标准编号:	GB/T 16886.10-2017
中文名称:	医疗器械生物学评价 第10部分：刺激与皮肤致敏试验
英文名称:	Biological evaluation of medical devices―Part 10:Tests for irritation and skin sensitization
中标分类:	C30    医疗器械综合
行业分类:	GB    国家标准
发布机构:	中华人民共和国国家质量监督检验检疫总局 中国国家标准化管理委员会
发布日期:	2017-12-29
实施日期:	2018-7-1
标准状态:	to be superseded
被新标准替代:	GB/T 16886.10-2024 医疗器械生物学评价　第10部分：皮肤致敏试验
被替代日期:	2025-9-1
替代旧标准:	GB/T 16886.10-2005 医疗器械生物学评价 第10部分:刺激与迟发型超敏反应试验
翻译语言:	英文
文件格式:	PDF
中文字符数:	54000 字
翻译价格(元):	850.0
交付时间:	付款后 1 个工作日

Codeofchina.com is in charge of this English translation. In case of any doubt about the English translation, the Chinese original shall be considered authoritative. GB/T 16886 Biological Evaluation of Medical Devices consists of the following parts under the general title: ——Part 1: Evaluation and Testing within a Risk Management Process; ——Part 2: Animal Welfare Requirements; ——Part 3: Test for Genotoxicity, Carcinogenicity and Reproductive Toxicity; ——Part 4: Selection of Tests for Interactions with Blood; ——Part 5: Test for In-vitro Cytotoxicity; ——Part 6: Tests for Local Effects after Implantation; ——Part 7: Ethylene Oxide Sterilization Residuals; ——Part 9: Framework for Identification and Quantification of Potential Degradation Products; ——Part 10: Tests for Irritation and Skin Sensitization; ——Part 11: Tests for Systemic Toxicity; ——Part 12: Sample Preparation 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; ——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 Characterization of Materials; ——Part 20: Principles and Methods for Immunotoxicology Testing of Medical Devices. This is Part 10 of GB/T 16886. With regards to other biological tests, there will be standards for other parts. This standard is developed in accordance with the rules given in GB/T 1.1-2009. This part replaces GB/T 16886.10-2005 Biological Evaluation of Medical Devices - Part 10: Tests for Irritation and Delayed Type Hypersensitivity, compared with which, the following technical changes have been made: ——The standard name is modified; ——Terms and definitions are modified (Chapter 3; Chapter 3 of 2005 edition); ——"Material identification" is cancelled (see 5.4 of 2005 edition); ——Intradermal reaction test is adjusted from annex to text (see 6.4; Annex B of 2005 edition); ——Human skin irritation test method is adjusted from text to annex (see Annex C; 6.4 of 2005 edition); ——Murine local lymph node assay is added in skin sensitization test (see 7.2); ——In vitro tests for skin irritation is added (Annex D); ——Method for the preparation of extracts from polymeric test materials is added (see Annex E). This part is identical to ISO 10993-10: 2010 Biological Evaluation of Medical Devices - Part 10: Tests for Irritation and Skin Sensitization by means of translation. Chinese counterparts of the international documents given as normative references in this part are: GB/T 16886.2-2011 Biological Evaluation of Medical Devices - Part 2: Animal Welfare Requirements (ISO 10993-2: 2006, IDT) GB/T 16886.9-2017 Biological Evaluation of Medical Devices - Part 9: Framework for Identification and Quantification of Potential Degradation Products (ISO 10993-9: 2009, IDT) GB/T 16886.12-2017 Biological Evaluation of Medical Devices - Part 12: Sample Preparation and Reference Materials (ISO 10993-12: 2012, 1DT) GB/T 16886.13-2017 Biological Evaluation of Medical Devices - Part 13: Identification and Quantification of Degradation Products from Polymeric Medical Devices (ISO 10993-13: 2010, IDT) GB/T 16886.14-2003 Biological Evaluation of Medical Devices - Part 14: Identification and Quantification of Degradation Products from Ceramics (ISO 10993-14: 2001, IDT) GB/T 16886.15-2003 Biological Evaluation of Medical Devices - Part 15: Identification and Quantification of Degradation Products from Metals and Alloys (ISO 10993-15: 2000, IDT) GB/T 16886.18-2011 Biological Evaluation of Medical Devices - Part 18: Chemical Characterization of Materials (ISO 10993-18: 2005, IDT) This part was proposed by China Food and Drug Administration. This part is under the jurisdiction of the National Technical Committee on Biological Evaluation on Medical Device of Standardization Administration of China (SAC/TC 248). The previous editions of the standard replaced by this part are as follows: ——GB/T 16886.10-2000; ——GB/T 16886.10-2005. Introduction This part of GB/T 16886 assesses possible contact hazards from chemicals released from medical devices, which may produce skin and mucosal irritation, eye irritation or skin sensitization. Some materials that are included in medical devices have been tested, and their skin or mucosal irritation or sensitization potential has been documented. Other materials and their chemical components have not been tested and may induce adverse effects when in contact with human tissue. The manufacturer is thus obliged to evaluate each device for potential adverse effects prior to marketing. Traditionally, small animal tests are performed prior to testing on humans to help predict human response. More recently, in vitro tests as well as human tests have been added as adjuncts or 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 eliminate 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 presents a step-wise approach, with review and analysis of test results 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. This part is intended for use by professionals, appropriately qualified by training and experience, who are able to interpret its requirements and judge the outcomes of the evaluation for each medical device, taking into consideration all the factors relevant to the device, its intended use and the current knowledge of the medical device provided by review of the scientific literature and previous clinical experience. The tests included in this part are important tools for the development of safe products, provided that these are executed and interpreted by trained personnel. This part is based on numerous standards and guidelines, including 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 dermal sensitization responses relevant to safety of medical materials and devices. Biological Evaluation of Medical Devices - Part 10: Tests for Irritation and Skin Sensitization 1 Scope This part of GB/T 16886 describes the procedure for the assessment of medical devices and their constituent materials with regard to their potential to produce irritation and skin sensitization. This part includes: a) pretest considerations for irritation, including in silico and in vitro methods for dermal exposure; b) details of in vivo (irritation and sensitization) test procedures; 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. In Annex B several special irritation tests are described for application of medical devices in areas other than skin. 2 Normative References The following referenced documents are indispensable for the application of this document. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amendments) applies. GB/T 16886.1-2011 Biological Evaluation of Medical Devices - Evaluation and Testing Within a Risk Management Process (ISO 10993-1: 2009, IDT) ISO 10993-2 Biological Evaluation of Medical Devices - Part 2: Animal Welfare Requirements 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 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 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 14155-1 Clinical Investigation of Medical Devices for Human Subjects - Part 1: General Requirement ISO 14155-2 Clinical Investigation of Medical Devices for Human Subjects - Part 2: Clinical Investigation Plants 3 Terms and Definitions For the purposes of this document, the terms and definitions given in GB/T 16886.1-2011 and the following apply. 3.1 allergen sensitizer substance or material that is capable of inducing a specific hypersensitivity reaction upon repeated contact with that substance or material 3.2 blank extraction vehicle not containing the test material, retained in a vessel identical to that which holds the test material and subjected to identical conditions to which the test material is subjected during its extraction Note: the purpose of the blank control is to evaluate possible confounding effects due to the extraction vessel, vehicle and extraction process. 3.3 challenge elicitation process following the induction phase, in which the immunological effects of subsequent exposures in an individual to the inducing material are examined 3.4 dose dosage amount of test sample administered (e.g. mass, volume) expressed per unit of body weight or surface area Note: the terms are often used interchangeably (more commonly dosage). 3.5 erythema reddening of the skin or mucous membrane 3.6 eschar scab or discolored slough of skin 3.7 extract liquid or suspension that results from exposing a test or control material to a solvent under controlled conditions 3.8 induction process that leads to the de novo generation of an enhanced state of immunological activity in an individual, to a specific material 3.9 irritant agent that produces irritation 3.10 irritation localized non-specific inflammatory response to single, repeated or continuous application of a substance/material Note: skin irritation is a reversible reaction and is mainly characterized by local erythema (redness) of the skin. 3.11 necrosis cell death as a direct result of irreversible changes caused by injury or disease Note: one should be aware that tissue repair will occur either resulting in complete functional restoration or resulting in scar formation. 3.12 negative control any well-characterized material or substance that, when tested by a specific procedure, demonstrates the suitability of the procedure to yield a reproducible, appropriately negative, non-reactive or minimal response in the test system Note: in practice, negative controls include blanks, vehicles/solvents and reference materials. 3.13 oedema swelling due to abnormal infiltration of fluid into the tissues 3.14 positive control any well-characterized material or substance that, when evaluated by a specific test method, demonstrates the suitability of the test system to yield a reproducible, appropriately positive or reactive response in the test system 3.15 skin corrosion production of irreversible damage to the skin, manifested as visible necrosis through the epidermis and into the dermis, following application of a test sample Example: the action of a compound/chemical/test sample resulting in ulceration of skin (see 3.19). 3.16 skin sensitization allergic contact dermatitis immunologically mediated cutaneous reaction to a substance Note: in the human, the responses can be characterized by pruritis, erythema, oedema, papules, vesicles, bullae or a combination of these. In other species the reactions can differ and only erythema and oedema can be seen. 3.17 test material material, device, device portion or component thereof that is sampled for biological or chemical testing 3.18 test sample material, device, device portion, component, extract or portion thereof that is subjected to biological or chemical testing or evaluation 3.19 ulceration open sore representing loss of superficial tissue 3.20 vehicle liquid used to moisten, dilute, suspend, extract or dissolve the test substance/material 4 General Principles - Step-Wise Approach The available methods for testing irritation and sensitization were developed specifically to detect skin and mucous membrane irritation and skin sensitization potential. Other types of adverse effect are generally not predicted by these tests. For medical devices that are used as implants or external communicating devices, intradermal testing is more relevant in approaching the application and so for detection of irritation activity, intracutaneous testing shall be used as described in 6.4. This part requires a step-wise approach, which shall include one or more of the following: a) characterization of 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 information on the irritation and sensitization potential of any product constituent as well as structurally-related chemicals and materials; c) in accordance with ISO 10993-2, in vitro tests in preference to in vivo tests shall be considered, and replacement of the latter as new in vitro tests are scientifically validated and become reasonably and practicably available. For the evaluation of skin irritation and corrosion, in vitro alternatives are available for chemicals; there are currently no internationally validated and accepted in vitro tests to detect sensitizers; d) in vivo animal tests: in order to ensure reproducibility and sensitivity, a test of a positive-control substance for irritation and skin sensitization shall be included in each assay by the testing laboratory in order to validate the test system and demonstrate a positive response; for guinea pig sensitization assays, however, when consistency has been demonstrated over a six month or more extended period, a positive control does not need to be included in every assay, but may be run at regular intervals which shall not exceed six months. Note 1: sensitization can at the moment only be determined by an in vivo assay. This can be accomplished by using the local lymph node assay (LLNA) in mice, the occluded patch test in guinea pigs or the guinea pig maximization test (GPMT). For single chemicals the LLNA is now the preferred assay for determining the sensitizing potential. See References [69], [88], [90]. Note 2: in vivo animal tests are appropriate when test materials cannot be characterized and risk assessments cannot be undertaken using information obtained by the means set out in a), b) and c). Note 3: for sensitization assays in guinea pigs, ten animals are normally used for positive control once every six months. Fewer guinea pigs can be used when an assay with a positive control substance is performed more frequently than once every six months. At least five test animals with a positive substance and five control animals should be used. e) non-invasive human tests/clinical trials; if the material has been demonstrated not to be an irritant, a sensitizer or toxic in animals, studies on skin irritation may then be considered in humans. Clinical studies in accordance with ISO 14155-1, ISO 14155-2 and to ethics principles shall not be performed before the results of the other evaluations in a) to d) are known. 5 Pretest Considerations 5.1 General It is important to emphasize that pretest considerations may result in the conclusion that testing for irritation and/or sensitization is not necessary. The requirements given in Chapter 5 of GB/T 16886-1: 2011 and the following apply. Non-sterile samples shall be investigated by topical investigation only, as the possibility of microbial contamination of the test sample could confound the final assay interpretation. In cases where the sterility of a test sample cannot be guaranteed, but the sample is still considered to be non-contaminated, intradermal administration may be justified. 5.2 Types of material 5.2.1 Initial considerations It shall be taken into consideration that, during manufacture and assembly of medical devices, additional chemical components may be used as processing aids, e.g. lubricants or mould-release agents. In addition to the chemical components of the starting material and manufacturing process aids, adhesive/solvent residues from assembly and also sterilant residues or reaction products resulting from the sterilization process may be present in a finished product. Whether these components pose a health hazard/risk depends on the leakage or degradation characteristics of the finished products. These components shall be taken into account for their potential irritation/sensitization activity. 5.2.2 Ceramics, metals and alloys These materials are normally less complex than polymers and biologically derived materials in terms of the number of chemical constituents. 5.2.3 Polymers These materials are normally chemically more complex than those in 5.2.2 in terms of composition. A number of reaction products/impurities/additives may be present and the completeness of polymerization may vary.

Foreword i Introduction iv 1 Scope 2 Normative References 3 Terms and Definitions 4 General Principles - Step-Wise Approach 5 Pretest Considerations 6 Irritation Tests 7 Skin Sensitization Tests 8 Key Factors in Interpretation of Test Results Annex A (Normative) Preparation of Materials for Irritation/Sensitization Testing Annex B (Normative) Special Irritation Tests Annex C (Normative) Human Skin Irritation Test Annex D (informative) In Vitro Tests for Skin Irritation Annex E (Informative) Method for the Preparation of Extracts from Polymeric Test Materials Annex F (Informative) Background Information Bibliography

ICS 11.100.20 C 30 中华人民共和国国家标准 GB/T 16886.10—2017/ISO 10993-10：2010 代替GB/T 16886.10—2005 医疗器械生物学评价 第10部分：刺激与皮肤致敏试验 Biological evaluation of medical devices— Part 10：Tests for irritation and skin sensitization (ISO 10993—10：2010，IDT) 2017-12-29发布 2018-07-01实施 中华人民共和国国家质量监督检验检疫总局 中国国家标准化管理委员会 发布 前言 GB/T 16886《医疗器械生物学评价》，由下列部分组成： ——第1部分：风险管理过程中的评价与试验； ——第2部分：动物福利要求； ——第3部分：遗传毒性、致癌性和生殖毒性试验； ——第4部分：与血液相互作用试验选择； ——第5部分：体外细胞毒性试验； ——第6部分：植入后局部反应试验； ——第7部分：环氧乙烷灭菌残留量； ——第9部分：潜在降解产物的定性与定量框架； ——第10部分：刺激与皮肤致敏试验； ——第11部分：全身毒性试验； ——第12部分：样品制备与参照材料； ——第13部分：聚合物医疗器械降解产物的定性与定量； ——第14部分：陶瓷降解产物定性与定量； ——第15部分：金属与合金降解产物定性与定量； ——第16部分：降解产物与可沥滤物毒代动力学研究设计； ——第17部分：可沥滤物允许限量的建立； ——第18部分：材料化学表征； ——第19部分：材料物理化学、形态学和表面特性表征； ——第20部分：医疗器械免疫毒理学试验原则和方法。 本部分为GB/T 16886的第10部分。 有关其他方面的生物试验将有其他部分的标准。 本部分按照GB/T 1.1—2009给出的规则起草。 本部分代替GB/T 16886.10—2005《医疗器械生物学评价 第10部分刺激与迟发型超敏反应试验》，与GB/T 16886.10—2005相比，主要技术变化如下： ——修改了标准名称； ——修改了术语和定义(第3章，2005年版的第3章)； ——取消了“材料鉴别”(见2005年版的5.4)； ——皮内反应试验由附录调整到正文中(见6.4，2005年版的附录B)； ——人体皮肤刺激试验方法由正文调整到附录(见附录C，2005年版的6.4)； ——皮肤致敏试验增加小鼠局部淋巴结检验法(见7.2)； ——增加了体外皮肤刺激试验(见附录D)； ——增加了聚合物试验材料浸提液制备方法(见附录E)。 本部分使用翻译法等同采用ISO 10993—10：2010《医疗器械生物学评价 第10部分：刺激与皮肤致敏试验》。 与本部分中规范性引用的国际文件有一致性对应关系的我国文件如下： GB/T 16886.2—2011医疗器械生物学评价 第2部分：动物福利要求(ISO 10993—2：2006，IDT) GB/T 16886.9—2017 医疗器械生物学评价 第9部分：潜在降解产物的定性和定量框架(ISO 10993—9：2009，IDT) GB/T 16886.12—2017 医疗器械生物学评价 第12部分：样品制备与参照材料(ISO 10993—12：2012，1DT) GB/T 16886.13—2017 医疗器械生物学评价 第13部分：聚合物医疗器械的降解产物的定性与定量(ISO 10993—13：2010，IDT) GB/T 16886.14—2003 医疗器械生物学评价 第14部分：陶瓷降解产物的定性与定量(ISO 10993—14：2001，IDT) GB/T 16886.15—2003 医疗器械生物学评价 第15部分：金属与合金降解产物的定性与定量(ISO 10993—15：2000，IDT) GB/T 16886.18—2011医疗器械生物学评价 第18部分：材料化学表征(ISO 10993—18：2005，IDT) 本部分由国家食品药品监督管理总局提出。 本部分由全国医疗器械生物学评价标准化技术委员会(SAC/TC 248)归口。 本部分起草单位：国家食品药品监督管理局济南医疗器械质量监督检验中心；深圳市医疗器械检测中心。 本部分主要起草人：王昕、曹苹、范春光、刘尧、徐伟区。 本部分所代替标准的历次版本发布情况为： ——GB/T 16886.10—2000； ——GB/T 16886.10—2005。 引 言 GB/T 16886的本部分用于评定从医疗器械中释放出的化学物可能引起的接触性危害，包括导致皮肤与黏膜刺激、眼刺激或皮肤致敏反应。 医疗器械中所含有的某些材料已进行过试验.其潜在的皮肤、黏膜刺激或致敏作用已被确认。其他一些未做过试验的材料及其化学成分在与人体组织接触时可能会产生不良作用。因此，制造商有责任在投放市场前评价器械的潜在不良作用。 传统上，人体试验之前要先进行小动物试验，以有助于预测人体反应。最近，还增加了作为辅助或可供选择的体外试验以及人体试验。尽管在这方面已做了很大努力并取得了一些进展，但结果显示目前所设计的体外试验尚不能令人满意，因此还不能够取消体内试验。适宜时，本部分鼓励将体外预试方法作为动物试验前的筛选试验。为了减少所用动物数量，本部分提出逐步评价方法，在每一阶段都对试验结果进行评审和分析。人体试验之前一般要求先进行动物试验。 进行这些研究时应遵循良好实验室质量管理规范并遵守与动物福利有关的规则。建议在适宜的情况下对数据进行统计分析。 本部分由经过培训有经验、有适当资格的专业人员使用，能够解释标准要求并能考虑与器械全部相关因素，包括器械的预期用途、由科学文献的评审和先前临床经验给出的该医疗器械的当前知识，来判定每一医疗器械的评价结果。 本部分所包括的试验是安全产品开发的重要工具，由受过培训的人员进行试验并解释试验结果。 本部分以诸多标准和导则为基础，包括OECD导则、美国药典和欧洲药典。本部分可作为基础文件，用于选择和实施能评价与医用材料和器械安全性相关的刺激和皮肤致敏反应的试验。 医疗器械生物学评价 第10部分：刺激与皮肤致敏试验 1 范围 GB/T 16886的本部分描述了医疗器械及其组成材料潜在刺激和皮肤致敏的评价步骤。 本部分包括： a)刺激试验前的考虑，包括皮肤接触方面的生物模拟实验和体外方法； b)详细的体内(刺激和致敏)试验步骤； c)结果解释的关键因素。 附录A给出了与上述试验有关的特定材料制备说明。附录B给出了适用于医疗器械的除皮肤部位之外的几种特殊刺激试验。 2规范性引用文件 下列文件对于本文件的应用是必不可少的。凡是注日期的引用文件，仅注日期的版本适用于本文件。凡是不注日期的引用文件，其最新版本(包括所有的修改单)适用于本文件。 GB/T 16886.1—2011 医疗器械生物学评价 第1部分：风险管理过程中的评价与试验(ISO 10993—1：2009，IDT) ISO 10993-2 医疗器械生物学评价 第2部分：动物福利要求(Biological evaluation of medical devices—Part 2：Animal welfare requirements) ISO 10993—9 医疗器械生物学评价 第9部分：潜在降解产物的定性和定量框架(Biological eval—uation of medical devices—Part 9：Framework for identification and quantification of potential degra-dation products) ISO 10993—12 医疗器械生物学评价 第12部分：样品制备与参照样品(Biological evaluation of medical devices—Part 12：Sample preparation and reference materials) ISO 10993-13 医疗器械生物学评价 第13部分：聚合物医疗器械的降解产物的定性与定量(Bi-ological evaluation of medical devices—Part 13：Identification and quantification of degradation products from polymeric medical devices) ISO 10993—14 医疗器械生物学评价 第14部分：陶瓷降解产物的定性与定量(Biological evalua-tion of medical devices—Part 14：Identification and quantification of degradation products from ceram-ics) ISO 10993—15医疗器械生物学评价 第15部分：金属与合金降解产物的定性与定量(Biological evaluation of medical devices—Part 15：Identification and quantification of degradation products from metals and alloys) ISO 10993—18医疗器械生物学评价 第18部分：材料化学表征(Biological evaluation of medical devices—Part 18：Chemical characterization of materials) ISO 14155—1 用于人体的医疗器械临床研究 第1部分：通用要求(Clinical Investigation of Med—ical Devices for Human Subjects—Part 1：General Requirement) ISO 14155—2用于人体的医疗器械临床研究 第2部分：临床研究方案(Clinical investigation of medical devices for human subjects—Part 2：Clinical investigation plants) 3术语和定义 GB/T 16886.1—2011界定的以及下列术语和定义适用于本文件。 3.1 变应原 allergen 致敏原 sensitizer 在反复接触后能引起某一类特异性超敏反应的物质或材料。 3.2 空白 blank 不加试验材料的浸提介质，置于与试验材料相同的容器中，并经受与试验材料相同的浸提条件。 注：空白对照的目的是评价浸提容器、浸提介质和浸提过程可能的干扰作用。 3.3 激发 challenge 诱发 elicitation 诱导阶段后的过程，在这一阶段检验个体后续接触诱导材料的免疫学反应。 3.4 剂量dose 用量dosage 按单位重量或表面积表示的试验样品的给予量(如质量、体积)。 注：这两个术语通常可交换使用(用量较为常用)。 3.5 红斑 erythema 皮肤或黏膜发红。 3.6 焦痂 eschar 皮肤结痂或变色的蜕皮。 3.7 浸提液 extract 某一试验材料或对照材料在控制条件下与溶剂接触后获取到的液体或悬浮液。 3.8 诱导 induction 导致个体对某一特定材料重新形成免疫学活性增强状态的过程。 3.9 刺激物 irritant 引起刺激的物质。 3.10 刺激 irritation 一次、多次或持续与一种物质/材料接触所引起的局部非特异性炎症反应。 注：皮肤刺激是一种可逆反应，主要以皮肤局部红斑(发红)为特征。 3.11 坏死 necrosis 由于损伤或疾病造成的不可逆改变直接导致细胞死亡。 注：宜注意组织修复会导致完全性功能恢复或瘢痕形成。 3.12 阴性对照 negative control 当按规定步骤试验时，在试验系统中证明试验步骤适宜性的出现可再现的适当的阴性、无反应或最小反应的经充分表征的材料或物质。 注：实际操作中，阴性对照包括空白、介质/溶剂和参照材料。 3.13 水肿 oedema 液体向组织内异常渗透引起的肿胀。 3.14 阳性对照positive control 当按规定试验方法评价时，在试验系统中证明试验步骤适宜性的出现可再现的适当的阳性或反应性应答的经充分表征的材料或物质。 3.15 皮肤腐蚀 skin corrosion 应用某一试验样品后皮肤的不可逆性损伤结果，表现为从表皮至真皮的明显坏死。 示例：混合物/化学物/试验样品作用所导致的皮肤溃疡(见3.19)。 3.16 皮肤致敏 skin sensitization 变应性接触性皮炎 免疫介导的对某种物质的皮肤反应。 注：这种反应在人体上以瘙痒、红斑、水肿、丘疹、大(小)水泡、或此类综合症状为特征，其他种属表现可能不同，仅出现红斑和水肿。 3.17 试验材料test material 取样供生物学或化学试验用的材料、器械、器械的一部分或其组件。 3.18 试验样品test sample 供生物学或化学试验或评价用的材料、器械、器械的一部分、组件、浸提液或浸提液的一部分。 3.19 溃疡 ulceration 表现为表浅组织缺损的开放性溃烂。 3.20 介质 vehicle 用于湿化、稀释、悬浮、浸提或溶解试验物质/材料的液体。 4基本原则一逐步评价法 现有的检验刺激与致敏的试验方法特别设定为测定潜在的皮肤刺激和黏膜刺激以及皮肤致敏作用，这些试验一般不预示其他类型的不良作用。对于植入医疗器械或外部接入医疗器械，皮内注射试验更为接近实际应用，因此用于检验刺激作用，应按照6.4的描述进行皮内试验。 本部分要求逐步评价法，应包括下列一项或多项内容： a)按照ISO 10993—9、ISO 10993—13、ISO 10993—14、ISO 10993—15和ISO 10993—18的基本原则，对试验材料进行表征，涉及对试验样品进行化学表征和分析； b)文献检索，包括对试验材料化学和物理性能的评价、任何产品组分以及相关结构的化学物和材料的潜在刺激和致敏信息； c)按照ISO 10993.2，应考虑体外试验优先于体内试验，若新的体外法经科学认可并具有合理性和实用性时，可取代体内试验。已有体外替代方法用于化学物皮肤刺激和腐蚀的评价，目前尚没有经国际确认并接受的检验致敏物的体外试验； d)体内动物试验：为了确保试验的再现性和敏感性，检测实验室应在每次刺激与致敏试验中包括阳性对照物试验，以验证试验系统并证实阳性反应。然而，对于豚鼠致敏试验，当试验系统一致性在6个月或更长持续时间得以证实时，则每次试验中无需包括阳性对照，但每隔一定时间(不应超过6个月)要进行阳性对照试验； 注1：目前对致敏作用只能通过体内试验进行测定，可采用小鼠局部淋巴结试验(LLNA)、豚鼠封闭贴敷试验或豚鼠最大剂量试验(GPMT)。LLNA为目前测定单一化学物潜在致敏作用的首选方法，见参考文献[69]、[88]、[90]。 注2：试验材料不能表征或采用在a)、b)和c)阶段获取的信息不能进行风险评定时，体内动物试验适用。 注3：对于豚鼠致敏试验，每6个月一般要采用10只动物用于阳性对照。在比每6个月更频繁的时间内进行阳性对照物质试验时，可采用较少的豚鼠，宜至少采用5只试验动物用于阳性物质和5只对照动物。 e)非侵入性人体试验/临床试验：如材料经证实对动物无刺激、无致敏或无毒性，可考虑进行人体皮肤刺激研究。 在获知a)～d)中的其他评价结果之前，按照ISO 14155-1和ISO 14155—2和伦理准则不应进行临床试验。 5试验前的考虑 5.1 总则 需要强调的是试验前的考虑是非常重要的，其可以得出无需进行刺激和/或致敏试验的结论。 GB/T 16886.1—2011的第5章中给出的和下列条款的要求是适用的。 非无菌样品只应通过局部试验进行研究，因为试验样品微生物污染的可能性会干扰最终试验解释。对不能保证无菌但仍认为是无污染的试验样品，皮内试验可能要进行论证。 5.2材料类型 5.2.1 基本考虑 应考虑在医疗器械制造和装配期间可能用做加工助剂(如润滑剂或脱模剂)的其他化学成分。除了原材料和制造加工助剂的化学成分外，装配黏合剂/溶剂残留物以及灭菌残留物或灭菌过程所致的反应性产物可能存在于终产品中，这些成分是否产生健康危害(风险)取决于终产品的渗漏或降解性能，应考虑这些成分潜在的刺激/致敏活性。 5.2.2 陶瓷、金属和合金 这些材料在化学成分数量方面一般比聚合物和生物衍生材料简单。 5.2.3聚合物 这类材料在化学成分方面一般要比5.2.2中复杂一些，可能有若干反应性产物/杂质/添加剂，而且聚合反应的完全程度可能会有不同。 5.2.4生物衍生材料 这类材料在其成分方面特别复杂，也常含有加工残留物，如交联剂和抗生素。生物材料样品之间的成分可能是不一致的。 本部分中的方法不是为检验生物衍生材料而设计，因此不足以检验该类材料，例如本部分中的试验未考虑跨物种致敏作用。 5.3化学成分方面的信息 5.3.1 总则 应确立材料化学成分方面的完整的定性数据，也应获取与生物安全性相关的信息及定量数据。如没有定量数据，说明应形成文件并进行论证。 5.3.2现有的数据来源 可能的情况下应从原材料供应商处索取化学成分方面的定性与定量信息。 聚合物常要求专利信息的使用权，宜签署转让和使用这种机密信息的条款。 还应从产品制造的制造链的适宜成员中(包括半成品和零件制造商)索取其他任何生产过程中的添加剂(如脱模剂)的定性信息。 在没有任何化学成分数据的情况下建议研究文献，以确定原材料和添加剂的大概特性，这样有助于选择相关材料最适宜的分析方法。 应按照ISO 10993—18测定最终产品的化学成分。 注：可依据ISO或美国试验材料协会(ASTM)标准和/或用户的要求规定陶瓷、金属和合金的成分，但为了获取完整的成分定性与定量资料，可能还需要要求原材料供应商或制造厂以及零件制造厂提供这些信息，以保证还能鉴别加工助剂。能够获取这些数据的另一来源是主管部门掌控的材料文件。 6刺激试验 6.1体外刺激试验 体外试验，即大鼠皮肤经皮电阻抗(TER)试验和人体皮肤模型试验，已被国际间确认并接受为评价化学物皮肤腐蚀性的替代试验(OECD导则430[9]和43[10])方法。在研究替代方法的同时，各国际和各国家组织一直在进行体外皮肤刺激试验的建立和确认工作，有些团体正在研究试验方法中动物和人体反应的量化指标，以能够应用无创技术更好地限定终点(见F.1)。 注：欧洲替代方法验证中心咨询委员会(ESAC)2007年对用于化学物皮肤刺激测定的一种体外人体皮肤模型的确认过程进行了评价，见参考文献[101]。附录D描述了应用体外人体模型评定化学物引起皮肤刺激的潜能。 目前体外皮肤刺激试验仅确认用于纯化学物，不适用于医疗器械浸提液。为了应用这些方法检验医疗器械的刺激潜能，有必要对这种特定应用进一步确认。 6.2体内刺激试验一体内试验设计和选择中应考虑的因素 医疗器械的刺激试验可用终产品和/或浸提液进行。 影响刺激试验结果的因素包括： a)器械用于斑贴试验时的特性； b)试验材料的剂量； c)试验材料的应用方法； d)封闭的程度； e)应用部位； f)接触周期和接触次数； g)评价试验所采用的技术。 附录F提供了其他背景信息。 下列详细的试验方案的灵活性有时可使研究者提高试验的敏感性，以适应各种使用和人群接触条件，但试验步骤的一致性有助于不同材料和不同实验室的试验结果具有可比性。 评价多次和/或长期接触的器械和材料的要求已包括在试验步骤中，试验设计应高于预期的实际临床接触条件(时间和/或浓度)，在解释试验结果时应注意到该因素。 试验样品的pH如≤2.0或≥11.5，应认为是一种刺激物，不必进一步试验。然而，试验结果也显示，试验材料的酸碱度并非是导致严重损伤的能力的唯一因素，试验材料的浓度、接触时间以及许多其他理化性能也都是重要的因素。 特殊情况下需要进一步的风险表征/评定，可能需要检验材料的刺激性或材料的pH在上述范围之外，这种情况应论证并形成文件。 6.3动物刺激试验 6.3.1 原理 采用相关动物模型对材料在试验条件下产生皮肤刺激反应的潜能做出评定。 家兔为首选试验动物。 6.3.2 试验材料 固体或液体试验材料应按附录A规定进行制备。 应证明试验的敏感性，可通过在试验中设置一组阳性对照来加以证实。然而，采用阳性对照来证实敏感性仅限于实验室在之前的6个月内应用该试验方法未产生阳性结果的情况。 注：十二烷基硫酸钠(SLS)是适宜的阳性对照。 6.3.3动物与管理 应使用3只健康、初成年的白化兔，雌雄不限，同一品系，体重不低于2 kg。如预期有刺激反应，初试应考虑使用1只动物。除非出现明确的阳性反应[红斑或水肿记分大于2(见表1)]，否则应至少再使用2只动物进行试验。在使用了至少3只动物后，如为疑似反应，应考虑进行复试。 应使动物适应环境，并按ISO 10993—2的规定饲养。 表1 皮肤反应记分系统 反 应 刺激记分 红斑和焦痂形成 无红斑 0 极轻微红斑(勉强可见) 1 清晰红斑 2 中度红斑 3 重度红斑(紫红色)至无法进行红斑分级的焦痂形成 4 表1(续) 反 应 刺激记分 水肿形成 无水肿 0 极轻微水肿(勉强可见) 1 清晰水肿(肿起边缘清晰) 2 中度水肿(肿起约1 mm) 3 重度水肿(肿起超过1 mm，并超出接触区) 4 刺激最高记分 8 应记录并报告皮肤部位的其他异常情况。 6.3.4试验步骤 6.3.4.1动物准备 动物的皮肤状况是试验的关键因素，只能使用皮肤健康无损伤的动物。一般在试验4 h～24 h前在动物背部脊柱两侧除去足够面积被毛(约10 cm×15 cm区域)，用作试验和观察部位。为了便于观察和/或再次试验，可能需反复除毛。如果试验机构确认了脱毛剂的使用过程，则可由专业人员使用脱毛剂除毛。如需反复接触，则按照下列6.3.4.2.1、6.3.4.2.2或6.3.4.2.3步骤进行，时间最长为21 d。 6.3.4.2试验样品的应用 6.3.4.2.1 粉剂或液体样品的应用 将0.5 g或0.5 mL的试验材料直接置于图1所示皮肤部位。固体和疏水性材料无需湿化处理，粉剂使用前宜用水或其他适宜的溶剂稍加湿化(见附录A)。 用2.5 cm×2.5 cm非封闭式的敷料(如吸水性纱布块)覆盖接触部位，然后用绷带(半封闭性或封闭性)固定敷贴片至少4 h。接触期结束后取下敷贴片，用持久性墨水对接触部位进行标记，并用适当的方法除去残留试验材料，如用温水或其他适宜的无刺激性溶剂清洗并小心拭干。 6.3.4.2.2浸提液和浸提介质的应用 将相应的浸提液滴到2.5 cm×2.5 cm大小的吸水性纱布块上，浸提液的用量以能浸透纱布块为宜，一般每块纱布滴0.5 mL，按图1所示部位敷贴于动物背部两侧。按图1所示将滴有浸提介质的纱布块敷贴在对照接触部位。 用绷带(半封闭性或封闭性)覆盖敷贴部位至少4 h。接触期结束后取下敷贴片，用持久性墨水对接触部位进行标记，并用适当的方法除去残留试验材料，如用温水或其他适宜的无刺激性溶剂清洗并小心拭干。