SIST EN ISO 10993-17:2024

SLOVENSKI STANDARD
01-marec-2024
Biološko ovrednotenje medicinskih pripomočkov - 17. del: Toksikološka ocena
tveganja glede sestavin medicinskih pripomočkov (ISO 10993-17:2023)
Biological evaluation of medical devices - Part 17: Toxicological risk assessment of
medical device constituents (ISO 10993-17:2023)
Biologische Beurteilung von Medizinprodukten - Teil 17: Toxikologische Risikobewertung
von Medizinproduktbestandteilen (ISO 10993-17:2023)
Évaluation biologique des dispositifs médicaux - Partie 17: Appréciation du risque
toxicologique des constituants des dispositifs médicaux (ISO 10993-17:2023)
Ta slovenski standard je istoveten z: EN ISO 10993-17:2023
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 10993-17
EUROPEAN STANDARD
NORME EUROPÉENNE
November 2023
EUROPÄISCHE NORM
ICS 11.100.20 Supersedes EN ISO 10993-17:2009
English Version
Biological evaluation of medical devices - Part 17:
Toxicological risk assessment of medical device
constituents (ISO 10993-17:2023)
Évaluation biologique des dispositifs médicaux - Partie Biologische Beurteilung von Medizinprodukten - Teil
17: Appréciation du risque toxicologique des 17: Toxikologische Risikobewertung von
constituants des dispositifs médicaux (ISO 10993- Medizinproduktbestandteilen (ISO 10993-17:2023)
17:2023)
This European Standard was approved by CEN on 2 July 2023.

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, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway,
Poland, Portugal, Republic of North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Türkiye 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
© 2023 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-17:2023 E
worldwide for CEN national Members.

Contents Page
European foreword . 3
Annex ZA (informative) Relationship between this European Standard and the General
Safety and Performance Requirements of Regulation (EU) 2017/745 aimed to be
covered. 4
European foreword
This document (EN ISO 10993-17:2023) 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 May 2024, and conflicting national standards shall be
withdrawn at the latest by May 2024.
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 10993-17:2009.
This document has been prepared under a Standardization Request given to CEN by the European
Commission and the European Free Trade Association, and supports essential requirements of EU
Directive(s) / Regulation(s).
For the relationship with EU Directive(s) / Regulation(s), see informative Annex ZA, which is an integral
part of this document.
Any feedback and questions on this document should be directed to the users’ national standards
body/national committee. A complete listing of these bodies can be found on the CEN website.
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, France, Germany, Greece, Hungary, Iceland,
Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Republic of
North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Türkiye and the
United Kingdom.
Endorsement notice
The text of ISO 10993-17:2023 has been approved by CEN as EN ISO 10993-17:2023 without any
modification.
Annex ZA
(informative)
Relationship between this European Standard and the General Safety and
Performance Requirements of Regulation (EU) 2017/745 aimed to be
covered
This European standard has been prepared under M/575 to provide one voluntary means of
conforming to the General Safety and Performance Requirements of Regulation (EU) 2017/745 of 5
April 2017 concerning medical devices [OJ L 117] and to system or process requirements including
those relating to quality management systems, risk management, post-market surveillance systems,
clinical investigations, clinical evaluation or post-market clinical follow-up.
Once this standard is cited in the Official Journal of the European Union under that Regulation,
compliance with the normative clauses of this standard given in Table ZA.1 and application of the
edition of the normatively referenced standards as given in Table ZA.2 confers, within the limits of the
scope of this standard, a presumption of conformity with the corresponding General Safety and
Performance Requirements of that Regulation, and associated EFTA Regulations.
Where a definition in this harmonised standard differs from a definition of the same term set out in
Regulation (EU) 2017/745, the differences shall be indicated in the Annex Z. For the purpose of using
this standard in support of the requirements set out in Regulation (EU) 2017/745, the definitions set
out in this Regulation prevail.
Where the European standard is an adoption of an International Standard, the scope of this document
can differ from the scope of the European Regulation that it supports. As the scope of the applicable
regulatory requirements differ from nation to nation and region to region the standard can only
support European regulatory requirements to the extent of the scope of the European Regulation for
medical devices ((EU) 2017/745).
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 Regulation (EU) 2017/745. This means that risks have to be
‘reduced as far as possible’, ‘reduced to the lowest possible level’, ‘reduced as far as possible and appropriate’,
‘removed or reduced as far as possible’, ‘eliminated or reduced as far as possible’, ’removed or minimized as far as
possible’, or ‘minimized’, according to the wording of the corresponding General Safety and Performance
Requirement.
NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with General Safety
and Performance Requirements 1, 2, 3, 4, 5, 8, 9, 10, 11, 14, 16, 17, 18, 19, 20, 21 and 22 of the Regulation.
NOTE 3 When a General Safety and Performance 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 Regulation (EU) 2017/745 [OJ L 117] and to system or process requirements including those
relating to quality management systems, risk management, post-market surveillance systems, clinical
investigations, clinical evaluation or post-market clinical follow-up
General Safety and
Clause(s)/subclause(s)
Performance Requirements
of Remarks/Notes
of Regulation
this EN
(EU) 2017/745
EN ISO 10993-17 addresses the choice of
materials as regards toxicity, but 10.1 is
only partly covered. Flammability and
mechanical or physical (e.g., surface)
properties are not covered. This standard
provides requirements for a toxicological
risk assessment process for constituents
present in or on, or released from, a
medical device.
This risk assessment process involves the
identification of substances that have the
capacity to interact with biological
tissues, cells or body fluids and the
assessment of the nature and likelihood
of any associated harm to health arising
as a result of the intended use of the
medical device. While such an assessment
can confirm the absence of appreciable
toxicological risk, it does not necessarily
5, 6, 7, 8, 9, 10 and Annex
demonstrate the ability of a medical
10.1 a), b), d), e), and h) A, Annex B, Annex C and
device or material to perform with an
Annex E
appropriate host response in a specific
application.
The toxicological risk assessment is based
on the composition of the finished
medical device, which is dependent, in
part, on the processing materials used
and the impact of processes on the
materials of manufacture.
Where appropriate and necessary for the
risk assessment, quantitative structure-
activity relationships or mathematical
models can be used as part of the process
specified.
The standard provides requirements for a
process for specifying a level of exposure
to a constituent of a medical device that
is without appreciable harm to health
and for confirming that a medical device
meets the specification so defined.
EN ISO 10993-17 addresses risks posed by
contaminants and residues. However,
10.2 is only partly covered by this
standard, since the standard does not
provide requirements for design,
manufacture and packaging. Although
this standard does not oblige
manufacturers to minimize the risk posed
by contaminants and residues in medical
devices, it provides a means to estimate
5, 6, 7, 8, 9, 10 and Annex
those risks and demonstrate that they
10.2 A, Annex B, Annex C and
have been minimized.
Annex E
The primary focus of this standard is the
risk to patients, but risks to users coming
into contact with a medical device are
also addressed. However the standard is
not applicable to medical device
constituents that do not contact the body,
so risks to persons involved in the
transport or storage of medical devices
would not normally be addressed.
EN ISO 10993-17 addresses risks posed by
substances, including degradation
products and processing residues.
However, 10.4.1 is only partly covered by
this standard, since the standard does not
provide requirements for design and
manufacture, nor does it address risks
associated with particles, including wear
debris, from medical devices. Although
this standard does not oblige
manufacturers to minimize the
toxicological risk posed by substances in
medical devices, it provides a means to
estimate those risks and demonstrate
5, 6, 7, 8, 9, 10 and Annex
that they have been minimized.
10.4.1 A, Annex B, Annex C and
Annex E
The process specified by this standard
includes the identification of substances
which are carcinogenic, mutagenic or
toxic to reproduction or that have
endocrine-disrupting properties. Where
such substances are identified, it provides
a means for estimation of potential
patient or user exposure to the substance
that can form a basis for a justification
regarding the presence of the substance
and for appropriate labelling. However
the standard does not include
acceptability criteria or labelling
requirements.
Table ZA.2 — Applicable Standards to confer presumption of conformity as described in this
Annex ZA
Column 1 Column 2 Column 3 Column 4
Reference in International
Title Corresponding European
Clause 2 Standard Edition
Standard Edition
ISO ISO 10993-1:2018 Biological evaluation of medical EN ISO 10993-1:2020
10993-1:2018 devices — Part 1: Evaluation and
testing within a risk management
process
ISO ISO 10993-18:2020 Biological evaluation of medical EN ISO 10993-18:2020
10993-18:2020 devices — Part 18: Chemical
characterization of medical device
materials within a risk
management process
ISO/TS ISO/TS Biological evaluation of medical For applicable standard
21726:2019 21726:2019 devices — Application of the edition see Column 2
threshold of toxicological concern
(TTC) for assessing
biocompatibility of medical device
constituents
ISO 14971:2019 ISO 14971:2019 Medical devices — Application of EN ISO 14971:2019
risk management to medical
EN ISO
devices
14971:2019/A11:2021
The documents listed in the Column 1 of table ZA.2, in whole or in part, are normatively referenced in
this document, i.e. are indispensable for its application. The achievement of the presumption of
conformity is subject to the application of the edition of Standards as listed in Column 4 or, if no
European Standard Edition exists, the International Standard Edition given in Column 2 of table ZA.2.
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 product(s) falling within the scope of
this standard.
INTERNATIONAL ISO
STANDARD 10993-17
Second edition
2023-09
Biological evaluation of medical
devices —
Part 17:
Toxicological risk assessment of
medical device constituents
Évaluation biologique des dispositifs médicaux —
Partie 17: Appréciation du risque toxicologique des constituants des
dispositifs médicaux
Reference number
ISO 10993-17:2023(E)
ISO 10993-17:2023(E)
© ISO 2023
All rights reserved. Unless otherwise specified, or required in the context of its implementation, 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
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
ii
ISO 10993-17:2023(E)
Contents Page
Foreword .iv
Introduction . vi
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 Abbreviated terms and symbols .7
5 Toxicological risk assessment within the biological evaluation process .9
5.1 General . 9
5.1.1 Risk assessment principles . 9
5.1.2 Hazard identification . 9
5.1.3 Risk estimation . 10
5.2 Toxicological risk assessment process .12
6 Constituent specific toxicological information .14
6.1 General . 14
6.2 Identification of hazardous constituents . 14
6.2.1 General . 14
6.2.2 Application of the toxicological screening limit . 16
6.2.3 Identification of human carcinogens or suspected human carcinogens . 17
6.2.4 Selection of the point of departure . 17
7 Tolerable contact level, tolerable intake and threshold of toxicological concern .18
7.1 Derivation of TCL and TI . 18
7.2 Application of TTC . 18
8 Exposure dose estimation .19
9 Margin of safety .20
9.1 General . 20
9.2 Calculating the margin of safety . 20
9.2.1 General .20
9.2.2 Combining MoS values to address additivity of harm .22
10 Toxicological risk acceptance criteria .23
10.1 General .23
10.2 Further risk analysis or risk evaluation or risk control . 23
11 Reporting requirements .24
Annex A (normative) Evaluation of toxicological data quality when selecting a point of
departure .25
Annex B (normative) Derivation of toxicological screening limits .26
Annex C (normative) Derivation of constituent TI or TCL for select endpoints .33
Annex D (informative) Typical assumptions for biological parameters .41
Annex E (normative) Estimation of an exposure dose . 44
Annex F (informative) Reporting of toxicological risk assessment information.53
Bibliography .58
iii
ISO 10993-17:2023(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 document 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).
ISO draws attention to the possibility that the implementation of this document may involve the use
of (a) patent(s). ISO takes no position concerning the evidence, validity or applicability of any claimed
patent rights in respect thereof. As of the date of publication of this document, ISO had not received
notice of (a) patent(s) which may be required to implement this document. However, implementers are
cautioned that this may not represent the latest information, which may be obtained from the patent
database available at www.iso.org/patents. ISO shall not be held responsible for identifying any or all
such patent rights.
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation of 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
www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of
medical devices, in collaboration with the European Committee for Standardization (CEN) Technical
Committee CEN/TC 206, Biocompatibility of medical and dental materials and devices, in accordance
with the Agreement on technical cooperation between ISO and CEN (Vienna Agreement).
This second edition cancels and replaces the first edition (ISO 10993-17:2002), which has been
technically revised.
The main changes are as follows:
— the title has been changed;
— the scope has been revised and a new statement on its applicability has been added;
— the following terms have been removed: allowable limit, benefit factor, concomitant exposure
factor, health benefit, health hazard, health risk, health risk analysis, leachable substance, multiple
exposure, physiologically based pharmacokinetic modelling, proportional exposure factor, repeated
use, simultaneous use, TCL modifying factor, tolerable exposure, and tolerable risk, utilization
factor;
— the following terms have been added: analogue (3.1), benchmark dose low (3.2), carcinogen (3.3),
constituent (3.4), dose-response (3.6), exposure dose (3.7), harmful dose (3.9), human carcinogen
(3.10), identified constituent (3.11), irritation (3.12), margin of safety (3.14), point of departure (3.19),
release kinetics (3.20), slope factor (3.21), suspected human carcinogen (3.22), systemic toxicity (3.23),
threshold of toxicological concern (3.24), total quantity (3.27), toxicological risk, (3.28), toxicological
risk assessment (3.29), toxicological screening limit (3.30) and worst-case estimated exposure dose
(3.32);
iv
ISO 10993-17:2023(E)
— the following clauses have been removed: former Clause 4 on the general principles for establishing
allowable limits, former Clause 5 on the establishment of tolerable intake for specific leachable
substances, former Clause 6 on the calculation of tolerable exposure, former Clause 7 on the
feasibility evaluation, former Clause 8 on benefit evaluation, and former Clause 9 on allowable
limits;
— the following clauses have been added: Clause 4 on abbreviated terms and symbols, Clause 5 on
toxicological risk assessment within the biological evaluation process, Clause 6 on constituent
toxicological information, Clause 7 on the tolerable contact level, tolerable intake and the threshold
of toxicological concern, Clause 8 on the exposure dose estimation, and Clause 9 on margin of safety;
— former Annex A has been moved to Annex D;
— Annex B and Annex C have been deleted;
— the following annexes have added: Annex A on evaluating toxicological data quality when selecting
a POD, Annex B on derivation of toxicological screening limits, Annex C on deriving constituent TI
or TCL for select endpoints, Annex E on estimating an exposure dose, and Annex F on reporting
toxicological risk assessment information.
A list of all parts in the ISO 10993 series can be found on the ISO website.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www.iso.org/members.html.
v
ISO 10993-17:2023(E)
Introduction
A medical device or material that has direct or indirect contact with the patient's body or the user’s
body is expected to perform its intended use while being free from unacceptable risks, including
biological and toxicological risks. For this reason, medical devices are typically subject to a biological
evaluation within a risk management process to assess their safety. The ISO 10993 series specifies a
process through which the manufacturer of a medical device can identify biological hazards associated
with the medical device, estimate and evaluate the risks associated with these hazards, control these
risks, and monitor the effectiveness of the controls throughout the life cycle of the medical device.
ISO 10993-1, in line with ISO 14971, facilitates a common understanding of biological evaluation within
a risk management process. ISO 10993-18 includes methods for identifying and quantifying hazardous
medical device constituents so that their toxicological risk can be evaluated. Furthermore, ISO 10993-18
specifies when to consider conducting a toxicological risk assessment per this document.
This document specifies requirements for a toxicological risk assessment process for specific medical
device constituents that is used within the biological evaluation process specified by ISO 10993-1 and
Clause 1. For example, the biological risk analysis of a medical device includes obtaining constituent
information as described in ISO 10993-1:2018, 6.2 and ISO 10993-18. The extent to which constituent
information is needed depends on what is known about the material formulation, manufacturing
process (i.e. processing aid chemicals, process steps, etc.), what nonclinical or clinical information
exist, and on the nature and duration of body contact with the medical device. This toxicological risk
assessment process is based on the principle that the biological evaluation and risk assessment process
is most efficient and effective when the minimum information necessary is used to assess if exposure
to a harmful dose of any medical device constituent can occur. The process, requirements, criteria and
methods specified in this document are intended to yield the following information, which is useful in
the overall biological risk assessment of the final product:
— whether constituents present in, on or extracted from the medical device are at a quantity that can
be a potential source of harm to health;
— derivation of a tolerable intake or tolerable contact level, for a constituent over a specified time
period, on the basis of body mass or surface area, that is considered to be without appreciable harm
to health;
— a worst-case estimated exposure dose for each constituent and subsequent toxicological risk
estimation;
— a toxicological risk estimate based on the tolerable intake or tolerable contact level, and on the
worst-case estimated exposure dose for each constituent.
This document is intended for use by toxicologists or other knowledgeable and experienced
professionals, appropriately qualified by training and experience, capable of making informed decisions
based upon scientific data and a knowledge of medical devices.
Lastly, this latest revision of this document is more extensive that the previous edition as it clarifies
when a toxicological risk assessment is recommended, how to calculate the worst-case estimated
exposure dose of a constituent and when the probability of occurrence of harm to health should be
addressed by other means (e.g. frequency based dose-response (if available), probabilistic dose-
response, or biological testing).
vi
INTERNATIONAL STANDARD ISO 10993-17:2023(E)
Biological evaluation of medical devices —
Part 17:
Toxicological risk assessment of medical device
constituents
1 Scope
This document specifies the process and requirements for the toxicological risk assessment of medical
device constituents. The methods and criteria used to assess whether exposure to a constituent
is without appreciable harm are also specified. The toxicological risk assessment can be part of the
biological evaluation of the final product, as described in ISO 10993-1.
The process described in this document applies to chemical characterization information obtained in
line with ISO 10993-18. When a toxicological risk assessment of either the compositional information or
analytical chemistry data (e.g. extractable data or leachable data) are required to determine whether
the toxicological risks related to the constituents are negligible or tolerable.
The process described in this document is not intended to apply to circumstances where the
toxicological risk has been estimated by other means, such as:
— constituents, excluding cohort of concern or excluded chemicals, that are present in or extracted from
a medical device at an amount representative of patient exposure below a relevant, toxicologically-
based reporting threshold (see applicable requirements in ISO 10993-18:2020, Annex E and
ISO/TS 21726);
— a new or changed medical device for which chemical or biological equivalence has been established
with an existing biocompatible or clinically established medical device (see applicable requirements
in ISO 10993-18:2020, Annex C).
The process described in this document is also not applicable to:
— medical device constituents that do not contact the body (e.g. in vitro diagnostics);
— biological risks associated with physical interactions of the medical device with the body (i.e.
application of mechanical forces, energy or surface morphology, etc.), provided that the chemical
exposure is not changed;
— active pharmaceutical ingredients of device-drug combination products or biologic components of
device-biologic combination products as additional regulatory considerations can apply;
— exposure to a particular constituent that arises from sources other than the device, such as food,
water or air.
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 10993-1:2018, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management process
ISO 10993-17:2023(E)
ISO 10993-18:2020, Biological evaluation of medical devices — Part 18: Chemical characterization of
medical device materials within a risk management process
ISO/TS 21726:2019, Biological evaluation of medical devices — Application of the threshold of toxicological
concern (TTC) for assessing biocompatibility of medical device constituents
ISO 14971:2019, Medical devices — Application of risk management to medical devices
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 terminology databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at https:// www .electropedia .org/
3.1
analogue
substance with similar molecular, physical, chemical or toxicological properties
3.2
benchmark dose low
BMD
L
lower one-sided confidence limit of a dose derived from dose-response (3.6) modelling that is associated
with a specified change (e.g. 5 % or 10 %) in the dose-response relationship
Note 1 to entry: A specified change of 5 % is applied when a reported harm applies to individual animals. A
specified change of 10 % is applied when a reported harm applies to a fraction of animals in a population.
[2]
[SOURCE: EPA 2012 ]
3.3
carcinogen
constituent (3.4) that causes cancer in humans or experimental animals as determined by valid
experimental or observational evidence
Note 1 to entry: Carcinogens are either genotoxic carcinogens or non-genotoxic carcinogens. A genotoxic
carcinogen is a constituent capable of causing cancer by a mechanism that involves direct alteration of the genetic
material of target cells, as a key event at an early stage in tumour development. A non-genotoxic carcinogen is
a constituent capable of producing cancer by a mechanism where direct gene damage is not the key event in
tumour development (C.3.1).
[3]
[SOURCE: International Agency for Research on Cancer ]
3.4
constituent
chemical that is present in or on the finished medical device or its materials of construction
Note 1 to entry: Constituents can be intentionally or unintentionally added chemicals or compounds, such as:
additives (e.g. plasticizers, lubricants, stabilizers, anti-oxidants, colouring agents, fillers), manufacturing process
residues (e.g. monomers, catalysts, solvents, sterilant and cleaning agents), degradation products or impurities
[5]
(e.g. byproducts or side products) or contaminants .
[SOURCE: ISO 10993-18:2020, 3.10, modified — "or on" has been added to the definition and Note 1 to
entry has been replaced.]
ISO 10993-17:2023(E)
3.5
default value
value or factor used in the derivation of a worst-case exposure dose (3.32), tolerable contact level (3.25)
or tolerable intake (3.26), in the absence of specific data [e.g. an uncertainty factor (3.31)]
3.6
dose-response
relationship of dosage to observable harm
Note 1 to entry: In general, there are two types of dose-response relationships. The first type is the change in
the response of an individual to a range of doses. The second type is the distribution of the response among
individuals to a range of doses.
3.7
exposure dose
quantity of a constituent (3.4) that does or can contact the body by an exposure route over a specified
time period
Note 1 to entry: The exposure dose is expressed in microgram per kilogram of body mass per day (µg/kg/d) or in
microgram per centimetre squared (µg/cm ).
Note 2 to entry: The exposure dose is different from the absorbed dose. The absorbed dose is the quantity of the
constituent that traverses the portal of entry, which is dependent on the absorption rate of the constituent.
3.8
harm to health
adverse reaction, such as altered morphology, physiology, growth, development, reproduction or
lifespan that
a) impairs function of an organ or system, organism, or (sub)population,
b) reduces capacity to tolerate an impaired function, or
c) increases susceptibility to other influences that impair function
Note 1 to entry: Examples of (sub)population include, but are not limited to, male, female, preterm neonates,
adults.
3.9
harmful dose
dose capable of eliciting appreciable harm to health (3.8)
3.10
human carcinogen
carcinogen (3.3) for which human data demonstrates a causal association between exposure to the
constituent (3.4) and occurrence of cancer
EXAMPLE Human carcinogens include, but are not limited to, International Agency for Research on Cancer
[6][7]
(IARC) Group I carcinogens or US National Toxicology Program (NTP) "known to be a human carcinogen".
3.11
identified constituent
constituent (3.4) for which molecular structure information is complete
Note 1 to entry: The identity of a constituent can be obtained by information gathering or non-targeted or
targeted analytical approaches as described in ISO 10993-18.
ISO 10993-17:2023(E)
EXAMPLE Examples of molecular structure information include molecular structure illustration or
simplified molecular input line entry system (SMILES) code, molecular formula, and Chemical Abstract Service
1) ®
Registry Number (CAS RN ). Molecular structure information includes its atomic elements (type, number,
arrangement) and bond information.
3.12
irritation
localized non-specific inflammatory response to single, repeated or continuous application of a
substance/material
Note 1 to entry: Skin irritation is a reversible reaction and is mainly characterized by local erythema (redness)
and swelling (oedema) of the skin.
[SOURCE: ISO 10993-23:2021, 3.7]
3.13
lowest observed adverse effect level
LOAEL
lowest concentration or amount of an identified constituent (3.11) found by experiment or observation
which causes detectable harm to health (3.8) to the target organism under defined conditions of
exposure
Note 1 to entry: The lowest observed adverse effect level is expressed in microgram per kilogram of body mass
per day (µg/kg/d).
3.14
margin of safety
MoS
ratio of the constituent’s tolerable contact level (3.25) (numerator), tolerable intake (3.26) (numerator)
and its exposure dose (3.7) (denominator)
Note 1 to entry: Margin of safety addresses irritation (3.12), genotoxicity, systemic toxicity (3.23), carcinogenicity
or reproductive or developmental endpoints.
3.15
minimally irritating level
MIL
lowest amount per surface area of an identified constituent (3.4) that is irritating to the tissue at the
contact site as determined by valid experimental or observational evidence
Note 1 to entry: The minimally irritating level is expressed in microgram per centimetre squared (µg/cm ).
3.16
modifying factor
MF
mathematical product of uncertainty factors (3.31)
3.17
non-irritating level
NIL
greatest amount per surface area of an identified constituent (3.4) that does not elicit irritation to the
tissue at the contact site as determined by valid experimental or observational evidence
Note 1 to entry: The non-irritating level is expressed in microgram per centimetre squared (µg/cm ). ®
1) Chemical Abstracts Service (CAS) Registry Number is a trademark of the American Chemical Society (ACS).
This information is given for the convenience of users of this document and does not constitute an endorsement by
ISO of the product named. Equivalent products may be used if they can be shown to lead to the same results.
ISO 10993-17:2023(E)
3.18
no observed adverse effect level
NOAEL
greatest concentration or amount of an identified constituent (3.11) found by experiment or observation
which causes no detectable harm to health (3.8) to the target organism under defined conditions of
exposure
Note 1 to entry: The no observed adverse effect level is expressed in microgram per kilogram of body mass per
day (µg/kg/d).
3.19
point of departure
POD
low point on a toxicological dose-response curve established from experimental or observational data
that corresponds to the benchmark dose low (3.2), or a lowest observed adverse effect level (3.13), or a
minimally irritating level (3.15), or a non-irritating level (3.17), or a no observed adverse effect level (3.18)
Note 1 to entry: The POD is used to derive a tolerable contact level (3.25) or a tolerable intake (3.26).
[8]
[SOURCE: EPA Integrated Risk Information System (IRIS) ]
3.20
release kinetics
quantity of a constituent (3.4) that is released from a medical device as a function of time
Note 1
...