v/EPA
United States
Environmental Protection Agency
EPA Document** 743-D1-5001
         August 2015
Office of Chemical Safety and
     Pollution Prevention
                  TSCA Work Plan Chemical
         Problem Formulation and Initial Assessment

               Cyclic Aliphatic Bromides Cluster
                      Flame Retardants
                         Br
                                    Br
CASRN
25637-99-4
3194-55-6
3194-57-8
NAME
Hexabromocyclododecane
1,2,5,6,9,10-Hexabromocyclododecane
1,2,5,6-Tetrabromocyclooctane
                          August 2015

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TABLE OF CONTENTS

TABLE OF CONTENTS	2

AUTHORS / CONTRIBUTORS / ACKNOWLEDGEMENTS	5

ABBREVIATIONS	6

EXECUTIVE SUMMARY	8

1    INTRODUCTION	11

  1.1    SCOPE OF THE ASSESSMENT	12
  1.2    REGULATORY AND ASSESSMENT HISTORY	14

2    PROBLEM FORMULATION	16

  2.1    PHYSICAL AND CHEMICAL PROPERTIES	16
  2.2    PRODUCTION VOLUME AND USES	17
     2.2.1  Production Volume	17
     2.2.2  Uses	18
       2.2.2.1   Use in Expanded Polystyrene Foam (EPS) and Extruded Polystyrene Foam (XPS)	18
       2.2.2.2   Use in Textiles	19
          2.2.2.2.1  Use in Automotive Textiles	19
          2.2.2.2.2  Historic Use in Textiles	20
       2.2.2.3   Use in High Impact Polystyrene (HIPS)	20
       2.2.2.4   Other Identified Uses	20
       2.2.2.5   Summary of All Uses	21
          2.2.2.5.1  Summary of CDR Information	21
          2.2.2.5.2  Summary of EU Data	21
     2.2.3  Future Market Trends	21
  2.3    FATE AND TRANSPORT	21
  2.4    EXPOSURES	22
     2.4.1  Releases to the Environment	22
     2.4.2  Presence in the Environment	23
       2.4.2.1   Surface Water	23
       2.4.2.2   Wastewater	23
       2.4.2.3   Sludge	23
       2.4.2.4   Soil	23
       2.4.2.5   Sediment	24
       2.4.2.6   Biota	24
     2.4.3  Occupational Exposure	24
     2.4.4  General Population Exposure	25
       2.4.4.1   Ambient Air	25
       2.4.4.2   Drinking Water	25
       2 A A3   Fish Consumption	25
       2.4.4.4   Biomonitoring	25
     2.4.5  Consumer Exposures	26
  2.5    HAZARD ENDPOINTS	26
     2.5.1  Ecological Hazard	26
     2.5.2  Human Health Hazard	27
  2.6    RESULTS OF PROBLEM FORMULATION	27
     2.6.1  Conceptual Model	27
     2.6.2  Analysis Plan	31
       2.6.2.1   Workers	31
       2.6.2.2   Risks to General Population and Environmental Biota (aquatic, terrestrial and avian)	32
       2.6.2.3   Consumers	33

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     2.6.3  Sources and Pathways Excluded From Further Assessment	34
     2.6.4  Uncertainties and Data Gaps	34
       2.6A.I  Exposure Assessment	34
          2.6.4.1.1   Releases to the Environment	34
          2.6.4.1.2   Occupational Exposure	35
          2.6.4.1.3   General Population and Consumer Exposure	35
       2.6.4.2  Ecological Endpoints	36
       2.6.4.3  Human Health Endpoints	36
REFERENCES	37
APPENDICES	61
Appendix A  Regulatory and Assessment History	61
Appendix B  Uses Supplement Tables	64
Appendix C  Exposure Supplement Tables	69
Appendix D  Environmental Hazard Study Summaries	74
  D-l     PERSISTENCE IN ENVIRONMENTAL MEDIA	74
     D-l-1   Air and Water	74
     D-l-2   Soil, Sediment and Sludge	74
     D-l-3   Water and Wastewater	76
     D-l-4   Bioaccumulation	76
  D-2     TOXICITY TO AQUATIC ORGANISMS	77
     D-2-1   Aquatic Plant Toxicity	77
     D-2-2   Aquatic Invertebrate Toxicity.	78
     D-2-3   Fish Toxicity	80
  D-3     TOXICITY TO TERRESTRIAL ORGANISMS	83
     D-3-1   Terrestrial Plant Toxicity	83
     D-3-2   Soil Invertebrate Toxicity	83
     D-3-3   Avian Toxicity	84
Appendix E  Human Health Hazard Study Summaries	85
  E-l     TOXICOKINETICS	85
  E-2     ACUTE TOXICITY STUDIES	85
  E-3     REPEATED-DOSE TOXICITY STUDIES	86
  E-4     REPRODUCTIVE AND  DEVELOPMENTAL TOXICITY STUDIES	88
  E-5     SKIN IRRITATION AND SENSITIZATION STUDIES	94
  E-6     GENOTOXICITY AND CANCER STUDIES	94

LIST OF TABLES
Table 2-1: Select Physical-Chemical Properties *	17
Table 2-2: Summary of Use/Exposure Scenarios Considered for Assessment	28
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LIST OF APPENDIX TABLES
Table_Apx A-l: Regulatory and Assessment History of HBCD	61
Table_Apx B-l: 2012 CDR Production Data (Data Reported for 2011)	64
Table_Apx B-2: Historic IUR and CDR Production Volumes	65
Table_Apx B-3: Summary of 2011 CDR Production Volume and Use Information	65
Table_Apx B-4: Uses of HBCD as Listed in the 2008 EU Risk Assessment	67
Table_Apx C-l: 2012 CDR Data (Data Reported for 2011) for Release Assessment	69
Table_Apx C-2: Compilation of Release Factors and Other Release-Related Information in
Various Risk Assessments	70
Table_Apx C-3: Preliminary Values of Input Variables for Calculation of the Range of Release
Rates from Manufacturing Sites or the Processing Sites of Each Processing Step	72
Table_Apx D-l: Percent Decrease in Total Initial Radioactivity in Viable Systems and Abiotic
Controls During Sludge, Sediment, and Soil Simulation Tests Using 14C-labeled HBCD	75
Table_Apx D-2: Toxicity of HBCD to Aquatic Plants	78
Table_Apx D-3: Toxicity of HBCD to Aquatic Invertebrates	79
Table_Apx D-4: Toxicity of HBCD to Sediment Organisms	80
Table_ApxD-5: Toxicity of HBCD to Fish	82
Table_Apx D-6: Toxicity of HBCD to Terrestrial Plants	83
Table_Apx D-7: Toxicity of HBCD to Terrestrial Invertebrates	83
Table_ApxD-8: Toxicity of HBCD to Avian Species	84
Table_Apx E-l: Acute Oral Toxicity of HBCD	85
Table_Apx E-2: Acute Inhalation Toxicity of HBCD	86
Table_Apx E-3: Repeated-Dose Toxicity of HBCD	87
Table_Apx E-4: Reproductive and Developmental Toxicity of HBCD*	89
Table_Apx E-5: Summary of Effects in Parental and Fl Rats After Dietary, Gestational,
Lactational and Postnatal Exposure to HBCD	93
Table_Apx E-6: Genotoxicity of HBCD	96

LIST OF FIGURES
Figure 1-1: Generic Structure of Cyclic Aliphatic Bromides	12
Figure 2-1: Conceptual Model for HBCD	28

LIST OF APPENDIX FIGURES
Figure_Apx 2.6.4-1: Stepwise Reductive Dehalogenation of HBCD	76
Figure_Apx 2.6.4-2: Exposure-Response Array for Developmental and  Reproductive Toxicity
Studies of HBCD	92
Figure_Apx 2.6.4-3: Exposure-Response Array for Neurological Effects of HBCD	94
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AUTHORS / CONTRIBUTORS /ACKNOWLEDGEMENTS

This report was developed by the United States Environmental Protection Agency (US EPA),
Office of Chemical Safety and Pollution Prevention (OCSPP), Office of Pollution Prevention and
Toxics (OPPT). The Work Plan Chemical Problem Formulation for the cyclic aliphatic bromides
cluster was prepared based on currently available data. Mention of trade names does not
constitute endorsement by EPA.

EPA Assessment Team
Leads:
Susan A. Laessig, OPPT/Risk Assessment Division (RAD)
Maria Szilagyi, OPPT/RAD

Team Members:
Katherine Anitole, OPPT/RAD
Charles Bevington, OPPT/RAD
Christina Cinalli, OPPT/RAD
Ana Corado, OPPT/Environmental Assistance Division (EAD)
Majd El-Zoobi, OPPT/RAD
Conrad Flessner, OPPT/RAD
Greg Fritz, OPPT/Chemistry, Economics & Sustainable Strategies Division (CESSD)
Amuel Kennedy, OPPT/RAD
Emma Lavoie, OPPT/CESSD
Timothy Lehman, OPPT/CESSD
Laurence Libelo, OPPT/RAD
Sue Slotnick, OPPT/National Program Chemicals Division (NPCD)
Teresa Washington, OPPT/RAD
Eva Wong, OPPT/RAD

Management Leads:
MarkTownsend, OPPT/RAD
Nhan Nguyen, OPPT/RAD

Acknowledgements
Andrea Pavlick, visiting AAAS Science & Technology Policy Fellow, contributed to discussions
during problem formulation.

Portions of this document were prepared for EPA/OPPT by Abt Associates, the Eastern Research
Group (ERG), Inc., the Syracuse Research Corporation (SRC) and Versar.

Docket
Please visit the public docket (Docket: EPA-HQ-OPPT-2015-0081) to view supporting
information.

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ABBREVIATIONS
BFR          Brominated Flame Retardant
CASRN       Chemical Abstract Service Registry Number
CBI          Confidential Business Information
CDR          Chemical Data Reporting
CEC          Commission for Environmental Cooperation
CPSC         Consumer Product Safety Commission
EC           European Commission
ECHA         European Chemicals Agency
EFAST        Exposure and Fate Assessment Screening Tool
EPA          Environmental Protection Agency
EPS          Expanded Polystyrene
EU           European Union
FR           Flame Retardant
GD          Gestation Day
GLP          Good Laboratory Practices
HBCD         Hexabromocyclododecane
HIPS         High Impact Polystyrene
HPV          High Production Volume
HQ          Hazard Quotient
IRIS          Integrated Risk Information System
IUR          Inventory Update Reporting Rule
kg           Kilogram(s)
KOW          OctanohWater partition coefficient
Ib           Pound
LOEL         Lowest Observed Effect Level
Log KOW      Logarithmic Octanol:Water partition coefficient
mg          Milligram(s)
MOE         Margin of Exposure
ng           nanogram
NHANES      National Health and Nutrition  Examination Survey
NICNAS      National Industrial Chemicals Notification  and Assessment Scheme
NKRA         Not Known or Reasonably Ascertainable
NOAEL       No-observed-adverse-effect level
OCSPP       Office of Chemical Safety and Pollution Prevention
OECD         Organisation for Economic Co-operation and Development
OPPT         Office of Pollution Prevention and Toxics
OSHA         Occupational  Safety and Health Administration
PBT          Persistent, Bioaccumulative and Toxic
pg           picogram
PMN         Premanufacturing Notice
PS           Polystyrene

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PV           Production Volume
PVC          Polyvinylchloride
RA           Risk Assessment
RAR          Risk Assessment Report
REACH       Registration, Evaluation, Authorisation and Restriction of Chemicals
SNUR        Significant New Use Rule
SVOCs       Semi-volatile organic chemicals
TSCA         Toxic Substances Control Act
TG           Test Guideline
US           United States
WHO         World Health Organisation
WWTP       Wastewater Treatment Plant
XPS          Extruded polystyrene
yr           Year
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EXECUTIVE SUMMARY

As part of EPA's comprehensive approach to enhance the Agency's management of existing
chemicals, EPA/OPPT identified a work plan of chemicals for further assessment under the Toxic
Substances Control Act (TSCA) in March 2012. Chemical risk assessments will be conducted if,
as a result of scoping and problem formulation, there are exposures of concern, identified
hazards and sufficient data for quantitative analysis. If an assessment identifies unreasonable
risks to humans or the environment, EPA will pursue  risk reduction. This document presents the
problem formulation and initial assessment for the cyclic aliphatic bromides cluster as part of
the TSCA Work Plan.

EPA/OPPT has identified a cluster of cyclic aliphatic bromide flame retardant chemicals,
including, hexabromocyclododecane (HBCD; CASRN 25637-99-4), 1,2,5,6,9,10-
hexabromocyclododecane (1,2,5,6,9,10-HBCD; CASRN 3194-55-6) and 1,2,5,6-
tetrabromocyclooctane (CASRN 3195-57-8), for risk assessment. These three chemicals have
similar physical and chemical properties, and environmental fate characteristics. Uses for
1,2,5,6-tetrabromocyclooctane have not been identified; the remaining two members of the
cluster are used as flame retardants in polystyrene foams. HBCD and 1,2,5,6,9,10-HBCD have
similar toxicological properties: known effects on the liver and reproductive system.

For the purposes of this assessment, the use of "HBCD" refers to either CASRN (25637-99-4 or
3194-55-6), or both. In addition, the conclusions drawn for this assessment will be applicable to
both CASRNs.

The conclusions from this problem formulation and initial assessment are that EPA/OPPT will
evaluate current risk assessments, and if needed, conduct additional analyses as follows:

   •   Workers: Evaluate the applicability of data from published risk assessments to US
       occupational exposure scenarios to determine if further assessment is needed. If the
       available data are not applicable, develop estimates of occupational exposures based on
       modeling and assumptions (e.g. approaches used in the new chemicals program).
   •   General population and biota (aquatic, terrestrial and avian):  Estimate releases to the
       environment in the US to evaluate potential exposure of general population and biota
       (aquatic, terrestrial and avian) to HBCD. The estimation approach may be based on
       information in available assessments, coupled with US specific information and/or
       estimation methods and assumptions.
   •   Consumers: Use available or modeled data relevant to US exposure scenarios to
       estimate consumer exposure using available or modeled data relevant to US exposure
       scenarios with particular emphasis on sensitive populations.

Several scenarios were identified where exposure to  HBCD is expected to be low or unknown
and further analysis is not recommended by EPA/OPPT under TSCA:
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   •   General population and environmental exposure from HBCD in landfills is not being
       assessed due to uncertainties in release from these sites.

   •   General population exposure from HBCD in drinking water is not being assessed because
       drinking water monitoring data for the US are not available and conclusions from
       available risk assessments indicate a low concern from this exposure pathway (EC, 2008;
       Environment CA and Health CA, 2011; NICNAS, 2012).

   •   Consumer exposure to HBCD in High Impact Polystyrene (HIPS) is not being assessed
       because the level of HBCD in HIPS in the US is unknown, it is not used in typical
       consumer products (e.g. computer or TV chassis), its use in other consumer products
       (e.g. electrical appliances) is enclosed limiting potential exposure and a low risk to
       consumers was indicated  in available risk assessments.

   •   Consumer exposure to HBCD in textile finishings is not being assessed because it was
       considered low risk by the CPSC in upholstered furnishings (CPSC, 2001), it was not
       reported to be used in consumer fabrics or textiles in the 2012 CDR (EPA, 2012a) and
       the extent of institutional (e.g. prisons), military or aviation use is unknown.

   •   There are no adequate toxicological data based on inhalation or dermal exposures, nor
       is there a PBPK model readily available for route-to-route extrapolation. Therefore
       EPA/OPPT will not assess  inhalation or dermal contact in this assessment. However, EPA
       is considering the quantification of incidental ingestion  of particulates that would result
       from exposure to HBCD dust in occupational settings. A similar approach will be  used to
       address consumer exposure to HBCD in dust.

   •   There are no adequate lifetime exposure or carcinogenicity studies for HBCD.

   •   Inhalation, dermal and lifetime exposure assessments are data gaps that add
       uncertainty to EPA's risk assessment of HBCD.

Hexabromocyclododecane (HBCD) has been used as a flame retardant in plastics (additive) and
textiles (backcoating) since the 1980s. Evidence suggests that HBCD is bioaccumulative,
environmentally persistent and toxic. Consequently, risk to human health and the environment
have been assessed by several countries and global organizations. In 2010, OPPT prepared an
action plan for HBCD. Subsequently, HBCD has been nominated for listing on the Toxic Releases
Inventory (TRI; in review 2014) and EPA proposed a significant  new use rule (SNUR) for use in
consumer textiles (EPA, 2012e).

During problem formulation, EPA/OPPT identified available fate, exposure and hazard data, and
characterized potential exposures, receptors and effects. Data  adequacy was determined by
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following published EPA/OPPT criteria1. EPA/OPPT reviewed the public literature (nominally to
September 2014) and Agency information sources (public and confidential) to explore the
sources, pathways, receptors and effects for consideration in the assessment. EPA also
identified areas of data uncertainty and assumptions.

Likely sources and pathways considered for analysis include: use of HBCD as a flame retardant
in expanded  polystyrene foam (EPS) and extruded polystyrene foam (XPS) in the building and
construction industry accounting for 95% of HBCD use mainly in the form of insulation boards.
The remaining uses are for high  impact polystyrene (HIPS), mainly used for electronics,
appliances and possible HBCD-containing textiles for institutional (e.g. prisons), military and
aviation uses only (EPA, 2012e). HBCD is not used in consumer textiles that are manufactured in
or imported  into the US except for limited uses in certain automotive textiles.

As outlined in the Conceptual Model for HBCD (Figure 2-1) EPA/OPPT identified the relevant
TSCA use of HBCD for this assessment as its use as flame retardants in EPS and XPS products
found in commercial and residential environments. EPA/OPPT determined that the major
source of exposure to HBCD for  human health and the environment was via HBCD dust and/or
HBCD in dust generated during the manufacture and processing of HBCD, and the processing
and use of products containing HBCD. HBCD in the form of dust or attached to particulates has
been measured in indoor domestic and  commercial environments, therefore there may be risks
to consumers. Preliminary exposure calculations for the US population suggest that the
methodology used in available assessments underestimates consumer exposure to HBCD from
dust for US consumers. Of particular interest for evaluation are toddlers whose exposure to
HBCD from dust in non-residential microenvironments contributes to their total HBCD exposure
(Abdallah and Harrad, 2011). HBCD may also make its way into the outdoor environment by
transportation through the air and/or washed down the drains (or storm drains) to enter
waterways.

These exposure scenarios have been considered in risk assessments conducted by other
countries and the toxicity and risk of HBCD to aquatic organisms and human health have been
assessed and summarized  in several publications (EC, 2008; Environment CA and Health CA,
2011; EPA, 2008a, 2014b; NICNAS, 2012; OECD, 2007). However, it is unknown how these
conclusions apply to  current HBCD manufacture,  processing, use and exposure in the US.
Therefore, EPA plans to evaluate information in the non-US published risk assessments to
determine whether data from other countries are relevant and applicable to  US exposures, and
where appropriate, supplementing these risk assessments with current and US specific
information.
1 Generally followed guidance outlined for the High Production Volume Challenge Program at:
http://www.epa.gov/chemrtk/pubs/general/datadfin.htm and
http://www.epa.gov/champ/pubs/hpv/Methodology%20for%20HBP%20under%20ChAMP March%202009.pdf
and EPA Risk Assessment Guidance at: http://www.epa.gov/raf/

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The results of problem formulation as illustrated in the conceptual model and described under
the assessment questions indicate that:

   •   There is the potential for occupational exposure to HBCD during HBCD manufacture and
       processing and polystyrene foam manufacture and processing.
   •   There is potential for general population exposure to HBCD from releases to the
       environment (air, water, soil and fish consumption).
   •   There is potential for environmental exposure in water, sediment and soil to HBCD from
       releases to the environment.
   •   There is potential for consumer exposure to HBCD from the use of consumer products in
       indoor environments.

In summary, as a result of problem formulation, EPA/OPPT plans to evaluate current risk
assessments and conduct additional risk analysis on potential worker, general population,
consumer and  environmental exposures under the TSCA Existing Chemicals Program using
existing data and methods. EPA/OPPT plans to review and evaluate available exposure (See
Section 2.4 and Appendix C) and hazard benchmarks (Section 2.5, Appendix D and Appendix E)
and to evaluate the potential  non-cancer risk to humans using a margin of exposure approach
and potential risks to environment using a hazard quotient approach.
As a part of EPA's comprehensive approach to enhance the Agency's management of existing
chemicals, in March 2012 EPA/OPPT identified a work plan of chemicals for further assessment
under the Toxic Substances Control Act (TSCA)2. After gathering input from stakeholders,
EPA/OPPT developed criteria used for identifying chemicals for further assessment3. The
criteria focused on chemicals that meet one or more of the following factors: (1) potentially of
concern to children's health (for example, because of reproductive or developmental effects);
(2) neurotoxic effects; (3) persistent, bioaccumulative, and toxic (PBT); (3) probable or known
carcinogens; (4) used in children's products; or (5) detected in biomonitoring programs. Using
this methodology, EPA/OPPT identified a TSCA Work Plan of chemicals as candidates for risk
assessment in the next several years. In the prioritization process, the Cyclic Aliphatic Bromides
Cluster, specifically hexabromocyclododecane (HBCD), was identified for assessment based on
its high production volume and PBT characteristics (persistent, bioaccumulative and toxic).

EPA/OPPT is performing risk assessments on chemicals in the work plan. If an assessment
identifies unacceptable risks to humans or the environment, EPA/OPPT will pursue risk
reduction. The target audience for this risk assessment is primarily EPA risk managers; however,
it may also be of interest to the broader risk assessment community as well as US stakeholders
interested in HBCD. The information presented in the risk assessment may be of assistance to
2 http://www.epa.gov/oppt/existingchemicals/pubs/workplans.html
3 http://www.epa.gov/oppt/existingchemicals/pubs/wpmethods.pdf
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other federal, state, and local agencies as well as to members of the general public who are
interested in the risks of HBCD.

The initial step in EPA/OPPT's risk assessment development process, which is distinct from the
initial prioritization exercise, includes scoping and problem formulation. During these steps
EPA/OPPT reviews currently available data and information, including but not limited to,
assessments conducted by others (e.g., authorities in other countries), published or readily
available reports and published scientific literature. During scoping and problem formulation
the more robust review of the factors influencing initial prioritization may result in refinement •
either addition/expansion or removal/contraction - of specific hazard or exposure concerns
previously identified in the prioritization methodology.

This document includes the results of scoping and problem formulation and initial assessment
for HBCD. During problem formulation, EPA/OPPT identified available exposure and hazard
data, and characterized potential exposures, receptors and effects. EPA/OPPT developed a
conceptual model (Figure  2-1) and analysis plan (Section 2.6.2) as a result of problem
formulation.

    1.1      Scope of the Assessment

The members of the cyclic aliphatic bromides cluster are the brominated flame retardants
(BFR):  Hexabromocyclododecane (HBCD; CASRN 25637-99-4)
       1,2,5,6,9,10-Hexabromocyclododecane (1,2,5,6,9,10-HBCD; CASRN 3194-55-6)
       1,2,5,6-Tetrabromocyclooctane (CASRN 3194-57-8)4

EPA prioritized the different BFR chemicals and grouped them into different clusters based on
structure. The cyclic aliphatic bromide cluster included chemicals that contain a ring of 6 to 12
saturated carbon atoms with different bromine atoms replacing some of the H atoms on the
ring or attached in sidechains.
                                                    (Br)x
                   Figure 1-1: Generic Structure of Cyclic Aliphatic Bromides

Chemicals considered for this cluster were: l,2-Dibromo-4-(l,2-dibromoethyl) cyclohexane
[CASRN: 3322-93-8], 1,2,3,4,5,6-hexabromocyclohexane [CASRN: 1837-91-8], 1,2,3,4,5-
Pentabromo-6-chlorocyclohexane [CASRN: 87-84-3] and 1,2,5,6-tetrabromocyclooctane
[CASRN: 3194-57-8]. One other chemical, Accession number 27248, with generic name
polybromocycloalkane would be a member of this Work Plan of chemicals; however, no
4 No domestic uses were identified for 1,2,5,6-Tetrabromocyclooctane (CASRN 3194-57-8). This flame retardant is
not functional in current EPS and XPS manufacturing processes. Its thermal stability does not meet operating
temperature requirements for the manufacture of XPS foam (EPA, 2014b).

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production volume has been reported since 1977. Therefore, these chemicals were rejected,
along with the individual 1,2,5,6,9,10-HBCD diastereomers, because they were either not on
the TSCA Inventory or were not manufactured at sufficient production volume to be reported in
the IUR/CDR data collection.

Two  HBCD commercial chemicals meet this cluster criteria and are the subject of this
assessment. These are the only two chemicals being considered for problem formulation in this
work plan which differs from the action plan (EPA, 2010a) inclusion criteria.

   •   Hexabromocyclododecane [CASRN 25637-99-4] is produced as a mixture of 16 possible
       isomers of 1,2,5,6,9,10-hexabromocyclododecane from the bromination of 1,5,9-
       cyclododecatriene. HBCD is the only member of this cluster that is on the TSCA
       Inventory that has a significant production volume (as reported in the IUR and CDR).

   •   1,2,5,6,9,10-hexabromocyclododecane [CASRN 3194-55-6] is a mixture of three main
       diastereomers of the 16 possible 1,2,5,6,9,10-hexabromocyclododecane isomers. Each
       individual isomer in this HBCD cluster member contains a ring  of 12 saturated carbon
       atoms with 6 bromine atoms replacing 6 hydrogen atoms. Each isomer has a  molecular
       formula of C12H18Br6. The three most common individual diastereomers are
       designated as alpha-, beta-, and gamma-HBCD and each has an individual CAS Registry
       Number (as do all 16 isomers)5.

For the purposes of this assessment, the use of "HBCD" refers to either CASRN (25637-99-4 and
3194-55-6), or both. In addition, the conclusions drawn for this assessment will be applicable to
both CASRNs.

Section 2.6.1 presents the  conceptual model developed by EPA/OPPT for HBCD. Using available
tools and approaches, the  Agency identified the relevant  TSCA use of  HBCD for this assessment
is its use as flame retardants in EPS and XPS products found in commercial and residential
environments. Its use in HIPS is not being assessed because the level of HBCD in HIPS in the US
is unknown, it is not used in typical consumer products (e.g. computer or TV chassis), its use in
other consumer products (e.g. electrical appliances) is enclosed limiting potential exposure and
a low risk to consumers was indicated in available risk assessments. Consumer exposure to
HBCD in textile finishings is not being assessed because it was considered low risk by the CPSC
in upholstered furnishings (CPSC, 2001), it was not reported to be used in consumer  fabrics or
textiles in the 2012 CDR (EPA, 2012a) and the extent of institutional (e.g. prisons),  military or
aviation use is unknown (EPA, 2012e).

EPA determined that the major source of exposure to HBCD for human health and the
environment was via HBCD dust and/or HBCD in dust generated during the manufacture and
processing of HBCD, and the processing and use of products containing HBCD. HBCD in the form
of dust or attached to particulates has been measured in  indoor domestic and commercial
5 This is significant because much of the data are reported for the individual alpha, beta, and gamma isomers
rather than for the two commercial products.
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environments, therefore there may be risks to consumers. Preliminary exposure calculations
for the US population suggest that the methodology used in available assessments
underestimates consumer exposure to HBCD from dust for US consumers. Of particular interest
for evaluation are toddlers whose exposure to HBCD from dust in non-residential
microenvironments contributes to their total HBCD exposure (Abdallah and Harrad, 2011).
HBCD may also make its way into the outdoor environment by transportation through the air
and/or washed down the drains (or storm drains) to enter waterways.

These exposure scenarios have been considered in risk assessments conducted by other
countries and the toxicity and risk of HBCD to aquatic organisms and human health have been
assessed and summarized in several publications (EC, 2008; Environment CA and Health CA,
2011; EPA, 2008a, 2014b; NICNAS, 2012; OECD, 2007). However, it is unknown how these
conclusions apply to current HBCD manufacture, processing, use and exposure in the US.
Therefore, EPA plans to evaluate information in the non-US published risk assessments to
determine whether data from other countries are relevant and applicable to those in the US,
and where appropriate, supplement these risk assessments with current and US specific
information.

   1.2      Regulatory and Assessment History

The regulatory and assessment history of HBCD in the US and internationally are summarized in
Table_Apx A-l.

United States - National

HBCD was sponsored in the HPV Challenge Program by BFRIP (BFRIP, 2001). Subsequently,
EPA/OPPT prepared a risk based prioritization document in 2008 (EPA, 2008a) which concluded
that there was a high concern for potential risk to aquatic organisms, a medium concern for
potential  risk to the general  population from environmental releases and a high concern for
potential  risk to workers, consumers and children. In 2010, EPA/OPPT prepared an action plan
for HBCD  (EPA, 2010a). Subsequently, HBCD has been nominated for listing on the Toxic
Releases Inventory (TRI; in review 2014) and is subject to rulemaking for use in textiles (EPA,
2012e). In addition, OPPT/DfE (OPPT Design for the Environment) published a flame retardant
alternatives assessment for HBCD in 2014 (EPA, 2014).

HBCD is currently on the EPA Integrated Risk Information System (IRIS) program agenda. The
anticipated date for a completed assessment has not yet been determined (EPA, 2015c). HBCD
is not regulated in drinking water under the National Primary Drinking Water Regulations (EPA,
2015b) and is not on the Contaminant Candidate List (CCL) (EPA, 2015a). Published risk
assessments indicate low risk to the general  population from drinking water exposure (EC,
2008; Environment CA and Health CA, 2011; NICNAS, 2012). HBCD is under consideration for
inclusion in the NHANES human bio-monitoring program.
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In 2006, the Consumer Product Safety Commission (CPSC) assessed the risk of exposure to
HBCD in residential upholstered furniture (CPSC, 2001) and concluded that HBCD did not
present a hazard to consumers, as defined by the Federal Hazardous Substances Act (FHSA).

The Occupational Safety and Health Administration (OSHA) has not established occupational
exposure limits for HBCD.

United States-States

In California, HBCD is listed as an initial informational candidate under California's Safer
Consumer Products regulations (DISC, 2010), on the state's Proposition 65 list (OEHHA, 2007)
and is designated a priority chemical for biomonitoring; however, California  has not yet started
biomonitoring HBCD (SGP, 2014). In Maine, Minnesota and Washington, HBCD is considered a
chemical of high concern (DEP, 2013; MDH, 2013; WSDE, 2013). Oregon considers HBCD a
priority persistent pollutant (DEQ, 2010a, 2011) and publishes use, exposure pathways and
release data for HBCD under this program (DEQ, 2010b).

International

HBCD is of international concern because of its PBT properties. The toxicity of HBCD to aquatic
organisms and human health have been assessed and summarized in several publications (EC,
2008; Environment CA and Health CA, 2011; EPA, 2008a, 2014b; NICNAS, 2012; OECD, 2007).
HBCD was added to ECHA's list of Substances of Very High Concern (SVHCs) on October 28,
2008 (ECHA, 2008). Risk assessments have been published by Australia (NICNAS, 2012), Canada
(Environment CA and Health CA, 2011) and the European Union (EC, 2008). The conclusions
from these assessments are as follows:

Occupational, General Population and Consumer Exposure
In the Health Canada assessment, the margin of exposure for neurobehavioral effects in infants
and children was determined using the LOAEL (0.9 mg/kg-day) from a 90-day study in mice
(Eriksson et al., 2006) (Environment CA and Health CA, 2011). This study was not used by the
European Commission or the Australian Government (EC, 2008; NICNAS, 2012). For
reproductive effects, all three assessments used the NOAEL (10 mg/kg-day) from the two-
generation study in rats (Ema et al., 2008). In addition, the European Commission used the
NOAEL (22.9 mg/kg-day) from the 28-day study in rats (van der Ven et al., 2006). All three risk
assessments concluded that the risk to general population and consumers was of low concern.
The occupational risk conclusions vary in different countries due to variations in exposure (e.g.
HBCD is not manufactured in Australia) and the risk varies with the activity associated with the
extent of exposure to HBCD; low to high, depending on the activity relevant  to each country.

Environmental Exposure
HBCD is persistent and bioaccumulative and is considered a  risk to the environment in all three
published risk assessments (EC, 2008; Environment CA and Health CA, 2011; NICNAS, 2012). In
May 2013, HBCD was added to the United Nation's Stockholm Convention list of Persistent

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Organic Pollutants (Stockholm Convention, 2013). The chemical is scheduled to be eliminated
by November 2014 with specific exemptions for production and uses in expanded or extruded
polystyrene building insulation. As required by the convention, parties that use these
exemptions must register with the secretariat and the exemptions will expire in November
2019.

Currently, under the Commission for Environmental Cooperation (CEC), Canada, Mexico and the
US are evaluating the presence and migration of flame retardants, including HBCD, from
consumer products (CEC, 2015). The information gathered from this effort will inform exposure
assessors and risk managers and the executive summary of the final report(s) will be available
to the public.


2 PROBLEM FORMULATION

Problem formulation aims to determine the major factors to be considered in an assessment,
including exposure pathways, receptors and health endpoints (EPA, 1998a, 2014c). Accordingly,
this problem formulation summarizes the exposure pathways, receptors and health endpoints
EPA/OPPT considered to determine whether to conduct further risk analysis and what
exposure/hazard scenarios to include in a potential risk assessment. To make this
determination, EPA/OPPT conducted a preliminary data review to identify available fate,
exposure and hazard data and determine its likely suitability for quantitative analysis and to
identify exposure pathways, receptors and health endpoints for quantitative analysis.

The outcome of this evaluation is summarized  in a conceptual model (Figure 2-1) that illustrates
the exposure pathways, receptors and effects that were considered for potential risk
assessment. An analysis plan is developed if the results of problem formulation indicate the
need for further analysis.

   2.1      Physical and Chemical  Properties

The physical-chemical properties of HBCD are shown in Table 2-1. Commercial preparations of
HBCD may contain some impurities,  such as tetrabromocyclododecene or other isomeric HBCDs
(UNEP, 2010) which are not separately included in this problem formulation.
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Table 2-1: Select Physical-Chemical Properties *
Properties3

Melting Point
Boiling Point
Vapor Pressure
Water Solubility
Octanol Water Partition
Coefficient (Log Kow)
Br
Br , 	 (
V^^Br
Br -/ <^
Br Br
1,2,5,6,9,10-Hexabromocyclododecane
HBCD
175 - 195 ฐC
> 200 ฐC [decomposes] b
6.27 E-5 Pa at 21ฐC
66ug/Lat20ฐC c
5.625 at 25 ฐC
*PCHEM Properties reported in the HPV Robust Summary (BFRIP, 2001) are measured values from a composite of
commercial products from 3 different manufacturers.
aHPV Data Summary and Test Plan for Hexabromocyclododecane (HBCD) CASRN 3194-55-6
bEC HBCD RAR (EC, 2008)
cSum of solubilities for 3 major isomers [alpha, beta, and gamma] in commercial product (ECHA, 2008)
   2.2
Production Volume and Uses
This section discusses the production volume and uses of the cyclic aliphatic bromides cluster
chemicals and is organized as follows:
   •   The 2012 Chemical Data Reporting (CDR) production, import, and export volumes for
       these chemicals are listed in Appendix B.
   •   Additional details on production volume for HBCD can be found in Section 2.2.1.
   •   Use information can be found in Section 2.2.2.
   •   Future market trends are discussed in Section 2.2.3.

       2.2.1  Production Volume

EPA/OPPT's 2012 public Chemical Data Reporting (CDR) database (EPA, 2012a), formerly the
Inventory Update Reporting (IUR) database includes national-level production volume data;
however, the 2012 public CDR database provides limited information on the domestic
production volumes of HBCD. For both CAS numbers, site-specific production volumes and
national level production volumes were withheld as TSCA Confidential Business Information
(CBI) for the 2011 reporting year (EPA, 2012a). Therefore, EPA/OPPT proposes to assess the
production volume of HBCD based on the best publicly available production volume data which
is the historical IUR and CDR data presented in Appendix B .  EPA/OPPT assumes that current
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production volumes are equal to the most recently reported production volumes (the 2002 and
2006 data for CASRNs 25637-99-4 and 3194-55-6, respectively).

For the 2011 reporting year, the data indicate that two sites currently import at least one of the
chemicals and that three sites domestically manufacture the chemicals. However, according to
the US International Trade Commission, the US imported 92,270 pounds of HBCD (CASRN
25637-99-4) in 2012 (USITC, 2013). This volume does not include HBCD imported as part of an
article. Three sites reported export volumes as CBI, and two sites reported no exports (EPA,
2012a).

Five sites are identified by the 2012 CDR database as manufacturers or importers of HBCD:
BASF Corporation, Albemarle Corporation, The Dow Chemical Company, and two CBI sites (EPA,
2012a). Albemarle manufactures HBCD flame retardants under the SaytexฎHP-900 trade name
(Albemarle Corporation, 2000). Both Dow and BASF indicate in the CDR data that they are
importers; however, trade names of the BASF or Dow Chemical products that use or contain
HBCD could not be found in a literature search. For more detailed information on
manufacturers of HBCD who reported for the 2012 CDR collection period, see Appendix B.

      2.2.2  Uses

          2.2.2.1    Use in Expanded Polystyrene Foam (EPS) and Extruded
             Polystyrene Foam (XPS)

HBCD is used as a flame retardant in polystyrene foam, textiles, and high impact polystyrene.
The chemical has been in production since the 1960s although there is limited data about the
historical use of HBCD in products.

The main use of HBCD in the US, the EU, Japan, and Switzerland is as a flame retardant in
expanded polystyrene foam (EPS) and extruded polystyrene foam (XPS) (UNEP, 2010; Weil and
Levchik, 2009). Use in EPS and XPS accounts for 95 percent of all HBCD applications and began
in the 1980s (EPA, 2014b; UNEP, 2010). EPS and XPS are used in the US for thermal insulation
boards and laminates for sheathing products used in the building and construction industry. In
addition,  EPS is used to provide protection from moisture, prevent freezing, provide a stable fill
material,  and create high-strength composites in construction applications. XPS foam board is
used mainly for roofing applications and architectural molding. HBCD is used in both types of
foams, because it is highly effective at low-use levels, and therefore maintains the insulation
properties of the EPS and XPS foam (Morose, 2006). EPS boards contain approximately 0.5
percent HBCD by weight in the final product while XPS boards contain 0.5 to 1 percent HBCD by
weight (Extruded Polystyrene Foam Association,  2011; Morose, 2006).

The National Institute of Heath's (NIH) Household Products Database lists HBCD as an
ingredient in several extruded and foam insulation products, all of which are manufactured by
Owens Corning for use in the US. Currently, Owens Corning lists HBCD in two of its products:
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Foamularฎ Extruded Polystyrene Insulation and Foamularฎ Extruded Polystyrene Insulation -
Zero Ozone Depletion Formula, at levels between 0.5 and 1.0 percent (Owens Corning, 2005).

The Australian Department of Health and Aging reports that EPS resins are also used in
industrial packaging including packaging durable goods and beanbag fill (NICNAS, 2012).
Historic data indicate that EPS was used in packaging in North America (Kinshore, 2007),
however EPA/OPPT was unable to confirm if this is a current use of HBCD in the US. It should be
noted that uses of polystyrene foam in consumer products, such as packaging, generally do not
require the use of a flame retardant (EPA, 2014b).

          2.2.2.2    Use in Textiles

In the US, HBCD was historically used as a flame retardant in the back coating of textiles.
However, supported by information gathered from research, industry, and consumer product
organizations, EPA/OPPT believes that  HBCD is no longer used in consumer textile applications
outside of the auto industry. EPA/OPPT received information from a group of textile
formulators that the end uses of HBCD-containing textiles are for military, institutional, and
aviation applications such as durable carpet tiles for hospitals or prisons (EPA, 2012e; Friddle,
2011). Use in this application is quite small; in 2005 only 1 percent of total production volume
of HBCD was used in textiles in the US (EPA, 2012e). HBCD is typically found in textile back
coatings at  levels of 10-25 percent (Harscher, 2011).

In Europe, only 2 percent of HBCD was used in textile applications in 2007 (ECHA, 2009).

             2.2.2.2.1     Use in Automotive Textiles

Within the US auto industry, EPA/OPPT found that a small amount of HBCD is used in floor
mats, headliners, and possibly other interior fabrics in automobiles made or imported to the US
(EPA, 2012e).

HBCD is currently regulated under Annex XIV of European Union's Regulation on Registration,
Evaluation,  Authorisation and Restriction of Chemicals (REACH), which sets a "sunset date" for
the use of the chemical of August 21, 2015. In response to the REACH regulation, the auto
industry has formed a consortium  to help US manufacturers understand the new requirements;
develop tools, processes and best  practices; and coordinate compliance efforts. The consortium
consists of five North American sponsoring companies, Chrysler, Ford, General Motors, Honda,
and Toyota  (AIAG, 2011). It is likely that as companies discontinue the use of HBCD in European
cars to comply with the REACH regulation, they will discontinue its use in North American
automobiles as well.
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             2.2.2.2.2     Historic Use in Textiles
HBCD was historically used as a flame retardant in the US in the back-coating of textiles,
upholstered furniture, draperies, wall coverings, and interior textiles such as roller blinds
(ECHA, 2009; Morose, 2006). The majority of HBCD used in textiles was for upholstered
furniture, because textiles treated with the chemical meet the stringent fire safety laws of the
United Kingdom (UK) and California (Morose, 2006).

In the 2006 IUR data, one manufacturer/importer of HBCD (CASRN 3194-55-6) reported the use
of the chemical substance under the NAICS code for textile and fabric finishing mills (EPA,
2006a). For this use, less than 1 percent of the total production volume of the chemical
substance was in consumer and commercial products. The reporting does not distinguish
between commercial and consumer use (EPA, 2006a).

EPA/OPPT conducted  research to determine whether HBCD was used in textile applications for
end products sold to consumers in the US. In 2010, an HBCD expert with the Consumer Product
Safety Commission (CPSC) expressed to  EPA/OPPT his understanding that HBCD is used only in
non-consumer textiles such as firefighters' suits (EPA, 2012e). In 2011, EPA/OPPT requested
information from current and former manufacturers of HBCD. The responses indicated that
only one manufacturer sells HBCD for textile uses. The company did not know whether the end
use of any of those textiles is a consumer article (EPA, 2012e). Additionally, a representative of
the furniture manufacturing company Herman  Miller told EPA/OPPT that HBCD is not in its
products (EPA, 2012e). HBCD was not reported to be used in fabrics or textiles in the 2012 CDR
(EPA,  2012a).

          2.2.2.3    Use in High Impact Polystyrene (HIPS)

In both the US and Europe, HBCD is used as a flame retardant in high impact polystyrene (HIPS)
for electrical and electronic appliances such as audio-visual equipment, refrigerator lining, and
some  wire and cable applications (ECHA, 2009; Morose, 2006). Use in television sets is the
predominant application of HIPS (Weil and Levchik, 2009). HBCD is found in  HIPS products in
levels of 1-7% by weight (EC, 2008). Similar data for the US are not available.

          2.2.2.4    Other Identified Uses

The Australian Department of Health and Aging also reports that minimal amounts of HBCD are
imported into the country already incorporated into various articles such as inkjet printers,
projectors, scanners, ventilation units for offices, compact fluorescent lights, and LCD digital
audiovisual systems (NICNAS, 2012). There are  no data to indicate that HBCD is used in the US
for these  uses.
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          2.2.2.5   Summary of All Uses

             2.2.2.5.1      Summary of CDR Information

Appendix B summarizes the HBCD use data as reported in the 2012 CDR. This Appendix also
presents information on potential end uses of the chemical beyond what is reported in the
CDR. The information is based on additional sources as described in the preceding sections of
the report.
             2.2.2.5.2      Summary of EU Data

Table_Apx B-4 provides a summary of HBCD uses and potential end products as presented in
the EU risk assessment report (EC, 2008). Although the EU market and industry for HBCD are
considered to be similar to those in the US, differences do exist in building technologies,
climate, and consumption patterns, limiting the comparison of the two markets.

      2.2.3  Future Market Trends

EPA/OPPT expects future use of HBCD to decrease worldwide as the result of forthcoming
international regulations. HBCD is listed under Annex XIV of European Union's  REACH, which
sets a "sunset date" for August 21, 2015. After this date, only persons with approved
authorization applications may continue to use the chemical (BSEF, 2012). In addition, in May of
2013, the Conference of the Parties (COP) to the Stockholm  Convention on Persistent Organic
Pollutants (Convention) decided to list HBCD on the Convention's "elimination" annex, with
specific exemptions for production and use for expanded polystyrene and extruded polystyrene
in buildings for parties listed in the register of specific exemptions for the substance. The
specific exemptions can last up to 5 years and, subject to approval by the COP, can be renewed
for a period of up to 5 years. However, the US is not a  party  to the Stockholm Convention and
therefore this action is not applicable to the US.

Given that HBCD is going to be phased out for some  uses in the majority of the world, including
the EU, Canada, Australia, and most of Asia, it is  likely that global processors and users of HBCD
will work towards phasing out the chemical  rather than endure the cost of maintaining a
separate supply chain for the US. It is expected that the Stockholm Convention may incentivize
US processors, manufacturers, and importers to consider alternatives to HBCD for some
applications, which may impact future demand growth for the chemical.

    2.3      Fate and Transport

The environmental fate of HBCD has been summarized in several publications (EC, 2008;
Environment CA and Health CA, 2011; EPA, 2008a, 2014b; NICNAS, 2012; OECD, 2007). A
general overview of persistence and bioaccumulation is presented below. Additional details can
be found in Appendix D.
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HBCD is persistent in environmental media. It is expected to be stable to hydrolysis and direct
photolysis. Measured aerobic biodegradation half-lives either range up to months, or are
greater than months. Anaerobic biodegradation may be more rapid but in anaerobic conditions
degradation is also slow with half-lives ranging to months or greater. HBCD is expected to sorb
to particulates and sediments and have limited mobility in soil. It is expected to volatilize to
some extent from soils and water surfaces. In the atmosphere, HBCD is expected to occur
primarily as particulates and may undergo long range transport. It will  be removed from the
atmosphere by wet or dry deposition, and has an estimated vapor phase half-life of 2.1 days for
reaction with hydroxyl radicals. HBCD is highly bioaccumulative with measured fish
bioconcentration factor (BCF) values of greater than 18,000.

   2.4      Exposures

       2.4.1 Releases to the Environment

HBCD is manufactured or imported as a powder or pellets (EPA, 2012a) and incorporated into a
polymer matrix, including polystyrene foam, as an additive that is incorporated into the matrix
(EC, 2008). The life cycle of HBCD includes the manufacture and processing of HBCD followed by
the commercial  and consumer use, service life, and disposal of products that contain HBCD (EC,
2008; Stockholm Convention, 2010). HBCD is released to the environment throughout the life
cycle (EC, 2008;  EPA, 2014; Stockholm Convention, 2010).

TRI data are not yet available for  HBCD, but releases from  industrial sites to waste water
treatment plants (WWTP), surface water, air and landfill are expected (EC, 2008; Environment
Canada, 2011; NICNAS, 2012). HBCD is expected to remain largely immobile in landfills (EPA,
2014) and therefore industrial releases to water and air are of greater interest to EPA/OPPT
than industrial releases to landfills. Sawing of EPS or XPS during commercial and consumer use
results in release of HBCD (EC, 2008). Emissions of HBCD from EPS and XPS and wear of these
products result in release of HBCD during their service life (EC,  2008). The total of releases of
HBCD from  construction sites to air or surface water from  professional use of EPS or XPS is large
in comparison with the total releases to each of these media from the  manufacture of HBCD or
processing of HBCD (to make EPS and XPS) (EC, 2008). However, releases from construction
sites are dispersed and therefore are likely to be lower than industrial releases on a per-site
basis. Disposal of EPS and XPS may result in releases to the environment as a result of
demolition of buildings or material that is left on or in the  soil (EPA, 2014);  EPA/OPPT believes
these releases are likely to be lower than industrial releases on a per-site basis.

Manufacturing and processing steps to be assessed are summarized in Appendix C.
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       2.4.2  Presence in the Environment

          2.4.2.1   Surface Water

Studies of surface water in the US are limited to a study of suspended sediment from the
Detroit River, a highly industrialized area. The maximum measured concentration in suspended
sediment was 3.7 u.g/kg dw (Marvin et al., 2006) with similar values measured in China and
Sweden (Arnot et al., 2009; He, S. et al., 2013). HBCD was identified in lakes, tributaries and
streams in China and the UK with measured concentrations in the ng/L levels (BRE, 2009;
Harrad et al., 2009; MOE, 2000, 2005). Measurements of marine water were not found, and
these values would be expected to be low. Geographically and temporally distributed
monitoring data of this cluster in US surface waters were not found.

          2.4.2.2   Waste water

HBCD in wastewater influent (dissolved phase) at sewage treatment plants in South Africa and
the UK were measured at concentrations of ng/L to <1 u.g/L levels (Chokwe et al., 2012; De Boer
et al., 2002). Measurements of the suspended phase of influent from sewage treatment plants
in the UK and Netherlands were as high as 3800 u.g/kg dw (De Boer et al 2002, Morris et al.,
2004).  Measurements of suspended phase in effluent were as high as 18 u.g/kg dw (Morris et
al., 2004). Measured concentrations of HBCD in wastewater in the US are not available.

          2.4.2.3   Sludge

Measurements of HBCD levels in sludge have been made throughout Europe (Covaci et al.,
2006; De Boer et al., 2002; Gorga et al., 2013; Guerra et al.,  2010; Morris et al., 2004) and Asia
(Feng et al., 2012;  Hwang et al., 2012) with values ranging from non-detect (detection limit = 4
ng/g) at a WWTPs  in Spain (Gorga et al., 2013)(Guerra et al., 2010) to as high as 29 mg/kg dw in
industrial sludge from Korea (Hwang et al., 2012). A study in the US of processed sludge from
activated sludge-type secondary treatment facility treating domestic  & industrial waste
(including automotive interior manufacturer) found comparatively high levels of HBCD,  on the
order of g/kg (La Guardia et al., 2010). Samples analyzed from the EPA 2001 National Sewage
Sludge Survey showed approximately 20 ug/kg HBCD (Venkatesan and Halden, 2014).

          2.4.2.4   Soil

Soil sampling is limited to measurements from Sweden (Arnot et al., 2009), Germany and
Belgium (Arnot et al., 2009; Covaci et al., 2006), and throughout Asia  (Eguchi et al., 2013; Li et
al., 2012b; Wang et al., 2013) with the highest values (u.g/kg dw) found in the soil near a HBCD
manufacturing plant in the Laizhou Bay area. Studies with measured levels of HBCD in soils in
the US were not available.
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          2.4.2.5    Sediment

Sediment measurements have been made in numerous countries throughout the world
including Asia, South America, North America, Europe and South Africa (Al-Odaini et al., 2013;
Arnot et al., 2009; Baron et al., 2013; Canton et al., 2008; Covaci et al., 2006; De Boer et al.,
2002; de Boer et al., 2004; Feng et al., 2012; Guerra et al., 2012; Harrad et al., 2009; He, M.-J. et
al., 2013; Klosterhaus et al., 2012; La Guardia  et al., 2012; La Guardia et al., 2013; Li et al., 2013;
Li et al., 2012b; Managaki et al., 2012; MOE, 2000, 2005; Morris et al.,  2004; Xu et al., 2013;
Zhang et al., 2013) with the highest value (>300 mg/kg dw) found at the Yadkin River at the
outfall downstream from a textile facility in North Carolina, US (La Guardia et al., 2012).

          2.4.2.6    Biota

HBCD has been reported in several fresh water and marine species throughout North America.
In the US, carp from the Hyco River in Virginia were reported with mean HBCD levels of 4640
u.g/kg lipid weight (Chen et al., 2011). HBCD was also measured in the  blubber or liver of various
marine mammals: Bottlenose dolphin (Johnson-Restrepo et al., 2008), Bull shark (Johnson-
Restrepo et al., 2008), Atlantic Sharpnose shark (Johnson-Restrepo et al., 2008), White Sided
dolphin (Peck et al., 2008), and California sea  lions (Stapleton et al., 2006) with the highest
mean concentration of 130 u.g/kg lipid weight reported  in the White Sided dolphin (Peck et al.,
2008). Similarly, HBCD has been detected in the blubber or liver of  marine species (Budakowski
and Tomy, 2003; Muir et al., 2006; Tomy et al., 2009) and in whole or  the muscle of fresh water
fish in Canada (Law et al., 2006a; Tomy et al.,  2008).

       2.4.3  Occupational Exposure

EPA/OPPT considers inhalation and dermal exposure to  be important exposure pathways for
workers. Sometimes,  the inhalation of air-suspended particulate matter that is subsequently
trapped in mucous and moved from the respiratory system to the gastrointestinal tract (EPA,
2011b) is a contributor to aggregate exposures. This will be referred to here as incidental
ingestion of inhaled particulates.

HBCD is manufactured as a  powder at two US sites and  is imported as  pellets at two other sites.
The processing of HBCD for the manufacture of EPS and XPS and the subsequent commercial
use of these products by workers is described in EC (2008) and EPA (2014b). Industrial and
commercial workers are potentially exposed to HBCD (EC, 2008; Kuo et al., 2014; NICNAS, 2012;
Zhang et al., 2012). Exposure monitoring data for workers in the US is not available in the
scientific literature. The number of potentially exposed  industrial workers in the US is estimated
to be less than 2100 (EPA, 2012a).

The greatest potential for occupational exposure is expected at industrial sites. Inhalation
exposure concentrations of HBCD dust in the form of inhalable particles for workers handling
standard grade HBCD powder at sites for the manufacture or processing (for the  manufacture
of XPS or EPS) of HBCD are in the range of 0.1 to 2.5 mg/m3 (EC, 2008). For dermal exposures,

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the exposure range is 84 to 840 mg/day of HBCD dust (EC, 2008). Workers who cut EPS or XPS
boards (e.g., at construction sites) are potentially exposed to HBCD via inhalation at much lower
concentrations of HBCD in air in the form of respirable particles (Kuo et al., 2014; Zhang et al.,
2012).

       2.4.4 General Population Exposure

          2.4.4.1    Ambient Air

The concentrations of HBCD are generally higher indoors than outdoors. However, spatial
variation is likely with proximity to point sources. Concentrations are generally reported in
picograms/m3. Samples have been collected in a wide variety of locations including remote
locations in the arctic far removed from sources indicating long-range transport. Some studies
characterized vapor and particulate phase of HBCD with HBCD most often reported in the
particulate phase (Abdallah et al., 2008b; Alaee et al., 2003; Li et al., 2012a; Takigami et al.,
2009a;Tueetal., 2013).

          2.4.4.2    Drinking Water

Measured concentrations of HBCD in drinking water are limited to one study in the UK (BRE,
2009) where sampling from main water inlet and borehole water indicated concentration of 5-
16 u.g/L and samples of process water from the Netherlands were an order of magnitude lower.
Monitoring studies identifying HBCD in drinking water in the US are not readily available.

          2.4.4.3    Fish Consumption

Measured concentrations of HBCD in fish are reported throughout the world, typically in the
u.g/kg range and are expected to vary spatially and temporally (Law et al., 2014). Fewer studies
are available in the US and Canada (Arnot et al., 2009; Covaci et al., 2006; Ismail et al., 2009;
Klosterhausetal., 2012).

          2.4.4.4    Biomonitoring

While fewer studies have characterized HBCD levels in humans compared to wildlife, several
studies have shown detection in human breast milk, blood, adipose tissue and hair in the US
and other countries. HBCD has been detected in breast milk at ng/gram lipid levels. (Arnot et
al., 2009; Carignan et al., 2012; Covaci et al., 2006; Croes et al., 2012; Devanathan et al., 2012;
Malarvannan et al., 2013; Marvin et al., 2011; Pratt et al., 2013; Shi et al., 2013). Two studies
have detected HBCD in adipose tissue (Arnot et al., 2009; Johnson-Restrepo et al.,  2008). HBCD
has also been detected in human blood at ng/g lipid levels (Arnot et al., 2009; Covaci et al.,
2006; de Winter-Sorkina et al., 2006; Kicinski et al., 2012; Kim et al., 2013; WWF, 2004).
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       2.4.5  Consumer Exposures

Consumer exposure to HBCD may include inhalation exposure, dermal exposure through direct
skin contact with HBCD on the surface of objects or articles, incidental ingestion of inhaled
particulates (see 2.4.3), and incidental ingestion of indoor settled dust via hand-to-mouth
behaviors.

Based on HBCD's relatively low vapor pressure and relatively high octanol-air partition
coefficient, it is likely to preferentially partition to smaller suspended particles in the air and
larger settled particles in dust (Blanchard et al., 2014; Law et al., 2014). HBCD has been
detected in the dust of residences, commercial buildings, automobiles, and airplanes both in
the US and other countries. The available assessments have addressed data relevant to US
exposure scenarios up to and including 2011.

Concentrations vary widely across different microenvironments and within microenvironments
and are generally reported in the nanograms/gram or micrograms/gram range (Abdallah et al.,
2008a; Abdallah and Harrad, 2010; AN et al., 2012; Allen et al., 2013a; Allen et al., 2013b;
Bjorklund et al., 2012; Covaci et al., 2006; D'Hollander et al., 2010; de Wit et al., 2012; Dodson
et al., 2012; Harrad et al., 2010; Johnson et al., 2013; Kalachova et al., 2012; Kopp et al., 2012;
Kukucka P*, 2013; Ni and Zeng, 2013; Sahlstrom et al., 2012; Shoeib et al., 2012; Stapleton et
al., 2008a; Stapleton et al., 2009; Stapleton et al., 2014; Takigami et al., 2008, 2009a; Thuresson
et al., 2012; Tue et al., 2013; van den Eede  et al., 2012; Wang et al.,  2013). HBCD was detected
at nanogram levels in handwipe samples in a recent  study (Stapleton et al., 2014). HBCD has
also been also detected in indoor air. Concentrations are generally reported in picograms/m3
(Abdallah et al., 2008b; Abdallah and Harrad, 2010;  de Wit et al., 2012; Ni and Zeng, 2013; Tue
etal., 2013).

   2.5      Hazard Endpoints

       2.5.1  Ecological Hazard

The ecological hazard of HBCD has been summarized in several publications (EC, 2008;
Environment CA and Health CA, 2011; EPA, 2008a, 2014b; NICNAS, 2012; OECD, 2007). A
general overview is presented below. Additional  details and tabulated data summaries can be
found in Appendix D.

HBCD has been tested for acute and chronic aquatic toxicity, soil organisms, sediment
organisms, avian species, and terrestrial plants. EPA/OPPT concludes that HBCD is hazardous to
the environment. This conclusion is based on the potential for bioaccumulation (fish
bioconcentration factor [BCF]=8,974-18,100) and biomagnification (fish biomagnification factor
[BMF]=4.3-9.1), observed acute toxicity values as low as 0.009 mg HBCD/L (72-hour EC5o) in the
marine algae, Skeletonema costatum, that indicates  high aquatic toxicity to plants, a chronic
aquatic toxicity value of 0.0042 mg HBCD/L (maximum acceptable toxicant concentration,
MATC) in Daphnia magna that indicates high chronic aquatic invertebrate toxicity, and reduced

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chick survival in Japanese quails (Coturnix coturnixjaponica) at 15 ppm in diet (2.1 mg HBCD/kg-
body weight/day) that indicates high terrestrial toxicity (Drottar and  Krueger, 1998, 2000; Law
et al., 2006b; MOEJ, 2009; Walsh et al., 1987).

       2.5.2  Human Health Hazard

The human health hazard of HBCD has been summarized in several publications (EC, 2008;
Environment CA and Health CA, 2011; EPA, 2008a, 2014b; NICNAS, 2012; OECD, 2007). A
general overview is presented below. Additional details and tabulated data summaries can be
found in Appendix E.

For humans, there is a potential for oral, inhalation and dermal exposure. Available
toxicokinetics data in rodents indicate that HBCD is moderately absorbed via the
gastrointestinal tract, metabolized, and distributed to a number of tissues, with preferential
distribution and accumulation of unchanged HBCD in fatty tissue. Elimination of HBCD is
predominantly via feces (as unchanged parent compound), but is also eliminated in the urine
(as secondary metabolites). The acute hazard concern is low via the oral, dermal and inhalation
routes. The chronic hazard concern is based on reproductive effects which are described in
detail in Appendix E. There is also some evidence of neurodevelopmental toxicity suggestive of
hearing impairment, however, it is difficult to determine if the effect  is due to developmental
exposure to HBCD, a result of repeated-dose exposure, or a combination of the two. Available
data suggest that HBCD is not genotoxic. No adequate carcinogenicity studies are available
(EPA, 2014b). Existing assessments have also concluded, based on genotoxicity information and
one limited lifetime study, that HBCD is not carcinogenic (NICNAS, 2012; TemaNord, 2008)  or
that further study of carcinogenicity is not warranted (EC, 2008; OECD, 2007). However, the
only available dietary study evaluating the carcinogenic potential of HBCD in mice is not
considered adequate to draw conclusions regarding carcinogenicity (EC, 2008; Environment CA
and Health CA, 2011; EPA, 2014b; OECD, 2007). Given this data gap, EPA's HBCD assessment
will not include carcinogenicity assessment.

   2.6      Results of Problem Formulation

The results of problem  formulation are a conceptual model, key assessment questions and an
analysis plan for human health and the environment (EPA, 1998a, 2014b).

       2.6.1  Conceptual Model

During problem formulation, a conceptual model (see Figure 2-1) was developed to identify
important sources, pathways, and  receptors of exposure (See Sections 2.3 and 2.4). Potential
exposures to HBCD (derived from the manufacture,  processing and use of HBCD-containing
polystyrene products) in homes, offices, the environment, and occupational settings were
linked to hazard endpoints in human and non-human receptors.
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                           EXPOSURE PATHWAYS
Commercial Use of
PUT

PUF/Products
	 *
k

Dust from
Product
Installation
&Use
                                 Legend
                                 Solid lines = Pathway can be quantified
                                 Dashed lines = Pathway of unknown significance
                                 Shaded boxes = Elements proposed for inclusion in assessment
                                 Unshaded boxes = Elements lacking adequate data for
                                 assessment
Figure 2-1: Conceptual Model for HBCD

In the conceptual model, the schematic depicts the pathways (denoted by arrows) of potential
exposure to HBCD and HBCD dust generated during the manufacture and processing of HBCD
and use of HBCD containing products. The solid lines denote the exposure pathways considered
likely and with available exposure and hazard data to assess them. The dashed lines designate
pathways which are of unknown significance i.e. uncertain, have limited data or which are not
quantifiable. The shaded boxes indicate elements proposed for assessment while the unshaded
boxes indicate elements lacking adequate data for assessment. These scenarios are elaborated
in Table 2-2.
Table 2-2: Summary of Use/Exposure Scenarios Considered for Assessment
f
1









USE/EXPOSURE
SCENARIO
CONSIDERED
Worker exposure
to HBCD during
manufacturing and
processing






POTENTIAL
ROUTE OF
EXPOSURE
ORAL-
Unintended
oral exposure
via the
incidental
ingestion of
inhaled
particles of
HBCD and
HBCD in dust
PROPOSED
FOR
ASSESSMENT
YES









RATIONALE/LIMITATIONS/
UNCERTAINTIES
Risk identified for HBCD handling in occupational
settings in non-US assessments








                                       Page 28 of 97

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#





2










3





4a








4b





4c










USE/EXPOSURE
SCENARIO
CONSIDERED



General
population
exposure from
HBCD resulting
from releases to
the environment






Ecological
Receptors




Consumer
exposure to HBCD
from the use of
consumer
products in indoor
environments



Consumer
exposure to HBCD
from the use of
consumer
products in indoor
environments
Consumer
exposure to HBCD
from use of EPS/
XPS commercial
products.






POTENTIAL
ROUTE OF
EXPOSURE
DERMAL


ORAL-
Ingestion of
HBCD particles
ORAL -Fish
Consumption
ORAL -Drinking
Water
ORAL -Food
other than fish
from ambient
water
INHALATION
WATER

SEDIMENT

SOIL

ORAL-
Incidental
ingestion of
inhaled
particles of
HBCD in dust
Hand-to-mouth
exposure of
HBCD from dust
INHALATION
DERMAL




ORAL
INHALATION
DERMAL








PROPOSED
FOR
ASSESSMENT
NO


YES

YES

NO

NO



NO
YES

YES

YES

YES








NO





NO










RATIONALE/LIMITATIONS/
UNCERTAINTIES

Experimental data for reliable route extrapolation
from oral to inhalation & dermal routes are not
available
NoTRI data

Low risk in available non-US assessments;
confirm low risk using US data
Low risk in available non-US assessments;
No US drinking water monitoring data
Low risk in available non-US assessments;
Not regulated under TSCA


Low risk in available non-US assessments
Available US monitoring data and
estimated/modeled releases from industrial sites
Available US monitoring data and
estimated/modeled releases from industrial sites
Available US monitoring data and
estimated/modeled releases from industrial sites
Data available for oral exposures only








Experimental data for reliable route extrapolation
from oral to dermal route is not available.
Inhalation of neat HBCD potentially released from
products is expected to contribute less to overall
exposure than the ingestion pathway due to low
volatility.
Exposure considered insignificant and not assessed
in EURAR;
Risk to workers low in NICNAS;
The HBCD content of these boards 1-5%;
EPS/XPS boards may generate dust during cutting
during construction, renovations or DIY projects.
Consumer dust exposure captured in "1.0" above;
Experimental data for reliable route extrapolation
from oral to dermal route is not available.
Inhalation of neat HBCD potentially released from
products is not expected due to low volatility.
Page 29 of 97

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#


4d





4e





USE/EXPOSURE
SCENARIO
CONSIDERED
Consumer
exposure to HBCD
in specific articles
made with high
impact
polystyrene (HIPS)
Consumer
exposure to HBCD
in textile finishings



POTENTIAL
ROUTE OF
EXPOSURE
ORAL
INHALATION
DERMAL



DERMAL





PROPOSED
FOR
ASSESSMENT
NO





NO





RATIONALE/LIMITATIONS/
UNCERTAINTIES

Low risk in available non-US assessments;
Level of HBCD in HIPS in the US is unknown;
Not used in typical consumer products (computer
or TV chassis);
Use in other consumer products (e.g. electrical
appliances) is enclosed limiting potential exposure
Low risk in available non-US assessments;
Low risk in CPSC study with furnishings;
In the 2012 CDR, HBCD was not reported to be
used in consumer fabrics or textiles;
The extent of HBCD institutional (e.g. prisons),
military or aviation use is unknown.
EPA developed four key questions from the conceptual model.

1.     Are there risks to workers exposed to HBCD during manufacturing and processing of
      HBCD for the manufacture of EPS and XPS?

HBCD has been assessed globally (EC, 2008; Environment CA and Health CA, 2011; NICNAS,
2012). For human health, the toxicological point of departure (POD; NOAEL for the two-
generation toxicity study) used in the published risk assessments (EC, 2008; Environment CA
and Health CA, 2011; NICNAS, 2012) to calculate the margin of exposure (MOE) is based on a
study that EPA would consider adequate for the oral route of exposure. No chronic hazard data
are available for the dermal and inhalation routes of exposure. To address these exposure
scenarios and minimize uncertainty in the  risk conclusions, EPA uses physiologically-based
pharmacokinetic (PBPK) modeling for route-to-route extrapolation; however, these data are
not robust for HBCD. Therefore, EPA/OPPT proposes to evaluate the methodology used in the
published risk assessments, confirm the  study used for the POD, and in conjunction with
EPA's assessment of the exposure of workers in the US (Section 2.6.2), determine if there are
risks to workers.

2.     Are there risks to the general population from HBCD released to the environment during
      the lifecycleof HBCD?

Releases of HBCD to air, including releases to air during manufacture and processing of EPS and
XPS,  are expected to partition to particulate matter and deposit in the environment (water and
soil) and is expected to be bioaccumulated up the food chain. Therefore, for the general
population, exposures to HBCD are expected to occur indirectly through water or fish
consumption.

Drinking Water: No monitoring data for  HBCD in drinking water are available. However,
published risk assessments indicate low  risk to the general population from drinking water
exposure.
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Fish Consumption:
   •   For the general population, available risk assessments (EC, 2008; Environment CA and
       Health CA, 2011; NICNAS, 2012) concluded that risk to general population from
       consumption of HBCD in fish is low. In addition, the Canadian assessment included
       sensitive subpopulations such as indigenous populations (Nunavut) and nursing infants
       and concluded that risks to these populations is low.
   •   However, recent publications (Abdallah and  Harrad, 2011; Aylward and Hays, 2011;
       Carignan et al., 2012; Gheorghe et al., 2013; Kalachova et al., 2012) containing
       additional information warrant evaluation.

A biomonitoring-based risk assessment (Aylward and Hays, 2011) (i.e., based on HBCD
concentrations found in breast  milk and serum) indicated that the margins of exposure (MOE)
were greatly in excess of target values, suggesting that the risk to the general population is low.

3.      Are there risks to ecological receptors from HBCD found in the environment?

Available risk assessments (EC,  2008; Environment CA and Health CA, 2011; NICNAS, 2012)
concluded that HBCD poses a risk to the environment. EPA/OPPT plans to evaluate the
potential risk to the environment based on US release estimates and exposure.

4.      Are there risks to consumers from HBCD found in household dust?

Dust: Available risk assessments (EC, 2008; Environment CA and Health  CA, 2011; NICNAS,
2012) concluded that risk to consumers from exposure to HBCD in household dust is low. These
assessments included  hand-to-mouth transfer of dust by children. Preliminary evaluation of
recent data for the US population suggest that the available assessments underestimate
consumer exposure to HBCD from  dust for US consumers. In addition, for toddlers, exposure to
HBCD from dust in other microenvironments, such as vehicles and childcare environments,
may contribute to their total HBCD exposure (Harrad and Abdallah, 2011). Therefore,
EPA/OPPT plans to evaluate the methodology used in the published risk assessments, confirm
the study used for the hazard assessment and in conjunction with the current and aggregate
exposure information  relevant to the US population,  assess potential risks to  US consumers.

       2.6.2  Analysis Plan

Based on problem formulation  EPA/OPPT plans to conduct the following additional analyses.

          2.6.2.1   Workers

EPA/OPPT plans to evaluate the applicability of data for worker exposure to HBCD through
manufacturing and processing for the manufacture of EPS and XPS reported in EC (2008) and
NICNAS (2012) to US occupational  exposure scenarios. If the available data are not applicable,
develop estimates of occupational exposures based on modeling and assumptions (e.g.
approaches used in the new chemicals program).

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          2.6.2.2    Risks to General Population and Environmental Biota (aquatic,
             terrestrial and avian)

Robust monitoring datasets for US locations do not exist. EPA/OPPT plans to use estimates of
releases to the environment during HBCD manufacture and processing for the manufacture of
EPS and XPS from manufacturing, processing and use to estimate surface water, sediment and
soil concentrations. EPA/OPPT does not plan to consider degradation losses but may consider
partitioning.

EPA/OPPT plans to estimate releases to the environment from industrial sites based on CDR
(EPA, 2012a) data on production volume and number of sites and emission factors (i.e. 'loss
factors')6 reported in various HBCD risk assessment reports (EC,  2008; Environment CA and
Health CA, 2011; NICNAS, 2012). EPA/OPPT will assume emission factors for releases from
manufacturing and processing, in processes in other countries, are applicable to the US.

The release factor of a chemical is dependent on the design and operation of a chemical
process. EPA/OPPT assumes the basic process design and operation of the processes for the
manufacture or processing of HBCD in the US to be similar to those of the corresponding
processes in other countries. The descriptions of the processes for the manufacture of EPS resin
beads, the manufacture of foamed plastics including EPS and XPS, and plastics compounding in
general that are reported in the literature (Burkhardt et al., 2011; EPA, 2014b; Maul et al.,
2007; Suh, 2000) are similar to descriptions reported in EC (2008) and NICNAS (2012) of the
corresponding processes. EPA/OPPT's compilation of the non-site specific emission factors
reported in EC (2008), NICNAS (2012) and Environment CA and Health CA (2011) is given in
Table_Apx C-2 in Appendix C.  EPA/OPPT's preliminary estimate of the values of input variables
for the assessment of releases is reported in Table_Apx C-3; EPA/OPPT plans to assess a range
of release values from the ranges of input variables given in this table.

Additionally, EPA/OPPT may consider other available information to assess releases and
concentrations to other media (i.e. air).  For a discussion of the approach for how air releases
could be modeled to estimate concentrations in nearby media see EPA/OPPT's TBBPA problem
formulation document
(http://www.epa.gov/oppt/existingchemicals/pubs/workplans.html). However, there will  be
important differences in the assessments because site-specific modeling parameters were used
with TBBPA and those are not likely to be available for HBCD industrial sites.

Mathematical modeling approaches may be necessary to yield exposure estimates. EPA/OPPT
will consider the use of sensitivity analyses to determine key elements of uncertainty.
EPA/OPPT plans to estimate MOE for fish consumption (including sensitive  populations) using
US exposure information not captured in previous assessments and modeled fish ingestion
(EPA, 2007) from release estimates. EPA/OPPT is considering values for adult general
population consumption typically used by EPA Office of Water (e.g., 22 g/day for adults in  the
6 Ratio of amount of chemical released to amount manufactured or processed

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general population and 142.5g/day for subsistence fishers in the absence of local or similar fish
ingestion data). Based on NHANES data from 2003 to 2010 (EPA, 2014a), this value represents
the 90th percentile consumption rate of freshwater and estuarine fish for the US adult
population 21 years of age and older.

EPA/OPPT will identify hazard endpoints and benchmarks from published assessments (EC,
2008; Environment CA and Health CA, 2011; NICNAS, 2012) and data sources (See Appendix D
and Appendix E). EPA/OPPT will calculate non-cancer risks using MOE or HQ approaches.

          2.6.2.3    Consumers

Mathematical modeling approaches may be necessary to yield exposure estimates. EPA/OPPT
will consider the use of sensitivity analyses to determine key elements of uncertainty.
EPA/OPPT plans to use available or modeled (to be determined) data relevant to US exposure
scenarios to estimate consumer exposure using available or modeled data relevant to US
exposure scenarios with particular emphasis on sensitive populations (e.g. toddlers exposed in
microenvironments).

Consumer exposures to HBCD will be evaluated based on incidental ingestion of dust (as
described above), and incidental ingestion of indoor settled dust via hand-to-mouth behaviors.
Oral exposure by incidental ingestion of house  dust and hand-to-mouth transfer can be
quantified based on US values of monitored house dust. Several recent studies of house dust
are available which are expected  to be representative of US households. The EPA Exposure
Factors Handbook (EPA, 2011b) can be utilized  to determine typical quantities of dust ingested
and time-activity patterns.

EPA/OPPT will identify hazard endpoints and benchmarks from published assessments (EC,
2008; Environment CA and Health CA, 2011; NICNAS, 2012) and data sources (See Appendix E).
EPA/OPPT will calculate non-cancer risks using  MOE.

Aggregate oral exposures will be assessed considering hand-to-mouth dust ingestion, incidental
ingestion of dust and high-end fish consumption.

Conclusion
EPA/OPPT plans to evaluate potential risk to workers, the general population, consumers and
environmental biota under the TSCA Existing Chemicals Program using existing data and
methods. EPA/OPPT plans to review and evaluate available exposure and hazard benchmarks
and determine margins of exposure to evaluate the potential risk from  human and
environmental exposure to HBCD. EPA/OPPT plans to estimate releases to the environment
from industrial sites based on CDR (EPA, 2012a) data on production volume and number of sites
and emission factors (i.e. 'loss factors')7 reported in various HBCD risk assessment reports (EC,
2008; Environment CA and Health CA, 2011; NICNAS, 2012).
7 Ratio of amount of chemical released to amount manufactured or processed

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       2.6.3  Sources and Pathways Excluded From Further Assessment

Several scenarios were identified where exposure to HBCD is expected to be low or unknown,
and where further analysis is not recommended by EPA/OPPT under TSCA:

   •   Exposure from HBCD in landfills is not being assessed due to uncertainties in release
       from these sites.

   •   General population exposure from HBCD in drinking water is not being assessed because
       drinking water monitoring data for the US are not available and conclusions from
       available risk assessments indicate a low concern from this exposure pathway (EC, 2008;
       Environment CA and Health CA, 2011; NICNAS, 2012).

   •   Consumer exposure to HBCD in HIPS is not being assessed because the level of HBCD in
       HIPS in the US is unknown, it is not used in typical consumer products (e.g. computer or
       TV chassis), its use in other consumer products (e.g. electrical appliances) is enclosed
       limiting potential exposure and a low risk to consumers was indicated in available risk
       assessments.

   •   Consumer exposure to HBCD in textile finishings is not being assessed because it was
       considered low risk by the CPSC in upholstered furnishings (CPSC, 2001), it was not
       reported to be used in consumer fabrics or textiles in the 2012 CDR (EPA, 2012a) and
       the extent of institutional (e.g. prisons), military or aviation use is unknown.

   •   There are no adequate toxicological data based on inhalation or dermal exposures or a
       PBPK model readily available for route-to-route extrapolation. Therefore EPA/OPPT will
       not assess inhalation or dermal contact in this assessment. However, EPA is considering
       the quantification of incidental ingestion of particulates that would result from exposure
       to HBCD dust in occupational settings. A similar approach will be used to address
       consumer exposure to HBCD in dust.

       2.6.4  Uncertainties and Data Gaps

          2.6.4.1   Exposure Assessment

             2.6.4.1.1      Releases to the Environment

The major uncertainties in EPA's proposed approach are the following:

Production and Processing  Volumes and Number of Sites:
HBCD production and processing volumes are uncertain because CDR information on  current
production, export and import volumes is CBI. EPA will assume the HBCD production volume to
be in a range of values that is derived from the most recent publically reported CDR information
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and will assume the processing volume to be equal to the production volume. Refer to
Table_Apx C-3 for EPA's preliminary values for production and processing volumes.

The number of sites for most processing steps is uncertain. EPA will estimate the number of
sites based on CDR data which is data on ranges of number of sites. Furthermore, the
processing and product descriptions reported in CDR are general and preclude an accurate
determination of specific processing steps. Refer to Table_Apx C-l for EPA's preliminary
assessment of the number of sites. The share of the HBCD production volume that is processed
to manufacture XPS using HBCD powder or HBCD masterbatch is unknown.

             2.6.4.1.2     Occupational Exposure

Exposure monitoring data for workers in the US are not available in the scientific literature. The
greatest potential for occupational exposure is expected at industrial sites. Maximum exposure
occurs while workers load or unload HBCD powder or pellets  (EC, 2008), which is a worker
activity that EPA expects in the US. Data are available for inhalation and dermal exposures to
workers (EC, 2008). Workers who cut EPS or XPS boards (e.g., at construction sites) are
potentially exposed to  HBCD via inhalation at much lower concentrations of HBCD in air in the
form of respirable particles.

There is no PBPK model readily available for route-to-route extrapolation. EPA/OPPT has
identified this as a critical data gap since the exclusion of dermal and inhalation exposure
routes will result in the underestimation of risks.

             2.6.4.1.3     General Population and Consumer Exposure

Some of the available measured environmental concentrations were outside the US and it is
not clear how representative they are of exposure scenarios within the US. Significant
uncertainties  may exist in a quantitative evaluation. There are limited US surface water,
sediment, and soil measurements.

Available monitoring data may not be representative of concentrations in the environment
across all areas of the US. There are very limited data of HBCD in fish from the US and it is
uncertain if concentrations in fish in Canada  and abroad would  be similar to the US. Fish
ingestion exposures will need to be modeled based on releases to the environment from
manufacturing/processing/use. Exposure factors exist for fish consumption, however there
would be uncertainty in determining the concentration of HBCD in edible fish. If specific
receiving waters are not identified, there will be uncertainty in the amount of dilution that may
occur. EPA/OPPT will clearly document the uncertainty and limitations associated with the fish
consumption analyses.

Modeled releases to water from industrial facilities may result in the over- or under-estimation
of concentrations in the aquatic environment. Modeling default values will need to be modified
                                     Page 35 of 97

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(e.g., fish consumption) to account for high-end consumption. EPA/OPPT will consider the use
of sensitivity analyses to determine key elements of uncertainty.

The concentration of HBCD in indoor air or dust in offices or workplaces may be greater than in
homes. There are uncertainties using existing methodologies to estimate exposure for the
different sub-environments. Incidental ingestion of dust by adults is expected to be low
whereas ingestion of dust through incidental ingestion or hand to mouth behavior is expected
to be higher for small children due to their activity patterns and increased proximity to indoor
areas where dust may gather. Concentrations of HBCD in dust are likely to vary by
microenvironment and will need to be a consideration in exposure estimations.
It is not  possible to develop source-to-dose exposure models with currently available
information. Sources such as dust and presence in fish must be considered integrative metrics
for the purposes of exposure assessment. Source-to-dose models are absent or limited for most
of the identified exposure scenarios, therefore linking the exposure to specific products or the
use patterns of any one product will be challenging.

          2.6.4.2    Ecological Endpoints

Overall,  adequate aquatic toxicity data are available to characterize the hazard to the
environment for HBCD.

          2.6.4.3    Human Health Endpoints

Toxicokinetics (by the oral route), acute, repeated-dose, developmental, and reproductive
toxicity data are available to characterize the potential human health hazard of HBCD.
Although no standard neurotoxicity or developmental neurotoxicity studies on HBCD are
available, information on neurotoxicity was obtained from Functional Observational Battery,
locomotor activity evaluations, neurobehavioral testing, surface righting reflex, negative
geotaxis reflex, mid-air righting reflex, and brainstem auditory evoked potentials (BAEPs) in
several repeated-dose and reproductive toxicity studies.  Several  assays testing for genotoxicity,
and irritation/sensitization are also available. The only available dietary study evaluating the
carcinogenic potential of HBCD in mice is not considered adequate to draw conclusions
regarding carcinogenicity (EC, 2008; Environment CA and Health CA, 2011; EPA, 2014b; OECD,
2007). EPA agrees with these conclusions and therefore  in its HBCD assessment will not
consider carcinogenicity to be an endpoint of concern.

Neither  a complete mechanistic PBPK model for HBCD, nor a PBPK model for humans is
available. This precludes the use of a model for cross-route or cross-species extrapolation.
There is no PBPK model readily available for route-to-route extrapolation. Exclusion of dermal
and inhalation exposure routes will result in the underestimation of risks. The lack of a lifetime
exposure study and/or adequate assessment of carcinogenicity increases uncertainty in EPA's
assessment of long-term exposures to HBCD. Therefore, inhalation, dermal and lifetime
exposure assessment data gaps add uncertainty to EPA's risk assessment of HBCD.
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REFERENCES

Abdallah, M., and S. Harrad. 2011. Tetrabromobisphenol-a, Hexabromocyclododecane and Its
      Degradation Products in UK Human Milk: Relationship to External Exposure.
      Environment International, 37(1), 443-448.

Abdallah, M. A.-E., S. Harrad, and A. Covaci. 2008b. Hexabromocyclododecanes and
      Tetrabromobisphenol-a in Indoor Air and Dust in Birmingham, UK: Implications for
      Human Exposure. Environmental Science &Technology, 42(18), 6855-6861.

Abdallah, M. A.-E., S. Harrad, C. Ibarra, M. Diamond,  L. Melymuk, M. Robson, and A. Covaci.
      2008a. Hexabromocyclododecanes in Indoor Dust from Canada, the United Kingdom,
      and the United States. Environmental Science &Technology, 42(2), 459-464.

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APPENDICES

Appendix A     Regulatory and Assessment History

Table_Apx A-l: Regulatory and Assessment History of HBCD8
COUNTRY/ORGANIZATION
UNITED STATES

ASSESSMENT
Environmental Protection Agency
• Office of Environmental Information - Proposed HBCD for listing to the Toxic Release
Inventory (TRI) Program (2014). For current list of chemicals see:
http://www2.epa.gov/toxics-release-inventorv-tri-program/tri-listed-chemicals
• Office of Research and Development - Draft Toxicological Review Scoping Document to
support an IRIS assessment
(http://www.ecv.wa.gov/programs/wq/swqs/IRISAgendaChemicals.pdf)
• Office of Pollution Prevention and Toxics (OPPT) - Flame retardant alternatives to
hexabromocyclododecane (2014)
(http://www.epa.gov/dfe/pubs/proiects/hbcd/hbcd-full-report-508.pdf)
• OPPT - Proposed SNUR (Mar 2012) to designate manufacture or processing of HBCD for
use as a flame retardant in consumer textiles as a significant new use
• OPPT Action Plan for HBCD (2010) (all congeners;
http://www.epa.gov/oppt/existingchemicals/pubs/actionplans/RIN2070-
AZ10 HBCD%20action%20plan Final 2010-08-09.pdf)
• OPPT Risk Based Prioritization (RBP) including Hazard Characterization (2008)
(http://www.epa.gov/chemrtk/hpvis/rbp/HBCD.3194556.Web.RBP.31308.pdf) for CASRNs
3194-55-6 and 25637-99-4
• OPPT - CASRN 3194-55-6 (2001) High Production Volume Challenge Program test plan and
robust summaries submission
(http://www.epa.gov/chemrtk/pubs/summaries/cyclodod/cl3459cv.pdf)
Occupational Safety and Health Administration (OSHA)
• No occupational exposure limits (OSHA PEL, NIOSH REL, ACGIH TLV) are established
(www.osha.gov)
Consumer Product Safety Commission (CPSC)
• CPSC staff exposure and risk assessment of flame retardant chemicals in residential
upholstered furniture (2001) (http://www.cpsc.gov/en/)
• CPSC staff preliminary risk assessment of flame retardant (FR) chemicals in upholstered
furniture foam (2006) (http://www.cpsc.gov/en/)
• Quantitative assessment of potential health effects from the use of fire retardant (FR)
chemicals in mattresses (2006) (http://www.cpsc.qov/en/)
State -California
• HBCD is listed as an informational initial candidate chemical under California's Safer
Consumer Products regulations. (DTSC, 2010) (http://www.dtsc.ca.gov/SCP/ChemList.cfm)
• HBCD is listed on the state's Proposition 65 list because it is known to cause cancer or
birth defects or other reproductive harm (OEHHA, 2007, 2014).
(http://oehha.ca.qov/) (http://oehha.ca.qov/prop65/prop65 Nst/files/P65sinqle050214.pdf)
8 The risk assessment conclusions summarized in the table are selected conclusions from the reports that address
the pertinent US exposure scenarios and should not be construed as EPA's conclusions. EPA refers the reader to
the full reports for detailed explanations of the context of the conclusions reached in all risk assessments.

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COUNTRY/ORGANIZATION

CANADA
EUROPEAN UNION

AUSTRALIA
ASSESSMENT
• California lists HBCD as a designated and priority chemical for biomonitoring. However,
California has not yet started biomonitoring HBCD (SGP, 2014).
(httD://www.biomonitorina.ca.aov/chemicals/chemicals-biomonitored-california)
State - Maine
• Maine classifies HBCD as a chemical of high concern (DEP, 2013).
(httD://www.maine.aov/deD/safechem/hiahconcern/)
State - Minnesota
• Minnesota classifies HBCD as a chemical of high concern (MDH, 2013).
(httD://www.health. state. mn.us/divs/eh/hazardous/toDics/toxfreekids/chclist/mdhchc2013.Ddf)
State - Oregon
• The Oregon Department of Environmental Quality lists HBCD as a priority persistent
pollutant (DEQ, 2010a, 2011).
(http://www.deq.state.or.us/wq/SB737/docs/LeaRpAtt20100601.pdf)
(http://www.deq.state.or.us/wq/SB737/)
• Oregon posts use, exposure pathways and release data for HBCD under this program (DEQ,
2010b). (httD://www.dea.state.or.us/wa/SB737/docs/LeaRDAtt420100601.Ddf)
State - Washington
• Washington classifies HBCD as a chemical of high concern to children (WSDE, 2013).
(http://www.ecv.wa.qov/proqrams/swfa/cspa/chcc.html)
• HBCD meets Canada's regulatory criteria for persistence and bioaccumulation potential.
(http://www.ec.gc.ca/ese-ees/default. asp?lang=En&n=7882C148-l#a4)
• On November 1, 2012, Canada added HBCD to Schedule 1 of CEPA 1999 (Virtual
Elimination List). Proposed risk reduction measures would prohibit the manufacture,
import, use, sale, and offer for sale of HBCD and products containing HBCD.
(http://www.ec.gc.ca/lcpe-cepa/eng/regulations/detailReg.cfm?intReg=82)
• Health Canada (Health CA) and Environment Canada (ENVCA) have published a screening-
level assessment, (http://www.ec.gc.ca/ese-ees/default. asp?lang=En&n=7882C148-l#a4)
• HBCD is listed as a substance of very high concern (SVHC) and it is also listed under Annex
XIV (Authorisation list) of European Union's REACH. After August 21, 2015, only persons
with approved authorization applications may continue to use the chemical.
(http://echa.europa.eu/candidate-list-table)
(http://echa.europa.eu/documents/10162/13640/prioritisation hbccd en.pdf)
• The European Chemicals Agency (ECHA) is currently considering two applications to
authorize the use of HBCD: (i) formulation of flame retarded expanded polystyrene (EPS) to
solid unexpanded pellets using HBCD as the flame retardant additive (for onward use in
building applications); and (i) manufacture of flame retarded expanded polystyrene (EPS)
articles for use in building applications.
(http://echa.europa.eu/documents/10162/18584504/afa opinion hbcdd use 2 en.pdf)
• HBCD is recommended to be reviewed for the ED Directive's list of banned substances
under the restriction of hazardous substances (RoHS) in electrical and electronic
equipment.
(http://ec.europa.eu/environment/waste/weee/pdf/hazardous substances report.pdf)
• The WEEE (Waste Electrical and Electronic Equipment) directive in the European Union
requires the separation of plastics containing brominated flame retardants prior to
recycling, (http://ec.europa.eu/environment/waste/weee/index en. htm)
• The European Commission published a European Union Risk Assessment Report (EC, 2008)
on HBCD. (http://ec.europa.eu/health/ph risk/com mittees/04 scher/docs/scher o 093.pdf)

• HBCD is listed as a Priority Existing Chemical, (http://www.nicnas.gov.au/chemical-
information/pec-assessments)
Page 62 of 97

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COUNTRY/ORGANIZATION

JAPAN
STOCKHOLM CONVENTION
ON PERSISTENT ORGANIC
POLLUTANTS (POPs)
ORGANISATION FOR
ECONOMIC CO-
OPERATION AND
DEVELOPMENT (OECD)
ASSESSMENT
• Australia (National Industrial Chemicals Notification and Assessment Scheme) has prepared
a risk assessment for HBCD.
(http://www.nicnas.aov.au/Publications/CAR/PEC/PEC34/HBCD Report June 2012 PDF.pdf)
• HBCD is subject to mandatory reporting requirements in Japan under the Chemical
Substances Control Law (CSCL), specifically Japan requires type III monitoring for all
substances that may interfere with the survival and/or growth of flora and fauna.
(http://www.meti.go.ip/policy/chemical management/english/cscl/files/about/150408Progres.pdf)
• In May 2013, HBCD was added to the United Nation's Stockholm Convention list of
Persistent Organic Pollutants. The chemical is scheduled to be eliminated by November
2014 with specific exemptions for production and uses in expanded or extruded
polystyrene building insulation. As required by the convention, parties that use these
exemptions must register with the secretariat and the exemptions will expire in November
2019. (http://chm.pops.int/default.aspx)
• Published SIDS Initial Assessment Profile (SIAP) and SIAR in 2007 for CASRNs 3194-55-6 and
25637-99-4. (http://webnet.oecd.org/HPV/UI/SIDS Details.aspx?key=39a31bc9-3719-
4c55-a7d4-a8bbdd9afe04&idx=0)
(http://webnet.oecd. org/HPV/UI/handler.axd?id=ea58acll-e090-4b24-b281-
200ae351686c)
Page 63 of 97

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Appendix B    Uses Supplement Tables
Table_Apx B-l: 2012 CDR Production Data (Data Reported for 2011)
CASRN
25637-99-4
3194-55-6
Manufacturing Site
CBI
CBI
BASF Corporation
100 Campus Drive
Florham Park, NJ 07932
Albemarle Corporation
1550 Hwy. 371 W.
Magnolia, AR 71753
The Dow Chemical Company
2020 Dow Center
Midland, Ml 48674
Domestic
Manufacturing
CBI
CBI
ND
CBI
ND
Imported
ND
ND
CBI
ND
CBI
Volume
Exported
(Ibs)
CBI
0
CBI
CBI
0
Volume Used
on the Site
(Ibs)1
0
0
CBI
CBI
N/A
2010 Past
Production
Volume
(import+
manufacture)
CBI
CBI
CBI
CBI
CBI
2011
National
Production
Volume
(Ibs/yr)
Withheld
Withheld
^he total volume (domestically manufactured and imported) of the chemical used at the reporting site. This number represents the volume of the chemical that did not
leave the manufacturing site.
CBI = Confidential Business Information
ND = No Data; the company did not provide the requested information.
N/A = Not Applicable; the imported chemical was never physically at the site.
"Withheld" in the CDR public database indicates that the national production volume of a chemical was unable to be aggregated in order to protect CBI claims.

-------
Table_Apx B-2: Historic IUR and CDR Production Volumes
CASRN
25637-99-4
3194-55-6
Year
1986
10K-500K
XLM-10M
1990
No Reports
>1M-10M
1994
No Reports
>10M - 50M
1998
10K - 500K
>10M - 50M
2002
10K - 500K
>10M - 50M
2006
No Reports
10 to < 50M
2010
CBI
CBI
2011
Withheld
Withheld
^The total volume (domestically manufactured and imported) of the chemical used at the reporting site. This number represents the volume of the chemical that did not
leave the manufacturing site.
CBI = Confidential Business Information
"Withheld" in the CDR public database indicates that the national production volume of a chemical was unable to be aggregated in order to protect the CBI claims.
Table_Apx B-3: Summary of 2011 CDR Production Volume and Use Information
CAS
Number
25637-99-4
Industrial
Sector
Reported in
CDR
Plastics
Material and
Resin
Manufacturing
Construction
Description
of
Industrial
Use
Flame
retardant
in electrical
and
electronic
equipment
Flame
retardant
in
insulation
boards
Commercial or Consumer
Product Category
Plastic and Rubber
Products not Covered
Elsewhere (Commercial
and Consumer use)
Building/Construction
Materials Not Covered
Elsewhere (Commercial
and Consumer use)
Building/Construction
Materials Not Covered
Elsewhere (Commercial
use)
Potential End Product
• Electric housings for VCR
• Electrical and electronic
equipment (e.g., distribution
boxes for electrical lines)
• Video cassette housings
• Construction, insulation boards
(packaging material)
• Insulation boards (against cold
or warm) of transport vehicles
(e.g., lorries and caravans)
• Insulation boards in building
constructions, e.g. houses' walls,
cellars and indoor ceilings and
"inverted roofs" (outdoor)
• Insulation boards against frost
heaves of road and railway
embankments
2011 PV
CBI
CBI
CBI
Approximate % of 2011
National PV
CBI
CBI
100
                                                     Page 65 of 97

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CAS
Number







3194-55-6









Industrial
Sector
Reported in
CDR






Utilities









Description
of
Industrial
Use




Flame
retardant
in
insulation
boards








Commercial or Consumer
Product Category


Building/Construction
Materials Not Covered
Elsewhere (Consumer use)





Building/Construction
Materials Not Covered
Elsewhere (Commercial
use)





Potential End Product

• Construction, insulation boards
(packaging material)
• Insulation boards in building
constructions, e.g., houses'
walls, cellars and indoor ceilings
and "inverted roofs" (outdoor)
• Construction, insulation
boards,(packaging material)
• Insulation boards (against cold
or warm) of transport vehicles
(e.g., lorries and caravans)
• Insulation boards in building
constructions e.g. houses' walls,
cellars and indoor ceilings and
"inverted roofs" (outdoor)
• Insulation boards against frost
heaves of road and railway
embankments

2011 PV


CBI







CBI







Approximate % of 2011
National PV


100







50






Note:
1) Plastic and rubber products with consumer/commercial categories in the CDR data include:
• Food packaging
• Toys, playground, and sporting equipment
2) Building and construction materials with consumer/commercial categories in the CDR data include:
• Building/construction materials - wood and engineered wood products
CBI = Confidential Business Information
PV= Production Volume
Page 66 of 97

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Table_Apx B-4: Uses of HBCD as Listed in the 2008 EU Risk Assessment
Material1
  Use/
Function1
Percent of
  HBCD
Production
 Volume2
End Products1
Ongoing Use in the United States (US)?
   EPS
Insulation
   45%
Construction, insulation boards (packaging material)


Packaging material (minor use and not in food packaging)


Insulation boards (against cold or warm) of transport vehicles
(e.g., lorries and caravans)
Insulation boards in building constructions e.g. houses' walls,
cellars and indoor ceilings and "inverted roofs" (outdoor)
Insulation boards against frost heaves of road and railway
embankments
Yes; based on use in construction insulation boards
in 2012 CDR data2
Unknown; it is unclear if this is an ongoing use in the
US, and uses of polystyrene foam in consumer
products generally do not require the use of a flame
retardant3
Possibly;  based on use in insulation boards in 2012
CDR data2
Yes; based on use in construction insulation boards
in 2012 CDR data2
Possibly;  based on use in insulation boards in 2012
CDR data2
  XPS
Insulation
   51%
Construction, insulation boards

Insulation boards (against cold or warm) of transport vehicles
(e.g. lorries and caravans)
Insulation boards in building constructions e.g. houses' walls,
cellars and indoor ceilings and "inverted roofs" (outdoor)
Insulation boards against frost heaves of road and railway
embankments
Yes; based on use in construction insulation boards
in 2012 CDR data2
Possibly; based on use in insulation boards in 2012
CDR data2
Yes; based on use in construction insulation boards
in 2012 CDR data2
Possibly; based on use in insulation boards in 2012
CDR data2
  HIPS
Electrical
   and
electronic
  parts
    2%
Electric housings for VCR

Electrical and electronic equipment, e.g., distribution boxes
for electrical lines

Video cassette housings
Possibly, based on use in electronic plastics in 2012
CDR2
Possibly, based on use in electronic plastics in 2012
CDR2
Possibly, based on use in electronic plastics in 2012
CDR2
                                                                 Page 67 of 97

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 Material1
  Use/
Function1
Percent of
   HBCD
Production
 Volume2
End Products1
Ongoing Use in the United States (US)?
 Polymer
dispersion
on cotton
or cotton/
synthetic
  blends
 Textile
 coating
  agent
    2%
Upholstery fabric
Bed mattress ticking
Flat and pile upholstered furniture (residential and
commercial furniture)
Upholstery seating in transportation
Draperies, and wall coverings
Interior textiles e.g. roller blinds
Automobile interior textiles
Historic Use in the US4
Historic Use in the US4
Historic Use in the US4

Possibly, based industry response to SNUR2
Historic Use in the US4
Historic Use in the US4
Possibly, based industry response to SNUR2
Note: The uses in this table describe recorded HBCD applications for both the US and other countries. Given that HBCD will be phased out internationally under REACH and the
Stockholm Convention, it is unclear to what extent HBCD is currently used in these applications outside of the US.
Sources:
    1)   EC, 2008
    2)   EPA, 2012a
    3)   EPA, 2014
    4)   EPA, 2012e	
                                                                   Page 68 of 97

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Appendix C    Exposure Supplement Tables
Table_Apx C-l: 2012 CDR Data (Data Reported for 2011) for Release Assessment
Table Line
Number
1
2
3
4
5
6
7
Manufacture / Import
Site Identity
CBI
BASF, Florham
Park, NJ
Albemarle
Corporation,
Magnolia, AR
The Dow
Chemical
Company,
Midland, Ml
Max
Concentration and
Physical Form
90%+; Dry Powder
or Other Solid
lto<30%; Pellets
/ Large Crystals
90%+; Dry Powder
60 to < 90%;
Pellets/ Large
Crystals
Industrial Processing/ Use
Processing Use
Processing-incorporation
into formulation, mixture, or
reaction product
Processing-incorporation
into article
Processing-incorporation
into article
Processing-incorporation
into article
Processing-incorporation
into article
Processing-incorporation
into formulation, mixture, or
reaction product
Processing Sector
Plastics Material
and Resin
Manufacturing
Construction
Construction
Plastics Material
and Resin
Manufacturing
Utilities
Utilities
Function
Flame
retardants
Flame
retardants
Other
Other
Flame
retardants
Flame
retardants
%PV
50
50
CBI
CBI
NKRA
NKRA
Number
of Sites
<10
<10
10 to 24
25 to 99
10 to 24
10 to 24
Commercial/
Consumer Use
Use Product
Category
Building/
Construction
Materials Not
Covered Elsewhere
Building/
Construction
Materials not
covered elsewhere
Plastic and Rubber
Products not covered
elsewhere
Building/
Construction
Materials not
covered elsewhere
Not Reported
CBI = Confidential Business Information
NKRA = Not Known or Reasonably Ascertainable
PV = Production Volume

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Table_Apx C-2: Compilation of Release Factors and Other Release-Related Information in Various Risk Assessments
Operation
(Manufacture or
Processing Step)
Manufacture of EPS
resin beads that
contain HBCD (also
referred to as
"formulation of EPS
compound" (EC,
2008) or
"compounding raw
HBCD into resins"
(NICNAS, 2012))
Manufacture of EPS
that contains HBCD
(also referred to as
"industrial use of EPS
compound" (EC,
2008) or "conversion
or processing of
polymeric resin into
EPS foam products"
(NICNAS, 2012))
Compounding of
Polystyrene Resin to
Produce XPS
Masterbatch
containing HBCD
(also referred to as
"formulation of XPS
compound for the
manufacture of
Reference
EC (2008)
NICNAS
(2012)
EC (2008)
NICNAS
(2012)
EC (2008)
Release
Media
water
air
water
air
water
air
water
air
water
air
Loss Factor (Emission Factor)
Value
7.6E-06
7.3E-06
6.8E-03
2.5E-04
3.0E-05
3.0E-05
1.6E-03
1.6E-03
7.4E-06
7.3E-06
Description
This is the emission factor for a generic site and was
determined based on the 90th percentile of measurements
of concentration in the effluent from the on-site sewer
treatment plants of 9 of the total of 13 sites.
This is the emission factor for a generic site and is equal to
the maximum emission factor calculated from site-specific
data that pertain to three processing steps including
formulation of EPS and XPS compounds.
These values are reasonable worst case values that are the
sums of emission factors for handling and compounding
solid flame retardants with particle sizes <40 urn that are
also of relatively high volatility as reported in OECD
(2004b).
These are the emission factors for the generic site and are
reported in OECD (2004b) as the emission factors for
organic flame-retardants of relatively low volatility in
partially open plastics conversion processes.
These emission factors are weighted averages of emission
factors for organic flame of relatively high volatility in
closed plastics conversion processes that are reported in
OECD (2004b). The emission factors that were averaged
include values for high process temperature and low
plastics production volume.
This is the emission factor for a generic site and is equal to
the maximum of emission factors calculated from site-
specific data for three sites.
This is the emission factor for a generic site and is equal to
the maximum emission factor calculated from site-specific
data that pertain to three processing steps including
formulation of EPS and XPS compounds.
Number of Release Days
Value
300
150
300
200
300
Description
This is the value is for the generic
site and was determined in
accordance with the general risk
assessment guidance of the EU.
Site-specific values are in the
range of 61 to 350 with the
exception of one value that is
equal to 1.
This is a site-specific value.
This is the value for the generic
site and was determined in
accordance with the general risk
assessment guidance of the EU.
This is an assumed value.
This is the value for the generic
site and was determined in
accordance with the general risk
assessment guidance of the EU.
                                                        Page 70 of 97

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Operation
(Manufacture or
Processing Step)
flame retarded XPS"
(EC, 2008)
Manufacture of XPS
using XPS
Masterbatch
containing HBCD
Reference
Environment
CAand
Health CA
(2011)
EC (2008)
Release
Media
water
water
air
Loss Factor (Emission Factor)
Value
6.6E-03
2.6E-05
5.8E-05
Description
This is the emission factor for a generic site and is the sum
of emission factors for handling and compounding organic
solid flame retardants with particle sizes <40 urn that are of
relatively medium volatility as reported in OECD (2004b).
These are the emission factors for the generic site and are
equal to the maxima of the emission factors that were
derived from site-specific data but were not explicitly
reported. EPA calculated these factors, each of which is
equal to the ratio of total annual releases from 13 sites for
which site-specific data was not reported and the total
annual processing rate for these sites.
Number of Release Days
Value
60 or
200
1
300
Description
These values are for generic sites,
are functions of the processing
rate, and were determined in
accordance with the general risk
assessment guidance of the EU.
This value was assumed as a
reasonable worst case for the
number of release days from a
generic site. Site-specific values
are in the range of 1 to 15.
The number of release days for the
generic site is not reported. Site-
specific values are in the range of
15 to 300.
Page 71 of 97

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Table_Apx C-3: Preliminary Values of Input Variables for Calculation of the Range of Release Rates from Manufacturing Sites or the Processing
Sites of Each Processing Step
Operation
(Manufacture or
Processing Step)
manufacture of
HBCD
manufacture of
EPS resin beads
manufacture of
EPS
manufacture of
XPS using HBCD
powder
compounding of
polystyrene resin
to produce XPS
masterbatch
containing HBCD
manufacture of
XPS using XPS
masterbatch
containing HBCD
Processing Rates
as Fractions of the
HBCD
Manufacturing
Rate1
Not Applicable
0.45
0.45
0.51
0.51
0.51
Manufacturing or Processing
Rate (kg/yr)2
lower limit of
range
4.540.E+06
2.043.E+06
2.043.E+06
2.316.E+06
2.316.E+06
2.316.E+06
upper limit of
range
2.290.E+07
1.031. E+07
1.031. E+07
1.168.E+07
1.168.E+07
1.168.E+07
Number of Sites3
minimum
maximum
3
1
5
6
10
10
4
15
18
29
24
Number of
Release
Days4
250
250
250
1 (water)
250 (air)
250
1 (water)
250 (air)
The Minimum and Maximum Values of the
Compiled5 and Calculated6 Loss Factors for
Each Medium of Release (kg of HBCD released
per kg of HBCD manufactured or processed)
water
min
1.2E-07
7.6E-06
3.0E-05
l.OE-05
7.4E-06
max
4.0E-04
6.8E-03
1.6E-03
l.OE-05
6.6E-03
2.6E-05
air
min max
3.3E-07 6.8E-04
7.3E-06 2.5E-04
3.0E-05 1.6E-03
7.3E-06
7.3E-06
5.8E-05
  Note:
       1)  The share of production volume that is processed to manufacture of EPS or XPS is reported in Table_Apx B-4. The share
          of production volume that is processed to manufacture of XPS using HBCD powder or HBCD masterbatch is unknown and
          therefore EPA will conservatively assume this share is equal to the total share that is processed to manufacture XPS.
                                                      Page 72 of 97

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2) EPA estimated the lower-end of the current range of production volumes by summing the lower-ends of the ranges of
   production volumes for CAS number 25637-99-4 reported in 2002 and CAS number 3194-55-6 reported in 2006 that are
   given in Table_Apx B-2. EPA estimated the upper-end of the current range of production volume by summing the upper-
   ends of these two ranges.
3) The number of sites was estimated from data reported in EPA (2014b) and Table_Apx C-l.
4) EPA estimated the number of release days to be equal to 250 assuming each facility has an operation schedule of five
   days per week and 50 weeks per year, allowing for two-week annual downtime for maintenance. The values of the
   number of release days given Table_Apx C-2 are of similar magnitude. The exceptions are the values for releases to
   water from the manufacture of XPS using  HBCD powder and XPS using XPS masterbatch; EPA assessed each of these
   parameters to be 1 day per year in consideration of the data presented in Table_Apx C-2.
5) The compilation of non-site specific release factors is given in Table_Apx C-2.
6) EPA calculated release factors for HBCD manufacturing and the manufacture of XPS using HBCD powder from data
   reported in EC (2008) because non-site specific release factors are not reported for these two operations.
                                             Page 73 of 97

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Appendix D    Environmental Hazard Study Summaries


   D-l      Persistence in Environmental Media

        D-l-1    Air and Water

HBCD does not absorb light in the UV/Visible frequencies so is not expected to undergo direct
photolysis in air or water (Zhou et al., 2014). Kajiwara et al (Kajiwara and Takigami, 2013)
studied photolysis of HBCD on  textiles (4% by wt.) and reported "no substantial loss of any of
the HBCD diastereomers during the entire exposure period (371 days)" confirming that
photolytic degradation did not occur.Indirect photolysis with methane as a  co-solvent has been
observed to result in debromination (Zhou et al., 2012) and indirect photolysis with Fe(lll) and
H2O2 also can occur (Zhou et al., 2014).

Although HBCD is expected to exist primarily in the particulate phase in the atmosphere,  a
small percentage is expected to exist in the vapor phase based on its vapor pressure (Bidleman,
1988; CMA, 1997; Covaci et al., 2006). HBCD in the vapor phase can be degraded by reaction
with hydroxyl radicals in the atmosphere with an estimated rate constant of
5.01xlO"12 cm3/iTiolecules-sec at 25 ฐC corresponding to an atmospheric half-life of 2.1 days
(EPA, 1993, 2011a).  HBCD associated with particulates is expected to be removed from the
atmosphere through wet or dry deposition. Removal rates are unknown and the widespread
detection of HBCD in air samples and biota from remote locations far from  release locations
indicate that long-range atmospheric transport occurs (Covaci et al., 2006; EPA, 2010a; Ueno et
al., 2006).

        D-l-2    Soil, Sediment and Sludge

Based on an estimated Koc value of 7.6xl04 HBCD is expected to be fairly immobile in soil and to
bind strongly to soil, sediment, and suspended organic matter. It may undergo abiotic and
microbial degradation while associated with solids. The limited data available show that
biodegradation is slow and that anaerobic processes may be faster than aerobic.

A soil simulation test was conducted according to OECD TG 307 for commercial HBCD (BFRIP,
2001; EC, 2008). Activated sludge was inoculated with soil and HBCD at a nominal
concentration of 34-89 u.g/kg dry weight for 120 days. The disappearance half-life was 63 days
in aerobic soil and >120 days in abiotic aerobic controls. In the anaerobic soil, the half-life was 7
days compared to 82 days in abiotic anaerobic controls.

A closed bottle screening-level test for ready biodegradability (OECD TG 301D) was performed
using an initial HBCD concentration of 7.7 mg/L and an activated domestic sludge inoculum
(BFRIP, 2001; EC, 2008). No biodegradation was observed (0% of the theoretical oxygen
demand) over the test period of 28 days. Gerecke et al (Gerecke et al., 2006) studied

-------
degradation of BFRs, including HBCD, under anaerobic conditions in digested sewage sludge.
They reported a half-live for a technical HBCD mixture of 0.66 days. They found no statistically
significant enantioselective degradation of alpha-, beta-, or gamma-HBCD. The reported
reduction in concentration the HBCD mixture decreased in sterile controls at a rate 50 times
slower in incubations under non-sterile conditions.

A water-sediment OECD TG 308 study for commercial HBCD with a nominal concentration of
34-89 u.g/kg dry weight found that aerobic half-lives were 11-32 days in aerobic sediments and
30-190 days in abiotic aerobic controls (BFRIP, 2001; EC, 2008). In the anaerobic sediments,
disappearance half-lives were 1.1-1.5 days compared to 9.9-10 days in abiotic anaerobic
controls.

Davis et al (2006) studied degradation of 14C radiolabeled HBCD with sludge, sediment, and soil
simulation tests with initial concentrations of HBCD of 3.6-4.2 mg/L in the sludge systems and
3.0-4.7 mg/kg dry weight in the sediment and soil systems. As shown in Table_Apx D-l below,
they observed decrease in total initial radioactivity in the viable systems and abiotic controls.

Table_Apx D-l: Percent Decrease in Total Initial Radioactivity in Viable Systems and Abiotic Controls
During Sludge, Sediment, and Soil Simulation Tests Using 14C-labeled HBCD
Compartment
Anaerobic digester sludge
Aerobic activated sludge
Anaerobic freshwater
sediment
Aerobic freshwater sediment
Aerobic soil
Viable System
87%
21%
61%
44%
10%
Abiotic Control
84%
15%
33%
15%
6%
Time Period
60 days
65 days
112-113 days
112 days
112 days
Source: (BFRIP, 2001; Davis et al., 2006; EC, 2008)

HBCD degradation observed in these tests was attributed to abiotic reductive dehalogenation.
Degradation proceeded through a stepwise process to form TETRABROMOCYCLODODECENE,
DIBROMOCYCLODODECADIENE, AND 1,5,9-CYCLODODECATRIENE (See

Figure_Apx 2.6.4-1). Further degradation of 1,5,9-CYCLODODECATRIENE was not observed. General
trends observed were increased HBCD degradation under anaerobic conditions compared to
aerobic conditions and slower degradation of a-HBCD compared to the (3- and v-stereoisomers.
                                      Page 75 of 97

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   Br'
     Br
        HBCD
 tetrabromo-
cyclododecene
   dibromo-
cyclododecadiene
                                                                            1,5,9-
                                                                        cyclododecatriene
    Source: Davis et al., 2006; ECB, 2008
Figure_Apx 2.6.4-1: Stepwise Reductive Dehalogenation of HBCD
        D-l-3    Water and Wastewater
HBCD is not expected to undergo hydrolysis in environmental waters because of its low
solubility and lack of hydrolyzable functional groups. Based on the studies described above it is
not expected to be readily degradable in WWTPs and is expected to be persistent in surface and
groundwater. It may undergo indirect photolysis or abiotic degradation catalyzed by iron or
organic matter and can be biodegraded slowly under aerobic and anaerobic conditions.
Degradation rates in the environment are expected to be slower than those in lab studies. This
is consistent with environmental observations. For example the detection of HBCD at
concentrations ranging from 112 to 70,085 u.g/kg dry weight in sediment at locations near a
production site in Aycliffe, UK collected two years after the facility was closed down
demonstrates the persistence of this substance in the environment (EC, 2008).


        D-l-4    Bioaccumulation
High bioconcentration of HBCD in aquatic organisms has been observed in fish. Veith et al.
(Veith et al., 1979) measured a BCF of 18,100 for HBCD in fathead minnows. In a flow-through
bioconcentration test, BCF values of 8974 and 13,085 were determined for HBCD in rainbow
trout (EC, 2008). These BCF values indicate that HBCD has a very high potential to
bioconcentrate in aquatic organisms. The widespread detection of this substance in aquatic
organisms also suggests that HBCD bioconcentrates in the environment (Covaci et al., 2006; EC,
2008). Biomagnification of HBCD in the aquatic food web has also been reported based on
measurements in invertebrates, fish, birds, and marine mammals, with the highest levels of
HBCD measured in seals and porpoises (Covaci et al., 2006; EC, 2008; EPA, 2010a). Higher
concentrations of HBCD were measured in eggs from wild peregrine falcons feeding on birds
from terrestrial food webs in southwestern Sweden than in the eggs of captive falcons feeding
on domestic chickens, indicating that HBCD bioaccumulation in terrestrial food chains may also
be important (EPA, 2010a; Lindberg et al., 2004). Bioaccumulation may be isomer specific with
Y-HBCD is the dominant stereoisomer present in commercial HBCD formulations (>75%)

                                    Page 76 of 97

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(Becher, 2005). Similar proportionality is observed with HBCD stereoisomers detected in
environmental media (Covaci et al., 2006). However, in living organisms, a-HBCD is the
predominant stereoisomer, accounting for 70-90% of all HBCD detected (Covaci et al., 2006).
The reason for the difference in HBCD composition found in the environment compared to that
found in living organisms is unknown. Possible explanations include different rates of
bioconcentration for the a- and y- stereoisomers or different rates of metabolism within
organisms (Covaci et al., 2006;  EC, 2008).
   D-2      Toxicity to Aquatic Organisms

The toxicity to aquatic organisms has been summarized in several publications (EC, 2008;
Environment CA and Health CA, 2011; EPA, 2008a, 2014b; NICNAS, 2012; OECD, 2007).
Guideline studies in freshwater fish, daphnia, and green algae mostly reported no lethal or
sublethal effects at concentrations approaching saturation (Calmbacher, 1978; EPA, 2014b;
Graves and Swigert, 1997a, 1997b; Roberts and Swigert, 1997; Siebel-Sauer and  Bias, 1990).
        D-2-1    Aquatic Plant Toxicity

The toxicity to aquatic plants is summarized below and presented in Table_Apx D-2. The study
denoted with an asterisk is proposed for use by EPA/OPPT for risk assessment. Those studies
not considered adequate for risk assessment by EPA/OPPT are shaded in the table.

Green algae (Selanastrum capricornutum) were exposed to nominal test concentrations of
HBCD ranging from 1.5 to 6.8 u.g HBCD/L (Roberts and Swigert, 1997). The mean measured
concentration of HBCDs (3.7 u.g HBCD/L) at the maximum nominal test concentration of 6.8 u.g
HBCD/L (with solvent) was similar to the independently measured water solubility limit (8.6
u.g/L). No effects were observed at any test concentration. Another freshwater aquatic plant
study reported that green algae (S. subspicatus) had no effects at nominal test concentrations
ranging from 7.8 to 500  mg HBCD/L (Siebel-Sauer and Bias, 1990). However, the actual
concentrations of HBCD in test solution are unknown. No effects were observed at the highest
tested concentration.

Adverse effects observed following exposure were found in studies with the estuarine/marine
algae species Skeletonema costatum (Desjardins et al., 2004, 2005; Walsh et al., 1987). Walsh et
al. (1987) reported measured 72-hour ECso values in S. costatum ranging from 0.009 to 0.012
mg HBCD/L based  on reduced growth rate in five different types of saltwater media. The study
also tested two species,  Chlorella sp. and  Thalassiosira pseudonana, that were found to be less
sensitive. Desjardins et al. (2005) further substantiated observed toxicity in S. costatum when a
single saturated solution of 0.0545 mg HBCD/L (without a solvent) resulted in 51% growth
inhibition after 72  hours of exposure. Desjardins et al. (2004) also reported 19, 21, and 7.3%
inhibition of cell density, biomass, and growth rate, respectively, following exposure of S.
costatum to 0.041 mg HBCD/L (with a solvent), the only concentration tested, for 72 hours.

                                     Page 77 of 97

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Table_Apx D-2: Toxicity of HBCD to Aquatic Plants
Test Species
Green algae (Selanastrum
capricornutum)
Green algae (S.
subspicatus)
Algae (S. costatum)
Algae (S. costatum)
Algae (S. costatum)
*Algae (S. costatum)
Algae (Thalassiosira
pseudonana)
Algae (Chlorella Sp.)
Fresh/ Salt
Water
Fresh
Fresh
Marine
Marine
Marine
Marine
Marine
Marine
Duration
96-hour
96-hour
72-hour
72-hour
72-hour
72-hour
72-hour
72-hour
End-
point
ECso
ECso
ECso
ECso
ECso
ECso
ECso
ECso
Cone.
(mg/L)
>0.0037
>500
>0.041
>0.01
0.052
0.009-
0.012
0.05-0.37
>1.5
Test
Analysis
Static,
Measured
Static,
Nominal
Static,
Measured
Static,
Measured
Static,
Measured
Static,
Measured
Static,
Measured
Static,
Measured
Effect
Biomass/Growth
rate


Growth inhibition
Growth rate
References
Roberts and
Swigert, 1997
Siebel-Sauer and
Bias, 1987
Desjardins et al.,
2004
Desjardins et al.,
2005
Walsh etal.,
1987
       * The study denoted with an asterisk is proposed for use by EPA/OPPTfor risk assessment.
       Shaded studies will not be used to evaluate the risk of HCBD because inadequate test methods or
       incomplete information were provided for the study.
        D-2-2     Aquatic Invertebrate Toxicity
The toxicity to aquatic invertebrates is summarized below and presented in Table_Apx D-3. The
study denoted with an asterisk is proposed for use by EPA/OPPT for risk assessment. Those
studies not considered adequate for risk assessment by EPA/OPPT are shaded in the table.

Water fleas, (Daphnia magna; 10 animals per replicate) were exposed to nominal
concentrations of 0.0015, 0.0022, 0.0032, 0.0046 and 0.0068 mg/L HBCD under flow through
conditions for 48 hours (Graves and  Swigert, 1997a). On day 0, mean measured exposure
concentrations were 0.0021, 0.0018, 0.0018, 0.0026 and 0.0031mg/L and on day two, the mean
measured exposure concentrations were 0.0024, 0.0017, 0.0023, 0.0015, and 0.0034 mg/L. The
reported 48-hr EC5o was >0.0032 mg/L.

Jatzek (Jatzek, 1990) reported a lowest-observed-effect-concentration (LOEC) of 10 mg HBCD/L
and an ECso of 146.34 mg HBCD/L for daphnia immobility based on nominal test concentrations
that greatly exceeded measured water solubility values for HBCD (0.0488, 0.0147, and 0.0021
u.g/L for a-, (3-, and v-HBCD); however, because the appearance of the test solutions was not
reported, it is possible that reduction in daphnid swimming was related to the presence of
insoluble material at higher concentrations.

For chronic toxicity, hazard was determined  based on reduced size (length) of surviving young
daphnids, resulting in a measured MATC of 0.0042 mg HBCD/L (Drottar and Krueger, 1998).
                                     Page 78 of 97

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This study used a flow-through test system and reported additional effects, including decreased
reproductive rate and decreased mean weight of surviving young at 0.011 mg HBCD/L.
Mortality of adult daphnids in HBCD treatment groups was not significantly different from
control mortality.

Sublethal effects to invertebrates following chronic exposure were found in supporting studies
that assessed endpoints beyond those evaluated in guideline studies. In invertebrates,
degenerative changes in the gills of clams (Macoma balthica), manifested by the increased
frequency of nuclear and nucleolar abnormalities and the occurrence of dead cells, were
observed at nominal  concentrations of 0.1 mg HBCD/L (50-day LOEC) (Smolarz and Berger,
2009).

Table_Apx D-3: Toxicity of HBCD to Aquatic Invertebrates
Test Species

Fresh/ Salt
Water
Duration

End-
point
Cone.
(mg/L)
Test
Analysis
Effect

References

Aquatic Invertebrates - Acute Toxicity
*Waterflea
(Daphnia magna)

Water flea
(D. magna Straus)
Fresh


Fresh

48-hour


48-hour

ECso


ECso

>0.0032


146.34
Exceed WS
Flow-
through,
Measured
Static,
Nominal
Immobilization


Immobilization

Graves and
Swigert, 1997a

Jatzek, 1990

Aquatic Invertebrates - Chronic Toxicity
Clam (Macoma balthica)









*Waterflea
(Daphnia magna)


Marine









Fresh



50-day









21-day



LOEC









LOEC

NOEC

0.1









0.0056
mg/L
0.0031
mg/L
Static,
Nominal








Flow-
through,
Measured

degenerative
changes in the
gills manifested
by the increased
frequency of
nuclear and
nucleolar
abnormalities and
the occurrence of
dead cells
reduced length of
surviving young


Smolarz and
Berger, 2009








Drottar and
Krueger, 1998


       * The study denoted with an asterisk is proposed for use by EPA/OPPTfor risk assessment.
       Shaded studies will not be used to evaluate the risk of HCBD because inadequate test methods or
       incomplete information were provided for the study.

Toxicity studies for sediment organisms are summarized in Table_Apx D-4. The study denoted
with an asterisk is proposed for use by EPA/OPPT for risk assessment. Those studies not
considered adequate for risk assessment by EPA/OPPT are shaded in the table.
                                      Page 79 of 97

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In two prolonged sediment toxicity tests (Thomas et al., 2003a, 2003b) with Hyalella azteca
exposed to spiked sediment in the presence of 2 or 5% TOC, no effects were seen at the highest
concentration tested (1000 mg HBCD/kg dry weight sediment). Results of a non-GLP range-
finding test were submitted in conjunction with the definitive tests that showed reduced
survival of H. azteca at 500 mg HBCD/kg dry weight sediment in the presence of 2 or 5% TOC.

In another study, Lumbriculus variegatus were tested at nominal test concentrations of 0.05,
0.5, 5, 50, and 500 mg HBCD/kg dry weight sediment. Corresponding measured concentrations
were  ND, 0.2, 3.1, 28.7, 303.2 mg HBCD/kg dry weight. No HBCD was detected in the overlaying
water or in the pore water. Study details were excerpted from a secondary source (Oetken et
al., 2001).

Table_Apx D-4: Toxicity of HBCD to Sediment Organisms
Test Species
*Amphipod (Hyalella
azteca)
Amphipod (H. azteca)
*Amphipod (H. azteca)
Chironomid
(Chironomus riparius)
Lumbriculus variegatus
Fresh/ Salt
Water
Fresh
Fresh
Fresh
Fresh
Fresh
Duration
28-day
28-day
28-day
28-day
28-day
End-
point
LOEC
NOEC
NOEC
NOEC
No
Dose
LOEC
NOEC
Cone.
500 mg/kg dwt
sediment
100 mg/kg dwt
sediment
1,000 mg/kg
dwt sediment
1,000 mg/kg
dwt sediment
Not dose-
responsive
28.7 mg/kg dwt
sediment
3.1 mg/kg dwt
sediment
Test
Analysis
Flow-
through,
Measured
Flow-
through,
Measured
Flow-
through,
Measured
N/A
Static,
Measured
Effect
reduced
survivability
Unspecified
Unspecified
Not dose-
responsive
reduction in
worm number
References
Thomas et al.,
2003a, b
Thomas et al.,
2003b
Thomas et al.,
2003a
Thomas et al.,
2003a
Oetken et al.,
2001
       * The study denoted with an asterisk is proposed for use by EPA/OPPTfor risk assessment; N/A = not
       applicable
       Shaded studies will not be used to evaluate the risk of HCBD because inadequate test methods or
       incomplete information were provided for the study.
        D-2-3     Fish Toxicity
The toxicity to fish is summarized below and presented in Table_Apx D-5. The study denoted
with an asterisk is proposed for use by EPA/OPPT for risk assessment. Those studies not
considered adequate for risk assessment by EPA/OPPT are shaded in the table.
                                     Page 80 of 97

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Acute Effects

Rainbow trout (Oncorhynchus mykiss) were exposed to mean measured concentration of
HBCDs of 0.00075, 0.0015, 0.0023, 00.23 and 0025 mg/L (with solvent) under flow through
conditions for 96 hours. No effects were observed at any test concentration (Graves and
Swigert, 1997b).

Bluegill sunfish (Lepomis macrochirus) were exposed to nominal concentrations ranged from 10
to 100 mg/L under static conditions for 96 hours. These test concentrations exceeded the test
substance water solubility. A white flocculate was formed on the surface of the water in all test
solutions. No effects were seen at the highest test concentration of 100 mg/L (Calmbacher,
1978)(Calmbacher, 1978).

Acute effects observed following acute exposure were found in a 96-hour test with zebrafish
embryos (Deng et al., 2009). In a 96-hour toxicity study with zebrafish embryos, increased
malformation rate was observed at a nominal concentration of 0.1 mg HBCD/L and decreased
survival and increased heart rate were observed at a nominal concentration of 0.05 mg HBCD/L
(lowest concentration tested); an ECso or LCso value was not reported (Deng et al., 2009).

Chronic Effects

A chronic study in rainbow trout conducted following EPA recommended guidelines, found no
effects at concentrations approaching saturation (Drottar et al., 2001). No effects were
observed in European flounder (Platichthys flesus) following 78 days of diet or sediment
exposure to maximum concentrations of 3000 u.g HBCD/g lipid in food and 8000 u.g HBCD/g
total organic carbon (TOC), respectively (Kuiper et al., 2007).

Sublethal effects to fish following chronic exposure were found in supporting studies that
assessed endpoints beyond those evaluated in guideline studies. Effects observed in fish
include increased formation of reactive oxygen species (ROS) resulting in oxidative damage to
lipids, proteins, and DNA, decreased antioxidant capacities in fish tissue (e.g., brains,
hepatocytes, or erythrocytes), and increasing levels of ethyoxyresorufin-O-deethylase (EROD,
detoxification enzyme) and pentoxyresorufin-O-deethylase (PROD, detoxification enzyme)
levels in hepatocytes of fish exposed to the nominal concentration of >0.1 mg HBCD/L
(corresponds to ~0.2  mg HBCD/g whole fish [wet weight]) for 42 days (Zhang et al., 2008).
Indications of endocrine disruption were reported following dietary exposure to HBCD that
impacted the thyroid system of juvenile rainbow trout (Oncorhynchus mykiss). Each of the
diastereoisomers of HBCD (administered separately via diet at concentrations of 5 ng/g of a-,
P-, or y-HBCD) disrupted thyroid homeostasis, as indicated by lower free circulating
triiodothyronine (T3) and thyroxine (T4) levels (Palace et al., 2010; Palace et al., 2008).
                                     Page 81 of 97

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Table_Apx D-5: Toxicity of HBCD to Fish
Test Species
Fresh/ Salt
Water
Duration
End-
point
Cone.
(mg/L)
Test
Analysis
Effect
References
Fish - Acute Toxicity
Bluegill sunfish (Lepomis
macrochirus)
*Rainbow trout
(Oncorhynchus mykiss)
Zebra fish embryos
(Danio rand]
Fresh
Fresh
Fresh
96-hour
96-hour
96-hour
LCso
LCso
LCso
>100
>0.0025
0.05
Static,
Nominal
Flow-
through,
Measured
Static,
Nominal
Mortality
Mortality
decreased
survival, reduced
heart rate
Calmbacher,
1978
Graves and
Swigert, 1997b
Denget al., 2009
Fish - Chronic Toxicity
Rainbow trout
(Oncorhynchus mykiss)
Rainbow trout
(Oncorhynchus mykiss)
Chinese rare minnow
(Gobiocypris rarus)
European flounder
(Platichthysflesus)
*Rainbow trout (O.
mykiss)
Fresh

Fresh
Fresh
Fresh
88-day
28-day
42-day
78-day
32-day
NOEC

LOEC
MATC
NOEC
LOEC
0.0037

0.1
0.032
8,000 ng/g
TOC
3000 ng/g
lipid in
muscle
5 ng/g of
a-, P-, or v-
HBCD
Flow-
through,
Measured
Intraperi-
toneal
injection
using 50
and<500
mg/kg-bw
Static,
Nominal
Sediment
exposed
Diet
exposed
Diet
exposed
No effects
Significant
catalase activity
at 50 and<500
mg/kg-bw; EROD
activity; LSI
increase; No
effects on blood
plasma,
vitellogenin levels
or DNA adducts
formation.
DNA damage in
erythrocytes;
induction of
EROD and PROD
in hepatocytes;
ROS formation in
brain tissue
No effects on
behavior,
survival, growth
rate, relative liver
and gonad
weights
thyroid effects
Drottar et al.,
2001
(Ronisz et al.,
2004)
Zhang et al.,
2008
Kuiper et al.,
2007
Palace et al.,
2010
        * The study denoted with an asterisk is proposed for use by EPA/OPPTfor risk assessment.
        Shaded studies will not be used to evaluate the risk of HCBD because inadequate test methods or
        incomplete information were provided for the study.
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   D-3      Toxicity to Terrestrial Organisms
        D-3-1    Terrestrial Plant Toxicity
Available toxicity studies for terrestrial plants are summarized in Table_Apx D-6.

Studies using monocot and dicot plant species exhibited no toxicity up to the maximum test
concentration of 5,000 mg HBCD/kg soil (Porch et al., 2002).

Table_Apx D-6: Toxicity of HBCD to Terrestrial Plants
Test Species
Corn (Zea mays)
Cucumber (Cucumis
sativa)
Onion (Allium cepa)
Ryegrass (Lolium
perenne)
Duration
21-day
End-point
NOEC
Cone.
>5,000 mg
HBCD/kg soil
Test
Analysis
Nominal
Effect
No treatment-
related effects
on emergence,
survival or
growth
References
Porch et al., 2002
        D-3-2    Soil Invertebrate Toxicity
The available toxicity study in soil organisms summarized below and presented in Table_Apx
D-7 is adequate for risk assessment*.

Aufderheide et al., (Aufderheide et al., 2003) reported an ECioand no-observed-effect-
concentration (NOEC) values of 21.6 and 128 mg HBCD/kg dry soil, respectively, based on
reproductive effects in earthworms following 56 days of exposure. High variability in the data at
the lower test concentrations (as indicated in ECB, 2008) resulted in wide confidence limits for
the ECio, differences from the control that were not significant, and a NOEC that was greater
than the ECio. Two worms from the lowest test concentrations were lost during the study and
treated as dead (as reported in ECB, 2008), which may have contributed to the high variability
by reducing the sample size at the lowest test concentration; however, study details, data
tables, and statistical methodology were not available.

Table_Apx D-7: Toxicity of HBCD to Terrestrial Invertebrates
Test Species
*Earthworm (Eisenia
fetida)
Duration
56-day
End-point
ECio
NOEC
Cone.
21.6 mg
HBCD/kg dry
soil
128 mg
HBCD/kg dry
soil
Test
Analysis
Nominal,
Static, Soil
Effect
reproduction
References
Aufderheide et al., 2003
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        D-3-3     Avian Toxicity
Available toxicity studies to avian species are summarized in Table_Apx D-8.

Japanese quail eggs exposed for 6 weeks to an isomeric mixture of HBCD in the diet
experienced a reduction in hatchability at all tested concentrations (12-1000 ppm) (MOEJ,
2009). Additional effects included a significant reduction in egg shell thickness starting at 125
ppm, decreases in egg weights and egg production rates starting at 500 ppm, increases in
cracked eggs starting at 500 ppm, and adult mortality at 1000 ppm. A subsequent test,
conducted at lower dietary concentrations, determined a lowest-observed-adverse-effect-level
(LOAEL) and no-observed-adverse-effect-level (NOAEL) values of 15 and 5 ppm, respectively,
based on significant reduction of survival of chicks hatched from eggs of HBCD-fed quails
(MOEJ, 2009). In another study, a number of effects were reported in American Kestrels
exposed in ovo to 164.13 ng HBCD/g wet weight (Kobiliris, 2010).
Table_Apx D-8: Toxicity of HBCD to Avian Species
Test Species

Japanese quail
(Coturnix coturnix
japonica)



American kestrel
(Falco sparverius)










Duration

6-week

















End-point

LOAEL





LOAEL











Cone.

125 ppb

15 ppm (2.1
mg/kg body
wt/day
5 ppm
164.3 ng/g wet
weight of egg










Test
Analysis
Diet
exposed




In ovo
exposed










Effect

reduction in
hatchability
reduced chick
survival


reduced
corticosterone
response in male
nestling kestrels,
reduced flying
activities in
juvenile males,
delayed
response time to
predator
avoidance in
juvenile females
References

MOEJ, 2009





Kobiliris, 2010











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Appendix E    Human Health Hazard Study Summaries
   E-l
Toxicokinetics
For humans, there is a potential for oral, inhalation and dermal exposure. Available
toxicokinetics data in rodents indicate that HBCD is moderately absorbed via the
gastrointestinal tract, metabolized, and distributed to a number of nonfat tissues including
blood, muscle, and the liver, where it accumulates unchanged (Arita et al., 1983; Brandsma et
al., 2009; Hakk et al., 2012; Reistad et al., 2006; Sanders et al., 2013; Szabo et al., 2010; Szabo et
al., 2011b; van der Ven et al., 2009; van der Ven et al., 2006; Yu and Atallah, 1980). Elimination
of HBCD is predominantly via feces (as the parent compound), but it is also eliminated in urine
(as secondary metabolites) (Arita et al., 1983; Yu and Atallah, 1980; Szabo et al., 2010). In
humans, HBCD has been detected in breast milk, adipose tissue, blood, and both maternal and
umbilical serum (Abdallah and Harrad, 2011; Antignac et al., 2008; Covaci et al., 2006;
Fangstrom et al., 2008; Fangstrom et al., 2005; Johnson-Restrepo et al., 2008; Kakimoto et al.,
2008; Meijer et al., 2008; Rawn et al., 2014; Thomsen et al., 2007; Weiss et al., 2006)

   E-2     Acute Toxicity Studies
Several acute toxicity studies in rats and rabbits by the oral, dermal, and inhalation routes with
HBCD are available (BASF, 1990; Gulf South Research Institute, 1988; IRDC, 1977,1978a, 1978b;
Lewis and  Palanker, 1978; Momma et al., 1993). The acute toxicity of HBCD is low via the oral
route in rats and low via the dermal route in rabbits (Lewis and Palanker, 1978), with LDso
values >680 mg/kg-bw. Acute inhalation exposure to HBCD resulted in some minor symptoms
(such as eye squint, slight dyspnea, salivation, lacrimation, and nasal discharge), but no LCso has
been identified.

The acute toxicity of HBCD is summarized in Table_Apx E-l (oral) and Table_Apx E-2
(inhalation).
Table_Apx E-l: Acute Oral Toxicity of HBCD
Species/strain/
test
Rat/Charles
River/LDso
Rat/Charles River
CD/ LD5o test of
HBCD residue
Exposure
Single gavage (corn
oil)
Single gavage (corn
oil)
Result
LD5o > 10,000
mg/kg
LD5o = 1258
mg/kg (male);
680 mg/kg
(female)
Notes
No mortality; transient hypoactivity
and diarrhea; corneal opacity and
ptosis in 3/5 males, which did not
resolve by end of 14-day
observation.
Tested Firemaster 100; increased
activity, eye squint, dyspnea,
lacrimation, and nasal discharge.
Reference
IRDC, 1977
IRDC, 1978a
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Species/strain/
test

Mouse/NR/LDso
Rat/Sprague-
Dawley/limit test
of HBCD bottoms
Rat/NR/LDsotest
Exposure

Single gavage (30%
aqueous tragacanth)
Single gavage (corn
oil)
Single gavage (corn
oil)
Result

LD5o >6,400
mg/kg; data
not shown
LD5o >5,000
mg/kg; clinical
signs
LD5o > 10,000
mg/kg
Notes
Weight loss in all animals; recovery
noted by conclusion of study.
7-day observation period; increasing
apathy, trembling and late
mortalities; peritonitis at necropsy.
This study tested HBCD bottoms
described as black solids,
lacrimation, and facial swelling
resolved by post-exposure day 4; no
gross lesions were observed.
No significant changes observed.
Reference

BASF, 1990
Pharmakon
Research
International
Inc., 1990
Gulf South
Research
Institute, 1988
Abbreviations: NR, not reported
Table_Apx E-2: Acute Inhalation Toxicity of HBCD
Species/strain/test
Rat/Charles River/LD5o
Rat/Wistar/limittest
Rat/Charles River/LC5o
test of Firemaster 100
residue (liquid)
Rat/NR/LCsotest
Exposure
4-hr exposure to
Firemaster 100 dust:
202. 14 mg/L
1-hr exposure to
200 mg/L GLS-S6-
41A (highest
possible
concentration)
4-hr exposure to
Firemaster 100
residue: 22.9 mg/L
1 hr. whole-body
inhalation exposure
to GLS-S6-41A
Result
No mortality;
slight dyspnea at
the end of
exposure only
No mortality; no
clinical signs
Notes
All rats gained weight over
the observation period, but
no control data were
reported.
All rats gained weight over
the observation period, but
no control data were
reported.
One death (female, Day 3 post-exposure);
dyspnea, salivation, lacrimation, and nasal
discharge during exposure, resolved by Day 3;
significant body weight loss through Day 3, but
beginning to recover by Day 14 post exposure;
signs of nasal and lung irritation at gross
necropsy of rat that died.
LC5o >200 mg/L
No significant effects
observed.
Reference
IRDC, 1977
Lewis and Palanker,
1978
IRDC, 1978b
Gulf South Research
Institute, 1988
Abbreviations: NR, not reported
   E-3      Repeated-Dose Toxicity Studies
Short-term and subchronic toxicity studies on HBCD are available and summarized Table_Apx
E-3. In these studies, HBCD demonstrated effects on the thyroid and liver (Chengelis, 2002;
                                    Page 86 of 97

-------
Chengelis, 1997, 2001; van der Ven et al., 2006). However, most of these effects were not
significant after a recovery period of 14 days and 28 days, respectively (Chengelis, 2002;
Chengelis, 1997, 2001). Older short-term and chronic toxicity studies using an HBCD product
that is no longer manufactured concluded that observed liver findings were adaptive rather
than adverse (Zeller and  Kirsch, 1969,1970). Developmental behavioral defects were observed
in 3-month old mice after a single oral exposure on postnatal day (PND) 10 (Eriksson et  al.,
2006).

This following summary is extracted from the hazard characterization found in the supporting
documents for Initial Risk-Based Prioritization  of High Production Volume Chemicals (EPA,
2008a):

The potential toxicity from repeated oral exposure to HBCD was assessed in a variety of studies
in laboratory animals. Liver effects were observed in several studies but based on the
inconsistency of effects between studies and sexes, and lack of dose-response, it is not  clear if
the observed effects are treatment-related. Effects on the thyroid (one or both sexes) were
observed at moderate to high doses in some repeated-dose studies but not others, but could
be due to the fact that the thyroid system was not thoroughly studied in the early studies. More
recent studies showed increased thyroid weights in females only. One study indicates
decreased serum T4 and increased serum TSH in both sexes, whereas another study only shows
effects in females. Taken together, however, the data are suggestive of possible treatment-
related thyroid effects in adult animals. Several recent in vivo and in vitro studies have been
conducted to try and elucidate the possible mechanisms for both the observed liver and
thyroid effects,  but with no clear conclusions.  Functional observation battery and motor activity
evaluations in adult animals showed no evidence of neurotoxicity.

Table_Apx E-3: Repeated-Dose Toxicity of HBCD
Species/strain
Sprague-Dawley rats








Sprague-Dawley rats







Exposure
28-days








90-days







Result
Liver weight
increase from the
lowest dose (940
mg/kg-day) in both
sexes. Thyroid
hyperplasia from
the lowest dose
(940 mg/kg-day) in
both sexes.
Liver weight
increases from the
lowest dose (120
mg/kg-day) in both
sexes. No
histopathological
effects in thyroid
were reported.
Notes
The authors attributed the
increased liver weight to
hyperactivity as a result of
increased thyroid activity
and concluded the
increased liver weights
were not pathologic.
NOAEL = 940 mg/kg-day.

Demonstrates a low order
of toxicity and may reflect
a reversible adaptive
change. Data supports
that the liver and thyroid
glands are targets.


Reference
Zeller and Kirsch,
1969







Zeller and Kirsch,
1970






                                     Page 87 of 97

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Species/strain
Sprague-Dawley rats









Sprague-Dawley rats












Wistar rats


Exposure
28-days









90 days












28 days


Result
Liver weight
increase in females
from the lowest
dose (125 mg/kg-
day) and in males
from the mid dose
(350 mg/kg-day). No
histological effects
observed in the
thyroid in either sex.
Liver weight
increase from the
lowest dose (100
mg/kg-day) in both
sexes.








Liver weight
increases in females
at 23 mg/kg-day

Notes
The effects on the liver
especially in female rats
indicate a LOAELof 125
mg/kg-day.






Thyroid weight was
increased from the mid-
dose in females (300
mg/kg-day), but not in
males. Serum T4 was
decreased and TSH
increased in all dose
groups of both sexes.
LOAEL of 100 mg/kg-day
based on increases in liver
weights and changes in
thyroid serum
concentrations.
Most sensitive endpoint
was a 10% increase in
thyroid weight in females
at 3 mg/kg-day.
Reference
Chengelis, 1997









Chengelis, 2001












Van der Ven et al.,
2006


   E-4      Reproductive and Developmental Toxicity Studies
The available toxicity data for HBCD also includes evidence of reproductive, developmental, and
neurological toxicity in rats and mice which are summarized in Table_Apx E-4 and Table_Apx
E-5. An exposure-response array for reproductive and developmental toxicity is presented in
Figure_Apx 2.6.4-2 and for neurological effects is presented in Figure_Apx 2.6.4-3.

Information on the developmental and reproductive toxicity of HBCD comes from a single-
generation reproductive toxicity study (van der Ven et al., 2009), a study incorporating
gestational and post-natal exposure (Saegusa et al., 2009), a two-generation reproduction
toxicity study (Ema et al., 2008), a gestational exposure study (Murai et al., 1985), and a
neurotoxicity study of adult mice neonatally exposed to HBCD (Eriksson  et al., 2006).
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Table_Apx E-4: Reproductive and Developmental Toxicity of HBCD*
Species/strain
Wistar rats











CrhCD(SD) rats










Wistar rats






Crj:CD(SD)IGS rats








Wistar rats





Exposure
One full
spermatogenic or
two full estrous
cycles (males: 70 d
prior to mating;
females: 14 d prior
to mating) and
continued during
pregnancy and
lactation for a total
of 11 wks post
weaning
10 wks prior to
mating and through
gestation, lactation,
and for two
generations (multi-
generation
reproductive
toxicity study)



GD 0-20






GD 10-PND 20
(weaning)







See Van der Ven et
al., 2009





Result
No exposure related
changes in
reproductive
parameters,
including mating
success, time to
gestation, gestation
duration, number of
implantation sites,
litter size, and sex
ratio.

A significant
decrease in the
number of
primoridal follicles
in the ovary;
decreased size of
the thyroid follicles
in both sexes and an
increase in pup
mortality during
lactation
No significant
changes in the
number of implants,
resorptions, live or
dead fetuses or
external, visceral or
skeletal anomalies
No exposure-related
changes in
reproductive
parameters;
however, increased
thyroid weight and
decreased serum Ta
in male offspring at
~146 mg/kg-day
Effect on Brainstem
Auditory Evoked
Potentials (BAEPs)
observed in the low
frequency range
and only in male off-
spring (see text)
Notes
NOAEL ~100 mg/kg-day
(highest dose tested)










LOAEL- 101 mg/kg-day
NOAEL- 10 mg/kg-day









NOAEL- 750 mg/kg-day
(highest dose tested)





NOAEL -1505 mg/kg-day
(highest dose tested)







Neurobehavioral
assessment of the rats in
the Van der Ven et al.,
2009 study.



Reference
Van der Ven et al.,
2009










Ema et al., 2008










Murai et al., 1985






Saegusa et al., 2009








Lilienthal et al.,
2009





 "Only studies considered adequate for risk assessment are presented in the table.
                                        Page 89 of 97

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Signs of developmental toxic effects in Wistar rats included immune system effects, indications
of liver toxicity, and decreases in bone mineral density at very low doses, i.e., <1.3 mg/kg-day
(van der Ven et al., 2009); however, the authors noted that the vehicle used (corn oil) may have
affected observations at higher doses, including: increased mortality during lactation,
decreased liver weight in males, decreased adrenal weight in females, decreased plasma
cholesterol in females, and other immunological markers of toxicity. Saegusa et al. (2009)
observed an increased relative thyroid weight and decreased triiodothyronine (T3) levels in Fl
male Sprague-Dawley rats at postnatal week (PNW) 11 following dietary exposure to 1,000 ppm
(approximately 146.3 mg/kg-day) HBCD. Saegusa et al. (2009) also reported a significant
reduction in the number of CNPase-positive oligodendrocytes at 10,000 ppm (approximately
1,504.8 mg/kg-day). Developmental toxicity was not observed in Fl Wistar rats following
dietary exposure to HBCD during gestation (Murai et al., 1985).

Ema et al. (2008) reported a reduced viability index on Day 4 and Day 21 of lactation among
second generation (F2) offspring at 15,000 ppm (approximately 1,363 mg/kg-day). Ema et al.
(2008) observed additional developmental effects at doses as low as 1,500 ppm (approximately
115 and 138 mg/kg-day for Fl males and females, respectively), including: an increase in
dihydrotestosterone (DHT) in Fl males and an increased incidence of animals with decreased
thyroid follicle size in both sexes and generations. These authors reported no effects on sexual
development indicated by anogenital distance, vaginal opening, or preputial separation among
Fl or F2 generations.

Reproductive toxic effects have also been observed  in Ema et al. (2008). A decrease in the
number of primordial follicles in first generation (Fl) female Crl:CD(SD) rats at 1,500 ppm
(approximately 138 mg/kg-day) and a significant increase in the number of litters lost in the Fl
generation at 15,000 ppm (approximately 1,363 mg/kg-day) were  reported. No other
treatment-related adverse effects were reported in  any generation for indicators of
reproductive health, including: estrous cyclicity, sperm count and morphology, copulation
index, fertility index, gestation index, delivery index, gestation length, number of pups
delivered, number of litters, or sex ratios.

Neither van der Ven et al. (2009) nor Saegusa et al. (2009) observed reproductive effects at the
doses tested (up to 100 mg/kg-day in Wistar rats and approximately 1,504.8 mg/kg-day in
Sprague-Dawley rats, respectively).

No standard neurotoxicity or developmental neurotoxicity studies on HBCD are available.
Information on neurotoxicity was obtained from Functional Observational Battery, locomotor
activity evaluations,  neurobehavioral testing, surface righting reflex, negative geotaxis reflex,
mid-air righting reflex, and brainstem auditory evoked potentials (BAEPs) in several repeated-
dose and reproductive toxicity studies.

For example, in a subacute toxicity study, HBCD was administered orally by gavage in corn oil to
Sprague-Dawley CrhCD BR rats for 28 days at doses of 0, 125, 350, or 1,000 mg/kg-day (6

                                     Page 90 of 97

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rats/sex/dose in 125 and 350 mg/kg-day groups and 12 rats/sex/dose in the control and 1,000
mg/kg-day groups) (Chengelis, 1997). At the end of 28 days, 6 rats/sex/dose were necropsied,
while the remaining rats in the control and 1,000 mg/kg-day groups were untreated for a 14-
day recovery period prior to necropsy. Functional Observational Battery and motor activity
evaluations were carried out prior to study initiation, during the last week of HBCD
administration (Week 3), and during the recovery period (Week 5). No changes in the
Functional Observational Battery and motor activity tests were reported.

In another subchronic toxicity study, (Chengelis,  2002; Chengelis, 2001) administered HBCD by
oral gavage in corn oil daily to Crl:CD(SD)IGS BR rats (15/sex/dose) at dose levels of 0,100, 300,
or 1,000 mg/kg-day for 90 days. At the end of 90 days, 10 rats/sex/dose were necropsied, while
the remaining rats were untreated for a 28-day recovery period prior to necropsy. Functional
Observational Battery and locomotor activity evaluations were carried out on 5
a ni ma Is/sex/dose prior to study initiation, during the last week of HBCD administration (Week
13), and during the recovery period. There were no treatment-related effects on Functional
Observational Battery and locomotor activity observed.

In a one-generation study that included additional immunological, endocrine and
neurodevelopmental endpoints, van der Ven (2009) exposed Wistar rats (10/sex/dose) to a
composite mixture of technical-grade HBCD in the diet at concentrations resulting in doses of
0.1, 0.3, 1.0, 3.0,  10, 30, or 100 mg/kg-day. This study followed OECD Guidelines 415 and 407
(OECD, 1983,1995).  Just prior to the end  of the  study, at approximately 8 weeks of age, the
remaining Fl pups were assigned to separate groups for necropsy (5/sex/dose), immunological
testing (4 males/dose), or neurobehavioral testing (6/sex/dose plus additional males and
females from selected dose groups). Lilienthal  et al.  (Lilienthal et al., 2009) reported the results
of the neurobehavioral assessment from the one-generation study conducted by van der Ven et
al. (2009). Lilienthal et al. (2009) examined 110 day-old Fl rats for haloperidol-induced
catalepsy to determine possible effects of HBCD  on the dopaminergic system. One month after
the catalepsy measurements, brainstem auditory evoked potentials (BAEPs) to broadband click
and frequency-specific tone stimuli were recorded in males and females to examine potential
effects on auditory functions. The study authors concluded that the observed dose-dependent
decreases in latencies may be due to HBCD-related effects  on dopaminergic activity or to HBCD-
related induction of metabolizing liver enzymes resulting in enhanced metabolism of
haloperidol. HBCD-related effects on BAEP were observed in the low frequency range and only
in male offspring. The study authors hypothesized that HBCD exerts a cochlear effect on males
based on the results of the BAEPs. The authors noted that an alternative explanation could be
HBCD-induced changes in retinoids, which may be involved in development of the inner ear.
Too little information is available in this study to determine the significance of its findings.

Finally, in a  two-generation reproductive toxicity study, Ema et al. (2008) administered HBCD to
Crl:CD(SD) rats conducted according to OECD Guideline 416 (OECD, 2001), US EPA Guidelines
(EPA, 1991,1996), and good laboratory practices (GLP). Groups of male and female rats

                                     Page 91 of 97

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(24/sex/dose) were fed HBCD (as a mixture of a-HBCD, (3 -HBCD, and v-HBCD with proportions
of 8.5, 7.9, and  83.7%, respectively) in the diet at concentrations of 0,150,1,500, or 15,000
ppm from 10 weeks prior to mating through mating, gestation, and lactation. Reproductive and
developmental  milestones were monitored, including: surface righting reflex, negative geotaxis
reflex, mid-air righting reflex, and anogenital distance. F2 females exposed to 15,000 ppm  HBCD
completed the  mid-air righting reflex (76.9%) than control F2 females (100%). These findings
were not consistent over generations or sexes and were not considered treatment related. No
other effects of HBCD exposure on the development of reflexes were observed in either Fl or
F2 progeny.

An additional study on the neurotoxicity of HBCD is  available. Eriksson et al. (2006) observed
effects on spontaneous motor behavior, learning, and memory in adult NMRI mice following
exposure to HBCD on postnatal day (PND) 10. At 0.9 mg/kg, the authors reported significantly
reduced mean  locomotor activity. However, this study was not conducted according to current
guidelines (EPA, 1998b) and GLP, therefore EPA reserves judgment on the significance of these
findings. The authors used too few dose groups and the behavioral alterations were induced at
doses that did not produce clinical signs or affect weight gain. Additionally, effects due to litter
size were not considered. However, this study did demonstrate good repeatability for control
values and for relevant active substances tested several times.




an
en _
Art _

n

,




t 138





i





^ 146.3





..
T21.3
14.3 "114 (Male)

| Dose Range
ALnAEL
• NOAEL
• BMDL



A 13.5
I 0.9 _ o.056
    Decreased number   Increased pup   Increasedthvroid Effects not observed   Decreased     Decreased bone
    of primordial follicles  mortality in F2     weightand    -rat [Muraietal.,     habituation,    mineral density in
     in Fl females-rat  generation-rat(Ema decreasedTSinFl     1985)       locomotion, and  females-ratfvan der
     [Emaetsl., 2008)     etal.. 2008)   males - rat [Saegusa                rearing-mouse    Venetal., 2009)
                                 etal., 2009)                (Eriksson etal., 2006)

Figure_Apx 2.6.4-2: Exposure-Response Array for Developmental and Reproductive Toxicity Studies of
HBCD
                                       Page 92 of 97

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Table_Apx E-5: Summary of Effects in Parental and Fl Rats After Dietary, Gestational, Lactational and
Postnatal Exposure to HBCD


Generation
HBCD (ppm in diet)
Males'
0
100
1,000
10,000
Females0
0
100
1,000
10,000
FO
Thyroid
Relative weight (mg/100
gBW)
Histopathology: diffuse
follicular cell hypertrophy
(ฑ/+/++/+++)a
ND
ND
ND
ND
ND
ND
ND
ND
5.73
3/10
(0/3/0/0)b
6.75
5/10
(2/3/0/0)
6.30
6/10
(1/3/2/0)
7.47*
9/10#
(0/3/4/2)งง
Fl
Relative organ weights, PND 20
Liver (g/100 g BW)
3.68
3.82
3.98
4.66*
3.77
3.83
4.01
4.83*
Relative organ weights, PNW 11
Liver (g/100 g BW)
Thyroid (mg/100 g BW)
Epididymides (mg/100 g
BW)
3.45
4.85
0.23
3.81"
5.66
0.21*
3.58
5.78*
0.22
3.53
6.20"
0.21
3.35
8.20
NA
3.59
6.84
NA
3.44
7.35
NA
3.30
7.72
NA
Thyroid-related hormones
PND 20
T3 (ng/ml)
T4(ug/dl)
TSH (ng/ml)
1.09
4.39
5.40
1.13
4.20
6.66
1.06
4.78
6.07
0.93"
4.20
7.00*
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
PNW 11
T3 (ng/ml)
T4(ug/dl)
TSH (ng/ml)
0.96
4.77
4.74
0.93
4.84
5.81
0.88*
5.21
5.36
0.89"
5.20
4.96
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
Histopathology
PND 20
Liver: Vacuolar
degeneration, liver
cells, diffuse (+/++)a
0/10
0/10
0/10
6/10*
(6/0)
0/10
0/10
0/10
6/10* (0/6)งง
PNW 11
Adrenal: Vacuolar
degeneration, diffuse,
cortical cells (+/++)a
0/10
0/10
0/10
4/10*
(2/2)ง
ND
ND
ND
ND
Abbreviations: BW, body weight; PND, postnatal day; ppm, parts per million; PNW, postnatal week; ND, no data; NA, not
applicable; aGrade of change: (ฑ) minimal; (+) slight; (++) moderate; (+++) severe; bNumber of animals with each grade; cn=10
rats/sex/group; * Significantly different from the controls by Dunnett's test or Dunnett-type rank-sum test (p<0.05)
" Significantly different from the controls by Dunnett's test or Dunnett-type rank-sum test (p<0.01)
"Significantly different from the controls by Fisher's exact probability test (p<0.05)
ง Significantly different from the controls by Mann-Whitney's U-test (p<0.05)
งง Significantly different from the controls by Mann-Whitney's U-test (p<0.01)
Source: (Saegusa et al.,  2009)
                                                Page 93 of 97

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tro-
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  FOB evaluations consists of open field, home cage, sensory, neut omuscular and physiological observations
Figure_Apx 2.6.4-3: Exposure-Response Array for Neurological Effects of HBCD

Source: (EPA, 2014d)


   E-5      Skin Irritation and Sensitization Studies	

The available literature indicates that HBCD is not a dermal irritant in guinea pigs at
concentrations up to 0.5 ml, but one study found HBCD to be a mild skin allergen (Momma et
al., 1993). Acute eye irritation studies in rabbits showed HBCD to be a mild transient ocular
irritant (Gulf South Research Institute, 1988).


   E-6      Genotoxicity and Cancer Studies	

A limited number of studies investigated the genotoxicity of HBCD. These studies, summarized
in Table_Apx E-6, indicate that HBCD is not likely to be genotoxic.

The majority of these studies were standard Ames tests for detecting mutagenic potential in
Salmonella typhimurium (S. typhimurium). Most Ames tests conducted with HBCD yielded
negative results (Huntington Research Center, 1978; IBT, 1990; Litton Bionetics Inc, 1990;
Pharmakoligisches Institute, 1978; SRI, 1990; Zeiger et al., 1987). Two Ames tests showed
positive, dose-dependent results for strain TA1535; one for TA1535 only using a liquid residue
of HBCD in DMSO  (IBT, 1990); and one for strains TA1535 and TA100 using an unidentified
                                     Page 94 of 97

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mixture characterized only as HBCD bottoms in acetone (Ethyl Corporation, 1985a). Both of
these strains detect reversions by base pair substitution. However, the Ames tests in the strains
that were positive in these two studies (TA1535 and TA100) were negative in the other studies
cited above.

In mammalian systems, a reverse mutation assay with Chinese hamster ovary (CHO) Sp5 and
SPD8 cell lines exposed to HBCD yielded positive results (Helleday et al., 1990). A test of
unscheduled DNA synthesis with rat hepatocytes exposed to HBCD bottoms was also  positive
with a dose-response relationship (Ethyl Corporation, 1985b). The reverse mutation assay in
CHO cells (Helleday et al., 1999) and the unscheduled DNA synthesis assay in F344 hepatocytes
(Ethyl Corporation, 1985b) were not repeated by any other group.

Several assays performed to determine the genotoxicity of HBCD were negative even when
testing at cytotoxic concentrations, including: one in yeast (Litton Bionetics Inc., 1990), one
detecting chromosomal aberrations in human peripheral lymphocytes in vitro (Microbiological
Associates Inc, 1996), and one in vivo  mouse micronucleus test following intraperitoneal
injection of HBCD (BASF, 2000). Several previous assessments have concluded that based on
the lack of mutagenicity in vitro and in vivo, HBCD does not have genotoxic potential in vitro or
in vivo (EC, 2008; Environment CA and Health CA, 2011; NICNAS, 2012; OECD, 2007). EPA agrees
with this conclusion.

Existing assessments have also concluded, based on genotoxicity information and one limited
lifetime study, that HBCD is not carcinogenic (NICNAS, 2012; TemaNord, 2008) or that further
study of carcinogenicity is not warranted (EC, 2008; OECD, 2007). However, the only available
dietary study evaluating the carcinogenic potential of HBCD in mice is not considered adequate
to draw conclusions regarding carcinogenicity (EC, 2008; Environment CA and Health CA, 2011;
EPA, 2014b; OECD, 2007). Given this data gap, EPA's HBCD assessment will not include
carcinogenicity assessment.
                                     Page 95 of 97

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Table_Apx E-6: Genotoxicity of HBCD
Test/species/strain/
route
Test doses
(per plate)3
Results'3
-S9
+S9
Notes
Reference
Eukaryotic systems, in vitro
S. typhimurium TA98,
TA100, TA1537
S. typhimurium TA98,
TA100, TA1535,
TA1537, TA1538
S. typhimurium TA98,
TA100, TA1535
S. typhimurium TA98,
TA100, TA1535,
TA1537
S. typhimurium TA98,
TA100, TA1535,
TA1537, TA1538
S. typhimurium TA98,
TA100, TA1535,
TA1537
S. typhimurium TA98,
TA100, TA1535,
TA1537, TA1538
3,000 ng
in DMSO
250 ug
(Firemaster, FM-
100, Lot 53, white
powder)
in DMSO
1,000 ug (FM-
100, Lot 3322,
liquid residue)
in DMSO
10,000 ug
in DMSO
10,000 ug
in DMSO
5,000 ug
in DMSO
50 Ug
(HBCD bottoms )
in acetone
50 ug
-
-
-
-
-
-
+
(TA1535
and 100
only)
-
-
-
+
(TA1535
only)
-
-
-
+
(TA100
only)
-
Doses >1,000 u.g were partially
insoluble.
Doses >250 u.g were insoluble.
Positive in TA1535 at highest
dose only; lower doses showed
positive trend with dose.
Insoluble at 10,000 ug.


No cytotoxicity observed. Dose-
response only in TA1535 (-S9)
>100 ng/plate. TA100 positive at
highest dose only (5,000
ug/plate). All doses had a black
precipitate thought to be
carbon.

Pharmako-
logisches
Institute, 1978
IBT, 1990
Huntingdon
Research Center,
1978
Zieger et al.,
1987
SRI, 1990
Ethyl
Corporation,
1985a
Litton Bionetics,
1990
Prokaryotic non-mammalian systems, in vitro
Saccharomyces
cerevisiae D4
50 ug
-
-

Litton Bionetics,
1990
Mammalian systems, in vitro
Chromosomal
aberration test
In human peripheral
blood lymphocytes
750 ng/mL (-S9)
and
250 ng/mL (+S9)
in DMSO
-m
-m
Doses 750 - 2,500 were partially
insoluble, and fully insoluble
>2,500 ng/mL Repeated test for
two harvest time points: 20 hr (-
S9) or 4 hr (+S9) incubations, and
20 or 44 hr incubations (-S9 and
+S9).
Microbiological
Associates, 1996
                                      Page 96 of 97

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Test/species/strain/
route
Unscheduled DNA
Synthesis
rat/F344
male/primary
hepatocytes


Reversion assay
CHO/V79/Sp5 and
SPD8
Intragenic
recombination at hprt
locus in Sp5 (non-
homologous
recombination) and
SPD8 (homologous
recombination)
duplication cell lines
Test doses
(per plate)3
5-1,000 ug/well
in acetone
(HBCD bottoms)




3-20 ng/mL
in DMSO









Results'3
-S9



+








+





+S9



NA








NA






Notes
Five highest doses (from 5
Hg/well) showed an increased
response with dose over solvent
control, but only four highest
were statistically significant (x2).
Highest dose (1,000 ng/well) was
cytotoxic.
A statistically significant increase
in reversion frequency was
observed in both assays in the
highest dose group as
determined by linear regression
analysis.






Reference
Ethyl
Corporation,
1985b




Helleday et al.,
1999









Mammalian systems, in vivo
Micronucleus test
mouse/NMRI/intraper
itoneal injection
2,000 mg/kg
in DMSO


-m


NA




BASF, 2000


aLowest effective dose for positive results; highest dose tested
b+ = positive, ฑ = equivocal or weakly positive, - = negative, T =
for negative results.
cytotoxicity, NA = not applicable, ND = no data.
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