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Sa f e t y As p e c t s o fEn gi n e e re dNan o m a t e r i a l s

EDITED B YWolfgang LutherAxel ZweckSa f e t y As p e c t s o fEn gi n e e re dNan o m a t e r i a l s

Published byPan Stanford Publishing Pte. Ltd.Penthouse Level, Suntec Tower 38 Temasek BoulevardSingapore 038988Email: editorial@panstanford.comWeb: www.panstanford.comBritish Library Cataloguing-in-Publication DataA catalogue record for this book is available from the British Library.Safety Aspects of Engineered NanomaterialsCopyright © 2013 by Pan Stanford Publishing Pte. Ltd.All rights reserved. This book, or parts thereof, may not be reproduced in any formor by any means, electronic or mechanical, including photocopying, recordingor any information storage and retrieval system now known or to be invented,without written permission from the publisher.For photocopying of material in this volume, please pay a copying fee throughthe Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923,USA. In this case permission to photocopy is not required from the publisher.ISBN 978-981-4364-85-0 (Hardcover)ISBN 978-981-4364-86-7 (eBook)Printed in the USA

ContentsPrefacexv1. Definition and Standardization of Nanomaterials 1Georg Reiners1.1 Introduction 11.1.1 General Meaning of Standards 11.1.2 History of International Standardizationin Nanotechnologies 31.1.3 Importance of the Definition of the TermNanomaterial 41.1.4 Definition of “Nanoscale” 51.2 Organisation of Nanotechnology Standardization 61.2.1 ISO/TC 229 Nanotechnologies 71.2.2 IEC/TC 113 NanotechnologiesStandardization for Electrical andElectronic Products and Systems 81.2.3 Cooperation between ISO and OECD 81.2.4 CEN/TC 352 Nanotechnologies 91.3 Nanomaterial Standardisation: Status Quo 101.3.1 Terminology Standards 101.3.1.1 Core terms 101.3.1.2 Nanomaterial 111.3.1.3 Nano-objects and carbon nanoobjects121.3.1.4 Nanostructured material 141.3.1.5 Other nanomaterial definitionsfor regulative purposes 161.3.1.6 REACH and standardization 191.3.2 Measurement and CharacterizationStandards 201.3.3 Reference Materials 221.3.4 Environment, Health, and Safety (EHS)Standards 231.3.5 Materials Specification Standards 241.4 Conclusion and Outlook 25

2. Industrial Relevant Production Processes forNanomaterials and Nanostructures 29Karl-Heinz Haas2.1 Types of Nanomaterials/Nanostructures 292.2 General Production Process Types 312.3 Classical Nanomaterials: Carbon Black andSilica 342.4 Top-Down Approaches 342.4.1 High-Energy Milling 352.4.2 Electrospinning 372.5 Bottom-Up Approaches 372.5.1 Liquid Phase Processing 372.5.1.1 Precipitation 392.5.1.2 Sol-gel processing 392.5.1.3 Solvo-/hydrothermaltreatment 402.5.1.4 Polymers for controllednanostructures 412.5.1.5 Emerging use of ultrasound 422.5.2 Gas Phase Processes 422.5.2.1 Inert gas condensation 422.5.2.2 Plasma-assisted synthesis 422.5.2.3 Chemical vapor deposition 432.5.2.4 Flame synthesis 452.5.2.5 Spray pyrolysis 462.6 Conclusions: Processes, Production Volumesand Sustainability 463. Economic Impact and Applications of Nanomaterials 63Wolfgang Luther and Axel Zweck3.1 Introduction 633.2 Tailoring Material Properties at the Nanoscale 643.3 Industrial Use and Commercial Relevance ofNanomaterials 693.3.1 Assessment of Production and MarketVolume of Nanomaterials 733.3.1.1 Market volume 733.3.1.2 Production volume 773.3.1.3 Economic leverage effect ofnanomaterials 80

3.3.2 Applications of Nanomaterials inDifferent Industrial Sectors 813.3.2.1 Chemistry 823.3.2.2 Medicine 833.3.2.3 Energy 843.3.2.4 Environmental technology 853.3.2.5 Optics/photonics 863.3.2.6 Mechanical engineering 863.3.2.7 Civil engineering 873.3.2.8 Automotive 883.3.2.9 Information andcommunication 883.3.2.10 Consumer goods 893.4 Summary and Outlook 914. Engineered Nanoparticle Release, Exposure Pathwayand Dose, Measures and Measuring Techniques forNanoparticle Exposure in Air 99Heinz Fißan and Hans-Georg Horn4.1 Introduction 994.2 ENP Release into Air 1014.3 ENP Exposure Pathway in Air and Dose 1094.4 Relevant Measures 1124.5 Concentration Measurement Techniques 1154.5.1 Near Real-Time MeasurementTechniques for Total Concentration 1174.5.2 Property-Resolving Near Real-TimeMeasurement Techniques 1194.5.3 Combining the Measurement of TotalConcentration with Size-Selective Pre-Separators 1224.6 Exposure Measurements 1234.7 Conclusions and Outlook 1275. Ecotoxicological Aspects of Nanomaterials in theAquatic Environment 135Kristin Schirmer, Renata Behra, Laura Sigg, andMarc J.-F. Suter5.1 Introduction 1355.2 Fate in the Aquatic Environment 137

viiiContents5.3 Fate in Model Ecosystems 1395.4 Routes and Mechanisms of Uptake intoAquatic Organisms 1405.4.1 Uptake Routes 1415.4.2 Mechanisms of Uptake 1435.5 Nanoparticle–Biomolecule Interactions 1445.5.1 Biologically Induced Transformationof Nanoparticles 1455.5.2 Nanoparticle-Induced Changes toBiological Target Sites 1465.6 Research Needs 1476. Biological Responses to Nanoparticles 157R. Zellner, J. Blechinger, C. Bräuchle, I. Hilger, A. Janshoff,J. Lademann, V. Mailänder, M. C. Meinke, G. U. Nienhaus,A. Patzelt, F. Rancan, B. Rothen-Rutishauser, R. H. Stauber,A. A. Torrano, L. Treuel, and A. Vogt6.1 Introduction 1586.2 Interactions of Nanoparticles with Proteins 1616.2.1 Dependence on Particle Size 1626.2.2 Binding Affinities 1636.2.3 Dependence on SurfaceFunctionalization 1666.3 Transfer of Nanoparticles Across Membranesand Cellular Uptake Mechanisms 1676.3.1 Endocytosis 1696.3.2 Nanoparticle Entry into Cells 1736.4 Trafficking and Intracellular Distribution ofNanoparticles 1756.4.1 Particle Dynamics 1756.4.2 Fractional Particle Uptake 1766.4.3 Subcellular Distribution ofNanoparticles 1796.5 Impact of Nanoparticles on BiologicalFunctions 1806.5.1 Interactions of Nanoparticles withCells 1816.5.2 Impact of Gold NPs on Cells 1846.5.3 Impact of Semiconductor QuantumDots on Cells 186

Contentsix6.6 Uptake of Nanoparticles by the Lung 1866.6.1 Nanotoxicological Dynamics andKinetics 1896.6.2 Cell Culture Models of the HumanEpithelial Airway and Alveolar Barrier 1906.7 Interaction of Nanoparticles with the Skin 1926.7.1 Follicular Penetration: A Phenomenonof Open and Closed Hair Follicles 1936.7.2 Follicular Reservoir for ParticulateSubstances 1936.7.3 Dependence of Particle Penetrationon the Particle Size 1946.7.4 Transfollicular Penetration ofParticulate Substances 1976.8 Conclusions 1997. Health Hazards of Nanomaterials: Anxiety versusScience 219Thomas Gebel7.1 Introduction 2197.2 Scope of This Chapter 2207.3 Possible Toxicological Modes of Action andApproaches for Grouping 2227.4 Distribution and Retention of Nanomaterialsin the Body 2227.5 Relevant Health Hazards 2247.5.1 When Chemical Toxicity Is Determinanta Nanomaterial-Specific Evaluation IsNeeded 2257.5.2 Does the Fibre Principle Apply? 2267.5.3 Relevant Health Hazards for GBPNanomaterials 2277.6 Conclusion 2298. Nanomaterials at the Workplace: Occupational Safetyand Health 235Rolf Packroff and Miriam Baron8.1 The Regulatory Framework for a Safe Handlingof Nanomaterials at the Workplace 2358.1.1 Chemical Safety 235

xContents8.1.1.1 Classification and labeling(CLP) 2388.1.1.2 REACH 2408.1.1.3 Safety data sheet 2428.1.2 Occupational Safety and Health 2448.1.2.1 EU minimum standards 2448.1.2.2 EU precautionary approach 2458.1.2.3 Germany: HazardousSubstances Ordinance(GefStoffV) 2468.1.2.4 Germany: Technical Rules forHazardous Substances (TRGS) 2468.1.2.5 Control banding 2478.2 Practical Aspects of Occupational Safety andHealth for Nanomaterials 2498.2.1 Gathering Information 2498.2.2 Risk Assessment 2508.2.3 Control Strategies 2509. International Activities on Nanosafety: OECD WorkingParty on Manufactured Nanomaterials 259Klaus Günter Steinhäuser9.1 Introduction 2599.2 Mandate and Objectives of OECD WPMN 2619.3 Projects of the OECD Working Party onNanomaterials 2619.3.1 Safety Testing of a Representative Setof Manufactured Nanomaterials 2619.3.2 Manufactured Nanomaterials and TestGuidelines 2679.3.3 The Role of Alternative Methods inNanotoxicology 2689.3.4 OECD Database on ManufacturedNanomaterials to Inform and AnalyseEHS Activities 2699.3.5 Exposure Measurement and ExposureMitigation 2719.3.6 Risk Assessment 2729.3.7 Voluntary Schemes and RegulatoryProgrammes 273

Contentsxi9.3.8 Environmentally Sustainable Use ofManufactured Nanomaterials 2749.4 Conclusions 27510. Chances of Nanomaterials for PharmaceuticalApplications 279Loretz Brigitta, Jain Ratnesh, Dandekar Prajakta, ThieleCarolin, Yamada Hiroe, Mostaghaci Babak, Lian Qiong,and Lehr Claus Michael10.1 Introduction 27910.2 Therapeutic Needs and Opportunities forNanopharmaceuticals 28110.2.1 Delivery of Small-Molecule Drugs 28110.2.2 Macromolecular Biopharmaceuticals 28310.2.2.1 Proteins, peptides 28310.2.2.2 Nucleic acids 28510.2.3 Drugs that Need Efficient Targeting 28610.2.3.1 “Nano-oncology” 28610.2.3.2 Drug delivery over theblood–brain barrier 28710.2.3.3 Autoimmune diseases 28810.2.3.4 Vaccination 28910.3 Current Arsenal of Nanocarriers 29010.4 Translation of Nanopharmaceuticals intoClinics 29310.4.1 Approved Nanopharmaceuticals 29310.4.2 Nanopharmaceuticals Currently inClinical Trials 29310.4.3 Upcoming Technologies 29510.4.3.1 Nanoparticle-basedtechnologies 29510.4.3.2 Nanoemulsion-basedtechnologies 29710.4.3.3 Micelle-based technologies 29810.4.3.4 Liposome-based technologies 29810.4.3.5 Dendrimer-basedtechnologies 29810.4.3.6 Cationic nanoparticles fornucleic acid delivery 29910.4.4 Requirements/Needed Support 299

xiiContents10.4.4.1 Social and ethicalrequirements 30010.4.4.2 Regulatory requirements 30010.4.4.3 Technological and industrialrequirements 30110.5 Challenges for Developing FutureNanopharmaceuticals 30210.5.1 New Materials 30210.5.1.1 Biodegradability 30210.5.1.2 Multifunctional, smartpolymers 30310.5.1.3 Mimicing biologicalstructures 30410.5.2 In silico Approaches and Databases 30510.5.3 Ensuring Quality ofNanopharmaceuticals 30510.5.3.1 Characterization techniques 30610.5.3.2 Reproducibility and scale-up 30610.5.3.3 Sterilization methods 30610.5.3.4 Quality control and qualityassurance 30710.6 Conclusions and Perspective 30711. Sustainability Assessment of Nanoproducts 319Martin Möller11.1 Introduction 32011.2 PROSA as Methodological Background 32211.3 Life-Cycle Thinking and Systemic Approach 32511.4 Key Performance Indicators 32611.5 Nano-SWOT Matrix and Strategic Optimization 32911.6 Case Studies 33111.6.1 Case Study: pro.Glass ® Barrier 401 33111.6.2 Case Study: X-SEED ® 33311.7 Proposed Areas of Application, Strengths andLimitations of the Tool 33612. Risk Perception and Risk Communication on the Issueof Nanotechnology 341Gaby-Fleur Böl, Guido Correia Carreira, Astrid Epp,Eva Häffner, and Mark Lohmann

Contentsxiii12.1 Introduction 34112.2 Risk Perception of Nanotechnology:Differences between Experts and Laypeople 34412.2.1 Risk Perception of Nanotechnologyamong Laypeople 34412.2.2 Risk Perception of Nanotechnologyamong Experts 34612.3 The Role of the Media in the Perception ofNanotechnology Risks 34812.4 Citizen Involvement and Participation 35212.4.1 Citizens as Stakeholders in RiskCommunication 35212.4.2 Citizen Involvement in RiskCommunication on Nanotechnology 35512.5 Risk Communication on New Technologies:Best Practice 36012.5.1 Fundamental Aspects of RiskCommunication 36012.5.2 Special Characteristics of RiskCommunication in the Case ofNanotechnology 36312.5.3 Participatory Risk Communication 36412.5.4 The Challenge of the Media 36712.5.5 Conclusion 368Index 377

PrefaceIn numerous prospective studies on technological development,technologies are identified which in future will have a significantand supporting impact on the global economic development. Thesetechnologies, for example, cover information and communicationtechnology, biotechnology, and also materials technologies. Thechallenge here is that these technologies often show differentlevels of abstraction and are clearly distinguishable from oneanother. At a time when the overlaps between the basic disciplinesphysics, chemistry and biology as natural sciences have increasedsignificantly in the sense of forming so-called convergingtechnologies, this difficult challenge is not getting any easier. Thisapplies to just a few of the identified key technologies which in mostcases form the subject matter of such studies and is especially trueof nanotechnology, which, so to speak, is one if not the very primeexample of a converging technology. This also applies to the partialarea of nanomaterials.In the past three decades, nanotechnology has developed from ascientific field, only known by experts, to a prominent internationalresearch and development trend. The dynamics of nanotechnologydevelopment manifest themselves not only in a steep rise in publicsubsidies, the number of patents and publications of the past yearsbut also in the increasing spread of nanotechnological products in theworld markets. Nanotechnology opens up new market opportunitiesdue to smaller, quicker, more efficient and “more intelligent” systemcomponents. This applies both to new products with substantiallyimproved functions and to completely new functionalities. Althougha number of products with nanotechnological componentshave already been established on the market, the major part ofnanotechnological knowledge will only unfold its potential inproducts in a few years, partially even in decades.One important issue is to ensure the safe and responsible useof nanomaterials. Potential (eco)toxicological side effects haveto be taken into account. Potential risks of nanotechnology inthe field of consumer, work and environmental protection willinfluence the public perception as well as the general acceptance

xviPrefaceof nanotechnology. Risks can turn out to be an impediment to themerchandizing of nanotechnological products and might influence thelevel of public funding. Comprehensive risk research, precautionaryrisk management and transparent and open risk communicationare, therefore, of utmost importance. Open questions regardingstandardization and the regulatory handling of nanotechnology areonly answerable at the supranational level and require intensiveinternational coordination.This book deals with the question regarding the current statusof the safety aspects of engineered nanomaterials. Apart from adefinition which is viable in this context, it discusses economicpotentials and the time perspectives for the realization of possiblefields of application. This forms the basis for a comprehensiveapproach to security-relevant aspects of nanomaterials and theirapplications, as well as for a debate on risk communication andregulatory issues.Axel ZweckWolfgang LutherMay 2013