SIST EN ISO 10993-16:2018

Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables (ISO 10993-16:2017)

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.

Biologische Beurteilung von Medizinprodukten - Teil 16: Entwurf und Auslegung toxikokinetischer Untersuchungen hinsichtlich Abbauprodukten und herauslösbaren Substanzen (ISO 10993-16:2017)

Dieser Teil von ISO 10993 beschreibt Prinzipien dafür, wie toxikokinetische Untersuchungen, die bei Medizinprodukten von Bedeutung sind, entworfen und durchgeführt werden sollten. Anhang A beschreibt die Überlegungen zur Durchführung toxikokinetischer Untersuchungen zur biologischen Beurteilung von Medizinprodukten.

Évaluation biologique des dispositifs médicaux - Partie 16: Conception des études toxicocinétiques des produits de dégradation et des substances relargables (ISO 10993-16:2017)

ISO 10993-16:2017 énonce les principes de conception et de mise en ?uvre des études toxicocinétiques relatives aux dispositifs médicaux. L'Annexe A décrit les considérations relatives à l'inclusion d'études toxicocinétiques dans l'évaluation biologique des dispositifs médicaux.

Biološko ovrednotenje medicinskih pripomočkov - 16. del: Načrt toksikokinetičnih raziskav razgradnih produktov in izlužnin (ISO 10993-16:2017)

Ta dokument določa načela za načrtovanje in izvajanje toksikokinetičnih študij, ki se nanašajo na medicinske pripomočke. Dodatek A podaja razloge za vključitev toksikokinetičnih študij pri biološkem vrednotenju medicinskih pripomočkov.

General Information

• Status: Published
• Public Enquiry End Date: 19-Apr-2016
• Publication Date: 09-Jan-2018
• ICS: 11.100.20 - Biological evaluation of medical devices
• Technical Committee: VAZ - Healthcare
• Current Stage: 6060 - National Implementation/Publication (Adopted Project)
• Start Date: 19-Dec-2017
• Due Date: 23-Feb-2018
• Completion Date: 10-Jan-2018
• Directive: 2007/47/EC - Directive 2007/47/EC of the European Parliament and of the council of 5 September 2007 amending Council Directive 90/385/EEC on the approximation of the laws of the Member States relating to active implantable medical devices, Council Directive 93/42/EEC concerning medical devices and Directive 98/8/EC concerning the placing of biocidal products on the market
• Directive: 90/385/EEC - Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical devices
• Directive: 93/42/EEC - Council Directive 93/42/EEC of 14 June 1993 concerning medical devices
• Mandate: M/023 - Standardization mandate to CEN/CENELEC concerning the development of European standards relating to medical devices
• Mandate: M/095 - In vitro diagnostic (prog.)
• Ref Project: EN ISO 10993-16:2017 - Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables (ISO 10993-16:2017)

Relations

• Replaces: SIST EN ISO 10993-16:2010 - Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables (ISO 10993-16:2010)
• Effective Date: 01-Feb-2018
• Replaces: SIST EN ISO 10993-16:2010 - Biological evaluation of medical devices - Part 16: Toxicokinetic study design for degradation products and leachables (ISO 10993-16:2010)
• Effective Date: 08-Jun-2022

Standards Content (Sample)

SLOVENSKI STANDARD
SIST EN ISO 10993-16:2018
01-februar-2018
1DGRPHãþD
SIST EN ISO 10993-16:2010
%LRORãNRRYUHGQRWHQMHPHGLFLQVNLKSULSRPRþNRYGHO1DþUWWRNVLNRNLQHWLþQLK
UD]LVNDYUD]JUDGQLKSURGXNWRYLQL]OXåQLQ,62

Biological evaluation of medical devices - Part 16: Toxicokinetic study design for

degradation products and leachables (ISO 10993-16:2017)
Biologische Beurteilung von Medizinprodukten - Teil 16: Entwurf und Auslegung
toxikokinetischer Untersuchungen hinsichtlich Abbauprodukten und herauslösbaren
Substanzen (ISO 10993-16:2017)

Évaluation biologique des dispositifs médicaux - Partie 16: Conception des études

toxicocinétiques des produits de dégradation et des substances relargables (ISO 10993-

16:2017)
Ta slovenski standard je istoveten z: EN ISO 10993-16:2017
ICS:
11.100.20 %LRORãNRRYUHGQRWHQMH Biological evaluation of
PHGLFLQVNLKSULSRPRþNRY medical devices
SIST EN ISO 10993-16:2018 en

2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

---------------------- Page: 1 ----------------------
SIST EN ISO 10993-16:2018
---------------------- Page: 2 ----------------------
SIST EN ISO 10993-16:2018
EN ISO 10993-16
EUROPEAN STANDARD
NORME EUROPÉENNE
December 2017
EUROPÄISCHE NORM
ICS 11.100.20 Supersedes EN ISO 10993-16:2010
English Version
Biological evaluation of medical devices - Part 16:
Toxicokinetic study design for degradation products and
leachables (ISO 10993-16:2017)

Évaluation biologique des dispositifs médicaux - Partie Biologische Beurteilung von Medizinprodukten - Teil

16: Conception des études toxicocinétiques des 16: Entwurf und Auslegung toxikokinetischer

produits de dégradation et des substances relargables Untersuchungen hinsichtlich Abbauprodukten und

(ISO 10993-16:2017) herauslösbaren Substanzen (ISO 10993-16:2017)
This European Standard was approved by CEN on 9 August 2017.

CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this

European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references

concerning such national standards may be obtained on application to the CEN-CENELEC Management Centre or to any CEN

member.

This European Standard exists in three official versions (English, French, German). A version in any other language made by

translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management

Centre has the same status as the official versions.

CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,

Finland, Former Yugoslav Republic of Macedonia, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania,

Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland,

Turkey and United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels

© 2017 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN ISO 10993-16:2017 E

worldwide for CEN national Members.
---------------------- Page: 3 ----------------------
SIST EN ISO 10993-16:2018
EN ISO 10993-16:2017 (E)
Contents Page

European foreword ....................................................................................................................................................... 3

Annex ZA (informative) Relationship between this European Standard and the essential

requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered ...................................... 5

Annex ZB (informative) Relationship between this European Standard and the essential

requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered .................................... 7

---------------------- Page: 4 ----------------------
SIST EN ISO 10993-16:2018
EN ISO 10993-16:2017 (E)
European foreword

The text of ISO 10993-16:2017 has been prepared by Technical Committee ISO/TC 194 "Biological and

clinical evaluation of medical devices" of the International Organization for Standardization (ISO) and

has been taken over as EN ISO 110993-16:2017 by Technical Committee CEN/TC 206 “Biological and

clinical evaluation of medical devices” the secretariat of which is held by DIN.

This European Standard shall be given the status of a national standard, either by publication of an

identical text or by endorsement, at the latest by June 2018, and conflicting national standards shall be

withdrawn at the latest by June 2018.

Attention is drawn to the possibility that some of the elements of this document may be the subject of

patent rights. CEN shall not be held responsible for identifying any or all such patent rights.

This document supersedes EN ISO 10993-16:2010.

This document has been prepared under a mandate given to CEN by the European Commission and the

European Free Trade Association, and supports essential requirements of EU Directive(s).

For relationship with EU Directive(s), see informative Annex ZA and Annex ZB, which is an integral part

of this document.

The following referenced documents are indispensable for the application of this document. For

undated references, the latest edition of the referenced document (including any amendments) applies.

For dated references, only the edition cited applies. However, for any use of this standard ‘within the

meaning of Annex ZA’, the user should always check that any referenced document has not been

superseded and that its relevant contents can still be considered the generally acknowledged state-of-

art.

When an IEC or ISO standard is referred to in the ISO standard text, this shall be understood as a

normative reference to the corresponding EN standard, if available, and otherwise to the dated version

of the ISO or IEC standard, as listed below.

NOTE The way in which these referenced documents are cited in normative requirements determines the

extent (in whole or in part) to which they apply.

Table — Correlations between undated normative references and dated EN and ISO standards

Normative references Equivalent dated standard
as listed in Clause 2 of
EN ISO or IEC
the ISO standard
ISO 10993-1 EN ISO 10993-1:2009 ISO 10993-1:2009

NOTE This part of EN ISO 10993 refers to ISO 10993-1 which itself refers to ISO 14971. In Europe, it should

be assumed that the reference to ISO 14971 is to EN ISO 14971:2012.
---------------------- Page: 5 ----------------------
SIST EN ISO 10993-16:2018
EN ISO 10993-16:2017 (E)

According to the CEN-CENELEC Internal Regulations, the national standards organizations of the

following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria,

Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, Former Yugoslav Republic of Macedonia,

France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta,

Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland,

Turkey and the United Kingdom.
Endorsement notice

The text of ISO 10993-16:2017 has been approved by CEN as EN ISO 10993-16:2017 without any

modification.
---------------------- Page: 6 ----------------------
SIST EN ISO 10993-16:2018
EN ISO 10993-16:2017 (E)
Annex ZA
(informative)
Relationship between this European Standard and the essential
requirements of Directive 93/42/EEC [OJ L 169] aimed to be covered

This European Standard has been prepared under a Commission’s joint standardization request

M/BC/CEN/89/9 concerning harmonized standards relating to horizontal aspects in the field of medical

devices to provide one voluntary means of conforming to essential requirements of Council Directive

93/42/EEC of 14 June 1993 concerning medical devices [OJ L 169].

Once this standard is cited in the Official Journal of the European Union under that Directive,

compliance with the normative clauses of this standard given in Table ZA.1 confers, within the limits of

the scope of this standard, a presumption of conformity with the corresponding essential requirements

of that Directive and associated EFTA regulations.

NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the risk

management process needs to be in compliance with Directive 93/42/EEC as amended by 2007/47/EC. This

means that risks have to be reduced ‘as far as possible’, ‘to a minimum’, ‘to the lowest possible level’, ‘minimized’

or ‘removed’, according to the wording of the corresponding essential requirement.

NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with Essential

Requirements 1, 2, 5, 6, 7, 8, 9, 11 and 12 of the Directive.

NOTE 3 This Annex ZA is based on normative references according to the table of references in the European

foreword, replacing the references in the core text.

NOTE 4 When an Essential Requirement does not appear in Table ZA.1, it means that it is not addressed by this

European Standard.

Table ZA.1 — Correspondence between this European Standard and Annex I of Directive

93/42/EEC [OJ L 169]
Essential Requirements of Clause(s)/subclause(s) Remarks/Notes
Directive 93/42/EEC of this EN
ER 7.1 is only partly covered by EN ISO
10993-16, since the standard does not
provide requirements on design and
manufacture, and the compatibility
between the materials used and
biological tissues, cells and body fluids.
However, this standard provides a
means to evaluate the absorption,
7.1 (First and second indent) 4, 5, and Annex A
distribution, metabolism and excretion,
with time, of degradation products and
leachables from materials which are
used in the device and circumstances in
which such studies shall be considered.
Other forms of toxicity and
flammability are not dealt with in this
standard.
---------------------- Page: 7 ----------------------
SIST EN ISO 10993-16:2018
EN ISO 10993-16:2017 (E)
ER 7.2 is not covered by EN ISO 10993-
16, since the standard does not provide
requirements on design and
manufacture and does not oblige to
minimize risk.
However, this standard provides a
means to evaluate the absorption,
7.2 4, 5, and Annex A
distribution, metabolism and excretion,
with time, of residuals in exposed
persons and circumstances in which
such studies shall be considered. This
evaluation can be a preliminary step
for risk minimization. Other forms of
toxicity are not dealt with in this
standard.
ER 7.5 is not covered by EN ISO 10993-
16, since the standard does not provide
requirements on design and
manufacture and does not oblige to
minimize risk.
However, this standard provides a
means to evaluate the absorption,
7.5 (First paragraph) 4, 5, and Annex A
distribution, metabolism and excretion,
with time, of substances leaking from
the device and circumstances in which
such studies shall be considered. This
evaluation can be a preliminary step
for risk minimization. Other forms of
toxicity are not dealt with in this
standard.

General Note: Presumption of conformity depends on also complying with all relevant

clauses/subclauses of ISO 10993-1.

WARNING 1 — Presumption of conformity stays valid only as long as a reference to this European

Standard is maintained in the list published in the Official Journal of the European Union. Users of this

standard should consult frequently the latest list published in the Official Journal of the European

Union.

WARNING 2 — Other Union legislation may be applicable to the products falling within the scope of

this standard.
---------------------- Page: 8 ----------------------
SIST EN ISO 10993-16:2018
EN ISO 10993-16:2017 (E)
Annex ZB
(informative)
Relationship between this European Standard and the essential
requirements of Directive 90/385/EEC [OJ L 189] aimed to be covered

This European Standard has been prepared under a Commission’s joint standardization request

M/BC/CEN/89/9 concerning harmonized standards relating to horizontal aspects in the field of medical

devices to provide one voluntary means of conforming to essential requirements of Council Directive

90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active

implantable medical devices [OJ L 189].

Once this standard is cited in the Official Journal of the European Union under that Directive,

compliance with the normative clauses of this standard given in Table ZB.1 confers, within the limits of

the scope of this standard, a presumption of conformity with the corresponding essential requirements

of that Directive and associated EFTA regulations.

NOTE 1 Where a reference from a clause of this standard to the risk management process is made, the risk

management process needs to be in compliance with Directive 90/385/EEC as amended by 2007/47/EC. This

means that risks have to be reduced ‘as far as possible’, ‘to a minimum’, ‘to the lowest possible level’, ‘minimized’

or ‘removed’, according to the wording of the corresponding essential requirement.

NOTE 2 The manufacturer’s policy for determining acceptable risk must be in compliance with Essential

Requirements 1, 4, 5, 8, 9 and 10 of the Directive.

NOTE 3 This Annex ZB is based on normative references according to the table of references in the European

foreword, replacing the references in the core text.

NOTE 4 When an Essential Requirement does not appear in Table ZB.1, it means that it is not addressed by this

European Standard.

Table ZB.1 — Correspondence between this European Standard and Annex I of Directive

90/385/EEC [OJ L 189]
Essential Requirements of Clause(s)/subclause(s) Remarks/Notes
Directive 90/385/EEC of this EN
The first and second indents of this
relevant Essential Requirement are
only partly covered by EN ISO 10993-
16, since the standard does not
provide requirements on design and
manufacture.
However, this standard provides a
means to evaluate the absorption,
9 (only first and second indent) 4, 5, and Annex A
distribution, metabolism and
excretion, with time, of degradation
products and leachables from
materials which are used in the device
and circumstances in which such
studies shall be considered.
Other forms of toxicity are not
covered.
---------------------- Page: 9 ----------------------
SIST EN ISO 10993-16:2018
EN ISO 10993-16:2017 (E)

General Note: Presumption of conformity depends on also complying with all relevant

clauses/subclauses of ISO 10993-1.

WARNING 1 — Presumption of conformity stays valid only as long as a reference to this European

Standard is maintained in the list published in the Official Journal of the European Union. Users of this

standard should consult frequently the latest list published in the Official Journal of the European

Union.

WARNING 2 — Other Union legislation may be applicable to the products falling within the scope of

this standard.
---------------------- Page: 10 ----------------------
SIST EN ISO 10993-16:2018
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
---------------------- Page: 11 ----------------------
SIST EN ISO 10993-16:2018
ISO 10993-16:2017(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2017, Published in Switzerland

All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized otherwise in any form

or by any means, electronic or mechanical, including photocopying, or posting on the internet or an intranet, without prior

written permission. Permission can be requested from either ISO at the address below or ISO’s member body in the country of

the requester.
ISO copyright office
Ch. de Blandonnet 8 • CP 401
CH-1214 Vernier, Geneva, Switzerland
Tel. [phone]
Fax [phone]
[e-mail]
www.iso.org
ii © ISO 2017 – All rights reserved
---------------------- Page: 12 ----------------------
SIST EN ISO 10993-16:2018
ISO 10993-16:2017(E)
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

© ISO 2017 – All rights reserved iii
---------------------- Page: 13 ----------------------
SIST EN ISO 10993-16:2018
ISO 10993-16:2017(E)
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: w w w . i s o .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.
iv © ISO 2017 – All rights reserved
---------------------- Page: 14 ----------------------
SIST EN ISO 10993-16:2018
ISO 10993-16:2017(E)
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.
© ISO 2017 – All rights reserved v
---------------------- Page: 15 ----------------------
SIST EN ISO 10993-16:2018
---------------------- Page: 16 ----------------------
SIST EN ISO 10993-16:2018
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:// www .electropedia .org/
— ISO Online browsing platform: available at http:// www .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
© ISO 2017 – All rights reserved 1
---------------------- Page: 17 ----------------------
SIST EN ISO 10993-16:2018
ISO 10993-16:2017(E)
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
max
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. c , liver, and be expressed in mass per unit volume or mass.

max
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
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
3.12
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
max
time at which c (3.6) is observed
max
2 © ISO 2017 – All rights reserved
---------------------- Page: 18 ----------------------
SIST EN ISO 10993-16:2018
ISO 10993-16:2017(E)
3.17
volume of distribution

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
...