SIST EN ISO 10993-11:2006
(Main)Biological evaluation of medical devices - Part 11: Tests for systemic toxicity (ISO 10993-11:2006)
Biological evaluation of medical devices - Part 11: Tests for systemic toxicity (ISO 10993-11:2006)
This standard 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 standard is not overly prescriptive. While 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 standard are prescriptive in nature, including those aspects that address compliance with good laboratory practices and elements for inclusion in reporting.
Biologische Beurteilung von Medizinprodukten - Teil 11: Prüfungen auf systemische Toxizität (ISO 10993-11:2006)
Dieser Teil von ISO 10993 legt Anforderungen an Verfahren fest und gibt eine Anleitung, die bei der Beurteilung des Potenzials von Materialien für Medizinprodukte zur Auslösung nachteiliger systemischer Re¬aktionen zu befolgen sind.
Évaluation biologique des dispositifs médicaux - Partie 11: Essais de toxicité systémique (ISO 10993-11:2006)
Biološko ovrednotenje medicinskih pripomočkov – 11. del: Preskusi sistemske toksičnosti (ISO 10993-11:2006)
General Information
Relations
Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN ISO 10993-11:2006
01-oktober-2006
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Biological evaluation of medical devices - Part 11: Tests for systemic toxicity (ISO 10993-
11:2006)
Biologische Beurteilung von Medizinprodukten - Teil 11: Prüfungen auf systemische
Toxizität (ISO 10993-11:2006)
Évaluation biologique des dispositifs médicaux - Partie 11: Essais de toxicité systémique
(ISO 10993-11:2006)
Ta slovenski standard je istoveten z: EN ISO 10993-11:2006
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-11:2006 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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EUROPEAN STANDARD
EN ISO 10993-11
NORME EUROPÉENNE
EUROPÄISCHE NORM
August 2006
ICS 11.100.20 Supersedes EN ISO 10993-11:1995
English Version
Biological evaluation of medical devices - Part 11: Tests for
systemic toxicity (ISO 10993-11:2006)
Évaluation biologique des dispositifs médicaux - Partie 11: Biologische Beurteilung von Medizinprodukten - Teil 11:
Essais de toxicité systémique (ISO 10993-11:2006) Prüfungen auf systemische Toxizität (ISO 10993-11:2006)
This European Standard was approved by CEN on 7 August 2006.
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 Central Secretariat 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 Central Secretariat has the same status as the official
versions.
CEN members are the national standards bodies of Austria, Belgium, Cyprus, Czech Republic, Denmark, Estonia, Finland, France,
Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania,
Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.
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EUROPÄISCHES KOMITEE FÜR NORMUNG
Management Centre: rue de Stassart, 36 B-1050 Brussels
© 2006 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-11:2006: E
worldwide for CEN national Members.
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EN ISO 10993-11:2006 (E)
Foreword
This document (EN ISO 10993-11:2006) has been prepared by Technical Committee ISO/TC 194
"Biological evaluation of medical devices" in collaboration with Technical Committee CEN/TC 206
"Biocompatibility of medical and dental materials and devices", the secretariat of which is held by
NEN.
This European Standard shall be given the status of a national standard, either by publication of an
identical text or by endorsement, at the latest by February 2007, and conflicting national standards
shall be withdrawn at the latest by February 2007.
This document supersedes EN ISO 10993-11:1995.
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, which is an integral part of this
document.
According to the CEN/CENELEC Internal Regulations, the national standards organizations of the
following countries are bound to implement this European Standard: Austria, Belgium, Cyprus,
Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland,
Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania,
Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom.
Endorsement notice
The text of ISO 10993-11:2006 has been approved by CEN as EN ISO 10993-11:2006 without any
modifications.
2
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EN ISO 10993-11:2006 (E)
Annex ZA
(informative)
Relationship between this European Standard and the Essential
Requirements of EU Directives 90/385/EEC and 93/42/EEC
This European Standard has been prepared under a mandate given to CEN by the European
Commission to provide one means of conforming to Essential Requirements of the New Approach
Directives 90/385/EEC and 93/42/EEC.
Once this standard is cited in the Official Journal of the European Communities under that Directive
and has been implemented as a national standard in at least one Member State, compliance with the
normative clauses of this standard confers, within the limits of the scope of this standard, a
presumption of conformity with the relevant Essential Requirements of that Directive and associated
EFTA regulations.
WARNING: Other requirements and other EU Directives may be applicable to the products falling
within the scope of this standard.
3
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INTERNATIONAL ISO
STANDARD 10993-11
Second edition
2006-08-15
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 10993-11:2006(E)
©
ISO 2006
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ISO 10993-11:2006(E)
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ii © ISO 2006 – All rights reserved
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ISO 10993-11:2006(E)
Contents Page
Foreword. iv
Introduction . vi
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
4.6 Route of exposure . 4
4.7 Sample preparation . 4
4.8 Dosing. 5
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
5.3 Evaluation criteria. 9
5.4 Final report . 10
6 Repeated exposure systemic toxicity (subacute, subchronic and chronic systemic
toxicity) . 11
6.1 General. 11
6.2 Study design . 12
6.3 Evaluation criteria. 14
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) Information on material-mediated pyrogens . 24
Bibliography . 26
© ISO 2006 – All rights reserved iii
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ISO 10993-11:2006(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 10993-11 was prepared by Technical Committee ISO/TC 194, Biological evaluation of medical devices.
This second edition cancels and replaces the first edition (ISO 10993-11:1993) which has been technically
revised.
ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices:
⎯ Part 1: Evaluation and testing
⎯ Part 2: Animal welfare requirements
⎯ Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
⎯ Part 4: Selection of tests for interactions with blood
⎯ Part 5: Tests for in vitro cytotoxicity
⎯ Part 6: Tests for local effects after implantation
⎯ Part 7: Ethylene oxide sterilization residuals
⎯ Part 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
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ISO 10993-11:2006(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
⎯ Part 20: Principles and methods for immunotoxicology testing of medical devices
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ISO 10993-11:2006(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 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.
Pyrogenicity (see Annex F) represents an additional systemic effect which has historically been included in
this part of ISO 10993. However, efforts are being taken to address pyrogenicity in a dedicated, stand-alone
standard.
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 2006 – All rights reserved
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INTERNATIONAL STANDARD ISO 10993-11:2006(E)
Biological evaluation of medical devices —
Part 11:
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
ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference
materials
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 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 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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ISO 10993-11:2006(E)
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 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 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 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.
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 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.
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.
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ISO 10993-11:2006(E)
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
[9]
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 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 the number or
choice of species for study.
It is preferred that a single animal species and strain is 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.
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.
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ISO 10993-11:2006(E)
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 40 (20 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 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 group size is
recommended. The number of animals tested should be based on the
minimum required to provide meaningful data. Enough animals must
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.
Group numbers may increase when attempting to exaggerate the dose. The following examples for
exaggerating dose should be considered:
⎯ multiples of the clinical surface area 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 shall be justified.
4.5.3 Treatment controls
Depending on the objective of the study, the nature of the test article and the route of exposure, negative,
vehicle and/or sham-treated controls should be incorporated into all systemic toxicity studies. These controls
shall mimic the test sample preparation and treatment procedure.
4.6 Route of exposure
Medical devices or their leachable substances may gain access to the body by multiple routes of exposure.
The test route of exposure shall be the most clinically relevant to the use of the device, where possible. If an
alternative route of exposure is necessary, it shall be justified. Examples of routes of administration can be
found in Annex A.
4.7 Sample preparation
Guidance on sample preparation and stability is given in ISO 10993-12.
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ISO 10993-11:2006(E)
4.8 Dosing
4.8.1 Test sample administration
Procedures should be designed to avoid physiological changes or animal welfare problems not directly related
to the toxicity of the test material. If a single daily dose of a sufficient volume or concentration is not possible,
the dose may be given in smaller fractions over a period not exceeding 24 h.
Test samples shall be delivered at a physiologically acceptable temperature. In general, room or body
temperature is a common practice. Deviations shall be justified.
Vehicles administered by a parenteral route should be physiologically compatible. When necessary, sample
filtration to remove particulates should be used and documented.
Restraint of animals in repeated exposure systemic toxicity studies should generally be limited to between 4 h
and 6 h per day. The nature and the duration of restraint should be the minimum required to meet the
scientific objectives and should not of themselves compromise the welfare of the test animals. Deviations shall
be justified.
When restraint is required animals should be acclimatized to the restraint device prior to test sample
adm
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