SIST EN ISO 10993-11:2000

SLOVENSKI STANDARD
SIST EN ISO 10993-11:2000
01-januar-2000
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Biological evaluation of medical devices - Part 11: Tests for systemic toxicity (ISO 10993-
11:1993)
Biologische Beurteilung von Medizinprodukten - Teil 11: Prüfungen auf systemische
Toxizität (ISO 10993-11:1993)
Evaluation biologique des dispositifs médicaux - Partie 11: Essais de toxicité systémique
(ISO 10993-11:1993)
Ta slovenski standard je istoveten z: EN ISO 10993-11:1995
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-11:2000 en
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

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SIST EN ISO 10993-11:2000

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SIST EN ISO 10993-11:2000

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SIST EN ISO 10993-11:2000

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SIST EN ISO 10993-11:2000

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SIST EN ISO 10993-11:2000

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SIST EN ISO 10993-11:2000
INTERNATIONAL
Is0
STANDARD
10993-11
First edition
1993-l 2-l 5
Biological evaluation of medical devices -
Part II:
Tests for systemic toxicity
halua tion biologique des dispositifs medica ux -
Partie 11: Essais de toxicit systdmique
Reference number
IS0 10993-I 1 :I 993(E)

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SIST EN ISO 10993-11:2000
IS0 10993-l 1:1993(E)
Contents
Page
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .~. 1
1 Scope
2 Normative references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
3 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
4 Test sample requirements and recommendations . . . . . . . . . . . . . . . . . . . 2
5 Method for extraction from medical devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Selection of test procedures for systemic toxicity . 4
6
7 Selection of test procedures for pyrogenicity . 6
.............................................................. 6
8 Assessment of results
................................................................................. 7
9 Test report
Annex
A Addresses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
0 IS0 1993
All rights reserved. No part of this publication may be reproduced or utilized in any form or
by any means, electronic or mechanical, including photocopying and microfilm, without per-
mission in writing from the publisher.
International Organization for Standardization
Case Postale 56 l CH-1211 Geneve 20 l Switzerland
Printed in Switzerland
ii

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SIST EN ISO 10993-11:2000
IS0 10993=11:1993(E)
Foreword
IS0 (the International Organization for Standardization) is a worldwide
federation of national standards bodies (IS0 member bodies). The work
of preparing International Standards is normally carried out through IS0
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. IS0
collaborates closely with the International Electrotechnical Commission
(IEC) on all matters of electrotechnical standardization.
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.
International Standard IS0 10993-l 1 was prepared by Technical Com-
mittee lSO/TC 194, Biological evaluation of medical devices.
IS0 10993 consists of the following parts, under the general title Biological
evaluation of medical devices:
- Part I: Guidance on selection of tests
- 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 cytotoxicity: in vitro methods
- Part 6: Tests for local effects after implantation
- Part 7: Ethylene oxide sterilization residuals
- Pati 8: Clinical investigation
- Part 9: Degradation of materials related to biological testing
[Technical Report]
- Part IO: Tests for irritation and sensitization
- Part 11: Tests for systemic toxicity
- Part 12: Sample preparation and reference materials
- Part 13: identification and quantification of degradation products
from polymers
. . .
Ill

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SIST EN ISO 10993-11:2000
- IS0 10993=11:1993(E)
- Part 14: ldentifica tion and quantification of degradation products
from ceramics
- Part 15: lden tifica tion and quantification of degradation products
from coated and uncoated metals and alloys
- Part 16: General guidance on toxicokinetic study design for degra-
dation products and leachables from medical devices
- Part 17: Glutaraldehyde and formaldehyde residues
Future parts will deal with other relevant aspects of biological testing.
Annex A of this part of IS0 10993 is for information only.

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SIST EN ISO 10993-11:2000
IS0 10993=11:1993(E)
-Introduction
When a device releases constituents into the body, the constituents may,
in sufficiently large concentrations, lead to systemic toxicity. Clinical and
experimental evidence of the systemic effects in this area is extremely
sparse.
This part of IS0 10993 provides methodologies for the evaluation of the
systemic toxicity potential of medical devices. In addition, it includes
pyrogenicity testing.
Systemic toxicity is a developing experimental science and it is expected
that each expert, in carrying out tests, will exercise judgement in the
selection of a procedure from the lists of standards and documents
quoted! thereby ensuring that the document that will best suit the needs
of a particular device is chosen. It is assumed that, in selecting the most
appropriate test method from the list, the individual method(s) may have
to be adapted, to evaluate the device under test more appropriately.
It must be borne in mind that subchronic and/or chronic systemic toxicity
testing is not always necessary for a risk assessment. Such assessment
might be made on the basis of qualitative and quantitative analytical
measurements to evaluate the exposure of possible leachables from the
device.
This adaptation is intentional because of the developing nature of the sci-
ence and because excessive rigidity or over-detailed specifications of
methods could prevent application of more appropriate test methods. It is
indeed intended that toxicological skill and judgement be applied during
the course of study. However, it is equally necessary that, where changes
from proposed methodologies are implemented, the rationale should be
fully explained and supported scientifically. (See 6.4.)
It is essential, when evaluating the results of toxicological tests, to bear
in mind the limitations and the potential variability of the tests. Similarly,
it may not always be appropriate to extrapolate from animal studies to the
human situation. While in vivo testing is designed to indicate possible
health hazards, it does not eliminate the need for continuing monitoring
and observation in humans.

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SIST EN ISO 10993-11:2000
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SIST EN ISO 10993-11:2000
IS0 109934 1:1993(E)
INTERNATIONAL STANDARD
Biological _ evaluation of medical devices -
-
Part 11:
Tests for systemic toxicity
ASTM F 619:1986, Practice for Extraction of Medical
1 Scope
Plastics, Vol. 13.01.
This part of IS0 10993 specifies methodologies for
ASTM F 750: 1987, Practice for Evaluating Material
the evaluation of the systemic toxicity potential of
Extracts by Systemic Injection in the Mouse.
medical devices which release constituents into the
body. In addition, it includes pyrogenicity testing.
BS 5736: Part 5:1982, Evaluation of medical devices
Part 5: Method of test for
for biological hazards -
The test methods cited in this part of IS0 10993 are
systemic toxicity; assessment of p yrogenicity in
from International Standards, national standards, di-
rabbits of extracts from medical devices.
rectives and regulations. This part of IS0 10993 is
concerned with either the actual product or its
SN 119 800, Biological Evaluation of Dental Materials,
leachab es. It is intended that tests for extracts or
Swiss Association for Standardization.
leachab es be conducted by choosing appropriate ex-
traction vehicles to yield a maximum extraction of
European Pharmacopoeia XXII, 1990.
leachab I e materials, in order to conduct biological
OECD - Guidelines for Testing of Chemicals.
testing.
Official Journal of the European Communities, 791831.
2 Normative references
Official Journal of the European Communities, 841449.
The following standards contain provisions which,
Official Journal of the European Communities, 871302.
through reference in this text, constitute provisions
of this part of IS0 10993. At the time of publication,
US Code of Federal Regulation 1500.40: Method of
the editions indicated were valid. All standards are
Testing Toxic Substances.
subject to revision, and parties to agreements based
on this part of IS0 10993 are encouraged to investi- US/EPA PB 86/l 08958.
gate the possibility of applying the most recent edi-
US/EPA PB 89/l 24077.
tions of the standards indicated below. Members of
IEC and IS0 maintain registers of currently valid
US/FDA Toxicological Principles for the Safety As-
International Standards.
sessment of Direct Food Additives, 1982.
IS0 10993-I : 1992, Biological evaluation of medica
United States Pharmacopeia XXI I: Biological Reactivity
devices - Part 1: Guidance on selection of tests.
Tests, In-Vivo; The National Formulary XVII, Rockville,
MD; Pharmacopeial Convention, 1990, pp. 1497-l 500.
IS0 10993-2: 1992, Biological evaluation of medica
devices - Part 2: Animal welfare requirements.
IS0 10993-3: 1992, Biological evaluation of medical
3 Definitions
devices - Pati 3: Tests for genotoxicity,
carcinogenicity and reproductive toxicity.
For the purposes of this part of IS0 10993, the defi-
ANSI/ADA No. 41, Biological Evaluation of Dental nitions in IS0 10993-l and the following definitions
Materials.
apply.

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SIST EN ISO 10993-11:2000
- IS0 10993=11:1993(E)
3.1 extraction vehicle: Liquid for use in the ex-
4.3 Polished materials
traction of leachables from a device.
If the final device is habitually polished, then the
3.2 extract liquid: Liquid which is tested for biolog-
sample surface shall be similarly treated. The polish-
ical response after the device has been extracted
ing medium shall be carefully and completely re-
within it.
moved. Sharp edges should be rounded as
appropriate for the application.
3.3 specimen: Unit(s) of device placed into the ex-
traction vehicle.
3.4 blank: Extraction vehicle not containing the
specimen under test which is used for comparison 44 . Production conditions
with the extract liquid.
The component or device used in the sample prep-
35 . systemic toxicity: Toxicity involving the entire
aration shall be exposed to the same conditions and
organjsm.
substances as it would encounter during production,
such as washing, packaging and sterilization.
3.6 acute toxicity: Adverse effects occurring after
administration of a single dose or multiple doses of a
test sample given within 24 h.
4.5 Sterilization
3.7 subacute toxicity: Adverse effects occurring
after administration of a single dose or multiple doses
of a test sample per day given during a period of from hich are intended for sterilization shall be
Devices w
- 14 days to 28 days. intended procedures.
used after sterilization by the
3.8 subchronic toxicity: Adverse effects occurring
after administration of a single dose or multiple doses
of a test sample per day given during a part of the
4.6 Physical state of sample
lifespan (usually 90 days but not exceeding IO % of
lifespan).
3.9 test sample: Device or extract thereof used for
4.6.1 Materials which are conducive to direct appli-
systemic toxicity testing.
cation (e.g. liquid, paste or gel) may be tested without
modification in dermal and oral studies.
4 Test sample requirements and
recommendations
4.ll General 4.6.2 Powders (e.g. products classed as super-
absorbents) may be tested by direct deposition or by
The patient may be exposed to a variety of conditions
making a paste in an appropriate solvent or liquid
or states of the device. Test samples shall be selected
dispersant and then applying it.
primarily for the conditions under which the device is
normally used. If deviations are necessary, they shall
be recorded in the test report, together with their
justification. 4.6.3 Liquids may be tested by direct deposition or
after dilution.
Testing should be performed on the final product,
and/or representative component samples of the final
For liquid materials such as sprays or inks which will
product and/or materials. In some cases it may be
be used by the end-user in a dried form, thin layers
advisable also to test the individual components sep-
are prepared on slides, dried and then extracted.
arately or immediately after the final product has been
assembled.
4.6.4 Solid materials may be used directly on the
4.2 Use of mould
skin. If it is considered necessary, the solid may be
If a mould is used for the preparation of samples, it pulverized or moistened sufficiently with water or a
shall not interact with or negatively influence the suitable non-irritating vehicle to ensure good contact
sample material. If appropriate a suitable insulation with the tissues. Appropriate solvents are listed in
medium should be used. 54 . .

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SIST EN ISO 10993-11:2000
IS0 10993=11:1993(E)
5 Method for extraction from medical
devices
Table 1
5.1 Rationale
5.M The following procedure outlines the basis to
obtain extracts from medical devices for testing. This
procedure may supplement but does not supersede
methods contained in specific study protocols.
Extraction conditions may attempt to exagger-
5.1.2
ate the clinical-use conditions so as to define the po-
tential toxicological hazard without causing significant
changes in the material pieces, which would not be
c) Slabs, tubing
experienced in actual practice, e.g. solidification or
and moulded
melting. Alternatively, because of well-defined clinical
exposure and actual commercial product-processing
parameters, it may be more appropriate for product
0,2 g sample per
testing to simulate in-use exposure time and tem-
ders, pellets,
perature.
5.2 Specimen preparation
1) Both sides combined.
2) Sum of internal and external surfaces.
The specimen may be prepared by subdividing it into
3) All exposed surfaces combined.
portions; it may also be tested as a whole entity, if
appropriate.
For materials that cannot be subdivided without loss
5.3.4 Conduct rinsing and drying procedures when
of specimen character, identity or integrity, and for
the specimen to be extracted does not appear free
which the calculated volume of e
...