INTERNATIONAL ISO

STANDARD 10993-16

Third edition
2017-05

Biological evaluation of medical

devices —
Part 16:
Toxicokinetic study design for
degradation products and leachables
Évaluation biologique des dispositifs médicaux —
Partie 16: Conception des études toxicocinétiques des produits de
dégradation et des substances relargables

Reference number
ISO 10993-16:2017(E)

© ISO 2017
ISO 10993-16:2017(E)


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Contents Page

Foreword......................................................................................................................................................................................................................................... iv
Introduction...................................................................................................................................................................................................................................v
1 Scope.................................................................................................................................................................................................................................. 1
2 Normative references....................................................................................................................................................................................... 1
3 Terms and definitions...................................................................................................................................................................................... 1
4 Principles for design of toxicokinetic studies......................................................................................................................... 3
5 Guidance on test methods............................................................................................................................................................................ 3
5.1 General considerations..................................................................................................................................................................... 3
5.2 Guidance on specific types of test............................................................................................................................................ 5
5.2.1 General...................................................................................................................................................................................... 5
5.2.2 Absorption.............................................................................................................................................................................. 5
5.2.3 Distribution........................................................................................................................................................................... 5
5.2.4 Metabolism and excretion........................................................................................................................................ 6
Annex A (normative) Circumstances in which toxicokinetic studies shall be considered............................ 7
Bibliography................................................................................................................................................................................................................................. 9

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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.
This third edition cancels and replaces the second edition (ISO 10993-16:2010), which has been
technically revised with the following changes:
a) definition in 3.1 has been modified for clarification;
b) Clause 4 has been modified for clarification;
c) Clause 5 has been modified for clarification;
d) information regarding toxicokinetic studies on nano-objects have been added;
e) A.4 has been modified for clarification.
A list of all the parts in the ISO 10993 series can be found on the ISO website.

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Introduction
Toxicokinetics describe the absorption, distribution, metabolism and excretion, with time, of foreign
compounds in the body. Essential to the evaluation of the safety of a medical device is consideration of
the stability of the material(s) in vivo and the disposition of intended and unintended leachables and
degradation products. Toxicokinetic studies can be of value in assessing the safety of materials used
in the development of a medical device or in elucidating the mechanism of observed adverse reactions.
Toxicokinetic studies can also be applicable to medical devices containing active ingredients, in which
case, pharmaceutical legislation are to be considered. The need for and extent of toxicokinetic studies
should be carefully considered based on the nature and duration of contact of the device with the body
(see A.2). Existing toxicological literature and toxicokinetic data can be sufficient for this consideration.
The potential hazard posed by a medical device can be attributed to the interactions of its components
or their metabolites with the biological system. Medical devices can release leachables (e.g. residual
catalysts, processing aids, residual monomers, fillers, antioxidants, plasticizers, etc.) and/or degradation
products which migrate from the material and have the potential to cause adverse effects in the body.
A considerable body of published literature exists on the use of toxicokinetic methods to study the
fate of chemicals in the body (see Bibliography). The methodologies and techniques utilized in such
studies form the basis of the guidance in this document. Annex A provides a rationale for the use of this
document.

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INTERNATIONAL STANDARD ISO 10993-16:2017(E)

Biological evaluation of medical devices —

Part 16:
Toxicokinetic study design for degradation products and
leachables

1 Scope
This document provides principles on designing and performing toxicokinetic studies relevant to
medical devices. Annex A describes the considerations for inclusion of toxicokinetic studies in the
biological evaluation of medical devices.

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, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management process

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 http://​w ww​.electropedia​.org/​
— ISO Online browsing platform: available at http://​w ww​.iso​.org/​obp
3.1
absorption
process of uptake of substance into or across tissue, blood and/or lymph system
3.2
bioavailability
extent of systemic absorption (3.1) of specified substance
3.3
biodegradation
degradation due to the biological environment
Note 1 to entry: Biodegradation might be modelled by in vitro tests.

3.4
bioresorption
process by which a biomaterial is degraded in the physiological environment and the product(s)
eliminated and/or absorbed

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3.5
clearance
rate of removal of a specified substance from the body or parts of the body by metabolism (3.14) and/or
excretion (3.9)
3.6
cmax
maximum concentration of a specified substance in plasma
Note 1 to entry: When the maximum concentration in fluid or tissue is being referred to, it should have an
appropriate identifier, e.g. cmax, liver, and be expressed in mass per unit volume or mass.

3.7
degradation product
product of a material which is derived from the chemical breakdown of the original material
3.8
distribution
process by which an absorbed substance and/or its metabolites circulate and partition within the body
3.9
excretion
process by which an absorbed substance and/or its metabolites are removed from the body
3.10
extract
liquid that results from extraction of the test substance (3.15) or control
3.11
half-life
t1/2
time for the concentration of a specified substance to decrease to 50 % of its initial value in the same
body fluid or tissue
3.12
leachable
chemical that can migrate from a device or component under storage conditions or conditions of use
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.

3.13
mean residence time
statistical moment related to half-life (3.11) which provides a quantitative estimate of the persistence of
a specified substance in the body
3.14
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 (3.9).

3.15
test substance
degradation product (3.7) or leachable (3.12) used for toxicokinetic study
3.16
tmax
time at which cmax (3.6) is observed

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3.17
volume of distribution
Vd
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 Principles for design of toxicokinetic studies

4.1 Toxicokinetic studies should be designed on a case-by-case basis, see Annex A.

4.2 A study protocol shall be written prior to commencement of the study. The study design, including
methods, shall be defined in this protocol. Details of areas to be defined are given in 4.3 to 4.7 and in
Clause 5.

4.3 The results of extraction studies (see ISO 10993-12 and ISO 10993-18) should be considered in
order 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 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.

4.4 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 (see ISO 10993-12), 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.

4.5 Analytical methods shall be able to detect and characterize degradation products, leachables and
metabolites in biological fluids and tissues.

For analytical methods, other parts of ISO 10993 shall be used as relevant. The methods shall be fully
described in the study report (see 5.1.10). Quantitative analytical methods shall be specific, sensitive
and reproducible (see ISO 10993-18). Limit of detection/quantification shall be defined and justified.
Validation/qualification of the method shall be performed.

4.6 The study design shall state the physiological fluid, tissue or excreta in which analyte levels will be
determined. 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.

4.7 There should 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.

5 Guidance on test methods

5.1 General considerations

5.1.1 The study should be performed on an appropriate sex and species; consider utilizing the same
species used for the systemic toxicity studies. The animal welfare conditions should be as recommended
in guidelines for the care and use of animals (see ISO 10993-2).

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5.1.2 A non-radiolabelled test substance may be utilized provided that suitable validated assay
procedures for the test substance in the relevant samples exist and the metabolism of the test substance
is well characterized.

5.1.3 If necessary, the test substance should be radiolabelled in a metabolically stable position,
preferably with 14C or 3H, and of suitable radiochemical purity (>97 %). When using 3H, the possibility
of tritium exchange should be considered. The specific activity and radiochemical purity of the test
substance shall be known and reported.

5.1.4 The test substance should be administered by an appropriate route. This route should be relevant
to the use of the medical device. The test substance should be prepared in a suitable vehicle taking into
account the physicochemical properties of the test substance (leachable or degradation product) using
appropriate route and dose of administration. The stability of the test substance in the vehicle shall be
known and reported.
NOTE The study design might require the inclusion of other route(s) for comparison of percent absorption.

5.1.5 In dose balance studies, animals should be housed only in metabolism cages.

5.1.6 Urine and faeces should be collected in low temperature vessels (or in vessels containing
preservative that does not interfere with the analysis) to prevent post-elimination microbial or
spontaneous modification. Blood for whole-blood or plasma analysis should be collected in the presence
of a suitable anticoagulant.

5.1.7 Controls should, wherever possible, be collected prior to dosing. In some studies, collection
of controls (e.g. tissues) is not possible from the test animals and these should be obtained from a
control group.

5.1.8 Collection times should be appropriate to the type of study being performed, and may be carried
out, as necessary, over periods of minutes, hours, days, weeks or even months. For studies involving
excreta, this is usually a 24 h period over at least 96 h. Where blood sampling is required, blood is
collected according to a specified schedule ranging from minutes to hours over a period up to 72 h.

5.1.9 Toxicokinetic studies should be performed in accordance with good laboratory practice.

5.1.10 The study report shall include the following information, where relevant:

a) strain and source of animals, age, sex (if females indicate reproductive state), environmental
conditions, diet;
b) test substance and sample, purity, stability, formulation, amount administered;
c) test conditions, including route of administration;
d) assay methods, extraction, detection, validation/qualification;
e) overall recovery of material;
f) tabulation of individual results at each time point;
g) quality standard or good laboratory practice compliance statement;
h) presentation and discussion of results;
i) interpretation of results.

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5.2 Guidance on specific types of test

5.2.1 General

5.2.1.1 The study should be designed to provide the necessary information for risk assessment, and
therefore it is usually not necessary to examine all aspects.

5.2.1.2 Absorption, distribution, metabolism and excretion studies are a range of studies capable of
being performed either individually, examining one of these aspects, or collectively, examining several
aspects in one study.

5.2.1.3 Depending on the design of the study, a number of kinetic parameters may be determined
including absorption rate, area under the plasma concentration versus time curve, area under the first
moment plasma concentration versus time curve, volume of distribution, cmax, tmax, half-life, mean
residence time, elimination rate and clearance.

5.2.1.4 Kinetic parameters can only be determined for a particular molecular species and hence the
assay needs to be specific and sensitive to this molecular species. True kinetic parameters of a relevant
compound can only be determined following intravenous administration. It may therefore be necessary
to include a limited intravenous administration study in the design of the kinetic parameter studies. This
allows the fraction of the dose absorbed to be calculated and this serves as a correction in estimating
parameters in other studies.

In some instances, intra-arterial administration should be considered as some compounds are known
to be cleared through the pulmonary system.

5.2.1.5 The appropriate kinetic model should be used in determining the kinetic parameters. A number
of computer programs exist for estimating kinetic parameters. The software should be validated prior
to use and this validation should be documented. The assumptions entered into the program and the
choices in modelling should be documented.

5.2.2 Absorption

Absorption depends on the route of administration, the physicochemical form of the test substance and
the vehicle. It can be estimated from blood, serum, excreta and tissue concentrations. Bioavailability
studies may be considered. The choice of the appropriate type of study depends on the other information
required, availability of radiolabelled material and assay method. The absorption rate constant can be
estimated reliably only if sufficient samples are taken in the absorption phase.
NOTE In vitro methods exist which can give important information on gastrointestinal and dermal
absorption of chemicals.

5.2.3 Distribution

5.2.3.1 Distribution studies generally require radiolabelled compounds.

Studies may be
— quantitative, determining levels in dissected tissues,
— qualitative, using whole-body autoradiography (WBA), or
— semiquantitative, using graded WBA reference doses.

5.2.3.2 In general, sampling times in distribution studies may be based on kinetic data and will depend
on test sample elimination. Multiple sampling times may be used. Sampling is normally more frequent in

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the early phase of absorption and elimination; however, samples need to be obtained over as much of the
elimination phase as possible. The major determinant is often assay sensitivity.

5.2.4 Metabolism and excretion

5.2.4.1 Metabolism cages should permit a separate collection of urine and faeces throughout the
study. The use of metabolic cages designed for the collection of CO2 and volatile metabolites should
be considered if relevant for the excretion. For studies of up to 14 d, the urine and faeces should be
individually collected over 24 h intervals until the end of the experiment. In some study designs, animals
may be sacrificed at intermediate times. Samples may be collected prior to 24 h when it is probable that
the test substance or its metabolites will be rapidly excreted. For studies of longer duration, sampling
over the initial period should occur as for the short-term studies. Thereafter, samples should be obtained
for a continuous 24 h period per assessment period.
NOTE The use of metabolism cages for prolonged periods might be detrimental to animal welfare. Therefore,
at the longer times, representative discontinuous samples can be collected and these results extrapolated to
continuous sampling.

5.2.4.2 The carcasses and/or target organs of the individual animals should be retained for analysis,
and blood collected for analysis of plasma and whole-blood concentrations. After collection of the
samples from the metabolism cages at the sacrifice time, the cages and their traps should be washed with
an appropriate solvent. The resulting washes can be pooled and a representative fraction retained for
analysis.

5.2.4.3 The recovery or calculated recovery of a test substance should ideally be (100 ± 10) % when a
radiolabelled compound is used. The recovery range specified might not be achievable in all cases, and
reasons for any deviation should be stated and discussed in the report. The amount of test substance
in each fraction should be analysed by suitably validated procedures for either a radiolabelled or non-
radiolabelled compound in the appropriate milieu. Where a radiolabelled compound is used, both parent
compound and metabolites are assessed unless a specific assay is used.

5.2.4.4 Levels of radioactivity in the biological milieu should be determined, for example, by liquid
scintillation counting; however, it should be stressed that this represents a mixed concentration of
compound and metabolites, and no kinetic parameters can be derived from it. Where isolation of
metabolites is considered necessary, this may involve a number of extractions and chromatographic
procedures (e.g. high-pressure liquid chromatography, thin layer chromatography, gas-liquid
chromatography), and the resulting material should be characterized by chemical methods and a variety
of physical chemistry techniques (e.g. mass spectrometry, nuclear magnetic resonance spectroscopy).

5.2.4.5 The use of tissues, cells, homogenates and isolated enzymes for the study of metabolism in vitro
is well documented. These methods identify potential metabolism which may not occur in vivo unless the
compound is available at the appropriate site. The extents and rates of metabolism in vitro compared to
in vivo will often differ.

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Annex A
(normative)

Circumstances in which toxicokinetic studies shall be considered

A.1 Potential hazards exist in the use of most medical devices. Chemical characterization identifies
chemical hazards (for potential risks, see ISO 10993-18 and ISO 14971) and should precede toxicokinetic
considerations. However, it is neither necessary nor practical to conduct toxicokinetic studies for all
identifiable intended and unintended leachables and degradation products, nor for all medical devices.

A.2 The need for toxicokinetic studies as part of the biological evaluation of a medical device shall be
considered taking into account the final product 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.

Possible toxicokinetic interaction between active ingredients and leachables and/or degradation
products should also be considered.

A.3 In vitro methods, which are appropriately validated, reasonable and practically available, reliable
and reproducible, shall be considered for use in preference to in vivo tests (see ISO 10993-1). Where
appropriate, in vitro experiments (e.g. tissue, homogenates or cells) should be conducted to investigate
probable rather than possible degradation products. ISO 10993-2 applies to any in vivo testing being
considered.

A.4 Toxicokinetic studies shall be considered if the following conditions are met:

a) the device is designed to undergo bioresorption;

b) the device is a permanent contact implant, and significant corrosion (of metallic materials) or
biodegradation is known or likely, and/or migration of leachables from the device occurs;
c) substantial quantities of potentially toxic degradation products and leachables are likely or known
to be released from a medical device into the body during clinical use;
d) substantial quantities of active ingredients/components 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/nano-
objects in question.

NOTE 2 See ISO/TR 10993-22 for information on toxicokinetic studies on nano-objects.

A.5 Considerations for toxicokinetic 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 ingredients already exist;
c) the achieved or expected rates of release of degradation products and leachables from a particular
device have been judged (see ISO 10993-17) to demonstrate safe levels of clinical exposure;

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d) clinical exposure of degradation products and leachables is documented as safe with reference to
historical experience.

A.6 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 study is
usually not feasible.

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