oSIST prEN 455-5:2023
(Main)Medical gloves for single use - Part 5: Extractable chemical residues
Medical gloves for single use - Part 5: Extractable chemical residues
This document provides requirements for label information about chemicals used in product manufacture, particularly potentially allergenic substances employed and remaining in medical gloves. It also provides information on extraction media, methods of extraction and quantitative assay of residual chemicals.
This document does not provide information on the allergenic potential or safety to the user of any product. This is expected to be assessed in the light of all available toxicity and biocompatibility data on the products concerned as part of a risk management process.
Medizinische Handschuhe zum einmaligen Gebrauch - Teil 5: Extrahierbare chemische Rückstände
Dieses Dokument enthält Anforderungen an die Kennzeichnung von Chemikalien, die bei der Herstellung von Produkten verwendet werden, insbesondere von potenziell allergenen Stoffen, die in medizinischen Handschuhen verwendet werden und dort verbleiben. Es enthält auch Informationen über Extraktionsmedien, Extraktionsverfahren und die quantitative Bestimmung von chemischen Rückständen.
Dieses Dokument enthält keine Informationen über das allergieauslösende Potential oder die Sicherheit eines Produkts für den Anwender. Es wird erwartet, dass dies unter Berücksichtigung aller verfügbaren Daten zur Toxizität und Biokompatibilität der betreffenden Produkte als Teil eines Risikomanagementprozesses bewertet wird.
Gants médicaux non réutilisables - Partie 5: Résidus de substances chimiques extractibles
Le présent document fournit les exigences d'étiquetage des substances chimiques utilisées lors de la fabrication de produits, en particulier les substances potentiellement allergisantes employées et restant dans les gants médicaux. Il fournit des informations sur les milieux d’extraction ainsi que sur les méthodes d’extraction et de dosage quantitatif des substances chimiques résiduelles.
Le présent document ne fournit pas d'informations sur le potentiel allergisant ou la sécurité pour l’utilisateur du produit. Cela devrait être évalué à la lumière de toutes les données de toxicité et de biocompatibilité disponibles sur les produits concernés, dans le cadre du processus de gestion des risques.
Medicinske rokavice za enkratno uporabo - 5. del: Izločljivi kemični ostanki
General Information
Standards Content (Sample)
SLOVENSKI STANDARD
oSIST prEN 455-5:2023
01-junij-2023
Medicinske rokavice za enkratno uporabo - 5. del: Izločljivi kemični ostanki
Medical gloves for single use - Part 5: Extractable chemical residues
Medizinische Handschuhe zum einmaligen Gebrauch - Teil 5: Extrahierbare chemische
Rückstände
Gants médicaux non réutilisables - Partie 5: Résidus de substances chimiques
extractibles
Ta slovenski standard je istoveten z: prEN 455-5
ICS:
11.140 Oprema bolnišnic Hospital equipment
oSIST prEN 455-5:2023 en,fr,de
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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oSIST prEN 455-5:2023
DRAFT
EUROPEAN STANDARD
prEN 455-5
NORME EUROPÉENNE
EUROPÄISCHE NORM
April 2023
ICS 11.140
English Version
Medical gloves for single use - Part 5: Extractable chemical
residues
Medizinische Handschuhe zum einmaligen Gebrauch -
Teil 5: Extrahierbare chemische Rückstände
This draft European Standard is submitted to CEN members for enquiry. It has been drawn up by the Technical Committee
CEN/TC 205.
If this draft becomes a European Standard, 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.
This draft European Standard was established by CEN 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, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway,
Poland, Portugal, Republic of North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Türkiye and
United Kingdom.
Recipients of this draft are invited to submit, with their comments, notification of any relevant patent rights of which they are
aware and to provide supporting documentation.
Warning : This document is not a European Standard. It is distributed for review and comments. It is subject to change without
notice and shall not be referred to as a European Standard.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels
© 2023 CEN All rights of exploitation in any form and by any means reserved Ref. No. prEN 455-5:2023 E
worldwide for CEN national Members.
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Contents Page
European foreword . 4
Introduction . 5
1 Scope . 6
2 Normative references . 6
3 Terms and definitions . 6
4 Requirements . 8
4.1 General. 8
4.2 Chemicals . 8
4.3 Chemicals leachable . 8
4.4 Labelling . 9
5 Test methods . 9
5.1 General. 9
5.2 Chemicals leachable . 9
5.3 Extraction and assay methods . 9
6 Test report . 9
Annex A (normative) Outline method for the determination of solvent extractable
chemicals in medical gloves . 11
A.1 General. 11
A.2 Principle . 11
A.3 Procedure . 11
Annex B (normative) Outline method for the determination of leachable chemicals in
medical gloves . 13
B.1 General. 13
B.2 Principle . 13
B.3 Reagents . 13
B.4 Apparatus . 13
B.5 Procedure . 14
Annex C (normative) Known contact allergens in medical gloves . 16
Annex D (informative) Test method validation . 18
Annex E (informative) Analysis of chemical residues by high pressure liquid
chromatography (HPLC), method 1 . 19
E.1 General. 19
E.2 Chemicals . 19
E.3 Solutions . 19
E.4 Apparatus . 19
E.5 Procedure . 20
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E.6 References . 20
Annex F (informative) Analysis of chemical residues by high pressure liquid
chromatography (HPLC), method 2 . 21
F.1 General . 21
F.2 Chemicals . 21
F.3 Solutions . 21
F.4 Apparatus . 21
F.5 Procedure . 22
F.6 References . 22
Annex G (informative) Analysis of chemical residues by high pressure liquid
chromatography (HPLC), method 3 . 23
G.1 General . 23
G.2 Chemicals . 23
G.3 Solutions . 23
G.4 Apparatus . 23
G.5 Procedure . 23
G.6 References . 24
Annex H (informative) Example for exhaustive extraction method . 25
H.1 General . 25
H.2 Extraction solvent. 25
H.3 Apparatus . 25
H.4 Procedure . 25
Annex ZA (informative) Relationship between this European standard and the General
Safety and Performance Requirements of Regulation (EU) 2017/745 aimed to be
covered . 27
Bibliography . 29
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European foreword
This document (prEN 455-5:2023) has been prepared by Technical Committee CEN/TC 205 “Non-active
medical devices”, the secretariat of which is held by DIN.
This document is currently submitted to the CEN Enquiry.
This document has been prepared under a Standardization Request given to CEN by the European
Commission and the European Free Trade Association, and supports essential requirements of
EU Directive(s) / Regulation(s).
For relationship with EU Directive(s) / Regulation(s), see informative Annex ZA, which is an integral
part of this document.
EN 455 consists of the following parts under the general title “Medical gloves for single use”:
— Part 1: Requirements and testing for freedom from holes;
— Part 2: Requirements and testing for physical properties;
— Part 3: Requirements and testing for biological evaluation;
— Part 4: Requirements and testing for shelf life determination;
— Part 5: Extractable chemical residues.
A list of all parts in a series can be found on the CEN website.
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Introduction
Adverse reactions to residual chemicals present in medical gloves have been reported over many years
in variable rates of prevalence. These chemicals are part of the manufacturing process including but not
limited to accelerators, activators, antioxidants, or donning aids. Reactions range from dermal irritation
to contact dermatitis including type IV allergic responses. These effects are localised to the area of
contact with the offending chemicals and unlike type I allergic reactions do not show any systemic non-
localised effects. Though they are potentially career altering, they do not escalate to more serious life-
threatening responses.
Such adverse reactions are possible with gloves made of any material whose manufacture involves use
of chemical additives at any stage of the manufacturing process. Factors which contribute to the risk of
reaction include
— the concentration and ease of release of the chemicals;
— the duration and frequency of skin contact with gloves; and
— the occlusive nature of the glove/skin interaction during glove use.
The EN ISO 10993 series specifies requirements and test methods for biological evaluation of medical
devices. Historically EN ISO 10993-10 has used animal testing to determine irritation and sensitisation
potential of products which related to their residual chemical content. This is a fairly crude screen and
simply prevents poor quality products containing excessive levels of bioavailable chemicals from
reaching the market. It can neither predict changes in chemical availability during product shelf life nor
potential for sensitisation or provocation of allergic responses in users.
This document gives requirements for quantitative measurement of potentially harmful residual
extractable chemicals in medical gloves as part of a risk management process, in accordance with the
EN ISO 10993 series.
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1 Scope
This document provides requirements for label information about chemicals used in product
manufacture, particularly potentially allergenic substances employed and remaining in medical gloves.
It also provides information on extraction media, methods of extraction and quantitative assay of
residual chemicals.
This document does not provide information on the allergenic potential or safety to the user of any
product. This is expected to be assessed in the light of all available toxicity and biocompatibility data on
the products concerned as part of a risk management process.
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.
1
FprEN 455-3:2023, Medical gloves for single use — Part 3: Requirements and testing for biological
evaluation
EN ISO 10993-1:2020, Biological evaluation of medical devices - Part 1: Evaluation and testing within a
risk management process (ISO 10993-1:2018, including corrected version 2018-10)
EN ISO 14971:2019, Medical devices - Application of risk management to medical devices (ISO
14971:2019)
EN ISO 20417:2021, Medical devices - Information to be supplied by the manufacturer (ISO 20417:2021,
Corrected version 2021-12)
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminology 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
allergenic
having the potential to provoke an allergic response
Note 1 to entry: The allergens of concern in this document are those that provoke type IV delayed contact
dermatitis reactions.
3.2
chemicals
substances added or formed during any step of the manufacturing process, including sterilisation, or in
storage which may be available in the final product
Note 1 to entry: These can include but are not limited to lubricants, chemical coatings and sterilizing agents.
Several chemical ingredients are commonly used during processing of gloves, some of them are known to cause
type IV allergic reactions. The type and amount of residual chemicals added and finally present are variable
1
EN 455-3:2023 is planned to be published 2023-10.
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Note 2 to entry: For glove materials curing agents are used. These are chemicals which cause crosslinking to
occur. The curing agent is most commonly sulfur, or can be a sulfur donor in a process known as vulcanisation.
Examples of other curing agents would include those employed in peroxide or radiation curing.
[SOURCE: EN 455-3:2015, definition 3.1 – modified, “ , including sterilisation, “ within the definition and
Note 2 to entry added]
3.3
curing agent
chemical which causes crosslinking to occur
Note 1 to entry: For glove materials, this is commonly sulfur, or may be a sulfur donor in a process known as
vulcanisation. Examples of other curing agents would include those employed in peroxide or radiation curing.
3.4
chemicals leachable
substances which can be extracted from the product by contact with body fluid (sweat) or other liquids
3.5
extraction media
liquids used to extract residual chemicals from the glove
Note 1 to entry: These can range from aggressive organic solvents which can achieve exaggerated extraction of
the target chemicals but not degrade the glove material or more biologically related mild
solvent/aqueous/vegetable oil-based solutions which are used to mimic the leaching effect of wearer body fluids
in glove usage.
3.6
exaggerated extraction
extraction that is intended to result in a greater amount of a chemical constituent being released as
compared to the amount generated under the simulated conditions of use
Note 1 to entry: It is important to ensure that the exaggerated extraction does not result in a chemical change of
the material.
[SOURCE: EN ISO 10993-12:2021, definition 3.4]
3.7
exhaustive extraction
extraction conducted until the amount of extractable material in a subsequent extraction is less than
10 % by gravimetric analysis of that detected in the initial extraction
[SOURCE: EN ISO 10993-12:2021, definition 3.5 – modified, Note to entry has been deleted.]
3.8
simulated-use extraction
extraction conducted to demonstrate compliance with the requirements of ISO 10993-12 by evaluating
leachable material levels available to the patient or user from devices during the routine use of a device,
using an extraction method that simulates product use
[SOURCE: EN ISO 10993-12:2021, definition 3.14 – modified, “this part of ISO 10993” has been replaced
with “ISO 10993-12” and the Note to entry has been deleted]
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3.9
contact allergen
substance known or suspected to cause Type IV allergy
3.10
accelerator
activator
chemical which catalyses the chemical reactions necessary to bring about curing (vulcanisation)
Note 1 to entry: A catalyst is a substance which speeds up a chemical reaction without being consumed by the
process.
4 Requirements
4.1 General
EN ISO 10993-1:2020 describes the general principles governing the biological evaluation of medical
devices and shall be used to select the appropriate tests as described in other parts of the series.
NOTE Based on EN ISO 10993-1:2020, medical gloves are classified as surface devices with limited contact
duration. EN ISO 10993-1:2020 combines the review and evaluation of existing data from all resources with,
where necessary, the selection and application of additional tests, thus enabling a full evaluation to be made of the
biological responses to each medical device, relevant to its safety in use. The classification of medical gloves
according to EN ISO 10993-1:2020 cannot be confused with the definitions provided in the medical device
regulation for these products.
A risk management process in accordance with EN ISO 14971:2019 shall be established.
4.2 Chemicals
A list of chemicals which are relevant contact allergens often found in medical gloves is provided in
Annex C.
The manufacturer shall disclose a list of chemicals used in all stages of the manufacturing process
which, based on current state of the art, are known or suspected to be contact allergens, i.e. to cause
Type IV allergy. These may include but are not limited to chemicals such as curing agents (vulcanising
agents), accelerators, stabilisers, surfactants, antioxidants, plasticisers and biocides. Examples of such
chemicals are given in Annex C.
The manufacturer shall provide evidence of the steps taken to reduce the risk to the end-user of
exposure to such chemicals. Manufacturers may only declare the absence of a substance if the substance
is not used in any part of the manufacturing process. No compound shall be used in the manufacture of
the product that is known to form a substance that is subject of such a declaration.
FprEN 455-3:2023 specifies requirements for chemicals, which should also be complied with.
4.3 Chemicals leachable
Manufacturers shall provide information on the levels of extractable contact allergen present in their
gloves both by exhaustive extraction and simulated-use extraction. The manufacturer shall validate
their processes to ensure the process limit of leachable chemicals in the finished gloves by the
extraction methods outlined in 5.1 and described in Annexes A and B, and using fully validated methods
for quantitative measurement. The documentation of these results shall be retained. The results of the
test and applied test method shall be made available on request.
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4.4 Labelling
In addition to the labelling specified in EN ISO 20417:2021 and FprEN 455-3:2023, information of each
of the leachable chemicals of concern shall be provided either on primary packaging or in an
accompanying document. The claimed chemical content of the gloves shall be the process limit as
measured according to 5.3. If simulated-use extraction data is provided it shall be demonstrated that
this is based on the worst-case scenario following extreme temperature accelerated storage of gloves
for 7 days at 0°C.
5 Test methods
5.1 General
All test methods used to show conformity to this document shall be validated and documented by the
laboratory performing the test.
Sources of guidance on test method validation can be found in Annex D.
5.2 Chemicals leachable
The test method for the analytical determination of leachable chemicals shall specify the following
parameters:
2
— name and CAS number of chemical and function, e.g. accelerators, activators, antioxidants or
donning aids;
— means of extraction, whole glove, glove inner surface or glove pieces;
— extraction medium, organic solvent, physiological saline solution, simulated sweat, vegetable oil;
— time and temperature of extraction;
— means of agitation;
— preconditioning temperature and duration;
— separation and assay method, e.g. TLC, GC, HPLC, MS, UV.
5.3 Extraction and assay methods
Extraction methods are described in Annexes A and B. Examples of suitable assay methods are shown in
Annexes E, F, G and H.
6 Test report
The test report shall include at least the following information:
— reference to this part of EN 455;
— the type of gloves and the manufacturing batch code;
— the name and address of the manufacturer or distributor and of the test laboratory, if different;
— the date when the testing was performed;
2
CAS number means Chemical Abstracts Service Registry Number.
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— the description of the test method applied;
— the test results.
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Annex A
(normative)
Outline method for the determination of solvent extractable chemicals in
medical gloves
A.1 General
This annex provides an outline of the procedures to be followed in determining the solvent extractable
chemical content of a medical glove. It is meant to guide the laboratory through the process of
exaggerated/exhaustive extraction of the chemicals their separation and quantitation. Procedures and
conditions for the extraction process are specified and alternative means of quantitative assay are
suggested. It is the responsibility of the laboratory to establish the suitability of any proposed method
and establish the validity of the method in relation to the product in question.
A.2 Principle
Residual chemicals are extracted from a measured weight of glove material taken from a specified area
of the glove. The extraction medium is selected to be one which is aggressive to the material of the glove
and a good solvent for the chemicals in question. Examples of solvents which are widely published in
the literature include: acetone, acetonitrile, dichloromethane, ethanol, methanol. The quantities of
extracted chemical are assayed according to a validated method of chromatographic separation,
detection and measurement. Results are reported in mg/gram or % w/w of glove material.
A.3 Procedure
A.3.1 Preparation of standard solutions
Weigh the required amount, approximately 0,01 g, of each chemical separately in a 10 ml beaker and
dissolve in selected solvent.
Transfer each dissolved chemical into a 100 ml volumetric flask. Rinse the beaker with solvent
thoroughly. Loosely cap the volumetric flask with stopper and sonicate the mixture for a few minutes or
until the chemicals are dissolved completely.
Allow the sonicated mixture to cool in the fume cupboard. Fill the volumetric flask containing the
mixture of chemicals with solvent to the 100 ml mark. Mix well.
A.3.2 Glove extraction procedure
Samples shall be taken from at least 4 separate gloves.
The test specimen may be sampled at several different points i.e. digits, palm or wrist portions.
Wash and dry hands before handling each glove and cut samples using clean scissors.
From the specified sampling area, cut into approximately 1 cm × 1 cm small pieces and weigh
approximately 1,0 g of glove sample.
Place the glove sample into a 100 ml Duran bottle with approximately 80 ml of solvent. Ensure the
bottle cap is tightly secured and shake the sample for 1 hour on a flask shaker at 300 oscillations/min.
After 1 hour, transfer the extract solution quantitatively to 100 ml volumetric flask by using a funnel
and filter paper (54 hardened). Rinse the Duran bottle with two approximately 10 ml portions of
solvent and make up to the 100 ml mark.
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The short-term stability of all extracts shall be established and extracts shall be analysed before there is
any possibility of degradation.
A.3.3 Chemical separation
The extracted chemicals need to be separated before they can be quantified and this is normally
achieved by chromatography. The most common types of separation methods involve thin layer
chromatography (TLC), gas chromatography (GC) and high pressure liquid chromatography (HPLC).
A.3.4 Chemical quantitation
Detection and quantitation of chemicals is usually by m
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