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1、 Reference number ISO 10993-10:2002(E) ISO 2002 INTERNATIONAL STANDARD ISO 10993-10 Second edition 2002-09-01 Biological evaluation of medical devices Part 10: Tests for irritation and delayed-type hypersensitivity valuation biologique des dispositifs mdicaux Partie 10: Essais dirritation et dhypers
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5、riat at the address given below. ISO 2002 All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying and microfilm, without permission in writing from either ISO at the addre
6、ss below or ISOs member body in the country of the requester. ISO copyright office Case postale 56 CH-1211 Geneva 20 Tel. + 41 22 749 01 11 Fax + 41 22 749 09 47 E-mail copyrightiso.ch Web www.iso.ch Printed in Switzerland ii ISO 2002 All rights reserved ISO 10993-10:2002(E) ISO 2002 All rights rese
7、rved iii Contents Page Foreword iv Introduction vi 1 Scope 1 2 Normative references 1 3 Terms and definitions. 2 4 General principles Step-wise approach. 3 5 Pretest considerations 4 5.1 General. 4 5.2 Types of material. 4 5.3 Information on chemical composition 4 5.4 Material characterization 5 6 I
8、rritation tests 5 6.1 In vitro irritation tests . 5 6.2 Factors to be considered in design and selection of in vivo tests 5 6.3 Animal skin irritation test. 6 6.4 Human skin irritation test. 10 7 Delayed hypersensitivity tests. 14 7.1 Choice of test. 14 7.2 Choice of test sample concentrations 14 7.
9、3 Other important factors affecting the outcome of the test. 14 7.4 Maximization test for delayed hypersensitivity . 15 7.5 Closed-patch test for delayed hypersensitivity . 18 8 Key factors in interpretation of test results 20 Annex A (normative) Preparation of materials for irritation/sensitization
10、 testing. 21 Annex B (informative) Additional irritation tests. 23 Annex C (informative) Background information 41 Bibliography 45 ISO 10993-10:2002(E) iv ISO 2002 All rights reserved Foreword ISO (the International Organization for Standardization) is a worldwide federation of national standards bo
11、dies (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 represented on that committee. International organizatio
12、ns, 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 Standards are drafted in accordance with the rules given in the
13、ISO/IEC Directives, Part 3. 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 International Standard requires approval by at least 75 % of th
14、e member bodies casting a vote. Attention is drawn to the possibility that some of the elements of this part of ISO 10993 may be the subject of patent rights. ISO shall not be held responsible for identifying any or all such patent rights. ISO 10993-10 was prepared by Technical Committee ISO/TC 194,
15、 Biological evaluation of medical devices. This second edition cancels and replaces the first edition (ISO 10993-10:1995), which has been technically revised. ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices: Part 1: Evaluation and testing P
16、art 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 implantation Part 7: Ethylene oxide sterilization residual
17、s Part 8: Selection and qualification of reference materials for biological tests 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
18、 and reference materials Part 13: 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 ISO 10
19、993-10:2002(E) ISO 2002 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 Future parts will deal with other relevant aspects of biologic
20、al testing. This part of ISO 10993 is a harmonization of numerous standards and guidelines, including BS 5736, OECD Guidelines, U.S. Pharmacopoeia and the European Pharmacopoeia. It is intended to be the basic document for the selection and conduct of tests enabling evaluation of irritation and derm
21、al sensitization responses relevant to safety of medical materials and devices. Annex A forms a normative part of this part of ISO 10993. Annexes B and C are for information only. ISO 10993-10:2002(E) vi ISO 2002 All rights reserved Introduction This part of ISO 10993 assesses possible contact hazar
22、ds from chemicals released from medical devices that may produce skin and mucosal irritation, eye irritation and delayed contact hypersensitivity Some materials that are included in medical devices have been tested, and their skin or mucosal irritation or sensitization potential has been documented.
23、 Other materials and their chemical components have not been tested and may induce adverse effects when in contact with biological tissues. The manufacturer is thus obliged to evaluate each device for potential adverse effects prior to marketing. Traditionally, small animal tests are performed prior
24、 to testing on humans to help predict human response. More recently, in vitro tests as well as human tests have been added as alternatives. Despite progress and considerable effort in this direction, a review of findings suggests that currently no satisfactory in vitro test has been devised to elimi
25、nate the requirement for in vivo testing. Where appropriate, the preliminary use of in vitro methods is encouraged for screening purposes prior to animal testing. In order to reduce the number of animals used, this part of ISO 10993 presents a step-wise approach, with review and analysis of test res
26、ults at each stage. An animal test is usually required prior to human testing. It is intended that these studies be conducted using Good Laboratory Practice and comply with regulations related to animal welfare. Statistical analysis of data is recommended and should be used whenever appropriate. The
27、 tests included in this part of ISO 10993 are important tools for the development of safe products, provided that these are executed and interpreted by trained personnel. INTERNATIONAL STANDARD ISO 10993-10:2002(E) ISO 2002 All rights reserved 1 Biological evaluation of medical devices Part 10: Test
28、s for irritation and delayed-type hypersensitivity 1 Scope This part of ISO 10993 describes the procedure for the assessment of medical devices and their constituent materials with regard to their potential to produce irritation and delayed-type hypersensitivity. This part of ISO 10993 includes a) p
29、retest considerations, b) details of the test procedures, and c) key factors for the interpretation of the results. Instructions are given in annex A for the preparation of materials specifically in relation to the above tests. Supplementary tests which are required specifically for devices used int
30、radermally in the ocular, oral, rectal, penile and vaginal areas are given in annex B. 2 Normative references The following normative documents contain provisions which, through reference in this text, constitute provisions of this part of ISO 10993. For dated references, subsequent amendments to, o
31、r revisions of, any of these publications do not apply. However, parties to agreements based on this part of ISO 10993 are encouraged to investigate the possibility of applying the most recent editions of the normative documents indicated below. For undated references, the latest edition of the norm
32、ative document referred to applies. Members of ISO and IEC maintain registers of currently valid International Standards. ISO 10993-1:1997, Biological evaluation of medical devices Part 1: Evaluation and testing ISO 10993-2, Biological evaluation of medical devices Part 2: Animal welfare requirement
33、s ISO 10993-9, Biological evaluation of medical devices Part 9: Framework for identification and quantification of potential degradation products ISO 10993-12, Biological evaluation of medical devices Part 12: Sample preparation and reference materials ISO 10993-13, Biological evaluation of medical
34、devices Part 13: Identification and quantification of degradation products from polymeric medical devices ISO 10993-14 Biological evaluation of medical devices Part 14: Identification and quantification of degradation products from ceramics ISO 10993-15, Biological evaluation of medical devices Part
35、 15: Identification and quantification of degradation products from metals and alloys ISO 10993-18, Biological evaluation of medical devices Part 18: Chemical characterization of materials ISO 10993-10:2002(E) 2 ISO 2002 All rights reserved ISO 14155-1, Clinical investigation of medical devices for
36、human subjects Part 1: General requirements ISO 14155-2, Clinical investigation of medical devices for human subjects Part 2: Clinical investigation plans 3 Terms and definitions For the purposes of this part of ISO 10993, the terms and definitions given in ISO 10993-1 and the following apply. 3.1 a
37、llergen sensitizer substance/material which is capable of inducing specific hypersensitivity such that, on subsequent exposure to the same substance/material characteristic, allergic effects are produced 3.2 blank liquid solvent portion treated in the same manner as the identical solvent used for th
38、e preparation of test samples but without test material, and which is intended for the determination of a background response of the solvent 3.3 challenge elicitation process following the induction phase in which the immunological effects of subsequent exposures in an individual to the inducing mat
39、erial are examined 3.4 corrosion slow destruction of the texture or material of a tissue EXAMPLE The action of a strong irritant. 3.5 delayed-type hypersensitization induction of specific T-cell mediated immunological memory for an allergen to which an individual is exposed, resulting in a delayed-t
40、ype hypersensitivity reaction after secondary contact with the allergen 3.6 dose quantity to be administered to the test system at one time 3.7 erythema reddening of the skin or mucous membrane 3.8 eschar scab or discoloured slough of skin 3.9 induction process that leads to the de novo generation o
41、f an altered state of immunological reactivity in an individual to a specific material 3.10 irritant agent that produces irritation ISO 10993-10:2002(E) ISO 2002 All rights reserved 3 3.11 irritation localized non-specific inflammatory response to single, repeated or continuous application of a subs
42、tance/material 3.12 necrosis death of one or more cells, or portion of tissue or organ, resulting in irreversible damage 3.13 negative control material or substance which, when tested by the procedure described, demonstrates the suitability of the procedure to yield a reproducible, appropriate negat
43、ive, nonreactive or background response in the test system 3.14 oedema swelling due to abnormal infiltration of fluid into the tissues 3.15 positive control material or substance which, when tested by the procedure described, demonstrates the suitability of the procedure to yield a reproducible, app
44、ropriate positive or reactive response in the test system 3.16 solvent material or substance used to moisten, dilute, suspend, extract or dissolve the test substance material EXAMPLES Chemical, vehicle, medium, etc. 3.17 test material material, device, device portion or component thereof that is sam
45、pled for biological or chemical testing 3.18 test sample extract or portion of the test material that is subjected to biological or chemical testing 3.19 ulceration open sore representing loss of superficial tissue 4 General principles Step-wise approach The available methods for testing irritation
46、and sensitization were developed specifically to detect skin irritation and sensitization potential. Other types of adverse affect are generally not predicted by these tests. This part of ISO 10993 requires a step-wise approach, which shall include one or more of the following: a) characterization o
47、f test material, involving chemical characterization and analysis of the test sample according to the general principles described in ISO 10993-9, ISO 10993-13, ISO 10993-14, ISO 10993-15 and ISO 10993-18; b) literature review, including an evaluation of chemical and physical properties, and informa
48、tion on the irritation and sensitization potential of any product constituent as well as structurally related chemicals and materials; c) consideration of in vitro tests in preference to in vivo tests, and replacement of the latter as new in vitro methods become available and validated. At the prese
49、nt time there are no validated in vitro tests (other than simple screens) to detect irritants or sensitizers. d) in vivo animal tests; ISO 10993-10:2002(E) 4 ISO 2002 All rights reserved NOTE Acute in vivo animal studies are undertaken to test for materials not already classified as severe irritants or strong sensitizers by step a) or b). Materials that do not demonstrate an acute dermal irritation at single exposure may then be further evaluated following repeated exposure.