Technical articles

Toxicological risk assessment and 2023 revision of ISO 10993-17 standard


The new revision of ISO 10993-17: Biological evaluation of medical devices – Part 17: Toxicological risk assessment of medical device constituents was published on September 13, 2023.

Chemical characterization and toxicological evaluation of extractables/leachables:

The 2018 revision of ISO 10993-1 standard has reinforced the need for chemical characterization of medical devices (ISO 10993-18 standard). The toxicological evaluation of extractables/leachables identified following this chemical characterization has become a central element in the biocompatibility assessment of a medical device.

The toxicological evaluation of medical devices’ extractables/leachables is governed by ISO 10993-17 standard. Although the approach for performing a Toxicological Risk Assessment (TRA) remains broadly the same, this new 2023 revision of ISO 10993-17 provides practical solutions for the analysis of these constituents and adds numerous clarifications to harmonize the methodology of toxicological risk assessment in the TRA.     

In order to carry out a toxicological risk analysis of a medical device, the manufacturer must have all the information concerning its chemical composition. To this end, he can carry out analytical studies of extractables or leachables (ISO 10993-18) to identify the substances extracted or released by the medical device, to which the patient could be exposed.

Once the list of extractables has been established, it is important to gather toxicological information on each of them. This data can be obtained from the available scientific literature or generated by testing. Thethreshold below which the substance has no harmful effect on the patient under normal conditions of use of the medical device is then determined by the toxicologist. This threshold is specific to each substance and depends on its contact with the patient: duration and route of exposure (inhalation, parenteral, oral, cutaneous/dermal).

The threshold without adverse effect for the patient is compared to the dose received – patient exposure to this substance. This ratio, more commonly known as the Margin of Safety (MoS), must be greater than 1 for the risks associated with the substance to be considered acceptable. If all constituents have a Margin of Safety (MoS) greater than 1, then it is considered that the medical device should not cause any adverse toxicological effect during use.

A TRA is therefore used to assess the risks of systemic toxicity to which the patient may be exposed during clinical use of a medical device.

New features of 2023 revision of ISO 10993-17 standard:

2023 revision of the standard refines the toxicological evaluation method for extractables/leachables:

  • First, a new concept is introduced: the Toxicological Screening Limit (TSL), limiting the quantity of constituents for which a toxicological evaluation must be carried out. It is important to specify that the TSL does not replace the AET (Analytical Evaluation Threshold presented in the previous revision of the standard) but applies to extractables whose extracted quantities exceed the AET. This process requires expert judgment to determine whether the chemical constituents in question may present a toxicological risk in the context of their intended use.
  • The method for calculating Tolerable Intake (TI) has not changed, however, new factors have been incorporated, such as the consideration of bioavailability, and a clarification of uncertainty factors has been added. Additional uncertainty factors are also to be considered for specific cases, e.g., a factor of 3 for pediatric populations exposed to substances excreted predominantly via the hepatic or renal route.
  • The new version of the standard also introduces a new method for calculating exposure dose (EEDmax). This method converts the results of chemical characterization, often in µg/medical device, into an exposure dose in µg/kg/day, thus facilitating comparison with the Tolerable Intake (TI). The notion of Tolerable Exposure (TE) thus disappears from the 2023 revision, and exposure to the substance in µg/kg/day is compared directly with the Tolerable Intake, also in µg/kg/day.
  • With ISO 10993-17:2023 standard, the aim is also to assess toxicity by taking into account periods of exposure of the patient to the device. This new version of the standard also makes it possible to consider the release kinetics of substances, leading to a more relevant estimate of the patient’s daily exposure. Release kinetics are studied via simulated extraction, for devices in contact for less than 24 hours with the patient, or via a release kinetics study where information is collected at given periods. If release kinetics are not known, the standard proposes a calculation method for estimating exposure over the four periods corresponding to acute toxicity, sub-acute toxicity, sub-chronic toxicity, and chronic toxicity. With the new revision of the standard, it may therefore be necessary to calculate a Margin of Safety (MoS) for each exposure period, whether or not the substance’s release kinetics are known. The lowest Margin of Safety (MoS) will then be used, in order to consider worst-case conditions for the patient.
  • The weights and categories of patients to be considered have also evolved, from 58 kg to 60 kg for adult women. Weights for children and newborns have been specified, with new considerations for very low-weight newborns (1.5 kg) and premature babies (0.5 kg).
  • A final important point is the introduction of the concept of Margin of Safety (MoS) into the standard. This notion was already used by most toxicologists in toxicological assessments, without being mentioned in the standard. From now on, this notion is formalized in the 2023 version.

The 2023 revision of ISO 10993-17 introduces new calculation methods and numerous clarifications, harmonizing toxicological assessments and providing more relevant conclusions adapted to the clinical use of the device.

The steps involved in toxicological evaluation according to ISO 10993-17:2002 and ISO 10993-17:2023 are summarized and compared in the table below.

Toxicological analysis steps per ISO 10993-17 :2002 and ISO 10993-17 :2023

ISO 10993-17 : 2002
and common practices
ISO 10993-17 : 2023
Toxicological data gatheringToxicological data gathering
TSL calculation
TSL (µg)= TTC x D
A TTC value of 120 µg/day (contact duration ≤ 30 day) or 20 µg/day (contact duration > 30 days) is to be considered by default.
D is the duration of exposition to the medical device, in days, by default equal to 1 (contact duration ≤ 30 day) or 30 (contact duration > 30 days).
Tolerable Intake (TI) calculation

TI (µg/kg/jr)= PoD/MF

PoD (Point of Departure, in µg/kg/day) is selected from the data available in the literature, as the toxicological reference value for Safety Margin calculations. MF (Modifying Factor) corresponds to uncertainty factors.
Tolerable Intake (TI) calculation

TI (µg/kg/day) = PoD/MF

PoD (Point of Departure, in µg/kg/day) is selected from the data available in the literature, as the toxicological reference value for Safety Margin calculations. MF (Modifying Factor) corresponds to uncertainty factors.
Tolerable Exposure (TE) calculation

TE (µg/day)= TI x mB x UTF 

mB is the patient body weight (kg).
UTF is the utilisation factor.
Exposure estimation


Quantity of substance released estimated on the basis of chemical characterization results (µg/day).

Exposure dose (EEDmax) calculation

EEDmax (µg/kg/day)= (HQ x SF)/(BW_l )
EEDmax(µg/kg/day)= ((TQ x SF))⁄((BW_l)⁄Rd)

HQ (µg/day) or TQ (µg) is the quantity of substance released by the device.
SF is the scaling factor.
BWl is the worst-case patient weight (in kg).
Rd is the worst-case duration of substance release (in days), depending on the classification of the medical device.
Several EEDmax may be calculated, depending on the duration of the medical device’s contact with the patient.
Admissible limits establishment and Margin Of Safety calculation

MOS = TE / Exposure

Margin Of Safety calculation if applicable

MOS = TI / EEDmax

One MOS per EEDmax is calculated, depending on the duration of contact between the medical device and the patient.
Application of acceptance criteria

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