prEN ISO 10993-17

Biological evaluation of medical devices - Part 17: Toxicological risk assessment of medical device constituents (ISO/DIS 10993-17:2021)

Biologische Beurteilung von Medizinprodukten - Teil 17: Toxikologische Risikobewertung von Medizinproduktbestandteilen (ISO/DIS 10993-17:2021)

In diesem Teil der ISO 10993 sind das Verfahren für und die Anforderungen an die Bewertung des toxikologischen Risikos von Bestandteilen von Medizinprodukten festgelegt, die im Rahmen der in ISO 10993-1 beschriebenen biologischen Beurteilung des Endprodukts anzuwenden sind, einschließlich der Verfahren und Kriterien zur Beurteilung, ob die Exposition gegenüber einem oder mehreren chemischen Bestandteilen ohne nennenswerten Schaden bleibt.
Das in diesem Dokument beschriebene Verfahren ist anzuwenden, nachdem die chemische Charakterisierung des Zusammensetzungsprofils nach ISO 10993-18 durchgeführt wurde und eine toxikologische Risikobewertung entweder der Informationen über die Zusammensetzung oder der Daten zu den extrahierbaren oder herauslösbaren Substanzen erforderlich ist, um festzustellen, ob die mit den Bestandteilen verbundenen Risiken annehmbar sind oder nicht.
Das in diesem Dokument beschriebene Verfahren ist nicht für Fälle vorgesehen, in denen das toxikologische Risiko auf andere Weise geschätzt wurde, wie z. B.
- Bestandteile, mit Ausnahme der Kohorte bedenklicher/ausgeschlossener Chemikalien, die in einer für die Patientenexposition repräsentativen Menge unterhalb einer relevanten, toxikologisch begründeten Berichtsschwelle vorhanden oder extrahierbar sind (siehe ISO 10993-18:2020, Anhang E und ISO/TS 21726), und
- ein neues oder geändertes Medizinprodukt, für das die chemische oder biologische Gleichwertigkeit mit einem vorhandenen biokompatiblen oder klinisch etablierten Medizinprodukt festgestellt wurde (siehe ISO 10993-18:2020, Anhang C).
Außerdem ist das in diesem Dokument beschriebene Verfahren nicht anwendbar auf
- Bestandteile von Medizinprodukten, die nicht mit dem Körper in Kontakt kommen (z. B. In-vitro-Diagnostika),
- alle mit einem Medizinprodukt verbundenen biologischen Risiken (z. B. Schäden, die sich aus einer physikalischen Wechselwirkung (d. h. Anwendung von mechanischen Kräften, Energie oder Oberflächenmorphologie usw.) des Medizinprodukts mit dem Körper ergeben), sofern die chemische Exposition unverändert ist,
- arzneilich wirksame Bestandteile von Produkt-Arzneimittel-Kombinationen oder biologische Komponenten von Produkt-Biologikum-Kombinationen, da hier möglicherweise zusätzliche rechtliche Erwägungen gelten, und
- die Exposition gegenüber einem bestimmten chemischen Bestandteil, der aus anderen Quellen als dem Produkt stammt, z. B. aus der Nahrung, dem Wasser oder der Luft. Dieses Dokument behandelt nicht die mögliche Exposition infolge solcher Quellen.

Évaluation biologique des dispositifs médicaux - Partie 17: (ISO/DIS 10993-17:2021)

Biološko ovrednotenje medicinskih pripomočkov - 17. del: Toksikološka ocena tveganja glede sestavin medicinskih pripomočkov (ISO/DIS 10993-17:2021)

General Information

• Status: Not Published
• Publication Date: 14-Nov-2023
• ICS: 11.100.20 - Biological evaluation of medical devices
• Technical Committee: CEN/TC 206 - Biocompatibility of medical and dental materials and devices
• Drafting Committee: CEN/TC 206 - Biocompatibility of medical and dental materials and devices
• Current Stage: 4599 - Dispatch of FV draft to CMC - Finalization for Vote
• Start Date: 13-Sep-2022
• Completion Date: 13-Sep-2022
• Directive: 2017/745 - Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC
• Mandate: M/481 - Mandate to CEN, CENELEC and ETSI for Standardisation in the fieid of household dishwasher
• Mandate: M/575 - Medical devices in support of Regulation (EU) 2017/745 and in vitro diagnostic medical devices in support of Regulation (EU) 2017/746
• Ref Project: oSIST prEN ISO 10993-17:2022 - Biological evaluation of medical devices - Part 17: Toxicological risk assessment of medical device constituents (ISO/DIS 10993-17:2021)

Relations

• Revises: EN ISO 10993-17:2009 - Biological evaluation of medical devices - Part 17: Establishment of allowable limits for leachable substances (ISO 10993-17:2002)
• Effective Date: 01-Aug-2018

Standards Content (Sample)

SLOVENSKI STANDARD
oSIST prEN ISO 10993-17:2022
01-januar-2022
Biološko ovrednotenje medicinskih pripomočkov - 17. del: Toksikološka ocena
tveganja glede sestavin medicinskih pripomočkov (ISO/DIS 10993-17:2021)

Biological evaluation of medical devices - Part 17: Toxicological risk assessment of

medical device constituents (ISO/DIS 10993-17:2021)

Biologische Beurteilung von Medizinprodukten - Teil 17: Toxikologische Risikobewertung

von Medizinproduktbestandteilen (ISO/DIS 10993-17:2021)

Évaluation biologique des dispositifs médicaux - Partie 17: (ISO/DIS 10993-17:2021)

Ta slovenski standard je istoveten z: prEN ISO 10993-17
ICS:
11.100.20 Biološko ovrednotenje Biological evaluation of
medicinskih pripomočkov medical devices
oSIST prEN ISO 10993-17:2022 en,fr,de

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

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oSIST prEN ISO 10993-17:2022
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oSIST prEN ISO 10993-17:2022
DRAFT INTERNATIONAL STANDARD
ISO/DIS 10993-17
ISO/TC 194 Secretariat: DIN
Voting begins on: Voting terminates on:
2021-11-18 2022-02-10
Biological evaluation of medical devices —
Part 17:
Toxicological risk assessment of medical device
constituents
ICS: 11.100.20
This document is circulated as received from the committee secretariat.
THIS DOCUMENT IS A DRAFT CIRCULATED
FOR COMMENT AND APPROVAL. IT IS
ISO/CEN PARALLEL PROCESSING
THEREFORE SUBJECT TO CHANGE AND MAY
NOT BE REFERRED TO AS AN INTERNATIONAL
STANDARD UNTIL PUBLISHED AS SUCH.
IN ADDITION TO THEIR EVALUATION AS
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BE CONSIDERED IN THE LIGHT OF THEIR
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WHICH REFERENCE MAY BE MADE IN
Reference number
NATIONAL REGULATIONS.
ISO/DIS 10993-17:2021(E)
RECIPIENTS OF THIS DRAFT ARE INVITED
TO SUBMIT, WITH THEIR COMMENTS,
NOTIFICATION OF ANY RELEVANT PATENT
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PROVIDE SUPPORTING DOCUMENTATION. © ISO 2021
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ISO/DIS 10993-17:2021(E)
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All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may

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oSIST prEN ISO 10993-17:2022
ISO/DIS 10993-17:2021(E)
Contents Page

Foreword ........................................................................................................................................................................................................................................iv

Introduction .................................................................................................................................................................................................................................v

1 Scope ................................................................................................................................................................................................................................. 1

2 Normative references ..................................................................................................................................................................................... 1

3 Terms and definitions .................................................................................................................................................................................... 2

4 Abbreviations and terms ............................................................................................................................................................................6

5 Toxicological risk assessment within the biological evaluation process ...............................................7

6 Chemical constituent toxicological information ............................................................................................................10

6.1 General ........................................................................................................................................................................................................ 10

6.2 Obtain and evaluate toxicological information ...................................................................................................... 11

6.2.1 Application of toxicological screening limit (TSL) ............................................................................12

6.2.2 Further evaluation of toxicological information.................................................................................12

7 Tolerable contact level (TCL), tolerable intake (TI), and threshold of toxicological

concern (TTC) ......................................................................................................................................................................................................13

7.1 Derivation of TCL and TI .............................................................................................................................................................13

7.2 Application of TTC ............................................................................................................................................................................ 14

7.2.1 General ..................................................................................................................................................................................... 14

7.2.2 Selecting the TTC ............................................................................................................................................................ 14

8 Exposure dose estimation ......................................................................................................................................................................15

9 E valuation of the MOS ..................................................................................................................................................................................16

9.1 General ........................................................................................................................................................................................................ 16

9.2 Calculating a margin of safety (MOS) ............................................................................................................................. 16

9.2.1 Example of calculating a margin of safety (MOS) .............................................................................. 17

9.3 Requirements and criteria in the evaluation of the MOS ............................................................................... 17

9.3.1 General ..................................................................................................................................................................................... 17

9.3.2 Addressing residual uncertainty ...................................................................................................................... 17

10 Reporting requirements ...........................................................................................................................................................................18

Annex A (informative) Evaluating toxicological data quality when selecting a POD ...................................19

Annex B (normative) Derivation of toxicological screening limits ..................................................................................20

Annex C (normative) Deriving constituent TI or TCL for select end points ............................................................23

Annex D (informative) Some typical assumptions for biological parameters .....................................................30

Annex E (normative) Calculating an estimated exposure dose ...........................................................................................33

Annex F (informative) Reporting toxicological risk assessments ....................................................................................38

Annex ZA (informative) Relationship between this European standard and the General

Safety and Performance Requirements of Regulation (EU) 2017/745 aimed to be

covered ....................................................................................................................................................................................................................... 44

Bibliography .............................................................................................................................................................................................................................47

iii
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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 of 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

www.iso.org/iso/foreword.html.

This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of

medical devices.

This second edition cancels and replaces the first edition (ISO 10993-17:2002), which has been

technically revised.
The main changes compared to the previous edition are as follows:
— To follow
A list of all parts in the ISO 10993 series can be found on the ISO website.

Any feedback or questions on this document should be directed to the user’s national standards body. A

complete listing of these bodies can be found at www.iso.org/members.html.
© ISO 2021 – All rights reserved
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Introduction

A medical device or material that comes in direct or indirect contact with the patient's body or the

user’s body is expected to perform its intended use while being free from unacceptable risks, including

biological and toxicological risks. For this reason, medical devices are typically subject to a biological

evaluation within a risk management process to assess the safety of the medical device. The ISO 10993

standard series specifies a process through which the manufacturer of a medical device can identify

biological hazards associated with the medical device, estimate and evaluate the risks associated with

these hazards, control these risks, and monitor the effectiveness of the controls throughout the life

cycle of the medical device.

ISO 10993-1, in line with ISO 14971, defines key terms that facilitate a common understanding of

biological risk assessment. For example, biological risk is defined as the combination of the probability

of harm to health occurring as a result of adverse reactions associated with medical device or material

interactions, and the severity of that harm. Toxicological risk is defined as the probability of a specified

degree of an adverse reaction occurring in response to a specified level of exposure. Toxicological

hazard is defined as the potential for a chemical substance or material to cause an adverse biological

reaction, taking into account the nature of the reaction and the dose required to elicit it. ISO 10993-

18 includes methods for obtaining the necessary data for the toxicological risk assessment of medical

device constituents. Furthermore, ISO 10993-18 specifies when to consider conducting a toxicological

risk assessment per this Standard.

This Part of ISO 10993 specifies requirements for a toxicological risk assessment process for specific

medical device constituents that is used within the biological evaluation process specified by ISO 10993-

1 and Clause 1 of this Standard. For example, biological risk analysis of a medical device includes

obtaining chemical constituent information as described in ISO 10993-1 (Clause 6.1) and ISO 10993-

18. The extent to which constituent information can be obtained depends on what is known about the

material formulation, manufacturing process (i.e. processing aid chemicals, process steps, etc.), what

nonclinical and/or clinical information exist, and on the nature and duration of body contact with the

medical device. This toxicological risk assessment process is based on the principle that the biological

evaluation and risk assessment process is most efficient and effective when the minimum information

necessary is used to assess whether or not exposure to a harmful dose(s) of all constituents could occur

during the time period that a medical device contacts the body. The process, requirements, criteria and

methods specified in this Standard are intended to yield the following information, which are useful in

the overall biological risk assessment of the final product.
― the presence of constituents that are a potential source of harm to health

― a worst-case exposure estimate(s) for each chemical constituent(s) to determine whether or not it

could cause appreciable harm to health

― derivation of a tolerable intake or tolerable contact level, to a chemical constituent over a specified

time period, on the basis of body mass or surface area, that is considered to be without appreciable

harm to health

― an evaluation of exposure data for each chemical constituent(s) that is/are without appreciable

harm to health, or alternatively, is or could be a harmful dose

Lastly, this latest revision of ISO 10993-17 extends the previous version by clarifying when a toxicological

risk assessment is necessary, how to calculate worst case exposure of a chemical constituent, and when

the probability of occurrence of harm to health should be addressed by other means. (e.g. frequency

dose-response (if available), probabilistic dose-response, or biological test).
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DRAFT INTERNATIONAL STANDARD ISO/DIS 10993-17:2021(E)
Biological evaluation of medical devices —
Part 17:
Toxicological risk assessment of medical device
constituents
1 Scope

This part of the ISO 10993 specifies the process and requirements for the toxicological risk assessment

of medical device constituents to be used within the biological evaluation of the final product described

in ISO 10993-1, which includes the methods and criteria used to assess if exposure of a chemical

constituent(s) is without appreciable harm(s).

The process described in this document is intended to apply after chemical characterization

compositional profiling is performed as required by ISO 10993-18, and thus a toxicological risk

assessment of either the compositional information, extractable data or leachable data are required to

conclude if the risks related to the constituents are acceptable or not.

The process described in this document is not intended to apply to circumstances where the

toxicological risk has been estimated by other means, such as:

— constituents, excluding cohort of concern/excluded chemicals, that are present or extracted at

an amount representative of patient exposure below a relevant, toxicologically-based reporting

threshold (see ISO 10993-18:2020, Annex E and ISO/TS 21726);

— a new or changed medical device for which chemical or biological equivalence has been established

with an existing biocompatible or clinically established medical device (see ISO 10993-18:2020,

Annex C).
The process described in this document is also not applicable to

— medical device constituents that do not contact the body (e.g., in vitro diagnostics),

— all biological risks applicable to a medical device (e.g., harm(s) that result(s) from physical interaction

(i.e., application of mechanical forces, energy, or surface morphology, etc.) of the medical device with

the body), provided that the chemical exposure is unchanged,

— active pharmaceutical ingredients of device-drug combination products or biologic components of

device-biologic combination products as additional regulatory considerations may apply,

— exposure to a particular chemical constituent that arises from sources other than the device, such

as food, water, or air. This document does not address the potential for exposure from such sources

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 10993-1:2018, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk

management process

ISO 10993-18:2020, Biological evaluation of medical devices — Part 18: Chemical characterization of

medical device materials within a risk management process
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ISO/TS 21726:2019, Biological evaluation of medical devices — Application of the threshold of toxicological

concern (TTC) for assessing biocompatibility of medical device constituents

ISO 14971:2019, Medical devices — Application of risk management to medical devices

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:

— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at https:// www .electropedia .org/
3.1
analogue

substance(s) with similar molecular, physical, chemical and toxicological properties

3.2
benchmark dose low
BMD

dose derived from dose-response modelling that is associated with a specified change (e.g., 5% or 10%)

in the dose-response relationship

Note 1 to entry: A specified change of 5 % is applied when reported harm applies to individual animals. Specified

change of 10 % is applied when reported harm applies to a fraction of animals in a population.

[SOURCE: Crump 1984 [1], EPA 2012 [2]]
3.3
carcinogen

constituent that causes cancer in humans or animals as determined by valid experimental evidence

[SOURCE: International Agency for Research on Cancer [3]; National Cancer Institute [4]]

3.4
constituent

chemical that is present in or on the finished medical device or its materials of construction

Note 1 to entry: Constituent is also defined in ISO/TC 21726 and ISO 10993-18, which includes intentionally or

unintentionally added chemicals/compounds, such as: additives (e.g., plasticizers, lubricants, stabilizers, anti-

oxidants, colouring agents, fillers), manufacturing process residues (e.g., monomers, catalysts, solvents, sterilant

and cleaning agents), and degradation products. The term also includes side products and intermediates released

from a medical device.
3.5
default value

value or factor used in the derivation of a tolerable contact level (3.24) or tolerable intake (3.25), in the in

the absence of specific data (e.g., an uncertainty factor (30))
3.6
dose-response
relationship of dosage to harm(s) related to exposure

Note 1 to entry: In general, there are two types of dose-response relationships. The first type is the change in

response for an individual to a range of doses. The second type is the distribution of a response among individuals

to a range of doses.
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3.7
exposure dose

quantity of a chemical constituent that does, or could contact the body over a specified time period

Note 1 to entry: to entry: Exposure dose is normally expressed as mg/kg/day or as mg/cm /day.

3.8
harm to health

an adverse reaction, such as altered morphology, physiology, growth, development, reproduction

or lifespan that (a) impairs function of an organ/system, organism, or (sub)population, (b) reduces

capacity to tolerate impaired function, or (c) increases susceptibility to other influences that impair

function

Note 1 to entry: Examples of (sub) population include, but are not limited to, male versus female, preterm

neonates versus adults, etc.
3.9
harmful dose
dose capable of eliciting appreciable harm to health (3.8)
3.10
human carcinogen

carcinogen (3.3) for which human data demonstrates a causal association between exposure to the

chemical constituent and occurrence of cancer
3.11
identified constituent
constituent (3.4) for which molecular structure information is complete

Note 1 to entry: The identity of a medical device constituent can be obtained by information gathering or non-

targeted/targeted analytical approaches as described in ISO 10993-18.

Note 2 to entry: Examples of molecular structure information include (e.g., illustration or SMILES code),

molecular formula, and CAS registry number (RN) of constituents; molecular structure includes its elements

(type, number, arrangement) and bond information.
3.12
irritation

localized non-specific inflammatory response to single, repeated or continuous application of a

substance/material
[SOURCE: ISO 10993-23]

Note 1 to entry: Skin irritation is a reversible reaction and is mainly characterized by local erythema (redness)

of the skin.
3.13
lowest observed adverse effect level
LOAEL

lowest concentration or amount of an identified constituent found by experiment or observation which

causes detectable harm to health (3.8) of the target organism under defined conditions of exposure

Note 1 to entry: Lowest observed adverse effect level is normally expressed as mg/kg/day.

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3.14
margin of safety
MOS

ratio of the chemical constituent’s tolerable contact level (3.24) (numerator), tolerable intake

(3.25) (numerator), or threshold of toxicological (if applicable) (numerator), and its exposure dose

(denominator)

Note 1 to entry: to entry: Margin of Safety (MOS) addresses irritation, genotoxicity, systemic toxicity,

carcinogenicity or reproductive/developmental endpoints
3.15
minimally irritating level
MIL

lowest amount of an identified chemical constituent that is irritating to the body

Note 1 to entry: Minimally irritating level is normally expressed as mg/cm .
3.16
modifying factor
mathematical product of uncertainty factors
3.17
non-irritating level
NIL

greatest amount of an identified chemical constituent that does not elicit irritation to the body

Note 1 to entry: Non-irritating level is normally expressed as milligram per centimetre squared (mg/cm ).

3.18
no observed adverse effect level
NOAEL

greatest concentration or amount of an identified constituent found by experiment or observation

which causes no detectable harm to health (3.8) of the target organism under defined conditions of

exposure

Note 1 to entry: No observed adverse effect level is normally expressed as milligram (mg) per kilogram (kg) of

body weight per day (i.e., mg/kg/day).
3.19
point of departure
POD

dose used to derive a tolerable contact level (3.24) or a tolerable intake (3.25)

Note 1 to entry: Note to entry: Examples of a POD include: non-irritating level (3.17), or a minimally irritating level

(3.15), or a benchmark dose low (3.2), or a no observed adverse effect level (3.18), or lowest observed adverse effect

level (3.13) for an observed incidence or change in level of response
[SOURCE: EPA Integrated Risk Information System (IRIS) [5]]
3.20
release kinetics

quantity of a constituent that is released from a medical device as a function of time

Note 1 to entry: Release kinetics data can be obtained experimentally (e.g., simulated use study, leachables study,

or other type of extractables study). Alternatively, if supporting chemical and material data are available, a

qualified or validated release model can be used. Experimental release kinetics test methods and release models

to a subset of medical device constituents and materials have been published in the scientific literature for

phthalates and colour additives. [6][7]
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Note 2 to entry: Factors that impact release (e.g., linear versus nonlinear) include, but are not limited to,

physicochemical properties of the chemical constituent (e.g., molecular size, solubility, and thermal stability),

physicochemical properties of the extracting solvent (e.g., solubility and thermal stability), as well as, impact of

the extraction temperature on the device material(s) in the test sample (e.g., increased free volume of a polymer

system at elevated temperature).
3.21
slope factor

upper-bound estimate of risk per increment of dose that can be used to estimate risk probabilities for

different exposure levels

Note 1 to entry: Slope factor is expressed as a pre-determined frequency of occurrence (i.e., the number of

individuals that the response is expected to occur in a larger population per unit exposure dose. For example,

slope factor that represents a frequency of occurrence in a specified population is commonly expressed as 1 in

100 000 for every 1 mg/kg/day increase in exposure to the chemical constituent.
3.22
suspected human carcinogen

carcinogen (3.3) for which toxicological data indicates a causal relationship between exposure to the

chemical constituent and cancer

Note 1 to entry: Suspected human carcinogen applies when human data are inadequate to establish an association

between exposure to the chemical constituent and cancer. Suspected human carcinogens are established by

experts in chemical carcinogenesis based on a weight-of-evidence assessment.
3.23
systemic toxicity

harm(s) that occur at a different organ/system other than at the site of contact between the body and

the medical device

Note 1 to entry: Systemic toxicity can occur within a few days of a one-time exposure (i.e., acutely) or delayed

after repeated/ongoing exposure (subacute and subchronic, and chronic) to a harmful dose (3.9) of a chemical

constituent released from a single medical device or from use of multiple medical devices.

3.24
tolerable contact level
TCL

estimate of the daily surface-contact exposure to an identified constituent (3.11) over a specified time

period that is without appreciable irritation (3.12)

Note 1 to entry: Tbolerable contact level is normally expressed as mg/cm /day of body or tissue surface.

3.25
tolerable intake

estimate of the daily exposure of an identified constituent (3.11) over a specified time period (e.g.,

acute, subacute, subchronic, or chronic), on the basis of body mass, on the basis of body mass, that is

considered to be without appreciable harm to health (3.8)

Note 1 to entry: Tolerable intake is normally expressed as milligram (mg) per kilogram (kg) of body weight (bw)

per day (i.e., mg/kg/day). It is derived to establish a toxicological exposure limit for a medical device constituent

(3.4).
3.26
total quantity

amount of an identified constituent (3.11) present in, or that which can be extracted from, the medical

device

Note 1 to entry: Total quantity is normally expressed as milligram per device (mg/devi

...