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)
ISO 10993-11:2017 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.
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
Relations
Standards Content (Sample)
SLOVENSKI STANDARD
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
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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.
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
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.
Endorsement notice
The text of ISO 10993-11:2017 has been approved by CEN as EN ISO 10993-11:2018 without any
modification.
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
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.
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
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.
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
ISO 10993-11:2017(E)
© 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
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Tel. +41 22 749 01 11
Fax +41 22 749 09 47
copyright@iso.org
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ii © ISO 2017 – All rights reserved
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 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
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 standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www.iso.org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation on the voluntary nature of standards, the meaning of ISO specific terms and
expressions related to conformity assessment, as well as information about ISO's adherence to the
World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT) see the following
URL: www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 194 Biological and clinical evaluation of
medical devices.
This third edition cancels and replaces the second edition (ISO 10993-11:2006), which has been
technically revised with the following changes:
a) reduction in group size for chronic toxicity testing in Table 1;
b) a new Annex F was added;
c) the original Annex F was moved to Annex G;
d) a new Annex H was added;
e) the Bibliography was updated.
A list of all parts in the ISO 10993 series can be found on the ISO website.
ISO 10993-11:2017(E)
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
document 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 document
is not overly prescriptive. While it addresses specific methodological aspects to be considered in the
design of systemic toxicity tests, proper study design has to be uniquely tailored to the nature of the
device’s materials and its intended clinical application.
Other elements of this document 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 end points are addressed in ISO 10993-3, ISO 10993-6,
ISO 10993-10 and ISO/TS 10993-20.
Prior to conducting a systemic toxicity study, all reasonably available data and scientifically sound
methods in the planning and refinement of the systemic toxicity study design should be reviewed.
This includes the suitability of use of input data such as existing toxicological data, data from chemical
characterization studies and/or other biological tests (including in vitro tests and less invasive in vivo
tests) for the refinement of study design, dose selection, and/or selection of pathological end points to
cover in the evaluation of a study. For the repeated exposure systemic toxicity study in particular, the
use of scientifically sound study design, the use of pilot studies and statistical study design and the
use of unbiased, quantitative end points/methods in the pathological (including histopathological) and
clinical chemistry methods are important so as to obtain data which have sufficient scientific validity.
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.
vi © ISO 2017 – All rights reserved
INTERNATIONAL STANDARD ISO 10993-11:2017(E)
Biological evaluation of medical devices —
Part 11:
Tests for systemic toxicity
1 Scope
This document 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 documents are referred to in the text in such a way that some or all of their content
constitutes requirements of this document. For dated references, only the edition cited applies. For
undated references, the latest edition of the referenced document (including any amendments) applies.
ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management process
ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 10993-1 and the following apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— IEC Electropedia: available at http://www.electropedia.org/
— ISO Online browsing platform: available at http://www.iso.org/obp
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.
ISO 10993-11:2017(E)
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.
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 within 72 h after single, multiple or continuous exposures of a
test sample for 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 non-rodents, 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
2 © ISO 2017 – All rights reserved
ISO 10993-11:2017(E)
4 General considerations
4.1 General
Before a decision to perform a systemic toxicity test is made, ISO 10993-1 shall be taken into account.
The decision to perform a test shall be justified on the basis of an assessment of the risk of systemic
toxicity. 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.
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, all reasonably and practically available replacement, reduction and
refinement alternatives should be identified and implemented to satisfy the provisions of ISO 10993-2.
For in vivo acute toxicity testing, in vitro cytotoxicity data are useful in estimating starting 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
rodent (mouse or rat) is preferred with the option of the rabbit (lagomorph) in the case of dermal and
implantation studies. Other non-rodent species may also need to be considered for testing, recognizing
that a number of factors might dictate the number or choice of species for study.
It is preferred that a single animal species and strain are used when a series of systemic toxicity studies
of different durations are performed, e.g. acute, subacute, subchronic and/or chronic systemic toxicity.
This controls the variability between species and strains and facilitates an evaluation related solely
to study duration. Should multiple species or strains be used, justification for their selection shall be
documented.
4.3 Animal status
Generally, healthy purpose-bred young adult animals of known origin and with defined microbiological
health status should be used. At the commencement of the study, the weight variation of animals used
within a sex should not exceed ±20 % of the mean weight. When females are used, they should be
nulliparous and non-pregnant. Animal selection shall be justified.
4.4 Animal care and husbandry
Care and handling of animals shall conform to accepted animal husbandry guidelines. Animals shall
be acclimatized to the laboratory conditions prior to treatment and the period of time documented.
Control of environmental conditions and proper animal care techniques are necessary for meaningful
results. Dietary constituents and bedding materials that are known to produce or influence toxicity
should be properly characterized and their potential to influence test results taken into account.
ISO 10993-11:2017(E)
4.5 Size and number of groups
4.5.1 Size of groups
The precision of the systemic toxicity test is dependent to a large extent on the number of animals
used per dose level. The degree of precision needed and, in turn, the number of animals per dose group
needed depends on the purpose of the study.
Group sizes should logically increase with the duration of treatment, such that at the end of the study
enough animals in every group are available for thorough biological evaluation. However, the minimum
number of animals should be used consistent with obtaining meaningful results (see ISO 10993-2).
Recommended minimum group sizes, all routes considered, are given in Table 1.
Table 1 — Recommended minimum group sizes
Study type Rodent Non-rodent
a
Acute 5 3
a a
Subacute 10 (5 per sex) 6 (3 per sex)
a a
Subchronic 20 (10 per sex) 8 (4 per sex)
b, c c
Chronic 30 (15 per sex)
a
Testing in a single sex is acceptable. When a device is
intended for use in only one sex, testing should be done in
that sex.
b
The recommendation for rodents refers to one dose-level
group testing. Where additional exaggerated dose groups are
included the recommended group size may be reduced to 10
per sex.
c
Expert statistical consultation for chronic study non-
rodent group size is recommended. The number of animals
tested should be based on the minimum required to provide
meaningful data. Enough animals shall remain at the
termination of the study to ensure proper statistical evaluation
of the results.
4.5.2 Number of groups
One dose group treated at a suitable dosage of test sample in a single species could delineate the
presence or absence of a toxic hazard (i.e. limit test). However, other multi-dose or dose response
studies require multiple groups to delineate the toxic response.
The number of treatment groups may be increased when attempting to characterize a dose response
using exaggerated doses. The following examples for exaggerating the dose should be considered:
— multiples of the clinical surface area of exposure;
— multiples of the duration of exposure;
— multiples of the extractable fraction or the individual chemicals;
— multiple administrations within a 24-h period.
Other methods to exaggerate the dose may be acceptable. The method used shal
...
SLOVENSKI STANDARD
01-september-2018
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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
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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.
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
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.
Endorsement notice
The text of ISO 10993-11:2017 has been approved by CEN as EN ISO 10993-11:2018 without any
modification.
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
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.
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
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.
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
ISO 10993-10:2010(E)
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Published in Switzerland
ii © ISO 2010 – All rights reserved
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 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
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 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
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, Biological evaluation of medical devices — Part 9: Framework for identification and
quantification of potential degradation products
ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference materials
ISO 10993-13, Biological evaluation of medical devices — Part 13: Identification and quantification of
degradation products from polymeric medical devices
ISO 10993-14 Biological evaluation of medical devices — Part 14: Identification and quantification of
degradation products from ceramics
ISO 10993-15, Biological evaluation of medical devices — Part 15: Identification and quantification of
degradation products from metals and alloys
ISO 10993-18, Biological evaluation of medical devices — Part 18: Chemical characterization of materials
ISO 14155-1, Clinical investigation of medical devices for human subjects — Part 1: General requirements
ISO 14155-2, Clinical investigation of medical devices for human subjects — Part 2: Clinical investigation plans
ISO 10993-10:2010(E)
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
allergen
sensitizer
substance or material that is capable of inducing a specific hypersensitivity reaction upon repeated contact
with that substance or material
3.2
blank
extraction vehicle not containing the test material, retained in a vessel identical to that which holds the test
material and subjected to identical conditions to which the test material is subjected during its extraction
NOTE The purpose of the blank control is to evaluate possible confounding effects due to the extraction vessel,
vehicle and extraction process.
3.3
challenge
elicitation
process following the induction phase, in which the immunological effects of subsequent exposures in an
individual to the inducing material are examined
3.4
dose
dosage
amount of test sample administered (e.g. mass, volume) expressed per unit of body weight or surface area
NOTE The terms are often used interchangeably (more commonly dosage).
3.5
erythema
reddening of the skin or mucous membrane
3.6
eschar
scab or discoloured slough of skin
3.7
extract
liquid or suspension that results from exposing a test or control material to a solvent under controlled
conditions
3.8
induction
process that leads to the de novo generation of an enhanced state of immunological activity in an individual, to
a specific material
3.9
irritant
agent that produces irritation
3.10
irritation
localized non-specific inflammatory response to single, repeated or continuous application of a substance/material
NOTE Skin irritation is a reversible reaction and is mainly characterized by local erythema (redness) of the skin.
2 © ISO 2010 – All rights reserved
ISO 10993-10:2010(E)
3.11
necrosis
cell death as a direct result of irreversible changes caused by injury or disease
NOTE One should be aware that tissue repair will occur either resulting in complete functional restoration or resulting
in scar formation.
3.12
negative control
any well-characterized material or substance that, when tested by a specific procedure, demonstrates the
suitability of the procedure to yield a reproducible, appropriately negative, non-reactive or minimal response in
the test system
NOTE In practice, negative controls include blanks, vehicles/solvents and reference materials.
3.13
oedema
swelling due to abnormal infiltration of fluid into the tissues
3.14
positive control
any well-characterized material or substance that, when evaluated by a specific test method, demonstrates
the suitability of the test system to yield a reproducible, appropriately positive or reactive response in the test
system
3.15
skin corrosion
production of irreversible damage to the skin, manifested as visible necrosis through the epidermis and into
the dermis, following application of a test sample
EXAMPLE The action of a compound/chemical/test sample resulting in ulceration of skin (see 3.19).
3.16
skin sensitization
allergic contact dermatitis
immunologically mediated cutaneous reaction to a substance
NOTE In the human, the responses can be characterized by pruritis, erythema, oedema, papules, vesicles, bullae or
a combination of these. In other species the reactions can differ and only erythema and oedema can be seen.
3.17
test material
material, device, device portion or component thereof that is sampled for biological or chemical testing
3.18
test sample
material, device, device portion, component, extract or portion thereof that is subjected to biological or
chemical testing or evaluation
3.19
ulceration
open sore representing loss of superficial tissue
3.20
vehicle
liquid used to moisten, dilute, suspend, extract or dissolve the test substance/material
ISO 10993-10:2010(E)
4 General principles — Step-wise approach
The available methods for testing irritation and sensitization were developed specifically to detect skin and
mucous membrane irritation and skin sensitization potential. Other types of adverse effect are generally not
predicted by these tests. For medical devices that are used as implants or external communicating devices,
intradermal testing is more relevant in approaching the application and so for detection of irritation activity,
intracutaneous testing shall be used as described in 6.4.
This part of ISO 10993 requires a step-wise approach, which shall include one or more of the following:
a) characterization of test material, involving chemical characterization and analysis of the test sample
according to the general principles described in ISO 10993-9, ISO 10993-13, ISO 10993-14,
ISO 10993-15 and ISO 10993-18;
b) literature review, including an evaluation of chemical and physical properties, and information on the
irritation and sensitization potential of any product constituent as well as structurally-related chemicals
and materials;
c) in accordance with ISO 10993-2, in vitro tests in preference to in vivo tests shall be considered, and
replacement of the latter as new in vitro tests are scientifically validated and become reasonably and
practicably available. For the evaluation of skin irritation and corrosion, in vitro alternatives are available
for chemicals; there are currently no internationally validated and accepted in vitro tests to detect
sensitizers;
d) in vivo animal tests: in order to ensure reproducibility and sensitivity, a test of a positive-control substance
for irritation and skin sensitization shall be included in each assay by the testing laboratory in order to
validate the test system and demonstrate a positive response; for guinea pig sensitization assays,
however, when consistency has been demonstrated over a six month or more extended period, a positive
control does not need to be included in every assay, but may be run at regular intervals which shall not
exceed six months.
NOTE 1 Sensitization can at the moment only be determined by an in vivo assay. This can be accomplished by using
the local lymph node assay (LLNA) in mice, the occluded patch test in guinea pigs or the guinea pig maximization test
(GPMT). For single chemicals the LLNA is now the preferred assay for determining the sensitizing potential.
See References [69] [88] [90].
NOTE 2 In vivo animal tests are appropriate when test materials cannot be characterized and risk assessments cannot
be undertaken using information obtained by the means set out in a), b) and c).
NOTE 3 For sensitization assays in guinea pigs, ten animals are normally used for positive control once every six
months. Fewer guinea pigs can be used when an assay with a positive control substance is performed more frequently
than once every six months. At least five test animals with a positive substance and five control animals should be used.
e) Non-invasive human tests/clinical trials; if the material has been demonstrated not to be an irritant, a
sensitizer or toxic in animals, studies on skin irritation may then be considered in humans.
Clinical studies in accordance with ISO 14155-1, ISO 14155-2 and to ethics principles shall not be performed
before the results of the other evaluations in a) to d) are known.
5 Pretest considerations
5.1 General
It is important to emphasise that pretest considerations may result in the conclusion that testing for irritation
and/or sensitization is not necessary.
The requirements given in Clause 5 of ISO 10993-1:2009 and the following apply.
4 © ISO 2010 – All rights reserved
ISO 10993-10:2010(E)
Non-sterile samples shall be investigated by topical investigation only, as the possibility of microbial
contamination of the test sample could confound the final assay interpretation. In cases where the sterility of a
test sample cannot be guaranteed, but the sample is still considered to be non-contaminated, intradermal
administration may be justified.
5.2 Types of material
5.2.1 Initial considerations
It shall be taken into consideration that, during manufacture and assembly of medical devices, additional
chemical components may be used as processing aids, e.g. lubricants or mould-release agents. In addition to
the chemical components of the starting material and manufacturing process aids, adhesive/solvent residues
from assembly and also sterilant residues or reaction products resulting from the sterilization process may be
present in a finished product. Whether these components pose a health hazard/risk depends on the leakage
or degradation characteristics of the finished products. These components shall be taken into account for their
potential irritation/sensitization activity.
5.2.2 Ceramics, metals and alloys
These materials are normally less complex than polymers and biologically derived materials in terms of the
number of chemical constituents.
5.2.3 Polymers
These materials are normally chemically more complex than those in 5.2.2 in terms of composition. A number
of reaction products/impurities/additives may be present and the completeness of polymerization may vary.
5.2.4 Biologically derived materials
These materials are inherently complex in their composition. They often also contain process residues,
e.g. cross-linkers and anti-microbial agents. Biological materials can be inconsistent from sample to sample.
The methods in this part of ISO 10993 have not been designed for testing of biologically derived materials and
can therefore be less adequate. For example, the tests in this part of ISO 10993 do not consider cross-
species sensitization.
5.3 Information on chemical composition
5.3.1 General
Full qualitative data on the chemical constituents of the material shall be established. Where relevant to
biological safety, quantitative data shall also be obtained. If quantitative data are not obtained, the rationale
shall be documented and justified.
5.3.2 Existing data sources
Qualitative and quantitative information on the composition shall be obtained where possible from the supplier
of the starting material.
For polymers this often requires access to proprietary information; provision should be made for the transfer
and use of such confidential information.
Qualitative information about any additional processing additives (for example, mould-release agents) shall
also be obtained from appropriate members of the manufacturing chain, including converters and component
manufacturers.
ISO 10993-10:2010(E)
In the absence of any data on composition, a literature study to establish the likely nature of the starting
material and any additives is recommended, so as to assist in the selection of the most appropriate methods
of analysis for the material concerned.
The chemical composition of finalized products shall be determined in accordance with ISO 10993-18.
NOTE The composition of ceramics, metals and alloys can be specified in accordance with ISO or American Society
of Testing Materials (ASTM) standards and/or can be specified by the user. However, in order to obtain full qualitative and
quantitative details on composition, it can be necessary to request these from the supplier or manufacturer of the starting
material and also from component manufacturers to ensure that processing aids are also identified. Material master files
held by regulatory authorities are another source of data, where they are accessible.
6 Irritation tests
6.1 In vitro irritation tests
In vitro methods, the rat skin Transcutaneous Electrical Resistance (TER) test and the Human skin model test,
have been internationally validated and accepted as alternative tests to assess the skin corrosivity of
[9] [10]
chemicals (OECD Guidelines 430 and 431 ). National and international organizations continue working to
develop and validate in vitro tests for skin irritancy in parallel with the search for alternative methods; others
have been developing methods to quantify the responses of animals and humans in order to better define
endpoints using non-invasive techniques (see F.1).
NOTE In 2007 the ECVAM Scientific Advisory Committee (ESAC) evaluated the validation process of an in vitro
human skin model for the determination of skin irritation of chemicals. See Reference [101]. The use of in vitro human skin
models for assessing the potential of chemicals to induce skin irritation is described in Annex D.
The in vitro test for skin irritation has so far been validated only for neat chemicals and not for medical device
extracts. In order to apply these assays for the testing of irritation potential of medical devices, further
validation for this specific area is essential.
6.2 In vivo irritation tests — Factors to be considered in design and selection of in vivo
tests
Irritation testing of medical devices can be performed with the finished product and/or extracts thereof.
Factors affecting the results of irritation studies include the following:
a) the nature of the device used in a patch test;
b) the dose of the test material;
c) the method of application of the test material;
d) the degree of occlusion;
e) the application site;
f) the duration and number of exposures;
g) the techniques used in evaluating the test.
Additional background information is provided in Annex F.
Whilst flexibility with respect to the precise protocol followed allows the investigator to enhance the sensit
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