Handbook of Green Chemistry

Green Processes

Edited by Paul T. Anastas

Volume Editors:Robert BoethlingAdelina Voutchkova

Volume 9: Designing Safer Chemicals

Handbook of Green Chemistry

Volume 9

Designing Safer Chemicals

Edited by

Robert Boethling and

Adelina Voutchkova

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Handbook of Green Chemistry

Volume 9Designing Safer Chemicals

Edited byRobert Boethling and Adelina Voutchkova

The Editor

Prof. Dr. Paul T. AnastasYale UniversityCenter for Green Chemistry & Green Engineering225 Prospect StreetNew Haven, CT 06520UAS

Volume Editors

Dr. Robert BoethlingU.S. Environmental ProctectionAgency1200 Pennsylvania Ave. N.W.Washington, DC 20460USA

Dr. Adelina VoutchkovaYale UniversityDepartment of Chemistry225 Prospect StreetNew Haven, CT 06520USA

Handbook of Green Chemistry – Green ProcessesVol. 7: Green SynthesisISBN: 978-3-527-32602-0Vol. 8: Green NanoscienceISBN: 978-3-527-32628-0Vol. 9: Designing Safer ChemicalsISBN: 978-3-527-32639-6

Set III (3 volumes):ISBN: 978-3-527-31576-5

Handbook of Green ChemistrySet (12 volumes):ISBN: 978-3-527-31404-1oBook ISBN: 978-3-527-62869-8

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Print ISBN: 978-3-527-32639-6ePDF ISBN: 978-3-527-63997-7oBook ISBN: 978-3-527-63995-3ePub ISBN: 978-3-527-63996-0mobi ISBN: 978-3-527-63998-4

Contents

About the Editors XVIIList of Contributors XIXPreface XXIII

1 The Design of Safer Chemicals: Past, Present, and Future Perspectives 1Stephen C. DeVito

1.1 Evolution of the Concept 11.1.1 In the Development of Drug Substances: Emergence of the Medicinal

Chemist 21.1.2 In the Development of Pesticide Substances 41.1.3 In the Development of Industrial Chemical Substances 51.1.3.1 Stagnation of the Concept Because of Section 5 of the TSCA 71.2 Characteristics of a ‘‘Safer Chemical’’ 91.2.1 Types of Safer Chemicals 111.2.2 The Ideal Chemical 141.3 The Future of the Concept 161.4 Disclaimer 18

References 18

2 Differential Toxicity Characterization of Green Alternative Chemicals 21Richard Judson

2.1 Introduction 212.2 Chemical Properties Related to Differential Toxicity 232.3 Modeling Chemical Clearance – Metabolism and Excretion 252.4 Predicting Differential Inherent Molecular Toxicity 282.4.1 Cell Types/Cell Lines 282.4.2 High-Throughput Screening (HTS) 292.4.3 High-Content Screening (HCS) 302.4.4 Whole-Genome Approaches 302.5 Integrating In Vitro Data to Model Toxicity Potential 312.6 Databases Relevant for Toxicity Characterization 332.7 Example of Differential Toxicity Analysis 342.8 Conclusion 39

V

2.9 Disclaimer 40References 40

3 Understanding Mechanisms of Metabolic Transformationsas a Tool for Designing Safer Chemicals 47Thomas G. Osimitz and John L. Nelson

3.1 Introduction 473.2 The Role of Metabolism in Producing Toxic Metabolites 473.2.1 Phase I Metabolism 483.2.2 Phase II Metabolism 483.3 Mechanisms by Which Chemicals Produce Toxicity 593.3.1 Covalent Binding to Macromolecules 593.3.2 Enzyme Inhibition 613.3.3 Ischemia/Hypoxia 633.3.4 Oxidative Stress 653.3.5 Receptor–Ligand Interactions 693.4 Conclusion 69

References 72

4 Structural and Toxic Mechanism-Based Approaches toDesigning Safer Chemicals 77Stephen C. DeVito

4.1 Toxicophores 774.1.1 Electrophilic Toxicophores 774.2 Designing Safer Electrophilic Substances 824.3 Structure–Activity Relationships 864.3.1 Aliphatic Carboxylic Acids 874.3.2 Organonitriles 904.4 Quantitative Structure–Activity Relationships (QSARs) 924.5 Isosteric Substitution as a Strategy for the Design of Safer Chemicals 954.5.1 Isosteric Substitution in the Design of Safer Drug Substances 974.5.2 Isosteric Substitution in the Design of Safer Pesticides 974.5.3 Isosteric Substitution in the Design of Safer Commercial Chemicals 984.6 Conclusion 1004.7 Disclaimer 102

References 102

5 Informing Substitution to Safer Alternatives 107Emma Lavoie, David DiFiore, Meghan Marshall, Chuantung Lin,Kelly Grant, Katherine Hart, Fred Arnold, Laura Morlacci, Kathleen Vokes,Carol Hetfield, Elizabeth Sommer, Melanie Vrabel, Mary Cushmac,Charles Auer, and Clive Davies

5.1 Design for Environment Approaches to Risk Reduction: Identifying andEncouraging the Use of Safer Chemistry 107

5.2 Assessment of Safer Chemical Alternatives: Enabling Scientific,Technological, and Commercial Development 108

VI Contents

5.3 Informed Substitution 1115.3.1 Functional Use as an Analytical Construct 1125.3.2 Defining Safer Chemistry – the DfE Criteria for Safer

Chemical Ingredients 1145.3.3 Continuous Improvement to Advance Green Chemistry 1145.3.4 Best Practices to Manage Risks in the Absence of Safer Substitutes 1155.3.5 Life-Cycle Thinking: A Holistic Approach 1165.4 Examples that Illustrate Informed Substitution 1165.4.1 Informing Real-Time Substitution Decisions: Chemical Alternative

Assessment for Pentabromodiphenyl Ether 1165.4.1.1 The Partnership 1175.4.1.2 The Alternatives Assessment 1185.4.2 Encouraging Informed Substitution: Safer Product Labeling Program 1205.4.2.1 Substituting to Safer Surfactants 1215.4.2.2 The Safer Detergents Stewardship Initiative 1255.4.2.3 CleanGredients1 1255.4.3 Developing and Applying Best Practices in the Absence of Safer

Substitutes: Isocyanates 1265.4.3.1 Best Practices as an Important Risk Management Approach 1265.4.3.2 New Developments in Manufacturing Polyurethanes Without Using

Isocyanates 1275.4.3.3 Safer Manufacture of Diisocyanates Without Using Phosgene 1275.4.4 Life-Cycle Assessment to Inform Alternatives to Leaded Solder for

Electronics 1295.5 Conclusion 1325.6 Disclaimer 133

References 133

6 Design of Safer Chemicals – Ionic Liquids 137Ian Beadham, Monika Gurbisz and Nicholas Gathergood

6.1 Introduction 1376.2 Environmental Considerations 1376.3 Ionic Liquids – a Historical Perspective 1386.3.1 First-Generation ILs 1396.4 From Ionic Liquid Stability to Biodegradability 1416.4.1 Overcoming the Inertness of 1-Substituted–3-

Methylimidazolium Cation 1476.5 Conclusion 152

References 155

7 Designing Safer Organocatalysts – What Lessons Can Be Learned Whenthe Rebirth of an Old Research Area Coincides with the Advent of GreenChemistry? 159Ian Beadham, Monika Gurbisz and Nicholas Gathergood

7.1 Introduction 159

Contents VII

7.2 A Brief History of Organocatalysis 1597.2.1 Pre-1950s: From Humble Beginnings 1597.2.2 1950s–1960s 1607.2.3 1970s: Organocatalysis Begins in Earnest 1607.2.4 1980s 1607.2.5 1990s 1617.2.6 2000–Present 1627.2.7 Advantages of Organocatalysts 1627.3 Catalysts from the Chiral Pool 1637.4 ‘‘Rules of Thumb’’ for Small Molecule Biodegradability Applied to

Organocatalysts 1677.4.1 Selecting Simple Guidelines for Biodegradability 1697.5 Cinchona Alkaloids – Natural Products as a Source of Organocatalysts:

Appendix 7.A 1747.6 Proline, the Most Extensively Studied Organocatalyst:

Appendix 7.B 1757.7 Process of Catalyst Development 1777.7.1 Analogy Between Organocatalyst Development and Drug Design 1787.8 Analogs of Nornicotine – an Aldol Catalyst Exemplifying ‘‘Natural’’

Toxicity 1797.9 Pharmaceutically Derived Organocatalysts and the Role of

Cocatalysts 1807.9.1 Criteria to Assess the Environmental Impact of an Organocatalyst 1847.10 Conclusion 1857.11 Summary 185

References 221

8 Life-Cycle Concepts for Sustainable Use of Engineered Nanomaterials inNanoproducts 227Bernd Nowack, Fadri Gottschalk, Nicole C. Mueller and Claudia Som

8.1 Introduction 2278.2 Life-Cycle Perspectives in Green Nanotechnologies 2288.3 Release of Nanomaterials from Products 2308.4 Exposure Modeling of Nanomaterials in the Environment 2378.5 Designing Safe Nanomaterials 2438.6 Conclusion 245

References 245

9 Drugs 251Klaus Kümmerer

9.1 Introduction 2519.2 Pharmaceuticals – What They Are 2519.3 Pharmaceuticals in the Environment – Sources, Fate, and Effects 2529.3.1 Sources 252

VIII Contents

9.3.2 Fate 2549.3.3 Effects 2559.4 Risk Management 2579.4.1 (Advanced) Effluent Treatment and Its Limitations 2589.4.2 Role of Patients, Pharmacists, and Doctors 2599.4.3 Role of the Drugs 2599.5 Designing Environmentally Safe Drugs 2599.5.1 What are Safe Drugs? 2599.5.2 Improvements Related to Use and After-Use Life 2609.5.2.1 Lower Activity Thresholds 2609.5.2.2 Prodrugs 2609.5.2.3 Drug Targeting, Drug Delivery, Degree of Metabolism 2619.5.2.4 Biopharmaceuticals 2619.5.3 Benign by Design 2629.5.3.1 Why? 2629.5.3.2 How? 2629.5.3.3 Degradable Drugs – a Contradiction per se? 2649.5.3.4 Structure Matters 2649.5.3.5 Stability Versus Reactivity – How Stable Is Reactive Enough 2679.5.3.6 Examples Demonstrating Feasibility 2689.6 Conclusion 271

References 272

10 Greener Chelating Agents 281Nicholas J. Dixon

10.1 Introduction 28110.2 Chelants 28210.3 Common Chelants 28410.3.1 Aminocarboxylates 28410.3.2 Phosphonates 28410.3.3 Carboxylates 28510.4 Issues with Current Chelants 28510.4.1 EDTA and DTPA 28510.4.2 NTA 28810.4.3 Phosphonates 28810.4.4 Ecolabels 28910.5 Green Design Part 1 – Search for Biodegradable Chelants 29010.5.1 10th Principle of Green Chemistry: Design Chemicals and Products

to Degrade After Use 29010.5.2 Aminocarboxylate NTA Variants 29110.5.3 Polysuccinates 29110.5.3.1 Ethylenediaminedisuccinic Acid [(S,S)-EDDS] 29110.5.3.2 Iminodisuccinic Acid (IDS) 29310.6 Comparing Chelating Agents 29310.6.1 Stability Constants 293

Contents IX

10.6.2 Selectivity 29410.6.3 pH 29510.6.4 Speciation Modeling 29510.6.5 Comparison of Strengths and Weaknesses 29610.6.6 Application Chemistry 29810.7 Six Steps to Greener Design 29910.7.1 2nd Principle of Green Chemistry: Design Safer Chemicals

and Products 29910.7.2 Step 1. What is the Role of the Incumbent Chemical in

the Application? 29910.7.3 Step 2. What Environmental and Regulatory Constraints Exist? 30010.7.4 Step 3. What are the Performance and Cost Requirements? 30010.7.5 Step 4. How Do the Properties of Alternatives Compare with

the Incumbent? 30110.7.6 Step 5. Can Combinations of ‘‘Greener’’ Chemicals Be Used? 30110.7.7 Step 6. Choose Likely Solutions and Test in the Application 30110.8 Case Study – Six Steps to Greener Chelants for Laundry 30210.8.1 Step 1. Role of Incumbent Chelant 30210.8.2 Step 2. Environmental and Regulatory Constraints 30310.8.3 Step 3. Performance and Cost Requirements 30310.8.4 Step 4. Comparison of Phosphonates with Biodegradable Chelants 30310.8.5 Step 5. Combinations of Chelants 30410.8.6 Step 6. Test in Application 30410.9 Conclusion 30510.10 Abbreviations 305

References 306

11 Improvements to the Environmental Performance of Synthetic-BasedDrilling Muds 309Sajida Bakhtyar and Marthe Monique Gagnon

11.1 Introduction 30911.2 Drilling Mud Composition 31011.2.1 Water or Saline Brine 31111.2.2 Weighting Agent 31111.2.3 Viscosifiers 31111.2.4 Emulsifiers and Wetting Agents 31111.2.5 Base Fluids/Oils 31211.3 Characteristics and Biodegradability of SBFs 31211.4 Case Study: Improvements in the Environmental Performance of

Synthetic-Based Drilling Muds 31411.4.1 Importance of Study 31411.4.2 Origins of Drilling Muds and Emulsifiers 31511.4.3 Aquatic Toxicity 31511.4.3.1 Study Organism and Conditions 31511.4.3.2 Biomarkers and Physiological Indices 316

X Contents

11.4.3.3 Results 31611.4.4 Biodegradation 32111.4.5 Conclusions of Study 32311.5 Conclusion 323

References 323

12 Biochemical Pesticides: Green Chemistry Designs by Nature 329Russell S. Jones

12.1 Introduction 32912.2 The Historical Path to Safer Pesticides 32912.3 Reduced-Risk Conventional Pesticides 33112.4 The Biopesticide Alternative: an Overview 33112.5 Biochemical Pesticides 33312.5.1 Natural Occurrence 33312.5.2 Nontoxic Mode of Action Against the Target Pest 33412.5.2.1 Plant Regulators 33612.5.2.2 Semiochemicals 33612.5.2.3 Biological Barriers 33812.5.2.4 Induced Plant Resistance 33812.5.3 History of Nontoxic Exposure to Humans and

the Environment 34012.6 Are Biochemical Pesticides the Wave of the Future? 34012.7 Conclusion 34312.8 Disclaimer 343

References 344

13 Property-Based Approaches to Design Rules for Reduced Toxicity 349Adelina Voutchkova, Jakub Kostal, and Paul Anastas

13.1 Possible Approaches to Systematic Design Guidelines for ReducedToxicity 349

13.2 Analogy with Medicinal Chemistry 35413.3 Do Chemicals with Similar Toxicity Profiles Have Similar Physical/

Chemical Properties? 35613.4 Proposed Design Guidelines for Reduced Human Toxicity 35813.4.1 Considerations for Reducing Human Absorption 35813.4.1.1 Example: Reducing Carcinogenicity by Decreasing Oral

Bioavailability 35813.5 Using Property Guidelines to Design for Reducing Acute Aquatic

Toxicity 36213.6 Predicting the Physicochemical Properties and Attributes Needed for

Developing Design Rules 36513.6.1 Solvent-Related Properties 36513.6.1.1 Hydrophobicity 36513.6.1.2 Solubility 36713.6.1.3 pKa 367

Contents XI

13.6.2 Electronic Properties 36813.6.2.1 Orbital Energies 36813.6.2.2 Molecular Dipole Moment and Polarizability 36913.6.2.3 Molecular Surface Area 37013.7 Conclusion 371

References 371

14 Reducing Carcinogenicity and Mutagenicity Through Mechanism-BasedMolecular Design of Chemicals 375David Y. Lai and Yin-tak Woo

14.1 Introduction 37514.2 Mechanisms of Chemical Carcinogenesis and Structure–Activity

Relationship (SAR) 37614.3 General Molecular Parameters Affecting the Carcinogenic and

Mutagenic Potential of Chemicals 37814.3.1 Physicochemical Properties 37914.3.1.1 Molecular Weight 37914.3.1.2 Molecular Size and Shape 37914.3.1.3 Solubility 37914.3.1.4 Volatility 38014.3.2 Nature and Position of Substituents 38114.3.3 Molecular Flexibility, Polyfunctionality, and Spacing/Distance Between

Reactive Groups 38114.3.4 Resonance Stabilization of the Electrophilic Metabolites 38114.4 Specific Structural Criteria of Different Classes of Chemical Carcinogens

and Mutagens 38214.4.1 Aromatic Amines and Azo Dyes/Pigments 38314.4.2 Polycyclic Aromatic Hydrocarbons (PAHs) 38514.4.3 N-Nitrosamines 38614.4.4 Hydrazo, Aliphatic Azo and Azoxy Compounds,

and Arydialkyltriazenes 38814.4.5 Organophosphorus Compounds 38814.4.6 Carbamates 38914.4.7 Epoxides and Aziridines 39014.4.8 Lactones and Sultones 39114.4.9 Alkyl Esters of Moderately Strong and Strong Acids 39114.4.10 Haloalkanes and Substituted Haloalkanes 39214.4.11 N-Mustards and S-Mustards 39314.4.12 N-Nitrosamides 39414.4.13 Aldehydes and Substituted Aldehydes 39514.4.14 Michael Addition Acceptors 39514.4.15 Arylating Agents 39614.4.16 Acylating Agents and Isocyanates 39614.4.17 Organic Peroxides 39714.4.18 Quinones and Quinoid Compounds 397

XII Contents

14.5 Molecular Design of Chemicals of Low Carcinogenic and MutagenicPotential 398

14.5.1 General Approaches 39814.5.2 Specific Approaches 39914.5.2.1 Aromatic Amines and Azo Dyes/Pigments 39914.5.2.2 Polycyclic Aromatic Hydrocarbons (PAHs) 40014.5.2.3 N-Nitrosamines 40014.5.2.4 Hydrazo, Aliphatic Azo and Azoxy Compounds, and

Arydialkyltriazenes 40014.5.2.5 Organophosphorus Compounds 40014.5.2.6 Carbamates 40114.5.2.7 Epoxides and Aziridines (Ethylenimines) 40114.5.2.8 Lactones and Sultones 40114.5.2.9 Alkyl Esters of Moderately Strong and Strong Acids 40114.5.2.10 Haloalkanes and Substituted Haloalkanes 40214.5.2.11 N-Mustards and S-Mustards 40214.5.2.12 N-Nitrosamides 40214.5.2.13 Aldehydes and Substituted Aldehydes 40214.5.2.14 Michael Addition Acceptors 40214.5.2.15 Arylating Agents 40214.5.2.16 Acylating Agents and Isocyanates 40214.5.2.17 Organic Peroxides 40314.5.2.18 Quinones and Quinoid Compounds 40314.6 Conclusion 40314.7 Disclaimer 404

References 404

15 Reducing Ecotoxicity 407Keith R Solomon and Mark Hanson

15.1 Introduction to Key Aspects of Ecotoxicology 40715.1.1 Protection Goals and Assessment Endpoints 40815.1.2 Structure and Function in Ecosystems 41015.1.3 Diversity of Sensitivity in Ecosystems 41115.1.4 Hazard Assessment and Uncertainty 41215.2 Environmental Fate and Pathways of Exposure to Chemicals in the

Environment 41315.2.1 Properties Affecting Bioavailability 41315.2.2 Properties Affecting Bioconcentration and Biomagnification 41515.2.3 Absorption, Distribution, Metabolism, and Excretion of Chemicals 41615.2.4 Modeling Exposure 41815.3 Mechanisms of Toxic Action 41915.3.1 Properties Affecting Toxicity 42015.3.2 Modeling Toxicity 42215.4 Examples of Methods That Can Be Used in Designing Chemicals with

Reduced Ecological Risks 424

Contents XIII

15.4.1 Fluorinated Surfactants 42515.4.2 Pesticides 42615.4.2.1 Designing Pesticides for Lack of Persistence 42715.4.2.2 Designing Specific Isomers to Reduce Risk in the Environment 42915.4.2.3 Developing Pesticides That Are More Specific to the

Target Organism 43115.4.2.4 Ranking and Prioritizing Pesticides in Terms of Risk to

the Environment 43215.4.3 Pharmaceuticals 43315.4.4 Macro- and Micro-Contaminants Produced During Manufacture 43515.5 Overview, Conclusions, and the Path Forward 437

References 440

16 Designing for Non-Persistence 453Philip H. Howard and Robert S. Boethling

16.1 Introduction 45316.2 Finding Experimental Data 45416.2.1 Chemical Identity 45416.2.1.1 Discrete Substances 45416.2.1.2 Ionic Substances 45516.2.2 Database Resources for Chemical Design 45616.2.2.1 CleanGredients1 45916.2.2.2 UMBBD 45916.2.2.3 Other Databases 46016.2.3 AFAR: the Aggregated Fate Assessment Resource 46016.3 Predicting Biodegradation from Chemical Structure 46116.3.1 Rules of Thumb That Relate Chemical Structure

and Biodegradability 46116.3.2 Identifying Analogs and Using Them to Estimate

Biodegradability 46416.3.3 The BIOWIN and BioHCwin Models 46516.3.4 Pathways and Their Prediction: UMBBD/PPS and CATABOL 46616.3.4.1 CATABOL 46616.3.4.2 UM-BBD Pathway Prediction System 46616.4 Predicting Chemical Hydrolysis 46716.5 Predicting Atmospheric Degradation by Oxidation

and Photolysis 46916.6 Designing for Biodegradation I: Musk Fragrances Case Study 47016.7 Designing for Biodegradation II: Biocides Case Study 47216.8 Designing for Abiotic Degradation: Case Studies for Hydrolysis and

Atmospheric Degradation 47716.9 Conclusion 47916.10 Disclaimer 479

Abbreviations 480References 480

XIV Contents

17 Reducing Physical Hazards: Encouraging InherentlySafer Production 485Nicholas A. Ashford

17.1 Introduction 48517.2 Factors Affecting the Safety of a Production System [1] 48517.2.1 The Scale of Production 48517.2.2 The Quantity of Hazardous Chemicals Involved 48617.2.3 The Hazardousness of the Chemicals Involved 48617.2.4 Batch Versus Continuous Processing 48617.2.5 The Presence of High Pressures or Temperatures 48717.2.6 Storage of Intermediates versus Closed-Loop Processing 48717.2.7 Multi-Stream Versus Single-Stream Plants 48717.3 Chemical Safety and Accident Prevention: Inherent Safety and

Inherently Safer Production 48817.4 Incentives, Barriers, and Opportunities for the Adoption of Inherently

Safer Technology 49117.5 Elements of an Inherently Safer Production Approach [2, 3] 49317.5.1 Timing and Anticipation of Decisions to Adopt (or Develop) Inherent

Safety 49317.5.2 Life-Cycle Aspects 49517.6 A Methodology for Inherently Safer Production 495

References 499

18 Interaction of Chemicals with the Endocrine System 501Thomas G. Osimitz

18.1 Interaction with the Endocrine System 50118.1.1 Introduction 50118.1.2 Importance of SAR and QSAR in Understanding the Chemical Nature

of Endocrine Active Chemicals 50318.2 Estrogens 50418.2.1 General 50418.2.2 Features of the Natural Ligand E2 That Contribute to ER Binding 50518.2.3 Features of Xenobiotics That Contribute to ER Binding 50618.2.4 Criteria for Binding With the Estradiol Template 50618.2.5 Prediction of Potential ER Binding 50718.2.5.1 Initial Filters 50718.2.5.2 Structural Alerts 50718.2.5.3 Decision Tree-Based Model 50718.2.6 Predictive Approach for Priority Setting 51018.2.6.1 Phase I: Rejection Filters 51018.2.7 Alkylphenols 51118.2.8 Polybrominated Diphenyl Ethers (PBDEs) 51218.2.9 Phytoestrogens and Mycoestrogens 51318.2.10 Hydroxylated Triphenylacrylonitrile Derivatives 51418.3 Androgens 515

Contents XV

18.3.1 General 51518.3.2 General Structure–Activity Relationships 51518.4 Hypothalamic-Pituitary-Thyroid (HPT) Axis 51618.4.1 General 51618.4.2 General Structure–Activity Relationships 51818.4.3 Brominated Flame Retardants 51918.4.4 Monohydroxylated Polychlorinated Biphenyls (PCBs) 51918.5 Endocrine Disruptor Data Development Efforts 51918.6 Research Needs and Future 521

References 522

Index 525

XVI Contents

About the Editors

Series Editor

Paul T. Anastas joined Yale University as Professor and servesas the Director of the Center for Green Chemistry and GreenEngineering there. From 2004–2006, Paul was the Director ofthe Green Chemistry Institute in Washington, D.C. UntilJune 2004 he served as Assistant Director for Environmentat the White House Office of Science and Technology Policywhere his responsibilities included a wide range of environ-mental science issues including furthering internationalpublic-private cooperation in areas of Science for Sustainabil-

ity such as Green Chemistry. In 1991, he established the industry-government-university partnership Green Chemistry Program, which was expanded to includebasic research, and the Presidential Green Chemistry Challenge Awards. He haspublished and edited several books in thefield ofGreenChemistry and developed the12 Principles of Green Chemistry.

Volume Editors

Robert S. Boethling has been at the US EnvironmentalProtection Agency headquarters in Washington, DC, Officeof Pollution Prevention and Toxics (OPPT) since 1980. Afterearning his PhD degree in microbiology at UCLA (1976) hespent 2 years in Martin Alexander�s soil microbiology lab atCornell University, and came to EPA as it began its imple-mentation of the Toxic Substances Control Act (TSCA). Formany years he led environmental fate review for new chemical(Premanufacture Notice) substances under TSCA, the pro-gram from which predictive capabilities, tools and software in

environmental chemistry emerged starting in the 1980s. He was a principal con-tributor in the development of several widely used computer programs, notably EPI

jXVII

Suite, the PBT Profiler, and the BIOWIN biodegradability estimation program. He isthe recipient of many EPAmedals for distinguished service and several EPA Scienceand Technology Achievement Awards (STAA), including awards for review of newchemical substances underTSCAand theHandbook of Property EstimationMethods forChemicals: Environmental Health Sciences (Lewis/CRC, 2000, with Don Mackay).

Adelina Voutchkova is an Assistant Professor at the Depart-ment of Chemistry at the George Washington University. Shereceived her Ph.D. from Yale University and subsequentlyjoined theCenter forGreenChemistry andGreenEngineeringat Yale as a research associate. Dr. Voutchkova�s currentresearch interests span both facets of green chemistry - thedesign of tools that chemists can apply to the rational designsafer industrial chemicals, and the development of greenermetal-catalyzed organic transformations.

XVIIIj About the Editors

List of Contributors

XIX

Paul AnastasYale UniversityDepartment of Chemistry225 Prospect StreetNew Haven, CT 06520USA

Fred ArnoldU.S. Environmental Protection AgencyOffice of Pollution Prevention and Toxics1200 Pennsylvania Avenue NWWashington, DC 20460USA

Nicholas A. AshfordMassachusetts Institute of TechnologyTechnology and Law Program77 Mass Avenue, Room E40-239Cambridge, MA 02139USA

Charles AuerCharles Auer & Associates, LLC17116 Campbell Farm RoadPoolesville, MD 20837USA

Sajida BakhtyarCurtin UniversityDepartment of Environment andAgricultureKent StreetPerth, WA 6845Australia

Ian BeadhamDublin City UniversitySchool of Chemical SciencesCollins AvenueDublin 9Ireland

Robert S. BoethlingU.S. Environmental Protection AgencyOffice of Pollution Prevention andToxics1200 Pennsylvania Avenue NWWashington, DC 20460USA

Mary Cushmac (Retired)U.S. Environmental Protection AgencyDesign for the Environment Program1200 Pennsylvania Avenue NWWashington, DC 20460USA

Clive DaviesU.S. Environmental Protection AgencyDesign for the Environment Program1200 Pennsylvania Avenue NWWashington, DC 20460USA

Stephen C. DeVitoU.S. Environmental Protection AgencyOffice of Environmental InformationToxics Release Inventory Program1200 Pennsylvania Avenue NWWashington, DC 20004USA

David DiFioreU.S. Environmental Protection AgencyDesign for the Environment Program1200 Pennsylvania Avenue NWWashington, DC 20460USA

Nicholas J. DixonInnospec Ltd.Oil Sites RoadEllesmere Port, Cheshire CH65 4EYUK

Marthe Monique GagnonCurtin UniversityDepartment of Environment andAgricultureKent StreetPerth, WA 6845Australia

Nicholas GathergoodDublin City UniversitySchool of Chemical SciencesCollins AvenueDublin 9Ireland

Fadri GottschalkEMPA – Swiss Federal Laboratories forMaterials Science and TechnologyTechnology and Society LaboratoryLerchenfeldstrasse 59014 St. GallenSwitzerland

Kelly Grant (Former AAAS Science andTechnology Policy Fellow)U.S. Environmental Protection AgencyDesign for the Environment Program1200 Pennsylvania Avenue NWWashington, DC 20460USA

Monika GurbiszDublin City UniversitySchool of Chemical SciencesCollins AvenueDublin 9Ireland

Mark HansonUniversity of ManitobaDepartment of Environment andGeographyWinnipeg, MB R3T 2N2Canada

Katherine HartU.S. Environmental Protection AgencyDesign for the Environment Program1200 Pennsylvania Avenue NWWashington, DC 20460USA

Carol HetfieldU.S. Environmental Protection AgencyOffice of Pollution Prevention and Toxics1200 Pennsylvania Avenue NWWashington, DC 20460USA

Philip H. HowardSRC, Inc.7502 Round Pond RoadNorth Syracuse, NY 13212USA

XX List of Contributors

Russell S. JonesU.S. Environmental Protection AgencyBiopesticides and Pollution PreventionDivisionOffice of Pesticide Programs1200 Pennsylvania Avenue NWWashington, DC 20460USA

Richard JudsonU.S. Environmental Protection AgencyNational Center for ComputationalToxicology109 T.W. Alexander DriveResearch Triangle Park, NC 27711USA

Jakub KostalYale UniversityDepartment of Chemistry225 Prospect StreetNew Haven, CT 06520USA

Klaus KümmererLeuphana University LüneburgInstitute of Sustainable andEnvironmental ChemistryScharnhorststraße 121335 LüneburgGermany

David Y. LaiU.S. Environmental Protection AgencyOffice of Pollution Prevention andToxicsRisk Assessment Division1200 Pennsylvania Avenue NWWashington, DC 20460USA

Emma LavoieU.S. Environmental Protection AgencyDesign for the Environment Program1200 Pennsylvania Avenue NWWashington, DC 20460USA

Chuantung LinU.S. Environmental Protection AgencyOffice of Pollution Prevention and Toxics1200 Pennsylvania Avenue NWWashington, DC 20460USA

Meghan Marshall (Former StudentCareer Experience Program Intern)U.S. Environmental Protection AgencyDesign for the Environment Program1200 Pennsylvania Avenue NWWashington, DC 20460USA

Michael McDavitU.S. Environmental Protection AgencyBiopesticides and Pollution PreventionDivisionOffice of Pesticide Programs1200 Pennsylvania Avenue NWWashington, DC 20460USA

Laura MorlacciSRC, Inc.2451 Crystal Drive, Suite 475Arlington, VA 22202USA

Nicole C. MuellerEMPA – Swiss Federal Laboratories forMaterials Science and TechnologyTechnology and Society LaboratoryLerchenfeldstrasse 59014 St. GallenSwitzerland

List of Contributors XXI

John L. NelsonEastern Michigan UniversityChemistry DepartmentYpsilanti, MI 48197USA

Bernd NowackEMPA – Swiss Federal Laboratories forMaterials Science and TechnologyTechnology and Society LaboratoryLerchenfeldstrasse 59014 St. GallenSwitzerland

Thomas G. OsimitzScience Strategies, LLCCitizens Commonwealth Center300 Preston AveCharlottesville, VA 22902USA

Keith R SolomonUniversity of GuelphCentre for Toxicology and School ofEnvironmental Sciences2120 Bovey BuildingGordon StreetGuelph, ON N1G 2W1Canada

Claudia SomEMPA – Swiss Federal Laboratories forMaterials Science and TechnologyTechnology and Society LaboratoryLerchenfeldstrasse 59014 St. GallenSwitzerland

Elizabeth SommerU.S. Environmental Protection AgencyDesign for the Environment Program1200 Pennsylvania Avenue NWWashington, DC 20460USA

Kathleen VokesU.S. Environmental Protection AgencyOffice of Air and RadiationOffice of Atmospheric ProgramsClimate Protection Partnership DivisionENERGY STAR Labeling Branch1200 Pennsylvania Avenue NWWashington, DC 20460USA

Adelina VoutchkovaYale UniversityDepartment of Chemistry225 Prospect StreetNew Haven, CT 06520USA

Melanie VrabelU.S. Environmental Protection AgencyDesign for the Environment Program1200 Pennsylvania Avenue NWWashington, DC 20460USA

Yin-tak WooU.S. Environmental Protection AgencyOffice of Pollution Prevention andToxicsRisk Assessment Division1200 Pennsylvania Avenue NWWashington, DC 20460USA

XXII List of Contributors

Preface

Design is a statement of human intention. You can�t design by accident. It has to be aconscious decision. Tomake the design decisions you need considerations; you needcriteria. If you want to design molecules for reduced hazard, those criteria need tobe based on an understanding of themolecular basis of hazard. Fortunately, there aredata from the world of molecular toxicology that provide us with insights forthe foundations for our problems and concerns around chemicals. At some level,the only reason to deeply understand a problem is to use that understanding toinform and empower the solution to the problem. That is what this volume ofDesigning Safer Chemicals is about; solving (and avoiding) problems.

Synthetic chemistry is a highly advanced field, and chemists have developed theexpertise in designing chemicals for specific industrial or pharmaceutical functions.Unfortunately, even today relatively little systematic consideration is given torationally minimizing undesired toxic and environmental effects at the design stage.

Principle 4 of the Twelve Principles of Green Chemistry, �Designing saferchemicals,� stresses preserving useful function while reducing toxicity, and is anemerging field. This volume highlights illustrative examples of how chemicals havebeen designed, or redesigned, to minimize toxicity, and provides some basic guide-lines forminimizing some types of unintended biological activity. It also underscoresthe important need for research and development focusing on design strategies thatare based on mechanisms of biological action and relevant physical and chemicalproperties.

If we consider the design of commercial chemicals that are not only benign tohumans but also to the environment, we see that toxicity is not the only consid-eration. In fact, we can broadly segregate hazards into three types, as shown inFigure 1: toxicological (human and environmental), physical (such as explosivity,material corrosion and flammability) and global (large scale effects on our planet:influencing climate change, causing an increased loading of persistent andbioaccumulative chemicals). The majority of this text focuses on toxicologicalhazards, but several chapters, such as Chapter 16 (Howard/Boethling) and Chap-ter 17 (Ashford) introduce the topic of global and physical hazards.

The idea of deriving molecular design strategies for reduced intrinsic hazard mayseem idealistic to chemists, who are trained to think of all chemicals as potentially

jXXIII

hazardous.However, the achievements of thefield ofmedicinal chemistry has shownus that it is possible to design chemicals with highly specific and desirable biologicalactivity, and those lessons can be extended to inform the design of other commercialchemicals for reducing undesirable biological activity. Although this is unquestion-ably challenging due to the plethora of possible biological mechanisms of action, thistext aims to show that there are strategies that can be applied.

The focus of this text, therefore, is minimization —at the molecular level— ofpotential health and environmental chemical hazard. This is distinct from riskassessment, which seeks to characterize the probability of harm. Implicit in riskassessment is knowledge of the potential toxicity and associated dose-responserelationships, as well as a reasonable estimate of the exposure that an organismwill receive under certain circumstances (the external dose).While risk assessment isa useful tool in evaluating comparative risks of existing chemicals and the identi-fication of risk management strategies when needed, we submit that the focus fornew chemicals should be on the reduction of intrinsic hazard, as exposure cannotalways be predicted or controlled. �Benign by design� is the ultimate precautionaryapproach and this volume seeks to empower that approach.

The current understanding of how to design safer chemicals is an emergingfield ofresearch and application. Prior to this volume, there have been foundational treat-ments of the topic that laid the conceptual framework for how this idea can bedeveloped and implemented. It is the hope of the editors and chapter authors that thistext is built upon by others with further explorations that demonstrate how com-mercial chemicals can be rationally designed to minimize biological and environ-mental activity.

Figure 1. Classification of intrinsic chemical hazard into physical, toxicological and global.

XXIVj Preface

1The Design of Safer Chemicals: Past, Present, andFuture PerspectivesStephen C. DeVito

1.1Evolution of the Concept

Recognition of the need for chemists to design chemicals that are not only useful butof minimal hazard can be traced back to at least 1928, when Alice Hamilton, awell-known physician and pioneer in industrial medicine, made the followingstatements in her chapter �Protection against industrial poisoning� in the bookChemistry in Medicine [1]:

Chemistry and medicine have thus made possible real progress in theprotection of working men and women against industrial poisons. . . . Muchremains to be done in this field, even in the light of our present knowledge,and greater progress will be made possible in the future through advances inchemistry. For instance, substitutes which are relatively non-toxic may befound to take the place of toxic compounds now in use. . . . Toxicology mustjoin with chemistry in testing the new compounds which chemistry intro-duces into industry. . . . Synthetic chemistry must have as one of its greatobjectives the further safeguarding of health and of life in the industries intowhich chemistry itself has introduced new poisons.

In the era when these statements were made they were quite bold, if not radical,and likely to have been received with much indifference and perhaps opposition,especially since the statements were made by a woman. In 1928, only 8 years hadelapsed since the Nineteenth Amendment to the US Constitution had, after intensedebate, become law and allowedwomen to vote. TheUS economywas doingwell andjobs were plentiful. Although it undoubtedly existed, pollution was not viewed as aproblem by the general population or the federal government. As such, very fewfederal laws or regulatory authorities existed that regulated the development andmarketing of commercial industrial chemicals, pesticides, or pharmaceutical sub-stances to protect human health and the environment from risks posed by suchsubstances.

Handbook of Green Chemistry Volume 9: Designing Safer Chemicals, First Edition. Edited by Robert Boethlingand Adelina Voutchkova.� 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA.

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Over time, it became apparent that many chemicals have the potential to poseserious risks to human health and the environment. To address these concerns,federal regulatory agencies such as the Food andDrugAdministration (FDA) and theEnvironmental Protection Agency (EPA) were established in the USA. Theseorganizations were empowered by many laws to control the risks posed by newand existing drug substances (FDA), pesticides (EPA), and industrial chemicals(EPA). Similar organizations were established and laws enacted in many othercountries. Hamilton�s views on the importance of chemical safety and the need forsynthetic chemists to develop chemicals that are �relatively nontoxic� were bothbrilliant and far ahead of her time.

As discussed below, not only have the above organizations helped to protecthuman health and the environment from the risks posed by chemicals, but also theirregulatory requirements and mandates have effectively forced changes in the way inwhich chemists are trained and their approach to chemical design. This is especiallyso in drug and pesticide development, but to much lesser extent in the design ofindustrial chemicals.

1.1.1In the Development of Drug Substances: Emergence of the Medicinal Chemist

The Federal FoodDrug andCosmetic Act (FFDCA) became effective in 1938, and hassince been amended several times to address emerging societal concerns regardingthe safety of drug substances. Among other provisions, this law, as amended,authorizes the FDA to require that pharmaceutical firms provide evidence of safetyand efficacy of new drug substances before such substances can be marketed.Through the FFDCA, the FDA requires pharmaceutical firms to conduct extensivetesting to identify and characterize a candidate drug substance�s clinical pharma-cological efficacy, bioavailability, bodily distribution, metabolites, excretion, and anyadverse or toxic effects the substance may cause in experimental animals and inhumans during pre-market clinical trials. Pharmaceuticalfirmshave to develop thesedata, ostensibly as proof that their new drug is safe and effective.

This information is submitted to the FDA as part of an application for new drugapproval, and undergoes extensive review. If the FDA determines that the drugsubstance is clinically efficacious and has minimal adverse effects, it will approve itsmarketing and use. Even with the streamlined processes currently used, thedevelopment and marketing of a new drug product are time consuming andresource intensive. Typically, for every new drug that reaches the market, morethan 8000 potential drug candidates were synthesized, tested to varying extents alongthe way, and judged to be unsuitable. The identification of a candidate drugsubstance, its testing, and FDA approval usually take many years and, nowadays,cost upwards of hundreds of millions of dollars. Because of the costs and rigorousapproval process outlined above, relatively fewnewdrug substances are approved andregistered by the FDA on an annual basis.

Promulgation of the FFDCA in 1938, specifically the pre-market testing that itmandates, led to the publication of many studies that reported the metabolism,

2j 1 The Design of Safer Chemicals: Past, Present, and Future Perspectives

pharmacological, and toxicological properties of many classes of chemicals under-going evaluation as potential pharmaceuticals. This wealth of information allowedthe characterization of relations between structure, pharmacological activity, potency,and toxicity of many classes of organic chemicals. Identification of these relation-ships would provide organic chemists with a rational basis from which molecularmodifications expected to maximize the desired pharmacological effect while min-imizing toxicity could be inferred and, thereby, used to design new molecules inwhich therapeutic effectiveness was maximized and toxicity minimized.

The problem was that organic chemists received none of the academic training inthe biological sciences that was needed to enable them to analyze and interpret suchinformation, and integrate it with their training in organic synthesis to design newand improved drug substances. There was a need for a new type of organic chemist, a�medicinal chemist�: a chemist hybrid who received extensive training not only insynthetic organic chemistry but also in biochemistry, pharmacology, and toxicology,and the relationships between chemical structure with physical properties, pharma-cological action, and toxicological effects. Such a chemist would be well prepared todesign new, clinically efficacious drug substances of low toxicity.

The noted biochemist R. Tecwyn Williams and the noted organic chemist AlfredBurger recognized this need. In 1947, Williams published the first edition of hisclassic text on mechanisms of drug metabolism, Detoxication Mechanisms: theMetabolism of Drugs and Allied Organic Compounds [2], which is an extensivecompilation of the metabolic pathways that many of the drugs and industrialchemicals in use at the time undergo in experimental animals and humans. Burger,in 1951 and 1952, published a two-volume book set entitled Medicinal Chemistry:Chemistry, Biochemistry, Therapeutic and Pharmacological Action of Natural andSynthetic Drugs [3, 4], to provide graduate students majoring in organic chemistrywho plan to pursue careers in drug development, and organic chemists working forpharmaceutical firms, a framework fromwhich safe and efficacious drug substancescould be designed [5].

Burger�s book helped to establish the field of medicinal chemistry. Soon afterpublication of the two volumes in 1951 and 1952, many drug companies formeddepartments of medicinal chemistry, and many colleges, particularly colleges ofpharmacy, did the same. This eventually led to the availability of professionals whowere specifically and formally trained to design and develop therapeutically usefulbut safe drug substances. Within 10 years, the Journal of Medicinal Chemistry wasfounded, also by Burger [5], and the American Chemical Society established itssection on Medicinal Chemistry. The important lesson to be learned here is that thefield of medicinal chemistry evolved, largely by necessity, from the FFDCA.

The environmental fate and environmental impact of a planned drug substanceare also considered as part of the design strategy of the substance. In 1969, theNational Environmental Policy Actwas passed. This Act requires the FDA to considerthe environmental impacts of drug substances as an integral part of its process forreviewing and approving new drug applications. Pharmaceutical firms are required,under certain circumstances, to provide the FDAwith an assessment that focuses oncharacterizing the fate of the drug substance in the environment, and the effects that

1.1 Evolution of the Concept j3

the drug substance or its environmental metabolites may have on the environmentfollowing discharges of the drug from patients, or industrial manufacture orprocessing [6].

More recently, it has become apparent that genetics play a major role in deter-mining how an individual will metabolize a drug substance (or any chemicalsubstance) and respond to the drug. The implications of genetic causes of individualvariations in drug response (pharmacogenomics) are beginning to affect drug devel-opment issues such as drug safety, productivity, and personalizedhealthcare [7], and anincreasing number of drug labels approved by the FDA contain pharmacogenomicinformation [8, 9]. Integration and use of genetic biomarkers in drug development,regulation, and clinical practice will undoubtedly continue to increase [9, 10].

1.1.2In the Development of Pesticide Substances

In June 1947, the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) wasenacted, to provide the US federal government with authority to regulate thedistribution, sale, and use of pesticide substances. Similarly to the FFDCA and therigorous pre-market approval process established by the FDA for registering drugsubstances in theUSA, under FIFRA, all pesticides intended to be distributed or soldin the USAmust first be registered by the EPA. Before the EPA registers a pesticide,the applicant must show, among other things, that the use of the pesticide accordingto specifications will not generally lead to unreasonable risk to humans or theenvironment, taking into account the economic, social, and environmental costs andbenefits of the pesticide�s use.

As with the FFDCA, the FIFRA requires pesticide firms to conduct batteries ofextensive testing to identify and characterize a candidate pesticide�s bioavailability,distribution, metabolites, routes of excretion in experimental animals, and anyadverse or toxic effects that the substance may cause, so that the safety of thepesticide can be assessed. In addition, in cases of pesticides intended to have fooduses, extensive field trialsmust be conducted to characterize residues of the pesticideor metabolites thereof remaining on or in raw agricultural commodities.

Pesticide registrants must also submit environmental fate and effects data to theEPA as part of an application for pesticide registration. The EPA uses suchenvironmental data to characterize the persistence and partitioning of a pesticidein the environment and the pesticide�s environmental metabolites and degradates.This information is used by the EPA to assess the potential for human exposure viadrinking water contamination and environmental exposure of organisms such asfish, wildlife, and plants to the pesticide or its metabolites.

The above information undergoes extensive review by the EPA, and is submitted tothe EPAas part of an application for approval and registration of a newpesticide substance,or re-registration of an existing pesticide. Development of a candidate pesticide substance,its testing, and EPA approval usually take many years and are expensive.

The stringent pre-market health-related and environmental testing requirementsof the FIFRA effectively caused changes in the way in which organic chemists are

4j 1 The Design of Safer Chemicals: Past, Present, and Future Perspectives