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.
THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001
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
Additional copies of this report are available for sale from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu/.
Copyright 2014 by the National Academy of Sciences. All rights reserved.
Printed in the United States of America
THE NATIONAL ACADEMIES
Advisers to the Nation on Science, Engineering, and Medicine
The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences.
The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. C. D. Mote, Jr., is president of the National Academy of Engineering.
The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Victor J. Dzau is president of the Institute of Medicine.
The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. C. D. Mote, Jr., are chair and vice chair, respectively, of the National Research Council.
This page intentionally left blank.
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
This page intentionally left blank.
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:
Lawrence Barnthouse, LWB Environmental Services
Linda Birnbaum, National Institute of Environmental Health Sciences
Edward Carney, The Dow Chemical Company
Matthew Eckleman, Northeastern University
John Giesy, University of Saskatchewan
Robert Hamilton, Amway/Access Business Group
Philip J. Landrigan, Mount Sinai School of Medicine
Alexander MacLachlan, Retired, E.I du Pont de Nemours & Co.
Jennifer McPartland, Environmental Defense Fund
Warren Muir, Retired, National Academy of Sciences
Kristi Pullen, Natural Resources Defense Council
Mark Ratner, Northwestern University
Patricia Ruiz, Agency for Toxic Substances and Disease Registry
Katherine von Stackelberg, Harvard School of Public Health
James Stevens, The Dow Chemical Company
Alex Stone, State of Washington
Donna Vorhees, Boston University
Margaret Whittaker, ToxServices LLC
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.
This page intentionally left blank.
Contents
Recent Drivers Resulting in Chemical Alternatives Assessment
Governmental Efforts to Drive Adoption of Safer Chemicals
Growth in Evaluative Approaches
2 EXISTING FRAMEWORKS AND APPROACHES
Specific Frameworks Considered by the Committee
Specific Tools Considered by the Committee
Step 1: Identify Chemical of Concerns
Step 2: Scoping and Problem Formulation
Step 3: Identify Potential Alternatives
Step 5: Assess Physicochemical Properties
Step 6: Assess Human Health, Ecotoxicity, and Comparative Exposure
Step 7: Integration of Information to Identify Safer Alternatives
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
Ecotoxicity Assessment in Other Frameworks
Committee’s Framework for Ecotoxicity Assessment
Methods for Hazard Determination
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
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
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
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
Case Study 1: Chemical Substitution of a Restricted Substance (decaBDE)
Case Study 2: Chemical Substitution of a Hazardous Biologically Active Compound (Glitazone)
13 CHEMICAL DESIGN: AN OPPORTUNITY FOR INNOVATION
Innovation Within the Committee’s Alternatives Assessment Framework
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
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
8-3 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
10-1 Elements of Life Cycle Analysis in the Committee’s Framework
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
13-5 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
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)
7-1 Committee’s framework with the ecotoxicity assessment highlighted
7-2 Illustrative ToxPi showing relative hazard to aquatic, sediment, and terrestrial organisms
7-4 Scatter plots of the octanol-water distribution coefficient at pH 7.4
8-1 Committee’s Framework highlighting the human health assessment
8-3 Selected chemical compounds to illustrate structural similarities and differences
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
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
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
5-3 High-Priority Data Set of Physicochemical Processes and Rationale for their Inclusion
5-4 Changes in Physicochemical Properties to Favor Reduced Aquatic Toxicity
6-1 Comparison of Exposure Potential Using Simple Exposure Models
6-2 Selected Human Health Comparative Exposure Assessment Tools
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
8-4 Hypothetical Tabulation Evaluations of Human Health Impact
9-2 Sample Results of Comparative Exposure Assessment
9-3 Excerpt of an Evidence Table Demonstrating Different Levels of Uncertainty among Alternatives
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
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
12-5 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
12-9 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
12-17 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-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