COMMENTS AND RESPONSE TO COMMENTS ON ANNEX XV SVHC: PROPOSAL AND JUSTIFICATION
Disclaimer
The Response to Comments table has been prepared by the competent authority of the Member State preparing the proposal for identification of a
Substance of Very High Concern. The comments were received during the public consultation of the Annex XV dossier. The table has been used as a
meeting document of the Member State Committee. The table does not contain any confidential information provided. Furthermore it has not been
revised taking into account the discussions and conclusions of the Member State Committee.
Substance name: Bis(2-ethylhexyl)phthalate
CAS number 117-81-7
EC number: 204-211-0
Reason of the submission of the Annex XV: It is proposed to identify the substance as a CMR according to Article 57 (a), (b) and/or (c).
General comments
Date
Submitted
by
20080714 Ellen
Sweeny
20080714 Zbigniev
Slezak
Organisation/
MSCA
Individual
Comment
Response
I support the nomination of Bis (2-ethyl(hexyl)phthalate) (DEHP) to the
Candidate List, and believe it is important, given its properties, for it to
be as strictly controlled as possible.
Individual on Our company Zakłady Azotowe Kedzierzyn S.A. in Poland is one of the
behalf
of biggest producers of phthalate plasticizers. In the fifties, we started with
organisation
production of dibutyl phthalate and in the sixties with di-2-ethylhexyl
phthalate. These plasticizers were and are widely used.
For all of these years millions of people had a contact with phthalates so
we could say that it was carried out colossal experiment. In the result of
this, there are no diseases or death case caused by phthalates. Many
scientists in different countries are of the same opinion about. So we
would like to ask why dibutyl phthalate and di-2-ethylhexyl phthalate
are located in a pre-candidate list for authorization? Is there sureness
that suggested alternative phthalates, that are much less known, will be
more hazardous? This is the comment arisen on many conferences.
-1-
Thank you for the support.
It is often difficult to provide
evidence of effects on humans
even for known hazardous
substances that have been used
extensively in the society for a
long time. For instance, many
toxic effects known to occur in
experimental
animals
are
difficult to study in humans. It
is also often difficult to
quantify exposure to the
substance within a human
population or in an individual,
because of, e.g., very different
or varying habits / living or
working conditions / food
preferences / use of consumer
articles.
Lack of proofs for effects in
humans can therefore not be
considered a strong argument
against concern raised based
on a thorough risk assessment
showing substantial human
exposure and hazardous effects
in reliable animal studies of
good quality. In this case,
DEHP is well-known to be
hazardous, being classified as a
reproductive toxicant by the
EU, and an EU risk assessment
has indicated unacceptable
risks for many uses leading to
high
exposure
to
this
substance. To our knowledge,
there are no new studies that
challenge these conclusions
that have been agreed among
the EU member states.
20080721 Dr.
Ralf On behalf of DEHP has been used since decades as plasticizer in PVC formulations See the response to the next
Ziembinski organisation:
for manufacturing blood-bags and medical tubings. There have been no comment.
RAUMEDIC
reports about negative effects on patients related to the use of DEHP.
AG, Germany
It is also of great concern that DEHP is the only plasticizer listed in the
European Pharmacopeia § 3.1.1 for such medical products. It is
-2-
20080807 Hilde
Viroux
absolutely in-consistent to classify DEHP as substance of concern in
REACh, but on the other hand recommend the use of this substance in
critical medical devices such as blood-bags!!!
On behalf of Alcon Laboratories, Inc. is the worldwide leader in ophthalmic
organisation
products: pharmaceuticals and medical devices. Alcon Laboratories, Inc.
Alcondevelops manufactures and markets surgical, pharmaceutical, and
Couvreur,
consumer vision care products. In the eye care industry, we have the
Belgium
broadest product portfolio and possess leading market share in most
product
categories.
Alcon Laboratories, Inc. welcomes the opportunity to respond to the
Consultation on the Annex XV SVHC dossiers. We support initiatives
aimed at ensuring a high level of protection of human health and safety.
Alcon Laboratories, Inc. however questions the basis for selecting
DEHP to be incorporated in the first SVHC list as:
• DEHP has been used safely in Medical Devices for decades and is
regulated
by
the
Medical
Device
Directive
(MDD)
[http://ec.europa.eu/enterprise/medical_devices/guide-stdsdirectives/cons_vers_93-42-eec.pdf] .
• It is still the only plasticizer that is recommended by the European
Pharmacopoeia
• There are not enough data on suitable alternatives for these
applications
• The information presented on health hazards and risks are not well
balanced,
ignoring
key
studies
Two recent developments are of special importance: the revision of the
Medical Device Directive 93/42/EEC by Directive 2007/47/EC
[http://ec.europa.eu/enterprise/medical_devices/guide-stdsdirectives/cons_vers_93-42-eec.pdf] and
the
2008
SCENIHR
(Scientific Committee on Emerging and newly-identified Health Risks)
Opinion
[http://ec.europa.eu/health/ph_risk/committees/04_scenihr/docs/scenihr
-3-
Thank you for the information.
The purpose of the dossier is to
identify a substance as a
SVHC. DEHP is classified as
toxic to reproduction according
to directive 67/548/EEC and
thereby meets the criteria for a
substance of very high
concern. Medical devices are
only a part of the variety of
different applications where
DEHP is used. The REACH
legislation acknowledges that
medical devices are subject to
specific regulations e.g. in
article 2(6)(c) and article
60(2). In addition, it is possible
to exempt uses or categories of
uses from the authorisation
requirement if risks are
considered to be properly
controlled through existing
specific
Community
legislation, see article 58(2).
Further discussions on risks
and benefits of different uses,
such as in medical devices,
should take place later in the
_o_014.pdf].
authorisation process.
(a) The latest MDD 2007/47/EC regulates the use of CMR substances
and especially Phthalates in Medical Devices. Following a long
consultation process, it has been recognized by the SCENIHR that
Phthalates are safe and provide unique advantages to medical devices.
Therefore there was no action to restrict their use, but to provide
additional
information
to
users
where
necessary.
“The devices must be designed and manufactured in such a way as to
reduce to a minimum the risks posed by substances leaking from the
device. Special attention shall be given to substances which are
carcinogenic, mutagenic or toxic to reproduction, in accordance with
Annex
I
to
Directive
67/548/EEC.
We agree that the SCHENIR
opinion, “Scientific opinion on
the safety of medical devices
containing DEHP-plasticized
PVC or other plasticizers on
neonates and other groups
possibly at risk, 6 February
2008” (see abstract below)
should be considered in the
future process.
If parts of a device (or a device itself) intended to administer and/or
remove medicines, body liquids or other substances to or from the body,
or devices intended for transport and storage of such body fluids or
substances, contain Phthalates which are classified as carcinogenic,
mutagenic or toxic to reproduction, of category 1 or 2, in accordance
with Annex I to Directive 67/548/EEC, these devices must be labeled on
the device itself and/or on the packaging for each unit or, where
appropriate, on the sales packaging as a device containing phthalate.
If the intended use of such devices includes treatment of children or
treatment of pregnant or nursing women, the manufacturer must provide
a specific justification for the use of these substances with regard to
compliance with the essential requirements of this Section, in particular
of this paragraph, within the technical documentation and within the
instructions for use information on residual risks for these patient
groups and, if applicable, on appropriate precautionary measures.”
(b) The SCENIHR opinion on the safety of Medical Devices containing
-4-
ABSTRACT:
The Scientific Committee on
Emerging
and
Newly
Identified
Health
Risks
(SCENIHR) has evaluated the
exposure to DEHP for the
general population and patients
during medical procedures. In
some cases the exposure is
significant and exceeds the
toxic doses observed in animal
studies. There is limited
evidence suggesting a relation
between DEHP exposures and
some effects in humans. There
is a reason for some concern
for prematurely born male
neonates for which the DEHP
exposure may be transiently
DEHP-plasticized PVC or other plasticizers stated that “so far there is
no conclusive scientific evidence that DEHP exposure via medical
treatments has harmful effects in humans”. Furthermore, it states that
there is not sufficient data yet on so called “alternative materials.
On the initiative of GHTF (the Global Harmonization Task Force) a
new working group has started within ISO, ISO TC194/WG11 that is
dealing with applicable limits of DEHP in medical devices and
standards
for
measuring
these.
We would like to have a more balanced view among all stakeholders
which also considers the positive benefits of DEHP plasticized PVC and
research that has failed to show adverse effects in humans.
-5-
above the dose inducing
reproductive toxicity in animal
studies. So far, there is no
conclusive scientific evidence
that DEHP exposure via
medical treatments has harmful
effects in humans. But, it is
recognised that especially the
potentially high exposure
during medical treatments may
raise a concern, even in the
absence
of
clinical
or
epidemiological evidence, for
harmful effects in humans.
Further studies are required to
confirm
or
reject
the
suggestions of adverse effects
of DEHP in humans. For
certain
uses
of
DEHP
alternative plasticizers for PVC
are available. The Committee
got access to toxicity data for
eight
possible
alternative
plasticizers and compared their
toxicity with that of DEHP. In
respect to reproductive toxicity
in animal studies DEHP
induces more severe effects
compared with some of the
alternatives. A risk assessment
of these available alternative
plasticizers could not be
performed due to a lack of
exposure data from medical
devices. Each alternative to
DEHP, however, must also be
evaluated with regard to their
functionality in respect to
medical devices. The risk and
benefits of using alternative
plasticizers
should
be
evaluated case by case.
See also the response to
comment
submitted
Zbigniev Slezak above,
relation to lack of proof
effects in humans.
20080808 Thecla Sterk On behalf of This reflects the view of Eucomed which represents approx. 4500 See the response
organisation
designers, manufacturers and suppliers of medical technology. previous comment.
Eucomed,
Belgium
We are concerned about the inclusion of DEHP in the first SVHC
candidate list as the specific use of DEHP in our industry is crucial for
providing safe and efficient medical devices to the health care system.
Medical Device Industry is of the opinion that DEHP should not be on
this
list
as:
• DEHP has been used safely in Medical Devices for decades and is
regulated
by
the
Medical
Device
Directive
(MDD).
• It is still the only plasticizer that is recommended by the European
Pharmacopoeia.
• There are not enough data on suitable alternatives for these
applications
-6-
to
the
by
in
for
the
• The information presented on health hazards and risks are not well
balanced,
ignoring
key
studies
Two recent developments are of special importance: the revision of the
Medical Device Directive 2007/47/EC and the 2008 SCENIHR
(Scientific Committee on Emerging and newly-identified Health Risks)
opinion.
(a) The latest MDD regulates the use of CMR substances and especially
Phthalates in Medical Devices. Following a long consultation process, it
has been recognized by the SCENIHR that Phthalates are safe and
provide unique advantages to medical devices. Therefore there was no
action to restrict their use, but to provide additional information to users
where necessary (See official consolidated text of the MDD: http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:1993L0042:2
0071011:EN:PDF and Eucomed draft proposal for Guidance to
Directive 2007/47/EC, amending Council Directive 93/42/EEC
concerning
phthalates
in
attachment).
“The devices must be designed and manufactured in such a way as to
reduce to a minimum the risks posed by substances leaking from the
device. Special attention shall be given to substances which are
carcinogenic, mutagenic or toxic to reproduction, in accordance with
Annex
I
to
Directive
67/548/EEC.
If parts of a device (or a device itself) intended to administer and/or
remove medicines, body liquids or other substances to or from the body,
or devices intended for transport and storage of such body fluids or
substances, contain Phthalates which are classified as carcinogenic,
mutagenic or toxic to reproduction, of category 1 or 2, in accordance
with Annex I to Directive 67/548/EEC, these devices must be labeled on
the device itself and/or on the packaging for each unit or, where
appropriate, on the sales packaging as a device containing phthalate.
-7-
If the intended use of such devices includes treatment of children or
treatment of pregnant or nursing women, the manufacturer must provide
a specific justification for the use of these substances with regard to
compliance with the essential requirements of this Section, in particular
of this paragraph, within the technical documentation and within the
instructions for use information on residual risks for these patient
groups and, if applicable, on appropriate precautionary measures.”
(b) The SCENIHR opinion on the safety of Medical Devices containing
DEHP-plasticized PVC or other plasticizers stated that “so far there is
no conclusive scientific evidence that DEHP exposure via medical
treatments has harmful effects in humans”. Furthermore, it states that
there is not sufficient data yet on so called “alternative materials” (See
SCENIHR
opinion:
http://ec.europa.eu/health/ph_risk/committees/04_scenihr/docs/scenihr_
o_014.pdf).
We want to draw your attention also to the fact that the Global
Harmonization Task Force (GHTF) has led the initiative to start a
working group (ISO TC194/WG11) that is dealing with applicable
limits of DEHP and standards for measuring these. [See
http://www.iso.org/iso/iso_catalogue/catalogue_tc/catalogue_detail.htm
?csnumber=45651]
We would like to have a more balanced view among all stake holders
which also considers the positive benefits of DEHP plasticized PVC and
research that has failed to show adverse effects in humans.
20080813 Sarah
Dunagan
On behalf of We support the nomination of this chemical to the Candidate List, and Thank you for the support.
Silent
Spring believe it is important, given its properties, for the EU to take strong
Institute, United precautionary measures. As a chemical with clear evidence of endocrine
-8-
States.
20080819 Ryuichi
Hasegawa
disruption it has been under study by Silent Spring Institute, which is
dedicated to investigating the links between environmental pollution
and breast cancer. Breast cancer is the most common invasive cancer in
women worldwide (1) and the leading cause of death in US women in
mid-life and beyond the sheer number of women affected the public
health significance of the disease stems also from the pattern of risk for
women in mid-life when they are raising children and contributing to
work and communities. Screening and improved treatment have
contributed to improved survival, however treatment is likely to remain
arduous and debilitating for the foreseeable future, with potential
adverse effects on cardiovascular health, secondary cancers, physical
mobility, cognition, sexuality, and social factors. Financial costs of
treatment are substantial, amounting to US$8.1 billion in the US in 2004
according to the National Cancer Institute. Because breast cancer is so
common, has such substantial societal impacts, and the environmental
chemical exposures hypothesized to affect risk are so widespread, the
public health impact of reducing exposures would be profound even if
the true relative risks are modest.
Reference: Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer
statistics, 2002. CA Cancer J Clin. 2005; 55: 74-108.
Affiliated With The DEHP risk assessment has been completed in Japan, the U.S.A.,
Organisation
Europe, and other areas, and the risk of DEHP is adequately controlled
Japan
except for some uses of DEHP in toys and other products. New DEHP
Plasticizer
regulation
is
therefore
unnecessary.
Industry
The risk assessment report (RAR) by the EU has concluded that the
Association
regulations based on Directive 76/769/EEC on CMR substances and
Directive 2005/84/EC on phthalates in toys and childcare articles are
sufficient to solve risks known to consumers. Therefore, the scientific
conclusion from the risk assessment is that this substance should be
used given the measures already taken for reducing risks. New
information and new studies referenced in the dossier do not constitute
-9-
The purpose of the dossier is to
identify a substance as a
SVHC. DEHP is classified as
toxic to reproduction according
to directive 67/548/EEC and
thereby meets the criteria for a
substance of very high
concern. Further discussions
on risks and benefits of
different uses should take
place later in the authorisation
the argument to reconsider the conclusions in RAR. process.
Especially, this dossier deals with exposure data (the 95th percentile
value on children) published after RAR, and expresses that the exposure
value exceeds the DNEL set up by this dossier. It is stated, however,
that the exposure data are uncertain because these data are subject to
daily variations and different individuals (p. 37, 38). Furthermore, RAR
sought a margin of safety (MOS) from the exposure level and NOAEL,
and found that the MOS of oral exposure from toys and childcare
articles alone was less than 100, leading to the conclusion as in (iii). On
the other hand, other exposures were concluded as in (ii) without taking
up as problems (p. 497, 498 in RAR). The use of DEHP in toys and
childcare articles is already regulated. There is no reason why the
dossier regards DEHP as a SVHC and seeks again the authorization in
uses that are not questioned in RAR. Accordingly, we demand that
DEHP be removed from the SVHC Candidate List.
20080819 Lisette Van Behalf Of An
We support this substance to be included in the Candidate list on the Thank you for the support.
Vliet
Organisation
basis of the criteria summarized on page 5 of the submitted Annex XV
Health
& dossier in the section entitled “Summary of how the substance meets the
Environment
CMR (Cat 1 or 2), PBT or vPvB criteria, or is considered to be a
Alliance
substance
of
an
equivalent
level
of
concern”.
20080819 Jean_Pierre
Behalf Of An
The Annex XV dossier mainly builds on EU RAR written by Swedish
KEMI. Though the EU RAR was published in 2008, the year of last
literature search is stated to be 2005. Containing approximately 1.000
references, the latest from 2005, the RAR can be considered to be
comprehensive. The Annex XV dossier adds 18 references to the RAR
data basis, the latest study from 2007. Given the fact that 401 studies on
DEHP were published between 2005 and 2008, the comments
exclusively focus on this new literature available. Date of last literature
search: 08/03/2008 on ISI Web of Knowledge. Comment by Martin
Wagner, Dipl. Biol, Goethe University, Frankfurt am Main.
ECVM ( The European Council of Vinyl Manufacturers represents the The purpose of the dossier is to
- 10 -
De Grève
20080819 Shigetaka
Seki
20080819 Tim Edgar
Organisation
European
Council
of
Vinyl
Manufacturers
European PVC resin producing companies and is a division of
PlasticsEurope. Its membership includes the14 European PVC resin
producers which together account for 100% of EU 27 production.
ECVM is also a leading partner of Vinyl 2010 - the organisation
implementing the Voluntary Commitment of the PVC Industry together with ESPA - representing the stabiliser producers, ECPI representing the plasticiser producers and EuPC - representing the PVC
converters.
identify a substance as a
SVHC. DEHP is classified as
toxic to reproduction according
to directive 67/548/EEC and
thereby meets the criteria for a
substance of very high
concern. Further discussions
on risks and benefits of
different uses should take
ECVM’s view is that the inclusion of DEHP in the list is scientifically place later in the authorisation
unfounded. DEHP has been fully and thoroughly risk assessed process.
according to the EU procedure. All required risk management measures
have been agreed between the authorities and industry, and are in most
cases
already
implemented.
DEHP remains an important plasticizer for the PVC industry, which is
confident in its use.
Behalf Of An
The fundamental objective of the REACH is to use chemicals safely
Organisation
based on risk assessments. DEHP is one of the rare chemicals on which
Vinyl
solid scientific studies of risk assessments have been conducted with
Environmental
extensive hazard and exposure data. Its risk has been well understood
Council, Japan
and well controlled. The conclusions of both Japanese and EU risk
assessments are that there is no need to introduce additional regulations
on top of the existing ones. Since extensive risk assessments have
already been conducted, additional risk assessment by DEHP users is
not considered necessary.
Behalf Of An
The European Council for Plasticisers and Intermediates (ECPI) points
Organisation
out that DEHP has undergone an extensive EU Risk Assessment (EUR
European
23384 EN, 2008, Volume 80). Therefore, EU Member States have
Council
for already agreed and in most cases implemented measures that needed to
Plasticisers and be taken to control any risk from DEHP to human health or to the
Intermediates
environment. They have effectively agreed that no further measures
- 11 -
See the response
previous comment.
to
the
See the response to the two
previous comments.
(ECPI)
20080819 JACQUES
WARNON
need to be taken to manage the substance in any of its key end-use
applications.
The only areas of possible risks identified in the risk assessment related
to:
§ The use of DEHP in children's toys: Under regulations introduced in
January 2007 DEHP is no longer permitted in toys and childcare articles
in
the
EU.
§ Possible exposure of workers in factories: But adequate precautions
are already taken based on occupational exposure limit values.
§ Some localised environmental exposure near to factories: The
European Union will finalise measures relating to emissions controls
from
converters
plants
during
2008.
§ The use of DEHP in certain medical devices: in March 2008, the EU
Scientific committee provides positive advice on the use of DEHP in
medical
devices.
§ Possible environmental risk to river basins: to be addressed through
the use of Environmental Quality Standards (which already exist for
DEHP).
Behalf Of An
We would like to inform you that following its classification as Thank you for the information.
Organisation
reprotoxic category 2 DEHP is no longer used in printing inks by We agree that the following
Industry
or CEPE/EuPIA members.
information
should
be
trade
considered in the future
association,
process:
CEPE
According to CEPE (European
Council of producers and
importers of paints, printing
inks and artists’ colours),
DEHP is no longer used in
printing inks by CEPE/EuPIA
(European
Printing
Ink
Association)
members
- 12 -
20080819 Jette Rank
ENSPAC,
Roskilde
University
following its classification as
reprotoxic category 2.
To
ECHA Thank you for the support.
Three Phthalic Acid Esters (BBP, DBP, DEHP) on the List of
Substances
of
Very
High
Concern
Comments by Jette Rank, Associate Professor, Department of
Environmental, Social and Spatial Change, ENSPAC, Roskilde
University,
Denmark
Among the chemicals newly listed by ECHA as substances of very high
concern (SVHC) are three phthalic acid esters: Bis(2ethylhexyl)phthalate (DEHP, dibutyl phthalate (DBP), and Benzyl butyl
phthalate (BBP). All three substances are classified as toxic to
reproduction and therefore meet the CMR criteria and should be
processed under the authorization system within REACH. The
arguments for such a decision are plenty and well known. However, I
will summaries the most important reasons in the following.
Toxicology
Toxicological studies have shown that the three phtalates can disrupt the
endocrine hormone system in various mammals and cellular test
systems (EU, 2008). The overall picture is that the antiandrogenic
effects when these substances are exposed in utero can cause severe
malformations in male rats as e.g. chryptorchism, reduced anogenital
distance, hypospadi, reduced weight of testes, and development of
nipples. Because we cannot make experiments with humans, we are
compelled to use the data from animal testing on human risk
assessment. Therefore, it is absolutely required to protect pregnant
women against exposure to these chemicals as the unborn babies are of
highest risk. Further, there is growing suspicion that DBP interfere with
the female thyroid hormone system (Huang et al. 2007) and that allergic
- 13 -
symptoms in children exposed to house dust containing phthalates can
be associated with rhinitis and eczema (BBP), and asthma
(DEHP)(Bornehag
et
al.,
2004).
Exposure
In a study by Wormuth et al. (2006) they showed that DBP, BBP and
DEHP can be found in all kind of food. Cereals, eggs, poultry, nut and
animal fat had very high concentrations of particularly DEHP. This
indicates an uncontrolled environmental fate of the chemicals coming
from sources as gloves, paints, adhesives, aftershaves and other
everyday necessities. The paper also shows that the main exposure route
is ingestion of food with some exceptions: female and male teenagers
had the highest exposure of BBP from spray paints, and female
teenagers had a very high exposure of DBP from personal care products.
However, when considering that the most vulnerable group is females in
their reproductive period, it is important to try to reduce their intake of
phthalates from the food as this is the main exposure route for this
group. Obviously, the best way to protect the unborn babies is to
eliminate phthalate exposure of females, either by reducing or banning
the
use
of
these
compounds.
Limit
values
and
risk
reduction
In theory it could be possible to find limit values for specific effects and
reduce the phthalates in specific products. However, when considering
that phthalates can migrate uncontrolled from numerous products and
that they have an uncontrolled fate in the environment ending up in
foods, it is not wise to manage the problems by the use of limit values.
The phthalates are already wide spread in the environment and the most
responsible way to reduce the risk for the human population is to reduce
or
stop
the
application
of
the
chemicals.
Conclusion
- 14 -
I strongly recommend that these three substances remain on the list of
chemicals for authorization. Many other chemicals are alternatives and
therefore the three substances could easily be substituted. The two main
reasons for this recommendation are, firstly the potential hazardous
effects on human reproduction, and secondly the uncontrolled
environmental fates causing the chemicals to seep out of the products
and
subsequently
accumulate
in
human
food.
References
Bornehag, C.-G., Sundell, J., Weschler, C.J., Sigsgaard, T., Lundgren,
B., Hasselgren, M., Häherhed-Engman, L. (2004) The association
between asthma and allergic symptoms in children and phthalates in
house dust: A nested case-control study. Environmental Health
Perspectives
112,
14,
1393-1397.
EU (2008) Annex XV – Identification of SVHC format. Proposal for
identification of a substance as a CMR CAT 1 or 2, PBT, vPvB or a
substance of an equivalent level of concern. Dossier’s on DBP, BBP and
DEHP. Part of: Regulation (EC) No 1907/2006 of the European
Parliament and of the Council of 18 December 2006 concerning the
Registration, Evaluation, Authorisation and Restriction of Chemicals
(REACH).
Huang, P.-O., Kuo, P.-L., Guo, Y.-L., Liao, P.-C., Lee, C.-C. (2007)
Associations between urinary phthalate monoesters and thyroid
hormones in pregnant women. Human Reproduction 22, 10, 2715-2722.
Wormuth, M., Scheringer, M., Vollenweider, M., Hungerbühler, K.
(2006) What are the sources of exposure to eight frequently used
phthalic acid esters in Europeans? Risk Analysisi 26, 3, 803-824.
- 15 -
20080819 Fe de Leon
Behalf Of An
Organisation
Canadian
Environmental
Law
Association
The Canadian Environmental Law Association (CELA) (www.cela.ca) Thank you for the support.
is a Canadian based non-profit, public interest organization, established
in 1970 to use existing laws to protect the environment and to advocate
environmental law reforms. It is also a free legal advisory clinic for the
public, and will act at hearings and in courts on behalf of citizens or
citizens’ groups who are otherwise unable to afford legal assistance.
CELA is funded by Legal Aid Ontario (LAO). It is one of 80
community legal clinics located across Ontario, 18 of which offer
services in specialized areas of the law. CELA also undertakes
educational and law and policy reform projects that are funded by LAO
as well as government and private foundations. CELA’s public policy
reform programs focus on four issue areas: pollution and health, water
sustainability, land use planning and access to justice.
CELA has a long, rich history advocating for effective chemicals
management policy in Canada as well as on the global level through the
Stockholm Convention on Persistent Organic Pollutants. CELA
participated and responded to the government of Canada’s proposals in
categorizing the 23, 000 substances under the Domestic Substances List
as part of its legal obligations under the Canadian Environmental
Protection Act, Canada’s main environmental statute addressing toxic
substances. CELA’s interest in the implementation of the REACH
policy and the process to establish a list of substances for authorization
are seen as significant in the efforts to protect human health and
environment from exposure to toxic substances.
Furthermore,
Canadians see the results of REACH as important initiatives that are
relevant and essential to the efforts being undertaken in Canada under
its Chemicals Management Plan (CMP). The results of REACH will
inform priorities for action to be taken in Canada under CMP, confirm if
there are other substances that should be focused for action and most
importantly inform appropriate measures of phase out for PBT
substances and non-threshold substances in following the precautionary
- 16 -
principle. Under section 75 (3) of the Canadian Environmental
Protection Act, our government is obligated to review the “…a decision
to specifically prohibit or substantially restrict any substance by or
under the legislation of another jurisdiction for environmental or health
reasons,…”
CELA supports the initial list of substances (Anthracene; 4,4'Diaminodiphenylmethane; Dibutyl phthalate; Cyclododecane; Cobalt
dichloride; Diarsenic pentaoxide; Diarsenic trioxide; Sodium
dichromate, dehydrate; 5-tert-butyl-2,4,6-trinitro-m-xylene (musk
xylene);
Bis
(2-ethyl(hexyl)phthalate)
(DEHP);
Hexabromocyclododecane (HBCDD); Alkanes, C10-13, chloro (Short
Chain Chlorinated Paraffins); Bis(tributyltin)oxide; Lead hydrogen
arsenate; Triethyl arsenate; Benzyl butyl phthalate) for inclusion to the
candidate list for authorization. We are please to see the initial list of
substances nominated for authorization.
We recognize that importance of this first list and milestone in the
implementation of the REACH policy. However, based on our
experience with the Canadian categorization process, we strongly urge
the EU to ensure that an explicit timeframe for adding new nominations
to the candidate list and the release of full list of nominated substances
for authorization be provided to ensure that the momentum established
with the passing of the REACH policy does not decline over time. In
our experience with Canadian categorization process, the release of the
complete list of substances meeting the criteria outlined under the
Canadian Environmental Protection Act required a significant response
by the Canadian government. We trust that it would be similar for the
EU context and the authorization list.
In Canada, Bis (2-ethyl(hexyl)phthalate) (DEHP) has been assessed as
toxic under the Canadian Environmental Protection Act. However no
policies that aim at reduction or implementation of safe alternatives to
- 17 -
these substances has been developed. According to the National
Pollutant release Inventory for 2005, over 8,300 kg of DEHP was
release to air by facilities reporting to NPRI.
20080819 Federal
German MS CA
Institute for
Occupationa
l Safety and
Health Fb 5
The dossier is in accordance with the requirements set out in an Annex Amended.
XV
dossier
for
SVHC.
P5 the conclusion on proposal: The proposal does not exactly specify
the scope for including the substance in Annex XIV. We suggest the
supplement that the proposal applies to CMR according to Article 57
(c). The reference to an Annex I of Directive 67/548/EEC entry is given.
WWF supports inclusion in the candidate list based on the identified Thank you for the support.
CMR properties and high relevance for consumers.
20080819 Ninja
Reineke
Behalf Of An
Organisation
WWF European
Policy Office
20080819 Dietrich
Sinnaeve
Behalf Of An
Organisation
3M Company
Specific comments below in section use, exposure, ... submitted on
behalf
of
the
3M
Medical
Division.
Contact
:
Michael
J.
Walt
Clinical
Research
Specialist
Medical
Division,
3M
Health
Care
270-4N-01
3M
Center,
St
Paul,
MN
55144
mjwalt1@mmm.com
20080819 Bureau
REACH
RIVM
Behalf Of An
Organisation
NL CA
The Netherlands CA is submitting their comments in separate files for
each substance that follows the headings of this webpage. We do this for
internal QA purposes and for ease of submission. Each heading is
numbered chronologically according to the headings on this page. We
assume this is acceptable.
See the response to the
comment in section Use,
Exposure, Alternative and
Risks, submitted on behalf of
the 3M Medical Division.
We agree that the following
information
should
be
considered in the future
process: An occupational
exposure assessment was
conducted in the EU RAR
Copied from comment:
mainly based on measured
Exposure information: In the EU RAR, information on occupational or modelled inhalation data
exposure is available. The NL-CA would like to suggest including this from the 1990-ties and
- 18 -
information also in the dossier.
20080819 Eva Stocker
20080819
20080819 Bureau
REACH
RIVM
modelled dermal exposure
data. The RAR concluded on
reasonable worst case total
internal exposure in the order
of 1 mg/kg/day for all
scenarios (with the inhalation
route contributing >50%). The
scenarios included some 10
production
facilities,
560
formulators/processors
of
product containing DEHP, and
over 1000 industrial end-users
of DEHP-products. The total
number of workers potentially
exposed to DEHP is not
known, but is likely to be very
high. As a comparison, the US
EPA estimated in 1996 that
340,000 employees may be
exposed to DEHP in the US.
Austria has identified DEHP in an internal project as suitable candidate Thank you for the support
substance for authorisation and therefore supports the dossier.
Behalf Of An
Organisation
Austrian
Competent
Authority
on
REACH
Affiliated With I am agree with the conclusion that DEHP is a CMR substance and Thank you for the support
Organisation
support its inclusion in the candidate list according to article 57(d).
Behalf Of An
Organisation
NL CA
We agree with the proposal to identify bis(2-ethylhexyl)phthalate as a We
apologise
for
not
substance of very high concern, based on the listing of Annex I - specifying that we propose to
identify DEHP as an SVHC
regulation 67/548/EEC.
- 19 -
It is mentioned that the substance is identified as CMR according to according to Article 57(c). The
Article 57 (a), (b) and/or (c). To our opinion this should only be Article Support Document has been
57 (c). Article 57 (c) refers to “substances meeting the criteria for revised accordingly.
classification as toxic to reproduction category 1 or 2 in accordance with
Directive 67/548/EEC”. This substance is classified as a toxic to
reproduction category 2 in Annex I of Directive 67/548/EEC.
If the member country wants to identify the substance as an endocrine
disruptor giving rise to an equivalent level of concern to those of other
substances listed in points (a) to (c) of Article 57, then reference should
also be made to Article 57(f).
20080819 Bureau
REACH
RIVM
Behalf Of An
Organisation
NL CA
Reference has been made to classification in Annex I of Directive
67/548/EEC. For CMR substances, if a relevant harmonised
classification is already included in Annex I the reference made to this
classification is considered sufficient for justification. The member
country has included all data related to human health hazards in the
section on justification. To our opinion, this is not necessary for
substances, which have an agreed classification on Annex I. However,
in this case data on the possible endocrine disrupting properties, if
considered relevant, should be included in chapter 5 of the justification.
As the guidance has not been
crystal clear to us, we have
given information about all
endpoints to be on the safe
side, even though we agree
that some end-points are not
relevant in this case.
The potential endocrine disrupting effects may be an additional factor
for identifying the substance as a substance of very high concern. A
separate section on endocrine disrupting effects, both for humans and
the environment (for instance in Section 5.10 – Other effects), would
strengthen this argument.
Classification and labelling
Date
Submitted
Organisation
by
/MSCA
20080812
Ryuichi
Japan
Hasegawa
Plasticizer
Comment
Response
Because the reproductive toxicity of DEHP is classified into category 2, There is no scientific basis for
we comment on this matter here. In 5.9.5, it mentions that the data on quantifying the species variation in
- 20 -
20080814
20080819
Federal
Institute for
Occupationa
l Safety and
Health
Bureau
REACH
RIVM
sensitivity, and to know which species
humans would compare best with, and
we therefore have to assume that
humans may be as sensitive as rodents.
Classification and labelling is agreed in
the EU.
Industry
Association
reproductive toxicity in marmosets are insufficient to connect with those
in humans, but the results of the marmoset studies below show that there
are species differences in reproductive toxicity including testicular
toxicity. Furthermore, the data obtained from rodents cannot be applied
to humans because of noticeable difference in the kinetics between
humans and rodents, and the classification of DEHP into category 2 is
not appropriate.
German CA
P8 the conclusion on classification: The substance is classified Amended
according to the 28th ATP of Directive 67/548/EEC as: T (Toxic); Repr.
Cat. 2; R60 (May impair fertility), R61 (May cause harm to the unborn
child).
Behalf Of An
Organisation
NL CA
Classification and labeling:
Amended.
Please hold on to format as given in the Guidance for the preparation of
an Annex XV dossier.
Identity of the substance and physico-chemical properties
Date
Submitted Organisation/ Comment
by
MSCA
20080807
Hilde
On behalf of p 6 This Annex XV document refers to the general class of Phthalates
Viroux
organisation
but should be restricted to DEHP only
AlconCouvreur,
Belgium
20080807
Hilde
On behalf of p 8 As raw material only: toxic, category 2, R60 & 61 [RAR report
Viroux
organisation
2006,
Council
Directive
67/548/EEC]
AlconThe revised MDD 2007/47/EC defines the following labeling
Couvreur,
Belgium
requirements for a medical device that contains DEHP:
- 21 -
Response
The document refers specifically to
DEHP.
Thank you for the information, which
has been included in the dossier.
20080808
Thecla
Sterk
20080808
Thecla
Sterk
“If parts of a device (or a device itself) intended to administer and/or
remove medicines, body liquids or other substances to or from the body,
or devices intended for transport and storage of such body fluids or
substances, contain Phthalates which are classified as carcinogenic,
mutagenic or toxic to reproduction, of category 1 or 2, in accordance
with Annex I to Directive 67/548/EEC, these devices must be labeled on
the device itself and/or on the packaging for each unit or, where
appropriate, on the sales packaging as a device containing phthalate.”
On behalf of The Annex XV document refers to general class of Phthalates but The document refers specifically to
organisation
should be restricted to DEHP only.
DEHP.
Eucomed,
Belgium
On behalf of As raw material only: toxic, category 2, R60 & 61 [RAR report 2006, Thank you for the information, which
organisation
Council
Directive
67/548/EEC] has been included in the dossier.
Eucomed,
Belgium
Labeling requirements of DEHP as a substance in a Medical Device of a
finished medical device according to the revised MDD.
“If parts of a device (or a device itself) intended to administer and/or
remove medicines, body liquids or other substances to or from the body,
or devices intended for transport and storage of such body fluids or
substances, contain Phthalates which are classified as carcinogenic,
mutagenic or toxic to reproduction, of category 1 or 2, in accordance
with Annex I to Directive 67/548/EEC, these devices must be labeled on
the device itself and/or on the packaging for each unit or, where
appropriate, on the sales packaging as a device containing phthalate.”
Environmental fate properties
Date
Submitted Organisation/
by
MSCA
20080819
Lisette
Behalf Of An
Van Vliet Organisation
Comment
Response
The information on distribution and degradation seems justifiable, Thanks for the information. This recent
although
mainly
based
on
modelling
data. paper shows that DEHP is indeed
- 22 -
20080819
Bureau
REACH
RIVM
Health
&
Interestingly there is a new study on the fate of phthalates in arctic
Environment
regions (Xie et al. 2007), calculating an annual gas deposition of 190
Alliance
t DEHP per year in the Arctic. Because degradation is supposed to be
slower and the arctic ecosystem could be especially susceptible this
information
might
be
relevant.
No new studies on bioaccumulation and biomagnification are
available. It should be noted that the conclusion DEHP does not
biomagnify is based on a single study focused on one single marine
food web (Mackintosh et al. 2004).
Behalf Of An
Environmental fate properties:
Organisation
Although detailed information is given, this section is not required
NL CA
for a CMR substance. This section may become relevant if the
substance is also proposed to be a substance of equivalent concern
(because of potential endocrine disrupting effects).
Human health hazard assessment
Date
Submitted
Organisation
by
/MSCA
20080807
Hilde
On behalf of
Viroux
organisation
AlconCouvreur,
Belgium
transported (particle-bound) in the air to
the Arctic region, supporting widespread geographic distribution of
DEHP. A model calculation indicates a
total deposition of 190 tonnes DEHP per
year in the Arctic region (Xie et al,
2007, Environ. Sci. Tech. 41 (13),
4555).
We agree that strictly speaking, this
environmental information is not
needed. However, it is included as
environmental concerns have
been
identified and will be of relevance later
when prioritisation and regulations are
discussed. For instance, there are
conclusions 3 in the RAR, and, in
addition, emissions may sometimes be
higher than allowed by the EQS set in
the WFD.
Comment
Response
p 17 The data presented concentrate on developmental toxicity studies
on rodents which suggest some possible effects but ignore other studies
that see no discernable effect in humans. Experience in translating other
rodent studies e.g. with regards to carcinogenicity to humans has
indicated that simple extrapolation may not be valid due to different
metabolic
pathways.
There is no scientific basis for
quantifying the species variation in
sensitivity, and to know which species
humans would compare best with, and
we therefore have to assume that
humans may be as sensitive as
rodents.
- 23 -
20080808
20080819
20080819
No
human
hazard:
Jon
N.
Cammack
et
al
2003
Positive effect on red blood cells: Byron A. Myhre et al 1987, Labov et
al
1987
General Endocrine Disruption: Weinberg ED 2007 status report
No human effect: K. Rais-Bahrami et al 2004
Thecla Sterk On behalf of The data presented concentrates on developmental toxicity studies on
organisation
rodents which suggests some possible effects but ignores other studies
Eucomed,
which suggest no discernable effect in humans. Experience in translating
Belgium
other rodent studies e.g. Carcinogenicity to humans has indicated that
simple extrapolation may not be valid due to different metabolic
pathways.
There is no scientific basis for
quantifying the species variation in
sensitivity, and to know which species
humans would compare best with, and
we therefore have to assume that
humans may be as sensitive as
rodents.
No
human
hazard:
Jon
N.
Cammack
et
al
2003
Positive effect on red blood cells: Byron A. Myhre et al 1987, Labov et
al
1987
General Endocrine Disruption: Weinberg ED 2007 status report
No human effect: K. Rais-Bahrami et al 2004
Federal
German CA
P8 the conclusion on classification: Requirements are fulfilled. The Noted.
Institute for
substance fulfils the criteria for the identification of a toxic substance
Occupationa
according
to
Annex
XIII
(1.3).
l Safety and
The substance is classified and labelled as T (Toxic), Repr. Cat. 2; R60
Health Fb 5
(May impair fertility), R61 (May cause harm to the unborn child). The
reference to the 28th ATP of Directive 67/548/EEC is given.
P12ff conclusion on human health hazard assessment, section 5: Detailed
information is given as described in EU RAR (2008).
Tim Edgar
Behalf Of An Page 13: Human Health Hazard Assessment, Section 5.2.4. Acute The text in section 5.2.4 has been
Organisation
toxicity:
other
routes revised.
European
The
Annex
XV
dossier
states:
Council
for “5.2.4
Acute
toxicity:
other
routes
Plasticisers
Following a single iv administration of DEHP in rats, effects were
and
observed on the lungs including oedema of the alveolar wall together
Intermediates with infiltration by leukocytes, hemorrage, and lethality (LD50:200 mg
- 24 -
(ECPI)
20080819
Shigetaka
Seki
DEHP
/kg).”
ECPI
comments:
According to the Risk Assessment Report of DEHP (p337), the studies
used for acute toxicity “are, however, not useful for the RAR due to
inappropriate study design or poorly reported test methods and results.”
We recommend therefore to change the text in section 5.2.4. to “not
relevant for this type of dossier” (as in section 5.3.).
Behalf Of An The dossier argues that there is no evidence to support that the results
Organisation
obtained in pre-pubertal rats are not relevant for man or that use of adult
Vinyl
marmosets should be preferred (P24). However, various studies, not
Environmenta only on marmosets but also on crab-eating monkeys and humans have
l
Council, confirmed that there are significant species differences with regard to
Japan
metabolic mechanisms of DEHP between rodents and primates. The
argument in the dossier, which neglects the differences between rodents
and primates, is surprisingly crude. In fact, the conclusions of the
toxicology studies and risk assessments conducted in Japan and the US
recognize the species differences of the effects of DEHP, confirming the
fact
that
rodents
have
particular
sensitivities.
The dossier tries to argue that reproductive toxicity could involve
endocrine disruption (P25). This argument does not have any sound
scientific basis. Testicular toxicity should be distinguished from and
should not be confused with endocrine properties. In reality, extensive
studies conducted in Japan on the possibility of endocrine disruption of
DEHP deny that DEHP is an endocrine disrupter.
20080819
Lisette Van Behalf Of An
Vliet
Organisation
Health
&
Environment
Alliance
Great advance has been made in recent years studying the metabolism of
DEHP and other phthalates (Wittassek and Angerer 2008). Measuring
phthalate metabolites in urine now is the “standard” for calculating
human exposure. However knowledge about the distribution of DEHP in
the human body is still limited (Frederiksen et al. 2007).
- 25 -
The kinetics and toxicity of DEHP has
been very thoroughly reviewed in the
EU risk assessment report on DEHP,
and it is clear that the total database is
very extensive for DEHP. It is clear
that DEHP is toxic to many species
(excluding some primates), and that
there exists species variation both with
regard to kinetics and sensitivity.
However, there is no scientific basis
for quantifying the species variation in
sensitivity, and to know which species
humans would compare best with, and
we therefore have to assume that
humans may be as sensitive as
rodents.
Thanks for the information, which is
valuable and supports DEHP being a
SVHC substance. Some of the
information (relating to reproductive
toxicity at low dose exposure) is
54 studies involving phthalate metabolites were published between 2005
and 2008, most of them are omitted in the Annex XV dossier. DEHP is
believed to be bioactivated - (i.e. more toxic) when metabolised. Recent
studies (Koch et al. 2006) show that the secondary the secondary DEHP
metabolites (oxidised forms) are more suitable for calculating the human
exposure than MEHP. Moreover given the longer half-life of these
metabolites the authors conclude, that “DEHP or some of its oxidized
metabolites might accumulate in the body. Furthermore, recent studies
give first hints that these oxidized metabolites might be the ultimate
developmental DEHP toxicants.” (Koch et al. 2006)
In the light of these new data the dossier should focus on the toxicity of
the metabolites as well.
There is a recent inhalation study (Kurahashi et al. 2005), where
prepubertal Wistar rats where exposed to 5 and 25 mg DEHP per m³ for
four and six weeks (6 hrs per day). The LOAEL determined in this study
was 1.0 mg/kg bw for increase in plasma testosterone concentration and
relative weight of seminal vesicles. Interestingly these effects occur at
lower concentrations than in a similar study that used oral exposure
(gavage). Inhalative exposure therefore may result in more severe effects
than oral exposure.
In another study (Ma et al. 2006) prepubertal female rats where exposed
to 0, 5, and 25 mg DEHP per m³ from post natal day 22 to 84(6 hrs per
day, 5 days per week). The authors report: “DEHP exposure advanced
the age of vaginal opening and first estrous cycle, and serum cholesterol,
luteinizing hormone, and estradiol levels were significantly elevated in
the 25-mg/m³ DEHP group.”
Both studies indicate that inhalative exposure, that is relevant to humans
(given the high concentration found in indoor air and from exposure
- 26 -
mentioned in the dossier. We take note
of the two new studies on the
carcinogenicity of DEHP, which could
challenge the present view by IARC
and the EU risk assessment of DEHP
that the carcinogenicity of DEHP is
not relevant to humans. However, as
the new information is not really
affecting the basis for appointing
DEHP a SVHC, and there is too
limited time available for reviewing
the literature, we will at present not
update the dossier with this new
information.
from medical devices) can affect parameters that are important for
human reproductive functions.
The information provided by the Annex XV dossier seems justifiable.
No new studies have been published, providing lower NOAELs or
NOAELs. In vitro data remains equivocal. Some recent studies provide a
deeper insight in DEHP mediated carcinogenicity:
A study with PPARalpha negative mice (Ito et al. 2007) reports that
hepatic tumorigenesis is not mediated via PPARalpha, contrasting the
current belief. Moreover a higher tumor incidence was seen in the KOmice compared to wt animals. The authors conclude that oxidative stress
due to DEHP exposure might lead to inflammation and the expression of
protooncogens. These pathways of tumor induction may be relevant for
humans.
Still there are in vitro evidences for PPAR activation: Venkata et al.
(2006) found that both human PPARalpha and PPARgamma were
activated by MEHP in human breast cancer cells, whereas MEHP could
not activate PPARbeta. From a 28 d study with Sprague-Dawley male
rats orally treated with 250, 500, or 750 mg/kg/d DEHP Ryu et al. (2007)
conclude: “DEHP exposure may induce the expression of apoptosisrelated genes in testes through induction of PPARgamma and activation
of the ERK1/2 pathway.” Therefore tumour induction via PPARgamma
may be probable.
An in vitro study with SHE cells (Maire et al. 2005) reports another
effect: 50 µM DEHP inhibited apoptosis: The authors state “The
defective regulation of apoptosis caused by DEHP treatment could
contribute to its carcinogenicity.” This could imply that besides PPAR
mediated toxicity the inhibition of apoptosis could promote
tumorigenesis.
- 27 -
Besides well documented hepatocarcinogenicity two studies provide
information on additional target organs of DEHP:
From in vitro studies Buteau-Lozano et al. (2008) conclude: “Our in
vitro results show for the first time that genistein and xenoestrogens
(BPA, OP, dieldrin, BBP, and DEHP at high concentrations) up-regulate
VEGF expression in MELN cells by an ER-dependent mechanism.” It is
documented that VEGF increases breast tumour angiogenesis in vivo,
implying DEHP could potentially induce breast cancer.
Another target could be the testis, since Voss et al. (2005) found
significantly increased tumour incidences in Sprague–Dawley rats after
exposure to 300 mg/kg per day DEHP in liver and testes. They conclude:
“animals exposed to the highest DEHP dose showed a significantly
increased rate of testicular tubular atrophy (P < 0.01). In conclusion, this
study shows for the first time that the rat testes are a target organ of
DEHP carcinogenicity in Sprague–Dawley rats upon lifetime exposure.”
The LOAELs and NOAELs used in the Annex XV dossier are based on
the EU RAR and therefore on high-dose studies. The dossier is thus
missing recent low-dose studies.
A series of studies on the reproductive effects following in utero and
lactational exposure of Wistar rats with DEHP was done by Dr.
Chahouds group at Charité in Berlin. The studies are published between
2006 and 2007 in Toxicology and focus on low dose effects:
Andrade et al. (2006b) observed a significant increase in testis weight on
PND 22 in animals exposed to 5, 15, 45 and 135 mg/kg/day. The authors
calculate a NOAEL for the endpoints evaluated up to puberty of 1.215
mg DEHP/kg bw/day that is four times lower than the one used in the
EU RAR. A follow up study with male rats (Andrade et al. 2006a)
- 28 -
confirmed the NOAEL (1.215 mg/kg bw/day) for incidence of
cyrptorchidism. Interestingly a reduction of daily sperm production was
observed at concentrations higher than 5 mg/kg bw/day. When looking
at female rats (Grande et al. 2006) in utero and lactational exposure to
DEHP at 405 mg/kg/day increases the incidence of ovarian tertiary
atretic follicles, the only endpoint affected during adulthood. Therefore
the male offspring seems to be more susceptible.
A recent review (Matsumoto et al. 2008) excellently summarises the
actual state of human effects of phthalic acid esters. A number of recent
studies that are not included in the Annex XV dossier are referenced
herein.
Additionally the Journal of Toxicology and Environmental Health, Part
B Critical Reviews published a special issue on “Endocrine Toxicants
and Human Health Risks” in 2008 (Volume 11 Issue 3 & 4). Some of the
reviews can be useful, for example Phillips and Tanphaichitr (2008).
From the plethora of studies some are notable because they provide an
insight into the multiple effects of DEHP. The influence of phthalates on
allergies and obesity are emerging topics, that should be included in the
Annex XV dossier:
Takano et al. (2006) for example found that “Exposure to DEHP at a
dose of 0.8–20 µg caused deterioration of atopic dermatitis-like skin
lesions related to mite allergen”.
Stahlhut et al. (2007) concluded from a national cross-section of U.S.
men that “concentrations of several prevalent phthalate metabolites
showed statistically significant correlations with abdominal obesity and
insulin resistance. If confirmed by longitudinal studies, our findings
would suggest that exposure to these phthalates may contribute to the
- 29 -
20080819
Ryuichi
Hasegawa
Affiliated
With
Organisation
Japan
Plasticizer
Industry
Association
population burden of obesity, insulin resistance, and related clinical
disorders.”
Another study is remarkable because of its far reaching implications:
Takeshita et al. (2006) showed that DEHP induces MDR1 gene in vitro.
They summarise: “the leaching of DEHP from the PVC medical devices
may […] may induce resistance to drugs in certain populations of cancer
cells.”
The data on rodents are employed at the endpoint of human testicular or
reproductive toxicities, but the literature below on marmosets shows that
there are species differences in juvenile testicular toxicity as mentioned
above. In addition, there are species differences in the kinetics and
metabolic mechanisms of DEHP as mentioned in the exposure
information section (References 7 to 10 below). Therefore, we request
you emphasize the data obtained in primates for assessing the effects of
DEHP on humans.
1) M.R. Millar, R.M. Sharpe, G.F. Weinbauer, H.M. Fraser, P.T.
Saunders, Marmoset Spermatogenesis organizational similarities to the
human. Int J Androi, 2000, 23 (5), 266-277
2) Y Tomonari; Y Kurata; T Kawasuso; R David; G Gans; M Tsuchitani;
M Katoh. Effect of Di(2-Ethylhexyl)Phthalate (DEHP) on Genital
Organs from Juvenile Common Marmosets: 1. Morphological and
Biochemical Investigation in 65-Week Toxicity Study, Journal of
Toxicity and Environmental Health vol. 69 issue 17 (2006) 1651-1672
In 5.11.1, the toxic effects of DEHP on the testis are described as being
due to its serious endocrine disruption action, but there are no data that
connect the endocrine disruption action with testicular or reproductive
toxicity. The cited data of Wolfe, Poon, Arcadi, et al. are on classic
toxicity. The results of endocrine disruption action tests conducted by
the Ministry of Environment of Japan (Life cycle tests of medaka
(killifish) and the one- generation tests in rats) have shown that
- 30 -
There is no scientific basis for
quantifying the species variation in
sensitivity, and to know which species
humans would compare best with, and
we therefore have to assume that
humans may be as sensitive as
rodents. With regard to the
reproductive toxicity, we agree that
‘classical’ tissue toxicity seems to be
the main mechanism for the testicular
toxicity. However, as some studies
shows a decreased production of
testosterone hormones without evident
testicular toxicity, which is a case that
would fall under the present definition
of endocrine disruption (An endocrine
disrupter is an exogenous substance or
mixture that alters function(s) of the
endocrine
system;
http://ec.europa.eu/environment/endoc
rine/definitions/endodis_en.htm), we
think it is possible to use this term.
However, please, note that we are
nominating DEHP as a SVHC because
of the reproductive toxicity and not
phthalates including DEHP have no clear endocrine disruption action based on endocrine disruption.
(refer to the URLs given below).
Because the toxic effects of the endocrine disruption action are
doubtful and uncertain, we request you remove the description that
associates the effects of DEHP on the reproduction process with the
endocrine disruption action.
http://www.env.go.jp/en/chemi/ed/extend2005 full.pdf
http://www.env.go.jp/en/chemi/ed/bda_speed98.pdf
http://www.env.go.jp/chemi/end/speed98/pamph.pdf
http://www.env.go.jp/en/chemi/ed/rt_medaka.pdf
http://www.env.go.jp/en/chemi/ed/rt_rat.pdf
In 5.11.3 and 5.11.4, DNEL is set up as a new index, which is not
described in RAR. It is mentioned that the oral DNEL of DEHP on
children is 0.02 mg/kg/day based on the testicular toxicity, and there are
cases where the exposure amount of DEHP for children (the 95th
percentile value) exceeds the DNEL value. As mentioned in the general
comments, the exposure data are uncertain and differ from the RAR
contents.
A follow-up investigation was conducted after the report of the U.S.
CERHR that considered the exposure from medical apparatus to be the
greatest risk for infants with serious illness. In this investigation, it is
reported that no effects of DEHP on sexual maturity were observed in
any males or females who undergone ECMO therapy (reference 3).
Furthermore, DEHP has been used for medical devices in large
quantity for decades, but no effects on humans have been reported. The
effects of DEHP on rodents cannot be applied to humans. From the
results of studies so far, there are clearly species differences in
carcinogenicity and testicular (reproductive) toxicity. It is a conclusion
unsupported by fact, therefore, that there is an exposure level (the 95th
percentile) that exceeds the low DNEL value set for children (p. 45).
- 31 -
20080819
Bureau
REACH
RIVM
Behalf Of An
Organisation
NL CA
3) Khodayar Rais-Bahrami, Suzan Nunez, et al. Follow-Up Study of
Adolescents Exposed to di-2-Ethylhexyl Phthalate (DEHP) as Neonates
on Extracorporeal Membrane Oxygenation (ECMO) Support.
Environmental Health Perspective doi: 10.1289/ehp.6901 (available at
http://dx.doi.org/) Online 7 April 2004.
We do not understand at which
Human health hazard assessment:
position of the text a reference should
p. 28: In the last paragraph the reference is missing.
be included.
Human health hazard assessment of physico-chemical properties
Date
Submitted
Organisation/ Comment
by
MSCA
20080807
Hilde
On behalf of p30 The level of human exposure to DEHP depends on its availability
Viroux
organisation
(solubility, leachability). As DEHP has a very low solubility in an
Alconaqueous or hydrophilic environment, direct contact or a lipophilic
Couvreur,
environment is necessary.
Belgium
20080808
Response
We agree that the availability of
DEHP has an influence on human
exposure. However, this is not
critical for the identification of
DEHP as an SVHC. In addition,
measured data included in the
dossier show that humans are
exposed to DEHP.
Thecla Sterk On behalf of The level of human exposure to DEHP depends on its availability See the response to the previous
organisation
(solubility, leachability). As DEHP has very low solubility in an comment.
Eucomed,
aqueous or hydrophilic environment, direct contact or a lipophilic
Belgium
environment is necessary.
Environmental hazard assessment
Date
Submitted
Organisation/
Comment
Response
by
MSCA
20080807
Hilde
On behalf of p 31 The only data presented indicates possible toxicity in Atlantic As stated on the front page of the
Viroux
organisation
salmon but results are contradictory and no reference is provided. dossier, references available in the EU
- 32 -
AlconCouvreur,
Belgium
20080808
Thecla Sterk On behalf of
organisation
Eucomed,
Belgium
20080819
Shigetaka
Seki
Behalf Of An
Organisation
Vinyl
Environmental
Council, Japan
Lisette Van
Vliet
Behalf Of An
Organisation
Health
&
Environment
Alliance
Ryuichi
Affiliated With
Hasegawa
Organisation
Japan
Plasticizer
Industry
Association
DEHP used by the medical devices industry has a very low impact on Risk Assessment Report for DEHP are
the environment as most of the medical devices containing DEHP are not included in the reference list of the
treated as hospital hazardous waste because they are bio-contaminated dossier.
after use.
We agree that proper incineration of
the waste will also decompose the
DEHP.
The only data presented indicates possible toxicity in Atlantic salmon Noted.
but results are contradictory and no reference is provided.
DEHP used in the medical devices industry has very low impact on the We agree that proper incineration of
environment as most of the devices are treated as hazardous waste the waste will also decompose the
because they are bio-contaminated after use.
DEHP.
The summary of toxicity in the Environmental Hazard Assessment No change. Rodents may be very
Section (p34) states that “In mammals, testicular toxicity is the most sensitive, but the principle is to use
sensitive endpoint, with a NOEC….” It is not appropriate to generalise data from the most sensitive species.
the testicular toxicity to include mammals since very significant
species differences are recognised on the toxicity. It should read that
“rodents have been confirmed to have particularly strong sensitivities
but primates did not.”
There is a review entitled “A Critical Evaluation of the Environmental Thank you for the information.
Risk Assessment for Plasticizers in the Freshwater Environment in
Europe, with Special Emphasis on Bisphenol A and Endocrine
Disruption” by Oehlmann et al., which is accepted for publication in
Environmental Research.
The recent studies below strongly suggest that marine algae Thank you for the information.
biosynthesize DEHP and DBP. DEHP found in the environment is not
only an artificial synthetic compound. For hazard assessment of the
ecological
system,
see
references
4,
5,
and
6.
4) Lee, K.H, Anti-leukemic and anti-mutagenic effects of DEHP
isolated from Aloe vera Linne, J. Pharm. Pharmacol. 2000.
- 33 -
5) Chen, C.Y. Biosynthesis of DEHP and DBP from red alga. Wat Res.
2004
6) Namikoshi, M. et al. Natural abundance 14C content of DBP from
three marine algae. Mar. Drug 2006
20080819
Bureau
REACH
RIVM
Behalf Of An Environmental hazard assessment:
Organisation
Although detailed information is given, this section is not required for
NL CA
a CMR substance. This section may become relevant if the substance
is also proposed to be a substance of equivalent concern (because of
potential endocrine disrupting effects).
PBT/vPvB or equivalent level of concern assessment
Date
Submitted
Organisation/ Comment
MSCA
by
20080807
Hilde
On behalf of p 35 DEHP used by the medical devices industry has a very low impact
Viroux
organisation
on the environment as most of the medical devices containing DEHP are
Alcontreated as hospital hazardous waste because they are bio-contaminated
Couvreur,
after use.
Belgium
20080808
Thecla Sterk On behalf of DEHP used in the medical devices industry has very low impact on the
organisation
environment as most of the devices are treated as hazardous waste
Eucomed,
because they are bio-contaminated after use.
Belgium
- 34 -
We agree that strictly speaking, this
environmental information is not
needed. However, it is included as
environmental concerns have been
identified and will be of relevance
later
when
prioritisation
and
regulations are discussed.
Response
We agree that proper
incineration of the waste will
also decompose the DEHP.
We agree that proper
incineration of the waste will
also decompose the DEHP.
INFORMATION ON USE, EXPOSURE, ALTERNATIVE AND RISKS ON ANNEX XV SVHC1
Substance name: Bis(2-ethylhexyl)phthalate
CAS number 117-81-7
EC number: 204-211-0
Reason of the submission of the Annex XV: It is proposed to identify the substance as a CMR according to Article 57 (a), (b) and/or (c).
Information on manufacture and uses
Date
Submitted
Organisation/
by
MSCA
20080707
Paula
Individual
Moreira
20080807
Hilde
On behalf of
Viroux
organisation
AlconCouvreur,
Belgium
20080808
Thecla Sterk On behalf of
organisation
Eucomed,
Belgium
20080819
Dietrich
Sinnaeve
Comment
Response
We use DEHP in order to clean machines - low pressure and high
pressure polyurethane machines
p 38 Medical applications of PVC plasticized with DEHP account
for less than 1% of the total use in the EU. Medical applications
are already highly regulated for human safety aspects under the
Medical Device Directives.
Noted.
Medical applications of PVC plasticized with DEHP account for
less than 1% of the total use in the EU. Such applications are
already highly regulated for human safety aspects under the
Medical Device Directives.
Behalf Of An Currently the sound tubes of most stethoscopes are fabricated from
Organisation
polyvinyl chloride (PVC) plastic that contains some form of
3M Company
phthalate plasticizer to make them flexible and pliable. This
includes the plasticizer di(2-ethylhexyl) phthalate, commonly
1
Further discussions on risks
and benefits of different uses,
such as in medical devices,
should take place later in the
authorisation process.
Further discussions on risks
and benefits of different uses,
such as in medical devices,
should take place later in the
authorisation process.
Thank you for the information.
The purpose of the dossier is to
identify a substance as a
SVHC. DEHP is classified as
The information (comments and responses) on use, exposure, alternatives and risks were not considered by the Member State Committee for the identification of substances of
very high concern, but will be taken into account in the later stages of the authorisation process. For clarity, this information is now indicated with shaded background.
- 35 -
know as DEHP. We believe the use of this material poses little toxic
to
reproduction
risk of unsafe exposure to either the patient or stethoscope user for according
to
directive
the following reasons.
67/548/EEC and thereby meets
the criteria for a substance of
(1) The scientific consensus does not currently support either the very high concern. Medical
banning or limitation of the use of DEHP-containing PVC in devices are only a part of the
medical devices. A consensus report authored by former U.S. variety
of
different
Surgeon General C. Everett Koop, MD, and others states the applications where DEHP is
following:
used. The REACH legislation
acknowledges that medical
(1a) "DEHP, as used in medical devices, is not harmful to humans devices are subject to specific
even under chronic or higher-than-average conditions of exposure. regulations e.g. in article
DEHP confers considerable benefits to certain medical devices 2(6)(c) and article 60(2). In
and procedures, and its elimination without a suitable substitute addition, it is possible to
could pose a significant health risk to some individuals."
exempt uses or categories of
uses from the authorisation
Review and Consensus Statement: A Scientific Evaluation of requirement if risks are
Health Effects of Two Plasticizers Used in Medical Devices and considered to be properly
Toys: A Report from the American Council on Science and controlled through existing
Health, C Everett Koop, Medscape General Medicine 1(1), 1999] specific
Community
legislation, see article 58(2).
(2) The primary concern regarding the use of phthalate-containing Further discussions on risks
PVC in medical devices has focused on devices where there is and benefits of different uses,
intimate and prolonged contact with blood, body fluids and such as in medical devices,
internal or mucosal surfaces which permits the leaching of should take place later in the
phthalates from the plastic with subsequent absorption by the authorisation process.
body. Devices such as intravenous bags and tubing, umbilical
artery catheters, blood bags and infusion tubing, enteral nutrition
feeding bags, nasogastric tubes, peritoneal dialysis bags and tubing
fall into this category. The U.S. Food and Drug Administration
(FDA) notes the following:
- 36 -
(2a) “Everyone is exposed to small levels of DEHP in everyday
life. However, some individuals can be exposed to high levels of
DEHP through certain medical procedures. DEHP can leach out
of plastic medical devices into solutions that come in contact with
the plastic. The amount of DEHP that will leach out depends on
the temperature, the lipid content of the liquid, and the duration of
contact with the plastic.” [Public Health Notification: PVC
Devices Containing the Plasticizer DEHP, David W. Feigal, Jr.,
MD, MPH, Director, Center for Devices and Radiological Health,
Food and Drug Administration, July 12, 2002.]
(3) There is no evidence to suggest that exposure of a patient to
PVC stethoscope tubes containing phthalates increases the
patient's risk of unsafe exposure to phthalates. In virtually all
cases, the exposure of the patient to the sound tube of the
stethoscope is extremely transitory and occurs with the patient's
intact skin, not oral or internal surfaces. Even though the health
care workers (physician, nurse, emergency worker, etc.) have
repeated and prolonged contact with PVC tubing, based on current
evidence, this exposure is unlikely to pose a significant risk since
DEHP is poorly absorbed through the skin.
(3a) “In comparison to other chemicals when applied as the neat
chemical, the phthalate esters were absorbed slowly through
human skin, with rates measured through rat skin higher than
through human.”
[In vitro absorption of some o-phthalate diesters through human
and rat skin. Scott, RC, Dugard, PH,, Ramsey, JD and Rhodes, C.
(1987). Environ. Health Perspect. 74:223-227.
(3b) “In summary, this experiment showed that only trace amounts
- 37 -
of the DEHP contained in DEHP-plasticized PVC plastic film
were released from the film during dermal exposure, and that the
DEHP released was only slowly absorbed through rat skin in vivo.
An absorption rate of 0.24 mg/cm2/hr was calculated from the
data.
[In Vivo Percutaneous Absorption of [14C]DEHP from
[14C]DEHP-Plasticized Polyvinyl Chloride Film in Male Fischer
344 Rats P J Deisinger, L G Perry and D Guest, Food and
Chemical Toxicology 36 (1998) 521-527.]
20080819
Federal
German
Institute for Member
Occupationa CA
l Safety and
Health Fb 5
JACQUES
WARNON
Therefore, we believe that the PVC stethoscope sound tubes are
safe and pose little risk of unsafe exposure to phthalates either for
the patient or stethoscope user when used as intended.
P36ff information on use, exposure, alternatives and risks,
State information on use: Requirements are fulfilled. The presented data
includes detailed information on use. Manufactured volumes were
not available.
Behalf Of An
Organisation
CEPE Industry
and
trade
organisation
Sweden has submitted an Annex XV Dossier on Bis (2ethylhexyl) phthalate (DEHP) proposing to include this substance
in
the
Candidate
List.
CEPE that is representing European manufacturers of coatings and
printing inks would like to comment on this subject.
We would like to inform you that following its classification as
reprotoxic category 2 DEHP is no longer used in printing inks by
CEPE/EuPIA
members.
In Chapter 1 ‘Production and use of DEHP’ page 38 of the Annex
XV Dossier reference is made to use in printing inks and this
- 38 -
Noted.
Table 9 on page 38 in the
dossier provides a summary of
production and consumption
volumes in EU15 that were
provided by industry.
Thank you for the information.
We agree that the following
information
should
be
considered in the future
process: According to CEPE
(European
Council
of
producers and importers of
paints, printing inks and
artists’ colours), DEHP is no
longer used in printing inks by
CEPE/EuPIA
(European
Printing Ink Association)
information
should
be
corrected: members
following
its
“The remaining 3% was used in non-polymer applications such as classification as reprotoxic
…
printing
inks” category 2.
This information is not correct; DEHP is no more used in printing
inks. Therefore CEPE would kindly ask for this information to be
deleted from the Annex XV Dossier.
Exposure information
Date
Submitted
by
20080807
Hilde
Viroux
20080808
20080813
Organisation/
MSCA
On behalf of
organisation
AlconCouvreur,
Belgium
Comment
Response
On behalf of
Silent
Spring
Institute, United
States.
In the Silent Spring Institute study of household exposures from
air and dust on Cape Cod in Massachusetts, benzyl butyl phthalate
was detected above the reporting limit (RL) in 68% (69 of 102)
homes in air samples and 100% of 101 homes in dust samples. In
We agree that the availability
of DEHP has an influence on
human exposure. However,
this is not critical for the
identification of DEHP as an
SVHC. In addition, measured
data included in the dossier
show that humans are exposed
to DEHP.
Thecla Sterk On behalf of The level of human exposure to DEHP depends on its availability See the response to the
organisation
(solubility, leachability). As DEHP has very low solubility in an previous comment.
Eucomed,
aqueous or hydrophilic environment, direct contact or a lipophilic
Belgium
environment is necessary, therefore leaching is very much
dependent on use and contact fluid/tissue: Welle et al 2005.
Sarah
Dunagan
p 36 The level of human exposure to DEHP depends on its
availability (solubility, leachability). As DEHP has very low
solubility in an aqueous or hydrophilic environment, direct contact
or a lipophilic environment is necessary, therefore leaching is very
much dependent on use and contact fluid/tissue: Welle et al 2005.
- 39 -
Thank you for the information.
As mentioned in the dossier,
we are concerned for the
potential additive effects of
air samples, the median value was 77 ng/cu m; the adjusted
geometric mean, 80 ng/cu m; and the range, <RL- 1000 ng/cu m.
In dust samples, the median value was 5.97 mg/g; the adjusted
geometric mean, 6.52 mg/g; and the range 0.935-391 mg/g.
20080818
20080818
20080818
AffiliatedWith
Organisation
Federal
Institute for
Occupationa
l Safety and
Health Fb 5
Tim Edgar
Behalf Of An
Organisation
European
Council
for
Plasticisers and
Intermediates
(ECPI)
several phthalates causing
reproductive toxicity. The
provided information shows
that there are simultaneous
exposures to phthalates via
e.g., indoor dust. Discussions
on alternatives to DEHP
should take place later in the
authorisation process.
Reference: Rudel RA, Camann DE, Spengler JD, Korn LR, Brody
JG. Phthalates, Alkylphenols, Pesticides, Polybrominated
Diphenyl Ethers, and Other Endocrine-Disrupting Compounds in
Indoor Air and Dust. Environmental Science and Technology.
2003; 37 (20); 4543-4553.
I can send you data from analysis of levels of DEHP in house dust Noted.
in the Czech Republic (in offices, flats and preschools).
P36ff information on use, exposure, alternatives and risks, Noted.
exposure information: Requirements are fulfilled. Data as
described in EU RAR (2008) is presented. Information allows an
evaluation.
Page 36: Information on Use, Exposure, Alternatives and Risks –
section
1,
Information
on
exposure
The
Annex
XV
dossier
states:
Release to the environment can occur during the production and
industrial use of DEHP. The plasticiser can also be emitted from
the finished material or article during its use and disposal.
DEHP is not chemically bound to the PVC polymer matrix and
can be released throughout the lifecycle of polymer products. The
leaching rates may vary considerably between different products.
Occupational exposure may occur during the production and
industrial use of DEHP. Consumer exposure to DEHP may occur
via medical products and diffuse emissions from the use of articles
containing DEHP. Human exposure via food, water and air may
occur as a result of emissions to the environment from all life
- 40 -
It is often difficult to provide
evidence of effects on humans
even for known hazardous
substances that have been used
extensively in the society for a
long time. For instance, many
toxic effects known to occur in
experimental
animals
are
difficult to study in humans. It
is also often difficult to
quantify exposure to the
substance within a human
population or in an individual,
because of, e.g., very different
cycle
stages.
ECPI
comments:
Indeed, migration of plasticiser to the surface of the article could
potentially occur to a limited extent. The amount that might
migrate from the article is dependant on how the article is
manufactured and how it is used. The amounts potentially released
from articles are far too low to induce any adverse effect for
human
health.
The fact is that, in the 50 years during which phthalates have been
used, there is no reliable evidence that they have caused health
problems for anyone when used as intended. The presence of
phthalates in household items does not mean that they will enter
the
body
at
harmful
levels.
Further evidence that people are not being put at risk from
exposure to phthalates comes from work conducted by the US
Center for Disease Control and Prevention (CDC). In studies they
conducted on the levels of low-level metabolites of various
chemicals in urine samples among human volunteers they found
nothing alarming about the levels of phthalates. The levels were
all within those considered safe by the US Environmental
Protection Agency.
20080818
20080818
Lisette Van Behalf Of An
Vliet
Organisation
Health
&
Environment
Alliance
Ryuichi
Affiliated With
Hasegawa
Organisation
In an actual publication Heudorf et al. (2007) review the exposure
data available on phthalates. One recent study is not mentioned in
the review: Montuori et al. (2008) found hight concentrations in
mineral water from PET bottles, therefore plastic food packaging
might be one underestimated source of human exposure to DEHP.
As mentioned in the general comments, there is no risk for
children from other than toys and childcare articles regulated at
- 41 -
or varying habits / living or
working conditions / food
preferences / use of consumer
articles.
Lack of proofs for effects in
humans can therefore not be
considered a strong argument
against concern raised based
on a thorough risk assessment
showing hazardous effects in
reliable animal studies of good
quality and substantial human
exposure. In this case, DEHP
is well-known to be hazardous,
being
classified
as
a
reproductive toxicant by the
EU, and an EU risk assessment
has indicated unacceptable
risks for many uses leading to
high
exposure
to
this
substance. To our knowledge,
there are no new studies that
challenge these conclusions
that have been agreed among
the EU member states.
Thank you for the information.
Further discussions on risks
and benefits of different uses
should take place later in the
authorisation process.
The kinetics and toxicity of
DEHP
has
been
very
Japan
Plasticizer
Industry
Association
present in view of exposure levels and NOAEL in RAR. The
conclusion in p.45 that there are cases where the 95th percentile
value of exposure level of DEHP exceeds the DNEL are not
supported because the new exposure data discussed in this section
are subject to great fluctuations of everyday and uncertainty.
In addition, species differences in the kinetics and metabolic
functions of DEHP are being made clear. That is, the marmoset,
one of the primates, is known to greatly differ from the rat in that
the former neutralizes and excretes DEHP and its metabolite as a
glucuronic acid conjugate. References 7 to 10 below describe that
almost all human metabolites are conjugates, suggesting that
humans are thought to have different metabolic mechanisms from
rats. The exposure amount of DEHP should be connected with its
effects by clarifying the kinetics of DEHP in humans.
thoroughly reviewed in the EU
risk assessment report on
DEHP, showing a lack of
scientific basis for quantifying
species variation in sensitivity
and kinetics, and to know
which species humans would
compare best with. We
therefore have to assume that
humans may be as sensitive as
rodents.
7) Rubin RJ and Schiffer CA. (1976) Fate in humans of the
plasticizer, di-2-ethylhexyl phthalate, arising from transfusion of
platelets stored in vinyl plastic bag. Transfusion 16, 330-335
8) Schmid P. and Schlatter C. (1985) Excretion and metabolism of
di(2-ethylhexyl)phthalate in man. Xenobiotica 15, 251-256
9) Lhuguenot JC and Cornu MC (1993) Metabolism of di-2ethylhexyl phthalate (DEHP) and di-2-ethylhexyl adipate (DEHA)
and their relationship to peroxisome proliferation in different
species. In Peroxisomes Biology and Importance in Toxicology
and
Medicine,
pp.
465-483.
10) Huber WW, Grasl-Kraupp B, Schulte-Hermann R, (1996)
Hepatocarcinogenic potential of di(2-ethylhexyl)phthalate in
rodents and its implications on human risk. Crit Rev. Toxicol. 26,
365-481
Information on risks related to the substance
Date
Submitted
Organisation/
Comment
Response
- 42 -
20080807
by
Hilde
Viroux
MSCA
On behalf of p 37 The SCENIHR opinion from 2008 on the safety of Medical
organisation
Devices containing DEHP-plasticized PVC or other plasticizers
Alconstated that “so far there is no conclusive scientific evidence that
Couvreur,
DEHP exposure via medical treatments has harmful effects in
Belgium
humans”.
Noted.
We agree that the SCHENIR
opinion, “Scientific opinion on
the safety of medical devices
containing DEHP-plasticized
PVC or other plasticizers on
neonates and other groups
possibly at risk, 6 February
2008” (see abstract below)
should be considered in the
future process.
ABSTRACT:
The Scientific Committee on
Emerging
and
Newly
Identified
Health
Risks
(SCENIHR) has evaluated the
exposure to DEHP for the
general population and patients
during medical procedures. In
some cases the exposure is
significant and exceeds the
toxic doses observed in animal
studies. There is limited
evidence suggesting a relation
between DEHP exposures and
some effects in humans. There
is a reason for some concern
for prematurely born male
neonates for which the DEHP
- 43 -
exposure may be transiently
above the dose inducing
reproductive toxicity in animal
studies. So far, there is no
conclusive scientific evidence
that DEHP exposure via
medical
treatments
has
harmful effects in humans.
But, it is recognised that
especially the potentially high
exposure
during
medical
treatments may raise a
concern, even in the absence of
clinical or epidemiological
evidence, for harmful effects
in humans. Further studies are
required to confirm or reject
the suggestions of adverse
effects of DEHP in humans.
For certain uses of DEHP
alternative plasticizers for
PVC are available. The
Committee got access to
toxicity data for eight possible
alternative plasticizers and
compared their toxicity with
that of DEHP. In respect to
reproductive toxicity in animal
studies DEHP induces more
severe effects compared with
some of the alternatives. A risk
assessment of these available
- 44 -
20080808
20080818
20080819
alternative plasticizers could
not be performed due to a lack
of exposure data from medical
devices. Each alternative to
DEHP, however, must also be
evaluated with regard to their
functionality in respect to
medical devices. The risk and
benefits of using alternative
plasticizers
should
be
evaluated case by case.
Thecla Sterk On behalf of The SCENIHR opinion from 2008 on the safety of Medical Noted.
organisation
Devices containing DEHP-plasticized PVC or other plasticizers
Eucomed,
stated that “so far there is no conclusive scientific evidence that See the response to the
Belgium
DEHP exposure via medical treatments has harmful effects in previous comment.
humans”.
Federal
German CA
P44-45 information on use, exposure, alternatives and risks, Noted
Institute for
conclusion on (3) risk-related information: Requirements are
Occupationa
fulfilled. Data as described in EU RAR (2008) is presented
l Safety and
corresponded to regulation EEC 793/93 and the corresponding
Health Fb 5
Risk Reduction Strategy (RRS). Information allows an evaluation
Shigetaka
Behalf Of An The dossier concludes, “whereas the 95%-il exposure of child may The EU approach to risk
Seki
Organisation
be similar or higher than the proposed child DNEL“(p45). The assessment is to base the
Vinyl
conclusion refers to 2-25 microgram/kg/day as the indicative 95%- exposure assessment on the
Environmental
il. However, this is NOT the AVERAGE daily intake which 95-%il exposure value within a
Council, Japan
should be used to estimate the exposure. As the dossier admits, population. Using average
the day to day variation in the urinary excretion of DEHP is so exposure values would result
significant that the original reference data of 15-25 in risk assessments only
microgram/kg/day is not a reliable data. Thus this conclusion on protecting half of the exposed
child exposure is overestimated. Therefore it is not appropriate to population.
conclude as “whereas the 95-%il exposure of children may be
similar or higher than the proposed child DNEL”(page 45) .
- 45 -
Information on alternative substances and techniques
Date
Submitted
Organisation/
Comment
by
MSCA
20080707
Paula
Individual
I don't know if there is an alterantive product to this use.
Moreira
20080807
Hilde
On behalf of p 42 The suggested use of Latex, glass, Polyethylene as alternative
Viroux
organisation
materials does not apply in many cases to the specific applications
Alconand
needs
of
Medical
Devices.
Couvreur,
The SCENIHR opinion 2008 states that there is not enough data
Belgium
on suitable alternatives. Each alternative to DEHP must be
evaluated with regard to their functionality in respect to Medical
Devices. The risk and benefits of using alternative plasticizers
should be evaluated case by case.
Response
Noted.
Noted.
We agree that the SCHENIR
opinion, “Scientific opinion on
the safety of medical devices
containing DEHP-plasticized
PVC or other plasticizers on
neonates and other groups
possibly at risk, 6 February
2008” (see abstract below)
should be considered in the
future process.
ABSTRACT:
The Scientific Committee on
Emerging
and
Newly
Identified
Health
Risks
(SCENIHR) has evaluated the
exposure to DEHP for the
general population and patients
during medical procedures. In
some cases the exposure is
significant and exceeds the
toxic doses observed in animal
studies. There is limited
- 46 -
evidence suggesting a relation
between DEHP exposures and
some effects in humans. There
is a reason for some concern
for prematurely born male
neonates for which the DEHP
exposure may be transiently
above the dose inducing
reproductive toxicity in animal
studies. So far, there is no
conclusive scientific evidence
that DEHP exposure via
medical
treatments
has
harmful effects in humans.
But, it is recognised that
especially the potentially high
exposure
during
medical
treatments may raise a
concern, even in the absence of
clinical or epidemiological
evidence, for harmful effects
in humans. Further studies are
required to confirm or reject
the suggestions of adverse
effects of DEHP in humans.
For certain uses of DEHP
alternative plasticizers for
PVC are available. The
Committee got access to
toxicity data for eight possible
alternative plasticizers and
compared their toxicity with
- 47 -
20080808
20080819
that of DEHP. In respect to
reproductive toxicity in animal
studies DEHP induces more
severe effects compared with
some of the alternatives. A risk
assessment of these available
alternative plasticizers could
not be performed due to a lack
of exposure data from medical
devices. Each alternative to
DEHP, however, must also be
evaluated with regard to their
functionality in respect to
medical devices. The risk and
benefits of using alternative
plasticizers
should
be
evaluated case by case.
Thecla Sterk On behalf of The suggested use of Latex, glass, Polyethylene does not apply in Noted.
organisation
many cases to the specific applications and needs of Medical
Eucomed,
Devices.
See the response to the
Belgium
The SCENIHR opinion 2008 states that there is not enough data previous comment.
on suitable alternatives. Each alternative to DEHP, however, must
also be evaluated with regard to their functionality in respect to
Medical Devices. The risk and benefits of using alternative
plasticizers should be evaluated case by case.
Bureau
Behalf Of An
In the guidance for the preparation of Annex XV SVHC dossiers it Thank you for supporting the
REACH
Organisation
is indicated that available information on alternatives should be way
we
have
handled
RIVM
NL CA
included. The NL-CA considers the information in section 2 in these sections.
this part of the Annex XV dossier as the most appropriate way to
include an overview of the relevant data on alternatives and would
like to set it as an example for other Annex XV dossiers. The same
accounts for section 3 on risk-related information.
- 48 -
20080819
20080819
Federal
Institute for
Occupationa
l Safety and
Health Fb 5
Tim Edgar
Behalf Of An
Organisation
European
Council
for
Plasticisers and
Intermediates
(ECPI)
Noted.
P40ff information on use, exposure, alternatives and risks,
conclusion on alternative substances: Requirements are fulfilled.
There are detailed information to alternative substances and
alternative techniques. Data allows an evaluation.
Page 40: Information on Use, Exposure, Alternatives and Risks –
section
2,
Information
on
alternative
The
Annex
XV
dossier
states:
Several studies have been performed on alternatives to DEHP and
other phthalates. This section provides a summary of information
that was collected during the work with the Risk Reduction
Strategy (RRS). In general, there is no single alternative suitable
for all applications of DEHP. Instead a number of alternatives are
available; such as other phthalates and other plasticisers. Other
materials are also available that do not need additives to become
flexible.
ECPI
comments:
The direct substitution of DEHP as plasticiser or DEHP-plasticised
PVC is not a simple procedure to apply. DEHP is a plasticiser
which offers a good all-round performance and is therefore used
for a great many cost-effective, general purpose products. It
possesses reasonable plasticising efficiency, fusion rate and
viscosity (of great importance for plastisol applications).
Page 41: Information on Use, Exposure, Alternatives and Risks –
section
2,
Information
on
alternative
The
Annex
XV
dossier
states:
The Dutch Ministry has commissioned a report designed to
quickly analyse to what extent phthalates used in PVC can be
replaced by alternative substances or by alternative materials
(TNO,2002). The study concentrates on an assessment of technical
possibilities and an environmental comparison. The report
concludes that in general there is a broad range of alternatives to
- 49 -
Thank you for the information.
We acknowledge that the
section on alternatives can be
developed further.
The purpose of the dossier is to
identify a substance as a
SVHC. The dossier should
include
information
on
exposure, alternatives and
risks. This information is not
given on a very detailed level
since it is not critical for the
identification of a SVHC, and
the information will, if needed,
be further elaborated later in
the authorisation process.
The
REACH
legislation
acknowledges that medical
devices are subject to specific
regulations e.g. in article
2(6)(c) and article 60(2). In
addition, it is possible to
exempt uses or categories of
uses from the authorisation
requirement if risks are
most of the product groups with the exception of medical devices
where
legal
quality
rules
apply.
In terms of risk reduction the report cautiously states that the use
of benzoates and possibly citrates, instead of phthalates might
have some benefits for human health and the environment.
Another conclusion is that it is likely that the use of plasticisers
that are known not to give rise to emissions will result in a
significant reduction of risks. In Table 13 alternative substances
and
materials
are
listed.
Among the applications cited in Table 13, medical devices are
mentioned, with trimellitates and citrates as alternatives to DEHP.
ECPI
comments:
We would like to make some additional comments on the
application
of
DEHP
in
medical
devices.
DEHP-plasticised medical devices have become vital to modern
healthcare. DEHP-plasticised PVC is a popular choice for many
medical applications because it is clear, affordable, strong, flexible
easily
sterilised
and
won't
kink.
The European Union’s Scientific Committee on Emerging and
Newly
Identified
Health
Risks
(SCENIHR) has published in March 2008 an opinion on the use of
DEHP in medical devices. The advice, which comes from the
European Union’s highest independent scientific authority, makes
some comments on the use of DEHP in medical devices:
• EU scientists recognise the benefits of DEHP in medical device
applications. The Committee concludes that medical devices made
from PVC provide many effective treatments and that DEHP is a
particularly effective plasticiser. In addition to its beneficial effect
on mechanical properties, DEHP also stabilises the membranes of
red blood cells enabling blood product storage in PVC blood bags
for
several
weeks.
• There is no conclusive evidence of effects on humans from the
- 50 -
considered to be properly
controlled through existing
specific
Community
legislation, see article 58(2).
Further discussions on risks
and benefits of different uses,
such as in medical devices,
should take place later in the
authorisation process.
We agree that the SCHENIR
opinion, “Scientific opinion on
the safety of medical devices
containing DEHP-plasticized
PVC or other plasticizers on
neonates and other groups
possibly at risk, 6 February
2008” (see abstract below)
should be considered in the
future process.
ABSTRACT:
The Scientific Committee on
Emerging
and
Newly
Identified
Health
Risks
(SCENIHR) has evaluated the
exposure to DEHP for the
general population and patients
during medical procedures. In
some cases the exposure is
significant and exceeds the
toxic doses observed in animal
use of DEHP in medical devices. The Committee examined recent
scientific literature that has sought to link adverse effects in
humans to exposure to DEHP. The Committee rejects the
conclusions of these controversial studies, both individually and as
a group, due to the fact that in each case there is limited or no
evidence
of
effects.
• The benefits of the medical procedures justify the use of DEHP
in many cases despite the lack of conclusive evidence for effects
on humans. the Committee observes that in a limited number of
medical device applications, the data from animal studies suggests
that there may still be cause for concern for highly exposed patient
groups. The Committee points to premature and newborn male
babies in particular. However, the Committee underlines that the
benefits of the medical procedures involved may justify any
potential risks to such patient groups. (See as well next comment
on
neonates’
exposure)
• The risk and benefits need to be taken into account for each
plasticiser. The risks and benefits of using other plasticisers in
medical devices should be examined on a case by case basis. The
Committee examined eight alternative plasticisers to DEHP in
medical devices. In its evaluation, the Committee notes that in
some cases the toxicity data available may indicate a lower hazard
compared to DEHP. However, some of these plasticisers may not
deliver the same functional performance as DEHP and that for
some of the alternatives it could not complete an evaluation due to
a
lack
of
data.
In the United States, the FDA expressed little concern for adults
receiving medical treatments such as intravenous or dialysis. The
concerns about possible risks are based on the effects seen in
rodents. However, tests on primates, which are much better
predictors of effects of DEHP in humans than rodents, have
demonstrated that they are much less susceptible to effects from
- 51 -
studies. There is limited
evidence suggesting a relation
between DEHP exposures and
some effects in humans. There
is a reason for some concern
for prematurely born male
neonates for which the DEHP
exposure may be transiently
above the dose inducing
reproductive toxicity in animal
studies. So far, there is no
conclusive scientific evidence
that DEHP exposure via
medical
treatments
has
harmful effects in humans.
But, it is recognised that
especially the potentially high
exposure
during
medical
treatments may raise a
concern, even in the absence of
clinical or epidemiological
evidence, for harmful effects
in humans. Further studies are
required to confirm or reject
the suggestions of adverse
effects of DEHP in humans.
For certain uses of DEHP
alternative plasticizers for
PVC are available. The
Committee got access to
toxicity data for eight possible
alternative plasticizers and
DEHP
than
rodents.
Regulatory agencies in many countries that have approved DEHPplasticised vinyl for use in medical devices make the point that
substitutes may expose patients to hazards not present with
devices made with DEHP. Any alternative to DEHP in vinyl
would have to undergo scientific scrutiny and receive approval
from such authorities
before it could be
used.
The medical device industry is one of the most highly regulated in
the world. All such products, including their components,
therefore have to conform to rigorous safety standards.
The original study usually referred to is the one carried out by
Labow et al from the Canadian Red Cross Blood Transfusion
Service : Labow R S, Card R T and Rock G, The effect of the
plasticiser DEHP on red cell deformability, Blood, Vol 70. No 1
(July), 1987: pp 319-323. The conclusions are clear - it is not
possible to store red blood cells in DEHP free blood bags for more
than 21 days because they become more fragile. The presence of
DEHP improves the red cell flexibility with out altering its
function.
A similar study by Estep et al showed that DEHP inhibits the
deterioration of red blood cell membranes that occurs during the
refrigerated
storage
of
whole
blood.
Page 42: Information on Use, Exposure, Alternatives and Risks –
section 2, Information on alternative – HCWH report on neonatal
exposure
to
DEHP
The
Annex
XV
dossier
states:
Health Care Without Harm (HCWH) is a campaign for
environmentally responsible health care. It consists of 319
organisations, healthcare institutions and associations in 29
countries. Members of the campaign are hospitals, nurses,
environmental organisations, religious organisations, trade unions
and
patient
groups.
- 52 -
compared their toxicity with
that of DEHP. In respect to
reproductive toxicity in animal
studies DEHP induces more
severe effects compared with
some of the alternatives. A risk
assessment of these available
alternative plasticizers could
not be performed due to a lack
of exposure data from medical
devices. Each alternative to
DEHP, however, must also be
evaluated with regard to their
functionality in respect to
medical devices. The risk and
benefits of using alternative
plasticizers
should
be
evaluated case by case.
Their report on neonatal exposure discusses two alternative ways
to substitute DEHP in medical devices; by replacing PVCproducts with PVC-free products or replacing DEHP with an
alternative plasticiser (Rossi and Muehlberger, 2000). According
to HCWH both PVC-free and DEHP-free products are available
on the market for most of the medical applications of concern, e.g.
for applications in intensive care units for neonates.
ECPI
comments:
It has been demonstrated that adolescents exposed to DEHP via
ECMO as neonates show no adverse effects on growth or sexual
maturity. Thyroid, liver, renal and male/female gonodal functions
were within normal range for age and sex distribution. (“FollowUp Study of Adolescents Exposed to Di(2-Ethylhexyl) Phthalate
(DEHP) as Neonates on Extracorporeal Membrane Oxygenation
(ECMO) Support”, Children’s Health, 2004, Rais-Bahrami, Susan
Nunez, Mary E. Revenis, Naomi L.C. Luban, and Billie L. Short).
Information on risks related to alternatives
Date
Submitted Organisation/M
by
SCA
20080807 Hilde
On behalf of
Viroux
organisation
Alcon-Couvreur,
Belgium
Comment
Response
p 42 The SCENIHR opinion 2008 states that there is not enough
data
on
suitable
alternatives.
Per
MEDDEV
2.5/9,
Rev.1
[http://ec.europa.eu/enterprise/medical_devices/meddev/2_5_9rev
_latex.pdf] there is a prevalence of Latex allergy with health care
workers of 2.7% to 15%. With regard to glass, the risks related to
its physical properties (brittleness) are obvious.
Noted.
- 53 -
We agree that the SCHENIR
opinion, “Scientific opinion on
the safety of medical devices
containing DEHP-plasticized
PVC or other plasticizers on
neonates and other groups
possibly at risk, 6 February
2008” (see abstract below)
should be considered in the
future process.
ABSTRACT:
The Scientific Committee on
Emerging
and
Newly
Identified
Health
Risks
(SCENIHR) has evaluated the
exposure to DEHP for the
general population and patients
during medical procedures. In
some cases the exposure is
significant and exceeds the
toxic doses observed in animal
studies. There is limited
evidence suggesting a relation
between DEHP exposures and
some effects in humans. There
is a reason for some concern
for prematurely born male
neonates for which the DEHP
exposure may be transiently
above the dose inducing
reproductive toxicity in animal
studies. So far, there is no
conclusive scientific evidence
that DEHP exposure via
medical
treatments
has
harmful effects in humans.
But, it is recognised that
especially the potentially high
exposure
during
medical
treatments may raise a
concern, even in the absence of
- 54 -
20080808
Thecla
Sterk
On behalf
organisation
clinical or epidemiological
evidence, for harmful effects
in humans. Further studies are
required to confirm or reject
the suggestions of adverse
effects of DEHP in humans.
For certain uses of DEHP
alternative plasticizers for
PVC are available. The
Committee got access to
toxicity data for eight possible
alternative plasticizers and
compared their toxicity with
that of DEHP. In respect to
reproductive toxicity in animal
studies DEHP induces more
severe effects compared with
some of the alternatives. A risk
assessment of these available
alternative plasticizers could
not be performed due to a lack
of exposure data from medical
devices. Each alternative to
DEHP, however, must also be
evaluated with regard to their
functionality in respect to
medical devices. The risk and
benefits of using alternative
plasticizers
should
be
evaluated case by case.
of The SCENIHR opinion 2008 states that there is not enough data Noted.
on
suitable
alternatives.
- 55 -
Eucomed,
Belgium
20080819
20080819
Federal
German CA
Institute for
Occupation
al
Safety
and Health
Fb 5
Tim Edgar Behalf Of An
Organisation
European
Council
for
Plasticisers and
Intermediates
(ECPI)
Per
MEDDEV
2.5/9,
Rev.1, See the response
(http://ec.europa.eu/enterprise/medical_devices/meddev/2_5_9rev previous comment.
_latex.pdf) there is prevalence of Latex allergy with health care
workers of 2.7% to 15%. With regard to glass, the risks related to
physical properties (brittleness) are obvious.
P40ff information on use, exposure, alternatives and risks, Noted.
conclusion on risk-related to alternatives: Requirements are
fulfilled. The data allows an evaluation.
Page
40:
Information
on
Alternatives
It is requested that the Annex XV dossier is updated to reflect the
actual situation with regard to replacements for DEHP as provided
in
the
comments
below:
ECPI
comments:
Health and environmental safety are very important criteria for the
selection of alternative chemical substances. Among the technical
performance criteria for selecting alternative plasticisers to DEHP,
the
most
important
ones
are:
•
Compatibility
with
PVC
• Efficiency (amount of plasticiser required to achieve the desired
flexibility)
•
Permanency
•
Ease
of
processing
•
Cost-effectiveness
Plasticisers are essentially selected to meet product end-use
specifications (e.g. heat ageing properties of a flexible electrical
cable) but also to meet industrial process constraints (speed,
temperature, viscosity, emissions, and VOC requirements).
Because DEHP meets the above technical performance criteria in a
balanced and effective way it remains the largest volume
- 56 -
to
the
Thank you for the information.
We acknowledge that the
section on alternatives can be
developed further.
The purpose of the dossier is to
identify a substance as a
SVHC.
Information
on
alternatives is not given on a
very detailed level since it is
not
critical
for
the
identification of a SVHC, and
the information will, if needed,
be further elaborated later in
the authorisation process.
Regarding the risk assessment
of DINP, the Annex XV
dossier will be updated to
reflect the following:
It is correct that the SCTEE
plasticiser worldwide used to make flexible PVC.
However, some PVC manufacturers choose other plasticisers,
including phthalates such as DINP and DIDP as highlighted in
table 11 on page 40. ECPI strongly objects to the repeated
suggestions in the nomination dossier that the use of such other
phthalates is unsuitable. DINP and DIDP are frequently used in
plasticised PVC applications because of their ease of processing,
and permanency as well as the fact they are not classified or
labelled
for
any
health
or
environmental
effect.
opinion was rejected by the TC
NES (Technical Committee on
new and existing substances).
Further, it is stated in the
Commission Communication
on the results of the risk
evaluation and the risk
reduction strategy for DINP
(OJ C 90, 13.4.2006, p.4.
Official Journal of the
On the other hand, there are substances listed as plasticisers which European Union) that the risk
are
clearly
unsuitable. assessment shows that risks for
On page 41, Table 12, it should be noted that Butane ester and consumers are not expected.
TXIB are not primary plasticisers and they are much too volatile
for flooring and wall covering applications. They are a potential In the same document,
source of indoor VOC emissions with associated implications for however, it is further stated
indoor air quality. Di-2-(ethylhexyl) adipate is a plasticiser that that: “In light of the divergent
requires higher processing (fusion) temperatures to be scientific views between the
incorporated into PVC. Those higher temperatures are CSTEE and the conclusions of
incompatible with the processing speed required to make vinyl the assessment of the risk for
flooring. Alternative plasticisers in that application are di and consumers
under
this
mono benzoates due to their fast fusing properties. Regulation, and taking into
For toys, it should be noted that polyethylene does not provide the account the uncertainties in the
same softness or flexibility that plasticized PVC provides. Many evaluation of exposure to
toys (like a playball) are produced by rotational molding in which DINP from toys and childcare
a mold is filled with a liquid paste at room temperature. articles,
precautionary
Polyethylene, like the majority of thermoplastic polymers, can not considerations support the
form a paste and is therefore not suitable for this type of toy. consideration at Community
On page 42 - Table 13, it should be noted that most of the level
of
proportionate
suggested alternatives, with the exception of trimellitates and restrictions
in
Council
polymeric plasticisers, have not been evaluated in the suggested Directive
76/769/EEC
applications against the key technical performance criteria noted (Markering and Use Directive)
- 57 -
above. Trimellitates and polymeric plasticisers require much
higher processing temperatures and result in much slower
processing speeds, with implications for energy consumption and
productivity. They cannot be considered as general purpose
plasticisers.
As noted above health and environmental safety is a very
important criterion when selecting alternatives. It is an important
point that proposed alternatives should be subject to the same
degree of health and environmental testing and evaluation as the
substance for which replacement is proposed. It should be clearly
demonstrated that they are as safe or safer than the substance
which they are proposed to replace. Very often alternatives do not
have the same amount of testing and evaluation. This is typically
the case when alternatives to phthalates are being proposed. It is
therefore very difficult to state when alternatives are as safe or
safer than the phthalate which they are proposed to replace. On
page 43 of the Annex XV dossier it is noted that Acetyl Tributyl
Citrate (ATBC) was found by the SCTEE to have no safety
concerns. This assessment was done on a much smaller data set
than is available for DEHP and the general purpose phthalates. For
example a rodent carcinogenicity study was not available on
ATBC. This is an essential study for the evaluation of potential
long term effects to chemical substances, and is included in Annex
X
of
the
REACH
regulation.
The three main general purpose plasticisers i.e. DEHP, DINP and
DIDP have all been subject to extensive testing and evaluations,
with all three having recently completed 10 year EU risk
assessments.
On page 43 it is noted that “For DINP the risk assessment
concluded that there was “no need for risk reduction measures” for
consumer exposure” (this includes children’s toys for under 3’s).
The Annex XV dossier goes on to state that the SCTEE could not
- 58 -
for the use of DINP in toys and
childcare
articles.
Such
measures should be reviewed
after 3-4 years, in light of
further
scientific
developments.”
endorse this conclusion. This is not correct since the SCTEE
report
states:
“The health part of the document is of excellent quality. The
CSTEE agrees with the general conclusion for most exposure
scenarios that there is at present no need for further information
and/or testing and for risk reduction measures beyond those that
are
being
applied
already.”
The Annex XV dossier goes on to state that “The SCTEE
maintained that there are reasons for concern for child health
related to this use of DINP”. The SCTEE report (Final report, May
2001) did not state this. The SCTEE did disagree with the choice
of NOAEL in the EU Risk Assessment and this resulted in a
margin of safety of 48 for the use of DINP in toys for under 3’s
versus the lowest margin of safety of 172 reported in the EU Risk
Assessment.
The Annex XV dossier does not state that the SCTEE Opinion was
subsequently rejected by the Risk Assessment Technical Experts
from 15 Member States on the grounds that the critical endpoint
“spongiosis hepatis” chosen by SCTEE is specific to aging rats,
and therefore not relevant to risk assessment for children. In
addition the benchmark dose approach used by the SCTEE is not
appropriate when a clear NOAEL is established (which is the case
for DINP). This is noted in the EUs own Technical Guidance
Document. The above conclusion on spongiosis hepatis was
developed by an independent Pathology Working Group which
was formed under strict conditions to examine the available data
as well as the actual tissue slides from the chronic rodent studies
on DINP. The data from two comprehensive chronic rodent
studies were reviewed by the independent experts and they
concluded “when data from both studies are considered, the noeffect level [for spongiosis hepatis] of the test article (DINP),
based on the dosages used is 88.3 mg/kg/day in male rats and 184
- 59 -
mg/kg/day in female rates. Using these no-effect levels results in
margins of safety well in excess of 100. The independent
Pathology Working Group report was submitted to both the
European Chemicals Bureau (for inclusion in the Risk Assessment
and to the SCTEE). The conclusions of the report are fully
referenced in the EU Risk Assessment. The report was also
submitted to the SCTEE but as of the current date ECPI is not
aware that they have been requested to review this report. In
addition there is a 90-day oral study with DINP on primates
(marmosets) which shows only minor effects at 2500 mg/kg/day
with a clear NOAEL at 500 mg/day. This study suggests that using
rodent NOAELs for risk assessment purposes for DINP is a
conservative
approach.
ECPI therefore disagrees with the statement in the Annex XV
dossier that “This disagreement [between SCTEE and the EU Risk
Assessment] cannot be resolved until new and unequivocal
toxicological evidence is made available”. As noted above there is
available today unequivocal toxicological evidence that DINP is
safe for use in children’s toys and this is documented in the EU
Risk Assessment. The EU Member State Technical Experts
developed the DINP Risk Assessment over several years with
intensive discussions and reviews. The SCTEE opinion was
developed over a matter of weeks or months. It would be
appropriate that SCTEE (now SCHER) are requested to carry out
an in-depth review of all of the data on DINP including the
independent Pathology Working Group report. In addition there is
new exposure data available from the US Consumer Product
Safety Commission (CPSC November 2001, Celestine T. Kiss,
M.A. “A Mouthing Observation Study of Children under 6 Years
of
Age).
In fact the Marketing and Use Restrictions on phthalates in toys
which were finalized in 2005 require the Commission to “re-
- 60 -
evaluate, by 16 January, 2010, the measures provided for in
relation to this point in the light of new scientific information on
such substances and their substitutes, and if justified, these
measures shall be modified accordingly”. It will be important for
this re-evaluation that all the above information is taken into
consideration.
Page 44: Information on Use, Exposure, Alternatives and Risks –
section
3,
Risk-related
information
The
Annex
XV
dossier
states:
From 16 January 2007 restrictions on the marketing and use of six
phthalates apply (directive 2005/84/EC, now Reach annex XVII).
The three phthalates bis (2-ethylhexyl) phthalate (DEHP), dibutyl
phthalate (DBP) and benzyl butyl phthalate (BBP) shall not be
used as substances or as constituents of preparations, at
concentrations of greater than 0,1 % by mass of the plasticised
material, in toys and childcare articles. Such toys and childcare
articles containing these phthalates in a concentration greater than
the limit mentioned above shall not be placed on the market.
The same restrictions apply to the three phthalates di-”isononyl”
phthalate (DINP), di-”isodecyl” phthalate (DIDP) and di-n-octyl
phthalate (DNOP) in toys and childcare articles which can be
placed
in
the
mouth
by
children.
The restrictions impact the use of DEHP and some common
alternative phthalates in toys and childcare articles. However
recent information shows that children may be exposed to DEHP
in a similar way from other articles e.g. school supplies.
ECPI
response:
In terms of school supplies, the only route of exposure to be
considered should be related to the potential sucking on an eraser.
The other routes of exposure pose no health risk. Indeed, for
inhalation, head space measurements confirmed exposure is
negligible. Considering dermal exposure, the worst case scenario
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20080819
Ryuichi
Hasegawa
leads to a MOS (margin of safety) equal to 12000.
For erasers, assuming that it would be realistic to consider a
surface of 11.3 cm2 that could be sucked, with a rate of DEHP
extraction by saliva 0.065mg/cm2 and a NOAEL of 4.8 mg/kg bw
/day (see Risk assessment, value considered as worse case
scenario), the MOS value would be equal to 133. Hence this MOS
is reliable and adequate to demonstrate that exposure to DEHP via
this
route
does
not
pose
a
risk.
The
Annex
XV
dossier
states:
In addition, the risks from indirect exposure via the environment
of all humans, from many different sources, were highlighted
although never quantified in the risk assessment. It has been
described as a continuous low dose exposure of all humans. The
risk assessment suggests that outdoor applications of polymers
plasticized with DEHP like roofing, coil coating, coated fabric,
hoses, profiles, car undercoating and shoe soles give rise to the
major
part
of
DEHP
emissions.
ECPI
response:
The risks from indirect exposure via the environment to all human
were not quantified in the Risk assessment report of DEHP. We
recommend therefore that the two entire paragraphs be deleted as
they are not based on scientific evidence of risk hazard. As a
reminder, the risk hazard is derived from the hazard risk
multiplied by the exposure. If the exposure cannot be quantified, it
is therefore irrelevant to talk about the potential risk hazard.
Affiliated With We do not know how much safety data there are for the substances
Organisation
recommended
as
DEHP
alternatives.
Japan Plasticizer
DINP and DIDP whose RARs have been completed can be
Industry
accepted as candidates for alternatives, but because other
Association
substances are not clarified to have safety equivalent to or higher
than DEHP, these substances should not easily be recommended
as
alternatives.
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We acknowledge that the
section on alternatives can be
developed further.
The purpose of the dossier is to
identify a substance as a
SVHC. The dossier should
Many studies show that DEHP is safe, and the use of DEHP over include
information
on
many years demonstrates that DEHP has no clear effects on exposure, alternatives and
humans and is extremely safe.
risks. This information is not
given on a very detailed level
since it is not critical for the
identification of a SVHC, and
the information will, if needed,
be further elaborated later in
the authorisation process.
Attached documents (please click on the links below to see the attachments)
Comments (DEHP-phtalates guidance) from Thecla Sterk, on behalf of Eucomed, Belgium
Comments (Risk benefit) from Thecla Sterk, on behalf of Eucomed, Belgium
Comments from Sarah Dunagan, on behalf of Silent Spring Institute, United States
Comments from Bureau REACH RIVM
Comments from Jacques Warnon, on behalf of CEPE Industry and trade organisation
Comments from Jean-Pierre de Greve, on behalf of European Council of Vinyl Manufacturers
Comments from Lisette van Vlet, on behalf of Health and Environment Alliance
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