Handbook of green chemistry / Vol. 9 = Set 3,[3 ...
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Handbook of Green Chemistry Volume 9 Designing Safer Chemicals Edited by Robert Boethl'mg and Adelina Voutchkova WILEY- VCH WILEY-VCH Verlag GmbH & Co. KGaA
Transcript of Handbook of green chemistry / Vol. 9 = Set 3,[3 ...
Handbook of Green Chemistry
Volume 9
Designing Safer Chemicals
Edited byRobert Boethl'mg and Adelina Voutchkova
WILEY-VCH
WILEY-VCH Verlag GmbH & Co. KGaA
V
Contents
About the Editors XVII
List of Contributors XIX
Preface XXIII
1 The Design ofSafer Chemicals: Past, Present, and Future Perspectives 1
Stephen C. DeVito
1.1 Evolution of the Concept 1
1.1.1 In the Development of Drug Substances: Emergence of the Medicinal
Chemist 2
1.1.2 In the Development of Pesticide Substances 4
1.1.3 In the Development of Industrial Chemical Substances 5
1.1.3.1 Stagnation ofthe Concept Because of Section S ofthe TSCA 7
1.2 Characteristics of a "Safer Chemical" 9
1.2.1 Types of Safer Chemicals 11
1.2.2 The Ideal Chemical 14
1.3 The Future of the Concept 16
1.4 Disclaimer 18
References 28
2 Differential Toxicity Characterization of Green Alternative Chemicals 21
RichardJudson2.1 Introduction 21
2.2 Chemical Properties Related to Differential Toxicity 23
2.3 Modeling Chemical Clearance - Metabolism and Excretion 25
2.4 Predicting Differential Inherent Molecular Toxicity 28
2.4.1 Cell Types/Cell Lines 28
2.4.2 High-Throughput Screening (HTS) 29
2.4.3 High-Content Screening (HCS) 30
2.4.4 Whole-Genome Approaches 30
2.5 Integrating In Vitro Data to Model Toxicity Potential 31
2.6 Databases Relevant for Toxicity Characterization 33
2.7 Example of Differential Toxicity Analysis 34
2.8 Conclusion 39
VI Contents
2.9 Disclaimer 40
References 40
3 Understanding Mechanisms of Metabolic Transformations
as a Tool for Designing Safer Chemicals 47
Thomas C, Osimitz andJohn L. Nelson
3.1 Introduction 47
3.2 The Role of Metabolism in Producing Toxic Metabolites 47
3.2.1 Phase I Metabolism 48
3.2.2 Phase II Metabolism 48
3.3 Mechanisms by Which Chemicals Produce Toxicity 59
3.3.1 Covalent Binding to Macromolecules 59
3.3.2 Enzyme Inhibition 61
3.3.3 Ischemia/Hypoxia 63
3.3.4 Oxidative Stress 65
3.3.5 Receptor-Ligand Interactions 69
3.4 Conclusion 69
References 72
4 Structural and Toxic Mechanism-Based Approaches to
Designing Safer Chemicals 77
Stephen C. DeVito
4.1 Toxicophores 77
4.1.1 Electrophilic Toxicophores 77
4.2 Designing Safer Electrophilic Substances 82
4.3 Structure-Activity Relationships 86
4.3.1 Aliphatic Carboxylic Acids 87
4.3.2 Organonitriles 90
4.4 Quantitative Structure-Activity Relationships (QSARs) 92
4.5 Isosteric Substitution as a Strategy for the Design ofSafer Chemicals 95
4.5.1 Isosteric Substitution in the Design of Safer Drug Substances 97
4.5.2 Isosteric Substitution in the Design of Safer Pesticides 97
4.5.3 Isosteric Substitution in the Design ofSafer Commercial Chemicals 98
4.6 Conclusion 100
4.7 Disclaimer 102
References 102
5 Informing Substitution to Safer Alternatives 107
Emma 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 and
Encouraging the Use of Safer Chemistry 107
5.2 Assessment of Safer Chemical Alternatives: Enabling Scientific,
Technological, and Commercial Development 108
Contents VII
5.3 Informed Substitution 111
5.3.1 Functional Use as an Analytical Construct 112
5.3.2 Defining Safer Chemistry - the DfE Criteria for Safer
Chemical Ingredients 114
5.3.3 Continuous Improvement to Advance Green Chemistry 114
5.3.4 Best Practices to Manage Risks in the Absence of Safer Substitutes 215
5.3.5 Life-Cycle Thinking: A Holistic Approach 116
5.4 Examples that Illustrate Informed Substitution 116
5.4.1 Informing Real-Time Substitution Decisions: Chemical Alternative
Assessment for Pentabromodiphenyl Ether 116
5.4.1.1 The Partnership 117
5.4.1.2 The Alternatives Assessment 118
5.4.2 Encouraging Informed Substitution: Safer Product Labeling Program 220
5.4.2.1 Substituting to Safer Surfactants 122
5.4.2.2 The Safer Detergents Stewardship Initiative 225
5.4.2.3 CleanGredients® 125
5.4.3 Developing and Applying Best Practices in the Absence of Safer
Substitutes: Isocyanates 126
5.4.3.1 Best Practices as an Important Risk Management Approach 126
5.4.3.2 New Developments in Manufacturing Polyurethanes Without Using
Isocyanates 227
5.4.3.3 Safer Manufacture of Diisocyanates Without Using Phosgene 227
5.4.4 Life-Cycle Assessment to Inform Alternatives to Leaded Solder for
Electronics 229
5.5 Conclusion 232
5.6 Disclaimer 233
References 133
6 Design ofSafer Chemicals - Ionic Liquids 137
Ian Beadham, Monika Gurbisz and Nicholas Cathergood6.1 Introduction 237
6.2 Environmental Considerations 137
6.3 Ionic Liquids - a Historical Perspective 238
6.3.1 First-Generation ILs 139
6.4 From Ionic Liquid Stability to Biodegradability 141
6.4.1 Overcoming the Inertness of l-Substituted-3-
Methylimidazolium Cation 147
6.5 Conclusion 152
References 155
7 Designing Safer Organocatalysts - What Lessons Can Be Learned When
the Rebirth of an Old Research Area Coincides with the Advent ofGreen
Chemistry? 159
Ian Beadham, Monika Gurbisz and Nicholas Gathergood7.1 Introduction 159
VIII Contents
7.2 A Brief History of Organocatalysis 159
7.2.1 Pre-19S0s: From Humble Beginnings 259
7.2.2 1950s-1960s 160
7.2.3 1970s: Organocatalysis Begins in Earnest 160
7.2.4 1980s 160
7.2.5 1990s 161
7.2.6 2000-Present 162
7.2.7 Advantages of Organocatalysts 162
7.3 Catalysts from the Chiral Pool 163
7.4 "Rules ofThumb" for Small Molecule Biodegradability Applied to
Organocatalysts 167
7.4.1 Selecting Simple Guidelines for Biodegradability 169
7.5 Cinchona Alkaloids - Natural Products as a Source of Organocatalysts:
Appendix 7.A .774
7.6 Proline, the Most Extensively Studied Organocatalyst:
Appendix 7.B 175
7.7 Process of Catalyst Development 277
7.7.1 Analogy Between Organocatalyst Development and Drug Design 178
7.8 Analogs of Nornicotine - an Aldol Catalyst Exemplifying "Natural"
Toxicity 179
7.9 Pharmaceutical^ Derived Organocatalysts and the Role of
Cocatalysts 280
7.9.1 Criteria to Assess the Environmental Impact of-an Organocatalyst 184
7.10 Conclusion 185
7.11 Summary 285
References 222
8 Life-Cycle Concepts for Sustainable Use of Engineered Nanomaterials in
Nanoproducts 227
Bemd Nowack, Fadri Cottschalk, Nicole C. Mueller and Claudia Som
8.1 Introduction 227
8.2 Life-Cycle Perspectives in Green Nanotechnologies 228
8.3 Release of Nanomaterials from Products 230
8.4 Exposure Modeling ofNanomaterials in the Environment 237
8.5 Designing Safe Nanomaterials 243
8.6 Conclusion 245
References 245
9 Drugs 251
Klaus KUmmerer
9.1 Introduction 252
9.2 Pharmaceuticals - What They Are 251
9.3 Pharmaceuticals in the Environment - Sources, Fate, and Effects 252
9.3.1 Sources 252
Contents IX
9.3.2 Fate 254
9.3.3 Effects 255
9.4 Risk Management 257
9.4.1 (Advanced) Effluent Treatment and Its Limitations 258
9.4.2 Role of Patients, Pharmacists, and Doctors 259
9.4.3 Role ofthe Drugs 259
9.5 Designing Environmentally Safe Drugs 259
9.5.1 What are Safe Drugs? 259
9.5.2 Improvements Related to Use and After-Use Life 260
9.5.2.1 Lower Activity Thresholds 260
9.5.2.2 Prodrugs 260
9.5.2.3 Drug Targeting, Drug Delivery, Degree of Metabolism 261
9.5.2.4 Biopharmaceuticals 261
9.5.3 Benign by Design 262
9.5.3.1 Why? 262
9.5.3.2 How? 262
9.5.3.3 Degradable Drugs - a Contradiction per se? 264
9.5.3.4 Structure Matters 264
9.5.3.5 Stability Versus Reactivity - How Stable Is Reactive Enough 267
9.5.3.6 Examples Demonstrating Feasibility 268
9.6 Conclusion 271
References 272
10 Greener Chelating Agents 281
Nicholas J. Dixon
10.1 Introduction 281
10.2 Chelants 282
10.3 Common Chelants 284
10.3.1 Aminocarboxylates 284
10.3.2 Phosphonates 284
10.3.3 Carboxylates 285
10.4 Issues with Current Chelants 285
10.4.1 EDTA and DTPA 285
10.4.2 NTA 288
10.4.3 Phosphonates 288
10.4.4 Ecolabels 289
10.5 Green Design Part 1 - Search for Biodegradable Chelants 290
10.5.1 10th Principle of Green Chemistry Design Chemicals and Products
to Degrade After Use 290
10.5.2 Aminocarboxylate NTA Variants 291
10.5.3 Polysuccinates 291
10.5.3.1 EthylenediaminedisuccinicAcid[(S,S)-EDDS] 291
10.5.3.2 Iminodisuccinic Acid (IDS) 293
10.6 Comparing Chelating Agents 293
10.6.1 Stability Constants 293
X Contents
10.6.2 Selectivity 294
10.6.3 pH 295
10.6.4 Speciation Modeling 295
10.6.5 Comparison of Strengths and Weaknesses 296
10.6.6 Application Chemistry 298
10.7 Six Steps to Greener Design 299
10.7.1 2nd Principle of Green Chemistry: Design Safer Chemicalsand Products 299
10.7.2 Step 1. What is the Role of the Incumbent Chemical in
the Application? 299
10.7.3 Step 2. What Environmental and Regulatory Constraints Exist? 300
10.7.4 Step 3. What are the Performance and Cost Requirements? 300
10.7.5 Step 4. How Do the Properties ofAlternatives Compare with
the Incumbent? 301
10.7.6 Step 5. Can Combinations of "Greener" Chemicals Be Used? 301
10.7.7 Step 6. Choose Likely Solutions and Test in the Application 301
10.8 Case Study - Six Steps to Greener Chelants for Laundry 302
10.8.1 Step 1. Role of Incumbent Chelant 302
10.8.2 Step 2. Environmental and Regulatory Constraints 303
10.8.3 Step 3. Performance and Cost Requirements 303
10.8.4 Step 4. Comparison ofPhosphonates with Biodegradable Chelants 303
10.8.5 Step 5. Combinations of Chelants 304
10.8.6 Step 6. Test in Application 304
10.9 Conclusion 305
10.10 Abbreviations 305
References 306
11 Improvements to the Environmental Performance of Synthetic-BasedDrilling Muds 309
Sajida Bakhtyar and Marthe Monique Gagnon11.1 Introduction 309
11.2 Drilling Mud Composition 310
11.2.1 Water or Saline Brine 311
11.2.2 Weighting Agent 312
11.2.3 Viscosifiers 311
11.2.4 Emulsifiers and Wetting Agents 311
11.2.5 Base Fluids/Oils 312
11.3 Characteristics and Biodegradability of SBFs 312
11.4 Case Study: Improvements in the Environmental Performance of
Synthetic-Based Drilling Muds 314
11.4.1 Importance of Study 314
11.4.2 Origins of Drilling Muds and Emulsifiers 315
11.4.3 Aquatic Toxicity 335
11.4.3.1 Study Organism and Conditions 315
11.4.3.2 Biomarkers and Physiological Indices 316
Contents XI
11.4.3.3 Results 316
11.4.4 Biodegradation 321
11.4.5 Conclusions of Study 323
11.5 Conclusion 323
References 323
12 Biochemical Pesticides: Green Chemistry Designs by Nature 329
Russell S.Jones
12.1 Introduction 329
12.2 The Historical Path to Safer Pesticides 329
12.3 Reduced-Risk Conventional Pesticides 331
12.4 The Biopesticide Alternative: an Overview 331
12.5 Biochemical Pesticides 333
12.5.1 Natural Occurrence 333
12.5.2 Nontoxic Mode ofAction Against the Target Pest 334
12.5.2.1 Plant Regulators 336
12.5.2.2 Semiochemicals 336
12.5.2.3 Biological Barriers 338
12.5.2.4 Induced Plant Resistance 338
12.5.3 History of Nontoxic Exposure to Humans and
the Environment 340
12.6 Are Biochemical Pesticides the Wave of the Future? 340
12.7 Conclusion 343
12.8 Disclaimer 343
References 344
13 Property-Based Approaches to Design Rules for Reduced Toxicity 349
Adelina Voutchkova, Jakub Kostal, and Paul Anastas
13.1 Possible Approaches to Systematic Design Guidelines for Reduced
Toxicity 349
13.2 Analogy with Medicinal Chemistry 354
13.3 Do Chemicals with Similar Toxicity Profiles Have Similar Physical/Chemical Properties? 356
13.4 Proposed Design Guidelines for Reduced Human Toxicity 358
13.4.1 Considerations for Reducing Human Absorption 358
13.4.1.1 Example: Reducing Carcinogenicity by Decreasing Oral
Bioavailability 358
13.5 Using Property Guidelines to Design for Reducing Acute Aquatic
Toxicity 362
13.6 Predicting the Physicochemical Properties and Attributes Needed for
Developing Design Rules 365
13.6.1 Solvent-Related Properties 365
13.6.1.1 Hydrophobicity 365
13.6.1.2 Solubility 367
13.6.1.3 pKB 367
XII Contents
13.6.2 Electronic Properties 368
13.6.2.1 Orbital Energies 368
13.6.2.2 Molecular Dipole Moment and Polarizability 369
13.6.2.3 Molecular Surface Area 370
13.7 Conclusion 371
References 371
14 Reducing Carcinogenicity and Mutagenicity Through Mechanism-Based
Molecular Design ofChemicals 375
David Y. Lai and Yin-tak Woo
14.1 Introduction 375
14.2 Mechanisms of Chemical Carcinogenesis and Structure-Activity
Relationship (SAR) 376
14.3 General Molecular Parameters Affecting the Carcinogenic and
Mutagenic Potential ofChemicals 378
14.3.1 Physicochemical Properties 379
14.3.1.1 Molecular Weight 379
14.3.1.2 Molecular Size and Shape 379
14.3.1.3 Solubility 379
14.3.1.4 Volatility 380
14.3.2 Nature and Position of Substituents 381
14.3.3 Molecular Flexibility, Polyfunctionality, and Spacing/Distance Between
Reactive Groups 381
14.3.4 Resonance Stabilization ofthe Electrophilic Metabolites 381
14.4 Specific Structural Criteria ofDifferent Classes ofChemical Carcinogensand Mutagens 382
14.4.1 Aromatic Amines and Azo Dyes/Pigments 383
14.4.2 Polycyclic Aromatic Hydrocarbons (PAHs) 385
14.4.3 N-Nitosamines 386
14.4.4 Hydrazo, Aliphatic Azo and Azoxy Compounds,and Arydialkyltriazenes 388
14.4.5 Organophosphorus Compounds 388
14.4.6 Carbamates 389
14.4.7 Epoxides and Aziridines 390
14.4.8 Lactones and Sultones 391
14.4.9 Alkyl Esters ofModerately Strong and Strong Acids 391
14.4.10 Haloalkanes and Substituted Haloalkanes 392
14.4.11 N-Mustards and S-Mustards 393
14.4.12 N-Nitrosamides 394
14.4.13 Aldehydes and Substituted Aldehydes 395
14.4.14 Michael Addition Acceptors 395
14.4.15 Arylating Agents 396
14.4.16 Acylating Agents and Isocyanates 396
14.4.17 Organic Peroxides 397
14.4.18 Quinones and Quinoid Compounds 397
Contents
14.5 Molecular Design of Chemicals of Low Carcinogenic and MutagenicPotential 398
14.5.1 General Approaches 398
14.5.2 Specific Approaches 399
14.5.2.1 Aromatic Amines and Azo Dyes/Pigments 399
14.5.2.2 Polycyclic Aromatic Hydrocarbons (PAHs) 400
14.5.2.3 N-Nitrosamines 400
14.5.2.4 Hydrazo, Aliphatic Azo and Azoxy Compounds, and
Arydialkyltriazenes 400
14.5.2.5 Organophosphorus Compounds 400
14.5.2.6 Carbamates 401
14.5.2.7 Epoxides and Aziridines (Ethylenimines) 401
14.5.2.8 Lactones and Sultones 401
14.5.2.9 Alkyl Esters of Moderately Strong and Strong Acids 401
14.5.2.10 Haloalkanes and Substituted Haloalkanes 402
14.5.2.11 N-Mustards and S-Mustards 402
14.5.2.12 N-Nitrosamides 402
14.5.2.13 Aldehydes and Substituted Aldehydes 402
14.5.2.14 Michael Addition Acceptors 402
14.5.2.15 Arylating Agents 402
14.5.2.16 Acylating Agents and Isocyanates 402
14.5.2.17 Organic Peroxides 403
14.5.2.18 Quinones and Quinoid Compounds 403
14.6 Conclusion 403
14.7 Disclaimer 404
References 404
15 Reducing Ecotoxicity 407
Keith R Solomon and Mark Hanson
15.1 Introduction to Key Aspects of Ecotoxicology 407
15.1.1 Protection Goals and Assessment Endpoints 408
15.1.2 Structure and Function in Ecosystems 410
15.1.3 Diversity of Sensitivity in Ecosystems 411
15.1.4 Hazard Assessment and Uncertainty 412
15.2 Environmental Fate and Pathways of Exposure to Chemicals in the
Environment 413
15.2.1 Properties Affecting Bioavailability 413
15.2.2 Properties Affecting Bioconcentration and Biomagnification 415
15.2.3 Absorption, Distribution, Metabolism, and Excretion of Chemicals 416
15.2.4 Modeling Exposure 418
15.3 Mechanisms of Toxic Action 429
15.3.1 Properties Affecting Toxicity 420
15.3.2 Modeling Toxicity 422
15.4 Examples of Methods That Can Be Used in Designing Chemicals with
Reduced Ecological Risks 424
Contents
15.4.1 Fluorinated Surfactants 425
15.4.2 Pesticides 426
15.4.2.1 Designing Pesticides for Lack of Persistence 427
15.4.2.2 Designing Specific Isomers to Reduce Risk in the Environment 429
15.4.2.3 Developing Pesticides That Are More Specific to the
Target Organism 431
15.4.2.4 Ranking and Prioritizing Pesticides in Terms of Risk to
the Environment 432
15.4.3 Pharmaceuticals 433
15.4.4 Macro- and Micro-Contaminants Produced During Manufacture 435
15.5 Overview, Conclusions, and the Path Forward 437
References 440
16 Designing for Non-Persistence 453
Philip H. Howard and Robert S. Boethling16.1 Introduction 453
16.2 Finding Experimental Data 454
16.2.1 Chemical Identity 454
16.2.1.1 Discrete Substances 454
16.2.1.2 Ionic Substances 455
16.2.2 Database Resources for Chemical Design 456
16.2.2.1 CleanGredients® 459
16.2.2.2 UMBBD 459
16.2.2.3 Other Databases 460
16.2.3 AFAR: the Aggregated Fate Assessment Resource 460
16.3 Predicting Biodegradation from Chemical Structure 461
16.3.1 Rules ofThumb That Relate Chemical Structure
and Biodegradabiliiy 461
16.3.2 Identifying Analogs and Using Them to Estimate
Biodegradability 464
16.3.3 The BIOWIN and BioHCwin Models 465
16.3.4 Pathways and Their Prediction: UMBBD/PPS and CATABOL 466
16.3.4.1 CATABOL 466
16.3.4.2 UM-BBD Pathway Prediction System 466
16.4 Predicting Chemical Hydrolysis 467
16.5 Predicting Atmospheric Degradation by Oxidation
and Photolysis 469
16.6 Designing for Biodegradation I: Musk Fragrances Case Study 470
16.7 Designing for Biodegradation II: Biocides Case Study 472
16.8 Designing for Abiotic Degradation: Case Studies for Hydrolysis and
Atmospheric Degradation 477
16.9 Conclusion 479
16.10 Disclaimer 479
Abbreviations 480
References 480
Contents XV
17 Reducing Physical Hazards: Encouraging InherentlySafer Production 485
Nicholas A. Ashford17.1 Introduction 485
17.2 Factors Affecting the Safety of a Production System [1] 485
17.2.1 The Scale of Production 485
17.2.2 The Quantity of Hazardous Chemicals Involved 486
17.2.3 The Hazardousness of the Chemicals Involved 486
17.2.4 Batch Versus Continuous Processing 486
17.2.5 The Presence of High Pressures or Temperatures 487
17.2.6 Storage of Intermediates versus Closed-Loop Processing 487
17.2.7 Multi-Stream Versus Single-Stream Plants 487
17.3 Chemical Safety and Accident Prevention: Inherent Safety and
Inherently Safer Production 488
17.4 Incentives, Barriers, and Opportunities for the Adoption of InherentlySafer Technology 491
17.5 Elements of an Inherently Safer Production Approach [2, 3] 493
17.5.1 Timing and Anticipation of Decisions to Adopt (or Develop) Inherent
Safety 493
17.5.2 Life-Cycle Aspects 495
17.6 A Methodology for Inherently Safer Production 495
References 499
18 Interaction ofChemicals with the Endocrine System 501
Thomas C. Osimitz
18.1 Interaction with the Endocrine System 501
18.1.1 Introduction 501
18.1.2 Importance of SAR and QSAR in Understanding the Chemical Nature
of Endocrine Active Chemicals 503
18.2 Estrogens 504
18.2.1 General 504
18.2.2 Features of the Natural Ligand E2 That Contribute to ER Binding 505
18.2.3 Features of Xenobiotics That Contribute to ER Binding 506
18.2.4 Criteria for Binding With the Estradiol Template 506
18.2.5 Prediction of Potential ER Binding 507
18.2.5.1 Initial Filters 507
18.2.5.2 Structural Alerts 507
18.2.5.3 Decision Tree-Based Model 507
18.2.6 Predictive Approach for Priority Setting 510
18.2.6.1 Phase I: Rejection Filters 510
18.2.7 Alkylphenols 511
18.2.8 Polybrominated Diphenyl Ethers (PBDEs) 512
18.2.9 Phytoestrogens and Mycoestrogens 513
18.2.10 Hydroxylated Triphenylacrylonitrile Derivatives 514
18.3 Androgens 515
XVI Contents
18.3.1 General 515
18.3.2 General Structure-Activity Relationships 515
18.4 Hypothalamic-Pituitary-Thyroid (HPT) Axis 516
18.4.1 General 526
18.4.2 General Structure-Activity Relationships 518
18.4.3 Brominated Flame Retardants 519
18.4.4 Monohydroxylated Polychlorinated Biphenyls (PCBs) 519
18.5 Endocrine Disrupter Data Development Efforts 519
18.6 Research Needs and Future 521
References 522
Index 525
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