EN 30993-3:1993
(Main)Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity (ISO 10993-3:1992)
Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity (ISO 10993-3:1992)
This part of ISO 10993 specifies tests for the following biological aspects: - genotoxicity, - carcinogenicity; and - reproductive and developmental toxicity. These are relevant in the biological evaluation of some categories of medical and dental materials and devices (see note). Guidance on selection of tests is provided in ISO 10993-1. Where the need for the evaluation of the potential for genotoxicity, carcinogenicity or reproductive toxicity has been identified, they should be evaluated in accordance with this part of ISO 10993. Most tests included in this part of the International Standard refer to the OECD guidelines for testing of chemicals. Reference to these tests is made by the term 'OECD guideline(s)' followed by the appropriate test number(s). At the time of testing, these tests are to be performed according to current OECD guidelines. Note: The term 'devices' corresponds to the definition given in ISO 10993-1 and covers materials, as well as dental materials and devices. The definition is in accordance with the CEN standard document.
Biologische Beurteilung von Medizinprodukten - Teil 3: Prüfungen auf Gentoxizität, Karzinogenität und Reproduktionstoxizität (ISO 10993-3:1992)
Dieser Teil von EN 30993 nennt Prüfungen für folgende biologische Risiken: Gentoxizität, Karzinogenität und Reproduktionstoxizität. Diese Aspekte sind relevant im Rahmen der biologischen Bewertung einiger Kategorien medizinischer und zahnmedizinischer Werkstoffe und Produkte. Eine Anleitung zur Auswahl von Prüfungen ist in EN 30993-1 gegeben. Sofern sich daraus die Erfordernis für die Bewertung des Risikos der Gentoxizitä, Karzinogenität oder Reproduktionstoxizität ergibt, sollten diese Risiken in Übereinstimmung mit diesem Teil von EN 30993 geprüft werden.
Essais biologiques des matériaux médicaux - Partie 3: Essais concernant la génotoxicité, la cancérogénicité et la toxicité sur la reproduction (ISO 10993-3:1992)
Cette partie de l'ISO 10993 spécifie des essais pour les aspects biologiques suivants: Génotoxicité, carcinogénécité et la toxicité sur la reproduction. Ces aspects concernent lors de l'évaluation biologique, certaines catégories de matériels et dispositfs dentaires et médicaux. Le guide pour le choix des essais est fourni par l'ISO 10993-1. Lorsqu'il est nécessaire d'évaluer le potentiel de génotoxicité, de carcinogénécité ou de toxicité sur la reproduction et que cela a été identifié, cette évaluation sera feaite en suivant cette 3ème partie de l'ISO 10993.
Biološko ovrednotenje medicinskih pripomočkov - 3. del: Preskusi genske toksičnosti, kancerogenosti in toksičnosti za razmnoževanje (ISO 10993-3:1992)
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2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.JHQVNHBiologische Beurteilung von Medizinprodukten - Teil 3: Prüfungen auf Gentoxizität, Karzinogenität und Reproduktionstoxizität (ISO 10993-3:1992)Essais biologiques des matériaux médicaux - Partie 3: Essais concernant la génotoxicité, la cancérogénicité et la toxicité sur la reproduction (ISO 10993-3:1992)Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity (ISO 10993-3:1992)11.100.20Biological evaluation of medical devicesICS:Ta slovenski standard je istoveten z:EN 30993-3:1993SIST EN 30993-3:2000en01-januar-2000SIST EN 30993-3:2000SLOVENSKI
STANDARD
SIST EN 30993-3:2000
SIST EN 30993-3:2000
SIST EN 30993-3:2000
INTERNATIONAL STANDARD ISO 10993-3 First edition 1992-12-15 Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity haha tion biologique des dispositifs medicaux - Partie 3: Essais concernant Ia ghotoxicit6, Ia canc&og&icitk et Ia toxicit6 sur Ia reproduction Reference number ISO 10993-3:1992(E) SIST EN 30993-3:2000
ISO 10993=3:1992(E) Contents Page Scope . 1 Normative references . . 1 Definitions . .*. 2 Genotoxicity tests . 2 Carcinogenicity tests . 3 Reproductive toxicity tests . 4 Annex A Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 0 ISO 1992 All rights reserved. No part of this publication may be reproduced or utilized in any form or by any means, electronie or mechanical, including photocopying and microfilm, without per- mission in writing from the publisher. International Organization for Standardization Case Postale 56 l CH-l 211 Geneve 20 l Switzerland Printed in Switzerland ii SIST EN 30993-3:2000
ISO 10993=3:1992(E) Foreword ISO (the International Organization for Standardization) is a worldwide federation of national Standards bodies (ISO member bodies). The work of preparing International Standards is normally carried out through ISO technical committees. Esch member body interested in a subject for which a technical committee has been established has the right to be represented on that committee. International organizations, governmental and non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization. Draft International Standards adopted by the technical committees are circulated to the member bodies for voting. Publication as an International Standard requires approval by at least 75 % of the member bodies casting a vote. International Standard ISO 10993-3 was prepared by Technical Committee ISO/TC 194, Biological evalua tion of medical devices. ISO 10993 consists of the following Parts, under the general title Biological evaluation of medical devices: - Part 1: Guidance on selection of tests - Part 2: Animal welfare requirements - Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity - Part 4: Selection of tests for interactions with blood - Part 5: Tests for cytotoxicity: in vitro methods - Part 6: Tests for local effects after implantation - Part 7: Ethylene Oxide sterilization residuals - Part 8: Clinical investigation - Part 9: Degradation of ma terials rela ted to biological testing - Part YO: Tests for irrita tion and sensitization - Part 11: Tests for s ys temic toxicity - Part 12: Sample preparation and reference materials Future Parts will deal with other relevant aspects of biological testing. Annex A of this part of ISO 10993 is for information only. .‘ . Ill SIST EN 30993-3:2000
ISO 10993=3:1992(E) Introduction The basis for biocompatibility evaluation of medical devices is often em- pirical and driven by the relevant concerns for human safety. Not all test methods for the assessment of genotoxicity, carcinogenicity or repro- ductive toxicity are equally weil developed, nor is their validity weil estab- lished for the testing of medical devices. Significant issues in test Sample size and preparation, scientific under- standing of disease processes and test Validation tan be cited as limi- tations of available methods. For example the biological significance of solid state carcinogenesis is poorly understood. lt is expected that ongoing scientific and medical advances will alter our understanding and ap- proaches to these important toxicity test methods. At the time the docu- ment was prepared, the test methods proposed were those most acceptable. Sound scientific alternatives to the proposed testing should be acceptable insofar as they address relevant matters of safety assess- ment. In the selection of tests needed to evaluate a particular device, there is no Substitute for a careful assessment of expected human uses and po- tential interactions of the device with various biological Systems. These considerations will be particularly important in such areas as reproductive and developmental toxicology. This part of ISO 10993 presents test methods for the detection of specific biological hazards, and therefore maximum test sensitivity is required. The interpretation of findings and implications for human health effects are beyond the scope of this part of ISO 10993. Because of the multitude of possible outcomes and the importante of such factors as extent of expo- Sure, species differentes and mechanical or physical considerations, risk assessment has to be performed on a case-by-case basis. IV SIST EN 30993-3:2000
INTERNATIONAL STANDARD ISO 10993=3:1992(E) Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity 1 Scope This part of ISO 10993 specifies tests for the follow- ing biological aspects: - genotoxicity, - carcinogenicity, and - reproductive and developmental toxicity. These are relevant in the biological evaluation of some categories of medical devices (see note 1). Guidance on selection of tests is provided in ISO 10993-1. Where the need for the evaluation of the potential for genotoxicity, carcinogenicity or reproductive toxicity has been identified, they should be evaluated in ac- cordante with this part of ISO 10993. Most tests included in this part of the International Standard refer to the OECD guidelines for testing of chemicals. Reference to these tests is made by the term “OECD guideline(s)” followed by the appropriate test number(s). At the time of testing, these tests are to be per- formed according to current OECD guidelines. NOTE 1 The term “devices” corresponds to the defi- nition given in ISO 10993-1 and covers materials, as weil as dental materials and devices. The definition is in accordance with the CEN Standard document. 2 Normative references The following Standards contain provisions which, through reference in this text, constitute provisions of this International Standard. At the time of publica- tion, the editions indicated were valid. All Standards are subject to revision, and Parties to agreements based on this International Standard are encouraged to investigate the possibility of applying the most re- cent editions of the Standards indicated below. Members of IEC and ISO maintain registers of cur- rently valid International Standards. ISO 10993-1: 1992, Biological evaluation of medical devices - Part 1: Guidance on selection of tests. ISO 10993-2: -l) Biological evaluation of medical de- vices - Part 2: Animal welfare requirements. OECD Guidelines for testing of chemicals - Se- lected assays - ln vitro genotoxicity tests 471 Genetic Toxicology: Salmonella typhimurium, Reverse Mutation Assay. 472 Genetic Toxicology: Escheric Mutation Assay. iia coli, Reverse 473 Genetic Toxicology: In v Cytogene tic Test. tro Mammalian 476 Genetic Toxicology: In vitro Gene Mutation Test. Mammalian Cell 479 Genetic Toxicology: I n vitro Sis ter Chroma tid Exchange Assay in Mammalian Cells. 480 Genetic Toxicology: Saccharomyces cerevisiae, Gene Mutation Assay. 481 Genetic Toxicology: Saccharomyces cerevisiae, Mito tic Recombina tion Assa y. 1) To be published. SIST EN 30993-3:2000
ISO 10993=3:1992(E) 482 Genetic Toxicology: DNA Darnage and ßepair/ Unscheduled DNA Synthesis in Mammalian Cells I n vitro. - In vivo genotoxicity tests 474 Genetic Toxicology: Micronucleus Test. 475 Genetic Toxicology: In vivo Mammalian Bone Marrow Cytogenetic Test - Chromosomal Analysis. 478 Gene tic Toxicology: Roden t Dominant Le thal Test. 483 Gene tic Toxicology: Mammalian Germ-Cell Cytogenetic Assay. 484 Genetic Toxicology: Mouse Spot Test. 485 Genetic Toxicology: Mouse Heritabie Translo- ca tion Assay. - Carcinogenicity tests 451 Carcinogenicity Studies. 453 Combined Chronic Toxicityl Carcinogenicity Studies. - Tests for reproductive toxicity 4 14 Tera togenicity. 4 i 5 One-Genera tion Reproduction Taxicity Study. ßules Governing Medicinal Products in the European Community. Volume 3. Guidelines on the Quality, Safety and Efficacy of Medicinal Products for Human Use. Commission of the European Community 1989. ISBN 92-825-9619-2. 3 Definitions For the purposes of this part of ISO 10993, the defi- nitions given in ISO 10993-1 and the following defi- nitions apply. 3.1 genotoxicity test: Test that applies mammalian or non-mammalian cells, bacteria, yeasts or fungi to determine whether gene mutations, changes in chro- mosome structure, or other DNA or gene changes are caused by the test materials, devices and/or extracts from materials. NOTE 2 Tests on whole animals may also address these endpoints. 3.2 carcinogenicity test: Test to determine the tumorigenic potential of devices, materials, and/or extracts to either a Single or multiple exposures over a period of the total life-span of the test animal. NOTE 3 These tests may be designed to examine both chronic toxicity and tumorigenicity in a Single experimental study. 3.3 reproductive and developmental toxicity tests: Tests to evaluate the potential effects of de- vices, materials, and/or extracts on reproductive function, embryonie development (teratogenicity), and prenatal and early postnatal development. 3.4 maximum implantable dose (MID): Maximum amount of implant material (dose) that a test animal tan tolerate without any adverse physical or mechan- ical effects. NOTE 4 To avoid unnecessary morbidity in animals on a long-term test, preliminary testing may be necessary. 3.5 energy-depositing device: Device intended to exert its therapeutic or diagnostic effect by the ab- sorption of electromagnetic, ionic or ultrasonic radi- ation. NOTE 5 This does not include devices which deliver simple electrical current, such as electrocautery devices, Pacemakers or functional electrical stimulators. 4 Genotoxicity tests 4.1 General When the genetic toxicity of a medical device has to be experimentally assessed, a series of in vitro tests shall be used. This series shall include at least three assays. At least two of these should preferably use mammalian cells as a target. The tests should prefer- ably cover the three levels of genotoxic effects: DNA effects, gene mutations and chromosomal aber- rations. NOTE 6 OECD tests 471 and 473 have proven useful in the first instance, supported where necessary by test 476. In vivo testing on animals shall only be carried out in accordance with subclause 4.1 of ISO 10993-2. Medical devices shall be tested for genotoxicity as specified in ISO 10993-1 :1992, except those made only from materials known to show no genotoxicity, when, moreover, all major components of extracts tan be identified by suitable analytical methods and have been shown to have no genetic toxicity (see also table 1 of ISO 10993-1:1992). 4.2 Sample preparation Any material or device shall be in its “ready-to-use” form (i.e. as a final product) Prior to any extraction or test procedure. Tests shall be performed either on extracts or the dissolved material using appropriate media. Where mean ingful, two app ropriate extractant s shall be used, one of which is a p hysiological mediu m, the 2 SIST EN 30993-3:2000
second a solvent such as dimethylsulfoxide (DMSO), which is reasonably compatible with the test System. WARNING - DMSO is known to be cytotoxic in selected assay Systems at greater than 5 g/l con- centrations of aqueous solvent. The highest reasonably possible surface area per vol- ume of extractant (expressed in Square centimetres per millilitre) shall be used. Materials and devices which are cured in situ shall be tested in the cured as well as in the non-cured state. Extraction shall be performed in closed Containers with minimum headspace. To ensure comparability of results, the extraction temperature should preferably be 37 OC and the ex- traction time at least 24 h. When biphasic release characteristics are to be ex- pected, this shall be taken into account. NOTE 7 A general guideline on Sample preparation is under way (ISO 10993-12; see page iii) and may amend or partly Substitute this section on Sample preparation. 4.3 Test methsds 4.3.1 ln vitro genotoxicity Test methods shall normally be Chosen from the OECD Guidelines for testing of chemicals: 471, 472, 473, 476, 479, 480, 481 and 482. NOTE 8 Some devices incorporate substances designed to have an effect on cells, e.g. antibiotics or antiseptics that are designed to incorporate an effect on cells. 4.3.2 ln vivo genotoxicity If scientifically indicated or M7 vjtro test results indicate potential genotoxicity, then in vivo genotoxicity tests shall be undertaken. Test methods shall normally be Chosen from the OECD Guidelines for testing of chemicals: 474, 475, 478, 483, 484 and 485. NOTE 9 Recently transgenic animal test Systems are be- ing developed for genotoxicity testing. These tests may prove valuable for implant testing but their use had not been validated at the time of pu
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