SIST EN ISO 10993-10:2023
(Main)Biological evaluation of medical devices - Part 10: Tests for skin sensitization (ISO 10993-10:2021)
Biological evaluation of medical devices - Part 10: Tests for skin sensitization (ISO 10993-10:2021)
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.
Biologische Beurteilung von Medizinprodukten - Teil 10: Prüfungen auf Hautsensibilisierung (ISO 10993-10:2021)
Dieses Dokument legt das Verfahren für die Beurteilung von Medizinprodukten und ihren Bestandteilen hinsichtlich ihres Potentials, eine Hautsensibilisierung auszulösen, fest.
Dieses Dokument enthält:
Einzelheiten zur Durchführung von In-vivo-Hautsensibilisierungsprüfungen;
Schlüsselfaktoren für die Interpretation der Ergebnisse.
ANMERKUNG Anhang A enthält Anweisungen für die spezielle Vorbereitung von Materialien im Zusammenhang mit den vorstehend angeführten Prüfungen.
Évaluation biologique des dispositifs médicaux - Partie 10: Essais de sensibilisation cutanée (ISO 10993-10:2021)
Le présent document spécifie le mode opératoire pour l'évaluation du potentiel des dispositifs médicaux et de leurs matériaux constitutifs à provoquer une sensibilisation cutanée.
Le présent document comprend:
— des informations détaillées relatives aux modes opératoires d'essai de sensibilisation cutanée in vivo;
— les facteurs clés pour l'interprétation des résultats.
NOTE Des instructions pour la préparation des matériaux spécifiquement pour les essais ci-dessus sont données dans l'Annexe A.
Biološko ovrednotenje medicinskih pripomočkov - 10. del: Preskusi preobčutljivosti kože (ISO 10993-10:2021)
Ta dokument določa postopek za presojo medicinskih pripomočkov in njihovih sestavnih materialov glede potenciala za povzročitev preobčutljivosti kože.
Dokument vsebuje:
– podrobnosti preskusnih postopkov za preobčutljivost kože;
– ključne dejavnike za razlago rezultatov.
OPOMBA Navodila za pripravo materialov posebej za zgoraj navedene preskuse so podana v dodatku A.
General Information
Relations
Standards Content (Sample)
SLOVENSKI STANDARD
01-maj-2023
Nadomešča:
SIST EN ISO 10993-10:2013
Biološko ovrednotenje medicinskih pripomočkov - 10. del: Preskusi
preobčutljivosti kože (ISO 10993-10:2021)
Biological evaluation of medical devices - Part 10: Tests for skin sensitization (ISO 10993
-10:2021)
Biologische Beurteilung von Medizinprodukten - Teil 10: Prüfungen auf
Hautsensibilisierung (ISO 10993-10:2021)
Évaluation biologique des dispositifs médicaux - Partie 10: Essais de sensibilisation
cutanée (ISO 10993-10:2021)
Ta slovenski standard je istoveten z: EN ISO 10993-10:2023
ICS:
11.100.20 Biološko ovrednotenje Biological evaluation of
medicinskih pripomočkov medical devices
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
EN ISO 10993-10
EUROPEAN STANDARD
NORME EUROPÉENNE
February 2023
EUROPÄISCHE NORM
ICS 11.100.20 Supersedes EN ISO 10993-10:2010
English Version
Biological evaluation of medical devices - Part 10: Tests for
skin sensitization (ISO 10993-10:2021)
Évaluation biologique des dispositifs médicaux - Partie Biologische Beurteilung von Medizinprodukten - Teil
10: Essais de sensibilisation cutanée (ISO 10993- 10: Prüfungen auf Hautsensibilisierung (ISO 10993-
10:2021) 10:2021)
This European Standard was approved by CEN on 13 September 2021.
CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this
European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references
concerning such national standards may be obtained on application to the CEN-CENELEC 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
translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management
Centre has the same status as the official versions.
CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,
Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway,
Poland, Portugal, Republic of North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Türkiye and
United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels
© 2023 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-10:2023 E
worldwide for CEN national Members.
Contents Page
European foreword . 3
Annex ZA (informative) Relationship between this European standard and the General
Safety and Performance requirements of Regulation (EU) 2017/745 aimed to be
covered. 4
European foreword
This document (EN ISO 10993-10:2023) has been prepared by Technical Committee ISO/TC 194
"Biological and clinical evaluation of medical devices" in collaboration with Technical Committee
CEN/TC 206 “Biological and clinical evaluation of medical devices” the secretariat of which is held by
DIN.
This European Standard shall be given the status of a national standard, either by publication of an
identical text or by endorsement, at the latest by August 2023, and conflicting national standards shall
be withdrawn at the latest by August 2023.
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. CEN shall not be held responsible for identifying any or all such patent rights.
This document supersedes EN ISO 10993-10:2010.
This document has been prepared under a Standardization Request given to CEN by the European
Commission and the European Free Trade Association, and supports essential requirements of EU
Directive(s) / Regulation(s).
For the relationship with EU Directive(s) / Regulation(s), see informative Annex ZA, which is an integral
part of this document.
Any feedback and questions on this document should be directed to the users’ national standards
body/national committee. A complete listing of these bodies can be found on the CEN website.
According to the CEN-CENELEC Internal Regulations, the national standards organizations of the
following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria,
Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland,
Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Republic of
North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Türkiye and the
United Kingdom.
Endorsement notice
The text of ISO 10993-10:2021 has been approved by CEN as EN ISO 10993-10:2023 without any
modification.
Annex ZA
(informative)
Relationship between this European standard and the General Safety and
Performance requirements of Regulation (EU) 2017/745 aimed to be
covered
This European standard has been prepared under M/575 to provide one voluntary means of
conforming to the General Safety and Performance Requirements of Regulation (EU) 2017/745 of 5
April 2017 concerning medical devices [OJ L 117] and to system or process requirements including
those relating to quality management systems, risk management, post-market surveillance systems,
clinical investigations, clinical evaluation or post-market clinical follow-up.
Once this standard is cited in the Official Journal of the European Union under that Regulation,
compliance with the normative clauses of this standard given in Table ZA.1 and application of the
edition of the normatively referenced standards as given in Table ZA.2 confers, within the limits of the
scope of this standard, a presumption of conformity with the corresponding General Safety and
Performance Requirements of that Regulation, and associated EFTA Regulations.
Where a definition in this standard differs from a definition of the same term set out in Regulation (EU)
2017/745, the differences shall be indicated in this Annex Z. For the purpose of using this standard in
support of the requirements set out in Regulation (EU) 2017/745, the definitions set out in this
Regulation prevail.
Where the European standard is an adoption of an International Standard, the scope of this standard
can differ from the scope of the European Regulation that it supports. As the scope of the applicable
regulatory requirements differ from nation to nation and region to region, the standard can only
support European regulatory requirements to the extent of the scope of the European regulation for
medical devices (EU) 2017/745).
NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the risk
management process needs to be in compliance with Regulation (EU) 2017/745. This means that risks have to be
‘reduced as far as possible’, ‘reduced to the lowest possible level’, ‘reduced as far as possible and appropriate’,
‘removed or reduced as far as possible’, ‘eliminated or reduced as far as possible’, ’removed or minimized as far as
possible’, or ‘minimized’, according to the wording of the corresponding General Safety and Performance
Requirement.
NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with General Safety
and Performance Requirements 1, 2, 3, 4, 5, 8, 9, 10, 11, 14, 16, 17, 18, 19, 20, 21 and 22 of the Regulation.
NOTE 3 When a General Safety and Performance Requirement does not appear in Table ZA.1, it means that it is
not addressed by this European Standard.
Table ZA.1 — Correspondence between this European Standard and Annex I of Regulation (EU)
2017/745 [OJ L 117] and to system or process requirements including those relating to quality
management systems, risk management, post-market surveillance systems, clinical investigations,
clinical evaluation or post-market clinical follow-up
General Safety and Clause(s)/sub-clause(s) Remarks/Notes
Performance Requirements of of this EN
Regulation (EU) 2017/745
10.1 [(a) and (b)] 4, 5, 6 and 7 ER 10.1 [(a) and (b)] are only
partly covered by this document,
since the standard does not
provide requirements on design
and manufacture and packaging.
However, this standard provides
a means to assess skin
sensitization to substances used
in the manufacture of medical
devices. Other forms of toxicity
and flammability are not
covered.
10.2 4, 5, 6 and 7 ER 10.2 is only partly covered by
this document, since the
standard does not provide
requirements on design and
manufacture. However, this
standard provides a means to
assess skin sensitization to
substances leaking from medical
devices
10.4.1 (First paragraph) 4, 5, 6 and 7 ER 10.4.1 (first paragraph) is
only partly covered by this
document, since the standard
does not provide requirements
on design and manufacture.
However, this standard provides
a means to assess skin
sensitization to substances used
in the manufacture of medical
devices. Other forms of toxicity
are not covered.
NOTE This part of EN ISO 10993 refers to ISO 10993-1 which itself refers to ISO 14971. In Europe, it should
be assumed that the reference to ISO 14971 is to EN ISO 14971:2020.
General Note: Presumption of conformity depends on also complying with the relevant parts of the
ISO 10993 series.
Table ZA.2 — Applicable Standards to confer presumption of conformity as described in this
Annex ZA
Column 1 Column 2 Column 3 Column 4
Reference in International
Title Corresponding European
Clause 2 Standard Edition
Standard Edition
ISO 10993-1 ISO 10993-1:2018 Biological evaluation of EN ISO 10993-1:2020
medical devices — Part 1:
Evaluation and testing within
a risk management process
ISO 10993-2 ISO 10993-2:2006 Biological evaluation of EN ISO 10993-2:2006
medical devices — Part 2:
Animal welfare requirements
ISO 10993-12 ISO 10993-12:2021 Biological evaluation of EN SO 10993-12:2021
medical devices - Part 12:
Sample preparation and
reference materials
ISO 10993-18 ISO 10993-18:2020 Biological evaluation of EN ISO 10993-18:2020
medical devices - Part 18:
Chemical characterization of
medical device materials
within a risk management
process
The documents listed in the Column 1 of Table ZA.2, in whole or in part, are normatively referenced in
this document, i.e. are indispensable for its application. The achievement of the presumption of
conformity is subject to the application of the edition of Standards as listed in Column 4 or, if no
European Standard Edition exists, the International Standard Edition given in Column 2 of Table ZA.2.
WARNING 1 — Presumption of conformity stays valid only as long as a reference to this European
Standard is maintained in the list published in the Official Journal of the European Union. Users of this
standard should consult frequently the latest list published in the Official Journal of the European
Union.
WARNING 2 — Other Union legislation may be applicable to the product(s) falling within the scope of
this standard.
INTERNATIONAL ISO
STANDARD 10993-10
Fourth edition
2021-11
Biological evaluation of medical
devices —
Part 10:
Tests for skin sensitization
Évaluation biologique des dispositifs médicaux —
Partie 10: Essais de sensibilisation cutanée
Reference number
ISO 10993-10:2021(E)
ISO 10993-10:2021(E)
© ISO 2021
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting on
the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address below
or ISO’s member body in the country of the requester.
ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii
ISO 10993-10:2021(E)
Contents Page
Foreword .v
Introduction . vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 General principles — Step-wise approach . 3
5 Pretest considerations.4
5.1 General . 4
5.2 Types of material . 4
5.2.1 Initial considerations . 4
5.2.2 Ceramics, metals and alloys . 4
5.2.3 Polymers . 4
5.2.4 Biologically derived materials . 4
5.3 Information on chemical composition . 4
5.3.1 General . 4
5.3.2 Existing data sources . 5
6 Skin sensitization tests . 5
6.1 Choice of test methods . 5
6.2 Murine local lymph node assay . 6
6.2.1 Principle . 6
6.2.2 Test sample preparation . 6
6.2.3 Animals and husbandry . 6
6.2.4 Test procedure. 7
6.2.5 Treatment groups . 8
6.2.6 Determination of cellular proliferation and tissue preparation . 8
6.2.7 Results and interpretation . 9
6.2.8 Test report . 9
6.3 Guinea pig assays for the detection of skin sensitization . 9
6.3.1 Principle . 9
6.3.2 Choice of test sample concentrations . 10
6.3.3 Induction . 10
6.3.4 Challenge . 10
6.4 Important factors affecting the outcome of the test . 10
6.5 Guinea pig maximization test . 11
6.5.1 Principle . 11
6.5.2 Test sample preparation . 11
6.5.3 Animals and husbandry . 11
6.5.4 Test procedure.12
6.5.5 Observation of animals . 14
6.5.6 E valuation of results . 14
6.5.7 Test report .15
6.6 Closed-patch test (Buehler test) . 15
6.6.1 Principle . 15
6.6.2 Test sample preparation . 15
6.6.3 Animals and husbandry . 15
6.6.4 Test procedure. 16
6.6.5 Observation of animals . 17
6.6.6 E valuation of results . 17
6.6.7 Test report . 17
7 Key factors in interpretation of test results .18
Annex A (normative) Preparation of materials for skin sensitization testing .19
iii
ISO 10993-10:2021(E)
Annex B (informative) Method for the preparation of extracts from polymeric test
materials .21
Annex C (informative) Non-animal methods for skin sensitization .24
Annex D (informative) Background information on sensitization tests for skin sensitization .37
Bibliography .40
iv
ISO 10993-10:2021(E)
Foreword
ISO (the International Organization for Standardization) 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 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.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).
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. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www.iso.org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation on the voluntary nature of standards, the meaning of ISO specific terms and
expressions related to conformity assessment, as well as information about ISO's adherence to the
World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT) see the following
URL: www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 194 Biological and clinical evaluation of
medical devices, in collaboration with the European Committee for Standardization (CEN) Technical
Committee CEN/TC 206, Biological and clinical evaluation of medical devices, in accordance with the
Agreement on technical cooperation between ISO and CEN (Vienna Agreement).
This fourth edition cancels and replaces the third edition (ISO 10993-10:2010), which has been
technically revised.
The main changes compared to the previous edition are as follows:
— this document now contains a description of skin sensitization testing only;
— Annex C on non-animal methods for skin sensitization (formerly Annex D) has been updated;
— the testing for irritation is now described in ISO 10993-23.
A list of all parts in the ISO 10993 series can be found on the ISO website.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www.iso.org/members.html.
v
ISO 10993-10:2021(E)
Introduction
This document assesses possible contact hazards from chemicals released from medical devices, which
may produce skin sensitization.
Some materials that are included in medical devices have been tested, and their skin sensitization
potential has been documented. Especially for dental materials, sensitizing properties were reported
—see Reference [51]. 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 (background information is provided in Annex D). Since 2015, several in chemico and in vitro
assays have been validated and Organization for Economic Co-operation and Development (OECD) test
[75][79][104]
guidelines released to assess the skin sentization potential of chemicals. An overview of
available alternative skin sensitization tests for neat chemicals is given in Annex C. These test methods,
each developed to address a specific key event, can possibly not be sufficient alone to conclude on
the presence or absence of skin sensitization potential of chemicals and should be considered in the
context of integrated approaches such as integrated approaches to testing and assessment (IATA),
combining them with other complementary information. Note that the in vitro and in chemico tests for
skin sensitization in Annex C have thus far been validated only for neat chemicals and not for medical
devices. To confirm that they are applicable for evaluation of the skin sensitization potential of medical
devices, their assays need to be assessed and validated.
Where appropriate, the preliminary use of in vitro methods is encouraged for screening purposes prior
to animal testing. To reduce the number of animals used, this document presents a step-wise approach,
with review and analysis of test results at each stage. It is intended that, for regulatory submission, skin
sensitization studies be conducted using GLP or ISO/IEC 17025 as applicable to the respective country
and comply with regulations related to animal welfare. Statistical analyses of data are recommended
and used whenever appropriate. This document includes important tools for the development of safe
products and is intended for use by professionals, appropriately qualified by training and experience,
who can 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.
This document is based on numerous standards and guidelines, including OECD Guidelines,
US Pharmacopoeia and the European Pharmacopoeia. It is intended to be the basic document for the
selection and conduct of tests enabling the evaluation of dermal sensitization responses relevant to the
safety of medical materials and devices.
vi
INTERNATIONAL STANDARD ISO 10993-10:2021(E)
Biological evaluation of medical 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
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
materials
ISO 10993-18, Biological evaluation of medical devices — Part 18: Chemical characterization of medical
device materials within a risk management process
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
ISO 10993-10:2021(E)
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 1 to entry: 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 10993-12:2021, 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 1 to entry: 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 1 to entry: In practice, negative controls include blanks (3.3), vehicles (3.17)/solvents and reference
materials.
[SOURCE: ISO 10993-12:2021, 3.10, modified — Note 1 to entry has been replaced.]
ISO 10993-10:2021(E)
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 1 to entry: 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).
ISO 10993-10:2021(E)
5 Pretest considerations
5.1 General
It is important to emphasize that pretest considerations can result in the conclusion that testing for
skin sensitization is not necessary.
The requirements given in ISO 10993-1:2018, Clause 5, and the following apply.
In vivo, non-sterile samples shall be investigated by topical investigation only, as the possibility of
microbial contamination of the test sample can 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 free from
microbial contamination, 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 risk depends on the
leaching or degradation characteristics of the finished products. Those chemical components which
have skin sensitization potential shall be identified.
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
The chemical composition of these materials is typically more complex than those in 5.2.2. A number
of reaction products/impurities/additives/residual catalyst can be present and the degree or extent of
polymerization can vary.
5.2.4 Biologically derived materials
These materials are inherently complex in their composition. They often also contain process residues,
for example, cross-linkers and anti-microbial agents. Biological materials can be inconsistent from
sample to sample.
The methods in this document have not been designed for testing of biologically derived materials and
can therefore be less adequate. For example, the tests in this document do not consider cross-species
sensitization.
5.3 Information on chemical composition
5.3.1 General
Full qualitative data on the chemical constituents of the material shall be established. Quantitative data
on the chemical composition shall also be obtained. If quantitative data are not obtained, the rationale
shall be documented and justified.
ISO 10993-10:2021(E)
5.3.2 Existing data sources
Qualitative and quantitative information on the composition shall be obtained where possible from the
supplier of the starting material.
For polymers, this often requires access to proprietary information; provision should be made for the
transfer and use of such confidential information.
Qualitative information about any additional processing additives (e.g. mould-release agents) shall
also be obtained from appropriate members of the manufacturing chain, including converters and
component manufacturers.
If information on composition is incomplete, a literature study to establish the likely nature of
the starting material and any additives is recommended, so as to assist in the selection of the most
appropriate methods of analysis for the material concerned.
The chemical composition of finalized products shall be determined in accordance with ISO 10993-18.
NOTE The composition of ceramics, metals and alloys can be specified in accordance with ISO or ASTM
international standards and/or can be specified by the user. However, in order to obtain full qualitative and
quantitative details on composition, it can be necessary to request these from the supplier or manufacturer of
the starting material and also from component manufacturers to ensure that processing aids are also identified.
Material master files held by regulatory authorities are another source of data, where they are accessible.
6 Skin sensitization tests
6.1 Choice of test methods
In vitro and in chemico alternative approaches have been developed for neat chemicals using a
combination of different assays to identify skin sensitizers. Several of these methods have been included
[75] [79] [104]
in the OECD test guidelines (TG 442C , TG 442D and TG 442E ) or in the OECD test guideline
[121]
program (see Annex C).
Together, the assays described in these test guidelines cover three key events of the now identified
adverse outcome pathway (AOP) for skin sensitization, including the molecular initiating event (protein
binding), induction of inflammation, and activation of dendritic cells. These test methods developed to
address a specific key event can possibly not alone be sufficient to conclude on the presence or absence
of skin sensitization potential of chemicals and should be considered in the context of integrated
approaches such as IATA, combining them with other complementary information.
In accordance with ISO 10993-2, such integrated approaches shall be taken into consideration for
assessing skin sensitization potential of neat chemicals. Whether these approaches are also applicable
for medical devices or medical device extracts is not yet known. An overview of available alternative
skin sensitization tests for neat chemicals is presented in Annex C.
There are currently three animal assays available for the determination of the skin sensitizing potential
of chemicals. These include two guinea pig assays and one murine assay. The two guinea pig assays are
the guinea pig maximization test (GPMT) and the closed-patch test (Buehler test). Of these two assays,
the maximization test is the most sensitive method. See Reference [9]. The closed-patch test is suitable
for topical products.
The murine local lymph node assay (LLNA) was internationally accepted as an OECD test guideline in
[33]
2010 for testing single chemicals as a stand-alone alternative to the guinea pig assays, and is now
the preferred in vivo assay for chemicals. See References [19] and [32]. In some instances, guinea pig
assays can be necessary for the evaluation of the sensitizing potential of certain test samples. Such can
be true for certain metals (see Reference [44]) that can give false negative findings in the LLNA or skin
ISO 10993-10:2021(E)
irritants that can give false positive findings, as well as high molecular weight substances, which do not
penetrate the skin or substances that are not soluble in the recommended vehicles.
NOTE All three animal assays were developed for the detection of skin sensitizing potential of chemicals, i.e.
contact dermatitis, delayed type (type IV) hypersensitivity.
In view of the provisions laid down in ISO 10993-2 on animal welfare requirements, when an in
vivo assay is performed, the LLNA shall be taken into conside
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