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1、BRITISH STANDARD BS EN ISO 10993-11:1996 Biological evaluation of medical devices Part 11: Tests for systemic toxicity The European Standard EN ISO 10993-11:1995 has the status of a British Standard ICS 11.020 Licensed Copy: sheffieldun sheffieldun, na, Wed Nov 15 11:12:17 GMT+00:00 2006, Uncontroll
2、ed Copy, (c) BSI BS EN ISO 10993-11:1996 This British Standard, having been prepared under the direction of the Health and Environment Sector Board, was published under the authority of the Standards Board and comes into effect on 15 May 1996 BSI 03-1999 The following BSI references relate to the wo
3、rk on this standard: Committee reference CH/26 Draft for comment 94/504043 DC ISBN 0 580 25761 4 Committees responsible for this British Standard The preparation of this British Standard was entrusted to Technical Committee CH/26, Biological testing of medical and dental materials and devices, upon
4、which the following bodies were represented: Association of British Health-care Industries Association of Clinical Pathologists Association of Contact Lens Manufacturers British Medical Association British Orthopaedic Association British Plastics Federation British Society for Dental Research Britis
5、h Surgical Trades Association Department of Health Department of Trade and Industry (Laboratory of the Government Chemist) Disposable Hypodermic and Allied Equipment Manufacturers Association (UK) Electro Medical Trade Association Limited Home Office Medical Sterile Products Association National Blo
6、od Transfusion Service Royal College of Pathologists Royal College of Surgeons of England Society for Tissue Viability Sterilized Suture Manufacturers Association Surgical Dressings Manufacturers Association Amendments issued since publication Amd. No.DateComments Licensed Copy: sheffieldun sheffiel
7、dun, na, Wed Nov 15 11:12:17 GMT+00:00 2006, Uncontrolled Copy, (c) BSI BS EN ISO 10993-11:1996 BSI 03-1999i Contents Page Committees responsibleInside front cover National forewordii Foreword2 Introduction3 1Scope3 2Normative references3 3Definitions4 4Test sample requirements and recommendations4
8、5Method for extraction from medical devices5 6Selection of test procedures for systemic toxicity6 7Selection of test procedures for pyrogenicity8 8Assessment of results8 9Test report8 Annex A (informative) Addresses9 Annex ZA (normative) Normative references to international publications with their
9、relevant European publications10 Table 15 List of referencesInside back cover Licensed Copy: sheffieldun sheffieldun, na, Wed Nov 15 11:12:17 GMT+00:00 2006, Uncontrolled Copy, (c) BSI BS EN ISO 10993-11:1996 ii BSI 03-1999 National foreword This British Standard has been prepared by Technical Commi
10、ttee CH/26 and is the English language version of EN ISO 10993-11:1995 Biological evaluation of medical devices Part 11 Tests for systemic toxicity published by the European Committee for Standardization (CEN). It is identical with ISO 10993-11:1995 published by the International Organization for St
11、andardization (ISO). EN ISO 10993-11:1995 was produced as a result of international discussions in which the United Kingdom took an active part. It supersedes BS 5736-3:1988 and BS 5736-5:1988 which are withdrawn. Part 1 of BS EN 30993 provides guidance on the selection of tests for the initial asse
12、ssment of biological hazards in medical devices. For in vivo tests, attention is drawn to the provisions of the Animals (Scientific Procedures) Act 1986. A British Standard does not purport to include all the necessary provisions of a contract. Users of British Standards are responsible for their co
13、rrect application. Compliance with a British Standard does not of itself confer immunity from legal obligations. Cross-references Publication referred toCorresponding British Standard ISO 10993-1:1992BS EN 30993 Biological evaluation of medical devices Part 1:1994 Guidance on selection of tests ISO
14、10993-3:1993BS EN 30993 Biological evaluation of medical devices Part 3:1994 Tests for genotoxicity, carcinogenicity and reproductive toxicity Summary of pages This document comprises a front cover, an inside front cover, pages i and ii, the EN ISO title page, pages 2 to 10, an inside back cover and
15、 a back cover. This standard has been updated (see copyright date) and may have had amendments incorporated. This will be indicated in the amendment table on the inside front cover. Licensed Copy: sheffieldun sheffieldun, na, Wed Nov 15 11:12:17 GMT+00:00 2006, Uncontrolled Copy, (c) BSI EUROPEAN ST
16、ANDARD NORME EUROPENNE EUROPISCHE NORM EN ISO 10993-11 November 1995 ICS 11.020 Descriptors: Medical equipment, surgical equipment, surgical implants, dental equipment, dental materials, tests, biological tests, determination, toxicity English version Biological evaluation of medical devices Part 11
17、: Tests for systemic toxicity (ISO 10993-11:1993) Evaluation biologique des dispositifs mdicaux Partie 11: Essais de toxicit systmique (ISO 10993-11:1993) Biologische Beurteilung von Medizinprodukten Teil 11: Prfungen auf systemische Toxizitt (ISO 10993-11:1993) This European Standard was approved b
18、y CEN on 1994-12-17. CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references concerning such national standards
19、 may be obtained on application to the Central Secretariat or to any CEN member. This European Standard exists in three official versions (English, French, German). A version in any other language made by translation under the responsibility of a CEN member into its own language and notified to the
20、Central Secretariat has the same status as the official versions. CEN members are the national standards bodies of Austria, Belgium, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Luxembourg, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland and United Kingdom. CEN Europ
21、ean Committee for Standardization Comit Europen de Normalisation Europisches Komitee fr Normung Central Secretariat: rue de Stassart 36, B-1050 Brussels 1995 All rights of reproduction and communication in any form and by any means reserved in all countries to CEN and its members. Ref. No. EN ISO 10
22、993-11:1995 E Licensed Copy: sheffieldun sheffieldun, na, Wed Nov 15 11:12:17 GMT+00:00 2006, Uncontrolled Copy, (c) BSI EN ISO 10993-11:1995 BSI 03-1999 2 Foreword The text of the International Standard from ISO/TC 194, Biological evaluation of medical devices, of the International Standardization
23、Organization (ISO) has been taken over as a European Standard by the Technical Committee CEN/TC 206, Biocompatibility of medical and dental materials and devices. ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices: Part 1: Guidance on selectio
24、n 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 o
25、xide sterilization residuals; Part 9: Degradation of materials related to biological testing; Part 10: Tests for irritation and sensitization; Part 11: Tests for systemic toxicity; Part 12: Sample preparation and reference materials; Part 13: Identification and quantification of degradation products
26、 from polymers; Part 14: Identification and quantification of degradation products from ceramics; Part 15: Identification and quantification of degradation products from coated and uncoated metals and alloys; Part 16: General guidance on toxicokinetic study design for degradation products and leacha
27、bles; Part 17: Glutaraldehyde and formaldehyde residues in industrially sterilized medical devices. Future parts will deal with other relevant aspects of biological testing. Annex A of this part of ISO 10993 is for information only. This European Standard shall be given the status of a national stan
28、dard, either by publication of an identical text or by endorsement, at the latest by May 1996, and conflicting national standards shall be withdrawn at the latest by May 1996. This European Standard has been prepared under a mandate given to CEN by the European Commission and the European Free Trade
29、 Association, and supports essential requirements of EU Directive(s). According to the CEN/CENELEC Internal Regulations, the following countries are bound to implement this European Standard: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Luxembourg, Netherland
30、s, Norway, Portugal, Spain, Sweden, Switzerland and United Kingdom. Licensed Copy: sheffieldun sheffieldun, na, Wed Nov 15 11:12:17 GMT+00:00 2006, Uncontrolled Copy, (c) BSI EN ISO 10993-11:1996 BSI 03-19993 Introduction When a device releases constituents into the body, the constituents may, in su
31、fficiently large concentrations, lead to systemic toxicity. Clinical and experimental evidence of the systemic effects in this area is extremely sparse. This part of ISO 10993 provides methodologies for the evaluation of the systemic toxicity potential of medical devices. In addition, it includes py
32、rogenicity testing. Systemic toxicity is a developing experimental science and it is expected that each expert, in carrying out tests, will exercise judgement in the selection of a procedure from the lists of standards and documents quoted, thereby ensuring that the document that will best suit the
33、needs of a particular device is chosen. It is assumed that, in selecting the most appropriate test method from the list, the individual method(s) may have to be adapted, to evaluate the device under test more appropriately. It must be borne in mind that subcronic and/or chronic systemic toxicity tes
34、ting is not always necessary for a risk assessment. Such assessment might be made on the basis of qualitative and quantitative analytical measurements to evaluate the exposure of possible leachables from the device. This adaptation is intentional because of the developing nature of the science and b
35、ecause excessive rigidity or over-detailed specifications of methods could prevent application of more appropriate test methods. It is indeed intended that toxicological skill and judgement be applied during the course of the study. However, it is equally necessary that, where changes from proposed
36、methodologies are implemented, the rationale should be fully explained and supported scientifically. (See 6.4). It is essential, when evaluating the results of toxicological tests, to bear in mind the limitations and the potential variability of the tests. Similarly, it may not always be appropriate
37、 to extrapolate from animal studies to the human situation. While in vivo testing is designed to indicate possible health hazards, it does not eliminate the need for continuing monitoring and observations in humans. 1 Scope This part of ISO 10993 specifies methodologies for the evaluation of the sys
38、temic toxicity potential of medical devices which release constituents into the body. In addition, it includes pyrogenicity testing. The test methods cited in this part of ISO 10993 are from International Standards, national standards, directives and regulations. This part of ISO 10993 is concerned
39、with either the actual product or its leachables. It is intended that tests for extracts or leachables be conducted by choosing appropriate extraction vehicles to yield a maximum extraction of leachable materials, in order to conduct biological testing. 2 Normative references The following standards
40、 contain provisions which, through reference in this text, constitute provisions of this part of ISO 10993. At the time of publication, the editions indicated were valid. All standards are subject to revision, and parties to agreements based on this part of ISO 10993 are encouraged to investigate th
41、e possibility of applying the most recent editions of the standards indicated below. Members of IEC and ISO maintain registers of currently valid International Standards. ISO 10993-1:1992, Biological evaluation of medical devices Part 1: Guidance on selection of tests. ISO 10993-2:1992, Biological e
42、valuation of medical devices Part 2: Animal welfare requirements. ISO 10993-3:1992, Biological evaluation of medical devices Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity. ANSI/ADA No. 41, Biological Evaluation of Dental Materials. ASTM F 619:1986, Practice for Extraction
43、 of Medical Plastics, Vol. 13.01. ASTM F 750:1987, Practice for Evaluating Material Extracts by Systemic Injection in the Mouse. BS 5736-5:1982, Evaluation of medical devices for biological hazards Part 5: Method of test for systemic toxicity; assessment of pyrogenicity in rabbits of extracts from m
44、edical devices. SN 119 800, Biological Evaluation of Dental Materials, Swiss Association for Standardization. European Pharmacopoeia XXII, 1990. OECD Guidelines for Testing of Chemicals. Official Journal of the European Communities, 79/831. Official Journal of the European Communities, 84/449. Offic
45、ial Journal of the European Communities, 87/302. US Code of Federal Regulation 1500.40: Method of Testing Toxic Substances. US/EPA PB 86/108958. US/EPA PB 89/124077. Licensed Copy: sheffieldun sheffieldun, na, Wed Nov 15 11:12:17 GMT+00:00 2006, Uncontrolled Copy, (c) BSI EN ISO 10993-11:1996 4 BSI
46、03-1999 US/FDA Toxicological Principles for the Safety Assessment of Direct Food Additives, 1982. United States Pharmacopeia XXII: Biological Reactivity Tests, In-Vivo; The National Formulary XVII, Rockville, MD; Pharmacopeial Convention, 1990, pp. 1497-1500. 3 Definitions For the purposes of this p
47、art of ISO 10993, the definitions in ISO 10993-1 and the following definitions apply. 3.1 extraction vehicle liquid for use in the extraction of leachables from a device 3.2 extract liquid liquid which is tested for biological response after the device has been extracted within it 3.3 specimen unit(
48、s) of device placed into the extraction vehicle 3.4 blank extraction vehicle not containing the specimen under test which is used for comparison with the extract liquid 3.5 systemic toxicity toxicity involving the entire organism 3.6 acute toxicity adverse effects occurring after administration of a
49、 single dose or multiple doses of a test sample given within 24 h 3.7 subacute toxicity adverse effects occurring after administration of a single dose or multiple doses of a test sample per day given during a period of from 14 days to 28 days 3.8 subchronic toxicity adverse effects occurring after administration of a single dose or multiple doses of a test sample per day given during a part of the lifespan (usually 90 days but not exceeding 10 % of lifespan) 3.9 test sample device or extract thereof used for syste