| | Collection of information on enzymes |
| | 2,71 | | MB |
| | 396 | | stron |
| | 4389 | | ID | Federal Environment Agency Austria |
| | 2003 | | rok |
| | TABLE OF CONTENTS |
| | LIST OF ABBREVATIONS 21 |
| | 1 TERMINOLOGY USED IN THIS REPORT 25 |
| | 2 INTRODUCTION . 27 |
| | 2.1 Addressing the problems 27 |
| | 2.2 Terms of reference. 27 |
| | 2.3 Project approach . 28 |
| | 3 TECHNICAL ASPECTS OF ENZYMES 31 |
| | 3.1 Introduction 31 |
| | 3.2 Application of enzymes. 31 |
| | 3.2.1 Enzymes in technical applications 31 |
| | 3.2.2 Enzymes in food industry. 32 |
| | 3.2.3 Enzymes in feed industry. 32 |
| | 3.2.4 Enzymes in cosmetics . 33 |
| | 3.2.5 Enzymes in medicinal products 33 |
| | 3.2.6 Enzymes for scientific and analytical use . 34 |
| | 3.3 Manufacturing of enzymes 34 |
| | 3.3.1 Large-scale fermentation of enzymes 34 |
| | 3.3.1.1 Organism and enzyme production . 35 |
| | 3.3.1.2 Media . 36 |
| | 3.3.1.3 Sterilization . 36 |
| | 3.3.1.4 Inoculation . 36 |
| | 3.3.1.5 Fermentation 37 |
| | 3.3.2 Downstream processing 37 |
| | 3.3.2.1 Preparation of biological starting materials 38 |
| | 3.3.2.2 Separation of solid matter. 39 |
| | 3.3.2.3 Concentration . 40 |
| | 3.3.2.4 Purification . 42 |
| | 3.3.3 Formulation of the final enzyme product 43 |
| | 3.4 The nature of enzyme products 44 |
| | 3.4.1 The enzyme concentrate . 46 |
| | 3.4.1.1 Factors affecting the purity of enzyme concentrates 47 |
| | 3.4.2 Enzyme preparations . 47 |
| | 3.5 Recent developments in enzyme manufacturing 49 |
| | 3.5.1 Introduction 49 |
| | 3.5.2 Genetic engineering. 49 |
| | 3.5.2.1 Increasing enzyme expression. 50 |
| | 3.5.2.2 New enzymes . 51 |
| | 3.5.2.3 Improving enzyme properties – protein engineering 54 |
| | 3.5.2.4 New enzyme production systems. 58 |
| | 3.5.2.5 Improved product safety. 59 |
| | 14 Table of Contents |
| | 3.5.3 Chemical modification of enzymes. 59 |
| | 3.6 Summary 60 |
| | 4 INDUSTRIAL ENZYMES PRESENTLY MARKETED IN THE EU. 63 |
| | 5 REGULATION OF ENZYMES – REVIEW. 67 |
| | 5.1 Introduction 67 |
| | 5.2 Enzymes in the context of the regulation of chemicals 67 |
| | 5.2.1 EU – present state and practice. 67 |
| | 5.2.2 Enzymes in EINECS 68 |
| | 5.2.3 Enzymes notified according to Directive 67/548/EEC. 69 |
| | 5.2.4 Enzymes in Annex I of Directive 67/548/EEC. 69 |
| | 5.2.5 Possibly enzyme-relevant issues in the Manual of Decisions non-confidential version (MoD) . |
| | 69 |
| | 5.2.5.1 Definition of substance . 70 |
| | 5.2.5.2 Identification of mixtures. 70 |
| | 5.2.5.3 Extracts from genetically-modified plants. 71 |
| | 5.2.5.4 Substances produced by means of biotechnology. 71 |
| | 5.2.5.5 Notification of substances (enzymes) produced and processed in different Member States |
| | and substance to test 72 |
| | 5.2.6 Experience of EU Member States in enzyme notification . 72 |
| | 5.2.6.1 Austria 72 |
| | 5.2.6.2 Germany 73 |
| | 5.2.6.3 Denmark 74 |
| | 5.2.7 Premanufacturing notification of chemical substances in the U.S.A. 74 |
| | 5.2.7.1 Scope of TSCA. 75 |
| | 5.2.7.2 Definitions in TSCA 76 |
| | 5.2.7.3 The distinction between existing and new substances 77 |
| | 5.2.7.4 The premanufacturing-notification procedure. 78 |
| | 5.2.7.5 Content of the premanufacturing-notification dossier. 79 |
| | 5.2.7.6 Testing of the substances properties . 81 |
| | 5.2.7.7 Risk assessment 82 |
| | 5.2.7.8 Further actions after premanufacturing-notification 82 |
| | 5.2.8 Notification of technical enzymes in Canada 84 |
| | 5.2.8.1 Scope of the New Substances Notification Regulation (NSNR) 84 |
| | 5.2.8.2 Definitions 86 |
| | 5.2.8.3 The distinction between existing and new substances 87 |
| | 5.2.8.4 Exemptions . 87 |
| | 5.2.8.5 The notification procedure 87 |
| | 5.2.8.6 Post-notification responsibilities . 89 |
| | 5.2.8.7 Content of the notification dossier 89 |
| | 5.2.8.8 Testing and assessment of the substance’s properties . 93 |
| | 5.2.8.9 Standards for testing and data . 94 |
| | 5.2.8.10Further actions after notification . 94 |
| | 5.2.9 Notification of chemicals in Australia 96 |
| | 5.2.9.1 Scope of the Industrial Chemicals (Notification and Assessment) Act 96 |
| | 5.2.9.2 Definitions according to the Act 97 |
| | 5.2.9.3 The distinction between existing and new substances 98 |
| | 5.2.9.4 Exemptions . 98 |
| | 5.2.9.5 The notification procedure 98 |
| | 5.2.9.6 Content of the notification dossier 100 |
| | 5.2.9.7 Prescribed standards for testing and data quality 105 |
| | 5.2.9.8 Assessment of unreasonable risk 106 |
| | 5.2.9.9 Further actions after notification . 106 |
| | 5.2.10 Comparative Analysis of enzymes in chemicals regulation in the EU, USA, Canada and |
| | Australia. 108 |
| | 5.2.10.1Legislative framework. 108 |
| | 5.2.10.2Identity of an enzyme . 109 |
| | 5.2.10.3Differentiation between new and existing substances . 111 |
| | 5.2.10.4Tonnage thresholds and notification requirements 112 |
| | 5.2.10.5Information required on the production organism 114 |
| | 5.2.10.6Information required for substances with enzymatic properties. 114 |
| | 5.2.10.7Data available on toxicological and ecotoxicological effects 115 |
| | 5.2.10.8Experience gained in the notification and assessment of enzymes. 116 |
| | 5.3 Enzymes in the context of food regulation 119 |
| | 5.3.1 Introduction 119 |
| | 5.3.2 Harmonised regulation in the EU . 120 |
| | 5.3.2.1 SCF-Guidelines 121 |
| | 5.3.3 National regulation in EU-Member States 123 |
| | 5.3.3.1 Denmark 123 |
| | 5.3.3.2 France 124 |
| | 5.3.3.3 United Kingdom 124 |
| | 5.3.3.4 Other Member States . 125 |
| | 5.3.4 JECFA Guidelines . 125 |
| | 5.3.5 Perspectives from the industry. 127 |
| | 5.3.6 Regulation of food enzymes in the US . 128 |
| | 5.3.7 Comparison of information requirements . 129 |
| | 5.3.8 Summary . 131 |
| | 5.4 Enzymes used as additives in animal nutrition. 131 |
| | 5.4.1 Harmonised regulation in the EU . 131 |
| | 5.4.2 Summary . 134 |
| | 5.5 Enzymes used in cosmetics products . 135 |
| | 5.5.1 The harmonised EU cosmetic regulation 135 |
| | 5.5.2 Summary . 138 |
| | 5.6 Enzymes used in medicinal products 138 |
| | 5.6.1 The EU system for the authorisation of medicinal products 138 |
| | 5.6.2 EMEA Guidelines for medicinal products for human use 139 |
| | 5.6.3 Discussion of selected centrally authorised medicinal products including protein with |
| | enzymatic activity. 140 |
| | 5.6.4 Summary . 141 |
| | 5.7 Summary of „Regulation of Enzymes“. 142 |
| | 6 HEALTH RISK OF ENZYMES REGARDING ALLERGOLOGICAL AND DEMATOLOGICAL |
| | ASPECTS. 147 |
| | 6.1 General introduction 147 |
| | 6.2 Historical perspective, public awareness and concern 147 |
| | 6.3 Medical terminology regarding enzyme exposure 149 |
| | 6.3.1 Immunological terms 149 |
| | 6.3.2 Allergic diseases, described in association with enzyme exposure 150 |
| | 16 Table of Contents |
| | 6.3.2.1 Respiratory allergy 150 |
| | 6.3.2.2 Skin allergy . 151 |
| | 6.3.2.3 Food allergy. 152 |
| | 6.3.2.4 Drug allergy 152 |
| | 6.3.2.5 Test methods for allergy. 152 |
| | 6.3.3 Irritation (of skin and respiratory system) caused by enzyme exposure 154 |
| | 6.3.3.1 Respiratory tract irritation . 154 |