SIST EN ISO 10993-10:2009

Biological evaluation of medical devices - Part 10: Tests for irritation and delayed-type hypersensitivity (ISO 10993-10:2002, including Amd 1:2006)

This part of ISO 10993 describes the procedure for the assessment of medical devices and their constituent materials with regard to their potential to produce irritation and delayed-type hypersensitivity. This part of ISO 10993 includes a) pretest considerations, b) details of the test procedures, and c) key factors for the interpretation of the results. Instructions are given in annex A for the preparation of materials specifically in relation to the above tests. Supplementary tests which are required specifically for devices used intradermally in the ocular, oral, rectal, penile and vaginal areas are given in annex B.

Biologische Beurteilung von Medizinprodukten - Teil 10: Prüfung auf Irritation und Allergien vom verzögerten Typ (ISO 10993-10:2002, einschließlich Änderung 1:2006)

Dieser Teil der ISO 10993 beschreibt Verfahren für die Beurteilung von Medizinprodukten und ihren
Bestandteilen hinsichtlich ihres Potentials, eine Irritation und eine Allergie vom verzögerten Typ
hervorzurufen.
Dieser Teil der ISO 10993 enthält:
a) vor der Prüfung durchzuführende Überlegungen;
b) Einzelheiten zur Durchführung der Prüfungen und
c) Schlüsselfaktoren für die Interpretation der Ergebnisse.
Anhang A enthält Anweisungen für die spezielle Vorbereitung von Materialien im Zusammenhang mit den
genannten Prüfungen.
Zusätzliche Prüfungen, die speziell für intrakutan und im Bereich der Augen, im Bereich der Mundhöhle, des
Enddarms, des Penis oder der Vagina anzuwendende Produkte erforderlich sind, gibt der Anhang B.

Evaluation biologique des dispositifs médicaux - Partie 10 : Essais d'irritation et d'hypersensibilité retardée (ISO 10993-10:2002, Amd 1:2006 inclus)

Biološko ovrednotenje medicinskih pripomočkov - 10. del: Preskusi draženja in zakasnjene preobčutljivosti (ISO 10993-10:2002, vključno z Amd 1:2006)

General Information

• Status: Withdrawn
• Public Enquiry End Date: 09-Mar-2009
• Publication Date: 11-Jun-2009
• Withdrawal Date: 26-Aug-2010
• ICS: 11.100.20 - Biological evaluation of medical devices
• Technical Committee: VAZ - Healthcare
• Current Stage: 9900 - Withdrawal (Adopted Project)
• Start Date: 27-Aug-2010
• Due Date: 19-Sep-2010
• Completion Date: 27-Aug-2010
• Directive: 2007/47/EC - Directive 2007/47/EC of the European Parliament and of the council of 5 September 2007 amending Council Directive 90/385/EEC on the approximation of the laws of the Member States relating to active implantable medical devices, Council Directive 93/42/EEC concerning medical devices and Directive 98/8/EC concerning the placing of biocidal products on the market
• Directive: 90/385/EEC - Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical devices
• Directive: 93/42/EEC - Council Directive 93/42/EEC of 14 June 1993 concerning medical devices
• Mandate: M/BC/CEN/89/9 - Joint Standardization request to CEN/CENELEC concerning harmonized standards relating to horizontal aspects in the field of medical devices
• Ref Project: EN ISO 10993-10:2009 - Biological evaluation of medical devices - Part 10: Tests for irritation and delayed-type hypersensitivity (ISO 10993-10:2002, including Amd 1:2006)

Relations

• Replaced By: SIST EN ISO 10993-10:2010 - Biological evaluation of medical devices - Part 10: Tests for irritation and skin sensitization (ISO 10993-10:2010)
• Effective Date: 01-Oct-2010
• Replaced By: SIST EN ISO 10993-10:2010 - Biological evaluation of medical devices - Part 10: Tests for irritation and skin sensitization (ISO 10993-10:2010)
• Effective Date: 08-Jun-2022
• Replaces: SIST EN ISO 10993-10:2003/A1:2006 - Biological evaluation of medical devices - Part 10: Tests for irritation and delayed-type hypersensitivity - Amendment 1 (ISO 10993-10:2002/Amd 1:2006)
• Effective Date: 01-Jul-2009
• Replaces: SIST EN ISO 10993-10:2003 - Biological evaluation of medical devices - Part 10: Tests for irritation and delayed-type hypersensitivity (ISO 10993-10:2002)
• Effective Date: 01-Jul-2009

Standards Content (Sample)

SLOVENSKI STANDARD
SIST EN ISO 10993-10:2009
01-julij-2009
1DGRPHãþD
SIST EN ISO 10993-10:2003
SIST EN ISO 10993-10:2003/A1:2006
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO3UHVNXVLGUDåHQMDLQ
]DNDVQMHQHSUHREþXWOMLYRVWL,62YNOMXþQR]$PG
Biological evaluation of medical devices - Part 10: Tests for irritation and delayed-type
hypersensitivity (ISO 10993-10:2002, including Amd 1:2006)
Biologische Beurteilung von Medizinprodukten - Teil 10: Prüfung auf Irritation und
Allergien vom verzögerten Typ (ISO 10993-10:2002, einschließlich Änderung 1:2006)
Evaluation biologique des dispositifs médicaux - Partie 10 : Essais d'irritation et
d'hypersensibilité retardée (ISO 10993-10:2002, Amd 1:2006 inclus)
Ta slovenski standard je istoveten z: EN ISO 10993-10:2009
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-10:2009 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

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SIST EN ISO 10993-10:2009

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SIST EN ISO 10993-10:2009
EUROPEAN STANDARD
EN ISO 10993-10
NORME EUROPÉENNE
EUROPÄISCHE NORM
April 2009
ICS 11.100.20 Supersedes EN ISO 10993-10:2002
English Version
Biological evaluation of medical devices - Part 10: Tests for
irritation and delayed-type hypersensitivity (ISO 10993-10:2002,
including Amd 1:2006)
Evaluation biologique des dispositifs médicaux - Partie 10 : Biologische Beurteilung von Medizinprodukten - Teil 10:
Essais d'irritation et d'hypersensibilité retardée (ISO 10993- Prüfung auf Irritation und Allergien vom verzögerten Typ
10:2002, Amd 1:2006 inclus) (ISO 10993-10:2002, einschließlich Änderung 1:2006)
This European Standard was approved by CEN on 12 April 2009.
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 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 Management Centre has the same status as the
official versions.
CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland,
France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal,
Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
Management Centre: Avenue Marnix 17, B-1000 Brussels
© 2009 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-10:2009: E
worldwide for CEN national Members.

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SIST EN ISO 10993-10:2009
EN ISO 10993-10:2009 (E)
Contents Page
Foreword .3
Annex ZA (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 93/42/EEC on Medical Devices .4
Annex ZB (informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 90/385/EEC on Active Implantable Medical Devices .5

2

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SIST EN ISO 10993-10:2009
EN ISO 10993-10:2009 (E)
Foreword
The text of ISO 10993-10:2002, including Amd 1:2006 has been prepared by Technical Committee
ISO/TC 194 “Biological evaluation of medical devices” of the International Organization for Standardization
(ISO) and has been taken over as EN ISO 10993-10:2009 by Technical Committee CEN/TC 206 “Biological
evaluation of medical devices” the secretariat of which is held by NEN.
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 October 2009, and conflicting national standards shall be withdrawn at
the latest by March 2010.
Attention is drawn to the possibility that some of the elements of this document may be the subject of patent
rights. CEN [and/or CENELEC] shall not be held responsible for identifying any or all such patent rights.
This document supersedes EN ISO 10993-10:2002.
This document has been prepared under a mandate given to CEN by the European Commission and the
European Free Trade Association, and supports essential requirements of EU Directives 93/42/EEC on
Medical Devices and 90/385/EEC on Active Implantable Medical Devices.
For relationship with EU Directives, see informative Annex ZA and ZB, which is an integral part of this
document.
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, Cyprus, Czech
Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia,
Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain,
Sweden, Switzerland and the United Kingdom.
Endorsement notice
The text of ISO 10993-10:2002, including Amd 1:2006 has been approved by CEN as a EN ISO 10993-
10:2009 without any modification.
3

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SIST EN ISO 10993-10:2009
EN ISO 10993-10:2009 (E)
Annex ZA
(informative)

Relationship between this European Standard and the Essential Requirements of
EU Directive 93/42/EEC on Medical Devices

This European Standard has been prepared under a mandate given to CEN by the European Commission
and the European Free Trade Association to provide a means of conforming to Essential Requirements of the
New Approach Directive 93/42/EEC on medical devices.
Once this standard is cited in the Official Journal of the European Communities under that Directive and has
been implemented as a national standard in at least one Member State, compliance with the clauses of this
standard given in table ZA confers, within the limits of the scope of this standard, a presumption of conformity
with the corresponding Essential Requirements of that Directive and associated EFTA regulations.
Table ZA — Correspondence between this European Standard and Directive 93/42/EEC on medical
devices
Clause(s)/sub-clause(s) of this Essential Requirements (ERs) of Qualifying remarks/Notes
EN Directive 93/42/EEC
4, 5, 6, 7, 8 and annex A and B Annex I:
7.1, 7.2, 7.5


WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within
the scope of this standard.

4

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SIST EN ISO 10993-10:2009
EN ISO 10993-10:2009 (E)
Annex ZB
(informative)

Relationship between this European Standard and the Essential Requirements of
EU Directive 90/385/EEC on Active Implantable Medical Devices
This European Standard has been prepared under a mandate given to CEN by the European Commission
and the European Free Trade Association to provide a means of conforming to Essential Requirements of the
New Approach Directive 90/385/EEC on active implantable medical devices.
Once this standard is cited in the Official Journal of the European Communities under that Directive and has
been implemented as a national standard in at least one Member State, compliance with the clauses of this
standard given in table ZB confers, within the limits of the scope of this standard, a presumption of conformity
with the corresponding Essential Requirements of that Directive and associated EFTA regulations.

Table ZB — Correspondence between this European Standard and Directive 90/385/EEC on active
implantable medical devices
Clause(s)/sub-clause(s) of this Essential Requirements (ERs) of Qualifying remarks/Notes
EN Directive 90/385/EEC
4, 5, 6, 7, 8 and annex A and B
Annex I :
9

WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within
the scope of this standard.



5

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SIST EN ISO 10993-10:2009

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SIST EN ISO 10993-10:2009


INTERNATIONAL ISO
STANDARD 10993-10
Second edition
2002-09-01


Biological evaluation of medical devices —
Part 10:
Tests for irritation and delayed-type
hypersensitivity
Évaluation biologique des dispositifs médicaux —
Partie 10: Essais d'irritation et d'hypersensibilité retardée




Reference number
ISO 10993-10:2002(E)
©
 ISO 2002

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SIST EN ISO 10993-10:2009
ISO 10993-10:2002(E)
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All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized in any form or by any means, electronic
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ii © ISO 2002 – All rights reserved

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SIST EN ISO 10993-10:2009
ISO 10993-10:2002(E)
Contents Page
Foreword . iv
Introduction. vi
1 Scope. 1
2 Normative references. 1
3 Terms and definitions. 2
4 General principles — Step-wise approach . 3
5 Pretest considerations. 4
5.1 General . 4
5.2 Types of material. 4
5.3 Information on chemical composition . 4
5.4 Material characterization . 5
6 Irritation tests . 5
6.1 In vitro irritation tests . 5
6.2 Factors to be considered in design and selection of in vivo tests . 5
6.3 Animal skin irritation test . 6
6.4 Human skin irritation test. 10
7 Delayed hypersensitivity tests. 14
7.1 Choice of test. 14
7.2 Choice of test sample concentrations . 14
7.3 Other important factors affecting the outcome of the test . 14
7.4 Maximization test for delayed hypersensitivity . 15
7.5 Closed-patch test for delayed hypersensitivity . 18
8 Key factors in interpretation of test results. 20
Annex A (normative) Preparation of materials for irritation/sensitization testing. 21
Annex B (informative) Additional irritation tests.23
Annex C (informative) Background information. 41
Bibliography. 45

© ISO 2002 – All rights reserved iii

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SIST EN ISO 10993-10:2009
ISO 10993-10:2002(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.
International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 3.
The main task of technical committees is to prepare International Standards. Draft International Standards adopted
by the technical committees are circulated to the member bodies for voting. Publication as an International
Standard requires approval by at least 75 % of the member bodies casting a vote.
Attention is drawn to the possibility that some of the elements of this part of ISO 10993 may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights.
ISO 10993-10 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices.
This second edition cancels and replaces the first edition (ISO 10993-10:1995), which has been technically revised.
ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices:
 Part 1: Evaluation and testing
 Part 2: Animal welfare requirements
 Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
 Part 4: Selection of tests for interactions with blood
 Part 5: Tests for in vitro cytotoxicity
 Part 6: Tests for local effects after implantation
 Part 7: Ethylene oxide sterilization residuals
 Part 8: Selection and qualification of reference materials for biological tests
 Part 9: Framework for identification and quantification of potential degradation products
 Part 10: Tests for irritation and delayed-type hypersensitivity
 Part 11: Tests for systemic toxicity
 Part 12: Sample preparation 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
iv © ISO 2002 – All rights reserved

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SIST EN ISO 10993-10:2009
ISO 10993-10:2002(E)
 Part 16: Toxicokinetic study design for degradation products and leachables
 Part 17: Establishment of allowable limits for leachable substances
 Part 18: Chemical characterization of materials
Future parts will deal with other relevant aspects of biological testing.
This part of ISO 10993 is a harmonization of numerous standards and guidelines, including BS 5736, OECD
Guidelines, U.S. Pharmacopoeia and the European Pharmacopoeia. It is intended to be the basic document for the
selection and conduct of tests enabling evaluation of irritation and dermal sensitization responses relevant to safety
of medical materials and devices.
Annex A forms a normative part of this part of ISO 10993. Annexes B and C are for information only.

© ISO 2002 – All rights reserved v

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SIST EN ISO 10993-10:2009
ISO 10993-10:2002(E)
Introduction
This part of ISO 10993 assesses possible contact hazards from chemicals released from medical devices that may
produce skin and mucosal irritation, eye irritation and delayed contact hypersensitivity
Some materials that are included in medical devices have been tested, and their skin or mucosal irritation or
sensitization potential has been documented. Other materials and their chemical components have not been tested
and may induce adverse effects when in contact with biological tissues. The manufacturer is thus obliged to
evaluate each device for potential adverse effects prior to marketing.
Traditionally, small animal tests are performed prior to testing on humans to help predict human response. More
recently, in vitro tests as well as human tests have been added as alternatives. Despite progress and considerable
effort in this direction, a review of findings suggests that currently no satisfactory in vitro test has been devised to
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
of ISO 10993 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.
The tests included in this part of ISO 10993 are important tools for the development of safe products, provided that
these are executed and interpreted by trained personnel.

vi © ISO 2002 – All rights reserved

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SIST EN ISO 10993-10:2009
INTERNATIONAL STANDARD ISO 10993-10:2002(E)

Biological evaluation of medical devices —
Part 10:
Tests for irritation and delayed-type hypersensitivity
1 Scope
This part of ISO 10993 describes the procedure for the assessment of medical devices and their constituent
materials with regard to their potential to produce irritation and delayed-type hypersensitivity.
This part of ISO 10993 includes
a) pretest considerations,
b) details of the test procedures, and
c) key factors for the interpretation of the results.
Instructions are given in annex A for the preparation of materials specifically in relation to the above tests.
Supplementary tests which are required specifically for devices used intradermally in the ocular, oral, rectal, penile
and vaginal areas are given in annex B.
2 Normative references
The following normative documents contain provisions which, through reference in this text, constitute provisions of
this part of ISO 10993. For dated references, subsequent amendments to, or revisions of, any of these publications
do not apply. However, parties to agreements based on this part of ISO 10993 are encouraged to investigate the
possibility of applying the most recent editions of the normative documents indicated below. For undated
references, the latest edition of the normative document referred to applies. Members of ISO and IEC maintain
registers of currently valid International Standards.
ISO 10993-1:1997, Biological evaluation of medical devices — Part 1: Evaluation and testing
ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare 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 2002 – All rights reserved 1

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SIST EN ISO 10993-10:2009
ISO 10993-10:2002(E)
ISO 14155-1, Clinical investigation of medical devices for human subjects — Part 1: General requirements
ISO 14155-2, Clinical investigation of medical devices for human subjects — Part 2: Clinical investigation plans
3 Terms and definitions
For the purposes of this part of ISO 10993, the terms and definitions given in ISO 10993-1 and the following apply.
3.1
allergen
sensitizer
substance/material which is capable of inducing specific hypersensitivity such that, on subsequent exposure to the
same substance/material characteristic, allergic effects are produced
3.2
blank liquid
solvent portion treated in the same manner as the identical solvent used for the preparation of test samples but
without test material, and which is intended for the determination of a background response of the solvent
3.3
challenge
elicitation
process following the induction phase in which the immunological effects of subsequent exposures in an individual
to the inducing material are examined
3.4
corrosion
slow destruction of the texture or material of a tissue
EXAMPLE The action of a strong irritant.
3.5
delayed-type hypersensitization
induction of specific T-cell mediated immunological memory for an allergen to which an individual is exposed,
resulting in a delayed-type hypersensitivity reaction after secondary contact with the allergen
3.6
dose
quantity to be administered to the test system at one time
3.7
erythema
reddening of the skin or mucous membrane
3.8
eschar
scab or discoloured slough of skin
3.9
induction
process that leads to the de novo generation of an altered state of immunological reactivity in an individual to a
specific material
3.10
irritant
agent that produces irritation
2 © ISO 2002 – All rights reserved

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SIST EN ISO 10993-10:2009
ISO 10993-10:2002(E)
3.11
irritation
localized non-specific inflammatory response to single, repeated or continuous application of a substance/material
3.12
necrosis
death of one or more cells, or portion of tissue or organ, resulting in irreversible damage
3.13
negative control
material or substance which, when tested by the procedure described, demonstrates the suitability of the procedure
to yield a reproducible, appropriate negative, nonreactive or background response in the test system
3.14
oedema
swelling due to abnormal infiltration of fluid into the tissues
3.15
positive control
material or substance which, when tested by the procedure described, demonstrates the suitability of the procedure
to yield a reproducible, appropriate positive or reactive response in the test system
3.16
solvent
material or substance used to moisten, dilute, suspend, extract or dissolve the test substance material
EXAMPLES Chemical, vehicle, medium, etc.
3.17
test material
material, device, device portion or component thereof that is sampled for biological or chemical testing
3.18
test sample
extract or portion of the test material that is subjected to biological or chemical testing
3.19
ulceration
open sore representing loss of superficial tissue
4 General principles — Step-wise approach
The available methods for testing irritation and sensitization were developed specifically to detect skin irritation and
sensitization potential. Other types of adverse affect are generally not predicted by these tests.
This part of ISO 10993 requires a step-wise approach, which shall include one or more of the following:
a) characterization 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) consideration of in vitro tests in preference to in vivo tests, and replacement of the latter as new in vitro
methods become available and validated. At the present time there are no validated in vitro tests (other than
simple screens) to detect irritants or sensitizers.
d) in vivo animal tests;
© ISO 2002 – All rights reserved 3

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SIST EN ISO 10993-10:2009
ISO 10993-10:2002(E)
NOTE Acute in vivo animal studies are undertaken to test for materials not already classified as severe irritants or
strong sensitizers by step a) or b). Materials that do not demonstrate an acute dermal irritation at single exposure may then
be further evaluated following repeated exposure.
A test of a positive-control substance for skin sensitization [7] shall be run at least every six months by the
testing laboratory to validate the test system and demonstrate a positive response.
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.
5 Pretest considerations
5.1 General
It is important to emphasise that pretest considerations may result in the conclusion that testing for irritation and/or
sensitization is not necessary.
The requirements given in clause 5 of 10993-1:1997 and in the subclauses below apply.
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 compounds pose a health hazard/risk depends on the leakage or degradation
characteristics of the finished products.
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 5.2.1 in terms of composition. A number of
additives may be present and the completeness of polymerization may vary.
5.2.4 Biologically derived materials
These materials are inherently complex in their composition. They often also contain process residues, e.g.cross-
linkers and anti-microbial agents. Biological materials may not b
...

2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.Biologische Beurteilung von Medizinprodukten - Teil 10: Prüfung auf Irritation und Allergien vom verzögerten Typ (ISO 10993-10:2002, einschließlich Änderung 1:2006)Evaluation biologique des dispositifs médicaux - Partie 10 : Essais d'irritation et d'hypersensibilité retardée (ISO 10993-10:2002, Amd 1:2006 inclus)Biological evaluation of medical devices - Part 10: Tests for irritation and delayed-type hypersensitivity (ISO 10993-10:2002, including Amd 1:2006)11.100.20Biological evaluation of medical devicesICS:Ta slovenski standard je istoveten z:prEN ISO 10993-10kSIST prEN ISO 10993-10:2009en01-marec-2009kSIST prEN ISO 10993-10:2009SLOVENSKI
STANDARD



kSIST prEN ISO 10993-10:2009



EUROPEAN STANDARDNORME EUROPÉENNEEUROPÄISCHE NORMFINAL DRAFTprEN ISO 10993-10December 2008ICS 11.100.20Will supersede EN ISO 10993-10:2002
English VersionBiological evaluation of medical devices - Part 10: Tests forirritation and delayed-type hypersensitivity (ISO 10993-10:2002,including Amd 1:2006)Evaluation biologique des dispositifs médicaux - Partie 10:Essais d'irritation et d'hypersensibilité retardée (ISO 10993-10:2002, Amd 1:2006 inclus)Biologische Beurteilung von Medizinprodukten - Teil 10:Prüfung auf Irritation und Allergien vom verzögerten Typ(ISO 10993-10:2002, einschließlich Änderung 1:2006)This draft European Standard is submitted to CEN members for unique acceptance procedure. It has been drawn up by the TechnicalCommittee CEN/TC 206.If this draft becomes a European Standard, CEN members are bound to comply with the CEN/CENELEC Internal Regulations whichstipulate the conditions for giving this European Standard the status of a national standard without any alteration.This draft European Standard was established by CEN in three official versions (English, French, German). A version in any other languagemade by translation under the responsibility of a CEN member into its own language and notified to the CEN Management Centre has thesame status as the official versions.CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland,France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal,Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.Warning : This document is not a European Standard. It is distributed for review and comments. It is subject to change without notice andshall not be referred to as a European Standard.EUROPEAN COMMITTEE FOR STANDARDIZATIONCOMITÉ EUROPÉEN DE NORMALISATIONEUROPÄISCHES KOMITEE FÜR NORMUNGManagement Centre: rue de Stassart, 36
B-1050 Brussels© 2008 CENAll rights of exploitation in any form and by any means reservedworldwide for CEN national Members.Ref. No. prEN ISO 10993-10:2008: EkSIST prEN ISO 10993-10:2009



prEN ISO 10993-10:2008 (E) 2 Contents Page Foreword .3Annex ZA (informative)
Relationship between this
European
Standard and the Essential Requirements
of EU Directive 93/42/EEC on Medical Devices .4Annex ZB (informative)
Relationship between this
European
Standard and the Essential Requirements
of EU Directive 90/385/EEC on Active Implantable Medical Devices .5 kSIST prEN ISO 10993-10:2009



prEN ISO 10993-10:2008 (E) 3 Foreword The text of ISO 10993-10:2002, including Amd 1:2006 has been prepared by Technical Committee ISO/TC 194 “Biological evaluation of medical devices” of the International Organization for Standardization (ISO) and has been taken over as prEN ISO 10993-10:2008 by Technical Committee CEN/TC 206 “Biological evaluation of medical devices” the secretariat of which is held by NEN. This document is currently submitted to the Unique Acceptance Procedure. This document will supersede EN ISO 10993-10:2002. This document has been prepared under a mandate given to CEN by the European Commission and the European Free Trade Association, and supports essential requirements of EU Directives 93/42/EEC on Medical Devices and 90/385/EEC on Active Implantable Medical Devices. For relationship with EU Directives, see informative Annex ZA and ZB, which is an integral part of this document. Endorsement notice The text of ISO 10993-10:2002, including Amd 1:2006 has been approved by CEN as a prEN ISO 10993-10:2008 without any modification. kSIST prEN ISO 10993-10:2009



prEN ISO 10993-10:2008 (E) 4 Annex ZA (informative)
Relationship between this
European
Standard and the Essential Requirements
of EU Directive 93/42/EEC on Medical Devices
This European Standard has been prepared under a mandate given to CEN by the European Commission and the European Free Trade Association to provide a means of conforming to Essential Requirements of the New Approach Directive 93/42/EEC on medical devices. Once this standard is cited in the Official Journal of the European Communities under that Directive and has been implemented as a national standard in at least one Member State, compliance with the clauses of this standard given in table ZA confers, within the limits of the scope of this standard, a presumption of conformity with the corresponding Essential Requirements of that Directive and associated EFTA regulations. Table ZA — Correspondence between this European Standard and Directive 93/42/EEC on medical devices Clause(s)/sub-clause(s) of this EN Essential Requirements (ERs) of Directive 93/42/EEC Qualifying remarks/Notes 4, 5, 6, 7, 8 & Annexes A, B, C
Annex I: 7.1, 7.2, 7.5
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this standard.
kSIST prEN ISO 10993-10:2009



prEN ISO 10993-10:2008 (E) 5 Annex ZB (informative)
Relationship between this
European
Standard and the Essential Requirements
of EU Directive 90/385/EEC on Active Implantable Medical Devices This European Standard has been prepared under a mandate given to CEN by the European Commission and the European Free Trade Association to provide a means of conforming to Essential Requirements of the New Approach Directive 90/385/EEC on active implantable medical devices. Once this standard is cited in the Official Journal of the European Communities under that Directive and has been implemented as a national standard in at least one Member State, compliance with the clauses of this standard given in table ZB confers, within the limits of the scope of this standard, a presumption of conformity with the corresponding Essential Requirements of that Directive and associated EFTA regulations.
Table ZB — Correspondence between this European Standard and Directive 90/385/EEC on active implantable medical devices Clause(s)/sub-clause(s) of this EN Essential Requirements (ERs) of Directive 90/385/EEC Qualifying remarks/Notes 4, 5, 6, 7, 8 & Annexes A, B, C Annex I : 9
WARNING — Other requirements and other EU Directives may be applicable to the product(s) falling within the scope of this standard.
kSIST prEN ISO 10993-10:2009



kSIST prEN ISO 10993-10:2009



Reference numberISO 10993-10:2002(E)© ISO 2002
INTERNATIONAL STANDARD ISO10993-10Second edition2002-09-01Biological evaluation of medical devices —Part 10: Tests for irritation and delayed-type hypersensitivity Évaluation biologique des dispositifs médicaux — Partie 10: Essais d'irritation et d'hypersensibilité retardée
kSIST prEN ISO 10993-10:2009



ISO 10993-10:2002(E) PDF disclaimer This PDF file may contain embedded typefaces. In accordance with Adobe's licensing policy, this file may be printed or viewed but shall not be edited unless the typefaces which are embedded are licensed to and installed on the computer performing the editing. In downloading this file, parties accept therein the responsibility of not infringing Adobe's licensing policy. The ISO Central Secretariat accepts no liability in this area. Adobe is a trademark of Adobe Systems Incorporated. Details of the software products used to create this PDF file can be found in the General Info relative to the file; the PDF-creation parameters were optimized for printing. Every care has been taken to ensure that the file is suitable for use by ISO member bodies. In the unlikely event that a problem relating to it is found, please inform the Central Secretariat at the address given below.
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ISO 2002 All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying and microfilm, without permission in writing from either ISO at the address below or ISO's member body in the country of the requester. ISO copyright office Case postale 56 • CH-1211 Geneva 20 Tel.
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ii © ISO 2002 – All rights reserved
kSIST prEN ISO 10993-10:2009



ISO 10993-10:2002(E) © ISO 2002 – All rights reserved iii Contents Page Foreword.iv Introduction.vi 1 Scope.1 2 Normative references.1 3 Terms and definitions.2 4 General principles — Step-wise approach.3 5 Pretest considerations.4 5.1 General.4 5.2 Types of material.4 5.3 Information on chemical composition.4 5.4 Material characterization.5 6 Irritation tests.5 6.1 In vitro irritation tests.5 6.2 Factors to be considered in design and selection of in vivo tests.5 6.3 Animal skin irritation test.6 6.4 Human skin irritation test.10 7 Delayed hypersensitivity tests.14 7.1 Choice of test.14 7.2 Choice of test sample concentrations.14 7.3 Other important factors affecting the outcome of the test.14 7.4 Maximization test for delayed hypersensitivity.15 7.5 Closed-patch test for delayed hypersensitivity.18 8 Key factors in interpretation of test results.20 Annex A (normative)
Preparation of materials for irritation/sensitization testing.21 Annex B (informative)
Additional irritation tests.23 Annex C (informative)
Background information.41 Bibliography.45
kSIST prEN ISO 10993-10:2009



ISO 10993-10:2002(E) iv © ISO 2002 – All rights reserved Foreword ISO (the International Organization for Standardization) is a worldwide federation of national standards 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. International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 3. The main task of technical committees is to prepare International Standards. Draft International Standards adopted by the technical committees are circulated to the member bodies for voting. Publication as an International Standard requires approval by at least 75 % of the member bodies casting a vote. Attention is drawn to the possibility that some of the elements of this part of ISO 10993 may be the subject of patent rights. ISO shall not be held responsible for identifying any or all such patent rights. ISO 10993-10 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices. This second edition cancels and replaces the first edition (ISO 10993-10:1995), which has been technically revised. ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices:  Part 1: Evaluation and testing  Part 2: Animal welfare requirements  Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity  Part 4: Selection of tests for interactions with blood  Part 5: Tests for in vitro cytotoxicity  Part 6: Tests for local effects after implantation  Part 7: Ethylene oxide sterilization residuals  Part 8: Selection and qualification of reference materials for biological tests  Part 9: Framework for identification and quantification of potential degradation products  Part 10: Tests for irritation and delayed-type hypersensitivity  Part 11: Tests for systemic toxicity  Part 12: Sample preparation 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 kSIST prEN ISO 10993-10:2009



ISO 10993-10:2002(E) © ISO 2002 – All rights reserved v  Part 16: Toxicokinetic study design for degradation products and leachables  Part 17: Establishment of allowable limits for leachable substances  Part 18: Chemical characterization of materials Future parts will deal with other relevant aspects of biological testing. This part of ISO 10993 is a harmonization of numerous standards and guidelines, including BS 5736, OECD Guidelines, U.S. Pharmacopoeia and the European Pharmacopoeia. It is intended to be the basic document for the selection and conduct of tests enabling evaluation of irritation and dermal sensitization responses relevant to safety of medical materials and devices. Annex A forms a normative part of this part of ISO 10993. Annexes B and C are for information only.
kSIST prEN ISO 10993-10:2009



ISO 10993-10:2002(E) vi © ISO 2002 – All rights reserved Introduction This part of ISO 10993 assesses possible contact hazards from chemicals released from medical devices that may produce skin and mucosal irritation, eye irritation and delayed contact hypersensitivity Some materials that are included in medical devices have been tested, and their skin or mucosal irritation or sensitization potential has been documented. Other materials and their chemical components have not been tested and may induce adverse effects when in contact with biological tissues. The manufacturer is thus obliged to evaluate each device for potential adverse effects prior to marketing. Traditionally, small animal tests are performed prior to testing on humans to help predict human response. More recently, in vitro tests as well as human tests have been added as alternatives. Despite progress and considerable effort in this direction, a review of findings suggests that currently no satisfactory in vitro test has been devised to 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 of ISO 10993 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. The tests included in this part of ISO 10993 are important tools for the development of safe products, provided that these are executed and interpreted by trained personnel.
kSIST prEN ISO 10993-10:2009



INTERNATIONAL STANDARD ISO 10993-10:2002(E) © ISO 2002 – All rights reserved 1 Biological evaluation of medical devices — Part 10: Tests for irritation and delayed-type hypersensitivity 1 Scope This part of ISO 10993 describes the procedure for the assessment of medical devices and their constituent materials with regard to their potential to produce irritation and delayed-type hypersensitivity. This part of ISO 10993 includes a) pretest considerations, b) details of the test procedures, and c) key factors for the interpretation of the results. Instructions are
given in annex A for the preparation of materials specifically in relation to the above tests.
Supplementary tests which are required specifically for devices used intradermally in the ocular, oral, rectal, penile and vaginal areas are given in annex B. 2 Normative references The following normative documents contain provisions which, through reference in this text, constitute provisions of this part of ISO 10993. For dated references, subsequent amendments to, or revisions of, any of these publications do not apply. However, parties to agreements based on this part of ISO 10993 are encouraged to investigate the possibility of applying the most recent editions of the normative documents indicated below. For undated references, the latest edition of the normative document referred to applies. Members of ISO and IEC maintain registers of currently valid International Standards. ISO 10993-1:1997, Biological evaluation of medical devices — Part 1: Evaluation and testing ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare 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 kSIST prEN ISO 10993-10:2009



ISO 10993-10:2002(E) 2 © ISO 2002 – All rights reserved ISO 14155-1, Clinical investigation of medical devices for human subjects — Part 1: General requirements ISO 14155-2, Clinical investigation of medical devices for human subjects — Part 2: Clinical investigation plans 3 Terms and definitions For the purposes of this part of ISO 10993, the terms and definitions given in ISO 10993-1 and the following apply. 3.1 allergen sensitizer substance/material which is capable of inducing specific hypersensitivity such that, on subsequent exposure to the same substance/material characteristic, allergic effects are produced 3.2 blank liquid solvent portion treated in the same manner as the identical solvent used for the preparation of test samples but without test material, and which is intended for the determination of a background response of the solvent 3.3 challenge elicitation process following the induction phase in which the immunological effects of subsequent exposures in an individual to the inducing material are examined 3.4 corrosion slow destruction of the texture or material of a tissue EXAMPLE The action of a strong irritant. 3.5 delayed-type hypersensitization induction of specific T-cell mediated immunological memory for an allergen to which an individual is exposed, resulting in a delayed-type hypersensitivity reaction after secondary contact with the allergen 3.6 dose quantity to be administered to the test system at one time 3.7 erythema reddening of the skin or mucous membrane 3.8 eschar scab or discoloured slough of skin 3.9 induction process that leads to the de novo generation of an altered state of immunological reactivity in an individual to a specific material 3.10 irritant agent that produces irritation kSIST prEN ISO 10993-10:2009



ISO 10993-10:2002(E) © ISO 2002 – All rights reserved 3 3.11 irritation localized non-specific inflammatory response to single, repeated or continuous application of a substance/material 3.12 necrosis death of one or more cells, or portion of tissue or organ, resulting in irreversible damage 3.13 negative control material or substance which, when tested by the procedure described, demonstrates the suitability of the procedure to yield a reproducible, appropriate negative, nonreactive or background response in the test system 3.14 oedema swelling due to abnormal infiltration of fluid into the tissues 3.15 positive control material or substance which, when tested by the procedure described, demonstrates the suitability of the procedure to yield a reproducible, appropriate positive or reactive response in the test system 3.16 solvent material or substance used to moisten, dilute, suspend, extract or dissolve the test substance material EXAMPLES Chemical, vehicle, medium, etc. 3.17 test material material, device, device portion or component thereof that is sampled for biological or chemical testing 3.18 test sample extract or portion of the test material that is subjected to biological or chemical testing 3.19 ulceration open sore representing loss of superficial tissue 4 General principles — Step-wise approach The available methods for testing irritation and sensitization were developed specifically to detect skin irritation and sensitization potential. Other types of adverse affect are generally not predicted by these tests.
This part of ISO 10993 requires a step-wise approach, which shall include one or more of the following: a) characterization 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) consideration of in vitro tests in preference to in vivo tests, and replacement of the latter as new in vitro methods become available and validated. At the present time there are no validated in vitro tests (other than simple screens) to detect irritants or sensitizers. d) in vivo animal tests; kSIST prEN ISO 10993-10:2009



ISO 10993-10:2002(E) 4 © ISO 2002 – All rights reserved NOTE Acute in vivo animal studies are undertaken to test for materials not already classified as severe irritants or strong sensitizers by step a) or b). Materials that do not demonstrate an acute dermal irritation at single exposure may then be further evaluated following repeated exposure.
A test of a positive-control substance for skin sensitization [7] shall be run at least every six months by the testing laboratory to validate the test system and demonstrate a positive response. 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.
5 Pretest considerations 5.1 General It is important to emphasise that pretest considerations may result in the conclusion that testing for irritation and/or sensitization is not necessary. The requirements given in clause 5 of 10993-1:1997 and in the subclauses below apply. 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 compounds pose a health hazard/risk depends on the leakage or degradation characteristics of the finished products. 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 5.2.1 in terms of composition. A number of additives may be present and the completeness of polymerization may vary. 5.2.4 Biologically derived materials These materials are inherently complex in their composition. They often also contain process residues, e.g.cross-linkers and anti-microbial agents. Biological materials may not be consistent from sample to sample. The methods in this part of ISO 10993 have not been designed for testing of biologically derived materials and may therefore be less adequate. For example, the tests in this part of ISO 10993 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. Where relevant to biological safety, quantitative data shall also be obtained. If quantitative data are not obtained, the rationale shall be documented and justified. kSIST prEN ISO 10993-10:2009



ISO 10993-10:2002(E) © ISO 2002 – All rights reserved 5 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 (for example, mould-release agents) shall also be obtained from appropriate members of the manufacturing chain, including converters and component manufacturers. In the absence of any data on composition, a literature study to establish the likely nature of the starting material and any additives is recommended to assist in the selection of the most appropriate methods of analysis for the material concerned. NOTE The composition of ceramics, metals and alloys may be in accordance with ISO or American Society of Testing Materials (ASTM) standards and/or may be specified by the user. However, in order to obtain full qualitative and quantitative details on composition, it may be necessary to request these from the supplier or manufacturer of the starting material and also from component manufacturers to ensure processing aids are also identified. Material master files held by regulatory authorities are another source of data, where they are accessible. 5.4 Material characterization When details of composition are unavailable, or only qualitative information is available, or new or unknown substances may be expected to develop during the manufacturing process, it may be necessary to undertake analysis of a material. Analytical methods appropriate for the material under investigatio
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