GB/T 16886.10-2024 Biological evaluation of medicat devices - Part 10: Tests for skin sensitization
1 Scope
This document specifies the procedure for the assessment of medical devices and their constituent materials with regard to their potential to induce skin sensitization.
This document includes:
——details of in vivo skin sensitization test procedures;
——key factors for the interpretation of the results.
Note: Instructions for the preparation of materials specifically in relation to the above tests are given in Annex A.
2 Normative references
The following documents are referred to in the text in such a way that some or all of their content constitutes requirements 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.
ISO 10993-1 Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process
Note: GB/T 16886.1-2022, Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process (ISO 10993-1:2018, IDT)
ISO 10993-2 Biological evaluation of medical devices - Part 2: Animal welfare requirements
Note: GB/T 16886.2-2011, Biological evaluation of medical devices - Part 2: Animal welfare requirements (ISO 10993-2:2006, IDT)
ISO 10993-12 Biological evaluation of medical devices - Part 12: Sample preparation and reference materials
Note: GB/T 16886.12-2023, Biological evaluation of medical devices - Part 12: Sample preparation and reference materials (ISO 10993-12:2021, IDT)
ISO 10993-18 Biological evaluation of medical devices - Part 18: Chemical characterization of medical device materials within a risk management process
Note: GB/T 16886.18-2022, Biological evaluation of medical devices - Part 18: Chemical characterization of medical device materials within a risk management process (ISO 10993-18:2020, IDT)
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 10993-1 and the following apply.
ISO and IEC maintain terminology databases for use in standardization at the following addresses:
——ISO Online browsing platform: available at https://www.iso.org/obp
——IEC Electropedia: available at https://www.electropedia.org/
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
allergic contact dermatitis
clinical diagnosis based on an observed immunologically-mediated cutaneous reaction to a substance
3.3
blank
extraction vehicle (3.17) not containing the test material (3.15), 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.
3.4
challenge
process following the induction (3.8) phase, in which the immunological effects of subsequent exposures in an individual to the inducing material are examined
3.5
elicitation
immunological reaction to exposure to a sensitizer in a previously sensitized individual
3.6
erythema
reddening of the skin or mucous membrane
3.7
extract
liquid that results from extraction of the test sample (3.16) or control
[SOURCE: ISO 10993-12:2023, 3.6]
3.8
induction
process that leads to the de novo generation of an enhanced state of immunological activity in an individual, after initial exposure to a specific material
3.9
irritant
agent that produces irritation (3.10)
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 symptoms like local erythema (3.6) (redness), swelling, itching, peeling, cracking and scaling of the skin.
3.11
negative control
well-characterized material or substance that, when evaluated by a specific test method, 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 (3.3), vehicles (3.17)/solvents and reference materials.
[SOURCE: GB/T 16886.12-2023, 3.10, modified]
3.12
oedema
swelling due to abnormal infiltration of fluid into the tissues
3.13
positive control
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
3.14
skin sensitization
T-cell mediated delayed-type hypersensitivity reaction induced by low molecular weight reactive chemicals (allergens) comprising two phases, induction and elicitation
Note: In humans, the responses can be characterized by pruritis, erythema (3.6), oedema (3.12), papules, vesicles, bullae or a combination of these. In other species, the reactions can differ and only erythema and oedema can be seen.
3.15
test material
material, device, device portion or component thereof that is sampled for biological or chemical testing
3.16
test sample
material, device, device portion, component, extract (3.7) or portion thereof that is subjected to biological or chemical testing or evaluation
3.17
vehicle
liquid used to moisten, dilute, suspend, extract (3.7) or dissolve the test substance/material
4 General principles - Step-wise approach
The available methods for testing sensitization were developed specifically to detect skin sensitization potential. Other types of adverse effects are generally not predicted by these tests.
This document requires a step-wise approach, considering that any stage can result in the conclusion that further testing for skin sensitization is not necessary:
a) literature and supplier information review, including chemical and physical properties, and information on the skin sensitization potential of any medical device constituent as well as structurally-related chemicals and materials; refer to ISO 10993-1 for details; conduct risk assessment based on existing information to determine whether skin sensitization risk is acceptable or whether further testing is necessary;
b) additional characterization and risk assessment, if needed, of the device material, involving chemical characterization and analysis of the test sample according to the general principles described in ISO 10993-18;
c) in vitro tests shall be considered in preference to in vivo tests in accordance with ISO 10993-2, and the replacement of the latter as new in vitro tests are scientifically validated and become reasonably and practicably available;
Note: There are currently a number of internationally validated and accepted in vitro tests to detect the skin sensitization potential of chemicals; however, these in vitro tests are not yet validated for medical devices. Work is ongoing for some of these tests to qualify them for use with medical devices.
d) in vivo animal tests are only 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).
Foreword IV
Introduction VI
1 Scope
2 Normative references
3 Terms and definitions
4 General principles — Step-wise approach
5 Pretest considerations
5.1 General
5.2 Types of material
5.2.1 Initial considerations
5.2.2 Ceramics, metals and alloys
5.2.3 Polymers
5.2.4 Biologically derived materials
5.3 Information on chemical composition
5.3.1 General
5.3.2 Existing data sources
6 Skin sensitization tests
6.1 Choice of test methods
6.2 Murine local lymph node assay
6.2.1 Principle
6.2.2 Test sample preparation
6.2.3 Animals and husbandry
6.2.4 Test procedure
6.2.5 Treatment groups
6.2.6 Determination of cellular proliferation and tissue preparation
6.2.7 Results and interpretation
6.2.8 Test report
6.3 Guinea pig assays for the detection of skin sensitization
6.3.1 Principle
6.3.2 Choice of test sample concentrations
6.3.3 Induction
6.3.4 Challenge
6.4 Important factors affecting the outcome of the test
6.5 Guinea pig maximization test
6.5.1 Principle
6.5.2 Test sample preparation
6.5.3 Animals and husbandry
6.5.4 Test procedure
6.5.4.1 Preparation
6.5.4.2 Preliminary tests
6.5.4.3 Main test
6.5.5 Observation of animals
6.5.6 Evaluation of results
6.5.7 Test report
6.6 Closed-patch test (Buehler test)
6.6.1 Principle
6.6.2 Test sample preparation
6.6.3 Animals and husbandry
6.6.4 Test procedure
6.6.4.1 Preparation
6.6.4.2 Preliminary tests
6.6.4.3 Main test
6.6.5 Observation of animals
6.6.6 Evaluation of results
6.6.7 Test report
7 Key factors in interpretation of test results
Annex A (Normative) Preparation of materials for skin sensitization testing
A.1 General
A.2 Materials for direct-contact exposure
A.2.1 Solid test materials
A.2.2 Liquid test materials
A.3 Extracts of test materials
A.4 Solvents
A.5 Sterile test materials
Annex B (Informative) Method for the preparation of extracts from polymeric test materials
B.1 General
B.2 Preparation method
B.2.1 Preliminary extraction
B.2.2 Final extraction
B.3 Guinea pig maximization test
B.3.1 General
B.3.2 Challenge phase
Annex C (Informative) Non-animal methods for skin sensitization
C.1 Introduction
C.1.1 Background on alternative methods for skin sensitization testing
C.1.2 OECD’s adverse outcome pathway for skin sensitization
C.1.3 Integrated approaches to testing and assessment (IATA)
C.2 In vitro assays for skin sensitization testing
C.2.1 General
C.2.2 Test methods
C.3 Discussion
C.3.1 OECD-validated assays
C.3.2 Genomic assays
C.3.3 Other assays
C.3.4 General considerations for validation of in vitro methods for medical device testing
C.4 Conclusions
Annex D (Informative) Background information on sensitization tests for skin sensitization
Bibliography
GB/T 16886.10-2024 Biological evaluation of medicat devices - Part 10: Tests for skin sensitization
1 Scope
This document specifies the procedure for the assessment of medical devices and their constituent materials with regard to their potential to induce skin sensitization.
This document includes:
——details of in vivo skin sensitization test procedures;
——key factors for the interpretation of the results.
Note: Instructions for the preparation of materials specifically in relation to the above tests are given in Annex A.
2 Normative references
The following documents are referred to in the text in such a way that some or all of their content constitutes requirements 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.
ISO 10993-1 Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process
Note: GB/T 16886.1-2022, Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process (ISO 10993-1:2018, IDT)
ISO 10993-2 Biological evaluation of medical devices - Part 2: Animal welfare requirements
Note: GB/T 16886.2-2011, Biological evaluation of medical devices - Part 2: Animal welfare requirements (ISO 10993-2:2006, IDT)
ISO 10993-12 Biological evaluation of medical devices - Part 12: Sample preparation and reference materials
Note: GB/T 16886.12-2023, Biological evaluation of medical devices - Part 12: Sample preparation and reference materials (ISO 10993-12:2021, IDT)
ISO 10993-18 Biological evaluation of medical devices - Part 18: Chemical characterization of medical device materials within a risk management process
Note: GB/T 16886.18-2022, Biological evaluation of medical devices - Part 18: Chemical characterization of medical device materials within a risk management process (ISO 10993-18:2020, IDT)
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 10993-1 and the following apply.
ISO and IEC maintain terminology databases for use in standardization at the following addresses:
——ISO Online browsing platform: available at https://www.iso.org/obp
——IEC Electropedia: available at https://www.electropedia.org/
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
allergic contact dermatitis
clinical diagnosis based on an observed immunologically-mediated cutaneous reaction to a substance
3.3
blank
extraction vehicle (3.17) not containing the test material (3.15), 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.
3.4
challenge
process following the induction (3.8) phase, in which the immunological effects of subsequent exposures in an individual to the inducing material are examined
3.5
elicitation
immunological reaction to exposure to a sensitizer in a previously sensitized individual
3.6
erythema
reddening of the skin or mucous membrane
3.7
extract
liquid that results from extraction of the test sample (3.16) or control
[SOURCE: ISO 10993-12:2023, 3.6]
3.8
induction
process that leads to the de novo generation of an enhanced state of immunological activity in an individual, after initial exposure to a specific material
3.9
irritant
agent that produces irritation (3.10)
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 symptoms like local erythema (3.6) (redness), swelling, itching, peeling, cracking and scaling of the skin.
3.11
negative control
well-characterized material or substance that, when evaluated by a specific test method, 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 (3.3), vehicles (3.17)/solvents and reference materials.
[SOURCE: GB/T 16886.12-2023, 3.10, modified]
3.12
oedema
swelling due to abnormal infiltration of fluid into the tissues
3.13
positive control
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
3.14
skin sensitization
T-cell mediated delayed-type hypersensitivity reaction induced by low molecular weight reactive chemicals (allergens) comprising two phases, induction and elicitation
Note: In humans, the responses can be characterized by pruritis, erythema (3.6), oedema (3.12), papules, vesicles, bullae or a combination of these. In other species, the reactions can differ and only erythema and oedema can be seen.
3.15
test material
material, device, device portion or component thereof that is sampled for biological or chemical testing
3.16
test sample
material, device, device portion, component, extract (3.7) or portion thereof that is subjected to biological or chemical testing or evaluation
3.17
vehicle
liquid used to moisten, dilute, suspend, extract (3.7) or dissolve the test substance/material
4 General principles - Step-wise approach
The available methods for testing sensitization were developed specifically to detect skin sensitization potential. Other types of adverse effects are generally not predicted by these tests.
This document requires a step-wise approach, considering that any stage can result in the conclusion that further testing for skin sensitization is not necessary:
a) literature and supplier information review, including chemical and physical properties, and information on the skin sensitization potential of any medical device constituent as well as structurally-related chemicals and materials; refer to ISO 10993-1 for details; conduct risk assessment based on existing information to determine whether skin sensitization risk is acceptable or whether further testing is necessary;
b) additional characterization and risk assessment, if needed, of the device material, involving chemical characterization and analysis of the test sample according to the general principles described in ISO 10993-18;
c) in vitro tests shall be considered in preference to in vivo tests in accordance with ISO 10993-2, and the replacement of the latter as new in vitro tests are scientifically validated and become reasonably and practicably available;
Note: There are currently a number of internationally validated and accepted in vitro tests to detect the skin sensitization potential of chemicals; however, these in vitro tests are not yet validated for medical devices. Work is ongoing for some of these tests to qualify them for use with medical devices.
d) in vivo animal tests are only 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).
Contents of GB/T 16886.10-2024
Foreword IV
Introduction VI
1 Scope
2 Normative references
3 Terms and definitions
4 General principles — Step-wise approach
5 Pretest considerations
5.1 General
5.2 Types of material
5.2.1 Initial considerations
5.2.2 Ceramics, metals and alloys
5.2.3 Polymers
5.2.4 Biologically derived materials
5.3 Information on chemical composition
5.3.1 General
5.3.2 Existing data sources
6 Skin sensitization tests
6.1 Choice of test methods
6.2 Murine local lymph node assay
6.2.1 Principle
6.2.2 Test sample preparation
6.2.3 Animals and husbandry
6.2.4 Test procedure
6.2.5 Treatment groups
6.2.6 Determination of cellular proliferation and tissue preparation
6.2.7 Results and interpretation
6.2.8 Test report
6.3 Guinea pig assays for the detection of skin sensitization
6.3.1 Principle
6.3.2 Choice of test sample concentrations
6.3.3 Induction
6.3.4 Challenge
6.4 Important factors affecting the outcome of the test
6.5 Guinea pig maximization test
6.5.1 Principle
6.5.2 Test sample preparation
6.5.3 Animals and husbandry
6.5.4 Test procedure
6.5.4.1 Preparation
6.5.4.2 Preliminary tests
6.5.4.3 Main test
6.5.5 Observation of animals
6.5.6 Evaluation of results
6.5.7 Test report
6.6 Closed-patch test (Buehler test)
6.6.1 Principle
6.6.2 Test sample preparation
6.6.3 Animals and husbandry
6.6.4 Test procedure
6.6.4.1 Preparation
6.6.4.2 Preliminary tests
6.6.4.3 Main test
6.6.5 Observation of animals
6.6.6 Evaluation of results
6.6.7 Test report
7 Key factors in interpretation of test results
Annex A (Normative) Preparation of materials for skin sensitization testing
A.1 General
A.2 Materials for direct-contact exposure
A.2.1 Solid test materials
A.2.2 Liquid test materials
A.3 Extracts of test materials
A.4 Solvents
A.5 Sterile test materials
Annex B (Informative) Method for the preparation of extracts from polymeric test materials
B.1 General
B.2 Preparation method
B.2.1 Preliminary extraction
B.2.2 Final extraction
B.3 Guinea pig maximization test
B.3.1 General
B.3.2 Challenge phase
Annex C (Informative) Non-animal methods for skin sensitization
C.1 Introduction
C.1.1 Background on alternative methods for skin sensitization testing
C.1.2 OECD’s adverse outcome pathway for skin sensitization
C.1.3 Integrated approaches to testing and assessment (IATA)
C.2 In vitro assays for skin sensitization testing
C.2.1 General
C.2.2 Test methods
C.3 Discussion
C.3.1 OECD-validated assays
C.3.2 Genomic assays
C.3.3 Other assays
C.3.4 General considerations for validation of in vitro methods for medical device testing
C.4 Conclusions
Annex D (Informative) Background information on sensitization tests for skin sensitization
Bibliography
