## TSCA Work Plan Chemical

Problem Formulation and Initial Assessment

Cyclic Aliphatic Bromides Cluster
Flame Retardants

CASRN NAME 25637-99-4 Hexabromocyclododecane 3194-55-6 1,2,5,6,9,10-Hexabromocyclododecane 3194-57-8 1,2,5,6-Tetrabromocyclooctane

August 2015 United States Environmental Protection Agency EPA Document# 743-D1-5001 August 2015 Office of Chemical Safety and
Pollution PreventionPage 2 of 97



## TABLE OF CONTENTS

TABLE OF CONTENTS .................................

................................................... ......................... 2
AUTHORS / CONTRIBUTORS / ACKNOWLEDGEMENTS .........

................................................... 5

ABBREVIATIONS .....................................

................................................... ............................ 6

EXECUTIVE SUMMARY .................................

................................................... ....................... 8

1 INTRODUCTION ......................................

................................................... ................... 11

1.1 S COPE OF THE A SSESSMENT

.................................................. ................................................... ......................... 12
1.2 R EGULATORY AND A SSESSMENT H ISTORY

.................................................. ................................................... ....... 14

2 PROBLEM FORMULATION ...............................

................................................... ........... 16

2.1 P HYSICAL AND C HEMICAL P ROPERTIES

.................................................. ................................................... ............ 16
2.2 P RODUCTION V OLUME AND U SES

.................................................. ................................................... ................. 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 F ATE AND T RANSPORT

.................................................. ................................................... ................................ 21
2.4 E XPOSURES

.................................................. ................................................... ............................................... 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
2.4.4.3 Fish Consumption ..................................

................................................... ................................................... ..... 25
2.4.4.4 Biomonitoring .....................................

................................................... ................................................... ........ 25
**2.4.5 Consumer Exposures ................................** 

**................................................... ............................................ 26** 
2.5 H AZARD E NDPOINTS

.................................................. ................................................... ................................... 26
**2.5.1 Ecological Hazard .................................** 

**................................................... ............................................... 26** 
**2.5.2 Human Health Hazard ...............................** 

**................................................... .......................................... 27** 
2.6 R ESULTS OF P ROBLEM F ORMULATION

.................................................. ................................................... ............ 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 .........................................

................................................... ................................................... ......... 33Page 3 of 97

**2.6.3 Sources and Pathways Excluded From Further Assessme**  **nt ................................................ ................... 34** 
**2.6.4 Uncertainties and Data Gaps .......................** 

**................................................... ....................................... 34** 

2.6.4.1 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-1 P ERSISTENCE IN E NVIRONMENTAL M EDIA

.................................................. ................................................... ..... 74

**D-1-1 Air and Water .....................................** 

**................................................... ................................................ 74** 

**D-1-2 Soil, Sediment and Sludge .........................** 

**................................................... .......................................... 74** 

**D-1-3 Water and Wastewater ..............................** 

**................................................... ........................................ 76** 

**D-1-4 Bioaccumulation ...................................** 

**................................................... .............................................. 76** 

D-2 T OXICITY TO A QUATIC O RGANISMS

.................................................. ................................................... .............. 77

**D-2-1 Aquatic Plant Toxicity ............................** 

**................................................... ............................................. 77** 

**D-2-2 Aquatic Invertebrate Toxicity......................** 

**................................................... ........................................ 78** 

**D-2-3 Fish Toxicity .....................................** 

**................................................... ...................................................**  **80**

D-3 T OXICITY TO T ERRESTRIAL O RGANISMS

.................................................. ................................................... ......... 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-1 T OXICOKINETICS

.................................................. ................................................... ....................................... 85

E-2 A CUTE T OXICITY S TUDIES

.................................................. ................................................... ........................... 85

E-3 R EPEATED -D OSE T OXICITY S TUDIES

.................................................. ................................................... .............. 86

E-4 R EPRODUCTIVE AND D EVELOPMENTAL T OXICITY S TUDIES

.................................................. .................................... 88

E-5 S KIN I RRITATION AND S ENSITIZATION S TUDIES

.................................................. ................................................... 94

E-6 G ENOTOXICITY AND C ANCER S TUDIES

.................................................. ................................................... ........... 94

LIST OF TABLES Table 2-1: Select Physical-Chemical Properties * ..

................................................... .................... 17 Table 2-2: Summary of Use/Exposure Scenarios Consid ered for Assessment ............................. 2 8Page 4 of 97

LIST OF APPENDIX TABLES Table_Apx A-1: Regulatory and Assessment History of HBCD ............................................. ........ 61 Table_Apx B-1: 2012 CDR Production Data (Data Repor ted for 2011) ..................................... ... 64 Table_Apx B-2: Historic IUR and CDR Production Volu mes................................................ .......... 65 Table_Apx B-3: Summary of 2011 CDR Production Volum e and Use Information ...................... 65 Table_Apx B-4: Uses of HBCD as Listed in the 2008 E U Risk Assessment ................................. ... 67 Table_Apx C-1: 2012 CDR Data (Data Reported for 201 1) for Release Assessment .................... 69 Table_Apx C-2: Compilation of Release Factors and O ther Release-Related Information in
Various Risk Assessments ..........................

................................................... ................................ 70 Table_Apx C-3: Preliminary Values of Input Variable s for Calculation of the Range of Release Rates from Manufacturing Sites or the Processing Si tes of Each Processing Step ...................... 72 Table_Apx D-1: Percent Decrease in Total Initial Ra dioactivity in Viable Systems and Abiotic Controls During Sludge, Sediment, and Soil Simulati on Tests Using 14 C-labeled HBCD ............... 75 Table_Apx D-2: Toxicity of HBCD to Aquatic Plants .

................................................... .................. 78 Table_Apx D-3: Toxicity of HBCD to Aquatic Inverteb rates.............................................. ............ 79 Table_Apx D-4: Toxicity of HBCD to Sediment Organis ms ................................................ ........... 80 Table_Apx D-5: Toxicity of HBCD to Fish ...........

................................................... ........................ 82 Table_Apx D-6: Toxicity of HBCD to Terrestrial Plan ts ................................................ ................. 83 Table_Apx D-7: Toxicity of HBCD to Terrestrial Inve rtebrates ......................................... ............ 83 Table_Apx D-8: Toxicity of HBCD to Avian Species ..

................................................... .................. 84 Table_Apx E-1: 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 Toxic ity of HBCD* ...................................... ... 89 Table_Apx E-5: Summary of Effects in Parental and F 1 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 B romides ........................................... ............... 12 Figure 2-1: Conceptual Model for HBCD .............

................................................... ....................... 28

LIST OF APPENDIX FIGURES Figure_Apx 2.6.4-1: Stepwise Reductive Dehalogenati on of HBCD ........................................ ..... 76 Figure_Apx 2.6.4-2: Exposure-Response Array for Dev elopmental and Reproductive Toxicity
Studies of HBCD ...................................

................................................... ...................................... 92 Figure_Apx 2.6.4-3: Exposure-Response Array for Neu rological Effects of HBCD ....................... 9 4Page 5 of 97



## AUTHORS / CONTRIBUTORS / ACKNOWLEDGEMENTS

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

EPA Assessment Team
**Leads** : Susan A. Laessig, OPPT/Risk Assessment Division (RA D) 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 & Sustainabl e 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 Divis ion (NPCD) Teresa Washington, OPPT/RAD Eva Wong, OPPT/RAD

**Management Leads** : Mark Townsend, 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/OPP T by Abt Associates, the Eastern Research Group (ERG), Inc., the Syracuse Research Corporatio n (SRC) and Versar.

Docket Please visit the public docket (Docket: EPA-HQ-OPPT -2015-0081) to view supporting
information.Page 6 of 97



## 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)

K OW Octanol:Water partition coefficient

lb Pound
LOEL Lowest Observed Effect Level Log K OW Logarithmic Octanol:Water partition coefficient
mg Milligram(s) MOE Margin of Exposure

ng nanogram NHANES National Health and Nutrition Examination Su rvey 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 Pre vention OECD Organisation for Economic Co-operation and D evelopment
OPPT Office of Pollution Prevention and Toxics OSHA Occupational Safety and Health Administration PBT Persistent, Bioaccumulative and Toxic pg picogram PMN Premanufacturing Notice PS PolystyrenePage 7 of 97

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 YearPage 8 of 97



## 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 chemi cals for further assessment under the Toxic Substances Control Act (TSCA) in March 2012. Chemic al risk assessments will be conducted if, as a result of scoping and problem formulation, the re are exposures of concern, identified hazards and sufficient data for quantitative analys is. 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 aliphat ic bromide flame retardant chemicals, including, hexabromocyclododecane (HBCD; CASRN 2563 7-99-4), 1,2,5,6,9,10- hexabromocyclododecane (1,2,5,6,9,10-HBCD; CASRN 31 94-55-6) and 1,2,5,6- tetrabromocyclooctane (CASRN 3195-57-8), for risk a ssessment. These three chemicals have similar physical and chemical properties, and envir onmental fate characteristics. Uses for 1,2,5,6-tetrabromocyclooctane have not been identif ied; 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 “HB CD” refers to either CASRN (25637-99-4 or**  **3194-55-6), or both. In addition, the conclusions d rawn for this assessment will be applicable to** 
**both CASRNs.**

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

• Workers: Evaluate the applicability of data from pu blished risk assessments to US occupational exposure scenarios to determine if fur ther assessment is needed. If the available data are not applicable, develop estimate s of occupational exposures based on modeling and assumptions (e.g. approaches used in t he new chemicals program).

• General population and biota (aquatic, terrestrial and avian): Estimate releases to the environment in the US to evaluate potential exposur e of general population and biota (aquatic, terrestrial and avian) to HBCD. The estim ation 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 t o US exposure scenarios to estimate consumer exposure using available or model ed data relevant to US exposure scenarios with particular emphasis on sensitive pop ulations.

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:Page 9 of 97

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

• Consumer exposure to HBCD in High Impact Polystyren e (HIPS) is not being assessed
because the level of HBCD in HIPS in the US is unkn own, it is not used in typical consumer products (e.g. computer or TV chassis), it s use in other consumer products (e.g. electrical appliances) is enclosed limiting p otential exposure and a low risk to
consumers was indicated in available risk assessmen ts.

• Consumer exposure to HBCD in textile finishings is not being assessed because it was considered low risk by the CPSC in upholstered furn ishings (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), militar y or aviation use is unknown.

• There are no adequate toxicological data based on i nhalation or dermal exposures, nor is there a PBPK model readily available for route-t o-route extrapolation. Therefore EPA/OPPT will not assess inhalation or dermal conta ct in this assessment. However, EPA is considering the quantification of incidental ing estion 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 carcinog enicity studies for HBCD.

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

Hexabromocyclododecane (HBCD) has been used as a fl ame retardant in plastics (additive) and textiles (backcoating) since the 1980s. Evidence su ggests 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 n ominated 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 ava ilable fate, exposure and hazard data, and characterized potential exposures, receptors and ef fects. Data adequacy was determined byPage 10 of 97

following published EPA/OPPT criteria 1 . EPA/OPPT reviewed the public literature (nominall y to September 2014) and Agency information sources (pub lic and confidential) to explore the sources, pathways, receptors and effects for consid eration in the assessment. EPA also identified areas of data uncertainty and assumption s.

Likely sources and pathways considered for analysis include: use of HBCD as a flame retardant in expanded polystyrene foam (EPS) and extruded pol ystyrene foam (XPS) in the building and construction industry accounting for 95% of HBCD us e 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 fo r institutional (e.g. prisons), military and aviation uses only (EPA, 2012e). HBCD is not used i n 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 (Figur e 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. E PA/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 p rocessing of HBCD, and the processing and use of products containing HBCD. HBCD in the fo rm of dust or attached to particulates has
been measured in indoor domestic and commercial env ironments, therefore there may be risks to consumers. Preliminary exposure calculations for the US population suggest that the methodology used in available assessments underesti mates consumer exposure to HBCD from dust for US consumers. Of particular interest for e valuation 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 it s way into the outdoor environment by transportation through the air and/or washed down t he drains (or storm drains) to enter
waterways.

These exposure scenarios have been considered in ri sk assessments conducted by other countries and the toxicity and risk of HBCD to aqua tic 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, proc essing, 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 rel evant and applicable to US exposures, and where appropriate, supplementing these risk assessm ents 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.ht m 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/Page 11 of 97

The results of problem formulation as illustrated i n 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 pro cessing.

• 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 wa ter, sediment and soil to HBCD from
releases to the environment.

• There is potential for consumer exposure to HBCD fr om 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 hu mans using a margin of exposure approach and potential risks to environment using a hazard q uotient approach.



## 1 INTRODUCTION

As a part of EPA’s comprehensive approach to enhanc e 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 ch emicals for further assessment 3 . 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, bioaccumula tive, 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 P lan of chemicals as candidates for risk assessment in the next several years. In the priori tization 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 chemical s in the work plan. If an assessment identifies unacceptable risks to humans or the envi ronment, EPA/OPPT will pursue risk reduction. The target audience for this risk assess ment is primarily EPA risk managers; however, it may also be of interest to the broader risk asse ssment community as well as US stakeholders interested in HBCD. The information presented in th e risk assessment may be of assistance to

2 http://www.epa.gov/oppt/existingchemicals/pubs/work plans.html

3 http://www.epa.gov/oppt/existingchemicals/pubs/wpme thods.pdfPage 12 of 97

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 deve lopment process, which is distinct from the initial prioritization exercise, includes scoping a nd problem formulation. During these steps EPA/OPPT reviews currently available data and infor mation, including but not limited to, assessments conducted by others (e.g., authorities in other countries), published or readily available reports and published scientific literatu re. During scoping and problem formulation the more robust review of the factors influencing i nitial prioritization may result in refinement – either addition/expansion or removal/contraction – of specific hazard or exposure concerns previously identified in the prioritization methodo logy.

This document includes the results of scoping and p roblem formulation and initial assessment for HBCD. During problem formulation, EPA/OPPT iden tified available exposure and hazard data, and characterized potential exposures, recept ors and effects. EPA/OPPT developed a conceptual model (Figure 2-1) and analysis plan (Se ction 2.6.2) as a result of problem
formulation.



### 1.1 Scope of the Assessment

The members of the cyclic aliphatic bromides cluste r 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 gro uped them into different clusters based on structure. The cyclic aliphatic bromide cluster inc luded 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.

Figure 1-1: Generic Structure of Cyclic Aliphatic B romides

Chemicals considered for this cluster were: 1,2-Dib romo-4-(1,2-dibromoethyl) cyclohexane [CASRN: 3322-93-8], 1,2,3,4,5,6-hexabromocyclohexan e [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 n umber 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-Tetra bromocyclooctane (CASRN 3194-57-8). This flame reta rdant is not functional in current EPS and XPS manufacturing processes. Its thermal stability does not meet oper ating temperature requirements for the manufacture of XPS foam (EPA, 2014b).Page 13 of 97

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

Two HBCD commercial chemicals meet this cluster cri teria 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 produc ed as a mixture of 16 possible isomers of 1,2,5,6,9,10-hexabromocyclododecane fro m 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-hexab romocyclododecane isomers. Each
individual isomer in this HBCD cluster member conta ins a ring of 12 saturated carbon atoms with 6 bromine atoms replacing 6 hydrogen ato ms. Each isomer has a molecular
formula of C12H18Br6. The three most common indivi dual diastereomers are designated as alpha-, beta-, and gamma-HBCD and eac h has an individual CAS Registry Number (as do all 16 isomers) 5

.

**For the purposes of this assessment, the use of “HB CD” refers to either CASRN (25637-99-4 and**  **3194-55-6), or both. In addition, the conclusions d rawn for this assessment will be applicable to** 
**both CASRNs.**

Section 2.6.1 presents the conceptual model develop ed by EPA/OPPT for HBCD. Using available tools and approaches, the Agency identified the rel evant TSCA use of HBCD for this assessment is its use as flame retardants in EPS and XPS produ cts 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 prod ucts (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 be cause 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 exten t 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 g enerated during the manufacture and processing of HBCD, and the processing and use of p roducts containing HBCD. HBCD in the form of dust or attached to particulates has been measur ed in indoor domestic and commercial

5 This is significant because much of the data are r eported for the individual alpha, beta, and gamma i somers rather than for the two commercial products.Page 14 of 97

environments, therefore there may be risks to consu mers. 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 e xposure (Abdallah and Harrad, 2011). HBCD may also make its way into the outdoor environ ment by transportation through the air and/or washed down the drains (or storm drains) to enter waterways.

These exposure scenarios have been considered in ri sk assessments conducted by other countries and the toxicity and risk of HBCD to aqua tic 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, proc essing, 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 rel evant and applicable to those in the US, and where appropriate, supplement these risk assess ments with current and US specific
information.



### 1.2 Regulatory and Assessment History

The regulatory and assessment history of HBCD in th e US and internationally are summarized in Table_Apx A-1.

United States - National

HBCD was sponsored in the HPV Challenge Program by BFRIP (BFRIP, 2001). Subsequently, EPA/OPPT prepared a risk based prioritization docum ent 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 envir onmental 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 sub ject 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 Inform ation 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 Nation al 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 popula tion from drinking water exposure (EC, 2008; Environment CA and Health CA, 2011; NICNAS, 2 012). HBCD is under consideration for inclusion in the NHANES human bio-monitoring progra m.Page 15 of 97

In 2006, the Consumer Product Safety Commission (CP SC) assessed the risk of exposure to HBCD in residential upholstered furniture (CPSC, 20 01) and concluded that HBCD did not present a hazard to consumers, as defined by the Fe deral 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 informa tional candidate under California’s Safer Consumer Products regulations (DTSC, 2010), on the state’s Proposition 65 list (OEHHA, 2007) and is designated a priority chemical for biomonito ring; 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; WSD E, 2013). Oregon considers HBCD a priority persistent pollutant (DEQ, 2010a, 2011) an d publishes use, exposure pathways and release data for HBCD under this program (DEQ, 2010 b).

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 s ummarized in several publications (EC, 2008; Environment CA and Health CA, 2011; EPA, 2008 a, 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 publi shed by Australia (NICNAS, 2012), Canada (Environment CA and Health CA, 2011) and the Europe an Union (EC, 2008). The conclusions
from these assessments are as follows:

**Occupational, General Population and Consumer Expos ure**  In the Health Canada assessment, the margin of expo sure 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 (E C, 2008; NICNAS, 2012). For reproductive effects, all three assessments used th e NOAEL (10 mg/kg-day) from the twogeneration study in rats (Ema et al., 2008). In add ition, the European Commission used the NOAEL (22.9 mg/kg-day) from the 28-day study in rat s (van der Ven et al., 2006). All three risk assessments concluded that the risk to general popu lation 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 consi dered a risk to the environment in all three published risk assessments (EC, 2008; Environment C A and Health CA, 2011; NICNAS, 2012). In May 2013, HBCD was added to the United Nation’s Sto ckholm Convention list of PersistentPage 16 of 97

Organic Pollutants (Stockholm Convention, 2013). Th e chemical is scheduled to be eliminated by November 2014 with specific exemptions for produ ction 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 t he exemptions will expire in November

2019.

Currently, under the Commission for Environmental C ooperation (CEC), Canada, Mexico and the US are evaluating the presence and migration of fla me retardants, including HBCD, from consumer products (CEC, 2015). The information gath ered from this effort will inform exposure assessors and risk managers and the executive summa ry of the final report(s) will be available to the public.



## 2 PROBLEM FORMULATION

Problem formulation aims to determine the major fac tors to be considered in an assessment, including exposure pathways, receptors and health e ndpoints (EPA, 1998a, 2014c). Accordingly, this problem formulation summarizes the exposure pa thways, 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 dat a review to identify available fate, exposure and hazard data and determine its likely s uitability for quantitative analysis and to identify exposure pathways, receptors and health en dpoints for quantitative analysis.

The outcome of this evaluation is summarized in a c onceptual model (Figure 2-1) that illustrates the exposure pathways, receptors and effects that w ere considered for potential risk assessment. An analysis plan is developed if the r esults 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 tetrabrom ocyclododecene or other isomeric HBCDs (UNEP, 2010) which are not separately included in t his problem formulation.Page 17 of 97

Table 2-1: Select Physical-Chemical Properties *

Properties a

1,2,5,6,9,10-Hexabromocyclododecane

HBCD

Melting Point 175 – 195 °C

Boiling Point > 200 °C [decomposes] b

Vapor Pressure 6.27 E-5 Pa at 21°C

Water Solubility 66 μg/L at 20°C c

Octanol Water Partition Coefficient (Log K ow ) 5.625 at 25 °C

* PCHEM Properties reported in the HPV Robust Summary (BFRIP, 2001) are measured values from a composite of commercial products from 3 different manufacturers.

a HPV Data Summary and Test Plan for Hexabromocyclodod ecane (HBCD) CASRN 3194-55-6

b EC HBCD RAR (EC, 2008)

c Sum of solubilities for 3 major isomers [alpha, bet a, and gamma] in commercial product (ECHA, 2008)



### 2.2 Production Volume and Uses

This section discusses the production volume and us es 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 ca n 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 infor mation on the domestic production volumes of HBCD. For both CAS numbers, s ite-specific production volumes and national level production volumes were withheld as TSCA Confidential Business Information (CBI) for the 2011 reporting year (EPA, 2012a). The refore, EPA/OPPT proposes to assess the production volume of HBCD based on the best publicl y available production volume data which is the historical IUR and CDR data presented in App endix B . EPA/OPPT assumes that current Br Br Br

Br

Br BrPage 18 of 97

production volumes are equal to the most recently r eported production volumes (the 2002 and 2006 data for CASRNs 25637-99-4 and 3194-55-6, resp ectively).

For the 2011 reporting year, the data indicate that two sites currently import at least one of the chemicals and that three sites domestically manufac ture the chemicals. However, according to the US International Trade Commission, the US impor ted 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 Ch emical Company, and two CBI sites (EPA, 2012a). Albemarle manufactures HBCD flame retardant s under the Saytex®HP-900 trade name (Albemarle Corporation, 2000). Both Dow and BASF in dicate 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 fo am, 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 polyst yrene 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 mo isture, prevent freezing, provide a stable fill material, and create high-strength composites in co nstruction applications. XPS foam board is used mainly for roofing applications and architectu ral molding. HBCD is used in both types of foams, because it is highly effective at low-use le vels, 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 X PS 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 P roducts 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 C orning lists HBCD in two of its products:Page 19 of 97

Foamular® Extruded Polystyrene Insulation and Foamu lar® 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 repor ts that EPS resins are also used in industrial packaging including packaging durable go ods and beanbag fill (NICNAS, 2012). Historic data indicate that EPS was used in packagi ng 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 pro ducts, 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 re tardant in the back coating of textiles. However, supported by information gathered from res earch, industry, and consumer product organizations, EPA/OPPT believes that HBCD is no lo nger used in consumer textile applications outside of the auto industry. EPA/OPPT received inf ormation from a group of textile formulators that the end uses of HBCD-containing te xtiles 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 2 005 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 texti le 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 fabri cs in automobiles made or imported to the US (EPA, 2012e).

HBCD is currently regulated under Annex XIV of Euro pean Union’s Regulation on Registration, Evaluation, Authorisation and Restriction of Chemic als (REACH), which sets a “sunset date” for the use of the chemical of August 21, 2015. In resp onse to the REACH regulation, the auto industry has formed a consortium to help US manufac turers understand the new requirements; develop tools, processes and best practices; and co ordinate compliance efforts. The consortium consists of five North American sponsoring companie s, Chrysler, Ford, General Motors, Honda, and Toyota (AIAG, 2011). It is likely that as compa nies 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.Page 20 of 97 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, a nd interior textiles such as roller blinds (ECHA, 2009; Morose, 2006). The majority of HBCD us ed in textiles was for upholstered furniture, because textiles treated with the chemic al 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 to tal 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 HB CD 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 o f 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 t old 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 au dio-visual equipment, refrigerator lining, and some wire and cable applications (ECHA, 2009; Moros e, 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 f or 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 da ta to indicate that HBCD is used in the US
for these uses.Page 21 of 97 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 c hemical 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 p otential 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, differ ences do exist in building technologies, climate, and consumption patterns, limiting the com parison of the two markets

.

2.2.3 Future Market Trends

EPA/OPPT expects future use of HBCD to decrease wor ldwide as the result of forthcoming international regulations. HBCD is listed under Ann ex XIV of European Union’s REACH, which sets a “sunset date” for August 21, 2015. After thi s 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 St ockholm Convention on Persistent Organic Pollutants (Convention) decided to list HBCD on the Convention’s “elimination” annex, with specific exemptions for production and use for expa nded 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, sub ject to approval by the COP, can be renewed for a period of up to 5 years. However, the US is n ot 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 t han endure the cost of maintaining a separate supply chain for the US. It is expected th at the Stockholm Convention may incentivize US processors, manufacturers, and importers to cons ider 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, 201 4b; NICNAS, 2012; OECD, 2007). A general overview of persistence and bioaccumulation is presented below. Additional details can be found in Appendix D.Page 22 of 97

HBCD is persistent in environmental media. It is ex pected to be stable to hydrolysis and direct photolysis. Measured aerobic biodegradation half-li ves either range up to months, or are greater than months. Anaerobic biodegradation may b e 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 mobi lity in soil. It is expected to volatilize to
some extent from soils and water surfaces. In the a tmosphere, HBCD is expected to occur primarily as particulates and may undergo long rang e transport. It will be removed from the atmosphere by wet or dry deposition, and has an est imated vapor phase half-life of 2.1 days for reaction with hydroxyl radicals. HBCD is highly bio accumulative with measured fish bioconcentration factor (BCF) values of greater tha n 18,000.



### 2.4 Exposures

2.4.1 Releases to the Environment

HBCD is manufactured or imported as a powder or pel lets (EPA, 2012a) and incorporated into a polymer matrix, including polystyrene foam, as an a dditive that is incorporated into the matrix (EC, 2008). The life cycle of HBCD includes the man ufacture 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, 2 010).

TRI data are not yet available for HBCD, but releas es from industrial sites to waste water treatment plants (WWTP), surface water, air and lan dfill are expected (EC, 2008; Environment Canada, 2011; NICNAS, 2012). HBCD is expected to r emain largely immobile in landfills (EPA, 2014) and therefore industrial releases to water an d air are of greater interest to EPA/OPPT than industrial releases to landfills. Sawing of EP S 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 ser vice life (EC, 2008). The total of releases of

HBCD from construction sites to air or surface wate r from professional use of EPS or XPS is large in comparison with the total releases to each of th ese 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 relea ses 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 industri al releases on a per-site basis.

Manufacturing and processing steps to be assessed a re summarized in Appendix C.Page 23 of 97

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 ma ximum measured concentration in suspended sediment was 3.7 μg/kg dw (Marvin et al., 2006) wit h similar values measured in China and Sweden (Arnot et al., 2009; He, S. et al., 2013). H BCD was identified in lakes, tributaries and
streams in China and the UK with measured concentra tions in the ng/L levels (BRE, 2009; Harrad et al., 2009; MOE, 2000, 2005). Measurement s of marine water were not found, and these values would be expected to be low. Geographi cally and temporally distributed monitoring data of this cluster in US surface water s were not found.

2.4.2.2 Wastewater

HBCD in wastewater influent (dissolved phase) at se wage treatment plants in South Africa and the UK were measured at concentrations of ng/L to < 1 μg/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 μg/k g dw (De Boer et al 2002, Morris et al., 2004). Measurements of suspended phase in effluent were as high as 18 μg/kg dw (Morris et al., 2004). Measured concentrations of HBCD in was tewater in the US are not available.

2.4.2.3 Sludge

Measurements of HBCD levels in sludge have been mad e throughout Europe (Covaci et al., 2006; De Boer et al., 2002; Gorga et al., 2013; Gue rra 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)(Guer ra 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 an alyzed from the EPA 2001 National Sewage Sludge Survey showed approximately 20 ug/kg HBCD (V enkatesan and Halden, 2014).

2.4.2.4 Soil

Soil sampling is limited to measurements from Swede n (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 val ues (μg/kg dw) found in the soil near a HBCD manufacturing plant in the Laizhou Bay area. Studie s with measured levels of HBCD in soils in
the US were not available.Page 24 of 97 2.4.2.5 Sediment

Sediment measurements have been made in numerous co untries throughout the world including Asia, South America, North America, Europ e and South Africa (Al-Odaini et al., 2013; Arnot et al., 2009; Baron et al., 2013; Canton et a l., 2008; Covaci et al., 2006; De Boer et al., 2002; de Boer et al., 2004; Feng et al., 2012; Guer ra 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 m arine species throughout North America. In the US, carp from the Hyco River in Virginia wer e reported with mean HBCD levels of 4640 μg/kg lipid weight (Chen et al., 2011). HBCD was al so measured in the blubber or liver of various marine mammals: Bottlenose dolphin (Johnson-Restre po et al., 2008), Bull shark (JohnsonRestrepo et al., 2008), Atlantic Sharpnose shark (J ohnson-Restrepo et al., 2008), White Sided dolphin (Peck et al., 2008), and California sea lio ns (Stapleton et al., 2006) with the highest mean concentration of 130 μg/kg lipid weight report ed in the White Sided dolphin (Peck et al., 2008). Similarly, HBCD has been detected in the blu bber or liver of marine species (Budakowski and Tomy, 2003; Muir et al., 2006; Tomy et al., 20 09) and in whole or the muscle of fresh water fish in Canada (Law et al., 2006a; Tomy et al., 200 8).

2.4.3 Occupational Exposure

EPA/OPPT considers inhalation and dermal exposure t o 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 sy stem to the gastrointestinal tract (EPA, 2011b) is a contributor to aggregate exposures. Thi s will be referred to here as incidental ingestion of inhaled particulates.

HBCD is manufactured as a powder at two US sites an d is imported as pellets at two other sites. The processing of HBCD for the manufacture of EPS a nd 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 w orkers in the US is not available in the scientific literature. The number of potentially ex posed 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 o f inhalable particles for workers handling standard grade HBCD powder at sites for the manufac ture or processing (for the manufacture of XPS or EPS) of HBCD are in the range of 0.1 to 2 .5 mg/m 3 (EC, 2008). For dermal exposures,Page 25 of 97

the exposure range is 84 to 840 mg/day of HBCD dus t (EC, 2008). Workers who cut EPS or XPS boards (e.g., at construction sites) are potentiall y exposed to HBCD via inhalation at much lower concentrations of HBCD in air in the form of respir able 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 ind oors than outdoors. However, spatial variation is likely with proximity to point sources . Concentrations are generally reported in picograms/m 3 . Samples have been collected in a wide variety of locations including remote
locations in the arctic far removed from sources in dicating long-range transport. Some studies characterized vapor and particulate phase of HBCD w ith HBCD most often reported in the particulate phase (Abdallah et al., 2008b; Alaee et al., 2003; Li et al., 2012a; Takigami et al., 2009a; Tue et al., 2013).

2.4.4.2 Drinking Water

Measured concentrations of HBCD in drinking water a re limited to one study in the UK (BRE, 2009) where sampling from main water inlet and bore hole water indicated concentration of 5- 16 μg/L and samples of process water from the Nethe rlands were an order of magnitude lower. Monitoring studies identifying HBCD in drinking wat er in the US are not readily available.

2.4.4.3 Fish Consumption

Measured concentrations of HBCD in fish are reporte d throughout the world, typically in the μg/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., 2 009; Covaci et al., 2006; Ismail et al., 2009; Klosterhaus et al., 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 bre ast milk at ng/gram lipid levels. (Arnot et al., 2009; Carignan et al., 2012; Covaci et al., 20 06; Croes et al., 2012; Devanathan et al., 2012; Malarvannan et al., 2013; Marvin et al., 2011; Prat t 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; Kiciński et a l., 2012; Kim et al., 2013; WWF, 2004).Page 26 of 97

2.4.5 Consumer Exposures

Consumer exposure to HBCD may include inhalation ex posure, 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 r elatively high octanol-air partition coefficient, it is likely to preferentially partiti on 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 buil dings, automobiles, and airplanes both in
the US and other countries. The available assessme nts have addressed data relevant to US exposure scenarios up to and including 2011.

Concentrations vary widely across different microen vironments and within microenvironments and are generally reported in the nanograms/gram or micrograms/gram range (Abdallah et al., 2008a; Abdallah and Harrad, 2010; Ali et al., 2012 ; Allen et al., 2013a; Allen et al., 2013b; Bjorklund et al., 2012; Covaci et al., 2006; D'Holl ander 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; Kukučka P*, 2013; Ni and Zeng, 2013; Sahlström 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. Concentrati ons are generally reported in picograms/m 3 (Abdallah et al., 2008b; Abdallah and Harrad, 2010 ; de Wit et al., 2012; Ni and Zeng, 2013; Tue et al., 2013).



### 2.5 Hazard Endpoints

2.5.1 Ecological Hazard

The ecological hazard of HBCD has been summarized i n several publications (EC, 2008; Environment CA and Health CA, 2011; EPA, 2008a, 201 4b; NICNAS, 2012; OECD, 2007). A general overview is presented below. Additional det ails 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. E PA/OPPT concludes that HBCD is hazardous to the environment. This conclusion is based on the po tential for bioaccumulation (fish bioconcentration factor [BCF]=8,974–18,100) and bio magnification (fish biomagnification factor [BMF]=4.3–9.1), observed acute toxicity values as l ow as 0.009 mg HBCD/L (72-hour EC 50 ) 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 t oxicity, and reducedPage 27 of 97

chick survival in Japanese quails ( **Coturnix coturnix japonica** ) at 15 ppm in diet (2.1 mg HBCD/kgbody weight/day) that indicates high terrestrial to xicity (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, 201 4b; NICNAS, 2012; OECD, 2007). A general overview is presented below. Additional det ails and tabulated data summaries can be found in Appendix E.

For humans, there is a potential for oral, inhalati on and dermal exposure. Available
toxicokinetics data in rodents indicate that HBCD i s moderately absorbed via the gastrointestinal tract, metabolized, and distribute d 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 compou nd), but is also eliminated in the urine (as secondary metabolites). The acute hazard concer n is low via the oral, dermal and inhalation routes. The chronic hazard concern is based on repr oductive effects which are described in detail in Appendix E. There is also some evidence o f neurodevelopmental toxicity suggestive of hearing impairment, however, it is difficult to det ermine if the effect is due to developmental exposure to HBCD, a result of repeated-dose exposur e, or a combination of the two. Available data suggest that HBCD is not genotoxic. No adequat e carcinogenicity studies are available (EPA, 2014b). Existing assessments have also conclu ded, based on genotoxicity information and one limited lifetime study, that HBCD is not carcin ogenic (NICNAS, 2012; TemaNord, 2008) or that further study of carcinogenicity is not warran ted (EC, 2008; OECD, 2007). However, the only available dietary study evaluating the carcino genic potential of HBCD in mice is not considered adequate to draw conclusions regarding c arcinogenicity (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 expos ure (See Sections 2.3 and 2.4). Potential exposures to HBCD (derived from the manufacture, pr ocessing and use of HBCD-containing polystyrene products) in homes, offices, the enviro nment, and occupational settings were linked to hazard endpoints in human and non-human r eceptors.Page 28 of 97

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 line s 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. unc ertain, have limited data or which are not quantifiable. The shaded boxes indicate elements pr oposed for assessment while the unshaded boxes indicate elements lacking adequate data for a ssessment. These scenarios are elaborated
in Table 2-2.

Table 2-2: Summary of Use/Exposure Scenarios Consid ered for Assessment

# USE/EXPOSURE

SCENARIO
CONSIDERED POTENTIAL

ROUTE OF
EXPOSURE PROPOSED

FOR
ASSESSMENT RATIONALE/LIMITATIONS/

UNCERTAINTIES

1 Worker exposure to HBCD during manufacturing and processing ORAL –

Unintended oral exposure
via the
incidental ingestion of
inhaled particles of
HBCD and
HBCD in dust YES Risk identified for HBCD handling in occupation al settings in non-US assessmentsPage 29 of 97

# USE/EXPOSURE

SCENARIO
CONSIDERED POTENTIAL

ROUTE OF
EXPOSURE PROPOSED

FOR
ASSESSMENT RATIONALE/LIMITATIONS/

UNCERTAINTIES

DERMAL NO Experimental data for reliable route extr apolation
from oral to inhalation & dermal routes are not
available

2 General population exposure from HBCD resulting
from releases to
the environment ORAL –

Ingestion of HBCD particles YES No TRI data

ORAL – Fish Consumption YES Low risk in available non-US assessments; confirm low risk using US data ORAL – Drinking

Water NO Low risk in available non-US assessments; No US drinking water monitoring data
ORAL – Food
other than fish
from ambient

water NO Low risk in available non-US assessments; Not regulated under TSCA

INHALATION NO Low risk in available non-US assessme nts 3 Ecological Receptors WATER YES Available US monitoring data and estimated/modeled releases from industrial sites

SEDIMENT YES Available US monitoring data and estimated/modeled releases from industrial sites

SOIL YES Available US monitoring data and estimated/modeled releases from industrial sites

4a Consumer exposure to HBCD
from the use of

consumer products in indoor

environments ORAL –

Incidental ingestion of
inhaled particles of
HBCD in dust
Hand-to-mouth exposure of
HBCD from dust YES Data available for oral exposures only

4b Consumer exposure to HBCD
from the use of

consumer products in indoor

environments INHALATION

DERMAL NO Experimental data for reliable route extrapolati on 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.

4c Consumer exposure to HBCD from use of EPS/
XPS commercial products. ORAL

INHALATION

DERMAL NO Exposure considered insignificant and not assess ed 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 30 of 97

# USE/EXPOSURE

SCENARIO
CONSIDERED POTENTIAL

ROUTE OF
EXPOSURE PROPOSED

FOR
ASSESSMENT RATIONALE/LIMITATIONS/

UNCERTAINTIES

4d Consumer exposure to HBCD in specific articles made with high impact polystyrene (HIPS) ORAL

INHALATION

DERMAL NO 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

4e Consumer exposure to HBCD in textile finishings DERMAL NO 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 conceptua l model.

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

HBCD has been assessed globally (EC, 2008; Environm ent CA and Health CA, 2011; NICNAS, 2012). For human health, the toxicological point o f departure (POD; NOAEL for the twogeneration toxicity study) used in the published ri sk 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 conc lusions, EPA uses physiologically-based pharmacokinetic (PBPK) modeling for route-to-route extrapolation; however, these data are not robust for HBCD. Therefore, EPA/OPPT proposes t o 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 lifecycle of HBCD?

Releases of HBCD to air, including releases to air during manufacture and processing of EPS and XPS, are expected to partition to particulate matte r and deposit in the environment (water and soil) and is expected to be bioaccumulated up the f ood 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 a vailable. However, published risk assessments indicate low risk to the general population from drinking water

exposure.Page 31 of 97

**Fish Consumption:**

• For the general population, available risk assessme nts (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, th e Canadian assessment included sensitive subpopulations such as indigenous populat ions (Nunavut) and nursing infants and concluded that risks to these populations is lo w.

• However, recent publications (Abdallah and Harrad, 2011; Aylward and Hays, 2011; Carignan et al., 2012; Gheorghe et al., 2013; Kalac hova 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) indi cated 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 HB CD found in the environment?

Available risk assessments (EC, 2008; Environment C A 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 relea se estimates and exposure.

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

**Dust:** Available risk assessments (EC, 2008; Environment C A and Health CA, 2011; NICNAS, 2012) concluded that risk to consumers from exposur e 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 consumer s. 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 con junction 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 cond uct the following additional analyses.

2.6.2.1 Workers

EPA/OPPT plans to evaluate the applicability of dat a 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 o n modeling and assumptions (e.g. approaches used in the new chemicals program).Page 32 of 97 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 cons ider degradation losses but may consider partitioning.

EPA/OPPT plans to estimate releases to the environm ent from industrial sites based on CDR (EPA, 2012a) data on production volume and number o f 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 assum e 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 th e 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 s imilar to those of the corresponding processes in other countries. The descriptions of t he 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 (Burkha rdt et al., 2011; EPA, 2014b; Maul et al., 2007; Suh, 2000) are similar to descriptions report ed 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 Environmen t 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 variable s 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 dis cussion of the approach for how air releases
could be modeled to estimate concentrations in near by media see EPA/OPPT’s TBBPA problem
formulation document ( http://www.epa.gov/oppt/existingchemicals/pubs/work plans.html ). However, there will be important differences in the assessments because si te-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 t o yield exposure estimates. EPA/OPPT will consider the use of sensitivity analyses to de termine key elements of uncertainty. EPA/OPPT plans to estimate MOE for fish consumption (including sensitive populations) using US exposure information not captured in previous as sessments and modeled fish ingestion (EPA, 2007) from release estimates. EPA/OPPT is con sidering 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 man ufactured or processedPage 33 of 97

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

EPA/OPPT will identify hazard endpoints and benchma rks from published assessments (EC, 2008; Environment CA and Health CA, 2011; NICNAS, 2 012) 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 t o yield exposure estimates. EPA/OPPT will consider the use of sensitivity analyses to de termine key elements of uncertainty. EPA/OPPT plans to use available or modeled (to be d etermined) data relevant to US exposure scenarios to estimate consumer exposure using avail able or modeled data relevant to US exposure scenarios with particular emphasis on sens itive 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 indoo r 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 du st. Several recent studies of house dust are available which are expected to be representati ve of US households. The EPA Exposure Factors Handbook (EPA, 2011b) can be utilized to de termine typical quantities of dust ingested and time-activity patterns.

EPA/OPPT will identify hazard endpoints and benchma rks from published assessments (EC, 2008; Environment CA and Health CA, 2011; NICNAS, 2 012) and data sources (See Appendix E). EPA/OPPT will calculate non-cancer risks using MOE.

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

Conclusion EPA/OPPT plans to evaluate potential risk to worker s, the general population, consumers and environmental biota under the TSCA Existing Chemica ls Program using existing data and methods. EPA/OPPT plans to review and evaluate avai lable exposure and hazard benchmarks and determine margins of exposure to evaluate the p otential risk from human and environmental exposure to HBCD. EPA/OPPT plans to e stimate releases to the environment from industrial sites based on CDR (EPA, 2012a) dat a 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, 2 012).

7 Ratio of amount of chemical released to amount man ufactured or processedPage 34 of 97

2.6.3 Sources and Pathways Excluded From Further Assessme nt

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

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

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

• Consumer exposure to HBCD in HIPS is not being asse ssed because the level of HBCD in HIPS in the US is unknown, it is not used in typica l 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 consu mers 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 furn ishings (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), militar y or aviation use is unknown.

• There are no adequate toxicological data based on i nhalation or dermal exposures or a PBPK model readily available for route-to-route ext rapolation. Therefore EPA/OPPT will
not assess inhalation or dermal contact in this ass essment. However, EPA is considering the quantification of incidental ingestion of parti culates that would result from exposure to HBCD dust in occupational settings. A similar ap proach 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 Sit es:**  HBCD production and processing volumes are uncertai n because CDR information on current production, export and import volumes is CBI. EPA w ill assume the HBCD production volume to be in a range of values that is derived from the mo st recent publically reported CDR informationPage 35 of 97

and will assume the processing volume to be equal t o the production volume. Refer to Table_Apx C-3 for EPA’s preliminary values for prod uction and processing volumes.

The number of sites for most processing steps is un certain. 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 t o Table_Apx C-1 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 master batch 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 exp ected 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 avail able for inhalation and dermal exposures to workers (EC, 2008). Workers who cut EPS or XPS boar ds (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 ex clusion 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 concen trations were outside the US and it is not clear how representative they are of exposure s cenarios within the US. Significant uncertainties may exist in a quantitative evaluatio n. 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 a broad would be similar to the US. Fish ingestion exposures will need to be modeled based o n releases to the environment from manufacturing/processing/use. Exposure factors exis t for fish consumption, however there would be uncertainty in determining the concentrati on 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 uncertain ty and limitations associated with the fish consumption analyses.

Modeled releases to water from industrial facilitie s may result in the over- or under-estimation of concentrations in the aquatic environment. Model ing default values will need to be modifiedPage 36 of 97

(e.g., fish consumption) to account for high-end co nsumption. EPA/OPPT will consider the use of sensitivity analyses to determine key elements o f 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 metho dologies 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 ingest ion or hand to mouth behavior is expected to be higher for small children due to their activi ty 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 consideratio n in exposure estimations. It is not possible to develop source-to-dose exposu re models with currently available information. Sources such as dust and presence in f ish 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 lin king 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 availab le 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 pot ential human health hazard of HBCD. Although no standard neurotoxicity or developmental neurotoxicity studies on HBCD are available, information on neurotoxicity was obtaine d from Functional Observational Battery, locomotor activity evaluations, neurobehavioral tes ting, surface righting reflex, negative geotaxis reflex, mid-air righting reflex, and brain stem auditory evoked potentials (BAEPs) in several repeated-dose and reproductive toxicity stu dies. Several assays testing for genotoxicity, and irritation/sensitization are also available. Th e only available dietary study evaluating the carcinogenic potential of HBCD in mice is not consi dered adequate to draw conclusions regarding carcinogenicity (EC, 2008; Environment CA and Health CA, 2011; EPA, 2014b; OECD, 2007). EPA agrees with these conclusions and theref ore in its HBCD assessment will not consider carcinogenicity to be an endpoint of conce rn.

Neither a complete mechanistic PBPK model for HBCD, nor a PBPK model for humans is available. This precludes the use of a model for cr oss-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 u nderestimation of risks. The lack of a lifetime exposure study and/or adequate assessment of carcin ogenicity increases uncertainty in EPA’s assessment of long-term exposures to HBCD. Therefor e, inhalation, dermal and lifetime exposure assessment data gaps add uncertainty to EP A’s risk assessment of HBCD.Page 37 of 97



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## APPENDICES

Appendix A Regulatory and Assessment History

Table_Apx A-1: Regulatory and Assessment History of HBCD 8

COUNTRY/ORGANIZATION ASSESSMENT

UNITED STATES 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-inventory-tri-pr ogram/tri-listed-chemicals

• Office of Research and Development – Draft Toxicolo gical Review Scoping Document to support an IRIS assessment ( http://www.ecy.wa.gov/programs/wq/swqs/IRISAgendaCh emicals.pdf )

• Office of Pollution Prevention and Toxics (OPPT) – Flame retardant alternatives to hexabromocyclododecane (2014) ( http://www.epa.gov/dfe/pubs/projects/hbcd/hbcd-full -report-508.pdf )

• OPPT - Proposed SNUR (Mar 2012) to designate manufa cture 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/acti onplans/RIN2070- AZ10_HBCD%20action%20plan_Final_2010-08-09.pdf )

• OPPT Risk Based Prioritization (RBP) including Haza rd Characterization (2008) ( http://www.epa.gov/chemrtk/hpvis/rbp/HBCD.3194556.W eb.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/ c13459cv.pdf ) Occupational Safety and Health Administration (OSHA )

• No occupational exposure limits (OSHA PEL, NIOSH RE L, ACGIH TLV) are established ( www.osha.gov ) Consumer Product Safety Commission (CPSC)

• CPSC staff exposure and risk assessment of flame re tardant chemicals in residential upholstered furniture (2001) ( http://www.cpsc.gov/en/ )

• CPSC staff preliminary risk assessment of flame ret ardant (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.gov/en/ )
State – California

• HBCD is listed as an informational initial candidat e 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, 20 07, 2014). ( http://oehha.ca.gov/

) ( http://oehha.ca.gov/prop65/prop65_list/files/P65sin gle050214.pdf )

8 The risk assessment conclusions summarized in the table are selected conclusions from the reports tha t address the pertinent US exposure scenarios and should not be construed as EPA’s conclusions. EPA refers the r eader to the full reports for detailed explanations of the c ontext of the conclusions reached in all risk asses sments.Page 62 of 97 COUNTRY/ORGANIZATION ASSESSMENT

• California lists HBCD as a designated and priority chemical for biomonitoring. However, California has not yet started biomonitoring HBCD ( SGP, 2014). ( http://www.biomonitoring.ca.gov/chemicals/chemicals -biomonitored-california )
State – Maine

• Maine classifies HBCD as a chemical of high concern (DEP, 2013). ( http://www.maine.gov/dep/safechem/highconcern/ )
State – Minnesota

• Minnesota classifies HBCD as a chemical of high con cern (MDH, 2013). ( http://www.health.state.mn.us/divs/eh/hazardous/top ics/toxfreekids/chclist/mdhchc2013.pdf ) State - Oregon

• The Oregon Department of Environmental Quality list s HBCD as a priority persistent pollutant (DEQ, 2010a, 2011). ( http://www.deq.state.or.us/wq/SB737/docs/LegRpAtt20 100601.pdf ) ( http://www.deq.state.or.us/wq/SB737/ )

• Oregon posts use, exposure pathways and release dat a for HBCD under this program (DEQ, 2010b). ( http://www.deq.state.or.us/wq/SB737/docs/LegRpAtt42 0100601.pdf ) State – Washington

• Washington classifies HBCD as a chemical of high co ncern to children (WSDE, 2013). ( http://www.ecy.wa.gov/programs/swfa/cspa/chcc.html )
CANADA • HBCD meets Canada’s regulatory criteria for persist ence and bioaccumulation potential. ( http://www.ec.gc.ca/ese-ees/default.asp?lang=En&n=7 882C148-1#a4 )

• On November 1, 2012, Canada added HBCD to Schedule 1 of CEPA 1999 (Virtual Elimination List). Proposed risk reduction measure s would prohibit the manufacture, import, use, sale, and offer for sale of HBCD and p roducts containing HBCD. ( http://www.ec.gc.ca/lcpe-cepa/eng/regulations/detai lReg.cfm?intReg=82 )

• **Health Canada (Health CA)** and **Environment Canada (ENV CA)** have published a screeninglevel assessment. ( http://www.ec.gc.ca/ese-ees/default.asp?lang=En&n=7 882C148-1#a4 )
EUROPEAN UNION • 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. A fter August 21, 2015, only persons with approved authorization applications may contin ue to use the chemical. ( http://echa.europa.eu/candidate-list-table ) ( http://echa.europa.eu/documents/10162/13640/priorit isation_hbccd_en.pdf )

• The European Chemicals Agency (ECHA) is currently c onsidering 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 re tardant additive (for onward use in building applications); and (i) manufacture of flam e 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 EU Dire ctive’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/haza rdous_substances_report.pdf )

• The WEEE (Waste Electrical and Electronic Equipment ) directive in the European Union requires the separation of plastics containing brom inated 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/committees/04_sc her/docs/scher_o_093.pdf )

AUSTRALIA • HBCD is listed as a Priority Existing Chemical. ( http://www.nicnas.gov.au/chemicalinformation/pec-assessments )Page 63 of 97 COUNTRY/ORGANIZATION ASSESSMENT

• Australia ( National Industrial Chemicals Notification and Asse ssment Scheme ) has prepared
a risk assessment for HBCD. ( http://www.nicnas.gov.au/Publications/CAR/PEC/PEC34 /HBCD_Report_June_2012_PDF.pdf )
JAPAN • HBCD is subject to mandatory reporting requirements in Japan under the Chemical Substances Control Law (CSCL), specifically Japan r equires type III monitoring for all substances that may interfere with the survival and /or growth of flora and fauna. ( http://www.meti.go.jp/policy/chemical_management/en glish/cscl/files/about/150408Progres.pdf )
STOCKHOLM CONVENTION
ON PERSISTENT ORGANIC POLLUTANTS (POPs) • In May 2013, HBCD was added to the United Nation’s Stockholm Convention list of Persistent Organic Pollutants. The chemical is sche duled to be eliminated by November 2014 with specific exemptions for production and us es in expanded or extruded polystyrene building insulation. As required by the convention, parties that use these exemptions must register with the secretariat and t he exemptions will expire in November 2019. ( http://chm.pops.int/default.aspx )
ORGANISATION FOR
ECONOMIC COOPERATION AND DEVELOPMENT (OECD) • Published SIDS Initial Assessment Profile (SIAP) an d 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=ea58ac 11-e090-4b24-b281-

200ae351686c )Appendix BUses Supplement TablesTable_Apx B-1: 2012 CDR Production Data (Data Reported for 2011)CASRNManufacturing SiteDomesticManufacturingImportedVolumeExported(lbs)Volume Usedon the Site(lbs)12010 PastProductionVolume(import+manufacture)2011NationalProductionVolume(lbs/yr)25637-99-4CBI CBI ND CBI 0 CBI WithheldCBI CBI ND 0 0 CBIBASF Corporation100 Campus DriveFlorham Park, NJ 07932ND CBI CBI CBI CBI3194-55-6Albemarle Corporation1550 Hwy. 371 W.Magnolia, AR 71753CBI ND CBI CBI CBI WithheldThe Dow Chemical Company2020 Dow CenterMidland, MI 48674ND CBI 0 N/A CBI1The total volume (domestically manufactured and imported) of the chemical used at the reporting site.This number represents the volume of the chemical that did notleave the manufacturing site.CBI = Confidential Business InformationND = 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 wasunable to be aggregated in order to protect CBI claims.Page 65 of 97Table_Apx B-2: Historic IUR and CDR Production VolumesCASRNYear1986199019941998200220062010201125637-99-410K - 500K No Reports No Reports 10K - 500K 10K - 500K No Reports CBI Withheld3194-55-6>1M - 10M >1M - 10M >10M - 50M >10M - 50M >10M - 50M10 to < 50M CBI Withheld1The total volume (domestically manufactured and imported) of the chemical used at the reporting site.This number represents the volume of the chemical that did notleave the manufacturing site.CBI = Confidential Business Information“Withheld” in the CDR public database indicates that the national production volume of a chemical wasunable to be aggregated in order to protect the CBI claims.Table_Apx B-3: Summary of 2011 CDR Production Volume and Use InformationCASNumberIndustrialSectorReported inCDRDescriptionofIndustrialUseCommercial or ConsumerProduct CategoryPotential End Product2011 PVApproximate % of 2011National PV25637-99-4PlasticsMaterial andResinManufacturingFlameretardantin electricalandelectronicequipmentPlastic and RubberProducts not CoveredElsewhere (Commercialand Consumer use)•Electric housings for VCR•Electrical and electronicequipment (e.g., distributionboxes for electrical lines)•Video cassette housingsCBI CBIConstructionFlameretardantininsulationboardsBuilding/ConstructionMaterials Not CoveredElsewhere (Commercialand Consumer use)•Construction, insulation boards(packaging material)•Insulation boards (against coldor warm) of transport vehicles(e.g., lorries and caravans)•Insulation boards in buildingconstructions, e.g. houses’ walls,cellars and indoor ceilings and”inverted roofs” (outdoor)•Insulation boards against frostheaves of road and railwayembankmentsCBI CBIBuilding/ConstructionMaterials Not CoveredElsewhere (Commercialuse)CBI 100Page 66 of 97CASNumberIndustrialSectorReported inCDRDescriptionofIndustrialUseCommercial or ConsumerProduct CategoryPotential End Product2011 PVApproximate % of 2011National PV3194-55-6 UtilitiesFlameretardantininsulationboardsBuilding/ConstructionMaterials Not CoveredElsewhere (Consumer use)•Construction, insulation boards(packaging material)•Insulation boards in buildingconstructions, e.g., houses’walls, cellars and indoor ceilingsand ”inverted roofs” (outdoor)CBI 100Building/ConstructionMaterials Not CoveredElsewhere (Commercialuse)•Construction, insulationboards,(packaging material)•Insulation boards (against coldor warm) of transport vehicles(e.g., lorries and caravans)•Insulation boards in buildingconstructions e.g. houses’ walls,cellars and indoor ceilings and”inverted roofs” (outdoor)•Insulation boards against frostheaves of road and railwayembankmentsCBI 50Note:1)Plastic and rubber products with consumer/commercial categories in the CDR data include:•Food packaging•Toys, playground, and sporting equipment2)Building and construction materials with consumer/commercial categories in the CDR data include:•Building/construction materials - wood and engineered wood productsCBI = Confidential Business InformationPV = Production VolumePage 67 of 97Table_Apx B-4: Uses of HBCD as Listed in the 2008 EU Risk AssessmentMaterial1Use/Function1Percent ofHBCDProductionVolume2End Products1Ongoing Use in the United States (US)?EPS Insulation 45%Construction, insulation boards (packaging material)Yes; based on use in construction insulation boardsin 2012 CDR data2Packaging material (minor use and not in food packaging)Unknown; it is unclear if this is an ongoing use intheUS, and uses of polystyrene foam in consumerproducts generally do not require the use of a flameretardant3Insulation boards (against cold or warm) of transport vehicles(e.g., lorries and caravans)Possibly; based on use in insulation boards in 2012CDR data2Insulation boards in building constructions e.g. houses’ walls,cellars and indoor ceilings and “inverted roofs” (outdoor)Yes; based on use in construction insulation boardsin 2012 CDR data2Insulation boards against frost heaves of road andrailwayembankmentsPossibly; based on use in insulation boards in 2012CDR data2XPS Insulation 51%Construction, insulation boardsYes; based on use in construction insulation boardsin 2012 CDR data2Insulation boards (against cold or warm) of transport vehicles(e.g. lorries and caravans)Possibly; based on use in insulation boards in 2012CDR data2Insulation boards in building constructions e.g. houses’ walls,cellars and indoor ceilings and “inverted roofs” (outdoor)Yes; based on use in construction insulation boardsin 2012 CDR data2Insulation boards against frost heaves of road andrailwayembankmentsPossibly; based on use in insulation boards in 2012CDR data2HIPSElectricalandelectronicparts2%Electric housings for VCRPossibly, based on use in electronic plastics in 2012CDR2Electrical and electronic equipment, e.g., distribution boxesfor electrical linesPossibly, based on use in electronic plastics in 2012CDR2Video cassette housingsPossibly, based on use in electronic plastics in 2012CDR2Page 68 of 97Material1Use/Function1Percent ofHBCDProductionVolume2End Products1Ongoing Use in the United States (US)?Polymerdispersionon cottonor cotton/syntheticblendsTextilecoatingagent2%Upholstery fabricHistoric Use in the US4Bed mattress tickingHistoric Use in the US4Flat and pile upholstered furniture (residential andcommercial furniture)Historic Use in the US4Upholstery seating in transportationPossibly, based industry response to SNUR2Draperies, and wall coverings Historic Use in the US4Interior textiles e.g. roller blinds Historic Use in the US4Automobile interior textiles Possibly, based industry response to SNUR2Note:The uses in this table describe recorded HBCD applications for both the US and other countries. Giventhat HBCD will be phased out internationally underREACH and theStockholm Convention, it is unclear to what extentHBCD is currently used in these applications outside of the US.Sources:1)EC, 20082)EPA, 2012a3)EPA, 20144)EPA, 2012eAppendix CExposure Supplement TablesTable_Apx C-1: 2012 CDR Data (Data Reported for 2011) for Release AssessmentTable LineNumberManufacture / ImportIndustrial Processing / UseCommercial /Consumer UseSite IdentityMaxConcentration andPhysical FormProcessing UseProcessing SectorFunction% PVNumberof SitesUse ProductCategory1CBI90%+; Dry Powderor Other SolidProcessing-incorporationinto formulation, mixture, orreaction productPlastics Materialand ResinManufacturingFlameretardants50 < 10Building /ConstructionMaterials NotCovered Elsewhere2Processing-incorporationinto articleConstructionFlameretardants50 < 103BASF, FlorhamPark, NJ1 to < 30%; Pellets/ Large CrystalsProcessing-incorporationinto articleConstruction Other CBI 10 to 24Building /ConstructionMaterials notcovered elsewhere4Processing-incorporationinto articlePlastics Materialand ResinManufacturingOther CBI 25 to 99Plastic and RubberProducts not coveredelsewhere5AlbemarleCorporation,Magnolia, AR90%+; Dry PowderProcessing-incorporationinto articleUtilitiesFlameretardantsNKRA 10 to 24Building /ConstructionMaterials notcovered elsewhere6Processing-incorporationinto formulation, mixture, orreaction productUtilitiesFlameretardantsNKRA 10 to 247The DowChemicalCompany,Midland, MI60 to < 90%;Pellets / LargeCrystalsNot ReportedCBI = Confidential Business InformationNKRA = Not Known or Reasonably AscertainablePV = Production VolumePage 70 of 97Table_Apx C-2: Compilation of Release Factors and Other Release-Related Information in Various Risk AssessmentsOperation(Manufacture orProcessing Step)ReferenceReleaseMediaLoss Factor (Emission Factor)Number of Release DaysValueDescriptionValueDescriptionManufacture of EPSresin beads thatcontain HBCD (alsoreferred to as“formulation of EPScompound” (EC,2008) or“compounding rawHBCD into resins”(NICNAS, 2012))EC (2008)water 7.6E-06This is the emission factor for a generic site andwasdetermined based on the 90th percentile of measurementsof concentration in the effluent from the on-site sewertreatment plants of 9 of the total of 13 sites.300This is the value is for the genericsite and was determined inaccordance with the general riskassessment guidance of the EU.Site-specific values are in therange of 61 to 350 with theexception of one value that isequal to 1.air 7.3E-06This is the emission factor for a generic site andis equal tothe maximum emission factor calculated from site-specificdata that pertain to three processing steps includingformulation of EPS and XPS compounds.NICNAS(2012)water 6.8E-03These values are reasonable worst case values thatare thesums of emission factors for handling and compoundingsolid flame retardants with particle sizes <40 μm that arealso of relatively high volatility as reported in OECD(2004b).150 This is a site-specific value.air 2.5E-04Manufacture of EPSthat contains HBCD(also referred to as“industrial use of EPScompound” (EC,2008) or “conversionor processing ofpolymeric resin intoEPS foam products”(NICNAS, 2012))EC (2008)water 3.0E-05These are the emission factors for the generic siteand arereported in OECD (2004b) as the emission factors fororganic flame-retardants of relatively low volatility inpartially open plastics conversion processes.300This is the value for the genericsite and was determined inaccordance with the general riskassessment guidance of the EU.air 3.0E-05NICNAS(2012)water 1.6E-03These emission factors are weighted averages of emissionfactors for organic flame of relatively high volatility inclosed plastics conversion processes that are reported inOECD (2004b). The emission factors that were averagedinclude values for high process temperature and lowplastics production volume.200 This is an assumed value.air 1.6E-03Compounding ofPolystyrene Resin toProduce XPSMasterbatchcontaining HBCD(also referred to as“formulation of XPScompound for themanufacture ofEC (2008)water 7.4E-06 This is the emission factor for a generic site and is equal tothe maximum of emission factors calculated from sitespecific data for three sites.300This is the value for the genericsite and was determined inaccordance with the general riskassessment guidance of the EU.air 7.3E-06 This is the emission factor for a generic site and is equal tothe maximum emission factor calculated from site-specificdata that pertain to three processing steps includingformulation of EPS and XPS compounds.Page 71 of 97Operation(Manufacture orProcessing Step)ReferenceReleaseMediaLoss Factor (Emission Factor)Number of Release DaysValueDescriptionValueDescriptionflame retarded XPS”(EC, 2008)EnvironmentCA andHealth CA(2011)water 6.6E-03 This is the emission factor for a generic site and is the sumof emission factors for handling and compounding organicsolid flame retardants with particle sizes <40 μm that are ofrelatively medium volatility as reported in OECD (2004b).60 or200These values are for generic sites,are functions of the processingrate, and were determined inaccordance with the general riskassessment guidance of the EU.Manufacture of XPSusing XPSMasterbatchcontaining HBCDEC (2008)water 2.6E-05These are the emission factors for the generic siteand areequal to the maxima of the emission factors that werederived from site-specific data but were not explicitlyreported. EPA calculated these factors, each of which isequal to the ratio of total annual releases from 13sites forwhich site-specific data was not reported and the totalannual processing rate for these sites.1This value was assumed as areasonable worst case for thenumber of release days from ageneric site. Site-specific valuesare in the range of 1 to 15.air 5.8E-05300The number of release days for thegeneric site is not reported. Sitespecific values are in the range of15 to 300.Page 72 of 97Table_Apx C-3: Preliminary Values of Input Variables for Calculation of the Range of Release Rates from Manufacturing Sites or the ProcessingSites of Each Processing StepOperation(Manufacture orProcessing Step)Processing Ratesas Fractions of theHBCDManufacturingRate1Manufacturing or ProcessingRate (kg/yr)2Number of Sites3Number ofReleaseDays4The Minimum and Maximum Values of theCompiled5and Calculated6Loss Factors forEach Medium of Release (kg of HBCD releasedper kg of HBCD manufactured or processed)lower limit ofrangeupper limit ofrangeminimummaximumwaterairminmaxminmaxmanufacture ofHBCDNot Applicable 4.540.E+06 2.290.E+07 3 250 1.2E-074.0E-04 3.3E-07 6.8E-04manufacture ofEPS resin beads0.45 2.043.E+06 1.031.E+07 1 4 250 7.6E-06 6.8E-037.3E-06 2.5E-04manufacture ofEPS0.45 2.043.E+06 1.031.E+07 5 15 250 3.0E-05 1.6E-033.0E-05 1.6E-03manufacture ofXPS using HBCDpowder0.51 2.316.E+06 1.168.E+07 6 181 (water)250 (air)1.0E-051.0E-057.3E-06compounding ofpolystyrene resinto produce XPSmasterbatchcontaining HBCD0.51 2.316.E+06 1.168.E+07 10 29 250 7.4E-06 6.6E-03 7.3E-06manufacture ofXPS using XPSmasterbatchcontaining HBCD0.51 2.316.E+06 1.168.E+07 10 241 (water)250 (air)2.6E-05 5.8E-05Note:1)The share of production volume that is processed tomanufacture of EPS or XPS is reported in Table_ApxB-4. The shareof production volume that is processed to manufacture of XPS using HBCD powder or HBCD masterbatch is unknown andtherefore EPA will conservatively assume this shareis equal to the total share that is processed to manufacture XPS.Page 73 of 972)EPA estimated the lower-end of the current range ofproduction volumes by summing the lower-ends of the ranges ofproduction volumes for CAS number 25637-99-4 reported in 2002 and CAS number 3194-55-6 reported in 2006 that aregiven in Table_Apx B-2. EPA estimated the upper-end of the current range of production volume by summing the upperends of these two ranges.3)The number of sites was estimated from data reported in EPA (2014b) and Table_Apx C-1.4)EPA estimated the number of release days to be equal to 250 assuming each facility has an operation schedule of fivedays per week and 50 weeks per year, allowing for two-week annual downtime for maintenance. The valuesof thenumber of release days given Table_Apx C-2 are of similar magnitude. The exceptions are the values for releases towater from the manufacture of XPS using HBCD powderand XPS using XPS masterbatch; EPA assessed each oftheseparameters to be 1 day per year in consideration ofthe 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 fromdatareported in EC (2008) because non-site specific release factors are not reported for these two operations.

## Appendix D Environmental Hazard Study Summaries

D-1 Persistence in Environmental Media

D-1-1 Air and Water

HBCD does not absorb light in the UV/Visible freque ncies so is not expected to undergo direct photolysis in air or water (Zhou et al., 2014). Ka jiwara 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 p eriod (371 days)” confirming that photolytic degradation did not occur.Indirect photo lysis with methane as a co-solvent has been observed to result in debromination (Zhou et al., 2 012) and indirect photolysis with Fe(III) 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 es timated rate constant of

5.01×10 -12 cm 3 /molecules-sec at 25 °C corresponding to an atmosph eric half-life of 2.1 days (EPA, 1993, 2011a). HBCD associated with particulat es is expected to be removed from the atmosphere through wet or dry deposition. Removal r ates are unknown and the widespread detection of HBCD in air samples and biota from rem ote locations far from release locations indicate that long-range atmospheric transport occu rs (Covaci et al., 2006; EPA, 2010a; Ueno et al., 2006).



### D-1-2 Soil, Sediment and Sludge

Based on an estimated K oc value of 7.6×10 4 HBCD is expected to be fairly immobile in soil and to bind strongly to soil, sediment, and suspended orga nic 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 O ECD TG 307 for commercial HBCD (BFRIP, 2001; EC, 2008). Activated sludge was inoculated wi th soil and HBCD at a nominal concentration of 34-89 μg/kg dry weight for 120 day s. The disappearance half-life was 63 days in aerobic soil and >120 days in abiotic aerobic co ntrols. In the anaerobic soil, the half-life was 7 days compared to 82 days in abiotic anaerobic contr ols.

A closed bottle screening-level test for ready biod egradability (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 obse rved (0% of the theoretical oxygen demand) over the test period of 28 days. Gerecke et al (Gerecke et al., 2006) studiedPage 75 of 97

degradation of BFRs, including HBCD, under anaerobi c conditions in digested sewage sludge. They reported a half-live for a technical HBCD mixt ure 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 decreas ed in sterile controls at a rate 50 times
slower in incubations under non-sterile conditions.

A water-sediment OECD TG 308 study for commercial H BCD with a nominal concentration of 34-89 μg/kg dry weight found that aerobic half-live s were 11-32 days in aerobic sediments and 30-190 days in abiotic aerobic controls (BFRIP, 200 1; 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 14 C radiolabeled HBCD with sludge, sediment, and soil
simulation tests with initial concentrations of HBC D 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 s ystems. As shown in Table_Apx D-1 below, they observed decrease in total initial radioactivi ty in the viable systems and abiotic controls.

Table_Apx D-1: Percent Decrease in Total Initial Ra dioactivity in Viable Systems and Abiotic Controls During Sludge, Sediment, and Soil Simulation Tests Using 14 C-labeled HBCD

Compartment Viable System Abiotic Control Time Period
Anaerobic digester sludge 87% 84% 60 days
Aerobic activated sludge 21% 15% 65 days

Anaerobic freshwater
sediment 61% 33% 112-113 days

Aerobic freshwater sediment 44% 15% 112 days
Aerobic soil 10% 6% 112 days

Source: (BFRIP, 2001; Davis et al., 2006; EC, 2008)

HBCD degradation observed in these tests was attrib uted 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 und er anaerobic conditions compared to aerobic conditions and slower degradation of α-HBCD compared to the β- and γ-stereoisomers.Page 76 of 97

Figure_Apx 2.6.4-1: Stepwise Reductive Dehalogenati on of HBCD



### D-1-3 Water and Wastewater

HBCD is not expected to undergo hydrolysis in envir onmental waters because of its low solubility and lack of hydrolyzable functional grou ps. 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 t o 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 μg/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 t he environment (EC, 2008).



### D-1-4 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 H BCD in fathead minnows. In a flow-through bioconcentration test, BCF values of 8974 and 13,08 5 were determined for HBCD in rainbow trout (EC, 2008). These BCF values indicate that HB CD has a very high potential to bioconcentrate in aquatic organisms. The widespread detection of this substance in aquatic organisms also suggests that HBCD bioconcentrates i n 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 mar ine 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 w ild peregrine falcons feeding on birds
from terrestrial food webs in southwestern Sweden t han in the eggs of captive falcons feeding on domestic chickens, indicating that HBCD bioaccum ulation in terrestrial food chains may also be important (EPA, 2010a; Lindberg et al., 2004). B ioaccumulation may be isomer specific with γ-HBCD is the dominant stereoisomer present in comm ercial HBCD formulations (>75%)Page 77 of 97

(Becher, 2005). Similar proportionality is observed with HBCD stereoisomers detected in environmental media (Covaci et al., 2006). However, in living organisms, α-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 f ound in the environment compared to that found in living organisms is unknown. Possible expl anations include different rates of bioconcentration for the α- and γ- 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 summariz ed in several publications (EC, 2008; Environment CA and Health CA, 2011; EPA, 2008a, 201 4b; NICNAS, 2012; OECD, 2007). Guideline studies in freshwater fish, daphnia, and green algae mostly reported no lethal or sublethal effects at concentrations approaching sat uration (Calmbacher, 1978; EPA, 2014b; Graves and Swigert, 1997a, 1997b; Roberts and Swi gert, 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 μg HBCD/L (Roberts and Swigert, 1997). The mean measured concentration of HBCDs (3.7 μg HBCD/L) at the maxim um nominal test concentration of 6.8 μg HBCD/L (with solvent) was similar to the independen tly measured water solubility limit (8.6 μg/L). No effects were observed at any test concent ration. 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 fo und 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 EC 50 values in **S. costatum** ranging from 0.009 to 0.012 mg HBCD/L based on reduced growth rate in five diff erent 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 substan tiated observed toxicity in **S. costatum** when a single saturated solution of 0.0545 mg HBCD/L (with out a solvent) resulted in 51% growth inhibition after 72 hours of exposure. Desjardins e t al. (2004) also reported 19, 21, and 7.3% inhibition of cell density, biomass, and growth rat e, respectively, following exposure of **S.**

**costatum** to 0.041 mg HBCD/L (with a solvent), the only conc entration tested, for 72 hours.Page 78 of 97

Table_Apx D-2: Toxicity of HBCD to Aquatic Plants

Test Species Fresh/ Salt

Water Duration Endpoint Conc. (mg/L) Test

Analysis Effect References

Green algae ( **Selanastrum capricornutum**  ) Fresh 96-hour EC 50 >0.0037 Static,
Measured Biomass/Growth

rate Roberts and

Swigert, 1997 Green algae ( **S. subspicatus**  ) Fresh 96-hour EC 50 >500 Static,
Nominal Siebel-Sauer and Bias, 1987 Algae ( **S. costatum** ) Marine 72-hour EC 50 >0.041 Static,
Measured Desjardins et al.,

2004 Algae ( **S. costatum** ) Marine 72-hour EC 50 >0.01 Static,
Measured Growth inhibition Desjardins et al.,

2005 Algae ( **S. costatum** ) Marine 72-hour EC 50 0.052 Static,
Measured *Algae ( **S. costatum** ) Marine 72-hour EC 50 0.009-
0.012 Static,

Measured Growth rate Walsh et al.,

1987 Algae ( **Thalassiosira pseudonana**  ) Marine 72-hour EC 50 0.05-0.37 Static,
Measured Algae ( **Chlorella** Sp.) Marine 72-hour EC 50 >1.5 Static,
Measured * The study denoted with an asterisk is proposed fo r use by EPA/OPPT for risk assessment.
Shaded studies will not be used to evaluate the ris k 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 an d 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, 0.001 7, 0.0023, 0.0015, and 0.0034 mg/L. The reported 48-hr EC 50 was >0.0032 mg/L.

Jatzek (Jatzek, 1990) reported a lowest-observed-ef fect-concentration (LOEC) of 10 mg HBCD/L
and an EC 50 of 146.34 mg HBCD/L for daphnia immobility based o n nominal test concentrations that greatly exceeded measured water solubility val ues for HBCD (0.0488, 0.0147, and 0.0021 μg/L for α-, β-, and γ-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 o n reduced size (length) of surviving young daphnids, resulting in a measured MATC of 0.0042 mg HBCD/L (Drottar and Krueger, 1998).Page 79 of 97

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

Sublethal effects to invertebrates following chroni c exposure were found in supporting studies that assessed endpoints beyond those evaluated in g uideline studies. In invertebrates, degenerative changes in the gills of clams ( **Macoma balthica** ), manifested by the increased frequency of nuclear and nucleolar abnormalities an d 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 Inverteb rates

Test Species Fresh/ Salt

Water Duration Endpoint Conc. (mg/L) Test

Analysis Effect References

Aquatic Invertebrates

– Acute Toxicity

*Water flea ( **Daphnia magna** ) Fresh 48-hour EC 50 >0.0032 Flowthrough,
Measured Immobilization Graves and Swigert, 1997a

Water flea ( **D. magna Straus** ) Fresh 48-hour EC 50 146.34
Exceed WS Static,

Nominal Immobilization Jatzek, 1990

Aquatic Invertebrates

– Chronic Toxicity

Clam **(Macoma balthica)** Marine 50-day LOEC 0.1 Static,
Nominal degenerative

changes in the gills manifested by the increased frequency of
nuclear and
nucleolar
abnormalities and
the occurrence of
dead cells Smolarz and

Berger, 2009

*Water flea ( **Daphnia magna** ) Fresh 21-day LOEC 0.0056 mg/L Flowthrough,
Measured reduced length of

surviving young Drottar and

Krueger, 1998

NOEC 0.0031 mg/L * The study denoted with an asterisk is proposed fo r use by EPA/OPPT for risk assessment.
Shaded studies will not be used to evaluate the ris k of HCBD because inadequate test methods or incomplete information were provided for the study.

Toxicity studies for sediment organisms are summari zed in Table_Apx D-4. The study denoted with an asterisk is proposed for use by EPA/OPPT fo r risk assessment. Those studies not considered adequate for risk assessment by EPA/OPPT are shaded in the table.Page 80 of 97

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 se diment). Results of a non-GLP rangefinding 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 prese nce 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 weigh t. No HBCD was detected in the overlaying water or in the pore water. Study details were exce rpted from a secondary source (Oetken et al., 2001).

Table_Apx D-4: Toxicity of HBCD to Sediment Organis ms

Test Species Fresh/ Salt

Water Duration Endpoint Conc. Test

Analysis Effect References

*Amphipod **(Hyalella azteca)**  Fresh 28-day LOEC 500 mg/kg dwt
sediment Flowthrough,
Measured reduced

survivability Thomas et al.,

2003a, b NOEC 100 mg/kg dwt
sediment Amphipod **(H. azteca)** Fresh 28-day NOEC 1,000 mg/kg
dwt sediment Flowthrough,
Measured Unspecified Thomas et al.,
2003b

*Amphipod **(H. azteca)** Fresh 28-day NOEC 1,000 mg/kg
dwt sediment Flowthrough,
Measured Unspecified Thomas et al.,

2003a

Chironomid ( **Chironomus riparius** ) Fresh 28-day No

Dose Not doseresponsive N/A Not doseresponsive Thomas et al.,

2003a **Lumbriculus variegatus** Fresh 28-day LOEC 28.7 mg/kg dwt
sediment Static,

Measured reduction in

worm number Oetken et al.,

2001

NOEC 3.1 mg/kg dwt
sediment * The study denoted with an asterisk is proposed fo r use by EPA/OPPT for risk assessment; N/A = not applicable
Shaded studies will not be used to evaluate the ris k 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 presen ted in Table_Apx D-5. The study denoted with an asterisk is proposed for use by EPA/OPPT fo r risk assessment. Those studies not considered adequate for risk assessment by EPA/OPPT are shaded in the table.Page 81 of 97

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 a t any test concentration (Graves and Swigert, 1997b).

Bluegill sunfish ( **Lepomis macrochirus** ) were exposed to nominal concentrations ranged fro m 10 to 100 mg/L under static conditions for 96 hours. T hese 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 wer e 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 concent ration 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 EC 50 or LC 50 value was not reported (Deng et al., 2009).

Chronic Effects

A chronic study in rainbow trout conducted followin g EPA recommended guidelines, found no effects at concentrations approaching saturation (D rottar 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 μg HBCD/ g lipid in food and 8000 μg HBCD/g total organic carbon (TOC), respectively (Kuiper et al., 2007).

Sublethal effects to fish following chronic exposur e were found in supporting studies that assessed endpoints beyond those evaluated in guidel ine studies. Effects observed in fish include increased formation of reactive oxygen spec ies (ROS) resulting in oxidative damage to lipids, proteins, and DNA, decreased antioxidant ca pacities in fish tissue (e.g., brains, hepatocytes, or erythrocytes), and increasing level s of ethyoxyresorufin-O-deethylase (EROD, detoxification enzyme) and pentoxyresorufin-O-deeth ylase (PROD, detoxification enzyme) levels in hepatocytes of fish exposed to the nomina l concentration of ≥0.1 mg HBCD/L (corresponds to ~0.2 mg HBCD/g whole fish [wet weig ht]) for 42 days (Zhang et al., 2008). Indications of endocrine disruption were reported f ollowing dietary exposure to HBCD that impacted the thyroid system of juvenile rainbow tro ut ( **Oncorhynchus mykiss** ). Each of the diastereoisomers of HBCD (administered separately v ia diet at concentrations of 5 ng/g of α-, β-, or γ-HBCD) disrupted thyroid homeostasis, as in dicated by lower free circulating triiodothyronine (T3) and thyroxine (T4) levels (Pa lace et al., 2010; Palace et al., 2008).Page 82 of 97

Table_Apx D-5: Toxicity of HBCD to Fish

Test Species Fresh/ Salt

Water Duration Endpoint Conc. (mg/L) Test

Analysis Effect References

Fish

– Acute Toxicity

Bluegill sunfish ( **Lepomis**
**macrochirus** ) Fresh 96-hour LC 50 >100 Static,
Nominal Mortality Calmbacher,

1978
*Rainbow trout ( **Oncorhynchus mykiss** ) Fresh 96-hour LC 50 >0.0025 Flowthrough,
Measured Mortality Graves and Swigert, 1997b

Zebra fish embryos ( **Danio rario** ) Fresh 96-hour LC 50 0.05 Static,
Nominal decreased

survival, reduced
heart rate Deng et al., 2009

Fish

– Chronic Toxicity

Rainbow trout ( **Oncorhynchus mykiss** ) Fresh 88-day NOEC 0.0037 Flowthrough,
Measured No effects Drottar et al.,

2001

Rainbow trout ( **Oncorhynchus mykiss** ) 28-day Intraperitoneal injection using 50
and<500 mg/kg-bw 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. (Ronisz et al.,

2004)

Chinese rare minnow ( **Gobiocypris rarus** ) Fresh 42-day LOEC 0.1 Static,
Nominal DNA damage in

erythrocytes;
induction of
EROD and PROD in hepatocytes;
ROS formation in
brain tissue Zhang et al.,

2008 MATC 0.032

European flounder ( **Platichthys flesus** ) Fresh 78-day NOEC 8,000 μg/g

TOC Sediment

exposed No effects on

behavior, survival, growth rate, relative liver and gonad weights Kuiper et al.,

2007 3000 μg/g lipid in
muscle Diet

exposed

*Rainbow trout ( **O. mykiss**  ) Fresh 32-day LOEC 5 ng/g ofα-, β-, or γHBCD Diet

exposed thyroid effects Palace et al.,

2010

* The study denoted with an asterisk is proposed fo r use by EPA/OPPT for risk assessment.
Shaded studies will not be used to evaluate the ris k of HCBD because inadequate test methods or incomplete information were provided for the study.Page 83 of 97



### D-3 Toxicity to Terrestrial Organisms

D-3-1 Terrestrial Plant Toxicity

Available toxicity studies for terrestrial plants a re summarized in Table_Apx D-6.

Studies using monocot and dicot plant species exhib ited 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 Plan ts

Test Species Duration End-point Conc. Test Analysis Effect References

Corn ( **Zea mays** ) 21-day NOEC >5,000 mg HBCD/kg soil Nominal No treatmentrelated effects

on emergence, survival or growth Porch et al., 2002

Cucumber ( **Cucumis**
**sativa** ) Onion ( **Allium cepa** )

Ryegrass ( **Lolium**

**perenne** )



### D-3-2 Soil Invertebrate Toxicity

The available toxicity study in soil organisms summ arized below and presented in Table_Apx D-7 is adequate for risk assessment*.

Aufderheide et al., (Aufderheide et al., 2003) repo rted an EC 10 and no-observed-effectconcentration (NOEC) values of 21.6 and 128 mg HBCD /kg dry soil, respectively, based on reproductive effects in earthworms following 56 day s of exposure. High variability in the data at the lower test concentrations (as indicated in ECB, 2008) resulted in wide confidence limits for
the EC 10 , differences from the control that were not signific ant, and a NOEC that was greater
than the EC 10 . Two worms from the lowest test concentrations wer e lost during the study and treated as dead (as reported in ECB, 2008), which m ay have contributed to the high variability by reducing the sample size at the lowest test conc entration; however, study details, data tables, and statistical methodology were not availa ble.

Table_Apx D-7: Toxicity of HBCD to Terrestrial Inve rtebrates

Test Species Duration End-point Conc. Test Analysis Effect References

*Earthworm **(Eisenia fetida)**  56-day EC 10 21.6 mg HBCD/kg dry
soil Nominal,

Static, Soil reproduction Aufderheide et al., 2003

NOEC 128 mg

HBCD/kg dry
soilPage 84 of 97



### D-3-3 Avian Toxicity

Available toxicity studies to avian species are sum marized in Table_Apx D-8.

Japanese quail eggs exposed for 6 weeks to an isome ric mixture of HBCD in the diet experienced a reduction in hatchability at all test ed concentrations (12–1000 ppm) (MOEJ, 2009). Additional effects included a significant re duction in egg shell thickness starting at 125 ppm, decreases in egg weights and egg production ra tes starting at 500 ppm, increases in cracked eggs starting at 500 ppm, and adult mortali ty at 1000 ppm. A subsequent test, conducted at lower dietary concentrations, determin ed 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 chick s 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 Duration End-point Conc. Test Analysis Effect References

Japanese quail ( **Coturnix coturnix japonica**  ) 6-week LOAEL 125 ppb Diet exposed reduction in

hatchability MOEJ, 2009

15 ppm (2.1 mg/kg body wt/day reduced chick
survival

5 ppm

American kestrel **(Falco sparverius)** LOAEL 164.3 ng/g wet weight of egg In ovo

exposed reduced

corticosterone response in male nestling kestrels, reduced flying

activities in juvenile males, delayed response time to predator
avoidance in juvenile females Kobiliris, 2010Page 85 of 97



## Appendix E Human Health Hazard Study Summaries

E-1 Toxicokinetics

For humans, there is a potential for oral, inhalati on and dermal exposure. Available
toxicokinetics data in rodents indicate that HBCD i s moderately absorbed via the gastrointestinal tract, metabolized, and distribute d 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 e t al., 2006; Yu and Atallah, 1980). Elimination of HBCD is predominantly via feces (as the parent c ompound), 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, adip ose tissue, blood, and both maternal and umbilical serum (Abdallah and Harrad, 2011; Antign ac et al., 2008; Covaci et al., 2006; Fangstrom et al., 2008; Fangstrom et al., 2005; Joh nson-Restrepo et al., 2008; Kakimoto et al., 2008; Meijer et al., 2008; Rawn et al., 2014; Thoms en 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 LD 50 values >680 mg/kg-bw. Acute inhalation exposure to HBCD resulted in some minor symptoms (such as eye squint, slight dyspnea, salivation, la crimation, and nasal discharge), but no LC 50 has
been identified.

The acute toxicity of HBCD is summarized in Table_A px E-1 (oral) and Table_Apx E-2 (inhalation).

Table_Apx E-1: Acute Oral Toxicity of HBCD

Species/strain/

test Exposure Result Notes Reference

Rat/Charles River/LD 50 Single gavage (corn

oil) LD 50 >10,000

mg/kg No mortality; transient hypoactivity

and diarrhea; corneal opacity and ptosis in 3/5 males, which did not resolve by end of 14-day
observation. IRDC, 1977

Rat/Charles River CD/ LD 50 test of
HBCD residue Single gavage (corn

oil) LD 50 = 1258

mg/kg (male); 680 mg/kg (female) Tested Firemaster 100; increased

activity, eye squint, dyspnea, lacrimation, and nasal discharge. IRDC, 1978aPage 86 of 97

Species/strain/

test Exposure Result Notes Reference

Weight loss in all animals; recovery noted by conclusion of study.
Mouse/NR/LD 50 Single gavage (30%

aqueous tragacanth) LD 50 >6,400

mg/kg; data
not shown 7-day observation period; increasing

apathy, trembling and late mortalities; peritonitis at necropsy. BASF, 1990

Rat/SpragueDawley/limit test
of HBCD bottoms Single gavage (corn

oil) LD 50 >5,000

mg/kg; clinical signs This study tested HBCD bottoms

described as black solids, lacrimation, and facial swelling resolved by post-exposure day 4; no gross lesions were observed. Pharmakon
Research
International Inc., 1990

Rat/NR/LD 50 test Single gavage (corn

oil) LD 50 >10,000

mg/kg No significant changes observed. Gulf South
Research Institute, 1988 Abbreviations: NR, not reported

Table_Apx E-2: Acute Inhalation Toxicity of HBCD

Species/strain/test Exposure Result Notes Reference

Rat/Charles River/LD 50 4-hr exposure to

Firemaster 100 dust: 202.14 mg/L No mortality;

slight dyspnea at
the end of exposure only All rats gained weight over

the observation period, but
no control data were reported. IRDC, 1977

Rat/Wistar/limit test 1-hr exposure to

200 mg/L GLS-S6- 41A (highest possible concentration) No mortality; no

clinical signs All rats gained weight over

the observation period, but
no control data were reported. Lewis and Palanker,

1978

Rat/Charles River/LC 50 test of Firemaster 100 residue (liquid) 4-hr exposure to

Firemaster 100 residue: 22.9 mg/L 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. IRDC, 1978b

Rat/NR/LC 50 test 1 hr. whole-body

inhalation exposure

to GLS-S6-41A LC 50 >200 mg/L No significant effects
observed. 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 87 of 97

Chengelis, 1997, 2001; van der Ven et al., 2006). H owever, 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 chroni c toxicity studies using an HBCD product that is no longer manufactured concluded that obser ved liver findings were adaptive rather than adverse (Zeller and Kirsch, 1969, 1970). Deve lopmental 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 da ta are suggestive of possible treatmentrelated thyroid effects in adult animals. Several r ecent **in vivo** and **in vitro** studies have been conducted to try and elucidate the possible mechani sms for both the observed liver and thyroid effects, but with no clear conclusions. Fun ctional 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 Exposure Result Notes Reference

Sprague-Dawley rats 28-days 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. 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. Zeller and Kirsch,

1969

Sprague-Dawley rats 90-days Liver weight
increases from the lowest dose (120 mg/kg-day) in both

sexes. No histopathological effects in thyroid were reported. Demonstrates a low order

of toxicity and may reflect a reversible adaptive change. Data supports that the liver and thyroid glands are targets. Zeller and Kirsch,

1970Page 88 of 97

Species/strain Exposure Result Notes Reference

Sprague-Dawley rats 28-days Liver weight
increase in females
from the lowestdose (125 mg/kgday) and in males
from the mid dose (350 mg/kg- day). No histological effects
observed in the thyroid in either sex. The effects on the liver

especially in female rats
indicate a LOAEL of 125 mg/kg-day. Chengelis, 1997

Sprague-Dawley rats 90 days Liver weight
increase from the lowest dose (100 mg/kg-day) in both

sexes. Thyroid weight was

increased from the middose 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. Chengelis, 2001

Wistar rats 28 days Liver weight
increases in females at 23 mg/kg-day Most sensitive endpoint

was a 10% increase in thyroid weight in females at 3 mg/kg-day. 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 su mmarized in Table_Apx E-4 and Table_Apx E-5. An exposure-response array for reproductive an d 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 t oxicity of HBCD comes from a singlegeneration 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 ex posure study (Murai et al., 1985), and a neurotoxicity study of adult mice neonatally expose d to HBCD (Eriksson et al., 2006).Page 89 of 97

Table_Apx E-4: Reproductive and Developmental Toxic ity of HBCD*

Species/strain Exposure Result Notes Reference

Wistar rats 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 No exposure related

changes in reproductive
parameters, including mating success, time to gestation, gestation duration, number of implantation sites, litter size, and sex

ratio. NOAEL ~ 100 mg/kg-day

(highest dose tested) Van der Ven et al.,

2009

Crl:CD(SD) rats 10 wks prior to

mating and through gestation, lactation,
and for twogenerations (multigeneration reproductive toxicity study) 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 LOAEL ~ 101 mg/kg-day

NOAEL ~ 10 mg/kg-day Ema et al., 2008

Wistar rats GD 0-20 No significant changes in the number of implants, resorptions, live or
dead fetuses or external, visceral or
skeletal anomalies NOAEL ~ 750 mg/kg-day

(highest dose tested) Murai et al., 1985

Crj:CD(SD)IGS rats GD 10–PND 20

(weaning) No exposure- related

changes in reproductive
parameters; however, increased thyroid weight and
decreased serum T 3 in male offspring at ~146 mg/kg-day NOAEL ~ 1505 mg/kg-day

(highest dose tested) Saegusa et al., 2009

Wistar rats See Van der Ven et

al., 2009 Effect on Brainstem

Auditory Evoked Potentials (BAEPs)
observed in the low frequency rangeand only in male offspring (see text) Neurobehavioral

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

2009

*Only studies considered adequate for risk assessm ent are presented in the table.Page 90 of 97

Signs of developmental toxic effects in Wistar rats included immune system effects, indications of liver toxicity, and decreases in bone mineral de nsity at very low doses, i.e., <1.3 mg/kg-day (van der Ven et al., 2009); however, the authors no ted that the vehicle used (corn oil) may have affected observations at higher doses, including: i ncreased mortality during lactation, decreased liver weight in males, decreased adrenal weight in females, decreased plasma cholesterol in females, and other immunological mar kers of toxicity. Saegusa et al. (2009) observed an increased relative thyroid weight and d ecreased triiodothyronine (T3) levels in F1 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 oligoden drocytes at 10,000 ppm (approximately 1,504.8 mg/kg-day). Developmental toxicity was not observed in F1 Wistar rats following dietary exposure to HBCD during gestation (Murai et al., 1985).

Ema et al. (2008) reported a reduced viability inde x on Day 4 and Day 21 of lactation among second generation (F2) offspring at 15,000 ppm (app roximately 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 F1 males and females, res pectively), including: an increase in dihydrotestosterone (DHT) in F1 males and an increa sed 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, vagin al opening, or preputial separation among F1 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 (F1) female Crl:CD(SD) rats at 1,500 ppm (approximately 138 mg/kg-day) and a significant inc rease in the number of litters lost in the F1 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 i ndex, 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 an d approximately 1,504.8 mg/kg-day in Sprague-Dawley rats, respectively).

No standard neurotoxicity or developmental neurotox icity studies on HBCD are available. Information on neurotoxicity was obtained from Func tional Observational Battery, locomotor activity evaluations, neurobehavioral testing, surf ace righting reflex, negative geotaxis reflex, mid-air righting reflex, and brainstem auditory evo ked potentials (BAEPs) in several repeateddose and reproductive toxicity studies.

For example, in a subacute toxicity study, HBCD was administered orally by gavage in corn oil to Sprague-Dawley Crl:CD BR rats for 28 days at doses of 0, 125, 350, or 1,000 mg/kg-day (6Page 91 of 97

rats/sex/dose in 125 and 350 mg/kg-day groups and 1 2 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 m g/kg-day groups were untreated for a 14- day recovery period prior to necropsy. Functional O bservational Battery and motor activity evaluations were carried out prior to study initiat ion, during the last week of HBCD administration (Week 3), and during the recovery pe riod (Week 5). No changes in the Functional Observational Battery and motor activity tests were reported.

In another subchronic toxicity study, (Chengelis, 2 002; Chengelis, 2001) administered HBCD by oral gavage in corn oil daily to Crl:CD(SD)IGS BR r ats (15/sex/dose) at dose levels of 0, 100, 300, or 1,000 mg/kg-day for 90 days. At the end of 90 da ys, 10 rats/sex/dose were necropsied, while the remaining rats were untreated for a 28-day reco very period prior to necropsy. Functional Observational Battery and locomotor activity evalua tions were carried out on 5 animals/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 observ ed.

In a one-generation study that included additional immunological, endocrine and neurodevelopmental endpoints, van der Ven (2009) ex posed Wistar rats (10/sex/dose) to a composite mixture of technical-grade HBCD in the di et 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 s tudy, at approximately 8 weeks of age, the remaining F1 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 a l. (Lilienthal et al., 2009) reported the results of the neurobehavioral assessment from the one-gene ration study conducted by van der Ven et al. (2009). Lilienthal et al. (2009) examined 110 d ay-old F1 rats for haloperidol-induced catalepsy to determine possible effects of HBCD on the dopaminergic system. One month after the catalepsy measurements, brainstem auditory evok ed potentials (BAEPs) to broadband click and frequency-specific tone stimuli were recorded i n males and females to examine potential effects on auditory functions. The study authors co ncluded that the observed dose-dependent decreases in latencies may be due to HBCD-related e ffects on dopaminergic activity or to HBCDrelated induction of metabolizing liver enzymes res ulting in enhanced metabolism of haloperidol. HBCD-related effects on BAEP were obse rved in the low frequency range and only in male offspring. The study authors hypothesized t hat HBCD exerts a cochlear effect on males
based on the results of the BAEPs. The authors note d that an alternative explanation could be HBCD-induced changes in retinoids, which may be inv olved in development of the inner ear. Too little information is available in this study t o 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 Guideli ne 416 (OECD, 2001), US EPA Guidelines (EPA, 1991, 1996), and good laboratory practices (G LP). Groups of male and female ratsPage 92 of 97

(24/sex/dose) were fed HBCD (as a mixture of α-HBCD , β -HBCD, and γ-HBCD with proportions of 8.5, 7.9, and 83.7%, respectively) in the diet a t concentrations of 0, 150, 1,500, or 15,000 ppm from 10 weeks prior to mating through mating, g estation, and lactation. Reproductive and developmental milestones were monitored, including: surface righting reflex, negative geotaxis reflex, mid-air righting reflex, and anogenital dis tance. 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 w ere not considered treatment related. No other effects of HBCD exposure on the development o f reflexes were observed in either F1 or F2 progeny.

An additional study on the neurotoxicity of HBCD is available. Eriksson et al. (2006) observed effects on spontaneous motor behavior, learning, an d 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 stud y was not conducted according to current guidelines (EPA, 1998b) and GLP, therefore EPA rese rves 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 d emonstrate good repeatability for control
values and for relevant active substances tested se veral times.

Figure_Apx 2.6.4-2: Exposure-Response Array for Dev elopmental and Reproductive Toxicity Studies of

HBCDPage 93 of 97

Table_Apx E-5: Summary of Effects in Parental and F 1 Rats After Dietary, Gestational, Lactational and Postnatal Exposure to HBCD

HBCD (ppm in diet)

Males c Females c
Generation 0 100 1,000 10,000 0 100 1,000 10,000

F0
Thyroid Relative weight (mg/100 g BW) ND ND ND ND 5.73 6.75 6.30 7.47 *

Histopathology: diffuse follicular cell hypertrophy (±/+/++/+++) a ND ND ND ND 3/10 (0/3/0/0) b 5/10

(2/3/0/0) 6/10

(1/3/2/0) 9/10 #

(0/3/4/2) §§

F1
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) 3.45 3.81 ** 3.58 3.53 3.35 3.59 3.44 3.30 Thyroid (mg/100 g BW) 4.85 5.66 5.78 * 6.20 ** 8.20 6.84 7.35 7.72 Epididymides (mg/100 g BW) 0.23 0.21 * 0.22 0.21 NA NA NA NA

Thyroid-related hormones

PND 20

T 3 (ng/ml) 1.09 1.13 1.06 0.93 ** ND ND ND ND

T 4 (μg/dl) 4.39 4.20 4.78 4.20 ND ND ND ND TSH (ng/ml) 5.40 6.66 6.07 7.00 * ND ND ND ND

PNW 11

T 3 (ng/ml) 0.96 0.93 0.88 * 0.89 ** ND ND ND ND

T 4 (μg/dl) 4.77 4.84 5.21 5.20 ND ND ND ND
TSH (ng/ml) 4.74 5.81 5.36 4.96 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) §§

PNW 11

Adrenal: Vacuolar degeneration, diffuse, cortical cells (+/++) a 0/10 0/10 0/10 4/10 * (2/2) § ND ND ND ND

Abbreviations: BW, body weight; PND, postnatal day; ppm, parts per million; PNW, postnatal week; ND, n o data; NA, not applicable; a Grade of change: (±) minimal; (+) slight; (++) mode rate; (+++) severe; b Number of animals with each grade; c n=10 rats/sex/group; * Significantly different from the controls by Dunne tt’s test or Dunnett-type rank-sum test (p<0.05)

** Significantly different from the controls by Dunnet t’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)

§ Significantly different from the controls by Mann-W hitney’s U-test (p<0.05)

§§ Significantly different from the controls by Mann-W hitney’s U-test (p<0.01) Source: (Saegusa et al., 2009)Page 94 of 97

Figure_Apx 2.6.4-3: Exposure-Response Array for Neu rological 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 HB CD to be a mild skin allergen (Momma et al., 1993). Acute eye irritation studies in rabbit s 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 genoto xicity 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 te sts 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; Zeige r 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 TA 1535 and TA100 using an unidentifiedPage 95 of 97

mixture characterized only as HBCD bottoms in aceto ne (Ethyl Corporation, 1985a). Both of these strains detect reversions by base pair substi tution. 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 re sults (Helleday et al., 1990). A test of unscheduled DNA synthesis with rat hepatocytes expo sed to HBCD bottoms was also positive with a dose-response relationship (Ethyl Corporatio n, 1985b). The reverse mutation assay in CHO cells (Helleday et al., 1999) and the unschedul ed DNA synthesis assay in F344 hepatocytes (Ethyl Corporation, 1985b) were not repeated by any other group.

Several assays performed to determine the genotoxic ity of HBCD were negative even when testing at cytotoxic concentrations, including: one in yeast (Litton Bionetics Inc., 1990), one detecting chromosomal aberrations in human peripher al lymphocytes **in vitro** (Microbiological Associates Inc, 1996), and one **in vivo** mouse micronucleus test following intraperitoneal injection of HBCD (BASF, 2000). Several previous as sessments 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; NIC NAS, 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 (NICN AS, 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 96 of 97

Table_Apx E-6: Genotoxicity of HBCD

Test/species/strain/

route Test doses

(per plate) a Results b

Notes Reference

–S9 +S9
Eukaryotic systems, in vitro
**S. typhimurium** TA98, TA100, TA1537 3,000 μg

in DMSO – – Doses ≥1,000 μg were partially
insoluble. Pharmakologisches Institute, 1978 **S. typhimurium** TA98, TA100, TA1535, TA1537, TA1538 250 μg

(Firemaster, FM100, Lot 53, white powder)

in DMSO – – Doses ≥250 μg were insoluble. IBT, 1990

1,000 μg (FM100, Lot 3322, liquid residue)

in DMSO – + (TA1535 only) Positive in TA1535 at highest dose only; lower doses showed positive trend with dose.

**S. typhimurium** TA98, TA100, TA1535 10,000 μg

in DMSO – – Insoluble at 10,000 μg. Huntingdon Research Center,

1978 **S. typhimurium** TA98, TA100, TA1535,
TA1537 10,000 μg

in DMSO – – Zieger et al.,

1987

**S. typhimurium** TA98, TA100, TA1535, TA1537, TA1538 5,000 μg

in DMSO _ _ SRI, 1990

**S. typhimurium** TA98, TA100, TA1535,
TA1537 50 μg

(HBCD bottoms )

in acetone +

(TA1535
and 100 only) + (TA100 only) No cytotoxicity observed. Doseresponse only in TA1535 (–S9) ≥100 μg/plate. TA100 positive at highest dose only (5,000 ug/plate). All doses had a black precipitate thought to be
carbon. Ethyl Corporation,
1985a

**S. typhimurium** TA98, TA100, TA1535, TA1537, TA1538 50 μg

– – Litton Bionetics,
1990

Prokaryotic non-mammalian systems, in vitro **Saccharomyces**
**cerevisiae** D4 50 μg

– – Litton Bionetics,
1990 Mammalian systems, in vitro

Chromosomal
aberration test In human peripheral blood lymphocytes 750 μg/mL (-S9)

and 250 μg/mL (+S9) in DMSO – (T) – (T) Doses 750 – 2,500 were partially insoluble, and fully insoluble >2,500 μg/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, 1996Page 97 of 97

Test/species/strain/

route Test doses

(per plate) a Results b

Notes Reference

–S9 +S9

Unscheduled DNA Synthesis rat/F344 male/primary hepatocytes 5 – 1,000 μg/well

in acetone (HBCD bottoms)

+ NA Five highest doses (from 5 μg/well) showed an increased response with dose over solvent control, but only four highest were statistically significant (χ 2 ). Highest dose (1,000 μg/well) was cytotoxic. Ethyl Corporation,
1985b

Reversion assay CHO/V79/Sp5 and

SPD8 Intragenic
recombination at **hprt**locus in Sp5 (nonhomologous recombination) and SPD8 (homologous recombination) duplication cell lines 3–20 μg/mL

in DMSO

+ NA A statistically significant increase in reversion frequency was observed in both assays in the highest dose group as determined by linear regression analysis. Helleday et al.,

1999

Mammalian systems, in vivo

Micronucleus test mouse/NMRI/intraper itoneal injection 2,000 mg/kg

in DMSO – (T) NA BASF, 2000

a Lowest effective dose for positive results; highest dose tested for negative results.

b + = positive, ± = equivocal or weakly positive, – = negative, T = cytotoxicity, NA = not applicable, N D = no data.