GB/T 16886.17-2025 Biological evaluation of medical devices - Part 17: Toxicological risk assessment of medical device constituents
1 Scope
This document specifies the process and requirements for the toxicological risk assessment of medical device constituents. The methods and criteria used to assess whether exposure to a constituent is without appreciable harm are also specified. The toxicological risk assessment can be part of the biological evaluation of the final product, as described in ISO 10993-1.
The process described in this document applies to chemical characterization information obtained in line with ISO 10993-18. When a toxicological risk assessment of either the compositional information or analytical chemistry data (e.g. extractable data or leachable data) are required to determine whether the toxicological risks related to the constituents are negligible or tolerable.
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 or excluded chemicals, that are present in or extracted from a medical device at an amount representative of patient exposure below a relevant, toxicologically-based reporting threshold (see applicable requirements in GB/T 16886.18-2022, 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 applicable requirements in GB/T 16886.18-2022, 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);
——biological risks associated with physical interactions of the medical device with the body (i.e. application of mechanical forces, energy or surface morphology, etc.), provided that the chemical exposure is not changed;
——active pharmaceutical ingredients of device-drug combination products or biologic components of device-biologic combination products as additional regulatory considerations can apply;
——exposure to a particular constituent that arises from sources other than the device, such as food, water or air.
2 Normative references
The following documents contain provisions which, through reference in this text, constitute provisions 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.
GB/T 16886.1-2022 Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process (ISO 10993-1:2018, IDT)
GB/T 42062-2022 Medical devices - Application of risk management to medical devices (ISO 14971:2019, IDT)
ISO 10993-1 Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process
Note: GB/T 16886.1-2022 Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process (ISO 10993-1: 2018, IDT)
ISO 10993-18 Biological evaluation of medical devices - Part 18: Chemical characterization of medical device materials within a risk management process
Note: GB/T 16886.18-2022 Biological evaluation of medical devices - Part 18: Chemical characterization of medical device materials within a risk management process (ISO 10993-18:2020, IDT)
ISO 14971 Medical devices - Application of risk management to medical devices
Note: GB/T 42062-2022 Medical devices - Application of risk management to medical devices (ISO 14971:2019, IDT)
ISO/TS 21726:2019 Biological evaluation of medical devices - Application of the threshold of toxicological concern (TTC) for assessing biocompatibility of medical device constituents
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 10993-1 and the following apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
——ISO Online browsing platform: available at http://www.iso.org/obp;
——IEC Electropedia: available at http://www.electropedia.org/.
3.1
analogue
substance with similar molecular, physical, chemical or toxicological properties
3.2
benchmark dose low; BMDL
lower one-sided confidence limit of a dose derived from dose-response (3.6) modelling that is associated with a specified change (e.g. 5% or 10%) in the dose-response relationship
Note: A specified change of 5% is applied when a reported harm applies to individual animals. A specified change of 10% is applied when a reported harm applies to a fraction of animals in a population.
[Source: EPA 2012]
3.3
carcinogen
constituent (3.4) that causes cancer in humans or experimental animals as determined by valid experimental or observational evidence
Note: Carcinogens are either genotoxic carcinogens or non-genotoxic carcinogens. A genotoxic carcinogen is a constituent capable of causing cancer by a mechanism that involves direct alteration of the genetic material of target cells, as a key event at an early stage in tumour development. A non-genotoxic carcinogen is a constituent capable of producing cancer by a mechanism where direct gene damage is not the key event in tumour development (C.3.1).
[Source: International Agency for Research on Cancer]
3.4
constituent
chemical that is present in or on the finished medical device or its materials of construction
Note: Constituents can be intentionally or unintentionally added chemicals or 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), degradation products or impurities (e.g. byproducts or side products) or contaminants.
[Source: GB/T 16886.18-2022, 3.10, modified]
3.5
default value
value or factor used in the derivation of a worst-case estimated exposure dose (3.32), tolerable contact level (3.25) or tolerable intake (3.26), in the absence of specific data [e.g. an uncertainty factor (3.31)]
3.6
dose-response
relationship of dosage to observable harm
Note: In general, there are two types of dose-response relationships. The first type is the change in the response of an individual to a range of doses. The second type is the distribution of the response among individuals to a range of doses.
3.7
exposure dose
quantity of a constituent (3.4) that does or can contact the body by an exposure route over a specified time period
Note 1: The exposure dose is expressed in microgram per kilogram of body mass per day [μg/(kg·d)] or in microgram per centimetre squared (µg/cm2).
Note 2: The exposure dose is different from the absorbed dose. The absorbed dose is the quantity of the constituent that traverses the portal of entry, which is dependent on the absorption rate of the constituent.
3.8
harm to health
adverse reaction, such as altered morphology, physiology, growth, development, reproduction or lifespan that
a) impairs function of an organ or system, organism, or (sub)population,
b) reduces capacity to tolerate an impaired function, or
c) increases susceptibility to other influences that impair function.
Note: Examples of (sub)population include, but are not limited to, male, female, preterm neonates, adults.
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 constituent (3.4) and occurrence of cancer
Example: Human carcinogens include, but are not limited to, International Agency for Research on Cancer (IARC) Group I carcinogens or US National Toxicology Program (NTP) "known to be a human carcinogen".
3.11
identified constituent
constituent (3.4) for which molecular structure information is complete
Contents
Foreword i
Introduction iv
1 Scope
2 Normative references
3 Terms and definitions
4 Symbols and abbreviated terms
5 Toxicological risk assessment within the biological evaluation process
5.1 General
5.1.1 Risk assessment principles
5.1.2 Hazard identification
5.1.3 Risk estimation
6 Constituent specific toxicological information
6.1 General
6.2 Identification of hazardous constituents
6.2.1 General
6.2.2 Application of the toxicological screening limit
6.2.3 Identification of human carcinogens or suspected human carcinogens
6.2.4 Selection of the point of departure
7 Tolerable contact level, tolerable intake and threshold of toxicological concern
7.1 Derivation of TCL and TI
7.2 Application of TTC
8 Exposure dose estimation
9 Margin of safety
9.1 General
9.2 Calculating the margin of safety
10 Toxicological risk acceptance criteria
10.1 General requirements
10.2 Further risk analysis or risk evaluation or risk control
11 Reporting requirements
Annex A (Normative) Evaluation of toxicological data quality when selecting a POD
Annex B (Normative) Derivation of TSL
B.1 General
B.2 Calculation of the TSL
B.3 Application of TSL
Annex C (Normative) Derivation of constituent TI or TCL for select endpoints
C.1 General
C.2 Setting of TI for non-cancer endpoints
C.2.1 General
C.2.2 Determination of uncertainty factors
C.2.3 Determination of the MF
C.2.4 Derivation of the non-cancer TI value
C.3 Setting of TI for cancer endpoints
C.3.1 General
C.3.2 Cancer risk estimation
C.4 Establishment of TCLs
C.4.1 General
C.4.2 Setting of TCL for the irritation endpoint
C.4.3 Determination of TCL uncertainty factors
C.4.4 Determination of the TCL modifying factor
Annex D (Informative) Typical assumptions for biological parameters
D.1 General
D.2 Assumptions
D.2.1 Human
D.2.2 Rat
D.2.3 Mouse
D.2.4 Hamster
D.2.5 Guinea pig
D.2.6 Dog
D.2.7 Rabbit
Annex E (Normative) Estimation of an exposure dose
E.1 General
E.2 Exposure dose estimation based on release kinetics information
E.3 Worst-case exposure dose estimation based on maximum release
E.3.1 General
E.3.2 Alternative method to calculating an EEDmax based on maximum release
E.4 Exposure dose estimation of an irritant
Annex F (Informative) Reporting of toxicological risk assessment information
F.1 General
F.2 Required justifications
F.3 Constituent, medical device use and constituent specific toxicological risk assessments
F.4 Examples of tabulating toxicological risk assessments
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