Final Version  
 
Guidelines on the benefit -risk assessment of the presence of phthalates in certain 
medical devices  
  
 
 
 
 
 
Scientific Committee on Health, Environmental and Emerging Risks  
SCHEER  
 
GUIDELINES   
on the benefit -risk assessment of the presence of  
phthalates in certain medical devices  
covering phthalates which are carcinogenic, mutagenic, toxic to 
reproduction (CMR) or have endocrine -disrupting (ED) 
properties  
 
 
 
 
 
The SCHEER adopted this document at plenary meeting on 18 June 2019  
  
Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 ABSTRACT  
The SCHEER was requested to provide Guidelines on the benefit -risk assessment (BRA)  
of the presence, in the medical devices specified in the regulation , of phthalates , which 
have one or more of the following properties: carcinogenic, mutagenic, toxic to 
reproduction (CMR) or endocrine -disrupt ing (ED), according to the criteria outlined in the 
legal obligation section from the mandate.  
  
Phthalates are widely used in industry as plastici sers of polymers, in a variety of 
applications such as coated fabrics and roofing membranes, as well as in me dical 
devices, adhesives, paints, inks and enteric -coated tablets. Di -(2-(ethylhexyl) phthalate 
(DEHP) is the most widely used phthalate in medical devices. Dimethyl phthalate (DMP) 
and diethyl phthalate  (DEP) are not used as plasticis ers but e.g. as addit ives in 
cosmetics, medical devices, and household products.  
The interaction of phthalates with the polymers they are embedded in is weak, so they 
may be released from the plastic product into the environment and into the human body 
if the product is in con tact with it.  
 
The Medical Device Regula tion, Regulation (EU) 2017/745 allows the use of CMR 1A/1B 
and/or ED substances in medical devices above a concentration of 0.1% w/w. when a 
proper justification can be provided (Annex I, Chapter II Section  10.4). Fo r such a 
justification several steps need to be considered including  the availability  of alternative 
substances, materials, designs, and medical treatments. In addition, the risk associated 
with such alternatives should be weighed against the risk of the u se of CMR 1A/1B and/or 
ED identified phthalates covered under MDR Annex I Chapter II Section  10.4.1 . However, 
the risk by itself is not the only parameter to consider:  also the impact of the possible 
alternatives on the functionality, performance and the overall benefit -risk ratio of the 
medical device shall be evaluated.  
 
These Guidelines describe the methodology on how to perform a BRA for the justification of 
the presence of CMR 1A or 1B and/or ED phthalates (CMR/ED phthalates) in medical devices 
and/or or parts or materials used therein  at percentages above 0.1% by weight (w/w).  
They also describe  the evaluation of possible alternatives for these phthalates used in 
medical devices , including  alternative materials, designs or medical treatments .  
They are intended to be used by the relevant stakeholders e.g. manufacturers, notified 
bodies and regulatory bodies.  
The approach of these Guidelines may also be used for a BRA of other CMR/ED 
substances present in medical devices.  
 
During the preparation of these Guidelines for BRA of the use of CMR/ED phthalates in 
medical devices, SCHEER noticed that a number of BRA methodologies are theoretically 
available. However , there is a considerable lack of data  needed for the BRA  for potential 
relevant  alternatives to be used in medical devices. Therefore, SCHEER encourages 
manufacturers to generate data of high quality on  such alternatives  for CMR/ED 
phthalates in medical devices.  
Pending on new scientific evidence, it is recommended to evaluate the use and 
usefulness of these Guidelines after an application  period of three years.  
 
Keywords: Guidelines, benefit -risk assessment , CMR/ED phthalates, medical devices, 
SCHEER . 
Guidelines  to be cited as:  SCHEER (Scientific Committee on Health, Environmental and 
Emerging Risks), Guidelines on the benefit -risk assessment of the presence of phthalates 
in certain medical devices  covering phthalates which are ca rcinogenic, mutagenic, toxic 
to reproduction (CMR)  or have endocrine -disrupting (ED) properties, final version 
adopted at  SCHEER plenary on 18 June 2019.  Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
(final version)  
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ACKNOWLEDGMENTS  
 
 
Members of the Working Group are acknowledged for their valuable contribution to this 
opinion. The members of the Working Group are:  
 
SCHEER members:  
Teresa Borges  
Rodica Mariana Ion  
Wim H. de Jong    (Chair and Rapporteur)  
Demosthenes Panagiotakos   
Emanuela Testai  
Theo Vermeire  
 
 
SCCS members:  
Ulrike Bernauer  
Christophe Rousselle  
 
 
External experts:  
Stéphane Bégué  (Etablissement Français du Sang, EFS, Paris, France)  
Hilde B. M. Kopperud  (Nordic Institute of Dental Materials, Oslo, Norway)  
Maria Rosaria Milana   (Istituto Superiore di Sanità, Dip. Ambiente e Salute, Roma, Italy)  
Tanja Schmidt   (Ansbach University of Applied Science,  Ansbach,  Germany)  
 
 
Experts from EU Agencies : 
Francesco Pignatti   (European Medicines  Agency ) 
Evgenia Stoyanova   (European Chemicals Agency ) 
Katarina Volk    (European Food & Safety Authority ) 
  
 
 
 
 
All Declarations of Working Group members are available at  the following webpage:  
http://ec.europa.eu/health/scientific_committees/experts/declarations/scheer_wg_en   
 
 
 
 
 
 Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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4About the Scientific Committees (2016 -2021)  
Two independent non -food Scientific Committees provide the Commission with the 
scientific advice it needs when preparing policy and proposals relating to consumer 
safety, public health and the environment. The Committees also draw the Commissio n's 
attention to the new or emerging problems which may pose an actual or potential threat . 
They are: the Scientific Committee on Consumer Safety (SCCS) and the Scientific 
Committee on Health, Environmental and Emerging Risks (SCHEER). The Scientific 
Comm ittees review and evaluate relevant scientific data and assess potential risks. Each 
Committee has top independent scientists from all over the world who are committed to 
work in the public interest. 
In addition, the Commission relies upon the work of other Union bodies, such as the 
European Food Safety Authority (EFSA), the European Medicines Agency (EMA), the 
European Centre for Disease prevention and Control (ECDC) and the European Chemicals 
Agency (ECHA).  
SCHEER  
This Committee, on request of Commission services, provides Opinions on questions 
concerning health, environmental and emerging risks. The Committees addresses 
questions on: 
-health and environmental risks related to pollutants in the environmental media  and
other biological and physical factors in relation to air quality, water, waste and soils.
-complex or multidisciplinary issues requiring a comprehensive assessment of risks to
consumer safety or public health, for example antimicrobial resistance, n anotechnologies,
medical devices and physical hazards such as noise and electromagnetic fields.
SCHEER members  
Roberto Bertollini, Teresa Borges, Wim de Jong, Pim de Voogt, Raquel Duarte -Davidson, 
Peter Hoet, Rodica Mariana Ion, Renate Kraetke, Demosthen es Panagiotakos, Ana 
Proykova, Theo Samaras, Marian Scott , Remy Slama, Emanuela Testai, Theo Vermeire, 
Marco Vighi, Sergey Zacharov  
Contact  
European Commission  
DG Health and Food Safety  
Directorate C: Public Health, Country Knowledge, Crisis management  
Unit C2 – Country Knowledge and Scientific Committees 
Office: HTC 03/073   L -2920 Luxembourg
SANTE- C2-SCHEER@ec.europa.eu   
ISBN 978-92-76-15387-0© European Union, 2020 
ISSN 2467-4559
doi: 10.2875/784367 EW-CA-20-001-EN-N
The Opinions of the Scientific Committees present the views of the independent scientists 
who are members of the committees. They do not necessarily reflect the views of the 
European Commission. The Opinions are published by the European Commission in their 
original language only. 
http://ec.europa.eu/health/scientific_committees/policy/index_en.htm  Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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TABLE OF CONTENTS  
 
ACKNOWLEDGMENTS  ................................ ................................ ................................ ...........  3 
A. GUIDELINES on benefit -risk assessment for CMR and/or endocrine -disrupting phthalates 
used in medical devices  ................................ ................................ ..............................  6 
1. Introduction  ................................ ................................ ................................ ..............  7 
2. Framework for Benefit -Risk Assessment  ................................ ................................ ..... 10 
3. Assessment of the presence of phthalates in a medical device  ................................ ....... 15 
4. Assessment of possible alternative substances, materials, designs or medical treatments  . 18 
5. Assessment of potential relevant alternative substances, materials, designs or medical 
treatments versus CMR/ED phthalates  ................................ ................................ ........  23 
6. Justification for the use of CMR/ED phthalate  ................................ ..............................  25 
7. Benefit assessment  ................................ ................................ ................................ .. 27 
7.1 Material benefit  ................................ ................................ ................................ ....... 28 
7.2 Clinical benefits  ................................ ................................ ................................ ....... 28 
8. Methodologies for Benefit –Risk Assessment  ................................ ...............................  29 
9. Uncertainty analysis  ................................ ................................ ................................ . 30 
10. Conclusions  ................................ ................................ ................................ .............  34 
11. Consideration of the responses received during the public consultation process  ...............  35 
B. REFERENCES  ................................ ................................ ................................ ...........  36 
C. ANNEXES  ................................ ................................ ................................ ................  40 
Annex  1: SCHEER mandate on benefit -risk assessment on the use of CMR/ED phthalates  ...........  40 
Annex 2: Medical Device Regulation (Regulation 2017/745) on CMR and/or ED substances  .........  44 
Annex 3: Definitions/descriptions – References - Glossary  ................................ .......................  45 
Annex 4: CMR and/or ED substances  ................................ ................................ ....................  51 
Annex 5: Legislation on CMR and/or ED phthalates  ................................ ................................ . 53 
Annex 6: Use of phthalates in medical devices  ................................ ................................ ....... 57 
Annex 7: Approaches for Benefit -Risk Assessment  ................................ ................................ .. 60 
 
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A. GUIDELINES  on benefit -risk assessment  for CMR and/or endocrine -
disrupting phthalates used in medical devices  
 
Scope  
The Regulation  (EU) 2017/745 on m edical devices (MDR), Annex I “General Safety and 
Performance Requirements”, Chapter II “Requirements regarding design and 
manufacture”, Section  10.4 deals with the presence of substances that may be released 
from a medical device. Annex I Chapter II Section  10.4.1 state s that substances that are 
carcinogenic, mutagenic, or reprotoxic (CMR) of category 1A and 1B, or substances 
having endocrine -disrupting (ED) properties for which there is scientific evidence of 
probable serious effects on humans, shall only be present in device s, or parts thereof or 
those materials used therein , above 0.1% weight by weight (w/w) when justified 
according to a set of criteria listed under Section  10.4.2.  
These Guidelines1 describe the methodology on how to perform a BRA for the justification 
of the presence of CMR 1A or 1B and/or ED phthalates (CMR/ED phthalates) in medical 
devices at percentages above 0.1% by weight (w/w). They also describe the evaluation 
of possible alt ernatives for these phthalates used in medical devices , including  alternative 
materials, designs or medical treatments . They are intended to be used by the relevant 
stakeholders e.g. manufacturers, notified bodies and regulatory bodies.  
These Guidelines apply to those medical devices and components thereof indicated in 
Annex I section 10.4.1.of the MDR . They do not provide information for the BRA of the 
use of a medical device itself . However, the BRA as described can be integrated within 
the risk management system for individual medical devices. For the BRA of medical 
devices in general, stakeholders are referred to  section A7.2. of MEDDEV 2.7/1, revision 
4. Additional information may be found elsewhere, for example in the following 
documents  FDA 2 016, 2018, EN ISO 14971,  ISO/TR 24971. It should be noted that the 
acceptability of any risk is evaluated in relation to the benefit of the use of the medical 
device.  
When the word “patient” is used in these Guidelines, this also covers  professional users  
and other persons (e.g. donors in case of blood donation) exposed to the medical device 
as well.  
Annex 1 to these Guidelines describes the mandate, Annex 2 describes Annex I Chapter 
II Section  10.4. of the MDR regarding the use of substances  that could be  released from 
the medical device and pose a risk to patients,  and Annex 3 describes the definitions 
used in these Guidelines.  
 
 
 
                                                           
1 It should be noted that, in accordance with Regulation (EC) 2017/745, Annex I, Chapter II Section 10.4.3. 
and 10.4.4., updates of these Guidelines might be available in the future.  Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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1. Introduction  
 
Placing medical devices  on the market,  making them available on the market and putting 
them into service are all activities governed by Regulation (EU) 2017/745 that replaces 
Directive s 90/385/EEC and  93/42/EEC . Medical devices are defined in the MDR as 
presented in the text box below:  
For the purposes of this Regulation, the following definitions apply  
(1) ‘medical device’ means any instrument, apparatus, appliance, software, implant, 
reagent, material or other article intended by the manufacturer to be used, alone 
or in combination, for human beings for one or more of the following specific 
medical purposes :  
— diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of 
disease,  
— diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or 
disability,  
— investigation, replacement or modification of the anat omy or of a physiological or 
pathological process or state,  
— providing information by means of in vitro examination of specimens derived from 
the human body, including organ, blood and tissue donations, and which does not 
achieve its principal intended a ction by pharmacological, immunological or metabolic 
means, in or on the human body, but which may be assisted in its function by such 
means.  
The following products shall also be deemed to be medical devices:  
— devices for the control or support of conce ption;  
— products specifically intended for the cleaning, disinfection or sterilisation of 
devices as referred to in Article 1(4) and of those referred to in the first paragraph of 
this point.  
As a general requirement , the medical device shall perform acc ording to its intended 
purpose and be safe for professional  users and patients , or where applicable other 
persons (e.g. donor s) on which the device is used. The conformity of medical devices 
shall be evaluated against the requirements of the Regulation (EU) 2017/745. They shall 
be presumed to be in conformity with this Regulation if they are in conformity with EU -
harmonised standa rds or the relevant parts of those standards, the references of which 
have been published in the Official Journal  of the European Union. Although not 
mandatory, these standards provide a route to comply with the MDR.  
For medical devices the horizontal standards EN ISO 14971 and EN ISO 10993 -1 are 
especially relevant. EN ISO 14971 describes the application of a risk management 
process for medical devices, whereas EN ISO 10993 -1 deals with the biological evaluation 
and t esting of medical devices within a risk management process. According to EN ISO 
10993 -1, evaluation of the biological safety of a medical device should be a strategy Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 planned on a case -by-case basis to identify the hazards and estimate the risks of known 
hazards. In Annex A of EN ISO 10993 -1, a series of endpoints is indicated from which a 
selection can be made for the biological evaluation of a medical device. The selection is 
based on the nature of the device's contact with the body (device category: surfa ce 
device, external communicating device, or implant device; type of contact: skin, mucosal 
membrane, compromised surface, blood, tissues, organs; duration of the contact: limited 
≤24 h, prolonged >24 h to 30 days, permanent >30 days). A systematic literat ure 
review is part of the biological evaluation of a medical device in order to avoid 
unnecessary testing  (EN ISO 10993 -1). This systemic literature review should also be 
performed for a CMR/ED phthalate or potential relevant alternatives identified for a given  
in a medical device.  
In addition to EN ISO 10993 -1, a series of EN ISO 10993 standards has been published 
describing various assays and approaches for the evaluation of the endpoints identified in 
EN ISO 10993 -1 for the biological evaluation of medic al devices. Assays described in the 
various standards include cytotoxicity, sensitisation, irritation, systemic toxicity, 
implantation, haemocompatibility, genotoxicity, and carcinogenicity endpoints.  
Additionally immunotoxicity and organ -specific toxiciti es need to be considered, if 
appropriate.  In addition, reproductive and developmental toxicity should be addressed for 
novel materials, materials containing substances with a known reproductive or 
developmental toxicity, medical devices with relevant targe t populations (e.g. pregnant 
women), and/or medical devices where there is the potential for local presence of device 
materials in the reproductive organs (EN ISO 10993 -1:2018). For the risk assessment EN 
ISO 10993 -17 describes determination of allowable l imits for leachable substances, 
whereas EN ISO 10993 -18 describes methods for chemical characterization of materials 
used in medical devices. In addition to the horizontal standards, vertical i.e. device 
specific standards and standards for clinical investigation are available ( e.g. EN ISO 
14155).  
Furthermore, the EU also provides guidance in MEDDEV documents (e.g. MEDDEV 2.7/1 
rev.4 for clinical evaluation of medical devices).  
The MDR states that substances that are classified as carcinogenic, muta genic, or toxic to 
reproduction (CMR) of category 1A or 1B, or substances identified at EU level as having 
endocrine -disrupting (ED) properties for which there is scientific evidence of probable 
serious effects on humans  (CMR/ED substances, in this text) , shall only be present in a 
device s or parts thereof or those materials used therein  above 0.1% weight  by weight 
(w/w) when justified. Annex 4 provides further information on the classification of CMR 
and on identification of ED substances. The justificatio n for the use of CMR/ED 
substances in a medical device above 0.1% w/w, shall be based on an analysis of 
potential patient and user exposure, availability of possible alternatives, an 
argumentation why possible alternatives are appropriate or inappropriate,  and on the 
most recent Guidelines of this Scientific Committee.  
Phthalates are a group of substances widely used in medical devices. When  used as  
plastici sers they may comprise a substantial part of the medical device. A typical 
concentration of Bis(2 -ethylhexyl) phthalate (DEHP; CAS 117 -81-7) in plastici sed 
polyvinyl chloride (PVC) can be 30% based on weight (ECB 2008, SCENIHR 201 5). For 
many years the reproductive toxicity and the possible endocrine disrupting activity of 
certain phthalates has been a source for debate.  Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 Phthalates currently classified as reproductive toxicants category 1B under the 
Classification, Labelling and Pa ckaging (CLP) regulation (EC 1272/2008) and identified as 
substances of very high concern (SVHC)  under Article 57 (c) of REACH Regulation (EC) 
1907/2006 are listed in Annex 5  of this document . This list may be updated, so it is 
recommended to consult the An nex VI of the CLP Regulation.  
In addition, the Commission Implementing Decision (EU) 2017/1210 and Commission 
Implementing Decision (EU) 2018/636 identified some phthalates as substances of very 
high concern (SVHC) according to Article 57(f) of REACH Regu lation (EC) 1907/2006,  
due to their endocrine disrupting properties with probabl e serious effects to humans, 
namely Bis(2 -ethylhexyl) phthalate (DEHP), Benzyl butyl phthalate (BBP), Dibutyl 
phthalate (DBP) , Diisobutyl phthalate (DIBP) , and Dicyclohexylphthalate  (DCHP) . Bis(2-
ethylhexyl) phthalate (DEHP), was also identified in 2014 as a substance of very high 
concern in  accordance with Article 57(f) of Regulation (EC) 1907/2006 (REACH) because 
it is a substance with endocrine disrupting prop erties for which there is scientific evidence 
of probable serious effects to the environment which give rise to an equivalent level of 
concern to those of other substances listed in points (a) to (e) of Article 57 REACH. 
https://echa.europa.eu/documents/10162/21837b30 -0318-8b45-92db-9e8c39f89dee  
SCENIHR adopted an Opinion on the safety of medical devices containing DEHP -
plasticised PVC in 2008, and a revision of this  Opinion in 201 5 (SCENIHR 2008, 201 5). 
The main source for DEHP exposure of the general population was determined to be food. 
In addition, the use of medical devices can increase the exposure considerably in the 
course of specific medical treatments, for e xample during massive blood transfusions, 
haemodialysis, and in neonatal intensive care units (NICU) for prematurely born 
neonates (SCENIHR 201 5). Although quite a number of alternative substances were 
available for DEHP, for some of them serious data gaps were observed regarding hazard 
identification and exposure estimation (Bui et al., 2016, SCENIHR 201 5). The Danish EPA 
assessed different alternatives and concluded that to various degrees some substances 
can be considered to be relevant alternatives to DEHP in terms of human health hazards, 
especially regarding the endpoints reproductive and developmental toxicity (Nielsen et al. 
2014). However, for a number of possible alternatives the data set was limited. Some 
alternatives showed a low  migration rate and some of them are already used as 
substitutes in medical devices for traditional DEHP -applications. For example, four 
additional plasticisers for PVC (BTHC, DEHT, DINCH, and TOTM) used in medical devices 
have recently been included in th e updated chapters of the European Pharmacopoeia 
(Council of Europe, EDQM 2018).  
Phthalates classified as CMR of category 1A or 1B according to the procedure described in 
Annex 4 are listed in Annex VI of the CLP regulation (CLP -Regulation (EC) No 1272/200 8, 
OJ L353). According to  article 57 (f) of REACH (Regulation (EC) 1907/2006) or the 
Biocides Regulation ( Regulation (EC)  528/2012) phthalates can be identified as having 
ED-properties when  there is scientific evidence of probable serious effects to human 
health .  
These Guidelines provide a framework of how to perform a BRA for the presence of such 
CMR and/or ED phthalates in medical devices or parts or materials used therein at 
percentages above 0.1% weight by weight (w/w) , and shall be used by all relevant 
stakeholders, e.g. manufacturers and notified bodies, and regulatory bodies for the 
justification of the presence of CMR/ED phthalates . The evaluation according to the Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 Guidelines should be performed by a multidisciplinary team including amongst others  e.g. 
a material scientist, medical device specialist, toxicologist and clinician.  
A justification for the use of a CMR/ED phthalate can also be based on an already 
availabl e justification relating to a medical device for which equivalence with the device 
in question can be demonstrated according to the MDR Annex XIV Section 3. The existing 
justification can be used as a reference, and the data used for this justification sho uld be 
available . 
The approach of these Guidelines can also be u sed for a BRA of other CMR/ED substances 
present in medical devices.  
Other descriptions for BRA may be “benefit -risk analysis” or “benefit -risk determination” 
as defined in the MDR. As Annex I Section 10.4.3 indicates a benefit -risk assessment this 
terminology is used in these Guidelines.  
 
 
2. Framework for Benefit -Risk A ssessment   
 
The MDR allows the use of CMR 1A/1B and/or ED substances in medical devices above a 
concentration of 0.1% w/w when a proper justification can be provided ( MDR Annex I, 
Chapter II  Section  10.4). For such a justification several steps need to be considered 
including the availability  of alternative substances, materials, designs, and medical 
treatments. In addition, the r isk associated with such alternatives shall be weighed 
against the risk of the use of CMR 1A/1B and/or ED identified phthalates covered  under 
MDR Annex I Chapter II Section  10.4.1. However, the risk is not the only parameter to 
consider . The impact of the possible alternatives on the functionality, performance and 
the overall benefit -risk ratio of the medical device should also be evaluated.   
The justification for the presence of CMR 1A or 1B and/or ED phthalates for which there 
is scientific evidence of probable  serious effects on humans should be based on a number 
of considerations as described below and in Figure 1 .  
In order to perform the BRA as indicated above , it is important to describe the 
terminology to compare the risk s of the presence of the phthalates  to be evaluated (see 
text box below). Annex 3  provides  a selection of definitions as present in the MDR and/or 
the OECD Substitution and Alternatives Assessment Toolbox. (http://www.oecdsaatoolbox.org/ ) 
For the purpose of these Guidelines the following definition for "alternatives" is used:  
“alternatives  are defined as substances, materials, designs  and medical treatments  that 
can be used to replace the use of CMR and/or ED  substances in medical devices”  
The alternative therefore is not limited to a possible substitute substance or material but 
could also be another device design (e.g. coating/production process/ techniques /lower 
concentration  of substances)  or medical treatment (e.g. procedure, device) or a 
combination of technical and substance alternatives that can substitute or eliminate the 
use of the CMR/ED phthalate (modified from the ECHA REACH guidance on the 
preparation of an application for authori sation).  
The functionality and performance of the alternative should  be comparable to the extent 
that there would be no clinical ly relevant  difference foreseen in the performance of the Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 device or in the outcome of the alternative medical procedure. Conside rations of 
functionality and performance shall be based on proper scientific justification. In order to 
justify the use of a CMR 1A or 1B and/or ED phthalate, the manufacturer shall clearly 
demonstrate that the identified alternative(s) are not appropriate  to maintain the 
functionality, performance and benefit -risk ratios of the medical device.  
A number of aspects need to be considered for the justification of the presence of a 
phthalate classified as CMR category 1A or 1B and/or identified as ED above  content > 
0.1% w/w in a medical device , or parts thereof or those materials used therein, as 
intended to be used.   
In summary, these aspects can be considered by a stepwise approach given below and 
presented in Figure 1. Further details and examples on the steps used in the Guidelines 
are given in the following chapters.  
Assessment of the CMR/ED phthalate  (CMR/ED scenario)  
Step 1:  
Description and characterisation of the composition of the medical device  (or parts 
or materials thereof) . Identif ication  of the  presence and concentration of CMR/ED 
phthalate (s) in weight by weight percentage (% w/w) . 
 
Step 2:  
Description of the use and function of the CMR/ED phthalate used in medical 
device.  
2a. Description of functionality/performance provided by the presence of the 
CMR/ED phthalate.  
2b. Description of the benefit (material and/or clinical) of the presence  of CMR/ED 
phthalate in the medical device.  
 
Step 3:  
Assessment of the risks of the CMR/ED phthalate.  
3a. Determin ation of  the patient exposure based on realistic worst -case2 use 
scenario  in the intended use . 
3b. Identif ication of  biocompatibility, general toxicological and specific CMR/ED 
hazards associated with the phthalate.  
3c. Determin ation of  the maxim um tolerable/ acceptable exposure for the patient,  
based on pre -clinical and clinical information (if available).  
3d. Determination of the risks for various intended  use scenarios and patient 
groups.  
 
Assessment of possible alternative (s) (non CMR/ED  phthalate scenario)  
Step 4:  
Inventory of possible alternative (s).  
4a. Substances.  
4b. Materials.  
                                                           
2 Realistic worst case is the situation where the exposure is estimated us ing a range of factors (i.e. duration, 
amount, exposure controls), where applicable, the ones that would be expected to lead to maximum amount of 
exposure (e.g. exposure might be assessed under realistic simulated -use scenarios by EN ISO 10993 -12 and 
EN IS O 10993 -18 or a non-volatile  residue test (USP <661>)). The realistic worst case does not include 
deliberate misuse. (EU Biocides Regulation 528/2012).  Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 4c. Designs and/or medical treatments3. 
 
Step 5:  
Identification of the potential relevant candidates for assessment as alternatives 
to CMR/ED  phthalates and justification for the selection and exclusion of possible 
alternatives.  This also includes assessment of the availability of the potential 
alternative (s). 
 
Step 6:  
Description of identified potential relevant alternative(s).  
6a. Description of functionality and performance  of the potential alternative(s).  
6b. Description of the benefit (material and/or clinical) of the use o f the potential 
alternative(s).  
 
Step 7:  
Assessment of the risk of identified potential relevant alternative (s). 
7a. Determination of patient exposure o f the alternative based on a realistic 
worst -case use scenario in the intended use.  
7b. Identification, where available, of biocompatibility, toxicological and CMR/ED 
hazards associated with the alternative.  
7c. Determination of maximum tolerable/acceptabl e exposure of the alternative 
for patient (if available).  
7d. Determination of risk of potential alternatives for various use scenarios and 
patient groups.  
 
Assessment of potential relevant alternative (s) versus CMR/ED phthalate  
Step 8:  
Comparison of functionality and performance of CMR/ED phthalate as used in the 
medical device with functionality and performance of identified potential relevant 
alternative (s). 
 
Step 9:  
Comparison of hazard (s) of original CMR/ED phthalate as used in the medical 
device with hazard (s) of identified potential relevant alternative (s). 
 
Step 10:  
Comparison of benefit and risk of CMR/ED phthalate used in the medical device 
with identified potential relevant alternatives.  
 
In addition to patients, the same  approach shall be used for the justification of the 
presence of CMR/ED phthalate in medical devices to evaluate the risk for professional 
users and for other persons (e.g. donors) exposed to the CMR/ED phthalates. When 
alternative designs or medical treat ments were identified as potential alternatives in step 
5, adequately adopted endpoints for risks and benefits shall be chosen.  
It should be noted that scientific developments may be available after the initial 
assessment regarding the use of alternatives for CMR/ED phthalates . Therefore, a 
                                                           
3 It should be noted that for alternative designs and/or medical treatments, appropriate endpoints for r isks and 
benefits shall be selected.  Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 revision of the BRA of the presence of the CMR and/or ED phthalate may be necessary. 
Revisions of the above indicated BRA shall occur as indicated in the relevant sections of 
MDR for the general risk assessment of the me dical device.   
Figure 1 illustrates the BRA and is based on Eliason and Morose (2011), EMA (2014), FDA 
(2016) and a critical selection from the OECD Substitution and Alternatives Assessment 
Toolbox ( http://www.oecdsaatoolbox.org ). It presents the stepwise approach described 
above including a general description of factors to consider when performing a BRA.  
Figure 1 presents a use scenario in which the CMR/ED is used in a medical device versus 
a non -use scenario in which a proper potential alternative is evaluated.  
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 Figure 1 . BRA for evaluation of presence  of CMR/ED phthalates and their  
potential alternatives in medical devices  (relevant sections between brackets) . 
Step 3 (3)
Use scenario
Assessment of the risks of phthalate
3a. Exposure assessment patient
3b. Biocompatibility, hazard assessment
3c. Maximum tolerable /acceptable dose
3d. Risk characterisation Step 4 (4)
Inventory of possible alternatives
4a. Substitute substances
4b. Substitute materials
4c. Alternative designs/treatmentsDefine aim and 
scope
Step 1 (3)
Description and characterisation of 
composition of medical device, 
IdentifIcation of presence and 
amount of CMR/ED phthalate
Step 2
Description of phthalate 
2a. Use, functionality and performance of 
phthalate (3)
2b. Benefit (7)Step 5 (4) 
Identification of  potential candidates for 
alternatives and justification for the 
selection and exclusion
Step 6
Description of identified potential 
relevant alternatives
6a. Functionality, performance (4)
6b. Material and clinical benefit of the 
use (7)
Step 7 (4)
Assessment of the risks of Identified 
potential relevant alternative(s)
7a. Exposure assessment patient or user
7b. Biocompatibility, hazard assessment
7c. Maximum tolerable /acceptable dose
7d. Risk characterisation
Step 8 (5)
ComparIson of  functionality,  
performance of use and non- 
use scenario
Overall summary report
Justification for continued use of 
CMR/ED phthalate (6)Step 9 (5)
Comparison of hazard(s) of use 
and non-use scenario
Step 10 (5,7, 8)
Comparison of benefit and risk 
of  use and non-use scenario
Uncertainty analysis (9)Non-CMR/ED 
phthalate 
scenarioCMR/ED 
phthalate 
scenario
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3. Assessment of the presence of phthalates in a medical device4 
 
It is already necessary to provide most of the information as indicated for the use of 
CMR/ED phthalates in order to prove compliance with the general safety and 
performance requirements for the phthalate containing medical device.  
 
When more than one CMR/ED phthalate is used simultaneously in the medical device, a 
justification shall be provided for each of the phthalates and their combination.  Some risk 
assessment data regarding the combinat ion of phthalates are available, as EFSA has 
recently proposed a Group TDI for some of them, having a similar Mode of Action (MOA) 
in vivo  (EFSA 2019, see Annex 5). Information on assessment of combined exposures to 
phthalates can be found for example at the report by the National Research Council 
Committee on the Health Risk of Phthalates (2008) and the ECHA website on the  
restriction of f our phthalates ( https://echa.europa.eu/registry -of-restriction -intentions/ -
/dislist/details/0b0236e180d73895 ) and EFSA guidance on cumulative expos ure (EFSA, 
2019 https://doi.org/10.2903/j.efsa.2019.5634 )  
 
Step 1: Description and characterisation of the composition of the medical device.  
Provide a description of the medical device and its composition including identification 
and the concentration of each CMR/ED phthalate in the device , and the type of chemical 
/physical binding of the phthalate in the formulation/device, when there is an impact on 
leakage.  Use available chemical information  for identifying target phthalates (e.g. CAS 
Nº; EINECS Nº; IUPAC name).  The chemical composition of a medical device can be 
evaluated by using e.g. EN ISO 10993 -18 (FDIS published in 2019) . 
 
Step 2: Use and function of CMR/ED phthalates in the medical dev ice.  
Characterise the function and use of the CMR/ED phthalates in the medical device and 
the properties it imparts to the device. Provide a description of the intended use, 
functionality and performance of the medical device containing the CMR/ED phthala te 
and how the use of the phthalate is critical for its functionality and performance . For 
example, for PVC consider, with regard to the performance of the medical device, 
maintenance, flexibility, durability and for the phthalate viscosity and PVC compatibility. 
Provide a description of the patients targeted (e.g. with respect to sex, age, probable 
vulnerable groups5). Provide a description of use types of the medical device for which it 
is intended (e.g. single  vs repeated exposure ). Other aspects that can be relevant include 
the critical properties (e.g., flexibility), the conditions of use, critical quality criteria, 
process/treatment and performance constraints (e.g., sterilization, device/drug 
interactions), regulatory or clinical or other requi rements that the CMR/ED phthalates 
and the phthalate -containing device need to deliver. Key criteria for the function,  
                                                           
4 The analysis presented in section 3 (steps 1 -3) describes the current use scenario of the CMR/ED phthalate, 
i.e., the scenario that would continue in the future if no additional action (other than, e.g., a planned regulatory 
action entering into force) is taken to limit, substitute or eliminate the presence of the CMR/ED phthalate in the 
medical device. The current scenario can also be referred to as baseline, business as usual or continued use 
scenario.  
5 Vulnerabl e Groups (in these Guidelines): vulnerable groups of the population such as children and individuals 
with increased susceptibility due to pre -existing disease, medication, compromised immunity, pregnancy or 
breastfeeding, women and men in reproductive age.  These vulnerable groups also include infants, elderly 
people or people with poor health conditions.  
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 performance and overall use should be outlined and applied as the basis for an 
identification and screening of possible alternatives and a more detailed assessment of 
potential alternatives. Justification for the selection of these criteria should be provided.  
 
Benefits of the device with CMR/ED phthalates should also be considered  e.g. treatment 
of specific patients groups due to tuning of  flexibility of the medical device . Present an 
inventory of the benefits of the CMR/ED phthalates in the medical device for the patients 
(separately for vulnerable groups). More detailed information on the benefit assessment 
is presented in section 7.  
 
Step 3: Assessment of the risks of the CMR/ED phthalate.  
Perform a risk assessment of the CMR/ED phthalate present in the medical device. The 
risk assessment should contain a description of the potential phthalate exposure of 
various patient groups for which  the medical device is intended (e.g. single  vs repeated 
exposure ). This should separately include vulnerable groups. EN ISO 10993 -1 provides 
information on use type in terms of exposure potential (e.g.  limited ( ≤24h), prolonged 
(>24h to 30d) and permanen t (>30d))  that slightly differs from the duration of use as 
defined in the MDR (Annex VIII, 1, transient <60 minutes, short term 60 minutes to 30 
days, long term >30 days).  
 
Exposure estimation  
 
Provide information , preferably based on data from direct measurement or, when not 
available, an estimation based on worst -case scenario or from scientific literature , on the 
release of the CMR/ED phthalate from the medical device when used in various clinical 
modalities. For  data generation , analytical contact conditions for the evaluation of 
leaching of substances from medical device s, should consider fo r example temperature, 
contact duration and frequency, polarity of contact liquids, flow rates, contact surface, 
and volume  of contact liquids (EN ISO 10993 -1, EN ISO 10993 -12, EN ISO 10993 -18,  USP 
661). The contact conditions should be set to represent realistic worst -case conditions 
taking into account the intended use of the medical device.  
 
Estimate exposure to the phtha late(s) considering data on the release of the substance 
from the device. Consider repeated use scenarios (e.g. dialysis, apheresis donation, 
chronic treatment)  and different population groups. The combined exposure to different  
CMR/ED  phthalates also needs to be considered  when present in a medical device. More 
details on the use of phthalates in medical devices  are presented in Annex 6.  Risk 
management measures in place and their effectiveness should be described and taken 
into account in the assessme nt (EN ISO 14971, EN ISO 10993 -1). In addition, data from 
biomonitoring programs may become available that could also provide information on 
exposure levels of phthalates in the general population and more specifically during 
medical treatment.   
 
Hazard id entification  
 
Describe hazards associated with the CMR/ED phthalate by considering all relevant 
toxicological endpoints for acute as well as for repeated dose toxicity. EN ISO 10993 -1 
provides information on hazard endpoints to be considered depending on the exposure 
and use category of a medical device, whereas allowable limits can be determined 
according to EN ISO 10993 -17.  Possible hazardous effects of combined exposure  should Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 also be assessed.  Identify  an adequate point of departure (PoD) for risk ass essment. In 
case of a threshold Mode of Action, such a PoD could be the most sensitive no-observed -
adverse -effect -level (NOAEL ) or lowest -observ ed-adverse -effect -levels (LOAEL ), or a 
dose that causes a predefined response (Benchmark dose – BMD) obtained by  
Benchmark dose modelling. In case of non -threshold effects (e.g. in the case of 
genotoxic carcinogens or for certain substances acting via an ED -mediated MoA), such a 
dose descriptor could be a T256 value or the benchmark dose associated with a 10% 
response (BMD10) (ECHA, 2012).  
 
Where a reference DNEL and /or a reference DMEL have already been derived in the 
context of other EU legislations, the analysis could refer to these derived figures without 
referring to detailed assessment how these data have been derived (e.g. under REACH 
legislation, Food Contact Material legislation). However, as some of these data may have 
been derived in the past, relevant up -to-date scientific evidence (based upon a 
systematic li terature review) and up -to-date risk assessment methodology for all 
relevant toxicological endpoints needs to be considered . If such DNEL/DMELs are not 
used in the assessment, a justification should be presented (e.g. new 
information /studies). Some of thes e other legislations  are defined under Annex 4. In 
addition, information can also be obtained in the SCENIHR 201 5 Opinion on DEHP.  
 
The ED property of the phthalate can be described according to the recently published 
EFSA/ECHA guidance document . 
https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2018.5311   
This includes impacts on fertility, birth defects (e.g., cryptorchidism, hypospadias), 
developmental effects, and other effects associated with the CMR/ED phthalates.   
 
Describe risk (risk characterisation)  
 
The risk can be described by comparing exposure levels that are considered safe with the 
expected exposure (worst -case scenario) to obtain a risk characterisation ratio (RCR). 
Starting points (points of departure, PoD) for exposure levels that are considered safe 
could be the most sensitive no -observed -adverse -effect -level (NOAEL) or lowest -
observed -adverse -effect -levels (LOAEL), or a dose that causes a predefined response 
(Benchmark dose – BMD) for threshold substances. For non -threshold substances, a T25 
value or the benchmark dose associated with a 10% response (BMD10) could be used. 
From these PoDs, acceptable expo sure values can be derived such as “Der ived No -Effect 
Level ” (DNEL), “Derived Minimum Effect Level” (DMEL) or intakes over lifetime without 
presenting an appreciable risk to health (ADI or TDI/TWI or TE).  As such data are often 
obtained in rat studies, th e use of the TDI seems more appropriate in view of the critical 
effect window for androgenic reproductive toxicity in rats has been reported to be a few 
days (Welsh et al. , 2008). In addition, patients may be exposed to medical devices only 
for a limited p eriod of time.  EN ISO 10993 -17:2002 7 calculates for medical devices a 
Tolerable Exposure (TE), which is based on a product of the tolerable intake, the body 
mass and the utilization factor.  When necessary, acceptable exposure levels  can be 
derived by dividing the point of departure for risk assessment by appropriate assessment 
or uncertainty factors . Specifically for ED effects additional assessment factors might be 
considered as proposed recently (Hass et al.,  2019).  
                                                           
6 Animal dose -descriptor; chronic dose rate that will give 25% of the animal's tumours at a specific tissue site 
after correction for spontaneous incidenc e (Dybing et al.,  1997)  
7 EN ISO 10993 -17:2002 is currently under revision. It is discussed to replace in the updated version TE by TI.  Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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The risks can also be described by calculation of the Margin of Safety (MoS), which is the 
ratio between the lowest PoD and the expected exposure (worst case scenario) and 
comparison with a reference MoS (see SCCS Notes of Guidance – SCCS/1602/18).  
Perform this evaluation for e very group (patients/donors) for which the device is 
intended to be used.  
 
Determine and describe in which situation the risk can be acceptable for the use of the 
CMR/ED phthalate in the medical device. The benefit -risk assessment for the use of the 
CMR/ED  phthalate can be performed using for example MEDDEV 2.7/1rev4 and EN ISO 
14971 (see also Section 8).  The MDR considers a risk acceptable when outweighed by 
the benefit of using the device in patients (Chapter I of MDR , Chapter VI Article 62 ). 
 
In addition to potential CMR/ED effects, discuss any other potential hazards associated 
with the composition of the device (e.g. by using the EN ISO 10993 series of standards).  
Evaluate if such effects are associated with the use of the CMR/ED phthalates i n the 
device.  
 
Note: It should be noted that for some genotoxic carcinogens a no effect level is 
assumed not to exist.  Similarly, a scientific debate is ongoing about whether this also 
applies to ED activity.  
 
The assessment of the risk should be accompan ied by an estimation of the impact of 
uncertainties in the described outcomes  (see section  9). 
 
 
4. Assessment of possible alternative substances, materials, designs or 
medical treatments8 
 
In general a similar risk assessment as presented in step 3 above has to be performed 
for the alternative (substance s, material s, designs or medical treatment ). An inventory 
should be prepared  in order to be able to evaluate possible alternative s. An alternative 
could be another substance/material or device design modifi cation or it could be a clinical 
procedure (e.g. a process, technique, treatment or modification) or a combination of 
technical and substance alternatives.  
 
Step 4: Inventory of possible alternatives  
Prepare a list of possible alternatives ( such as  substances, materials, designs or medical 
treatments)9.  
A description of the alternative scenario (CMR/ED phthalate "non -use scenario”) needs to 
be presented including identification of alternative substances , materials, designs or 
medical treatment , e.g.  by includ ing consideration of all available information, such as 
alternative medical devices available on the market, information about independent 
research, published peer-reviewed studies, systematic literature reviews, risk assessment 
reports or scient ific opinions from relevant scientific committees and the results of in -
                                                           
8 The analysis presented in section 4 constitutes the non -use scenario or the scenario that would transpire if the 
CMR/ED phthalates would no longer be used in the medical device.  
9 Information source for alternatives might be the European Pharmacopoeia.  Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 house research and development.  The identif ication of  possible  alternatives should be 
properly documented.  
Step 5: Identification of the candidates for assessment as potential relevant  alternatives 
for phthalates  
The MDR indicates that an analysis of all possible alternatives shall be performed. 
However, when many alternatives are available it would not be feasible to do an 
extensive evaluation of all alternatives. It is therefo re recommended to select a number 
of potential relevant  alternatives  based on screening against key criteria for function, 
performance, toxicity, and overall use in the medical device in question  (see below). In 
addition, analysis of availability and technical feasibility might affect choices for 
alternatives as well.   
A preliminary analysis of possible alternative substances, materials or designs or medical 
treatments should be performed . This preliminary analysis  should include a description of 
their possible use as alternative substance , material , designs or medical treatment s. 
Justification on how and why alternatives are rejected for further assessment by defining 
inclusion and exclusion criteria should be provided.  
Information/data on functionalit y (e.g. level of flexibility in tubes) as well as performance 
and/or chemical safety assessment (e.g. hazard profile) may be used for rejection of the 
less likely alternatives (see below ) and no further risk assessment for the alternative is 
required. The rejection of the less likely alternatives requires justification and 
documentation.  The chemical safety assessment should be done after assessment of the 
functionality and performance.  
In addition to the comparison in terms of functionality, technical per formance and risks 
to patients and users, which are critical elements for the benefit -risk assessment, Annex 
I Section 10.4.2 of the MDR states that the justification for the presence of CMR/ED 
substances should also be based on an analysis of the availabi lity of possible alternatives. 
Availability has several aspects, including for example the availability of necessary 
quantity (volumes) of the alternative on the market within a required timeframe and the 
ability to gain access to alternatives that may be proprietary (e.g., via licensing).   
If potential alternatives can be identified, a shortlist of the potential alternatives can be 
established  for further detailed assessment with regard to technical feasibility, health 
benefits, comparison of risks, exist ing legal requirements, availability (e.g. sufficient 
availability or accessible to the manufacturer), and technical performance.  In the event 
that no alternative  is identified, i nformation should be presented on the actions 
undertaken  to identify alternat ives. 
 
A compilation of resources and elements in support of chemical substitution and an 
assessment of alternatives can be found on the OECD webpage : 
http://www.oecdsaatoolbox.org/  
Step 6: Description of identified potential relevant  alternative(s)  and conclusion on their 
technical feasibility  
CMR/ED phthalates are present in medical devices for a specific purpose depending on 
the intended use of the medical device. For example, phthalates offer the possibility for 
fine tuning the flexibility  (e.g. optimal flexibility without kinking)  of a PVC -based medical Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 device. In addition, DEHP has a stabilising effect on red blood cells in blood bags 
(SCENIHR 201 5). Technical feasibility of an alternative is based on the alternative 
fulfilling the function of the CMR/ED phthalate. Therefore, the assessment of the 
functional properties in relation to the intended use of the medical device is essential. 
Besides functionality, performance under intended use conditi ons should also be 
considered.  
 
Argumentation shall be provided for justifying why possible substances and/or material 
substitutes, if available, or design or medical treatment changes, if feasible, are 
inappropriate in relation to main taining the functionality and/or performance of the 
medical device. For example, it might be the case that replacement is possible for one 
specific functional use whereas for another functionality the use of the CMR/ED phthalate 
remains necessary . Also oth er aspects related to performance of the alternatives need to 
be considered like material processing conditions (Crespo et al.,  2007), material quality 
after sterilisation (Burgos and Jiménez 2009), and possible interaction with drugs in 
therapeutic infusi on systems (Treleano et al. , 2009, Salloum et al. , 2015, Tortolano et 
al., 2018).  
 
The benefit(s) should also be considered. An inventory of the benefit(s) of the potential 
alternative substances, materials, designs or medical treatments for patient populations 
(separately for vulnerable patient groups) should be presented (see section 7 ).  
 
The evaluation of the identified potential relevant alternatives can be done in a tiered 
way to avoid full assessments for each candidate alternative. For example, based on the 
outcome of the functionality evaluation, the choice of the potential relev ant candidates 
might be reconsidered and some might be discarded before performing the risk 
assessment (see Step 7).  
 
The ECHA guidance on the preparation of an application for authorisation  and ECHA 
formats for Analysis of Alternatives  provide more detailed information on how to conduct 
an initial screening of possible alternatives and to assess the technical feasibility of 
potential alternatives. Submitted applications for authorisations contain a number of  
examples (https://echa.europa.eu/applying -for-authorisation/preparing -applications -for-
authorisation ) of technical feasibility assessment for uses of substances of very high 
concern. 
Step 7:  Assessment of the risk of identified potential relevant  alternatives  
The risk assessment of alternatives is comparative in nature. Its aim is to assist in the 
conclusion in section 5 whether the transition to the alternatives would lead to lower 
benefit and/or risk to human health for patients when compared to the current u se of the 
CMR/ED phthalates in the medical device. Th e methodology of the assessment in this  
step is similar to that in step 3 as performed for the phthalate to be evaluated with 
reference to the alternative.  
 
If potential relevant alternative s were identified under Steps 1 -6, a risk  assessment of 
these potential relevant  alternative substance/material or designs or medical treatments 
should be performed. The risk assessment should contain a description of the potential 
substance/material (alternative  medical procedure) exposure of various person groups 
(e.g. including patients, donors, professional users)  for which the medical device is 
intended to be used (considering single or repeated use). This should include separately Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 vulnerable groups . For each  subgroup a different level of risk may be accepted based on 
the potential benefit of the medical device for that particular group . Risk management 
measures (EN ISO 14971, EN ISO 10993 -1) and their effectiveness to reduce exposure 
should be described and t aken into account in the assessment.  
 
Exposure estimation  
 
Estimate the potential release of the alternative substance(s) when used in various 
treatment modalities. Consider also the rate of leaching to estimate the potential 
exposure to the alternative substance. Multiple use scenarios (including various types of 
possible contact) should be considered for the exposure estimation of the alternative 
substance (e.g. frequent use of dialyzer) and different population groups.  
 
Hazard identification  
 
Identify hazards based on literature, supplier documentation and other information (such 
as risk assessments performed by regulatory bodies). Describe hazards associated with 
the alternative substance/material by considering all relevant toxicological endpoints for  
acute as well as for repeated dose toxicity including human data. Identify an adequate 
point of departure (PoD) for risk assessment. In case of a threshold Mode of Action, such 
a PoD could be the most sensitive no -observed -adverse -effect -level (NOAEL) or lowest -
observed -adverse -effect -levels (LOAEL), or a dose that causes a predefined response 
(Benchmark dose – BMD) obtained by Benchmark dose modelling. In case of non -
threshold effects (e.g. in the case of genotoxic carcinogens or for substances acting via  
an ED -mediated MoA), such a dose descriptor could be a T25 value or the benchmark 
dose associated with a 10% response (BMD10) (ECHA, 2012).  Hazards should preferably 
be evaluated by a relevant exposure route for the intended use of the assessed medical 
device. 
 
For the hazard identification  special attention should be on the determination of any 
potential CMR and/or ED property of the alternative substance used . For further 
information purposes, a procedure is described in ECHA Guidance on the application of 
the CLP criteria  
https://echa.europa.eu/documents/10162/23036412/clp_en.pdf/58b5dc6d -ac2a-4910-
9702-e9e1f5051cc5   
or by searching Annex VI of  CLP regulation. ED propert ies of the alternative 
substance/material can be described according to the recently published EFSA/ECHA 
guidance document . 
https://echa.europa.eu/documents/10162/23036412/bpr_guidance_identif_ed_en.pdf/1a
4d2811 -3faa-fe61-1de2-3cbce8fd4d95   
These effects include impacts on fertility, birth defects (e.g., cryptorchidism, 
hypospadias), developmental eff ects, and other potential toxic effects associated with 
phthalates with ED properties and reprotoxic effects category 1A/B.  It needs also to be 
considered that the potential alternative (substances, materials, designs or medical 
treatments) could also have  other hazards than those of the CMR/ED activity. These 
other hazards and their possible associated risks should be discussed for example by 
using the EN ISO 14971 and the EN ISO 10993 series. See also Table 1.  
 
Descri ption of  risk (risk characteri sation)  
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 The risk can be described by comparing exposure levels that are considered safe with the 
expected exposure (realistic worst case use scenario). Exposure levels that are 
considered safe could be “Derived  No Effect-Levels” (DNEL s) for threshold substances, 
“Derived Minim um Effect Levels” (DMEL s) for non -threshold substances or intakes over 
lifetime without presenting an appreciable risk to health (ADI or TDI/TWI or TE ). As such 
data are often obtained in rat studies, the use of the TDI seems more appropriate in view 
of the critical effect window for androgenic reproductive toxicity in rats has been reported 
to be a few days (Welsh et al. , 2008). In addition, patients may be exposed to medical 
devices only for a limited period of time. EN ISO 10993 -17:2002 calculates for medical 
devices a Tolerable Exposure (TE), which is based on a product of the tolerable intake, 
the body mass and the utilization factor. When necessary, a cceptable exposure levels   
can be derived by dividing the point of departure for risk assessment by appropriate 
assessment or uncertainty factors.  For medical devices allowable limits of their chemical 
constituents can be determined by EN ISO 10993 -17. 
 
The risks can also be described by calculation of the Margin of Exposure (MoE) or the 
Margin of Safety (MoS)  due to the substances present in a medical device , which  is the 
ratio between the lowest PoD and the expected exposure (e.g. realistic worst case  use 
scenario) and comparison with a reference MoS (see SCCS Notes of Guidance – 
SCCS/1602/18 ). 
Perform this evaluation for every patient group for which the device is intended to be 
used.  
 
Where a reference DNEL and /or a reference DMEL have already been derived in the 
context of other EU legislations, the assessment  could refer to these derived figures 
without referring to a detailed assessment of how these data have been derived (e.g. 
under REACH legislation, Food Contact Material legislation). Data on the relevant 
exposure route of the medical device application (e.g. intravenously) are preferred (see 
also Table 1A, EN ISO 10993 -1). The risk can be described by the so -called risk 
characterisation ratio (RCR), being a ratio between the exposure and the DNEL /DMEL . If 
such DNEL/DMELs are not used in the assessment, a justification should be stated (e.g. 
new information /studies).  
 
Determine and describe acceptability of the risk for the use of the potential alternative s. 
Risks may be acceptable when they are outweighed by the benefits for the patient.   
 
Consider any known adverse events associated with the operation of the device using the 
phthalate, and whether the potential alternatives might affect these adverse event s. 
These considerations can be based upon a systematic literature review  (see MEDDEV 
2.7/1rev4) . 
 
This exercise has to be performed for each potential relevant  alternative substance  
and/or materials .  
A large number of phthalates exist and some may be potential relevant alternatives  for 
the CMR/ED phthalate used in the medical device. However, a number of these  
phthalates are also classified as CMR and/or designated ED (see above  and Table 1 
Annex 5 ). Such phthalates might be identified as alternatives when the CMR/ED risk is 
reduced compared to the phthalate intended to be  used.  In addition, different 
substances , have also been proposed as alternative plastici sers. In 201 5 SCENIHR 
published an updated Opinion of potential alternative plastici sers for DEHP (SCENIHR Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 2015). Although many alternatives were potentially available, it was also observed that 
for many of them the information on potential risks and the necessary risk assessment 
was rather limited precluding their use as alternative s. For DEHP an extensive amount of 
literature is available, allowing a very careful evaluation of the risk associated to its use .  
 
In the event that the risk assessment of a potential relevant alternative cannot be 
performed due to lack of information, document ation should be presented on the actions 
undertaken to obtain information to characterise the risk, including the outcome (for 
example, QSAR /read across could be performed).  
 
Note shall be taken that alternative designs or medical treatments might lead to  
adaptation of  endpoints for the benefit -risk assessme nt when compared to the 
toxicological endpoints of CMR/ED phthalates.  
 
The assessment of the risk should be accompanied by an estimation of the uncertainties 
in the described outcomes which might be qua ntitative (e.g. confidence interval, 
standard deviation) or qualitative (see section 9).  
Conclude the analysis of the potential  relevant alternative(s) with a summary describing 
the possible  scenario(s) ( see Fig ure 1).  
 
 
5. Assessment of potential relevant  alternative substances, materials, 
designs or medical treatments versus CMR/ED phthalates  
 
Based on the information obtained above a decision can be made on the appropriateness 
of potential relevant alternative s (substance, material , design or medical treatment ). In 
this evaluation several factors need to be included such as weighing of technical 
feasibility, benefits and risks . And, if possible, quantification of benefits and risks. These 
steps entail a comparison of the CMR/ED phthalate  “use-scenario”  (summarised in step 
3) with the “Non-use scenario ” (summarised in step 4)  as shown in Figure 1.  
 
Step 8: Comparison of functionality and performance of CMR/ED phthalate as used in the 
medical device with functionality and performance of identified potential relevant 
alternative (s). 
 
Compare the functionality and performance of CMR/ED phthalate in the medical device 
and the potential relevant alternative substance/material (or designs or medical 
treatments by choosing adequate endpoints).  
Perform step 8 for each candidate identified as the potential relevant alternative in 
section 4.  
If several potential relevant alternatives have a similar functionality and hazard profile, 
exposure conditions and possibilities for Risk Management Measures (RMM) res ulting in 
risk reduction should be considered (see below).  Risk management is described in EN 
ISO 14971.  
In this comparison also additional issues not directly related to the functionality and 
performance of the alternative itself, like technical possibili ties, sterilisation effects and Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 interactions with infusion liquids, are important for the application of the alternative and 
the comparison with the CMR/ED phthalates, and thus should be considered.  
Step 9:  Comparison of risk(s) of CMR/ED phthalate as used in the medical device with 
risk(s) of identified potential relevant alternatives.  
 
Compare the risk of both CMR/ED phthalate and alternative substance/material (or 
designs or medical treatments by choosing adequate endpoints).  
Perform step 9 for each potential relevant alternative.  
 
There may be difficulties in comparing the risks of a substance e.g. a phthalate, and the 
risks of a technical alternative such as medical design or medical treatment. For example, 
there may be risks as sociated with alternative technologies but these may not be of the 
same nature of the risk of the phthalate. However, the potential relevant alternative 
must represent a reduction in the overall risks to human health  (Step 10) . Therefore, a 
comparison of risks must be conducted and the applicant will need to consider how these 
different risks might be compared in terms of risks to human health. Note that an 
alternative medical design or medical treatment may also result in expo sure to other 
risks previously not present  in the treatment modality. Possible risks of these substances 
will also need to be considered in the assessment. The comparison with technological 
alternatives such as a medical design or medical treatment can nor mally not be fully 
quantitative (i.e. with directly comparable numeric values), as the hazards and 
associated risks will not be expressed in similar terms, but will in most cases be 
qualitative or semi -quantitative.  Nevertheless, a clear and transparent de scription can 
give a good basis to conclude whether overall risks are reduced  or not  (Step 10) .  
Step 10: Comparison of benefit and risk of CMR/ED phthalate used in the medical device 
with identified potential relevant alternatives.  
 
Present summary/overvi ew of comparison of benefit and risk of CMR/ED phthalate used 
in the medical device with the potential relevant alternatives, including uncertainties  
about the estimates or reliability of the data, assumptions, etc. for the parameters 
presented. The summary should contain various aspects of functionality, performance, 
risk and benefit of the use of the original CMR/ED phthalate used in the medical devic e 
and the potential relevant  alternative (s). In section  6 below the justification of the use of 
a CMR/ED phthalate is described based on the summary table comparing an alternative 
with the CMR/ED phthalate.  
Perform step 10 for every potential relevant alternative.  
 
Each of the assessments performed in steps 1 to 1 0 is associated with uncertainties. 
Certain uncertainties can be described by the use of measures  like the standard deviation 
or confidence interval. For other uncertainties , a description may be necessary to explain 
the extent of the uncertainty  and its impact on the final outcome . 
 
Benefit and risks should be described and weighted against each other in the use of the 
potential alternative substance /material  in the medical device (or designs or medical 
treatments  by choosing adequate endpoints)  similar to the procedure for the CMR/ED 
phthalate (see step 2).  
 
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6. Justification for the u se of CMR/ED phthalate  
 
Based on the comparison of functionality, performance, availability, risk and benefit, an 
argumentation can be built as to why a possible substance and/or material alternative, if 
available, or changes in designs or medical treatment, if feasible, are inap propriate in 
relation to maintaining the functionality, performance and the benefit -risk ratio or profile 
(quantitative/semi -quantitative or qualitative) of the medical device containing a CMR/ED 
phthalate.  
 
Explain the importance of any difference in ter ms of benefits and risks between the 
CMR/ED phthalate to be used in the medical device and potential relevant alternatives 
using value judg ements and explain how  the use of the CMR/ED phthalate can be 
justified over the alternatives by describing the accep tability of trade -offs in the 
achievement of some criteria against others.  Any advantage in benefits needs to be 
weighed against possible disadvantages in terms of functionality and risks. Both 
differences in benefits and risks need to be considered jointly.  
  
In building the argumentation for the use of a CMR/ED phthalate, note can be taken of 
the Memorandum on weight of evidence and uncertainties of SCHEER (SCHEER 2018). 
This Memorandum describes a  methodology  that classifies the strength of evidenc e in the 
human health risk assessment  based on integration of different lines of evidence  into 
strong, moderate, weak, uncertain and inconclusive (no suitable evidence available).  Any 
weight of evidence evaluation needs to show the overall confidence in t he assessment.   
 
The argumentation should specifically take into account the intended use of such devices. 
This should include consideration and discussion of possible high risk groups such as 
children or pregnant or breastfeeding women, and other patient groups considered 
particularly vulnerable to such substances and/or materials. In addition, where applicable 
and available, any future update of these Guidelines shall be considered. A Table with the 
most relevant information and values should be used to p resent an overview of the 
performed assessment comparing the CMR/ED phthalate with potential alternative(s). A 
non-exhaustive example of such Table is presented below. The Table should  be extended 
depending on the number of criteria evaluated and the numbe r of potential alternatives 
identified.  
 
Table 1:  Example for a comparison of CMR/ED phthalate with potential relevant 
alternative(s).  
  
Assessment criteria  Description 
(examples)  Reference 
phthalate  Alternative I  Alternative 
II etc.  
Identification of 
substances/material etc  
Name and CAS number  Chemical 
information  CAS 
117-81-7  
   
Functionality/performance  Used as 
plasticiser  e.g. DEHP    
Clinical 
benefit/performance  Treatment 
possibility  e.g. Flexibility 
of tubing / 
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 cells storage  
Material benefit      
Concentration (% w/w)      
Leaching  from medical 
device for relevant 
conditions e.g. media, 
temperature, etc  
(mg per hour/day)      
Exposure estimation 
(realistic worst case use 
scenario ) for relevant 
route of exposure      
Hazard identification  Local and 
systemic 
acute and 
repeat -dose 
toxicity, ED -
properties, 
organ 
toxicity, CMR 
properties, 
biocompatibili
ty, and 
others     
Identification of a point of 
departure for risk 
assessment ( LOAEL, 
NOAEL, BMD, T25, 
BMD10)  
     
Identification of dose 
levels associated with 
minimal or negligible risk  
(e.g. DNEL, DMEL, TDI , 
TE, TI)     
Risk characterisation 
(MoE, MoS, RCR)      
Confidence  estimation 
(see Table 2)      
Technical feasibility       
Other      
 
This Table shall be completed for every component of the medical device that contains 
CMR/ED phthalate(s ) above the 0.1% w/w level. For some medical devices used as a 
system (e.g. blood bag system) the whole system might be evaluated.  Note that in case 
of alternative designs or medical treatments adequate endpoints for the comparison shall 
be chosen. These endpoints may represent risks that may be of a different nature than 
that of the risk of the phthalate.  
When the outcome of the comp arison shows that the alternative fulfils a comparable or 
better intended functionality as well as performance and shows a reduced risk, the use of 
a CMR/ED phthalate is not possible. The risk assessment should also indicate whether 
there would be a reduce d hazard concerning CMR and/or ED properties, and/or reduced 
exposure overall resulting in reduced risk. In this evaluation, other toxicities (e.g. for any Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 other organ  or system ) of the potential relevant alternatives shall also be considered. So, 
the full  toxicological profile of the potential relevant alternatives shall be taken into 
account.  
A balanced weighing of the benefit  versus the risk has to be performed . For example it is 
possible to use a combination of a CMR/ED phthalate and PVC/material with h igh intrinsic 
toxicological hazards, thus accepting a risk from a toxicological perspective, in case the 
clinical benefit is very high . In contrast, a minor loss in medical  functionality might be 
acceptable if there is a large reduction  or even absence of risk. Each comparison of a 
potential alternative for the use of a phthalate should be based on the combination of 
functionality , risk and benefits for patients.  
In this final evaluation , the assessment  of uncertainties associated with the alternatives 
(e.g. on the nature of the risks; assumptions made) should also be considered (see Table 
2 below section 9). Therefore, where possible, quantitative results should be collected 
and compared (e.g. NOAEL, estimated exposure in mg/kg) and their uncertainties should 
be reported. Also a qualitative description of the uncertainties may be useful (see Table 2 
below sec tion 9). Their impact on the conclusions should also be discussed.  
Although not the main subject of these Guidelines, it should be realised that availability 
and accessibility on the market  might be a limitation for the introduction of an alternative 
subst ance/material. Some chemicals proposed as alternatives are widely available (e.g. 
BTHC, DEHT, DINCH, and TOTM) however, this may not be the case for other alternatives 
identified . The lack of the availability of a potential alternative for a medical device might 
result in the conclusion that replacement is not feasible and that the use of a phthalate 
with CMR and/or ED property continues in order to keep the device available for pat ients. 
So, besides technical feasibility in terms of functionality and risk reduction (risk 
assessment of the phthalate versus the alternative), also availability and accessibility on 
the market needs to be considered.  
The BRA of the CMR/ED phthalate shoul d be updated when new scientific information 
becomes available on alternatives for the use of phthalates, when new Guidelines are 
released, or as the "overall" benefit -risk determination of the medical device is updated.  
A plan to perform an update of the relevant part of the technical file of the device needs 
to be submitted during the certification process (post -market surveillance plan referred 
to in Article 84, the requirements are set out in  Section 1.1 of Annex III MDR) and this 
should also cover upd ates needed on the justification for the presence of CMR/ED 
phthalates .  
 
7. Benefit assessment  
 
These Guidelines do not provide information for the benefit -risk assessment of the use of 
a medical device itself but are limited to the methodology on how to perform a BRA for 
the justification of the  presence  of CMR 1A or 1B and/or ED phthalates in a medical 
device  above 0.1% (w/w).  
The evaluation of the overall benefit -risk assessment of a medical device is  presented in 
other documents (e.g. MEDDEV 2.7/1 rev4, EN ISO 14971).   
The benefits of the CMR/ED phthalate use in a medical device need to be compared to 
the benefits of the potential relevant alternatives, with the focus of the analysis being on Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 the net or incremental benefits of use of the CMR/ED phthalate in comparison to the 
alternatives. These benefits may include material or clinical benefits. Uncertainties about 
the estimates or reliability of the data, assumptions, etc. for the parameters need to b e 
presented.  
 
7.1 Material benefit  
 
A medical device does not achieve its principal intended action by pharmacological, 
immunological or metabolic means, in or on the human body, but may be assisted in its 
function by such means.  For the use of phthalates in medical devices, additional 
functionalit ies need to be considered. One of the functionalit ies is the fine -tuning of the 
flexibility of PVC when  used as plasticiser s e.g. in intubation devices. For blood bag 
materials other requirements are , for example,  resistance to heat and chemicals, 
especially during sterili sation, and permeability of gases to assure that pH and oxygen 
levels remain stable .  In addition, DEHP has an additional property namely the stabilising 
effect on red blood cells (RBCs) (SCENIHR 2015). A number of alternatives were 
evaluated as alternative for DEHP in blood bags (Simmchen et al., 2012, SCHENIR 
2015).  
Platelets are extremely sensitive to changes in the pH of the medium in which they are 
suspended, so sufficient gas permeability to O2 and CO 2 has to be assured in the 
containers devoted to their storage (Simmchen et al. , 2012). For this reason, DEHP has 
been almost fully replaced with  BTHC, DINCH, and/or Trioctyltrimellitate (TOTM or  Tri( 2 -
ethyl hexyl)trimellitate (TEHTM) ) (Simmchen et al.  2012, Prowse et al.  2014).  A better 
gas exchange has been found in bags plasticised with these chemicals . Also other 
materials, like polyolefins, are currently used for platelet storage bags (Prowse et al.  
2014).  This potentially will allow  the stor age of platelet concentrates for up to 7 days, if 
measures to prevent bacterial contamination can be safely implemented.  
It should be noted that the benefit of phthalates in terms of material  functionality and 
performance may differ from device to device. An alternative may be available  for one 
application while this may not be available  for another in view of added or specific 
demands on the functionality  of the p hthalate .  
 
 
7.2 Clinical benefits  
 
Clinical benefit of medical devices is defined in the MDR as follows:  
‘clinical benefit’ means the positive impact of a device on the health of an individual, 
expressed in terms of a meaningful, measurable, patient -relevant clinical outcome(s), 
including outcome(s) related to diagnos is, or a positive impact on patient management or 
public health; (Regulation (EU)2017/745: Article 2 Definitions: (53)):  
This “clinical benefit” has to  be substantiated by the manufacturers in the “clinical 
evaluation” of the medical device, which includes a number of considerations. These  
include a discussion and overall conclusions covering safety and performance results, 
assessment  of risks and clinic al benefits, discussion of clinical relevance in accordance Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 with clinical state of the art, any specific precautions for specific patient populations, 
implications for the investigational device  and limitations of the investigation.  
A ”clinical benefit ” could include any meaningful, measurable, patient -relevant outcome 
as presented below. SCHEER identified the following examples  that may be relevant for 
the use of phthalates (list not exclusive):  
 Improved survival rates  
 Improved length of hospital stay  
 Improved time of intervention  
 Improved time of placing ( among others  in tubes and catheters)  
 Improved product quality/ clinical performance ( among others in tubes and 
catheters) in terms of:  
o Improved leakage rates  
o Improved breakage rates  
o Improved knotting rates  
o Improved blockage rates  
o Improved bending performance rates  
o Improved release rates of toxic substances  
o Improved release rates of (nano -)particles  
 Improved displacement  rates 
 Improved possibilities for sterili sation 
 Reduction of diameters in relation to performance  
 Possibility to produce “multiple -purpose” devices, (e.g. inclusion of additional 
sensors), and therefore reduction of over -all patient -stress and patient -impact  
 Improved observability (safety) in terms of translucence, printability, radiopaque 
lines included, identifiab ility, traceability, etc. ( among others  in tubes and 
catheters)  
 Fewer  adverse events , e.g. r educed mucosal or endothelial irritation or injury 
rates ( among others  in tubes and catheters)  
 Fewer serious adve rse events  and serious incidents  
The benefit of the use of the CMR/ED phthalate should always be judged with respect to 
the “intended use” of the medical device and the exposed patient -group to the medical 
device and weighed in its clinical impact (“clinically relevant difference”). These aspects 
should be judged by clinical experts.  
Quantitative information on the benefits should be provided where possible or at a 
minimum qualitative description of their magnitude. Information on the probability of  the 
benefit to occur and/or the duration of the benefit should also be included.  
 
 
8. Methodologies for Benefit –Risk A ssessment  
 
In general, a Benefit - Risk A ssessment  (BRA) aims to evaluate the desired effects of 
therapeutic mean s, medicine s or device s, against their undesired effects, i.e., risks for 
human health. An appropriate BRA can contribute to a more objective analysis and help  
conformity verification bodies and  authorities towards a more objective and transparent 
decision -making process. Weighi ng the benefits and risks can be a complex task. It may 
involve the evaluation of a large amount of data that should be as accurate  as possible , Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 without methodological weaknesses  and biases. There is always some uncertainty around 
the actual benefits and r isks, because they can only be determined by looking at the 
information that is available at a given point in time  which may contain various sources 
of uncertainty.  
For the BRA of medical devices in general, guidance is available in section A7.2. of  
MEDDEV 2.7/1, revision 4   “Clinical evaluation: A guide for manufacturers and notified 
bodies under directives 93/42/EEC and 90/385/EEC” . EN ISO 14971  (FDIS published in 
2019)  and the accompanying  ISO/TR 24971 provide information on the risk benefit 
analys is to be performed within a risk management process. Additional information may 
be found elsewhere, for example in the documents  of the FDA 2016,  2018,. It should be 
noted that the acceptability of any risk is weighted against the benefit of the use of the 
medical device.   
Several methodologies for BRA have been proposed (Guo et al, 2010 , Mt-Isa et al.  
2014), of which most methodologies  are so far , mainly used for pharmaceutical products. 
However, it should be underlined that f or medical devices the quantitative determination 
of a benefit -risk ratio may be rather difficult to be made  and expressed in a figure. In 
such cases a qualitative approach of weighing the benefit based on expert judgement 
might be used.  One methodology, namely the multi criteria decision analysis (MCDA), 
can be generally applied to various areas of BRA. Therefore, this methodology might also 
be suitable for performing the BRA of medical devices (see Annex 7).  The MCDA 
methodology has its origins in decisi on theory aiming to evaluate multiple conflicting 
criteria in decision making. These criteria can include the benefits and risks of the use of 
a medical device on human health.   
The final BRA of both the used CMR/ED  phthalate and potential relevant alterna tives 
should contain all aspects as indicated in the framework above. A quantitative or semi -
quantitative description of the risks (e.g. MoS, RCR) and of the benefits of a medical 
device containing a CMR/ED phthalate or alternative should  be the basis for a BRA. 
However, a lthough quantitative approaches for a BRA are preferable, a qualitative 
description of the value judgements about the balance of benefits and risks might also be 
an acceptable approach when justified (see step 10).  
 
 
9. Uncertainty analysis  
 
Uncertainty plays an important role in medical decision making. It is widely accepted 
that, despite the methodological and technological improvements that were achieved in 
the past decades, there is never absolute certainty regarding the safety, effective ness, or 
performance  of a medical treatment or use of a device. Therefore, the degree of certainty 
and thus uncertainty of the benefits and risks of a medical device is a factor that should 
always be considered when making BRA.  
There are various sources of uncertainty in bio -medical studies; a major source of 
uncertainty is the biological differences among individuals. Another source of uncertainty 
is the intra - and inter - variability of the laboratories, with respect to equipmen t, 
reagents, and methods used. It is also accepted that diagnostic tools which evaluate 
benefit and risk share several limitations , giving false negative and false positive results 
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 into account. Other factors that may influence the degree of uncertainty include: the type 
of clinical information available (e.g., clinical investigation  data, observational studies, 
evidence derived from registries or use experience), the re presentativeness of the 
information (e.g., sample size, relevance  of the sample to the referent population 
exposed to the device), as well as the statistical inferences derived from the information.  
A number of techniques for uncertainty analysis are descr ibed in t he Guidance for Socio -
Economic Analysis of ECHA (ECHA 2011). The aim is to determine whether uncertainties 
in the estimation of impacts could affect the overall conclusions. More accurately , the 
techniques shown can be used to either reduce the va riability of estimates, or to help 
test whether uncertainties affect the conclusions drawn. The only way to actually reduce 
uncertainty is through better data, better understanding and knowledge of the 
uncertainties and through further analysis. However, i n most cases residual uncertainties 
will remain.  
Recently EFSA published a guidance on uncertainty analysis (EFSA 2018 a) and a 
description of the principles and methods behind the guidance for uncertainty analysis 
(EFSA 2018 b). The EFSA Guidance recogni ses that the form and extent of uncertainty 
analysis, and how the conclusions should be reported, vary widely depending on the 
nature and context of each analysis and the degree of uncertainty that is present. 
Therefore it is important to identify appropriat e options for each BRA. The EFSA 
documents provide a flexible framework for uncertainty analysis within which different  
methods may be selected, according to the needs of each BRA. It seems likely that also 
for medical devices a similar flexibility is need ed in view of the broad range of medical 
devices used.  
EFSA describes a number of main elements of uncertainty that need to be considered in 
the uncertainty analysis:  
EFSA: Main elements of uncertainty analysis  
 Identifying uncertainties affecting the assessment. This is necessary in every 
assessment and should be done in a structured way to minimise the chance of 
overlooking relevant uncertainties. In assessments that follow standardised 
procedures, it is only necessary to identify nonstandard uncertai nties.  
 Prioritising uncertainties within the assessment plays an important role in planning 
the uncertainty analysis, enabling the assessor to focus detailed analysis on the 
most important uncertainties and address others collectively when evaluating 
overa ll uncertainty. Often prioritisation will be done by expert judgement during 
the planning process, but in more complex assessments it may be done explicitly 
using influence analysis or sensitivity analysis.  
 Dividing the uncertainty analysis into parts. In some assessments, it may be 
sufficient to characterise overall uncertainty for the whole assessment directly, by 
expert judgement. In other cases, it may be preferable to evaluate uncertainty for 
some or all parts of the assessment separately and then comb ine them, either by 
calculation or expert judgement.  
 Ensuring the questions or quantities of interest are well -defined. Each question or 
quantity of interest must be well -defined so that the true answer or value could be 
determined, at least in principle.  This is necessary to make the question or 
quantity a proper subject for scientific assessment, and to make it possible to 
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 Some assessments follow standardised procedures, within  which the questions 
and/or quantities of interest should be predefined. In other assessments, the 
assessors will need to identify and define the questions and/or quantities of 
interest case by case.  
 Characterising uncertainty for parts of the uncertainty analysis. This is needed for 
assessments where assessors choose to divide the uncertainty analysis into parts 
but may only be done for some of the parts, with the other parts being considered 
when characterising overall uncertainty.  
 Combining uncertainty f rom different parts of the uncertainty analysis. This is 
needed for assessments where the assessors quantify uncertainty separately for 
two or more parts of the uncertainty analysis.  
 Characterising overall uncertainty. Expressing quantitatively the overall  impact of 
as many as possible of the identified uncertainties, and describing qualitatively 
any that remain unquantified. This is necessary in all assessments except those 
standardised assessments where only standard uncertainties are identified  (e.g. 
inter-and intra -species uncertainty factors).  
 Prioritising uncertainties for future investigation. This is implicit or explicit in any 
assessment where recommendations are made for future data collection or 
research, and may be informed by influence or sensit ivity analysis.  
 Reporting uncertainty analysis. Required for all assessments, but extremely brief 
in standardised assessments where only standard  uncertainties  are identified.  
A number of methods that can be used in the uncertainty analysis include:  
 Sensitivity analysis  
 Scenario analysis  
 Expert judgement  
 Monte Carlo Simulations  
Some of these techniques can be used in combination (e.g. scenario analysis together 
with expert judgement to establish ranges for key variables) but also together with less  
commonly used techniques such as risk -risk analysis, Delphi techniques and portfolio 
analysis, which can be used to help reduce the variability of estimates but are not 
discussed in these Guidelines.  
After performing the uncertainty analysis , the observed overall confidence associated 
with a BRA can be expressed as a probability score. This score gives the risk assessor an 
indication what the uncertainty is in the BRA. 
In situations where sufficient data are available, a quantitative categori sation of 
probability levels is preferred. If this is not possible, the manufacturer should give a 
qualitative description. A good qualitative description is preferable to an inaccurate 
quantitative description ( EN ISO  14971).  
EFSA (EFSA, 2018 b) and SCHEER (2018) use a rather detailed probability scale  of 9 and 
7 probab ility levels, respectively. EFSA stresses that this scale may be used as an aid to 
support the development of judgements and that other ranges or qualitative descriptions 
can be used as well. EFSA (2018 b) also argues that presenting the numerical 
probabilities alongside verbal expressions of probability, e.g. ‘Likely (> 66% probability)’, 
increases the consistency of interpretation.  Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 A detailed scale does not seem to be applicable for the uncertainties that can be obtained 
during a  BRA evaluation of medical devices. For medical devices, a probability scale as 
indicated in Table 2  may b e used  EN ISO showing a 5-level scale recommended by ISO 
for semi -quantitative assessments ( EN ISO  14971, Table D4 ). Table 2 further show s the 
verbal terms and subjective probability ranges that are based on a simplification of the 
EFSA/SCHEER scales.  
 
Table 2: Probability scale for (semi -)quantitative  description of the overall 
confidence  
ISO probabil ity term  
 Subjective  probability range  Probability term  
 
Frequent  
 
Probable  
 
Occasional  
 
Remote  
 
Improbable  
  
> 90% 
 
66-90% 
 
33-66% 
 
10-33% 
 
<10%  
very l ikely 
 
likely 
 
as likely as not  
 
unlikely  
 
very unlikely  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.  Conclusions  
 
These G uidelines are intended to be used for  a BRA of the presence of phthalates in 
certain medical devices  covering phthalates which are carcinogenic, mutagenic, toxic to 
reproduction (CMR) or have endocrine -disrupting (ED) properties . The Guidelines can be 
used for the justification of the use of CMR/ED phthalates in a medical device according 
to the Regulation (EU) 2017/745 on medical devices. They also provide a framework on 
how to assess  and compare possible alternative substances, materials , designs  or 
medic al treatments  to the use of CMR/ED phthalates in medical devices. Major aspects 
include the functionality of phthalates, the performance  of the medical device using  the 
phthalate or the potential  relevant alternative for the phthalate, as well as the risk 
assessment of the phthalate or the alternative s. In the end , the benefit (s) shall be 
weighed against the possible risk s of the use of the CMR/ED phthalate and of the 
alternative substance, materials , desig ns or medical treatments . This overall analysis  will 
determine whether it is justified  or not  to use  a CMR/ED phthalat e in a medical device.  
In view of the concern of the CMR/ED properties of phthalates, further research to 
possibilities to replace these p hthalates in medical devices is highly encouraged  by the 
SCHEER .  
During the preparation of these Guidelines for BRA of the use of CMR/ED phthalates in 
medical devices , SCHEER noticed that a number of BRA methodologies are theoretically 
available. However , there is a considerable lack of data for the BRA for potential  relevant 
alternatives to be used in medical devices. Therefore, SCHEER encourages manufacturers 
to generate data of high quality on such alternatives for CMR/ED phthalates in medical 
devices . As the BRA of the presence of phthalates may have an impact on the 
conclusions of the "overall" benefit -risk determination of the medical device, a  periodic  
update of the BRA of the medical device may be needed. The BRA of the presence of the 
CMR/ ED phtha late should be updated when new scientific information becomes available 
on alternatives for the use of phthalates, when new Guidelines are released, or as the 
"overall" benefit -risk determination of the medical device is updated . A plan to perform 
an update of the general BRA for the medical device should be included in the dossier 
before marketing the device, and this should also include a plan regarding the necessary 
updates on the evaluation of alternatives for CMR/ED phthalate s.  
Pending on new scientific evidence, i t is recommended to evaluate the use and 
usefulness of these Guidelines after an application  period of three years.  
 
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11.  Consideration of the responses received during the public 
consultation process   
 
A public consultation on these Guidelines was opened on the website of the non -food 
scientific committees from 18 March to 29 April 2019 . Information about the public 
consultation was broadly communicated to national authorities, international 
organisation s and other stakeholders. A to tal of 197 submissions from 19  contributors 
(providing 378 comments  and additional references ) provided input to different chapters 
and subchapters of the document.  The vast majority of comments came from industry  
and were requesting clarifications .  Each submission was carefully considered by the 
SCHEER and the scientific opinion has been revised to take account of relevant 
comments. The literature has been accordingly updated with relevant publications. The 
SCHEE R expresses their thanks to all contributors for their comments and for the 
literature references provided during the public consultation. The text of the comments 
received and the response provided by the SCHEER is available at:   
https://ec.europa.eu/health/scientific_committees/consultations/public_consultations/sch
eer_consultation_08_en   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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B. REFERENCES  
 
 Bui TT, Giovanoulis G, Cousins AP, Magnér J, Cousins IT, de Wit CA. Human 
exposure, hazard and risk of alternative plasticizers to phthalate esters.  Sci Total 
Environ. 2016 Jan 15;541:451 -467. do i: 10.1016/j.scitotenv.2015.09.036 . 
 
 Burgos N, Jiménez A.Degradation of poly(vinyl chloride) plasticized with non -
phthalate plasticizers under sterilization conditions. Polymer Degradation and 
Stability 94 (2009) 1473 –1478.  
 
 Crespo JR, Balart R, Sanchez L,  López J. Substitution of Di(2 -ethylhexyl) Phthalate 
by Di(isononyl) Cyclohexane -1,2-Dicarboxylate as a Plasticizer for Industrial Vinyl 
Plastisol Formulations. Journal of Applied Polymer Science, 104, 1215 –1220, 
2007.  
 
 Dybing E, Sanner T, Roelfzema H, Kroese D, Tennant RW. T25: a simplified 
carcinogenic potency index: description of the system and study of correlations 
between carcinogenic potency and species/site specificity and mutagenicity.  
Pharmacol Toxicol. 80 , 272-279, 1997 . 
 
 ECB (European Chemical Bureau). European Union Risk Assessment Report for 
Bis(2-ethylhexyl) phthalate (Consolidated Final Report) 2008.  
 
 ECHA, 2011. Annex XV Restriction Report, Proposal for a Restriction Substance 
name: Bis(2 -ethylhexyl)phthal ate (DEHP), Benzyl butyl phthalate (BBP), Dibutyl 
phthalate (DBP), Diisobutylphthalate (DIBP). European Chemicals Agency 2011.  
 
 ECHA 2011 Guidance on the preparation of socio -economic analysis as part of an 
application for authorisation, European Chemicals  Agency 2011.  
 
 ECHA 2011 Guidance on the preparation of an application for authorisation, 
European Chemicals Agency 2011.  
 
 EFSA (European Food Safety Authority) Scientific Committee, Benford D,  
Halldorsson T, Jeger MJ, Knutsen HK, More S, Naegeli H, Notebo rn H, Ockleford C, 
Ricci A, Rychen G, Schlatter JR, Silano V, Solecki R, Turck D, Younes M, Craig P, 
Hart A, Von Goetz N, Koutsoumanis K, Mortensen A, Ossendorp B, Martino L, 
Merten C, Mosbach -Schulz O and Hardy A, 2018. Guidance on Uncertainty 
Analysis in  Scientific Assessments. EFSA Journal 2018;16(1):5123, 39 pp. 
(https://doi.org/10.2903/j.efsa.2018.5123 .) 
 
 EFSA Scientific Committee, Benford D, Halldorsson T, Jeger MJ, Knutsen HK,More 
S, Naegeli H, Noteborn H, Ockleford C, Ricci A, Rychen G, Schlatter JR, Silano V, 
Solecki R, Turck D, Younes M, Craig P, Hart A, Von Goetz N, Koutsoumanis K, 
Mortensen A, Ossend orp B, Germini A, Martino L, Merten C, Mosbach -Schulz O, 
Smith A and Hardy A, 2018. Scientific Opinion on the principles and methods Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
(final version)  
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 behind EFSA’s Guidance on Uncertainty Analysis in Scientific Assessment. EFSA 
Journal 2018;16(1):5122,235 pp. https://doi.org/10.2903/j.efsa.2018.5122  
 
 EFSA Scientiﬁc Com mittee, More SJ, Bampidis V, Benford D, Bennekou 
-Jerez AF, Koutsoumanis K, Naegeli H, 
Schlatter JR, Silano V,N ielsen SS, Schrenk D, Turck D, Younes M, Benfenati E, 
Castle L, Cedergreen N, Hardy A, Laskowski R,Leblanc JC, Kortenkamp A, Ragas 
A, Posthuma L, Svendsen C, Solecki R, Testai E, Dujardin B, Kass GEN,Manini P, 
Jeddi MZ , Dorne J -LCM and Hogstrand C, 2019. Guidance on harmonised method 
ologies forhuman health, animal health and ecological risk assessment of 
combined exposure to multiple chemicals.EFSA Journal 2019;17(3):5634, 77 pp. 
https://doi.org/10. 2903/j.efsa.2019.5634  
 
 Eliason P, Morose G Safer alternatives assessment: the Massachusetts process as 
a model for state governments. Journal of Cleaner Production 2011 , 19, 517-526 
 
 European Commission 2017 COMMISSION IMPLEMENTING DECISION (EU) 
2017/1210 of 4 July 2017 on the identification of bis(2 -ethylhexyl) phthalate 
(DEHP), dibutyl phthalate (DBP), benzyl butyl phthalate (BBP) and diisobutyl 
phthalate (DIBP) as substances of very high concern according to Article 57(f) of 
Regulation (EC) No 1907/2006 of the European Parliament and of the Council. 
Official Journal of the European Commission,  L173/35,  6.7.2017.  
 
 European Directorate for the Quality of Medicines and Healthcare (EDQM), 
European Pharmacopoeia (Ph. Eur.) 9th Edition 2019, Council of Europe, 
Strasbourg, France.   
 
 European Medicines Agency (2014)  Benefit -risk methodology project 
(https://www.ema.europa.eu/documents/report/benefit -risk-methodology -
project -update -work-package -5-effects -table-pilot-phase -i_en.pdf ) 
 
 FDA. US Food and Drug Administration.  Benefit -Risk Factors to Consider When 
Determining Substantial Equivalence in Premarket Notifications (510(k)) with 
Different Technological Characteristics.  Guidance for Industry and Food and Drug 
Administration Staff. September 25, 2018. Washington , USA. 
https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/G
uidanceDocuments/UCM404773.pdf  
 
 FDA. US Food and Drug Administration.  Factors to Consider Regarding Benefit -
Risk in Medical Device Product Availability, Compliance, and Enforcement 
Decisions.  Guidance for Industry and Food and Drug Administration Staff. 
December 27, 2016. Washington, USA.  
https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/G
uidanceDocuments/UCM506679.pdf  
 
 Guo JJ, Pandey S, Doyle J, Bian B, Lis Y, Raisch DW. A review of quantitative risk -
benefit methodologies for assessing drug safety and efficacy -report of the ISPOR 
risk-benefit management working group. Value Health. 2010;13(5):657 -66 
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  Hass U, Christiansen S, Andersson A -M, Holbech H, Bjerregaard P. Report on 
interpretation of knowledge on endocr ine disrupting substances (EDs) – what is 
the risk? Danish Centre on Endocrine Disruptors, Denmark . 
(http://www.cend.dk/files/ED_Risk_report -final-2019.pdf)  
 
 Katsikantami I, Sifakis S, Tzatzarakis MN, Vakonaki E, Kalantzi OI, Tsatsakis AM, 
Rizos AK. A global assessment of phthalates burden and related links to health 
effects.  Environ Int. 2016;97:212 -236. doi: 10.1016/j.envint.2016.09.013  
 
 Mariana M, Feiteiro J, Verde I, Cairrao E. The effects of phthalates in the 
cardiovascular and reproductive systems: A review.  Environ Int. 2016;94:758 -
776. doi: 10.1016 /j.envint.2016.07.004.  
 
 Mt-Isa S, Hallgreen C.E., Wang N., Callréus T.,  Genov G., Hirsch I., Hobbiger S., 
Hockley .S., Luciani D., Phillips L.D., Quartey G., Sarac S.B., Stoeckert I., Tzoulaki 
I., Micaleff A., Ashby D. , IMI-PROTECT benefit -risk participants.  Balancing benefit 
and risk of medicines a systematic review and clas sification of available 
methodologies, Pharmacoepidemiol Drug Saf. 23(7):667 -78, 2014. doi: 
10.1002/pds.3636.  
 
 Nielsen BS, Andersen BN, Giovalle E, Bjergstrom M, Larsen PB. Alternatives to 
classified phthalates in medical devices. The Danish Environmental Protection 
Agency 2014, Copenhagen, Denmark  
 
 Prowse CV, de Korte D, Hess JR, van der Meer PF; Biomedical Excellence for Safer 
Transfusion (BEST) Collaborative.Commercially available blood storage containers.  
Vox Sang. 106(1):1 -13, 2014. doi: 10.1111/vox.12 084.  
 
 Salloum HA, Saunier J, Aymes -Chodur C, Barakat H, Yagoubi N. Impact of the 
nature and concentration of plasticizers on the ability of PVC to sorb drug. 
International Journal of Pharmaceutics 496, 664 –675, 2015.  
 
 SCHEER 2018 Memorandum on weight of evidence and  uncertainties. Revision 
2018. 
https://ec.europa.eu/health/sites/health/files/scientific_committees/scheer/docs/s
cheer_o_014.pdf  
 
 SCENIHR Opinion on The safety of medical devices containing DEHP  plasticized   
PVC or other plasticizers on neonates and other groups possibly at risk (2015 
update).  2015 
https://ec.europa.eu/health/scientific_committees/emerging/docs/scenihr_o_047.
pdf 
 
 Simmchen J , Ventura R , Segura J . Progress in the removal of di -[2-ethylhexyl] -
phthalate as plasticizer in blood bags. Transfus Med Rev. 2012; 26(1):27 -37. doi: 
10.1016/j.tmrv.2011.06.001. Epub 2011 Aug 5.  
 
 Tortolano L, Matmati H, Bourhis M,Manerlax K, Lemare F, Saunier J,Yagoubi N. 
DinCH and ESBO actual migration from PVC infusion tubings used in an 
oncopediatric unit. J. Appl. Polym.  Sci. 135, 46649, 2018.  Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
(final version)  
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 Treleano A,Wolz  G,Brandsch  R, Welle  F. Investigation into the sorption of 
nitroglycerin and diazepam intoPVC tubes and alternative tube materials during 
application . Intl JPharmac 369, 30 –37, 2009.  
 
 Welsh M, Saunders PT, Fisken M, Scott HM, Hutchison GR, Smith LB, Sharpe RM.  
Identification in rats of a programming window for reproductive tract 
masculinization, disruption of which leads to hypospadias and cryptorchidism. J 
Clin Invest. 2008 ; 118(4):1479 -90. doi: 10.1172/JCI34241.  
 
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C. ANNEXES  
 
Annex   1: SCHEER mandate on benefit -risk assessment on the use of CMR/ED phthalates  
 
1. Background  
 
What are phthalates?  
Phthalates are the esters of 1,2 -benzenedicarboxylic acid (o -phthalic acid) and their 
chemical structure consists of one benzene  ring and two ester functional groups linked 
with two consecutive carbons on the ring10. The hydrocarbon chains of the ester groups 
are either straight or branching; they give each substance its name and they are 
responsible for the different properties amo ng phthalates. Phthalate esters (PEs) may be 
categori sed into three distinct groups according to the length of their carbon chain. High 
molecular weight (HMW) phthalates include those with 7 –13 carbon atoms in their carbon 
chain and low molecular weight (L MW) those with 3 –6 carbon atoms in their backbone. 
DEHP is classified as a LMW phthalate. A third group includes dimethyl phthalate (DMP) 
and diethyl phthalate (DEP)11. 
 
What are they used for?  
Phthalates are widely used in industry as plastici sers of polym ers such as polyvinyl 
chloride (PVC). HMW phthalates are used in a variety of applications such as coated 
fabrics and roofing membranes.  LMW phthalates are used in medical devices, adhesives, 
paints, inks and enteric -coated tablets. DEHP is the most widel y used phthalate in 
medical devices. DMP and DEP are not used as plastici sers but e.g. as  additives in 
cosmetics, medical devices, and household products.  
 
Potential CMR  or endocrine -disrupting properties  
The interaction of phthalates with the polymers the y are embedded in is weak, so they 
may migrate from the plastic product into the environment and into the human body if 
the product is in contact with it.  
Correlation between exposure to a range of phthalates and adverse health effects has 
been documented in animals and humans (see for example tables in Mariana et al. 2016 
and Katsikantami et al.  2016). A number of phthalates are suspected of and/or have 
been classified or identified as having CMR or endocrine -disrupting properties.  
                                                           
10 A global assessment of phthalates burden and related links to health effects. Katsikantami et al., Environ Int. 
2016 Dec;97:212 -236. https://www.ncbi.nlm.nih.gov/pubmed/?term=katsikantami   
11 Footnote added by SCHEER. It should be noted that there are hundreds of phthalates of which only a limited 
number is used as plasticiser in polymers. Phthalates can be categorised according to the length of the carbon 
chain and one of these categorisations is mentioned in the mandate of DG GROW.  Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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Previous work of Commission Scientific Committees on phthalates  
Previous opinions on the most commonly used phthalate DEHP [di -(2-(ethylhexyl) 
phthalate] in medical devices were issued by EU Scientific Committees in 2002 
(SCMPMD), 2008 and 2015 (SCENIHR). The 2008 Opinion concluded that "So far, there is 
no conclusive scientific evidence that DEHP exposure via medical treatments has harmful 
effects in humans",  but noted that "newborn and pre -term born male infants are of 
special concern" . In the 2015 Opinion, SCENIHR additi onally identified that "patients 
subject to haemodialysis procedure may be at risk of DEHP induced effects" . The 
Committee noted that "Food is the primary source of exposure to DEHP for the general 
population."  
In both opinions, the Committee emphasised th at "the benefit of the medical devices 
must also be considered"  and in the 2008 Opinion the Committee states that "each 
alternative to DEHP, however, must also be evaluated with regard to their functionality in 
respect to medical devices. The risk and bene fits of using alternative plasti cizers should 
be evaluated case by case."  In the 2015 opinion, the Committee states that “The 
potential for replacement of DEHP in these products should be considered against their 
efficiency in the treatment, as well as the  toxicological profile and leaching properties of 
the alternative materials.”  
 
The legal obligation  
Article 5 paragraph 2 of the Regulation 2017/745 on medical devices stipulates: "A 
device shall meet the general safety and performance requirements set out  in Annex I 
which apply to it, taking into account its intended purpose."   
Accordingly, Section 10.4 of Annex I, which deals with substances in medical devices, 
states that "Devices shall be designed and manufactured in such a way as to reduce as 
far as possible the risks posed by substances or particles, including wear debris, 
degradation products and  processing residues, that may be released from the device."  
Particular substances of concern are those which (a) are carcinogenic, mutagenic or toxic 
to reproduction (CMR),  of category 1A or 1B,12 or (b) have endocrine -disrupting 
properties (ED)13. The Regulation states that:  
 
"Devices, or those parts thereof or those materials used therein that:  
 are invasive and come into direct contact with the human body,   
 (re)administer medicines, body liquids or other substances, including gases, 
to/from the body, or  
 transport or store such medicines, body fluids or substances, including gases, to 
be (re)administered to the body"  
 
                                                           
12 in accordance with Part 3 of Annex VI to Regulation (EC) No 1272/2008  
13 identified as such in accordance with the relevant provisions of Regulation (EC) No 1907/2006 or respectively 
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 shall only contain any such substance ab ove the concentration of 0.1% weight by weight 
where justified pursuant to Section 10.4.2. The justification shall be based on several 
elements, including the latest relevant scientific committee guidelines on benefit -risk 
assessment of the presence of suc h substance in devices.  
According to Section 10.4.3, the Commission shall provide a mandate to the relevant 
scientific committee to prepare such guidelines for phthalates which are subject to these 
provisions. These guidelines are explicitly requested by t he Regulation to be available at 
the latest on the date of application of the Regulation, and are to be updated whenever 
appropriate on the basis of the latest scientific evidence, or at least every five years.  
 
2. Terms of reference  
 
The Scientific Committee  is requested to provide guidelines on the benefit -risk 
assessment of the presence, in the medical devices specified below, of phthalates which 
have one or more of the following properties: carcinogenic, mutagenic, toxic to 
reproduction or endocrine -disrup ting, according to the criteria outlined in the previous 
section.  
The devices covered, or those parts thereof of those materials used therein, are those 
which:  
 are invasive and come into direct contact with the human body,  
 (re)administer medicines, body l iquids or other substances, including gases, 
to/from the body, or  
 transport or store such medicines, body fluids or substances, including gases, to 
be (re)administered  to the body.  
 
The guidelines shall include guidance on how, for an individual device, to: 
 analyse and estimate potential patient or user exposure to the substance,  
 analyse possible alternative substances, materials, designs, or medical 
treatments,  
 to justify why possible substance and/or material substitutes, if available, or 
design change s, if feasible, are inappropriate in relation to maintaining the 
functionality, performance and the benefit -risk ratios of the product, including 
taking into account if the intended use of such devices includes treatment of 
children or treatment of pregnan t or breastfeeding women or treatment of other 
patient groups considered particularly vulnerable to such substances and/or 
materials.  
 
In addition, the Scientific Committee is requested to : 
 identify any relevant knowledge gap , and 
 to give consideration to what extent of new evidence would be deemed 
appropriate to justify an update of these guidelines before the maximum period of 
five years.  
 
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In order to ensure the appropriateness of this guidance the Scientific Committee should 
inter alia : 
 involve at the appropriate level the notified bodies active in the field of medical 
devices, or other relevant stakeholders such as Competent Authorities, 
professional and patient associations, industry associations, while maintaining 
scientific independence , 
 involve to the necessary extent the relevant EU Agencies  and Scientific 
Committees.  
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Annex  2: Medical Device Regulation (Regulation 2017/745) on CMR and/or ED 
substances  
 
The requirement for justification of the presence  of CMR 1A or 1B and/or ED hazardous 
substances is described in Annex I 10.4.2 as presented in the text box below.  
 
 
 
10.4. Substances  
 
10.4.1. Design and manufacture of devices  
 
Devices shall be designed and manufactured in such a way as to reduce as fa r as possible the 
risks posed by substances or particles, including wear debris, degradation products and 
processing residues that  may be released from the device.  
Devices, or those parts thereof or those materials used therein that:  
 
— are invasive and come into direct contact with the human body,  
 
— (re)administer medicines, body liquids or other substances, including gases, to/from the 
body, or  
 
— transport or store such medicines, body fluids or substances, including gases, to be 
(re)administered to the body,  
  
shall only contain the following substances in a concentration that is above 0,1 % weight by 
weight (w/w) where justified pursuant to Section 10.4.2:  
  
(a) substances which are carcinogenic, mutagenic or toxic to reproduction (‘CMR’), of category 
1A or 1B, in accordance with Part 3 of Annex VI to Regulation (EC) No 1272/2008 of the 
European Parliament and of the Council (1), or  
  
(b) substances having endocrine -disrupting properties for which there is scientific ev idence of 
probable serious effects to human health and which are identified either in accordance with the 
procedure set out in Article 59 of Regulation (EC) No 1907/2006 of the European Parliament 
and of the Council (2) or, once a delegated act has been ad opted by the Commission pursuant 
to the first subparagraph of Article 5(3) of Regulation (EU) No 528/2012 of the European 
Parliament and the Council (3), in accordance with the criteria that are relevant to human 
health amongst the criteria established the rein.  
 
10.4.2. Justification regarding the presence of CMR and/or endocrine -disrupting substances  
 
The justification for the presence of such substances shall be based upon:  
(a) an analysis and estimation of potential patient or user exposure to the subs tance;  
(b) an analysis of possible alternative substances, materials or designs, including, where 
available, information about independent research, peer -reviewed studies, scientific opinions 
from relevant scientific committees and an analysis of the avail ability of such alternatives;  
(c) argumentation as to why possible substance and/ or material substitutes, if available, or 
design changes, if feasible, are inappropriate in relation to maintaining the functionality, 
performance and the benefit -risk ratio s of the product; including taking into account if the 
intended use of such devices includes treatment of children or treatment of pregnant or 
breastfeeding women or treatment of other patient groups considered particularly vulnerable to 
such substances an d/or materials; and  
(d) where applicable and available, the latest relevant scientific committee guidelines in 
accordance with Sections 10.4.3 and 10.4.4.  
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Annex 3:  Definitions/descriptions – References - Glossary  
 
Definitions ( Regulation  (EU) 2017/745 ) 
 
Benefit -risk determination:  means the analysis of all assessments of benefit and risk 
of possible relevance for the use of the device for the intended purpose, when used in 
accordance with the intended purpose given by the manufacturer.  
 
Performance:  means the ability of a device to achieve its intended purpose as stated by 
the manufacturer.  
 
Clinical performance:  means the ability of a device, resulting from any direct or 
indirect medical effects which stem from its technical or functional characteri stics, 
including diagnostic characteristics, to achieve its intended purpose as claimed by the 
manufacturer, thereby leading to a clinical benefit for patients, when used as intended by 
the manufacturer.  
 
Clinical benefit:  means the positive impact of a de vice on the health of an individual, 
expressed in terms of a meaningful, measurable, patient -relevant clinical outcome(s), 
including outcome(s) related to diagnosis, or a positive impact on patient management or 
public health.  
 
Risk: means the combination of the probability of occurrence of harm and the severity of 
that harm.  
 
Adverse event:  means any untoward medical occurrence, unintended disease or injury 
or any untoward clinical signs, including an abnormal laboratory finding, in subjects, 
users or othe r persons, in the context of a clinical investigation, whether or not related to 
the investigational device.  
  
Serious adverse event:  means any adverse event that led to any of the following: (a) 
death, (b) serious deterioration in the health of the subjec t, that resulted in any of the 
following: (i) life -threatening illness or injury, (ii) permanent impairment of a body 
structure or a body function, (iii) hospitali sation or prolongation of patient hospitali sation, 
(iv) medical or surgical intervention to p revent life -threatening illness or injury or 
permanent impairment to a body structure or a body function, (v) chronic disease, (c) 
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Incident:  means any malfunction or deterioration in the characteristics or performance 
of a device made available on the market, including use -error due to ergonomic features, 
as well as any inadequacy in the information supplied by the manufacturer and any 
undesir able side -effect.  
 
Serious incident:  means any incident that directly or indirectly led, might have led or 
might lead to any of the following: (a) the death of a patient, user or other person, (b) 
the temporary or permanent serious deterioration of a pati ent's, user's or other person's 
state of health, (c) a serious public health threat.  
 
Serious public health threat : means an event which could result in imminent risk of 
death, serious deterioration in a person's state of health, or serious illness, that may 
require prompt remedial action, and that may cause significant morbidity or mortality in 
humans, or that is unusual or unexpected for the given place and time.  
 
Device deficiency:  means any inadequacy in the identity, quality, durability, reliability,  
safety or performance of an investigational device, including malfunction, use errors or 
inadequacy in information supplied by the manufacturer.  
 
Regulation (EU) 2017/745 Annex XIV Clinical evaluation and post -market 
clinical follow -up. Part A “Clinical evaluation” Section 3 describes the 
characteristics that shall be considered for demonstration of equivalence .  
“A clinical evaluation may be based on clinical data relating to a device for which 
equivalence to the device in question can be demonstrated. T he following technical, 
biological and clinical characteristics shall be taken into consideration for the 
demonstration of equivalence:  
 
Technical : the device is of similar design; is used under similar conditions of use; has 
similar specifications and pr operties including physicochemical properties such as 
intensity of energy, tensile strength, viscosity, surface characteristics, wavelength and 
software algorithms; uses similar deployment methods, where relevant; has similar 
principles of operation and cr itical performance requirements;  
  
Biological : the device uses the same materials or substances in contact with the same 
human tissues or body fluids for a similar kind and duration of contact and similar release 
characteristics of substances, including de gradation products and leachables;  
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Clinical : the device is used for the same clinical condition or purpose, including similar 
severity and stage of disease, at the same site in the body, in a similar population, 
including as regards age, anatomy and physiology; has the same kind of user; has 
simila r relevant critical performance in view of the expected clinical effect for a specific 
intended purpose.  
The characteristics shall be similar to the extent that there would be no clinically 
significant  difference in the safety and clinical performance of the device. Considerations 
of equivalence shall be based on proper scientific justification. It shall be clearly 
demonstrated that manufacturers have sufficient levels of access to the data relating  to 
devices with which they are claiming equivalence in or der to justify their claims of 
equivalence. ” 
 
Definitions on assessment of alternatives (OECD Toolbox Glossary)  
Note: The term "chemical" is used synonymously with "substance"  
 
Alternativ es assessment : A process for identifying and comparing potential chem ical 
and non -chemical alternatives that can be used as substitutes to replace chemicals or 
technologies of high concern1 
 
Chemical substitution : The process of replacing a chemical of concern with a safer 
chemical, material or product, or technology/process that eliminates the need to use that 
chemical  
 
Cost/benefits and availability : The negative (cost) and positive (benefit) implications, 
direct and indirect, resulting from some actio n. This includes both financial and non -
financial information. Availability refers to the production of an alternative and its market 
accessibility3 
 
Functional use approach : This approach starts with identifying the function that is 
desired. The concept is applied in two ways: ﬁrst and foremost, to characteri se the 
purpose a chemical or mixture serves, or the properties it imparts in a product or process 
(functional use), and second, to eva luate the function of the product and how its use may 
inﬂuence the assessment of alternatives4, 5 
 
Material substitution : The process of replacing a material containing a chemical of 
concern with a safer chemical, material, product or technology/process that eliminates 
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Mixture : A composition of at least two chemicals in which they do not react6 
 
Technical feasibility : The determination as to whether the performance or functional 
requirements of a chemical, material or product could be fulfilled or replaced by 
eliminating or using an alternative chemical, material, product, process or technology, 
while considering any need for process adaptations and changes3 
 
Process modification : Changes in manufacturing processes to eliminate, reduce or 
substitute chemicals of concern. Such changes may include synthesis pathways, waste 
reduction, and manufacturing procedures where chemicals are used.  
 
Product performance : The ability of a product to meet identified performance 
requirements. The boundaries of performance characteristics are defined by the user3 
 
Product substitution : The process of replacing a product containing a chemical of 
concern with a chemical, material or product or technology/process that eliminates, 
reduces or substitutes the need to use that chemical.  
 
1 Adapted from Alternatives Assessment Guide, version 1.0 . 2013. Interstate Chemicals 
Clearinghouse.  
2 REACH. Title I, Chapter 2, Article 3.  
3 Current Landscape of Alternatives Assessment Practice: A Meta -Review. Organisation 
for Economic Cooperation and Development. 2013.  
4 U.S. EPA. 2006. National Pollution Prevention and Toxics Advisory Committee (NPPTAC) 
Recommendation to the EPA Administrat or and Deputy Administrator on Incorporating 
the Functional Use Approach into OPPT Activities.  
5 Lavoie, E. T., et al.  2010. "Chemical Alternatives Assessment: Enabling Substitution to 
Safer Chemicals." Environmental Science & Technology 44(24): 9244 -9249.  
6 Adapted from U.N. Global Harmonized System of Classification and Labelling  of 
Chemicals . 2003.  
7 ECHA, 2008. Guidance on Socio -Economic Analysis - Restrictions.  
8 Adverse event means pre -clinical and clinical occurrences of an effect whereas incident 
indicates a clinical effect occurring during post -market surveillance.  
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Reference s 
 ECHA (2011) Guidance on the preparation of socio -economic analysis as part of 
an application for authorisation, European Chemicals Agency 2011 . 
 EFSA (2019)  Draft update of the risk assessment of di -butylphthalate 1 (DBP), 
butyl-benzyl -phthalate (BBP), bis(2 -2 ethylhexyl)phthalate (DEHP), di -
isononylphthalate (DINP) 3 and di -isodecylphthalate (DIDP) for use in food 
contact 4 materials  http://www.efsa.europa.eu/en/consultations/call/190221 .  
 Guo JJ, Pandey S, Doyle J, Bian B, Lis Y, Raisch DW. A review of quantitative risk -
benefit methodologies for assessing drug safety and efficacy -report o f the ISPOR 
risk-benefit management working group. Value Health. 2010;13(5):657 -66. 
 
Glossary  
BBP   Benzylbutylphthalate  
BMD  Bench Mark Dose  
BRA  Benefit -Risk Analysis  
BTHC   Butyryl -tri-n-hexylcitrate  
CAS  Chemical Abstracts Service  
CEN  European Committee for Standardization  
CLP  Classification Labelling and Packaging regulation (EC No 1272/2008)  
CMR  Carcinogenic, Mutagenic, toxic to Reproduction (Reprotoxic)  
DBP   DiButylphthalate,  
DCHP   Dicyclohexylphthalate  
DEHP   Diethylhexylphthalate  
DIBP   Diisobutylphthalate  
DIDP   Di isodecyl phthalate)  
DINCH  1,2- cyclohexan edicarboxylic acid, di isononyl ester)  
DINP   Di isononyl phthalate)  
DIPP  Diisopentylphthalate  
DMEP   Bis(2-methoxyethyl)phthalate  
DNHP   Dihexylphthalate  
DHNUP  1,2-Benzenedicarboxylic acid, di -C7-11-branched and linear alkyl esters  
DPP   Dipentyl phthalate  
DMEL   Derived Minimum Effect Level  
DNEL   Derived No Effect Level  
EC  European Commission  
ECB  European Chemicals Bureau (now ECHA)  
ECHA   European Chemicals Ag ency (formerly ECB)  Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 ED  Endocrine Disruptor  
EEC  European Economic Community  
EMA  European Medicines Agency  
EFSA  European Food Safety Authority  
EN-ISO CEN and ISO combined published document  
FDA  Food and Drug Administration (USA)  
FDIS  Final Draft International Standard  
ISO  International Organization  for Standardization  
LOAEL   Lowest Observed Adverse Effect Level  
MCDA   Multi Criteria Decision Analysis  
MDD  Medical Device Directive (Council Directive 93/42/EEC)  
MDR  Medical Device Regulation (EU 20 17/745)  
MoA  Mode of Action 
MoE  Margin of Exposure  
MoS  Margin of Safety  
NICU  Neonatal Intensive Care Unit  
NOAEL   No Observed Adverse Effect Level  
OECD   Organization for Economic Cooperation and Development  
PoD  Point of departure  
PVC  Polyvinyl chloride  
RBC  Red Blood Cell  
RCR  Risk Characterisation Ratio  
REACH   Registration, Evaluation, Authorisation and restriction of CHemicals.  
SCHEER  Scientific Committee on Health, Environmental and Emerging Risks  
SCENIHR  Scientific Committee on Emerging and Newly Identified Health Risks  
T25   25 % increase of the tumour rate over controls  
TDI  Tolerable Daily Intake  
TE  Tolerable Exposure (EN ISO 10993 -17:2002 in mg/day)  
TEHTM   Tri( 2 -ethyl hexyl)trimellitate also TOTM Trioctyltrimellitate  
TI  Tolerable Intake  
TOTM   Trioctyltrimellitate also TEHTM Tri( 2 -ethyl hexyl)trimellitate  
TWI    Tolerable Weekly Intake   Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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Annex 4:  CMR and/or ED substances  
 
CMR substances are substances identified and classified as carcinogenic, mutagenic or 
toxic for reproduction of different categories based on the intrinsic toxic properties of a 
substance for which categories 1A and 1B apply to these Guidelines. In Europe, 
classification for  these endpoints is harmonised through harmonised classification and 
labelling (CLH). Details  can be found at  
https://echa.europa.eu/regulations/clp/understanding -clp. For a specific substance to be 
classified as CMR 1A, 1B or 2 a dossier needs to be prepared and if the Commission finds 
that the proposed classification is appropriate, it submits a draft decision concerning the 
inclusion of that substance in Part 3 of Annex VI to the CL P Regulation (Regulation (EC) 
1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures).  
 Category 1A means that the substance is a known human carcinogen, mutagen or 
reproductive toxicant based on human evidence.  
 Category 1B means that the substance is a presumed human carcinogen, 
mutagen or reproductive toxicant based on animal studies.  
 Category 2 means that a substance is considered as suspected carcinogen, 
mutagen or reproductive toxicant based on limited evidence from ani mal studies 
or humans  (not part of these Guidelines) .  
Documents on the classification are publicly available , and  a tutorial to search entries is 
given here:  
http://www.chemsafetypro.com/Topics/EU/Annex_VI_to_CLP:_List_of_Harmonised_Class
ification_and_Labelling_for_Certain_Hazardous_Substances.html  
Guidance for the identification of endocrine disrupto rs (ED) in the context of Regulations 
(EU) No 528/2012 and (EC) No 1107/2009 has been published on 7th June 2018 by 
ECHA and EFSA (doi: 10.2903/j.efsa.2018.5311; EFSA Journal 2018;16(6):5311) which 
can be accessed via:   
https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2018.5311  
This EFSA/ECHA Guidance describes when a substance shall be considered as having 
endocrine disrupting  properties.  
“A  substance shall be considered as having endocrine disrupting properties  if it meets all 
of the following criteria:  
a) it shows an adverse effect in [an intact organism or its progeny]/[non -target 
organisms], which is a change in the morphology, physiology , growth, 
development, reproduction or life span of an organism, system or 
(sub)population6 that results in an impairment of functional capacity, an 
impairment of the capacity to compensate for additional stress or an increase in 
susceptibility to other in fluences;  
b) it has an endocrine mode of action, i.e. it alters the function(s) of the endocrine 
system;  
c) the adverse effect is a consequence of the endocrine mode of action.  
It should be highlighted that the ‘endocrine mode of action ’ as stated in point  (b) 
should be interpreted  as ‘endocrine activity ’ while the term ‘endocrine mode of Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 action’ in point (c) covers the link between the adverse effect and the endocrine activity 
identified in points a) and b), respectively.  
Keeping this in mind point (b) abo ve should be understood as (differences from above in 
italics ): 
it shows endocrine  activity, i.e. it has the potential to alter the function(s) of the 
endocrine system;  
Consequently point (c) above should be understood as (differences from above in italics ): 
the substance has an endocrine disrupting mode of action, i.e. there is a 
biologically plausible link between the adverse effect and the endocrine activity. ” 
EDs identified with the procedure set out in Article 59 of Regulation (EC) No 1907/2006 
concern ing the Registration, Evaluation, Authorisation and Restriction of Chemicals 
(REACH),   will finally enter the REACH candidate list of substances of very high concern 
for potential inclusion in REACH Annex XIV.  The information can be found in the 
respecti ve decision document accessible via : https://echa.europa.eu/candidate -list-table. 
For substances having endocrine -disrupting properties as indicated above, there is 
currently no information concer ning whether it is foreseen to publish them in central lists 
or annexed to a Regulation.  
EDs identified by the delegated act pursuant to the first subparagraph of Article 5(3) of 
Regulation (EU) No 528/2012 concerning the making available on the market and  use of 
biocidal products, can be accessed through the Biocidal Products Committee opinions on 
active substance approval which can be accessed via ECHA’s website 
(https://echa.europa.eu/regulations/biocidal -products -regulation/approval -of-active -
substances/bpc -opinions -on-active -substance -approval ).  
Substances undergoing an ED assessment under the REACH or Biocidal Products 
regulations that have been brought for discussion to ECHA’s ED Expert Group are 
included in ECHA’s endocrine disruptor (ED) assessment list: https://echa.europa.eu/ed -
assessment . For each substance, the table shows the assessing or evaluating Member 
State (submitter), the outcome and the suggested follow -up for the assessment, and the 
date of the latest update to the list entry.  
Recently the Commission Implementing Decision (EU) 2017/1210 was published that 
identified some phthalates (Bis(2 -ethylhexyl) phthalate (DEHP), Benzyl butyl phthalate 
(BBP), Dibutyl phthalate (DBP) and Diisobutyl phthalate (DIBP)) as substances of very 
high concern due to their endocrine disrupting properties with probable serious effects to 
humans (European Commission 2017).  
https://publications.europa.eu/en/publication -detail/ -/publication/357b3d45 -620f-11e7-
9dbe-01aa75ed71a1/language -en/format -PDF 
For completeness, even if not relevant for the purpose of this guidelines, Bis(2 -
ethylhexyl) phthalate (DEHP) was also  identified in 2014 as a substance of very high 
concern due to its endocrine disrupting properties with probable serious effects to the 
environment.  
In addition, Commission Implementing Decision (EU) 2018/636 identified 
Dicyclohexylphthalate (DCHP) as subs tance of very high concern (SVHC) according to 
Article 57(f) of REACH Regulation (EC) 1907/2006, due to its endocrine disrupting Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 properties with probable serious effects to humans.  https://eur -lex.europa.eu/legal -
content/EN/TXT/PDF/?uri=CELEX:32018D0636&fr om=EN     Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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Annex 5:  Legislation on CMR and/or ED phthalates  
 
Due to their reprotoxic properties and additionally since 2014 for DEHP due to their 
endocrine disrupting properties for the environment and since 2017 for DEHP, BBP, DBP, 
and DIBP  due to their endocrine disrupting properties  for human health , a considerable 
number of phthalates have been identified as substances of very high concern (SVHC) 
and therefore included in the candidate list for the inclusion in Annex XIV of the REACH 
regulation (Annex XIV of REACH EC 1907/2006 , see 
https://echa.europa.eu/de/candidate -list-table for the most recent update of the 
candidate list).  
Eight phthalates are also listed on the Authorisation list (Annex XIV of REACH), namely 
DEHP, BBP, DIBP, DBP, DIPP (diisopentylphthalate), Bis(2 -methoxyethyl) phthalate, 
dipentyl phthalate, and N -pentyl -isopentylphthalate. Since February 2015 DEHP, BBP, 
DIBP, and DBP cannot be used within the European Union withou t authorisation. The 
same provision would apply to the remaining four phthalates on Annex XIV from July 
2020. To date, applications for authorisation have been submitted for DEHP and DBP 
only. However, imported articles do not come under the authorisation requirement. For 
the purpose of evaluating applications for authorisation, the ECHA Committee for Risk 
Assessment (RAC) has developed reference DNELs for several substances, including 
DEHP, BBP, DBP, and DIPP. (See Evaluating Applications table/Ref erence D NELs on 
ECHA’s website:  
https://echa.europa.eu/applying -for-authorisation/evaluating -applications .) 
Risks to human health arising from the use of an Annex XIV substan ce in medical devices 
regulated by Directives 90/385/EEC, 93/42/EEC or 98/79/EC are exempted from 
authorisation requirements under Title VII of the REACH Regulation14. ECHA is currently 
preparing a recommendation on the inclusion of the ED properties for environment for 
DEHP in Annex XIV to REACH .15 If DEHP is included on Annex XIV for environmental 
hazards , applications for authorisations may need to be prepared for uses of the 
substance in medical devices in the future.  
REACH Annex XVII (entry 51) also restricts the placing on the market of articles 
containing DEHP, BBP, DBP, and DIBP in concentration greater than 0.1% weight by 
weight of the plasticised material, individually or in combination in a range of articles. 
These articles include toys16 and childcare articles, as well as other primarily consumer 
and professional use articles whic h lead to dermal or inhalation exposure. (For risk 
assessment conclusions, including derivation of a DNEL for DIBP, see Compiled RAC & 
SEAC opinion and background document on ECHA’s website:  
https://echa.europa.eu/previous -consultations -on-restriction -proposals/ -/substance -
rev/13919/term .)   
                                                           
14 These Regulations will be replaced by:  
 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  
•Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro  
diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU  
15 https://echa.europa.eu/draft -recommendation -for-amendment -of-authorisation -list-entries -previous -
consultation   
16 The Toy Safety Directive (2009/48/EC) stipulates that chemicals that are susceptible to cause cancer, change 
genetic information, harm fertility or harm an unborn child (CMR substances) are no longer allowed in 
accessible parts of toys beyond the concentration limits set in the CLP Regulation ((EC) No 1272/2008).  Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 REACH Annex XVII (entry 52) restricts the placing on the market and the use of DINP, 
DIDP, and DNOP, as a  substance or in mixture, in concentrations greater than 0.1% 
weight by weight of the plasticised material in toys and childcare articles which can be 
placed in the mouth of children. In 2010, the European Commission requested ECHA to 
review the scientific  evidence on the risks posed by articles containing these phthalates 
with the view to conclude on the need or not for further actions under REACH. The report 
and RAC risk assessment conclusions (including information on the derivation of DNELs) 
can be foun d on ECHA’s website: https://echa.europa.eu/consultations -draft-review -
report -previous -consultations/ -/substance -rev/1108/term .  
EFSA recently launched a consultation on its updated 2005 risk assessments of DBP, 
BBP, DEHP, DINP and DIDP which are authorised for use in plastic FCM, by using the 
same database as ECHA for its 2017 assessment of certain phthalates. The draft update 
of the ri sk assessment can be found here:  
http://www.efsa.europa.eu/en/consultations/call/190221  
In addition to the REACH legislation, there is also product -specific legislation which 
regulates certain phthalates, i.e. the Cosmetic Products’ Regulation (EC/1223/2009) and 
the Regulation on materials and articles intended to come into contact with food ( Food 
Contact Materials,  Regulation EC 1935/2004 , as general framework regulation and 
Regulation EU 10/2011 specific for plastic materials and articles destined to be in contact 
with foodstuffs , recently amended by Regulation 2018/831 ). Both in the MDD 
(93/42/EEC) and the more recent MDR (2017/745), phthalates are specifically mentioned 
for their use in medical devices.  
For a number of phthalates there is legislation available that might contain information 
relevant for the use of phthalates in medical devices. Of specific relevance for medical 
devices may be the Regulation EU 10/ 2011, which also incl udes provisions for the use of 
phthalates in food contact materials and articles with respect to migration limits. This 
may be a parallel with migration (and thus potential internal exposure) of phthalates as 
present in polymers used for medical device man ufacturing. In Annex I of the Regulation 
EU 10/2011 all substances are listed, which are authorised for the use as starting 
material or additive for plastic layers in plastic materials and articles. Each substance 
must not exceed its specific migration lim it (SML). The following phthalates and other 
plastici sers17 are authorised for use as additives:  
 
DBP (SML) = 0.3 mg/kg food  
only to be used as:  
(a) plasticiser in repeated use materials and articles in contact with  non -fatty foods;   
(b) technical supp ort agent in polyolefins in concentrations up to 0.05% in the final  
product  
 
BBP, SML = 30 mg/kg food  
Only to be used as:  
(a) plasticiser in repeated use materials and articles;  
                                                           
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 (b) plasticiser in single -use materials and articles in contact with  non -fatty foods, not for 
contact with infant formulae and follow -on formulae (Directive 2006/141/EC) and 
processed cereal -based foods and baby foods for infants and young children (Direc tive 
2006/125/EC);  
(c) technical support agent in concentrations up to 0.1% in the final product.  
 
DEHP, SML = 1.5 mg/kg food   
Only to be used as:  
(a) plasticiser in repeated use materials and articles in contact with non -fatty foods;  
(b) technical su pport agent in concentrations up to 0.1% in the final product.  
 
DINP SML = 9 mg/kg food (cumulative with DIDP)  
only to be used as  
(a) plasticiser in repeated use materials and articles;  
(b) plasticiser in single -use materials and articles in contact with  non -fatty foods , not 
for contact with  infant formulae and follow -on formulae ( Directive 2006/141/EC) and 
processed cereal -based foods and baby foods for infants and young children (Di rective 
2006/125/EC)  
(c) technical support agent in concentrations up to 0.1% in the final product.   
 
DIDP, SML = 9 mg/kg food ( cumulative with DINP)  
Only to be used as  
(a) plasticiser in repeated use materials and articles;  
(b) plasticiser in single -use materials and articles in contact with  non -fatty foods , not 
for contact with infant formulae and follow -on formulae ( Directive 2006/141/EC) and 
processed cereal -based foods and baby foods for infants and young children (Directive 
2006/125/EC)  
(c) te chnical support agent in concentrations up to 0.1% in the final product.   
 
Furthermore, for certain plasticizers listed in Regulation (EU) 10/2011, including a 
number of phthalates, applies a group restriction  (Group restriction number 32),  that is, 
the sum of these substances must not exceed an SML of 60 mg/kg foodstuff.  
DEHP, BBP, DBP and DIBP must not be contained in homogenous materials above the 
concentration of 0.1% w/w from July 2019 on according to the Restriction of Hazardous 
Substances Directive  in electrical and electronic equipment RoHS2 (2011/65/EC). For 
medical devices and  in vitro  diagnostic products this restriction takes effect in July 2021.  
 
 
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Table 1  CMR Classification*) and ED designation**) of phthalates (status Jan 2019)  
Phthalate  Abbreviation  CAS 
number  CMR 
Classification*  ED 
identification**  
bis(2-
methoxyethyl)phthalate  DMEP  117-82-
8 Repr 1B  - 
bis  
(2-ethylhexyl)phthalate  DEHP  117-81-
7 Repr 1B  ED 
dibutyl phthalate  DBP 84-74-2 Repr 1B  ED 
1,2-
benzenedicarboxylic 
acid, dipentylester, 
branched and linear   84777 -
06-0 Repr 1B  - 
n-pentyl -
isopentylphthalate  PIPP No CAS  
776297 -
69-9? Repr 1B  - 
di-n-pentyl phthalate  DnPP 131-18-
0 Repr 1B  - 
diisopentylphthalate  DiPeP  605-50-
5 Repr 1B  - 
benzyl butyl phthalate  BBP 85-68-7 Repr 1B - ED 
diisobutylphthalate  DIBP 85-69-5 Repr 1B  ED 
dihexylphthalate  DHP 84-75-3 Repr 1B   
dicyclohexylphthalate  DCHP  84-61-7 Repr 1B  ED 
*) as indicated in Annex VI to CLP_ATP10 (in force from 1 December 2018).  
**) according to the ECHA Candidate List of substances of very high concern for Authorisation  published in 
accordance with Article 59(10) of the REACH Regulation  https://echa.europa.eu/candidate -list-table  
 
As substances of concern, knowledge on the exposure to phthalates is important and 
biomonitoring of populations provides important information.  For some of the phthalates 
already human biomonitoring assessment values, namely Biomonitoring equi valents (BE) 
or human biomonitoring (HBM) values, have been derived – these are concentrations of 
biomarkers (metabolites) in urine, which reflect an acceptable chronic exposure, since 
the basic assumption is an equilibrium between external exposure and in ternal burden 
(Angerer et al.  2011, Apel et al.  2017). In the course of the work done within the 
HBM4EU project, Human Biomonitoring Guidance Values (HBM -GVs) could be derived for 
DEHP and DINCH (see HBM4EU Deliverable D5.2, https://www.hbm4eu.eu ). In addition, 
HBM-GVs for the following SVHC phthal ates are finalised in September 2019 (Deliverable 
D5.6) and will also be published on the website: BBzP, DiBP, and DnBP.   Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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Annex 6:  Use of phthal ates in medical devices  
 
Phthalates are abundantly used in polyvinyl chloride (PVC) medical devices such as blood 
bags, intravenous bags, nutrition pockets, tubing, catheters, respiratory masks or 
disposable gloves. More than 40% of all plastic -based disposable medical devices are  
made from PVC. Di -2-ethylhexyl phthalate (DEHP) has been for many years the most 
commonly used phthalate ester plasticiser in medical devices. A survey among the 
Danish Medical Device Industry found that 95% of the products contained DEHP [Huntley 
P, edit or The classified phthalates should be phased out of medical devices. Alternatives 
to Classified Phthalates in PVC Medical Devices Conference; 2014 Mar 27; Copenhagen, 
Denmark].  
 
Safety concerns have been expressed for several high -risk patients groups, s uch as 
neonates, infants, pregnant and breast -feeding women exposed to DEHP. The SCENIHR 
in its Opinion of 201 5 indicated that “a lack of evidence of causation between DEHP -PVC 
and any disease or adverse effect does not mean that there are no risks”. This lack of 
evidence applies to all phthalates classified as CMR and/or identified as ED. Therefore the 
requirement of patient subgroup analysis for the target patient groups as defined in the 
“Intended Use” of a medical device is now included in the Regulatio n (EU) 2017/745.  
 
For the use of DEHP, high risk groups were identified including patients undergoing 
haemodialysis, extracorporeal membrane oxygenation (ECMO), and prematurely born 
infants in Neonatal Intensive Care Units (NICU), (SCENIHR 201 5). The actua l exposure of 
such patient groups relative to the toxicity including CMR/ED property needs to be 
determined. However, even if the remaining risk is high, the benefit of the treatment 
should be considered as well. It might be useful to evaluate the patient subgroups 
separately:  
 
 Paediatric Population (see subgroups)  
 Peripubertal males  
 Pregnant women  
 Breast -feeding women  
 any other patient group considered particularly vulnerable or exposed to high 
levels of phthalates.  
 
For purposes of this Guideline, the following ranges of paediatric subpopulations are 
proposed to be used as a guide for manufacturers in medical devices (ref. SCCS Notes of 
Guidance – SCCS/1602/18, section 3 -6.9.1, page 7818) 
 
 
 
 
 
 
 
 
                                                           
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Definition of Paediatric Population Subgroups  
 
Paediatri c Subgroup  Approximate Age Range  
Full-term neonate  <1 week  
Newborn  1 week–2 months  
Early infant  2–6 months   
Crawlers/toddler  6 months –2 years  
Preadolescent  2–12 years   
Adolescent  12–18 years   
 
In view of ED activity, a dditional (paediatric ) subpopulations may need to be considered 
includ ing:  
 
 very low birth weight describes newborns less than 1.5 Kg  
 low birth weight describes newborns less than 2.5 Kg  
 preadolescent age group typically ranges from 11 to 13 years.  
 peripubertal males  or females  
 
It should be realised that the benefit of medical devices including the use of phthalates 
must also be considered: The survival of prematurely born infants often depends on the 
availability of the same medical devices that result in a relative ly high phthalate content 
exposure due to treatment. Whenever possible, material with low release potential 
should be used (see SCENIHR opinion 201 5). 
 
Besides the direct patient benefits of the treatment with a medical device containing 
phthalates, other functionalities may also need to be considered.  For example, DEHP has 
a stabilising effect on red blood cells (RBCs). RBCs have increased survival rates when 
stored in DEHP containing blood bags. DEHP is incorporated into the cell walls of RBCs 
and stabil ises the membrane integrity of the RBCs. This results in a prolonged shelf life 
and thus patient availability of blood stored in DEHP containing blood bags (SCENIHR 
2015). A maximum limit of extractable DEHP of 15 mg/100 mL for flexible PVC 
containing DEHP  is indicated in EN ISO 3826 -1 on containers for the collection of human 
blood and blood components.   
 
The plasticiser industry has been investing and developing alternatives to DEHP in 
medical devices. Today, other plasticisers such as Di -isononyl cyclohe xanoate (DINCH, 
CAS 166412 -78-8), Tri -2-ethylhexyl trimellitate (TEHTM, CAS 3319 -31-1), butyryl tri -n-
hexyl citrate (BTHC, CAS 102818 -95-1) and Dioctyl Terephthalate (DOTP, CAS ‎6422-86-
2) are being proposed in medical applications such as medical tubing and blood bags.  
https://www.plasticisers.org/applications/medical -applications/   
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 In conclusion, for any BRA on the use of phthalates and the development of alternatives 
in me dical devices, careful consideration should be used to appropriate patient subgroup 
analysis regarding medical device use and the resulting potential exposure.  
 
Reference  
Huntley P, Editor . The classified phthalates  should be phased out of medical devices. 
Program Meeting on Alternatives to Classified Phthalates in PVC Medical Devices 
Conference; 2014 Mar 27; Copenhagen, Denmark.  
https://pvc.dk/wp -content/uploads/2016/02/pvc -alternativer -til-klassificerede -ftalater -
program.pdf  
 
 
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Annex 7:  Approaches for Benefit -Risk Assessment  
 
Several approaches for BRA have been proposed especially in the context of medicinal 
products. The Innovative Medicines Initiative PROTECT Project (www.imiprotect.eu), 
presented a detailed review of approaches used for BRA (Mt -Isa et al.  2014). In this 
review, a large number of approaches were identified and classified as descriptive 
(qualitative or semi -qualitative) or quantitative frameworks (relying on quantitative 
methods of trading risks and benefits following mathematical principles), metrics 
(measure s for benefits and risks that are usually endpoint specific), estimation 
techniques (i.e., simulation techniques and meta -analysis) , and utility survey techniques 
(to elicit stakeholders’ preferences).  
Concerning quantitative frameworks, according to the European Medicines Agency (EMA) 
Project Report (EMA/227124/2011), there is no agreement on any one approach to be 
used in regulatory submission on the benefits and risks of medicines. However, EMA has 
encouraged the use of quantitative frameworks in regulatory submissions of applications 
for marketing authorisation of medicinal products.  
Although there is little experience with quantitative frameworks in the area of medical 
devices, some of the BRA appro aches used for pharmaceuticals may also be relevant for 
medical devices and particularly regarding the use of CMR/ED phthalates. In particular, 
approaches based on multicriteria decision analysis ( MCDA) have attracted much 
attention during the past years in the field of medical decisions. For an introduction to 
MCDA see Dodgson et al. (2009).  
In brief, MCDA is based on decision theory and belongs to the general class of multi -
criteria analysis mode ls that accommodate decision making with multiple objectives. The 
main purpose of MCDA is to bring together evaluations of options on different criteria into 
one overall evaluation.  The starting point for MCDA approaches include s identification of 
the alte rnatives and the criteria against which the alternatives are appraised.  MCDA 
includes weighting, which ensures that the units of value on all the criteria are 
comparable so that benefits and risks can be compared by using a common unit of value. 
In this wa y, the added value of benefits can be compared to the loss of value from the 
risks. A number of different weighting methods can be used, ranging from precise 
elicitation of weights, to weights based on qualitative judgements or including 
uncertainty.  
A generic framework for conducting an MCDA can be based on the steps of the PROACT -
URL framework (Hammond et al. , 1999), as presented below. A detailed description of 
the different implementations of MCDA techniques is beyond the scope of this guideline. 
The c hosen techniques and analyses should be presented and justified among others on 
the basis of internal consistency, logical soundness and transparency.  
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STEP Description and relation to framework for Benefit -Risk 
Assessment described in section A of the  Guidelines  
Problem  Describe the medical device, its intended use, and the 
therapeutic context; frame the decision problem in terms 
of potential alternatives to CMR/ED phthalate. See Step 1: 
Description and characterisation of the composition of the 
medic al device; and Step 2: Use and function of the 
phthalates in the medical device.  
Objectives  Identify the full set of criteria to evaluate different 
alternatives. See Step 2: Use and function of the 
phthalates in the medical device; and Step 3: Assessment  
of the risks of the CMR/ED phthalate. See 7 Benefit 
assessment . 
Alternatives  Identify alternatives that are being evaluated against each 
other. See Step 4: Inventory of possible alternatives; and 
Step 5: Identification of the candidates for assessment as  
potential relevant alternatives for phthalates . 
Consequences  Describe how the alternatives perform for each of the 
criteria, i.e., the magnitudes of all effects in terms of the 
different benefits and risks. See Step 2: Use and function 
of the phthalates in the medical device; Step 3: 
Assessment of the risks of the C MR/ED phthalate; Step 6: 
Description of identified relevant potential alternative(s); 
Step 7: Assessment of the risk of identified potential 
relevant alternatives. For a summary table see Table 1. 
Example for a comparison of CMR/ED phthalate with 
potential  alternative(s).  
Trade -offs Assess the balance between benefits and risks using 
judgements of weights associated with the criteria and the 
value associated with the benefits and risks of every 
alternative. MCDA techniques commonly achieve this 
through num erical analysis. A number of different 
weighting methods can be used. Conduct sensitivity 
analyses to explore uncertainties using different scenarios, 
and assess how different weights affect the overall 
ordering of the alternatives.  
See also Step 8: Compar ison of functionality and 
performance of CMR/ED phthalate as used in the medical 
device with functionality and performance of identified 
potential relevant alternatives; Step 9: Comparison of 
risk(s) of original CMR/ED phthalate as used in the medical 
device with risk(s) of identified potential relevant 
alternatives; and Step 10: Comparison of benefit and risk 
of CMR/ED phthalate used in the medical device with 
identified potential relevant alternatives.  
Uncertainty  Report the uncertainty associated with the benefits and  
Risks. Consider how the balance between benefits and 
risks is affected by uncertainty. A quantitative model will Guidelines o n the benefit -risk assessment of the presence of CMR/ED phthalates in certain medical devices  
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 explore in sensitivity analyses and scenario analyses (or by 
explicitly incorporating probability distributions in the 
model) the effects on the overall benefit -risk balance of all 
sources of uncertainty. See 1.9 Uncertainty analysis.  
Risk tolerance  Describe any considerations that could or should affect the 
decision maker’s attitude toward risks (e.g., special 
population, unmet  medical need).  
Linked -decisions  Discuss how the value judgements and data are consistent 
with similar decisions on medical devices.  
  
 
References  
 Dodgson J, Spackman M, Pearman A, Phillips LD. Multi -criteria analysis: A 
manual. London: Department for Communities and Local Government, First 
published in 2000 by the Department for Environment, Transport and the 
Regions; 2009.  
 
 ECHA 2011 Guidance on the preparation of socio -economic analysis as part of an 
application for authorisation, European Chemicals Agency 2011 . 
 
 Hammond JS, Keeney RL, Raiffa H, Smart Choices: A Practical Guide to making 
Better Decisions, Boston, MA: Harvard Business School Press; 1999.  
 
 Mt-Isa S, Hallgreen C.E., Wang N., Callréus T., Genov G., Hirsch I., Hobbiger S., 
Hockley .S., Luciani D., Phillips L.D., Quartey G., Sarac S.B., Stoeckert I., Tzoulaki 
I., Micaleff A., Ashby D. - Balancing benefit and risk of medicines a systematic 
review and classification of available methodologies, Pharmacoepidemiology and 
Drug Safety, May 2014 .