標準編號:	GB/T 16886.10-2017
中文名稱:	醫療器械生物學評價 第10部分：刺激與皮膚致敏試驗
英文名稱:	Biological evaluation of medical devices―Part 10:Tests for irritation and skin sensitization
中標分類:	C30    醫療器械綜合
行業分類:	GB    國家標準
發布機構:	中華人民共和國國家質量監督檢驗檢疫總局 中國國家標準化管理委員會
發布日期:	2017-12-29
實施日期:	2018-7-1
標準狀態:	to be superseded
被新標準替代:	GB/T 16886.10-2024 醫療器械生物學評價　第10部分：皮膚致敏試驗
被替代日期:	2025-9-1
替代舊標準:	GB/T 16886.10-2005 醫療器械生物學評價 第10部分:刺激與遲發型超敏反應試驗
翻譯語言:	英文
文件格式:	PDF
中文字符數:	54000 字
翻譯價格(元):	850.0
交付時間:	付款后 1 個工作日

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 中華人民共和國國家標準 GB/T 16886.10—2017/ISO 10993-10：2010 代替GB/T 16886.10—2005 醫療器械生物學評價 第10部分：刺激與皮膚致敏試驗 Biological evaluation of medical devices— Part 10：Tests for irritation and skin sensitization (ISO 10993—10：2010，IDT) 2017-12-29發布 2018-07-01實施 中華人民共和國國家質量監督檢驗檢疫總局 中國國家標準化管理委員會 發布 前言 GB/T 16886《醫療器械生物學評價》，由下列部分組成： ——第1部分：風險管理過程中的評價與試驗； ——第2部分：動物福利要求； ——第3部分：遺傳毒性、致癌性和生殖毒性試驗； ——第4部分：與血液相互作用試驗選擇； ——第5部分：體外細胞毒性試驗； ——第6部分：植入后局部反應試驗； ——第7部分：環氧乙烷滅菌殘留量； ——第9部分：潛在降解產物的定性與定量框架； ——第10部分：刺激與皮膚致敏試驗； ——第11部分：全身毒性試驗； ——第12部分：樣品制備與參照材料； ——第13部分：聚合物醫療器械降解產物的定性與定量； ——第14部分：陶瓷降解產物定性與定量； ——第15部分：金屬與合金降解產物定性與定量； ——第16部分：降解產物與可瀝濾物毒代動力學研究設計； ——第17部分：可瀝濾物允許限量的建立； ——第18部分：材料化學表征； ——第19部分：材料物理化學、形態學和表面特性表征； ——第20部分：醫療器械免疫毒理學試驗原則和方法。 本部分為GB/T 16886的第10部分。 有關其他方面的生物試驗將有其他部分的標準。 本部分按照GB/T 1.1—2009給出的規則起草。 本部分代替GB/T 16886.10—2005《醫療器械生物學評價 第10部分刺激與遲發型超敏反應試驗》，與GB/T 16886.10—2005相比，主要技術變化如下： ——修改了標準名稱； ——修改了術語和定義(第3章，2005年版的第3章)； ——取消了“材料鑒別”(見2005年版的5.4)； ——皮內反應試驗由附錄調整到正文中(見6.4，2005年版的附錄B)； ——人體皮膚刺激試驗方法由正文調整到附錄(見附錄C，2005年版的6.4)； ——皮膚致敏試驗增加小鼠局部淋巴結檢驗法(見7.2)； ——增加了體外皮膚刺激試驗(見附錄D)； ——增加了聚合物試驗材料浸提液制備方法(見附錄E)。 本部分使用翻譯法等同采用ISO 10993—10：2010《醫療器械生物學評價 第10部分：刺激與皮膚致敏試驗》。 與本部分中規范性引用的國際文件有一致性對應關系的我國文件如下： GB/T 16886.2—2011醫療器械生物學評價 第2部分：動物福利要求(ISO 10993—2：2006，IDT) GB/T 16886.9—2017 醫療器械生物學評價 第9部分：潛在降解產物的定性和定量框架(ISO 10993—9：2009，IDT) GB/T 16886.12—2017 醫療器械生物學評價 第12部分：樣品制備與參照材料(ISO 10993—12：2012，1DT) GB/T 16886.13—2017 醫療器械生物學評價 第13部分：聚合物醫療器械的降解產物的定性與定量(ISO 10993—13：2010，IDT) GB/T 16886.14—2003 醫療器械生物學評價 第14部分：陶瓷降解產物的定性與定量(ISO 10993—14：2001，IDT) GB/T 16886.15—2003 醫療器械生物學評價 第15部分：金屬與合金降解產物的定性與定量(ISO 10993—15：2000，IDT) GB/T 16886.18—2011醫療器械生物學評價 第18部分：材料化學表征(ISO 10993—18：2005，IDT) 本部分由國家食品藥品監督管理總局提出。 本部分由全國醫療器械生物學評價標準化技術委員會(SAC/TC 248)歸口。 本部分起草單位：國家食品藥品監督管理局濟南醫療器械質量監督檢驗中心；深圳市醫療器械檢測中心。 本部分主要起草人：王昕、曹蘋、范春光、劉堯、徐偉區。 本部分所代替標準的歷次版本發布情況為： ——GB/T 16886.10—2000； ——GB/T 16886.10—2005。 引 言 GB/T 16886的本部分用于評定從醫療器械中釋放出的化學物可能引起的接觸性危害，包括導致皮膚與黏膜刺激、眼刺激或皮膚致敏反應。 醫療器械中所含有的某些材料已進行過試驗.其潛在的皮膚、黏膜刺激或致敏作用已被確認。其他一些未做過試驗的材料及其化學成分在與人體組織接觸時可能會產生不良作用。因此，制造商有責任在投放市場前評價器械的潛在不良作用。 傳統上，人體試驗之前要先進行小動物試驗，以有助于預測人體反應。最近，還增加了作為輔助或可供選擇的體外試驗以及人體試驗。盡管在這方面已做了很大努力并取得了一些進展，但結果顯示目前所設計的體外試驗尚不能令人滿意，因此還不能夠取消體內試驗。適宜時，本部分鼓勵將體外預試方法作為動物試驗前的篩選試驗。為了減少所用動物數量，本部分提出逐步評價方法，在每一階段都對試驗結果進行評審和分析。人體試驗之前一般要求先進行動物試驗。 進行這些研究時應遵循良好實驗室質量管理規范并遵守與動物福利有關的規則。建議在適宜的情況下對數據進行統計分析。 本部分由經過培訓有經驗、有適當資格的專業人員使用，能夠解釋標準要求并能考慮與器械全部相關因素，包括器械的預期用途、由科學文獻的評審和先前臨床經驗給出的該醫療器械的當前知識，來判定每一醫療器械的評價結果。 本部分所包括的試驗是安全產品開發的重要工具，由受過培訓的人員進行試驗并解釋試驗結果。 本部分以諸多標準和導則為基礎，包括OECD導則、美國藥典和歐洲藥典。本部分可作為基礎文件，用于選擇和實施能評價與醫用材料和器械安全性相關的刺激和皮膚致敏反應的試驗。 醫療器械生物學評價 第10部分：刺激與皮膚致敏試驗 1 范圍 GB/T 16886的本部分描述了醫療器械及其組成材料潛在刺激和皮膚致敏的評價步驟。 本部分包括： a)刺激試驗前的考慮，包括皮膚接觸方面的生物模擬實驗和體外方法； b)詳細的體內(刺激和致敏)試驗步驟； c)結果解釋的關鍵因素。 附錄A給出了與上述試驗有關的特定材料制備說明。附錄B給出了適用于醫療器械的除皮膚部位之外的幾種特殊刺激試驗。 2規范性引用文件 下列文件對于本文件的應用是必不可少的。凡是注日期的引用文件，僅注日期的版本適用于本文件。凡是不注日期的引用文件，其最新版本(包括所有的修改單)適用于本文件。 GB/T 16886.1—2011 醫療器械生物學評價 第1部分：風險管理過程中的評價與試驗(ISO 10993—1：2009，IDT) ISO 10993-2 醫療器械生物學評價 第2部分：動物福利要求(Biological evaluation of medical devices—Part 2：Animal welfare requirements) ISO 10993—9 醫療器械生物學評價 第9部分：潛在降解產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 醫療器械生物學評價 第12部分：樣品制備與參照樣品(Biological evaluation of medical devices—Part 12：Sample preparation and reference materials) ISO 10993-13 醫療器械生物學評價 第13部分：聚合物醫療器械的降解產物的定性與定量(Bi-ological evaluation of medical devices—Part 13：Identification and quantification of degradation products from polymeric medical devices) ISO 10993—14 醫療器械生物學評價 第14部分：陶瓷降解產物的定性與定量(Biological evalua-tion of medical devices—Part 14：Identification and quantification of degradation products from ceram-ics) ISO 10993—15醫療器械生物學評價 第15部分：金屬與合金降解產物的定性與定量(Biological evaluation of medical devices—Part 15：Identification and quantification of degradation products from metals and alloys) ISO 10993—18醫療器械生物學評價 第18部分：材料化學表征(Biological evaluation of medical devices—Part 18：Chemical characterization of materials) ISO 14155—1 用于人體的醫療器械臨床研究 第1部分：通用要求(Clinical Investigation of Med—ical Devices for Human Subjects—Part 1：General Requirement) ISO 14155—2用于人體的醫療器械臨床研究 第2部分：臨床研究方案(Clinical investigation of medical devices for human subjects—Part 2：Clinical investigation plants) 3術語和定義 GB/T 16886.1—2011界定的以及下列術語和定義適用于本文件。 3.1 變應原 allergen 致敏原 sensitizer 在反復接觸后能引起某一類特異性超敏反應的物質或材料。 3.2 空白 blank 不加試驗材料的浸提介質，置于與試驗材料相同的容器中，并經受與試驗材料相同的浸提條件。 注：空白對照的目的是評價浸提容器、浸提介質和浸提過程可能的干擾作用。 3.3 激發 challenge 誘發 elicitation 誘導階段后的過程，在這一階段檢驗個體后續接觸誘導材料的免疫學反應。 3.4 劑量dose 用量dosage 按單位重量或表面積表示的試驗樣品的給予量(如質量、體積)。 注：這兩個術語通常可交換使用(用量較為常用)。 3.5 紅斑 erythema 皮膚或黏膜發紅。 3.6 焦痂 eschar 皮膚結痂或變色的蛻皮。 3.7 浸提液 extract 某一試驗材料或對照材料在控制條件下與溶劑接觸后獲取到的液體或懸浮液。 3.8 誘導 induction 導致個體對某一特定材料重新形成免疫學活性增強狀態的過程。 3.9 刺激物 irritant 引起刺激的物質。 3.10 刺激 irritation 一次、多次或持續與一種物質/材料接觸所引起的局部非特異性炎癥反應。 注：皮膚刺激是一種可逆反應，主要以皮膚局部紅斑(發紅)為特征。 3.11 壞死 necrosis 由于損傷或疾病造成的不可逆改變直接導致細胞死亡。 注：宜注意組織修復會導致完全性功能恢復或瘢痕形成。 3.12 陰性對照 negative control 當按規定步驟試驗時，在試驗系統中證明試驗步驟適宜性的出現可再現的適當的陰性、無反應或最小反應的經充分表征的材料或物質。 注：實際操作中，陰性對照包括空白、介質/溶劑和參照材料。 3.13 水腫 oedema 液體向組織內異常滲透引起的腫脹。 3.14 陽性對照positive control 當按規定試驗方法評價時，在試驗系統中證明試驗步驟適宜性的出現可再現的適當的陽性或反應性應答的經充分表征的材料或物質。 3.15 皮膚腐蝕 skin corrosion 應用某一試驗樣品后皮膚的不可逆性損傷結果，表現為從表皮至真皮的明顯壞死。 示例：混合物/化學物/試驗樣品作用所導致的皮膚潰瘍(見3.19)。 3.16 皮膚致敏 skin sensitization 變應性接觸性皮炎 免疫介導的對某種物質的皮膚反應。 注：這種反應在人體上以瘙癢、紅斑、水腫、丘疹、大(小)水泡、或此類綜合癥狀為特征，其他種屬表現可能不同，僅出現紅斑和水腫。 3.17 試驗材料test material 取樣供生物學或化學試驗用的材料、器械、器械的一部分或其組件。 3.18 試驗樣品test sample 供生物學或化學試驗或評價用的材料、器械、器械的一部分、組件、浸提液或浸提液的一部分。 3.19 潰瘍 ulceration 表現為表淺組織缺損的開放性潰爛。 3.20 介質 vehicle 用于濕化、稀釋、懸浮、浸提或溶解試驗物質/材料的液體。 4基本原則一逐步評價法 現有的檢驗刺激與致敏的試驗方法特別設定為測定潛在的皮膚刺激和黏膜刺激以及皮膚致敏作用，這些試驗一般不預示其他類型的不良作用。對于植入醫療器械或外部接入醫療器械，皮內注射試驗更為接近實際應用，因此用于檢驗刺激作用，應按照6.4的描述進行皮內試驗。 本部分要求逐步評價法，應包括下列一項或多項內容： a)按照ISO 10993—9、ISO 10993—13、ISO 10993—14、ISO 10993—15和ISO 10993—18的基本原則，對試驗材料進行表征，涉及對試驗樣品進行化學表征和分析； b)文獻檢索，包括對試驗材料化學和物理性能的評價、任何產品組分以及相關結構的化學物和材料的潛在刺激和致敏信息； c)按照ISO 10993.2，應考慮體外試驗優先于體內試驗，若新的體外法經科學認可并具有合理性和實用性時，可取代體內試驗。已有體外替代方法用于化學物皮膚刺激和腐蝕的評價，目前尚沒有經國際確認并接受的檢驗致敏物的體外試驗； d)體內動物試驗：為了確保試驗的再現性和敏感性，檢測實驗室應在每次刺激與致敏試驗中包括陽性對照物試驗，以驗證試驗系統并證實陽性反應。然而，對于豚鼠致敏試驗，當試驗系統一致性在6個月或更長持續時間得以證實時，則每次試驗中無需包括陽性對照，但每隔一定時間(不應超過6個月)要進行陽性對照試驗； 注1：目前對致敏作用只能通過體內試驗進行測定，可采用小鼠局部淋巴結試驗(LLNA)、豚鼠封閉貼敷試驗或豚鼠最大劑量試驗(GPMT)。LLNA為目前測定單一化學物潛在致敏作用的首選方法，見參考文獻[69]、[88]、[90]。 注2：試驗材料不能表征或采用在a)、b)和c)階段獲取的信息不能進行風險評定時，體內動物試驗適用。 注3：對于豚鼠致敏試驗，每6個月一般要采用10只動物用于陽性對照。在比每6個月更頻繁的時間內進行陽性對照物質試驗時，可采用較少的豚鼠，宜至少采用5只試驗動物用于陽性物質和5只對照動物。 e)非侵入性人體試驗/臨床試驗：如材料經證實對動物無刺激、無致敏或無毒性，可考慮進行人體皮膚刺激研究。 在獲知a)～d)中的其他評價結果之前，按照ISO 14155-1和ISO 14155—2和倫理準則不應進行臨床試驗。 5試驗前的考慮 5.1 總則 需要強調的是試驗前的考慮是非常重要的，其可以得出無需進行刺激和/或致敏試驗的結論。 GB/T 16886.1—2011的第5章中給出的和下列條款的要求是適用的。 非無菌樣品只應通過局部試驗進行研究，因為試驗樣品微生物污染的可能性會干擾最終試驗解釋。對不能保證無菌但仍認為是無污染的試驗樣品，皮內試驗可能要進行論證。 5.2材料類型 5.2.1 基本考慮 應考慮在醫療器械制造和裝配期間可能用做加工助劑(如潤滑劑或脫模劑)的其他化學成分。除了原材料和制造加工助劑的化學成分外，裝配黏合劑/溶劑殘留物以及滅菌殘留物或滅菌過程所致的反應性產物可能存在于終產品中，這些成分是否產生健康危害(風險)取決于終產品的滲漏或降解性能，應考慮這些成分潛在的刺激/致敏活性。 5.2.2 陶瓷、金屬和合金 這些材料在化學成分數量方面一般比聚合物和生物衍生材料簡單。 5.2.3聚合物 這類材料在化學成分方面一般要比5.2.2中復雜一些，可能有若干反應性產物/雜質/添加劑，而且聚合反應的完全程度可能會有不同。 5.2.4生物衍生材料 這類材料在其成分方面特別復雜，也常含有加工殘留物，如交聯劑和抗生素。生物材料樣品之間的成分可能是不一致的。 本部分中的方法不是為檢驗生物衍生材料而設計，因此不足以檢驗該類材料，例如本部分中的試驗未考慮跨物種致敏作用。 5.3化學成分方面的信息 5.3.1 總則 應確立材料化學成分方面的完整的定性數據，也應獲取與生物安全性相關的信息及定量數據。如沒有定量數據，說明應形成文件并進行論證。 5.3.2現有的數據來源 可能的情況下應從原材料供應商處索取化學成分方面的定性與定量信息。 聚合物常要求專利信息的使用權，宜簽署轉讓和使用這種機密信息的條款。 還應從產品制造的制造鏈的適宜成員中(包括半成品和零件制造商)索取其他任何生產過程中的添加劑(如脫模劑)的定性信息。 在沒有任何化學成分數據的情況下建議研究文獻，以確定原材料和添加劑的大概特性，這樣有助于選擇相關材料最適宜的分析方法。 應按照ISO 10993—18測定最終產品的化學成分。 注：可依據ISO或美國試驗材料協會(ASTM)標準和/或用戶的要求規定陶瓷、金屬和合金的成分，但為了獲取完整的成分定性與定量資料，可能還需要要求原材料供應商或制造廠以及零件制造廠提供這些信息，以保證還能鑒別加工助劑。能夠獲取這些數據的另一來源是主管部門掌控的材料文件。 6刺激試驗 6.1體外刺激試驗 體外試驗，即大鼠皮膚經皮電阻抗(TER)試驗和人體皮膚模型試驗，已被國際間確認并接受為評價化學物皮膚腐蝕性的替代試驗(OECD導則430[9]和43[10])方法。在研究替代方法的同時，各國際和各國家組織一直在進行體外皮膚刺激試驗的建立和確認工作，有些團體正在研究試驗方法中動物和人體反應的量化指標，以能夠應用無創技術更好地限定終點(見F.1)。 注：歐洲替代方法驗證中心咨詢委員會(ESAC)2007年對用于化學物皮膚刺激測定的一種體外人體皮膚模型的確認過程進行了評價，見參考文獻[101]。附錄D描述了應用體外人體模型評定化學物引起皮膚刺激的潛能。 目前體外皮膚刺激試驗僅確認用于純化學物，不適用于醫療器械浸提液。為了應用這些方法檢驗醫療器械的刺激潛能，有必要對這種特定應用進一步確認。 6.2體內刺激試驗一體內試驗設計和選擇中應考慮的因素 醫療器械的刺激試驗可用終產品和/或浸提液進行。 影響刺激試驗結果的因素包括： a)器械用于斑貼試驗時的特性； b)試驗材料的劑量； c)試驗材料的應用方法； d)封閉的程度； e)應用部位； f)接觸周期和接觸次數； g)評價試驗所采用的技術。 附錄F提供了其他背景信息。 下列詳細的試驗方案的靈活性有時可使研究者提高試驗的敏感性，以適應各種使用和人群接觸條件，但試驗步驟的一致性有助于不同材料和不同實驗室的試驗結果具有可比性。 評價多次和/或長期接觸的器械和材料的要求已包括在試驗步驟中，試驗設計應高于預期的實際臨床接觸條件(時間和/或濃度)，在解釋試驗結果時應注意到該因素。 試驗樣品的pH如≤2.0或≥11.5，應認為是一種刺激物，不必進一步試驗。然而，試驗結果也顯示，試驗材料的酸堿度并非是導致嚴重損傷的能力的唯一因素，試驗材料的濃度、接觸時間以及許多其他理化性能也都是重要的因素。 特殊情況下需要進一步的風險表征/評定，可能需要檢驗材料的刺激性或材料的pH在上述范圍之外，這種情況應論證并形成文件。 6.3動物刺激試驗 6.3.1 原理 采用相關動物模型對材料在試驗條件下產生皮膚刺激反應的潛能做出評定。 家兔為首選試驗動物。 6.3.2 試驗材料 固體或液體試驗材料應按附錄A規定進行制備。 應證明試驗的敏感性，可通過在試驗中設置一組陽性對照來加以證實。然而，采用陽性對照來證實敏感性僅限于實驗室在之前的6個月內應用該試驗方法未產生陽性結果的情況。 注：十二烷基硫酸鈉(SLS)是適宜的陽性對照。 6.3.3動物與管理 應使用3只健康、初成年的白化兔，雌雄不限，同一品系，體重不低于2 kg。如預期有刺激反應，初試應考慮使用1只動物。除非出現明確的陽性反應[紅斑或水腫記分大于2(見表1)]，否則應至少再使用2只動物進行試驗。在使用了至少3只動物后，如為疑似反應，應考慮進行復試。 應使動物適應環境，并按ISO 10993—2的規定飼養。 表1 皮膚反應記分系統 反 應 刺激記分 紅斑和焦痂形成 無紅斑 0 極輕微紅斑(勉強可見) 1 清晰紅斑 2 中度紅斑 3 重度紅斑(紫紅色)至無法進行紅斑分級的焦痂形成 4 表1(續) 反 應 刺激記分 水腫形成 無水腫 0 極輕微水腫(勉強可見) 1 清晰水腫(腫起邊緣清晰) 2 中度水腫(腫起約1 mm) 3 重度水腫(腫起超過1 mm，并超出接觸區) 4 刺激最高記分 8 應記錄并報告皮膚部位的其他異常情況。 6.3.4試驗步驟 6.3.4.1動物準備 動物的皮膚狀況是試驗的關鍵因素，只能使用皮膚健康無損傷的動物。一般在試驗4 h～24 h前在動物背部脊柱兩側除去足夠面積被毛(約10 cm×15 cm區域)，用作試驗和觀察部位。為了便于觀察和/或再次試驗，可能需反復除毛。如果試驗機構確認了脫毛劑的使用過程，則可由專業人員使用脫毛劑除毛。如需反復接觸，則按照下列6.3.4.2.1、6.3.4.2.2或6.3.4.2.3步驟進行，時間最長為21 d。 6.3.4.2試驗樣品的應用 6.3.4.2.1 粉劑或液體樣品的應用 將0.5 g或0.5 mL的試驗材料直接置于圖1所示皮膚部位。固體和疏水性材料無需濕化處理，粉劑使用前宜用水或其他適宜的溶劑稍加濕化(見附錄A)。 用2.5 cm×2.5 cm非封閉式的敷料(如吸水性紗布塊)覆蓋接觸部位，然后用繃帶(半封閉性或封閉性)固定敷貼片至少4 h。接觸期結束后取下敷貼片，用持久性墨水對接觸部位進行標記，并用適當的方法除去殘留試驗材料，如用溫水或其他適宜的無刺激性溶劑清洗并小心拭干。 6.3.4.2.2浸提液和浸提介質的應用 將相應的浸提液滴到2.5 cm×2.5 cm大小的吸水性紗布塊上，浸提液的用量以能浸透紗布塊為宜，一般每塊紗布滴0.5 mL，按圖1所示部位敷貼于動物背部兩側。按圖1所示將滴有浸提介質的紗布塊敷貼在對照接觸部位。 用繃帶(半封閉性或封閉性)覆蓋敷貼部位至少4 h。接觸期結束后取下敷貼片，用持久性墨水對接觸部位進行標記，并用適當的方法除去殘留試驗材料，如用溫水或其他適宜的無刺激性溶劑清洗并小心拭干。