prEN ISO 10993-17

SLOVENSKI STANDARD
oSIST prEN ISO 10993-17:2022
01-januar-2022
Biološko ovrednotenje medicinskih pripomočkov - 17. del: Toksikološka ocena
tveganja glede sestavin medicinskih pripomočkov (ISO/DIS 10993-17:2021)

Biological evaluation of medical devices - Part 17: Toxicological risk assessment of

Biologische Beurteilung von Medizinprodukten - Teil 17: Toxikologische Risikobewertung

Évaluation biologique des dispositifs médicaux - Partie 17: (ISO/DIS 10993-17:2021)

2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

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

Foreword ........................................................................................................................................................................................................................................iv

Introduction .................................................................................................................................................................................................................................v

1 Scope ................................................................................................................................................................................................................................. 1

2 Normative references ..................................................................................................................................................................................... 1

3 Terms and definitions .................................................................................................................................................................................... 2

4 Abbreviations and terms ............................................................................................................................................................................6

5 Toxicological risk assessment within the biological evaluation process ...............................................7

6 Chemical constituent toxicological information ............................................................................................................10

6.1 General ........................................................................................................................................................................................................ 10

6.2 Obtain and evaluate toxicological information ...................................................................................................... 11

6.2.1 Application of toxicological screening limit (TSL) ............................................................................12

6.2.2 Further evaluation of toxicological information.................................................................................12

7 Tolerable contact level (TCL), tolerable intake (TI), and threshold of toxicological

concern (TTC) ......................................................................................................................................................................................................13

7.1 Derivation of TCL and TI .............................................................................................................................................................13

7.2 Application of TTC ............................................................................................................................................................................ 14

7.2.1 General ..................................................................................................................................................................................... 14

7.2.2 Selecting the TTC ............................................................................................................................................................ 14

8 Exposure dose estimation ......................................................................................................................................................................15

9 E valuation of the MOS ..................................................................................................................................................................................16

9.1 General ........................................................................................................................................................................................................ 16

9.2 Calculating a margin of safety (MOS) ............................................................................................................................. 16

9.2.1 Example of calculating a margin of safety (MOS) .............................................................................. 17

9.3 Requirements and criteria in the evaluation of the MOS ............................................................................... 17

9.3.1 General ..................................................................................................................................................................................... 17

9.3.2 Addressing residual uncertainty ...................................................................................................................... 17

10 Reporting requirements ...........................................................................................................................................................................18

Annex A (informative) Evaluating toxicological data quality when selecting a POD ...................................19

Annex B (normative) Derivation of toxicological screening limits ..................................................................................20

Annex C (normative) Deriving constituent TI or TCL for select end points ............................................................23

Annex D (informative) Some typical assumptions for biological parameters .....................................................30

Annex E (normative) Calculating an estimated exposure dose ...........................................................................................33

Annex F (informative) Reporting toxicological risk assessments ....................................................................................38

Annex ZA (informative) Relationship between this European standard and the General

covered ....................................................................................................................................................................................................................... 44

Bibliography .............................................................................................................................................................................................................................47

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

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

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

Any trade name used in this document is information given for the convenience of users and does not

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

This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of

This second edition cancels and replaces the first edition (ISO 10993-17:2002), which has been

Any feedback or questions on this document should be directed to the user’s national standards body. A

A medical device or material that comes in 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 the safety of the medical device. The ISO 10993

standard 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

ISO 10993-1, in line with ISO 14971, defines key terms that facilitate a common understanding of

biological risk assessment. For example, biological risk is defined as the combination of the probability

of harm to health occurring as a result of adverse reactions associated with medical device or material

interactions, and the severity of that harm. Toxicological risk is defined as the probability of a specified

degree of an adverse reaction occurring in response to a specified level of exposure. Toxicological

hazard is defined as the potential for a chemical substance or material to cause an adverse biological

reaction, taking into account the nature of the reaction and the dose required to elicit it. ISO 10993-

18 includes methods for obtaining the necessary data for the toxicological risk assessment of medical

device constituents. Furthermore, ISO 10993-18 specifies when to consider conducting a toxicological

This Part of ISO 10993 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 of this Standard. For example, biological risk analysis of a medical device includes

obtaining chemical constituent information as described in ISO 10993-1 (Clause 6.1) and ISO 10993-

18. The extent to which constituent information can be obtained depends on what is known about the

material formulation, manufacturing process (i.e. processing aid chemicals, process steps, etc.), what

nonclinical and/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 whether or not exposure to a harmful dose(s) of all constituents could occur

during the time period that a medical device contacts the body. The process, requirements, criteria and

methods specified in this Standard are intended to yield the following information, which are useful in

― a worst-case exposure estimate(s) for each chemical constituent(s) to determine whether or not it

― derivation of a tolerable intake or tolerable contact level, to a chemical constituent over a specified

time period, on the basis of body mass or surface area, that is considered to be without appreciable

― an evaluation of exposure data for each chemical constituent(s) that is/are without appreciable

Lastly, this latest revision of ISO 10993-17 extends the previous version by clarifying when a toxicological

risk assessment is necessary, how to calculate worst case exposure of a chemical constituent, and when

the probability of occurrence of harm to health should be addressed by other means. (e.g. frequency

This part of the ISO 10993 specifies the process and requirements for the toxicological risk assessment

of medical device constituents to be used within the biological evaluation of the final product described

in ISO 10993-1, which includes the methods and criteria used to assess if exposure of a chemical

The process described in this document is intended to apply after chemical characterization

compositional profiling is performed as required by ISO 10993-18, and thus a toxicological risk

assessment of either the compositional information, extractable data or leachable data are required to

The process described in this document is not intended to apply to circumstances where the

— constituents, excluding cohort of concern/excluded chemicals, that are present or extracted at

an amount representative of patient exposure below a relevant, toxicologically-based reporting

— 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 ISO 10993-18:2020,

— medical device constituents that do not contact the body (e.g., in vitro diagnostics),

— all biological risks applicable to a medical device (e.g., harm(s) that result(s) from physical interaction

(i.e., application of mechanical forces, energy, or surface morphology, etc.) of the medical device with

— active pharmaceutical ingredients of device-drug combination products or biologic components of

device-biologic combination products as additional regulatory considerations may apply,

— exposure to a particular chemical constituent that arises from sources other than the device, such

as food, water, or air. This document does not address the potential for exposure from such sources

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

ISO 10993-18:2020, Biological evaluation of medical devices — Part 18: Chemical characterization of

ISO/TS 21726:2019, Biological evaluation of medical devices — Application of the threshold of toxicological

ISO 14971:2019, Medical devices — Application of risk management to medical devices

For the purposes of this document, the terms and definitions given in ISO 10993-1 and the following

ISO and IEC maintain terminological databases for use in standardization at the following addresses:

substance(s) with similar molecular, physical, chemical and toxicological properties

dose derived from dose-response modelling that is associated with a specified change (e.g., 5% or 10%)

Note 1 to entry: A specified change of 5 % is applied when reported harm applies to individual animals. Specified

change of 10 % is applied when reported harm applies to a fraction of animals in a population.

constituent that causes cancer in humans or animals as determined by valid experimental evidence

[SOURCE: International Agency for Research on Cancer [3]; National Cancer Institute [4]]

chemical that is present in or on the finished medical device or its materials of construction

Note 1 to entry: Constituent is also defined in ISO/TC 21726 and ISO 10993-18, which includes intentionally or

unintentionally added chemicals/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), and degradation products. The term also includes side products and intermediates released

value or factor used in the derivation of a tolerable contact level (3.24) or tolerable intake (3.25), in the in

Note 1 to entry: In general, there are two types of dose-response relationships. The first type is the change in

response for an individual to a range of doses. The second type is the distribution of a response among individuals

quantity of a chemical constituent that does, or could contact the body over a specified time period

Note 1 to entry: to entry: Exposure dose is normally expressed as mg/kg/day or as mg/cm /day.

an adverse reaction, such as altered morphology, physiology, growth, development, reproduction

or lifespan that (a) impairs function of an organ/system, organism, or (sub)population, (b) reduces

capacity to tolerate impaired function, or (c) increases susceptibility to other influences that impair

Note 1 to entry: Examples of (sub) population include, but are not limited to, male versus female, preterm

carcinogen (3.3) for which human data demonstrates a causal association between exposure to the

Note 1 to entry: The identity of a medical device constituent can be obtained by information gathering or non-

Note 2 to entry: Examples of molecular structure information include (e.g., illustration or SMILES code),

molecular formula, and CAS registry number (RN) of constituents; molecular structure includes its elements

localized non-specific inflammatory response to single, repeated or continuous application of a

Note 1 to entry: Skin irritation is a reversible reaction and is mainly characterized by local erythema (redness)

lowest concentration or amount of an identified constituent found by experiment or observation which

causes detectable harm to health (3.8) of the target organism under defined conditions of exposure

Note 1 to entry: Lowest observed adverse effect level is normally expressed as mg/kg/day.

ratio of the chemical constituent’s tolerable contact level (3.24) (numerator), tolerable intake

(3.25) (numerator), or threshold of toxicological (if applicable) (numerator), and its exposure dose

Note 1 to entry: to entry: Margin of Safety (MOS) addresses irritation, genotoxicity, systemic toxicity,

lowest amount of an identified chemical constituent that is irritating to the body

greatest amount of an identified chemical constituent that does not elicit irritation to the body

Note 1 to entry: Non-irritating level is normally expressed as milligram per centimetre squared (mg/cm ).

greatest concentration or amount of an identified constituent found by experiment or observation

which causes no detectable harm to health (3.8) of the target organism under defined conditions of

Note 1 to entry: No observed adverse effect level is normally expressed as milligram (mg) per kilogram (kg) of

dose used to derive a tolerable contact level (3.24) or a tolerable intake (3.25)

Note 1 to entry: Note to entry: Examples of a POD include: non-irritating level (3.17), or a minimally irritating level

(3.15), or a benchmark dose low (3.2), or a no observed adverse effect level (3.18), or lowest observed adverse effect

quantity of a constituent that is released from a medical device as a function of time

Note 1 to entry: Release kinetics data can be obtained experimentally (e.g., simulated use study, leachables study,

or other type of extractables study). Alternatively, if supporting chemical and material data are available, a

qualified or validated release model can be used. Experimental release kinetics test methods and release models

to a subset of medical device constituents and materials have been published in the scientific literature for

Note 2 to entry: Factors that impact release (e.g., linear versus nonlinear) include, but are not limited to,

physicochemical properties of the chemical constituent (e.g., molecular size, solubility, and thermal stability),

physicochemical properties of the extracting solvent (e.g., solubility and thermal stability), as well as, impact of

the extraction temperature on the device material(s) in the test sample (e.g., increased free volume of a polymer

upper-bound estimate of risk per increment of dose that can be used to estimate risk probabilities for

Note 1 to entry: Slope factor is expressed as a pre-determined frequency of occurrence (i.e., the number of

individuals that the response is expected to occur in a larger population per unit exposure dose. For example,

slope factor that represents a frequency of occurrence in a specified population is commonly expressed as 1 in

carcinogen (3.3) for which toxicological data indicates a causal relationship between exposure to the

Note 1 to entry: Suspected human carcinogen applies when human data are inadequate to establish an association

between exposure to the chemical constituent and cancer. Suspected human carcinogens are established by

harm(s) that occur at a different organ/system other than at the site of contact between the body and

Note 1 to entry: Systemic toxicity can occur within a few days of a one-time exposure (i.e., acutely) or delayed

after repeated/ongoing exposure (subacute and subchronic, and chronic) to a harmful dose (3.9) of a chemical

constituent released from a single medical device or from use of multiple medical devices.

estimate of the daily surface-contact exposure to an identified constituent (3.11) over a specified time

Note 1 to entry: Tbolerable contact level is normally expressed as mg/cm /day of body or tissue surface.

estimate of the daily exposure of an identified constituent (3.11) over a specified time period (e.g.,

acute, subacute, subchronic, or chronic), on the basis of body mass, on the basis of body mass, that is

Note 1 to entry: Tolerable intake is normally expressed as milligram (mg) per kilogram (kg) of body weight (bw)

per day (i.e., mg/kg/day). It is derived to establish a toxicological exposure limit for a medical device constituent

amount of an identified constituent (3.11) present in, or that which can be extracted from, the medical

Note 1 to entry: Total quantity is normally expressed as milligram per device (mg/devi