A Framework to Guide Selection of Chemical Alternatives (2014)

A Framework to Guide Selection of

CHEMICAL ALTERNATIVES

Committee on the Design and Evaluation of Safer Chemical Substitutions:
A Framework to Inform Government and Industry Decisions

Board on Chemical Sciences and Technology
Board on Environmental Studies and Toxicology

Division on Earth and Life Studies

National Research Council

THE NATIONAL ACADEMIES PRESS

Washington, D.C.

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NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance.

This project was supported by Contract EP-C-09-003, TO# 25 between the National Academy of Sciences and the U.S. Environmental Protection Agency Any opinions, findings, and conclusions, or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the sponsoring agencies or any of their subagencies.

International Standard Book Number-13: 978-0-309-31013-0
International Standard Book Number-10: 0-309-31013-X

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COMMITTEE ON THE DESIGN AND EVALUATION OF SAFER CHEMICAL SUBSTITUTIONS: A FRAMEWORK TO INFORM GOVERNMENT AND INDUSTRY DECISIONS

Members

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

ERIC J. BECKMAN, University of Pittsburgh, PA

PETER BEAK, University of Illinois, Urbana-Champaign

JEROME J. CURA, Woods Hole Group Inc., MA

ANNE FAIRBROTHER, Exponent Inc., WA

NIGEL GREENE, Pfizer, CT

CAROL HENRY, The George Washington University, DC

HELEN HOLDER, Hewlett-Packard Company, CA

JAMES E. HUTCHISON, University of Oregon

GREGORY M. PAOLI, Risk Sciences International, ON

JULIA B. QUINT, California Department of Public Health (retired)

IVAN RUSYN, University of North Carolina, NC

KATHLEEN SHELTON, DuPont, DE

JOEL A. TICKNER, University of Massachusetts, Lowell

ADELINA VOUTCHKOVA, The George Washington University, DC

MARTIN H. WOLF, Seventh Generation Inc., VT

Staff

MARILEE SHELTON-DAVENPORT, Study Director and Senior Program Officer, Board on Life Sciences

KATHRYN HUGHES, Senior Program Officer, Board on Chemical Sciences and Technology

ELLEN K. MANTUS, Senior Program Officer, Board on Environmental Studies and Toxicology

JANET MULLIGAN, Associate Program Officer, Board on Agriculture and Natural Resources

MARILYN FENICHEL, Editor, Cassell & Fenichel Communications

MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center

IVORY CLARKE, Senior Program Assistant, Board on Environmental Studies and Toxicology

Sponsor

U.S. ENVIRONMENTAL PROTECTION AGENCY

BOARD ON CHEMICAL SCIENCES AND TECHNOLOGY

Members

TIMOTHY SWAGER, (Co-Chair), Massachusetts Institute of Technology, Cambridge

DAVID WALT, (Co-Chair), NAE, Tufts University, Medford, Massachusetts

HÉCTOR D. ABRUÑA, Cornell University, Ithaca, New York

JOEL C. BARRISH, Bristol-Myers Squibb, Princeton, New Jersey

MARK A. BARTEAU, University of Michigan, Ann Arbor

DAVID BEM, The Dow Chemical Company, Philadelphia, PA

ROBERT G. BERGMAN, NAS, University of California, Berkeley

JOAN BRENNECKE, NAE, University of Notre Dame, Indiana

HENRY E. BRYNDZA, E. I. du Pont de Nemours & Company, Wilmington, Delaware

MICHELLE V. BUCHANAN, Oak Ridge National Laboratory, Oak Ridge, Tennessee

DAVID W. CHRISTIANSON, University of Pennsylvania, Philadelphia

RICHARD EISENBERG, NAS, University of Rochester, New York

JILL HRUBY, Sandia National Laboratories, Albuquerque, New Mexico

FRANCES S. LIGLER, NAE, North Carolina State University, Raleigh

SANDER G. MILLS, Merck Research Laboratories (Ret.), Scotch Plains, New Jersey

JOSEPH B. POWELL, Shell, Houston, Texas

ROBERT E. ROBERTS, Institute for Defense Analyses, Alexandria, Virginia

PETER J. ROSSKY, NAS, The University of Texas at Austin

DARLENE SOLOMON, Agilent Technologies, Santa Clara, California

National Research Council Staff

TERESA FRYBERGER, Director

KATHRYN HUGHES, Senior Program Officer

DOUGLAS FRIEDMAN, Senior Program Officer

CARL GUSTAV-ANDERSON, Research Associate

ELIZABETH FINKELMAN, Program Coordinator

NAWINA MATSHONA, Senior Program Assistant

CAMLY TRAN, Postdoctoral Fellow

BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY

Members

ROGENE F. HENDERSON (Chair), Lovelace Respiratory Research Institute, Albuquerque, NM

PRAVEEN AMAR, Independent Consultant, Lexington, MA

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

MICHAEL J. BRADLEY, M.J. Bradley & Associates, Concord, MA

JONATHAN Z. CANNON, University of Virginia, Charlottesville, VA

GAIL CHARNLEY ELLIOTT, HealthRisk Strategies, Washington, DC

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

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

CHARLES T. DRISCOLL, JR., Syracuse University, Syracuse, NY

WILLIAM H. FARLAND, Colorado State University, Fort Collins, CO

LYNN R. GOLDMAN, The George Washington University, Washington, DC

LINDA E. GREER, Natural Resources Defense Council, Washington, DC

WILLIAM E. HALPERIN, University of Medicine and Dentistry of New Jersey, Newark, NJ

STEVEN P. HAMBURG, Environmental Defense Fund, New York, NY

ROBERT A. HIATT, University of California, San Francisco, CA

PHILIP K. HOPKE, Clarkson University, Potsdam, NY

SAMEUL KACEW, University of Ottawa, Ontario

H. SCOTT MATTHEWS, Carnegie Mellon University, Pittsburgh, PA

THOMAS E. MCKONE, Univeristy of California, Berkeley, CA

TERRY L. MEDLEY, E. I. du Pont de Nemours & Company, Wilmington, DE

JANA MILFORD, University of Colorado at Boulder, Boulder, CA

MARK A. RATNER, Northwestern University, Evanston, IL

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

GINA M. SOLOMON, California Environmental Protection Agency, Sacramento, CA

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

JOYCE S. TSUJI, Exponent, Inc., Bellevue, WA

Senior Staff

JAMES J. REISA, Director

DAVID J. POLICANSKY, Scholar

ELLEN K. MANTUS, Senior Program Officer for Risk Analysis

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

RAYMOND A. WASSEL, Senior Program Officer for Environmental Studies

MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center

RADIAH ROSE, Manager, Editorial Projects

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Acknowledgments

This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for 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 wish to thank the following individuals for their review of this report:

Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Joseph V. Rodricks, ENVIRON and Lynn R. Goldman, The George Washington University. Appointed by the National Research Council, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Contents

SUMMARY

1    INTRODUCTION

Recent Drivers Resulting in Chemical Alternatives Assessment

Governmental Efforts to Drive Adoption of Safer Chemicals

Growth in Evaluative Approaches

The Committee’s Task

2    EXISTING FRAMEWORKS AND APPROACHES

Specific Frameworks Considered by the Committee

Specific Tools Considered by the Committee

3    THE COMMITTEE’S FRAMEWORK

Step 1: Identify Chemical of Concerns

Step 2: Scoping and Problem Formulation

Step 3: Identify Potential Alternatives

Step 4: Determine if Alternatives are Available; Refer Cases with Limited or No Alternatives to Research and Development

Step 5: Assess Physicochemical Properties

Step 6: Assess Human Health, Ecotoxicity, and Comparative Exposure

Step 7: Integration of Information to Identify Safer Alternatives

Step 8: Life Cycle Thinking

Step 9: Optional Assessments

Step 10: Identify Acceptable Alternatives and Refer Cases with No Alternatives to Research and Development

Step 11: Compare or Rank Alternatives

Step 12: Implement Alternatives

Step 13: Research/ De Novo Design

4    SCOPING, PROBLEM FORMULATION, AND IDENTIFYING ALTERNATIVES

Scoping, Problem Formulation, and Identifying Alternatives in Other Frameworks

Scoping in the Committee’s Framework

Problem Formulation in the Committee’s Framework

Identifying Alternatives in the Committee’s Framework

5    PHYSICOCHEMICAL PROPERTIES AND ENVIRONMENTAL FATE

Physicochemical Properties of Interest

Measured Physicochemical Property Values

Methods for Estimating Select Physicochemical Properties

Physicochemical Properties in Other Frameworks

Physicochemical Properties in the Committee’s Framework

Implementation of Step 5 in the Committee’s Framework

6    COMPARATIVE EXPOSURE ASSESSMENT

Exposure Assessment in Existing Frameworks

The Committee’s Approach to Exposure Assessment

7    ASSESSMENT OF ECOTOXICITY

Ecotoxicology

Ecotoxicity Assessment in Other Frameworks

Committee’s Framework for Ecotoxicity Assessment

Methods for Hazard Determination

8    HUMAN HEALTH

Types of Data for Human Health Assessment

How Human Health is Considered in Existing Frameworks

Human Health in the Committee’s Framework

In Vitro Data and In Silico Models for Chemical Alternatives Assessments

In Vitro and In Silico Data Integration: An Opportunity for New Insights

Implementation of Step 6.1: Human Health Assessment in the Committee’s Framework

Future Research Needs

Conclusions

9    INTEGRATION OF INFORMATION TO IDENTIFY SAFER ALTERNATIVES

Information Needed to Implement Step 7 in the Committee’s Framework

Strategies to Address Trade-Offs and Uncertainty

Conclusions

10  LIFE CYCLE, PERFORMANCE, AND ECONOMIC CONSIDERATIONS

Life Cycle, Social, Performance, and Economic Considerations in Other Frameworks

Life Cycle Considerations in the Committee’s Framework

Step 9: Optional Assessments

11  IDENTIFYING, COMPARING, AND IMPLEMENTING ALTERNATIVES

Identifying Acceptable Alternatives within Existing Frameworks

Step 10: Identifying Acceptable Alternatives in the Committee’s Framework

Step 11: Comparing Alternatives in the Committee’s Framework

Step 12: Implementing Alternatives

12  CASE STUDIES

Case Study 1: Chemical Substitution of a Restricted Substance (decaBDE)

Case Study 2: Chemical Substitution of a Hazardous Biologically Active Compound (Glitazone)

Conclusion

13  CHEMICAL DESIGN: AN OPPORTUNITY FOR INNOVATION

Innovation Within the Committee’s Alternatives Assessment Framework

Opportunities for Innovation

Summary

REFERENCES

APPENDIXES

APPENDIX A: BIOGRAPHIC INFORMATION ON THE COMMITTEE ON THE DESIGN AND EVALUATION OF SAFER CHEMICAL SUBSTITUTIONS- A FRAMEWORK TO INFORM GOVERNMENT AND INDUSTRY DECISIONS

APPENDIX B: ECOTOXICITY IN FRAMEWORKS

APPENDIX C: TOXICOLOGICAL PRIORITY INDEX (TOXPI)

APPENDIX D: OVERVIEW OF THE GHS CLASSIFICATION SCHEME IN HAZARD CLASSIFICATION

BOXES, FIGURES, AND TABLES

BOXES

1-1    Chemical Alternatives Assessment

4-1    Elements of Steps 2 and 3 in the Committee’s Framework

4-2    Definitions of Goal, Principles, and Decision Rules

4-3    Why Focus on Function?

5-1    Elements of Step 5 (Assessing Physicochemical Properties)

5-2    Structural Attributes that Enhance (Bio) degradation

6-1    Comparative Exposure Assessment at a Glance (step 6.3)

6-2    Comparison of Exposure Potential Using Physicochemical Properties for Dermal Exposure

7-1    Elements of Step 6.2 in the Committee’s Framework

8-1    Human Health Assessment at a Glance

8-2    Examples of Existing Guidance for Minimum Evidence Required to Establish that Specific Health Hazards Do or Do Not Exist

8-3    In Vitro Testing by End Point

8-4    Relationship Between In Vitro Concentration and In Vivo Dose that Elicits Adverse Health Effect

8-5    In Silico Prediction by End Point

8-6    Other Chemical Structure and Physicochemical Properties that Influence Toxicity

8-7    Use of In Vitro High Throughput Screening Data to Identify Chemicals with Higher or Lower Probability of Exerting Reproductive Effects- Information Useful for Filling Data Gaps

9-1    Types of Uncertainty

10-1    Elements of Life Cycle Analysis in the Committee’s Framework

10-2    Terms

10-3    Product System Mapping: A Procedure for Identifying Life Cycle Stages and Unit Processes in a Product System

10-4    Synthetic History

10-5    Elements of Step 9 in the Committee’s Framework

13-1    Design and Innovation at a Glance

13-2    Lessons from the Pharmaceutical Industry

13-3    Concept vs. Design

13-4    Qualitative Structure-Based Design Filters: Features Associated with Unwanted Biological Activity

13-5    Qualitative Property-Based Design Filters: Desirable/Undesirable Properties

FIGURES

S-1    The Committee’s alternatives assessment framework

3-1    Framework developed by the present committee

4-1    Committee’s framework highlighting scoping, problem formulation, and identification potential alternatives

5-1    The committee’s framework, with step 5 highlighted

5-2    Relationship between the three primary types of physicochemical properties

5-3    Relation of Frontier Molecular Orbital Energies

6-1    Committee’s framework highlighting comparative exposure assessment (step 6.3)

6-2    Approach to Comparative Exposure Assessment within the Committee’s Chemical Alternatives Assessment Framework

7-1    Committee’s framework with the ecotoxicity assessment highlighted

7-2    Illustrative ToxPi showing relative hazard to aquatic, sediment, and terrestrial organisms

7-3    Schematic representation of the use of chemical categories to fill data gaps, enabling read-across from a data-rich chemicals

7-4    Scatter plots of the octanol-water distribution coefficient at pH 7.4

8-1    Committee’s Framework highlighting the human health assessment

8-2    Decision contexts, data type, and availability determine the kind of human health assessment that can be performed on chemicals

8-3    Selected chemical compounds to illustrate structural similarities and differences

9-1    Selected portion of the committee’s framework highlighting the integration step described in this chapter

9-2    Strategies to address trade-offs and uncertainty in alternative assessment

10-1    Excerpt of committee’s framework highlighting the performance and life cycle assessments

10-2    Unit processes within a product system

10-3    Example of a product system for life cycle assessment

11-1    Committee’s framework highlighting steps to identify, compare, and implement alternatives

11-2    Additional information about Steps 10-12

11-3    Steps to follow in a substitution planning process requires for companies seeking authorization for a Substance of Very High Concern under REACH

12-1    Chemical structure of decabromodiphenyl ether (decaBDE), CAS number 1163-19-5

12-2    Chemical structure of Glitazone-T, CAS # 97322-87-7

12-3    Chemical structure of R-ThZD and P-ThZD

12-4    Formation of a reactive quinoid intermediate

12-5    Apredica assay profiles for Glitazone-T and P-ThZD

12-6    Attagene Nuclear Hormone Receptor panel assay profiles for Glitazone-T and P-ThZD

12-7    BioSeek panel assay profiles for Glitazone-T and P-ThZD

12-8    ToxPi visualization of data by data type and resultant rank ordering of chemicals

12-9    ToxPi visualization of data with in vivo safety heavily weighted

12-10    ToxPi visualization of data with functional efficacy heavily weighted

13-1    Committee’s framework highlighting where design and innovation occur

13-2    Flow diagram for the innovation process with the addition of alternatives assessment at the early stages

C-1    In vivo end points

C-2    Concentration response curve for six assays

C-3    Relative rank of compounds being compared

C-4    ToxPi confidence Intervals

TABLES

2-1    Comparison of Selected Attributes Found in Selected Frameworks

5-1    GHS Criteria used by the U.S. DfE for Classification of Physical Hazards

5-2    End Points, Thresholds, and Categories used to Evaluate Bioaccumulation Potential in Chemical Alternatives Assessment Frameworks Reviewed by the Committee

5-3    High-Priority Data Set of Physicochemical Processes and Rationale for their Inclusion

5-4    Changes in Physicochemical Properties to Favor Reduced Aquatic Toxicity

5-5    Combinations of Property Limits Associated with Increased Bioavailability through the Four Main Routes of Exposure in Mammals

6-1    Comparison of Exposure Potential Using Simple Exposure Models

6-2    Selected Human Health Comparative Exposure Assessment Tools

7-1    Aquatic Toxicity End Points, Thresholds, and Categories Used in Chemical Alternatives Assessment Frameworks

7-2    DfE Ecotoxicity Categories for Terrestrial and Aquatic Organisms

7-3    Standardized Aquatic Tests for Ecotoxicity Properties

7-4    Standardized Terrestrial Tests for Ecotoxicity Properties

8-1    Health End Points Established by Other Frameworks

8-2    Use of Authoritative Lists by the DfE Framework and GreenScreen Tool

8-3    Acute Mammalian Toxicity

8-4    Hypothetical Tabulation Evaluations of Human Health Impact

8-5    Toxicity and High Throughput Screening (HTS) Data amenable to the Evaluation of Human Health Hazard and the Relationship between Chemical Dose and Response

9-1    Sample Results from Step 6 Providing Categorical Evaluation of Select Ecotoxicity and Human Health Impacts and Physicochemical Properties

9-2    Sample Results of Comparative Exposure Assessment

9-3    Excerpt of an Evidence Table Demonstrating Different Levels of Uncertainty among Alternatives

9-4    Example of an Evidence Table Demonstrating Trade-offs with Alternatives with Adequate Information Indicated by Equal and Low Levels of Uncertainty

9-5    Example of an Evidence Table Demonstrating Both Trade-offs and Differences in the Level of Uncertainty in Toxicological Evaluations

10-1    Output of a Life Cycle Inventory (LCI)

10-2    Commonly Used Life Cycle Environmental and Human Health Impact Categories

10-3    Typical Social Impact Categories and Possible Characterization Factors

11-1    Example of a Summary Matrix for Multiple Alternatives across Several Criteria in a Case Study based on the TURI Framework

12-1    Mechanical Properties for the PPE/HIPS Resin Used in KayDisplay’s Kiosks

12-2    Physical Properties for the Injection Mold Process Used by KayDisplay’s Current supplier

12-3    Potential Alternatives

12-4    Remaining Alternatives

12-5    Physicochemical Properties of DecaBDE and Potential Alternatives (data from EPA 2014)

12-6    Human Health Effects Data from DfE’s DecaBDE Alternatives Assessment

12-7    Ecotoxicity Data from DfE’s Alternative Assessment

12-8    Toxicokinetic Data

12-9    Persistence Levels for DecaBDE and Alternatives

12-10    Transport for DecaBDE and Alternatives

12-11    Bioaccumulation for DecaBDE and Alternatives

12-12    Combined Hazard Table from DFE Alternatives Analysis

12-13    Clean Production Action Draft Benchmark Scores

12-14    Physicochemical Properties for Glitazone-T, P-ThZD, and R-ThZD

12-15    Various Predicted Properties for Glitazone-T, P-ThZD, and R-ThZD

12-16    In Vitro Safety Data

12-17    Summary of Mammalian Toxicity Assessment

12-18    Aquatic Toxicological End Points and Assigned Category from Chemical Alternatives Assessments

12-19    Summary of Toxicity Data for Pioglitazone

12-20    Incorporation of Data into a Single Rank Ordering of Alternatives

12-21    Components of ToxPi Slices in Case Study Illustration

B-1    Summary of Ecological Assessment Approach for Ten Chemical Assessment Alternative Methods

D-1    Acute Toxicity Hazard Categories and Acute Toxicity Estimate (ATE) Values Defining the Respective Categories

D-2    GHS Criteria to Categorize the Carcinogenicity of a Single Substance

D-3    GHS Criteria to Categorize the Germ Cell Mutagenicity of a Single Substance

D-4    GHS Criteria to Categorize the Reproductive Toxicity of a Single Substance

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