SIST EN ISO 10993-11:2018
(Main)Biological evaluation of medical devices - Part 11: Tests for systemic toxicity (ISO 10993-11:2017)
Biological evaluation of medical devices - Part 11: Tests for systemic toxicity (ISO 10993-11:2017)
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 skin sensitization.
This part of ISO 10993 includes:
a) pretest considerations for irritation, including in silico and in vitro methods for dermal exposure;
b) details of in vivo (irritation and sensitization) test procedures;
c) key factors for the interpretation of the results.
Instructions are given in Annex A for the preparation of materials specifically in relation to the above tests. In
Annex B several special irritation tests are described for application of medical devices in areas other than skin.
Biologische Beurteilung von Medizinprodukten - Teil 11: Prüfungen auf systemische Toxizität (ISO 10993-11:2017)
Dieses Dokument legt Anforderungen an Verfahren fest und gibt eine Anleitung, die bei der Beurteilung des Potenzials von Materialien für Medizinprodukte zur Auslösung nachteiliger systemischer Reaktionen zu befolgen sind.
Évaluation biologique des dispositifs médicaux - Partie 11: Essais de toxicité systémique (ISO 10993-11:2017)
ISO 10993-11:2017 spécifie des exigences et fournit des préconisations quant aux modes opératoires à suivre pour évaluer les éventuelles réactions systémiques défavorables causées par les matériaux de dispositifs médicaux.
Biološko ovrednotenje medicinskih pripomočkov - 11. del: Preskusi sistemske toksičnosti (ISO 10993-11:2017)
Ta del standarda ISO 10993 opisuje postopek za presojo medicinskih pripomočkov in njihovih sestavnih materialov glede njihovega potenciala za povzročitev draženja in preobčutljivosti kože.
Ta del standarda ISO 10993 vključuje:
a) premisleke glede draženja pred preskusom, vključno z metodami in silico in in vitro za izpostavljenost kože;
b) podrobnosti preskusnih postopkov in vivo (draženje in preobčutljivost);
c) ključne dejavnike za razlago rezultatov.
V Dodatku A so podana navodila za pripravo materialov, zlasti v zvezi z zgornjimi preskusi. V Dodatku B je opisanih več posebnih preskusov draženja pri uporabi medicinskih pripomočkov na drugih delih telesa (ne na koži).
General Information
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Buy Standard
Related Packages
Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 10993-11:2018
01-september-2018
Nadomešča:
SIST EN ISO 10993-11:2009
Biološko ovrednotenje medicinskih pripomočkov - 11. del: Preskusi sistemske
toksičnosti (ISO 10993-11:2017)
Biological evaluation of medical devices - Part 11: Tests for systemic toxicity (ISO 10993-
11:2017)
Biologische Beurteilung von Medizinprodukten - Teil 11: Prüfungen auf systemische
Toxizität (ISO 10993-11:2017)
Évaluation biologique des dispositifs médicaux - Partie 11: Essais de toxicité systémique
(ISO 10993-11:2017)
Ta slovenski standard je istoveten z: EN ISO 10993-11:2018
ICS:
11.100.20 Biološko ovrednotenje Biological evaluation of
medicinskih pripomočkov medical devices
SIST EN ISO 10993-11:2018 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN ISO 10993-11:2018
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SIST EN ISO 10993-11:2018
EN ISO 10993-11
EUROPEAN STANDARD
NORME EUROPÉENNE
May 2018
EUROPÄISCHE NORM
ICS 11.100.20 Supersedes EN ISO 10993-11:2009
English Version
Biological evaluation of medical devices - Part 11: Tests for
systemic toxicity (ISO 10993-11:2017)
Évaluation biologique des dispositifs médicaux - Partie Biologische Beurteilung von Medizinprodukten - Teil
11: Essais de toxicité systémique (ISO 10993-11:2017) 11: Prüfungen auf systemische Toxizität (ISO 10993-
11:2017)
This European Standard was approved by CEN on 31 July 2017.
CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this
European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references
concerning such national standards may be obtained on application to the CEN-CENELEC Management Centre or to any CEN
member.
This European Standard exists in three official versions (English, French, German). A version in any other language made by
translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management
Centre has the same status as the official versions.
CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,
Finland, Former Yugoslav Republic of Macedonia, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania,
Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland,
Turkey and United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels
© 2018 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-11:2018 E
worldwide for CEN national Members.
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SIST EN ISO 10993-11:2018
EN ISO 10993-11:2018 (E)
Contents Page
European foreword . 3
Endorsement notice . 4
Annex ZA (informative) Relationship between this European Standard and the essential
requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered . 5
Annex ZB (informative) Relationship between this European Standard and the essential
requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered . 7
2
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SIST EN ISO 10993-11:2018
EN ISO 10993-11:2018 (E)
European foreword
This document (EN ISO 10993-11:2018) has been prepared by Technical Committee ISO/TC 194 "
Biological and clinical evaluation of medical devices " in collaboration with Technical Committee
CEN/TC 206 “Biological and clinical evaluation of medical devices” the secretariat of which is held by
DIN.
This European Standard shall be given the status of a national standard, either by publication of an
identical text or by endorsement, at the latest by November 2018, and conflicting national standards
shall be withdrawn at the latest by November 2018.
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. CEN shall not be held responsible for identifying any or all such patent rights.
This document supersedes EN ISO 10993-11:2009.
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 Directive(s).
For relationship with EU Directive(s), see informative Annex ZA and ZB, which is an integral part of this
document.
The following referenced documents are indispensable for the application of this document. For
undated references, the latest edition of the referenced document (including any amendments) applies.
For dated references, only the edition cited applies. However, for any use of this standard ‘within the
meaning of Annex ZA’, the user should always check that any referenced document has not been
superseded and that its relevant contents can still be considered the generally acknowledged state-of-
art.
When an IEC or ISO standard is referred to in the ISO standard text, this shall be understood as a
normative reference to the corresponding EN standard, if available, and otherwise to the dated version
of the ISO or IEC standard, as listed below.
NOTE 1 The way in which these referenced documents are cited in normative requirements determines the
extent (in whole or in part) to which they apply.
Table 1 — Correlations between undated normative references and dated EN and ISO standards
Normative references Equivalent dated standard
as listed in Clause 2 of
EN ISO or IEC
the ISO standard
ISO 10993-1 EN ISO 10993-1:2009 ISO 10993-1:2009
ISO 10993-2 EN ISO 10993-2:2006 ISO 10993-2:2006
NOTE 2 This part of EN ISO 10993 refers to ISO 10993-1 which itself refers to ISO 14971. In Europe, it should
be assumed that the reference to ISO 14971 is to EN ISO 14971:2012.
According to the CEN-CENELEC Internal Regulations, the national standards organizations of the
following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria,
Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, Former Yugoslav Republic of Macedonia,
France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta,
Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland,
Turkey and the United Kingdom.
3
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SIST EN ISO 10993-11:2018
EN ISO 10993-11:2018 (E)
Endorsement notice
The text of ISO 10993-11:2017 has been approved by CEN as EN ISO 10993-11:2018 without any
modification.
4
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SIST EN ISO 10993-11:2018
EN ISO 10993-11:2018 (E)
Annex ZA
(informative)
Relationship between this European Standard and the essential
requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered
This European Standard has been prepared under a Commission’s joint standardization request
M/BC/CEN/89/9 concerning harmonized standards relating to horizontal aspects in the field of medical
devices to provide one voluntary means of conforming to essential requirements of Council Directive
93/42/EEC of 14 June 1993 concerning medical devices [OJ L 169].
Once this standard is cited in the Official Journal of the European Union under that Directive,
compliance with the normative 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.
NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the risk
management process needs to be in compliance with Directive 93/42/EEC as amended by 2007/47/EC. This
means that risks have to be reduced ‘as far as possible’, ‘to a minimum’, ‘to the lowest possible level’, ‘minimized’
or ‘removed’, according to the wording of the corresponding essential requirement.
NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with Essential
Requirements 1, 2, 5, 6, 7, 8, 9, 11 and 12 of the Directive.
NOTE 3 This Annex ZA is based on normative references according to the table of references in the European
foreword, replacing the references in the core text.
NOTE 4 When an Essential Requirement does not appear in Table ZA.1, it means that it is not addressed by this
European Standard.
Table ZA.1 — Correspondence between this European Standard and Annex I of Directive
93/42/EEC [OJ L 169]
Essential Requirements of Clause(s)/sub-clause(s) of Remarks/Notes
Directive 93/42/EEC this EN
ER 7.1 is only partly covered by ISO
10993-11, since the standard does not
provide requirements on design and
manufacture. However, this part of ISO
10993 specifies test methods for the
assessment of systemic toxicity of
materials intended for use in medical
devices. Therefore, this standard
provides a means to evaluate systemic
7.1 (First and second indent) 4, 5 and 6
toxicity risks associated with the
materials which are used.
These tests are not intended to evaluate
or determine the performance of the test
sample in terms of mechanical or
functional loading.
Systemic toxicity studies conducted by
5
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SIST EN ISO 10993-11:2018
EN ISO 10993-11:2018 (E)
Essential Requirements of Clause(s)/sub-clause(s) of Remarks/Notes
Directive 93/42/EEC this EN
implantation may satisfy the
requirements of this part of ISO 10993.
When conducting combined studies for
evaluating local effects and systemic
effects, the requirements of this part of
ISO 10993 and ISO 10993-6 shall be
fulfilled.
For ER 7.1 (first and second indent),
flammability is not covered
ER 7.2 is not covered by ISO 10993-11,
since the standard does not provide
requirements on design, manufacture
and packaging and does not oblige to
minimize risk. However, this part of ISO
10993 specifies test methods for the
assessment of systemic effects arising
7.2 4, 5 and 6
from the exposure of users or patients to
contaminants or residues present in
medical devices. This assessment can be
a preliminary step for risk minimization.
However it does not address risks to
persons involved in the transport or
storage of medical devices.
ER 7.5 is not covered by ISO 10993-11,
since the standard does not provide
requirements on design and manufacture
and does not oblige to minimize risk.
However, this part of ISO 10993 specifies
7.5, first paragraph, first sentence
4, 5 and 6
test methods for the assessment of
only
systemic effects arising from exposure to
substances released by or leaching from
medical devices. This evaluation can be a
preliminary step for risk minimization.
Other forms of toxicity are not dealt with
in this standard.
General Note: Presumption of conformity depends on also complying with all relevant
clauses/subclauses of ISO 10993-1.
WARNING 1 — Presumption of conformity stays valid only as long as a reference to this European
Standard is maintained in the list published in the Official Journal of the European Union. Users of this
standard should consult frequently the latest list published in the Official Journal of the European
Union.
WARNING 2 — Other Union legislation may be applicable to the products falling within the scope of
this standard.
6
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SIST EN ISO 10993-11:2018
EN ISO 10993-11:2018 (E)
Annex ZB
(informative)
Relationship between this European Standard and the essential
requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered
This European Standard has been prepared under a Commission’s joint standardization request
M/BC/CEN/89/9 concerning harmonized standards relating to horizontal aspects in the field of medical
devices to provide one voluntary means of conforming to essential requirements of 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 [OJ L 189].
Once this standard is cited in the Official Journal of the European Union under that Directive,
compliance with the normative clauses of this standard given in Table ZB.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.
NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the risk
management process needs to be in compliance with Directive 90/385/EEC as amended by 2007/47/EC. This
means that risks have to be reduced ‘as far as possible’, ‘to a minimum’, ‘to the lowest possible level’, ‘minimized’
or ‘removed’, according to the wording of the corresponding essential requirement.
NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with Essential
Requirements 1, 4, 5, 8, 9 and 10 of the Directive.
NOTE 3 This Annex ZB is based on normative references according to the table of references in the European
foreword, replacing the references in the core text.
NOTE 4 When an Essential Requirement does not appear in Table ZB.1, it means that it is not addressed by this
European Standard.
Table ZB.1 — Correspondence between this European Standard and Annex I of Directive
90/385/EEC [OJ L 189]
Essential Requirements of Clause(s)/sub-clause(s) Remarks/Notes
Directive 90/385/EEC of this EN
ER 9 is only partly covered by ISO
10993-11, since the standard does
not provide requirements on
design and manufacture. However,
this part of ISO 10993 specifies test
methods for the assessment of
systemic toxicity of materials
9 (only first and second
intended for use in medical
4, 5 and 6
indent)
devices. Therefore, this standard
provides a means to evaluate
systemic toxicity risks associated
with the materials which are used.
These tests are not intended to
evaluate or determine the
7
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SIST EN ISO 10993-11:2018
EN ISO 10993-11:2018 (E)
Essential Requirements of Clause(s)/sub-clause(s) Remarks/Notes
Directive 90/385/EEC of this EN
performance of the test sample in
terms of mechanical or functional
loading.
Systemic toxicity studies
conducted by implantation may
satisfy the requirements of this
part of ISO 10993. When
conducting combined studies for
evaluating local effects and
systemic effects, the requirements
of this part of ISO 10993 and
ISO 10993-6 shall be fulfilled.
Other forms of toxicity are not
covered.
General Note: Presumption of conformity depends on also complying with all relevant
clauses/subclauses of ISO 10993-1.
WARNING 1 — Presumption of conformity stays valid only as long as a reference to this European
Standard is maintained in the list published in the Official Journal of the European Union. Users of this
standard should consult frequently the latest list published in the Official Journal of the European
Union.
WARNING 2 — Other Union legislation may be applicable to the products falling within the scope of
this standard.
8
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SIST EN ISO 10993-11:2018
INTERNATIONAL ISO
STANDARD 10993-11
Third edition
2017-09
Biological evaluation of medical
devices —
Part 11:
Tests for systemic toxicity
Évaluation biologique des dispositifs médicaux —
Partie 11: Essais de toxicité systémique
Reference number
ISO 10993-11:2017(E)
©
ISO 2017
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SIST EN ISO 10993-11:2018
ISO 10993-11:2017(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2017, Published in Switzerland
All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized otherwise in any form
or by any means, electronic or mechanical, including photocopying, or posting on the internet or an intranet, without prior
written permission. Permission can be requested from either ISO at the address below or ISO’s member body in the country of
the requester.
ISO copyright office
Ch. de Blandonnet 8 • CP 401
CH-1214 Vernier, Geneva, Switzerland
Tel. +41 22 749 01 11
Fax +41 22 749 09 47
copyright@iso.org
www.iso.org
ii © ISO 2017 – All rights reserved
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SIST EN ISO 10993-11:2018
ISO 10993-11:2017(E)
Contents Page
Foreword .v
Introduction .vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 General considerations . 3
4.1 General . 3
4.2 Selection of animal species . 3
4.3 Animal status . 3
4.4 Animal care and husbandry . 3
4.5 Size and number of groups . 4
4.5.1 Size of groups . 4
4.5.2 Number of groups . 4
4.5.3 Treatment controls . 4
4.6 Route of exposure . 5
4.7 Sample preparation . 5
4.8 Dosing . 5
4.8.1 Test sample administration . 5
4.8.2 Dosage volumes . 5
4.8.3 Dosage frequency . 6
4.9 Body weight and food/water consumption . 6
4.10 Clinical observations . 6
4.11 Clinical pathology . 6
4.12 Anatomic pathology . 7
4.13 Study designs . 7
4.14 Quality of investigation . 7
5 Acute systemic toxicity . 7
5.1 General . 7
5.2 Study design . 8
5.2.1 Preparations . 8
5.2.2 Experimental animals. 8
5.2.3 Test conditions. 8
5.2.4 Body weights . 9
5.2.5 Clinical observations . 9
5.2.6 Pathology . 9
5.3 Evaluation criteria .10
5.3.1 General.10
5.3.2 Evaluation of results .10
5.4 Final report .10
6 Repeated exposure systemic toxicity (subacute, subchronic and chronic
systemic toxicity) .12
6.1 General .12
6.2 Study design .12
6.2.1 Preparations .12
6.2.2 Experimental animals.12
6.2.3 Test conditions.13
6.2.4 Body weights .13
6.2.5 Clinical observations .13
6.2.6 Pathology .13
6.3 Evaluation criteria .14
6.3.1 General.14
6.3.2 Evaluation of results .14
© ISO 2017 – All rights reserved iii
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SIST EN ISO 10993-11:2018
ISO 10993-11:2017(E)
6.4 Final report .15
Annex A (informative) Routes of administration .16
Annex B (informative) Dosage volumes .18
Annex C (informative) Common clinical signs and observations .19
Annex D (informative) Suggested haematology, clinical chemistry and urinalysis measurements 20
Annex E (informative) Suggested organ list for histopathological evaluation .22
Annex F (informative) Organ list for limited histopathology for medical devices subjected
to systemic toxicity testing .24
Annex G (informative) Information on material-mediated pyrogens .25
Annex H (informative) Subchronic rat — Dual routes of parenteral administration .26
Bibliography .28
iv © ISO 2017 – All rights reserved
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SIST EN ISO 10993-11:2018
ISO 10993-11:2017(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 standardizat
...
SLOVENSKI STANDARD
SIST EN ISO 10993-11:2018
01-september-2018
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SIST EN ISO 10993-11:2009
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Biological evaluation of medical devices - Part 11: Tests for systemic toxicity (ISO 10993-
11:2017)
Biologische Beurteilung von Medizinprodukten - Teil 11: Prüfungen auf systemische
Toxizität (ISO 10993-11:2017)
Évaluation biologique des dispositifs médicaux - Partie 11: Essais de toxicité systémique
(ISO 10993-11:2017)
Ta slovenski standard je istoveten z: EN ISO 10993-11:2018
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-11:2018 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
---------------------- Page: 1 ----------------------
SIST EN ISO 10993-11:2018
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SIST EN ISO 10993-11:2018
EN ISO 10993-11
EUROPEAN STANDARD
NORME EUROPÉENNE
May 2018
EUROPÄISCHE NORM
ICS 11.100.20 Supersedes EN ISO 10993-11:2009
English Version
Biological evaluation of medical devices - Part 11: Tests for
systemic toxicity (ISO 10993-11:2017)
Évaluation biologique des dispositifs médicaux - Partie Biologische Beurteilung von Medizinprodukten - Teil
11: Essais de toxicité systémique (ISO 10993-11:2017) 11: Prüfungen auf systemische Toxizität (ISO 10993-
11:2017)
This European Standard was approved by CEN on 31 July 2017.
CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this
European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references
concerning such national standards may be obtained on application to the CEN-CENELEC Management Centre or to any CEN
member.
This European Standard exists in three official versions (English, French, German). A version in any other language made by
translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management
Centre has the same status as the official versions.
CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,
Finland, Former Yugoslav Republic of Macedonia, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania,
Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland,
Turkey and United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels
© 2018 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-11:2018 E
worldwide for CEN national Members.
---------------------- Page: 3 ----------------------
SIST EN ISO 10993-11:2018
EN ISO 10993-11:2018 (E)
Contents Page
European foreword . 3
Endorsement notice . 4
Annex ZA (informative) Relationship between this European Standard and the essential
requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered . 5
Annex ZB (informative) Relationship between this European Standard and the essential
requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered . 7
2
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SIST EN ISO 10993-11:2018
EN ISO 10993-11:2018 (E)
European foreword
This document (EN ISO 10993-11:2018) has been prepared by Technical Committee ISO/TC 194 "
Biological and clinical evaluation of medical devices " in collaboration with Technical Committee
CEN/TC 206 “Biological and clinical evaluation of medical devices” the secretariat of which is held by
DIN.
This European Standard shall be given the status of a national standard, either by publication of an
identical text or by endorsement, at the latest by November 2018, and conflicting national standards
shall be withdrawn at the latest by November 2018.
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. CEN shall not be held responsible for identifying any or all such patent rights.
This document supersedes EN ISO 10993-11:2009.
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 Directive(s).
For relationship with EU Directive(s), see informative Annex ZA and ZB, which is an integral part of this
document.
The following referenced documents are indispensable for the application of this document. For
undated references, the latest edition of the referenced document (including any amendments) applies.
For dated references, only the edition cited applies. However, for any use of this standard ‘within the
meaning of Annex ZA’, the user should always check that any referenced document has not been
superseded and that its relevant contents can still be considered the generally acknowledged state-of-
art.
When an IEC or ISO standard is referred to in the ISO standard text, this shall be understood as a
normative reference to the corresponding EN standard, if available, and otherwise to the dated version
of the ISO or IEC standard, as listed below.
NOTE 1 The way in which these referenced documents are cited in normative requirements determines the
extent (in whole or in part) to which they apply.
Table 1 — Correlations between undated normative references and dated EN and ISO standards
Normative references Equivalent dated standard
as listed in Clause 2 of
EN ISO or IEC
the ISO standard
ISO 10993-1 EN ISO 10993-1:2009 ISO 10993-1:2009
ISO 10993-2 EN ISO 10993-2:2006 ISO 10993-2:2006
NOTE 2 This part of EN ISO 10993 refers to ISO 10993-1 which itself refers to ISO 14971. In Europe, it should
be assumed that the reference to ISO 14971 is to EN ISO 14971:2012.
According to the CEN-CENELEC Internal Regulations, the national standards organizations of the
following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria,
Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, Former Yugoslav Republic of Macedonia,
France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta,
Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland,
Turkey and the United Kingdom.
3
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SIST EN ISO 10993-11:2018
EN ISO 10993-11:2018 (E)
Endorsement notice
The text of ISO 10993-11:2017 has been approved by CEN as EN ISO 10993-11:2018 without any
modification.
4
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SIST EN ISO 10993-11:2018
EN ISO 10993-11:2018 (E)
Annex ZA
(informative)
Relationship between this European Standard and the essential
requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered
This European Standard has been prepared under a Commission’s joint standardization request
M/BC/CEN/89/9 concerning harmonized standards relating to horizontal aspects in the field of medical
devices to provide one voluntary means of conforming to essential requirements of Council Directive
93/42/EEC of 14 June 1993 concerning medical devices [OJ L 169].
Once this standard is cited in the Official Journal of the European Union under that Directive,
compliance with the normative 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.
NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the risk
management process needs to be in compliance with Directive 93/42/EEC as amended by 2007/47/EC. This
means that risks have to be reduced ‘as far as possible’, ‘to a minimum’, ‘to the lowest possible level’, ‘minimized’
or ‘removed’, according to the wording of the corresponding essential requirement.
NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with Essential
Requirements 1, 2, 5, 6, 7, 8, 9, 11 and 12 of the Directive.
NOTE 3 This Annex ZA is based on normative references according to the table of references in the European
foreword, replacing the references in the core text.
NOTE 4 When an Essential Requirement does not appear in Table ZA.1, it means that it is not addressed by this
European Standard.
Table ZA.1 — Correspondence between this European Standard and Annex I of Directive
93/42/EEC [OJ L 169]
Essential Requirements of Clause(s)/sub-clause(s) of Remarks/Notes
Directive 93/42/EEC this EN
ER 7.1 is only partly covered by ISO
10993-11, since the standard does not
provide requirements on design and
manufacture. However, this part of ISO
10993 specifies test methods for the
assessment of systemic toxicity of
materials intended for use in medical
devices. Therefore, this standard
provides a means to evaluate systemic
7.1 (First and second indent) 4, 5 and 6
toxicity risks associated with the
materials which are used.
These tests are not intended to evaluate
or determine the performance of the test
sample in terms of mechanical or
functional loading.
Systemic toxicity studies conducted by
5
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SIST EN ISO 10993-11:2018
EN ISO 10993-11:2018 (E)
Essential Requirements of Clause(s)/sub-clause(s) of Remarks/Notes
Directive 93/42/EEC this EN
implantation may satisfy the
requirements of this part of ISO 10993.
When conducting combined studies for
evaluating local effects and systemic
effects, the requirements of this part of
ISO 10993 and ISO 10993-6 shall be
fulfilled.
For ER 7.1 (first and second indent),
flammability is not covered
ER 7.2 is not covered by ISO 10993-11,
since the standard does not provide
requirements on design, manufacture
and packaging and does not oblige to
minimize risk. However, this part of ISO
10993 specifies test methods for the
assessment of systemic effects arising
7.2 4, 5 and 6
from the exposure of users or patients to
contaminants or residues present in
medical devices. This assessment can be
a preliminary step for risk minimization.
However it does not address risks to
persons involved in the transport or
storage of medical devices.
ER 7.5 is not covered by ISO 10993-11,
since the standard does not provide
requirements on design and manufacture
and does not oblige to minimize risk.
However, this part of ISO 10993 specifies
7.5, first paragraph, first sentence
4, 5 and 6
test methods for the assessment of
only
systemic effects arising from exposure to
substances released by or leaching from
medical devices. This evaluation can be a
preliminary step for risk minimization.
Other forms of toxicity are not dealt with
in this standard.
General Note: Presumption of conformity depends on also complying with all relevant
clauses/subclauses of ISO 10993-1.
WARNING 1 — Presumption of conformity stays valid only as long as a reference to this European
Standard is maintained in the list published in the Official Journal of the European Union. Users of this
standard should consult frequently the latest list published in the Official Journal of the European
Union.
WARNING 2 — Other Union legislation may be applicable to the products falling within the scope of
this standard.
6
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SIST EN ISO 10993-11:2018
EN ISO 10993-11:2018 (E)
Annex ZB
(informative)
Relationship between this European Standard and the essential
requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered
This European Standard has been prepared under a Commission’s joint standardization request
M/BC/CEN/89/9 concerning harmonized standards relating to horizontal aspects in the field of medical
devices to provide one voluntary means of conforming to essential requirements of 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 [OJ L 189].
Once this standard is cited in the Official Journal of the European Union under that Directive,
compliance with the normative clauses of this standard given in Table ZB.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.
NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the risk
management process needs to be in compliance with Directive 90/385/EEC as amended by 2007/47/EC. This
means that risks have to be reduced ‘as far as possible’, ‘to a minimum’, ‘to the lowest possible level’, ‘minimized’
or ‘removed’, according to the wording of the corresponding essential requirement.
NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with Essential
Requirements 1, 4, 5, 8, 9 and 10 of the Directive.
NOTE 3 This Annex ZB is based on normative references according to the table of references in the European
foreword, replacing the references in the core text.
NOTE 4 When an Essential Requirement does not appear in Table ZB.1, it means that it is not addressed by this
European Standard.
Table ZB.1 — Correspondence between this European Standard and Annex I of Directive
90/385/EEC [OJ L 189]
Essential Requirements of Clause(s)/sub-clause(s) Remarks/Notes
Directive 90/385/EEC of this EN
ER 9 is only partly covered by ISO
10993-11, since the standard does
not provide requirements on
design and manufacture. However,
this part of ISO 10993 specifies test
methods for the assessment of
systemic toxicity of materials
9 (only first and second
intended for use in medical
4, 5 and 6
indent)
devices. Therefore, this standard
provides a means to evaluate
systemic toxicity risks associated
with the materials which are used.
These tests are not intended to
evaluate or determine the
7
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SIST EN ISO 10993-11:2018
EN ISO 10993-11:2018 (E)
Essential Requirements of Clause(s)/sub-clause(s) Remarks/Notes
Directive 90/385/EEC of this EN
performance of the test sample in
terms of mechanical or functional
loading.
Systemic toxicity studies
conducted by implantation may
satisfy the requirements of this
part of ISO 10993. When
conducting combined studies for
evaluating local effects and
systemic effects, the requirements
of this part of ISO 10993 and
ISO 10993-6 shall be fulfilled.
Other forms of toxicity are not
covered.
General Note: Presumption of conformity depends on also complying with all relevant
clauses/subclauses of ISO 10993-1.
WARNING 1 — Presumption of conformity stays valid only as long as a reference to this European
Standard is maintained in the list published in the Official Journal of the European Union. Users of this
standard should consult frequently the latest list published in the Official Journal of the European
Union.
WARNING 2 — Other Union legislation may be applicable to the products falling within the scope of
this standard.
8
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SIST EN ISO 10993-11:2018
INTERNATIONAL ISO
STANDARD 10993-10
Third edition
2010-08-01
Biological evaluation of medical
devices —
Part 10:
Tests for irritation and skin sensitization
Évaluation biologique des dispositifs médicaux —
Partie 10: Essais d'irritation et de sensibilisation cutanée
Reference number
ISO 10993-10:2010(E)
©
ISO 2010
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SIST EN ISO 10993-11:2018
ISO 10993-10:2010(E)
PDF disclaimer
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shall not be edited unless the typefaces which are embedded are licensed to and installed on the computer performing the editing. In
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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.
COPYRIGHT PROTECTED DOCUMENT
© ISO 2010
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. + 41 22 749 01 11
Fax + 41 22 749 09 47
E-mail copyright@iso.org
Web www.iso.org
Published in Switzerland
ii © ISO 2010 – All rights reserved
---------------------- Page: 12 ----------------------
SIST EN ISO 10993-11:2018
ISO 10993-10:2010(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 .4
5 Pretest considerations.4
5.1 General .4
5.2 Types of material .5
5.3 Information on chemical composition .5
6 Irritation tests.6
6.1 In vitro irritation tests.6
6.2 In vivo irritation tests — Factors to be considered in design and selection of in vivo tests .6
6.3 Animal irritation test.7
6.4 Animal intracutaneous (intradermal) reactivity test .11
6.5 Human skin irritation test .14
7 Skin sensitization tests.15
7.1 Choice of test methods.15
7.2 Murine Local Lymph Node Assay (LLNA).15
7.3 Guinea pig assays for the detection of skin sensitization.18
7.4 Important factors affecting the outcome of the test .19
7.5 Guinea pig maximization test (GPMT).20
7.6 Closed-patch test (Buehler test) .23
8 Key factors in interpretation of test results.26
Annex A (normative) Preparation of materials for irritation/sensitization testing.27
Annex B (normative) Special irritation tests.29
Annex C (normative) Human skin irritation test .44
Annex D (informative) In vitro tests for skin irritation.48
Annex E (informative) Method for the preparation of extracts from polymeric test materials .54
Annex F (informative) Background information .57
Bibliography.61
© ISO 2010 – All rights reserved iii
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SIST EN ISO 10993-11:2018
ISO 10993-10:2010(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 10993-10 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices.
This third edition cancels and replaces the second edition (ISO 10993-10:2002), 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 within a risk management process
⎯ 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 9: Framework for identification and quantification of potential degradation products
⎯ Part 10: Tests for irritation and skin sensitization
⎯ Part 11: Tests for systemic toxicity
⎯ Part 12: Sample preparation and reference materials
⎯ Part 13: Identification and quantification of degradation products from polymeric medical devices
⎯ Part 14: Identification and quantification of degradation products from ceramics
⎯ Part 15: Identification and quantification of degradation products from metals and alloys
iv © ISO 2010 – All rights reserved
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SIST EN ISO 10993-11:2018
ISO 10993-10:2010(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
⎯ Part 19: Physico-chemical, morphological and topographical characterization of materials [Technical
Specification]
⎯ Part 20: Principles and methods for immunotoxicology testing of medical devices [Technical Specification]
© ISO 2010 – All rights reserved v
---------------------- Page: 15 ----------------------
SIST EN ISO 10993-11:2018
ISO 10993-10:2010(E)
Introduction
This part of ISO 10993 assesses possible contact hazards from chemicals released from medical devices,
which may produce skin and mucosal irritation, eye irritation or skin sensitization.
Some materials that are included in medical devices have been tested, and their skin or mucosal irritation or
sensitization potential has been documented. Other materials and their chemical components have not been
tested and may induce adverse effects when in contact with human tissue. The manufacturer is thus obliged
to evaluate each device for potential adverse effects prior to marketing.
Traditionally, small animal tests are performed prior to testing on humans to help predict human response.
More recently, in vitro tests as well as human tests have been added as adjuncts or alternatives. Despite
progress and considerable effort in this direction, a review of findings suggests that currently no satisfactory
in vitro test has been devised to eliminate the requirement for in vivo testing. Where appropriate, the
preliminary use of in vitro methods is encouraged for screening purposes prior to animal testing. In order to
reduce the number of animals used, this part 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.
This part of ISO 10993 is intended for use by professionals, appropriately qualified by training and experience,
who are able to interpret its requirements and judge the outcomes of the evaluation for each medical device,
taking into consideration all the factors relevant to the device, its intended use and the current knowledge of
the medical device provided by review of the scientific literature and previous clinical experience.
The tests included in this part of ISO 10993 are important tools for the development of safe products, provided
that these are executed and interpreted by trained personnel.
This part of ISO 10993 is based on numerous standards and guidelines, including OECD Guidelines,
U.S. Pharmacopoeia and the European Pharmacopoeia. It is intended to be the basic document for the
selection and conduct of tests enabling evaluation of irritation and dermal sensitization responses relevant to
safety of medical materials and devices.
vi © ISO 2010 – All rights reserved
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SIST EN ISO 10993-11:2018
INTERNATIONAL STANDARD ISO 10993-10:2010(E)
Biological evaluation of medical devices —
Part 10:
Tests for irritation and skin sensitization
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 skin sensitization.
This part of ISO 10993 includes:
a) pretest considerations for irritation, including in silico and in vitro methods for dermal exposure;
b) details of in vivo (irritation and sensitization) test procedures;
c) key factors for the interpretation of the results.
Instructions are given in Annex A for the preparation of materials specifically in relation to the above tests. In
Annex B several special irritation tests are described for application of medical devices in areas other than skin.
2 Normative references
The following referenced documents are indispensable for the application of this document. For dated
references, only the edition cited applies. For undated references, the latest edition of the referenced
document (including any amendments) applies.
ISO 10993-1:2009, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management process
ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements
ISO 10993-9, Bio
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01-januar-2016
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Biologische Beurteilung von Medizinprodukten — Teil 11: Prüfungen auf systemische
Toxizität (ISO/DIS 10993-11:2015)
Évaluation biologique des dispositifs médicaux - Partie 11: Essais de toxicité systémique
(ISO/DIS 10993-11:2015)
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---------------------- Page: 1 ----------------------
oSIST prEN ISO 10993-11:2016
---------------------- Page: 2 ----------------------
oSIST prEN ISO 10993-11:2016
DRAFT INTERNATIONAL STANDARD
ISO/DIS 10993-11
ISO/TC 194 Secretariat: DIN
Voting begins on: Voting terminates on:
2015-11-05
2016-02-05
Biological evaluation of medical devices —
Part 11:
Tests for systemic toxicity
Évaluation biologique des dispositifs médicaux —
Partie 11: Essais de toxicité systémique
ICS: 11.100.20
ISO/CEN PARALLEL PROCESSING
This draft has been developed within the International Organization for
Standardization (ISO), and processed under the ISO lead mode of collaboration
as defined in the Vienna Agreement.
This draft is hereby submitted to the ISO member bodies and to the CEN member
bodies for a parallel five month enquiry.
Should this draft be accepted, a final draft, established on the basis of comments
received, will be submitted to a parallel two-month approval vote in ISO and
THIS DOCUMENT IS A DRAFT CIRCULATED
formal vote in CEN.
FOR COMMENT AND APPROVAL. IT IS
THEREFORE SUBJECT TO CHANGE AND MAY
NOT BE REFERRED TO AS AN INTERNATIONAL
STANDARD UNTIL PUBLISHED AS SUCH.
To expedite distribution, this document is circulated as received from the
IN ADDITION TO THEIR EVALUATION AS
committee secretariat. ISO Central Secretariat work of editing and text
BEING ACCEPTABLE FOR INDUSTRIAL,
composition will be undertaken at publication stage.
TECHNOLOGICAL, COMMERCIAL AND
USER PURPOSES, DRAFT INTERNATIONAL
STANDARDS MAY ON OCCASION HAVE TO
BE CONSIDERED IN THE LIGHT OF THEIR
POTENTIAL TO BECOME STANDARDS TO
WHICH REFERENCE MAY BE MADE IN
Reference number
NATIONAL REGULATIONS.
ISO/DIS 10993-11:2015(E)
RECIPIENTS OF THIS DRAFT ARE INVITED
TO SUBMIT, WITH THEIR COMMENTS,
NOTIFICATION OF ANY RELEVANT PATENT
RIGHTS OF WHICH THEY ARE AWARE AND TO
©
PROVIDE SUPPORTING DOCUMENTATION. ISO 2015
---------------------- Page: 3 ----------------------
oSIST prEN ISO 10993-11:2016
ISO/DIS 10993-11:2015(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2015, Published in Switzerland
All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized otherwise in any form
or by any means, electronic or mechanical, including photocopying, or posting on the internet or an intranet, without prior
written permission. Permission can be requested from either ISO at the address below or ISO’s member body in the country of
the requester.
ISO copyright office
Ch. de Blandonnet 8 • CP 401
CH-1214 Vernier, Geneva, Switzerland
Tel. +41 22 749 01 11
Fax +41 22 749 09 47
copyright@iso.org
www.iso.org
ii © ISO 2015 – All rights reserved
---------------------- Page: 4 ----------------------
oSIST prEN ISO 10993-11:2016
ISO/DIS 10993-11
Contents Page
Foreword . v
Introduction . vii
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 General considerations . 2
4.1 General . 2
4.2 Selection of animal species . 3
4.3 Animal status . 3
4.4 Animal care and husbandry . 3
4.5 Size and number of groups . 3
4.5.1 Size of groups . 3
4.5.2 Number of groups . 4
4.5.3 Treatment controls . 4
4.6 Route of exposure . 5
4.7 Sample preparation . 5
4.8 Dosing . 5
4.8.1 Test sample administration . 5
4.8.2 Dosage volumes . 5
4.8.3 Dosage frequency . 6
4.9 Body weight and food/water consumption . 6
4.10 Clinical observations . 6
4.11 Clinical pathology . 7
4.12 Anatomic pathology . 7
4.13 Study designs . 7
4.14 Quality of investigation . 8
5 Acute systemic toxicity . 8
5.1 General . 8
5.2 Study design . 8
5.2.1 Preparations . 8
5.2.2 Experimental animals . 8
5.2.3 Test conditions . 9
5.2.4 Body weights . 9
5.2.5 Clinical observations . 9
5.2.6 Pathology . 9
5.3 Evaluation criteria. 10
5.3.1 General . 10
5.3.2 Evaluation of results . 10
5.4 Final report . 11
6 Repeated exposure systemic toxicity (subacute, subchronic and chronic systemic
toxicity) . 12
6.1 General . 12
6.2 Study design . 13
© ISO 2015 – All rights reserved
iii
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oSIST prEN ISO 10993-11:2016
ISO/DIS 10993-11
6.2.1 Preparations . 13
6.2.2 Experimental animals. 13
6.2.3 Test conditions . 13
6.2.4 Body weights . 14
6.2.5 Clinical observations . 14
6.2.6 Pathology. 14
6.3 Evaluation criteria . 15
6.3.1 General . 15
6.3.2 Evaluation of results . 15
6.4 Final report. 15
Annex A (informative) Routes of administration . 17
A.1 General . 17
A.2 Dermal . 17
A.3 Implantation . 17
A.4 Inhalation . 17
A.5 Intradermal . 17
A.6 Intramuscular . 17
A.7 Intraperitoneal . 18
A.8 Intravenous . 18
A.9 Oral . 18
A.10 Subcutaneous . 18
Annex B (informative) Dosage volumes . 19
B.1 General . 19
B.2 Dosage volume references . 19
Annex C (informative) Common clinical signs and observations . 20
Annex D (informative) Suggested haematology, clinical chemistry and urinalysis
measurements . 21
D.1 Haematology . 21
D.2 Clinical chemistry. 21
D.3 Urinalysis (timed collection, e.g., 16 h to 24 h) . 22
Annex E (informative) Suggested organ list for histopathological evaluation . 23
Annex F (informative) Organ list for limited histopathology for medical devices subjected
to systemic toxicity testing . 25
F.1 General . 25
F.2 Procedure. 25
Annex G (informative) Information on material-mediated pyrogens . 27
Annex H (informative) Subchronic rat – Dual routes of parenteral administration . 29
H.1 General . 29
H.2 Procedure. 29
H.3 Dosage Volume and Frequency Justification . 30
H.3.1 Intravenous . 30
H.3.2 Intraperitoneal . 30
Bibliography . 31
1. General . 31
2. Dosage volume references . 31
© ISO 2015 – All rights reserved
iv
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oSIST prEN ISO 10993-11:2016
ISO/DIS 10993-11
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national
standards bodies (ISO member bodies). The work of preparing International Standards is normally
carried out through ISO technical committees. Each member body interested in a subject for which a
technical committee has been established has the right to be represented on that committee.
International organizations, governmental and non-governmental, in liaison with ISO, also take part in
the work. ISO collaborates closely with the International Electrotechnical Commission (IEC) on all
matters of electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (www.iso.org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation on the meaning of ISO specific terms and expressions related to conformity
assessment, as well as information about ISO's adherence to the WTO principles in the Technical
Barriers to Trade (TBT) see the following URL: Foreword - Supplementary information
The committee responsible for this document is ISO/TC 194 "Biological and clinical evaluation of
medical devices"
This second edition cancels and replaces the first edition (2006).
The major technical changes are the following:
a) Reduction in group size for chronic toxicity testing in Table 1;
b) new Annex F (informative);
c) original Annex F moved to Annex G;
d) new Annex H (informative);
e) bibliography updated.
ISO 10993 consists of the following parts, under the general title Biological evaluation of medical
devices:
Part 1: Evaluation and testing within a risk management system
Part 2: Animal welfare requirements
© ISO 2015 – All rights reserved
v
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oSIST prEN ISO 10993-11:2016
ISO/DIS 10993-11
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 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
Part 16: Toxicokinetic study design for degradation products and leachables
Part 17: Method for the establishment of allowable limits for leachable substances
Part 18: Chemical characterization of materials
Part 19: Physico-chemical, morphological and topographical characterization of materials [Technical
specification]
Part 20: Principles and methods for immunotoxicology testing of medical devices [Technical specification]
© ISO 2015 – All rights reserved
vi
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oSIST prEN ISO 10993-11:2016
ISO/DIS 10993-11
Introduction
Systemic toxicity is a potential adverse effect of the use of medical devices. Generalized effects, as well
as organ and organ system effects can result from absorption, distribution and metabolism of leachates
from the device or its materials to parts of the body with which they are not in direct contact. This part
of ISO 10993 addresses the evaluation of generalized systemic toxicity, not specific target organ or
organ system toxicity, even though these effects may result from the systemic absorption and
distribution of toxicants.
Because of the broad range of medical devices, and their materials and intended uses, this part of
ISO 10993 is not overly prescriptive. Whilst it addresses specific methodological aspects to be
considered in the design of systemic toxicity tests, proper study design must be uniquely tailored to the
nature of the device’s materials and its intended clinical application.
Other elements of this part of ISO 10993 are prescriptive in nature, including those aspects that address
compliance with good laboratory practices and elements for inclusion in reporting.
While some systemic toxicity tests (e.g. long term implantation or dermal toxicity studies) can be
designed to study systemic effects as well as local, carcinogenic or reproductive effects, this document
focuses only on those aspects of such studies, which are intended to address systemic effects. Studies
which are intended to address other toxicological endpoints are addressed in ISO 10993-3,
ISO 10993-6, ISO 10993-10 and ISO/TS 10993-20.
Finally, toxicology is an imperfect science. The outcome of any single test should not be the sole basis
for making a determination of whether a device is safe for its intended use.
© ISO 2015 – All rights reserved
vii
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oSIST prEN ISO 10993-11:2016
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oSIST prEN ISO 10993-11:2016
DRAFT INTERNATIONAL STANDARD ISO/DIS 10993-11
Biological evaluation of medical devices — Tests for systemic
toxicity
1 Scope
This part of ISO 10993 specifies requirements and gives guidance on procedures to be followed in the
evaluation of the potential for medical device materials to cause adverse systemic reactions.
2 Normative references
The following referenced documents are indispensable for the application of this document. For
undated references, the latest edition of the referenced document (including any amendments) applies.
ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing
ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 10993-1 and the following
apply.
3.1
dose
dosage
amount of test sample administered (e.g. mass, volume) expressed per unit of body weight or surface
area
3.2
dose-effect
relationship between the dosage and the magnitude of a defined biological effect either in an individual
or in a population sample
3.3
dose-response
relationship of dosage to the spectrum of effects related to the exposure
Note 1 to entry: There are two types of dose-response relationships. The first type is the response of an
individual to a range of doses. The second type is the distribution of responses of a population of individuals to a
range of doses.
3.4
leachable substance
chemical removed from a device or material by the action of water or other liquids related to the use of
the device
Note 1 to entry: Examples of leachable substances are additives, sterilant residues, process residues,
degradation products, solvents, plasticizers, lubricants, catalysts, stabilizers, anti-oxidants, colouring agents, fillers
and monomers.
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3.5
limit test
use of a single group treated at a suitable dosage of test sample in order to delineate the presence or
absence of a toxic hazard
3.6
systemic toxicity
toxicity that is not limited to adverse effects at the site of contact between the body and the device
Note 1 to entry: Systemic toxicity requires absorption and distribution of a toxicant from its entry point to a
distant site at which deleterious effects are produced.
3.7
acute systemic toxicity
adverse effects occurring at any time after single, multiple or continuous exposures of a test sample
within 24 h
3.8
subacute systemic toxicity
adverse effects occurring after multiple or continuous exposure between 24 h and 28 d
Note 1 to entry: Since this term is semantically incorrect, the adverse effects occurring within the specified time
period may also be described as a short-term repeated exposure systemic toxicity study. The selection of time
intervals between 14 d and 28 d is consistent with most international regulatory guidelines and considered a
reasonable approach. Subacute intravenous studies are generally defined as treatment durations of > 24 h but
< 14 d.
3.9
subchronic systemic toxicity
adverse effects occurring after the repeated or continuous administration of a test sample for a part of
the lifespan
Note 1 to entry: Subchronic toxicity studies are usually 90 d in rodents but not exceeding 10 % of the lifespan of
other species. Subchronic intravenous studies are generally defined as treatment durations of 14 d to 28 d for
rodents and nonrodents, respectively.
3.10
chronic systemic toxicity
adverse effects occurring after the repeated or continuous administration of a test sample for a major
part of the life span
Note 1 to entry: Chronic toxicity studies usually have a duration of 6 months to 12 months.
3.11
test sample
material, device, device portion, component, extract or portion thereof that is subjected to biological or
chemical testing or evaluation
4 General considerations
4.1 General
Selection of the appropriate test(s) for a device shall be in accordance with ISO 10993-1, giving due
consideration to mode and duration of contact.
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Testing shall be performed on the final product and/or representative component samples of the final
product and/or materials. Test samples shall reflect the conditions under which the device is normally
manufactured and processed. If deviations are necessary, they shall be recorded in the test report,
together with their justification. For hazard identification purposes, it may be necessary to exaggerate
exposure to the test samples.
Physical and chemical properties of the test sample including, for example, pH, stability, viscosity,
osmolality, buffering capacity, solubility and sterility, are some factors to consider when designing the
study.
When animal tests are considered, to satisfy the provisions of ISO 10993-2, all reasonably and
practically available replacement, reduction and refinement alternatives should be identified and
implemented. For in vivo acute toxicity testing, in vitro cytotoxicity data are useful in estimating starting
[9]
doses .
4.2 Selection of animal species
There is no absolute criterion for selecting a particular animal species for systemic toxicity testing of
medical devices. However, the species used shall be scientifically justified and in line with the
provisions of ISO 10993-2. For acute oral, intravenous, dermal and inhalation studies of medical devices
the mouse or rat is preferred with the option of the rabbit in the case of dermal and implantation
studies. Non-rodent species may also need to be considered for testing, recognizing that a number of
factors might dictate
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