ISO/TS 21726:2019

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 2019
© ISO 2019
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ii © ISO 2019 – All rights reserved

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
Foreword
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This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of
medical devices.
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iv © ISO 2019 – All rights reserved

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
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.
2 © ISO 2019 – All rights reserved

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
...