1、BS EN ISO10993-11:2009ICS 11.100.20NO COPYING WITHOUT BSI PERMISSION EXCEPT AS PERMITTED BY COPYRIGHT LAWBRITISH STANDARDBiological evaluationof medical devicesPart 11: Tests for systemic toxicity(ISO 10993-11:2006)This British Standardwas published under theauthority of the StandardsPolicy and Stra
2、tegyCommittee on 30 June2009. BSI 2009ISBN 978 0 580 65828 0Amendments/corrigenda issued since publicationDate CommentsBS EN ISO 10993-11:2009National forewordThis British Standard is the UK implementation of EN ISO10993-11:2009. It is identical to ISO 10993-11:2006. It supersedes BS ENISO 10993-11:
3、2006 which is withdrawn.The UK participation in its preparation was entrusted to TechnicalCommittee CH/194, Biological evaluation of medical devices.A list of organizations represented on this committee can be obtained onrequest to its secretary.This publication does not purport to include all the n
4、ecessary provisionsof a contract. Users are responsible for its correct application.Compliance with a British Standard cannot confer immunityfrom legal obligations.EUROPEAN STANDARDNORME EUROPENNEEUROPISCHE NORMEN ISO 10993-11April 2009ICS 11.100.20 Supersedes EN ISO 10993-11:2006 English VersionBio
5、logical evaluation of medical devices - Part 11: Tests forsystemic toxicity (ISO 10993-11:2006)valuation biologique des dispositifs mdicaux - Partie 11:Essais de toxicit systmique (ISO 10993-11:2006)Biologische Beurteilung von Medizinprodukten - Teil 11:Prfungen auf systemische Toxizitt (ISO 10993-1
6、1:2006)This European Standard was approved by CEN on 12 April 2009.CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this EuropeanStandard the status of a national standard without any alteration. Up-to-date lists and bibliographical
7、references concerning such nationalstandards may be obtained on application to the CEN Management Centre or to any CEN member.This European Standard exists in three official versions (English, French, German). A version in any other language made by translationunder the responsibility of a CEN membe
8、r into its own language and notified to the CEN Management Centre has the same status as theofficial versions.CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland,France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latv
9、ia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal,Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.EUROPEAN COMMITTEE FOR STANDARDIZATIONCOMIT EUROPEN DE NORMALISATIONEUROPISCHES KOMITEE FR NORMUNGManagement Centre: Avenue Marnix 17, B-1000 Brussels 20
10、09 CEN All rights of exploitation in any form and by any means reservedworldwide for CEN national Members.Ref. No. EN ISO 10993-11:2009: EBS EN ISO 10993-11:2009EN ISO 10993-11:2009 (E) 3 Foreword The text of ISO 10993-11:2006 has been prepared by Technical Committee ISO/TC 194 “Biological evaluatio
11、n of medical devices” of the International Organization for Standardization (ISO) and has been taken over as EN ISO 10993-11:2009 by Technical Committee CEN/TC 206 “Biological evaluation of medical devices” the secretariat of which is held by NEN. This European Standard shall be given the status of
12、a national standard, either by publication of an identical text or by endorsement, at the latest by October 2009, and conflicting national standards shall be withdrawn at the latest by March 2010. Attention is drawn to the possibility that some of the elements of this document may be the subject of
13、patent rights. CEN and/or CENELEC shall not be held responsible for identifying any or all such patent rights. This document supersedes EN ISO 10993-11:2006. This document has been prepared under a mandate given to CEN by the European Commission and the European Free Trade Association, and supports
14、essential requirements of EU Directives 93/42/EEC on Medical Devices and 90/385/EEC on Active Implantable Medical Devices. For relationship with EU Directives, see informative Annex ZA and ZB, which are integral parts of this document. According to the CEN/CENELEC Internal Regulations, the national
15、standards organizations of the following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Polan
16、d, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and the United Kingdom. Endorsement notice The text of ISO 10993-11:2006 has been approved by CEN as a EN ISO 10993-11:2009 without any modification. BS EN ISO 10993-11:2009EN ISO 10993-11:2009 (E) 4 Annex ZA (informative) Relation
17、ship between this European Standard and the Essential Requirements of EU Directive 93/42/EEC on Medical Devices This European Standard has been prepared under a mandate given to CEN by the European Commission and the European Free Trade Association to provide a means of conforming to Essential Requi
18、rements of the New Approach Directive 93/42/EEC on medical devices. Once this standard is cited in the Official Journal of the European Communities under that Directive and has been implemented as a national standard in at least one Member State, compliance with the clauses of this standard given in
19、 table ZA confers, within the limits of the scope of this standard, a presumption of conformity with the corresponding Essential Requirements of that Directive and associated EFTA regulations. Table ZA Correspondence between this European Standard and Directive 93/42/EEC on medical devices Clause(s)
20、/sub-clause(s) of this EN Essential Requirements (ERs) of Directive 93/42/EEC Qualifying remarks/Notes 4, 5, 6 Annex I: 7.1, 7.2, 7.5 WARNING Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this standard. BS EN ISO 10993-11:2009EN ISO 10993-
21、11:2009 (E) 5 Annex ZB (informative) Relationship between this European Standard and the Essential Requirements of EU Directive 90/385/EEC on Active Implantable Medical Devices This European Standard has been prepared under a mandate given to CEN by the European Commission and the European Free Trad
22、e Association to provide a means of conforming to Essential Requirements of the New Approach Directive 90/385/EEC on active implantable medical devices. Once this standard is cited in the Official Journal of the European Communities under that Directive and has been implemented as a national standar
23、d in at least one Member State, compliance with the clauses of this standard given in table ZB confers, within the limits of the scope of this standard, a presumption of conformity with the corresponding Essential Requirements of that Directive and associated EFTA regulations. Table ZB Correspondenc
24、e between this European Standard and Directive 90/385/EEC on active implantable medical devices Clause(s)/sub-clause(s) of this EN Essential Requirements (ERs) of Directive 90/385/EEC Qualifying remarks/Notes 4, 5, 6 Annex I : 9 WARNING Other requirements and other EU Directives may be applicable to
25、 the product(s) falling within the scope of this standard. BS EN ISO 10993-11:2009ISO 10993-11:2006(E) ISO 2006 All rights reserved iiiContents Page Foreword iv Introduction . vi 1 Scope . 1 2 Normative references . 1 3 Terms and definitions. 1 4 General considerations 2 4.1 General. 2 4.2 Selection
26、 of animal species. 3 4.3 Animal status 3 4.4 Animal care and husbandry. 3 4.5 Size and number of groups . 3 4.6 Route of exposure 4 4.7 Sample preparation 4 4.8 Dosing 5 4.9 Body weight and food/water consumption 6 4.10 Clinical observations 6 4.11 Clinical pathology. 6 4.12 Anatomic pathology . 7
27、4.13 Study designs . 7 4.14 Quality of investigation 7 5 Acute systemic toxicity 7 5.1 General. 7 5.2 Study design . 8 5.3 Evaluation criteria. 9 5.4 Final report 10 6 Repeated exposure systemic toxicity (subacute, subchronic and chronic systemic toxicity) 11 6.1 General. 11 6.2 Study design . 12 6.
28、3 Evaluation criteria. 14 6.4 Final report 15 Annex A (informative) Routes of administration. 16 Annex B (informative) Dosage volumes. 18 Annex C (informative) Common clinical signs and observations. 19 Annex D (informative) Suggested haematology, clinical chemistry and urinalysis measurements . 20
29、Annex E (informative) Suggested organ list for histopathological evaluation 22 Annex F (informative) Information on material-mediated pyrogens . 24 Bibliography . 26 BS EN ISO 10993-11:2009ISO 10993-11:2006(E) iv ISO 2006 All rights reservedForeword ISO (the International Organization for Standardiz
30、ation) 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. Each member body interested in a subject for which a technical committee has been established has the right to be
31、 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. International Standar
32、ds are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2. The main task of technical committees is to prepare International Standards. Draft International Standards adopted by the technical committees are circulated to the member bodies for voting. Publication as an Intern
33、ational Standard requires approval by at least 75 % of the member bodies casting a vote. Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights. ISO shall not be held responsible for identifying any or all such patent rights. ISO 10993-11
34、 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices. This second edition cancels and replaces the first edition (ISO 10993-11:1993) which has been technically revised. ISO 10993 consists of the following parts, under the general title Biological evaluation of me
35、dical devices: Part 1: Evaluation and testing 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 in vitro cytotoxicity Part 6: Tests for local effects after implantatio
36、n Part 7: Ethylene oxide sterilization residuals Part 9: Framework for identification and quantification of potential degradation products Part 10: Tests for irritation and delayed-type hypersensitivity Part 11: Tests for systemic toxicity Part 12: Sample preparation and reference materials Part 13:
37、 Identification and quantification of degradation products from polymeric medical devices Part 14: Identification and quantification of degradation products from ceramics Part 15: Identification and quantification of degradation products from metals and alloys BS EN ISO 10993-11:2009ISO 10993-11:200
38、6(E) ISO 2006 All rights reserved v Part 16: Toxicokinetic study design for degradation products and leachables Part 17: Establishment of allowable limits for leachable substances Part 18: Chemical characterization of materials Part 19: Physico-chemical, morphological and topographical characterizat
39、ion Part 20: Principles and methods for immunotoxicology testing of medical devices BS EN ISO 10993-11:2009ISO 10993-11:2006(E) vi ISO 2006 All rights reservedIntroduction Systemic toxicity is a potential adverse effect of the use of medical devices. Generalized effects, as well as organ and organ s
40、ystem effects can result from absorption, distribution and metabolism of leachates from the device or its materials to parts of the body with which they are not in direct contact. This part of ISO 10993 addresses the evaluation of generalized systemic toxicity, not specific target organ or organ sys
41、tem toxicity, even though these effects may result from the systemic absorption and distribution of toxicants. Because of the broad range of medical devices, and their materials and intended uses, this part of ISO 10993 is not overly prescriptive. Whilst it addresses specific methodological aspects
42、to be considered in the design of systemic toxicity tests, proper study design must be uniquely tailored to the nature of the devices materials and its intended clinical application. Other elements of this part of ISO 10993 are prescriptive in nature, including those aspects that address compliance
43、with good laboratory practices and elements for inclusion in reporting. While some systemic toxicity tests (e.g. long term implantation or dermal toxicity studies) can be designed to study systemic effects as well as local, carcinogenic or reproductive effects, this document focuses only on those as
44、pects of such studies, which are intended to address systemic effects. Studies which are intended to address other toxicological endpoints are addressed in ISO 10993-3, ISO 10993-6, ISO 10993-10 and ISO/TS 10993-20. Pyrogenicity (see Annex F) represents an additional systemic effect which has histor
45、ically been included in this part of ISO 10993. However, efforts are being taken to address pyrogenicity in a dedicated, stand-alone standard. Finally, toxicology is an imperfect science. The outcome of any single test should not be the sole basis for making a determination of whether a device is sa
46、fe for its intended use. BS EN ISO 10993-11:2009INTERNATIONAL STANDARD ISO 10993-11:2006(E) ISO 2006 All rights reserved 1Biological evaluation of medical devices Part 11: Tests for systemic toxicity 1 Scope This part of ISO 10993 specifies requirements and gives guidance on procedures to be followe
47、d in the evaluation of the potential for medical device materials to cause adverse systemic reactions. 2 Normative references The following referenced documents are indispensable for the application of this document. For undated references, the latest edition of the referenced document (including an
48、y amendments) applies. ISO 10993-1, Biological evaluation of medical devices Part 1: Evaluation and testing ISO 10993-2, Biological evaluation of medical devices Part 2: Animal welfare requirements ISO 10993-12, Biological evaluation of medical devices Part 12: Sample preparation and reference mater
49、ials 3 Terms and definitions For the purposes of this document, the terms and definitions given in ISO 10993-1 and the following apply. 3.1 dose dosage amount of test sample administered (e.g. mass, volume) expressed per unit of body weight or surface area 3.2 dose-effect relationship between the dosage and the magnitude of a defined biological effect either in an individual or in a population sample 3.3 dose-response relationship of dosage to the spectrum of effects related to the exposure NOTE There a
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