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DRAFT EPA SCIENTIFIC ADVISORY COMMITTEE ON CHEMICALS
CHARGE TO THE PANEL - CYCLIC ALIPHATIC
BROMIDES CLUSTER (HBCD)
As amended by the Frank R. Lautenberg Chemical Safety for the 21st Century Act on June 22,
2016, the Toxic Substances Control Act (TSCA), requires the U.S. Environmental Protection
Agency (EPA) to conduct risk evaluations on existing chemicals. In December of 2016, EPA
published a list of the initial ten chemical substances that are the subject of the Agency's chemical
risk evaluation process (81 FR 919271 as required by TSCA. HBCD is one of the first ten chemical
substances to undergo a peer review by the Science Advisory Committee on Chemicals (SACC). In
response to this requirement, EPA has prepared and published a draft risk evaluation for HBCD.
The EPA has solicited comments from the public on the draft and will incorporate them as
appropriate, along with comments from peer reviewers, into the final risk evaluation.
The draft risk evaluation contains the following components:
Presentation of chemistry and physical-chemical properties
Characterization of uses/sources
Systematic review
Environmental fate and transport assessment
Environmental release assessment
Occupational exposure assessment
Environmental, general population, and consumer exposure assessment
Environmental hazard assessment
Human health hazard assessment
Risk characterization
Risk determination
The focus of this meeting is to conduct the peer review of the Agency's draft risk evaluation of
HBCD. At the conclusion of the peer review process, EPA will use the reviewers'
comments/recommendations, as well as public comment, to finalize the risk evaluation.
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CHARGE QUESTIONS:
EPA is seeking SACC advice on the clarity and scientific underpinnings of the overall
assessment. The peer review should consider whether the conclusions presented in the draft risk
evaluation are clearly presented, scientifically supported and based on the best available scientific
information. The SACC should also consider whether the methods employed to generate the
information are reasonable for and consistent with the intended use of the information. As per
TSCA, where unreasonable risks are identified, once finalized the risk evaluation will be used to
support rulemaking to mitigate identified risks.
Throughout the peer review, the SACC should be mindful that TSCA now requires that EPA use
data and/or information in a manner consistent with the "best available science" and that EPA
base decisions on the "weight of the scientific evidence". The EPA's Final Rule, Procedures for
Chemical Risk Evaluation Under the Amended Toxic Substances Control Act (82 FR 33726),
defines "best available science" as science that is reliable and unbiased. This involves the use of
supporting studies conducted in accordance with sound and objective science practices, including,
when available, peer reviewed science and supporting studies and data collected by accepted
methods or best available methods (if the reliability of the method and the nature of the decision
justifies use of the data). The Final Rule also defines the "weight of the scientific evidence" as a
systematic review method, applied in a manner suited to the nature of the evidence or decision,
that uses a pre-established protocol to comprehensively, objectively, transparently, and
consistently identify and evaluate each stream of evidence, including strengths, limitations, and
relevance of each study and to integrate evidence as necessary and appropriate based upon
strengths, limitations, and relevance.
Below, a set of charge questions for each major analysis are presented. The SACC is expected to
consider questions and issues raised during public comment as part of its deliberations.
1.	Content and Organization:
EPA's Final Rule, Procedures for Chemical Risk Evaluation Under the Amended Toxic
Substances Control Act (I	26) stipulates the process by which EPA is to complete risk
evaluations under the Frank R. Lautenberg Chemical Safety for the 21st Century Act. To that
end, EPA has completed a draft risk evaluation for HBCD.
As part of this risk evaluation for HBCD, EPA conducted an assessment of potential
environmental, occupational, consumer, and general population exposures. The evaluation
considered reasonably available information, including import, processing, distribution in
commerce, use, and disposal information. It is important that the information presented in the
risk evaluation and accompanying documents are clear and concise and describe the process in a
scientifically credible manner.
• Please comment on the overall content, organization, and presentation of the draft risk
evaluation of HBCD. Please provide suggestions for improving the clarity of the
information presented in the documents.
2.	Systematic Review:
To meet the scientific standards required by TSCA, EPA applied systematic review approaches
and methods to support the draft risk evaluation of HBCD. Information on the approaches and/or
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methods is described in the draft risk evaluation as well as the following documents:
•	Application of Systematic Review in TSCA Risk Evaluations
•	Strategy for Conducting Literature Searches for HBCD: Supplemental file for the TSCA
Scope Document
•	HBCD (C' ASRN: 25637-99-4. 3 194-55-6. 3194-57-8) Bibliography: Supplemental File for the
TSCA Scope Document
•	Problem Formulation for Cyclic Aliphatic Bromides Cluster (HBCD)
•	Risk Evaluation for Cyclic Aliphatic Bromides Cluster (HBCD), Systematic Review
Supplemental File: Updates to the Data Quality Criteria for Epidemiological Studies
•	Risk Evaluation for Cyclic Aliphatic Bromides Cluster (HBCD), Systematic Review
Supplemental File: Data Extraction Tables for Human Health Hazard Studies
•	Risk Evaluation for Cyclic Aliphatic Bromides Cluster (HBCD), Systematic Review
Supplemental File: Data Extraction Tables for Environmental Fate and Transport Studies
•	Risk Evaluation for Cyclic Aliphatic Bromides Cluster (HBCD), Systematic Review
Supplemental File: Data Extraction Tables for Environmental Hazard
•	Risk Evaluation for Cyclic Aliphatic Bromides Cluster (HBCD), Systematic Review
Supplemental File: Data Extraction Tables for General Population and Environmental
Exposure Studies
•	Risk Evaluation for Cyclic Aliphatic Bromides Cluster (HBCD), Systematic Review
Supplemental File: Data Quality Evaluation for Occupational Exposure and Release Data
•	Risk Evaluation for Cyclic Aliphatic Bromides Cluster (HBCD), Systematic Review
Supplemental File: Data Quality Evaluation of Ecological Hazard Studies
•	Risk Evaluation for Cyclic Aliphatic Bromides Cluster (HBCD), Systematic Review
Supplemental File: Data Quality Evaluation of Environmental Fate and Transport Studies
•	Risk Evaluation for Cyclic Aliphatic Bromides Cluster (HBCD), Systematic Review
Supplemental File: Data Quality Evaluation of General Population and Environmental
Exposure Studies
•	Risk Evaluation for Cyclic Aliphatic Bromides Cluster (HBCD), Systematic Review
Supplemental File: Data Quality Evaluation of Human Health Hazard Studies
•	Please comment on the approaches and/or methods used to support and inform the
gathering, screening, evaluation, and integration of data/information used in the Draft
Risk Evaluation for Cyclic Aliphatic Bromides Cluster (HBCD).
•	Please also comment on the clarity of the information as presented related to systematic
review and suggest improvements as warranted.
3. Environmental Fate and Transport:
a. Use of HBCD Bioconcentration Factors (BCF) and Bioaccumulation Factors (BAF)
Field measured HBCD BAF values in upper trophic level fish from heavily industrialized
areas of China (He et al. 2013, Wu et al. 2010) and laboratory BCF values from edible
portions of rainbow trout from Drottar (2000) were used to estimate potential human and
wildlife exposure through fish ingestion. BAFs were preferentially used because they
represent exposure to the chemical through aqueous and dietary routes. The BCF study
was selected to supplement the estimations because it was a guideline study conducted on
an upper trophic level edible species.
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•	Please comment on the use of field measured BAF values for upper trophic level fish
from He et al. 2013 and Wu et al. 2010 for use in assessing human or wildlife exposure
via fish ingestion and provide any specific suggestions or recommendations for
alternate approaches that could be considered for accounting for bioaccumulation of
HBCD into food webs/diet of humans or wildlife.
•	Please also comment on the use of the BAF data from Chinese predatory fish species
to address human exposure via fish ingestion.
b. Selection of HBCD Environmental Half-Lives for use in Risk Evaluation
A wide range of degradation half-lives have been reported for HBCD in aerobic and
anaerobic soil and aerobic and anaerobic sediment and were reviewed for the Risk
Evaluation Table 2-1, Section 2.1.3, Appendix CI, Appendix C3. The selected half-lives
(Table 2-2) were used as inputs to environmental and human exposure models. Three
studies addressing 5 biodegradation endpoints were used to derive half-lives and were
selected based on the relevance of the biodegradation studies to the environmental
compartment HBCD is expected to be released or partition to, i.e., water, aerobic soils and
sediments.
•	Please provide any specific suggestions or recommendations for alternate approaches to
derive media specific degradation half-lives for use in exposure assessments from data
sets where values for the same environmental fate endpoint (e.g., biodegradation half-
life in aerobic soil) vary widely.
4.	Environmental Release:
EPA used a combination of estimation methods and approaches to estimate releases for the various
conditions of use (COU). Key environmental release data and data sources that informed the
assessment of environmental releases include: release data from the European Communities'
HBCD risk assessment reports, USEPA Toxics Release Inventory (TRI) data, and Organization of
Economic Co-Operation and Development Emission Scenario Documents (OECD ESDs) and
USEPA Generic Scenarios (GSs).
•	Please comment on the methods and approaches used for environmental release
estimation and provide any specific suggestions or recommendations for alternative data
sources, or estimation methods that could be considered by the Agency for conducting
environment release assessment.
5.	Occupational Exposure
Workers and occupational non-users may be exposed to HBCD when workers perform activities
associated with the identified conditions of use. These activities include the following:
•	Handling of HBCD during repackaging or during transfer to storage or process vessels
•	Machining and shaping of HBCD-containing XPS/EPS foam at industrial sites
•	Cutting or breaking HBCD-containing XPS/EPS foam at construction and demolition sites
•	Handling of small transport containers of solder/flux paste containing HBCD
Approaches for estimating occupational exposure include use of monitoring data and modeling,
including methods used in EPA's TSCA New Chemicals Program. Key data and data sources that
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informed the occupational exposure assessment include monitoring data reported in the European
Communities HBCD Risk Assessment Report, data from the Bureau of Labor Statistics (BLS),
Organization of Economic Co-Operation and Development Emission Scenario Documents (OECD
ESDs) and USEPA Generic Scenarios (GSs).
• Please comment on the estimation methods and approaches used for occupational
exposure assessment and provide any specific suggestions or recommendations for
alternative data, or estimation methods that could be considered by the Agency for
conducting occupational exposure assessment.
6.	Environmental, General Population, and Consumer Exposure
Given the identified conditions of use, both monitoring and modeled data were used for estimating
environmental, general population, and consumer exposures. Key sources were identified for
integrating relevant monitoring data and three tools were used to estimate HBCD in surface water,
sediment, soil, and exposures to wildlife. These tools include the Exposure - Fate Assessment
Screening Tool (E-FAST), Variable Volume Waterbody Model - Point Source Calculator VVWM-
PSC, and Integrated Indoor-Outdoor Air Calculator (IIOAC). Key inputs for these exposure
modeling tools come from scenario-specific processing data as well as receptor-specific exposure
factors and human activity patterns.
•	Exposure modeling tools may have different levels of screening capacity such that one
might be more conservative than another given the scenario and inputs. Please comment on
EPA's approach to use a tiered method for identifying and prioritizing exposure scenarios
to be subjected to higher screening level modeling tools, based on their potential for risk by
first using a lower screening level tool.
•	Please comment on EPA's approach to use receptor-specific exposure factors and activity
patterns to estimate doses.
•	Related to (b) above, surveys have identified fish consumption rates far above those used in
this risk evaluation to estimate dietary exposure for subsistence fishing populations. Please
comment on the use of such information in estimating the contribution of fish and other
aquatic life to dietary exposure to HBCD.
•	Exposure modeling results may rely on various estimated inputs and ranges (e.g., physical-
chemical properties) given the available data, which results in variability and uncertainty in
the results. Please comment on EPA's approach to qualitatively characterize variability and
uncertainty for exposure estimates in Tables 2-111 and 2-112.
7.	Environmental Hazard
Data evaluation is a key component of the systematic review process. The evaluation of
environmental toxicity studies was designed to score a study based on its quality. Each metric of a
domain was carefully chosen to characterize the hazard of HBCD and for the other work plan
chemicals. If necessary, we would welcome input on the following:
•	Please comment on the metrics used to evaluate environmental hazard studies through the
Systematic Review process.
•	What additional language regarding metric descriptions should be considered?
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The environmental hazard of HBCD has been examined in several publications. The chemical has
been categorized as persistent, bioaccumulative, and toxic. This assessment addresses HBCD
environmental exposure to aquatic and terrestrial organisms and it's trophic transfer potential.
•	Please comment on the methodologies used to evaluate potential HBCD trophic transfer in
aquatic and terrestrial ecosystems.
•	What other information can be incorporated into the evaluation?
The available data on field studies on HBCD toxicity are limited, as presented in Risk Evaluation
for Cyclic Aliphatic Bromides Cluster (HBCD), Systematic Review Supplemental File: Data
Extraction Tables for Environmental Hazard.
•	Please comment on the use of mammalian studies, which were evaluated using human
health metrics through the Systematic Review process, in the evaluation of HBCD risk to
wildlife mammals.
8. Human Health Hazard
EPA considered the adverse human health effects for HBCD across organ systems and screened to
those that are relevant, sensitive, and found in multiple studies. The HBCD human health hazard
systematic review process screened 1,890 studies and obtained 53 studies that were relevant and
applicable to the PECO statement. Only two of these studies were unacceptable based on data
evaluation criteria. The remaining database of 51 studies included epidemiological studies that
examined associations between HBCD exposure and endpoints related to effects on the thyroid,
nervous system, and female reproductive system as well as repeat-dose experimental animal
studies. EPA examined dose-responses for the endpoints of thyroid effects, liver effects, male and
female reproductive effects, developmental toxicity, neurotoxicity, and immunotoxicity. Data on
toxicity following acute exposures, irritation, sensitization, genotoxicity, and carcinogenicity were
also considered. From these effects, EPA selected endpoints supported by the weight-of-evidence
for non-cancer that were amenable to quantitative analysis for dose-response assessment and
identified the appropriate toxicological studies to be used for acute and chronic exposure scenarios.
•	In the systematic review of key studies, numerous studies were identified as ranking high in
the quality review. EPA selected PODs for critical effects from two key studies: (WIL
Research. 2001)and (Ema et al.. 2008).. to carry forward for dose-response analysis and risk
estimations. Please provide comment on whether there are other comparable high-quality
studies that might be recommended for further consideration for dose-response for
additional critical effects and for acute or chronic exposure scenario consideration.
•	EPA considered both developmental toxicity endpoints of reduced pup weight and offspring
loss for estimating risks following acute oral exposures to HBCD in the general population.
The endpoint of offspring loss may be relevant to only child-bearing age groups in the
general population. This endpoint was only observed in the F2 generation in a two-
generation reproduction toxicity study (Ema et al.. 2008). suggesting a multigenerational
effect (possibly due to increasing bioaccumulation) over repeated/chronic exposures. EPA
additionally considered both reduced pup weight and offspring loss for evaluating risks
following acute oral exposures in the general population. While these neonatal effects are
not traditionally associated with acute exposures, the long half-life of HBCD suggests that
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even a single exposure may result in a retained body burden for an extended period of time.
Additionally, evidence from other thyroid disruptors suggests that acute or short-term
exposure can result in thyroid hormone effects (Paul et al.. 2010; Hedge et al.. 2009; Zhou
et al.. 2001). including in weanlings, and presumably resulting in downstream effects on
developmental endpoints. EPA considered both endpoints relevant for estimating risks
following acute general population exposures across all age groups, including children.
While developmental effects would not be expected to present in younger lifestages, the
bioaccumulation and persistence of HBCD in tissues suggests that initial exposure at an
earlier age could result in effects later in life. Additionally, it is unknown whether
developmental effects on neonates could also present in young exposed children. Please
comment on EPA's justification in the document for consideration of risks of
developmental toxicity following acute exposures in all age groups.
•	EPA estimated risks for effects on thyroid hormones only following chronic exposure.
However, evidence from other thyroid disruptors suggests that acute or short-term exposure
can potentially result in thyroid hormone effects (Paul et al.. 2010; Hedge et al.. 2009; Zhou
et al.. 2001). Please comment on whether EPA should consider thyroid hormone effects as
an acute endpoint.
•	In the study by (Ema et al.. 2008). the increased incidence of non-pregnancy in HBCD-
exposed F0 or F1 rats alone was not statistically significant with either pairwise test (as
reported by authors) or Cochran-Armitage trend test (conducted by EPA). Dose-response
curves were shallow and never reached a high response percentage. The results of several
statistical tests indicated that F0 and F1 datasets were compatible for combining. Therefore,
EPA considered this change to be biologically relevant and the log-logistic model (which
only demonstrated adequate fit after dropping the highest dose) from the combined dataset
was selected to derive the BMDL for this chronic endpoint. Please comment on EPA's
justification and approach to modeling this chronic endpoint based on the data available in
(Ema et al.. 2008).
•	Please comment on the evaluation of human health hazards and weight-of-evidence
characterization. Are there any additional HBCD specific data and/or information that
should be considered? Please comment on any other aspect of the human health hazard
assessment that has not been mentioned above.
9. Environmental Risk Characterization
•	EPA considered use of different model assumptions and ecological considerations in its
establishment of RQs (e.g. flow rate, partitioning in environmental media, percentage of
HBCD removal from direct releases, etc). Please comment on the appropriateness of EPA's
selections for deriving RQs.
•	EPA considered the use of KABAM (U. S EPA. 2009). a model used by the Office of
Pesticide Program, to estimate potential bioaccumulation of HBCD in freshwater aquatic
food webs to provide information regarding HBCD trophic transfer using predicted surface
water and sediment concentrations (E-FAST and PSC), in order to relate HBCD exposure
to specific conditions of use. Please comment on the appropriateness of using this
methodology for characterizing risk.
1 ft Human Health Risk Characterization
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EPA evaluated integrated risk estimates for the general population in order to account for
individuals who are chronically exposed across multiple lifestages. Exposure scenarios include
central tendency (13 year) and higher end (33 year) periods of residential mobility, based on the
Exposure Factors Handbook values. MOEs were integrated across each lifestage as a weighted
average. Please comment on EPA's approach.
•	Physiologically based pharmacokinetic (PBPK) models would be needed in order to be able
to accurately estimate bioaccumulation of HBCD in human tissue for different exposure
durations over time. Some simplistic models for HBCD exist (empirical two-compartment
open kinetic model; and a simple first-order elimination model to estimate the steady-state
lipid concentration); however, these models introduce significant uncertainties that reduce
the value of their use. Based on the absence of a robust peer reviewed PBPK model for
HBCD, EPA relied on the application of default uncertainty factors for interspecies,
intraspecies uncertainty factor and subchronic-to-chronic from subchronic exposure studies.
Please comment on EPA's approach.
11. General Risk Characterization
After consideration of all information identified by EPA that pertains to HBCD, EPA
concluded that HBCD does not present an unreasonable risk of injury to health or the environment.
EPA made these determinations considering risk to potentially exposed and susceptible
subpopulations identified as relevant, under the conditions of use without considering costs or other
non-risk factors.
•	Please comment on the objectivity of the underlying data used to support the risk
determinations and the sensitivity of the agency's conclusions to analytic assumptions
made.
•	Please comment on the characterization of uncertainties and assumptions including whether
EPA has presented a clear explication of underlying assumptions, accurate
contextualization of uncertainties and, as appropriate, the probabilities associated with both
optimistic and pessimistic projections, including best-case and worst-case scenarios.
•	Please provide information on additional uncertainties and assumptions that EPA has not
adequately presented.
•	Please comment on whether the information presented supports the findings outlined in the
draft risk characterization section. If not, please suggest alternative approaches or
information that could be used to develop a risk finding in the context of the requirements
of the EPA's Final Rule, Procedures for Chemical Risk Evaluation Under the Amended
Toxic Substances Control Act (82 FR 33726).
REFERENCES
Ema, M; Fuiii. S; Hirata-Koizumi. M; Matsumoto. M. (2008). Two-generation reproductive
toxicity study of the flame retardant hexabromocyclododecane in rats. Reprod Toxicol 25:
335-351. http://dx.doi.Org/10.1016/i.reprotox.2007.12.004
Hedge. JM; Devi to. MJ; Croft on. KM. (2009). In vivo acute exposure to poly chlorinated biphenyls:
effects on free and total thyroxine in rats. Int J Toxicol 28: 382-391.
http://dx.doi.org/10.1177/1091581809344631
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Paul KB; Hedge. JM; Devi to. MJ; Croft on. KM. (2010). Short-term exposure to triclosan
decreases thyroxine in vivo via upregulation of hepatic catabolism in Young Long-Evans
rats. Toxicol Sci 113: 367-379. http://dx.doi.org/10.1093/toxsci/kfp271
U S EPA. (2009). User's guide and technical documentation: KABAM version 1.0 (Kow (based)
Aquatic BioAccumulation Model), https://www.epa.gov/sites/production/files/2015-
07/documents/kabam vl 0 users guide.pdf
WIL Research. (2001). 90-Day oral (gavage) toxicity study of HBCD in rats. (WIL-186012).
Washington, DC: Chemical Manufacturers Association.
Zhou. T; Ross. DG: Devi to. MJ: Crofton. KM. (2001). Effects of short-term in vivo exposure to
polybrominated diphenyl ethers on thyroid hormones and hepatic enzyme activities in
weanling rats. Toxicol Sci 61: 76-82.
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