SIST EN ISO 10993-3:2009

Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity (ISO 10993-3:2003)

This part of ISO 10993 specifies strategies for hazard identification and tests on medical devices for the following biological aspects: - genotoxicity, - carcinogenicity, and - reproductive and developmental toxicity. This part of ISO 10993 is applicable for evaluation of a medical device whose potential for genotoxicity, carcinogenicity or reproductive toxicity has been identified.

Biologische Beurteilung von Medizinprodukten - Teil 3: Prüfungen auf Gentoxizität, Karzinogenität und Reproduktionstoxizität (ISO 10993-3:2003)

Évaluation biologique des dispositifs médicaux - Partie 3: Essais concernant la génotoxicité, la cancérogénicité et la toxicité sur la reproduction (ISO 10993-3:2003)

L'ISO 10993-3:2003 spécifie des stratégies pour l'identification des risques et des essais sur les dispositifs médicaux pour les aspects biologiques suivants: génotoxicité, cancérogénicité, et toxicité sur la reproduction et le développement.
L'ISO 10993-3:2003 est applicable pour l'évaluation d'un dispositif médical dont le risque potentiel de génotoxicité, de cancérogénicité ou de toxicité sur la reproduction a été identifié.
Des instructions relatives au choix des essais sont données dans l'ISO 10993-1.

Biološko ovrednotenje medicinskih pripomočkov - 3. del: Preskusi genske toksičnosti, kancerogenosti in toksičnosti za razmnoževanje (ISO 10993-3:2003)

General Information

• Status: Withdrawn
• Public Enquiry End Date: 14-Mar-2009
• Publication Date: 17-Aug-2009
• Withdrawal Date: 02-Dec-2014
• ICS: 11.100.20 - Biological evaluation of medical devices
• Technical Committee: VAZ - Healthcare
• Current Stage: 9900 - Withdrawal (Adopted Project)
• Start Date: 03-Dec-2014
• Due Date: 26-Dec-2014
• Completion Date: 03-Dec-2014
• 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: 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 10993-3:2009 - Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity (ISO 10993-3:2003)

Relations

• Replaced By: SIST EN ISO 10993-3:2015 - Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity (ISO 10993-3:2014)
• Effective Date: 01-Jan-2015
• Replaces: SIST EN ISO 10993-3:2004 - Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity (ISO 10993-3:2003)
• Effective Date: 01-Sep-2009

Standards Content (Sample)

SLOVENSKI STANDARD
SIST EN ISO 10993-3:2009
01-september-2009
1DGRPHãþD
SIST EN ISO 10993-3:2004
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO3UHVNXVLJHQVNH
WRNVLþQRVWLNDQFHURJHQRVWLLQWRNVLþQRVWL]DUD]PQRåHYDQMH,62
Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity
and reproductive toxicity (ISO 10993-3:2003)
Biologische Beurteilung von Medizinprodukten - Teil 3: Prüfungen auf Gentoxizität,
Karzinogenität und Reproduktionstoxizität (ISO 10993-3:2003)
Évaluation biologique des dispositifs médicaux - Partie 3: Essais concernant la
génotoxicité, la cancérogénicité et la toxicité sur la reproduction (ISO 10993-3:2003)
Ta slovenski standard je istoveten z: EN ISO 10993-3:2009
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-3:2009 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

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SIST EN ISO 10993-3:2009

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SIST EN ISO 10993-3:2009
EUROPEAN STANDARD
EN ISO 10993-3
NORME EUROPÉENNE
EUROPÄISCHE NORM
May 2009
ICS 11.100.20 Supersedes EN ISO 10993-3:2003
English Version
Biological evaluation of medical devices - Part 3: Tests for
genotoxicity, carcinogenicity and reproductive toxicity (ISO
10993-3:2003)
Évaluation biologique des dispositifs médicaux - Partie 3: Biologische Beurteilung von Medizinprodukten - Teil 3:
Essais concernant la génotoxicité, la cancérogénicité et la Prüfungen auf Gentoxizität, Karzinogenität und
toxicité sur la reproduction (ISO 10993-3:2003) Reproduktionstoxizität (ISO 10993-3:2003)
This European Standard was approved by CEN on 28 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 10993-3:2009: E
worldwide for CEN national Members.

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SIST EN ISO 10993-3:2009
EN ISO 10993-3:2009 (E)
Contents Page
Foreword .3
Annex ZA (Informative) Relationship between this European Standard and the Essential
Requirements of EU Directive 93/42/EEC .4

2

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SIST EN ISO 10993-3:2009
EN ISO 10993-3:2009 (E)
Foreword
The text of ISO 10993-3:2003 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 10993-3:2009 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 November 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 10993-3:2003.
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 EC Directive.
For relationship with EC Directive, see informative Annex ZA, 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 10993-3:2003 has been approved by CEN as a EN ISO 10993-3:2009 without any
modification.
3

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SIST EN ISO 10993-3:2009
EN ISO 10993-3:2009 (E)
Annex ZA
(Informative)

Relationship between this European Standard and the Essential
Requirements of EU Directive 93/42/EEC
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.1 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.1 – Correspondence between this European Standard and EU Directives

Clause(s)/sub-clause(s) of this Essential Requirements (ERs) of Qualifying
EN Directive 93/42/EEC remarks/Notes
4, 5, 6, 7

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 10993-3:2009


INTERNATIONAL ISO
STANDARD 10993-3
Second edition
2003-10-15


Biological evaluation of medical
devices —
Part 3:
Tests for genotoxicity, carcinogenicity
and reproductive toxicity
Évaluation biologique des dispositifs médicaux —
Partie 3: Essais concernant la génotoxicité, la cancérogénicité et la
toxicité sur la reproduction




Reference number
ISO 10993-3:2003(E)
©
ISO 2003

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SIST EN ISO 10993-3:2009
ISO 10993-3:2003(E)
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©  ISO 2003
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.
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Tel. + 41 22 749 01 11
Fax + 41 22 749 09 47
E-mail [e-mail]
Web www.iso.org
Published in Switzerland

ii © ISO 2003 — All rights reserved

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SIST EN ISO 10993-3:2009
ISO 10993-3:2003(E)
Contents Page
Foreword. iv
Introduction . vi
1 Scope. 1
2 Normative references. 1
3 Terms and definitions. 2
4 Genotoxicity tests. 3
4.1 General. 3
4.2 Test strategy. 3
4.3 Sample preparation. 4
4.4 Test methods. 4
4.4.1 In vitro genotoxicity tests. 4
4.4.2 In vivo genotoxicity tests . 4
5 Carcinogenicity tests. 5
5.1 General. 5
5.2 Test strategy. 5
5.3 Sample preparation. 5
5.4 Test methods. 5
6 Reproductive and developmental toxicity tests . 6
6.1 General. 6
6.2 Test strategy. 6
6.3 Sample preparation. 6
6.4 Test methods. 7
7 Test report. 7
Annex A (informative) Cell transformation test system . 8
Annex B (informative) Rationale of test systems. 9
Annex C (informative) Role of implantation carcinogenicity studies. 11
Bibliography . 13


© ISO 2003 — All rights reserved iii

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SIST EN ISO 10993-3:2009
ISO 10993-3:2003(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 2.
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 document may be the subject of patent
rights. ISO shall not be held responsible for identifying any or all such patent rights.
ISO 10993-3 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices.
This second edition cancels and replaces the first edition (ISO 10993-3:1992), 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 the 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
iv © ISO 2003 — All rights reserved

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SIST EN ISO 10993-3:2009
ISO 10993-3:2003(E)
 Part 15: Identification and quantification of degradation products from metals and alloys
 Part 16: Toxicokinetic study design for degradation products and leachables
 Part 17: Establishment of allowable limits for leachable substances
 Part 18: Chemical characterization of materials
Future parts will deal with other relevant aspects of biological testing.
© ISO 2003 — All rights reserved v

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SIST EN ISO 10993-3:2009
ISO 10993-3:2003(E)
Introduction
The basis for biological evaluation of medical devices is often empirical and driven by the relevant concerns
for human safety. The risk of serious and irreversible effects, such as cancer or second-generation
abnormalities, is of particular public concern. It is inherent in the provision of safe medical devices that such
risks be minimized to the greatest extent feasible. The assessment of mutagenic, carcinogenic and
reproductive hazards is an essential component of the control of these risks. Not all test methods for the
assessment of genotoxicity, carcinogenicity or reproductive toxicity are equally well developed, nor is their
validity well established for the testing of medical devices.
Significant issues in test sample size and preparation, scientific understanding of disease processes and test
validation can be cited as limitations of available methods. For example, the biological significance of solid
state carcinogenesis is poorly understood. It is expected that ongoing scientific and medical advances will
alter our understanding of and approaches to these important toxicity test methods. At the time this part of
ISO 10993 was prepared, the test methods proposed were those most acceptable. Scientifically sound
alternatives to the proposed testing may be acceptable insofar as they address relevant matters of safety
assessment.
In the selection of tests needed to evaluate a particular medical device, there is no substitute for a careful
assessment of expected human uses and potential interactions of the medical device with various biological
systems. These considerations will be particularly important in such areas as reproductive and developmental
toxicology.
This part of ISO 10993 presents test methods for the detection of specific biological hazards, and strategies
for the selection of tests, where appropriate, that will assist in hazard identification. Testing is not always
necessary or helpful in hazard identification but, where it is appropriate, it is important that maximum test
sensitivity be achieved. Most tests included in this part of ISO 10993 refer to Guidelines for Testing of
Chemicals, prepared by the Organization for Economic Cooperation and Development (OECD).
The interpretation of findings and their implications for human health effects are beyond the scope of this part
of ISO 10993. Because of the multitude of possible outcomes and the importance of factors such as extent of
exposure, species differences and mechanical or physical considerations, risk assessment has to be
performed on a case-by-case basis.

vi © ISO 2003 — All rights reserved

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SIST EN ISO 10993-3:2009
INTERNATIONAL STANDARD ISO 10993-3:2003(E)

Biological evaluation of medical devices —
Part 3:
Tests for genotoxicity, carcinogenicity and reproductive toxicity
1 Scope
This part of ISO 10993 specifies strategies for hazard identification and tests on medical devices for the
following biological aspects:
 genotoxicity,
 carcinogenicity, and
 reproductive and developmental toxicity.
This part of ISO 10993 is applicable for evaluation of a medical device whose potential for genotoxicity,
carcinogenicity or reproductive toxicity has been identified.
NOTE Guidance on selection of tests is provided in ISO 10993-1.
2 Normative references
The following referenced documents are indispensable for the application of this document. For dated
references, only the edition cited applies. For undated references, the latest edition of the referenced
document (including any amendments) applies.
ISO 10993-1:1997, Biological evaluation of medical devices — Part 1: Evaluation and testing
ISO 10993-2:1992, Biological evaluation of medical devices — Part 2: Animal welfare requirements
ISO 10993-6:1994, Biological evaluation of medical devices — Part 6: Tests for local effects after implantation
ISO 10993-12:2002, 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 materials.
1)
OECD 414 , Prenatal Development Toxicity Study
OECD 415, One-Generation Reproduction Toxicity Study
OECD 416, Two-Generation Reproduction Toxicity

1) Organization for Economic Cooperation and Development.
© ISO 2003 — All rights reserved 1

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SIST EN ISO 10993-3:2009
ISO 10993-3:2003(E)
OECD 421, Reproduction/Developmental Toxicity Screening Test
OECD 451, Carcinogenicity Studies
OECD 453, Combined Chronic Toxicity/Carcinogenicity Studies
OECD 471, Bacterial Reverse Mutation Test
OECD 473, In vitro Mammalian Chromosome Aberration Test
OECD 476, In vitro Mammalian Cell Gene Mutation Test
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 10993-1, ISO 10993-12 and the
following apply.
3.1
carcinogenicity test
test to determine the tumorigenic potential of medical devices, materials and/or extracts using either single or
multiple exposures over a major portion of the life span of the test animal
NOTE These tests may be designed to examine both chronic toxicity and tumorigenicity in a single experimental study.
When chronic toxicity and carcinogenicity are evaluated within a single study, care in study design with emphasis on dose
selection should be exercised. This will help to ensure that premature mortality from chronic/cumulative toxicity does not
compromise the statistical evaluation of animals that survive until scheduled study termination (i.e. normal life-span).
3.2
energy-depositing medical device
device intended to exert its therapeutic or diagnostic effect by the delivery of electromagnetic radiation,
ionizing radiation or ultrasound
NOTE This does not include medical devices that deliver simple electrical current, such as electrocautery medical
devices, pacemakers or functional electrical stimulators.
3.3
genotoxicity test
test using mammalian or non-mammalian cells, bacteria, yeasts or fungi to determine whether gene mutations,
changes in chromosome structure, or other DNA or gene changes are caused by the test samples
NOTE These tests can include whole animals.
3.4
maximum tolerated dose
MTD
maximum dose that a test animal can tolerate without any adverse physical effects
3.5
reproductive and developmental toxicity test
test to evaluate the potential effects of test samples on reproductive function, embryonic morphology
(teratogenicity), and prenatal and early postnatal development
2 © ISO 2003 — All rights reserved

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SIST EN ISO 10993-3:2009
ISO 10993-3:2003(E)
4 Genotoxicity tests
4.1 General
Before a decision to perform a genotoxicity test is made, ISO 10993-1 and the chemical characterization of
materials (ISO 10993-18) shall be taken into account. The rationale for a test programme, taking into
consideration all relevant factors, shall be documented.
ISO 10993-1 indicates circumstances where the potential for genotoxicity is a relevant hazard for
consideration in an overall biological safety evaluation (see ISO 10993-1:1997, Table 1). Testing for
genotoxicity, however, is not necessary for medical devices, and components thereof, made only from
materials known to show no genotoxicity. Testing for genotoxicity is indicated where a review of the
composition of the materials reveals the possible presence in the final medical device of compounds that
might interact with genetic material, or when the chemical composition of the medical device is unknown. In
such circumstances, the genotoxic potential of suspect chemical components should be assessed, bearing in
mind the potential for synergy, in preference to carrying out genotoxicity tests on the material or medical
device as a whole.
When the genotoxicity of a medical device has to be experimentally assessed, a series of in vitro tests shall
be used. This series shall include either two tests if 4.2.1.2 is performed which uses the mouse lymphoma
assay incorporating colony number and size determination, or three tests if 4.2.1.1 is performed. When tests
are performed, at least two tests, investigating different end-points, shall use mammalian cells.
4.2 Test strategy
4.2.1 Genotoxicity testing shall be performed on the basis of an initial decision to test in accordance with
either Option 1 (4.2.1.1) or Option 2 (4.2.1.2).
4.2.1.1 Option 1
a) a test for gene mutations in bacteria (OECD 471); and
b) a test for gene mutations in mammalian cells (OECD 476); and
c) a test for clastogenicity in mammalian cells (OECD 473)
4.2.1.2 Option 2
a) a test for gene mutations in bacteria (OECD 471); and
b) a test for gene mutations in mammalian cells (OECD 476), specifically a mouse lymphoma assay
incorporating colony number and size determination in order to cover both endpoints (clastogenicity and
gene mutations).
4.2.2 If the results of all in vitro tests performed in accordance with 4.2.1 are negative, further genotoxicity
testing in animals is not normally justified and should not be performed, in the interest of preventing undue use
of animals.
In vivo testing shall be performed in accordance with ISO 10993-2.
4.2.3 If any of the in vitro tests is positive, either in vivo mutagenicity tests shall be performed (see 4.2.4) or
the presumption shall be made that the compound is mutagenic.
4.2.4 Any in vivo test shall be chosen on the basis of the most appropriate endpoint identified by the in vitro
tests. An attempt shall be made to demonstrate that the test substance has reached the target organ. If this
cannot be demonstrated, a second in vivo test in another target organ may be required to verify the lack of in
vivo genotoxicity.
© ISO 2003 — All rights reserved 3

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SIST EN ISO 10993-3:2009
ISO 10993-3:2003(E)
In vivo tests commonly used are:
a) micronucleus test in rodents (OECD 474) or
b) metaphase analysis in rodent bone marrow (OECD 475) or
c) unscheduled DNA synthesis test with mammalian liver cells (OECD 486).
The decision as to the most appropriate test system shall be justified and documented.
4.2.5 If other in vivo test systems to investigate genotoxicity are used in order to obtain additional
information, the rationale for this shall be justified and documented.
4.3 Sample preparation
4.3.1 Where genotoxicity tests are carried out on the material or a medical device or as a whole, sample
preparation shall be in accordance with ISO 10993-12. Tests shall be performed on extracts, exaggerated
extracts or the individual chemical compounds of the material/medical device. The highest test concentration
shall be within OECD guidelines. If exaggerated extraction conditions are used, care shall be taken that this
does not alter the chemical characteristics.
4.3.2 An appropriate solvent shall be chosen on the basis of its compatibility with the test system and its
ability to maximize extraction of the material or medical device. The rationale for the choice of solvent shall be
documented.
4.3.3 Where relevant, two appropriate extractants shall be used, one of which is a polar solvent, the second
a non-polar solvent or liquid appropriate to the nature and use of the medical device, both of which are
compatible with the test system.
4.4 Test methods
4.4.1 In vitro genotoxicity tests
Test methods for in vitro genotoxicity tests shall be chosen from the OECD Guidelines for Testing of
Chemicals.
Preferred test methods are: OECD 471, OECD 473, OECD 476, OECD 479 and OECD 482. It may be
necessary to consider, in the design and selection of tests, that a number of materials or substances can
influence the test, e.g. antibiotics and antiseptics. If this is relevant, the rationale for the decision shall be
documented.
4.4.2 In vivo genotoxicity tests
Test methods for in vivo genotoxicity tests shall be chosen from the OECD Guidelines for Testing of
Chemicals.
Preferred test methods are: OECD 474, OECD 475, OECD 478, OECD 483, OECD 484, OECD 485 and
OECD 486.
NOTE Recently, transgenic animal test systems have been developed for genotoxicity testing. These tests may prove
valuable for medical device testing, but their use has not been validated at the time of publication of this part of ISO 10993.
References on test systems are given in the bibliography for transgenic animals.
4 © ISO 2003 — All rights reserved

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SIST EN ISO 10993-3:2009
ISO 10993-3:2003(E)
5 Carcinogenicity tests
5.1 General
Before a decision to perform a carcinogenicity test is made, ISO 10993-1 and ISO 10993-18 shall be taken
into account. The decision to perform a test shall be justified on the basis of an assessment of the risk of
carcinogenesis arising from the use of the medical device. Carcinogenicity testing shall not be performed
when risks can be adequately assessed or managed without generating new carcinogenicity test data.
NOTE There are suitable in vitro cell transformation systems that may be used for carcinogenicity prescreening. Cell
transformation tests have so far not been described in International Standards. Additional information on cell
transformation test systems are given in Annex A.
5.2 Test strategy
5.
...

2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.JHQVNHBiologische Beurteilung von Medizinprodukten - Teil 3: Prüfungen auf Gentoxizität, Karzinogenität und Reproduktionstoxizität (ISO 10993-3:2003)Évaluation biologique des dispositifs médicaux - Partie 3: Essais concernant la génotoxicité, la cancérogénicité et la toxicité sur la reproduction (ISO 10993-3:2003)Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity (ISO 10993-3:2003)11.100.20Biological evaluation of medical devicesICS:Ta slovenski standard je istoveten z:prEN ISO 10993-3kSIST prEN ISO 10993-3:2009en01-marec-2009kSIST prEN ISO 10993-3:2009SLOVENSKI
STANDARD



kSIST prEN ISO 10993-3:2009



EUROPEAN STANDARDNORME EUROPÉENNEEUROPÄISCHE NORMFINAL DRAFTprEN ISO 10993-3November 2008ICS 11.100.20Will supersede EN ISO 10993-3:2003
English VersionBiological evaluation of medical devices - Part 3: Tests forgenotoxicity, carcinogenicity and reproductive toxicity (ISO10993-3:2003)Évaluation biologique des dispositifs médicaux - Partie 3:Essais concernant la génotoxicité, la cancérogénicité et latoxicité sur la reproduction (ISO 10993-3:2003)Biologische Beurteilung von Medizinprodukten - Teil 3:Prüfungen auf Gentoxizität, Karzinogenität undReproduktionstoxizität (ISO 10993-3:2003)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 10993-3:2008: EkSIST prEN ISO 10993-3:2009



prEN ISO 10993-3:2008 (E) 2 Contents Page Foreword .3Annex ZA (Informative)
Relationship between this European Standard and the Essential Requirements of EU Directive 93/42/EEC .4 kSIST prEN ISO 10993-3:2009



prEN ISO 10993-3:2008 (E) 3 Foreword The text of ISO 10993-3:2003 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 10993-3:2008 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 10993-3:2003. 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 EC Directive. For relationship with EC Directive, see informative Annex ZA, which is an integral part of this document. Endorsement notice The text of ISO 10993-3:2003 has been approved by CEN as a prEN ISO 10993-3:2008 without any modification. kSIST prEN ISO 10993-3:2009



prEN ISO 10993-3:2008 (E) 4 Annex ZA (Informative)
Relationship between this European Standard and the Essential Requirements of EU Directive 93/42/EEC 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.1 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.1 – Correspondence between this European Standard and EU Directives
Clause(s)/sub-clause(s) of this EN
Essential Requirements (ERs) of Directive 93/42/EEC Qualifying remarks/Notes 4, 5, 6, 7
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 10993-3:2009



Reference numberISO 10993-3:2003(E)© ISO 2003
INTERNATIONAL STANDARD ISO10993-3Second edition2003-10-15Biological evaluation of medical devices — Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity Évaluation biologique des dispositifs médicaux — Partie 3: Essais concernant la génotoxicité, la cancérogénicité et la toxicité sur la reproduction
kSIST prEN ISO 10993-3:2009



ISO 10993-3:2003(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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ii © ISO 2003 — All rights reserved
kSIST prEN ISO 10993-3:2009



ISO 10993-3:2003(E) © ISO 2003 — All rights reserved iii Contents Page Foreword.iv Introduction.vi 1 Scope.1 2 Normative references.1 3 Terms and definitions.2 4 Genotoxicity tests.3 4.1 General.3 4.2 Test strategy.3 4.3 Sample preparation.4 4.4 Test methods.4 4.4.1 In vitro genotoxicity tests.4 4.4.2 In vivo genotoxicity tests.4 5 Carcinogenicity tests.5 5.1 General.5 5.2 Test strategy.5 5.3 Sample preparation.5 5.4 Test methods.5 6 Reproductive and developmental toxicity tests.6 6.1 General.6 6.2 Test strategy.6 6.3 Sample preparation.6 6.4 Test methods.7 7 Test report.7 Annex A (informative)
Cell transformation test system.8 Annex B (informative)
Rationale of test systems.9 Annex C (informative)
Role of implantation carcinogenicity studies.11 Bibliography.13
kSIST prEN ISO 10993-3:2009



ISO 10993-3:2003(E) iv © ISO 2003 — 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 2. 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 document may be the subject of patent rights. ISO shall not be held responsible for identifying any or all such patent rights. ISO 10993-3 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices. This second edition cancels and replaces the first edition (ISO 10993-3:1992), 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 the 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 kSIST prEN ISO 10993-3:2009



ISO 10993-3:2003(E) © ISO 2003 — All rights reserved v  Part 15: Identification and quantification of degradation products from metals and alloys  Part 16: Toxicokinetic study design for degradation products and leachables  Part 17: Establishment of allowable limits for leachable substances  Part 18: Chemical characterization of materials Future parts will deal with other relevant aspects of biological testing. kSIST prEN ISO 10993-3:2009



ISO 10993-3:2003(E) vi © ISO 2003 — All rights reserved Introduction The basis for biological evaluation of medical devices is often empirical and driven by the relevant concerns for human safety. The risk of serious and irreversible effects, such as cancer or second-generation abnormalities, is of particular public concern. It is inherent in the provision of safe medical devices that such risks be minimized to the greatest extent feasible. The assessment of mutagenic, carcinogenic and reproductive hazards is an essential component of the control of these risks. Not all test methods for the assessment of genotoxicity, carcinogenicity or reproductive toxicity are equally well developed, nor is their validity well established for the testing of medical devices. Significant issues in test sample size and preparation, scientific understanding of disease processes and test validation can be cited as limitations of available methods. For example, the biological significance of solid state carcinogenesis is poorly understood. It is expected that ongoing scientific and medical advances will alter our understanding of and approaches to these important toxicity test methods. At the time this part of ISO 10993 was prepared, the test methods proposed were those most acceptable. Scientifically sound alternatives to the proposed testing may be acceptable insofar as they address relevant matters of safety assessment. In the selection of tests needed to evaluate a particular medical device, there is no substitute for a careful assessment of expected human uses and potential interactions of the medical device with various biological systems. These considerations will be particularly important in such areas as reproductive and developmental toxicology. This part of ISO 10993 presents test methods for the detection of specific biological hazards, and strategies for the selection of tests, where appropriate, that will assist in hazard identification. Testing is not always necessary or helpful in hazard identification but, where it is appropriate, it is important that maximum test sensitivity be achieved. Most tests included in this part of ISO 10993 refer to Guidelines for Testing of Chemicals, prepared by the Organization for Economic Cooperation and Development (OECD). The interpretation of findings and their implications for human health effects are beyond the scope of this part of ISO 10993. Because of the multitude of possible outcomes and the importance of factors such as extent of exposure, species differences and mechanical or physical considerations, risk assessment has to be performed on a case-by-case basis.
kSIST prEN ISO 10993-3:2009



INTERNATIONAL STANDARD ISO 10993-3:2003(E) © ISO 2003 — All rights reserved 1 Biological evaluation of medical devices — Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity 1 Scope This part of ISO 10993 specifies strategies for hazard identification and tests on medical devices for the following biological aspects:  genotoxicity,  carcinogenicity, and  reproductive and developmental toxicity. This part of ISO 10993 is applicable for evaluation of a medical device whose potential for genotoxicity, carcinogenicity or reproductive toxicity has been identified.
NOTE Guidance on selection of tests is provided in ISO 10993-1. 2 Normative references The following referenced documents are indispensable for the application of this document. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amendments) applies. ISO 10993-1:1997, Biological evaluation of medical devices — Part 1: Evaluation and testing ISO 10993-2:1992, Biological evaluation of medical devices — Part 2: Animal welfare requirements ISO 10993-6:1994, Biological evaluation of medical devices — Part 6: Tests for local effects after implantation ISO 10993-12:2002, 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 materials. OECD 4141), Prenatal Development Toxicity Study
OECD 415, One-Generation Reproduction Toxicity Study OECD 416, Two-Generation Reproduction Toxicity
1) Organization for Economic Cooperation and Development. kSIST prEN ISO 10993-3:2009



ISO 10993-3:2003(E) 2 © ISO 2003 — All rights reserved OECD 421, Reproduction/Developmental Toxicity Screening Test OECD 451, Carcinogenicity Studies OECD 453, Combined Chronic Toxicity/Carcinogenicity Studies OECD 471, Bacterial Reverse Mutation Test OECD 473, In vitro Mammalian Chromosome Aberration Test OECD 476, In vitro Mammalian Cell Gene Mutation Test 3 Terms and definitions For the purposes of this document, the terms and definitions given in ISO 10993-1, ISO 10993-12 and the following apply. 3.1 carcinogenicity test test to determine the tumorigenic potential of medical devices, materials and/or extracts using either single or multiple exposures over a major portion of the life span of the test animal NOTE These tests may be designed to examine both chronic toxicity and tumorigenicity in a single experimental study. When chronic toxicity and carcinogenicity are evaluated within a single study, care in study design with emphasis on dose selection should be exercised. This will help to ensure that premature mortality from chronic/cumulative toxicity does not compromise the statistical evaluation of animals that survive until scheduled study termination (i.e. normal life-span). 3.2 energy-depositing medical device device intended to exert its therapeutic or diagnostic effect by the delivery of electromagnetic radiation, ionizing radiation or ultrasound NOTE This does not include medical devices that deliver simple electrical current, such as electrocautery medical devices, pacemakers or functional electrical stimulators. 3.3 genotoxicity test test using mammalian or non-mammalian cells, bacteria, yeasts or fungi to determine whether gene mutations, changes in chromosome structure, or other DNA or gene changes are caused by the test samples NOTE These tests can include whole animals. 3.4 maximum tolerated dose MTD maximum dose that a test animal can tolerate without any adverse physical effects 3.5 reproductive and developmental toxicity test test to evaluate the potential effects of test samples on reproductive function, embryonic morphology
(teratogenicity), and prenatal and early postnatal development kSIST prEN ISO 10993-3:2009



ISO 10993-3:2003(E) © ISO 2003 — All rights reserved 3 4 Genotoxicity tests 4.1 General Before a decision to perform a genotoxicity test is made, ISO 10993-1 and the chemical characterization of materials (ISO 10993-18) shall be taken into account. The rationale for a test programme, taking into consideration all relevant factors, shall be documented. ISO 10993-1 indicates circumstances where the potential for genotoxicity is a relevant hazard for consideration in an overall biological safety evaluation (see ISO 10993-1:1997, Table 1). Testing for genotoxicity, however, is not necessary for medical devices, and components thereof, made only from materials known to show no genotoxicity. Testing for genotoxicity is indicated where a review of the composition of the materials reveals the possible presence in the final medical device of compounds that might interact with genetic material, or when the chemical composition of the medical device is unknown. In such circumstances, the genotoxic potential of suspect chemical components should be assessed, bearing in mind the potential for synergy, in preference to carrying out genotoxicity tests on the material or medical device as a whole. When the genotoxicity of a medical device has to be experimentally assessed, a series of in vitro tests shall be used. This series shall include either two tests if 4.2.1.2 is performed which uses the mouse lymphoma assay incorporating colony number and size determination, or three tests if 4.2.1.1 is performed.
When tests are performed, at least two tests, investigating different end-points, shall use mammalian cells. 4.2 Test strategy 4.2.1 Genotoxicity testing shall be performed on the basis of an initial decision to test in accordance with either Option 1 (4.2.1.1) or Option 2 (4.2.1.2).
4.2.1.1 Option 1 a) a test for gene mutations in bacteria (OECD 471); and b) a test for gene mutations in mammalian cells (OECD 476); and c) a test for clastogenicity in mammalian cells (OECD 473) 4.2.1.2 Option 2 a) a test for gene mutations in bacteria (OECD 471); and b) a test for gene mutations in mammalian cells (OECD 476), specifically a mouse lymphoma assay incorporating colony number and size determination in order to cover both endpoints (clastogenicity and gene mutations). 4.2.2 If the results of all in vitro tests performed in accordance with 4.2.1 are negative, further genotoxicity testing in animals is not normally justified and should not be performed, in the interest of preventing undue use of animals.
In vivo testing shall be performed in accordance with ISO 10993-2. 4.2.3 If any of the in vitro tests is positive, either in vivo mutagenicity tests shall be performed (see 4.2.4) or the presumption shall be made that the compound is mutagenic. 4.2.4 Any in vivo test shall be chosen on the basis of the most appropriate endpoint identified by the in vitro tests. An attempt shall be made to demonstrate that the test substance has reached the target organ. If this cannot be demonstrated, a second in vivo test in another target organ may be required to verify the lack of in vivo genotoxicity.
kSIST prEN ISO 10993-3:2009



ISO 10993-3:2003(E) 4 © ISO 2003 — All rights reserved In vivo tests commonly used are:
a) micronucleus test in rodents (OECD 474) or b) metaphase analysis in rodent bone marrow (OECD 475) or c) unscheduled DNA synthesis test with mammalian liver cells (OECD 486). The decision as to the most appropriate test system shall be justified and documented. 4.2.5 If other in vivo test systems to investigate genotoxicity are used in order to obtain additional information, the rationale for this shall be justified and documented. 4.3 Sample preparation 4.3.1 Where genotoxicity tests are carried out on the material or a medical device or as a whole, sample preparation shall be in accordance with ISO 10993-12. Tests shall be performed on extracts, exaggerated extracts or the individual chemical compounds of the material/medical device. The highest test concentration shall be within OECD guidelines. If exaggerated extraction conditions are used, care shall be taken that this does not alter the chemical characteristics. 4.3.2 An appropriate solvent shall be chosen on the basis of its compatibility with the test system and its ability to maximize extraction of the material or medical device. The rationale for the choice of solvent shall be documented. 4.3.3 Where relevant, two appropriate extractants shall be used, one of which is a polar solvent, the second a non-polar solvent or liquid appropriate to the nature and use of the medical device, both of which are compatible with the test system. 4.4 Test methods 4.4.1 In vitro genotoxicity tests Test methods for in vitro genotoxicity tests shall be chosen from the OECD Guidelines for Testing of Chemicals. Preferred test methods are: OECD 471, OECD 473, OECD 476, OECD 479 and OECD 482. It may be necessary to consider, in the design and selection of tests, that a number of materials or substances can influence the test, e.g. antibiotics and antiseptics. If this is relevant, the rationale for the decision shall be documented.
4.4.2 In vivo genotoxicity tests Test methods for in vivo genotoxicity tests shall be chosen from the OECD Guidelines for Testing of Chemicals. Preferred test methods are: OECD 474, OECD 475, OECD 478, OECD 483, OECD 484, OECD 485 and OECD 486. NOTE Recently, transgenic animal test systems have been developed for genotoxicity testing. These tests may prove valuable for medical device testing, but their use has not been validated at the time of publication of this part of ISO 10993. References on test systems are given in the bibliography for transgenic animals. kSIST prEN ISO 10993-3:2009



ISO 10993-3:2003(E) © ISO 2003 — All rights reserved 5 5 Carcinogenicity tests 5.1 General Before a decision to perform a carcinogenicity test is made, ISO 10993-1 and ISO 10993-18 shall be taken into account. The decision to perform a test shall be justified on the basis of an assessment of the risk of carcinogenesis arising from the use of the medical device. Carcinogenicity testing shall not be performed when risks can be adequately assessed or managed without generating new carcinogenicity test data. NOTE There are suitable in vitro cell transformation systems that may be used for carcinogenicity prescreening. Cell transformation tests have so far not been described in International Standards. Additional information on cell transformation test systems are given in Annex A. 5.2 Test strategy 5.2.1 In the absence of evidence to rule out carcinogenic risks, situations in which the need for carcinogenicity testing shall be considered may include the following: a) resorbable materials and medical devices for which the resorption time is greater than 30 days, unless there are significant and adequate data on human use or exposure; b) materials and medical devices introduced in the body and/or its cavities with a permanent or cumulative contact of greater than 30 days, except when significant and adequate human-use history is available. Carcinogenicity testing of genotoxic materials is not scientifically justified. For genotoxic materials, a carcinogenic hazard shall be presumed and the risk managed accordingly. 5.2.2 When in accordance with ISO 10993-1, chronic toxicity and carcinogenicity have been considered, and it is determined that testing is necessary, tests shall be performed in accordance with OECD 453, if possible. 5.2.3 When in accordance with ISO 10993-1, only a carcinogenicity study has been considered, and it is determined that testing is necessary, tests shall be performed in accordance with OECD 451. 5.2.4 One animal species is sufficient for testing medical devices. The choice of species shall be justified and documented. NOTE Recently, transgenic animal tests have been developed for carcinogenicity testing, but they have not been validated for medical devices at the time of publication of this part of ISO 10993. References on test systems are given in the Bibliography for transgenic animal tests as alternatives to lifetime carcinogenicity tests. 5.3 Sample preparation Sample preparation shall be in accordance with ISO 10993-12. Whenever possible, the medical device shall be tested in a form representative of its “ready-to-use” state. 5.4 Test methods 5.4.1 If carcinogenicity tests are necessary as part of an evaluation of biological safety, these studies shall be performed with defined chemicals or characterized extracts of medical devices. The performance of implantation studies (see Annex C) shall be justified, and the role in the evaluation of human risk shall be described and documented. 5.4.2 If an implantation study is to be performed, consideration shall be given to the clinical use of the medical device in s
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