 (Measured)
0.72atl5°C
4.16at25°C
1.77 at 35°C (Measured)
0.082
at pH 7.6-8.1 (Measured)
0.148atpH5
1.26atpH7
2.34 at pH 9 (Measured)
4.54
(Measured)
Generator column method used to
evaluate Dow:
pH 3.05 = 6.53 ±0.12
(considered non-ionic form)
pH 7.53 =4.75 ±0.07
REFERENCE
1999
Danish EPA, 1999
Kuramochi et al., 2008
WHO, 1995
Submitted confidential study (as
cited in NOTOX, 2000)
Submitted confidential study (as
cited in MacGregor and Nixon,
2002; EU, 2006)
EU, 2006
Kuramochi et al., 2008
DATA QUALITY
available to assess the quality of this
study.
Limited study details provided.
Reported in a primary source;
demonstrates the relationship
between the pH conditions and the
water solubility of TBBPA as an
ionized and non-ionized compound.
Study details and test conditions
were not available. The original
study was in an unpublished report
submitted to the WHO.
The measured water solubility was
dependent on the flow rates through
the column. The cause of the flow
rate dependency is unknown. The
flow rate dependency is not caused
by a failure to reach equilibrium,
since higher flow rates gave higher
solubility. The samples were
centrifuged to remove dispersed
TBBPA.
Submitted confidential study. The
samples were not assessed for the
presence of colloidal material before
analysis.
Reported in a secondary source.
Reported in a primary source;
demonstrates the relationship
between the pH conditions and the
octanol-water partition coefficient
(log Kow) of TBBPA as an ionized
4-37
-------
Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
Flammability (Flash Point)
Explosivity
DATA
pH 8. 12 = 3.00 ±0.03
pH 9. 18 = 1.25 ±0.01
pH 10.19 = -0.293 ±0.020
pH 10.95 = -0.769 ±0.023
pHl 1.83 = -1.22 ±0.00
(Measured)
4.5
(Measured)
<4
(Measured)
6.4
HPLC method (Measured)
3.25
(Measured)
5.903
Reported as 5.90 ± 0.034; method based
on USEPA Product Properties Test
Guideline OPPTS 830.7560. (Measured)
5.3
Reported as a range: 4.5-5.3 (Measured)
Not flammable (Measured)
Dust Explosivity: Maximum Explosion
Pressure (Pmax) = 7.7 bar;
Maximum Rate of Pressure Rise
(dP/dt)max = 379 bar/s;
Kst value = 103 bar.m/s (weak explosion)
(Measured)
REFERENCE
Danish EPA, 1999
EU, 2006
EU, 2006
EU, 2006
MacGregor and Nixon, 200 1 (as
cited in EU, 2006)
WHO, 1995
ICL,2013
Churchwell and Ellis, 2007
DATA QUALITY
and non-ionized compound.
Valid study reported in a secondary
source.
Reported in a secondary source.
Study details and test conditions
were not available.
Reported in a secondary source.
Limited study details available.
Reported in a secondary source.
Reported in secondary source.
Study details and test conditions
were not available.
Reported in safety datasheet and
based on its use as a flame retardant.
Adequate supporting information
provided.
4-38
-------
Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
Pyrolysis
pH
pKa
Particle Size
DATA
Under certain high temperature pyrolysis
conditions, TBBPA can form and release
brominated dibenzofurans (PBDF) and
dibenzo-p-dioxins (PBDD). (Measured)
Purified TBBPA was pyrolyzed in open
quartz tubes for 10 minutes resulting
mainly in mono-, di-, tri- and tetra-PBDD
and PBDF.
The formation of PBDD and PBDF
occurred at 0.02, 0.16, and 0.1% for 700,
800, and 900°C. (Measured)
9.4
Method based on OECD Guideline 112.
(Measured)
pKal = 7.5
pKa2 = 8.5 (Measured)
REFERENCE
EU, 2006
WHO, 1995
Lezotte and Nixon, 2002; EU,
2006; ACC, 2006b
WHO, 1995; EU, 2006
DATA QUALITY
Adequate.
Adequate.
^o data located.
Adequate guideline study.
Study details and test conditions
were not available. Reported in a
secondary source.
^o data located.
4-39
-------
Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
HUMAN HEALTH EFFECTS
Toxicokinetics
A laboratory study using human skin indicates TBBPA is not well absorbed dermally. The results
indicated 0.73% of the applied dose penetrated through the skin. Oral administration to rats showed that
TBBPA is rapidly metabolized and eliminated in the feces (>80%). TBBPA and metabolites were detected
in plasma and traces of TBBPA and metabolites were detected in urine (glucuronic acid and sulfate ester
conjugates). The estimated bioavailability following oral dosing is 1.6%. Human volunteers had no
detectable TBBPA in plasma following ingestion of low doses; however, TBBPA metabolites (TBBPA-
glucuronide, TBBPA-sulfate) were detected. TBBPA-glucuronide (25% of the administered dose) was the
only metabolite detected in the urine. TBBPA has been detected in breast milk; although a study in
pregnant rats indicates that there is no significant transfer of TBBPA or its metabolites to the fetus (total
amount of radioactivity in the fetus was approximately 0.34% of the administered dose).
Dermal Absorption in vitro
Human split-thickness skin: Absorbed
dose = 0.73% applied dose (14.06
(ig/cm2); Dermal delivery = 1.60%
applied dose (32.05 (ig/cm2)
Roper, 2005; Roper et al., 2007
Sufficient study details reported in
primary source.
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal or Inhaled
Distribution of TBBPA and its conjugates
was observed in pregnant rats fed 0, 100,
1,000 or 10,000 ppm from gestational day
(GD) 0-16. Free-TBBPA detected in
blood, liver and kidney of dams and
amniotic fluid on GD10 and in the
placenta and amniotic fluid in fetuses on
GDI6. Free-TBBPA was also found in the
stomach of suckling pups from dams in
the high dose group. Conjugated TBBPA
was detected in the liver and kidney and
suckling pups.
Fujitani et al., 2007
Insufficient study details; study is in
Japanese with English abstract.
Male rats exposed to TBBPA via i.v.
injection (20 mg/kg), single oral bolus (2,
20 or 200 mg/kg) or repeated daily oral
doses (20 mg/kg for 5-10 days). TBBPA
is absorbed from the intestinal tract, but is
extracted and metabolized by the liver to
glucuronides that are exported into the
bile.
Solyom et al., 2006
Sufficient study details reported in
primary source.
4-40
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Intravenous injection: half-life in blood
was 82 minutes at a clearance rate of 2.44
mL/min. Major route of elimination was
the bile/feces; 82% eliminated within 36
hours; 0.5% eliminated in the urine.
Single oral bolus: 90-106% eliminated in
feces within 72 hours; 2% in urine.
Repeated dose: 85-98% eliminated in
feces
In an intraperitoneal injection study in
rats, peak concentrations of 14C-TBBPA
were found in all tissues within an hour;
highest concentrations found in fat
followed by the liver, sciatic nerve,
muscles, and adrenals. A small amount of
the administered dose was retained after
72 hours in fatty tissue and muscle (3-6%
and 11-14%, respectively). It has also
been observed that unmetabolized
TBBPA is rapidly excreted in feces (51-
95% of the administered dose) following
single exposure (route not specified).
Birnbaum and Staskal, 2004
Adequate study details reported in a
secondary source.
The half-life of TBBPA was estimated to
be 2 days in Swedish workers engaged in
the recycling process.
Sjodin et al., 2003
Adequate study details reported in a
secondary source.
TBBPA was poorly absorbed in the
gastrointestinal tract in rats following
single oral administration. Approximately
95% of the administered dose was
eliminated in feces and <1% was
eliminated in urine within 72 hours.
Levels in tissues were highest in the liver
and gonads. The maximum half-life in
WHO, 1995
Summary information from an
unpublished study.
4-41
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
any tissue was <3 days.
Placental transfer of hydroxylated BFRs
was observed in rats orally dosed with test
compounds (including TBBPA) on
gestation days (GDs) 10-16. There were
no associated developmental effects at the
dose used in the study (25 mg/kg).
Buitenhuis et al, 2004
Sufficient study details reported in
primary source.
TBBPA has been detected in breast milk,
although a study in pregnant rats indicates
that there is no significant transfer of
TBBPA or its metabolites to the fetus
(total amount of radioactivity in the fetus
was approximately 0.34% of the
administered dose).
EU, 2006
Summary of various studies in a
secondary source.
Only an extremely small percentage of
TBBPA particles are expected to be small
enough (1-2 (im) to be deposited into the
rat lung following inhalation. Particles
that do not reach the alveolar region are
expected to be exhaled. The remainder
will deposit in the respiratory tract, will be
swallowed and absorbed by the
gastrointestinal tract (70% absorbed by
gastrointestinal tract, <4% absorbed
through the lungs).
EU, 2006
General information summarized in
a secondary source.
Recovery of TBBPA (measured as
radioactivity) following single oral
administration to rats:
Feces: 90-95%
Urine: <1%
Tissues: 0.4% (Measured)
Recovery of TBBPA (measured as
radioactivity) following repeated oral
administration to rats (1, 5 or 10 days):
Feces: 82-98%
4-42
ACC, 2006b; Kuester et al.,
2007
Sufficient study details reported in
primary source.
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Urine: <0.5%
Tissues: <1%
Unexcreted intestinal contents: 1-10%.
The rats were sacrificed 24 hours after the
last dose. (Measured)
Following oral administration of 14C-
TBBPA to rats, 47% and 51% of the dose
was excreted in the bile within 2 hours,
primarily as 2 metabolites: TBBPA-
glucuronide and TBBPA-diglucuronide.
Estimated systemic bioavailability after
oral dosing: 1.6%
In a single dose study in rats, TBBPA was
rapidly metabolized following oral
administration of 300 mg/kg. Primary
metabolites were TBBPA-glucuronide
and TBBPA-sulfate. Diglucuronide of
TBBPA (a mixed glucuronide-sulfate
conjugate of TBBPA), tribromobisphenol
A, and the glucuronide of
tribromobisphenol A were also present in
low concentrations. A peak plasma
concentration of 103 (imol/L was
achieved within 3 hours with an
elimination half-life of 13 hours. Fecal
excretion of unchanged TBBPA was the
major excretory pathway with (>80%).
Schauer et al, 2006 (as cited in
ACC, 2006b)
Sufficient study details reported in
primary source.
In a single dose study in humans (3 males,
2 females), TBBPA was rapidly
metabolized following oral administration
via gel capsule of 0.1 mg/kg. Primary
metabolites were TBBPA-glucuronide
and TBBPA-sulfate. Only TBBPA-
glucuronide was detected in the urine;
approximately 25% of the administered
Schauer et al., 2006 (as cited in
ACC, 2006b)
Sufficient study details reported in
primary source.
4-43
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
Other
DATA
dose was eliminated in urine.
In a single oral dose and bile-cannulated
rat study, TBBPA was readily absorbed,
metabolized and eliminated within 72
hours after dosing of male Sprague-
Dawley rats.
Excretion in oral dosing study: 91.7% in
feces, 0.3% in urine. Residue in tissue was
2% of dose (Primarily large and small
intestines).
Excretion in bile-duct cannulated rat:
26.7% in feces, 71.3% in bile, <1%
residue in tissues. Primary metabolites:
Glucuronic acid and sulfate ester
conjugates. Over 95% of extractable fecal
14C was parent TBBPA.
Rapid clearance of [14C]-labeled TBBPA
from the blood of male F344 or female
Wistar Han rats; single oral or intravenous
administration. Tmax of 14C in blood was
observed at 32 ± 19 minutes in male rats
(200 mg/kg fasted) and 1 14 ± 42 minutes
in females (250 mg/kg nonfasted).
Terminal half-lives were > 5 hours and
systemic bioavailability was < 5%.
No accumulation of TBBPA in tissues of
male Sprague-Dawley rats receiving
1,000 mg/kg for 14 consecutic ve days.
TBBPA was present in breast milk, and
both maternal and fetal serum samples in
two studies, indicating a possible risk of
overexposure of newborns through
breastfeeding.
In bile-cannulated rats, 71% of
administered TBBPA was excreted in the
REFERENCE
Hakk et al., 2000 (as cited in
ACC, 2006b; EU, 2006; NTP,
2013)
Knudsen et al., 2013 Kuester et
al., 2007 (as cited in NTP, 2013)
Kang et al., 2009 (as cited in
NTP, 2013)
Antignac et al., 2008; Cariou et
al., 2008
Birnbaum and Staskal, 2004
DATA QUALITY
Sufficient study details reported in
primary source.
Sufficient study details reported in
NTP technical report.
Sufficient study details reported in
NTP technical report.
Sufficient information in primary
sources.
Sufficient information in review.
4-44
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
Acute Mammalian Toxicity
Acute Lethality
Oral
Dermal
DATA
bile. Metabolites found in bile were a
diglucuronide, a monoglucuronide, and a
glucuronide-sulfate ester.
REFERENCE
DATA QUALITY
LOW: Experimental studies indicate TBBPA, administered orally to rats and mice at levels up to 50,000
and 10,000 mg/kg, respectively, and TBBPA administered dermally to rabbits at levels up to 10,000 mg/kg
does not produce substantial mortality. Data from located inhalation studies are not sufficient to consider
for the hazard designation.
Rat oral LD50 >50 mg/kg
(range finding study in rats (2 rats/group)
administered 0.5-50 mg/kg)
Rat oral LD50 >2,000 mg/kg - >50,000
mg/kg
Mouse oral LD50 3,200 mg/kg - > 10,000
mg/kg
Rat oral LD50 >5,000 mg/kg
Mouse oral LD50 >7,000 mg/kg
Mouse oral LD50 > 10,000 mg/kg
Rabbit dermal LD50 >2,000 mg/kg
Guinea pig dermal LD50 >1,000 mg/kg
Rabbit dermal LD50 >2 g/kg (2,000
mg/kg)
Sterner, 1967c
Doyle and Elsea, 1966; WHO,
1995; EU, 2006
Dean et al, 1978b (as cited in
WHO, 1995; EU, 2006)
Mallory et al., 1981b (as cited in
EU, 2006; ECHA, 2013)
ECHA, 2013
ECHA, 2013
WHO, 1995
WHO, 1995
ECHA, 2013
Limited study details reported in an
unpublished study.
Sufficient study details reported.
Limited information in secondary
sources. Sufficient information in
unpublished study.
Sufficient data in unpublished study
conducted in accordance with good
laboratory practices (GLP).
Pre-dates standard guidelines and
GLP; no analytical verification of
test material; unequal amounts of
vehicle administered; no vehicle
control.
Pre-dates standard guidelines and
GLP; no analytical verification of
test material; unequal amounts of
vehicle administered; no vehicle
control.
Limited study details reported in a
secondary source.
Limited study details reported in a
secondary source.
Sufficient information in an
unpublished study conducted in
4-45
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Inhalation
accordance with GLP.
Rabbit dermal LD50 > 10,000 mg/kg
Doyle and Elsea, 1966 (as cited
inEU, 2006; ECHA, 2013)
Sufficient study details reported in
unpublished studies.
Rat, mouse, guinea pigs 8-hour aerosol
inhalation LC50 > 0.5 mg/L (whole-body,
aerosol)
Sterner, 1967b (as cited in EC,
2000; EU, 2006)
Inadequate unpublished study, due
to short observation period (2 days)
and because the particle size of the
aerosol was not measured.
Rat 1 hour inhalation LC50 >57 mg/L
(whole body, vapor)
ECHA, 2013
No GLP data; methodology predates
or was not conducted according to
standardized guidelines; no
analytical verification of test
compound concentrations.
Rat 1-hour inhalation LC50 >1,267 ppm
(whole-body)
Doyle and Elsea, 1966 (as cited
in EU, 2006)
Inadequate, methodological
deficiencies (lack of analysis of the
test atmosphere and stability of the
test compound) raise uncertainties
as to the reliability of this study.
Carcinogenicity
MODERATE: There is evidence of increased incidences of tumors of the uterus in female rats and
interstitial cell adenoma of the testes in male rats orally exposed to TBBPA for up to 105 weeks. There
were also increased incidences of tumors in male mice (hepatoblastoma and combined incidence of
hepatocellular carcinoma or hepatoblastoma of the large intestine and hemangiosarcoma in all organs);
however, there was no evidence of carcinogenicity reported in female mice. In addition, a marginal
concern was estimated based on structure-activity relationships and functional properties. The mechanism
of action of TBBPA carcinogenicity is not clearly understood. While there was some evidence of
carcinogenicity in animals (in male and female rats and male mice, but not in female mice), there is
inadequate evidence of carcinogenicity in humans.
OncoLogic Results
Marginal; likely to have equivocal
carcinogenic activity.
Carcinogenicity (Rat and
Mouse)
2-year oral gavage carcinogenicity study;
B6C3F1/N mice (50/sex/dose) were
administered 0, 250, 500, or 1,000 mg/kg-
day 5 days/week for up to 105 weeks.
Survival was decreased at 1000 mg/kg-
day, and therefore, effects are not reported
4-46
OncoLogic, 2008
NTP, 2011; NTP, 2012; NTP,
2013
Estimated by OncoLogic based on
structure-activity relationships and
functional properties.
Sufficient study details reported.
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
for this dose. There was an increase in
incidence of multiple hepatocellular
adenomas in male mice in the 500 mg/kg-
day dose group. Increased incidence of
hepatoblastoma and combined incidence
of hepatocellular carcinoma or
hepatoblastoma were reported in male
mice in the 250 mg/kg-day dose group
when compared to controls. Also, a
significant increased positive trend in the
incidence of adenoma or carcinoma
(combined) was seen in the large intestine
in males. In addition, there was a
significant trend for increased incidence
of hemangiosarcoma in all organs in male
mice.
There was no evidence of carcinogenicity
in female mice.
2-year oral gavage carcinogenicity study;
Wistar Han rats (50 or 60/sex/dose) were
administered 0, 250, 500, or 1,000 mg/kg-
day 5 days/week for up to 105 weeks.
There was a slight increase in incidence of
interstitial cell adenoma of the testis in
male rats (1/50 at 500 mg/kg-day; 3/50 at
1,000 mg/kg-day) as compared to controls
(0/50). There was a significant increase in
the incidences of adenomas and
carcinomas of the uterus in female rats at
500 and 1,000 mg/kg-day compared to
controls. There was also an increased
combined incidence of adenoma,
adenocarcinoma, and malignant mixed
Mullerian tumor of the uterus at these
dose groups (3/50, 7/50, 11/50, 13/50 in
the 0, 250, 500, and 1,000 mg/kg-day
NTP, 2013
Sufficient study details reported.
4-47
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
Combined Chronic
Toxicity/Carcinogenicity
Other
Genotoxicity
Gene Mutation in vitro
Gene Mutation in vivo
Chromosomal Aberrations in
vitro
DATA
groups, respectively).
Negative in a tumor promotion study in
male F344 rats exposed in utero and
directly via drinking water for 2 weeks
after weaning.
REFERENCE
CCRIS, 2013
DATA QUALITY
No data located.
Limited study details reported in a
secondary source.
LOW: Experimental studies indicate that TBBPA is not genotoxic to bacterial, mammalian, or yeast cells
in vitro. TBBPA was negative in a micronucleus test in mice in vivo.
Negative, Salmonella typhimurium strains
TA98, TA100, TA1535, or TA1537, orE.
coli strain WP2 zwA/pKMlOl, with or
without metabolic activation.
Negative, several Ames assays in
Salmonella typhimurium strains TA92,
TA98, TA100, TA1535, TA1537 and
TA1538 with and without metabolic
activation. Positive controls responded as
expected.
Negative, several gene mutation assays in
yeast (Saccharomyces cerevisiae D3 and
D4) with and without metabolic
activation. Positive controls responded as
expected.
Negative, induction of intragenic
recombination in two in vitro mammalian
cell assays. No information was provided
regarding positive controls.
Negative, chromosomal aberration in
human lymphocytes. Positive controls
responded as expected.
NTP, 2013
Brusick and Weir, 1976;
Jagannath and Brusick, 1977;
Simon et al., 1979; Curren et al.,
1981; WHO, 1995; EC, 2000;
Darnerud, 2003; EU, 2006
Brusick and Weir, 1976;
Jagannath and Brusick, 1977;
Simon etal., 1979; WHO, 1995
Simonsen et al., 2000; Darnerud,
2003
Gudi and Brown, 2001 (as cited
in EU, 2006)
Sufficient study details reported in
NTP technical report.
Sufficient information in secondary
sources and unpublished reports.
Sufficient information in secondary
sources and unpublished reports.
Limited data in secondary sources.
No data located.
Sufficient information in primary
source.
4-48
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Chromosomal Aberrations in
vivo
No increases in micronucleated
normochromatic erythrocytes in
B6C3F1/N mice administered TBBPA via
oral gavage for 3 months.
NTP, 2013; NTP, 2012
Sufficient study details reported in
NTP technical report.
DNA Damage and Repair
No data located.
Other
No data located.
Reproductive Effects
LOW: Experimental studies indicate TBBPA, administered orally to rats, produces no adverse effects on
reproductive performance or outcomes at levels up to 3,000 mg/kg-day. In some studies there were
changes in testis weights at low doses; the significance of these changes on testicular function is unclear
given the limitations of the studies.
Reproduction/Developmental
Toxicity Screen
In a dietary study, pregnant rats (8/group)
were fed 0, 100, 1,000, or 10,000 ppm
(-17, 149, and 1,472 mg/kg-day) TBBPA
( >98% pure) on GD 10 until day 20 after
delivery. There was no evidence of
maternal toxicity during the study.
Treatment with TBBPA did not affect the
number of implantation sites. No other
reproductive endpoint was assessed.
NOAEL: 10,000 ppm (-1,472 mg/kg-day,
highest dose tested)
LOAEL: Not established
In a dietary study, rats (8-13 males and 6-
10 females/group) were fed 0, 3, 10, 30,
100, 300, 1,000 and 3,000 mg/kg-day
TBBPA (98% pure) for 11 weeks (males)
or 2 weeks during premating and
throughout pregnancy and lactation
(females). Dosing continued in FI
offspring after weaning until necropsy at
approximately 6 weeks of age. Decreased
body weight in dams at highest dose. No
adverse effect on number of litters,
number of implantation sites or number of
Saegusaetal., 2009
Van der Yen etal., 2008
Sufficient study details reported in
primary source, but limited
reproductive data. Doses are TWA
for mean intakes of TBBPA during
GD 10-20, PND 1-9, and post natal
days [PND 10-20) estimated by the
investigators.
Sufficient details provided in the
primary source. Doses were
estimated by the investigators. As
stated in the study, dose-response
analysis of effects based on external
dosing (mg/kg-day) was done using
a nested family of purely descriptive
(exponential) models with the
PROAST software. The method
enables integrated evaluation of the
complete data set. From the best
fitted curve, indicated by
4-49
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
pups per litter.
Increased testicular and pituitary gland
weights in FI males (with BMDL values
of 0.5 and 0.6 mg/kg-day). No other effect
on FI gonads wes seen.
Other reproductive-related effects in
offspring were seen only at high doses
(e.g., decrease in anogenital distance in
females seen at day 7 only but not at day 4
or day 21; number of days until vaginal
opening). BMDLs for these effects are
2736 and 2745 mgkg-day, respectively.
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
Reproduction and Fertility
Effects
20-Week, 2-generation reproductive
assay, rats (30/sex/group), administered
TBBPA via oral gavage at 0, 10, 100 or
1,000 mg/kg-day. No effects on
reproductive performance or outcomes.
NOAEL: 1,000 mg/kg-day (highest dose
tested)
LOAEL: Not established
ACC, 2002
2-generation drinking water study in mice
administered TBBPA dissolved in water
at a concentration of 200 (ig/L. This
provided a dose of 0.035 mg TBBPA/kg-
day (reagent grade) based on body weight
and daily water consumption (estimated
by the investigators). In the parental
generation, only females were exposed
during gestation; In the FI generation,
4-50
Zatecka et al., 2013
significance at the 5% level, a
critical effect dose (CED) was
alculated most often using a critical
ffect size of 10%; there has been
some criticism of the modeling and
methodology used for this study
along (Banasik et al. 2009).
No data located.
Sufficient details provided in
primary source.
Study is inadequate because only
one dose level was tested. Unknown
toxicological significance of
alterations reported; therefore, study
was not used for hazard
lassification.
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Other
pups were exposed to TBBPA during
gestation, lactation, pre-pubertal and
pubertal period, and up to adulthood. No
adverse effect on progeny or sex ratio in
either generation. Significantly reduced
testicular weight, increased prostate and
seminal vesicle weight. No visible
abnormalities or pathological changes in
the morphology of seminiferous tubules.
Significantly increased number of
apoptotic cells in the testes and increased
expression pattern of genes encoding
proteins important during
spermatogenesis (F] generation).
Male rats were administered 0, 10, 100
and 1,000 (ig/kg (0, 0.01, 0.1, 1 mg/kg)
TBBPA via subcutaneous injection on
postnatal day (PND) 1-10. Increased
preputial gland weight; decreased
averages of preleptotene spermatocyte,
pachytene spermatocyte and round
spermatid; decreased cauda epididymal
sperm reserves. These effects were not
statistically different from controls.
Tada et al., 2005
Study in Japanese with English
summary.
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
Developmental Effects
Reproduction/
Developmental Toxicity
Screen
DATA REFERENCE DATA QUALITY
MODERATE: Based on several studies reporting potentially adverse effects in the range of moderate to
high hazard designations with effects on kidney, liver, thyroid and brain endpoints. Some of the studies
with effects in moderate to high hazard range have limitations in experimental design and/or statistical
methods but cannot be completely dismissed. A number of studies indicate no effects up to relatively high
oral or dietary doses of TBBPA. Based on this weight of evidence, a moderate hazard designation is
assigned.
Evidence of potential for moderate or high developmental toxicity:
Nonstandard experimental studies indicate TBBPA, administered orally, produces adverse hepatic effects
(very slight focal hepatocyte necrosis and enlargement of hepatocytes) at 140.5 mg/kg-day (NOAEL = 15.7
mg/kg-day) in mouse pups and kidney effects (polycystic lesions associated with the dilatation of the
tubules) at 200 mg/kg-day (NOAEL = 40 mg/kg-day) in rats postnatally exposed from PND 4-21. Increased
hearing latencies (most likely related to impairment of the development of the upper (apical) part of the
cochlea) were reported in a dietary 1-generation study at a BMDLio of 8 mg/kg-day. There were also
changes in plasma thyroid hormone levels (decreased TT4 at BMDLio of 30-60 mg/kg-day, and increased
TT3 at BMDLio of 5 mg/kg-day) in rat fetuses. Alterations in pup development were observed following
administration of TBBPA in the diet to pregnant rats at a dose of 10,000 ppm (NOAEL = 1,000 ppm).
These effects included increase in interneurons in the dentate hilus-expressing reelin suggestive of
aberration of neuronal migration. Cholinergic effects were observed in neonatal NMRI mice administered
TBBPA at doses up to 11.5 mg/kg body weight (highest dose tested) on postnatal (PND) 10.
Evidence of low developmental toxicity:
Six oral exposure studies with rats and one with mice using standard exposure scenarios showed no effects
in a range of endpoints including body weight, clinical signs, organ weights, alterations in development of
the fetus, neonatal viability and growth, onset of puberty, estrous cycles, organ histology and brain
morphometry at doses ranging from 1,000 to 10,000 mg/kg-day. Two studies with rats using oral exposure
to relatively low doses (<10 mg/kg-day) of TBBPA showed no changes in thyroid and sperm endpoints.
No data located.
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
20-Week, 2-generation developmental
neurotoxicity and neuropathology assay,
rats, administered TBBPA via oral gavage
at 0, 10, 100 or 1,000 mg/kg-day.
Treatment with TBBPA did not induce
significant alterations in FI or F2 pups
regarding body weight, clinical signs,
survival to weaning, or organ weight data.
FO rats exhibited a decrease in T3 at 1000
mg/kg. Decreases in T4 were seen in FO
rats and in Fl offspring at 100 and 1000
mg/kg-day.
NOAEL (developmental): 1,000 mg/kg-
day (highest dose tested)
LOAEL: Not established
ACC, 2002
Sufficient study details provided in
primary source.
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Prenatal Development
In a nonstandard assay for gestational and
lactational exposure, mice (6/group) were
fed 0, 0.01, 0.1 or 1.0%TBBPA (99.1%
pure) in the diet from GD 0 to postnatal
day (PND) 27. Approximate daily doses
were 15.7, 140.5 or 1,639.7 mg/kg-day for
gestational period (GDO-17) and 42.1,
379.9 or 4,155.9 mg/kg-day for lactational
period (PNDO-21). No standard
developmental effects. Very slight focal
hepatocyte necrosis and enlargement of
hepatocytes (female pups) were seen at
140.5 / 379.9 mg/kg-day and higher.
NOAEL: 15.7 mg/kg-day during gestation
and 42.1 mg/kg-day during lactation
LOAEL: 140.5 mg/kg-day during
gestation and 379.9 mg/kg-day during
lactation based on very slight focal
hepatocyte necrosis and enlarged
hepatocytes
Tada and Fujitani, 2006
In a dietary study, pregnant rats were fed
0, 100, 1,000, or 10,000 ppm (-17, 149,
and 1,472 mg/kg-day) TBBPA on GD 10
until day 20 after delivery. Treatment with
TBBPA did not result in maternal
toxicity. Maternal exposure to TBBPA did
not affect the number of live offspring,
birth weight, anogenital distance (AGD)
on postnatal day (PND) 1, neonatal
viability and growth, or organ histology
on PND 20, onset of puberty (males and
females), estrous cycle, or organ histology
and brain morphometry on post-natal
week 11.
Saegusaetal., 2009
TWA doses can be estimated for the
combined gestational and lactational
periods as 32, 287, and 2,614
mg/kg-day for the 0.01, 0.1, and 1%
dietary groups, respectively. The
TWA developmental LOAEL would
be 287 mg/kg-day. Study limitations
include statistical deficiencies due to
the failure to control for litter
effects. Littermates were utilized as
independent variables for the
experimental and statistical analysis.
The tendency of littermates to
respond more similarly to one
another than non-litter mates was
not taken into account.
Sufficient details provided in
primary source. Doses are TWA for
mean intakes of TBBPA during GD
10-20, PND 1-9, and PND 10-20)
estimated by the investigators.
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
NOAEL (developmental): 10,000 ppm
(-1,472 mg/kg-day, highest dose tested)
LOAEL: Not established
Pregnant rats (25/group) were orally
administered 0, 100, 300 and 1,000 mg/kg
TBBPA by gavage on gestation days
(GDs) 0-19; sacrifices were conducted on
GD 20. There were no lexicologically
significant maternal effects and no
adverse developmental effects.
NOAEL (maternal and developmental):
1,000 mg/kg-day (highest dose tested)
LOAEL: Not established
MPI Research 2001 (as cited in
EU, 2006)
Sufficiently detailed summary of
results in secondary source.
Pregnant rats were orally administered 0,
280, 830 and 2,500 mg/kg-day TBBPA by
gavage throughout gestation. No
lexicologically significant maternal
effects were observed. There were no
significant alterations in the development
of fetuses examined on GD 20 or on pups
monitored up to postnatal day (PND) 21.
NOAEL (maternal and developmental):
2,500 mg/kg-day (highest dose tested)
LOAEL: Not established
Noda et al., 1985 (as cited in
EU, 2006)
Sufficiently detailed summary of
results in secondary source.
Pregnant rats (5/group) were orally
administered 0, 30, 100, 300, 1,000, 3,000
and 10,000 mg/kg TBBPA by gavage on
GDs 6-15. Sacrifices were conducted on
GD 20. Maternal deaths occurred with the
highest dose, but there were no adverse
developmental effects.
NOAEL (maternal): 3,000 mg/kg-day
Goldenthal et al., 1978 (as cited
in EC, 2000; Simonsen et al.,
2000)
Sufficiently detailed summary of
results in primary source.
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DATA
REFERENCE
DATA QUALITY
Postnatal Development
LOAEL (maternal): 10,000 mg/kg-day
based on mortality
NOAEL (developmental): 10,000 mg/kg-
day (highest dose tested)
LOAEL (developmental): Not established
Pregnant rats were orally administered
14C-TBBPA (5 mg/kg) on gestation days
(GDs) 10-16 and were sacrificed on GD
20. No effect on plasma total and free T4
levels in dams and fetuses and on
maternal total and T3 levels. Significant
increase (196%) in TSH levels in fetuses'
plasma (but not in dams). TBBPA did not
seem to bind to transthyretin (TTR) in
vivo.
Darnerud, 2003
Limited scope study. Use of a single
dose level precludes drawing firm
conclusions.
In a nonstandard assay for postnatal
exposure, newborn rats (6/sex/group)
were orally administered 0, 40, 200 and
600 mg/kg-day TBBPA (99.5% pure) by
gavage from day 4-21 after birth and were
sacrificed after the last dose. Kidney
effects (polycystic lesions associated with
dilatation of the tubules) evident at > 200
mg/kg-day.
NOAEL: 40 mg/kg-day
LOAEL: 200 mg/kg-day (based on
polycystic lesions, dilation of tubules in
kidneys)
Fukuda et al., 2004
Sufficient details in primary source.
Male rats were administered 0, 10, 100
and 1,000 (ig/kg (0, 0.01, 0.1, 1 mg/kg)
TBBPA via subcutaneous injection on
postnatal days (PNDs) 1-10. Increased
preputial gland weight; decreased
averages of preleptotene spermatocyte,
Tada et al., 2005
Study in Japanese with English
abstract.
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
Prenatal and Postnatal
Development
Developmental Neurotoxicity
DATA
pachytene spermatocyte and round
spermatid; decreased cauda epididymal
sperm reserves. These effects were not
statistically different from controls.
NOAEL: 1 mg/kg bw-day (highest dose
tested)
LOAEL: Not established
In 5 -week old rats administered 0, 2,000
or 6,000 mg/kg-day TBBPA for 18 days,
no adverse effects were observed.
NOAEL: 6,000 mg/kg-day (highest dose
tested)
LOAEL: Not established
Pregnant Sprague Dawley rats were
exposed to 0, 100, 1,000 or 10,000 ppm
TBBPA in the diet from GD 10 through
day 20 after delivery (weaning).
Alterations in pup brain development on
postnatal day (PND) 20 (increase in
interneurons in the dentate hilus-
expressing reelin suggestive of aberration
of neuronal migration) in pups from the
high dose group.
NOAEL: 1,000 ppm (-80 mg/kg-day)
LOAEL: 10,000 ppm (-800 mg/kg-day)
based on alterations in pup brain
development
Newborn rats (6/sex/group) were
administered 0, 40, 300, or 600 mg/kg-
day TBBPA (99.5% pure) by gavage on
postnatal days (PNDs) 4 through 21. No
REFERENCE
Fukuda et al., 2004
Saegusa et al., 2012 (as cited in
NTP, 2013)
Fukuda et al., 2004
DATA QUALITY
Sufficient study details reported in a
primary study.
^o data located.
Sufficient study details reported in
NTP technical report. Doses were
reported as ppm in the diet but were
converted to mg/kg/day using EPA
1988 reference values for body
weight and food consumption.
Qualitative observations only.
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
significant effects on a variety of reflexes
tested on postnatal day 21.
NOAEL: 600 mg/kg-day (highest dose
tested)
LOAEL: Not established
TBBPA administered to male neonatal
NMRI mice at single oral doses of 0, 0.75,
or 11.5 mg/kg body weight on postnatal
(PND) 10; No neurotoxicity, changes in
spontaneous motor behavior, or clinical
signs of dysfunction; however,
cholinergic effects were observed.
NOAEL: 0.75 mg/kg
LOAEL: 11.5 mg/kg (based on
cholinergic effects)
Viberg and Eriksson, 2011 (as
cited in NTP, 2013)
Sufficient study details reported in
NTP technical report. Study
limitations include statistical
deficiencies due to the failure to
control for litter effects.
Sprague-Dawley rats administered
TBBPA at doses of 0, 100, 1,000 or
10,000 ppm in a soy-free diet from GD 10
- postnatal day (PND) 20. Slight decrease
in serum T3 concentrations in pups on
PND 20; however, no evidence for
developmental brain effects.
NOAEL: 10,000 ppm (-1,472 mg/kg-day;
highest dose tested)
LOAEL: Not established
Saegusaetal., 2009
Sufficient study details reported in
primary source.
In a dietary study, rats (8-13 males and 6-
10 females/group) were fed 0, 3, 10, 30,
100, 300, 1,000, or 3,000 mg/kg-day
TBBPA (98% pure) for 11 weeks (males)
or 2 weeks during premating and
throughout pregnancy and lactation for
females (doses estimated by the
investigators). After weaning, dosing of
van der Yen etal., 2008;
Lilienthal et al. (2008)
As stated in the study, dose-
response analysis of effects based
on external dosing (mg/kg-day) was
done using a nested family of purely
descriptive (exponential) models
with the PROAST software. The
method enables integrated
evaluation of the complete data set.
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DATA
REFERENCE
DATA QUALITY
I continued for life. Neurobehavioral
testing was conducted between postnatal
days (PNDs) 50 and 140.
Increase in hearing latencies were seen,
with a BMDL10 calculated to be 8 mg/kg-
day. Other changes in auditory responses
using other types of measures resulted in
higher BMDL values.
Changes in plasma thyroid hormone
levels were seen, with decreased T4 at
BMDL10 of 30.8 mg/kg-day (males) and
16.1 mg/kg-day (females). Increased T3
levels were seen in female offspring, with
a BMDLio of 2.3 mg/kg-day.
Increases in pituitary gland and testis
weights were seen in male F1 offpring
(with BMDLs of 0.6 and 0.5 mg/kg-
bw/day, respectively). Other offspring
effcts (e.g., changes in body weight) were
seen at much higher doses and not
necessarily seen throughout the study.
20-Week, 2-generation developmental
neurotoxicity and neuropathology assay,
rats, administered TBBPA via oral gavage
at 0, 10, 100 or 1,000 mg/kg-day. No
significant neurobehavioral or
neuropathological alterations in F2 pups
identified at various times up to postnatal
day 60.
NOAEL: 1,000 mg/kg-day (highest dose
tested)
LOAEL: Not established
ACC, 2002
From the best fitted curve, indicated
by significance at the 5% level, a
critical effect dose (CED, also
referred as Benchmark Dose) was
calculated most often using a critical
effect size of 10%; there has been
some criticism of the modeling and
methodology used for this study
along with noted study limitations
not consistent with recommended
study guidelines (Banasik et al.
2009; Strain et al. 2009; comparison
with OPPTS 870.6855).
Sufficient study details in primary
source.
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Other
No data located.
Neurotoxicity
LOW: An experimental study in rats produced no adverse neurotoxic effects in adults at levels up to 1,000
mg/kg-day. In an acute exposure study, TBBPA, administered orally to mice, resulted in neurobehavioral
effects; these effects were not clearly dose-dependent. Although one study with limitations appears to
result in neurobehavioral effects, a well-designed subchronic duration study did not identify any adverse
neurological effects. Based on study quality, a Low hazard designation was assigned.
Neurotoxicity Screening
Battery (Adult)
In a 90-day study, rats (10-15/sex/dose)
were administered daily doses of 0, 100,
300 or 1,000 mg/kg-day TBBPA via in
corn oil. A detailed functional
observational battery (FOB) was
conducted pre-test and at week 12. Motor
activity (MA) was also assessed at week
12. No neurobehavioral effect of
treatment with TBBPA was evident.
NOAEL: 1,000 mg/kg-day (highest dose
tested)
LOAEL: Not established
Male mice (14-15/group) were
administered 0, 0.1, 5, or 250 mg/kg-day
TBBPA (99% pure) by gavage 3 hours
before a series of neurobehavioral tests
(open field test, Y-maze test or training of
contextual fear conditioning paradigm).
No gross abnormalities. No significant
differences in the number of rearing and
grooming behaviors. Increased horizontal
movement activities (5 mg/kg-day),
increased freezing behavior in fear
conditioning paradigm (0.1 or 5 mg/kg-
day), increase in spontaneous alternation
behavior in Y-maze test at the low dose,
but no adverse effects occurred at higher
doses. Elevated levels of TBBPA were
detected in the striatum region of the brain
4-60
Nakajimaetal., 2009
MPI Research, 2002 (as cited in
EU, 2006)
Sufficient study details in secondary
source.
Sufficient details in primary source.
Difficult to establish a
NOAEL/LOAEL due to lack of
dose-response relationships; acute
study duration is not a standard
methodology for a neurotoxicity
screening study.
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
Other
DATA
at lower doses (0.1 or 5 mg/kg-day). At
the highest dose tested (250 mg/kg-day),
there was non-specific accumulation of
TBBPA in the brain.
Potential for neurotoxic effects based on a
structural alert for phenols
(Estimated)
REFERENCE
Professional judgment
DATA QUALITY
Estimated based on a structural alert
and professional judgment.
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DATA
REFERENCE
DATA QUALITY
Repeated Dose Effects
LOW: Based on a weight of evidence indicating that effects occur at doses >100 mg/kg-day. Mice
administered 500 mg/kg-day TBBPA for 3 months were reported to have increased liver weight and
kidney effects in males (NOAEL=100 mg/kg-day). There was decreased serum alanine aminotransferase
and sorbitol dehydrogenase activity at week 14 in male and female rats at 100 mg/kg-day following oral
exposure for 3 months. Increased liver weights and decreased spleen weight were reported in male rats in
the 500 and 1,000 mg/kg-day dose group, though no treatment-related histopathologic lesions were
observed. Experimental studies indicate that TBBPA, administered orally to mice, produced effects on the
liver (inflammatory cell infiltration) at > 350 mg/kg-day (lowest dose tested). In a dietary study in mice,
changes in hematology and clinical chemistry (decreased red blood cells, hemoglobin, hematocrit, serum
triglycerides and total serum proteins) and decreased body weight gain occurred at 2,200 mg/kg-day
(NOAEL: 700 mg/kg-day) while mortality was reported at the highest dose tested (7,100 mg/kg-day). In a
2-year oral gavage carcinogenicity study in mice, renal tubule cytoplasmic alteration and effects on the
forestomach (ulcer, mononuclear cell cellular infiltration, inflammation, and epithelium hyperplasia) were
observed at > 250 mg/kg-day (lowest dose tested). Mean body weight was reduced by at least 10% in this
study at 1,000 mg/kg-day. In a 2-year oral gavage carcinogenicity study in rats, mean body weight was
reduced by at least 10% following exposure to > 500 mg/kg-day and at 1,000 mg/kg-day. Thymus weight
was reduced and liver weight was also increased in this study. Clinical signs of toxicity (excessive salivation
and nasal discharge) were evident in rats following inhalation exposure at levels of 6 mg/L (NOAEC: 2
mg/L). Very slight dermal erythema was present in rabbits following application of 100 mg/kg-day
TBBPA; however, this occurred in the absence of any systemic effects (NOAEL: 2,500 mg/kg-day).
4-62
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Tetrabromobisphenol A CASRN 79-94-7
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DATA
REFERENCE
DATA QUALITY
3 month oral gavage study in F344/Ntac
rats (10/sex/dose); rats were administered
0, 10, 50, 100, 500, or 1,000 mg/kg-day, 5
days/week for 14 weeks.
Dose-related decrease in total thyroxine
concentrations were reported on day 4 at
the final week of the study at 500 and
1,000 mg/kg-day, but not consistently in
the 100 mg/kg-day dose group in males
and female rats. There was a small
decrease in hematocrit levels, hemoglobin
concentrations, and erythrocyte counts in
female rats in the 500 and 1,000 mg/kg-
day dose groups by week 14. There was
also decreased serum alanine
aminotransferase and sorbitol
dehydrogenase activity at week 14 in
males and females of the 100 mg/kg-day.
Increased liver weights and decreased
spleen weight were reported in male rats
in the 500 and 1,000 mg/kg-day dose
group. Although enzyme changes are seen
at lower doses, it is uncertain if this is
linked to any of the observed adverse
endpoints. No treatment-related
histopathologic lesions were observed.
NOAEL: 100 mg/kg-day
LOAEL: 500 mg/kg-day (based on
decreased serum enzyme activity)
NTP, 2013
Sufficient study details reported in
NTP technical report
3 month oral gavage study in B6C3F1/N
mice (10/sex/dose); Mice were
administered 0, 10, 50, 100, 500, or 1,000
mg/kg-day, 5 days/week for 14 weeks.
There was no mortality reported. Final
mean body weight of treated mice in all
NTP, 2013
Sufficient study details reported in
NTP technical report.
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DATA
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DATA QUALITY
dose groups was similar to controls. Liver
weights were significantly greater in male
mice in the 500 and 1,000 mg/kg-day dose
groups as compared to controls. Increased
spleen weights and decreased kidney
weights were reported in the male 1,000
mg/kg-day dose group. Increased
incidence of renal tubule cytoplasmic
alteration in the kidney at 500 and 1,000
mg/kg in male mice (greater severity at
1,000 mg/kg).
NOAEL: 100 mg/kg-day
LOAEL: 500 mg/kg-day (based on
alterations in the kidneys in male mice)
In a 2 8-day dietary study, rats
(25/sex/group) were fed a diet containing
TBBPA at 0, 1, 10, 100 and 1,000 ppm (~
0.07, 0.7, 7.2 and 75 mg/kg-day in males,
and 0.07, 0.77, 7.4 and 72 mg/kg-day in
females). No changes in general
appearance, behavior, body weight or
food consumption. No compound-related
mortality, gross or microscopic lesions in
the liver, kidneys, and thyroid.
NOAEL: 1,000 ppm (75 or 72 mg/kg-day
in males and females, respectively;
highest dose tested)
LOAEL: Not established
Sterner, 1967c (as cited in
Wazeter et al., 1972); Simonsen
et al., 2000; ACC, 2006b; EU,
2006; ECHA, 2013
Study limited by histological
examination of only the liver,
kidneys, and thyroid.
28-day repeated-dose study, rat, diet, no
treatment-related effects.
NOAEL: ~ 98 mg/kg-day (0.1%, highest
dose tested)
LOAEL: Not established
Wazeter et al., 1972
Inadequate, the high dose was
relatively low and failed to elicit
toxicity.
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Tetrabromobisphenol A CASRN 79-94-7
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DATA
REFERENCE
DATA QUALITY
In a 90-day repeated-dose study, rats were
fed 0.3, 3, 30 or 100 mg/kg-day TBBPA
in the diet. No lexicologically significant
effects.
NOAEL: ~ 100 mg/kg-day (highest dose
tested)
LOAEL: Not established
Quastetal., 1975
Sufficient details in a primary
source. However, it was tested at
relatively low doses.
In a 14-day oral study, male mice (7-
8/group) were dosed by gavage with 0,
350, 700 or 1,400 mg/kg-day TBBPA
(99.1% pure) in olive oil. No clinical
signs or mortality. Significant increase in
absolute and relative liver weight in high-
dose mice. Slight enlargement of
hepatocytes at > 700 mg/kg-day,
inflammatory cell infiltration at > 350
mg/kg-day, and focal necrosis of
hepatocytes at 1,400 mg/kg-day. In
treated mice the liver appeared swollen
and the pancreas looked slightly enlarged
and edematous.
NOAEL: Not established
LOAEL: 350 mg/kg-day (lowest dose
tested)
Tada et al., 2007
Sufficient details in primary source.
In a 14-day oral study, male rats (6/group)
were administered 0, 200, 500 or 1,000
mg/kg TBBPA (98% pure) by gavage in
corn oil. No significant adverse effects on
body weight, clinical chemistry
parameters, or enzymes' activities
indicative of lipid peroxidation in the
kidneys.
NOAEL: 1,000 mg/kg-day (highest dose
Kang et al., 2009
Study of limited toxicological
scope. There was no histological
examination of the kidneys.
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DATA
REFERENCE
DATA QUALITY
tested)
LOAEL: Not established
B6C3F1 mice (10/sex/group) were fed
TBBPA in the diet at 0, 71, 700, 2,200 or
7,100 mg/kg-day for 3 months. All
animals receiving 7,100 mg/kg-day died,
but no deaths occurred at lower doses.
Decreased body weight gain at the two
highest doses with no change in food
consumption. Decreased red blood cells,
hemoglobin, hematocrit, serum
triglycerides and total serum proteins at
2,200 mg/kg-day. Increased spleen weight
with blood observed outside the red pulp.
No other organ weight or pathological
changes.
NOAEL: 700 mg/kg-day
LOAEL: 2,200 mg/kg-day
IPCS, 1995; WHO, 1995;
HSDB, 2013; NTP, 2013
Sufficient study details reported in a
secondary source.
In a 90-day repeated-dose study, rats were
administered TBBPA via oral gavage at 0,
100, 300 or 1,000 mg/kg-day. No deaths.
No effect on clinical signs, body/organ
weight, histopathology, urinalysis,
ophthalmology, or serum chemistries.
NOAEL: 1,000 mg/kg-day (highest dose
tested)
LOAEL: Not established
MPI Research, 2002 (as cited in
EU, 2006)
Sufficient details in a secondary
source.
10-day developmental study, rats orally
gavaged with 0, 30, 100, 300, 1,000,
3,000 and 10,000 mg/kg TBBPA-day.
Maternal clinical signs, mortality and
reduced body weight gain at the high dose
only (10,000 mg/kg-day). No effects at
3,000 mg/kg-day or less.
Goldenthal et al., 1978
Sufficient details in primary source.
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DATA
REFERENCE
DATA QUALITY
NOAEL: 3,000 mg/kg-day
LOAEL: 10,000 mg/kg-day
In an oral study, 5-week old rats were
administered 0, 2,000 or 6,000 mg/kg-day
TBBPA (99.5% pure) by gavage for 18
days. There were no changes in general
behavior, body weight or kidney weight.
Microscopic examination of the kidneys
showed no abnormalities.
NOAEL: 6,000 mg/kg-day (highest dose
tested)
LOAEL: Not established
Fukuda et al., 2004
Limited scope study; only the
kidneys were examined.
In a 2 8-day dietary study, rats
(10/sex/group) were fed 0, 30, 100 and
300 mg/kg-day TBBPA (98% pure).
Decreased circulating T4 and increased
T3 levels in males (BMDLs = 48 and 124,
respectively). No histopathological
changes in the thyroid or pituitary gland.
Van der Yen etal., 2008
As stated in the study, dose-
response analysis of effects based
on external dosing (mg/kg-day) was
done using a nested family of purely
descriptive (exponential) models
with the PROAST software. The
method enables integrated
evaluation of the complete data set.
From the best fitted curve, indicated
by significance at the 5% level, a
critical effect dose (CED, also
referred as Benchmark Dose) was
calculated at a default critical effect
size of 10%.
2-year oral gavage carcinogenicity study;
Wistar Han rats (50 or 60/sex/dose) were
administered 0, 250, 500, or 1,000 mg/kg-
day 5 days/week for up to 105 weeks.
Survival was similar to controls.
Decreased mean body weight (by at least
10% compared to controls) after week 25
in males in the 500 and 1,000 mg/kg dose
NTP, 2013
Sufficient study details reported in
NTP technical report.
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PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
groups. At the 3-month interim sacrifice,
there were no treatment-related lesions in
either sex. However, thymus weight was
decreased and liver weight was increased
at 1,000 mg/kg.
NOAEL: 250 mg/kg
LOAEL: 500 mg/kg (based on decreased
mean body weight in males)
2-year oral gavage carcinogenicity study;
B6C3F1/N mice (50/sex/dose) were
administered 0, 250, 500, or 1,000 mg/kg-
day 5 days/week for up to 105 weeks.
Reduced survival in males and females in
the 1,000 mg/kg dose group. Decreased
mean body weight (by at least 10%
compared to controls) after week 25 in
females at 1,000 mg/kg. Increase in the
incidence of renal tubule cytoplasmic
alteration in 250 and 500 mg/kg males.
Significant increase in the incidences of
ulcer, mononuclear cell cellular
infiltration, inflammation, and epithelium
hyperplasia in the forestomach in males at
500 mg/kg and in females at 250 and 500
mg/kg.
NOAEL: Not established
LOAEL: 250 mg/kg (based on effects in
the forestomach in females)
NTP, 2013
Sufficient study details reported in
NTP technical report.
21-day repeated-dose study in rabbits with
dermal application of 0, 100, 500 and
2,500 mg/kg TBBPA to the intact or
abraded back 6 hours/day, 5 days/week.
Very slight erythema (> 100 mg/kg-day).
No compound-related changes in body
Sterner, 1967c (as cited in
Goldenthal et al., 1979;
Simonsen et al., 2000; EU,
2006; ECHA, 2013)
Sufficient details in secondary
source.
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
Skin Sensitization
Skin Sensitization
DATA
weights, hematologic and biochemical
parameters and urinalysis. No compound
induced gross or microscopic lesions in
any of the tissues examined. No
compound-related organ weight variations
occurred.
NOAEL: 2,500 mg/kg-day (highest dose
tested)
LOAEL: Not established
In a 14 -day inhalation study, rats
(4/sex/group) were exposed whole-body
to 0, 2, 6 or 18 mg/L TBBPA as dust 4
hours/day, 5 days/week. No significant
effects on body weight gain, food
consumption, hematology and clinical
chemistry parameters or urinalysis. No
deaths and no gross or microscopic
lesions. Excessive salivation at 2 mg/L;
excessive salivation, nasal discharge and
lacrimation at > 6 mg/L.
NOAEC: 2 mg/L
LOAEC: 6 mg/L
REFERENCE
Sterner, 1967c (as cited in
Wazeter et al., 1975; Simonsen
et al., 2000; EC, 2000; ECHA,
2013)
DATA QUALITY
No information regarding how the
exposure atmosphere was generated
or regarding analytical
measurements of exposure
concentrations.
LOW: TBBPA is not a skin sensitizer in humans or guinea pigs.
Non-sensitizing, human volunteers
In a modified Draize Multiple Insult test.
Non-sensitizing, guinea pigs
No irritation was elicited at either
induction or challenge in the group
exposed to TBBPA.
Not sensitizing, guinea pigs
Three treated animals showed a mild skin
reaction at the induction site, no treated
Sterner, 1967c; Dean et al.,
1978a; WHO, 1995; EC, 2000;
EU, 2006; ECHA, 2013
Mallory et al., 1981c (as cited in
EU, 2006)
Dean et al., 1978c (as cited in
EU, 2006)
Sufficient study details in secondary
sources.
Sufficient study details in a primary
source.
Sufficient study details in a primary
source.
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
Respiratory Sensitization
Respiratory Sensitization
*.«-.
Eye Irritation
Dermal Irritation
Dermal Irritation
DATA
animal showed a skin reaction at the
challenge site.
REFERENCE
DATA QUALITY
No data located
|No data located.
MODERATE: Slight pain, conjunctivitis and corneal damage lasting for three days were reported in
rabbits administered TBBPA in a 10% solution. In addition, moderate conjunctival erythema, clearing
within 72 hours, was also reported following application of TBBPA to the eyes of rabbits.
Application of the test material to the eye
of rabbits produced no irritation in one
rabbit, mild conjunctival erythema in
eight rabbits, and moderate conjunctival
erythema in the remaining three rabbits.
Effects diminished in intensity or
subsided completely during subsequent 72
hours.
Irritating, range-finding study in rabbits.
Undiluted test material caused very slight
immediate conjunctivitis (disappearing
within 48 hours). TBBPA administered as
10% solution in water caused slight pain,
conjunctivitis and corneal damage (lasting
for 3 days and then returning to normal
within a week).
Non-irritating, rabbits
Doyle and Elsea, 1966 (as cited
in EU, 2006)
EU, 2006
Sterner, 1967a (as cited in
Mallory et al., 198 la; WHO,
1995; EU, 2006)
Sufficient details in primary source.
Sufficient details in secondary
source.
Sufficient study details in secondary
sources.
LOW: Slightly irritating to rabbits in a 21-day dermal repeated dose study.
Irritating, rabbits
21 -day repeated dermal toxicity assay
with very slight dermal erythema
persisting for 1-3 days.
Non-irritating, rabbits
Undiluted test material was applied to
intact and abraded skin.
Sterner, 1967c; Goldenthal et al.,
1979; EU, 2006
Doyle and Elsea, 1966; Sterner,
1967c; Mallory etal., 198 Id;
EC, 2000; EU, 2006
Sufficient details in primary
sources.
Sufficient details in primary
sources.
4-70
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Non-irritating, human volunteers
In a modified Draize Multiple Insult test.
Sterner, 1967c; Dean et al.,
1978a; EC, 2000; EU, 2006
Sufficient details in primary source.
Endocrine Activity
Both whole animal and in vitro studies indicate that TBBPA may exhibit thyroid endocrine activity. In a
one-generation reproduction study in rats, TBBPA decreased circulating thyroxine (T4) and increased
circulating T3 levels in males. TBBPA was negative for agonistic and antagonistic estrogenic responses
following oral exposure and subcutaneous injection at doses up to 1,000 mg/kg-day in an uterotrophic
assay with adult female ovariectomized mice. TBBPA has a high potency in competing with thyroxine (T4)
for binding to transport protein transthyretin (TTR) in in vitro animal studies. In addition, TBBPA
exhibited significant thyroid hormonal activity towards rat pituitary cell line GH3, which releases growth
hormone in a thyroid hormone-dependent manner. TBBPA produced only mild effects during long-term
treatment on larval development using the amphibian Xenopus laevis; however, short-term exposure
revealed indirect evidence that TBBPA can function as a TH antagonist. There were no adverse effects on
tail resorption in tadpoles that were microinjected with TBBPA during development. TBBPA did not
induce Vitellogenin in immature rainbow trout after intraperitoneal injection.
TBBPA did not exhibit thyroid hormonal
activity in a thyroid hormone-responsive
reporter assay using a Chinese hamster
ovary cell line (CHO-K1) transfected with
thyroid hormone receptor alpha 1 or betal.
TBBPA showed significant anti-thyroid
hormone effects on the activity of T3 in
the concentration range of 3x10"6 to 5x10~5
M. In addition, TBBPA (in the
concentration range of IxlO"8 to IxlO"6 M
showed suppressive action on T3
enhancement of tadpole tail shortening.
One-generation reproduction study in
Wistar rats fed TBBPA at doses of 0, 3,
10, 30, 100, 300, 1,000 and 3,000 mg/kg-
day. Decreased circulating thyroxine (T4)
and increased circulating T3 levels in
males.
BMDL: 31 (male) and 16 (female) mg/kg-
day
Kitamura et al., 2005a
Van der Yen etal., 2008
Sufficient study details reported in a
primary source.
Sufficient study details summarized
in a primary source.
4-71
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
There were no adverse effects on tail
resorption in tadpoles microinjected with
TBBPA at doses up to 60 (ig at
developmental stage 58 (hind limbs
emerged; forelimbs formed, but not
emerged).
HSDB, 2013
Sufficient study details summarized
in a secondary source.
TBBPA inhibited the binding of
triiodothyronine (T3; IxlO"10 M) to
thyroid hormone receptor in the
concentration range of IxlO"6 M to IxlO"4
M. The thyroid hormonal activity of
TBBPA was also examined using rat
pituitary cell line GH3 cells. TBBPA
enhanced the proliferation of GH3 cells
and stimulated their production of growth
hormone (GH) in the concentration range
of IxlO'6 M to IxlO'4 M. TBBPA did not
show antagonistic action (did not inhibit
the hormonal activity of T3 to induce
growth and GH production of GH3 cells).
TBBPA enhanced the proliferation of
MtT/E-2 cells (growth is estrogen-
dependent).
Kitamura et al., 2002
Sufficient study details in a primary
source.
TBBPA gave a positive response in an in
vivo uterotrophic assay using
ovariectomized mice but was inactive for
effects on the androgenic activity of
Salpha-dihydrotestosterone in mouse
fibroblast cell line NIH3T3. TBBPA
exhibited significant thyroid hormonal
activity towards rat pituitary cell line
GH3, which releases growth hormone in a
thyroid hormone-dependent manner.
Kitamura et al., 2005b
Sufficient study details in a primary
source.
In a uterotrophic assay with adult female
ovariectomized mice, TBBPA was
administered by oral gavage and
Ohtaetal., 2012 cited in
Environment Canada, 2013
Sufficient study details in a
secondary source.
4-72
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
subcutaneous injection daily for 7 days.
TBBPA was negative for agonistic and
antagonistic estrogenic responses by both
routes of exposure at concentrations up to
1,000 mg/kg-day.
Positive for thyroid hormone agonist
activity in a yeast two-hybrid assay
incorporating human thyroid hormone
with and without metabolic activation.
Metabolic activation by rat liver S9
significantly increased the
agonist/antagonist potential.
HSDB, 2013
Sufficient study details summarized
in a secondary source.
Negative for estrogenic activity in yeast
two-hybrid assay. REC10(M) >lxlO"5
compared to 3xlO"10 for E2.
Nishiharaetal., 2000
Sufficient study details reported in a
primary source.
In vitro competition binding assays of T4
to TTR using human plasma samples; the
competing potency of TBBPA was 5
times greater than T4.
Bergman et al., 1997
Sufficient study details reported in a
primary source.
The human adrenocortical carcinoma cell
line (H295R cell line) was used to assess
possible effects of TBBPA on the activity
of adreno cortical enzyme CYP17. A
maximum of 2-fold induction of CYP17
activity occurred after 24 hours of
incubation. TBBPA was a potent inducer
of CYP17 activity, causing 50% induction
at the lowest concentration tested
(O.OljiM).
Canton et al., 2004
Sufficient study details reported in a
primary source.
In a 14-day oral study, male mice (7-
8/group) were dosed by gavage with 0,
350, 700 or 1,400 mg/kg-day TBBPA
(99.1% pure) in olive oil. No clinical
signs or mortality. In treated mice the
liver appeared swollen and the pancreas
Tada et al., 2007
Sufficient details in primary source.
4-73
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
looked slightly enlarged and edematous.
NOAEL: Not established
LOAEL: 350 mg/kg-day (lowest dose
tested)
Negative, thyroid hormone receptor (TR)-
binding activity of TBBPA using a yeast
two-hybrid assay; REC10(M) >3.0xlO'4
compared to 2. IxlO"8 for T3.
Kitagawa et al., 2003
Sufficient study details reported in a
primary source.
Hormonal effects of TBBPA were
investigated in vitro on recombinant
yeasts and in vivo on mosquitofish
(Gambusia affinis). TBBPA had a weak
androgenic activity with recombinant
yeast systems carrying human androgen
receptor (hAR). Following 60-days of
exposure in mosquitofish, significant up-
regulation of vitellogenin (Vtg), and
estrogen receptor (ER-alpha and ER-beta)
mRNAs was observed in the liver (500
nM of TBBPA). The lowest concentration
(50 nM) markedly induced Vtg, ER-beta
and AR-beta mRNA expression in the
testes and significantly inhibited AR-
alpha expression. TBBPA did not produce
histopathological alterations in the liver or
testis.
Huang etal., 2013
Sufficient study details reported in a
primary source.
TBBPA did not have anti-androgenic
activity in a recombinant cell-based in
vitro bioassay using the Chinese hamster
ovarian cell line (CHO Kl).
Roy et al., 2004
Sufficient study details reported in a
primary source.
In a transcriptional activation assay,
TBBPA suppressed the thyroid
replacement element (TRE) mediated
transcriptional activity of T3 on the
human HeLaTRDR4-luc cell line.
4-74
Sakai et al., 2003
Sufficient study details reported in a
primary source.
-------
Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
ER-, DR-CALUX® and T4-TTR
competitive binding assays; TBBPA did
not show estrogenic/antiestrogenic or
dioxin-like/anti-dioxin activity. TBBPA
was more potent than to thyroxine (T4) in
binding to transport protein transthyretin
(TTR).
Legler et al, 2002
Sufficient study details reported in a
primary source.
Vitellogenin induction in immature
rainbow trout after intraperitoneal
injection of TBBPA was studied.
Exposure to TBBPA did not induce
vitellogenin synthesis.
Christiansen et al., 2000
Sufficient study details reported in a
primary source.
The estrogen-dependent human breast
cancer cell line MCF-7 was used to
characterize estrogen-like profiles of high
volume chemicals.
The EC50 for the displacement of
radiolabeled 17 (3-estradiol from the
estrogen receptor = 2.5 (+/- 1.29) x 10"5;
Relative binding affinity (RBA) = 0.013.
Olsen et al., 2003
Sufficient study details reported in a
primary source.
Tadpoles were exposed to TBBPA at
concentrations ranging from 2.5 to 500
(ig/L for 21 days. Larval development was
inhibited only at the highest concentration
level. The TH receptor beta-mRNA was
not affected. Conversely, short-term
exposures to TBBPA slightly increased
the expression of TH receptor beta- and
basic region leucin zipper transcription
factor b/Zip-mRNA but inhibited their
T3-induced elevation in a dose-dependent
manner indicating that TBBPA can
function as a TH antagonist.
Jagnytsch et al., 2006
Sufficient study details reported in a
primary source.
Short (24 h) exposures of TBBPA
modulated the expression of a number of
TH target genes implicated in neural stem
4-75
Finietal., 2012
Sufficient study details reported in a
primary source.
-------
Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
cell function and neural differentiation.
TBBPA also reduced cell proliferation in
the brain ofXenopus laevis (African
clawed frog).
Thyroid hormone (TH) disrupting activity
of TBBPA was investigated in the rat
pituitary cell line GH3. The effect of a
strong antiestrogen, ICI (10~9 M), was also
analyzed on E2 and TBBPA.
TBBPA stimulated GH3 cell growth but
could not counteract the inhibiting growth
effect of 10"9 M ICI at the tested
concentrations. These data indicate that
the effect of TBBPA is TH-like and ER-
mediated.
Ghisari and Bonefeld-Jorgensen,
2005
Sufficient study details reported in a
primary source.
In vitro bioassay with phenobarbital-
induced rat liver microsomes. TBBPA and
TBBPA-DBPE significantly increased
TTR-binding potencies and E2SULT-
inhibiting potencies after
biotransformation. TBBPA-DBPE
became a more potent AR-antagonist after
biotransformation. TBBPA and TBBPA-
DBPE enhanced GH3 cell proliferation in
the T-Screen test.
Hamers et al., 2008
Sufficient study details reported in a
primary source.
TBBPA binded to crystal structures of the
hormone-metabolizing enzyme, estrogen
sulfotransferase (SULT1E1), and has the
potential to cause endocrine disruption.
Gosavi et al., 2013
Sufficient study details reported in a
primary source.
4-76
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Immunotoxicity
The data located had limited experimental details. TBBPA inhibits expression of CD25, which is essential
for proliferation of activated T lymphocyte cells, at concentrations > 3 uM. In a disease challenge study,
TBBPA administered to mice (1% in diet for 28 days; approximately 1,800 mg/kg-day) produced irregular
changes in cytokine production and immune cell populations, which were suggested to cause exacerbation
of pneumonia in respiratory syncytial virus-infected mice. Determination of significance of the response to
RSV infection is limited by the study design having only one, particularly high, dose of TBBPA. In an in
vitro study, TBBPA decreased the level of cell surface proteins, possibly interfering with NK cell function.
Immune System Effects
TBBPA is immunotoxic in culture;
inhibits expression of CD25 at
concentrations at > 3 (JVI; CD25 is
essential for proliferation of activated T
cells and is commonly used as a marker
for T-cell activation.
In a 90-day oral study in mice, there were
no adverse effects at doses up to 700
mg/kg-day; however, 2,200 mg/kg-day
produced increased spleen weight and
reduced concentrations of red blood cells,
serum proteins and serum triglycerides.
NOAEL: 700 mg/kg-bw
LOAEL: 2,200 mg/kg-bw
In vitro study in natural killer (NK) cells;
TBBPA (5 (iM) decreased the level of cell
surface proteins, possibly interfering with
NK cell function.
TBBPA administered to mice as 1% in
diet for 28 days. Irregular changes in
cytokine production and immune cell
populations were suggested to cause
exacerbation of pneumonia in respiratory
syncytial virus-infected mice.
Birnbaum and Staskal, 2004
Tobeetal., 1986; WHO, 1995;
Simonsen et al., 2000; Darnerud,
2003
Hurd and Whalen, 2011 (as cited
inNTP, 2013)
Watanabe et al., 2010 (as cited
inNTP, 2013)
Limited information in a secondary
source.
Limited details in secondary
sources.
Sufficient study details reported in
NTP technical report.
Sufficient study details reported in
NTP technical report.
4-77
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
ECOTOXICITY
ECOSAR Class
Acute Aquatic Toxicity
Fish LC50
Phenols, Poly
VERY HIGH: Based on measured LC50 values <1 mg/L in fish, daphnia and algae.
Freshwater fish (Salmo gairdneri) 96-hour
LC50 = 0.40 mg/L
(Experimental)
Freshwater fish (Lepomis macrochirus)
96-hour LC50 = 0.51 mg/L
(Experimental)
Freshwater fish (Pimephales promelas)
96-hour LC50 = 0.54 mg/L:
144-hour LC50 = 0.49 mg/L;
144-hour NOEC = 0.26 mg/L;
Flow-through test conditions; test
concentrations: 0.63, 0.45, 0.32, 0.26, and
0.19 mg active substance/L
(Experimental)
Freshwater fish (Cyprinus carpio) 96-hour
LC50 = 0.71 mg/L
48-hour LC50 = 0.80 mg/L
Static conditions; test concentrations:
0.42, 0.65, and 1.0 mg/L (nominal)
(Experimental)
Freshwater fish (Pimephales promelas}
96-hour LC50 = 710 (ig/L (0.71 mg/L)
(Experimental)
Freshwater fish (Pimephales promelas)
96-hour LC50 = 1,040 (ig/L (1.04 mg/L)
(Experimental)
Freshwater fish (Oncorhynchus mykiss)
96-hour LC50 = 1.1 mg/L
96-hour NOEC < 1.1 mg/L;
flow-through conditions; test
concentrations: 1.1 and 1.7 mg/L
Calmbacher, 1978 (as cited in
Simonsen et al., 2000)
EC, 2000
Suprenant, 1988 (as cited in EC,
2000; ECHA, 2013)
ECHA, 2013
ECOTOX, 2012
ECOTOX, 2012
Blankenship et al., 2003a;
ECHA, 2013
Insufficient information in primary
source.
Insufficient information in
secondary source.
Sufficient study details in primary
source.
Sufficient study details in a
secondary source; GLP study
following standard guidelines;
however, no analytical verification
of test compound concentrations.
Sufficient study summary reported
in a secondary source.
Sufficient study summary reported
in a secondary source.
Sufficient information in primary
source.
4-78
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
(measured); 1.2 and 1.8 mg/L (nominal)
(Experimental)
Freshwater fish (Danio rerio) 96-hour
EC50 = 1.1 mg/L
(Danio rerio) larvae 96-hour LC50 = 5.27
mg/L
(Experimental)
Freshwater fish (Danio rerio) LCioo = 1.5
mg/L
Exposure concentrations were 0, 0.002,
0.01, 0.05, 0.25, 0.75, and 1.5 mg/L;
nearly 100% of animals survived at
concentrations <1.5 mg/L, but some
embryos were malformed at 0.75 mg/L
(Experimental)
Freshwater fish (Lepomis macrochirus)
96-hour NOEC = 0.1 mg/L
(Experimental)
Freshwater fish (Salmo gairdneri} 96-hour
NOEC = 0.18mg/L
(Experimental)
Freshwater fish (Danio rerio) 96-hour
LC50 = 1.5 jig/L (0.0015 mg/L)
(Experimental)
Freshwater fish (Pimephales promelas}
96-hour LC50 = 60 (ig/L (0.06 mg/L)
(Experimental)
Freshwater fish (Pimephales promelas)
96-hour NOEC = 0.26 mg/L
(Experimental)
Freshwater fish (Oryzias latipes) 48-hour
LC50 = 8.2 mg/L
(Experimental)
Freshwater fish 96-hour LC50= 0.89 mg/L
REFERENCE
Chow etal., 2013
Hu et al., 2009
Simonsen et al., 2000
Simonsen et al., 2000
ECOTOX, 2012
ECOTOX, 2012
Simonsen et al., 2000
MITI, 1992 (as cited in EC,
2000)
ECOSARvl.ll
DATA QUALITY
Insufficient study details reported in
a primary source. EC50 is based on
hatching of zebrafish embryos.
Inconsistent with most other LC50
values reported for this compound.
Sufficient information in primary
source.
No study details in secondary
source.
No study details in secondary
source.
Insufficient study summary reported
in a secondary source.
Insufficient study summary reported
in a secondary source.
No study details in secondary
source.
No study details in secondary
source.
4-79
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
Daphnid LC50
DATA
(Estimated)
ECOSAR: Phenols, Poly
Freshwater fish 96-hour LC50 = 2.3 mg/L
(Estimated)
ECOSAR: Neutral organics
Daphnia magna 48-hour EC50 = 0.60
mg/L
(Experimental)
Daphnia magna 48-hour LC50 = 0.96
mg/L; NOEC <0.32 mg/L
(Experimental)
Daphnia magna 48-hour LC50 >0.9 - <1.2
jig/L (>0.0009 - <0.0012 mg/L)
(Experimental)
Daphnia magna 24 and 4 8 -hour LC50
>1.8mg/L
48-hour NOEC =1.8 mg/L
flow-through test conditions
Test concentrations: 1.2 and 1.8 mg a.i./L
(nominal); average measured
concentration: 1.2 and 1.8 mg a.i./L
(Experimental)
Daphnia magna 48-hour LC50 = 7,900
Hg/L (7.9 mg/L)
(Experimental)
Daphnia magna 4 8 -hour LC50= 2.6 mg/L
(Estimated)
ECOSAR: Phenols, Poly
Daphnia magna 4 8 -hour LC50 = 1.7 mg/L
REFERENCE
ECOSAR v 1.11
Waaijers et al., 2013
Morrissey et al., 1978; Simonsen
et al., 2000; EC, 2000;
Anonymous, 2003
ECOTOX, 2012
Blankenship et al., 2003b;
ECHA, 2013
ECOTOX, 2012
ECOSAR v 1.11
ECOSAR v 1.11
DATA QUALITY
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.
Sufficient study details reported in a
primary source.
Sufficient information in primary
source.
Sufficient details reported in a
secondary source.
Sufficient information in primary
source. GLP study, following
standard guidelines, with analytical
verification of test compound
concentrations.
Sufficient details reported in a
secondary source.
Narcosis classes (neutral organics)
4-80
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
(Estimated)
ECOSAR: 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.
Other Invertebrate LC50
Saltwater Mysid shrimp 96-hour LC50 =
0.86-1.2 mg/L (in 1, 5 or 10 day old
shrimp, respectively)
(Experimental)
Goodman et al., 1988 (as cited
in EC, 2000)
Sufficient information in primary
source.
Green Algae EC s
Green Algae (Skeletonema costatum ) 72-
hour EC50 = 0.09 - 0.89 mg/L
(Experimental)
Walsh etal., 1987; EC, 2000;
Simonsen et al., 2000; ACC,
2006b
Limited details in secondary
sources.
Green Algae (Skeletonema costatum ) 72-
hour EC50 = 0.09 - 1.14 mg/L
(Experimental)
Walsh et al., 1987; ACC, 2006b
Sufficient details in primary source.
Green Algae (Thalassiosira pseudonana )
72-hour EC50 = 0.13-1.0 mg/L
(Experimental)
Walsh et al., 1987 (as cited in
ACC, 2006b)
Sufficient details in primary source.
Green algae 96-hour EC50 = 1.6 mg/L
(Estimated)
ECOSAR: Phenols, poly
ECOSAR v 1.11
Green algae 96-hour EC50 = 3.3 mg/L
(Estimated)
ECOSAR: Neutral organics
ECOSAR v 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.
4-81
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Chronic Aquatic Toxicity
HIGH: Based on experimental LOECs and/or NOECs <1.0 mg/L in fish and daphnia.
Fish ChV
Freshwater fish (Pimephales promelas) 35
dayNOEC = 0.16mg/L;
LOEC = 0.31 mg/L;
MATC = 0.22 mg/L
Flow-through test conditions
Test concentrations: 0.025, 0.05, 0.1, 0.2,
and 0.4 mg a.i./L (nominal); 0.024, 0.04,
0.084, 0.16, and 0.31 mg a.i./L.
(measured)
(Experimental)
Surprenant, 1989; EC, 2000;
ACC, 2006b;ECHA, 2013;
Weltjeetal.,2013
Freshwater fish (Platichthys flesus) 105
day NOEC >0.8 \M (435 ng/mL or
0.000435 mg/L)
Test concentrations: 0; 0.001; 0.01; 0.1;
0.2; 0.4 and 0.8 jiM (0, 0.54, 5.4, 54.4,
109, 218, 435 ng/mL)
No adverse effect on behavior, survival,
growth rate, relative liver and gonad
weight. Increased levels of thyroid
hormone thyroxin (T4) with no signs of
altered thyroid gland activity.
(Experimental)
Zebra fish (Danio rerio) 2 8-day LCioo
(embryonic exposure) = 0.8 mg/L
Edema and hemorrhage, decreased heart
rate, edema of the trunk, tail malformation
Test concentrations: 0.27, 0.4, 0.54, 0.8,
1.6 mg/L
(Experimental)
Freshwater fish (Danio rerio) 30-day
partial life cycle test; LC^o = 1.5 (iM
(0.816 mg/L)
Exposure to 0, 0.023, 0.094, 0.375 and 1.5
. Reduced egg production (all
Kuiper et al., 2007a
McCormicketal., 2010
Kuiper etal., 2007b
Sufficient information in secondary
sources.
Sufficient details in primary source.
Sufficient details in primary source.
Sufficient study details reported in a
primary source.
4-82
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
exposure groups) and hatching ratios (all
groups other than 0.375 (iM). All larvae
died in the high dose group (1.5 (iM) and
mortality was preceded by retardation of
development.
(Experimental)
Freshwater fish ChV = 0.33 mg/L
(Estimated)
ECOSAR: Phenols, poly
ECOSARvl.ll
Freshwater fish ChV = 0.30 mg/L
(Estimated)
ECOSAR: Neutral organics
ECOSARvl.ll
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
Daphnia magnet 21 day EC50 >0.96 mg/L
21-day NOEC = 0.38 mg/L
21-day MATC >0.3 <0.98 mg/L
Flow-through test conditions.
Test concentrations: 0.13, 0.25, 0.5, 1.0,
2.0 mg/L (nominal); 0.037 - 0.078, 0.068 •
0.13, 0.14 - 0.26, 0.19 - 0.29, 0.65 - 1.3
mg/L (measured)
(Experimental)
ECHA, 2013
Sufficient study details in a
secondary source. GLP study with
analytical verification of test
compound concentrations;
methodology employed is well
described and designed specifically
to meet US EPA requirements.
Daphnia magna 21 day EC50 >0.98 mg/L
MATC = 0.54 mg/L
Flow-through test conditions.
Test concentrations: 0, 0.13, 0.25, 0.5, 1.0
and 2.0 (nominal)
(Experimental)
Suprenant, 1989 (as cited in EC,
2000; ACC, 2006b)
Sufficient study details
Daphnia magna ChV = 0.82 mg/L
(Estimated)
ECOSAR: Phenols, poly
ECOSARvl.ll
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
Green Algae ChV
DATA
Daphnia magna ChV = 0.31 mg/L
(Estimated)
ECOSAR: Neutral organics
Green algae ChV: 0.31 mg/L
(Estimated)
ECOSAR: Phenols, poly
Green algae ChV = 5.6 mg/L
(Experimental)
Green algae ChV =1.5 mg/L
(Estimated)
ECOSAR: Neutral organics
Green Algae (Pseudokirchneriella
subcapitatd) 96-hour EC50 >5.6 mg/L
96-hour NOEC = 5.6 mg/L;
Static test conditions; Test concentrations:
0.60, 1.2, 2.4, 4.8, and 9.6 mg/L
(nominal); Mean measured concentration:
0.34, 0.76, 1.5, 3.0, and 5.6 mg/L.
(Experimental)
REFERENCE
ECOSAR v 1.11
ECOSAR v 1.11
Giddings, 1988
ECOSAR v 1.11
Giddings, 1988; Anonymous,
2003; ACC, 2006b; ECHA,
2013
DATA QUALITY
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.
The effect level is greater than the
water solubility of 4. 16 mg/L; no
effects at saturation (NES) are
predicted.
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.
Sufficient study details in secondary
sources. The effect levels are greater
than the water solubility of 4. 16
mg/L; no effects at saturation (NES)
are predicted.
ENVIRONMENTAL FATE
4-84
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Transport
Level III fugacity models incorporating available physical and chemical property data indicate that at
steady state, TBBPA is expected to be found primarily in soil and to a lesser extent, sediment. TBBPA is
expected to have low mobility in soil based on its calculated Koc. Therefore, leaching of TBBPA through
soil to groundwater is not expected to be an important transport mechanism. Estimated volatilization half-
lives for a model river and lake indicate that it will have low potential to volatilize from surface water. In
the atmosphere, TBBPA is expected to exist primarily in the particulate phase. Particulate phase TBBPA
will be removed from air by wet or dry deposition.
Henry's Law Constant (atm-
m3/mole)
1.47xl(Tu at 298K (Measured)
<1(T (Estimated)
Sediment/Soil
Adsorption/Desorption - Koc
l.lxlO5 at 6.8% organic carbon;
2.0xl05at 2.7% organic carbon;
2.3xl06 at 0.25% organic carbon
(Measured)
TBBPA is shown to adsorb to soil based
on laboratory soil mobility tests. TBBPA
was not eluted from the soil column after
11 pore volumes were displaced. No
quantitative values for the rate of soil
migration were measured. (Measured)
>3 0,000 (Estimated)
Level III Fugacity Model
Air = 0%
Water =1.4%
Soil = 64%
Sediment = 35% (Estimated)
Kuramochi et al., 2008
EPIv4.11;EPA, 2012
Breteler et al., 1989
Larsen et al., 2001 (as cited in
ACC, 2006a; ACC, 2006b)
Nonguideline study reported in a
secondary sources.
EPIv4.11;EPA, 2004
EPIv4.11
Based on the measured enthalpy of
fusion and melting point used to
calculate the sub-cooled liquid
vapor pressure and infinite dilution
activity coefficient.
Cutoff value for nonvolatile
compounds.
The Koc values were calculated
from the reported Kd values and the
percent organic carbon for each
sediment sample.
Estimated value is greater than
>3 0,000 using the Kow method from
KOCWIN v2.00; the high estimated
soil adsorption coefficient is
consistent with nonmobile
compounds.
EPI v 4.11 was used to estimate
environmental fate values in the
absence of experimental data.
Measured values (log Kow) from
experimental studies, were
4-85
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
incorporated into the estimations.
Persistence
HIGH: Experimental aerobic and anaerobic biodegradation studies in soil and sediment indicate that the
aerobic primary biodegradation half-life is less than 180 days, but not less than 60 days. Mineralization
under both aerobic and anaerobic conditions in soil and sediment is low, indicating that persistent
degradation products are formed. An experimental photolysis half-life of 24 minutes at pH 7.4 in water
indicates that TBBPA may photolyze rapidly to 4-isopropyl-2,6-dibromophenol, 4-isopropylene-2,6-
dibromophenol and 4-(2-hydroxyisopropyl)-2,6-dibromophenol; however, it is not anticipated to partition
significantly to water. Although adequate experimental data are not available, degradation of TBBPA by
hydrolysis is not expected to be significant as the functional groups present on this molecule do not tend to
undergo hydrolysis. The atmospheric half-life for the gas phase reactions of TBBPA is estimated at 3.6
days, though it is expected to exist primarily as a particulate in air.
Water
Aerobic Biodegradation
Passes Ready Test: No
Test method: OECD TG 301C: Modified
MITI Test (I)
No biodegradation was observed
according to a Japanese MITI test using
TBBPA (100 mg/L) in activated sludge
(30 mg/L) for 2 weeks. (Measured)
Volatilization Half-life for
Model River
>1 year (Estimated)
Volatilization Half-life for
Model Lake
>1 year (Estimated)
MITI, 1992; ACC, 2006a; ACC,
2006b; CERIJ, 2007
EPIv4.11
EPIv4.11
Guideline study reported in a
secondary source.
EPI v 4.11 was used to estimate
environmental fate values in the
absence of experimental data.
Measured values (log Kow) from
experimental studies, were
incorporated into the estimations.
EPI v 4.11 was used to estimate
environmental fate values in the
absence of experimental data.
Measured values (log Kow) from
experimental studies, were
incorporated into the estimations.
4-86
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Soil
Aerobic Biodegradation
Study results: 50%/65-93 days
Test method: Other
Half-life values reported for two aerobic
series using activated or digested sludge.
An aerobic soil half-life of 65 days was
calculated for TBBPA in the experiment
with activated sludge and 93 days in the
experiment with digested sludge.
(Measured)
Nyholmetal.,2010
Adequate guideline study.
Aerobic biodegradation of TBBPA was
measured in three soil types. After 64
days, the amount of TBBPA in the soil
ranged from 43.7 to 90.6%. 0.5 to 2.5% of
the applied radioactivity was recovered as
CO2, suggesting only partial
biodegradation. (Measured)
Fackler et al., 1989b (as cited in
ACC, 2006a)
Nonguideline study reported in a
secondary source.
Study results: 17.5%/6 months
Test method: Other
A transformation study in soil calculated
an aerobic DT50 of 5.3-7.7 days for the
soil extracts. The disappearance appears
to be predominantly due to binding to soil
and not due to biodegradation. Insufficient
material was extracted to identify the
transformation products. After 6 months,
17.5-21.6% of the dose was mineralized
in the aerobic soils. (Measured)
Schaefer and Stenzel, 2006c (as
cited in Environment Canada,
2013)
DT50 values were calculated for the
soil extracts; however, the majority
of the material remained bound to
soil and was not extracted. The non-
extractable (bound) radioactivity or
residues in the soil were not
characterized as called for in the
OECD guidelines. The abiotic
degradation rate under sterile
conditions was not estimated as
called for in the OECD guidelines.
Anaerobic Biodegradation
12-18% complete mineralization of
TBBPA in different soil types observed
after 4 months and 3-9% complete
mineralization observed after six months
in two separate series of anaerobic
biodegradation experiments.
Schaefer and Stenzel, 2006c (as
cited in Environment Canada,
2013)
Nonguideline studies reported in a
secondary source. Full anaerobic
conditions were not used throughout
the duration of the study in soil.
Study results: 50%/430 days
Test method: Other
Using a testing method similar to OECD
4-87
Nyholmetal.,2010
Adequate guideline study.
-------
Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
Soil Biodegradation with
Product Identification
Sediment/Water
Biodegradation
DATA
Test Guideline 307. (Measured)
Study results: >43.7%/64 days
Test method: CO2 Evolution
Anaerobic biodegradation of TBBPA was
measured in three soil types. After 64
days, the amount of TBBPA remaining in
the soils ranged from 43.7 to 90.6%. Less
than 0.5% applied radioactivity was
recovered as CO2, suggesting only partial
biodegradation. (Measured)
Study results: 100%/45 days
Test method: Other
Under anaerobic conditions the results
initially reported TBBPA was mostly
dehalogenated within 10 days, and
complete dehalogenation to BPA was
achieved after 45 days. The resulting BPA
was not degraded anaerobically after 3
months. Di- and tribromobisphenol A
were observed as intermediates. Under
aerobic conditions, BPA was degraded to
4-hydroxybenzoic acid and 4-
hydroxyacetophenone. (Measured)
50%/84 days
Half-lives of 48 to 84 days were
determined in anaerobic natural river
sediment/water test system using 14C-
TBBPA. Less than 8% applied
radioactivity was recovered as CO2,
suggesting only partial biodegradation.
(Measured)
TBBPA was reductively dehalogenated to
BPA with tribromobisphenol A and
REFERENCE
Fackler et al., 1989b
Ronen and Abeliovich, 2000 (as
cited in ACC, 2006a; ACC,
2006b)
Fackler et al., 1989a (as cited in
ACC, 2006a; ACC, 2006b)
Ravit et al., 2005 (as cited in
Environment Canada, 2013)
DATA QUALITY
Adequate guideline study.
Nonguideline study reported in a
secondary report.
No data located.
Adequate guideline study reported
in a secondary source.
Adequate, nonguideline study.
4-88
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
dibromobisphenol A formed as
intermediates in sediment samples
through two species of salt marsh
macrophyte. (Measured)
An anaerobic mineralization and
transformation study in freshwater aquatic
sediment systems calculated an anaerobic
DT50 of 24-28 days for the whole system.
Very little mineralization was observed.
The transformation products included
BPA and 3 (Measured)
Schaefer and Stenzel, 2006a;
ACC, 2006b
Adequate nonguideline study.
An anaerobic mineralization and
transformation study in digester sludge
calculated an anaerobic DT50 of 19 days.
Very little mineralization was observed.
The transformation products included
BPA and 3 unidentified materials.
(Measured)
Schaefer and Stenzel, 2006b
Adequate nonguideline study.
Estuarine sediment; under methanogenic
conditions half-life was estimated to be
about 28 days. Under sulfate-reducing
conditions half-life was estimated to be 40
days. (Measured)
Voordeckers et al., 2002 (as
cited in ACC, 2006b)
Nonguideline study reported in a
secondary source.
Air
Atmospheric Half-life
3.6 days assuming 12-hr day/sunlight
(Estimated)
EPIv4.11
EPI v 4.11 was used to estimate
environmental fate values in the
absence of experimental data.
Measured values (log Kow) from
experimental studies, were
incorporated into the estimations.
Reactivity
Photolysis
50%/24 minutes
Photolysis half-lives in water of 16, 24,
and 350 minutes at pH values 10, 7.4, and
5.5, respectively, were measured under
fluorescent UV radiation representing
environmental wavelengths. Major
Eriksson et al., 2004 (as cited in
ACC, 2006a; ACC, 2006b; NTP.
2013)
Adequate nonguideline study.
4-89
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Hydrolysis
degradation products were 4-isopropyl-
2,6-dibromophenol, 4-isopropylene-2,6-
dibromophenol and 4-(2-
hydroxyisopropyl)-2,6-dibromophenol.
Other products include di- and
tribromobisphenol A, dibromophenol, 2,6-
dibromo-4-(bromoisopropylene)phenol,
2,6-dibromo-4-
(dibromoisopropylene)phenol and 2,6-
dibromo-1,4-hydroxybenzene. (Measured)
50%/33 hour
Photolysis of TBBPA in the presence of
UV light and hydroxyl radicals has also
been reported; TBBPA was no longer
detected after 5-6 days with an estimated
33 hour half-life. TBBPA decomposition
produced 2,4,6-tribromophenol and other
bromine containing compounds that were
not fully identified. (Estimated)
Eriksson and Jakobsson, 1998
(as cited in ACC, 2006a; ACC,
2006b)
Reported in a secondary source.
A study of TBBPA on silica gel was
reported. The wavelength studied was too
short to derive any environmental
conclusions. (Measured)
WHO, 1995 (as cited in ACC,
2006a)
Study details and test conditions
were not available. Reported in a
secondary source.
Reported half-lives in water of 6.6, 10.2,
25.9, and 80.7 days during summer,
spring, fall and winter, respectively.
(Measured)
WHO, 1995 (as cited in ACC,
2006a;NTP, 2013)
Study details and test conditions
were not available. Reported in a
secondary source.
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.
Environmental Half-life
360 days (Estimated)
PBT Profiler vl.301: EPIv4.11
Half-life estimated for the
predominant compartment (soil), as
determined by EPI methodology.
Measured values from experimental
4-90
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
studies, were incorporated into the
estimations.
Bioaccumulation
MODERATE: The measured fish BCF and estimated BAF values are greater than 100 but less than 1,000.
Fish BCF
485 Cyprinus carpio
BCF ranges of 30 to 341 and 52 to 485
were measured in carp during an 8-week
study at concentrations of 80 (ig/L and 8
(ig/L, respectively. (Measured)
300 Pimephales promelas
A BCF of 1,200 was measured based on
total 14C radioactivity; however,
extraction and thin layer chromatograph
of the residue in the body of the fish
determined that only 24.9% of the 14C
radioactivity was due to TBBPA, with the
remainder due to metabolites, giving a
BCF of 300 for TBBPA. Elimination half-
life <24 hours for total 14C radioactivity.
(Measured)
170 Lepomis macrochirus
Bluegill sunfish were exposed to 14C-
TBBPA for 28 days to 0.0098 mg/L
(flow-through) followed by a 14-day
withdrawal period. The bioconcentration
factor (BCF) in edible tissue was 20 and
170 in visceral tissue. These BCF values
were based on 14C-residues and therefore
represent the sum total of parent
compound, any retained metabolites and
assimilated carbon. (Measured)
1,200 in Fathead minnows (Pimephales
promelas}
Reported for the BCF wet weight; BCF
value for lipid weight = 24,000; 24 days
MITI, 1992 (as cited in HSDB,
2013)
Dionne et al., 1989; ACC, 2006b
ACC, 2006b
Geyeretal., 2000
Adequate guideline study reported
in secondary source.
Adequate nonguideline study
reported in secondary source.
Adequate nonguideline study
reported in secondary source.
The BCF value includes all the
metabolites of the test substance, as
well as the test substance, 14C-
labeled chemical was used.
4-91
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
Other BCF
BAF
Metabolism in Fish
DATA
uptake (Measured)
960 in Zebrafish; reported as BCF wet
weight
BCF value for lipid weight = 28,300;
kinetic approach in outdoor experiment at
pH7.5. (Measured)
<3,190 in Chironomus tentans
BCF values of 243-51 1 (6.8% organic
carbon sediment); 487-1,140 (2.7%
organic carbon sediment) and 646-3,190
(0.25% organic carbon sediment).
(Measured)
148 in Eastern oyster (Measured)
130 (Estimated)
REFERENCE
Geyeretal., 2000
ACC, 2006b
ACC, 2006b
EPIv4.11
DATA QUALITY
Adequate nonguideline study
reported in secondary source.
Reported in a secondary source.
This is nonguideline study using a
non-standard test species and is not
able to be evaluated with the
assessment criteria.
Adequate nonguideline study
reported in secondary source with
limited study details.
EPI v 4. 1 1 was used to estimate
environmental fate values in the
absence of experimental data.
Measured values (log Kow of 4.54)
from experimental studies, were
incorporated into the estimations.
No data located.
4-92
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Tetrabromobisphenol A CASRN 79-94-7
PROPERTY/ENDPOINT
DATA
ENVIRONMENTAL MONITORING AND
Environmental Monitoring
Ecological Biomonitoring
Human Biomonitoring
REFERENCE DATA QUALITY
BIOMONITORING
TBBPA has been detected in the air of electronic recycling plants, although its presence in the air of this facility
likely arises from products where it was used as an additive flame retardant. Studies on the release of TBBPA
from PCBs after disposal in landfills were not available but would likely be low due to the low levels of
unreacted TBBPA. TBBPA was reported in air and marine sediment samples collected from several locations in
the Arctic. TBBPA was reported in indoor dust and air, soil, and food in Europe and the United States. It has
been reported in surface water in Japan, Germany, France, and the United Kingdom (Sellstrom and Jansson,
1995; Sjodin et al., 2001; Sjodin et al., 2003; PBS Corporation, 2006; Environment Canada, 2013).
TBBPA was reported in eel, salmon, perch, pike, cod, whiting, starfish, whelk, hermit crab, bottlenose dolphin,
bull shark, sharpnose shark, cormorant, harbour porpoise blubber, predatory birds, tern eggs and moss samples
from Norway. (Environment Canada, 2013)
TBBPA was detected in human umbilical cord, blood/serum, adipose, milk and hair samples (DeCarlo, 1979;
Thomsen et al., 2002; Peters, 2005; NTP, 2013).
4-93
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ACC (2002) An oral two generation reproductive, fertility, and developmental neurobehavioral study of tetrabromobisphenol A in rats. American
Chemistry Council. Submitted to the U.S. Environmental Protection Agency under TSCA Section 8E.
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revision/updates, revised test plan. Robust summaries & test plans: Phenol, 4,4'-isopropylidenebis[2,6-dibromo-. American Chemistry Council
(ACC) Brominated Flame Retardant Industry Panel (BFRIP). Submitted under the HPV Challenge Program.
http://www.epa.gov/chemrtk/pubs/summaries/phenolis/cl3460rt3.pdf
ACC (2006b) Test plan revision/updates, revised summaries. Robust summaries & test plans: Phenol, 4,4'-isopropylidenebis[2,6-dibromo-.
American Chemistry Council Brominated Flame Retardant Industry Panel (BFRIP). Submitted under the HPV Challenge Program.
http://www.epa.gov/chemrtk/pubs/summaries/phenolis/cl3460rr3.pdf.
Anonymous (2003) Tetrabromobisphenol A. Beratergremium fuer umweltrelevante Altstoffe 239:122.
Antignac JP, Cariou R, Maume D, et al. (2008) Exposure assessment of fetus and newborn to brominated flame retardants in France: preliminary
data. Mol Nutr Food Res 52(2):258-265.
Arbeli Z and Ronen Z (2003) Enrichment of a microbial culture capable of reductive debromination of the flame retardant tetrabromobisphenol A,
and identification of the intermediate metabolites produced in the process. Biodegradation 14(6):385-395.
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BRE (2009) Brominated flame retardants - Risks to UK drinking water sources. UK Department for Environment, Food, and Rural Affairs
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Bergman A, Brouwer A, Ghosh M, et al. (1997) Risk of endocrine contaminants (RENCO). Aims and a summary of initial results. Organohalogen
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Birnbaum LS and Staskal DF (2004) Brominated flame retardants: Cause for concern? Environ Health Perspect 112(1):9-17.
Blankenship A, van Hoven R, Krueger H (2003a) Tetrabromobisphenol A: A 96-hour flow-through acute toxicity test with the rainbow trout
(Oncorhynchus mykiss). Easton, MD: Wildlife International, Ltd.
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Dionne E, Fackler PH, Grandy KA (1989) Bioconcentration and elimination of C-residues by fathead minnow (Pimephales promelas) exposed to
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DOPO
VL = Very Low hazard L = Low hazard = Moderate hazard = 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 predictive models and/or professional judgment.
This table contains hazard information for each chemical; evaluation of risk considers both hazard and exposure. Variations in end-of-life processes or degradation and combustion by-
products are discussed in the report but not addressed directly in the hazard profiles. The caveats listed below must be taken into account when interpreting the information in the table.
§ Based on analogy to experimental data for a structurally similar compound.
Chemical
CASRN
Human Health Effects
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ft
u
g
_u
'H
-*^
o
-------
DOPO
f
0
^,^^^
SMILES: O=Plc2ccccc2c3ccccc3Ol
CASRN: 35948-25-5
MW: 216.18
MF: C12H9O2P
Physical Forms:
Neat: Solid
Use: Flame retardant
Synonyms: DOP; DOPPO; 9,10-Dihydro-9-oxa-10-phosphaphenanthrene-10-oxide; 6H-dibenz[c,e][l,2]oxaphosphorin 6-oxide
Chemical Considerations: This is a discrete organic chemical with a MW below 1,000. EPI v 4. 1 1 was used to estimate physical/chemical and environmental fate
values in the absence of experimental data. Measured values from experimental studies were incorporated into the estimations. As described in the DfE Program
Alternatives Assessment Criteria for Hazard Evaluation, stable degradation products of the alternatives are evaluated. Therefore the hydrolysis product of DOPO was
evaluated in this assessment for endpoints typically obtained in the presence of water; based on a submitted guideline water solubility study reporting that 2-(2'-
hydroxyphenyl)phenyl phosphonic acid is readily formed by deesterification of DOPO in water. Although there were no separate experimental studies available for
the hydrolysis product, it was considered in the evaluation of the human health designations using structural alerts and professional judgment (ECHA, 2013).
Polymeric: No
Oligomeric: Not applicable
Metabolites, Degradates and Transformation Products: [2-(2'-Hydroxyphenyl)phenyl]phosphonic acid by hydrolytic deesterification (ECHA, 2013)
Analog: [2-(2'-Hydroxyphenyl)phenyl]phosphonic acid (the hydrolysis product of Analog Structure:
DOPO)
Endpoint(s) using analog values: Endpoints typically obtained in the presence f^"^
of water for [2-(2'-Hydroxyphenyl)phenyl]phosphonic acid, the hydrolysis L^
product of DOPO HO V
^iX
]
V°H
r°
Structural Alerts: Phosphinate esters - environmental toxicity (aquatic toxicity); Organophosphorus compounds - neurotoxicity; Phenols (for the hydrolysis product)
- neurotoxicity (EPA, 2010; EPA, 2012).
Risk Phrases: R43 - May cause sensitization by skin contact (ECHA, 2013).
Hazard and Risk Assessments: None located.
4-108
-------
DOPO CASRN 35948-25-5
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
Boiling Point (°C)
Vapor Pressure (mm Hg)
122
According to Organisation for Economic
Co-operation and Development (OECD)
102 (Measured)
117 (Measured)
359
(Extrapolated)
200 at 760 mmHg
pressure reported as 5 Torr (Measured)
>300 at 5 mmHg
(Estimated)
0.000022 at 25°C
(Extrapolated)
5 at 200°C
(Measured)
0.000012
(Estimated)
l.lxlO'8
for [2-(2'-hydroxyphenyl)phenyl]
phosphonic acid (Estimated)
Chang et al., 1998 (as cited in
ECHA, 2013)
Chernyshev et al., 1972
McEntee, 1987
International Resources, 2001
EPIv4.11;EPA, 1999
McEntee, 1987
International Resources, 2001
EPIv4.11
EPIv4.11
Adequate guideline study.
Consistent with other measured
values.
The boiling point at 760 mmHg was
extrapolated from the measured
boiling point at reduced pressure
using a computerized nomograph.
Value was obtained at a reduced
pressure, no further study details
reported.
Estimated value is greater than the
cutoff value, >300°C, according to
HPV assessment guidance.
The vapor pressure was extrapolated
from the measured boiling point at
reduced pressure using a
computerized nomograph.
Value reported at an elevated
temperature.
This value is applicable to the
hydrolysis product of DOPO, [2-(2'-
hydroxyphenyl)phenyl] phosphonic
acid.
4-109
-------
DOPO CASRN 35948-25-5
PROPERTY/ENDPOINT
Water Solubility (mg/L)
Log Kow
Flammability (Flash Point)
Explosivity
Pyrolysis
pH
DATA
3,574
at 25°C according to OECD 105 study.
DOPO is readily converted to [2-(2'-
hydroxyphenyl)phenyl] phosphonic acid
by deesterification in water; however, the
rate of hydrolysis and pH conditions were
not reported. (Measured)
460
(Estimated)
1.87
(Estimated)
1.33
for [2-(2'-hydroxyphenyl)phenyl]
phosphonic acid (Estimated)
Not readily combustible solid
EU Method A. 10 Flammability (Solids).
Fine powder sample melted to a clear
liquid and no ignition was observed.
(Measured)
Flash point: 222°C Cleveland open tester
(Measured)
Lower explosive limit: 980 g/m3
Considered non explosive. Vertical tube
test. (Measured)
Not applicable (Estimated)
REFERENCE
ECHA, 2013
EPIv4.11
EPIv4.11
EPIv4.11
ECHA, 2013
ECHA, 2013
ECHA, 2013
Professional judgment
DATA QUALITY
The reported water solubility is
measured for the hydrolysis product
of DOPO, in this guideline water
solubility study.
This compound hydrolyzes in
aqueous conditions.
This value is applicable to the
hydrolysis product of DOPO, [2-(2'-
hydroxyphenyl)phenyl] phosphonic
acid.
Guideline study reported in a
secondary source.
Nonguideline study reported in a
secondary source.
Nonguideline study reported in a
secondary source.
No data located.
The substance does not contain
functional groups that would be
expected to ionize; although this
compound hydrolyzes in aqueous
conditions.
4-110
-------
DOPO CASRN 35948-25-5
PROPERTY/ENDPOINT
pKa
Particle Size
DATA
Not applicable (Estimated)
REFERENCE
Professional judgment
DATA QUALITY
The substance does not contain
functional groups that would be
expected to ionize. Although this is
compound hydrolyzes in aqueous
conditions.
No data located.
HUMAN HEALTH EFFECTS
Toxicokinetics
Dermal Absorption in vitro
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal or Inhaled
Other
Acute Mammalian Toxicity
Acute Lethality
Oral
Dermal
Absorption of neat solid is expected to be negligible through skin. Absorption in solution is expected to be
moderate through skin, and moderate through lungs and gastrointestinal tract.
Absorption of neat solid negligible
through skin. Absorption in solution
moderate through skin. Absorption
moderate through lungs and GI tract.
(Estimated)
Professional judgment
No data located.
Estimated based on
physical/chemical properties
LOW: Based on experimental oral and dermal LD50 data in rats. No inhalation data were located.
Mouse (male) oral LD50 = 6,490 mg/kg,
Mouse (female) oral LD50 = 7,580 mg/kg
Rat oral LD50 > 2,000 mg/kg;
Observation period was 14 days. No
deaths occurred.
Rat dermal LD50 > 2,000 mg/kg
(semi-occlusive). Observation period was
14 days. No deaths occurred.
International Resources, 2001
ECHA, 2013
ECHA, 2013
Study details and test conditions
were not available.
Sufficient information in secondary
source. Study conducted in
accordance with OECD Guideline
40 1 and good laboratory practices
(GLP). Test substance was CASRN
35948-25-5 named Ukanol OOP 95
in study report. Primary reference
not identified; purity of test
substance not provided.
Sufficient information in secondary
source. Study conducted in
accordance with OECD guideline
402 and GLP. Test substance was
CASRN 35948-25-5 named HCA in
study report. Primary reference not
4-111
-------
DOPO CASRN 35948-25-5
PROPERTY/ENDPOINT
Inhalation
Carcinogenic!*
OncoLogic Results
Carcinogenicity (Rat and
Mouse)
Combined Chronic
Toxicity/Carcinogenicity
Other
Genotoxicity
Gene Mutation in vitro
Gene Mutation in vivo
DATA
REFERENCE
DATA QUALITY
identified. Neat test substance
(99.5% pure).
No data located.
MODERATE: OncoLogic estimates a low concern for carcinogenicity for the organophosphates chemical
class; However, there is uncertainty based on the lack of data and carcinogenic effects cannot be ruled out.
Low; although the structure of DOPO is
not fully represented by the phosphate and
phosphinate skeletons provided in the
program.
(Estimated)
OncoLogic, 2008
Estimated for the aryl phosphinate-
type compound.
No data located.
No data located.
No data located.
LOW: Experimental studies indicate that DOPO was not mutagenic to bacteria or mammalian cells and
did not cause chromosomal aberrations in vitro.
Negative in Ames assay; in Salmonella
typhimurium strains TA1535, TA97a,
TA98, TA100, and TA102 with and
without metabolic activation. Tested up to
5,024 (ig/plate (purity >99%). Positive
controls responded as expected.
Negative in Ames assay in Salmonella
typhimurium strains TA97, TA98, TA100,
and TA102 and Escherichia coli WP2 uvr
A pKM 101 with and without metabolic
activation. Tested up to 5,000 (ig/plate
(purity, industrial grade). Positive controls
responded as expected.
ECHA, 2013
Hachiya, 1987 (as cited in
ECHA, 2013)
Sufficient study details reported in a
secondary source. Study conducted
in accordance with OECD guideline
471 and GLP. Test substance was
CASRN 35948-25-5 named Ukanol
GK-F in study report. Primary
reference not identified.
Sufficient study details reported in a
secondary source. Not GLP study,
but adequate as supporting data.
No data located.
4-112
-------
DOPO CASRN 35948-25-5
PROPERTY/ENDPOINT
Chromosomal Aberrations in
vitro
Chromosomal Aberrations in
vivo
DNA Damage and Repair
Other
Reproductive Effects
Reproduction/Developmental
Toxicity Screen
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
Reproduction and Fertility
Effects
Other
Developmental Effects
Reproduction/
Developmental Toxicity
Screen
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
DATA
Negative in Chinese hamster lung cells
with and without activation. Tested up to
216 (ig/mL (purity not provided). Positive
controls responded as expected.
REFERENCE
Ryu et al., 1994 (as cited in
ECHA, 2013)
DATA QUALITY
Sufficient study details reported in a
secondary source. Study equivalent
to OECD Guideline 473; not GLP
study.
No data located.
No data located.
No data located.
LOW: Based on closely related analogs with similar structures, functional groups, and physical/chemical
properties, as well as professional judgment.
Low potential for reproductive effects.
(Estimated by analogy)
Professional judgment
No data located.
No data located.
No data located.
Estimated based on analogy to a
structurally similar compound and
professional judgment.
MODERATE: There is uncertain concern for developmental neurotoxicity based on the potential for
cholinesterase (ChE) inhibition in dams that may result in alterations of fetal neurodevelopment. There is
an estimated Low potential for developmental effects based on closely related analogs with similar
structures, functional groups, and physical/chemical properties, as well as professional judgment.
There were no experimental data for the developmental or neurodevelopmental endpoints.
No data located.
No data located.
4-113
-------
DOPO CASRN 35948-25-5
PROPERTY/ENDPOINT
Prenatal Development
Postnatal Development
Prenatal and Postnatal
Development
Developmental Neurotoxicity
Other
Neurotoxicity
Neurotoxicity Screening
Battery (Adult)
Other
DATA
Uncertain concern for developmental
neurotoxicity based on the potential for
cholinesterase (ChE) inhibition in dams
that may result in alterations of fetal
neurodevelopment. (Estimated)
Low potential for developmental effects.
(Estimated by analogy)
REFERENCE
Professional judgment
Professional judgment
DATA QUALITY
No data located.
No data located.
No data located.
Estimated based on a structural alert
for organophosphates for the
neurotoxicity endpoint.
Estimated based on analogy to a
structurally similar compound and
professional judgment.
MODERATE: There is uncertain potential for neurotoxic effects based on a structural alert for
organophosphates. There is also uncertain potential for neurotoxic effects for the hydrolysis product of
DOPO [2-(2'-hydroxyphenyl)phenyl] phosphonic acid based on the phenols structural alert and
professional judgment.
Potential for neurotoxic effects based on a
structural alert for organophosphates.
(Estimated by analogy)
Potential for neurotoxic effects based on a
structural alert for phenols.
Estimated for the hydrolysis product of
DOPO, [2-(2'-hydroxyphenyl)phenyl]
phosphonic acid. (Estimated by analogy)
Professional judgment
Professional judgment
No data located.
Estimated based on a structural alert
for organophosphates and
professional judgment.
Estimated based on a structural alert
for phenols and professional
judgment for the hydrolysis product
of DOPO, [2-(2'-
hydroxyphenyl)phenyl] phosphonic
acid.
4-114
-------
DOPO CASRN 35948-25-5
PROPERTY/ENDPOINT
Repeated Dose Effects
Skin Sensitization
Skin Sensitization
DATA
REFERENCE
DATA QUALITY
LOW: Based on no significant effects on multiple endpoints in a 16-week dietary study in rats at doses up
to 1,094 mg/kg-day.
Male and female Wistar rats (20/sex/dose)
were fed diets containing 0, 0.24, 0.6, or
1.5%HCA ( 0, 159, 399, or 1,023 mg
HCA/kg-day to males; 0, 177, 445, or
1,094 mg HCA/kg-day to females) for 16
weeks (purity of test substance not
provided).
There were no significant effects on body
weight, food consumption, hematology,
limited clinical chemistry, urinalysis,
organ weight, and gross and microscopic
examination of major organs.
NOAEL= 1,023 mg/kg-day (males), 1,094
mg/kg-day (females); highest dose tested
LOAEL= Not established
ECHA, 2013
Sufficient information in secondary
source; data lacking regarding
detailed clinical observations and
neurobehavioral examination. Study
equivalent to OECD guideline 408.
Study pre-dates GLP. Test substance
identified as HCA in study report.
Primary reference not identified.
MODERATE: Limited data were available to categorize this compound; however, because an SI of 4.2 was
seen at a 5% concentration, this compound is considered to have a Moderate concern for skin Sensitization.
Because the test concentrations started a 5%, there is uncertainty as to if there would be skin Sensitization
at a concentration < 2% resulting in an SI of 3 which would warrant a High hazard designation.
Local lymph node assay conducted in
female CBA/J Rj mice. HCA tested at 5,
10, and 25% (w/v); four mice/treatment
group. Test substance >98% pure.
Significant lymphoproliferative response
was noted for HCA at concentrations of
10% (SI 4.4) and 5% (SI 4.2). SI for
positive control was 16.6. HCA was a
sensitizer under the conditions of the
study.
Risk phrase: R43: May cause Sensitization
by skin contact
ECHA, 2013
ECHA, 2013
Sufficient information in secondary
source. Study conducted in
accordance with OECD guideline
429 and GLP. Test substance was
CASRN 35948-25-5 named HCA in
study report. Primary reference not
identified.
Reported in a secondary source.
4-115
-------
DOPO CASRN 35948-25-5
PROPERTY/ENDPOINT
Respiratory Sensitization
[Respiratory Sensitization
Eye Irritation
Eye Irritation
Dermal Irritation
Dermal Irritation
Endocrine Activity
Immunotoxicity
Immune System Effects
DATA
REFERENCE
DATA QUALITY
No data located.
No data located.
MODERATE: Based on moderate signs of eye irritation in rabbits that cleared in 7 days.
Neat test material (0. 1 mL) was instilled
in left eye of 3 female albino rabbits. Eyes
were monitored for up to 7 days.
Moderate signs of eye irritation that
cleared in 7 days were observed among
the rabbits.
ECHA, 2013
Sufficient information in secondary
source. Study conducted in
accordance with OECD guideline
405 and GLP. Test substance was
CASRN 35948-25-5 named Ukanol
DOP in study report. Primary
reference not identified.
VERY LOW: Based on no skin reactions in semi-occlusive test in rabbits.
Not irritating. Neat test material (0.5 mL)
was applied in gauze patches to a clipped
skin area of 3 female albino rabbits;
patches were secured for 4 hours. Skin
was examined from 1 to 72 hours after
patch removal and skin washing. No skin
reactions were noted at any time point.
ECHA, 2013
Sufficient information in secondary
source. Study conducted in
accordance with OECD guideline
404 and GLP. Test substance was
CASRN 35948-25-5 named Ukanol
DOP in study report. Primary
reference not identified.
No data located.
No data located.
Estimated by professional judgment to have low potential for immunotoxic effects based on closely related
analogs with similar structures, functional groups, and physical/chemical properties.
Low potential for immunotoxic effects.
(Estimated by analogy)
Professional judgment
Estimated by analogy to a
structurally similar compound and
professional judgment.
4-116
-------
DOPO CASRN 35948-25-5
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
ECOTOXICITY
ECOSAR Class
Phenols class; only the hydrolysis product [2-(2'-hydroxyphenyl)phenyl]phosphonic acid was assessed in
ECOSAR because DOPO hydrolyzes in water based on data from a water solubility study
Acute Aquatic Toxicity
LOW: Based on experimental acute aquatic toxicity values > 100 mg/L in fish, daphnia, and algae. DOPO
will hydrolyze in water; therefore only the hydrolysis product, [2-(2'-hydroxyphenyl)phenyl]phosphonic
acid, was assessed in ECOSAR, which is represented by the phenols class.
Fish LC50
Freshwater fish (Danio rerio) 96-hour
LC50 >100 mg/L;
96-hour NOEC = 100 mg/L;
The study was conducted under static
conditions.
(Experimental)
Oryzias latipes 48-hour LC50 = 370 mg/L
(95% CI, 280-500 mg/L)
Limit test conducted under static
conditions.
(Experimental)
96-hour LC50 = >100 mg/L
(Estimated)
ECOSAR: Phenols
Fish 96-hour LC50 = >100 mg/L
(Estimated)
ECOSAR: Neutral organics
ECHA, 2013
ECHA, 2013
ECOSAR v 1.11
ECOSAR v 1.11
4-117
Sufficient study details reported in a
secondary source. Study was
conducted in accordance with
OECD guideline 203. GLP
deviations were not considered
critical. Primary reference not
identified; test substance purity
>99%; Test substance
concentrations were kept within
20% of initial concentrations.
Test substance purity not reported;
sufficient study details reported in a
secondary source. The study follows
the methodology presented in the
Japanese Industrial Standard JIS K
0102-1986 No 71. Primary reference
not identified.
Estimation is for the hydrolysis
product; this compound hydrolyzes
in aqueous conditions.
Estimation is for the hydrolysis
product; this compound hydrolyzes
in aqueous conditions.
Narcosis classes (neutral organics)
are provided for comparative
purposes; DfE assessment
methodology will use the lowest
estimated toxicity value provided by
-------
DOPO CASRN 35948-25-5
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
ECOSAR classes that have a more
specific mode of action relative to
narcosis.
Daphnid LC50
Daphnia magna 48-hour EC50 >100
mg/L; 48-hour NOEC = 100 mg/L Limit
test conducted under static conditions.
Concentrations of test substance were
stable during study. Test substance purity
>99%.
(Experimental)
ECHA, 2013
Daphnia magna 48-hour EC50 = 240 mg/L Waaijers et al., 2013
(unbuffered);
no effect up to 289 mg/L when buffered to
pH7.5
Test conducted under static conditions.
Test substance purity =98%.
Concentrations of the test substance were
measured at the beginning and end of the
test.
(Experimental)
48-hour LC50 = 29 mg/L
(Estimated)
ECOSAR: Phenols
ECOSAR v 1.11
48-hour LC50 = >100 mg/L
(Estimated)
ECOSAR: Neutral organics
ECOSAR v 1.11
Sufficient study details reported in a
secondary source. Study was
conducted in accordance with
OECD guideline 202. GLP
deviations were not considered
critical. Primary reference not
identified.
Sufficient study details reported in a
primary source, Study was
conducted in accordance with
OECD Guideline 202 and GLP.
Estimation is for the hydrolysis
product; this compound hydrolyzes
in aqueous conditions.
Estimation is for the hydrolysis
product; this compound hydrolyzes
in aqueous conditions.
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.
4-118
-------
DOPO CASRN 35948-25-5
PROPERTY/ENDPOINT
Green Algae EC50
Chronic Aquatic Toxicity
Fish ChV
DATA
Green algae (Desmodesmus subspicatus)
72-hour ErC50 = 1 10 mg/L;
72-hour EbC50 = 100 mg/L;
EyC50 = 98 mg/L;
all nominal concentrations; concentrations
of test substance were stable during
study). EyC50 = biomass at the end of
exposure period minus biomass at the start
of the exposure period. Test substance
purity >99%.
(Experimental)
96-hour EC50 = >100 mg/L
(Estimated)
ECOSAR: Phenols
96-hour EC50 = >100 mg/L
(Estimated)
ECOSAR: Neutral organics
REFERENCE
ECHA, 2013
ECOSAR v 1.11
ECOSAR v 1.11
DATA QUALITY
Sufficient study details reported in a
secondary source. Study was
conducted in accordance with
OECD guideline 201 and GLP.
Primary reference not identified.
Estimation is for the hydrolysis
product; this compound hydrolyze s
in aqueous conditions.
Estimation is for the hydrolysis
product; this compound hydrolyze s
in aqueous conditions.
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.
MODERATE: Based on estimated chronic aquatic toxicity values for the primary degradation product [2-
(2'-hydroxyphenyl)phenyl]phosphonic acid of 5.6 mg/L for daphnid. DOPO will hydrolyze in water;
therefore only the hydrolysis product was assessed in ECOSAR, which is represented by the phenols class.
Fish ChV = 12 mg/L
(Estimated)
ECOSAR: Phenols
Fish ChV = 70 mg/L
(Estimated)
ECOSAR: Neutral organics
ECOSAR v 1.11
ECOSAR v 1.11
Estimation is for the hydrolysis
product; this compound hydrolyze s
in aqueous conditions.
Estimation is for the hydrolysis
product; This compound hydrolyzes
in aqueous conditions.
4-119
-------
DOPO CASRN 35948-25-5
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
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 = 5.6 mg/L
(Estimated)
ECOSAR: Phenols
ECOSAR v 1.11
Daphnid ChV = 34 mg/L
(Estimated)
ECOSAR: Neutral organics
ECOSAR v 1.11
Estimation is for the hydrolysis
product; this compound hydrolyzes
in aqueous conditions.
Estimation is for the hydrolysis
product; this compound hydrolyzes
in aqueous conditions.
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 ChV
Green algae ChV = 68 mg/L
(Estimated)
ECOSAR: Phenols
ECOSAR v 1.11
Green algae ChV = 54 mg/L
(Estimated)
ECOSAR: Neutral organics
ECOSAR v 1.11
4-120
Estimation is for the hydrolysis
product; this compound hydrolyzes
in aqueous conditions.
Estimation is for the hydrolysis
product; this compound hydrolyzes
in aqueous conditions.
Narcosis classes (neutral organics)
are provided for comparative
purposes; DfE assessment
methodology will use the lowest
estimated toxicity value provided by
-------
DOPO CASRN 35948-25-5
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
ECOSAR classes that have a more
specific mode of action relative to
narcosis.
ENVIRONMENTAL FATE
Transport
Henry's Law Constant (atm-
m3/mole)
Sediment/Soil
Adsorption/Desorption - Koc
Under aqueous conditions, DOPO is expected to hydrolyze to [2-(2'-hydroxyphenyl)phenyl] phosphonic
acid based on data from a water solubility study. Therefore, the transport and mobility of DOPO and the
hydrolysis product of DOPO are evaluated. Level III fugacity models incorporating available physical and
chemical property data indicate that at steady state DOPO and [2-(2'-hydroxyphenyl)phenyl] phosphonic
acid are expected to be found primarily in soil and to a lesser extent, water. DOPO and [2-(2'-
hydroxyphenyl)phenyl] phosphonic acid are expected to be highly mobile in soil based on an experimental
KOC value; these compounds have the potential to migrate from soil into groundwater. The estimated
Henry's Law constant indicates that the hydrolysis product, [2-(2'-hydroxyphenyl)phenyl] phosphonic
acid will not significantly volatilize from water to the atmosphere. Volatilization from dry surfaces is also
not expected. In the atmosphere, DOPO is expected to exist in both the vapor and particulate phase, based
on its vapor pressure and [2-(2'-hydroxyphenyl)phenyl] phosphonic acid is expected to exist primarily in
the particulate phase. Vapor-phase DOPO is expected to have limited potential for photodegradation.
Particulates will be removed from air by wet or dry deposition.
<10'8 for [2-(2'-hydroxyphenyl)phenyl]
phosphonic acid (Estimated)
5.4 xlO'8
(Estimated)
36
According to OECD 121 (Measured)
120 (Estimated)
EPIv4.11
EPIv4.11
ECHA, 2013
EPIv4.11
This compound hydrolyzes in
aqueous conditions. This value is
applicable to the hydrolysis product
of DOPO, [2-(2'-
hydroxyphenyl)phenyl] phosphonic
acid.
Estimated by the HENRYWIN
Bond SAR model.
Adequate guideline study reported
in a secondary source. This study
was performed in acetonitrile and
water; it is unclear if this value is for
DOPO or the hydrolysis product
since DOPO is expected to
hydrolyze in water based on data
from a water solubility study.
This compound hydrolyzes in
aqueous conditions. This value is
4-121
-------
DOPO CASRN 35948-25-5
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
applicable to the hydrolysis product
of DOPO, [2-(2'-
hydroxyphenyl)phenyl] phosphonic
acid.
Level III Fugacity Model
Air = 0.3%
Water =18.9%
Soil = 80.6%
Sediment = 0.1% (Estimated)
EPIv4.11
Air = 0%
Water =16%
Soil = 84%
Sediment = 0.2% (Estimated)
for [2-(2'-hydroxyphenyl)phenyl]
phosphonic acid
EPIv4.11
This compound hydrolyzes in
aqueous conditions. These values
are applicable to the hydrolysis
product of DOPO, [2-(2'-
hydroxyphenyl)phenyl] phosphonic
acid.
Persistence
HIGH: The persistence designation of DOPO is High considering ultimate degradation based on an
estimated environmental half-life of 75 days in soil. An intermediate, [2-(2'-hydroxyphenyl)phenyl]
phosphonic acid, is formed by hydrolysis of DOPO in aqueous environments. This primary degradation
product is expected to resist further environmental degradation based on an estimated half-life of 75 days
in soil. The rate of hydrolysis is expected to be dependent on pH, with increasing alkalinity resulting in
increasing rates of hydrolysis. A guideline OECD 301B Ready Biodegradability study indicated that
DOPO is not biodegradable under test conditions with activated sludge; however data from this protocol
are insufficient to determine a persistence designation. QSARs of aerobic and anaerobic biodegradation
estimate primary aerobic biodegradation in days-weeks and ultimate aerobic degradation in weeks-months
for both DOPO and the hydrolysis product. DOPO is not expected to undergo direct photolysis by sunlight
as it does not contain chromophores that absorb at wavelengths >290 nm. The atmospheric half-life for the
gas phase reactions of DOPO is estimated at 1.8 days, though it is not anticipated to partition significantly
to air.
Water
Aerobic Biodegradation
Passes Ready Test: No
Test method: OECD TG 30IB: CO2
Evolution Test
0% degradation after 28 days using an
activated sludge inoculum. (Measured)
Days-weeks (Primary Survey Model)
ECHA, 2013
EPIv4.11
Adequate guideline study reported
in a secondary source; this value is
expected to apply to both DOPO and
the hydrolysis product since DOPO
is expected to hydrolyze in water
based on data from a water
solubility study.
This compound hydrolyzes in
4-122
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DOPO CASRN 35948-25-5
PROPERTY/ENDPOINT
Soil
Air
Reactivity
Volatilization Half-life for
Model River
Volatilization Half-life for
Model Lake
Aerobic Biodegradation
Anaerobic Biodegradation
Soil Biodegradation with
Product Identification
Sediment/Water
Biodegradation
Atmospheric Half-life
Photolysis
Hydrolysis
DATA
Weeks-months (Ultimate Survey Model)
(Estimated)
>1 year (Estimated)
>1 year (Estimated)
Not probable (Anaerobic-methanogenic
biodegradation probability model)
1.8 days (Estimated)
Not a significant fate process (Estimated)
DOPO is readily converted to [2-(2'-
hydroxyphenyl)phenyl]phosphonic acid
by deesterification in water; however, the
rate of hydrolysis and pH conditions were
REFERENCE
EPIv4.11
EPIv4.11
EPIv4.11
EPIv4.11
Professional judgment; Mill,
2000
ECHA, 2013
DATA QUALITY
aqueous conditions. These values
are applicable to DOPO and for the
hydrolysis product of DOPO, [2-(2'-
hydroxyphenyl)phenyl] phosphonic
acid.
This compound hydrolyzes in
aqueous conditions. These values
are applicable to DOPO and for the
hydrolysis product of DOPO, [2-(2'-
hydroxyphenyl)phenyl] phosphonic
acid.
This compound hydrolyzes in
aqueous conditions. These values
are applicable to DOPO and for the
hydrolysis product of DOPO, [2-(2'-
hydroxyphenyl)phenyl] phosphonic
acid.
No data located.
No data located.
No data located.
The substance does not contain
functional groups that would be
expected to absorb light at
environmentally significant
wavelengths.
Summary statement reported in a
modified OECD 105 guideline water
solubility study; however, the rate of
hydrolysis and pH conditions was
4-123
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DOPO CASRN 35948-25-5
PROPERTY/ENDPOINT
Environmental Half-life
Bioaccumulation
Fish BCF
Other BCF
BAF
Metabolism in Fish
DATA
not reported. (Measured)
Phosphinate esters hydrolyze in water and
their rate of hydrolysis is correlated to pH;
increasing alkalinity results in increasing
rates of hydrolysis. (Estimated)
75 days (Estimated)
REFERENCE
EPA, 2010
PBT Profiler vl.301
DATA QUALITY
not reported.
Adequate summary statement from
guidance document.
Half-life estimated for the
predominant compartment (soil), as
determined by EPI methodology.
This value is applicable to DOPO
and for the hydrolysis product of
DOPO, for [2-(2'-
hydroxyphenyl)phenyl] phosphonic
acid.
LOW: The bioaccumulation hazard designation is based on the estimated BCF and BAF values that are
<100 for DOPO and the hydrolysis product of DOPO, [2-(2'-hydroxyphenyl)phenyl]phosphonic acid.
7.9 (Estimated)
3.5for[2-(2'-
hydroxyphenyl)phenyl]phosphonic acid
(Estimated)
7.7 (Estimated)
2.9 for [2-(2'-
hydroxyphenyl)phenyl]phosphonic acid
(Estimated)
EPIv4.11
EPIv4.11
EPIv4.11
EPIv4.11
This compound hydrolyzes in
aqueous conditions.
This value is applicable to the
hydrolysis product of DOPO, [2-(2'-
hydroxyphenyl)phenyl] phosphonic
acid.
No data located.
This compound hydrolyzes in
aqueous conditions.
This value is applicable to the
hydrolysis product of DOPO, [2-(2'-
hydroxyphenyl)phenyl] phosphonic
acid.
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
Ecological Biomonitoring
Human Biomonitoring
No data located.
No data located.
This chemical was not included in the NHANES biomonitoring report. (CDC, 2013).
4-124
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4-125
-------
CDC (2013) Fourth national report on human exposure to environmental chemicals, updated tables, March 2013.
http://www.cdc.gov/exposurereport/pdf/FourthReport_UpdatedTables_Mar2013.pdf.
Chang TC, Wu KH, Wu TR, et al. (1998) Thermogravimetric analysis study of a cyclic organo-phosphorus compound. Phosphorus Sulfur Silicon
139:45-56.
Chernyshev EA and et al. (1972) J Gen Chem USSR 42:88-91.
ECHA (2013) 6H-dibenz[c,e][l,2]oxaphosphorin 6-oxide. Registered substances. European Chemicals Agency.
http://apps.echa.europa.eu/registered/data/dossiers/DISS-db99cfP9-92de-Odla-e044-00144f67d031/DISS-db99cff9-92de-Odla-e044-
00144f67d031_DISS-db99cff9-92de-Odla-e044-00144f67d031.html.
ECOSAR Ecological Structure Activity Relationship (ECOSAR). Estimation Programs Interface (EPI) Suite for Windows, Version 1.11.
Washington, DC: EPIWIN/EPISUITE. U.S. Environmental Protection Agency, http://www.epa.gov/oppt/newchems/tools/21ecosar.htm.
EPA (1999) Determining the adequacy of existing data. High Production Volume (HPV) Challenge. Washington, DC: U.S. Environmental
Protection Agency, http://www.epa.gov/hpv/pubs/general/datadeqfn.pdf
EPA (2010) TSCA new chemicals program (NCP) chemical categories. Washington, DC: U.S. Environmental Protection Agency.
http://www.epa.gov/oppt/newchems/pubs/npcchemicalcategories.pdf
EPA (2012) Using noncancer screening within the SF initiative. Washington, DC: U.S. Environmental Protection Agency.
http://www.epa.gov/oppt/sf/pubs/noncan-screen.htm.
EPI Estimation Programs Interface (EPI) Suite, Version 4.11. Washington, DC: EPIWIN/EPISUITE. U.S. Environmental Protection Agency.
http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm.
HachiyaN (1987) Evaluation of chemical genotoxicity by a series of short term tests. Akita Igaku 14(2):269-292.
International Resources (2001) OPC/OPC super clean grade. MSDS: Material safety data sheet, http://www.iri-us.com/msds/clean.html.
McEntee TE (1987) PC-Nomograph — Programs to enhance PC-GEMS estimates of physical properties for organic chemicals. Version 2.0 -
EGA/CGA. MSDOS: 12/4/87. The Mitre Corporation.
Mill T (2000) Photoreactions in surface waters. In: Boethling R, Mackay D, eds. Handbook of Property Estimation Methods for Chemicals,
Environmental Health Sciences. Boca Raton: Lewis Publishers.:355-381.
OncoLogic (2008) Version 7.0. U.S. Environmental Protection Agency and LogiChem, Inc.
4-126
-------
PBT Profiler Persistent (P), Bioaccumulative (B), and Toxic (T) Chemical (PBT) Profiler, Version 1.301. Washington, DC: U.S. Environmental
Protection Agency, www.pbtprofiler.net.
Ryu JC, Lee S, Kim KR, et al. (1994) Evaluation of the genetic toxicity of synthetic chemicals (I). Chromosomal aberration test on Chinese
hamster lung cells in vitro. Environ Mutagens Carcinogens 14(2): 138-144.
Waaijers SL, Hartmann J, Soeter AM, et al. (2013) Toxicity of new generation flame retardants to Daphnia magna. Sci Total Environ 463-
464:1042-1048.
4-127
-------
Fyrol PMP
VL = Very Low hazard L = Low hazard = Moderate hazard H = High hazard VH = Very High hazard — Endpoints in colored text (VL, L, M, H, and VH) were
assigned based on empirical data. Endpoints in black italics (VL, L, M, H, and VH) were assigned using values from predictive models and/or professional judgment.
This table contains hazard information for each chemical; evaluation of risk considers both hazard and exposure. Variations in end-of-life processes or degradation and combustion
by-products are discussed in the report but not addressed directly in the hazard profiles. The caveats listed below must be taken into account when interpreting the information in the
table.
Based on analogy to experimental data for a structurally similar compound.; The highest hazard designation of any of the oligomers with MW <1,000.
Chemical
CASRN
Human Health Effects
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4-128
-------
Fyrol PMP
Representative Structure
CASRN: 63747-58-0
MW: > 1,000; with a significant
percentage of components
having MW<1,000
MF: (C13H1303P C6H602)X
Physical Forms: Solid
Neat: Solid
Use: Flame retardant
SMILES: cl(OP(C)(=O)Oc2cc(O)ccc2)cc(OP(C)(=O)Oc2ccccc2)cccl (n=l);
c 1 (OP(C)(=O)Oc4cc(OP(C)(=O)Oc3cc(O)ccc3)ccc4)cc(OP(C)(=O)Oc2ccccc2)ccc 1 (n=2);
c 1 (OP(C)(=O)Oc5cc(OP(C)(=O)Oc3cc(OP(C)(=O)Oc4cc(O)ccc4)ccc3)ccc5)cc(OP(C)(=O)Oc2ccccc2)ccc 1 (n=3);
c 1 (OP(C)(=O)Oc6cc(OP(C)(=O)Oc3cc(OP(C)(=O)Oc4cc(OP(C)(=O)Oc5cc(O)ccc5)ccc4)ccc3)ccc6)cc(OP(C)(=O)Oc2ccccc2)ccc 1 (n=4)
Synonyms: Phosphonic acid, P-methyl-, diphenyl ester, polymer with 1,3-benzenediol; Phosphonic acid, methyl-, diphenyl ester, polymer with 1,3-benzenediol; 1,3-
Benzenediol, polymer with diphenyl methylphosphonate; Diphenyl methylphosphonate-resorcinol copolymer; Aryl alkylphosphonate; Poly(m-phenylene
methylphosphonate)
Trade Name: Fyrolflex PMP
CASRN 124933-95-5 was identified by literature searches based on name as a related alternative. CASRN 124933-95-5 has a slightly different structure, and no other
applicable data were found for this CASRN.
Chemical Considerations: This alternative is a polymer consisting of oligomers with MWs above and below 1,000 daltons according to commercial product
datasheets.
The oligomers with a MW > 1,000, where n>5, are assessed using the available polymer assessment literature.
The components with a MW < 1,000 are evaluated with four representative structures, where n=l, 2, 3 and 4, as indicated in the SMILES entry. The low MW
components are assessed with EPI v4.11 and ECOSARvl.ll estimates due to an absence of publicly available experimental physical/chemical, environmental fate
and aquatic toxicity values. A typical phosphorus content of 17.5% was reported from the commercial product literature. (Hsu, 2013; ICL, 2013).
Polymeric: Yes
Oligomeric: This polymer is terminated with either resorcinol and/or phenyl groups based on the starting materials. The repeating units of this polymer are m-
phenylene methylphosphonate. A representative structure for n=l is identified in the SMILES section above.
Metabolites, Degradates and Transformation Products: None identified. Environmental degradation of Fyrol PMP has not been demonstrated in experimental
studies. Degradation of Fyrol PMP by sequential dephosphorylation could produce phosphinates, phenol (CASRN 108-95-2) or resorcinol (CASRN 108-46-3). The
importance of dephosphorylation relative to possible competing pathways has not been demonstrated in a published study. (Professional judgment)
Analog: Resorcinol bis-diphenylphosphate (RDP; CASRN 125997-21-9); tricresyl
phosphate (TCP; CASRN 1330-78-5);and confidential analogs
Endpoint(s) using analog values: Carcinogenicity, genotoxicity, reproductive,
Analog Structure:
4-129
-------
developmental, repeated dose
n=l-7
Resorcinol bis-diphenylphosphate (RDP; CASRN 125997-21-9}
\
Phosphoric acid, tris(methylphenyl) ester
(CDP; CASRN 1330-78-5)
Representative structure
Structural Alerts: Phenols - neurotoxicity; Organophosphorus compounds - neurotoxicity. (EPA, 2012).
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 2012).
Hazard and Risk Assessments: None located.
4-130
-------
Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
Boiling Point (°C)
Vapor Pressure (mm Hg)
Water Solubility (mg/L)
52 (Measured)
>300
(Estimated)
<10"8 for n= 1-4 (Estimated)
<10'8 (Estimated)
8.4
forn=l (Estimated)
0.1
for n=2 (Estimated)
0.001
for n=3 (Estimated)
l.SxlO'5
for n=4 (Estimated)
<0.001
for the n>5 oligomers (Estimated)
<0.01% (Measured)
ICL, 2010
EPA, 1999;EPIv4.11
EPA, 1999;EPIv4.11
Boethling and Nabholz, 1997;
Professional judgment
EPIv4.11
EPIv4.11
EPIv4.11
EPIv4.11;EPA, 1999
Boethling and Nabholz, 1997;
Professional judgment
ICL, 2010
Reported in a material safety
datasheet.
Estimate based on four
representative structures with MW
< 1,000. Also estimated for
oligomers with MWs > 1,000. Cutoff
value according to HPV assessment
guidance and cutoff value used for
large, high MW solids.
Estimates based on the
representative structures with MW
< 1,000. Cutoff value for nonvolatile
compounds according to HPV
assessment guidance.
Cutoff value for large, high MW
polymer components.
Estimates based on representative
oligomer where n=l .
Estimates based on representative
oligomer where n=2.
Estimates based on representative
oligomer where n=3 .
Estimates based on representative
oligomer where n=4. Values are less
than the cutoff value, <0.001 mg/L,
for non-soluble compounds
according to HPV assessment
guidance.
Cutoff value for large, high MW
non-ionic polymer components.
Reported in a material safety
datasheet.
4-131
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
Log Kow
Flammability (Flash Point)
Explosivity
Pyrolysis
pH
pKa
Particle Size
DATA
3.4
forn=l (Estimated)
4.4
for n=2 (Estimated)
5.3
for n=3 (Estimated)
6.3
for n=4 (Estimated)
Not flammable (Measured)
Not expected to form explosive mixtures
with air. (Estimated)
REFERENCE
EPIv4.11
EPIv4.11
EPIv4.11
EPIv4.11
ICL, 2010
Professional judgment
DATA QUALITY
Estimates based on representative
oligomer where n=l .
Estimates based on representative
oligomer where n=2.
Estimates based on representative
oligomer where n=3 .
Estimates based on representative
oligomer where n=4.
Reported in safety datasheet and
based on its use as a flame retardant.
No experimental data located; based
on its use as a flame retardant.
No data located.
No data located.
No data located.
No data located.
HUMAN HEALTH EFFECTS
Toxicokinetics
Dermal Absorption
Absorption,
Distribution,
Metabolism &
Excretion
in vitro
Oral, Dermal or Inhaled
Other
Acute Mammalian Toxicity
Acute Lethality
Oral
Dermal
No experimental data were located. Based on professional judgment, absorption is expected to be poor by
all routes for the low MW (<1,000) fraction. There is no absorption expected for any route of exposure for
the MW >1,000 components.
Absorption is expected to be negligible by
all routes for the neat material and poor
by all routes for the low MW fraction if in
solution.
Professional judgment
Estimated based on professional
judgment.
No data located.
LOW: Experimental data indicates that the LD50 are >2,000 mg/kg when administered orally and
dermally to rats. Experimental data for the analog, phosphoric trichloride, polymer with 1,3-benzenediol,
phenyl ester (CASRN 125997-21-9) indicates an LC50 > 4.14 mg/L.
Rat LD50 >2,000 mg/kg in a 75% DMSO
solution
Rabbit LD50 >5,000 mg/kg
ICL, 2010
ICL, 2010
Reported in a material safety
datasheet with limited study details.
Reported in a material safety
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
Inhalation
Carcinogenicity
OncoLogic Results
Carcinogenicity (Rat and
Mouse)
Combined Chronic
Toxicity/Carcinogenicity
DATA
Rat inhalation LC50 > 4.14 mg/L
REFERENCE
EPA, 2010
DATA QUALITY
datasheet with limited study details.
Estimated by analogy to Phosphoric
trichloride, polymer with 1,3-
benzenediol, phenyl ester (CASRN
125997-21-9)
LOW: Estimated based on analogy to tricresyl phosphate (TCP). There was no evidence of Carcinogenicity
in rats or mice following dietary exposure to a commercial mixture of TCP for 2 years. There were no
experimental data located for this substance.
2-Year dietary study in Fischer 344/N rats
(95/sex/concentration)
Test substance concentrations: 0, 75, 150,
300 ppm (approximately 0, 3, 6, and 13
mg/kg bw-day for males and 0, 4, 7, and
15 mg/kg bw-day for females)
Chronic toxicity: NOAEL =13 mg/kg
bw-day (males); 4 mg/kg bw-day for
females
LOAEL = 26 mg/kg bw-day (males) and
7 mg/kg bw-day (females) for
cytoplasmic vacuolization of adrenal
cortex
No evidence of carcinogenic activity
(Estimated by analogy)
2-Year dietary study in B6C3F1 mice
(95/sex/concentration)
Test substance concentrations: 0, 60, 125,
250 ppm (approximately 0, 7, 13, and 27
mg/kg bw-day for males and 0, 8, 18, and
37 mg/kg bw-day for females)
NTP, 1994
NTP, 1994
This polymer is not amenable to
available estimation methods.
No data located.
Estimated based on analogy to
tricresyl phosphate (TCP); study
details reported in a reliable primary
source; test substance: Tricresyl
phosphate (CASRN 1330-78-5) as a
commercial product comprised of
18% dicresyl phosphate esters
(unconfirmed isomeric composition)
and 79% tricresyl phosphate esters
(21% confirmed as tri-m-cresyl
phosphate, 4% as tri-p-cresyl
phosphate, and no detectable tri-o-
cresyl phosphate [<0.1%]).
Estimated based on analogy to
tricresyl phosphate (TCP); study
details reported in a reliable primary
source; test substance: Tricresyl
phosphate (CASRN 1330-78-5) as a
commercial product comprised of
4-133
-------
Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
Other
Genotoxicity
Gene Mutation in vitro
Gene Mutation in vivo
DATA
chronic toxicity NOAEL =18 mg/kg bw-
day for females, not established for males
LOAEL: 7 mg/kg bw-day (males) and 37
mg/kg bw-day (females) for ceroid
pigmentation of adrenal cortex
No evidence of carcinogenic activity
(Estimated by analogy)
REFERENCE
DATA QUALITY
18% dicresyl phosphate esters
(unconfirmed isomeric composition)
and 79% tricresyl phosphate esters
(21% confirmed as tri-m-cresyl
phosphate, 4% as tri-p-cresyl
phosphate, and no detectable tri-o-
cresyl phosphate [<0.1%]).
No data located.
LOW: Based on results from an Ames assay, analogy to RDP (CASRN 125997-21-9) and professional
judgment. The test substance was reported to be negative for gene mutations in an Ames assay; however,
there were no experimental chromosomal aberrations data for the test substance. The analog RDP did not
cause gene mutations or chromosomal aberrations in vitro and did not produce an increase in micronuclei
in mice in vivo.
Negative, Ames assay
Negative in Salmonella typhimurium
(strains not indicated) with and without
metabolic activation at concentrations up
to 5,000 (ig/plate.
No cytotoxicity was evident.
(Estimated by analogy)
Negative in Escherichia coll (strains not
indicated) with and without metabolic
activation at concentrations up to 5,000
(ig/plate.
No cytotoxicity was evident.
(Estimated by analogy)
ICL, 2010
EPA, 2010; Pakalin et al., 2007
EPA, 2010; Pakalin et al., 2007
Reported in a material safety
datasheet with limited study details.
Estimated based on analogy.
Guideline study. Data are for a
commercial polymeric mixture of
the analog RDP (CASRN 125997-
21-9).
Estimated based on analogy.
Guideline study. Data are for a
commercial polymeric mixture of
the analog RDP (CASRN 125997-
21-9).
No data located.
4-134
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
Chromosomal Aberrations in
vitro
Chromosomal Aberrations in
vivo
DNA Damage and Repair
Other
Reproductive Effects
Reproduction/Developmental
Toxicity Screen
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
DATA
Negative in chromosomal aberration test
(cultured human lymphocytes) with and
without metabolic activation at
concentrations up to 625 (ig/mL.
Cytotoxicity data not indicated.
(Estimated by analogy)
Negative in mammalian erythrocyte
micronucleus test (Swiss mice) following
a single oral dose of 5,000 mg/kg-bw.
(Estimated by analogy)
Negative in mammalian erythrocyte
micronucleus test (mice) following single
oral dose of 500 mg/kg-bw.
(Estimated by analogy)
Limited bioavailability expected for the
high MW (>1,000) components.
(Estimated for n >5 oligomers)
REFERENCE
EPA, 2010; Pakalin et al., 2007
EPA, 2010; Pakalin et al., 2007
Submitted confidential study
Boethling and Nabholz, 1997;
Professional judgment
DATA QUALITY
Estimated based on analogy.
Guideline study. Data are for a
commercial polymeric mixture of
the analog RDP (CASRN 125997-
21-9).
Estimated based on analogy.
Guideline study. Data are for a
commercial polymeric mixture of
the analog RDP (CASRN 125997-
21-9).
Estimated based on analogy.
Reported in a submitted confidential
study for the analog RDP (CASRN
125997-21-9) conducted in
accordance with GLP and OECD
Guideline 474.
No data located.
Based on polymer assessment
literature.
MODERATE: Based on data for a confidential analog and professional judgment. There were no
experimental data located for the substance Fyrol PMP. There is potential for reproductive toxicity based
on data for a confidential analog reporting reduced litter size and weight at 250 mg/kg-day (NOAEL: 50
mg/kg-day ) a An experimental study for the analog RDP indicated no adverse effects on reproductive
performance or fertility parameters at doses up to 1,000 mg/kg-day (highest dose tested) in a two
generation dietary study in parental rats. Developmental changes effecting the reproductive system were
also reported in F1 female rats at 250 mg/kg-day. In the absence of experimental data for this substance,
and conflicting results for analogs, a conservative approach was used to assign a Moderate hazard
designation.
Two generation dietary reproduction
study in rats. Sprague-Dawley rats
(30/sex/dose) were fed 0, 50, 500, or
EPA, 2010; Pakalin et al., 2007
No data located.
Estimated based on analogy.
Guideline study. Data are for a
commercial polymeric mixture of
4-135
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Screen
1,000 mg/kg-day to the analog RDP in the
diet for 10 weeks.
There were no reproductive or systemic
effects reported in parental rats at doses
as high as 1,000 mg/kg-day.
Developmental changes affecting the
reproductive system (delayed vaginal
opening and preputial separation) were
reported in FI female rats at 500 and
1,000 mg/kg-day. This effect was
considered by study authors to be
secondary to reduction of body weight in
I generation during week 1 (treated
animals had decreased body weights
compared to controls during week 1,
reportedly due to an initial aversion to
taste of diet)
Parental systemic and reproductive
toxicity:
NOAEL: > 1,000 mg/kg-day (highest dose
tested)
LOAEL: Not established
Offspring (developmental) reproductive
toxicity:
NOAEL(Figeneration): 50 mg/kg-day
LOAEL (Figeneration): 500 mg/kg-day
(for vaginal opening and preputial
separation)
(Estimated by analogy)
the analog RDP (CASRN 125997-
21-9).
4-136
-------
Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
Reproduction and Fertility
Effects
Other
Developmental Effects
Reproduction/
Developmental Toxicity
Screen
DATA
Potential for reproductive toxicity; no
pregnancies (1,000 mg/kg-day); reduced
litter size and weight (250 mg/kg-day).
NOAEL: 50 mg/kg-day
LOAEL: 250 mg/kg-day
(Estimated by analogy)
Limited bioavailability expected.
(Estimated for n >5 oligomers)
REFERENCE
Professional judgment;
Submitted confidential study
Boethling and Nabholz, 1997;
Professional judgment
DATA QUALITY
Estimated by analogy to confidential
analog.
Based on cutoff value for large, high
MW non-ionic polymers.
MODERATE: Based on analogy to RDP (CASRN 125997-21-9) and professional judgment. There were no
experimental data for the substance Fyrol PMP. An experimental study for the analog RDP reported a
NOAEL of 50 mg/kg-day in a two generation dietary reproduction study in rats. Adverse effects included
delayed vaginal opening and preputial separation at a dose of 500 mg/kg-day. Though the changes are
considered by the study authors to be secondary to reduced body weight in the Ft generation, reported
data were insufficient to determine if this was a secondary effect. No adverse developmental effects were
observed in rabbits following oral administration of the analog RDP at doses up to 1,000 mg/kg-day.
There were no data located for the developmental neurotoxicity endpoint. The analog RDP (CASRN
125997-21-9) has been shown to cause cholinesterase inhibition which may be an indicator of potential
developmental neurotoxicity.
No data located.
4-137
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
Two generation dietary reproduction
study in rats. Sprague-Dawley rats
(30/sex/dose) were fed 0, 50, 500, or
1,000 mg/kg-day to the analog RDP in the
diet for 10 weeks.
Vaginal opening and preputial separation
were delayed at 500 and 1,000 mg/kg-
day. This effect was considered by study
authors to be secondary to reduction of
body weight in FI generation during week
1 (treated animals had decreased body
weights compared to controls during
week 1, reportedly due to an initial
aversion to taste of diet).
NOAEL(Figeneration): 50 mg/kg-day
LOAEL (Figeneration): 500 mg/kg-day
(for vaginal opening and preputial
separation)
(Estimated by analogy)
EPA, 2010; Pakalin et al., 2007
Estimated based on analogy.
Guideline study. Data are for a
commercial polymeric mixture of
the analog RDP (CASRN 125997-
21-9); limited study details reported
to determine if the developmental
effect is secondary to reduced body
weight in Fl rats.
4-138
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
Prenatal Development
Postnatal Development
Prenatal and Postnatal
Development
Developmental Neurotoxicity
Other
DATA
Pregnant rabbits; oral gavage; gestation
days (GDs) 6-28; 0, 50, 200 or 1,000
mg/kg-day test material containing the
analog RDP
No clinical signs of toxicity. No adverse
effects on maternal food consumption,
body weight gain or organ weights. No
adverse effects on fetal body weights,
viability, or any developmental endpoint
measured.
NOAEL (maternal and developmental
toxicity): >1,000 mg/kg-day (highest dose
tested)
LOAEL: Not established
(Estimated by analogy)
There were no data located for the
developmental neurotoxicity endpoint. As
a result, there is uncertain potential for
developmental neurotoxicity for this
substance. The analog RDP (CASRN
125997-21-9) has been shown to cause
cholinesterase inhibition which may be an
indicator of potential developmental
neurotoxicity.
(Estimated)
Limited bioavailability expected.
(Estimated for n>5 oligomers)
REFERENCE
EPA, 2010; Environment
Agency, 2009
Professional judgment
Boethling and Nabholz, 1997;
Professional judgment
DATA QUALITY
Estimated based on analogy.
Guideline study reported in a
secondary source. Data are for a
commercial polymeric mixture of
the analog RDP (CASRN 125997-
21-9).
No data located.
No data located.
Estimated by analogy to RDP
(CASRN 125997-21-9).
Based on cutoff value for large, high
MW non-ionic polymers.
4-139
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Neurotoxicity
MODERATE: Based on data for the analog RDP (CASRN 125997-21-9) and professional judgment. There
were no experimental data for the substance Fyrol PMP. A study for the analog RDP reported a 28-day
inhalation LOAEL of 0.5 mg/L for inhibition of plasma ChE in rats (NOAEL = 0.1 mg/L). The
neurotoxicity criteria values are tripled for 28-day studies to correlate to the criteria values based on 90-
day repeated dose studies; the LOAEL and NOAEL of 0.5 mg/kg-day and 0.1 mg/kg-day, respectively, lie
within the MODERATE hazard range from 0.06 - 0.6 mg/L. There is also potential for neurotoxicity based
on the presence of the phenol and organophosphorus structural alerts.
Neurotoxicity Screening
Battery (Adult)
Other
2 8-day inhalation study in rats with the
analog RDP (CASRN 125997-21-9); 0,
0.1, 0.5 and 2.0 mg/L (aerosol)
Significant inhibition of plasma
cholinesterase (ChE) (0.5 and 2.0 mg/L).
No clinical signs suggestive of neurotoxic
effect. ChE was not affected after study
termination.
NOAEL: 0.1 mg/L
LOAEL: 0.5 mg/L (plasma ChE
inhibition)
(Estimated by analogy)
28-day oral (gavage) study in mice with
the analog RDP (CASRN 125997-21-9);
0, 500, 1,500, 5,000 mg/kg-day.
Dose-related decrease in plasma ChE
compared to controls, which was no
longer apparent after the 60 day recovery
period.
No NOAEL/LOAEL determined.
(Estimated by analogy)
Limited bioavailability expected.
(Estimated for n>5 oligomers)
Potential for neurotoxic effects based on a
Environment Agency, 2009
Environment Agency, 2009
Boethling and Nabholz, 1997;
Professional judgment
EPA, 2012; Professional
Estimated based on analogy to RDP
(CASRN 125997-21-9). Study
details reported in a secondary
source; study was not designed to
assess all neurological parameters;
criteria values are tripled for
chemicals evaluated in 28-day
studies; the LOAEL of 0.5 mg/kg-
day falls within the Moderate hazard
criteria (0.06-0.6 mg/L).
Estimated based on analogy. Study
details reported in a secondary
source; study was not designed to
assess all neurological parameters;
cannot rule out all neurotoxicity.
Based on cutoff value for large, high
MW non-ionic polymers.
Estimated based on a structural alert
4-140
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
structural alert for phenol and
organophosphorus compounds.
judgment
for phenols and organophosphorus
compounds and professional
judgment.
Repeated Dose Effects
MODERATE: Based on analogy to RDP (CASRN 125997-21-9), a confidential analog and professional
judgment. There were no experimental data for the test substance Fyrol PMP. A 4-week inhalation
exposure study in rats to 0.5 mg/L of the analog RDP as an aerosol resulted in alveolar histiocytosis
(NOAEC = 0.1 mg/L- day). No other exposure-related gross or microscopic pathology was identified in any
organ in this study. The repeated dose criteria values are tripled for 28-day studies to correlate to the
criteria values based on 90-day repeated dose studies; this study lies in the MODERATE hazard range
from 0.06 - 0.6 mg/L. There is also potential for liver toxicity based on a confidential analog (NOEL = 300
mg/kg-day).
4-141
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
Immune System Effects
DATA
In a 4-week inhalation study Sprague-
Dawley rats (10/sex/group) were exposed
(aerosol, nose only) to 0, 100, 500 or
2,000 mg/m3 (0, 0.1, 0.5, or 2 mg/L) of
the analog RDP.
No deaths or clinical signs of toxicity.
Decreased body weight and food
consumption in males. Significant
inhibition of plasma cholinesterase in
females at 500 and 2,000 mg/m3 and in
males at 2,000 mg/m3. White foci in the
lungs at 2,000 mg/m3 and alveolar
histiocytosis at 500 and 2,000 mg/m3.
Although lung changes are relevant, they
were not considered to be a reflection of a
specific toxic response to the analog
RDP; these changes are characteristic of
exposure to non-cytotoxic water-insoluble
materials.
No other gross or microscopic pathology
in any organ.
NOAEC: 100 mg/m3 (0.1 mg/L)
LOAEC: 500 mg/m3 (0.5 mg/L; based on
alveolar histiocytosis)
(Estimated based on analogy)
28-day oral study, rats
Potential for liver toxicity.
NOEL: 300 mg/kg-day
(Estimated based on analogy)
Limited bioavailability expected for the
high MW (>1,000) components.
(Estimated for n >5 oligomers)
Negative, oral gavage study in mice.
REFERENCE
EPA, 2010; Environment
Agency, 2009
Submitted confidential study;
Professional judgment
Boethling and Nabholz, 1997;
Professional judgment
EPA, 2010
DATA QUALITY
Estimated based on analogy.
Guideline study reported in a
secondary source. Data are for a
commercial polymeric mixture of
the analog RDP (CASRN 125997-
21-9).
Estimated based on analogy to
confidential analog.
Based on polymer assessment
literature.
Estimated based on analogy.
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
Skin Sensitization
Skin Sensitization
Respiratory Sensitization
[Respiratory Sensitization
Eye Irritation
Eye Irritation
DATA
Female B6C3F1 mice (50/group) were
exposed via oral gavage to 0, 500, 1,500,
or 5,000 mg/kg-day of the analog RDP
for 28 days.
No deaths, clinical signs of toxicity, or
effects on body or organ weights. No
adverse histopathological changes or
necropsy findings. No treatment-related
changes in peritoneal cell numbers or cell
types, peritoneal macrophage phagocytic
activity or host susceptibility to infection.
No adverse effect on splenic natural killer
cell activity, lymphocyte blastogenesis, or
antibody-forming cell function. There
were significant decreases in erythrocyte
cholinesterase activity and plasma
pseudocholinesterase activity in all dose
groups, but both enzyme activities
returned to control levels at the end of the
60 day recovery period.
REFERENCE
DATA QUALITY
Guideline study reported in a
secondary source. Data are for a
commercial polymeric mixture of
the analog RDP (CASRN 125997-
21-9).
LOW: Negative for skin Sensitization in guinea pigs.
Non-sensitizing, guinea pigs
Not a sensitizer, Modified Buehler
Method
Submitted confidential study
ICL, 2010
Adequate confidential study
Reported in a material safety
datasheet with limited study details.
No data located.
No data located.
LOW: Fyrol PMP was mildly irritating to rabbit eyes.
Mild, rabbits
Negative, rabbits
ICL, 2010
Submitted confidential study
Reported in a material safety
datasheet with limited study details.
Study details and test conditions
were not available.
4-143
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
Dermal Irritation
Dermal Irritation
Endocrine Activity
DATA
REFERENCE
DATA QUALITY
LOW: Fyrol PMP was mildly irritating to rabbit skin.
Mild irritant, rabbit
ICL, 2010
Reported in a material safety
datasheet with limited study details.
No experimental data were located to evaluate and determine if Fyrol PMP affects endocrine activity.
However, resorcinol, a metabolite of the analog RDP (CASRN 125997-21-9) and a starting material in
Fyrol PMP synthesis, is listed as a suspected endocrine disruptor by the EU.
Resorcinol (CASRN 108-46-3) is listed as
a potential endocrine disruptor on the EU
Priority List of Suspected Endocrine
Disrupters.
(Estimated by analogy)
European Commission, 2012
Estimated by analogy. "Potential for
endocrine disruption. In vitro data
indicating potential for endocrine
disruption in intact organisms. Also
included effects in-vivo that may, or
may not, be endocrine disruption-
mediated. May include structural
analyses and metabolic
considerations".
4-144
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
Immunotoxicity
Immune System Effects
DATA
REFERENCE
DATA QUALITY
The analog, RDP (CASRN 125997-21-9), had no effect on immunological parameters at doses up to 5,000
mg/kg-day (highest dose tested) in an oral gavage study in mice. The higher MW components of this
polymer (MW >1,000) are expected to have limited bioavailability and have low potential for
immunotoxicity.
Negative, oral gavage study in mice.
Female B6C3F1 mice (50/group) were
exposed via oral gavage to 0, 500, 1,500,
or 5,000 mg/kg-day for the analog RDP
for 28 days.
No deaths, clinical signs of toxicity, or
effects on body or organ weights. No
adverse histopathological changes or
necropsy findings. No treatment-related
changes in peritoneal cell numbers or cell
types, peritoneal macrophage phagocytic
activity or host susceptibility to infection.
No adverse effect on splenic natural killer
cell activity, lymphocyte blastogenesis, or
antibody-forming cell function. There
were significant decreases in erythrocyte
cholinesterase activity and plasma
pseudocholinesterase activity in all dose
groups, but both enzyme activities
returned to control levels at the end of the
60 day recovery period.
Limited bioavailability expected for the
high MW (>1,000) components.
(Estimated for n >5 oligomers)
EPA, 2010
Boethling and Nabholz, 1997;
Professional judgment
Estimated based on analogy.
Guideline study reported in a
secondary source. Data are for the
analog, a commercial polymeric
mixture of RDP (CASRN 125997-
21-9).
Based on polymer assessment
literature.
4-145
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
ECOTOXICITY
ECOSAR Class
Phenols
Acute Aquatic Toxicity
HIGH: Based on estimated acute aquatic toxicity values for fish, daphnia, and green algae using the
phenols SAR for a representative structure, where n=l, with a MW <1,000. The high MW components,
with a MW>1,000 have low water solubility and are expected to have no effects at saturation (NES).
Fish LC50
Freshwater fish 96-hour LC50:
6.2 mg/L (ECOSAR class: Phenols)
Freshwater fish 96-hour LC50:
n=2: 1.6 mg/L
n=3: 0.39 mg/L
n=4: 0.09 mg/L
(ECOSAR class: Phenols)
(Estimated)
NES
(Estimated)
ECOSAR v 1.11
ECOSAR v 1.11
Professional judgment
Estimate based on representative
oligomer n=l.
Estimates based on representative
oligomers n=2 through n=4. The
corresponding estimated effects
exceed the water solubilities (0.1
mg/L for n=2, 0.001 mg/L for n=3,
and 0.00001 mg/L for n=4) by more
than lOx. NES are predicted for
these endpoints.
The large MW, limited
bioavailability and low water
solubility suggest there will be NES
for the MW >1,000 components.
Daphnid LC50
Daphnia magna 48-hour LC50:
3.5 mg/L (ECOSAR class: Phenols)
ECOSAR v 1.11
Daphnia magna 48-hour LC50:
n=2: 1.4 mg/L
n=3: 0.52 mg/L
n=4: 0.18 mg/L
(ECOSAR class: Phenols)
(Estimated)
ECOSAR v 1.11
Estimate based on representative
oligomer n=l.
Estimates based on representative
oligomers n=2 through n=4. The
corresponding estimated effects
exceed the water solubilities (0.1
mg/L for n=2, 0.001 mg/L for n=3,
and 0.00001 mg/L for n=4) by more
than lOx. NES are predicted for
4-146
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
NES
(Estimated)
Professional judgment
these endpoints.
The large MW, limited
bioavailability and low water
solubility suggest there will be NES
for the MW >1,000 components.
Green Algae EC50
Green algae 96-hour EC50:
14 mg/L (ECOSAR class: Phenols)
ECOSARvl.ll
Green algae 96-hour EC50:
n=2: 5.1 mg/L
n=3: 1.7 mg/L
n=4: 0.55 mg/L
(ECOSAR class: Phenols)
(Estimated)
ECOSARvl.ll
NES
(Estimated)
Professional judgment
Estimate based on representative
oligomer n=l.
Estimates based on representative
oligomers n=2 through n=4. The
corresponding estimated effects
exceed the water solubilities (0.1
mg/L for n=2, 0.001 mg/L for n=3,
and 0.00001 mg/L for n=4) by more
than lOx. NES are predicted for
these endpoints.
The large MW, limited
bioavailability and low water
solubility suggest there will be NES
for the MW >1,000 components.
Chronic Aquatic Toxicity
HIGH: Based on estimated chronic aquatic toxicity values for fish, daphnia, and green algae using the
phenols SAR for representative structure, where n=l, with a MW <1,000. The high MW components, with
a MW>1,000 have low water solubility and are expected to have no effects at saturation (NES).
Fish ChV
Freshwater fish ChV:
0.77 mg/L (ECOSAR class: Phenols)
ECOSARvl.ll
Estimate based on representative
oligomer n=l.
4-147
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
ECOSARvl.ll
Freshwater fish ChV:
n=2: 0.23 mg/L
n=3: 0.06 mg/L
n=4: 0.02 mg/L
(ECOSAR class: Phenols)
(Estimated)
NES
(Estimated)
Professional judgment
Estimates based on representative
oligomers n=2 through n=4. The
estimated effect for n=2 exceeds the
water solubility of 0.1 mg/L, but not
by lOx as required to be considered
NES by ECOSAR. The chemical
may not be soluble enough to
measure the predicted effect. The
corresponding estimated effects for
n=3 and n=4 exceed the water
solubilities (0.001 mg/L and
0.00001 mg/L, respectively) by
more than lOx. NES are predicted
for these oligomers.
The large MW, limited
bioavailability and low water
solubility suggest there will be NES
for the MW >1,000 components.
Daphnid ChV
Daphnia magna ChV:
0.67 mg/L (ECOSAR class: Phenols);
ECOSARvl.ll
Daphnia magna ChV:
n=2: 0.27 mg/L
n=3: 0.1 mg/L
n=4: 0.03 mg/L
(ECOSAR class: Phenols)
(Estimated)
ECOSARvl.ll
Estimate based on representative
oligomer n=l.
Estimates based on representative
oligomers n=2 through n=4. The
estimated effect for n=2 exceeds the
water solubility of 0.1 mg/L, but not
by lOx as required to be considered
NES by ECOSAR. The chemical
may not be soluble enough to
measure the predicted effect. The
corresponding estimated effects for
n=3 and n=4 exceed the water
solubilities (0.001 mg/L and
0.00001 mg/L, respectively) by
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
Green Algae ChV
DATA
NES
(Estimated)
Green algae ChV:
6.5 mg/L (ECOSAR class: Phenols)
Green algae ChV:
n=2: 2.4 mg/L
n=3: 0.78 mg/L
n=4: 0.25 mg/L
(ECOSAR class: Phenols)
(Estimated)
NES
(Estimated)
REFERENCE
Professional judgment
ECOSAR v 1.11
ECOSAR v 1.11
Professional judgment
DATA QUALITY
more than lOx. NES are predicted
for these oligomers.
The large MW, limited
bioavailability and low water
solubility suggest there will be NES
for the MW >1,000 components.
Estimate based on representative
oligomer n=l.
Estimates based on representative
oligomers n=2 through n=4. The
corresponding estimated effects
exceed the water solubilities (0.1
mg/L for n=2, 0.001 mg/L for n=3,
and 0.00001 mg/L for n=4) by more
than lOx. NES are predicted for
these endpoints.
The large MW, limited
bioavailability and low water
solubility suggest there will be NES
for the MW >1,000 components.
ENVIRONMENTAL FATE
4-149
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
Transport
Henry's Law Constant (atm-
m3/mole)
Sediment/Soil
Adsorption/Desorption - Koc
Level III Fugacity Model
Persistence
Water
Aerobic Biodegradation
DATA
REFERENCE
DATA QUALITY
The estimated negligible water solubility and estimated negligible vapor pressure indicate that this
polymer is anticipated to partition predominantly to soil and sediment. The estimated Henry's Law
Constant of <10~8 atm-m3/mole indicates that it is not expected to volatilize from water to the atmosphere.
The estimated Koc of >30,000 indicates that it is not anticipated to migrate from soil into groundwater and
also has the potential to adsorb to sediment.
<10~8 for the n>5 oligomers (Estimated)
<10"8 for n= 1-4 (Estimated)
>3 0,000 for n= 1-4 (Estimated)
>3 0,000 for the n>5 oligomers
(Estimated)
Air = 0%
Water = 4.8%
Soil = 57%
Sediment = 39% (Estimated)
for n=l
Boethling and Nabholz, 1997;
Professional judgment
EPIv4.11
EPI v4. 1 1 ; Professional
judgment
Boethling and Nabholz, 1997;
Professional judgment
EPIv4.11
High MW polymers are expected to
have low vapor pressure and are not
expected to undergo volatilization.
Estimated value based on
representative structures with MW
< 1,000. Cutoff value for nonvolatile
compounds.
Estimated for the n>5 oligomers;
cutoff value used for large, high
MW polymers. High MW polymers
are expected to adsorb strongly to
soil and sediment.
Estimates based on a representative
structure where n=l. No data located
for the high MW component of the
polymers.
VERY HIGH: Although experimental data are not available, the high MW components of this polymer
(n>5; MW>1,000) are expected to be recalcitrant to biodegradation. Estimated half-lives for ultimate
aerobic biodegradation are >180 days for the n=l oligomer, representing MW <1,000 components of the
polymer. Degradation of this polymer by hydrolysis or direct photolysis is not expected to be significant as
the functional groups present do not tend to undergo these reactions under environmental conditions. The
atmospheric half-life is estimated to be <1 day; however, the polymer is not anticipated to partition
significantly to air.
Days-weeks (Primary Survey Model)
Weeks-months (Ultimate Survey Model)
(Estimated)
Recalcitrant
EPIv4.11
Boethling and Nabholz, 1997;
Estimates based on representative
oligomer where n=l .
High MW polymers are expected to
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
Soil
Air
Reactivity
Volatilization Half-life for
Model River
Volatilization Half-life for
Model Lake
Aerobic Biodegradation
Anaerobic Biodegradation
Soil Biodegradation with
Product Identification
Sediment/Water
Biodegradation
Atmospheric Half-life
Photolysis
Hydrolysis
DATA
for n>5 oligomers (Estimated)
>1 year (Estimated)
>1 year (Estimated)
Not probable (Anaerobic-methanogenic
biodegradation probability model) for
n=l-4
Recalcitrant
for n>5 oligomers (Estimated)
<0.15 days (Estimated)
Not a significant fate process (Estimated)
>1 year (Estimated)
REFERENCE
Professional judgment
EPIv4. 11; Professional
judgment
EPI v4. 1 1 ; Professional
judgment
EPIv4.11
Boethling and Nabholz, 1997;
Professional judgment
EPIv4.11
Mill, 2000; Professional
judgment
Professional judgment
DATA QUALITY
be non-biodegradable.
Estimated value based on
representative structures with MW
< 1,000. Also, the high MW polymer
components are anticipated to be
nonvolatile.
Estimated value based on
representative structures with MW
< 1,000. Also, the high MW polymer
components are anticipated to be
nonvolatile.
No data located.
Estimates based on representative
oligomer where n=l-4.
High MW polymers are expected to
be resistant to removal under anoxic
conditions due to their limited
bioavailability.
No data located.
No data located.
Estimated value based on four
confidential representative structures
withMW
-------
Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
Environmental Half-life
Bioaccumulation
Fish BCF
Other BCF
BAF
DATA
>1 year at pH 6
68 days at pH 7
6.8 days at pH 8
16 hours atpH9
(Estimated for n=l)
>75 days Half-life estimated for
representative structure where n=l; in the
predominant compartment, soil, as
determined by EPI and the PBT Profiler
methodology (Estimated)
REFERENCE
EPIv4.11
PBT Profiler vl.301; EPI v4. 1 1
DATA QUALITY
to an appreciable extent.
Hydrolysis rates are expected to be
pH-dependent and may be limited
by the low water solubility of this
compound. Under basic conditions,
sequential dephosphorylation
reactions may occur.
Half-life estimated for the
predominant compartment, soil, as
determined by EPI and the PBT
Profiler methodology.
HIGH: The estimated BCF and BAF for the low MW components (n=l-4; MW<1,000) result in a High
bioaccumulation designation. The higher MW oligomers that may be found in the polymeric mixture (n>5;
MW>1,000) are expected to have Low potential for bioaccumulation based on their large size and low
water solubility according to the polymer assessment literature and professional judgment.
6,600 for n=4 (Estimated)
1,500 forn=3 (Estimated)
360 forn=2 (Estimated)
85 forn=l (Estimated)
< 100 (Estimated)
2.1xl06 for n=4 (Estimated)
3.2xl04 for n=3 (Estimated)
EPIv4.11
EPIv4.11
EPIv4.11
EPIv4.11
Boethling and Nabholz, 1997;
Professional judgment
EPIv4.11
EPIv4.11
Estimates based on representative
structure where n=4.
Estimates based on representative
structure where n=3 .
Estimates based on representative
structure where n=2.
Estimates based on representative
structure where n=l.
Estimated for the oligomers with a
MW >1,000. Cutoff value for large,
high MW, insoluble polymers
according to polymer assessment
literature.
No data located.
Estimates based on representative
structure where n=4.
Estimates based on representative
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Fyrol PMP CASRN 63747-58-0
PROPERTY/ENDPOINT
Metabolism in Fish
DATA
1,200 forn=2 (Estimated)
170forn=l (Estimated)
REFERENCE
EPIv4.11
EPIv4.11
DATA QUALITY
structure where n=3 .
Estimates based on representative
structure where n=2.
Estimates based on representative
structure where n=l.
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
Ecological Biomonitoring
Human Biomonitoring
No data located.
No data located.
No data located.
4-153
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Boethling RS and Nabholz JV (1997) Environmental assessment of polymers under the U.S. Toxic Substances Control Act. Washington, DC: U.S.
Environmental Protection Agency.
ECOSAR Ecological Structure Activity Relationship (ECOSAR). Estimation Programs Interface (EPI) Suite for Windows, Version 1.11.
Washington, DC: EPIWIN/EPISUITE. U.S. Environmental Protection Agency, http://www.epa.gov/oppt/newchems/tools/21ecosar.htm.
EPA (1999) Determining the adequacy of existing data. High Production Volume (HPV) Challenge. Washington, DC: U.S. Environmental
Protection Agency, http://www.epa.gov/hpv/pubs/general/datadeqfn.pdf
EPA (2010) Screening level hazard characterization phosphoryl chloride, polymer with resorcinol phenyl ester.
http://www.epa.gov/chemrtk/hpvis/hazchar/125997219_Phosphoryl%20chloride,%20polymer%20with%20resorcinor/o20phenyr/o20ester_%20Ju
ne%202010.pdf.
EPA (2012) Using noncancer screening within the SF initiative. Washington, DC: U.S. Environmental Protection Agency.
http://www.epa.gov/oppt/sf/pubs/noncan-screen.htm.
EPI Estimation Programs Interface (EPI) Suite, Version 4.11. Washington, DC: EPIWIN/EPISUITE. U.S. Environmental Protection Agency.
http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm.
ESIS (2012) European chemical Substances Information System. European Commission, http://esis.jrc.ec.europa.eu/.
Environment Agency (2009) Environmental risk evaluation report: Tetraphenyl resorcinol diphosphate (CAS no. 57586-54-7). Environment
Agency, http://cdn.environment-agency.gov.uk/scho0809bqul-e-e.pdf
European Commission (2012) EU priority list of suspected endocrine disrupters.
http://ec.europa.eu/environment/endocrine/strategy/substances_en.htm#priority_list.
Hsu HH (2013) Halogen-free flame-retardant epoxy resin composition, and prepreg and printed circuit board using the same. Owner name:
Taiwan Union Technology Corporation, Taiwan. United States Patent and Trademark Office. IFI CLAIMS Patent Services.
http://www.google.com/patents/US8581107.
ICL (2010) Material safety data sheet: Fyrol PMP. ICL Industrial Products, http://daatsolutions.info/brom2/wp-
content/uploads/2012/03/7042_enFyrol_PMP.pdf
ICL (2013) Brochure on flame retardants. ICL Industrial Products, www.iclfr.com.
Mill T (2000) Photoreactions in surface waters. In: Boethling R, Mackay D, eds. Handbook of Property Estimation Methods for Chemicals,
Environmental Health Sciences. Boca Raton: Lewis Publishers.:355-381.
4-154
-------
NTP (1994) NTP technical report on the toxicology and carcinogenesis studies of tricresyl phosphate in F344/N rats and B6C3F1 mice (Gavage
and feed studies).
PBT Profiler Persistent (P), Bioaccumulative (B), and Toxic (T) Chemical (PBT) Profiler, Version 1.301. Washington, DC: U.S. Environmental
Protection Agency, www.pbtprofiler.net.
Pakalin S, Cole T, Steinkeliner J, et al. (2007) Review on production processes of decabromodiphenyl ether (DECABDE) used in polymeric
applications in electrical and electronic equipment, and assessment of the availability of potential alternatives to DECABDE. European Chemicals
Bureau, European Commission, http://publications.jrc.ec.europa.eu/repository/bitstream/l 1111111 l/5259/l/EUR%2022693.pdf.
4-155
-------
D.E.R. 500 Series
VL = Very Low hazard L = Low hazard = Moderate hazard H = High hazard VH = Very High hazard — Endpoints in colored text (VL, L, M, H, and VH) were
assigned based on empirical data. Endpoints in black italics (VL, L, M, H, and VH) were assigned using values from predictive models and/or professional judgment.
This table contains hazard information for each chemical; evaluation of risk considers both hazard and exposure. Variations in end-of-life processes or degradation and combustion
by-products are discussed in the report but not addressed directly in the hazard profiles. The caveats listed below must be taken into account when interpreting the information in the
table.
* The highest hazard designation of any of the oligomers with MW < 1,000. ¥ Aquatic toxicity: EPA/DfE criteria are based in large part upon water column exposures which may not
be adequate for poorly soluble substances such as many flame retardants that may partition to sediment and particulates.
Chemical
CASRN
Human Health Effects
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D.E.R. 500 Series*
26265-08-7 \L\M\M\M\M\M\M\
VH
4-156
-------
D.E.R. 500 Series
OH
Br
CASRN: 26265-08-7
MW: Average MW 900 (Measured)
MF: CsgH
MW=940
? as shown with n=l;
Physical Forms: Solid
Neat:
Use: Flame retardant
SMILES: OlCClCOc2ccc(cc2)C(C)(C)c3ccc(cc3)OCC(O)COc4c(Br)cc(cc4Br)C(C)(C)c5cc(Br)c(c(Br)c5)OCC6CO6 as shown with n = 1
Synonyms: Phenol, 4,4'(l-methylethylidene)bis[2,6-dibromo-, polymer with (chloromethyl)oxirane and 4,4'-(l-methylethylidene)bis[phenol] (The reaction product
of TBBPA), bisphenol A, epichlorohydrin and tetrabromobisphenol A polymer; Brominated epoxy resin; Epichlorohydrin, tetrabromobisphenol A polymer
Trade names: D.E.R.® 500 series epoxy resin; D.E.R. 538; Epikote 1145-B-70; EPON Resin 1123 (polymer of tetrabromobisphenol A epoxy resin, bisphenol A
diglycidyl ether, and epichlorohydrin)
The D.ER. 500 series epoxy resin product literature also lists CASRN 40039-93-8, Phenol, 4,4'-(l-methylethylidene)bis[2,6-dibromo-, polymer with 2-
(chloromethyl)oxirane; or Bisphenol A diglycidyl ether, brominated. This compound is a very close structural analog to Phenol, 4,4'(l-methylethylidene)bis[2,6-
dibromo-, polymer with (chloromethyl)oxirane and 4,4'-(l-methylethylidene)bis[phenol] (CASRN 26265-08-7).
Chemical Considerations: The D.E.R. 500 Series of polymers consist of components with MWs above and below 1,000 daltons.
The low MW components (MW <1,000) are expected to be present at levels requiring their assessment. The MW <1,000 components are assessed with EPI v4.11 and
ECOSAR vl. 11 estimates due to an absence of publicly available experimental physical/chemical, environmental fate and aquatic toxicity values. These include the
n=l component as shown in the SMILES entry and the n=0 component, as represented by the discrete organic 2,2',6,6'-tetrabromobisphenol A diglycidyl ether
(CASRN 3072-84-2).
The n>2 oligomers have a MW >1,000 and are assessed using the available polymer assessment literature.
Polymeric: Yes
Oligomeric: This is a tetrabromobisphenol A (TBBPA)-based epoxy resin; the oligomers are produced by reacting epichlorohydrin with bisphenol A (BPA) and
TBBPA (Dow, 2009).
Metabolites, Degradates and Transformation Products: None identified (Professional judgment)
Analog: None
Endpoint(s) using analog values: Not applicable
Analog Structure: Not applicable
4-157
-------
Structural Alerts: Polyhalogenated aromatic hydrocarbons: immunotoxicity; epoxy groups/epoxides: dermal sensitization, cancer, reproductive effects,
developmental toxicity (EPA, 2012; EPA, 2010).
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 2012).
Hazard and Risk Assessments: None identified.
4-158
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
Boiling Point (°C)
Vapor Pressure (mm Hg)
Water Solubility (mg/L)
>300
(Estimated)
<10"8 for MW <1,000 components
(Estimated)
<10"8 for the n>2 oligomers (Estimated)
3.3xlO~5 for a component (Estimated)
1.7xlO"9forn=l (Estimated)
<0.001
EPIv4.11;EPA, 1999
EPIv4.11;EPA, 1999
Boethling and Nabholz, 1997;
Professional judgment
EPIv4.11
EPIv4.11;EPA, 1999
Boethling and Nabholz, 1997;
No data located.
Estimates based on a representative
oligomer where n=l and for
2,2',6,6'-tetrabromobisphenol A
diglycidyl ether (CASRN 3072-84-
2), a component of the polymeric
mixture with a MW <1,000. Also
estimated for oligomers where n>2
with MWs >1,000. Cutoff value
according to HPV assessment
guidance and cutoff value used for
large, high MW solids.
Estimates based on representative
oligomer where n=l and for
2,2',6,6'-tetrabromobisphenol A
diglycidyl ether (CASRN 3072-84-
2), a component of the polymeric
mixture. Cutoff value for nonvolatile
compounds according to HPV
assessment guidance.
Cutoff value for large, high MW
polymers.
Estimated for 2,2',6,6'-
tetrabromobisphenol A diglycidyl
ether (CASRN 3072-84-2), a
component of the polymeric
mixture.
Estimates based on representative
oligomer where n=l. Values are less
than the cutoff value, <0.001 mg/L,
for non-soluble compounds
according to HPV assessment
guidance.
Cutoff value for large, high MW
4-159
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
Log Kow
Flammability (Flash Point)
Explosivity
Pyrolysis
pH
pKa
Particle Size
DATA
for the n>2 oligomers (Estimated)
7.4
for a component (Estimated)
11
forn=l (Estimated)
No data located;
for n>2 oligomers (Estimated)
Not flammable (Estimated)
Not expected to form explosive mixtures
with air (Estimated)
Not applicable (Estimated)
Not applicable (Estimated)
REFERENCE
Professional judgment
EPIv4.11
EPIv4.11;EPA, 1999
Professional judgment
Professional judgment
Professional judgment
Professional judgment
DATA QUALITY
non-ionic polymers.
Estimated for 2,2',6,6'-
tetrabromobisphenol A diglycidyl
ether (CASRN 3072-84-2), a
component of the polymeric
mixture.
Estimates based on representative
oligomer where n=l. Estimated
value is greater than the cutoff
value, >10, according to
methodology based on HPV
assessment guidance.
Polymers with a MW > 1,000 are
outside the domain of the available
estimation methods.
No experimental data located; based
on its use as a flame retardant.
No experimental data located; based
on its use as a flame retardant.
No data located.
Does not contain functional groups
that are expected to ionize under
environmental conditions.
Does not contain functional groups
that are expected to ionize under
environmental conditions.
No data located.
4-160
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
HUMAN HEALTH EFFECTS
Toxicokinetics
Dermal Absorption in vitro
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal or Inhaled
Other
Acute Mammalian Toxicity
Acute Lethality
Oral
Dermal
No experimental data were located. Based on professional judgment, absorption is expected to be poor by
all routes for the low MW (<1,000) fraction. There is no absorption expected for any route of exposure for
the large MW >1,000 components.
Absorption is expected to be poor by all
routes for the low molecular weight
fraction. There is no absorption expected
for any route of exposure for the large,
high molecular weight (> 1,000) fraction.
(Estimated)
Professional judgment
Estimated based on professional
judgment.
No data located.
LOW: Estimated based on experimental data for a component of D.E.R., professional judgment and by
analogy to structurally similar polymers. The large MW components, with a MW >1,000, are expected to
have limited bioavailability and therefore have low potential for acute mammalian toxicity. There was no
data located regarding the inhalation route of exposure.
Rat oral LD50 > 2,000 mg/kg
Rat oral LD50 = 7,160 mg/kg
Rat oral LD50 >3,663 mg/kg
(Estimated by analogy)
Rat LD50 >2,000 mg/kg
(Estimated by analogy)
ECHA, 2014
Ash and Ash, 2009
Submitted confidential study;
Professional judgment
ECHA, 2014
Study details reported in a secondary
source; test substance identified as
F-2200HM (CASRN 3072-84-2) a
component of the polymeric
mixture; purity: 100%; conducted
according to OECD 423.
Limited study details reported in a
secondary source; data are for
2,2',6,6'-tetrabromobisphenol A
diglycidyl ether (CASRN 3072-84-
2), a component of the polymeric
mixture.
Based on closely related confidential
analogs with similar structures,
functional groups, and
physical/chemical properties.
Estimated based on analogy; Study
details reported in a secondary
4-161
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
Inhalation
Carcinogenicity
OncoLogic Results
Carcinogenicity (Rat and
Mouse)
Combined Chronic
Toxicity/Carcinogenicity
Other
DATA
Rabbit LD50 >2,000 mg/kg
(Estimated by analogy)
REFERENCE
Submitted confidential study;
Professional judgment
DATA QUALITY
source for the test substance
bisphenol A diglycidyl ether,
brominated (CASRN 40039-93-8), a
very close structural analog.
Based on closely related confidential
analogs with similar structures,
functional groups, and
physical/chemical properties.
No data located.
MODERATE: There is uncertainty due to lack of data for this substance. In addition, there is potential for
Carcinogenicity based on a structural alert for epoxy groups/epoxides though this concern may be
mitigated by the high molecular weight; carcinogenic effects cannot be completely ruled out.
There is potential for Carcinogenicity
based on a structural alert for epoxy
groups/epoxides; however, the concern
may be mediated by the high molecular
weight.
(Estimated)
Professional judgment; EPA,
2010
Not amenable for OncoLogic
modeling.
No data located.
No data located.
Estimated based on a structural alert
for epoxy groups/epoxides and
professional judgment.
4-162
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D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Genotoxicity
MODERATE: There is uncertainty regarding the potential for genotoxicity due to the lack of sufficient
data for this substance. Conflicting results were reported for gene mutations; the test substance was
reported to be negative for gene mutations in one study, while there were positive results for gene
mutations in Ames and mouse lymphoma assays. There were also mixed results for sister chromatid
exchanges for analogs. There was no experimental chromosomal aberrations data for the test substance
located. Genotoxic effects cannot be completely ruled out; an estimated Moderate hazard designation was
assigned.
Gene Mutation in vitro
Negative, Salmonella typhimurium strains
TA98, TA100, TA1535, TA1537 and
TA1538 and E. coli strain WP2 uvrA
pKMlOl with and without metabolic
activation.
Negative, Salmonella typhimurium strains
TA98, TA100, TA1535, TA1537 andE.
coli strain WP2 uvrA pKMlOl with and
without metabolic activation.
(Estimated by analogy)
Positive, Ames assay
(Estimated by analogy)
Positive, mouse lymphoma test
(Estimated by analogy)
Gene Mutation in vivo
Chromosomal Aberrations in
vitro
Negative, chromosomal aberration test in
human lymphocytes with and without
metabolic activation
(Estimated by analogy)
4-163
Willett, 1991
ECHA, 2014
Submitted confidential study
Submitted confidential study
ECHA, 2014
Study details reported in the primary
source. Test substances reported as
Epikote 1145-B-70.
Estimated based on analogy; study
details reported in a secondary
source for the test substance
bisphenol A diglycidyl ether,
brominated (CASRN 40039-93-8), a
very close structural analog;
conducted according to OECD 471.
Limited study details reported in a
confidential study submitted to EPA.
Estimated based on a confidential
analog.
Limited study details reported in a
confidential study submitted to EPA.
Estimated based on a confidential
analog.
No data located.
Estimated based on analogy; study
details reported in a secondary
source for the test substance
bisphenol A diglycidyl ether,
brominated (CASRN 40039-93-8), a
very close structural analog;
conducted according to OECD 473.
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
Chromosomal Aberrations in
vivo
DNA Damage and Repair
Other
Reproductive Effects
Reproduction/Developmental
Toxicity Screen
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
Reproduction and Fertility
Effects
Other
Developmental Effects
Reproduction/
Developmental Toxicity
Screen
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
DATA
Positive, chromosomal aberration test in
human lymphocytes
(Estimated by analogy)
REFERENCE
Submitted confidential study
DATA QUALITY
Limited study details reported in a
confidential study submitted to EPA.
Estimated based on a confidential
analog.
No data located.
No data located.
No data located.
MODERATE: There is potential for reproductive toxicity for the low MW oligomers of the polymer
(<1,000) based on a structural alert for epoxy groups/epoxides.
There is potential for reproductive
toxicity based on a structural alert for
epoxy groups/epoxides.
(Estimated)
Professional judgment; EPA,
2010
No data located.
No data located.
No data located.
Estimated based on a structural alert
for epoxy groups/epoxides and
professional judgment.
MODERATE: There is potential for developmental toxicity for the low MW oligomers of the polymer
(<1,000) based on a structural alert for epoxides.
There were no data located for the developmental neurotoxicity endpoint.
No data located.
No data located.
4-164
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
Prenatal Development
Postnatal Development
Prenatal and Postnatal
Development
Developmental Neurotoxicity
Other
Neurotoxicity
Neurotoxicity Screening
Battery (Adult)
Other
Repeated Dose Effects
DATA
No data was located for the
developmental neurotoxicity endpoint.
There is potential for developmental
toxicity based on a structural alert for
epoxy groups/epoxides
(Estimated)
REFERENCE
Professional judgment; EPA,
2010
DATA QUALITY
No data located.
No data located.
No data located.
No data located.
Estimated based on a structural alert
for epoxy groups/epoxides and
professional judgment.
MODERATE: There is potential for neurotoxicity for the lower MW components based on professional
judgment.
Potential for neurotoxicity
(Estimated)
Professional judgment
No data located.
Estimated based on the lower MW
components and professional
judgment.
MODERATE: Estimated to have potential for immunotoxicity based on a structural alert for
polyhalogenated aromatic hydrocarbons and liver effects for the lower MW components. A 28-day oral
study in rats for a very close structural analog, bisphenol A diglycidyl ether, brominated (CASRN 40039-
93-8) indicated effects in males (reduced body weight gain) at a dose of 1,000 mg/kg bw-day (NOAEL =
300 mg/kg bw-day).
Potential for liver effects
(Estimated)
Potential for immunotoxicity based on
structural alert for polyhalogenated
aromatic hydrocarbons.
(Estimated)
28-day oral (gavage) study in male and
female Wistar rats; 30, 300 and 1,000
mg/kg bw-day
Reduced body weight gain in males at
Professional judgment
Professional judgment; EPA,
2012
ECHA, 2014
Estimated based on the lower MW
components and professional
judgment.
Estimated based on structural alert
for polyhalogenated aromatic
hydrocarbons and professional
judgment.
Study details reported in a secondary
source for the test substance
bisphenol A diglycidyl ether,
brominated (CASRN 40039-93-8), a
4-165
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
Skin Sensitization
Skin Sensitization
Respiratory Sensitization
[Respiratory Sensitization
DATA
1,000 mg/kg bw-day. Microscopic liver
changes (centrilobular hypertrophy) and
metabolic blood chemical changes
(increases in alanine aminotransferase,
aspartate aminotransferase or bile acids)
in males at 300 and 1,000 mg/kg bw-day
were not considered to be adverse health
effects.
NOAEL = 300 mg/kg bw-day (males)
LOAEL = 1,000 mg/kg bw-day (males,
based on reduction in body weight gain)
REFERENCE
DATA QUALITY
very close structural analog.
Conducted according to GLP and
OECD guideline 407.
HIGH: Positive for skin Sensitization in guinea pigs. In addition, there is an estimated potential for skin
Sensitization based on a structural alert for epoxy groups/epoxides.
Strong sensitizer, guinea pigs,
maximization test.
19/20 test animals showed positive
responses 24 hours after removal of
challenge patches and 16 continued to
have positive response at 48 hours.
Not sensitizing, mouse local lymph node
assay (LLNA)
There is potential for skin Sensitization
based on a structural alert for epoxy
groups/epoxide s .
(Estimated)
Willett, 1990
ECHA, 2014
Professional judgment
Adequate primary source; Test
substance reported as Epikote 1 120-
B-80.
Estimated based on analogy; Study
details reported in a secondary
source for the test substance
bisphenol A diglycidyl ether,
brominated (CASRN 40039-93-8), a
very close structural analog.
Estimated based on a structural alert
for epoxy groups/epoxides and
professional judgment.
No data located.
[No data located.
4-166
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
Eye Irritation
Eye Irritation
Dermal Irritation
Dermal Irritation
Endocrine Activity
DATA
REFERENCE
DATA QUALITY
MODERATE: Estimated based on mixed results for studies using the component F-2200HM (2,2',6,6'-
tetrabromobisphenol A diglycidyl ether (CASRN 3072-84-2)). The structural analog, bisphenol A
diglycidyl ether, brominated (CASRN 40039-93-8), was not an eye irritant in rabbits.
Mildly irritating in rabbit eyes; reported
eye irritation was resolved within 72
hours.
Eye irritant
ECHA, 2014
Ash and Ash, 2009
Study details reported in a secondary
source; test substance identified as
the component F-2200HM
(2,2',6,6'-tetrabromobisphenol A
diglycidyl ether (CASRN 3072-84-
2)); purity: 100%; conducted
according to OECD 404.
Reported in a secondary source with
limited details for the component
2,2',6,6'-tetrabromobisphenol A
diglycidyl ether (CASRN 3072-84-
2).
MODERATE: Estimated based on mixed results for studies using the component F-2200HM (2,2',6,6'-
tetrabromobisphenol A diglycidyl ether (CASRN 3072-84-2)).
Not a skin irritant in rabbits
Skin irritant
ECHA, 2014
Ash and Ash, 2009
Study details reported in a secondary
source; test substance identified as
the component F-2200HM
(2,2',6,6'-tetrabromobisphenol A
diglycidyl ether (CASRN 3072-84-
2)); purity: 100%; conducted
according to OECD 404.
Limited study details reported in a
secondary source for the component
2,2',6,6'-tetrabromobisphenol A
diglycidyl ether (CASRN 3072-84-
2).
No data located.
[No data located.
4-167
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
Immunotoxicity
Immune System Effects
DATA
REFERENCE
DATA QUALITY
Estimated to have potential for immunotoxicity based on a structural alert for polyhalogenated aromatic
hydrocarbons.
Potential for immunotoxicity based on
structural alert for polyhalogenated
aromatic hydrocarbons.
(Estimated)
Professional judgment; EPA,
2012
Estimated based on structural alert
for polyhalogenated aromatic
hydrocarbons and professional
judgment.
ECOTOXICITY
ECOSAR Class
Acute Aquatic Toxicity
Fish LC50
Epoxides, Poly
LOW: Non-ionic polymers with a MW >1,000 and negligible water solubility are estimated to display no
effects at saturation (NES). These polymers display NES because the amount dissolved in water is not
anticipated to reach a concentration at which adverse effects may be expressed. Guidance for the
assessment of aquatic toxicity hazard leads to a low potential for those materials that display NES. The
estimated acute toxicity values for fish, daphnid, and algae for the low MW components of the polymer
(<1,000) also suggest no effects at saturation (NES).
NES
(Estimated)
Freshwater fish 14-day LC50= 0.008
mg/L
(Estimated)
ECOSAR: Epoxides, Poly
Freshwater fish 96-hour LC50 = IxlO"5
mg/L
(Estimated)
ECOSAR: Neutral organics
Professional judgment
ECOSAR v 1.11
ECOSAR v 1.11
The large MW, limited
bioavailability and low water
solubility suggest there will be NES
for the MW >1,000 components.
Estimate based on representative
oligomer n=l. NES: The log Kow of
1 1 for this chemical exceeds the
SAR limitation for the log Kow of
5.0. In addition, the estimated effect
exceeds the water solubility of
1.68xlO"9mg/L by more than lOx.
NES are predicted for these
endpoints.
Estimate based on representative
oligomer n=l. NES: The log Kow of
1 1 for this chemical exceeds the
SAR limitation for the log Kow of
5.0. In addition, the estimated effect
exceeds the water solubility of
1.68xlO"9mg/L by more than lOx.
4-168
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Freshwater fish 14-day LC50 = 0.08 mg/L
(Estimated)
ECOSAR: Epoxides, poly
ECOSARvl.ll
Freshwater fish 96-hour LC50 = 0.008
mg/L
(Estimated)
ECOSAR: Neutral organics
ECOSARvl.ll
NES are predicted for these
endpoints.
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.
Estimated for 2,2',6,6'-
tetrabromobisphenol A diglycidyl
ether (CASRN 3072-84-2), a
component of the polymeric
mixture. NES: The log Kow of 7.4
for this chemical exceeds the SAR
limitation for the log Kow of 5.0. In
addition, the estimated effect
exceeds the water solubility of
3.26xlO"5mg/L by more than lOx.
NES are predicted for these
endpoints.
Estimated for 2,2',6,6'-
tetrabromobisphenol A diglycidyl
ether (CASRN 3072-84-2). NES:
The log Kow of 7.4 for this chemical
exceeds the SAR limitation for the
log Kow of 5.0. In addition, the
estimated effect exceeds the water
solubility of 3.26xlO"5mg/L by more
than lOx. NES are predicted for
these endpoints.
Narcosis classes (neutral organics)
are provided for comparative
4-169
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
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 LC50
NES
(Estimated)
Professional judgment
Daphnia magnet 48-hour LC50= 0.00065
mg/L
(Estimated)
ECOSAR: Epoxides, poly
ECOSAR v 1.11
Daphnia magna 48-hour LC50=1.28xlO"5
mg/L
(Estimated)
ECOSAR: Neutral organics
ECOSAR v 1.11
The large MW, limited
bioavailability and low water
solubility suggest there will be NES
for the MW >1,000 components.
Estimate based on representative
oligomer n=l. NES: The log Kow of
11 for this chemical exceeds the
SAR limitation for the log Kow of
5.0. In addition, the estimated effect
exceeds the water solubility of
1.68xlO"9 mg/L by more than lOx.
NES are predicted for these
endpoints.
Estimate based on representative
oligomer n=l. NES: The log Kow of
11 for this chemical exceeds the
SAR limitation for the log Kow of
5.0. In addition, the estimated effect
exceeds the water solubility of
1.68xlO'9 mg/L by more than lOx.
NES are predicted for these
endpoints.
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
4-170
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Daphnia magnet 48-hour LC50 = 0.036
mg/L
(Estimated)
ECOSAR: Epoxides, poly
ECOSARvl.ll
Daphnia magna 48-hour LC50 = 0.007
mg/L
(Estimated)
ECOSAR: Neutral organics
ECOSARvl.ll
narcosis.
Estimated for 2,2',6,6'-
tetrabromobisphenol A diglycidyl
ether (CASRN 3072-84-2), a
component of the polymeric
mixture. NES: The log Kow of 7.4
for this chemical exceeds the SAR
limitation for the log Kow of 5.0. In
addition, the estimated effect
exceeds the water solubility of
3.26xlO"5 mg/L by more than lOx.
NES are predicted for these
endpoints.
Estimated for 2,2',6,6'-
tetrabromobisphenol A diglycidyl
ether (CASRN 3072-84-2). NES:
The log Kow of 7.4 for this chemical
exceeds the SAR limitation for the
log Kow of 5.0. In addition, the
estimated effect exceeds the water
solubility of 3.26x10"5 mg/L by
more than lOx. NES are predicted
for these endpoints.
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 EC s
NES
(Estimated)
Professional judgment
The large MW, limited
bioavailability and low water
solubility suggest there will be NES
for the MW >1,000 components.
4-171
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Green algae 96-hour EC50 = 0.00027
mg/L
(Estimated)
ECOSAR: Neutral organics
ECOSARvl.ll
Green algae 96-hour EC50 = 0.041 mg/L
(Estimated)
ECOSAR: Neutral organics
ECOSARvl.ll
Estimate based on representative
oligomer n=l. NES: The log Kow of
11 for this chemical exceeds the
SAR limitation for the log Kow of
6.4. In addition, the estimated effect
exceeds the water solubility of
1.68xlO"9 mg/L by more than lOx.
NES are predicted for these
endpoints.
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.
Estimated for 2,2',6,6'-
tetrabromobisphenol A diglycidyl
ether (CASRN 3072-84-2), a
component of the polymeric
mixture. NES: The log Kow of 7.4
for this chemical exceeds the SAR
limitation for the log Kow of 6.4. In
addition, the estimated effect
exceeds the water solubility of
3.26xlO"5 mg/L by more than lOx.
NES are predicted for these
endpoints.
Narcosis classes (neutral organics)
are provided for comparative
purposes; DfE assessment
methodology will use the lowest
estimated toxicity value provided by
4-172
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
Chronic Aquatic Toxicity
Fish ChV
DATA
REFERENCE
DATA QUALITY
ECOSAR classes that have a more
specific mode of action relative to
narcosis.
LOW: Non-ionic polymers with a MW >1,000 and negligible water solubility are estimated to display NES.
These polymers display NES because the amount dissolved in water is not anticipated to reach a
concentration at which adverse effects may be expressed. Guidance for the assessment of aquatic toxicity
hazard leads to a low potential for those materials that display NES. The estimated chronic toxicity values
for fish, daphnid, and algae for the low MW components of the polymer (<1,000) also suggest no effects at
saturation (NES).
NES
(Estimated)
Freshwater fish ChV = 2.7x1 0"5 mg/L
(Estimated)
ECOSAR: Epoxides, poly
Freshwater fish ChV =2.5xlO'6 mg/L
(Estimated)
ECOSAR: Neutral organics
Professional judgment
ECOSAR v 1.11
ECOSAR v 1.11
The large MW, limited
bioavailability and low water
solubility suggest there will be NES
for the MW >1,000 components.
Estimate based on representative
oligomer n=l. NES: The log Kow of
1 1 for this chemical exceeds the
SAR limitation for the log Kow of
8.0. In addition, the estimated effect
exceeds the water solubility of
1.68xlO~9 mg/L by more than lOx.
NES are predicted for these
endpoints.
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.
Estimate based on representative
oligomer n=l. NES: The log Kow of
1 1 for this chemical exceeds the
SAR limitation for the log Kow of
4-173
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Freshwater fish ChV = 0.0008 mg/L
(Estimated)
ECOSAR: Epoxides, poly
ECOSARvl.ll
Freshwater fish ChV = 0.0013 mg/L
(Estimated)
ECOSAR: Neutral organics
ECOSARvl.ll
8.0. In addition, the estimated effect
exceeds the water solubility of
1.68xlO"9 mg/L by more than lOx.
NES are predicted for these
endpoints.
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.
Estimated for 2,2',6,6'-
tetrabromobisphenol A diglycidyl
ether (CASRN 3072-84-2), a
component of the polymeric
mixture. The estimated effect
exceeds the water solubility of
3.26xlO'5 mg/L by lOx. NES are
predicted for these endpoints.
Estimated for 2,2',6,6'-
tetrabromobisphenol A diglycidyl
ether (CASRN 3072-84-2). The
estimated effect exceeds the water
solubility of 3.26x10"5 mg/L by
more than lOx. NES are predicted
for these endpoints.
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
4-174
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
specific mode of action relative to
narcosis.
Daphnid ChV
NES
(Estimated)
Professional judgment
Daphnia magna ChV: = 3.2xlO~5 mg/L
(Estimated)
ECOSAR: Epoxides, poly
ECOSARvl.ll
Daphnia magna ChV = 1.2xlO~5 mg/L
(Estimated)
ECOSAR: Neutral organics
ECOSARvl.ll
Daphnia magna ChV = 0.002 mg/L
(Estimated)
ECOSAR: Epoxides, poly
4-175
ECOSARvl.ll
The large MW, limited
bioavailability and low water
solubility suggest there will be NES
for the MW >1,000 components.
Estimate based on representative
oligomer n=l. NES: The log Kow of
11 for this chemical exceeds the
SAR limitation for the log Kow of
8.0. In addition, the estimated effect
exceeds the water solubility of
1.68xlO"9 mg/L by more than lOx.
NES are predicted for these
endpoints.
Estimate based on representative
oligomer n=l. NES: The log Kow of
11 for this chemical exceeds the
SAR limitation for the log Kow of
8.0. In addition, the estimated effect
exceeds the water solubility of
1.68xlO"9 mg/L by more than lOx.
NES are predicted for these
endpoints.
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.
Estimated for 2,2',6,6'-
tetrabromobisphenol A diglycidyl
ether (CASRN 3072-84-2). The
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
Green Algae ChV
DATA
Daphnia magna ChV = 0.003 mg/L
(Estimated)
ECOSAR: Neutral organics
21-dayEC50>23(ig/L
Considered effects on Daphnia magna
immobility and reproduction
Static conditions; 1.9, 3.8, 7.5, 15, 30
(ig/L (nominal concentration).
(Estimated by analogy)
NES
(Estimated)
Green algae ChV: 0.00044 mg/L
REFERENCE
ECOSAR v 1.11
ECHA, 2014
Professional judgment
ECOSAR v 1.11
DATA QUALITY
estimated effect exceeds the water
solubility of 3. 26x1 0"5 mg/L by
more than lOx. NES are predicted
for these endpoints.
Estimated for 2,2',6,6'-
tetrabromobisphenol A diglycidyl
ether (CASRN 3072-84-2), a
component of the polymeric
mixture. The estimated effect
exceeds the water solubility of
3.26xlO"5 mg/L by more than lOx.
NES are predicted for these
endpoints.
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.
Reported for bisphenol A diglycidyl
ether, brominated (CASRN 40039-
93-8), a close structural analog.
Study was conducted in accordance
with OECD Guideline 211; Daphnia
magna Reproduction Test and GLP.
The estimated effect exceeds the
water solubility by lOx. NES are
predicted for these endpoints.
The large MW, limited
bioavailability and low water
solubility suggest there will be NES
for the MW >1,000 components.
Estimate based on representative
4-176
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
(Estimated)
ECOSAR: Neutral Organic SAR
Green algae ChV = 0.033 mg/L
(Estimated)
ECOSAR: Neutral organics
ECOSAR v 1.11
72-hour EC50>30(ig/L
ECHA, 2014
oligomer n=l. NES: The log Kow of
11 for this chemical exceeds the
SAR limitation for the log Kow of
8.0. In addition, the estimated effect
exceeds the water solubility of
1.68xlO"9 mg/L by more than lOx.
NES are predicted for these
endpoints.
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.
Estimated for 2,2',6,6'-
tetrabromobisphenol A diglycidyl
ether (CASRN 3072-84-2), a
component of the polymeric
mixture. The estimated effect
exceeds the water solubility of
3.26xlO"5 mg/L by more than lOx.
NES are predicted for these
endpoints.
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.
Reported for bisphenol A diglycidyl
4-177
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
DATA
Considered effects on area under the
growth curve, yield and growth rate
relative to the negative control group in
Pseudokirchneriella subcapitata
Static conditions; 1.8, 3.9, 7.6, 15, 24, 30
(ig/L (nominal concentration).
(Estimated by analogy)
REFERENCE
DATA QUALITY
ether, brominated (CASRN 40039-
93-8) a close structural analog.
Study was conducted in accordance
with OECD Guideline 201 (Alga,
Growth Inhibition Test) and GLP.
The estimated effect exceeds the
water solubility by lOx. NES are
predicted for these endpoints.
ENVIRONMENTAL FATE
Transport
Henry's Law Constant (atm-
m3/mole)
Sediment/Soil
Adsorption/Desorption - Koc
The estimated negligible water solubility, the estimated negligible vapor pressure and the estimated K0c of
>30,000 indicate the components of this polymer are anticipated to partition predominantly to soil and
sediment and these components are not anticipated to migrate from soil into groundwater. The estimated
Henry's Law constant values of <10"8 atm-m3/mole indicate that the polymer components are not expected
to volatilize from water to the atmosphere.
2 oligomers (Estimated)
>3 0,000 for MW < 1,000 components
(Estimated)
>30,000 forn>2 (Estimated)
EPIv4. 11; Professional
judgment
Boethling and Nabholz, 1997;
Professional judgment
EPIv4. 11; Professional
judgment
Boethling and Nabholz, 1997;
Professional judgment
Estimates based on representative
oligomer where n=l and for
2,2',6,6'-tetrabromobisphenol A
diglycidyl ether (CASRN 3072-84-
2), a component of the polymeric
mixture. Cutoff value for nonvolatile
compounds.
High MW polymers are expected to
have low vapor pressure and are not
expected to undergo volatilization.
Estimates based on representative
oligomer where n=l and for
2,2',6,6'-tetrabromobisphenol A
diglycidyl ether (CASRN 3072-84-
2), a component of the polymeric
mixture. Cutoff value fornonmobile
compounds.
Estimated for the n=2 oligomers;
cutoff value used for large, high
MW polymers. High MW polymers
are expected to adsorb strongly to
4-178
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
Level III Fugacity Model
DATA
2 15, 000 for n=l
>430,000forn=2and3
Reported for components of the mixture.
According to OECD Guideline 121;
Estimation of the Adsorption Coefficient
on Soil and on Sewage Sludge using High
Performance Liquid Chromatography
(HPLC). (Estimated by analogy)
Air = 0%
Water = 3. 3%
Soil = 88%
Sediment = 8.4% (Estimated)
Air = 0%
Water =3%
Soil = 60%
Sediment = 37% (Estimated)
REFERENCE
ECHA, 2014
EPIv4.11
EPIv4.11
DATA QUALITY
soil and sediment.
Adequate guideline study reported
for bisphenol A diglycidyl ether,
brominated (CASRN 40039-93-8).
The three components in this study
are close structural analogs to the
components of D.E.R. 500 Series
(CASRN 26265-08-7).
Estimated for 2,2',6,6'-
tetrabromobisphenol A diglycidyl
ether (CASRN 3072-84-2), a
component of the polymeric
mixture.
Estimates based on representative
oligomer where n=l .
4-179
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Persistence
VERY HIGH: Experimental data are not available. Estimated half-lives for ultimate aerobic
biodegradation are >180 days for the n=l oligomer and 2,2',6,6'-tetrabromobisphenol A diglycidyl ether
(CASRN 3072-84-2), representing MW <1,000 components of the polymeric mixture. Polymeric
components with a MW >1,000 are expected to have negligible water solubility and poor bioavailability to
microorganisms indicating that neither biodegradation nor hydrolysis are expected to be important
removal processes in the environment. Although debromination by photodegradation of polybrominated
benzenes has been observed, this process is not anticipated to lead to ultimate removal of the polymer. The
estimated degradation half-life by hydrolysis is also expected to be >1 year. Degradation of this polymer by
direct photolysis is not expected to be significant as the functional groups present do not tend to undergo
these reactions under environmental conditions. The atmospheric half-life is estimated to be <2 days;
however, the polymer is not anticipated to partition significantly to air.
Water
Aerobic Biodegradation
Passes Ready Test: No
Test method: OECD TG 301B: CO2
Evolution Test
-2.4% degradation after 28 days in
activated sludge. (Estimated by analogy)
Months (Primary Survey Model)
Recalcitrant (Ultimate Survey Model)
(Estimated)
Recalcitrant for the n=2 oligomers
(Estimated)
Microbial toxicity/inhibition: Water-
leachates of the polymer inhibited
bacterial growth by 8%. (Measured)
ECHA, 2014
EPIv4.11
Boethling and Nabholz, 1997
Willett, 1990
Adequate guideline study reported
for bisphenol A diglycidyl ether,
brominated (CASRN 40039-93-8), a
very close structural analog.
Estimates based on representative
oligomer where n=l and 2,2',6,6'-
tetrabromobisphenol A diglycidyl
ether (CASRN 3072-84-2), a
component of the polymeric
mixture.
Estimated for the n>2 oligomers;
high MW polymers are expected to
have low vapor pressure and are not
expected to undergo volatilization.
The study was performed on water-
leachates of the polymer, and not on
the polymer itself. Given the low
water solubility of the polymer, it is
not anticipated to be present in the
leachate.
4-180
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
Soil
Air
Volatilization Half-life for
Model River
Volatilization Half-life for
Model Lake
Aerobic Biodegradation
Anaerobic Biodegradation
Soil Biodegradation with
Product Identification
Sediment/Water
Biodegradation
Atmospheric Half-life
DATA
>1 year (Estimated)
>1 year (Estimated)
Not probable (Estimated)
1 .4 hours (Estimated)
0.6 days (Estimated)
REFERENCE
EPIv4.11
EPIv4.11
Holliger et al, 2004
EPIv4.11
EPIv4.11
DATA QUALITY
Estimates based on representative
oligomer where n=l and for
2,2',6,6'-tetrabromobisphenol A
diglycidyl ether (CASRN 3072-84-
2), a component of the polymeric
mixture.
Estimates based on representative
oligomer where n=l and for
2,2',6,6'-tetrabromobisphenol A
diglycidyl ether (CASRN 3072-84-
2), a component of the polymeric
mixture.
No data located.
The estimated value addresses the
potential for ultimate
biodegradation. However, there is
potential for primary anaerobic
biodegradation of the lower MW
(<1,000) haloaromatic compounds
by reductive dehalogenation.
No data located.
No data located.
Estimates based on representative
oligomer where n=l. This
compound is anticipated to exist as a
solid particulate in the atmosphere,
degradation by gas-phase reactions
are not expected to be important
removal processes.
Estimated for 2,2',6,6'-
tetrabromobisphenol A diglycidyl
ether (CASRN 3072-84-2), a
component of the polymeric
4-181
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
mixture. This compound is
anticipated to exist as a solid
particulate in the atmosphere,
degradation by gas-phase reactions
are not expected to be important
removal processes.
Reactivity
Photolysis
Not a significant fate process (Estimated)
Professional judgment
Hydrolysis
50%/>1 year at pH 7 (Estimated)
EPIv4.11
Bromine substituents may be
susceptible to photolysis in the
environment; however, this is
expected to be a relatively slow
process for a high MW brominated
epoxy polymer and is not anticipated
to result in the ultimate degradation
of this substance.
Estimates based on representative
oligomer where n=l and for
2,2',6,6'-tetrabromobisphenol A
diglycidyl ether (CASRN 3072-84-
2), a component of the polymeric
mixture. The estimated hydrolysis
rate is for the epoxide functional
group; hydrolysis is not expected to
be an important fate process for
other parts of the polymer.
Environmental Half-life
>180 days for the n>2 oligomers
(Estimated)
Professional judgment
>1 year in soil; for the n=l oligomer
(Estimated)
4-182
PBT Profiler v 1.301
Estimated for the n>2 oligomers; the
substance is a high MW polymer
and is not anticipated to be
assimilated by microorganisms.
Therefore, biodegradation is not
expected to be an important removal
process. It is also not expected to
undergo removal by other
degradative processes under
environmental conditions.
Half-life estimated for the n=l
oligomer for the predominant
-------
D.E.R. 500 Series CASRN 26265-08-7
PROPERTY/ENDPOINT
Bioaccumulation
Fish BCF
Other BCF
BAF
Metabolism in Fish
DATA
REFERENCE
DATA QUALITY
compartment, soil, as determined by
EPI and the PBT Profiler
methodology.
HIGH: The estimated BCF and BAF for 2,2',6,6'-tetrabromobisphenol A diglycidyl ether (CASRN 3072-
84-2), a component of the polymeric mixture and BAF for the n=l component are >1,000 resulting in a
High bioaccumulation designation. The higher MW oligomers that may be found in this mixture (n>2) are
expected to have Low potential for bioaccumulation based on their large size and low water solubility
according to the polymer assessment literature and professional judgment.
8,400 for a component (Estimated)
100forn=l (Estimated)
<100 for the n>2 oligomers (Estimated)
9.7xl06 for a component (Estimated)
69,000 forn=l (Estimated)
EPIv4.11
EPIv4.11
Boethling and Nabholz, 1997;
Professional judgment
EPIv4.11
EPIv4.11
Estimated for 2,2',6,6'-
tetrabromobisphenol A diglycidyl
ether (CASRN 3072-84-2), a
component of the polymeric
mixture.
Estimates based on representative
oligomer where n=l .
Estimated for the n>2 oligomers.
Cutoff value for large, high MW,
insoluble polymers according to
polymer assessment literature.
No data located.
Estimated for 2,2',6,6'-
tetrabromobisphenol A diglycidyl
ether (CASRN 3072-84-2), a
component of the polymeric
mixture.
Estimates based on representative
oligomer where n=l .
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
Ecological Biomonitoring
Human Biomonitoring
No data located.
No data located.
This chemical was not included in the NHANES biomonitoring report. (CDC, 2013).
4-183
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4-184
-------
Ash M and Ash I (2009) Specialty chemicals source book. 4th ed. Endicott, NY: Synapse Information Resources, Inc.: 1844.
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Environmental Protection Agency.
CDC (2013) Fourth national report on human exposure to environmental chemicals, updated tables, March 2013.
http://www.cdc.gov/exposurereport/pdf/FourthReport_UpdatedTables_Mar2013.pdf
Dow (2009) Product safety assessment Brominated epoxy resins.
ECHA (2014) [2,2',6,6'-Tetrabromo-4,4'-isopropylidenediphenol, oligomeric reaction products with l-chloro-2,3-epoxypropane]. Registered
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00144f67d031/AGGR-5c653501-06d9-4709-b33b-d53dcd845elO_DISS-dffb4072-e4c5-47ae-e044-00144f67d031.html#section_l.l.
ECOSAR Ecological Structure Activity Relationship (ECOSAR). Estimation Programs Interface (EPI) Suite for Windows, Version 1.11.
Washington, DC: EPIWIN/EPISUITE. U.S. Environmental Protection Agency, http://www.epa.gov/oppt/newchems/tools/21ecosar.htm.
EPA (1999) Determining the adequacy of existing data. High Production Volume (HPV) Challenge. Washington, DC: U.S. Environmental
Protection Agency, http://www.epa.gov/hpv/pubs/general/datadeqfn.pdf
EPA (2010) TSCA new chemicals program (NCP) chemical categories. Washington, DC: U.S. Environmental Protection Agency.
http://www.epa.gov/oppt/newchems/pubs/npcchemicalcategories.pdf
EPA (2012) Using noncancer screening within the SF initiative. Washington, DC: U.S. Environmental Protection Agency.
http://www.epa.gov/oppt/sf/pubs/noncan-screen.htm.
EPI Estimation Programs Interface (EPI) Suite, Version 4.11. Washington, DC: EPIWIN/EPISUITE. U.S. Environmental Protection Agency.
http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm.
ESIS (2012) European chemical Substances Information System. European Commission, http://esis.jrc.ec.europa.eu/.
Holliger C, Regeard C, Diekert G (2004) Dehalogenation by anaerobic bacteria. In: Haggblom MM, Bossert ID, eds. Dehalogenation: Microbial
processes and environmental applications. Kluwer Academic Publishers.: 115-157.
PBT Profiler Persistent (P), Bioaccumulative (B), and Toxic (T) Chemical (PBT) Profiler, Version 1.301. Washington, DC: U.S. Environmental
Protection Agency, www.pbtprofiler.net.
4-185
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Willett JC (1990) Toxicity of resins: The skin sensitizing potential of "Epikote" 1120-B-80. Shell Oil Company Submitted to the US EPA under
TSCA Section 8D.
Willett JC (1991) Bacterial mutagenicity studies with Epikote 1145-8-70 with cover sheets and letter dated 010891. Prepared by Shell Research
for Shell Oil Company Submitted to the US EPA under TSCA Section 8D.
4-186
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VL = Very Low hazard L = Low hazard = Moderate hazard H = High hazard VH = Very High hazard — Endpoints in colored text (VL, L, M, H, and VH) were
assigned based on empirical data. Endpoints in black italics (VL, L, M, H, and VH) were assigned using values from predictive models and/or professional judgment.
This table contains hazard information for each chemical; evaluation of risk considers both hazard and exposure. Variations in end-of-life processes or degradation and combustion
by-products are discussed in the report but not addressed directly in the hazard profiles. The caveats listed below must be taken into account when interpreting the information in the
table.
§ Based on analogy to experimental data for a structurally similar compound. * The highest hazard designation of any of the oligomers with MW <1,000. ¥ Aquatic toxicity: EPA/DfE
criteria are based in large part upon water column exposures which may not be adequate for poorly soluble substances such as many flame retardants that may partition to sediment
and particulates.
Chemical
CASRN
Human Health Effects
ute Toxicity
u
•<
rcinogenicit
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U
notoxicity
u
O
productive
O
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0)
0
urological
0)
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o
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isitization
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o
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0
Aquatic
Toxicity
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Environmental
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Confidential
M%
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H
VH
4-187
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Dow XZ-92547
SMILES: Confidential SMILES notations for representative structures of the MW < 1,000 components
CASRN: Confidential CASRN
MW: > 1,000; with a significant
percentage of components
having MW<1,000
MF: Confidential MF
Physical Forms: Solid
Neat:
Use: Flame retardant
Synonyms: Reaction product of an epoxy phenyl novolak with DOPO
Chemical Considerations: This alternative is a polymer consisting of components with MWs above and below 1,000 daltons. Lower MW components are expected
to be present at a level requiring their assessment. The components with a MW <1,000 are evaluated as four proprietary representative structures. In general, the
representative structures are different combinations of epoxy phenyl novolak and DOPO. These are assessed with EPI v4.11 andECOSARvl.il estimates due to an
absence of publicly available experimental physical/chemical, environmental fate and aquatic toxicity values. The oligomers with a MW >1,000 and are assessed
using the available polymer assessment literature.
Polymeric: Yes
Oligomeric: This polymer contains oligomers that are formed by the reaction of an epoxy phenyl novolak with DOPO.
Metabolites, Degradates and Transformation Products: None
Analog: None Analog Structure: Not applicabl
Endpoint(s) using analog values: Not applicable
Structural Alerts: Phosphinate esters - environmental toxicity; Epoxy groups/epoxides - dermal sensitization, cancer,
Organophosphorus compounds - neurotoxicity. (EPA, 2010; EPA, 2012).
e
reproductive effects, developmental toxicity;
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 2012).
Hazard and Risk Assessments: None located.
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PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
Boiling Point (°C)
Vapor Pressure (mm Hg)
Water Solubility (mg/L)
89 (Measured)
>300
(Estimated)
<10"8 (Estimated)
<10'8 (Estimated)
0.62
(Estimated)
0.0023
(Estimated)
7.7X10'6 (Estimated)
0.0082 (Estimated)
<0.001
(Estimated)
Submitted confidential study
EPIv4.11;EPA, 1999
EPA, 1999;EPIv4.11
Boethling and Nabholz, 1997;
Professional judgment
EPIv4.11
EPIv4.11
EPIv4.11;EPA, 1999
EPIv4.11;EPA, 1999
Boethling and Nabholz, 1997;
Professional judgment
Adequate, measured value from
submitted study.
Estimate based on four
representative structures with MW
< 1,000. Also estimated for
oligomers with MWs > 1,000. Cutoff
value according to HPV assessment
guidance and cutoff value used for
large, high MW solids.
Estimates based on four confidential
representative structures with MW
< 1,000. Cutoff value for nonvolatile
compounds according to HPV
assessment guidance.
Cutoff value for large, high MW
polymer components.
Estimates based on confidential
representative structure 1 with MW
<1,000.
Estimates based on confidential
representative structure 2 with MW
<1,000.
Estimates based on confidential
representative structure 3 with MW
< 1,000. Estimated value is less than
the cutoff value, <0.001 mg/L, for
non-soluble compounds according to
HPV assessment guidance.
Estimates based on confidential
representative structure 4 with MW
<1,000.
Cutoff value for large, high MW
non-ionic polymer components.
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PROPERTY/ENDPOINT
Log Kow
Flammability (Flash Point)
Explosivity
Pyrolysis
pH
pKa
Particle Size
DATA
3.7
(Estimated)
5.3
(Estimated)
7
(Estimated)
4.8
(Estimated)
Not flammable (Estimated)
Not expected to form explosive mixtures
with air (Estimated)
Not applicable (Estimated)
Not applicable (Estimated)
REFERENCE
EPIv4.11
EPIv4.11
EPIv4.11
EPIv4.11
Professional judgment
Professional judgment
Professional judgment
Professional judgment
DATA QUALITY
Estimates based on confidential
representative structure 1 with a
MW<1,000.
Estimates based on confidential
representative structure 2 with a
MW<1,000.
Estimates based on confidential
representative structure 3 with a
MW<1,000.
Estimates based on confidential
representative structure 4 with a
MW<1,000.
Mo experimental data located; based
on its use as a flame retardant.
No experimental data located; based
on its use as a flame retardant.
""Jo data located.
Does not contain functional groups
that are expected to ionize under
environmental conditions.
Does not contain functional groups
that are expected to ionize under
environmental conditions.
""Jo data located.
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PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
HUMAN HEALTH EFFECTS
Toxicokinetics
Dermal Absorption in vitro
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal or Inhaled
Other
Acute Mammalian Toxicity
Acute Lethality
Oral
Dermal
Inhalation
Based on the physical/chemical properties of this polymer, the higher MW fraction (>1,000) is estimated to
have limited bioavailability. Based on the physical/chemical properties, absorption is expected to be
negligible by all routes for the neat material and poor by all routes for the low molecular weight fraction if
in solution.
Absorption is expected to be negligible
by all routes for the neat material and
poor by all routes for the low MW
fraction if in solution.
(Estimated)
Professional judgment
Estimated based on professional
judgment.
No data located.
LOW: Based on experimental data that reported LD50 >2,000 mg/kg when administered orally and
dermally to rats. There were no data located for the inhalation route of exposure. The higher MW
components of this polymer (MW >1,000) are expected to have limited bioavailability and have low
potential for acute toxicity.
Estimated to have a low potential for
acute toxicity for the high MW
component. Limited bioavailability
expected.
(Estimated)
Rat, oral LD50 >2,000 mg/kg.
Rat, dermal LD50 >2,000 mg/kg.
Rat, dermal LD50 >2,000 mg/kg.
Boethling and Nabholz, 1997;
Professional judgment
Submitted confidential study
Submitted confidential study
Submitted confidential study
Estimated for the high MW
component (MW >1,000) based on
cutoff value for large, high MW
non-ionic polymer components.
Limited study details reported in a
confidential study.
Study details reported in a
confidential study.
Limited study details reported in a
confidential study.
^o data located.
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PROPERTY/ENDPOINT
Carcinogenicity
OncoLogic Results
Carcinogenicity (Rat and
Mouse)
Combined Chronic
Toxicity/Carcinogenicity
Other
DATA
REFERENCE
DATA QUALITY
MODERATE: There were no experimental data located for this substance. Carcinogenic effects cannot be
ruled out; therefore, uncertainty due to lack of data for this substance results in a Moderate designation.
In addition, there is an estimated potential for Carcinogenicity based on a structural alert for epoxy
groups/epoxides and for the low MW components (MW < 1,000). The higher MW components of this
polymer (MW >1,000) are expected to have limited bioavailability and have low potential for
Carcinogenicity.
Potential for Carcinogenicity based on a
structural alert for epoxy
groups/epoxides.
(Estimated)
Potential for Carcinogenicity for the low
MW components.
(Estimated)
Estimated to have a low potential for
Carcinogenicity for the high MW
component. Limited bioavailability
expected.
(Estimated)
Professional judgment; EPA,
2010
Professional judgment
Boethling and Nabholz, 1997;
Professional judgment
No data located.
No data located.
No data located.
Estimated based on a structural alert
for epoxy groups/epoxides and
professional judgment.
Estimated for the low MW
components based on professional
ludgment.
Estimated for the high MW
component (MW >1,000) based on
professional judgment and the cutoff
value for large, high MW non-ionic
3olymer components.
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PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Genotoxicity
MODERATE: Estimated based on positive gene mutation results for a confidential analog of the low MW
components (MW < 1,000) reported in a submitted confidential study. There were no gene mutation or
chromosomal aberrations data located for this substance. Negative results for mutagenicity and
chromosomal aberrations in vitro were reported in experimental data for the analog DOPO (CASRN
35948-25-5). In the absence of data for this substance and conflicting results reported for two analogs, a
conservative approach is used to assign a Moderate designation. The higher MW components of this
polymer (MW >1,000) are expected to have limited bioavailability and have low potential for genotoxicity.
Gene Mutation in vitro
Gene Mutation in vivo
There is potential for mutagenicity for the
low MW components.
Positive in Ames assay.
(Estimated by analogy)
Negative in Ames assay in Salmonella
typhimurium strains TA97, TA98,
TA100, and TA102 and Escherichia coli
WP2 uvr A pKM 101 with and without
metabolic activation. Tested up to 5,000
(ig/plate (purity, industrial grade).
Positive controls responded as expected.
(Estimated by analogy)
Negative in Ames assay; in Salmonella
typhimurium strains TA1535, TA97a,
TA98, TA100, and TA102 with and
without metabolic activation. Tested up to
5,024 (ig/plate (purity >99%). Positive
controls responded as expected.
(Estimated by analogy)
Professional judgment;
Submitted confidential study
ECHA, 2013
ECHA, 2013
Estimated based on experimental
data for a confidential analog for the
low MW components; reported in a
submitted confidential study and
srofessional judgment.
Estimated based on analogy to
DOPO (CASRN 35948-25-5).
Sufficient study details reported in a
secondary source. Non-GLP study,
3ut adequate as supporting data.
Estimated based on analogy to
DOPO (CASRN 35948-25-5).
Sufficient study details reported in a
secondary source. Study conducted
in accordance with OECD guideline
471 and GLP. Test substance was
CASRN 35948-25-5 named Ukanol
GK-F in study report. Primary
reference not identified.
No data located.
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PROPERTY/ENDPOINT
Chromosomal Aberrations in
vitro
Chromosomal Aberrations in
vivo
DNA Damage and Repair
Other
Reproductive Effects
Reproduction/Developmental
Toxicity Screen
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
Reproduction and Fertility
Effects
Other
DATA
Negative in Chinese hamster lung cells
with and without activation. Tested up to
216 (ig/mL (purity not provided). Positive
controls responded as expected.
(Estimated by analogy)
Estimated to have a low potential for
genotoxicity for the high MW
component. Limited bioavailability
expected.
(Estimated)
REFERENCE
ECHA, 2013
Boethling and Nabholz, 1997;
Professional judgment
DATA QUALITY
Estimated based on analogy to
DOPO (CASRN 35948-25-5).
Sufficient study details reported in a
secondary source. Study equivalent
to OECD Guideline 473; not a GLP
study.
No data located.
No data located.
Estimated for the high MW
component (MW >1,000) based on
srofessional judgment and the cutoff
value for large, high MW non-ionic
3olymer components.
MODERATE: There is an estimated potential for reproductive toxicity based on a structural alert for
epoxy groups/epoxides and an estimated potential for male reproductive toxicity for the low MW
components (MW < 1,000) based on professional judgment. The higher MW components of this polymer
(MW >1,000) are expected to have limited bioavailability and have low potential for reproductive toxicity.
There is potential for reproductive
toxicity based on a structural alert for
epoxy groups/epoxides.
(Estimated)
There is potential for male reproductive
toxicity for the low MW components.
(Estimated)
Estimated to have a low potential for
Professional judgment; EPA,
2010
Professional judgment
Boethling and Nabholz, 1997;
^o data located.
No data located.
No data located.
Estimated based on a structural alert
for epoxy groups/epoxides and
professional judgment.
Estimated for the low MW
components based on professional
ludgment.
Estimated for the high MW
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PROPERTY/ENDPOINT
Developmental Effects
Reproduction/
Developmental Toxicity
Screen
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
Prenatal Development
Postnatal Development
Prenatal and Postnatal
Development
Developmental Neurotoxicity
Other
DATA
reproductive effects for the high MW
component. Limited bioavailability
expected.
(Estimated)
REFERENCE
Professional judgment
DATA QUALITY
component (MW >1,000) based on
professional judgment and the cutoff
value for large, high MW non-ionic
polymer components.
MODERATE: There is an estimated potential for developmental toxicity based on a structural alert for
epoxy groups/epoxides and an estimated potential for developmental toxicity for the low MW components
(MW < 1,000) based on professional judgment. The higher MW components of this polymer (MW >1,000)
are expected to have limited bioavailability and have low potential for developmental toxicity.
There is uncertain concern for developmental neurotoxicity based on the potential for cholinesterase
(ChE) inhibition in dams that may result in alterations of fetal neurodevelopment. No experimental data
were located for this substance.
Uncertain concern for developmental
neurotoxicity based on the potential for
cholinesterase (ChE) inhibition in dams
that may result in alterations of fetal
neurodevelopment.
There is potential for developmental
toxicity based on a structural alert for
epoxy groups/epoxides.
(Estimated)
Estimated to have a low potential for
developmental effects for the high MW
component. Limited bioavailability
Professional judgment
Professional judgment; EPA,
2012
Boethling and Nabholz, 1997;
Professional judgment
^o data located.
No data located.
No data located.
No data located.
No data located.
Estimated based on a structural alert
for organophosphates for the
neurotoxicity endpoint.
Estimated based on a structural alert
for epoxy groups/epoxides and
srofessional judgment.
Estimated for the high MW
component (MW >1,000) based on
srofessional judgment and the cutoff
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PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
expected.
(Estimated)
value for large, high MW non-ionic
polymer components.
Neurotoxicity
MODERATE: There is an estimated potential for neurotoxicity based on a structural alert for
organophosphorus compounds and professional judgment. The higher MW components of this polymer
(MW >1,000) are expected to have limited bioavailability and have low potential for neurotoxicity. There
were no experimental data located for this substance.
Neurotoxicity Screening
Battery (Adult)
Other
There is potential for neurotoxicity based
on the structural alert of
organophosphorus compounds.
(Estimated)
Estimated to have a low potential for
neurotoxicity for the high MW
component. Limited bioavailability
expected.
(Estimated)
Professional judgment; EPA,
2012
Boethling and Nabholz, 1997;
Professional judgment
data located.
Estimated based on a structural alert
for organophosphorus compounds
and professional judgment.
Estimated for the high MW
Component (MW >1,000) based on
srofessional judgment and the cutoff
value for large, high MW non-ionic
3olymer components.
Repeated Dose Effects
MODERATE: There is an estimated potential for repeated dose effects for the low MW components
(<1,000) for the inhalation and dermal routes of exposure. Experimental data for the analog DOPO
(CASRN 35948-25-5) indicated a Low hazard designation with a reported NOAEL of 1,023 mg/kg-day
(highest dose tested) in a 16-week dietary study in rats. The higher MW components of this polymer (MW
>1,000) are expected to have limited bioavailability and have low potential for repeated dose effects. There
were no experimental data located for this substance.
There is potential for repeated dose
effects for the low MW component for
the inhalation and dermal routes of
exposure.
Male and female Wistar rats
(20/sex/dose) were fed diets containing 0,
0.24, 0.6, or 1.5%HCA (0, 159, 399, or
1,023 mg HCA/kg-day to males; 0, 177,
445, or 1,094 mg HCA/kg-day to
females) of the analog DOPO for 16
weeks (purity of test substance not
Professional judgment
Estimated for the low MW
component based on professional
judgment.
ECHA, 2013; Professional
judgment
Estimated based on analogy to
DOPO (CASRN 35948-25-5).
Sufficient information in secondary
source; data lacking regarding
detailed clinical observations and
neurobehavioral examination. Study
equivalent to OECD guideline 408.
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PROPERTY/ENDPOINT
Skin Sensitization
Skin Sensitization
Respiratory Sensitization
Respiratory Sensitization
DATA
provided).
There were no significant effects on body
weight, food consumption, hematology,
limited clinical chemistry, urinalysis,
organ weight, and gross and microscopic
examination of major organs.
NOAEL: 1,023 mg/kg-day (males), 1,094
mg/kg-day (females); highest dose tested
LOAEL: Not established
(Estimated based on analogy)
Estimated to have a low potential for
repeated dose effects for the high MW
component. Limited bioavailability
expected.
(Estimated)
REFERENCE
Boethling and Nabholz, 1997;
Professional judgment
DATA QUALITY
Study pre-dates GLP. Test substance
identified as HCA in study report.
Primary reference not identified.
Estimated for the high MW
component (MW >1,000) based on
professional judgment and the cutoff
value for large, high MW non-ionic
polymer components.
HIGH: Positive for skin Sensitization in guinea pigs; reported in a submitted confidential study for the low
MW components (MW < 1,000). In addition, there is an estimated potential for skin Sensitization based on
a structural alert for epoxy groups/epoxides.
Sensitizing, guinea pigs
Positive for skin Sensitization for the low
MW component.
There is potential for skin Sensitization
based on a structural alert for epoxy
groups/epoxides.
(Estimated)
Submitted confidential study
Submitted confidential study
Professional judgment; EPA,
2012
Data reported in a submitted
confidential study.
Data reported in a submitted
confidential study for the low MW
component.
Estimated based on a structural alert
for epoxy groups/epoxides and
professional judgment.
MODERATE: There is an estimated potential for respiratory Sensitization for the low MW component
(MW < 1,000) based on professional judgment.
There is potential for respiratory
Sensitization for the low MW component.
(Estimated)
OSHA, 1999; Professional
judgment
Estimated based presence of
epoxides and professional judgment
for the low MW component.
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PROPERTY/ENDPOINT
Eye Irritation
Eye Irritation
Dermal Irritation
Dermal Irritation
Endocrine Activity
Immunotoxicity
Immune System Effects
DATA
REFERENCE
DATA QUALITY
VERY LOW: Based on a submitted confidential study, the polymer did not produce eye irritation in
rabbits.
Negative, rabbits
Submitted confidential study
Limited study details reported in a
confidential study.
LOW: Negative for skin irritation in rabbits reported in a submitted confidential study. One study
reported positive results for skin irritation, but did not contain adequate study details for assessment.
Positive for skin irritation for the low
MW component.
Negative, rabbits
Submitted confidential study
Submitted confidential study
Inadequate study details reported in
a submitted confidential study for
the low MW component.
Data reported in a submitted
confidential study.
No data located.
|No data located.
Estimated to have a low potential for immunotoxic effects based on expert judgment. The higher MW
components of this polymer (MW >1,000) are expected to have limited bioavailability and have low
potential for immunotoxicity.
Low potential for immunotoxic effects
for the low MW component.
(Estimated)
Estimated to have a low potential for
immunotoxic effects for the high MW
component. Limited bioavailability
expected.
Expert judgment
Boethling and Nabholz, 1997;
Professional judgment
Estimated based on expert judgment.
Estimated for the high MW
component (MW >1,000) based on
professional judgment.
ECOTOXICITY
ECOSAR Class
Acute Aquatic Toxicity
Fish LC50
Epoxides, mono; Esters (Phosphinates)
LOW: Based on estimated acute aquatic toxicity values for fish, daphnia, and green algae, which all exceed
the water solubility. No Effects at Saturation (NES) are predicted for these endpoints.
NES
(Estimated)
Freshwater fish 96-hour LC50:
Professional judgment
ECOSAR v 1.11
Estimations for the oligomers with a
high MW; limited bioavailability
and low water solubility suggest
there will be NES.
Estimations for confidential
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PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
1.7 mg/L (ECOSAR class: Esters,
phosphinate);
10.4 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
Freshwater fish 96-hour LC50:
0.87 mg/L (ECOSAR class: Epoxides,
mono);
0.74 mg/L (ECOSAR class: Esters
phosphinates);
0.49 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
ECOSAR v 1.11
Freshwater fish 14-day LC50:
0.13 mg/L (ECOSAR class: Epoxides,
poly);
Freshwater fish 96-hour LC50: 0.28 mg/L
(ECOSAR class: Esters phosphinates);
ECOSAR v 1.11
representative structure 1. The
estimated values exceed the water
solubility (0.62 mg/L). The chemical
may not be soluble enough to
measure the predicted effect.
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.
Estimations for confidential
representative structure 2. NES: The
log Kow of 5.3 for this chemical
exceeds the SAR limitation for the
log Kow of 5.0; NES are predicted
for these endpoints.
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.
Estimations for confidential
representative structure 3. NES: The
log Kow of 6.9 for this chemical
exceeds the SAR limitation for the
log Kow of 5.0 or 6.0; NES are
predicted for these endpoints.
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PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Freshwater fish 96-hour LC50: 0.021
mg/L (ECOSAR class: Neutral organic
SAR)
(Estimated)
Freshwater fish 96-hour LC50:
1.7 mg/L (ECOSAR class: Epoxides,
mono);
1.1 mg/L (ECOSAR class: Esters
phosphinates);
1.5 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
ECOSAR v 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.
Estimations for confidential
representative structure 4. The
estimated values exceed the water
solubility (0.0082 mg/L). The
chemical may not be soluble enough
to measure the predicted effect.
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 LC50
NES
(Estimated)
Professional judgment
Daphnid 48-hour LC50:
1.2 mg/L (ECOSAR class: Esters,
phosphinate);
6.9 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
ECOSAR v 1.11
Estimations for the oligomers with a
high MW; limited bioavailability
and low water solubility suggest
there will be NES.
Estimations for confidential
representative structure 1. The
estimated values exceed the water
solubility (0.62 mg/L). The chemical
may not be soluble enough to
measure the predicted effect.
Narcosis classes (neutral organics)
are provided for comparative
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PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Daphnid 48-hour LC50:
0.69 mg/L (ECOSAR class: Epoxides,
mono);
0.56 mg/L (ECOSAR class: Esters
phosphinates);
0.38 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
ECOSAR v 1.11
Daphnid 48-hour LC50:
0.071 mg/L (ECOSAR class: Epoxides,
poly);
0.24 mg/L (ECOSAR class: Esters
phosphinates);
0.019 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
ECOSAR v 1.11
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.
Estimations for confidential
representative structure 2. The log
Kow of 5.3 for this chemical exceeds
the SAR limitation for the log Kow
of 5.0; NES are predicted for these
endpoints.
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.
Estimations for confidential
representative structure 3. NES: The
log Kow of 6.9 for this chemical
exceeds the SAR limitation for the
log Kow of 5.0; NES are predicted
for these endpoints.
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.
4-201
-------
Dow XZ-92547
PROPERTY/ENDPOINT
Green Algae EC50
DATA
Daphnid 48-hour LC50:
1.6 mg/L (ECOSAR class: Epoxides,
mono);
0.78 mg/L (ECOSAR class: Esters
phosphinates);
1.1 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
NES
(Estimated)
Green algae 96-hour EC50:
9.6 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
Green algae 96-hour EC50:
0.34 mg/L (ECOSAR class: Epoxides,
REFERENCE
ECOSAR v 1.11
Professional judgment
ECOSAR v 1.11
ECOSAR v 1.11
DATA QUALITY
Estimations for confidential
representative structure 4. The
estimated values exceed the water
solubility (0.0082 mg/L). The
chemical may not be soluble enough
to measure the predicted effect.
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.
Estimations for the oligomers with a
high MW; limited bioavailability
and low water solubility suggest
there will be NES.
Estimations for confidential
representative structure 1 . The
estimated value exceeds the water
solubility (0.62 mg/L). The chemical
may not be soluble enough to
measure the predicted effect.
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.
Estimations for confidential
representative structure 2. The
4-202
-------
Dow XZ-92547
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
mono);
0.99 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
Green algae 96-hour EC50: 0.093 mg/L
(ECOSAR class: Neutral organic SAR)
(Estimated)
ECOSAR v 1.11
Green algae 96-hour EC50:
0.9 mg/L (ECOSAR class: Epoxides,
mono);
2.3 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
ECOSAR v 1.11
estimated values exceed the water
solubility (0.0023 mg/L). The
chemical may not be soluble enough
to measure the predicted effect.
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.
Estimations for confidential
representative structure 3. NES: The
log Kow of 6.9 for this chemical
exceeds the SAR limitation for the
log Kow of 6.4; NES are predicted
for these endpoints.
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.
Estimations for confidential
representative structure 4. The
estimated values exceed the water
solubility (0.0082 mg/L). The
chemical may not be soluble enough
to measure the predicted effect.
Narcosis classes (neutral organics)
4-203
-------
Dow XZ-92547
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
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 estimated chronic aquatic toxicity values for the confidential representative structures 1
and 4 for fish and daphnia.
Fish ChV
NES
(Estimated)
Freshwater fish ChV:
0.041 mg/L (ECOSAR class: Esters,
phosphinate);
1.2 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
Freshwater fish ChV:
0.003 mg/L (ECOSAR class: Epoxides,
mono);
0.008 mg/L (ECOSAR class: Esters
phosphinates);
0.069 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
Professional judgment
ECOSAR v 1.11
ECOSAR v 1.11
Estimations for the oligomers with a
high MW; limited bioavailability
and low water solubility suggest
there will be NES.
Estimations for confidential
representative structure 1.
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.
Estimations for confidential
representative structure 2. The
estimated values exceed the water
solubility (0.0023 mg/L). The
chemical may not be soluble enough
to measure the predicted effect.
Narcosis classes (neutral organics)
are provided for comparative
purposes; DfE assessment
methodology will use the lowest
4-204
-------
Dow XZ-92547
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Freshwater fish ChV:
0.0014 mg/L (ECOSAR class: Epoxides,
poly);
0.0016 mg/L (ECOSAR class: Esters
phosphinates);
0.004 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
ECOSAR v 1.11
Freshwater fish ChV:
0.004 mg/L (ECOSAR class: epoxides,
mono);
0.02 mg/L (ECOSAR class: Esters
phosphinates);
0.20 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
ECOSAR v 1.11
estimated toxicity value provided by
ECOSAR classes that have a more
specific mode of action relative to
narcosis.
Estimations for confidential
representative structure 3. The
estimated values exceed the water
solubility (7.7xlO~6). The chemical
may not be soluble enough to
measure the predicted effect.
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.
Estimations for confidential
representative structure 4.
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
NES
(Estimated)
Professional judgment
Daphnid ChV:
0.042 mg/L (ECOSAR class: Esters,
4-205
ECOSAR v 1.11
Estimations for the oligomers with a
high MW; limited bioavailability
and low water solubility suggest
there will be NES.
Estimations for confidential
representative structure 1.
-------
Dow XZ-92547
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
phosphinate);
1.03 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
Daphnia ChV:
0.064 mg/L (ECOSAR class: Epoxides,
mono);
0.012 mg/L (ECOSAR class: Esters
phosphinates);
0.086 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
ECOSAR v 1.11
Daphnid ChV:
0.005 mg/L (ECOSAR class: Epoxides,
poly);
0.003 mg/L (ECOSAR class: Esters
phosphinates);
0.007 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
ECOSAR v 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.
Estimations for confidential
representative structure 2. The
estimated values exceed the water
solubility (0.0023 mg/L). The
chemical may not be soluble enough
to measure the predicted effect.
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.
Estimations for confidential
representative structure 3. The
estimated values exceed the water
solubility (7.7xlO~6). The chemical
may not be soluble enough to
measure the predicted effect.
Narcosis classes (neutral organics)
are provided for comparative
purposes; DfE assessment
methodology will use the lowest
estimated toxicity value provided by
4-206
-------
Dow XZ-92547
PROPERTY/ENDPOINT
Green Algae ChV
DATA
Daphnid ChV:
0.15 mg/L (ECOSAR class: Epoxides,
mono);
0.02 mg/L (ECOSAR class: Esters
phosphinates):
0.22 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
NES
(Estimated)
Green algae ChV: 3.6 mg/L (ECOSAR
class: Neutral organic SAR)
(Estimated)
Green algae ChV:
0.69 mg/L (ECOSAR class: Epoxides,
mono);
REFERENCE
ECOSAR v 1.11
Professional judgment
ECOSAR v 1.11
ECOSAR v 1.11
DATA QUALITY
ECOSAR classes that have a more
specific mode of action relative to
narcosis.
Estimations for confidential
representative structure 4.
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.
Estimations for the oligomers with a
high MW; limited bioavailability
and low water solubility suggest
there will be NES.
Estimations for confidential
representative structure 1 . The
estimated values exceed the water
solubility (0.62 mg/L). The chemical
may not be soluble enough to
measure the predicted effect.
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.
Estimations for confidential
representative structure 2. The
estimated values exceed the water
4-207
-------
Dow XZ-92547
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
0.51 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
Green algae ChV: 0.068 mg/L (ECOSAR
class: Neutral organic SAR)
(Estimated)
ECOSAR v 1.11
Green algae ChV:
1.5 mg/L (ECOSAR class: Epoxides,
mono);
1.0 mg/L (ECOSAR class: Neutral
organic SAR)
(Estimated)
ECOSAR v 1.11
solubility (0.0023 mg/L). The
chemical may not be soluble enough
to measure the predicted effect.
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.
Estimations for confidential
representative structure 3. The
estimated value exceeds the water
solubility (7.7xlO~6). The chemical
may not be soluble enough to
measure the predicted effect.
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.
Estimations for confidential
representative structure 4. The
estimated values exceed the water
solubility (0.0082 mg/L). The
chemical may not be soluble enough
to measure the predicted effect.
Narcosis classes (neutral organics)
are provided for comparative
4-208
-------
Dow XZ-92547
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
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
Henry's Law Constant (atm-
m3/mole)
Sediment/Soil
Adsorption/Desorption - Koc
The estimated negligible water solubility and estimated negligible vapor pressure indicate that this
polymer, including the low MW and high MW components, is anticipated to partition predominantly to
soil. The estimated Henry's Law Constant of <10~8 atm-m3/mole indicates that it is not expected to
volatilize from water to the atmosphere. Although estimates for one confidential representative structure
results in a moderate absorption coefficient of 1,596, the estimated Koc of >30,000 for the high MW
components and 3 other confidential representative substances indicate that the majority of this polymeric
mixture is not anticipated to migrate from soil into groundwater and also has the potential to adsorb to
sediment.
<10"8 Bond SAR Method (Estimated)
<10"8 (Estimated)
1,595 (Estimated)
>3 0,000 (Estimated)
>3 0,000 (Estimated)
EPI v4.1 1; Professional
judgment
Boethling and Nabholz, 1997;
Professional judgment
EPI v4. 11; Professional
judgment
EPI v4. 11; EPA, 1999
Boethling and Nabholz, 1997;
Professional judgment
Estimated value based on four
confidential representative structures
with MW <1,000. Cutoff value for
nonvolatile compounds.
Estimated for the MW > 1,000
oligomers. High MW polymers are
expected to have low vapor pressure
and are not expected to undergo
volatilization.
Estimate based on confidential
representative structure 1 .
Estimated values for confidential
representative structures 2, 3 and 4.
Cutoff value fornonmobile
compounds according to HPV
assessment guidance.
Estimated for the oligomers with
MW > 1,000; cutoff value used for
large, high MW polymers. High
4-209
-------
Dow XZ-92547
PROPERTY/ENDPOINT
Level III Fugacity Model
Persistence
Water
Soil
Aerobic Biodegradation
Volatilization Half-life for
Model River
Volatilization Half-life for
Model Lake
Aerobic Biodegradation
Anaerobic Biodegradation
DATA
Air = 0%
Water = 12%
Soil = 88%
Sediment =1% (Estimated)
REFERENCE
EPIv4.11
DATA QUALITY
MW polymers are expected to
adsorb strongly to soil and sediment.
Estimates based on confidential
representative structure 1 . No data
located for the high MW component
of the polymers.
VERY HIGH: The persistence designation for this polymer is based on its higher MW components (MW
>1,000). The higher MW components are expected to have Very High persistence because of their low
water solubility and poor bioavailability, indicating that neither biodegradation nor hydrolysis are
expected to be important environmental fate processes. The lower MW oligomers (MW <1,000) of this
polymer have higher estimated water solubility and increased bioavailability to microorganisms and
therefore would be expected to have lower persistence. This polymer does not contain functional groups
that would be expected to absorb light at environmentally significant wavelengths. Evaluation of these
degradation values suggest a half-life of >180 days.
Days-weeks (Primary Survey Model)
Weeks-months (Ultimate Survey Model)
(Estimated)
Recalcitrant
for MW >1,000 components (Estimated)
>1 year (Estimated)
>1 year (Estimated)
Recalcitrant
for MW >1,000 components (Estimated)
EPIv4.11
Professional judgment;
Boethling and Nabholz, 1997
EPIv4. 11; Professional
judgment
EPI v4.1 1; Professional
judgment
Professional judgment;
Boethling and Nabholz, 1997
Estimates based on confidential
representative structure 1 .
High MW polymers are expected to
3e non-biodegradable.
Estimated value based on four
confidential representative structures
with MW < 1,000; the high MW
polymer components are anticipated
to be nonvolatile.
Estimated value based on four
confidential representative structures
with MW < 1,000; the high MW
3olymer components are anticipated
to be nonvolatile.
^o data located.
High MW polymers are expected to
3e resistant to removal under anoxic
conditions due to their limited
sioavailability.
4-210
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Dow XZ-92547
PROPERTY/ENDPOINT
Air
Reactivity
Soil Biodegradation with
Product Identification
Sediment/Water
Biodegradation
Atmospheric Half-life
Photolysis
Hydrolysis
Environmental Half-life
DATA
<0. 19 days (Estimated)
Not a significant fate process (Estimated)
50%/>1 month (Estimated)
50%/>1 year (Estimated)
75 days in soil (Estimated)
REFERENCE
EPIv4.11
Professional judgment; Mill,
2000
Professional judgment
EPIv4.11
PBT Profiler vl.301; EPI v4.11
DATA QUALITY
No data located.
^o data located.
Estimated value based on four
confidential representative structures
withMW
-------
Dow XZ-92547
PROPERTY/ENDPOINT
Bioaccumulation
Fish BCF
Other BCF
BAF
DATA
REFERENCE
DATA QUALITY
HIGH: The bioaccumulation designation is based on the estimated BCF and BAF values >1,000; these
values are estimated using confidential representative structures of lower MW components (MW <1,000)
of Dow XZ-92547. The higher MW oligomers that may be found in this mixture are expected to have low
potential for bioaccumulation based on their large size and low solubility according to polymer assessment
literature.
9,900 (Estimated)
610 (Estimated)
820 (Estimated)
68 (Estimated)
<100 (Estimated)
620 (Estimated)
2,300 (Estimated)
600 (Estimated)
180 (Estimated)
EPIv4.11
EPIv4.11
EPIv4.11
EPIv4.11
Professional judgment
EPIv4.11
EPIv4.11
EPIv4.11
EPIv4.11
Estimates based on confidential
representative structure 3 with MW
<1,000.
Estimates based on confidential
representative structure 4 with MW
<1,000.
Estimates based on confidential
representative structure 2 with MW
<1,000.
Estimates based on confidential
representative structure 1 with MW
<1,000.
Estimated for the oligomers with a
MW >1,000. Cutoff value for large,
ligh MW, insoluble polymers.
No data located.
Estimates based on confidential
representative structure 4 with MW
<1,000.
Estimates based on confidential
representative structure 3 with MW
<1,000.
Estimates based on confidential
representative structure 2 with MW
<1,000.
Estimates based on confidential
representative structure 1 with MW
<1,000.
4-212
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Dow XZ-92547
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Metabolism in Fish
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
No data located.
Ecological Biomonitoring
No data located.
Human Biomonitoring
This chemical was not included in the NHANES biomonitoring report (CDC, 2013).
4-213
-------
Boethling RS and Nabholz JV (1997) Environmental assessment of polymers under the U.S. Toxic Substances Control Act. Washington, DC: U.S.
Environmental Protection Agency.
CDC (2013) Fourth national report on human exposure to environmental chemicals, updated tables, March 2013.
http://www.cdc.gov/exposurereport/pdf/FourthReport_UpdatedTables_Mar2013.pdf.
ECHA (2013) 6H-dibenz[c,e][l,2]oxaphosphorin 6-oxide. Registered substances. European Chemicals Agency.
http://apps.echa.europa.eu/registered/data/dossiers/DISS-db99cff9-92de-Odla-e044-00144f67d031/DISS-db99cff9-92de-Odla-e044-
00144f67d031_DISS-db99cff9-92de-Odla-e044-00144f67d031.html.
ECOSAR Ecological Structure Activity Relationship (ECOSAR). Estimation Programs Interface (EPI) Suite for Windows, Version 1.11.
Washington, DC: EPIWIN/EPISUITE. U.S. Environmental Protection Agency, http://www.epa.gov/oppt/newchems/tools/21ecosar.htm.
EPA (1999) Determining the adequacy of existing data. High Production Volume (HPV) Challenge. Washington, DC: U.S. Environmental
Protection Agency, http://www.epa.gov/hpv/pubs/general/datadeqfn.pdf
EPA (2010) TSCA new chemicals program (NCP) chemical categories. Washington, DC: U.S. Environmental Protection Agency.
http://www.epa.gov/oppt/newchems/pubs/npcchemicalcategories.pdf
EPA (2012) Using noncancer screening within the SF initiative. Washington, DC: U.S. Environmental Protection Agency.
http://www.epa.gov/oppt/sf/pubs/noncan-screen.htm.
EPI Estimation Programs Interface (EPI) Suite, Version 4.11. Washington, DC: EPIWIN/EPISUITE. U.S. Environmental Protection Agency.
http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm.
ESIS (2012) European chemical Substances Information System. European Commission, http://esis.jrc.ec.europa.eu/.
Mill T (2000) Photoreactions in surface waters. In: Boethling R, Mackay D, eds. Handbook of Property Estimation Methods for Chemicals,
Environmental Health Sciences. Boca Raton: Lewis Publishers.:355-381.
OSHA (1999) Polymer matrix materials Advanced composites. OSHA Technical Manual (OTM) Section III: Chapter 1.
https://www.osha.gov/dts/osta/otm/otm_iii/otm_iii_l.html.
PBT Profiler Persistent (P), Bioaccumulative (B), and Toxic (T) Chemical (PBT) Profiler, Version 1.301. Washington, DC: U.S. Environmental
Protection Agency, www.pbtprofiler.net.
4-214
-------
Aluminum Diethylphosphinate
VL = Very Low hazard L = Low hazard = Moderate hazard H = High hazard VH = Very High hazard — Endpoints in colored text (VL, L, M, H, and VH) were
assigned based on empirical data. Endpoints in black italics (VL, L, M, H, and VH) were assigned using values from predictive models and/or professional judgment.
This table contains hazard information for each chemical; evaluation of risk considers both hazard and exposure. Variations in end-of-life processes or degradation and combustion
by-products are discussed in the report but not addressed directly in the hazard profiles. The caveats listed below must be taken into account when interpreting the information in the
table.
§ Based on analogy to experimental data for a structurally similar compound. R Recalcitrant: Substance is comprised of metallic species (or metalloids) that will not degrade, but may
change oxidation state or undergo complexation processes under environmental conditions. ¥ Aquatic toxicity: EPA/DfE criteria are based in large part upon water column exposures
which may not be adequate for poorly soluble substances such as many flame retardants that may partition to sediment and particulates.
Chemical
CASRN
Human Health Effects
Acute Toxicity
Carcinogenicil
Genotoxicity
Reproductive
Developmenta
Neurological
Repeated Dost
.0
Skin Sensitizal
Respiratory
Sensitization
.0
"3
hH
0)
W
a
o
Dermal Irritat
Aquatic
Toxicity
1
Chronic
Environmental
Fate
Persistence
a
O
Bioaccumulati
Aluminum Diethylphosphinate
225789-38-8
VL
HR
4-215
-------
Aluminum Diethylphosphinate
vJ_v
\_p^
Cf
A!3*
A ^o" ox r
-p P-
) (
CASRN: 225789-38-8
MW: 390.27
MF: 3 C4HnPO2 Al
Physical Forms:
Neat: Solid
Use: Flame retardant
SMILES: CCP(=O)(CC)O[A1](OP(=O)(CC)CC)OP(=O)(CC)CC
Synonyms: Exolit OP 930, Aluminium diethylphosphinate, Aluminium tris(diethylphosphinate)
Chemical Considerations: This alternative is an inorganic compound and in the absence of experimental data, professional judgment using chemical class and
structural considerations were used to complete this hazard profile.
Polymeric: No
Oligomeric: Not applicable
Metabolites, Degradates and Transformation Products: Aluminum and diethylphosphinic acid may dissociate (Australia, 2005)
Analog: Confidential aluminum metal salts; aluminum hydroxide; phosphate
esters
Endpoint(s) using analog values: Absorption, distribution, metabolism &
excretion, carcinogenicity, developmental toxicity, immunotoxicity,
neurotoxicity, repeated dose effects
Structural Alerts: Not applicable
Analog Structure: Not applicable
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 201 1).
Hazard and Risk Assessments: Hazard assessment in Design for the Environment Alternatives Assessment for Flame Retardants in Printed Circuit Boards, Review
Draft, November 8, 2008 (EPA, 2008).
4-216
-------
Aluminum Diethylphosphinate CASRN 225789-38-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
Boiling Point (°C)
Vapor Pressure (mm Hg)
Water Solubility (mg/L)
Decomposes at 315 (Measured)
Decomposes at 300 (Measured)
>400 according to EU Method A. 1 using
differential scanning calorimetry
(Measured)
Decomposes at 330 (Measured)
Decomposes at > 300 (Measured)
>400 (Measured)
Expected to decompose before boiling
(Estimated)
<10"8 (Estimated)
2.5xl03 (Measured)
<1
Submitted confidential study
Submitted confidential study
ECHA, 20 13; Submitted
confidential study
DeBoysere and Dietz, 2005
Clariant, 2007
Australia, 2005
Professional judgment
EPA, 1999; Professional
judgment
Submitted confidential study
ECHA, 20 13; Submitted
Adequate.
Adequate.
Adequate.
Sufficient details were not available
to assess the quality of this study.
Sufficient details were not available
to assess the quality of this study.
Sufficient details were not available
to assess the quality of this study.
Reported for a commercial
formulation.
Based on available data for melting
point.
Cutoff value for nonvolatile
compounds according to HPV
assessment guidance.
Sufficient details were not available
to assess the quality of this study.
Aluminum diethylphosphinate has
low wettability and very slow
dissolution. This gives a kinetically
controlled solubility of <1 mg/L by
guideline 92/69/EEC A.6. If
aluminum diethylphosphinate is
formed by precipitation of a soluble
salt, the remaining equilibrium
solubility of 2.5x 103 mg/L is found.
This can be assumed to be the true
limit of solubility under ideal
conditions.
Guideline study; aluminum
4-217
-------
Aluminum Diethylphosphinate CASRN 225789-38-8
PROPERTY/ENDPOINT
Log Kow
Flammability (Flash Point)
Explosivity
Pyrolysis
DATA
According to EU Method A. 6 (Measured)
<1
According to EU Method A. 6 (Measured)
-0.44
(Estimated)
No self-ignition below 402°C (Measured)
Not readily combustible according to
guideline 96/69/EEC, test A. 10.
(Measured)
Not expected to form explosive mixtures
with air (Estimated)
Major products are diethylphosphinic
acid, ethylphosphonic acid, phosphoric
acid, and their respective salts
(Measured)
REFERENCE
confidential study
Australia, 2005; Submitted
confidential study
Beard and Marzi, 2005; Stuer-
Lauridsen et al., 2007
ECHA, 20 13; Submitted
confidential study
Submitted confidential study
Professional judgment
Beard and Marzi, 2005
DATA QUALITY
diethylphosphinate has low
wettability and very slow
dissolution. If aluminum
diethylphosphinate is formed by
precipitation of a soluble salt, the
remaining equilibrium solubility of
2.5 x 103 mg/L is found, which can be
assumed to be the true limit of
solubility under ideal conditions.
Reported in a secondary source for a
commercial formulation.
Reported in a secondary source with
limited study details; it is unclear
whether this value reflects the
chemical's low water solubility or its
lipophobicity.
Adequate.
Guideline study.
No data located; based on its use as a
flame retardant.
Study details and test conditions
were not available.
4-218
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Aluminum Diethylphosphinate CASRN 225789-38-8
PROPERTY/ENDPOINT
pH
pKa
Particle Size
DATA
pH of an aqueous suspension was 4.0;
aluminum diethylphosphinate completely
dissociated within 24 hours at pH 4.5
during Japanese Ministry of International
Trade and Industry (MITI) test.
(Measured)
DIG = mean ca. 0.4 < 2 (im
D50 = mean ca. 0.4 < 29 (im
According to Laser-Diffraction method.
(Estimated)
REFERENCE
Beard and Marzi, 2005;
Australia, 2005
ECHA, 2013
DATA QUALITY
Inadequate. Although this compound
does not contain acidic protons, the
reference indicates that the acidity
results from equilibria involving the
dissociated species in solution. Study
details and test conditions were not
available. Available data for
commercial formulations suggest
that this compound is likely to
dissociate under environmental
conditions. However, dissociation is
expected to vary as a function of pH
to a degree that will have a
significant influence on its
environmental fate. Available data
are not adequate to assess its
dissociation under typical
environmental conditions.
No data located.
Nonguideline study reported in a
secondary source.
4-219
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Aluminum Diethylphosphinate CASRN 225789-38-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
HUMAN HEALTH EFFECTS
Toxicokinetics
Dermal Absorption in vitro
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal or Inhaled
Other
Acute Mammalian Toxicity
Based on estimates of physical and chemical properties, analogs, and professional judgment, aluminum
diethylphosphinate is determined to not be readily absorbed through skin but may be absorbed through
the inhalation of dust and oral exposure. Absorption is estimated to be good through the gastrointestinal
tract based on physical/chemical properties and analogs; however, only a small amount of administered
dose was reported to be absorbed in the gastrointestinal tract in a submitted confidential rat study.
Elimination was reported primarily in the feces in a confidential study, while in contrast, elimination was
reported to occur primarily in the urine within 12 hours of oral administration in another study.
Absorption as neat solid expected to be
negligible through skin. Absorption good
through lungs. Absorption good through
gastrointestinal tract. (Estimated)
Following oral administration, excretion
was almost quantitative via the urine
within 12 hours.
Male rats (2/dose group) administered
(unradiolabeled) test substance via single
oral gavage at 180 and 1,000 mg/kg-day.
Only a small amount of the administered
dose was absorbed by the gastro-
intestinal tract. The major route of
elimination was in the feces (unabsorbed
fraction) and a small amount of free test
substance was detected in the urine. After
36 hours, no test substance was detected.
Professional judgment
Stuer-Lauridsen et al., 2007
Submitted confidential study
Estimates based on
physical/chemical properties and
confidential analogs.
Study details reported in a secondary
source
Study details from an abstract
reported in a confidential
submission; study conducted
according to OECD 417; small
number of animals tested.
No data located.
LOW: Experimental studies indicate that oral and dermal routes to rats do not produce mortality at oral
and dermal doses up to 2,000 mg/kg. No lethality data was located for inhalation exposure.
4-220
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Aluminum Diethylphosphinate CASRN 225789-38-8
PROPERTY/ENDPOINT
Acute Lethality
Oral
Dermal
Inhalation
Carcinogenicity
OncoLogic Results
Carcinogenicity (Rat and
Mouse)
Combined Chronic
Toxicity/Carcinogenicity
Other
Genotoxicity
Gene Mutation in vitro
Gene Mutation in vivo
Chromosomal Aberrations in
vitro
DATA
Rat oral LD50 >2,000 mg/kg
Rat dermal LD50 >2,000 mg/kg
REFERENCE
Australia, 2005; Submitted
confidential study
Australia, 2005; Submitted
confidential study
DATA QUALITY
Reported in a secondary source for a
commercial formulation. Test
substance was Exolit OP 930.
Conducted according to OECD TG
401.
Reported in a secondary source for a
commercial formulation. Test
substance was Exolit OP 930.
Conducted according to OECD TG
402.
No data located.
LOW: Aluminum diethylphosphinate is estimated to be of low hazard for Carcinogenicity based on
comparison to analogous metal salts and professional judgment.
Not expected to be carcinogenic.
(Estimated)
Professional judgment
No data located.
Estimated based on analogy to
confidential metal salts.
No data located.
No data located.
LOW: Experimental studies indicate that aluminum diethylphosphinate does not cause gene mutations in
bacteria or chromosomal aberrations in mammalian cells.
Negative, Salmonella typhimurium
strains TA1535, TA1537, TA1538, TA98
and TA100 with and without metabolic
activation
Negative, chromosomal aberrations in
Chinese hamster lung cells with and
without metabolic activation
Australia, 2005; Stuer-Lauridsen
et al., 2007; Submitted
confidential study
Australia, 2005; Submitted
confidential study
Reported in a secondary source for a
commercial formulation. Conducted
according to OECD TG 471.
No data located.
Reported in a secondary source for a
commercial formulation. Conducted
according to OECD TG 473.
4-221
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Aluminum Diethylphosphinate CASRN 225789-38-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Chromosomal Aberrations in
vivo
Negative, mammalian erythrocyte
micronucleus test in NMRI mice; oral
(unspecified)
Submitted confidential study
Study reported in a submitted
confidential study; Study conducted
according to OECD Guideline 474
(Mammalian Erythrocyte
Micronucleus Test).
DNA Damage and Repair
No data located.
Other
No data located.
Reproductive Effects
LOW: Changes (characterized as minor) in the number of days of pre-coital interval and a reduction in
copulation plugs were reported in a submitted confidential study at 1,000 mg/kg-day. The study-reported
NOAEL is on the margin of the Low to Very Low hazard designation; therefore a Low hazard designation
was assigned. Aluminum diethylphosphinate is also estimated to be of low hazard for reproductive effects
based on professional judgment and comparison to analogous metal salts.
Reproduction/Developmental
Toxicity Screen
Expected to have low hazard potential for
reproductive effects. (Estimated)
Rats (Sprague Dawley); oral
administration of 250 and 1,000 mg/kg
bw-day; 15 days prior to mating and
throughout gestation and lactation up to
post-partum Day 3.
Parental effects: No clinical signs of
toxicity or change in food consumption.
Slight reduction in body weight and body
weight gain (both sexes, 1,000 mg/kg-
day); Reduced terminal body weight and
absolute and relative kidney weights
(males, 1,000 mg/kg-day).
No adverse effect on oestrus cycle,
implantation, gestation length, corpora
lutea or sex ratios. No effect on sperm
(motility, morphology, concentration).
Increase in the number of days of pre-
coital interval and a reduction in
copulation plugs (1,000 mg/kg-day);
Professional judgment
Submitted confidential study
Estimated based on analogy to
confidential metal salts.
Study reported in a submitted
confidential study; Study conducted
according to OECD Guideline 421
(Reproductive/Developmental
Toxicity Screening Test).
4-222
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Aluminum Diethylphosphinate CASRN 225789-38-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
these changes were reported as "minor"
No treatment-related macroscopic
anomalies in pups dying or sacrificed at
term.
NOAEL: 1,000 mg/kg-day (highest dose
tested)
LOAEL: Not established
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
No data located.
Reproduction and Fertility
Effects
No data located.
Other
No data located.
Developmental Effects
MODERATE: There were no developmental effects reported in a reproduction/developmental toxicity
screen in rats at doses up to 1,000 mg/kg-day. There is moderate hazard for aluminum diethylphosphinate
given exposure may result in neurodevelopmental effects based on the presence of a phosphinate; there
were no experimental studies specifically designed to evaluate the neurodevelopmental endpoint located.
The potential for neurodevelopmental effects cannot be ruled out.
Reproduction/
Developmental Toxicity
Screen
Expected to have a moderate hazard
potential for developmental and
neurodevelopmental effects resulting
from the presence of a phosphinate.
(Estimated)
Rats (Sprague Dawley); oral
administration of 250 and 1,000 mg/kg
bw-day; 15 days prior to mating and
throughout gestation and lactation up to
post-partum Day 3.
Parental: No clinical signs of toxicity or
change in food consumption. Slight
reduction in body weight and body
4-223
Professional judgment
Submitted confidential study
Estimated based on analogy to
phosphate esters and associated
cholinesterase inhibition.
Study details reported in a
confidential submission; Study
conducted according to OECD
Guideline 421
(Reproductive/Developmental
Toxicity Screening Test).
-------
Aluminum Diethylphosphinate CASRN 225789-38-8
PROPERTY/ENDPOINT
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
Prenatal Development
Postnatal Development
Prenatal and Postnatal
Development
Developmental Neurotoxicity
Other
DATA
weight gain; reduced terminal body
weight and absolute and relative kidney
weights (males, 1,000 mg/kg-day). No
adverse effect on estrus cycle,
implantation, gestation length, corpora
lutea or sex ratios. No effect on sperm
(motility, morphology, concentration).
Increase in the number of days of pre-
coital interval and a reduction in
copulation plugs (1,000 mg/kg-day).
No treatment-related macroscopic
anomalies in pups dying or sacrificed at
term.
NOAEL = 1,000 mg/kg-day
REFERENCE
DATA QUALITY
No data located.
No data located.
No data located.
No data located.
No data located.
No data located.
4-224
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Aluminum Diethylphosphinate CASRN 225789-38-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Neurotoxicity
MODERATE: Aluminum diethylphosphinate is expected to be of Moderate hazard for based on analogy
to aluminum hydroxide and professional judgment. Exposure to the analog resulted in impaired learning
in a labyrinth maze test in a 90-day oral study in rats at 35 mg Al/kg/day as aluminum hydroxide with
citric acid. Impaired learning in a labyrinth maze test was also reported in rats orally exposed to 300 mg
Al/kg/day (only dose tested) as the analog aluminum hydroxide (without citric acid). There is uncertainty
in the threshold of response; the possibility that effects occur at doses <100 mg/kg/day (In the Moderate -
High hazard designation range) cannot be ruled out.
Neurotoxicity Screening
Battery (Adult)
Expected to have a moderate hazard
potential for neurotoxic effects resulting
from the presence of bioavailable metal
species.
(Estimated)
28-day, Rat, oral gavage, 0, 62.5, 250 or
1,000 mg/kg bw-day.
No treatment-related changes in behavior
or appearance, no changes in body
weight, food consumption, blood
chemistry or organ weight. No alterations
in gross or microscopic tissue
examination. RatNOAEL > 1,000 mg/kg
(highest dose tested).
90-day Rat, oral gavage, impaired
learning in a labyrinth maze test.
NOAEL: Not established
LOAEL: 35 mg Al/kg-day as aluminum
hydroxide with citric acid (only dose
tested)
(Estimated by analogy)
90-day Rat, oral gavage, impaired
learning in a labyrinth maze test.
NOAEL: Not established
Professional judgment
Estimated based on professional
judgment and analogy to aluminum
hydroxide.
Beard and Marzi, 2005; Stuer-
Lauridsen et al., 2007
Bilkei-Gorzo, 1993 (as cited in
ATSDR, 2008)
Bilkei-Gorzo, 1993
Reported in a secondary source;
study details and test conditions were
not available.
Reported in a secondary source; dose
reported as 35 mg/kg-day as
aluminum hydroxide with citric acid;
citric acid was added to increase
absorption; it is not proven that
negative effects only related to
aluminum hydroxide and not based
on citric acid; also, the background
aluminum content of the diet fed to
rats was not reported; only one dose
tested.
The background aluminum content
of the diet fed to rats was not
reported; only one dose tested
4-225
-------
Aluminum Diethylphosphinate CASRN 225789-38-8
PROPERTY/ENDPOINT
Other
Repeated Dose Effects
Skin Sensitization
Skin Sensitization
DATA
LOAEL: 300 mg Al/kg-day as aluminum
hydroxide (only dose tested)
(Estimated by analogy)
Oral exposure to aluminum is usually not
harmful. Some studies show that people
exposed to high levels of aluminum may
develop Alzheimer's disease, but other
studies have not found this to be true. It is
not known for certain that aluminum
causes Alzheimer's disease.
REFERENCE
ATSDR, 2008
DATA QUALITY
(aluminum hydroxide without citric
acid); study description lacks
sufficient details on individual
results.
Summary statement from a
secondary source.
MODERATE: Estimated to be of moderate hazard for immunotoxicity, due to the presence of a
bioavailable metal species, based on comparison to analogous metal salts and professional judgment.
Experimental studies indicate that oral exposure to rats produces no adverse effects at levels up to 1,000
mg/kg-day.
28-day, Rat, oral gavage, 0, 62.5, 250 or
l,000mg/kgbw-day.
No treatment-related changes in behavior
or appearance, no changes in body
weight, food consumption, blood
chemistry or organ weight. No alterations
in gross or microscopic tissue
examination.
28-day NOAEL > 1,000 mg/kg-day, rats.
Expected to have a moderate hazard
potential for immunotoxicity effects
resulting from the presence of
bioavailable metal species.
(Estimated)
Australia, 2005; Stuer-Lauridsen
et al., 2007; Submitted
confidential study
Professional judgment
Reported in a secondary source for a
commercial formulation. Test
substance was Exolit OP 930.
Estimated based on analogy to
confidential metal salts.
LOW: Negative for skin Sensitization in guinea pigs.
Non-sensitizing, guinea pigs.
Australia, 2005; Submitted
confidential study
Reported in a secondary source for a
commercial formulation. Conducted
according to OECD TG 406.
4-226
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Aluminum Diethylphosphinate CASRN 225789-38-8
PROPERTY/ENDPOINT
Respiratory Sensitization
Respiratory Sensitization
Eye Irritation
Eye Irritation
Dermal Irritation
Dermal Irritation
Endocrine Activity
Immunotoxicity
Immune System Effects
DATA
REFERENCE
DATA QUALITY
No data located.
[No data located.
LOW: Aluminum diethylphosphinate is slightly to non-irritating in rabbit eyes.
Slightly irritating, rabbits.
Not irritating, rabbits.
Australia, 2005
Submitted confidential study
Reported in a secondary source for a
commercial formulation. Conducted
according to OECD TG 405.
Study reported in a submitted
confidential study.
VERY LOW: Aluminum diethylphosphinate is not irritating to rabbit skin.
Non-irritating, rabbit.
Australia, 2005; Submitted
confidential study
Reported in a secondary source for a
commercial formulation. Conducted
according to OECD 404.
No data located.
[No data located.
Aluminum diethylphosphinate is estimated to be of moderate hazard for immunotoxicity, due to the
presence of a bioavailable metal species, based on comparison to analogous metal salts and professional
judgment.
Expected to have a moderate hazard
potential for immunotoxicity effects
resulting from the presence of
bioavailable metal species.
(Estimated)
ECOTOXICITY
ECOSAR Class
Acute Aquatic Toxicity
Fish LC50
Professional judgment
Estimated based on analogy to
confidential metal salts.
Not applicable
MODERATE: The measured green algae EC50 is between 50 and > 180 mg/L. For fish and Daphnia, LC50
values could not be determined because there were no effects at the highest concentrations tested.
Danio rerio (Zebra fish) 96-hour LC50
>1 1 mg/L
(Experimental)
Danio rerio (Zebra fish) 96-hour LC50
>9.2 mg/L
Australia, 2005
Submitted confidential study
Reported in a secondary source for a
commercial formulation.
Study reported in a submitted
confidential study.
4-227
-------
Aluminum Diethylphosphinate CASRN 225789-38-8
PROPERTY/ENDPOINT
Daphnid LC50
Green Algae EC so
Chronic Aquatic Toxicity
Fish ChV
DATA
(Experimental)
Danio rerio (Zebra fish) 96-hour LC50
>100mg/L
(Experimental)
Daphnia magna 48-hour LC50 >33.7
mg/L.
(Experimental)
Daphnia magna 48-hour LC50 >33 mg/L.
(Experimental)
Daphnia magna 48-hour EC50 >100
mg/L
48-hour NOEC = 100 mg/L.
(Experimental)
Scenedesmus subspicatus 72 -hour EbC50
of 60 mg/L;
Scenedesmus subspicatus 72-hour ErC50
of 76 mg/L.
(Experimental)
72-hour EC50 = 50 mg/L.
(Experimental)
Scenedesmus subspicatus 72 -hour EC50
>1 80 mg/L.
(Experimental)
REFERENCE
Submitted confidential study
Australia, 2005
Submitted confidential study
Submitted confidential study
Australia, 2005
Submitted confidential study
Submitted confidential study
DATA QUALITY
Study reported in a submitted
confidential study; Study conducted
according to EU Method C.I (Acute
Toxicity for Fish).
Reported in a secondary source for a
commercial formulation.
Study reported in a submitted
confidential study.
Study reported in a submitted
confidential study; Study conducted
according to OECD Guideline 202
(Daphnia sp. Acute Immobilization
Test).
Reported in a secondary source for a
commercial formulation.
Study reported in a submitted
confidential study.
Study details reported in a
confidential submission; Study
conducted according to EU Method
c.3 (Algal Inhibition Test).
MODERATE: An experimental value for green algae is 1.8 mg/L, while measured toxicity values for fish
and Daphnia are >10 mg/L.
ChV = 48 mg/L. (Estimated)
(Estimated)
Danio rerio (Zebra fish) 2 8 -day NOEC =
100 mg/L; LOEC >100 mg/L.
(Experimental)
Submitted confidential study
Submitted confidential study
Study reported in a submitted
confidential study.
Study reported in a submitted
confidential study; Study conducted
according to OECD Guideline 215
(Fish, Juvenile Growth Test).
4-228
-------
Aluminum Diethylphosphinate CASRN 225789-38-8
PROPERTY/ENDPOINT
Daphnid ChV
Green Algae ChV
DATA
Daphnia magna 21 -day EC50 =22.3
mg/L for immobility
Daphnia magna 21-day EC50 = 46.2
mg/L for reproduction
Daphnia magna 21 -day LOEC = 32
mg/L for immobility and reproduction
Daphnia magna 21 -day NOEC =10
mg/L for immobility and reproduction
(Experimental)
Green algae ChV = 1.8 mg/L.
(Experimental)
(Experimental)
REFERENCE
Australia, 2005; Submitted
confidential study
Submitted confidential study
DATA QUALITY
Reported in a secondary source for a
commercial formulation.
Study reported in a submitted
confidential study.
ENVIRONMENTAL FATE
Transport
Henry's Law Constant (atm-
m3/mole)
Sediment/Soil
Adsorption/Desorption - Koc
Level III Fugacity Model
Although the behavior of metal salts under environmental conditions is dependent on the characteristics of
the local environment (predominately pH), transport of both the metal species and the organic anion is
anticipated to be dominated by leaching through soil, runoff to aqueous environments, adsorption and/or
precipitation of the metal ion onto soil or sediment, and wet and dry deposition of dust particulates in air
to land or surface water. Volatilization of this ionic compound from either wet or dry surfaces is not
expected to be an important fate process. Nevertheless, the environmental fate of this organic salt will be
dependent on its pH-dependent dissociation, and adequate data are not available.
<10'8 (Estimated)
Approximately 0.38 according to OECD
Guideline 121 (Measured)
Professional judgment
ECHA, 20 13; Submitted
confidential study
Cutoff value for nonvolatile
compounds.
Guideline study.
This substance is not amenable to the
model.
4-229
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Aluminum Diethylphosphinate CASRN 225789-38-8
PROPERTY/ENDPOINT
Persistence
Water
Soil
Aerobic Biodegradation
Volatilization Half-life for
Model River
Volatilization Half-life for
Model Lake
Aerobic Biodegradation
Anaerobic Biodegradation
DATA
REFERENCE
DATA QUALITY
HIGH: For the organic counter-ion, estimates indicate that the half-life for ultimate aerobic
biodegradation in water is less than 60 days, which converts to moderate potential for persistence.
However, the metal ion is recalcitrant to biodegradation or other typical environmental removal processes.
Passes Ready Test: No
Test method: OECD TG 30 IF:
Manometric Respirometry Test
(Measured)
Not readily biodegradable (Measured)
Not readily biodegradable (Measured)
Organic counter-ion:
Days-weeks (primary survey model)
Weeks (ultimate survey model)
(Estimated)
Metal ion: Recalcitrant (Estimated)
Study results: Not indicated
Test method: 302C: Inherent - Modified
MITI Test (II)
Not inherently biodegradable (Measured)
Not inherently biodegradable (Measured)
>1 year
Not a significant fate process (Estimated)
>1 year
Not a significant fate process (Estimated)
No degradation according to ISO/DIS
14853
ECHA, 20 13; Submitted
confidential study
Australia, 2005
Stuer-Lauridsen et al., 2007
EPIv4.10
Professional judgment
ECHA, 20 13; Submitted
confidential study
Stuer-Lauridsen et al., 2007
Professional judgment
Professional judgment
Stuer-Lauridsen et al., 2007
Guideline study.
Reported in a secondary source for a
commercial formulation
Sufficient details were not available
to assess the quality of this study.
Metal ions will not degrade in the
environment.
Guideline study.
Sufficient details were not available
to assess the quality of this study.
Based on the magnitude of the
estimated Henry's Law constant.
Based on the magnitude of the
estimated Henry's Law constant.
No data located.
Guideline study reported in a
secondary source.
4-230
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Aluminum Diethylphosphinate CASRN 225789-38-8
PROPERTY/ENDPOINT
Air
Reactivity
Soil Biodegradation with
Product Identification
Sediment/Water
Biodegradation
Atmospheric Half-life
Photolysis
Hydrolysis
Environmental Half-life
Bioaccumulation
Fish BCF
Other BCF
BAF
Metabolism in Fish
DATA
Not a significant fate process (Estimated)
Not a significant fate process (Estimated)
Metal salts form a variety of
hydroxylation products as a function of
pH. Hydrolysis of the organic counter-ion
is not expected to be a significant fate
process (Estimated)
Organic counter-ion: <60 days
Metal ion: Recalcitrant (Estimated)
REFERENCE
Professional judgment
Mill, 2000; Professional
judgment
Professional judgment; Wolfe
and Jeffers, 2000
EPI v4.10; Professional
judgment
DATA QUALITY
No data located.
No data located.
This chemical is expected to exist
entirely in particulate form in air.
The substance does not contain
functional groups that would be
expected to absorb light at
environmentally significant
wavelengths.
The organic counter ion does not
contain functional groups that would
be expected to hydrolyze readily
under environmental conditions.
Based on estimated biodegradation
half-lives for the organic counter-ion
and metal ions will not degrade in
the environment.
LOW: Aluminum diethylphosphinate is not expected to have potential for bioaccumulation.
< 100 (Estimated)
Professional judgment
Available data suggests this chemical
will dissociate under environmental
conditions. The estimated log K0w
and limited lipophilicity are
indicative of a lower potential for
bioconcentration.
No data located.
No data located.
No data located.
4-231
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Aluminum Diethylphosphinate CASRN 225789-38-8
PROPERTY/ENDPOINT
DATA REFERENCE
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
Ecological Biomonitoring
Human Biomonitoring
DATA QUALITY
No data located.
No data located.
This chemical was not included in the NHANES biomonitoring report (CDC, 201 1).
4-232
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ATSDR (2008) Toxicological profile for aluminum. Atlanta, GA: Agency for Toxic Substances and Disease Registry, U.S. Department of Health
and Human Services, http://www.atsdr.cdc.gov/toxprofiles/tp22.pdf
Australia (2005) Chemical in Exolit OP 1312. Australia. National Industrial Chemicals Notification and Assessment Scheme.
Beard A and Marzi T (2005) New phosphorus based flame retardants for E&E applications: A case study on their environmental profile in view of
European legislation o chemicals and end-of-life (REACH, WEEE, RoHS). http://www.flameretardants-
online.com/images/userdata/pdf/175_EN.pdf
Bilkei-Gorzo A (1993) Neurotoxic effect of enteral aluminum. Food Chem Toxicol 31(5):357-361.
CDC (2011) Fourth national report on human exposure to environmental chemicals, updated tables, February 2011. Centers for Disease Control
and Prevention, Department of Health and Human Services, http://www.cdc.gov/exposurereport/.
Clariant (2007) Product data sheet- flame retardants. Exolit OP 930. Clariant International Ltd.
http://www.additives.clariant.com/bu/additives/PDS_Additives.nsf/www/DS-OSTS-7SHDYA?open.
DeBoysere J and Dietz M (2005) Halogen-free flame retardants for electronic applications. http://www.onboard-
technology.com/pdf_febbraio2005/020505.pdf
ECHA (2013) Confidential submitted study. Registered substances. European Chemicals Agency, http://apps.echa.europa.eu/registered/registered-
sub.aspx.
EPA (1999) Determining the adequacy of existing data. High Production Volume (HPV) Challenge. Washington, DC: U.S. Environmental
Protection Agency, http://www.epa.gov/hpv/pubs/general/datadeqfn.pdf
EPA (2008) Flame retardants in printed circuit boards. Cincinnati, OH: U.S. Environmental Protection Agency, Design for the Environment.
EPI Estimation Programs Interface (EPI) Suite, Version 4.10. Washington, DC: EPIWIN/EPISUITE. U.S. Environmental Protection Agency.
http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm.
ESIS (2011) European chemical Substance Information System. European Commission, http://esis.jrc.ec.europa.eu/.
Mill T (2000) Photoreactions in surface waters. In: Boethling R, Mackay D, eds. Handbook of Property Estimation Methods for Chemicals,
Environmental Health Sciences. Boca Raton: Lewis Publishers.:355-381.
4-233
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Stuer-Lauridsen F, Cohr KH, Andersen TT (2007) Health and environmental assessment of alternatives to Deca-BDE in electrical and electronic
equipment. Danish Ministry of the Environment Environmental Protection Agency. http://www2.mst.dk/Udgiv/publications/2007/978-87-7052-
351-6/pdf/978-87-7052-352-3.pdf
Wolfe N and Jeffers P (2000) Hydrolysis. In: Boethling RS, Mackay D, eds. Handbook of property estimation methods for chemicals
Environmental and Health Sciences. Boca Raton, FL: Lewis Publishers.:311-333.
4-234
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Aluminum Hydroxide
VL = Very Low hazard L = Low hazard = Moderate hazard H = High hazard VH = Very High hazard — Endpoints in colored text (VL, L, M, H, and VH) were
assigned based on empirical data. Endpoints in black italics (VL, L, M, H, and VH) were assigned using values from predictive models and/or professional judgment.
This table contains hazard information for each chemical; evaluation of risk considers both hazard and exposure. Variations in end-of-life processes or degradation and combustion
by-products are discussed in the report but not addressed directly in the hazard profiles. The caveats listed below must be taken into account when interpreting the information in the
table.
§ Based on analogy to experimental data for a structurally similar compound. R Recalcitrant: Substance is comprised of metallic species (or metalloids) that will not degrade, but may
change oxidation state or undergo complexation processes under environmental conditions. ¥ Aquatic toxicity: EPA/DfE criteria are based in large part upon water column exposures
which may not be adequate for poorly soluble substances such as many flame retardants that may partition to sediment and particulates.
Chemical
CASRN
Human Health Effects
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Aluminum Hydroxide
21645-51-2
V
V
VL VL
4-235
-------
Aluminum hydroxide
HO
Xl-OH
HO
SMILES: O[A1](O)O
CASRN: 21645-5 1-2
MW: 78.01
MF: A1H3O3
Physical Forms:
Neat: Solid
Use: Flame retardant
Synonyms: Aluminum hydroxide (A1(OH)3), Gibbsite, Bayersite, Nordstrandite, Aluminum trihydrate
Chemical Considerations: This alternative is an inorganic compound and in the absence of experimental data, professional judgment using chemical class and
structural considerations were used to complete this hazard profile.
Polymeric: No
Oligomeric: Not applicable
Metabolites, Degradates and Transformation Products: None
Analog: Unspecified analogous aluminum compounds were discussed in the Analog Structure: Not app
structural based professional judgment rationale
Endpoint(s) using analog values: Carcinogenicity, reproductive effects,
immunotoxicity
Structural Alerts: Aluminum compounds (EPA, 2010).
Risk Phrases: Not classified by Annex I Directive 67/548/European Economic Community & IUCLID (Pakalin
icable
et al., 2007).
Hazard and Risk Assessments: Risk assessment completed for aluminum hydroxide by the National Research Council Subcommittee on Flame-Retardant Chemicals
(NRC, 2000). Hazard assessment completed for Design for the Environment Alternatives Assessment for Flame Retardants in Printed Circuit Boards, Review Draft,
November 8, 2008. (EPA, 2008; NRC, 2000).
4-236
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Aluminum Hydroxide CASRN 21645-51-2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
Boiling Point (°C)
Vapor Pressure (mm Hg)
Water Solubility (mg/L)
Decomposes at approximately 200
(Measured)
Decomposes at approximately 150-220 to
A12O3 and H2O (Measured)
Decomposes (loses water) at 300 (Measured)
The substance is expected to decompose
before boiling. (Estimated)
<10'8 (Estimated)
< 0.09 at 20°C, pH 6-7
Organisation for Economic Cooperation and
Development (OECD) Guideline 105 Purity
calculated based on aluminum oxide
(Measured)
0.01 17 to 0.0947 at pH 7.5-8.1 and 21-24°C
Reported as 1 1.7 to 94.7 (ig/L A1(OH)3 and
4.06 to 32.75 jig/LAl
100 mg of A1(OH)3 was dissolved in 100 mL
distilled water or test media prepared
according to OECD 201, 202 or 21 1, filtered,
and then analyzed using Graphite Furnace
Atomic Absorption Spectrometry (GF AAS)
and Inductively coupled plasma atomic
emission spectroscopy (ICP-AES) (Measured)
1.5 at 20°C at pH 7 (Measured)
1.5xlO"2 at 20°C at pH 8-9 (Measured)
European Commission, 2000
European Commission, 2000
Lewis, 2000
Professional judgment
EPA, 1999; Professional
judgment
ECHA, 2013
Submitted confidential study
European Commission, 2000
European Commission, 2000
Adequate.
Adequate.
Adequate.
Based on the values included in the
melting point section of this assessment.
Cutoff value for compounds that are
anticipated to be nonvolatile accorded to
HPV assessment guidance
Guideline study reporting non-specific
value that is in agreement with other
experimental values indicating poor
solubility.
Reported in a nonguideline study done to
prepare for toxicity testing.
Measured values were not consistently
reported, but are sufficient for subsequent
components of the hazard assessment.
Measured values were not consistently
reported, but are sufficient for subsequent
components of the hazard assessment.
4-237
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Aluminum Hydroxide CASRN 21645-51-2
PROPERTY/ENDPOINT
Log Kow
Flammability (Flash Point)
Explosivity
Pyrolysis
pH
pKa
Particle Size
DATA
Insoluble in water (Estimated)
Practically insoluble in water (Estimated)
Not flammable (Measured)
Not explosive (Estimated)
Not flammable (Estimated)
pH of a saturated solution in water was 6 to 7
(Measured)
Not applicable (Estimated)
<100 (im; 88% for the fine unground hydrate
and 52-61% for the coarse unground hydrate
< 2 (im; 1.3-2% for the fine unground hydrate
and 1% for the coarse unground hydrate
According to OECD Guideline 110 (Particle
Size Distribution / Fibre Length and Diameter
Distributions)
(Measured)
REFERENCE
Lide, 2006
Lewis, 2000; O'Neil et al.,
2001
ECHA, 2013
European Commission, 2000
European Commission, 2000
ECHA, 2013
Professional judgment
ECHA, 2013
DATA QUALITY
Measured values were not consistently
reported, but are sufficient for subsequent
components of the hazard assessment.
Measured values were not consistently
reported, but are sufficient for subsequent
components of the hazard assessment.
No data located. This inorganic compound
is not amenable to available estimation
methods.
Reported in a secondary source and based
on its use as a flame retardant.
Adequate.
Adequate.
Determined in a water solubility study.
Determination of dissociation constant is
not possible due to the insolubility of the
test substance.
Guideline study reported in a secondary
source.
4-238
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Aluminum Hydroxide CASRN 21645-51-2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
HUMAN HEALTH EFFECTS
Toxicokinetics
Dermal Absorption in vitro
Absorption,
Distribution,
Metabolism
& Excretion
Oral, Dermal or Inhaled
Toxicokinetic data suggest that aluminum hydroxide is not readily absorbed in humans following oral exposure.
Excretion occurs primarily through feces, and less so in urine. Animal studies indicated that aluminum
accumulated in intestinal cells but was not found in other tissues.
26 Al labeled aluminum hydroxide (in water
suspension) was administered to rats by oral
gavage. The mean fractional uptake
(absorption) into the bloodstream of 26A1 from
aluminum hydroxide was 0.025±0.041%.
Compared to the uptake into the bloodstream
of rats injected with 0. 19 ng 26A1 labeled
aluminum citrate in solution, aluminum
hydroxide as an insoluble compound is less
bioavailable than soluble compounds (mean
fractional uptake of 26 Aluminum citrate: 0.079
±0.0057%; 26Aluminum hydroxide:
0.025±0.041%).
After rats were exposed to aluminum
hydroxide in drinking water for 10 weeks,
aluminum accumulated in intestinal cells but
not in other tissues.
In metabolic studies in humans, 12% of an
oral load of aluminum hydroxide was
retained, but absorption was not calculated.
The absorbed fraction of aluminum hydroxide
in two human males dosed orally was 0.01%.
Adult humans with renal failure who ingested
1.5-3.0 g aluminum hydroxide per day for 20-
32 days absorbed between 100 and 568 mg
aluminum per day (7-19% of the dose).
Adult humans taking aluminum antacids had
a 3 -fold increase of aluminum levels in the
ECHA, 2013
HSDB, 2013
HSDB, 2013
HSDB, 2013
HSDB, 2013
ATSDR, 2008
No data located.
Reported in a secondary source. Adequate,
performed in accordance with OECD
guidelines and Good Laboratory Practices
(GLP); Aluminum hydroxide, was
suspended in water with added 1%
carboxymethylcellulose (to maintain a
suspension).
Reported in a secondary source, study
details and test conditions were not
provided.
Reported in a secondary source, study
details and test conditions were not
provided.
Reported in a secondary source, study
details and test conditions were not
provided.
Reported in a secondary source, study
details and test conditions were not
provided.
Reported in a secondary source, study
details were not provided.
4-239
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Aluminum Hydroxide CASRN 21645-51-2
PROPERTY/ENDPOINT
Other
Acute Mammalian Toxicity
Acute
Lethality
Oral
Dermal
Inhalation
Carcinogenicity
Genotoxicity
OncoLogic Results
Carcinogenicity (Rat and
Mouse)
Combined Chronic
Toxicity/Carcinogenicity
Other
Gene Mutation in vitro
Gene Mutation in vivo
Chromosomal Aberrations in
vitro
DATA
urine; minimal aluminum was absorbed and
was mostly excreted in the feces.
Certain complexing agents such as citric acid
and lactic acid can increase the
bioavailability /absorption of aluminum
hydroxide.
REFERENCE
Gomez etal., 1991;Bilkei-
Gorzo, 1993; Colamina et al.,
1994; Professional judgment.
DATA QUALITY
Based on studies using citric acid and
lactic acid in conjunction with aluminum
hydroxide and professional judgment.
LOW: Aluminum hydroxide has low acute toxicity based on oral LD50 > 2,000 mg/kg in rats.
Rat oral LD50 >5,000 mg/kg
Rat oral LD50 >2,000 mg/kg
European Commission, 2000
ECHA, 2013
Reported in a secondary source, study
details and test conditions were not
provided.
Reported in a secondary source.
Performed in accordance with OECD
guidelines and GLP.
No data located.
No data located.
LOW: Aluminum hydroxide is estimated to be of low hazard for Carcinogenicity based on professional judgment
and comparison to analogous aluminum compounds.
Low potential for Carcinogenicity
(Estimated)
Professional judgment
No data located.
Estimated based on professional judgment
and comparison to analogous aluminum
compounds.
No data located.
No data located.
LOW: Aluminum hydroxide did not cause mutations in mammalian cells in vitro and did not result in an
increased incidence of micronuclei in rats in vivo.
Negative in mouse lymphoma cells with and
without metabolic activation
ECHA, 2013
Adequate, performed in accordance with
OECD guidelines and GLP.
No data located.
No data located.
4-240
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Aluminum Hydroxide CASRN 21645-51-2
PROPERTY/ENDPOINT
Chromosomal Aberrations in
vivo
DNA Damage and Repair
Other
Reproductive Effects
Reproduction/Developmental
Toxicity Screen
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
Reproduction and Fertility
Effects
Other
Developmental Effects
Reproduction/
Developmental Toxicity
Screen
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
DATA
Negative for induction of micronuclei in
polychromatic erythrocytes of bone marrow
in Sprague-Dawley rats
REFERENCE
ECHA, 2013
DATA QUALITY
Adequate, performed in accordance with
OECD guidelines and GLP.
No data located.
No data located.
LOW: Aluminum hydroxide is estimated to be of low hazard for reproductive effects based on professional
judgment and comparison to analogous aluminum compounds.
Low potential for reproductive effects
(Estimated)
Professional judgment
No data located.
No data located.
Estimated based on professional judgment
and comparison to analogous aluminum
compounds.
No data located.
LOW: Aluminum hydroxide does not show developmental toxicity when administered orally to rats or mice at
dose levels up to 266 mg/kg-day. There were no data located regarding developmental neurotoxicity.
No data located.
No data located.
4-241
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Aluminum Hydroxide CASRN 21645-51-2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Prenatal Development
Rat (Sprague-Dawley), oral (gavage), 384
mg/kg/day A1(OH)3 alone or 384 mg/kg/day
A1(OH)3 concurrent with 62 mg/kg/day citric
acid on GD 6-15.
No significant differences between controls
and Al-treated rats on pre- or
postimplantation loss, number of live fetuses
per litter, or sex ratio. Reduced fetal body
weight and increased incidence of skeletal
variations in groups receiving A1(OH)3 and
citric acid.
Gomez etal., 1991
Study details reported in a primary source.
Citric acid was added to increase
absorption; it is not proven that effects are
solely related to aluminum hydroxide and
not based on citric acid.
Swiss mice, oral (gavage), 166 mg/kg
A1(OH)3 alone or 166 mg/kg A1(OH)3
concurrent with 570 mg/kg lactic acid on GD
6-15.
Maternal toxicity was evident in groups
treated with A1(OH)3 and lactic acid. There
were no embryotoxic effects in any group.
There was a non-statistically significant
increased incidence of skeletal variations in
groups receiving A1(OH)3 and lactic acid.
Colominaetal., 1992
Study details reported in a primary source
Lactic acid was added to increase
absorption; it is not proven that effects are
solely related to aluminum hydroxide and
not based on lactic acid.
Rat (Sprague-Dawley), oral (gavage), 0 or
384 mg/kg-day on GD 6-15
There were no significant changes in pre- or
post-implantation losses, number of live
fetuses per litter, sex ratio, fetal body weight,
incidence of malformations, or skeletal
variations.
NOAEL: 384 mg/kg-day (only dose tested)
LOAEL: Not established
Gomez etal., 1991
Study details reported in a primary source;
only one dose tested.
Mouse, oral, no developmental effects.
NOAEL: 266 mg/kg-day (highest dose tested)
Domingo et al., 1989
Adequate.
Mouse, oral, no developmental effects.
NOAEL: 268 mg/kg-day (highest dose tested)
4-242
Gomez etal., 1989
Abstract only.
-------
Aluminum Hydroxide CASRN 21645-51-2
PROPERTY/ENDPOINT
Postnatal Development
Prenatal and Postnatal
Development
Developmental Neurotoxicity
Other
DATA
Mouse, oral, no developmental effects.
NOAEL: 300 mg/kg-day (only dose tested)
Rat, oral (gavage), 192, 384, 768 mg/kg-day
on GD 6-15
There were no significant changes in the
number of litters, corpora lutea, total
implants, pre- or post-implantation losses, and
live fetuses per litter. There were also no
significant differences in the sex ratio, fetal
body weight, or fetal malformations.
NOAEL: 768 mg/kg-day (highest dose tested)
LOAEL: Not established
Rat, oral, no developmental effects.
NOAEL: 384 mg/kg-day (only dose tested)
Low potential for developmental
neurotoxicity
(Estimated)
REFERENCE
Colamina et al., 1994
Gomez etal., 1990
Llobetetal., 1990
Professional judgment
DATA QUALITY
Abstract only.
Study details reported in a primary source.
Abstract only.
No data located.
No data located.
Estimated based on analogy to structurally
similar compounds.
No data located.
4-243
-------
Aluminum Hydroxide CASRN 21645-51-2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Neurotoxicity
MODERATE: Aluminum hydroxide is expected to be of moderate hazard for neurotoxicity. Impaired learning
in a labyrinth maze test was reported in a 90-day oral study in rats at 300 mg Al/kg/day as aluminum hydroxide
(only dose tested; a NOAEL was not identified). Impaired learning in a labyrinth maze test was also reported in
rats orally exposed to 100 mg Al/kg/day as aluminum hydroxide in combination with 30 mg/kg-day citric acid
(only dose tested; a NOAEL was not identified). There is uncertainty in the threshold of response for this effect
for exposure to aluminum hydroxide alone and in combination with citric acid. The possibility that effects occur
at doses <100 mg/kg/day (in the Moderate - High hazard designation range) cannot be ruled out; therefore a
Moderate hazard designation was assigned.
Neurotoxicity Screening
Battery (Adult)
30-day Rat, oral diet, no significant effects
noted.
NOAEL: 1,252 mg Al/kg-day (highest dose
tested)
90-day Rat, oral gavage, impaired learning in
a labyrinth maze test
NOAEL: not established
LOAEL: 300 mg/kg-bw (only dose tested)
Low potential for repeated dose effects but
moderate potential for immunotoxicity.
(Estimated)
Thorne et al., 1986; Thorne
etal., 1987; ATSDR, 2008
Bilkei-Gorzo, 1993
Professional judgment
Reported in a secondary source.
The background aluminum content of the
diet fed to rats was not reported; only one
dose tested; study description lacks
sufficient details on individual results.
Exposure to 100 mg /kg-day as aluminum
hydroxide combined with 30 mg/kg-day
citric acid (only dose tested) was also
investigated for which impaired learning
was observed; citric acid was added to
increase absorption; it is not proven that
negative effects only related to aluminum
hydroxide and not based on citric acid.
Estimated based on professional judgment
and comparison to analogous aluminum
compounds.
Other
Oral exposure to aluminum is usually not
harmful. Some studies show that people
exposed to high levels of aluminum may
develop Alzheimer's disease, but other
studies have not found this to be true. It is not
known for certain that aluminum causes
Alzheimer's disease.
ATSDR, 2008
Summary statement from a secondary
source.
4-244
-------
Aluminum Hydroxide CASRN 21645-51-2
PROPERTY/ENDPOINT
Repeated Dose Effects
Immune System Effects
Skin Sensitization
Skin Sensitization
Respiratory Sensitization
Respiratory Sensitization
Eye Irritation
Eye Irritation
DATA
REFERENCE
DATA QUALITY
MODERATE: Aluminum hydroxide is estimated to have potential for immunotoxicity based on professional
judgment and comparison to analogous aluminum compounds. Aluminum hydroxide is of low hazard for other
repeated dose effects based on an experimental study indicating no adverse effects in rats following oral doses up
to 14,470 ppm (302 mg/kg-day). In addition, a low potential for repeated dose effect is estimated based on
professional judgment and comparison to analogous aluminum compounds.
Low potential for repeated dose effects but
moderate potential for immunotoxicity
(Estimated)
2 8 -day Rat (male), oral diet, no systemic
effects noted. NOAEL: 14,470 ppm/diet (302
mg aluminum/kg-day; highest dose tested).
6-Week human, oral.
LOAEL: 25 mg Al/kg-day (Reduction in
primed cytotoxic T-cells, only dose tested).
Moderate potential for immunotoxicity.
(Estimated)
Professional judgment
Hicks etal., 1987
ATSDR, 2008
Professional judgment
Estimated based on professional judgment
and comparison to analogous aluminum
compounds.
Study details from primary source.
Study details reported in a secondary
source.
Estimated based on professional judgment
and comparison to analogous aluminum
compounds.
LOW: Aluminum hydroxide is not a skin sensitizer.
Low potential for skin Sensitization.
(Estimated)
Not sensitizing to guinea pigs in an in vivo
maximization test
Professional judgment
ECHA, 2013
Estimated based on professional judgment
and comparison to analogous aluminum
compounds.
Reported in a secondary source;
conducted in accordance with OECD
guidelines and GLP.
No data located.
No data located.
VERY LOW: Aluminum hydroxide is not irritating to rabbit eyes.
Not irritating, rabbits.
ECHA, 2013
Reported in a secondary source;
Conducted in accordance with OECD
guidelines and GLP.
4-245
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Aluminum Hydroxide CASRN 21645-51-2
PROPERTY/ENDPOINT
Dermal Irritation
Dermal Irritation
Endocrine Activity
Immunotoxicity
Immune System Effects
DATA
REFERENCE
DATA QUALITY
VERY LOW: Aluminum hydroxide is not irritating to skin.
Not irritating, rabbits.
Not irritating, rabbits, mice and pigs
ECHA, 2013
ECHA, 2013
Reported in a secondary source.
Conducted in accordance with OECD
guidelines and GLP.
Reported in a secondary source;
nonguideline studies.
No data located.
No data located.
Aluminum hydroxide is estimated to have potential for immunotoxicity based on professional judgment and
comparison to analogous aluminum compounds.
Moderate potential for immunotoxicity.
(Estimated)
6-Week human, oral.
LOAEL: 25 mg Al/kg-day (Reduction in
primed cytotoxic T-cells, only dose tested).
Professional judgment
ATSDR, 2008
Estimated based on professional judgment
and comparison to analogous aluminum
compounds.
Reported in a secondary source.
ECOTOXICITY
ECOSAR Class
Acute Aquatic Toxicity
Fish LC50
Daphnid LC50
Not applicable
LOW: Effect values from experimental studies for fish, daphnia and algae indicate no effects at the saturation
limit (NES).
Salmo trutta 96-hour NOEC >100 mg/L
(Experimental)
Daphnia magna 48-hour EC50 = NES
static test conditions.
(Experimental)
Daphnia magna 48 -hour NOEC >100 mg/L
(Experimental)
Daphnia magna 48 -hour NOEC > 0.135
European Commission, 2000
Tothova and Simo, 2013a
European Commission, 2000
ECHA, 2013
Reported in a secondary source. The effect
concentration is greater than the measured
water solubility.
Study details reported in an unpublished
study; conducted according to OECD 202;
no effects at test substance saturation limit
(> 0.079 mg/L).
Reported in a secondary source. Study
details and test conditions were not
available and the effect concentration is
greater than the measured water solubility.
Study conducted with aluminum powder.
4-246
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Aluminum Hydroxide CASRN 21645-51-2
PROPERTY/ENDPOINT
Green Algae EC50
Chronic Aquatic Toxicity
Fish ChV
Daphnid ChV
Green Algae ChV
DATA
mg/L
(Experimental)
Daphnia magna 48 -hr EC50 = 0.8240 mg/L
(Experimental)
Desmodesmus subspicatus 72-hour EC50 =
NES
(Experimental)
Selenastrum capricornutum 96-hour EC50 =
0.6560 mg/L
(Experimental)
Pseudokirchneriella subcapitata 96-hour
EC50 = 0.46 mg/L
(Experimental)
REFERENCE
TSCATS, 1996
Tothova and Simo, 2013c
TSCATS, 1996
ECHA, 2013
DATA QUALITY
Study incorrectly cited in source; results
are for a different test substance,
vanadium hydroxide oxide.
Study details reported in an unpublished
study; conducted according to OECD 201;
no effects at test substance saturation limit
(> 0.078 mg/L).
Study incorrectly cited in source; results
are for a different test substance,
vanadium hydroxide oxide.
Reported in a secondary source. EC50
range: 0.57 mg/L at pH of 7.6 and 0.46
mg/L at pH of 8.2. The water solubility of
aluminum hydroxide under basic pH
conditions is not available; experimental
details are not sufficient to address the
confidence limits of these data points.
LOW: Experimental data for daphnia and algae indicate NES. Although there were no experimental data for
fish located, the available chronic toxicity data for daphnia and algae suggests low chronic toxicity for fish.
Pimephales promelas 42-day NOEC = 0.102
mg/L, LOEC = 0.209 mg/L
(Experimental)
Daphnia magna 21 -day ChV = NES
semi-static test conditions
(Experimental)
Daphnia magna 21 -day NOEC = 0.091 mg/L,
LOEC = 0.1 97 mg/L
(Experimental)
Selenastrum capricornutum 72-hour NOEC
> 100 mg/L
(Experimental)
TSCATS, 1996
Tothova and Simo, 2013b
TSCATS, 1996
European Commission, 2000
Study incorrectly cited in source; results
are for a different test substance,
vanadium hydroxide oxide.
Study details reported in an unpublished
study; conducted according to OECD 211;
no effects at test substance saturation limit
(> 0.076 mg/L).
Study incorrectly cited in source; results
are for a different test substance,
vanadium hydroxide oxide.
Reported in a secondary source. The effect
concentration is greater than the measured
water solubility.
4-247
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Aluminum Hydroxide CASRN 21645-51-2
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
ENVIRONMENTAL FATE
Transport
Henry's Law Constant (atm-
m3/mole)
Sediment/Soil
Adsorption/Desorption - Koc
Level III Fugacity Model
Persistence
Water
Soil
Aerobic Biodegradation
Volatilization Half-life for
Model River
Volatilization Half-life for
Model Lake
Aerobic Biodegradation
Anaerobic Biodegradation
Soil Biodegradation with
Product Identification
Sediment/Water
Biodegradation
Although the behavior of aluminum salts under environmental conditions is dependent on the characteristics of
the local environment (predominately pH), transport of the aluminum (III) species is anticipated to be dominated
by leaching through soil; runoff to aqueous environments; adsorption and/or precipitation of the metal ion onto
soil or sediment; and wet and dry deposition dust particulates in air to land or surface water. Volatilization of
this ionic compound from either wet or dry surfaces is not expected to be an important fate process. Under acidic
pHs typically encountered in the environment, it may form insoluble polymeric aluminum hydroxide colloids
while under basic conditions; anionic aluminum hydroxide is expected to predominate. Other factors influencing
its behavior include the presence of dissolved organic matter, the extent of absorption on suspended particles,
and the presence of other aluminum species.
<10'8 (Estimated)
>30,000 (Estimated)
Professional judgment
EPA, 2004; Professional
judgment
Cutoff value for nonvolatile compounds.
Cutoff value fornonmobile compounds.
No data located.
HIGH: As an inorganic material, aluminum hydroxide is not expected to biodegrade or oxidize under typical
environmental conditions. Aluminum hydroxide does not absorb light at environmentally relevant wavelengths
and is not expected to photolyze. No degradation processes for aluminum hydroxide under typical environmental
conditions were identified.
Recalcitrant (Estimated)
>1 year (Estimated)
>1 year (Estimated)
Recalcitrant (Estimated)
Recalcitrant
Professional judgment
Professional judgment
Professional judgment
Professional judgment
Professional judgment
Substance is or contains inorganic
elements, such as metal ions or oxides,
that are expected to be found in the
environment >180 days after release.
Based on the magnitude of the estimated
Henry's Law constant.
Based on the magnitude of the estimated
Henry's Law constant.
Substance contains inorganic elements.
Substance contains inorganic elements.
No data located.
No data located.
4-248
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Aluminum Hydroxide CASRN 21645-51-2
PROPERTY/ENDPOINT
Air
Reactivity
Atmospheric Half-life
Photolysis
Hydrolysis
Environmental Half-life
Bioaccumulation
Fish BCF
Other BCF
BAF
Metabolism in Fish
DATA
>1 year (Estimated)
Not a significant fate process (Estimated)
REFERENCE
Professional judgment
Professional judgment
DATA QUALITY
Substance contains inorganic elements.
Aluminum hydroxide does not absorb UV
light at environmentally relevant
wavelengths and is not expected to
undergo photolysis.
Dissociation of aluminum hydroxide in
environmental waters is dependent both
on the pH and the local concentration of
other aluminum species; dissociation will
not occur unless in highly acidic waters,
e.g.,pH3.
No data located. Inorganic compounds are
outside the estimation domain (EPI).
LOW: Aluminum hydroxide is not expected to bioaccumulate.
<100 (Estimated)
<100 (Estimated)
Professional judgment
Professional judgment
Aluminum hydroxide is an inorganic
compound and is not anticipated to
bioaccumulate orbioconcentrate. This
inorganic compound is not amenable to
available quantitative structure activity
relationship (QSAR) models.
No data located.
Aluminum hydroxide is an inorganic
compound and is not anticipated to
bioaccumulate orbioconcentrate. This
inorganic compound is not amenable to
available QSAR models.
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
Ecological Biomonitoring
Human Biomonitoring
No data located.
No data located.
This chemical was not included in the NHANES biomonitoring report. (CDC, 201 1).
4-249
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ATSDR (2008) Toxicological profile for aluminum. Atlanta, GA: Agency for Toxic Substances and Disease Registry, U.S. Department of Health
and Human Services, http://www.atsdr.cdc.gov/toxprofiles/tp22.pdf
Bilkei-Gorzo A (1993) Neurotoxic effect of enteral aluminum. Food Chem Toxicol 31(5):357-361.
CDC (2011) Fourth national report on human exposure to environmental chemicals, updated tables, February 2011. Centers for Disease Control
and Prevention, Department of Health and Human Services, http://www.cdc.gov/exposurereport/.
Colomina MT, Gomez M, Domingo JL, et al. (1992) Concurrent ingestion of lactate and aluminum can result in developmental toxicity in mice.
77(1):95-106.
Colomina MT, Gomez M, Domingo JL, et al. (1994) Lack of maternal and developmental toxicity in mice given high doses of aluminum
hydroxide and ascorbic acid during gestation. Pharmacol Toxicol 74:236-239.
Domingo JL, Gomez M, Bosque MA, et al. (1989) Lack of teratogenicity of aluminum hydroxide in mice. Life Sci 45:243-247.
EC (2000) Aluminum hydroxide. IUCLID dataset. European Commission. European Chemicals Bureau.
ECHA (2013) Aluminum hydroxide. Registered substances. European Chemicals Agency.
http://apps.echa.europa.eu/registered/data/dossiers/DISS-9e9ede9a-Ofd5-2b35-e044-00144f67d031/DISS-9e9ede9a-Ofd5-2b35-e044-
00144f67d031_DISS-9e9ede9a-Ofd5-2b35-e044-00144f67d031.html.
EPA (1999) Determining the adequacy of existing data. High Production Volume (HPV) Challenge. Washington, DC: U.S. Environmental
Protection Agency, http://www.epa.gov/hpv/pubs/general/datadeqm.pdf
EPA (2004) Pollution prevention (P2) framework. Washington, DC: U.S. Environmental Protection Agency, Office of Pollution Prevention and
Toxics, http://www.epa.gov/oppt/sf/pubs/p2frame-june05a2.pdf
EPA (2008) Flame retardants in printed circuit boards. Cincinnati, OH: U.S. Environmental Protection Agency, Design for the Environment.
EPA (2010) TSCA new chemicals program (NCP) chemical categories. Washington, DC: U.S. Environmental Protection Agency.
http://www.epa.gov/oppt/newchems/pubs/npcchemicalcategories.pdf
Gomez M, Bosque MA, Domingo JL, et al. (1990) Evaluation of the maternal and developmental toxicity of aluminum from high doses of
aluminum hydroxide in rats. Vet Hum Toxicol 32(6):545-548.
4-250
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Gomez M, Domingo J, Llobet J (1991) Developmental toxicity evaluation of oral aluminum in rats: Influence of citrate. 13:323-328.
Gomez M, Domingo JL, Bosque A, et al. (1989) Teratology study of aluminum hydroxide in mice. Toxicologist 9(1):273.
HSDB (2013) Aluminum hydroxide. Hazardous Substances Data Bank. National Library of Medicine, http://toxnet.nlm.nih.gov/cgi-
bin/sis/htmlgen?HSDB.
Hicks JS, Hackett DS, Sprague GL (1987) Toxicity of aluminum concentration in bone following dietary administration of two sodium aluminum
phosphate formulations in rats. Food Chem Toxicol 25(7):533-538.
Lewis R (2000) Sax's dangerous properties of industrial materials. 10th ed. New York, NY: John Wiley & Sons, Inc.
Lide DR (2006) Handbook of chemistry and physics. Boca Raton, FL: CRC Press.
Llobet JM, Gomez M, Domingo JL, et al. (1990) Teratology studies of oral aluminum hydroxide, aluminum citrate, and aluminum hydroxide
together with citric acid in rats. Teratology 42(227A)
NRC (2000) Subcommittee on flame-retardant chemicals. Toxicological risks of selected flame retardant chemicals. Washington, DC: National
Research Council. National Academy Press.
O'Neil MJ, Budavari S, Smith A, et al. (2001) Merck Index. Whitehouse Station, NJ: Merck & Co.
Pakalin S, Cole T, Steinkeliner J, et al. (2007) Review on production processes of decabromodiphenyl ether (DECABDE) used in polymeric
applications in electrical and electronic equipment, and assessment of the availability of potential alternatives to DECABDE. European Chemicals
Bureau, European Commission, http://publications.jrc.ec.europa.eu/repository/bitstream/l 1111111 l/5259/l/EUR%2022693.pdf
TSCATS (1996) Toxic Substance Control Act Test Submission Database.
Thorne BM, Cook A, Donohoe T, et al. (1987) Aluminum toxicity and behavior in the weanling Long-Evans rat. 25(2): 129-132.
Thorne BM, Donohoe T, Lin K, et al. (1986) Aluminum ingestion and behavior in the Long-Evans rat. Physiol Behav 36:63-67.
Tothova E and Simo K (2013a) Final report of the study no. 13 - 018113: Ecotoxicological testing of product APYRAL 40CD by test OECD 202
Daphnia sp., acute immobilisation test [unpublished]. Slovakia: Sponsor-Nabaltec AG; Test Facility-Ekologicke Laboratoria.
Tothova E and Simo K (2013b) Final report of the study no. 13 - 018115: Ecotoxicological testing of product APYRAL 40CD by test OECD 211
Daphnia magna reproduction test [unpublished]. Slovakia: Sponsor-Nabaltec AG; Test Facility-Ekologicke Laboratoria.
4-251
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Tothova E and Simo K (2013c) Final report of the study no. 13 - 018114: Ecotoxicological testing of product APYRAL 40CD by test OECD 201
Alga, Growth Inhibition Test [unpublished]. Slovakia: Sponsor-Nabaltec AG; Test Facility-Ekologicke Laboratoria.
4-252
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Magnesium Hydroxide
VL = Very Low hazard L = Low hazard = Moderate hazard H = High hazard VH = Very High hazard — Endpoints in colored text (VL, L, M, H, and VH) were
assigned based on empirical data. Endpoints in black italics (VL, L, M, H, and VH) were assigned using values from predictive models and/or professional judgment.
This table contains hazard information for each chemical; evaluation of risk considers both hazard and exposure. Variations in end-of-life processes or degradation and combustion
by-products are discussed in the report but not addressed directly in the hazard profiles. The caveats listed below must be taken into account when interpreting the information in the
table.
R Recalcitrant: Substance is comprised of metallic species (or metalloids) that will not degrade, but may change oxidation state or undergo complexation processes under
environmental conditions. ¥ Aquatic toxicity: EPA/DfE criteria are based in large part upon water column exposures which may not be adequate for poorly soluble substances such
as many flame retardants that may partition to sediment and particulates.
Chemical
CASRN
Human Health Effects
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Magnesium Hydroxide
1309-42-8
4-253
-------
Magnesium Hydroxide
OH
H0.Mg
CASRN: 1309-42-8
MW: 58.32
MF: MgH2O2
Physical Forms:
Neat: Solid
Use: Flame retardant
SMILES: O[Mg]O
Synonyms: Magnesium hydroxide (Mg(OH)2); Brucite, Milk of Magnesia; AlcanexNHC 25, Asahi Glass 200-06, Baschem 12, Combustrol 500, Duhor, DuhorN,
Ebson RF, FloMag H, FloMag HUS, Hydro-mag MA, Hydrofy G 1.5, Hydrofy G 2.5, Hydrofy N, Kisuma 4AF, Kisuma 5, Kisuma 5A, Kisuma 5B, Kisuma 5B-N,
Kisuma 5BG, Kisuma 5E, Kisuma 78, Kisuma S 4, Kyowamag F, Lycal 96 HSE, Mag Chem MH 10, Magnesia hydrate, MagneClear 58, Magnesia magma,
Magnesiamaito, Magnesium dihydroxide, Magnesium hydroxide gel, Magnesium(II) hydroxide, Magnifin H 10, Magox, Marinco H, Marinco H 1241, Martinal VPF
8812, Milmag, Mint-O-Mag, Nemalite, Oxaine M, Phillips Magnesia Tablets, Phillips Milk of Magnesia Liquid, Reachim, Star 200, Versamag
Chemical Considerations: This alternative is an inorganic compound. In the absence of experimental data, professional judgment using chemical class and structural
considerations were used to complete this hazard profile.
Polymeric: No
Oligomeric: Not applicable
Metabolites, Degradates and Transformation Products: Not applicable
Analog: No analogs; Mg + ions are expected to form when Mg(OH)2 and other
magnesium containing compounds dissociate in aqueous conditions. Studies
included in this assessment include other sources of Mg2+ like MgCl2.
Endpoint(s) using analog values: Not applicable
Analog Structure: Not applicable
Structural Alerts: None
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 2011).
Hazard and Risk Assessments: Risk assessment completed for magnesium hydroxide by the National Academy of Sciences in 2000 (NAS, 2000).
4-254
-------
Magnesium Hydroxide CASRN 1309-42-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
Boiling Point (°C)
Vapor Pressure (mm Hg)
Water Solubility (mg/L)
Decomposes at 350 (Measured)
Decomposes at 380 (Measured)
350 (Measured)
Will decompose before boiling
(Measured)
<10"8 (Estimated)
1.78 at 20°C, pH 8.3 According to
Organisation for Economic Cooperation
and Development (OECD 105) Column
elution method. (Measured)
9 at 18°C (Measured)
1 at 20°C (Measured)
6 at 20°C (Measured)
<8 at 20°C (Measured)
Hodgman, 1959; Lewis, 1997;
Lewis, 2000
IUCLID, 2000
Lide, 2000; Aldrich Chemical
Company, 2006
IUCLID, 2000
EPA, 1999; Professional
judgment
ECHA, 2013
Hodgman, 1959; IUCLID, 2000
IUCLID, 2000
IUCLID, 2000
IUCLID, 2000
MgO and H2O are decomposition
products.
MgO and H2O are decomposition
products.
MgO and H2O are decomposition
products.
Decomposition occurs upon melting
as described in additional sources
above.
Cutoff value for nonvolatile
compounds according to HPV
assessment guidance. This inorganic
compound is not amenable to
available estimation methods.
Guideline study; results are in
agreement with other experimental
values.
Measured values, which span a
relatively narrow range, are
consistently reported in numerous
sources.
Measured values, which span a
relatively narrow range, are
consistently reported in numerous
sources.
Measured values, which span a
relatively narrow range, are
consistently reported in numerous
sources.
Measured values, which span a
relatively narrow range, are
consistently reported in numerous
4-255
-------
Magnesium Hydroxide CASRN 1309-42-8
PROPERTY/ENDPOINT
Log Kow
Flammability (Flash Point)
Explosivity
Pyrolysis
pH
pKa
Particle Size
DATA
40 at 100°C (Measured)
Not flammable (Measured)
Not explosive (Estimated)
Not applicable (Estimated)
pH of a saturated solution in water was
8.3 (Measured)
9.5-10.5 (Measured)
DIG = mean 2. 013 (im
D50 = mean 13.915 (im
D90 = mean 154.107 (im
According to OECD Guideline 1 10
(Particle Size Distribution / Fibre Length
and Diameter Distributions). (Estimated)
REFERENCE
Hodgman, 1959
IUCLID, 2000
IUCLID, 2000
Professional judgment
ECHA, 2013
O'Neiletal., 2011
ECHA, 2013
DATA QUALITY
sources.
Value obtained at an elevated
temperature.
No data located; inorganic
compounds are outside the
estimation domain of EPI.
Reported in a secondary source and
based on its use as a flame retardant.
Adequate.
Inorganic compounds do not
undergo pyrolysis.
Reported in a secondary source,
determined from a water solubility
study.
Reported in a secondary source,
limited study details provided.
No data located.
Guideline study reported in a
secondary source.
4-256
-------
Magnesium Hydroxide CASRN 1309-42-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
HUMAN HEALTH EFFECTS
Toxicokinetics
Dermal Absorption in vitro
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal or Inhaled
Other
Acute Mammalian Toxicity
Acute Lethality
Oral
Dermal
Inhalation
Carcinogenicity
OncoLogic Results
Carcinogenicity (Rat and
Mouse)
Some magnesium hydroxide is absorbed following ingestion and is excreted primarily in urine.
The magnesium ion is poorly absorbed;
when taken orally, only 5-15% of the
magnesium from a dose of magnesium
hydroxide is absorbed and this
magnesium is readily excreted in the
urine, if kidney function is normal.
IUCLID, 2000
Reported in a secondary source,
limited study details provided.
No data located.
LOW: Acute lethality values suggest that magnesium hydroxide is of low concern for acute toxicity for
oral exposure. There were no data located regarding acute dermal exposure.
Rat oral LD50 = 8,500 mg/kg
Mouse oral LD50 = 8,500 mg/kg.
Human infant oral TDLo (behavioral) =
2,747 mg/kg.
Probable human oral lethal dose = 5-15
g/kg.
Rat inhalation 4-hour LC50 >2. 1 mg/L
(whole-body inhalation to aerosol)
Lewis, 2000
Lewis, 2000
Lewis, 2000
HSDB, 2003
ECHA, 2013
Reported in a secondary source,
limited study details provided.
Reported in a secondary source,
limited study details provided.
Reported in a secondary source,
limited study details provided.
Reported in a secondary source,
limited study details provided.
No data located.
Reported in a secondary source.
There was no mortality at the
highest dose tested (2.1 mg/L);
conducted according to OECD 403.
LOW: Experimental studies indicate low concern for Carcinogenicity based on results from studies on
magnesium hydroxide and the related magnesium chloride.
5 -week, repeated-dose/carcinogenicity
study, oral (diet), rat; Decreased number
of carcinogen-induced DNA synthesis in
BIBRA, 1993
Structure could not be evaluated by
OncoLogic.
Reported in a secondary source,
limited study details provided; study
duration insufficient as a cancer
4-257
-------
Magnesium Hydroxide CASRN 1309-42-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
the large bowel epithelial cells.
NOAEL: 2,000 ppm (approximately 100
mg/kg-day, highest dose tested)
Combined Chronic
Toxicity/Carcinogenicity
Other
96-week chronic toxicity/carcinogenicity
study on MgCl2, oral, mouse;
no significant differences in tumor
incidence between treated and control
animals except for dose-related decrease
in the incidence of hepatocellular
carcinomas in males.
Kurataetal., 1989
227-day, chronic toxicity/ carcinogenicity
study, oral (diet), rat; decreased number
of colon tumors in rats pretreated with a
known colon carcinogen.
NOAEL: 50 mg/kg-day (highest dose
tested).
BIBRA, 1993
16-week carcinogenicity study, oral (diet),
rat; inhibitory effects on colon
carcinogenesis, carcinogen-induced
expression of c-myc proto-oncogene and
cell proliferation.
NOAEL: 0.2% in diet (highest
concentration tested)
Wangetal., 1993
Inhalation exposure of male rats to short
(4.9x0.31 mm) or long (12x0.44 mm)
MgSO4/5Mg(OH)2'3H2O filaments for 6
hour/day, 5 day/week for up to 1 year did
not increase the incidence of any tumor
types in animals sacrificed 1 day or 1 year
after cessation of exposure.
NAS, 2000
study.
Sufficient study details reported in a
primary source; test substance:
magnesium chloride.
Reported in a secondary source,
limited study details provided; study
duration insufficient as a cancer
study.
Sufficient study details reported in a
primary source; study duration
insufficient as a cancer study.
Reported in a secondary source,
limited study details provided; study
duration insufficient as a cancer
study.
No data located.
4-258
-------
Magnesium Hydroxide CASRN 1309-42-8
PROPERTY/ENDPOINT
Genotoxicity
Gene Mutation in vitro
Gene Mutation in vivo
Chromosomal Aberrations in
vitro
Chromosomal Aberrations in
vivo
DNA Damage and Repair
Other
Reproductive Effects
Reproduction/Developmental
Toxicity Screen
DATA
REFERENCE
DATA QUALITY
LOW: Experimental studies indicate that magnesium hydroxide is not mutagenic to bacteria or
mammalian cells in vitro and does not cause chromosomal aberrations in human lymphocytes in vitro.
Negative, Ames Assay in Salmonella and
Escherichia coli.
Negative; mouse lymphoma assay,
L5178Y cells; with and without metabolic
activation.
Negative; did not induce chromosomal
aberrations in human lymphocytes; with
and without metabolic activation.
BIBRA, 1993
ECHA, 2013
ECHA, 2013
Reported in a secondary source,
limited study details provided. Only
3 strains of Salmonella were tested;
current regulatory guidelines
suggest that at least 4 strains be used
in Ames tests.
Reported in a secondary source.
No data located.
Reported in a secondary source.
No data located.
No data located.
No data located.
LOW: There were no reproductive effects observed in rats in a repeated dose toxicity study with the
reproduction/developmental toxicity screen at doses of magnesium hydroxide as high as 1,000 mg/kg-day.
No data located.
4-259
-------
Magnesium Hydroxide CASRN 1309-42-8
PROPERTY/ENDPOINT
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
Reproduction and Fertility
Effects
Other
Developmental Effects
Reproduction/
Developmental Toxicity
Screen
DATA
Repeated dose toxicity study with the
reproduction/developmental toxicity
screen; rat, oral (gavage), 0, 110, 330,
1,000 mg/kg-day magnesium hydroxide.
Males exposed for 29 days: 2 weeks prior
to mating, during mating and up to
termination; females exposed for 41-45
days: 2 weeks premating, during mating,
post coitum, and 4 days of lactation.
There were no reproductive effects
observed in any dose group.
NOAEL: 1,000 mg/kg-day (highest dose
tested)
LOAEL: Not established
REFERENCE
ECHA, 2013
DATA QUALITY
Reported in a secondary source.
Study conducted according to
OECD 422.
No data located.
No data located.
LOW: Magnesium hydroxide is expected to be of low concern for developmental effects based on a
nonstandard experimental study indicating magnesium chloride produces no adverse effects on
developmental outcomes at levels up to 96 mg/kg/day of Mg2+ ion and an experimental study from a
secondary source showing no effect on human newborns.
No data located.
4-260
-------
Magnesium Hydroxide CASRN 1309-42-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
Repeated dose toxicity study with the
reproduction/developmental toxicity
screen; rat, oral (gavage), 0, 110, 330,
1,000 mg/kg-day. Males exposed for 29
days: 2 weeks prior to mating, during
mating and up to termination; females
exposed for 41-45 days: 2 weeks
premating, during mating, post coitum,
and 4 days of lactation.
There were no developmental effects
observed in any dose group.
NOAEL: 1,000 mg/kg-day (highest dose
tested)
LOAEL: Not established
ECHA, 2013
Reported in a secondary source.
Study conducted according to
OECD 422.
Repeated-dose/developmental study (fetal
exposure at unspecified dose levels during
3rd trimester), 27 hypertensive women
treated with magnesium hydroxide, no
effect on newborns except slightly
increased body weight and
hypermagnesiumemia. Cord serum Mg
levels reported to be 70-100% of maternal
levels after treatment (potentially causing
neurological depression in neonate,
characterized by respiratory depression,
muscle weakness, decreased reflexes).
Prolonged magnesium treatment during
pregnancy may be associated with
maternal and fetal hypocalcemia and
adverse effects on fetal bone
mineralization.
HSDB, 2003
Reported in a secondary source,
limited study details provided.
Maternal treatment doses not
specified.
4-261
-------
Magnesium Hydroxide CASRN 1309-42-8
PROPERTY/ENDPOINT
Prenatal Development
Postnatal Development
Prenatal and Postnatal
Development
Developmental Neurotoxicity
Other
Neurotoxicity
Neurotoxicity Screening
Battery (Adult)
Other
DATA
10-day (GD 6-15)
reproductive/developmental study on
MgCl2, oral, rat; no treatment-related
effects.
NOAEL: 96 mg/kg-day for Mg 2+ ion
(highest dose tested)
LOAEL: Not established
REFERENCE
NAS, 2000
DATA QUALITY
Reported in a secondary source,
limited study details provided.
No data located.
No data located.
No data located.
No data located.
LOW: Magnesium hydroxide is expected to be of low hazard for neurotoxicity based on expert judgment.
Low potential for neurotoxicity.
(Estimated)
Expert judgment
Estimated based on expert
judgment.
No data located.
4-262
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Magnesium Hydroxide CASRN 1309-42-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Repeated Dose Effects
LOW: Experimental studies indicate magnesium ions produce no adverse systemic effects in rats or mice
at levels > 1,000 mg/kg-day of magnesium hydroxide.
96-week repeated-dose study for MgCl2,
oral (0, 0.5, 2% in the diet), mouse;
decreased body weight gain, increased
food/water consumption and increased
relative brain, heart and kidney weights in
high dose (2%) females, no effects in
males.
Female:
NOAEL: 87 mg/kg-day for Mg
LOAEL: 470 mg/kg-day for Mg2+
2+ ion
ion
Male:
NOAEL: 336 mg/kg-day for Mg2
(highest dose tested)
LOAEL: Not established
ion
90-day repeated-dose study for MgQ2,
oral, mouse (M: 73, 146, 322, 650, 1,368
mg/kg-day for Mg2+ ion; F: 92, 190, 391,
817, 1,660 mg/kg-day for Mg2+ ion);
decreased body weight gain in males and
females at highest dose tested (1,660
mg/kg-day); renal tubular vacuolation in
males administered 650 mg/kg-day for
Mg2+ ion.
Female:
NOAEL: 817 mg/kg-day for Mg2+ ion
LOAEL: 1,660 mg/kg-day for Mg2+ ion
Male:
NOAEL: 322 mg/kg-day for Mg2+ ion
LOAEL: 650 mg/kg-day for Mg2+ ion
90-day repeated-dose study in B6C3F1
mice; MgCl2 administered orally at doses
4-263
Kurataetal., 1989
NAS, 2000
NAS, 2000
Adequate, primary source.
Reported in a secondary source, no
study details provided.
Reported in a secondary source, no
study details provided.
-------
Magnesium Hydroxide CASRN 1309-42-8
PROPERTY/ENDPOINT
DATA
of 0.3, 0.6, 1.25 and 2. 5% in the diet.
Effects included decreased body weight
gain and renal tubular vacuolation in
males in the high-dose group (840 mg/kg-
day).
Female:
NOAEL: 587 mg/kg-day for Mg2+ ion
Male:
NOAEL: 420 mg/kg-day for Mg2+ ion
LOAEL: 840 mg/kg-day for Mg2+ ion
32-week repeated-dose study, diet, rat; no
effects on body weight or liver weight.
NOAEL: 1,000 ppm (approximately 50
mg/kg-day, highest dose tested)
LOAEL: Not established
Repeated dose toxicity study with the
reproduction/developmental toxicity
screen; rat, oral (gavage), 0, 110, 330,
1,000 mg/kg-day MgOH2. Males exposed
for 29 days: 2 weeks prior to mating,
during mating and up to termination;
females exposed for 41-45 days: 2 weeks
premating, during mating, post coitum,
and 4 days of lactation.
There were no lexicologically relevant
changes in any of the parental parameters
examined.
NOAEL: 1,000 mg/kg-day (highest dose
tested)
LOAEL: Not established
4-week repeated-dose study, oral, human;
caused diarrhea, abdominal discomfort,
REFERENCE
BIBRA, 1993
ECHA, 2013
BIBRA, 1993
DATA QUALITY
Reported in a secondary source, no
study details provided.
Reported in a secondary source.
Study conducted according to
OECD 422.
Reported in a secondary source, no
study details provided.
4-264
-------
Magnesium Hydroxide CASRN 1309-42-8
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
and increased serum magnesium levels.
NOAEL: Not established
LOAEL: 400 mg/kg-day (only dose
reported)
Inhalation exposure of male rats to short
(4.9x0.31 mm) or long (12x0.44 mm)
MgSO4/5Mg(OH)23H2O filaments for 6
hour/day, 5 day/week for up to 1 year
(concentration not specified) exhibited a
slight increase in the incidence of
pulmonary lesions 1 year after cessation
of exposure. Histopathological
examination revealed a slight increase in
segmental calcification of the pulmonary
artery and thickening of the lung pleura in
rats exposed to both short and long
filaments for 4 weeks or 1 year. There
were no effects on survival or body, lung,
liver, kidney and spleen weights of
animals sacrificed 1 day or 1 year
following a 1-year exposure period.
NAS, 2000
Reported in a secondary source, no
study details provided.
Human systemic effects: chlorine level
changes, coma, somnolence in a neonate.
Lewis, 2000
A case study of intoxication after
oral exposure to magnesium in a
neonate. Reported in a secondary
source; no study details provided.
Repeated oral exposure in humans may
cause rectal stones composed of
magnesium carbonate and magnesium
hydroxide (rare occurrence).
IUCLID, 2000
Reported in a secondary source, no
study details provided.
4-265
-------
Magnesium Hydroxide CASRN 1309-42-8
PROPERTY/ENDPOINT
Skin Sensitization
Skin Sensitization
Respiratory Sensitization
[Respiratory Sensitization
Eye Irritation
Eye Irritation
DATA
REFERENCE
DATA QUALITY
LOW: A mouse local lymph node assay (LLNA) reported some Sensitization following exposure to
Mg(OH)2 (purity not reported), while negative results for Sensitization were reported in guinea pigs in a
maximization test. Magnesium hydroxide is not expected to cause skin Sensitization based on professional
judgment. Based on the weight-of-evidence (WOE), a hazard designation of Low is appropriate.
Not sensitizing in a modified Magnusson
and Kligman maximization test in Guinea
pigs; phase 1 induction: administered
intra-dermally at a concentration of 5%
v/v in 0.5% methyl cellulose; phase 2
induction: topically administered at a
concentration of 25% in petrolatum;
challenged: topical application of 25% in
petrolatum; no reaction was observed in
any treated animal in the challenge phase.
Sensitizing in a mouse local lymph node
assay (LLNA); application of 10, 25 or
50% w/w MgOH2 in propylene glycol to
the ears. Very slight erythema in all
animals treated with 50% MgOH2,
staining on the ears at 10, 25 and 50%. SI
(stimulation index) at 10, 25 and 50% was
2.0, 3.6 and 5.9, respectively. Dose
response and ECS value >/= 3.
Does not cause skin Sensitization.
(Estimated)
Submitted confidential study
ECHA, 2013
Professional judgment
Test substance identified as
Mg(OH)2; purity not reported;
negative and positive controls were
used.
Well documented secondary source;
GLP study conducted according to
guidelines. MgOH2, purity not
stated
Estimated by professional judgment.
No data located.
No data located.
MODERATE: Based on irritation and damage to the corneal epithelium in rabbits that cleared within 2-3
days.
Moderately irritating to rabbit eyes.
Administration of milk of magnesia twice
a day for 3-4 days caused damage to
corneal epithelium of rabbit eyes;
IUCLID, 2000
HSDB, 2003
Reported in a secondary source,
limited study details provided.
Reported in a secondary source,
limited study details provided. Milk
of magnesia is a mixture containing
4-266
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Magnesium Hydroxide CASRN 1309-42-8
PROPERTY/ENDPOINT
Dermal Irritation
Dermal Irritation
Endocrine Activity
Immunotoxicity
Immune System Effects
DATA
however, effects disappeared within 2-3
days.
REFERENCE
DATA QUALITY
magnesium hydroxide and inactive
ingredients.
LOW: An experimental study indicates that magnesium hydroxide is not an irritant to rabbit skin.
Moderate potential for dermal irritation
based on experimental aqueous pH
values.
(Estimated)
Not corrosive in an in vitro human skin
corrosion test.
Not irritating in an in vitro skin irritation
test.
Not irritating, rabbits.
Expert judgment
ECHA, 2013
ECHA, 2013
Submitted confidential study
Estimated based on expert
judgment.
Reported in a secondary source.
Study conducted according to
OECD guideline 431.
Reported in a secondary source. In
vitro skin irritation: reconstructed
human epidermis model test.
Reported in a submitted confidential
study.
No data located.
No data located.
Magnesium hydroxide is expected to have low potential for immunotoxicity based on expert judgment.
Low potential for immunotoxicity.
(Estimated)
Expert judgment
Estimated based on expert
judgment.
ECOTOXICITY
ECOSAR Class
Acute Aquatic Toxicity
Fish LC50
Not applicable
LOW: Estimated LC50 values for all of the standard toxicity test organisms are greater than 100 mg/L.
Experimental LC50 values are much greater than the anticipated water solubility, suggesting no effects at
saturation (NES).
96-hour LC50 =
MgCl2:2,120mg/L
MgSO4: 2,820 mg/L
(Estimated)
Mount etal., 1997
Estimated based on analogy to
MgCl2 and MgSO4; expected to
display NES because this amount of
test substance is not anticipated to
dissolve in water at a concentration
at which adverse effects may be
expressed.
4-267
-------
Magnesium Hydroxide CASRN 1309-42-8
PROPERTY/ENDPOINT
Daphnid LC50
Green Algae EC50
Chronic Aquatic Toxicity
Fish ChV
DATA
Pimephalis promelas 96-hour LC50 = 511
mg/L; static conditions.
(Experimental)
Onchorinchus mykiss 96-hour LC50 =
775.8 mg/L; static conditions.
(Experimental)
Daphnia magna 48-hour LC50 =
MgCl2: 1,330 mg/L
MgSO4: 1,820 mg/L
(Estimated)
Daphnia magna 48-hour LC50 = 284.76
mg/L; static conditions.
(Experimental)
Gammarus lacustris LC50 = 64.7 mg/L.
(Experimental)
Scenedesmus subspicatus and
Selenastrum capricornutum 72-hour EC50
>100 mg/L (for growth and biomass).
(Experimental)
REFERENCE
ECHA, 2013
ECHA, 2013
Biesinger and Christensen,
1972; Mount etal., 1997
ECHA, 2013
O'Connell et al., 2004
ECHA, 2013
DATA QUALITY
Reported in a secondary source.
Test material diluted to 61% in
aqueous suspension.
Reported in a secondary source.
Test material diluted to 61% in
aqueous suspension.
Estimated based on analogy to
MgCl2 and MgSO4; expected to
display NES because this amount of
test substance is not anticipated to
dissolve in water at a concentration
at which adverse effects may be
expressed.
Reported in a secondary source.
Test material diluted to 61% in
aqueous suspension.
Reported in a secondary source,
study details and test conditions
were not provided. Not a standard
test species.
Reported in a secondary source.
LOW: Estimated chronic values (ChV) are all >10 mg/L and exceed the anticipated water solubility,
suggesting NES.
Fish ChV: 50-80 mg/L
(Experimental)
Freshwater fish ChV = 403 mg/L.
ECHA, 2013
Professional judgment
An acute to chronic ratio of 10 was
applied to experimental acute data
for Pimephalis promelas and
Onchorinchus mykiss. Reported in a
secondary source. Test material
diluted to 61% in aqueous
suspension.
Estimated using an acute to chronic
4-268
-------
Magnesium Hydroxide CASRN 1309-42-8
PROPERTY/ENDPOINT
Daphnid ChV
Green Algae ChV
DATA
(Estimated)
Daphnia ChV = 82 mg/L
(Estimated)
Green algae NOEC: 980 mg/L
LOEC: 1,230 mg/L
(Estimated)
REFERENCE
Suter, 1996
ECOTOX, 2012
DATA QUALITY
ratio of 3:3; expected to display
NES because this amount of test
substance is not anticipated to
dissolve in water at a concentration
at which adverse effects may be
expressed.
Estimated based on analogy to the
measured ChV for Mg2+ ion; based
on tests that were not standard but
were judged to be of good quality;
expected to display NES because
this amount of test substance is not
anticipated to dissolve in water at a
concentration at which adverse
effects may be expressed.
Estimated based on analogy to
MgSO4; expected to display NES
because this amount of test
substance is not anticipated to
dissolve in water at a concentration
at which adverse effects may be
expressed.
ENVIRONMENTAL FATE
Transport
Henry's Law Constant (atm-
m3/mole)
Sediment/Soil
Adsorption/Desorption - Koc
Level III Fugacity Model
The low water solubility, the estimated vapor pressure of 30,000 and
estimated Henry's Law constant of 30,000 (Estimated)
Professional judgment
EPA, 2004; Professional
judgment
Cutoff value for nonvolatile
compounds.
Cutoff value fornonmobile
compounds.
Not all input parameters for this
model were available to run the
estimation software (EPI).
4-269
-------
Magnesium Hydroxide CASRN 1309-42-8
PROPERTY/ENDPOINT
Persistence
Water
Soil
Air
Reactivity
Aerobic Biodegradation
Volatilization Half-life for
Model River
Volatilization Half-life for
Model Lake
Aerobic Biodegradation
Anaerobic Biodegradation
Soil Biodegradation with
Product Identification
Sediment/Water
Biodegradation
Atmospheric Half-life
Photolysis
Hydrolysis
DATA
REFERENCE
DATA QUALITY
HIGH: As an inorganic compound, magnesium hydroxide is not expected to biodegrade, oxidize in air, or
undergo hydrolysis under environmental conditions. Magnesium hydroxide does not absorb light at
environmentally relevant wavelengths and is not expected to photolyze. Magnesium hydroxide is
recalcitrant and it is expected to be found in the environment >180 days after release. As a naturally
occurring compound, it may participate in natural cycles and form complexes in environmental waters.
Recalcitrant (Estimated)
>1 year (Estimated)
>1 year (Estimated)
Recalcitrant (Estimated)
Recalcitrant (Estimated)
>1 year (Estimated)
Not a significant fate process (Estimated)
Not a significant fate process (Estimated)
Professional judgment
Professional judgment
Professional judgment
Professional judgment
Professional judgment
Professional judgment
Professional judgment
Professional judgment
Substance is or contains inorganic
elements, such as metal ions or
oxides, that are expected to be found
in the environment >180 days after
release.
Based on the magnitude of the
estimated Henry's Law constant.
Based on the magnitude of the
estimated Henry's Law constant.
This inorganic compound is not
amenable to available estimation
methods.
This inorganic compound is not
amenable to available estimation
methods.
No data located.
No data located.
Substance does not contain
functional groups amenable to
atmospheric degradation processes.
Magnesium hydroxide does not
absorb UV light at environmentally
relevant wavelengths and is not
expected to undergo photolysis.
Substance does not contain
functional groups amenable to
hydrolysis.
4-270
-------
Magnesium Hydroxide CASRN 1309-42-8
PROPERTY/ENDPOINT
Environmental Half-life
Bioaccumulation
Fish BCF
Other BCF
BAF
Metabolism in Fish
DATA
REFERENCE
DATA QUALITY
Not all input parameters for this
model were available to run the
estimation software (EPI).
LOW: Magnesium hydroxide is not expected to bioaccumulate based on professional judgment.
<100 (Estimated)
<100 (Estimated)
Professional judgment
Professional judgment
This inorganic compound is not
amenable to available estimation
methods.
No data located.
This inorganic compound is not
amenable to available estimation
methods.
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
Ecological Biomonitoring
Human Biomonitoring
Magnesium hydroxide is a mineral that occurs naturally in the environment (HSDB, 2003).
No data located.
This chemical was not included in the NHANES biomonitoring report (CDC, 2013).
4-271
-------
Aldrich Chemical Company (2006) 2007-2008 Handbook of fine chemicals. Milwaukee, WI: Aldrich Chemical Company.
BIBRA (1993) Toxicity profile: Magnesium hydroxide.
Biesinger KE and Christensen GM (1972) Effects of various metals on survival, growth, reproduction, and metabolism ofDaphnia magna. J Fish
Res Board Can 29(12): 1691-1700.
CDC (2013) Fourth national report on human exposure to environmental chemicals, updated tables, March 2013.
http://www.cdc.gov/exposurereport/pdf/FourthReport_UpdatedTables_Mar2013.pdf
ECFiA (2013) Magnesium hydroxide. Registered substances. European Chemicals Agency.
http://apps.echa.europa.eu/registered/data/dossiers/DISS-9ea79197-lfe4-5688-e044-00144f67d031/AGGR-b7f868f3-337e-48ac-8f47-
d5d7445c8973_DISS-9ea79197-lfe4-5688-e044-00144f67d031.html#L-9adf9459-3347-4fcc-blc9-47f4c891001f
ECOTOX (2012) ECOTOX database. U.S. Environmental Protection Agency, http://cfpub.epa.gov/ecotox/.
EPA (1999) Determining the adequacy of existing data. High Production Volume (HPV) Challenge. Washington, DC: U.S. Environmental
Protection Agency, http://www.epa.gov/hpv/pubs/general/datadeqfn.pdf
EPA (2004) Pollution prevention (P2) framework. Washington, DC: U.S. Environmental Protection Agency, Office of Pollution Prevention and
Toxics, http://www.epa.gov/oppt/sf/pubs/p2frame-june05a2.pdf
ESIS (2011) European chemical Substance Information System. European Commission, http://esis.jrc.ec.europa.eu/.
HSDB (2003) Magnesium hydroxide. Hazardous Substances Data Bank. National Library of Medicine, http://toxnet.nlm.nih.gov/cgi-
bin/sis/htmlgen?HSDB.
Hodgman CD (1959) In: Hodgman CD, eds. CRC handbook of chemistry and physics. Cleveland, OH: Chemical Rubber Publishing Company.
IUCLID (2000) Dataset for magnesium hydroxide. International Uniform Chemical Information Database.
Kurata Y, Tamano S, Shibata MA, et al. (1989) Lack of carcinogenicity of magnesium chloride in a long-term feeding study in B6C31 mice. Food
Chem Toxicol 27(9):559-563.
Lewis RJ Sr (1997) Hawley's condensed chemical dictionary. New York, NY: John Wiley & Sons, Inc.:691.
Lewis RL (2000) Sax's dangerous properties of industrial materials. New York, NY: John Wiley & Sons, Inc.
4-272
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Lide DR (2000) 2000-2001 CRC handbook of chemistry and physics. 81st ed. Boca Raton, FL: CRC Press.
Mount DR, Gulley DD, Hockett JR, et al. (1997) Statistical models to predict the toxicity of major ions to Ceriodaphnia Dubia, Daphnia Magna
and Pimephales Promelas (Fathead minnows). Environ Toxicol Chem 16(10):2009-2019.
NAS (2000) Table 7-2 Selected oral animal toxicity data on magnesium hydroxide. National Academies Press.
http://www.nap.edu/openbook.php?record_id=9841&page=139#p2000a45a9960139001 (accessed June 23, 2008).
O'Connell D, Whitley A, Burkitt J, et al. (2004) DfE Phase II Rev 0.6. Scottsdale, AZ: HDP User Group International, Inc.
http://www.dell.com/downloads/global/corporate/environ/HDPUG_DfE_2.pdf
O'Neil M, Heckelman PE, Koch CB, et al. (2011) e-Merck index Basic Search. Whitehouse Station, NJ: Merck & Co.
https://themerckindex.cambridgesoft.com/TheMerckIndex/index.asp.
Suter GW (1996) Toxicological benchmarks for screening contaminants of potential concern for effects on freshwater biota. Environ Toxicol
Chem 15(7): 1232-1241.
Wang A, Yoshimi N, Tanaka T, et al. (1993) Inhibitory effects of magnesium hydroxide on c-myc expression and cell proliferation induced by
methylazoxymethanol acetate in rat colon. Cancer Lett 75:73-78.
4-273
-------
Melamine Polyphosphate
VL = Very Low hazard L = Low hazard = Moderate hazard H = High hazard VH = Very High hazard — Endpoints in colored text (VL, L, M, H, and VH) were
assigned based on empirical data. Endpoints in black italics (VL, L, M, H, and VH) were assigned using values from predictive models and/or professional judgment.
This table contains hazard information for each chemical; evaluation of risk considers both hazard and exposure. Variations in end-of-life processes or degradation and combustion
by-products are discussed in the report but not addressed directly in the hazard profiles. The caveats listed below must be taken into account when interpreting the information in the
table.
¥ Aquatic toxicity: EPA/DfE criteria are based in large part upon water column exposures which may not be adequate for poorly soluble substances such as many flame retardants
that may partition to sediment and particulates.
Chemical
CASRN
Human Health Effects
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Melamine Polyphosphate
15541-60-3 | L \M\M\H\M\M\M\L\
VL L
Hazard designations are based upon the component of the salt with the highest hazard designation, including the corresponding free acid or base.
4-274
-------
Melamine Polyphosphate
H
H*NYNVNh2 ° °
^ 0" " OH
NH2
CASRN: 15541-60-3
MW: >1,000
MF: C3H6N6 (H3PO4)n
Physical Forms:
Neat: Solid
Use: Flame retardant
SMILES: n(c(nc(nl)N)N)clN(H)(H)OP(=O)(O)OP(=O)(O)O (n =1) SMILES for the representative structure was created using the methodology described in the
EPI help file.
Synonyms: Diphosphoric acid, compound with l,3,5-triazine-2,4,6-triamine; Polyphosphoric acids, compounds with melamine.
The CASRN for the compound melamine pyrophosphate is 15541-60-3. The CASRN 218768-84-4 is associated with the product Melapur 200, not the chemical
melamine polyphosphate.
Chemical Considerations: This alternative contains a polymeric moiety. Although the chain length of the polyphosphoric acid is not specified, the smaller, water-
soluble polyphosphate ions were used in assessment (generally as the diphosphate ion, n=l). Melamine polyphosphate will freely dissociate under environmental
conditions based on professional judgment. Measured values from studies on the dissociated components were used to supplement data gaps as appropriate and EPI v
4.10 was used to estimate physical/chemical and environmental fate values in the absence of experimental data. Measured values from experimental studies were
incorporated into the estimations.
Polymeric: Yes
Oligomeric: Melamine polyphosphate is a complex mixture consisting of melamine and polyphosphate chains of varying length.
Metabolites, Degradates and Transformation Products: Melamine (CASRN 108-78-1)
Analog: Confidential structurally similar polymers; Polyphosphoric acid (CASRN Analog Structure:
8017-16-1) and melamine (CASRN 108-78-1) are the dissociated components of
this salt
Endpoint(s) using analog values: Reproductive effects, neurotoxicity,
immunotoxicity
H N N NH O O
~>^ M^ II II
^f OH " OH
2 Polyphosphoric acid
Melamine (CASRN 8017-16-1)
(CASRN 108-78-1)
4-275
-------
Structural Alerts: Aromatic amine, genetic toxicity (EPA, 2012).
Risk Phrases: Not classified by Annex I Directive 67/548/European Economic Community (EEC) & IUCLID (Pakalin et al., 2007).
Hazard and Risk Assessments: Australian Safety and Compensation Council National Industrial Chemicals Notification and Assessment Scheme (NICNAS),
October 30, 2006 (Australia, 2006).
4-276
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Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
Boiling Point (°C)
Vapor Pressure (mm Hg)
Water Solubility (mg/L)
Log Kow
Flammability (Flash Point)
Explosivity
Pyrolysis
pH
>400 (Measured)
>400 (Measured)
>300
(Estimated)
225
Decomposes
Reported for activated melamine
pyrophosphate (CASRN 15541-60-3)
(Measured)
<10'8
(Estimated)
20,000 (Measured)
20,000 (Measured)
<-2
(Estimated)
Not highly flammable (Measured)
Not a potential explosive (Measured)
Not a potential explosive (Measured)
May produce carbon monoxide,
ammonia, oxides of nitrogen, and oxides
of phosphorus by thermal decomposition.
Reported for activated melamine
pyrophosphate (CASRN 15541-60-3).
(Estimated)
7 Reported for activated melamine
pyrophosphate (CASRN 15541-60-3)
(Measured)
Submitted confidential study
Australia, 2006
EPI v4.10; Professional
judgment
New Line Safety, 2011
EPIv4.10;Boethlingand
Nabholz, 1997
Submitted confidential study
Australia, 2006
EPIv4.10
Submitted confidential study
Australia, 2006
Submitted confidential study
New Line Safety, 2011
New Line Safety, 2011
Adequate; value for the melamine
polyphosphate salt.
Adequate; value for the melamine
polyphosphate salt.
As an organic salt, it is expected to
decompose before boiling.
No study details reported in an
MSDS.
Cutoff value for nonvolatile
compounds.
Adequate; value for the melamine
polyphosphate salt.
Adequate.
Cutoff value for highly water soluble
substances.
Reported in a secondary source and
based on its use as a flame retardant.
Adequate.
Adequate.
No study details reported in an
MSDS.
No study details reported in an
MSDS.
4-277
-------
Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
pKa
Particle Size
DATA
Pyrophosphoric Acid:
pKal = 0.85
pKa2 = 1.96
pKa3 = 6.78
pKa4 = 10.39 (Estimated)
Melamine: pKM= 7.3;
pKb2=11.4
according to OECD 112 (Measured)
Melamine: pKM = 9
There are several amino groups that result
in basic properties. pKH = 9
pKb2 = 14
Kbi= l.lxlO'9
Kb2 = l.OxlO-14 at 25°C (Measured)
Melamine:
pKbl = 9
pKb2 = 14
Kbi= l.lxlO'9
Kb2 = l.OxlO-14 at 25°C (Measured)
Melamine: Considered a weak base
Neutral at pH values of 6 to 13;
Cation formation at the triazine ring
nitrogen at pH values of 1 to 4
(Measured)
Melamine: 5 (Measured)
REFERENCE
ECHA,2014
ECHA,2013
Baynes et al., 2008
Crews et al., 2006
OECD SIDS, 1998
HSDB, 2008; Weber, 1970
DATA QUALITY
Reported for pyrophosphoric acid
(CASRN 2466-09-3); study reported
in a secondary source.
Guideline study reported for
melamine in a secondary source.
Reported from a nonguideline study
for melamine.
For melamine; study details were not
available.
Supporting information provided in
a secondary source for melamine.
Reported in a secondary source for
melamine, value is assumed to be
the pKb .
No data located.
HUMAN HEALTH EFFECTS
4-278
-------
Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
Toxicokinetics
Dermal Absorption in vitro
Absorption,
Distribution,
Metabolism
& Excretion
Oral, Dermal or Inhaled
DATA
REFERENCE
DATA QUALITY
No toxicokinetic data were located for melamine polyphosphate or polyphosphoric acid; limited data for
melamine indicate that melamine was rapidly absorbed, distributed to body fluids, cleared from plasma
and excreted mainly via urine in monkeys. In rats, melamine was distributed to the stomach, small
intestine, cecum, and large intestine, and found in blood and urine. Following a single oral exposure to
pregnant rats, melamine was detected in the maternal serum, breast milk, whole foetus, amniotic fluid,
neonatal serum and neonatal kidney. There is evidence that Melamine passed through the placenta,
reached the fetus and accumulated in the lactating mammary gland. Excretion occurred through the
placenta of the fetus and the kidneys of neonates and was later excreted into amniotic fluid. Melamine was
transferred quickly to fetal circulation in studies where placentas from mothers following caesarean
section or normal delivery were perfused with melamine. Melamine was readily cleared by the kidney in
pigs administered melamine intravenously; distribution may be limited to the extracellular fluid
compartment. There was no concern for binding in tissues. The half-life was reported as 4.04 hours. In
monkeys, the half-life in plasma was ~4.41 hours. Other data for the melamine indicate an elimination
phase half-life of 2.7 hours from plasma and 3 hours for urine.
Melamine: Distributed to stomach, small
intestine, cecum, and large intestine, and
found in blood, and urine of rats.
Melamine: The elimination phase half-
life calculated from plasma data was 2.7
hours, and the urinary half-life was 3.0
hours. The renal clearance was
determined to be 2.5 mL/minute.
(Measured)
Melamine polyphosphate: Low for all
routes (Estimated)
Rhesus monkeys were orally
administered melamine at a single dose of
1.4 mg/kg bw. Melamine was rapidly
absorbed, distributed to body fluids,
rapidly cleared from plasma and excreted
mainly via urine. The half-life in plasma
was -4.41 hours. There was no
correlation (concentration-time curve in
plasma and urine) between melamine and
ECHA,2011b
Mastetal., 1983
Professional judgment
Liu etal., 2010
Study details reported in a secondary
source.
For melamine; adequate,
nonguideline study.
Estimates based on
physical/chemical properties.
Adequate, primary source
4-279
-------
Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
cyanuric acid, suggesting that melamine
may not be metabolized to cyanuric acid
in vivo.
Pregnant Sprague-Dawley rats were
administered a single oral dose of
melamine (-6-1 mg in <2 ml water) on
gestation day 17. Melamine was also
administered to neonates at postnatal day
14 (-0.3-0.6 mg in <0.2 ml in water).
Melamine was detected in the maternal
serum, breast milk, whole foetus,
amniotic fluid, neonatal serum and
neonatal kidney. This is evidence that
Melamine passed through the placenta,
reached the fetus and accumulated in the
lactating mammary gland. Excretion
occurred through the placenta of the fetus
and the kidneys of neonates and was later
excreted into amniotic fluid.
Chuetal., 2010
Adequate primary source
Other
Pigs (5 weanling) were administered
Melamine intravenously at a dose of 6.13
mg/kg.
Melamine is readily cleared by the
kidney; distribution may be limited to the
extracellular fluid compartment. No
concern for binding in tissues.
Half-life: 4.04 hours; clearance: 0.11
L/h/kg; volume distribution: 0.61 L/kg.
Baynes et al., 2008
Adequate primary source
Placentas from mothers following
caesarean section or normal delivery were
perfused with 0 mM or 1 mM melamine,
or 10 mM melamine with 10 nM cyanuric
acid (CYA). Melamine (34-45%) was
transferred quickly to fetal circulation
(0.12-1.34% within 5 minutes, 34%
within 4 hours); addition of CYA had no
Partanen et al., 2012
Adequate, primary study
4-280
-------
Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
Acute Mammalian Toxicity
Acute
Lethality
Oral
DATA
effect. Functionality of the placental
tissue was not affected. Viability of
BeWo cells was decreased. It is
concluded that melamine may be
fetotoxic.
REFERENCE
DATA QUALITY
LOW: Melamine polyphosphate is expected to be of low hazard for acute toxicity based on experimental
evidence for melamine polyphosphate, phosphoric acids and melamine with LDSOs > 1,000 mg/kg
following oral and dermal exposure. One inhalation study reported an LC50 of 3.25 mg/L; however, the
reported study details were too limited to consider for the hazard designation.
Melamine polyphosphate: Rat (Gavage)
LD50 >2,000 mg/kg
Melamine polyphosphate: Rat LD50
>2,000 mg/kg
Melamine polyphosphate: Rat (Gavage)
LD50 >2,000 mg/kg
Melamine polyphosphate: Rat LD50
>2,000 mg/kg
Polyphosphoric acid: LD50 = 4,000
mg/kg (species unknown)
Melamine: Rat LD50 = 3,161 mg/kg
(male), 3,828 mg/kg (females)
Melamine: Mouse LD50 = 3,296 mg/kg
(male), 7,014 mg/kg (female)
Melamine: Mouse LD50 = 4,550 mg/kg
Melamine: Rat LD50 = 3,160 mg/kg
(male) and 3,850 mg/kg (female)
Melamine: Rat LD50 >6,400 mg/kg
Ciba, 2005 (as cited in Australia,
2006)
NOTOX BV, 1998 (as cited in
Australia, 2006)
Submitted confidential study
Submitted confidential study
ARZNAD, 1957
NTP, 1983b;Melnicketal.,
1984
NTP, 1983b;Melnicketal.,
1984
American Cyanamid Company,
1955; May, 1979; Trochimowicz
etal., 2001
Trochimowicz et al., 2001
BASF, 1969 (as cited in OECD
SIDS, 1999; IUCLID, 2000a)
Sufficient study details reported.
Limited study details reported.
Study details reported in a
confidential study.
Limited study details reported in a
confidential study.
Limited study details reported. The
test substance was identified as
polyphosphates, and was described
as containing 1/3 Kurrol's potassium
salt and 2/3 pyrophosphate.
Sufficient study details reported.
Sufficient study details reported.
Limited study details reported.
Limited study details reported.
Limited study details reported.
4-281
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Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
Dermal
Inhalation
Carcinogenicity
OncoLogic Results
Carcinogenicity (Rat and Mouse)
DATA
Melamine: LD50 ~ 4,800 mg/kg
Melamine: Rabbit LD50 >1,000 mg/L
Melamine: Rat LC50 = 3.25 mg/L
REFERENCE
Hoechst, 1963 (as cited in
IUCLID, 2000a)
Unknown, 1990
Ubaidullajev, 1993 (as cited in
IUCLID, 2000a)
DATA QUALITY
Limited study details reported.
Limited study details reported.
Limited study details reported in a
secondary source.
MODERATE: Estimated based on the dissolution product melamine. There is experimental evidence that
oral melamine exposure to high doses of melamine causes Carcinogenicity in animals. However, there is no
evidence for Carcinogenicity to humans. In addition, Oncologic estimated a marginal concern that is
consistent with a Moderate hazard designation using DfE criteria. Tumor formation in animals appeared
to be due to mechanical irritation by bladder calculi/stones. IARC classifies melamine as Group 3: not
classifiable as to its Carcinogenicity to humans.
Melamine: Marginal (Estimated)
Melamine: Group 3: melamine is not
classifiable as to its Carcinogenicity to
humans; there is inadequate evidence in
humans for the Carcinogenicity of
melamine, and there is sufficient evidence
in experimental animals for the
Carcinogenicity of melamine under
conditions in which it produces bladder
calculi.
Melamine: Significant formation of
transitional cell carcinomas in the urinary
bladder of male rats and significant
chronic inflammation in the kidney of
dosed female rats were observed.
Carcinoma formation was significantly
correlated with the incidence of bladder
stones. A transitional -cell papilloma was
observed in the urinary bladder of a single
high dose male rat, and compound related
lesions were observed in the urinary tract
of dosed animals.
Melamine: Increased incidence of acute
and chronic inflammation and epithelial
OncoLogic, 2008
IARC, 1999
NTP, 1983b; Huff, 1984;
Melnick et al., 1984
NTP, 1983b; Huff, 1984;
Melnick et al., 1984
IARC classification statement.
Sufficient study details reported.
Sufficient study details reported.
4-282
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Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
hyperplasia of the urinary bladder was
observed in male mice. Bladder stones
and compound-related lesions were
observed in the urinary tract of test
animals. Melamine was not considered
carcinogenic.
Melamine: Melamine-induced
proliferative lesions of the rat urinary
tract were directly due to the irritant
stimulation of calculi, and not to
molecular interactions between melamine
or its metabolites with the bladder
epithelium.
Okumura et al, 1992
Sufficient study details reported.
Melamine: Water intake, used as an
index of urinary output, was increased by
NaCl treatment. Calculus formation
resulting from melamine administration
was suppressed dose-dependently by the
simultaneous NaCl treatment. The main
constituents of calculi were melamine and
uric acid (total contents 61.1- 81.2%).
The results indicate that melamine-
induced proliferative lesions of the
urinary tract of rats were directly due to
the irritation stimulation of calculi, and
not molecular interactions between
melamine itself or its metabolites with the
bladder epithelium.
Ogasawara et al., 1995
Sufficient study details reported.
Melamine: As an initiator, melamine
caused no significant increase in
papillomas per mouse when compared to
controls.
Perrella and Boutwell, 1983
Nonguideline study.
Melamine: Diffuse papillary hyperplasia
of the bladder epithelium and bladder
calculi were observed in all melamine
treated rats. Elevated
4-283
Matsui-Yuasi et al., 1992
Nonguideline study.
-------
Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
Combined Chronic
Toxicity/Carcinogenicity
Other
Genotoxicity
Gene Mutation in vitro
DATA
spermidine/spermine N 1 -acetyltransferase
activity following melamine treatment
was considered to be an indicator of cell
proliferation.
Melamine: Decreased antitumor activity
was correlated with increasing
demethylation; melamine was considered
inactive as an antitumor drug.
Melamine: In an in vitro cytotoxicity
study in cultured ADJ/PC6 plasmacytoma
ascites tumor cells, the ID50 was 470
(ig/mL after 72 hours of treatment.
Melamine: No effects were observed in
rats fed 1,000 ppm of melamine. 4 of the
10 rats fed 10,000 ppm melamine had
bladder stones associated with the
development of benign papillomas.
Melamine: Increased incidence of
urinary bladder stones (6/20 rats) was
noted in the 10,000 ppm dose group, and
was associated with an increase in benign
papillomata. The NOAEL was
determined to be 1,000 ppm (67 mg/kg-
day).
REFERENCE
Rutty and Connors, 1977
Rutty and Abel, 1980
Anonymous, 1958 (as cited in
Wolkowski Tyl and Reel, 1992)
American Cyanamid Company,
1955
DATA QUALITY
Limited study details reported.
Limited study details reported.
Limited study details reported.
Limited study details reported.
No data located.
MODERATE: Melamine polyphosphate is estimated to be a moderate hazard for genotoxicity based on a
weight of evidence from multiple studies for melamine. For melamine, positive results were observed for in
vivo chromosome aberration and sister chromatid exchange assays conducted by National Toxicology
Program (NTP) in 1988 and 1989. Available in vitro genotoxicity testing was conducted with metabolic
activation systems from the liver. NTP suggests this may not account for potential activation from bladder
epithelial cells, which is the target organ. Proposed genotoxicity testing using a metabolic activation system
from bladder epithelial cells (NTP, 1983) was never conducted (Personal Communication, 2007; 2008).
Melamine: Bacterial forward mutation
assay: Negative with and without liver
activation
Haworth et al., 1983; NTP,
1983a
Sufficient study details reported.
4-284
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Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
Gene Mutation in vivo
Chromosomal Aberrations in vitro
Chromosomal Aberrations in vivo
DATA
Melamine: Bacterial forward mutation
assay: Negative
Melamine: Bacterial reverse mutation
assay: Negative with and without liver
activation
Melamine: Bacterial reverse mutation
assay: Negative with and without
unspecified metabolic activation
Melamine: In vitro mouse lymphoma
test: Negative with and without liver
activation
Melamine: Chinese hamster ovary
(CHO) cells/hypoxanthine-guanine
phosphoribosyl-transferase forward
mutation assay: Negative with and
without liver activation.
Melamine: In vitro chromosomal
aberrations test: Negative in CHO with
and without liver activation.
Melamine: In vitro sister chromatid
exchange assay: Negative in CHO with
and without liver activation.
Melamine: In vitro sister chromatid
exchange assay: Negative in CHO with
and without liver activation.
Melamine: In vivo mouse micronucleus
test: The initial test gave a positive trend
(P = 0.003) for chromosomal damage;
however, both peripheral blood smears
and the repeat bone marrow test were
negative. The overall conclusion was that
melamine does not induce chromosomal
damage.
REFERENCE
Seiler, 1973
Lusbyetal., 1979
Mastetal., 1982b
NTP, 1983a; McGregor et al.,
1988
Mastetal., 1982b
NTP, 1983a; Galloway et al.,
1987
NTP, 1983a; Galloway et al.,
1987
Mastetal., 1982b
NTP, 1983b; Shelby et al., 1993
DATA QUALITY
Limited study details reported.
Limited study details reported.
Limited study details reported.
Sufficient study details reported.
Limited study details reported.
No data located.
Sufficient study details reported.
Sufficient study details reported
Limited study details reported.
Sufficient study details reported.
4-285
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Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
DNA Damage and Repair
Other
DATA
Melamine: In vivo mouse micronucleus
test: Negative
Melamine: In vivo chromosome
aberrations test in mice: Positive
Melamine: In vivo sister chromatid
exchange assay in mice: Positive
Melamine: In vivo and in vitro
unscheduled DNA synthesis (UDS) test:
None of the tested chemicals, including
melamine, were genotoxic
hepatocarcinogens in the in vivo assay,
and melamine was negative for UDS in
the in vitro assay.
Melamine: SOS/umu test: Negative for
its ability to result in DNA damage and
induce the expression of the umu operon.
Melamine: DNA synthesis-inhibition test
in Hela S3 cells: Inhibits DNA synthesis
by 50% at greater than 300 (iM.
Melamine: Sex-linked recessive
lethal/reciprocal translocation: Results
were considered equivocal based on
0.18% and 0.36% total lethal following
oral and injection exposure, respectively,
compared to control total lethal of 0.07%
for oral and 0.09% for injection.
Melamine: Drosophila Muller-5 test:
Negative for mutagenicity
Melamine: Drosophila melanogaster
Sex-linked recessive lethal: No mutagenic
effects were observed
Melamine: In vitro flow cytometric DNA
repair assay: Negative for genotoxic
effects
REFERENCE
Mastetal., 1982c
NTP, 1983a
NTP, 1983a
Mirsalis et al., 1983
Reifferscheid and Heil, 1996
Heil and Reifferscheid, 1992
NTP, 1983a
Rohrborn, 1959
Luers and Rohrborn, 1963
Seldonetal., 1994
DATA QUALITY
Limited study details reported.
Sufficient study details reported.
Sufficient study details reported.
Limited study details reported.
Nonguideline study.
Limited study details reported.
Sufficient study details reported.
Limited study details reported.
Limited study details reported.
Nonguideline study.
4-286
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Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Melamine: Microscreen assay: Positive
for genetic toxicity in E. coll WP2 cells
Rossman et al., 1991
Nonguideline study.
Melamine: Growth and genotoxic effects
to bacteria {Salmonella typhimurium) and
yeast (Saccharomyces cerevisiae): Non-
mutagenic in S. typhimurium with or
without S-9 mix. The growth of eight out
of nine strains tested was delayed by 10
mM melamine during 24 hour cultivation.
S. cerevisiae strain was tested, and did not
recover its growth following 48 hour
cultivation.
Ishiwata et al., 1991
Limited study details reported.
Proposed genotoxicity testing using a
metabolic activation system from bladder
epithelial cells (NTP, 1983) was never
conducted.
Lehner and Yokes, 2008;
Shigeru, 2007
Supporting information.
Reproductive Effects
HIGH: Estimated based on experimental data for melamine. A NOAEL of 10 mg/kg-day (LOAEL of 50
mg/kg-day) for increased apoptotic index of spermatogenic cells was reported in male mice orally
administered melamine for 5 days. In addition, altered epididymal sperm morphology and damage of
testicular DNA were reported at a dietary dose of 412 mg/kg-day (lowest dose tested). No experimental
data were located for melamine polyphosphate.
Reproduction/Developmental
Toxicity Screen
Rat, oral; potential for reproductive
toxicity
(Estimated by analogy)
Professional judgment
Estimated based on analogy to
confidential analog; LOAEL not
identified; study details not
provided.
Combined Repeated Dose with
Reproduction/ Developmental
Toxicity Screen
No data located.
Reproduction and Fertility Effects
Melamine: In a 5-day study, male mice
(8/group) were orally administered
melamine only at doses of 0, 2, 10 and 50
mg/kg-day or melamine in combination
with cyanuric acid at doses of 0, 1,5 and
25 mg/kg-day.
Sperm abnormalities were evaluated in a
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Yin etal., 2013
Adequate, primary study
-------
Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
separate select group of mice (8/group),
which were fed melamine only at doses of
0, 412, 824, and 1,648 mg/kg-day, or
melamine in combination with cyanuric
acid at doses of 0, 206, 412, or 824
mg/kg-day.
No deaths in mice fed 2, 10 and 50
mg/kg-day melamine or 1 and 5 mg/kg-
day melamine and cyanuric acid; 3 deaths
in co-administration group fed 25
mg/kg/day.
Grossly enlarged, pale yellow kidneys in
all mice that survived. Increase in
apoptotic index of spermatogenic cells in
mice fed 50 mg/kg-day melamine-only;
more severe apoptosis in co-administered
mice at 5 and 25 mg/kg-day.
NOAEL: 10 mg/kg-day
LOAEL: 50 mg/kg-day (increased
apoptotic index of spermatogenic cells)
Sperm abnormality group: no deaths in
mice administered melamine-only; all co-
administered mice died before day 6 and
exhibited anorexia, decreased activity and
hunched posture. Altered epididymal
sperm morphology (particularly the head
abnormality) and damage of testicular
DNA in all melamine-only treatment
groups.
NOAEL: Not established
LOAEL: 412 mg/kg-day (altered
epididymal sperm morphology; damage
of testicular DNA)
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Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
Other
Developmental Effects
Reproduction/ Developmental
Toxicity Screen
Combined Repeated Dose with
Reproduction/ Developmental
Toxicity Screen
DATA
Melamine: There were no treatment-
related macroscopic or microscopic
effects on mammary glands, ovaries,
prostate, seminal vesicles, testes and
uterus in rats and mice up to dietary
concentrations of 18,000 ppm in a 13-
week study.
Melamine: Reproductive dysfunction
was observed at 0.5 mg/m3 and included
effects on spermatogenesis (genetic
material, sperm morphology, motility,
and count), effects on the embryo/fetus
(fetal death), pre -implantation mortality
(reduction in the number of implants per
female), and total number of implants per
corpora lutea.
REFERENCE
Melnick et al., 1984 (as cited in
OECD SIDS, 1999)
Ubaidullajev, 1993
DATA QUALITY
Limited study details reported in a
secondary source.
Study details, if present, were not
translated into English.
No data located.
MODERATE: Estimated based on a structural alert for aromatic amines. Limited experimental data for
melamine indicated no developmental effects in rats exposed during gestation to doses up to 1,060 mg/kg-
day. This experimental data is insufficient to determine a hazard designation for this endpoint.
There was no data located for the developmental neurotoxicity endpoint for this substance or its analogs.
No data located.
No data located.
4-289
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Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
Prenatal Development
Postnatal Development
Prenatal and Postnatal
Development
Developmental Neurotoxicity
Other
Neurotoxicity
Neurotoxicity Screening Battery
DATA
Melamine: Signs of maternal toxicity at
136 mg/kg b.w. included decreased body
weight and feed consumption, hematuria
(23/25 rats), indrawn flanks (7/25 rats),
and piloerection (1/25 rats). No adverse
effects on gestational parameters and no
signs of developmental toxicity were
noted.
NOAEL > 1,060 mg/kg-day (highest
concentration tested);
LOAEL: Not established
Melamine: Only minor effects on the
fetuses or litters, including a non-
significant increase in resorptions in the
group treated on the 4th and 5th days of
gestation, were observed.
There was no data located for the
developmental neurotoxicity endpoint.
Potential for developmental toxicity
based on a structural alert for aromatic
amines.
(Estimated)
REFERENCE
Hellwig et al, 1996 (as cited in
OECD SIDS, 1999)
Thiersch, 1957
Professional judgment
DATA QUALITY
Sufficient study details reported.
Sufficient study details were not
available.
No data located.
No data located.
Estimated based on a structural alert
for aromatic amines and professional
judgment.
MODERATE: Estimated based on experimental data for melamine. Several neurological effects were
reported for different endpoints in 28-day studies evaluating mode of action in the brain. Impaired
memory abilities and cognition deficits were mediated by alterations of the pathways affecting the
hippocampus at a dose of 300 mg/kg-day (only dose tested). Design for the Environment (DfE) Alternatives
Assessment criteria values are tripled for chemicals evaluated in 28-day studies; the LOAEL of 300 mg/kg-
day falls on the threshold between Moderate and LOW hazard criteria. A NOAEL was not established and
it is assumed that effects would occur at a dose within the Moderate-High hazard criteria range; due to
this uncertainty, a Moderate hazard designation was assigned.
Melamine: In a 28-day study, male
Anetal. 2011
Sufficient study details reported in
4-290
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Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
(Adult)
Wistar rats (control group n = 8, treatment
group n = 10) were orally administered
tnelamine only at doses of 0, or 300
mg/kg-day.
A significant deficit of learning and
memory in a Morris water maze test was
•eported in the treated group. In addition
significantly lower field excitatory
postsynaptic potential (fEPSPs) slopes
were determined in a long term
potentiation (LTP) test from Schaffer
Collaterals to CA1 region in the
lippocampus in the treated group
ompared to the control group.
Authors concluded that melamine had a
;oxic effect on hippocampus resulting in
deficits of learning and memory in rats
associated with impairments of synaptic
plasticity.
NOAEL: Not established
GAEL: 300 mg/kg-day
primary source; only one dose tested.
Melamine: In a 28-day study, male
Wistar rats (10/group) were orally
administered melamine only at doses of 0,
or 300 mg/kg-day.
A significant deficit of learning and
memory in a Morris water maze test was
•eported in the treated group. In addition
significantly lower field excitatory
postsynaptic potential (fEPSPs) slopes
were determined in a long term
potentiation (LTP) test in the treated
group compared to the control group.
Decreased frequencies of spontaneous
EPSCs and minitura EPSCs were
observed in a long-time potentiation test,
4-291
Yang etal., 2011
Sufficient study details reported in
primary source; only one dose tested.
-------
Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
though there was no change in the
amplitude or kinetics of spontaneous or
initura EPSCs suggesting melamine's
[influence on glutamatergic transmission
ikely occurred presynaptic.
GAEL: Not established
LOAEL: 300 mg/kg-day
Melamine: In a 28-day study, male
Wistar rats (8/group) were orally
administered melamine only at doses of 0,
or 300 mg/kg-day.
A significant deficit of learning and
memory in a Morris water maze test was
reported in the treated group. Increased
evels of superoxide anion radical,
lydroxyl free radical and malonaldehyde
e reported. There was also decreased
superoxide dismutase and glutathione
seroxidase activity in the treated group
compared to the control. Hippocampal
energy metabolism analysis showed
ignificantly decreased adenosine-
riphosphate (ATP) content suggestive of
duced energy synthesis in the
ippocampal neurocytes possibly
associated with oxidative damage.
NOAEL = Not established
LOAEL = 300 mg/kg-day
Anetal, 2012
Sufficient study details reported in
primary source; only one dose tested.
Melamine: In a 28-day study, male
Wistar rats (8/group) were orally
administered melamine only at doses of 0,
or 300 mg/kg-day.
Anetal., 2013
Sufficient study details reported in
primary source; only one dose tested.
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Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
A significant deficit of learning and
memory in a Morris water maze test was
reported in the treated group. Increased
field excitatory postsynaptic potential
slopes was reported in the treated group.
There was decreased Ach levels and
increased AChE activity suggesting
damage to the function of cholinergic
system.
NOAEL = Not established
LOAEL = 300 mg/kg-day
Melamine: In a 28-day study, male
Wistar rats (8/group) were orally
administered melamine only at doses of 0,
or 300 mg/kg-day.
Impaired memory abilities were reported
in treated rats in the Morris water maze
ests compared to the control group.
Cognition deficits consistent with reduced
ong-term potentiation in the CA1 area of
he hippocampus were induced. Phase
ocking values showed reduced
synchronization between CA3 and CA1 in
theta and LG rhythms. Decreased
unidirectional indices for theta and LG
rhythms were reported in treated rats
suggesting that alterations of neural
information flow on CA3-CA1 pathway in
the hippocampus mediated cognitive
impairment in treated rats.
NOAEL = Not established
LOAEL = 300 mg/kg-day
4-293
Xuetal.,2013
Sufficient study details reported in
primary source; only one dose tested.
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Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Other
Potential for neurotoxicity is expected to
be low.
(Estimated)
Professional judgment
Estimated based on analogy and
professional judgment.
Repeated Dose Effects
MODERATE: Melamine polyphosphate is expected to be a moderate hazard for repeated dose effects
based on the data for melamine. Stones and diffuse epithelial hyperplasia in the urinary bladders were
observed in male rats at doses as low as 700 ppm (72 mg/kg-day; lowest dose tested). Exposure to
melamine has been associated with toxicity in humans.
Polyphosphoric Acid: Rat Repeated-
Dose Toxicity Study: An oral repeated-
dose toxicity test in rats resulted in a
TDLo of 450 mg/kg. The test substance
was identified as polyphosphates, and
was described as containing 1/3 Kurrol's
potassium salt and 2/3 pyrophosphate.
Toxic effects included changes in liver
weight, changes in tubules (including
acute renal failure, acute tubular
necrosis), and weight loss or decreased
weight gain.
Melamine: Rat 28-day dietary toxicity
study: Clinical signs included a dose-
related increase in pilo-erection, lethargy,
bloody urine spots in the cage and on the
pelage of animals, and
chromodacryorrhea. The incidence of
urinary bladder calculi and urinary
bladder hyperplasia in treated animals
was dose-dependent, with a significant
relationship between the calculi and
hyperplasia. Calculi composition
indicated the presence of an organic
matrix containing melamine, phosphorus,
sulfur, potassium, and chloride. Crystals
of dimelamine monophosphate were
identified in the urine.
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ARZNAD, 1957
RTI, 1983
Sufficient study details were not
available.
Sufficient study details reported.
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Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
NOAEL: estimated to be 2,000 ppm (240
mg/kg/day), excluding the observed
increase in water consumption and the
incidence of crystalluria.
LOAEL: 4,000 ppm (475 mg/kg/day)
based on the formation of calculi.
Melamine: Rabbit and dog 28-day
dietary toxicity study: No significant rise
in the body temperature of rabbits was
noted. Gross histological examination of
the heart, lung, liver, spleen, thyroid,
pancreas, intestines, kidneys and bladder
did not show pathological changes. A
zone of fat was found in the inner part of
the renal cortex in two dogs, but also in
the kidneys of 3 control dogs.
Lipschitz and Stokey, 1945
Sufficient study details were not
available.
Melamine: Rat 28-day dietary toxicity
study: Incidence and size of bladder
stones were directly related to the amount
of substance administered. The larger
stones were found to be unchanged
melamine in a matrix of protein, uric acid
and phosphate.
Lowest effective dose: 1,500 ppm (-125
mg/kg-day) in males
American Cyanamid Company,
1984
Sufficient study details were not
available.
Melamine: Rat 90-day dietary toxicity
study: one male rat receiving 18,000 ppm
and two males receiving 6,000 ppm died.
Mean body weight gain and feed
consumption were reduced. Stones and
diffuse epithelial hyperplasia in the
urinary bladders were observed in male
rats of all treatment groups. Focal
epithelial hyperplasia was observed in
NTP, 1983b;Melnicketal.
1984: ECHA, 201 la
Sufficient study details reported.
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Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
only 1 male. A second and third 13-week
repeated dose toxicity study was
conducted in rats at a dose range of 750 to
18,000 ppm; bladder stones were
observed at all dose levels.
LOAEL: 700 ppm (72 mg/kg/day)
Melamine: Mouse 90-day Dietary
Toxicity Study: A single female mouse
died after receiving 9,000 ppm. Mean
body weight gain relative to controls was
depressed. The incidence of mice with
bladder stones was dose-related and was
greater in males than in females. Sixty
percent of mice having bladder ulcers
also had urinary bladder stones. Bladder
ulcers were multifocal or associated with
inflammation (cystitis). Epithelial
hyperplasia and bladder stones were
observed together in 2 mice. Also,
epithelial cell atypia was seen.
NOAEL: 6,000 ppm (600 mg/kg-day)
LOAEL: 9,000 ppm (900 mg/kg-day)
NTP, 1983b;Melnicketal.
1984
Sufficient study details reported.
Melamine: Increased incidence of acute
and chronic inflammation and epithelial
hyperplasia of the urinary bladder was
observed in mice following oral (feed)
exposure for up to 103 weeks. There was
also increased incidence of bladder stones
in male mice.
LOAEL: 2,250 ppm (-380 mg/kg bw-
day; lowest dose tested)
NTP, 1983b;ECHA, 201 Ib
Repeated dose effects described in a
carcinogenicity bioassay study.
Melamine: Dog 1-year dietary toxicity
study: crystalluria started 60 to 90 days
into treatment, and persisted during the
study period. No other effects attributable
to melamine were observed.
American Cyanamid Company,
1955
Sufficient study details were not
available.
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Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Melamine: Rat 30-month dietary toxicity
study: neither accumulation of calculi nor
any treatment-related urinary bladder
lesions were found.
Mast et al., 1982a (as cited in
Wolkowski Tyl and Reel, 1992)
Sufficient study details were not
available.
Melamine: Rat 24- to 30-month dietary
toxicity study: a dose related trend for
dilated glands in glandular gastric mucosa
and inflammation in non glandular gastric
mucosa was observed. Urinary bladder
calculi formation was not observed.
American Cyanamid Company,
1983 (as cited in OECD SIDS,
1999)
Sufficient study details were not
available.
Melamine: Children affected by
melamine contaminated milk for
approximately 3 to 6 months before the
onset of kidney stones. The highest
content of melamine ranged from 0.090 to
619 mg/kg milk powder. A total of
52,857 children had received treatment
for melamine-tainted milk. 99.2% of the
children were younger than 3 yr. Some
children were asymptomatic; however
irritability, dysuria, difficulty in urination,
renal colic, hematuria, or stone passage,
hypertension, edema, or oliguria were
also reported. Mortality occurred in four
cases.
Hau et al., 2009
Summary of toxic effects from food
contamination.
Melamine: Renal damage is believed to
result from kidney stones formed from
melamine and uric acid or from melamine
and cyanuric acid. Cyanuric acid can be
produced in the gut by microbial
transformation of melamine. The bacteria
Klebsiella terrigena was shown to
convert melamine to cyanuric acid and
rats colonized by K. terrigena showed
exacerbated melamine-induced
nephrotoxicity.
Zheng etal, 2013
Supporting information about the
renal toxicity of melamine.
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Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
Skin Sensitization
Skin Sensitization
Respiratory Sensitization
Respiratory Sensitization
Eye Irritation
Eye Irritation
Dermal Irritation
Dermal Irritation
DATA
REFERENCE
DATA QUALITY
LOW: Melamine polyphosphate is not expected to be a skin sensitizer based on the data for melamine.
Melamine: No evidence of primary
dermal irritation or Sensitization in a
human patch test
Melamine: Non-sensitizing to guinea
pigs
American Cyanamid Company,
1955; Trochimowicz et al., 2001
Fasset and Roudabush, 1963 (as
cited in OECD SIDS, 1999;
Trochimowicz et al., 2001)
Limited study details reported.
Limited study details reported.
No data located.
No data located.
LOW: Melamine polyphosphate is slightly irritating to eyes.
Melamine polyphosphate: Slightly
irritating
Melamine polyphosphate: Slightly
irritating
Melamine: Non-irritating to rabbit eyes
Melamine: Non-irritating to rabbit eyes
following 0.5 mL of 10% melamine
Melamine: Mild irritant to rabbit eyes
following exposure to 30 mg of dry
powder
Melamine: Slightly irritating to rabbit
eyes
NOTOX BV, 1998 (as cited in
Australia, 2006)
Submitted confidential study
BASF, 1969 (as cited in OECD
SIDS, 1999; IUCLID, 2000a)
American Cyanamid Company,
1955; Trochimowicz et al., 2001
American Cyanamid Company,
1955; Trochimowicz et al., 2001
Marhold, 1972 (as cited in
IUCLID, 2000a; RTECS, 2009)
Limited study details reported.
Limited study details reported.
Limited study details reported.
Limited study details reported.
Limited study details reported.
Limited study details reported.
VERY LOW: Melamine polyphosphate is not a skin irritant.
Melamine polyphosphate: Not irritating
Melamine polyphosphate: Not irritating
Melamine: Not irritating to rabbit skin
Melamine: Not irritating to rabbit skin
NOTOX BV, 1998 (as cited in
Australia, 2006)
Submitted confidential study
Rijcken, 1995 (as cited in OECD
SIDS, 1999)
BASF, 1969 (as cited in OECD
SIDS, 1999; IUCLID, 2000a)
Limited study details reported.
Limited study details reported.
Organisation for Economic
Cooperation and Development
(OECD) 404 guideline study.
Limited study details reported.
4-298
-------
Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
Endocrine Activity
Immunotoxicity
Immune System Effects
DATA
Melamine: Not irritating to rabbit skin
Melamine: Not irritating to rabbit skin
REFERENCE
American Cyanamid Company,
1955; Trochimowicz et al., 2001
Fasset and Roudabush, 1963 (as
cited in OECD SIDS, 1999;
Trochimowicz et al., 2001)
DATA QUALITY
Limited study details reported.
Limited study details reported.
There were insufficient data located to describe the effect of melamine polyphosphate on the endocrine
system. In one study, melamine did not exhibit estrogenic activity in vitro in a yeast two-hybrid assay.
Melamine: Showed no estrogenic
activity (no change in B-galactosidase
activity) in an in vitro yeast two-hybrid
assay in Saccharomyces cerevisiae Y 190
ECHA,2011b
Reported in a secondary source.
Nonguideline study.
Potential for immunotoxic effects based on analogy to structurally similar polymers and professional
judgment.
Potential for immunotoxicity
Melamine: Did not inhibit the
mitogenesis of B- and T- lymphocytes in
an in vitro mouse lymphocyte
mitogenesis test.
Professional judgment
ECHA,2011a
Estimated based on confidential
analogs and professional judgment.
Data from a secondary source.
ECOTOXICITY
ECOSAR Class
Acute Aquatic Toxicity
Fish LC50
Melamine s
LOW: Melamine polyphosphate is expected to be of low hazard for acute toxicity to aquatic organisms
based on experimental data for melamine polyphosphate and experimental data for melamine. For
melamine, the weight of evidence suggests that the acute values are >100 mg/L. For melamine
polyphosphate, no effects were observed in algae at the highest concentration tested (3.0 mg/L). Melamine
polyphosphate is not predicted to cause eutrophication based on laboratory testing.
Melamine polyphosphate: Freshwater
fish 96-hour LC50 = 100 mg/L
(Experimental)
Melamine: Leuciscus idus melanotus 48-
hour LC50 >500 mg/L
(Experimental)
Melamine: Oryzias latipes 48-hour LC50
Ciba, 2005 (as cited in Australia,
2006)
OECD SIDS, 1999
OECD SIDS, 1999
Reported in a secondary source,
study details and test conditions
were not reported.
Study details reported in secondary
source.
Study details reported in secondary
4-299
-------
Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
Daphnid LC50
DATA
= 1,000 mg/L
(Experimental)
Melamine: Poecilia reticulata 96-hour
LC50 >3,000 mg/L
(Experimental)
Melamine: Poecilia reticulata 4,400
mg/L dose lethal to <10%
(Experimental)
Melamine: Fish 96-hour LC50 = >100
mg/L
(Estimated)
ECOSAR: Anilines (amino-meta)
Melamine: Fish 96-hour LC50 = >100
mg/L
(Estimated)
ECOSAR: Melamines
Melamine polyphosphate: Daphnia
magna 48-hour EC50 >100 mg/L
(Experimental)
Melamine: Daphnia magna 48-hour
LC50 >2,000 mg/L
(Experimental)
Melamine: Daphnid 48-hour LC50 = 6.23
mg/L
(Estimated)
ECOSAR: Anilines (amino-meta)
Melamine: Daphnid 48-hour LC50 =
>100 mg/L
ECOSAR: Melamines
(Estimated)
REFERENCE
OECD SIDS, 1999
OECD SIDS, 1999
ECOSAR v 1.11
ECOSAR v 1.11
Ciba, 2005 (as cited in Australia,
2006)
OECD SIDS, 1999
ECOSAR v 1.11
ECOSAR v 1.11
DATA QUALITY
source.
Study details reported in secondary
source.
Study details reported in secondary
source.
ECOSAR provided results for the
Anilines (amino-meta) class;
however, professional judgment
indicates that this compound does
not lie within the domain of the
ECOSAR model.
Reported in a secondary source,
study details and test conditions
were not reported.
Study details reported in secondary
source.
ECOSAR provided results for the
Anilines (amino-meta) class;
however, professional judgment
indicates that this compound does
not lie within the domain of the
ECOSAR model.
4-300
-------
Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
Green Algae EC50
Chronic Aquatic Toxicity
Fish ChV
DATA
Melamine polyphosphate: In a 96-hour
control growth test (Selenastrum
capricornutum), melamine polyphosphate
causes increased algal growth, but growth
is 95% less than growth in standard
medium with adequate phosphorous. This
indicates that melamine polyphosphate is
not a good source of phosphorous for
algal growth and does not cause
eutrophication.
(Experimental)
Melamine: Scenedesmus pannonicus 4-
day EC50 = 940 mg/L; 4-day NOEC =
320 mg/L
(Experimental)
Melamine: Green algae 96-hour EC50 =
2.79 mg/L
(Estimated)
ECOSAR: Anilines (amino-meta)
Melamine: Green algae 96-hour EC50 =
>100 mg/L
(Estimated)
ECOSAR: Melamines
REFERENCE
Submitted confidential study
OECD SIDS, 1999
ECOSAR v 1.11
ECOSAR v 1.11
DATA QUALITY
Sufficient study details reported in a
confidential study.
Reported in a secondary source,
study details and test conditions
were not provided.
ECOSAR provided results for the
Anilines (amino-meta) class;
however, professional judgment
indicates that this compound does
not lie within the domain of the
ECOSAR model.
LOW: Melamine polyphosphate is expected to be of low hazard for chronic toxicity to aquatic organisms
based on experimental data for melamine. For melamine, the weight of evidence suggests that the chronic
values are >10 mg/L. For melamine polyphosphate, no effects were observed in algae at the highest
concentration tested (3.0 mg/L).
Melamine: Jordanella floridae 35-day
NOEC> 1,000 mg/L
(Experimental)
Melamine: Salmo gairdneri NOEC
(macroscopic) = 500 mg/L; NOEC
(microscopic) <125 mg/L
OECD SIDS, 1999
OECD SIDS, 1999
Reported in a secondary source,
study details and test conditions
were not provided.
Reported in a secondary source,
study details and test conditions
were not provided.
4-301
-------
Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
Daphnid ChV
Green Algae ChV
DATA
(Experimental)
Melamine: Fish ChV = >100 mg/L
(Estimated)
ECOSAR: Anilines (amino-meta)
Melamine: Fish ChV = >100 mg/L
(Estimated)
ECOSAR: Melamines
Melamine: Daphnia magna 21 -day LC50
= 32-56 mg/L, 21-day LCioo = 56 mg/L,
21-dayNOEC= 18 mg/L
(Experimental)
Melamine: Daphnid ChV = 0.078 mg/L
(Estimated)
ECOSAR: Anilines (amino-meta)
Melamine: Daphnid ChV = 14.85 mg/L
(Estimated)
ECOSAR: Melamines
Melamine polyphosphate: Selenastrum
capricornutum 96-hour EC50 >3.0 mg/L;
96-hour NOEC = 3.0 mg/L
(Experimental)
Melamine polyphosphate: Selenastrum
capricornutum 96-hour EC50 >3.0 mg/L;
96-hour NOEC = 3.0 mg/L
(Experimental)
REFERENCE
ECOSAR v 1.11
ECOSAR v 1.11
OECD SIDS, 1999
ECOSAR v 1.11
ECOSAR v 1.11
Submitted confidential study
Australia, 2006
DATA QUALITY
ECOSAR provided results for the
Anilines (amino-meta) class;
however, professional judgment
indicates that this compound does
not lie within the domain of the
ECOSAR model.
Reported in a secondary source,
study details and test conditions
were not provided.
ECOSAR provided results for the
Anilines (amino-meta) class;
however, professional judgment
indicates that this compound does
not lie within the domain of the
ECOSAR model.
No effects observed at highest
concentration tested.
Reported in a secondary source,
study details and test conditions
were not provided; no effects
observed at highest concentration
tested.
4-302
-------
Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
DATA
Melamine: Green algae ChV = 0.70
mg/L
(Estimated)
ECOSAR: Anilines (amino-meta)
Melamine: Green algae ChV = 81.26
mg/L
(Estimated)
ECOSAR: Melamines
REFERENCE
ECOSAR v 1.11
ECOSAR v 1.11
DATA QUALITY
ECOSAR provided results for the
Anilines (amino-meta) class;
however, professional judgment
indicates that this compound does
not lie within the domain of the
ECOSAR model.
ENVIRONMENTAL FATE
Transport
Henry's Law Constant (atm-
m3/mole)
Sediment/Soil
Adsorption/Desorption - Koc
Level III Fugacity Model
Melamine polyphosphate has a high measured water solubility of 20 g/L and its Henry's Law constant and
vapor pressure are below cutoff values. It is expected to partition predominately to water and soil. It may
migrate from soil into groundwater. As a salt, volatilization from either wet or dry surfaces is not expected
to be an important fate process.
<10'8 (Estimated)
Melamine polyphosphate: 13
(Estimated)
Air = 0%
Water = 37%
Soil = 63%
Sediment = 0% (Estimated)
for Melamine Polyphosphate
EPIv4. 10; Professional
judgment
EPIv4.10
EPIv4.10
Cutoff value for nonvolatile
compounds.
4-303
-------
Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Persistence
HIGH: Melamine polyphosphate is expected to show high persistence in the environment based on the
data for melamine. Melamine polyphosphate is expected to be fully dissociated under environmental
conditions. The weight of evidence suggests that melamine will biodegrade at rates consistent with a High
hazard designation. Although pure culture studies showed evidence of biodegradation by enzymatic
hydrolytic deamination in less than 10 days, an original MITI test detected less than 30% degradation
after 14 days and two separate guideline OECD 302B studies observed no degradation after 28 days and
16% degradation after 20 days. This results in an expected environmental persistence half-life between 60
and 180 days. Degradation of melamine or its cation by hydrolysis or direct photolysis is not expected to be
significant as the functional groups present on this molecule do not tend to undergo these reactions under
environmental conditions. Polyphosphoric acid is expected to have low persistence in the environment. The
weight of evidence suggests that polyphosphoric acid will hydrolyze under environmental conditions. The
phosphates formed are expected to participate in natural cycles and be readily assimilated.
Water
Aerobic Biodegradation
Melamine polyphosphate:
Weeks (Primary survey model)
Months (Ultimate survey model)
(Estimated)
Melamine: 16% removal after 20 days
with activated sludge, 14% removal after
10 days with adapted sludge (Measured)
Melamine: 0% removal after 28 days
with activated sludge (Measured)
Melamine: 0% removal after 14 days
with activated sludge (Measured)
Melamine: <30% removal after 14 days
with activated sludge (Measured)
Melamine: <1% removal after 5 days
with an adapted inoculum (Measured)
4-304
EPIv4.10
OECD SIDS, 1999
OECD SIDS, 1999
OECD SIDS, 1999
OECD SIDS, 1999
IUCLID, 2000a
These values are for the dissociated
component, melamine. Reported in a
secondary source, study details and
test conditions were not provided.
These values are for the dissociated
component, melamine. Reported in a
secondary source, study details and
test conditions were not provided.
These values are for the dissociated
component, melamine. Reported in a
secondary source, study details and
test conditions were not provided.
These values are for the dissociated
component, melamine. Reported in a
secondary source, study details and
test conditions were not provided.
These values are for the dissociated
component, melamine. Reported in a
secondary source, study details and
-------
Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Melamine: 0% removal after 14 days
with activated sludge (Measured)
IUCLID, 2000a
Melamine: <30% removal after 14 days
with activated sludge (Measured)
IUCLID, 2000a
Melamine: <20% removal after 20 days,
14% removal after 10 days with adapted
inoculum (Measured)
IUCLID, 2000a
Study results: 100%/<10 days
Test method: Pure culture study
Melamine: Bacterium, Nocardioides sp.
Strain ATD6 rapidly degraded melamine
and accumulated cyanuric acid and
ammonium ion, via the intermediates
ammeline and ammelide. (Measured)
Takagietal., 2012
test conditions were not provided.
These values are for the dissociated
component, melamine. Reported in a
secondary source, study details and
test conditions were not provided.
These values are for the dissociated
component, melamine. Reported in a
secondary source, study details and
test conditions were not provided.
These values are for the dissociated
component, melamine. Reported in a
secondary source, study details and
test conditions were not provided.
Melamine degradation was found to
occur in species specific
biodegradation studies.
Volatilization Half-life for Model
River
>1 year for Melamine polyphosphate
(Estimated)
EPIv4.10
Based on the magnitude of the
estimated Henry's Law constant.
Volatilization Half-life for Model
Lake
>1 year for Melamine polyphosphate
(Estimated)
EPIv4.10
Based on the magnitude of the
estimated Henry's Law constant.
Soil
Aerobic Biodegradation
Study results: 0%/28 days
Test method: 302B: Inherent - Zahn-
Wellens/EMPA Test
Melamine: Not readily biodegradable:
0% biodegradation detected after 2 weeks
with 100 ppm in 30 ppm activated sludge
(OECD TG 301C) (Measured); 0%
degradation after 28 days with 100 mg
DOC/L in activated sludge (Zahn-
Wellens test, OECD 302B) (Measured)
4-305
MITI, 1998; OECD SIDS, 1999
Adequate values from guideline
studies for the dissociated
component, melamine.
-------
Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
Air
Reactivity
Anaerobic Biodegradation
Soil Biodegradation with Product
Identification
Sediment/Water Biodegradation
Atmospheric Half-life
Photolysis
Hydrolysis
DATA
Study results: 100%/4days
Test method: Pure culture study
Melamine: Bacterium, A. citntlli strain
B-12227 rapidly degraded melamine and
accumulated cyanuric acid, ammeline and
ammelide, via the intermediates
ammeline and ammelide. (Measured)
Melamine: A set of soil bacteria has been
identified whose members rapidly
metabolize melamine as their source of
nitrogen to support growth; these bacteria
contain an enzyme which hydrolytically
deaminates melamine. (Measured)
Study results: <8.9%/28 days
Test method: Other
Melamine: 0-8. 9% nitrification was
observed after 28 days incubation with
bacteria in Webster silty clay loam under
anaerobic conditions. (Measured)
Melamine: Nitrification of melamine
occurs in soil at a low rate (0.7% organic
N found as NO3-N in week 10, and 0 %
in week 28). (Measured)
Melamine polyphosphate: 21 days
(Estimated)
Melamine polyphosphate: Not a
significant fate process (Estimated)
Polyphosphoric acid: The half-life for
the hydrolysis to phosphoric acid is
several days at 25 °C (Measured)
REFERENCE
Shiomi and Ako, 2012
Cook and Hutter, 1981; Cook
andHutter, 1984
IUCLID, 2000a
ECHA, 20 1 Ib; ECHA, 20 1 la
EPIv4.10
Professional judgment; Mill,
2000
Gard, 2005
DATA QUALITY
Melamine degradation was found to
occur in species specific
biodegradation studies.
Melamine degradation was found to
occur in species specific
biodegradation studies.
This value is for the dissociated
component, melamine. Reported in a
secondary source, study details and
test conditions were not provided.
Non guideline studies for the
dissociated component, melamine.
No data located.
The substance does not contain
functional groups that would be
expected to absorb light at
environmentally significant
wavelengths.
This value is for the dissociated
component, polyphosphoric acid.
These studies indicate
polyphosphoric acid would undergo
4-306
-------
Melamine Polyphosphate CASRN 15541-60-3
PROPERTY/ENDPOINT
Environmental Half-life
Bioaccumulation
Fish BCF
Other BCF
BAF
Metabolism in Fish
DATA
Polyphosphoric acid: Hydrolysis occurs
in 2 months at 20°C (Measured)
Melamine polyphosphate: 120 days
(Estimated)
REFERENCE
IUCLID, 2000b
PBT Profiler vl.301
DATA QUALITY
hydrolysis under environmental
conditions to phosphate ions.
Reported in a secondary source,
study details and test conditions
were not provided.
This value is for the dissociated
component, polyphosphoric acid.
Reported in a secondary source,
study details and test conditions
were not provided available.
Half-life estimated for the
predominant compartment, as
determined by EPI and the PBT
Profiler methodology.
LOW: Based on the relatively high water solubility of melamine polyphosphate (20 g/L) and an estimated
BCF of 3.2. In addition, the experimental bioconcentration values for the melamine component are low,
BCF <3.8, and BAF <1.
Melamine polyphosphate: 3.2
(Estimated)
Melamine: <0.38 in carp (Cyprinus
carpio) after 6 weeks at 2.0 ppm
concentration;
<3.8 in carp (Cyprinus carpio) after 6
weeks at 0.2 ppm concentration (OECD
302B) (Measured)
Melamine polyphosphate: 0.9
(Estimated)
Melamine: 0.9 (Estimated)
Melamine: Uptake, bioaccumulation and
elimination study with 14C-melamine in
fathead minnow and rainbow trout: BCFs
<1 (Measured)
EPIv4.10
MITI, 1998
EPIv4.10
EPIv4.10
ECHA, 20 1 Ib; ECHA, 20 1 la
Adequate values from guideline
studies for the dissociated
component, melamine.
No data located.
Non guideline studies that support
the low potential for
bioaccumulation of this substance.
ENVIRONMENTAL MONITORING AND BIOMONITORING
4-307
-------
Melamine Polyphosphate CASRN
PROPERTY/ENDPOINT
Environmental Monitoring
Ecological Biomonitoring
Human Biomonitoring
DATA
No data located.
15541-60-3
REFERENCE
DATA QUALITY
No data located.
This chemical was not included in the NHANES biomonitoring report (CDC, 201 1).
4-308
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4-315
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Silicon Dioxide (amorphous)
VL = Very Low hazard L = Low hazard = Moderate hazard H = High hazard VH = Very High hazard — Endpoints in colored text (VL, L, M, H, and VH) were
assigned based on empirical data. Endpoints in black italics (VL, L, M, H, and VH) were assigned using values from predictive models and/or professional judgment.
This table contains hazard information for each chemical; evaluation of risk considers both hazard and exposure. Variations in end-of-life processes or degradation and combustion
by-products are discussed in the report but not addressed directly in the hazard profiles. The caveats listed below must be taken into account when interpreting the information in the
table.
§ Based on analogy to experimental data for a structurally similar compound. R Recalcitrant: Substance is comprised of metallic species (or metalloids) that will not degrade, but may
change oxidation state or undergo complexation processes under environmental conditions. °Concern linked to direct lung effects associated with the inhalation of poorly soluble
particles less than 10 microns in diameter.A Depending on the grade or purity of amorphous silicon dioxide commercial products, the crystalline form of silicon dioxide may be
present. The hazard designations for crystalline silicon dioxide differ from those of amorphous silicon dioxide, as follows: VERY HIGH (experimental) for carcinogenicity; HIGH
(experimental) genotoxicity; MODERATE (experimental) for acute toxicity and eye irritation.
Chemical
CASRN
Human Health Effects
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4-316
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Silicon Dioxide (amorphous)
O-
'Si
-
* indicates repeating units with indeterminate structure
CASRN: 7631-86-9
MW: 60.09 (for SiO2)
MF: (Si02)n
Physical Forms:
Neat: Solid
Use: Flame retardant
SMILES: Not applicable
Synonyms: Silica (CASRN 7631-86-9)
Silicon dioxide, amorphous: Silica, amorphous fumed, crystalline-free (CASRN 112945-52-5); Pyrogenic (fumed) amorphous silica (CASRN 112945-52-5); Silica,
vitreous (CASRN 60676-86-0); Amorphous silica gel, crystalline-free (CASRN 112926-00-8); Silica gel, precipitated, crystalline-free (CASRN 112926-00-8); Silica,
amorphous, diatomaceous earth (CASRN 61790-53-2); Silica, amorphous, flux-calcined diatomaceous earth (CASRN 68855-54-9)
Silicon dioxide, crystalline: Silica, crystalline, cristobalite (CASRN 14464-46-1), Silica, crystalline, tripoli (CASRN 1317-95-9); Silica, crystalline, tridymite
(CASRN 15468-32-3); Quartz (CASRN 14808-60-7); Sand
Trade names:
Silicon dioxide, amorphous: Aerosil, Art Sorb, Baykisol, Bindzil, Biogenic silica, Britesorb, Cab-O-Sil, Celatom, Celite, Clarcel, Colloidasilica, Decalite, Diamantgel,
Diatomaceous earth (flux-calcined), Diatomaceous earth (uncalcined), Diatomite, Fina/Optima, FK, Fused silica, Gasil, HDK, Hi-Sil, Hispacil, KC-Trockenperlen,
Ketjensil, Kieselguhr, Lucilite, Ludox, Nalcoag, Neosyl, Nipsil, Nyacol, Opal, Precipitated silica, Quartz glass, Reolosil, Seahostar, Sident, Silcron, Silica fibres
(biogenic), Silica-Perlen, Silica-Pulver, Sipernat, Skamol, Snowtex, Spherosil, Suprasil, Sylobloc, Syloid, Sylopute, Syton, TAFQ, Tixosil, Tripolite, Trisyl, Ultrasil
Silicon dioxide, crystalline: Agate, Chalcedony, Chert, Clathrasil, Coesite, alpha, beta Cristobalite, CSQZ, DQ 12, Flint, Jasper, Keatite, Min-U-Sil, Moganite,
Novaculite, Porosil, alpha-Quartz, alpha, beta Quartz, Quartzite, Sandstone, Sil-Co-Sil, Silica sand, Silica W, Snowit, Stishovite, Sykron F300, Sykron F600, alpha,
betal, beta2 Tridymite, Zeosil
Chemical Considerations: Silicon dioxide (also known as silica) is an inorganic compound that exists in several physical forms. This report assesses silicon dioxide
for flame retardant applications, in which amorphous silicon dioxide is more commonly used. Commercial products may contain crystalline silicon dioxide, depending
on the purity and grade.
Silicon dioxide, amorphous consists of randomly arranged rings of silicon dioxide that form a complex structure of roughly spherical particles. Silicon dioxide,
crystalline; however is a general term that refers to the many distinct crystal structures or polymorphs of silicon dioxide. Crystalline silicon dioxide includes naturally
occurring quartz (CASRN 14808-60-7), cristobalite (CASRN 14464-46-1), and tridymite (CASRN 15468-32-3).
The structural form of silicon dioxide is evaluated in this assessment as it influences the hazards posed to human health. It may be difficult for supply chains to know
the difference between the structural forms. Therefore, the hazard designations in this report are based on the amorphous form and a summary of the hazards
associated with the crystalline form is provided in the hazard summary table as a footnote () for reference, in case the crystalline form is present in the commercial
formulation. Concerns based on the nanoscale material were not included in this assessment; however, the potential health concerns from the inhalation of finely
divided particulates that are generally less than 10 microns in diameter were considered for human health endpoints.
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Although not all literature entries identified which form of silicon dioxide was being discussed, this information was provided whenever available. In the absence of
experimental data, structural considerations associated with this mineral were used to complete this hazard profile (IARC, 1997; HSDB, 2009; Waddell, 2013).
Polymeric: No
Oligomeric: Not applicable
Metabolites, Degradates and Transformation Products: None identified.
Analog: Confidential analogs; a general silicon dioxide CASRN is used to
represent all forms of silicon dioxide (CASRN 7631-86-9). Other CASRN for
specific silicon dioxide forms are listed in the synonyms section and noted in the
data quality column for relevant entries.
Endpoint(s) using analog values: Neurotoxicity
Analog Structure: Not applicable
Structural Alerts: Respirable, poorly soluble particulates - Human health, limited to effects on the lung as a result of inhaling the
particles (EPA, 2010).
Risk Phrases: Not classified by Annex VI Regulation (EC) No 1272/2008 (ESIS, 2012).
Hazard and Risk Assessments: An Organisation for Economic Co-operation and Development (OECD) Screening Information Dataset Initial Assessment Profile
(SIAP) for silicon dioxide was completed in 2004. Silicon dioxide is included in the International Agency for Research on Cancer (IARC) monographs on the
evaluation of carcinogenic risks to humans - summaries and evaluations. (IARC, 1997; OECD SIDS, 2004a).
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
PHYSICAL/CHEMICAL PROPERTIES
Melting Point (°C)
Boiling Point (°C)
Vapor Pressure (mm Hg)
Water Solubility (mg/L)
1,710 (Measured)
Crystalline silicon dioxide: 1,400-2,000
(Measured)
2,230 (Measured)
Amorphous and crystalline silicon
dioxide:
-------
Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
Log Kow
Flammability (Flash Point)
Explosivity
Pyrolysis
pH
pKa
DATA
Practically insoluble (Estimated)
Amorphous silicon dioxide: Used as a
fire-extinguishing agent, not combustible,
stable (Measured)
Amorphous and crystalline silicon
dioxide: Silicon dioxide is a fully
oxidized inorganic material and is not
expected to be explosive. (Estimated)
Amorphous and crystalline silicon
dioxide: Not applicable (Estimated)
3.5-9 for 5% aqueous suspension of wet
process silica. (Measured)
3.6-4.5 for 4% aqueous suspension of
fumed silica. (Measured)
REFERENCE
Merck, 1996
Daubert and Banner, 1989 (as
cited in ECHA, 2013)
Professional judgment
Professional judgment
EC, 2000a
EC, 2000a
DATA QUALITY
Adequate, non-quantitative value
provided. Test substance form not
specified.
No data located.
Reported in a secondary source for
Silica, amorphous, fumed,
crystalline-free (CASRN 112945-
52-5) and Silica gel, precipitated,
crystalline-free (CASRN 112926-
00-8).
No experimental data located; based
on its chemical structure and use as
a flame retardant.
Inorganic compounds do not
undergo pyrolysis.
Adequate values reported in a
secondary source. The values of 20
different types of wet process silica,
identified only by trade names, fall
within this range.
Adequate value reported in a
secondary source for fumed silica.
No data located.
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
Particle Size
DATA
Amorphous silicon dioxide:
D10 = <103 (im
D50 = <211 nm
D99 = <610(im
According to ISO 13320-1 (Part 1):
Particle size analysis - Laser diffraction
methods; OECD guideline 110: Particle
size distribution / fibre length and
diameter distributions and EN 481 (1993):
Workplaces atmospheres; size fraction
definitions for measurement of airborne
particles. (Measured)
Amorphous silicon dioxide:
D10 = <230(im
D50 = <615 (im
D99 = 99.8 %
SiO2 with limited study details.
Adequate guideline study reported
for Silica, amorphous, fumed,
crystalline-free (CASRN 112945-
52-5).
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
size distribution / fibre length and
diameter distributions and EN 481 (1993):
Workplaces atmospheres; size fraction
definitions for measurement of airborne
particles. (Measured)
Amorphous silicon dioxide:
ECHA, 2013
D90.6 = 2,000 (im
According to ISO 13320-1 (Part 1):
Particle size analysis - Laser diffraction
methods; OECD guideline 110: Particle
size distribution / fibre length and
diameter distributions and EN 481 (1993):
Workplaces atmospheres; size fraction
definitions for measurement of airborne
particles. (Measured)
Amorphous silicon dioxide:
ECHA, 2013
D50 = <480
According to ISO 13320-1 (Part 1):
Particle size analysis - Laser diffraction
methods; OECD guideline 110: Particle
size distribution / fibre length and
diameter distributions and EN 481 (1993):
Workplaces atmospheres; size fraction
definitions for measurement of airborne
particles. (Measured)
Amorphous silicon dioxide:
D 14.04 = <0.64(im
100 = <10.23(im
Using Anderson 7-stage cascade impactor
(Measured)
ECHA, 2013
Amorphous silicon dioxide:
Typical size ranges of:
ECHA, 2013
4-322
Adequate guideline study reported
for the commercial product HDK
T30: >99.8 % SiO2, Silica,
amorphous, fumed, crystalline-free
(CASRN 112945-52-5).
Reported for Syloid 74, CAS-Name:
Silica gel, crystalline-free; (CASRN
112926-00-8), purity ca. 100 %.
Non guideline study reported for
HDK T30: >99.8 % SiO2; Silica,
amorphous, fumed, crystalline-free;
(CASRN 112945-52-5).
Reported for Silica, amorphous,
fumed, crystalline-free (CASRN
-------
Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
0.1 - 1 (im for aggregates;
1 - 250 (im for Agglomerates
(Measured)
Amorphous silicon dioxide:
Typical size ranges of:
0.1-1 (im for aggregates;
1 - 250 (im for Agglomerates
1-20 (im for silica gel aggregates
(Measured)
REFERENCE
ECHA, 2013
DATA QUALITY
112945-52-5).
Reported for Silica gel and
amorphous silica, precipitated,
crystalline-free (CASRN 112926-
00-8) with limited study details.
HUMAN HEALTH EFFECTS
Toxicokinetics
Dermal Absorption in vitro
Absorption,
Distribution,
Metabolism &
Excretion
Oral, Dermal or Inhaled
Amorphous silicon dioxide (CASRNs 7631-86-9, 112945-52-5, 112926-00-8) is rapidly eliminated from the
lung tissue. Disposition in the mediastinal lymph nodes is substantial during and after prolonged
inhalation exposures in experimental animals; however the involvement of lymphatic elimination is not as
relevant following short exposure periods. Intestinal absorption of amorphous silicon dioxide is limited in
animals and humans, and there is evidence of ready renal elimination of the bioavailable fractions of silica.
In contrast, crystalline silicon dioxide forms tend to accumulate and persist in the lung and lymph nodes.
Amorphous silicon dioxide: After
prolonged exposure of rats to high
concentrations of amorphous silica (40-50
mg/m3), overall elimination was high and
was not found to accumulate in the lung:
only 5-6% of respirable material was
found after 120 exposure days. On the
other hand, following prolonged
exposure, there was substantial transfer to
mediastinal lymph nodes with about 31%
of total deposit = 1.5- 2% of the respirable
material. The involvement of lymphatic
elimination after short exposures is not as
relevant, particularly when there is a
lower body burden of amorphous silica.
Amorphous and crystalline silicon
dioxide: Crystalline forms of silicon
dioxide have a tendency to accumulate
OECD SIDS, 2004b
OECD SIDS, 2004a; OECD
SIDS, 2004b
Sufficient study details reported in a
secondary source. Aerosil 150,
pyrogenic silica (CASRN 112945-
52-5).
Sufficient study details reported in a
secondary source. Data are for
synthetic amorphous silica and
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
and persist in the lung and lymph nodes.
Intestinal absorption of silicon dioxide is
insignificant in animals and humans.
There is evidence of renal elimination of
the bioavailable fractions
Amorphous silicon dioxide: Female
Sprague-Dawley rats exposed via
inhalation to HDK V15 dust at a
concentration of 50 - 55 mg/m3 (nominal,
respirable about 30 mg/m3 with
aerodynamic diameter of <7 (im) for 12
months. No substantial increase in the
SiO2 deposition in the lung and the
mediastinal lymph nodes were observed
between exposure of 18 weeks and of 12
months. About 90 % of the SiO2 was
cleared from the lungs and 50 - 60% from
the mediastinal lymph nodes within 5
months. This corresponds to an
approximate half-life of 7 weeks, based
on first-order elimination kinetics.
ECHA, 2013
Amorphous silicon dioxide: Fischer 344
rats exposed via inhalation to Aerosil 200
dust at a concentration of 50.4 mg/m3 6
hours/day, 5 days/week for 13 weeks.
Lung burdens during treatment were as
follows: 755.9 jig at 6.5 weeks and 88.27
(ig at 13 weeks of exposure. Lung
burdens following treatment were 156.0
(ig at 12 weeks and 92.6 (ig at 32 weeks
post- exposure (during the recovery
phase).
ECHA, 2013
Amorphous silicon dioxide: Wistar rats
exposed via inhalation to Aerosil 200 at
concentrations of 0, 1.3, 5.9 or 31 mg/m3
for 90 days. Half-life was rapid from the
ECHA, 2013
crystalline silica.
Sufficient study details reported in a
secondary source. HDK V15: >99.8
% SiO2, 150 m2/g (BET), CAS-
Name: Silica, amorphous fumed,
crystalline-free (CASRN 112945-
52-5).
Sufficient study details reported in a
secondary source. Aerosil 200:
CAS-Name: Silica, amorphous,
fumed, crystalline-free (CASRN
112945-52-5).
Sufficient study details reported in a
secondary source. Aerosil 200:
Silica, amorphous, fumed,
crystalline-free (CASRN 112945-
4-324
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
lungs; No bioaccumulation potential
based on study results.
Amorphous silicon dioxide: Rats
receiving 20 daily oral doses of 100 mg
HDK V15 per animal (about 500 mg/kg
bw) each; tissue values (SiO2) apparently
were very slightly increased in liver and
kidney: in liver 4.2 (ig (control value 1.8
(ig), in the spleen 5.5 (ig (7.2 (ig) and in
the kidneys 14.2 (ig (7.8 (ig).
ECHA, 2013
Amorphous silicon dioxide: Human
subjects (10 males and 2 females per test
article) were given Aerosil or FK 700 as
0.5% suspensions in apple juice. Urinary
excretion for both test substances was
<0.5 % of the dose within 4 days. Overall.
increases in excretion of SiO2 after oral
ingestion were not unequivocally
detectable.
ECHA, 2013
Amorphous silicon dioxide: Silicon
dioxide is slowly absorbed from dusts
deposited in lungs, or from material taken
orally.
HSDB, 2009
52-5).
Sufficient study details reported in a
secondary source. HDK V15: >99.8
% SiO2, 150 m2/g (BET), CAS-
Name: Silica, amorphous, fumed,
crystalline-free (CASRN 112945-
52-5).
Sufficient study details reported in a
secondary source. Aerosil, CAS-
Name: Silica, amorphous, fumed,
crystalline-free (CASRN 112945-
52-5); or FK 700, Silica gel,
precipitated, crystalline-free
(CASRN 112926-00-8).
Limited data reported in a secondary
source for amorphous silica.
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
Other
Acute Mammalian Toxicity
Acute Lethality
Oral
Dermal
DATA
Amorphous silicon dioxide: Amorphous
silica (HDK VI 5), 10 mg subcutaneously
injected in 0.3 mL water in female
Sprague-Dawley rats, was rapidly
removed from the site of injection: mean
recovery 24 h post-treatment 6.90 mg,
after one month 0.65 mg (approx. 10 %
left) and after two months 0.30 mg (less
than 5 % left) Similar results were
obtained in rats after subcutaneous
application of 30, 40, and 50 mg
AEROSIL 150 as suspension in water or
in 0.5% Tween or as dry powder
(operative, subcutaneous): after 6 weeks
95 - 97 % of the substance was
eliminated.
REFERENCE
OECD SIDS, 2004b
DATA QUALITY
Sufficient study details reported in a
secondary source. HDK V15: >99.8
% SiO2, 150 m2/g (BET), CAS-
Name: Silica, amorphous, fumed
(CASRN 112945-52-5).
LOW: Amorphous silicon dioxide is not acutely toxic when administered via oral, dermal, or inhalation
routes. If the crystalline form of silicon dioxide is present, the hazard designation is Moderate based on an
oral LD50 of 500 mg/kg and lung effects following short-term inhalation exposure.
Amorphous silicon dioxide: Mouse oral
LD50>3, 160 mg/kg
Amorphous silicon dioxide: Rat oral
LD50 >3,300 - >20,000 mg/kg
Amorphous silicon dioxide: Rat oral
LD0 >3,300 - >40,000 mg/kg
Crystalline silicon dioxide: Rat oral
LD50 = 500 mg/kg
Amorphous silicon dioxide: Rabbit
ECHA, 2013
EC, 2000a;ECHA, 2013
EC, 2000a
EC, 2000b
EC,2000a;Waddell,2013
Silica, amorphous, fumed,
crystalline-free (CASRN 112945-
52-5).
Sufficient study details reported in a
secondary source. Silica,
precipitated, crystalline-free
(CASRN 112926-00-8).
Sufficient study details reported in a
secondary source. Amorphous
(CASRN 7631-86-9) or Silica,
precipitated, crystalline-free
(CASRN 112926-00-8).
Study details reported in a
secondary source; particle size of
quartz was 100-200 (im.
Sufficient study details reported in a
4-326
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Inhalation
dermal LD50 >2,000 - >5,000 mg/kg
secondary source. Silica,
precipitated, crystalline-free
(CASRN 112926-00-8).
Amorphous silicon dioxide: Rat 4-hour
inhalation LC50 >58.8 mg/L (nominal,
nose only, dust);
4-hour LC0 >58.8 mg/L (nominal)
ECHA, 2013
Sufficient study details reported in a
secondary source. Silica,
amorphous, fumed, crystalline-free
(CASRN 112945-52-5), purity ca.
100 %.
Amorphous silicon dioxide: Rat 4-hour
inhalation LC0 >0.139 - >0.69 mg/L
(nose only, dust);
Rat 1-hour inhalation LC0 >0.139;
Rat 7-hour inhalation LC0 >0.139 - >3.1
mg/L
EC, 2000a; ECHA, 2013
Sufficient study details reported in a
secondary source. Silica,
precipitated, crystalline-free
(CASRN 112926-00-8) or Silica,
amorphous, fumed, crystalline-free
(CASRN 112945-52-5).
Amorphous silicon dioxide: Rat 1-hour
inhalation LC50 >2.2 mg/L
ECHA, 2013
Insufficient study; significant
methodological deficiencies. Silica
gel, crystalline-free (CASRN
112926-00-8).
Crystalline silicon dioxide: 3-day
inhalation study in rats exposed to 0, 10,
or 100 mg/m3 of cristobalite (6
hours/day). Increased granulocytes and
other markers of cytotoxicity from the
lung lavage fluid were reported in all
treated animals.
LOAEC: 10 mg/m3 (0.01 mg/L)
OECDSIDS, 2011
Limited study details reported in a
secondary source; test substance
identified as cristobalite; an LC50
was not calculated for this study, but
supports a Moderate hazard
designation for the inhalation route.
Carcinogenicity
LOW: Based on the weight of evidence, amorphous silicon dioxide has a Low potential for carcinogenicity.
Amorphous silicon dioxide was not carcinogenic in rats or mice following dietary administration for 103 or
93 weeks, respectively. Amorphous silicon dioxide is not classifiable as to its carcinogenicity to humans.
Crystalline silicon dioxide was carcinogenic in several inhalation studies in rats and was shown to have an
excess cancer risk following workplace exposure in several epidemiology studies. In addition, estimation
software predicts a high-moderate carcinogenic risk for crystalline silicon dioxide. If the crystalline form
of silicon dioxide is present, a VERY HIGH hazard designation would be assigned based on the weight of
evidence that indicates sufficient evidence of carcinogenicity in humans.
4-327
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
OncoLogic Results
Amorphous silicon dioxide:
OncoLogic, 2008
This compound is not amenable to
available estimation methods.
Crystalline silicon dioxide: High-
moderate; there is clear evidence that
crystalline silica is a human and animal
carcinogen via the inhalation route.
(Estimated)
OncoLogic, 2008
Estimated based on silica,
crystalline (CASRN 14808-60-7).
Carcinogenicity (Rat and
Mouse)
Amorphous silicon dioxide: In a 103
week study, Fischer 344 rats
(40/sex/dose) were fed 0, 0.125, 2.5 and
5% Syloid 244 in the diet daily. The mean
daily intake was 143.46, 279.55 and
581.18 g/rat in males and 107.25,205.02
and 435.33 g/rat in females, respectively.
The tumor response was not statistically
different from controls.
EC, 2000a;ECHA, 2013
Sufficient study details reported in a
secondary source. Syloid 244: Silica
gel, crystalline-free (CASRN
112926-00-8).
Amorphous silicon dioxide: In a 93-
week study, B6C3F1 mice (40/sex/group)
were fed 0, 1.25, 2.5 and 5 % Syloid 244
in the diet daily. The mean cumulative
intake after 93 weeks was 38.45, 79.78
and 160 g/mouse in males and 37.02,
72.46 and 157.59 g/mouse in females,
respectively. No significant difference in
survival rats or behavior was observed.
No dose-related alteration in hematologic
parameters or organ weights. Malignant
lymphoma/leukemia, which occurred in
7/20 females in the 2.5% dose group, was
not statistically different than controls.
Non-neoplastic lesions were considered to
be of no toxicological significance.
EC, 2000a;ECHA, 2013
Sufficient study details reported in a
secondary source. Syloid 244: Silica
gel, crystalline-free (CASRN
112926-00-8).
Amorphous silicon dioxide: Intrapleural
implantation of synthetic amorphous
4-328
IARC, 1997
Reported in a secondary source; test
substance specified as amorphous
-------
Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
silica was negative for tumorigenesis.
silica.
Amorphous silicon dioxide: Oral
administration of food-grade, micronized,
amorphous silica to rats and mice was
negative for tumorigenesis.
IARC, 1997
Reported in a secondary source; test
substance specified as amorphous
silica.
Amorphous silicon dioxide: Slightly
increased incidence of intra-abdominal
lymphosarcomas was reported after
intraperitoneal injection of diatomaceous
earth to mice. Subcutaneous and oral
administration in mice produced no
increase in tumors.
IARC, 1997
Reported in a secondary source; test
substance specified as amorphous
silica.
Crystalline silicon dioxide: Several
epidemiological investigations have
shown an excess cancer risk following
workplace inhalational exposure to dust
containing respirable crystalline silica.
Lung cancer incidence tended to increase
with cumulative exposure; increased
duration of exposure; peak intensity of
exposure; presence of radiographically
defined silicosis; and length of follow-up
time from date of silicosis diagnosis.
IARC, 1997; OECD SIDS, 2011
Reported in a secondary source; test
substance specified as crystalline
silica.
Crystalline silicon dioxide: Study with
Balb/x mice (8 hours/day, 5 days/week in
three groups of 6 to 16 mice at a
concentration of 475 mg/m3 for 150 days,
1,800 mg/m3 for 300 days or 1,950 mg/m3
for 570 days. There was no statistically
significant difference in the number of
pulmonary adenomas reported in the
control or treated groups.
EC, 2000b
Limited study details reported in a
secondary source.
Crystalline silicon dioxide: 2-year study
with F344 rats (50/sex), exposed via
whole body inhalation for 6 hours/day, 5
EC, 2000b; OECD SIDS, 2011
Limited study details reported in a
secondary source.
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PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
days/week at a concentration of 1 mg/m3.
Inhalation exposure caused primary lung
tumors (majority were adenocarcinomas)
in 18 animals (12 in females, 5 in males).
Mean mass of particles in the lungs at the
end of the exposure period was 0.91
mg/lung.
Crystalline silicon dioxide: Four
experiments in rats by inhalation of quartz
and four experiments in rats by
intratracheal instillation of quartz
produced increased incidences of
adenocarcinomas and squamous-cell
carcinomas of the lungs. Animals that
developed tumors also showed fibrosis.
For the intratracheal instillation studies,
doses ranged from 4 to 57 mg/kg-bw (7,
12 or 20 mg/animal of Min-U-Sil (5)
quartz or 20 mg/animal of novaculite
quartz). Exposure ranged from single
instillation with observation for up to two
years, to weekly instillation for 10 weeks.
There was an increased incidence of
silicotic granulomas after 3 weeks and
lung tumors after 11 months following
single intratracheal administration of a
95% pure quartz particles (<5 (im).
IARC, 1997; OECD SIDS, 2011
Reported in a secondary source; test
substance specified as crystalline
silica.
Crystalline silicon dioxide: Thoracic and
abdominal malignant lymphomas,
primarily of the histiocytic type (MLHT)
were found following intrapleural or
intraperitoneal injections of several types
of quartz to rats.
IARC, 1997
Reported in a secondary source; test
substance specified as crystalline
silica.
Combined Chronic
Toxicity/Carcinogenicity
No data located.
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Other
Amorphous silicon dioxide:
Amorphous silica is not classifiable as to
its carcinogenicity to humans (Group 3:
This category is used most commonly for
agents for which the evidence of
carcinogenicity is inadequate in humans
and inadequate or limited in experimental
animals.
Exceptionally, agents for which the
evidence of carcinogenicity is inadequate
in humans but sufficient in experimental
animals may be placed in this category
when there is strong evidence that the
mechanism of carcinogenicity in
experimental animals does not operate in
humans. Agents that do not fall into any
other group are also placed in this
category.
An evaluation in Group 3 is not a
determination of non-carcinogenicity or
overall safety. It often means that further
research is needed, especially when
exposures are widespread or the cancer
data are consistent with differing
interpretations).
IARC, 1997
Summarized from a secondary
source.
Crystalline silicon dioxide: Crystalline
silica inhaled in the form of quartz or
cristobalite from occupational sources is
carcinogenic to humans (Group 1: This
category is used when there is sufficient
evidence of carcinogenicity in humans.
Exceptionally, an agent may be placed in
this category when evidence of
carcinogenicity in humans is less than
IARC, 1997
Summarized from a secondary
source.
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
sufficient but there is sufficient evidence
of carcinogenicity in experimental
animals and strong evidence in exposed
humans that the agent acts through a
relevant mechanism of carcinogenicity).
Genotoxicity
LOW: Based on the weight of evidence, amorphous silicon dioxide was negative both in vitro and in vivo
gene mutation and chromosome aberration assays.
If crystalline silicon dioxide is present, the hazard designation is assigned a HIGH based on weight of
evidence from multiple studies. Crystalline silicon dioxide induced gene mutations in vivo and
chromosomal aberrations in several in vitro and in vivo studies in experimental animals. In addition,
crystalline silicon dioxide induced cell transformation in mice and hamsters in vitro.
Gene Mutation in vitro
Amorphous silicon dioxide: Negative in
Escherichia coll WP2 with and without
metabolic activation.
Test concentrations: 0.033 - lOmg/plate,
suspended in DMSO.
Amorphous silicon dioxide: Negative in
HGPRT assay in Chinese hamster ovary
(CHO) cells with and without metabolic
activation.
Test concentrations: 10, 50, 100, 150, and
250 (ig/mL (without S9) and 100, 200,
300, 400, and 500 (ig/mL (with S9).
Amorphous silicon dioxide: Negative in
Saccharomyces cerevisiae strains TA98,
TA100, TA1535, TA1537 and TA1538
with and without metabolic activation.
Test concentrations: 667, 1,000, 3,333,
6,667, and 10,000 (ig/plate
Amorphous silicon dioxide: Negative in
Salmonella typhimurium and Escherichia
coli mutagenicity assay.
Crystalline silicon dioxide: Direct
treatment of rat lung epithelial cells with
IARC, 1997; EC, 2000a; ECHA,
2013
EC, 2000a; ECHA, 2013
EC, 2000a; ECHA, 2013
IARC, 1987
IARC, 1987
Sufficient study details reported in a
secondary source. Silcron G-190
(SCM Glidden): Silica gel,
crystalline-free (CASRN 112926-
00-8).
Sufficient study details reported in a
secondary source. Cab-O-Sil EH-5:
Silica, amorphous, fumed,
crystalline-free (CASRN 112945-
52-5).
Sufficient study details reported in a
secondary source. Silcron G-190
(SCM Glidden): Silica gel,
crystalline-free (CASRN 112926-
00-8).
Study details reported in a
secondary source; test substance
amorphous silica.
Study details reported in a
secondary source; test substance
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Gene Mutation in vivo
quartz in vitro did not cause HPRT
mutation.
Crystalline silicon dioxide: Negative;
Salmonella typhimurium reverse mutation
assay (with or without metabolic
activation)
EC, 2000b
Amorphous silicon dioxide: Negative;
alveolar type-II cells isolated from rats
exposed via whole body inhalation to 50-
mg/m3 Aerosil 200 showed no increased
mutation frequency. Exposure was for 6
hours/day, 5 days/week for 13 weeks.
Crystalline silica was examined
simultaneously as a positive control.
ECHA, 2013
Amorphous silicon dioxide: Negative,
gene mutations in host mediated assay;
male ICR mice orally gavaged with 1.4,
14, 140, 500 and 5,000 mg/kg suspended
in 0.85 % saline and then injected with
Salmonella typhimurium or
Saccharomyces cerevisiae.
ECHA, 2013
Crystalline silicon dioxide: Epithelial
cells from the lungs of rats intratracheally
exposed to quartz showed HPRT gene
mutations.
IARC, 1997
crystalline silica.
Limited study details reported in a
secondary source.
Sufficient study details reported in a
secondary source. Aerosil 200:
Silica, amorphous, fumed,
crystalline-free (CASRN 112945-
52-5).
Sufficient study details reported in a
secondary source. Syloid 244: Silica
gel, crystalline-free (CASRN
112926-00-8).
Study details reported in a
secondary source; test substance
crystalline silica.
Chromosomal Aberrations in
vitro
Amorphous silicon dioxide: Negative
for chromosomal aberrations in human
embryonic lung cells (Wi-38) without
metabolic activation. Test concentrations:
0.1, 1.0, and 10 (ig/mL.
EC, 2000a; ECHA, 2013
Sufficient study details reported in a
secondary source. Syloid 244: Silica
gel, crystalline-free (CASRN
112926-00-8).
Amorphous silicon dioxide: Negative
for chromosomal aberrations in CHO
cells with and without metabolic
activation;
Test concentrations: 38, 75, 150, 300
EC, 2000a; ECHA, 2013
Sufficient study details reported in a
secondary source. Silica,
amorphous, fumed, crystalline-free
(CASRN 112945-52-5).
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
(ig/mL (without S9) and 250, 500, 750,
1,000 (ig/mL (with S9).
Crystalline silicon dioxide: Tridymite
induced sister chromatid exchange in co-
cultures of human lymphocytes and
monocytes.
IARC, 1997
Crystalline silicon dioxide: Induces
micronuclei in Syrian hamster embryo
cells, Chinese hamster lung V79 cells,
and human embryonic lung Hel 299 cells
in vitro, but negative for inducing
chromosomal aberrations.
IARC, 1997
Crystalline silicon dioxide: Induced
micronuclei in Syrian hamster embryo
cells
EC, 2000b
Chromosomal Aberrations in
vivo
Amorphous silicon dioxide: Negative,
chromosomal aberration dominant lethal
assay in rats orally gavaged with 1.4,
14.0, 140, 500 and 5,000 mg/kg
suspended in 0.85 % saline.
ECHA, 2013
Crystalline silicon dioxide: Induced
chromosomal aberrations in human
peripheral blood lymphocytes following
in vivo exposure to dust containing
crystalline silica.
IARC, 1997
Crystalline silicon dioxide: Positive,
induced sister chromatid exchange in
human peripheral blood lymphocytes
following in vivo exposure to dust
containing crystalline silica.
IARC, 1997
Crystalline silicon dioxide: Quartz did
not induce micronuclei in mice in vivo.
IARC, 1997
Study details reported in a
secondary source; test substance
crystalline silica.
Study details reported in a
secondary source; test substance
crystalline silica.
Limited study details reported in a
secondary source; route and
duration of exposure were not
specified.
Sufficient study details reported in a
secondary source. Syloid 244: Silica
gel, crystalline-free (CASRN
112926-00-8).
Study details reported in a
secondary source; test substance
crystalline silica.
Study details reported in a
secondary source; test substance
crystalline silica.
Study details reported in a
secondary source; test substance
crystalline silica.
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DNA Damage and Repair
Other
DATA
Crystalline silicon dioxide: Negative;
did not cause sister chromatid exchange
or aneuploidy in Syrian hamsters exposed
to 2 (ig in vivo.
Crystalline silicon dioxide: Negative;
did not cause sister chromatid exchanges
in Chinese hamsters
Crystalline silicon dioxide: DQ 12
quartz did not induce micronuclei in
polychromatic erythrocytes of bone
marrow of mice at 500 mg/kg bw.
Negative for chromosomal aberrations in
two assays following single and subacute
oral gavage administration to rats.
Crystalline silicon dioxide: Five quartz
samples induced transformation in
BALB/C-3T3 cells in vitro.
Crystalline silicon dioxide: Two quartz
samples induced morphological
transformation in Syrian hamster cells in
vitro.
Negative, unscheduled DNA synthesis
assay in primary rat hepatocytes.
Negative in two dominant lethal assays in
rats following oral gavage administration.
REFERENCE
EC, 2000b
EC, 2000b
EC, 2000b
IARC, 1997
IARC, 1997
IARC, 1997
EC, 2000a
EC, 2000a
DATA QUALITY
Limited study details reported in a
secondary source; route of
administration, exposure duration
was not specified.
Limited study details reported in a
secondary source; route of
administration and exposure
duration were not specified.
Limited study details reported in a
secondary source.
Secondary source, study details and
test conditions were not provided.
The original study was in an
unpublished report. Test substance
unspecified silica.
No data located.
Study details reported in a
secondary source; test substance
crystalline silica.
Study details reported in a
secondary source; test substance
crystalline silica.
Secondary source, study details and
test conditions were not provided.
The original study was in an
unpublished report. Test substance
unspecified silica.
Secondary source, study details and
test conditions were not provided.
The original study was in an
unpublished report. Test substance
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
Reproductive Effects
Reproduction/Developmental
Toxicity Screen
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
Reproduction and Fertility
Effects
Other
DATA
REFERENCE
DATA QUALITY
unspecified silica.
LOW: There was no indication of adverse reproductive effects in an unpublished one-generation oral
study in rats administered amorphous silica, fumed.
It is estimated that crystalline silicon dioxide, if present, is not likely to produce reproductive effects based
on analogy to amorphous silicon dioxide and professional judgment.
Amorphous silicon dioxide: In a one-
generation oral dietary study, Wistar rats
(5 females, 1 male/dose) were fed test
substance at doses of 0, 497 mg/kg bw
(males) or 509 mg/kg bw (females) in the
diet daily. In parents: no clinical signs of
toxicity, no mortality, no abnormalities in
body-weight gain and feed consumption,
no hematological findings. In pups: no
behavioral or developmental/structural
abnormalities.
NOAEL (parental and offspring): 497
mg/kg-day (males); 509 mg/kg bw-day
(females) (highest concentrations tested)
LOAEL: Not established
Crystalline silicon dioxide: There is low
potential for reproductive effects based on
analogy to amorphous silicon dioxide.
(Estimated by analogy)
EC, 2000a;ECHA, 2013
Professional judgment
No data located.
No data located.
Significant methodological
deficiencies, acceptable as
screening. Aerosil, not further
specified, hydrophilic: CAS-Name:
Silica, amorphous, fumed,
crystalline free (CASRN 112945-
52-5).
Estimated based on analogy to
amorphous silicon dioxide and
professional judgment; no
experimental data located.
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Developmental Effects
LOW: Amorphous silicon dioxide did not produce adverse developmental effects in rats, mice, rabbits or
hamsters following oral administration at doses up to 1,600 mg/kg bw-day during gestation. It is estimated
that crystalline silicon dioxide, if present, is not likely to produce developmental effects based on analogy
to amorphous silicon dioxide and professional judgment.
There were no data located for the developmental neurotoxicity endpoint.
Reproduction/
Developmental Toxicity
Screen
Combined Repeated Dose
with Reproduction/
Developmental Toxicity
Screen
Prenatal Development
Amorphous silicon dioxide: Pregnant
CD-I mice (21-26 females/group) were
administered Syloid 244 via oral gavage
at doses of 0, 13.4, 62.3, 289 and 1,340
mg/kg bw-day from gestation days 6-15.
The number of abnormalities seen in
either soft or skeletal tissues of the test
groups did not differ from the number
occurring spontaneously in controls.
NOAEL (maternal and fetal): 1,340
mg/kg-day (highest dose tested)
LOAEL: Not established
Amorphous silicon dioxide: Pregnant
Wistar rats (20/25 females/group) were
administered Syloid 244 via oral gavage
at doses of 0, 13.5, 62.7, 292 and 1,350
mg/kg bw-day from gestation days 6-15.
No observable effects on maternal or fetal
survival or development. The number of
abnormalities seen in either soft or
skeletal tissues of the test groups did not
No data located.
No data located.
EC, 2000a:ECHA, 2013
EC, 2000a;ECHA, 2013
Sufficient study details reported in a
secondary source. Syloid 244: Silica
gel, crystalline-free (CASRN
112926-00-8).
Sufficient study details reported in a
secondary source. Syloid 244: Silica
gel, crystalline-free (CASRN
112926-00-8).
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PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Postnatal Development
Prenatal and Postnatal
Development
differ from the number occurring
spontaneously controls.
NOAEL (maternal and fetal): 1,350
mg/kg-day (highest dose tested)
LOAEL: Not established
Amorphous silicon dioxide: Pregnant
Dutch rabbits (10-14/dose) were
administered Syloid 244 via oral gavage
at doses of 0, 16.0, 74.3, 345 and 1,600
mg/kg bw-day from gestation days 6-18.
No adverse effect on maternal or fetal
survival. The number of abnormalities
seen in either soft or skeletal tissues of the
test groups did not differ from the number
occurring spontaneously in controls.
NOAEL (maternal and fetal): 1,600
mg/kg bw-day (highest dose tested)
LOAEL: Not established
EC, 2000a;ECHA, 2013
Sufficient study details reported in a
secondary source. Syloid 244: Silica
gel, crystalline-free (CASRN
112926-00-8).
Amorphous silicon dioxide: Pregnant
Syrian hamsters (21-22 females/group)
were administered Syloid 244 via oral
gavage at doses of 0, 16.0, 74.3, 345 and
1,600 mg/kg bw-day from gestations days
6-10. The number of abnormalities seen
in either soft or skeletal tissues of the test
groups did not differ from the number
occurring spontaneously in controls.
NOAEL (maternal and fetal): 1,600
mg/kg-day (highest dose tested)
LOAEL: Not established
EC, 2000a:ECHA, 2013
Sufficient study details reported in a
secondary source. Syloid 244: Silica
gel, crystalline-free (CASRN
112926-00-8).
No data located.
No data located.
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
Developmental Neurotoxicity
Other
Neurotoxicity
Neurotoxicity Screening
Battery (Adult)
Other
Repeated Dose Effects
DATA
No data were located for the
developmental neurotoxicity endpoint.
Crystalline silicon dioxide: There is low
potential for developmental effects based
on analogy to amorphous silicon dioxide.
(Estimated by analogy)
REFERENCE
Professional judgment
DATA QUALITY
No data located.
Estimated based on analogy to
amorphous silicon dioxide and
professional judgment; no
experimental data located.
LOW: Both amorphous and crystalline silicon are estimated to have low potential for neurotoxic effects
based on analogy to a similar compound and professional judgment.
Low potential for neurotoxic effects.
(Estimated by analogy)
Professional judgment
No data located.
Estimated for crystalline and
amorphous silica based on analogy
to a structurally similar chemical
compound and professional
judgment.
HIGH: Based on the weight of evidence, the hazard designation for both amorphous and crystalline silicon
dioxide is High. Extended workplace exposure to amorphous and crystalline silica dust induced silicosis in
humans. Effects on the lungs, such as increased weight, focal interstitial fibrosis, pulmonary inflammation
and/or granuloma, macrophage accumulation, lesions in the bronchi, and hypertrophy/hyperplasia of the
bronchiolar epithelium were observed following inhalation exposures to amorphous and crystalline silica
dust or aerosol at concentrations as low as 0.001 mg/L in rats.
Amorphous and crystalline silicon
dioxide: Silicosis in humans following
extended workplace exposure.
Amorphous silicon dioxide: 27-Month
inhalation study, rabbit. Dyspnea,
cyanosis, shortness of breath,
emphysema, vascular stenosis, alveolar
cell infiltration, sclerosis, granulomatous,
lesions in the liver, spleen, and kidney.
LOAEL: 28 mg/m3 (0.028 mg/L)
Amorphous silicon dioxide: 1-Year
inhalation study, rabbits. Progressive
NIOSH, 1978a;NIOSH, 1978b
EC, 2000a
EC, 2000a
Test substance amorphous silica and
crystalline silica.
Secondary source, test substance
amorphous silica, study details, test
concentrations, exposure protocol,
and test conditions were not
provided. The original study was in
an unpublished report.
Secondary source, test substance
amorphous silica, study details and
4-339
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
functional incapacitation, emphysema,
pulmonary vascular obstruction, blood
pressure changes, mural cellular
infiltration, peribronchiolar cellular
catarrh, perivascular cellular nodules,
ductal stenosis.
LOAEL: <53 mg/m3 (0.053 mg/L)
Amorphous silicon dioxide: 13-Week
inhalation study, rats.
LOAEC: 1 mg/m3 (0.001 mg/L),
increased lung weight, focal interstitial
fibrosis, pulmonary inflammation, and
pulmonary granulomas.
Reuzeletal., 1991
Amorphous silicon dioxide: In a 13-
week inhalation study, Wistar rats
(70/sex/dose) were exposed whole-body
to SiO2 at concentrations of 0, 1.3, 5.9 or
31 mg/m3 6 hours/day, 5 days/week.
Swollen and spotted lungs and enlarged
mediastinal lymph nodes. Increased
collagen content in the lungs (5.9 and 31
mg/m3). Accumulation of alveolar
macrophages and granular material,
cellular debris, polymorphonuclear
leucocytes, increased septal cellularity.
Accumulation of macrophages was seen
in the mediastinal lymph nodes.
Treatment-related microscopic changes in
the nasal region.
NOAEC: 1.3 mg/m3 (0.0013 mg/L)
LOAEC: 5.9 mg/m3 (0.0059 mg/L)
ECHA, 2013
Amorphous silicon dioxide: In a 13-
week inhalation study, Wistar rats
ECHA, 2013
test conditions were not provided.
The original study was in an
unpublished report.
Test substance amorphous silica;
test concentrations and exposure
protocol are unspecified.
Sufficient study details reported in a
secondary source. Comparative
study including Aerosil 200, Aerosil
R 974 (pyrogenic, hydrophobic),
Sipernat 22 S (precipitated,
hydrophilic) as well as quartz
(crystalline silica at a concentration
of 58 mg/m3) as a positive control).
Sufficient study details reported in a
secondary source. Comparative
4-340
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
(70/sex/dose) were exposed whole-body
to SiO2 at concentrations of 0 or 35
mg/m3 6 hours/day, 5 days/ week. Slight
mean increase in relative lung weight.
Swollen and spotted lungs and enlarged
mediastinal lymph nodes. Accumulation
of alveolar macrophages, intra-alveolar
polymorphonuclear leukocytes, and
increased septal cellularity. Treatment-
related microscopic changes in the nasal
region. Slightly increased collagen
content in the lungs at the end of the
exposure period. Changes were nearly all
reversed during the recovery period.
NOAEC: Not established
LOAEC: 35 mg/m3 (0.035 mg/L; only
dose tested)
Amorphous silicon dioxide: In a 13-
week inhalation study, male Fischer 344
rats were exposed whole body to Aerosil
200 dust at a concentration of 0 or 50
mg/m3 for 6 hours/day, 5 days/week.
Quartz (crystalline silica) was used as
positive control. Invasion of neutrophils
and macrophages into alveoli after both
amorphous and crystalline silica
exposure; more pronounced with the
amorphous type after 6.5 weeks but
decreased during post-exposure period.
Fibrosis was present in the alveolar
septae, but subsided during recovery.
NOAEC: Not established
LOAEC: 50 mg/m3 (0.05 mg/L; only
concentration tested)
ECHA, 2013
study including Aerosil 200, Aerosil
R 974 (pyrogenic, hydrophobic),
Sipernat 22 S (precipitated,
hydrophilic) as well as quartz
(crystalline silica at a concentration
of 58 mg/m3) as a positive control.
Sufficient study details reported in a
secondary source. Aerosil 200:
Silica, amorphous, fumed,
crystalline-free (CASRN 112945-
52-5).
4-341
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PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Amorphous silicon dioxide: In 13 and
18 month inhalation studies, male
monkeys (10/group) were exposed whole
body to 15 mg/m3 (total dust, pyrogenic
and precipitated; 15.9 mg/m3 total dust
silica gel; 6.9 - 9.9 mg/m3 (respirable
fraction) for 6 hours/day, 5 days/week.
Histopathological examination of the lung
revealed Incipient fibrosis, inflammatory
response: aggregation of great amounts of
macrophages, physiological impairment
of lung function.
NOAEC: Not established
LOAEC: « 15 mg/m3 (0.015 mg/L)
(nominal; only dose tested) LOAEC
(related to respirable fraction) > 6 < 9
mg/m3 air (analytical)
ECHA, 2013
Sufficient study details reported in a
secondary source. Three silica
subclasses: Cab-O-Sil type
(pyrogenic), named "fume" silica
(Silica F), (CASRN 112945-52-5):
commercial quality; Hi-Sil
(precipitated): silica P (CASRN
112926-00-8) commercial quality;
silica gel: silica G (CASRN 112926-
00-8) commercial quality.
Amorphous silicon dioxide: In a 14-day
inhalation study, Wistar rats
(40/sex/group) were exposed to Aerosil
200 at concentrations of 0, 17, 44 or 164
mg/m3 for 6 hours/day, 5 days/week.
Respiratory distress, increased lung
weight, decreased kidney and liver
weights, dose-dependent changes in lung
characteristics (pale, spotted, spongy,
alveolar interstitial pneumonia, early
granulomata).
NOAEL: Not established
LOAEL: <17 mg/m3 (<0.017 mg/L,
lowest concentration tested)
EC, 2000a; ECHA, 2013
Secondary source, test substance
identified as Aerosil 200: >99.8 %
(SiO2): CAS-Name: Silica,
amorphous, fumed, crystalline-free;
CASRN: 112945-52-5; limited
study details and test conditions
provided. The original study was in
an unpublished report.
Amorphous silicon dioxide: In a 14-day
inhalation study, Wistar rats were
exposed whole body to Sipernat 22S at
EC, 2000a; ECHA, 2013
Sufficient study details reported in a
secondary source. SIPERNAT 22S
>98 %(SiO2): CAS-Name: Silica,
4-342
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
concentrations of 46, 180 or 668 mg/m .
Respiratory distress, increased lung
weight, decreased liver weights, dose-
dependent changes in lung characteristics
(pale, spotted, spongy, alveolar interstitial
pneumonia, early granulomata),
accumulation of alveolar macrophages
and particulate material in lungs.
NOAEC: Not established
LOAEC: <46 mg/m3 (<0.046 mg/L,
lowest concentration tested)
Amorphous silicon dioxide: In a 5-day
inhalation study, male Wistar rats
(10/dose) were exposed whole body to
Syloid 74 at concentrations of 0, 1,5, and
25 mg/m3 for 6 hours/day. Quartz
(crystalline silica) was examined as a
positive control. Significant mean
increase in lung weight, very slight
hypertrophy of the bronchiolar
epithelium, accumulation of alveolar
macrophages accompanied by a few
granulocytes/neutrophils at high dose.
NOAEC: 5.13 mg/m3 (0.00513 mg/L)
LOAEC: 25.1 mg/m3 (0.0251 mg/L)
ECHA, 2013
Amorphous silicon dioxide: In a 5-day
inhalation study, Wistar rats
(10/sex/group) were exposed nose-only to
Zeosil 45 aerosol at concentrations of 0,
1, 5, 25 mg/m3 for 6 hours/day. Slight
increases in lung weights of the high-dose
group, increase in relative weights of
tracheobronchial lymph nodes in females.
Increased absolute numbers of
ECHA, 2013
precipitated, crystalline-free
(CASRN 112926-00-8).
Sufficient study details reported in a
secondary source. Syloid 74, CAS-
Name: Silica gel, crystalline-free
(CASRN 112926-00-8), purity ca.
100%.
Sufficient study details reported in a
secondary source. ZEOSIL 45: CAS
name, Silica, precipitated,
crystalline-free (CASRN 112926-
00-8); impurities: Na (1.9 %), S (0.8
%), Al (0.045 %), Fe (0.02 %), Ca
0.06 %.
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PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
neutrophils, hypertrophy and hyperplasia
of the bronchiolar epithelium at high
dose.
NOAEC: 5.39 mg/m3 (0.00539 mg/L)
LOAEC: 25.2 mg/m3 (0.0252 mg/L)
Amorphous silicon dioxide: In a 5-day
inhalation study, male Wistar rats
(10/group) were exposed nose-only to
CAB-O-SIL M5 at concentrations of 0,
1.39, 5.41 and 25 mg/m3 for 6 hours/day.
Significant mean increases in relative and
absolute lung weights of the mid- and
high-dose groups. Very slight
hypertrophy of the bronchiolar epithelium
(mid and high dose) and slight
hypertrophy (high dose). Accumulation of
alveolar macrophages accompanied by a
few granulocytes/neutrophils (mid and
high dose). Accumulation of macrophages
accompanied by infiltration of
polymorphonuclear leukocytes (high
dose). Very slight macrophage
accumulation still present following 3
months of recovery (high dose).
NOEC: 1.39 mg/m3 (0.00139 mg/L)
LOAEC: 5.41 mg/m3 (0.00541 mg/L)
ECHA, 2013
Sufficient study details reported in a
secondary source. CAB-O-SIL M5:
Silica, amorphous, fumed,
crystalline-free (CASRN 112945-
52-5), purity ca. 100%.
Amorphous silicon dioxide: In a 103
week study, Fischer 344 rats
(40/sex/group) were fed Syloid 44
continuously in the diet at concentrations
of 1.25, 2.5 and 5%. Interim sacrifice of
10/sex after 6 and 12 months. Reduced
liver weight in females after 12 and 24
months is not considered to be treatment-
ECHA, 2013
Sufficient study details reported in a
secondary source. Syloid 244:
Silica, precipitated, crystalline-free
(CASRN 112926-00-8).
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DATA QUALITY
related. There were no other treatment-
related effects.
NOAEL: 5% (~ 2,000 mg/kg bw-day for
average of male and female; highest dose
tested)
LOAEL: Not established
Amorphous silicon dioxide: In a 93
week study, B6C3F1 mice (40/sex/dose)
were fed Syloid 244 continuously in the
diet at concentrations of 0, 1.25, 2.5 or
5%. Interim sacrifice of 10/sex after 6 and
12 months. Transient retardation in body
weight gain was not biologically relevant.
No other adverse treatment-related
effects.
NOAEL: 5% (4,500 or 5,800 mg/kg bw-
day for average of male/female,
respectively; highest dose tested)
LOAEL: Not established
ECHA, 2013
Sufficient study details reported in a
secondary source. Syloid 244:
Silica, precipitated, crystalline-free
(CASRN 112926-00-8).
Amorphous silicon dioxide: In a 6-
month study, Charles River rats
(12/sex/group) were fed Syloid 244 in the
diet daily at doses of 0, 2,170 and 7,950
mg/kg bw-day (males) or 0, 2,420 and
8,980 mg/kg bw-day (females). There
were no treatment-related effects. Isolated
pathological findings were not related to
test substance.
NOAEL: 7,950 mg/kg bw-day (males) or
8,980 mg/kg bw-day (females) (highest
doses tested)
LOAEL: Not established
ECHA, 2013
Sufficient study details reported in a
secondary source. Syloid 244:
Silica, precipitated, crystalline-free
(CASRN 112926-00-8).
Amorphous silicon dioxide: In a 13- ECHA, 2013
Silica, amorphous, fumed,
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
week study, Charles River rats were fed
Cab-O-Sil(fluffy) (>99 % SiO2)
continuously in the diet at concentrations
of 1, 3, and 5% (mean estimated dose:
700, 2,100, and 3,500 mg/kg bw-day). No
clinical signs of toxicity. No gross
pathological or histopathological
treatment-related changes.
NOAEL: 5% (~ 3,500 mg/kg bw-day;
highest dose tested)
LOAEL: Not established
crystalline-free (CASRN 112945-
52-5).
Amorphous silicon dioxide: In a 13-
week dietary study, Wistar rats
(10/sex/dose) were fed SiO2 continuously
in the diet at concentrations of
approximately 0, 0.05, 2 and 6.7% (mean
estimated doses: 300-330, 1,200-1,400,
4,000-4,500 mg/kg-day). Slightly
increased mean food intake at high dose,
with no corresponding body weight gain.
No clinical signs of toxicity or other
findings (hematological, blood-chemical
and urinary parameters). Gross and
microscopic examination did not reveal
any treatment-related changes.
NOAEL: 6.7% (4,000-45,000 mg/kg bw-
day (nominal, highest dose tested)
LOAEL: Not established
ECHA, 2013
Sufficient study details reported in a
secondary source. Silica,
precipitated, crystalline-free
(CASRN 112926-00-8).
Amorphous silicon dioxide: Biogenic
silica fibers induced ornithine
decarboxylase activity of epidermal cells
in mice following topical application.
IARC, 1997
Test substance amorphous silica.
Crystalline silicon dioxide: 2-Year
inhalation (whole body) study, rats
Rice, 2000; OECD SIDS, 2011
Test substance identified as
crystalline silica (DQ-12 quartz,
4-346
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
(50/sex) exposed to air or 1 mg/m3 6
hours/day, 5 days/week). Subpleural and
peribronchial fibrosis, focal
lipoproteinosis cholesterol clefts, enlarged
lymph nodes, granulomatous lesions in
the walls of large bronchi.
LOAEL: 1 mg/m3 (0.001 mg/L; only dose
tested)
containing 74% respirable quartz.
Crystalline silicon dioxide: Silicotic
nodules with reticulin fibrosis was
reported by day 220 and dense, rounded
collagenous nodules were reported on day
300 in rats following inhalation exposure
(18 hours/day, 5 days/week) of 30,000
particles/mL (40% < 0.5 microns) for up
to 420 days.
EC, 2000b
Limited study details reported in a
secondary source.
Crystalline silicon dioxide: 6-Month
inhalation study, rats. Increased collagen
and elastin content in the lungs, induced
type II cell hyperplasia in alveolar
compartment and intralymphatic
microgranulomas around bronchioles.
NOAEL: Not established
LOAEL: 2 mg/m3 (0.002 mg/L)
Rice, 2000
Test substance identified as
crystalline silica (quartz); test
concentrations not specified.
Crystalline silicon dioxide: 13-week
inhalation study in male rats exposed to 0
or 3 mg/m3 (6 hours/day, 5 days/week).
Treated rats presented with pulmonary
inflammation and fibrosis.
NOAEL: Not established
LOAEL: 3 mg/m3 (0.003 mg/L; only dose
tested)
OECDSIDS, 2011
Study details reported in a
secondary source; test substance
identified at cristobalite.
Crystalline silicon dioxide: 4-week
4-347
OECDSIDS, 2011
Study details reported in a
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
inhalation study in female rats exposed to
0, 0.1, 1, or 10 mg/m3 (6 hours/day, 5
days/week). Evaluation of
bronchoalveolar lavage fluid occurred on
weeks 1, 8, and 24 following exposure.
Significantly increased levels of
granulocytes and increased levels of
lactate dehydrogenase and beta-
glucuronidase were reported at 24 weeks
post exposure at a concentration of 1
mg/m3.
NOAEL: 0.1 mg/m3 (0.0001 mg/L)
LOAEL: 1 mg/m3 (0.001 mg/L)
secondary source; test substance
identified at quartz.
Crystalline silicon dioxide: 9-day
inhalation study in mice
Minimal interstitial thickening,
accumulation of mononuclear cells, and
slight lymphoid hypertrophy in the lungs
were reported.
NOAEL: Not established
LOAEL: 10 mg/m3 (0.01 mg/L)
OECDSIDS, 2011
Limited study details reported in a
secondary source; test
concentrations were not specified.
Crystalline silicon dioxide: 3-day
inhalation study in rats exposed to 0, 10,
or 100 mg/m3 of cristobalite (6
hours/day).
Increased granulocytes and other markers
of cytotoxicity from the lung lavage fluid
were reported in all treated animals.
NOAEL: Not established
LOAEL: 10 mg/m3 (0.01 mg/L; lowest
dose tested)
OECDSIDS, 2011
Limited study details reported in a
secondary source; test substance
identified as cristobalite.
14-Day oral dietary study, rats. No
clinical signs or other findings.
EC, 2000a
Secondary source, test substance
unspecified silica, study details and
4-348
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
NOAEL: 24,200 mg/kg-day (highest dose
tested)
LOAEL: Not established
6-Month oral dietary study, rats. No
clinical signs or other findings.
NOAEL: 497 mg/kg-day (highest dose
tested)
LOAEL: Not established
13 -Week oral dietary study, rats. No
clinical signs or other findings.
NOAEL: 8% diet (highest dose tested)
LOAEL: Not established
Up to 1 year inhalation study, rats.
Enlarged and discolored lymph nodes,
perivascular and peribronchiolar dust cell
granuloma, necrotic cells.
NOAEL: Not established
LOAEL: <0.045 mg/L (lowest
concentration tested)
4-Week oral dietary study, dog. No
clinical signs or other findings.
NOAEL 800 mg/kg-day (highest dose
tested)
LOAEL: Not established
In a 3-week dermal study, SiO2 was
applied to the intact and abraded skin of
rabbits (2/sex/group) at doses of 0, 5,000,
10,000 mg/kg bw-day (nominal) for 18
hours/day, 5 days/week. No evidence of
systemic toxicity or of gross or
REFERENCE
EC, 2000a
EC, 2000a
EC, 2000a
EC, 2000a
ECHA, 2013
DATA QUALITY
test conditions were not provided.
The original study was in an
unpublished report.
Secondary source, test substance
unspecified silica, study details and
test conditions were not provided.
The original study was in an
unpublished report.
Secondary source, test substance
unspecified silica, study details and
test conditions were not provided.
The original study was in an
unpublished report.
Secondary source, test substance
unspecified silica, study details and
test conditions were not provided.
The original study was in an
unpublished report.
Secondary source, test substance
unspecified silica, study details and
test conditions were not provided.
The original study was in an
unpublished report.
Unassignable. 21 -Day dermal
exposure study using a prolonged
daily exposure regimen (18 h/d, 5
d/wk) instead of 6 h/d. Test
substance form not specified.
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PROPERTY/ENDPOINT
DATA
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microscopic pathology.
NOAEL: > 10,000 mg/kg bw-day
(highest dose tested)
LOAEL: Not established
Immune System Effects
Amorphous silicon dioxide: In a 12-
month study, male Hartley Guinea pigs
(20/dose) were exposed whole body to
concentrations of 15 mg/m3 (total dust,
pyrogenic and precipitated); 15.9 mg/m3
(total dust silica gel) and 6.9-9.9 mg/m3
(respirable <4.7 (im) for 5.5 - 6 hours/day,
5 days/week. A few macrophages
containing particles of amorphous silica
were observed in the lungs and lymph
nodes.
NOAEC: > 6 < 9 mg/m3 (> 0.006 < 0.009
mg/L)
LOAEC: Not established
ECHA, 2013
Crystalline silicon dioxide: 15- or 27-
week inhalation study in mice exposed to
0 or 5 mg/m3 (6 hours/day, 5 days/week).
Increased spleen weight and formation of
plaque in the spleen was reported.
NOAEL: Not established
LOAEL: 5 mg/m3 (0.005 mg/L; only dose
tested)
OECDSIDS, 2011
Sufficient study details reported in a
secondary source. Three silica
subclasses: Cab-O-Sil type
(pyrogenic), named "fume" silica
(Silica F), (CASRN 112945-52-5):
commercial quality; Hi-Sil
(precipitated): silica P (CASRN
112926-00-8) commercial quality;
silica gel: silica G (CASRN 112926-
00-8) commercial quality.
Study details reported in a
secondary source; test substance
identified as quartz.
4-350
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
Skin Sensitization
Skin Sensitization
Respiratory Sensitization
[Respiratory Sensitization
Eye Irritation
Eye Irritation
DATA
REFERENCE
DATA QUALITY
LOW: Amorphous silicon dioxide was not a dermal sensitizer in guinea pigs or humans.
No experimental data were located for crystalline silicon dioxide. It is estimated that crystalline silicon
dioxide, if present, is not likely to be a skin sensitizer based on analogy to amorphous silicon dioxide and
professional judgment.
Amorphous silicon dioxide: Not
sensitizing in a guinea pig maximization
test.
Amorphous silicon dioxide: Not
sensitizing, humans (occupational
surveys)
Crystalline silicon dioxide: There is low
potential for skin Sensitization based on
analogy to amorphous silicon dioxide.
(Estimated by analogy)
EC, 2000a
ECHA, 2013
Professional judgment
Secondary source, study details and
test conditions were not provided.
The original study was in an
unpublished report.
Not assignable (no further details).
Silica, amorphous, fumed,
crystalline-free (CASRN 112945-
52-5) or Silica gel, precipitated,
crystalline-free. (CASRN 112926-
00-8).
Estimated based on analogy to
amorphous silicon dioxide and
professional judgment; no
experimental data located.
No data located.
No data located.
LOW: Amorphous silicon dioxide was not irritating to slightly irritating in rabbits and slightly irritating
in humans. If present, crystalline silicon dioxide would be assigned a Moderate hazard designation based
on a study reporting fibrotic nodules in rabbit eyes.
Amorphous silicon dioxide: Slightly
irritating, rabbits
Amorphous silicon dioxide: Slightly
irritating, humans
Amorphous silicon dioxide: Not
irritating, rabbits (several studies)
EC, 2000a
EC, 2000a
EC, 2000a; ECHA, 2013
Secondary source, study details and
test conditions were not provided.
The original study was in an
unpublished report.
Secondary source, study details and
test conditions were not provided.
The original study was in an
unpublished report.
Sufficient study details reported in a
secondary source. Silica,
precipitated, crystalline-free
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PROPERTY/ENDPOINT
Dermal Irritation
Dermal Irritation
Endocrine Activity
DATA
Crystalline silicon dioxide: Quartz was
reported to cause fibrotic nodules in
rabbit eyes.
REFERENCE
EC, 2000b
DATA QUALITY
(CASRN 112926-00-8) or Silica,
amorphous, fumed, crystalline-free
(CASRN 112945-52-5).
Limited study details reported in a
secondary source; the severity and
duration of the irritation was not
specified. Irritation may be a result
of mechanical mechanisms and
scratching of the eye.
VERY LOW: Amorphous silicon dioxide was not irritating to the skin of rabbits or humans.
No experimental data was located for crystalline silicon dioxide for this endpoint. It is estimated that
crystalline silicon dioxide, if present, is not likely to be a skin irritant based on analogy to amorphous
silicon dioxide and professional judgment.
Amorphous silicon dioxide: Not
irritating, rabbits (several studies)
Amorphous silicon dioxide: Not
irritating, humans
Crystalline silicon dioxide: There is low
potential for skin irritation based on
analogy to amorphous silicon dioxide.
(Estimated by analogy)
EC, 2000a;ECHA, 2013
EC, 2000a
Professional judgment
Sufficient study details reported in a
secondary source. Silica,
precipitated, crystalline-free (CAS-
No. 112926-00-8) or Silica,
amorphous, fumed, crystalline-free
(CAS-No. 112945-52-5).
Secondary source, study details and
test conditions were not provided.
The original study was in an
unpublished report.
Estimated based on analogy to
amorphous silicon dioxide and
professional judgment; no
experimental data located.
No data located.
No data located.
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PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Immunotoxicity
Subjects that develop silicosis following exposure to crystalline silica have increased numbers of
macrophages in the lungs. Effects on the lungs, such as inflammatory response, accumulation of alveolar
macrophages, and infiltration of polymorphonuclear leukocytes were observed following inhalation
exposures to amorphous and crystalline silica dust or aerosols in experimental animals.
Immune System Effects
Amorphous silicon dioxide: In a 5-day
inhalation study, male Wistar rats
(10/group) were exposed nose-only to
CAB-O-SIL M5 at concentrations of 0,
1.39, 5.41 and 25 mg/m3 for 6 hours/day.
Accumulation of alveolar macrophages
accompanied by a few
granulocytes/neutrophils (mid and high
dose). Accumulation of macrophages
accompanied by infiltration of
polymorphonuclear leukocytes (high
dose). Very slight macrophage
accumulation still present following 3
months of recovery (high dose).
NOAEC: 1.39 mg/m3 (0.00139 mg/L)
LOAEC: 5.41 mg/m3 (0.00541 mg/L)
Amorphous silicon dioxide: In a 13-
week inhalation study, male Fischer 344
rats were exposed whole body to Aerosil
200 dust at a concentration of 0 or 50
mg/m3 for 6 hours/day, 5 days/week.
Quartz (crystalline silica) was used as
positive control. Invasion of neutrophils
and macrophages into alveoli after both
amorphous and crystalline silica
exposure; it was more pronounced with
the amorphous type after 6.5 weeks but
decreased during post-exposure period.
Fibrosis was present in the alveolar
septae, but subsided during recovery.
ECHA, 2013
ECHA, 2013
Sufficient study details reported in a
secondary source. CAB-O-SIL M5:
Silica, amorphous, fumed,
crystalline-free (CASRN 112945-
52-5), purity ca. 100%.
Sufficient study details reported in a
secondary source. Aerosil 200:
Silica, amorphous, fumed,
crystalline-free (CASRN 112945-
52-5).
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PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
NOAEC: Not established
LOAEC: 50 mg/m3 (0.05 mg/L; lowest
concentration tested)
Amorphous silicon dioxide: In a 13-
week inhalation study, Wistar rats
(70/sex/dose) were exposed whole-body
to SiO2 at concentrations of 0, 1.3, 5.9 or
31 mg/m3 6 hours/day, 5 days/week.
Swollen and spotted lungs and enlarged
mediastinal lymph nodes. Accumulation
of alveolar macrophages and granular
material, cellular debris,
polymorphonuclear leucocytes, increased
septal cellularity. Accumulation of
macrophages was seen in the mediastinal
lymph nodes. Treatment-related
microscopic changes in the nasal region.
NOAEC: 1.3 mg/m3 (0.0013 mg/L)
LOAEC: 5.9 mg/m3 (0.0059 mg/L)
ECHA, 2013
Amorphous silicon dioxide: In a 13-
week inhalation study, Wistar rats
(70/sex/dose) were exposed whole-body
to SiO2 at concentrations of 0 or 35
mg/m3 6 hours/day, 5 days/ week.
Swollen and spotted lungs and enlarged
mediastinal lymph nodes. Accumulation
of alveolar macrophages, intra-alveolar
polymorphonuclear leukocytes, and
increased septal cellularity.
NOAEC: Not established
LOAEC: 35 mg/m3 (0.035 mg/L; lowest
concentration tested)
ECHA, 2013
Sufficient study details reported in a
secondary source. Comparative
study including Aerosil 200, Aerosil
R 974 (pyrogenic, hydrophobic),
Sipernat 22 S (precipitated,
hydrophilic) as well as quartz
(crystalline silica at a concentration
f ^ & / ^ was used as a positive control).
Sufficient study details reported in a
secondary source. Comparative
study including Aerosil 200, Aerosil
R 974 (pyrogenic, hydrophobic),
Sipernat 22 S (precipitated,
hydrophilic) as well as quartz
(crystalline silica at a concentration
of 58 mg/m3 was used as a positive
control).
Amorphous silicon dioxide: In a 14-Day
inhalation study, Wistar rats were
EC, 2000a; ECHA, 2013
Sufficient study details reported in a
secondary source. SIPERNAT 22S
4-354
-------
Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
exposed whole body to Sipernat 22S at
concentrations of 46, 180 or 668 mg/m3.
Dose-dependent changes in lung
characteristics (pale, spotted, spongy,
alveolar interstitial pneumonia, early
granulomata), accumulation of alveolar
macrophages and particulate material in
lungs.
NOAEC: Not established
LOAEC: <46 mg/m3 (<0.046 mg/L;
lowest concentration tested)
Amorphous silicon dioxide: In a 12-
month study, male Hartley Guinea pigs
(20/dose) were exposed whole body to
concentrations of 15 mg/m3 (total dust,
pyrogenic and precipitated); 15.9 mg/m3
(total dust silica gel) and 6.9-9.9 mg/m3
(respirable <4.7 (im) for 5.5 - 6 hours/day,
5 days/week. A few macrophages
containing particles of amorphous silica
were observed in the lungs and lymph
nodes.
NOAEC: > 6 < 9 mg/m3 (> 0.006 < 0.009
mg/L)
LOAEC: Not established
ECHA, 2013
Amorphous silicon dioxide: In 13 and
18 month inhalation studies, male
monkeys (10/group) were exposed whole
body to 15 mg/m3 (total dust, pyrogenic
and precipitated); 15.9 mg/m3 (total dust
silica gel); and 6.9 - 9.9 mg/m3 (respirable
<4.7 (im) for 6 hours/day, 5 days/week.
Inflammatory response: aggregation of
great amounts of macrophages,
ECHA, 2013
>98 %(SiO2): CAS-Name: Silica,
precipitated, crystalline-free
(CASRN 112926-00-8).
Sufficient study details reported in a
secondary source. Three silica
subclasses: Cab-O-Sil type
(pyrogenic), named "fume" silica
(Silica F), (CASRN 112945-52-5):
commercial quality; Hi-Sil
(precipitated): silica P (CASRN
112926-00-8) commercial quality;
silica gel: silica G (CASRN 112926-
00-8) commercial quality.
Sufficient study details reported in a
secondary source. Three silica
subclasses: Cab-O-Sil type
(pyrogenic), named "fume" silica
(Silica F), (CASRN 112945-52-5):
commercial quality; Hi-Sil
(precipitated): silica P (CASRN
112926-00-8) commercial quality;
silica gel: silica G (CASRN 112926-
4-355
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
physiological impairment of lung
function.
NOAEC: Not established
LOAEC: ca. 15 mg/m3 (0.015 mg/L)
(nominal, lowest concentration tested)
00-8) commercial quality.
Crystalline silicon dioxide: Human
subjects with silicosis have increased
macrophages and lymphocytes in the
lungs, but minimal increases in
neutrophils.
IARC, 1997
Test substance crystalline silica.
Crystalline silicon dioxide: Exposure of
rats to high concentrations of quartz leads
to recruitment of neutrophils, marked
persistent inflammation, and proliferative
responses of the epithelium.
IARC, 1997
Test substance crystalline silica.
Crystalline silicon dioxide: In vitro
studies show that crystalline silica can
stimulate the release of cytokines and
growth factors from macrophages and
epithelial cells; some evidence exists that
these effects occur in vivo (species not
specified).
IARC, 1997
Test substance crystalline silica.
Crystalline silicon dioxide: Crystalline
silica results in inflammatory cell
recruitment in a dose-dependent manner
(species not specified).
IARC, 1997
Test substance crystalline silica.
Crystalline silicon dioxide: Crystalline
silica deposited in the lungs causes
macrophage injury and activation (species
not stated).
IARC, 1997
Test substance crystalline silica.
Crystalline silicon dioxide: 15- or 27-
week inhalation study in mice exposed to
0 or 5 mg/m3 (6 hours/day, 5 days/week).
Increased spleen weight and formation of
OECDSIDS, 2011
Study details reported in a
secondary source; test substance
identified as quartz.
4-356
-------
Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
plaque in the spleen was reported.
NOAEL: Not established
LOAEL: 5 mg/m3 (0.005 mg/L; only dose
tested)
REFERENCE
DATA QUALITY
ECOTOXICITY
ECOSAR Class
Acute Aquatic Toxicity
Fish LC50
Not applicable
LOW: Amorphous silicon dioxide experimental LC50 and EC50 values for fish, daphnia and green algae
are all >100 mg/L. The large MW, limited bioavailability and low water solubility suggest there will be no
effects at saturation (NES). It is estimated by professional judgment that crystalline forms of silicon
dioxide will also have low acute aquatic toxicity based on analogy to amorphous silicon dioxide. For some
organisms in marine habitats, silica and silicates are used as nutrients; they are used for building some cell
walls, skeletal structures or shells.
Amorphous silicon dioxide: Freshwater
fish Brachydanio rerio 96-hour LC50 =
5,000 mg/L
(Experimental)
Amorphous silicon dioxide: Freshwater
fish Brachydanio rerio 96-hour LC50
> 10,000 mg/L;
static test conditions; nominal
concentrations: 1,000 and 10,000 mg/L
(Experimental)
Amorphous and crystalline silicon
dioxide: Freshwater fish LC50 >100 mg/L
(Estimated)
EC, 2000a
ECHA, 2013
Professional judgment
Secondary source; test substance
form, study details and test
conditions were not provided.
Sufficient study details reported in a
secondary source. GLP guideline
study. Data are for amorphous silica.
The large MW, limited
bioavailability and low water
solubility suggest there will be NES.
For some organisms in marine
habitats, silica and silicates are used
as nutrients; they are used for
building some cell walls, skeletal
structures or shells.
4-357
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Daphnid LC50
Amorphous silicon dioxide: Daphnia
magna 24-hour effect level based on
mobility EL50 > 10,000 mg/L
(Experimental)
ECHA, 2013
Amorphous silicon dioxide:
Ceriodaphnia dubia EC50 ~ 7,600 mg/L
(Experimental)
EC, 2000a
Amorphous and crystalline silicon
dioxide: Daphnia magna LC50 >100
mg/L
(Estimated)
Professional judgment
Sufficient study details reported in a
secondary source. Guideline study
with acceptable restrictions (24 h
instead of 48 h). Data are for Silica,
amorphous.
Secondary source; test substance
form, study details and test
conditions were not provided. The
original study was in an unpublished
report.
The large MW, limited
bioavailability and low water
solubility suggest there will be NES.
For some organisms in marine
habitats, silica and silicates are used
as nutrients; they are used for
building some cell walls, skeletal
structures or shells.
Green Algae EC s
Amorphous silicon dioxide: Green algae
Selenastrum capricornutum EC50 = 440
mg/L
(Experimental)
EC, 2000a
Amorphous and crystalline silicon
dioxide: Green algae EC50 >100 mg/L
(Estimated)
Professional judgment
Secondary source; test substance
form, study details and test
conditions were not provided. The
original study was in an unpublished
report.
The large MW, limited
bioavailability and low water
solubility suggest there will be NES.
For some organisms in marine
habitats, silica and silicates are used
as nutrients; they are used for
building some cell walls, skeletal
structures or shells.
4-358
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
Chronic Aquatic Toxicity
LOW: No experimental chronic data were located. The large MW, limited bioavailability and low water
solubility suggest there will be no effects at saturation (NES). It is estimated by professional judgment that
crystalline forms of silicon dioxide will also have low chronic aquatic toxicity based on large MW, limited
bioavailability and low water solubility suggesting there will be no effects at saturation (NES). For some
organisms in marine habitats, silica and silicates are used as nutrients; they are used for building some cell
walls, skeletal structures or shells.
Fish ChV
Amorphous and crystalline silicon
dioxide: Freshwater fish ChV >10 mg/L
(Estimated)
Professional judgment
The large MW, limited
bioavailability and low water
solubility suggest there will be NES.
For some organisms in marine
habitats, silica and silicates are used
as nutrients; they are used for
building some cell walls, skeletal
structures or shells.
Daphnid ChV
Amorphous and crystalline silicon
dioxide: Daphnia magna ChV >10 mg/L
(Estimated)
Professional judgment
The large MW, limited
bioavailability and low water
solubility suggest there will be NES.
For some organisms in marine
habitats, silica and silicates are used
as nutrients; they are used for
building some cell walls, skeletal
structures or shells.
Green Algae ChV
Amorphous and crystalline silicon
dioxide: Green algae ChV >10 mg/L
(Estimated)
Professional judgment
The large MW, limited
bioavailability and low water
solubility suggest there will be NES.
For some organisms in marine
habitats, silica and silicates are used
as nutrients; they are used for
building some cell walls, skeletal
structures or shells.
ENVIRONMENTAL FATE
4-359
-------
Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
Transport
Henry's Law Constant (atm-
m3/mole)
Sediment/Soil
Adsorption/Desorption - Koc
Level III Fugacity Model
Persistence
Water
Soil
Aerobic Biodegradation
Volatilization Half-life for
Model River
Volatilization Half-life for
Model Lake
Aerobic Biodegradation
Anaerobic Biodegradation
DATA
REFERENCE
DATA QUALITY
Silicon dioxide is a component of sand, soil, and sediment. Silicon dioxide has low water solubility and as a
solid, it is expected to have a negligible estimated vapor pressure; these two factors correspond to an
expected low Henry's Law constant. Amorphous forms of silicon dioxide will be relatively immobile in the
environment with the exception of silicon dioxide dust in the atmosphere. Crystalline forms of silicon
dioxide are expected to behave similarly in the environment and be relatively immobile with the exception
of dust particulates.
Amorphous and crystalline silicon
dioxide: <10~8 (Estimated)
Amorphous and crystalline silicon
dioxide: Not applicable (Estimated)
Professional judgment
Professional judgment
Cutoff value for nonvolatile
compounds based on professional
judgment. This substance contains
inorganic compounds that are
outside the estimation domain of
EPI.
As a component of sand, soil, and
sediment, the soil-water partition
coefficient is not applicable for
silicon dioxide.
No data located.
HIGH: Amorphous silicon dioxide is expected to have high persistence in the environment because silicon
dioxide is a recalcitrant, fully oxidized, inorganic substance and therefore will not biodegrade, oxidize in
air, or undergo hydrolysis under environmental conditions. Silicon dioxide does not absorb light at
environmentally relevant wavelengths and is not expected to photolyze. No degradation processes for
silicon dioxide, under typical environmental conditions, were identified. It is also estimated that in the
environment crystalline forms of silicon dioxide will behave similarly and have high persistence based on
professional judgment.
Amorphous and crystalline silicon
dioxide: Recalcitrant (Estimated)
>1 year for both amorphous and
crystalline silicon dioxide (Estimated)
>1 year for both amorphous and
crystalline silicon dioxide (Estimated)
Amorphous and crystalline silicon
dioxide: Recalcitrant (Estimated)
Professional judgment; OECD
SIDS, 2004a
Professional judgment
Professional judgment
Professional judgment
No data located.
4-360
-------
Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
Air
Reactivity
Soil Biodegradation with
Product Identification
Sediment/Water
Biodegradation
Atmospheric Half-life
Photolysis
Hydrolysis
Environmental Half-life
Bioaccumulation
Fish BCF
Other BCF
DATA
Amorphous and crystalline silicon
dioxide: >1 year (Estimated)
Amorphous and crystalline silicon
dioxide: Not a significant fate process
(Estimated)
Amorphous and crystalline silicon
dioxide: >1 year (Estimated)
REFERENCE
Professional judgment
Professional judgment
Professional judgment
DATA QUALITY
No data located.
No data located.
Silicon dioxide does not absorb UV
light at environmentally relevant
wavelengths and is not expected to
undergo photolysis.
Silicon dioxide is a fully oxidized,
insoluble, inorganic material and is
not expected to undergo hydrolysis.
Not all input parameters for this
model were available to run the
estimation software (EPI). This
substance contains inorganic
compounds that are outside the
estimation domain of EPI.
LOW: Amorphous silicon dioxide is not expected to bioaccumulate based on professional judgment. Also
based on professional judgment crystalline forms of silicon dioxide are not expected to bioaccumulate.
Although for some organisms in marine habitats, silica and silicates are used as nutrients. They are used
for building some cell walls, skeletal structures or shells.
Amorphous and crystalline silicon
dioxide: <100 (Estimated)
For some organisms in marine habitats,
silica and silicates are used as nutrients;
they are used for building skeletal
structures or shells. For example, diatoms
absorb soluble silica from water and
metabolize it for an external skeleton.
Professional judgment
EC, 2000b; OECD SIDS, 2004a;
HSDB, 2009
This inorganic compound is not
amenable to available estimation
methods.
Supporting information about the
bioaccumulation of this compound
in marine environments. Some
organisms in marine habitats use
silica and silicates as nutrients; they
are used for building some cell
walls, skeletal structures or shells.
4-361
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Silicon dioxide (amorphous) CASRN 7631-86-9
PROPERTY/ENDPOINT
DATA
REFERENCE
DATA QUALITY
BAF
Amorphous and crystalline silicon
dioxide: <100 (Estimated)
Professional judgment
This inorganic compound is not
amenable to available estimation
methods.
Metabolism in Fish
No data located.
ENVIRONMENTAL MONITORING AND BIOMONITORING
Environmental Monitoring
Silicon dioxide is a ubiquitous mineral that occurs naturally in the environment as sand and quartz (HSDB,
2009).
Ecological Biomonitoring
No data located.
Human Biomonitoring
No data located.
4-362
-------
Alexander GB, Heston WM, Her RK (1954) J Phys Chem 58:453-455.
Daubert TE and Banner RP (1989) Physical and thermodynamic properties of pure chemicals data compilation. Washington, DC: Taylor and
Francis.
EC (2000a) Dataset for silicon dioxide, chemically prepared. European Commission, European Chemicals Bureau.
EC (2000b) [Quartz (SiO2)]. IUCLID Dataset. European Commission. European Chemicals Bureau.
http://esis.jrc.ec.europa.eu/doc/IUCLID/data_sheets/14808607.pdf
ECHA (2013) Silicon dioxide. Registered substances. http://apps.echa.europa.eu/registered/data/dossiers/DISS-76fd35eO-69c4-29a3-e044-
00144f26965e/DISS-76fd35eO-69c4-29a3 -e044-00144f26965e_DISS-76fd35eO-69c4-29a3-e044-00144f26965e.html.
EPA (2010) TSCA new chemicals program (NCP) chemical categories. Washington, DC: U.S. Environmental Protection Agency.
http://www.epa.gov/oppt/newchems/pubs/npcchemicalcategories.pdf.
ESIS (2012) European chemical Substances Information System. European Commission, http://esis.jrc.ec.europa.eu/.
Florke OW, Graetsch H, Brunk F, et al. (2000) Silica. Ullmann's Encyclopedia of Industrial Chemistry.
HSDB (2009) Amorphous silica. Hazardous Substances Data Bank. http://toxnet.nlm.gOv/cgi-bin/sis/search/f7.temp/~qZ735z:l:FULL.
IARC (1987) Silica. IARC Monogr Eval Carcinog Risk Chem Hum 42 International Agency for Research on Cancer.:39-143.
IARC (1997) SILICA: Crystalline silica - inhaled in the form of quartz or cristobalite from occupational sources (Group 1): Amorphous silica
(Group 3). IARC monographs on the evaluation of carcinogenic risks to humans summaries and evaluations.68 International Agency for Research
on Cancer, World Health Organization, http://www.inchem.org/documents/iarc/vol68/silica.html.
KEMI (2006) Silicon dioxide. Information on substances. KEMI Swedish Chemicals Agency.
http://apps.kemi.se/flodessok/floden/kemamne_eng/kiseldioxid_eng .htm.
Lewis RJ (1999) Sax's dangerous properties of industrial materials. 10th ed. New York, NY: John Wiley & Sons, Inc.
Lide DR (2000) 2000-2001 CRC handbook of chemistry and physics. 81st ed. Boca Raton, FL: CRC Press.
Merck (1996) Merck index. 12th ed. Whitehouse Station, NJ: Merck & Co. Inc.
NIOSH (1978a) Occupational health guideline for amorphous silica.
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NIOSH (1978b) Occupational health guideline for crystalline silica. National Institute of Occupational Safety and Health.
OECD SIDS (2004a) SIDS initial assessment profile silicon dioxide. Organisation for Economic Cooperation and Development. Screening
Information Data Set.
OECD SIDS (2004b) SIDS initial assessment profile synthetic amorphous silica and silicates. Organisation for Economic Cooperation and
Development. Screening Information Data Set.
OECD SIDS (2011) [Quartz and cristobalite]. Initial targeted assessment profile (human health). Organisation for Economic Cooperation and
Development Screening Information Data Set. http://webnet.oecd.org/Hpv/UI/handler.axd?id=b68bb357-e6dd-4db9-b05c-8148223fcOff.
OncoLogic (2008) Version 7.0. U.S. Environmental Protection Agency and LogiChem, Inc.
Reuzel PGJ, Bruijntjes JP, Feron VJ, et al. (1991) Subchronic inhalation toxicity of amorphous silicas and quartz dust in rats. Food Chem Toxicol
29(5):34-354.
Rice F (2000) Concise International Chemical Assessment Document (CICAD) - Crystalline Silica, Quartz. No. 24. United Nations Environment
Programme; International Labour Organization; World Health Organization, http://www.who.int/ipcs/publications/cicad/en/cicad24.pdf.
Waddell W (2013) Silica, amorphous. Kirk-Othmer encyclopedia of chemical technology. John Wiley & Sons.
4-364
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5 Potential Exposure to Flame Retardants and Other Life-
Cycle Considerations
Many factors must be considered to evaluate the risk to human health and the environment posed
by any flame-retardant chemical. Risk is a function of two parameters, hazard and exposure. The
hazard associated with a particular substance or chemical is its potential to impair human health,
safety, or ecological health. While some degree of hazard can be assigned to most substances, the
toxicity and harmful effects of other substances are not fully understood. The exposure potential
of a given substance is a function of the exposure route (inhalation, ingestion, and dermal), the
concentration of the substance in the contact media, and the frequency and duration of the
exposure.
The purpose of this chapter is to identify the highest priority routes of exposure to flame-
retardant chemicals used in printed circuit boards (PCBs). Section 5.1 through Section 5.4
provide general background regarding potential exposure pathways that can occur during
different life-cycle stages, discuss factors that affect exposure potential in an industrial setting,
provide process descriptions for the industrial operations involved in the PCB manufacturing
supply chain (identifying the potential primary release points and exposure pathways), and
discuss potential consumer and environmental exposures. Following this general discussion,
Section 5.5 highlights life-cycle considerations for the ten flame retardants evaluated by this
partnership. The chapter is intended to help the reader identify and characterize the exposure
potential of flame-retardant chemicals based on factors including physical and chemical
properties and reactive versus additive incorporation into the epoxy resin. The information
presented in this chapter should be considered with the chemical-specific hazard assesment
presented in Chapter 4.
Exposure can occur at many points in the life cycle of a flame-retardant chemical. There is a
potential for occupational exposures during industrial operations; exposure to consumers while
the flame-retardant product is being used; and exposure to the general population and
environment when releases occur from product disposal or end-of-life recycling. Figure 5-1
presents a simplified life cycle for a flame-retardant chemical used in a PCB, and Table 5-1
summarizes the potential exposure routes that can occur during each of these life-cycle stages.
The remaining sections of Chapter 5 discuss the information summarized in Figure 5-1 and Table
5-1 in more detail.
5-1
-------
Figure 5-1. Life Cycle of Flame-Retardant Chemicals in PCBs (example with Tetrabromobisphenol A
(TBBPA) as reactive FR)
TBBPA, Bisphenol-A,
Epichlorohydrin, and
Other Chemicals
Laminate Producer
Use of Electronics
Disposal of Electronics to:
Recycling
Incinerator Facility with
Controls
Recycling
Facility without
Controls
Shipping of
Laminate
Electronics Store
Landfi" Disassembly
and Smelting.
Shipping of Electronics
Original Equipment
Manufacturer
Printed Circuit Board (PCS)
Manufacturer
Shipping of PCB
5-2
-------
Table 5-1. Potential Exposure to Flame-Retardant Chemicals throughout Their Life Cycle in PCBs
Life Cycle Stage Potential Exposure
Reactive Flame Retardants
Manufacture: Chemical
manufacture, resin
formulation
Pre-impregnated
material (prepreg) and
laminate production
PCB manufacturing and
assembly
Use
End of Life
Manufacture emissions will vary based on manufacturing practices and physical/chemical
properties; direct exposure is possible because the neat chemical is handled.
Cutting of material can release minor amounts of dust that contains epoxy resin. Reactive flame
retardants are part of the polymer (chemically bound), and only trace amounts of unreacted flame
retardant are anticipated to remain in the polymer matrix. Trace quantities are currently
unknown* and/or will vary based on manufacturing methods and processes.
Remaining, unreacted flame retardant may offgas; PCB manufacturing processes, such as drilling,
edging, and routing, cut into the base material. In electronic assembly, some soldering processes
could induce thermal stress on resins, which could yield degradation products. Testing is needed
to determine the potential for formation of these products.
Only residual unreacted flame retardant is available to offgas during use. In order for exposure to
occur, offgassing from residual unreacted flame retardant would have to escape product casing.
Testing is needed to determine exposure potential.
Disassembly/Recycling: Disassembling electronics and shredding PCBs can release dust that
contains epoxy resin. Reactive flame retardants are chemically bound to the polymer; however,
levels of exposure and any subsequent effects of exposure to the reacted flame retardant products
during the disposal phase of the life cycle, in which flame retardants may become mobilized
through direct intervention processes, such as shredding, are unknown.
Landfill: Testing needs to be conducted to determine exposure potential from leaching from PCBs.
Incineration: Combustion by-products need to be considered (see combustion experiments).
Open Burning: Combustion by-products need to be considered (see combustion experiments).
Smelting: Combustion by-products need to be considered.
Additive Flame Retardants
Manufacture: Chemical
manufacture, resin
formulation
Prepreg and laminate
production
PCB manufacturing and
assembly
Use
End of Life
Manufacture emissions will vary based on manufacturing practices and physical/chemical
properties; direct exposure is possible because the neat chemical is handled.
Cutting of material can release minor amounts of dust that contains epoxy resin. Additive flame
retardants are not chemically bound to the polymer, and their potential to offgas or leach out of
the product is not known. Physical/chemical properties, such as vapor pressure and water
solubility, may contribute to the potential for exposure to these chemicals.
Additive flame retardant may offgas; PCB processes, such as drilling, edging, and routing, cut into
the base material. In electronic assembly, reflow or wave soldering processes could induce
thermal stress on resins, which could yield offgas products. Physical/chemical properties, such as
vapor pressure and water solubility, may contribute to the potential for exposure to these
chemicals.
Although flame retardants are embedded in the polymer matrix, testing needs to be conducted to
better understand the offgassing potential of additive flame retardants. Dermal exposure is not
anticipated since the flame retardants are embedded in the polymer matrix.
Disassembly/Recycling: Disassembling electronics and shredding PCBs can release dust that
contains epoxy resin. Additive flame retardants are not chemically bound to the polymer and can
be released through the dust. Physical/chemical properties, such as vapor pressure, may contribute
to the potential for exposure to these chemicals.
Landfill: Testing needs to be conducted to determine exposure potential from leaching from PCBs.
Incineration: Combustion by-products need to be considered (see combustion experiments).
Open Burning: Combustion by-products need to be considered (see combustion experiments).
Smelting: Combustion by-products need to be considered.
*For TBBPA, Sellstrom and Jansen (1995) found about 0.7 micrograms of residual (or "free") TBBPA per
gram of PCB.
5-3
-------
5.1 Potential Exposure Pathways and Routes (General)
The risk associated with a given chemical or substance is largely dependent on how the exposure
potentially occurs. For example, the toxicological effects associated with inhaling the chemical
are different from those associated with ingesting the chemical through food or water. As a
result, exposure is typically characterized by different pathways and routes.
An exposure pathway is the physical course a chemical takes from the source of release to the
organism that is exposed. The exposure route is how the chemical gets inside the organism. The
three primary routes of exposure are inhalation, dermal absorption, and ingestion. Depending on
the hazard of the chemical, exposure from only one or perhaps all three routes may result in risk.
Expected environmental releases and potential exposure routes of chemicals are dependent upon
their physical and chemical properties. For example, a highly volatile liquid can readily
evaporate from mix tanks, potentially resulting in fugitive air releases and potential exposures to
workers who breathe the vapors, while chemicals manufactured as solids may expose workers to
fugitive dust that may be generated, but are unlikely to generate vapors. Each potential exposure
route, along with appropriate endpoints, should be evaluated independently. Endpoints are the
specific toxicological effect, such as cancer, reproductive harm, or organ/tissue damage. There
are circumstances when a chemical has serious effects for a given endpoint, but due to physical
and chemical properties as well as environmental fate, there is minimal potential for the chemical
to be transported from the release point to the endpoint. This may essentially eliminate the
potential pathway and route of exposure and, therefore, eliminate the associated risk.
Table 5-2 highlights key physical, chemical, and fate properties that affect the likelihood for
exposure to occur: the physical state of the chemical, vapor pressure, water solubility, log Kow,
bioaccumulation potential, and persistence. The relevance of each physical, chemical, and fate
property, as well as its impact on exposure potential, is summarized in Table 5-2. Detailed
descriptions of these properties and how they can be used to assess potential environmental
release, exposure, and partitioning, as well as insight into a chemical's likelihood to cause
adverse toxicological effects, can be found in Chapter 4. More detailed information on physical,
chemical, and fate properties of each flame-retardant chemical can be found in the full chemical
hazard profiles in Section 4.9.
5-4
-------
Table 5-2. Key Physical/Chemical and Fate Properties of Flame-Retardant Chemicals
Physical State of Chemical (ambient conditions)
Relevance to exposure: Indicates if a chemical substance is a solid, liquid, or gas under ambient conditions. This is determined from the melting and boiling points. Chemicals
with a melting point more than 25°C are considered solid. Those with a melting point less than 25°C and a boiling point more than 25°C are considered liquid and those with a
boiling point less than 25°C are considered a gas. Physical state influences potential for dermal and inhalation exposure. For chemicals that exist as a gas, there is generally a
potential for direct inhalation but not dermal exposure. For solids, there is potential for the inhalation and ingestion of dust particles and dermal contact. For liquids, there is
potential for direct dermal contact but not for direct inhalation of the liquid (except in operations that produce aerosols).
TBBPA
Solid
D.E.R. 500
Series
Solid
DOPO
Solid
DowXZ-
92547
Solid
Fyrol PMP
Solid
Aluminum
Hydroxide
Solid
Aluminum
Diethylphos-
phinate
Solid
Melamine
Polyphosphate
Solid
Silicon
Dioxide
(amorphous)
Solid
Magnesium
Hydroxide
Solid
Vapor Pressure (mm Hg) at 25°C
Relevance to exposure: Indicates the potential for a chemical to volatilize into the atmosphere. If a chemical has a vapor pressure leading to volatilization at room temperature or
typical environmental conditions, then the chemical may evaporate and present the potential for inhalation of the gas or vapor. For a Design for the Environment (DIE) chemical
alternatives assessment, inhalation exposure is assumed to occur if the vapor pressure is greater than 1 x 10"8 mmHg. A default value of <10"8 was assigned for chemicals without
data that are anticipated to be nonvolatile this is based on EPA HPV assessment guidance (U.S. EPA 1999).
TBBPA
4.7xlO'8
D.E.R. 500
Series
<10-8b,c
DOPO
2.2xlO-5a
DowXZ-
92547
<10-8b,c
Fyrol PMP
<10-8b,c
Aluminum
Hydroxide
<10'8c
Aluminum
Diethylphos-
phinate
<10'8c
Melamine
Polyphosphate
<1Q-8d
Silicon
Dioxide
(amorphous)
<1Q-8d
Magnesium
Hydroxide
<10'8c
' Extrapolated. Estimated based on polymer assessment literature (Boethling and Nabholz, 1997). ° Estimated based on HPV guidance for nonvolatile compounds. Estimated.
Water Solubility (mg/L)
Relevance to exposure: Indicates the potential of a chemical to dissolve in water and form an aqueous solution. Water soluble chemicals present a higher potential for human
exposure through the ingestion of contaminated drinking water (including well water). In general, absorption after oral ingestion of a chemical with a water solubility less than
10"3 mg/L is not expected. Water soluble chemicals are more likely to be transported into groundwater, absorbed through the gastrointestinal tract or lungs, partition to aquatic
compartments, and undergo atmospheric removal by rain washout. A water solubility of 10"3 mg/L is used for large, high molecular weight (MW) non-ionic polymers according
to the literature concerning polymer assessment (Boethling and Nabholz, 1997). A substance with water solubility at or below 10"3 mg/L is considered insoluble.
TBBPA
4.16
D.E.R. 500
Series
<0.001a'b'c
DOPO
3,574e
DowXZ-
92547
<0.62d
0.001°
Fyrol PMP
8.4 (n=l)b
0.1 (n=2)b
0.001 (n>3)a'b'c
Aluminum
Hydroxide
0.09 at 20 °C,
pH6-7
Aluminum
Diethylphos-
phinate
2.5xl03
Melamine
Polyphosphate
2.0xl04
Silicon
Dioxide
(amorphous)
120
Magnesium
Hydroxide
1.78at20°C,
pH8.3
a Estimated based on EPA High Production Volume assessment guidance. Estimated. ° Estimated based on polymer assessment literature (Boethling and Nabholz, 1997).
Estimated based on proprietary components with MW < 1,000.e Measured value for the hydrolysis product of DOPO.
5-5
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Table 5-2. Key Physical/Chemical and Fate Properties of Flame-Retardant Chemicals (Continued)
Log Kow
Relevance to exposure: Indicates a chemical's tendency to partition between water and lipids in biological organisms. A high log Kow value indicates that the chemical is more
soluble in octanol (lipophilic) than in water, while a low log Kow value means that the chemical is more soluble in water than in octanol. Log Kow can be used to evaluate
absorption and distribution in biological organisms, potential aquatic exposure, and potential general population exposure via ingestion. Generally, chemicals with a log Kow <4
are water soluble and bioavailable, chemicals with a log Kow >4 tend to bioaccumulate. Chemicals with a high log Kow also tend to bind strongly to soil and sediment. Log Kow
cannot be measured for inorganic substances, polymers, and other materials that are not soluble in either water or octanol. This is indicated in the table with "No data".
TBBPA
4.54
D.E.R. 500
Series
7.4 (n=0)a
ll(n=l)a
No data (n>2)
DOPO
1.87a
DowXZ-
92547
3.7-7b
Fyrol PMP
3.4 (n=l)a
4.4 (n=2)a
5.3 (n=3)a
6.3 (n=4)a
Aluminum
Hydroxide
No data
Aluminum
Diethylphos-
phinate
-0.44a
Melamine
Polyphosphate
<-2a
Silicon
Dioxide
(amorphous)
No data
Magnesium
Hydroxide
No data
a Estimated. b Estimated based on proprietary components with MW <1,000.
Bioaccumulation Potential
Relevance to exposure: Indicates the degree to which a chemical substance may increase in concentration within a trophic level. Bioconcentration describes the increase in
tissue concentration relative to the water concentrations (environmental sources); bioaccumulation generally includes dietary and environmental sources. As chemicals
bioconcentrate or bioaccumulate, there is a higher potential for them to reach a level where a toxic effect may be expressed. Estimated and/or measured bioconcentration and
bioaccumulation values are presented as ranges based on relevant DIE hazard categories for each chemical. The DIE Alternatives Assessment criteria for bioaccumulation
potential considers both the bioaccumulation factor (BAF) and bioconcentration factor (BCF) values, as follows: Very High (VH) if BAF (log BAF) or BCF (log BCF) is
>5,000 (>3.7); High (H) if BAF or BCF is between 5,000 (3.7-3) and 1,000; Moderate (M) if BAF or BCF is between < 1,000 and 100 (<3-2); and Low (L) if BAF or BCF is
<100 (<2) (see DfE Program Alternatives Assessment Criteria for Hazard Evaluation).
TBBPA
Moderate
(100-<1,000)
D.E.R. 500
Series
High
(l,000-5,000)b
DOPO
Low
(<100)b
DowXZ-
92547
High
(l,000-5,000)b
Fyrol PMP
High
(l,000-5,000)b
Aluminum
Hydroxide
Low
(<100)a
Aluminum
Diethylphos-
phinate
Low
(<100)a
Melamine
Polyphosphate
Low
(<100)b
Silicon
Dioxide
(amorphous)
Low
(<100)a
Magnesium
Hydroxide
Low
(<100)a
a Based on professional judgment. b Based on estimated data.
5-6
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Table 5-2. Key Physical/Chemical and Fate Properties of Flame-Retardant Chemicals (Continued)
Persistence
Relevance to exposure: Indicates the length of time required for a chemical substance to be completely converted to small building blocks including water, carbon dioxide, and
ammonia ("ultimate degradation"). Persistence is typically expressed as a "half-life", which is the time for the amount of the substance to be reduced by one half. For a DfE
chemical alternatives assessment, persistent chemicals include those that have metabolic or degradation products that have long half-lives. The longer a chemical or its
degradation/metabolism products exist in the environment, the higher the likelihood for human or environmental exposure. "Compartments" refer to those environmental media
to which chemicals may partition and include soil, sediment, water and air as standard compartments for fate assessment. Persistence is considered Very High (VH) if the half-
life is >180 days or recalcitrant; High (H) if the half-life is 60-180 days; Moderate (M) if the half-life is <60 days but >16 days; Low (L) if half-life is <16 days OR readily
passes biodegradability test not including the 10-day window; and Very Low (VL) if passes biodegradability test with 10-day window (see DfE Program Alternatives
Assessment Criteria for Hazard Evaluation).
TBBPA
High
(60-180 days)
D.E.R. 500
Series
Very High
(>180 days)c
DOPO
High
(60-180 days)3
DowXZ-
92547
Very High
(>180 days)c
Fyrol PMP
Very High
(>180 days)c
Aluminum
Hydroxide
High
(60-180 days)b
Aluminum
Diethylphos-
phinate
High
(60-180 days)b
Melamine
Polyphosphate
High
(60-180 days)b
Silicon
Dioxide
(amorphous)
High
(60-180 days)b
Magnesium
Hydroxide
High
(60-180 days)b
' Based on results from biodegradation estimation model. b Based on professional judgment. ° Estimated based on polymer assessment literature (Boethling and Nabholz, 1997).
5-7
-------
5.2 Potential Occupational Releases and Exposures
The unit operations associated with each part of the PCB manufacturing supply chain result in a
unique set of potential release points and occupational exposures to flame-retardant chemicals.
This section provides a general overview of occupational pathways and routes of exposure, and
then identifies the specific processes and corresponding potential release and exposure points for
the unit operations associated with the manufacturing of flame retardants, epoxy resins,
laminates, and PCBs. It should be noted that many of the potential occupational exposures
identified here have been reduced or eliminated by the use of engineering controls and personal
protective equipment. Also, the level of exposure will vary considerably between workers and
the general population. Some releases will only result in exposure for workers, while other
releases result in exposures for the environment and the general population.
Inhalation Exposures
The physical state of the chemical during chemical manufacturing and downstream processing
significantly affects the potential for inhalation exposure of workers. In particular, the physical
state can result in three types of inhalation exposures that should be evaluated.
Dust: Chemicals that are manufactured, processed, and used as solids have the potential to result
in occupational exposure to fugitive dusts. The potential for fugitive dust formation depends on
whether the solid chemical is handled in the crystalline form, as an amorphous solid, or as a fine
powder, as well as the particle size distribution and solids handling techniques. If there is
exposure to dust, the level of exposure is directly proportional to the concentration of chemical in
the particulate form. Therefore, a flame retardant that is used at a lower concentration results in a
decreased exposure from this pathway and route (assuming that an equivalent amount of dust is
inhaled).
When assessing occupational exposures to flame-retardant chemicals, it is important to note the
physical state of the chemical at the potential point of release and contact. The pure chemical
may be manufactured as a solid powder, indicating a potential exposure to dust. However, it may
be formulated into solution before any workers come in contact with it, thereby eliminating
inhalation exposure to dust as a potential route. It is also important to note that the size of the
dust particles may have a profound influence on the potential hazards associated with inhalation
exposures for those materials that are not anticipated to be absorbed in the lungs. For these
materials, the potential hazards are typically associated with smaller, respirable particles
(generally those less than 10 microns in diameter).
Vapor: Exposure to vapors can occur when liquid chemicals volatilize during manufacturing,
processing, and use. Most chemical manufacturing operations occur in closed systems that
contain vapors. However, fugitive emissions are expected during open mixing operations,
transfer operations, and loading/unloading of raw materials. More volatile chemicals volatilize
more quickly and result in greater fugitive releases and higher occupational exposures than less
volatile chemicals. Therefore, vapor pressure is a key indicator of potential occupational
exposures to vapors.
5-S
-------
Mist: Both volatile and nonvolatile liquids can result in inhalation exposure if manufacturing or
use operations result in the formation of mist. It is unlikely that flame-retardant chemicals used
in PCBs will be applied as a mist.
Dermal Exposures
Occupational dermal exposure is also affected by the physical state of the chemical at the point
of release and contact. For example, the likelihood of liquids being splashed or spilled during
sampling and drumming operations is different than for similar operations involving polymerized
solids, powders, or pellets. Dermal exposure is also generally assumed to be proportional to the
concentration of chemical in the formulation. For example, the dermal exposure from contacting
a pure chemical is greater than the exposure from contacting a solution that contains only 10
percent of the chemical. Screening-level evaluations of occupational dermal exposure can be
based on the worker activities involving the chemical. For example, there may be significant
exposure when workers handle bags of solid materials during loading and transfer operations.
Maintenance and cleanup activities during shutdown procedures, connecting transfer lines, and
sampling activities also result in potential dermal exposures.
Ingestion Exposures
Occupational exposures via ingestion typically occur unintentionally when workers eat food or
drink water that has become contaminated with chemicals. Several pathways should be
considered. Often the primary pathway is poor worker hygiene (eating, drinking, or smoking
with unwashed hands). First, dust particles may spread throughout the facility and settle (or
deposit) on tables, lunchroom surfaces, or even on food itself. Vapors may similarly spread
throughout the facility and may adsorb into food and drinking water. Another potential pathway
for ingestion occurs from dust particles that are too large to be absorbed through the lungs. These
"non-respirable particles" are often swallowed, resulting in exposures from this route. While
ingestion is considered to be a realistic route of exposure to workers, it is often considered less
significant when compared to inhalation and dermal exposures, based on the relative exposure
quantities. On the other hand, ingestion during consumer use and to the general population is
often as significant as or more important than the inhalation and dermal routes. If persistent and
bioaccumulative compounds get into the environment and build up in the food chain, they can
become a significant exposure concern.
5.2.1 Flame Retardant and Epoxy Resin Manufacturing
The specific unit operations, operating conditions, transfer procedures, and packaging operations
vary with the manufacture of different flame-retardant and resin chemicals. Potential releases
and occupational exposures will depend on each of these parameters. While it is outside the
scope of this report to identify and quantify the releases and exposures associated with individual
chemicals, this section presents a general description of typical chemical manufacturing
processes and identifies potential releases.
Figure 5-2 presents a generic process flow diagram for epoxy resin manufacturing. Production
volumes and batch sizes associated with flame-retardant and epoxy resin chemicals typically
require the raw materials to be stored in large tanks or drums until use. The first step in most
5-9
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epoxy resin manufacturing processes for standard Flame Resistant 4 materials is to load the raw
materials into some type of reactor or mix tanks - as shown in Figure 5-2, the tanks labeled as
liquid epoxy resin and reactive flame retardant (e.g. TBBPA) hopper. Next, large-quantity
liquids are typically pumped into the reactor, and small-quantity raw materials may be manually
introduced or carefully metered via automated systems. Releases may occur from these
operations, but occupational exposure potential is typically small due to the number of safety
procedures and engineering controls in place.
Throughout the resin manufacturing process, there are several release points that may pose an
exposure risk to workers: packaging operations, leaks from pumps and tanks, fugitive emissions
from equipment, cleaning of process equipment, and product sampling activities. Additionally,
crude or finished products are often stored on-site in drums, day-tanks, or more permanent
storage vessels until the flame-retardant epoxy resin is packaged and shipped to the laminator.
The transfer and packaging operations, as well as any routine and unplanned maintenance
activities, may result in releases of and exposures to hazardous chemicals.
5-10
-------
Figure 5-2. Epoxy Resin Manufacturing Process (example with TBBPA as reactive FR)
-P
8isphenol-A
Ctiustk Carbonate
epiehlortiydrin
ci r.
.....
Sioroge
^^^,^^^
S'c-ngc
hi
___^^
Storage
Delivery to Limintfor
5-11
-------
5.2.2 Laminate and Printed Circuit Board Manufacturing
The laminate and PCB manufacturing processes, summarized in Figure 5-3 and Figure 5-4, can
result in occupational exposures to process chemicals if protective measures are not put in place.
The potential release of flame-retardant chemicals from laminates is not known, but is probably
very low, if there is any at all. As shown in Figure 5-3, the laminator combines the flame-
retardant epoxy resin with a curing agent (or hardener) and a catalyst in a mix tank as a first step
of the laminate manufacturing process. From there, woven fiberglass mats are embedded with
the epoxy resin, resulting in prepreg sheets. A copper clad laminate (CCL) is then assembled by
layering the prepreg sheets with copper sheets and stainless steel caul plates, as shown in Figure
5-3. The finished CCL is then shipped to the PCB manufacturing facility.
As summarized in Figure 5-4, PCB manufacturing involves numerous chemical and
electrochemical processes to cut, drill, clean, plate, and etch conductive pathways. Almost all of
these processes involve immersion of equipment or work pieces into a series of process baths,
with each bath followed by a rinsing step. For example, the process of drilling holes in the PCB
involves a series of individual steps, including cleaning (or desmearing) the holes with chemicals
or gas plasma and plating the holes with copper, and each step requires at least one process bath
and rinsing.
Many PCB manufacturers have implemented relatively simple techniques to reduce the amount
of chemicals that enter wastewater, such as withdrawing equipment from tanks slowly to allow
maximum drainage back into the process tank (CA EPA, 2005). Most manufacturing facilities
prevent worker exposure through use of engineering controls, personal protective equipment, and
safe work practices.
5-12
-------
Figure 5-3. Laminate Manufacturing Process
StairJess Stic!
Caul Pkries
Lamination
Quality Assurance
Packaging
Shipp -s
5-13
-------
Figure 5-4. Printed Circuit Board Manufacturing Process
1. Etch conductive pathways on inner layers
Laminate cares
Photoresist, developing cher^cals
etching salljtion, res*st stripp|.rg
soluticr, clecring and oxidairg
chemicals
2. Combine layers
I
t
5. Etch conductive
pathways on outer layers
4. Plate tin or tin-Iced etch
resist
Etching solution, resist stripping
solutoar.and cleaning chemicals
aoQ&ao
00004X1
Photcrcsiist and de
chemicals for plating etch resist
3. Drill clean (i
ond plate holes
0
a
QOaOOO
a
o
a
t
f "\
/ Chemicals or gas plasma fop \
desmeoi-irxj, chemicals and metal |
\ tons for ccppcr platir^ /
U LJ
V
6. Apply surface ftni:h(ei)
Chemicals for plating metals or
7. 5tencil legend, clean
circuit board (optional)
Irk. water, and/or civcr solvents
8. Attach electronic
component: to circuit board
(may be done at electronics
manufacturing facility)
5-14
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5.2.3 Best Practices
Incorporating best practices into the manufacturing process can reduce the potential for
exposure. The Bromine Science and Environmental Forum (BSEF) set up the Voluntary
Emissions Control Action Programme (VECAP) "to manage, monitor and minimize industrial
emissions of brominated flame retardants into the environment through partnership with Small
and Medium-sized Enterprises." The program started with decabromodiphenyl ether in Europe.
VECAP members follow six central steps to continually improve their processes and reduce
emissions: (1) commitment to the VECAP code of good practices; (2) self-audit; (3) mass
balance; (4) baseline emissions survey; (5) emissions improvement plan; and (6) implementation
and continuous improvement (BSEF, 2007).
ISO, the International Organization for Standardization, has also developed a series of
environmental management standards under the 14000 label. ISO 14000 standards establish a
"holistic, strategic approach" for continually reducing negative environmental impacts. They are
intended to cover a wide range of operations, and thus are not specific to brominated flame
retardants (ISO, 2007).
5.3 Potential Consumer and General Population Exposures
Exposures to consumers and the environment are different from exposures to workers and should
be evaluated separately for a number of reasons. Occupational exposures typically result from
direct contact with chemicals at relatively high concentrations while workers are conducting
specific tasks. Conversely, consumers may be exposed over a much longer period, but to a much
smaller level because the chemical is incorporated into the product. Also, the general population
and the environment will be exposed via different pathways and routes from workers and
consumers. For example, a person who does not own a product containing a flame-retardant PCB
may still be exposed if the chemical leaches from the disposed product into the drinking water
supply. Once in the water supply, groundwater, or surface water, it can be ingested by people or
consumed by fish and other animals. Similarly, if the chemical is released to the atmosphere
during manufacture, use, or disposal, it may settle out on food crops and be ingested directly by
people, or by cattle or other livestock. If the chemical is bioaccumulative, it may concentrate in
the animal and reach people through the food chain. For these reasons, exposure to the
environment and the general population should be assessed independently from occupational
exposure.
A quantitative exposure assessment is outside the scope of this report. However, the primary
pathways and routes from environmental, general population, and consumer exposures are
discussed in the following sections. Important chemical-specific factors that may help the reader
compare potential exposure between various flame-retardant alternatives are also discussed.
5.3.1 Physical and Chemical Properties Affecting Exposures
As previously discussed, the physical and chemical properties of a chemical often determine the
pathways and routes of exposure. In addition, the physical and chemical properties will affect
how the chemical becomes distributed in the environment once it is released, which will, in turn,
influence the potential for the chemical to be transported from the release point to the receptor.
5-15
-------
Information about persistence, bioaccumulation, and physical and chemical properties affecting
transport in the environment is presented in Section 4.3 of this report as well as Table 5-2.
As discussed in Chapter 3, flame-retardant chemicals can be classified as either additive or
reactive and this distinction may affect exposure. Additive flame retardants are added to a
manufactured product without bonding or reacting with the product, whereas reactive flame
retardants are chemically reacted into the raw materials that are used to make the final product.
As of 2008, most PCBs use reactive TBBPA, which loses the identity of the starting monomer
material during polymerization. Because they are chemically bound to PCBs, reactive flame
retardants are much less likely to pose occupational, consumer, or environmental exposure
concerns than additive flame retardants. Moreover, the polymerization processes are typically
conducted in totally enclosed systems, thus minimizing the potential for occupational exposure.
It should be noted, however, that reactive chemicals or close analogs could be released from the
finished product if a portion of the chemicals is not completely reacted during the polymerization
process. According to a 1995 study, a trace amount of starting TBBPA material is unreacted after
polymerization (4 micrograms per gram) (Sellstrom and Jansson, 1995).
5.3.2 Consumer Use and End-of-Life Analysis
Consumer Use
The nature of exposure to PCBs during use will vary with the composition of the product and the
manner in which the product is used. However, little information existed in the literature in 2008
about the emissions potential of alternative flame retardants from the use of electronic products.
Similarly, little to no research has addressed whether the type of flame retardants used in PCBs
potentially affects these emissions.
Several studies have examined the potential of brominated flame retardants to volatilize or offgas
from electronic devices. A study conducted by the German laboratory ERGO, which investigated
offgassing potential of TBBPA from computers under both real-world conditions and chamber
conditions, found that all emissions of TBBPA were associated with the housing material
(additive application of TBBPA), none with the printed circuit boards (reactive application of
TBBPA) (HDPUG, 2004). The German Federal Institute of Materials Testing also conducted
chamber emission testing of flame retardants from electronic articles and construction products.
They found very low emissions, even at the elevated operating temperatures of computers
(Kemmlein et al., 2003). Beard and Marzi (2006) investigated the offgassing potential of
thermoplastic polymers containing phosphorus-based and brominated flame retardants by
simulating extreme indoor car heat conditions as a worst case scenario; the study found very low
levels of volatilization (0 to 6 mg/kg).
Without further information on the exposure potential associated with printed circuit board use,
the differences between flame-retardant alternatives cannot be estimated. Additive flame
retardants, which are not commonly used in PCBs, are more likely to generate emissions than
reactive flame retardants. However, for additive flame retardants the potential for offgassing is
directly related to the volatility of the chemical (vapor pressure), which again is related to
molecule size and weight.
5-16
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End-of-Life Pathways
The amount of electronic waste (e-waste) generated annually in the U.S. is growing rapidly.
According to an EPA study, the amount of electronic products either recycled or disposed of
annually increased from an estimated 1.1 million tons in 1999 to 2.2 million tons in 2005 (OSW
1, 2007). While electronics represent less than 2 percent of the total municipal solid waste
stream, electronics contain many toxic substances that can adversely affect the environment and
human health (OSW 1, 2007).
In the U.S., used electronic goods are typically purchased by equipment handlers, such as
brokers and liquidation or auction services, or by equipment processors, such as refurbishers and
recyclers. Most used electronic goods then undergo a series of tests to determine their condition.
If a device is in good condition, it is reused either in part or in whole. Devices not in satisfactory
condition become e-waste, and are sent to demanufacturing and destruction facilities where raw
materials are either disposed of or recycled.
The manner in which electronic waste is disposed of or recycled determines the potential
environmental and human health impacts.11 An EPA study indicates that 15 to 20 percent of e-
waste is recycled, and 80 to 85 percent is disposed of (includes landfill and incineration) (OSW
1, 2007). Of the e-waste that is recycled, a portion is shipped overseas. For example, 61 percent,
or 107,500 tons of cathode ray tubes were shipped overseas in 2005 for remanufacture or
refurbishment (OSW 2, 2007). Of the e-waste shipped overseas, an unknown portion is
disassembled and recycled under largely unregulated conditions. The following sections describe
disassembly and recycling practices typical of unregulated overseas conditions and summarize
the nature of their potential impact.
Recycling
As Figure 5-5 shows, the PCB recycling process can involve both thermal processing, such as
smelting to recover precious metals, and nonthermal processing, such as disassembly, shredding,
separation, and chemical treatment. The potential level of exposure to workers and the general
population that results from these processes will vary depending on the type of operation
employed. Many recycling operations employ these methods in safe conditions that minimize the
potential for exposure, and recover valuable metals that are part of finished boards.
1: According to a 2005 UN report, up to 50 million metric tons of e-waste is generated annually. In the U. S., the
amount of e-waste is increasing at three times the rate of general waste, http://www.rrcap.unep.org/policy2/13-
Annex%204a-e-wastes%20SEPD2.pdf
5-17
-------
Figure 5-5. Sketch of the PCB Recycling Process (Li et al., 2004)
PCB
I
Composition Analysis
Hydrometallurgical
Processing
I
Disassembly
Reusable Units
Toxic Units
Shredding/Separation
Pyrolysis
Mechanical
Processing
Smelting
The thermal process of smelting separates valuable metals, such as gold, silver, platinum,
palladium, selenium, and copper, from impurities in PCBs (Figure 5-6). The process operates by
heating PCBs in a furnace to about 1,200 to 1,250°C in the presence of a reducing agent, which
is usually carbon from fuel oil or the organic portion of PCBs. Silicate, such as silicon dioxide, is
also added to help control reaction temperatures, and excess process gases are burned and
purified to remove contaminants (Kindesjo, 2002). Therefore, silicon dioxide-based flame
retardants are beneficial to the smelting process (Lehner, 2008).
PCBs
Figure 5-6. Smelting Process (Kindesjo, 2002)
Fuel
Oil Silicate
1 1
s * Smelting
1
Process
Furnace
1
Slag
Metals
^ continue
recovery
process
gasses
The smelting process generates two layers inside the furnace, a top layer of slag and a bottom
layer of "black copper." The bottom black copper layer can be directly sent to a copper recovery
unit, such as a copper converter or leaching and electrowinning facility (Umicore, 2007). The top
layer of slag is further processed to separate metals from impurities. After slag processing is
complete, leftover slag is deposited in impoundment areas (Kindesjo, 2002).
5-18
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In the absence of proper control equipment, the smelting process may pose risks to workers and
the public through exposure to toxic chemicals. Halogenated flame retardants, for example, can
lead to the formation of dioxins during the smelting process if proper safety measures are not
installed (Tohka, 2002). However, the three primary smelters in the world as of 2008 - Boliden,
Umicore, and Noranda - have learned how to operate with high loads of halogenated electronic
scrap and effectively control emissions of dioxins and furans, mercury, antimony, and other toxic
substances. In addition to the potential emission of toxic chemicals, high operating temperatures
may create occupational hazards. High loads of bromine or chlorine may induce corrosion of
gas-cleaning equipment. In sensitive areas, a process step for halogenide recovery may need to
be added (Lehner, 2008).
In contrast to the recycling practices described above, a large portion of the e-waste shipped
overseas to China, India, Pakistan, and other developing countries is subjected to unregulated
recycling practices that may pose significant exposure concerns. Much of the PCB waste in
unregulated operations is subject to open burning and acid leaching to recover precious metals.
The Basel Action Network (BAN), which has visited open burning sites in Asia, reports that the
general approach to recycling a circuit board first involves a de-soldering process. The PCBs are
placed on shallow wok-like grills that are heated underneath by a can filled with ignited coal. In
the wok-grill is a pool of molten lead-tin solder. The PCBs are placed in the pooled solder and
heated until the chips are removable, and then the chips are plucked out with pliers and placed in
buckets. The loosened chips are then sorted between those valuable for re-sale and those to be
sent to the acid chemical strippers for gold recovery. After the de-soldering process, the stripped
circuit boards go to another laborer who removes small capacitors and other less valuable
components for separation with wire clippers. After most of the board is picked over, it then goes
to large scale burning or acid recovery operations. It is this final burning process that potentially
emits substantial quantities of harmful heavy metals, dioxins, beryllium, and poly cyclic aromatic
hydrocarbons (PAHs) (BAN and SVTC, 2002). The chemicals released through these processes
can be inhaled by workers or could leach into the soil and water surrounding the area. In 2005,
Greenpeace collected industrial wastes, indoor dusts, soils, river sediments, and groundwater
samples from more than 70 industrial units and dump sites in Guiyu, China, and New Delhi,
India, and found elevated levels of lead, tin, copper, cadmium, antimony, polybrominated
diphenyl ethers, and polychlorinated biphenyls (Greenpeace, 2005).
In terms of the size of the population potentially at risk from open burning practices, the local
government website of Guiyu reported that the city processes 1.5 million tons of e-waste every
year, resulting in $75 million in revenue (Johnson, 2006). The People's Daily, the state-run
newspaper, reported in 2007 that Guiyu's more than 5,500 e-waste businesses employed more
than 30,000 people, and state media estimated that almost 9 out of 10 people in Guiyu suffered
from problems with their skin, nervous, respiratory, or digestive systems, which may be linked to
these practices (Chisholm and Bu, 2007).
In order to better understand the effects of combustion processes, the relationship between
specific combustion scenarios and the release of specific quantities of harmful substances has
been further analyzed as part of this project. The results of these tests are presented in Chapter 6.
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Landfills
E-waste sent to a landfill can lead to the creation of leachate (i.e., the mixture of rainwater and
liquids within the waste). This leachate has the potential to seep into the ground or drain into
nearby surface water, where it could affect the environment and have a negative impact on food
and water supplies.
Most teachability studies as of 2008 in the literature have focused on the potential for discarded
electronic devices to leach lead and other heavy metals. A relatively small number of these
studies have investigated teachability potential of brominated flame retardants, and in general,
have found either no or very small concentrations of brominated compounds in the leachate.
When brominated flame retardants are added versus reacted into the resin system, the potential
for the brominated flame retardants to leach from PCBs is much greater (KemI, 1995).
A study conducted by Beard and Marzi (2006) investigated the teachability potential of
phosphorus-based and brominated flame retardants from thermoplastic polymers and found that
small amounts of phosphorus and bromine respectively leached from the polymer. Another study
(Yoneda et al., 2002) reported that a small amount of phosphate ions leached from a Fujitsu-
developed dielectric material consisting of a bisphenol A epoxy with an additive type organic
phosphate in hot water and aqueous alkaline solutions. When Fujitsu developed and tested a
dielectric material consisting of a naphthalene-based epoxy with reactive-type organic
phosphate, no phosphate ions leached from the material.
Aside from the studies referenced above, little information exists in the literature about the
teachability potential of alternative flame retardants in landfill environments. Similarly, little to
no research has addressed whether the type of flame retardants used in PCBs potentially affects
the teachability of heavy metals.
5.4 Methods for Assessing Exposure
The European Union (EU)'s risk assessment of TBBPA offers insight into how personal and
environmental exposure can be evaluated for flame-retardant chemicals. The EU risk assessment
consists of two parts: the human health assessment, which was finalized in 2006, and the
environmental assessment, which remains in draft form. As part of the human health and
environmental risk assessments, exposure assessments have been conducted to estimate the
levels of TBBPA released in occupational settings and in the general environment. In both, the
EU differentiated between reactive and additive TBBPA and considered different stages of the
life cycle when estimating releases. While the results of the EU risk assessment are not being
used as part of this partnership project, Table 5-3 and Table 5-4 highlight some of the key
methods and assumptions used to estimate emissions of TBBPA used as a reactive flame
retardant in epoxy and other resins.
In the human health exposure assessment, the term exposure is used to denote personal exposure
without the use of any personal protective equipment. The EU used both measured and predicted
exposure data. Given the lack of TBBPA exposure data, the United Kingdom (UK) Health and
Safety Executive (HSE) commissioned sampling studies within the UK at four sites: two sites
involved in the production of polymers where TBBPA is incorporated into the finished product
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(one of which manufactures resin laminates), and two sites where polymer products are recycled.
The EU supplemented the measured exposure data with predicted data from the EASE
(Estimation and Assessment of Substance Exposure) model, which is widely used across the EU
for occupational exposure assessment of new and existing chemicals.
Table 5-3. Human Health Exposure Assessment (EU Risk Assessment, 2006)
Life-Cycle
Stage
Key Methods/Assumptions
Source of Data
Production
of laminates
Inhalation exposure;
HSE visited a manufacturing facility of copper/resin laminates used for PCBs in 2002
to measure personal inhalation exposure. Used one personal sampler during the
bromination step and multiple personal and static samplers during other steps of the
laminate process. Due to uncertainty surrounding the measured estimates, EU used
EASE model to estimate "typical" and "worst-case" inhalation values for bromination
and other laminate production steps.
Dermal exposure:
EASE model used to estimate "typical" and "worst-case" dermal values for
bromination and other laminate production steps.
Sampling results
from 2002 study at
UK laminate
manufacturing
facility; EASE model
Computer
recycling
Inhalation exposure;
HSE visited recycling facility where PCBs are shredded and exported for recovery of
precious metals in 2002. Used personal and static samplers during shift. EU used
EASE model to estimate "typical" and "worst-case" inhalation exposures.
Dermal exposure:
EASE model used to estimate dermal exposure values. Predicted to be very low;
consequently, dermal exposure values not used by EU in exposure assessment.
Sampling results
from 2002 study at
UK recycling facility;
EASE model
PCB
Assembly
Inhalation exposure;
Results of Sjodin et al., 2001 study, which measured levels of TBBPA in a factory that
assembles PCBs, used to establish "typical" and "worst-case" inhalation values.
Dermal exposure:
Dermal exposure assumed to be negligible given the low levels of free TBBPA in
PCBs.
Sjodin etal., 2001;
professional
judgment of risk
assessors
Office
environment
Inhalation exposure;
Results of Sjodin et al., 2001 study, which measured levels of TBBPA in a factory that
assembles PCBs, used to establish "typical" and "wo |