A Class Approach to Hazard
Assessment of Organohalogen
Flame Retardants

Committee to Develop a Scoping Plan to Assess the Hazards of
Organohalogen Flame Retardants

Board on Environmental Studies and Toxicology

Division on Earth and Life Studies

A Consensus Study Report of

THE NATIONAL ACADEMIES PRESS
Washington, DC
www.nap.edu

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This project was supported by Contract HHSP233201400020B between the National Academies of Sciences, Engineering, and Medicine and the Department of Health and Human Services. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project.

International Standard Book Number-13: 978-0-309-49118-1
International Standard Book Number-10: 0-309-49118-5
Digital Object Identifier: https://doi.org/10.17226/25412

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Suggested Citation: National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/25412.

COMMITTEE TO DEVELOP A SCOPING PLAN TO ASSESS THE HAZARDS OF ORGANOHALOGEN FLAME RETARDANTS

Members

DAVID C. DORMAN (Chair), North Carolina State University, Raleigh, NC

HUGH A. BARTON (retired), Pfizer, Groton, CT

KAREN BLACKBURN, Procter & Gamble Company, Cincinnati, OH

JOHN BUCHER, National Institute of Environmental Health Sciences, Durham, NC

JULIE L. DANIELS, University of North Carolina at Chapel Hill, Chapel Hill, NC

JENNIFER L. FREEMAN, Purdue University, West Lafayette, IN

KAMEL MANSOURI, Integrated Laboratory Systems, Raleigh, NC

CARMEN MESSERLIAN, Harvard T.H. Chan School of Public Health, Boston, MA

DAVID M. REIF, North Carolina State University, Raleigh, NC

GINA M. SOLOMON, Public Health Institute, Oakland, CA

CHIHAE YANG, Molecular Networks GMbH, Columbus, OH

Staff

ELLEN K. MANTUS, Project Director

SUSAN N.J. MARTEL, Senior Program Officer

RADIAH ROSE-CRAWFORD, Manager, Editorial Projects

JESSICA WOLFMAN, Senior Program Assistant

Sponsor

US CONSUMER PRODUCT SAFETY COMMISSION

BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY

Members

WILLIAM H. FARLAND (Chair), Colorado State University, Fort Collins, CO

LESA AYLWARD, Summit Toxicology, LLP, Falls Church, VA

ANN M. BARTUSKA, Resources for the Future, Washington, DC

RICHARD A. BECKER, American Chemistry Council, Washington, DC

E. WILLIAM COLGLAZIER, American Association for the Advancement of Science, Washington, DC

DOMINIC M. DITORO, University of Delaware, Newark, DE

DAVID C. DORMAN, North Carolina State University, Raleigh, NC

GEORGE GRAY, George Washington University, Washington, DC

R. JEFFREY LEWIS, ExxonMobil Biomedical Sciences, Inc., Annandale, NJ

GERMAINE M. BUCK LOUIS, George Mason University, Fairfax, VA

ROBERT PERCIASEPE, Center for Climate and Energy Solutions, Arlington, VA

REZA J. RASOULPOUR, Dow AgroSciences, Indianapolis, IN

JOAN B. ROSE, Michigan State University, East Lansing, MI

GINA M. SOLOMON, Public Health Institute, Oakland, CA

DEBORAH L. SWACKHAMER, University of Minnesota, St. Paul, MN

JOSHUA TEWKSBURY, Future Earth, Boulder, CO

PETER S. THORNE, University of Iowa, Iowa City, IA

Senior Staff

CLIFFORD DUKE, Director

ELLEN K. MANTUS, Scholar and Director of Risk Assessment

RAYMOND A. WASSEL, Scholar and Director of Environmental Studies

SUSAN N.J. MARTEL, Senior Program Officer for Toxicology

LAURA LLANOS, Financial Associate

TAMARA DAWSON, Program Associate

Acknowledgments

This Consensus Study Report was reviewed in draft form by persons chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets institutional standards of quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process.

We thank the following for their review of this report:

Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report, nor did they see the final draft before its release. The review of the report was overseen by David Allison, Indiana University, and Joseph Rodricks, Ram-boll Environ, who were responsible for making certain that an independent examination of the report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies.

The committee gratefully acknowledges the staff of the US Consumer Product Safety Commission for their presentations to the committee during open sessions. The committee is also grateful for the assistance of Norman Grossblatt who served as the report editor.

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Contents

SUMMARY

1 INTRODUCTION

Conceptual Advantages of a Class Approach

Petition to Ban Organohalogen Flame Retardants in Selected Consumer Products

Statement of Task

Committee’s Approach to Its Task

Organization of This Report

References

2 HAZARD ASSESSMENT SCOPING PLAN

Determine the Viability of a Class Approach

Survey the Literature

Search the Literature and Extract Data

Evaluate and Integrate Data

Integrating a Hazard Assessment That Uses a Class Approach into Risk Assessment

Improved Efficiency and Cost-Effectiveness

Conclusions

References

3 A CLASS APPROACH TO EVALUATING ORGANOHALOGEN FLAME RETARDANTS: CASE STUDIES

Can Organohalogen Flame Retardants Be Defined as a Single Class?

Definition of Subclasses of Organohalogen Flame Retardants

Survey of the Literature

Search of the Literature

Case Study 1: Polyhalogenated Organophosphates

Case Study 2: Polyhalogenated Bisphenol Aliphatics

Addressing Discordant Data

Projected Timeline and Costs

Conclusions

References

APPENDIXES

A BIOGRAPHIC INFORMATION ON THE COMMITTEE TO DEVELOP A SCOPING PLAN TO ASSESS THE HAZARDS OF ORGANOHALOGEN FLAME RETARDANTS

B METHODOLOGIC DETAILS OF ANALYSES TO EVALUATE FEASIBILITY OF CLASS APPROACH AND TO DEFINE SUBCLASSES

C METHODOLOGIC DETAILS OF LITERATURE SURVEYS AND SEARCHES

D SUMMARY OF ZEBRAFISH STUDIES

BOXES, FIGURES, AND TABLES

BOXES

1-1 Statement of Task

1-2 Definitions of Terms Used in This Report

2-1 OECD Guidance on Development of Categories under REACH

2-2 An Example of a Potentially Hazardous Subclass

2-3 A Tiered Approach for Assessing a Subclass on Which There Are No Relevant Toxicity Data

3-1 An OFR Inventory

3-2 Identification of Analogues to the OFR Seed Chemicals

3-3 Use of NAM Data in Regulatory Decision-Making

FIGURES

S-1 Scoping plan to conduct a hazard assessment for the Consumer Product Safety Commission by using a class approach

2-1 Scoping plan to conduct a hazard assessment for the Consumer Product Safety Commission by using a class approach

2-2 An illustrative example for building confidence in the derivation of health reference values when using a read-across approach

3-1 Substructures identified in OFR seed chemicals

3-2 Histogram of data availability for the seed chemicals

3-3 Histogram of data availability for the expanded set of chemicals

3-4 Representative members of the polyhalogenated organophosphate subclass

3-5 Representative members of polyhalogenated bisphenol aliphatics

B-1 Standardization of structures to provide QSAR-ready structures amenable to modeling: desalted, stereochemistry-stripped, tautomers and nitro groups standardized, valence corrected, structures neutralized when possible, and duplicates removed, among other steps

B-2 KNIME workflow used to identify organohalogens from DSSTox and determine analogues of OFR seed chemicals

B-3 Principal component analysis of the seed OFRs and analogues

B-4 Enrichment sites of OFRs from seed list and expanded set of analogues

B-5 Principal component analysis that used the highest selected descriptors that resulted from the GA procedure

B-6 Major chemotypes found in OFR seed set

B-7 Screenshot of OFR categories and matching structures in ChemoTyper

C-1 Explicit mapping of data availability for inventory chemicals

C-2 Histogram of data availability for inventory chemicals

C-3 Histogram of data availability for the expanded set of chemicals

C-4 Heatmap that represents availability of Tox21data on the chemicals in the OFR inventory

C-5 Heatmap that represents availability of ToxCast data on the chemicals in the OFR inventory

TABLES

3-1 Chemotypes Identified in OFR Seed Chemicals That Have Been Associated with Predicted Biologic Activity

3-2 OFR Subclasses Formulated by Using Chemotypes and Predicted Biologic Activity

3-3 Members of the Polyhalogenated Organophosphate Subclass

3-4 Genotoxicity Data on the Polyhalogenated Organophosphate Subclass

3-5 Polyhalogenated Organophosphate Chronic Toxicity Studies

3-6 Available Human Epidemiologic Data on Organophosphate Flame Retardants

3-7 Developmental Toxicity of Polyhalogenated Organophosphates

3-8 Zebrafish Teratology and Developmental Neurotoxicity Studies of Polyhalogenated Organophosphates

3-9 Summary of Experimental Evidence of Developmental Effects in Mammals and Zebrafish Associated with Polyhalogenated Organophosphates

3-10 Polyhalogenated Bisphenol Aliphatics

3-11 Genotoxicity Data on Polyhalogenated Bisphenol Aliphatics

3-12 Subchronic and Chronic Toxicity Studies of Polyhalogenated Bisphenol Aliphatics

3-13 Summary of Human Epidemiologic Studies of Polyhalogenated Bisphenol Aliphatics

3-14 Mammalian Developmental Toxicity Studies of Polyhalogenated Bisphenol Aliphatics

3-15 Summary of Evidence on TBBPA and Changes in Thyroid Homeostasis

3-16 Summary of Evidence on Developmental Effects in Mammals and Zebrafish Associated with Polyhalogenated Bisphenol Aliphatics

3-17 Options and Approaches for Handling Discordant Data

B-1 Sources Used to Identify Chemicals in the OFR Inventory

B-2 Fourteen OFR Subclasses Formulated on the Basis of Chemotypes and Predicted Biologic Activity

C-1 Number of Results of the PubChem Database Search

C-2 Number of Results of the PubMed Database Search

D-1 Summary of Zebrafish Studies That Evaluated Teratogenic or Developmental Neurotoxic Effects after Exposure to a Polyhalogenated Organophosphate Flame Retardant

D-2 Summary of Additional Zebrafish Studies after Exposure to a Polyhalogenated Organophosphate Flame Retardant

D-3 Effects of Tetrabromobisphenol A on Thyroid Homeostasis in Zebrafish

D-4 Effects of Polyhalogenated Bisphenols on Zebrafish Development or Behavior

D-5 Additional Zebrafish Studies of Polyhalogenated Bisphenol

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