ISO/TS 21726:2019

Overview

ISO/TS 21726:2019 provides guidance on applying the Threshold of Toxicological Concern (TTC) to the biological evaluation and biocompatibility assessment of medical device constituents. The technical specification explains the basis, selection and general applicability of TTC values for constituents present in, on, or released from a medical device. TTC in this document is intended to be protective for carcinogens, systemic toxicants, and reproductive toxicants, and is used when specific toxicity data are not available to derive a tolerable intake (TI).

Key topics and technical requirements

• TTC values and selection: Recommended TTC intake limits (µg/day) are provided according to device contact duration. Typical values include 120 µg/d, 20 µg/d, 10 µg/d, and 1.5 µg/d for increasing exposure durations and long-term contact categories.
• Device contact categories: Selection of the appropriate TTC is based on medical device contact duration (limited, prolonged, long‑term) and must be justified by use conditions.
• Applicability and exclusions:
  • TTC applies to individual constituents (identified or unidentified) in extracts or leachables for comparison against concentration or estimated exposure.
  • Not applicable where adequate toxicity data exist (see ISO 10993-17).
  • Not appropriate for cohorts of concern (highly potent toxicants) such as aflatoxin‑like compounds, N‑nitroso compounds, polyhalogenated dioxins/furans, heavy metals, steroids, organophosphorus compounds, strained heterocycles, etc.
  • Excluded substance types: high molecular weight polymers, particles (including nanoparticles), proteins, ceramics, radioactive constituents.
• Mixtures and interactions: TTC values can be applied to individual constituents within complex mixtures; the specification states additional aggregate adjustments generally are not required at very low exposure levels.
• Supporting evidence: Use of negative mutagenicity data or orthogonal in silico models may justify assignment to a Cramer class and selection of the corresponding TTC.

Applications and users

ISO/TS 21726 is practical for:

• Medical device manufacturers conducting biocompatibility and extractables & leachables (E&L) risk assessments.
• Toxicologists and regulatory affairs specialists preparing safety justifications or equivalence arguments.
• Contract testing laboratories interpreting analytical extract data against toxicological thresholds.
• Use cases include:
  • Comparing analytical extract concentrations to TTC (per ISO 10993-18 conversion guidance).
  • Supporting toxicological equivalence between materials.
  • Comparing TTC to estimated exposure doses (per ISO 10993-17) when specific TI values are not available.

Related standards

• ISO 10993-1: Biological evaluation framework
• ISO 10993-17: Establishment of allowable limits for leachable substances
• ISO 10993-18: Chemical characterization and converting TTC (µg/d) to concentration (µg/mL)
• ISO 18562 series: TTC considerations for gas pathway exposures
• ICH M7(R1): Basis for mutagenic impurity TTC values

Keywords: ISO/TS 21726, Threshold of Toxicological Concern, TTC, biocompatibility, medical devices, extractables and leachables, ISO 10993, cohort of concern, toxicological risk assessment.