ISO/TS 21726:2019

Biological evaluation of medical devices — Application of the threshold of toxicological concern (TTC) for assessing biocompatibility of medical device constituents

This document describes the basis for, selection of, and general applicability of a threshold of toxicological concern (TTC) value for a constituent present in/on a medical device or released from a medical device. The TTC values in this document can be used for: — comparing to a maximum concentration of an identified or unidentified constituent in an extract (see ISO 10993-18); — supporting toxicological equivalence; — comparing to a maximum exposure dose estimate of an identified constituent (see ISO 10993-17). NOTE Constituent is defined in 3.1. ISO 10993-18 specifies how to convert TTC (µg/d) into a concentration (µg/ml). TTC is not applicable to constituents with adequate toxicity data for deriving a tolerable intake (TI) value (see ISO 10993-17). The TTC values established in this document are protective for carcinogens, systemic toxicants, and reproductive toxicants (see Clause 5). This document does not include TTC values for other biological endpoints assessed as part of the biological evaluation of a medical device, per ISO 10993-1, for example: — cytotoxicity; — irritation; — sensitization; — hemocompatibility; — material mediated pyrogenicity; — local effects that occur in tissues at the site of contact between a medical device and the body (e.g. the observations from implantation studies). The TTC values in this document do not apply to potential exposure via gas pathways of medical devices. For application of TTC for constituents present/released from these devices, see the ISO 18562 series. The TTC values presented in this document are not applicable for the safety assessment of cohort of concern (see 5.3).

Évaluation biologique des dispositifs médicaux — Application du seuil de préoccupation toxicologique (TTC) pour évaluer la biocompatibilité des substances extractibles des dispositifs médicaux

General Information

• Status: Published
• Publication Date: 31-Jan-2019
• ICS: 11.100.20 - Biological evaluation of medical devices
• Technical Committee: ISO/TC 194 - Biological and clinical evaluation of medical devices
• Drafting Committee: ISO/TC 194/WG 11 - Allowable limits for leachable substances
• Current Stage: 9093 - International Standard confirmed
• Completion Date: 16-Jun-2022

Standards Content (Sample)

TECHNICAL ISO/TS
SPECIFICATION 21726
First edition
2019-02
Biological evaluation of medical
devices — Application of the threshold
of toxicological concern (TTC) for
assessing biocompatibility of medical
device constituents
Évaluation biologique des dispositifs médicaux — Application
du seuil de préoccupation toxicologique (TTC) pour évaluer la
biocompatibilité des substances extractibles des dispositifs médicaux
Reference number
ISO/TS 21726:2019(E)
©
ISO 2019

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ISO/TS 21726:2019(E)

COPYRIGHT PROTECTED DOCUMENT
© ISO 2019
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ii © ISO 2019 – All rights reserved

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ISO/TS 21726:2019(E)

Contents Page
Foreword .iv
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 2
4 Background . 2
4.1 General . 2
4.2 Protectiveness of TTC values . 3
5 Applicability of TTC to medical device constituents . 3
5.1 General . 3
5.2 Selection of TTC value based on duration of body contact . 3
5.3 Cohort of concern constituents . 4
5.3.1 General. 4
5.3.2 Identification of cohort of concern constituents . 5
5.4 Applicability to mixtures . 5
Bibliography . 6
© ISO 2019 – All rights reserved iii

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ISO/TS 21726:2019(E)

Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.
ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www .iso .org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation 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.
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.
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TECHNICAL SPECIFICATION ISO/TS 21726:2019(E)
Biological evaluation of medical devices — Application of
the threshold of toxicological concern (TTC) for assessing
biocompatibility of medical device constituents
1 Scope
This document describes the basis for, selection of, and general applicability of a threshold of
toxicological concern (TTC) value for a constituent present in/on a medical device or released from a
medical device. The TTC values in this document can be used for:
— comparing to a maximum concentration of an identified or unidentified constituent in an extract
(see ISO 10993-18);
— supporting toxicological equivalence;
— comparing to a maximum exposure dose estimate of an identified constituent (see ISO 10993-17).
NOTE Constituent is defined in 3.1.
ISO 10993-18 specifies how to convert TTC (µg/d) into a concentration (µg/ml).
TTC is not applicable to constituents with adequate toxicity data for deriving a tolerable intake (TI)
value (see ISO 10993-17).
The TTC values established in this document are protective for carcinogens, systemic toxicants, and
reproductive toxicants (see Clause 5). This document does not include TTC values for other biological
endpoints assessed as part of the biological evaluation of a medical device, per ISO 10993-1, for example:
— cytotoxicity;
— irritation;
— sensitization;
— hemocompatibility;
— material mediated pyrogenicity;
— local effects that occur in tissues at the site of contact between a medical device and the body (e.g.
the observations from implantation studies).
The TTC values in this document do not apply to potential exposure via gas pathways of medical devices.
For application of TTC for constituents present/released from these devices, see the ISO 18562 series.
The TTC values presented in this document are not applicable for the safety assessment of cohort of
concern (see 5.3).
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
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ISO/TS 21726:2019(E)

ISO 10993-17, Biological evaluation of medical devices — Part 17: Establishment of allowable limits for
leachable substances
ISO 10993-18, Biological evaluation of medical devices — Part 18: Chemical characterization of materials
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https: //www .iso .org/obp
— IEC Electropedia: available at http: //www .electropedia .org/
3.1
constituent
chemical or compound present in or on a finished medical device or material(s) of construction
Note 1 to entry: Constituents may be intentionally present (e.g. an additive such as an antioxidant) or
unintentionally present (e.g. an impurity).
Note 2 to entry: When applying TTC to an extractable or leachable, the identity of the extractable/leachable
represents a constituent to which individual(s) are potentially exposed due to medical device use.
3.2
extractable
constituent released when the medical device or material of construction is extracted using laboratory
extraction conditions and vehicles
Note 1 to entry: When applying TTC to an extractable, the extracted amount is assumed to potentially contact
the individual(s) to whom the medical device contacts during clinical use, see ISO 10993-17.
3.3
identified constituent
constituent assigned a full chemical structure
3.4
leachable
constituent released from a medical device and potentially contacts the individual(s) during its
clinical use
Note 1 to entry: When applying TTC to a leachable, the leached amount is assumed to potentially contact the
user(s) of the medical device during its clinical use, see ISO 10993-17.
3.5
threshold of toxicological concern
TTC
[1]
level of exposure for constituents, below which there would be no appreciable risk to human health
4 Background
4.1 General
The Threshold of Toxicological Concern (TTC) was originally developed for evaluating the toxicological
[2]
risk of impurities present at low levels when impurity toxicity data are not available . The concept was
developed to address impurities present in food contact materials, and was then adapted for impurities
[3]to[16][20][21]
in pharmaceutical products . The TTC concept can be used to evaluate constituents
present, or released, at low amounts from a medical device.
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ISO/TS 21726:2019(E)

4.2 Protectiveness of TTC values
Separate threshold values have been developed to be protective for cancer-based and non-cancer
effects. Threshold values for non-cancer effects are stratified into Cramer Class categories and
[2]
identified constituents can be assigned to a specific Cramer Class based on their chemical structure
[16]
. Although some evaluation schemes that employ the TTC concept use both non-cancer- and cancer-
based threshold values, only one set of TTC values is described in Table 1 to simplify the application of
TTC values for the safety assessment of constituents that may be released from medical devices.
The TTC values defined in this document are based on the Acceptable Daily Intake values derived in
[9][17]
ICH M7 (R1) (2017) for individual mutagenic impurities in pharmaceuticals . The threshold value
derived by ICH for mutagenic impurities in the longest exposure duration category (1,5 µg/d) is lower
than the threshold value assigned to the most protective Cramer Class non-carcinogenic TTC value
[2][9]
(90 µg/d), which is intended to be protective for chronic exposure to non-carcinogens .
[19]
Carcinogens elicit cancer via genotoxic or non-genotoxic mechanisms . The TTC values in Table 1 are
intended to be protective for exposure to carcinogens that exert their effect via either mechanism.
5 Applicability of TTC to medical device constituents
5.1 General
The applicability of the threshold values established by ICH for mutagenic
...