oSIST prEN ISO 10993-16:2026

SLOVENSKI STANDARD
01-februar-2026
Biološko ovrednotenje medicinskih pripomočkov - 16. del: Toksikokinetično
ovrednotenje razgradnih produktov in izlužnin (ISO/DIS 10993-16:2025)
Biological evaluation of medical devices - Part 16: Toxicokinetic evaluation for
degradation products and leachables (ISO/DIS 10993-16:2025)
Biologische Beurteilung von Medizinprodukten - Teil 16: Toxikokinetische Beurteilung
hinsichtlich Abbauprodukten und herauslösbaren Substanzen (ISO/DIS 10993-16:2025)
Évaluation biologique des dispositifs médicaux - Partie 16: Évaluation toxicocinétique
des produits de dégradation et des substances relargables (ISO/DIS 10993-16:2025)
Ta slovenski standard je istoveten z: prEN ISO 10993-16
ICS:
11.100.20 Biološko ovrednotenje Biological evaluation of
medicinskih pripomočkov medical devices
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

DRAFT
International
Standard
ISO/DIS 10993-16
ISO/TC 194
Biological evaluation of medical
Secretariat: DIN
devices —
Voting begins on:
Part 16: 2025-12-08
Toxicokinetic evaluation for
Voting terminates on:
2026-03-02
degradation products and
leachables
ICS: 11.100.20
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Reference number
ISO/DIS 10993-16:2025(en)
DRAFT
ISO/DIS 10993-16:2025(en)
International
Standard
ISO/DIS 10993-16
ISO/TC 194
Biological evaluation of medical
Secretariat: DIN
devices —
Voting begins on:
Part 16:
Toxicokinetic evaluation for
Voting terminates on:
degradation products and
leachables
ICS: 11.100.20
THIS DOCUMENT IS A DRAFT CIRCULATED
FOR COMMENTS AND APPROVAL. IT
IS THEREFORE SUBJECT TO CHANGE
AND MAY NOT BE REFERRED TO AS AN
INTERNATIONAL STANDARD UNTIL
PUBLISHED AS SUCH.
This document is circulated as received from the committee secretariat.
IN ADDITION TO THEIR EVALUATION AS
BEING ACCEPTABLE FOR INDUSTRIAL,
© ISO 2025
TECHNOLOGICAL, COMMERCIAL AND
USER PURPOSES, DRAFT INTERNATIONAL
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Published in Switzerland Reference number
ISO/DIS 10993-16:2025(en)
ii
ISO/DIS 10993-16:2025(en)
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 Guidance on toxicokinetic evaluation . 3
5 Circumstances in which toxicokinetic evaluation shall be considered . 5
6 Mathematical modelling for the evaluation of toxicokinetics . 5
6.1 General considerations.5
6.2 Rationale for the use of mathematical modelling .6
6.3 Data requirements .6
7 Principles for design of toxicokinetic animal studies . 6
8 Output of toxicokinetic evaluation . 7
Annex A (informative) Mathematical modelling . 8
Annex B (informative) Information on animal toxicokinetic testing .10
Annex ZA (informative) Relationship between this European Standard the General Safety and
Performance Requirements of Regulation (EU) 2017/745 aimed to be covered . 14
Bibliography . 17

iii
ISO/DIS 10993-16:2025(en)
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 on 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 the following URL:
www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of medical
devices, in collaboration with the European Committee for Standardization (CEN) Technical Committee CEN/
TC 206, Biological and clinical evaluation of medical devices, in accordance with the Agreement on technical
cooperation between ISO and CEN (Vienna Agreement).
This fourth edition cancels and replaces the third edition (ISO 10993-16:2017), which has been technically
revised with the following changes:
a) the title is changed to accommodate methods alternative to animal studies;
b) the introduction is modified;
c) the scope is modified;
d) a new clause 4 was added to include guidance on toxicokinetic evaluation;
e) normative Annex A has been moved to clause 5 and the title is changed to accommodate methods
alternative to animal studies;
f) a new clause 6 was added to include mathematical modelling for the evaluation of toxicokinetics;
g) a new clause 8 was added to address possible outcome of toxicokinetic evaluation;
h) a new informative Annex A was added to include additional information on mathematical modelling;
i) Clause 5 guidance on test methods, has been moved to new informative Annex B.
j) the bibliography has been updated.
A list of all the parts in the ISO 10993 series can be found on the ISO website.

iv
ISO/DIS 10993-16:2025(en)
Introduction
Medical devices can release leachables (e.g., residual catalysts, processing aids, residual monomers,
fillers, antioxidants, plasticizers, etc.) or degradation products which migrate from the material and have
the potential to cause adverse effects in the body. Toxicokinetic evaluation describes the fate of a foreign
chemical in the body with time by assessing absorption, distribution, metabolism, and excretion of the
chemical and can be of value in assessing the safety of medical devices. Toxicokinetic evaluation can also be
applicable to medical devices containing active ingredients, in which case, pharmaceutical legislation is to
be considered.
Traditionally, animal studies have been used for toxicokinetic evaluation. The need for and extent of
toxicokinetic animal study should be carefully considered; it is preferably to replace animal studies
with mathematical modelling or evaluation of existing toxicological and toxicokinetic data. The need for
consulting toxicokinetic experts for these considerations is emphasized.
A considerable body of published literature exists on the use of toxicokinetic methods to study the fate of
chemicals in the body (see Bibliography).

v
DRAFT International Standard ISO/DIS 10993-16:2025(en)
Biological evaluation of medical devices —
Part 16:
Toxicokinetic evaluation for degradation products and
leachables
1 Scope
This document describes the considerations for inclusion of toxicokinetic evaluation in the biological
evaluation of medical devices and provides principles on designing and performing toxicokinetic evaluation
relevant to medical devices.
2 Normative references
The following documents are referred to in the text in such a way that some of or all 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, Biological evaluation of medical devices — Part 1: Requirements and general principles for the
evaluation of biological safety within a risk management process
ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements
ISO 10993-17, Biological evaluation of medical devices — Part 17: Toxicological risk assessment of medical
device constituents
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 10993-1 and the following apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— IEC Electropedia: available at https:// www .electropedia .org/
— ISO Online browsing platform: available at http:// www .iso .org/ obp
3.1
absorbable device
medical device designed to biodegrade and to be absorbed by the body over time; typically serving a
temporary function
3.2
absorption
action of a material or substance, or its decomposition products passing through or being assimilated either
by cells or tissue or both over time
3.3
bioavailability
extent of systemic absorption (3.1) of specified substance

ISO/DIS 10993-16:2025(en)
3.4
biodegradation
degradation due to the biological environment
Note 1 to entry: Biodegradation might be modelled by in vitro tests.
3.5
constituent
chemical that is present in or on the finished medical device or its material of construction
3.6
clearance
rate of removal of a specified substance from the body or parts of the body by metabolism (3.15) or
excretion (3.10)
3.7
c
max
maximum concentration of a specified substance in plasma
Note 1 to entry: When the maximum concentration in fluid or tissue is being referred too, it should have an appropriate
identifier, e.g., c , liver, and be expressed in mass per unit volume or mass.
max
3.8
degradation product
product which is derived from breakdown of a material by physical, chemical or biological means
3.9
distribution
process by which an absorbed substance or its metabolites circulate and partition within the body
3.10
excretion
process by which an absorbed substance or its metabolites are removed from the body
3.11
extract
liquid that results from extraction of the test substance (3.16) or control
3.12
half-life
t
1/2
time for the concentration of a specified substance to decrease to 50 % of its initial value in the same body
fluid or tissue
3.13
leachable
constituent (3.5) released from a medical device under clinical use conditions
Note 1 to entry: A leachable (e.g., additives, monomeric or oligomeric constituent of polymeric material) can be
extracted under laboratory conditions that simulate normal conditions of exposure.
3.14
mean residence time
statistical moment related to half-life (3.12) which provides a quantitative estimate of the persistence of a
specified substance in the body

ISO/DIS 10993-16:2025(en)
3.15
metabolism
process by which an absorbed substance is structurally changed within the body by enzymatic and/or non-
enzymatic reactions
Note 1 to entry: The products of the initial reaction can subsequently be modified by either enzymatic or non-
enzymatic reactions prior to excretion (3.10).
3.16
test substance
degradation product (3.8) or leachable (3.13) used for toxicokinetic study
3.17
t
max
time at which c (3.6) is observed
max
3.18
volume of distribution
V
d
parameter for a single-compartment model describing the apparent volume which would contain the amount
of test substance (3.15) in the body if it were uniformly distributed
4 Guidance on toxicokinetic evaluation
4.1 Potential hazards exist in the use of most medical devices. Chemical characterization identifies
chemical hazards and shall precede toxicokinetic considerations. However, it is neither necessary nor
practical to conduct toxicokinetic evaluation for all identifiable intended and unintended leachables and
degradation products, nor for all medical devices.
NOTE More information on potential risks can be found in ISO 10993-17 and ISO 14971.
4.2 The need for toxicokinetic evaluation as part of the biological evaluation of a medical device shall be
considered taking into account the finished device and its constituent chemicals, intended and unintended
leachables and degradation products in combination with the intended use of the device, e.g. nature and
duration of contact (Figure 1).
Possible toxicokinetic interaction between active ingredients and leachables or degradation products should
also be considered.
4.3 Mathematic modelling shall be considered when sufficient relevant background data exist.
4.4 In vitro methods, which are appropriately validated using positive or negative controls or both,
reasonable and practically available, reliable and reproducible, shall be considered for use in preference to in
vivo tests. This shall be done in accordance with ISO 10993-1. Where appropriate, in vitro experiments (e.g.,

ISO/DIS 10993-16:2025(en)
tissue, homogenates or cells) may be conducted to investigate probable rather than possible degradation
products.
ISO/DIS 10993-16:2025(en)
Figure 1 — Process of assessing the need for toxicokinetic evaluation
5 Circumstances in which toxicokinetic evaluation shall be considered
5.1 Toxicokinetic evaluation shall be considered if the following conditions are met:
a) the device is designed to be absorbable;
b) the device is a permanent contact implant, and significant corrosion or biodegradation is known or
likely, and/or migration of leachables from the device occurs;
c) substantial quantities of potentially toxic or reactive degradation products or constituents released into
the body during clinical use;
d) substantial quantities of pharmacologically active constituents are likely or known to be released from
a medical device;
e) substantial quantities of nano-objects are likely or known to be released from a medical device into the
body during clinical use.
NOTE 1 The meaning of the term “substantial quantities” is dependent on the properties of the chemicals or nano-
objects in question and is based on expert judgements.
NOTE 2 See ISO/TR 10993-22 for information on nano-objects.
5.2 Toxicokinetic evaluation or in vivo studies are not required if:
a) sufficient toxicological data or toxicokinetic data relevant to the degradation products and leachables
already exist;
b) sufficient toxicological data or toxicokinetic data relevant to the active pharmacologically ingredients
already exist;
c) achieved or expected rates of release of degradation products and leachables from a particular device
have been judged to demonstrate safe levels of clinical exposure. This shall be done in accordance with
ISO 10993-17;
d) clinical exposure of degradation products and leachables is documented as safe with reference to
historical experience.
5.3 Where materials are complex and contain products which are either endogenous or they are so similar
to endogenous products that they cannot be analytically distinguished, a toxicokinetic evaluation is usually
not feasible.
NOTE 1 Other studies, such as implantation studies that include histological evaluation of the implant and implant
site, can yield useful information on the toxicokinetic behaviour of the device.
6 Mathematical modelling for the evaluation of toxicokinetics
6.1 General considerations
Mathematical functions can be used as an alternative to animal studies to describe the time- and dose-
dependent processes of absorption, distribution, metabolism, and elimination of a chemical substance and
metabolites thereof in animals and humans. For this purpose, classical compartment open models and
physiologically based toxicokinetic models are used. Both are applied to fit concentration-time data and

ISO/DIS 10993-16:2025(en)
to predict concentration-time courses of a xenobiotic and its metabolite(s) in organs, tissue, blood, plasma,
and/or other secrete such as urine after repeated or continuous exposures.
NOTE Validated commercial products for toxicokinetic modelling exist.
6.2 Rationale for the use of mathematical modelling
Toxicokinetic data are normally derived from animal studies. A major concern is that animal derived
toxicokinetic data are not always reliable for extrapolation to humans due to differences in physiology,
biochemical and metabolic pathways. For this reason and for a general attitude and regional legislation
in reducing animal testing there is an increasing pressure to develop and use alternative (non-animal)
toxicokinetic methods to reliably determine the necessary toxicokinetic parameters. See Annex A for
different mathematical models.
6.3 Data requirements
Such modelling requires the collection of physical and chemical properties, and physiological parameters
relating to tissue uptake and clearance. Physical and chemical information may include molecular weight,
octanol-water partition coefficient and pKa. If insufficient literature data exists, in vitro studies such as
metabolism or tissue uptake may be addressed via organ homogenates or tissue slices. The data shall be
created using appropriate quality assurance controls, e.g. positive or negative controls.
7 Principles for design of toxicokinetic animal studies
7.1 If a toxicokinetic evaluation is needed (see 5.1 and 5.2) and cannot be completed by mathematic
modelling (see clause 6) animal tests shall be considered. Toxicokinetic studies shall be designed on a case-
by-case basis.
NOTE Annex B provides information on animal toxicokinetic testing.
7.2 A study protocol shall be written prior to commencement of the study. The study design, including
methods, shall be defined in this protocol. The study design shall state the physiological fluid, tissue
or excreta in which analyte levels will be determined. Animal tests shall be done in accordance with
ISO 10993-2.
7.3 The results of extraction studies, chemical characterization, and toxicological risk assessment should
be considered to determine the methods to be used for toxicokinetic studies. Information on the chemical
and physicochemical properties, surface morphology of the material and biochemical properties of any
leachable should also be considered.
NOTE More information on extraction studies can be found in ISO 10993-12, on chemical characterization in
ISO 10993-18, and on toxicological risk assessment of device constituents in ISO 10993-17.
NOTE The extent and rate of release of leachables depend on the concentration at the surface, migration to the
surface within the material, solubility and flow rate in the physiological milieu.
7.4 It is recommended to undertake toxicokinetic studies with a characterized leachable or degradation
product that has the potential of being toxic. However, the performance of toxicokinetic studies on mixtures
is possible under certain conditions. An extract liquid, or a ground or powdered form of the material or
device may be used in exceptional circumstances and shall be justified in the study design. In either case,
the dose (both chemical/chemicals and amount) administered shall be documented.
NOTE More information on extraction studies can be found in ISO 10993-12.
7.5 Analytical methods shall be able to detect and characterize degradation products, leachables and
metabolites in biological fluids and tissues. Quantitative analytical methods shall be specific, sensitive and
reproducible. Limit of detection/quantification shall be defined and justified. Validation/qualification of the
method shall be performed.
ISO/DIS 10993-16:2025(en)
NOTE Use of radiolabelled compounds can be useful in detecting unknown metabolites.
7.6 Analyte recovery from the matrix shall be documented.
NOTE Blood is convenient to sample and thus is often the fluid of choice for kinetic parameter and absorption
studies. It is necessary to specify whether analysis is on whole blood, serum or plasma and to provide validation of
this choice. Binding to circulating proteins or red cells can be determined in vitro.
7.7 There shall be sufficient data points with adequate time intervals to allow determination of kinetic
parameters. In theory, this should cover several terminal half-lives; in practice, the constraints of the
analytical method may necessitate a compromise.
8 Output of toxicokinetic evaluation
Toxicokinetic evaluation of characterized leachables and degradation products can serve as an input
to various parts of the biological evaluation for a medical device. Use of toxicokinetic data in a biological
evaluation may include, but is not limited to:
a) estimating a clinically relevant systemic exposure dose from mathematical modelling for the
toxicological risk assessment of hazardous constituents known to be released from a device;
b) identification of potential target organs of toxicity that may require further investigation in a systemic
toxicity study;
c) determining the systemic absorption and tissue concentration of a pharmacologically active ingredient
at its target site and off target sites;
d) providing data on the presence or absence of device constituents in specific tissues and organs to inform
on bioaccumulation and potential health risks from long term exposure;
e) detection of metabolites;
f) understanding exposure route differences in bioavailability for route-to-route extrapolation.
Where toxicokinetic data has been generated via mathematical modelling or by an animal study, its use as
part of the overall biological evaluation for a device shall be justified and documented.

ISO/DIS 10993-16:2025(en)
Annex A
(informative)
Mathematical modelling
A.1 General
This annex provides an overview of mathematical models that may be used to determine toxicokinetic
parameters relevant to degradation products and leachables from medical devices. It is advisable to consult
toxicologist(s) or pharmacokineticist(s) with experience in toxicokinetics in the selection of method(s).
The models are usually categorized as classical compartment open models and physiologically based
toxicokinetic (PBTK) models.
A.2 Classical compartment open models
A.2.1 General
Classical compartment open models are used to estimate concentration-time course of a chemical and its
metabolite(s), usually in blood or plasma, or urine or tissue or organs for repeated or continuous exposures.
Several models are in use varying in complexity and information obtained.
A.2.2 Zero-order kinetics
The zero-order kinetic describes a situation where the elimination rate is constant without being dependant
on the concentration of the chemical. This occurs often with chemicals that saturate metabolic enzymes or
membrane transport systems increasing the risk of toxic reactions.
NOTE 1 Ethanol exhibits zero-order kinetics.
NOTE 2 The formula for calculating the rate (k) at time t where [A] is the initial concentration and [A] is the
0 t
concentration at time t is:
[]AA−[]
0 t
k = [A.1]
t
A.2.3 First order kinetics
First order kinetics describes a situation where the rate of elimination is proportional to the concentration
of the chemical. This implies that the elimination is more efficient when the concentration is high.
NOTE 1 Caffeine exhibits first-order kinetics
NOTE 2 The formula for calculating the rate (k) at time t where [A] is the initial concentration and [A] is the
0 t
concentration at time t is:
ln[]AA−ln[]
0 t
k = [A.2]
t
A.2.4 Two compartments model
The two-compartment model describes a situation involving a central and a peripheral compartment. The
chemical is introduced in the central compartment (i.e. blood stream, kidney, liver) and distributed to the
peripheral compartment. The chemical is assumed to be eliminated from the central compartment only and
redistributed from the peripheral compartment as the concentration in the central compartment decreases.

ISO/DIS 10993-16:2025(en)
For simplification, it is assumed that elimination from the central compartment and movement between the
compartments follow first order kinetics.
A.2.5 Michaelis-Menten kinetics
The Michaelis-Menten kinetics describe elimination that is dependent on rate limiting endogenous
substances and how the elimination rate of a chemical is dependent on concentration of the endogenous
substance(s). There are two distinct different situations, saturation of the endogenous substance i.e., carrier
molecules or cell receptors and a surplus of these. In the first case, the elimination rate is constant and
related to the rates of binding and release between the chemical and the endogenous substance.
A.3 Physiologically based toxicokinetic (PBTK) models
Physiologically based toxicokinetic (PBTK) models are mathematical descriptions of how a chemical
enters the body, absorbs into the blood, moves between body tissues and the blood, and how the body
metabolizes and eliminates the chemical. PBTK are useful tools for gaining rich insight into the kinetics
of toxicants beyond what classic toxicokinetic models can provide. Such models make possible to describe
the time course of distribution of toxicants to any organ or tissue, and to estimate the effects of changing
physiologic parameters on tissue concentrations. Physiologically based toxicokinetic (PBTK) modelling is
based on a priori knowledge of the physicochemical properties of a chemical coupled with biochemistry
and realistic anatomy and physiology of relevant organ or tissue. PBTK models integrate a chemical and
organ and tissue physiology into a mathematical modelling framework. An advantage of the PBTK is that the
model can be adapted to different exposure situations, physiological conditions, and species by using model
parameter values relevant to the system(s) in question. The availability and quality of the a priori data can
be a limitation for the outcome of PBTK modelling.
PBTK models can be simplistic, with a small number of parameters that are important for describing the
movement of a chemical in the body, or complex with many parameters that dictate chemical fate and
movement. The choice between simplistic or complex PBTK model depends on what health question is being
answered and the amount and type of information that is available to develop the model. Simplistic PBTK
models are often used to get a quick snapshot of a chemical’s fate and movement in the body, typically if the
target organ is known. In other instances, more complex PBTK models are used if the health question being
answered requires precise details on how the chemical distributes to multiple tissues and organs.

ISO/DIS 10993-16:2025(en)
Annex B
(informative)
Information on animal t
...