 |
| Opinion concerning Dialkyl- and Dialkanolamines and their salts in cosmetic products adopted by the SCCNFP during the 17th plenary meeting of 12 June 2001 | |
| |
| |
| |
Executive
Summary
1. Terms
of Reference
The SCCNFP
has been asked to respond to
following questions:
2. Context of the
question
Cosmetic
products marketed in the EU
should not contain those
substances which are listed
in the Cosmetics Directive
76/768/EEC, Annex II :"List
of substances which must not
form part of the composition
of cosmetic products".
Furthermore, the Inventory of
ingredients employed in
cosmetic products, provided
for in Article 5a of the said
Directive, should not contain
substances included in Annex
II, despite the fact that it
is an indicative list, not
constituting a list of
substances authorised for use
in cosmetic products.
The
Cosmetics Inventory annexed
to the Commission Decision
96/335/EC of 8 May 1996
"establishing an inventory
and common nomenclature of
ingredients employed in
cosmetic products" contains a
number of salts of secondary
dialkanolamines, which should
not form part of the
composition of cosmetic
products since Annex II
includes N
o 411, "Secondary
dialkanolamines". The SCCNFP,
during its 7
th plenary session
of 17 February 1999 has
already adopted an opinion
SCCNFP/0110/98 concerning the
"Banning of Dialkanolamines
which are still in the
Inventory".
3. Assessment
Dialkanolamines,
being strong bases (pK =
11-12), occur in cosmetic
products almost exclusively
in the form of the salts with
organic or inorganic acids,
functioning as buffering
agents, emulsifiers, or
surfactants, i.e. functions
due just to the properties of
their salts. Therefore, there
is no doubt that all the
reports previously evaluated
by the Scientific Committee
on Cosmetology (SCC),
concerning either nitrosamine
contents of commercial
cosmetic products, or basic
research on the mechanism(s)
of nitrosamine formation,
apply directly to
dialkanolamine salts rather
than to free
dialkanolamines.
Furthermore, the
respective dialkylamine
analogs share quite similar
properties with
dialkanolamines with respect
to their potential as
nitrosamine precursors.
Therefore, the same
restrictions should apply to
both classes.
4. Opinion
The
toxicological effects of the
dialkanolamine salts, and, in
particular their readiness
for nitrosamines' formation
are similar to the respective
properties of the
dialkanolamines since there
is a pH-dependent equilibrium
between the salt and the
respective free base. In
addition, dialkylamines and
their salts have very similar
properties with the
respective dialkanolamines'
analogs with respect to
nitrosamines'
formation.
Therefore,
it is the opinion of the
SCCNFP that Entry N° 411 of
Annex II and Entries N° 60,
61 and 62 of Annex III must
be amended accordingly, as
indicated below.
Annex II
N° 411.
Dialkyl- and dialkanolamines
and their salts.
Annex III
Full
Report
1. Terms
of Reference -
Mandate
The SCCNFP
has been asked to respond to
following questions:
2. Context of the
question
2.1. Background -
Current legislation on
cosmetic ingredients
Cosmetic
products marketed in the EU
should not contain those
substances which are listed
in the Cosmetics Directive
76/768/EEC, Annex II:"List of
substances which must not
form part of the composition
of cosmetic products".
Furthermore, the Inventory of
ingredients employed in
cosmetic products, provided
for in Article 5a of the said
Directive, should not contain
substances included in Annex
II, despite the fact that it
is an indicative list, not
constituting a list of
substances authorized for use
in cosmetic products.
2.2. Previous opinion of
SCCNFP - Current
situation
The
Cosmetics Inventory annexed
to the Commission Decision
96/335/EC of 8 May 1996
"establishing an inventory
and common nomenclature of
ingredients employed in
cosmetic products" contains a
number of salts of secondary
dialkanolamines, which should
not form part of the
composition of cosmetic
products since Annex II
includes N
o 411, "Secondary
dialkanolamines".
The
SCCNFP, during its 7
th plenary session
of 17 February 1999 adopted
an opinion SCCNFP/0110/98
concerning the "Banning of
Dialkanolamines which are
still in the Inventory".
However it was not specified
that, for the sake of
clarity, N
o 411 of Annex II
should be amended in order to
include dialkanolamine salts.
As a result, these substances
have not been removed from
the 1
st Update of the
Inventory.
3. Assessment
3.1. History
The
nitrosamine problem in
cosmetics was originally
raised during the 23
rd plenary session
of the Scientific Committee
on Cosmetology (SCC) on 21-22
May, 1984 and, during the
following 4 years, it was
extensively discussed by the
Working Group on "Guidelines"
(1) on the basis of a
document submitted by the
Federal German authorities
(CSC/439/84), a lengthy
report from the FDA
(CSC/474/85), and several
other documents and
publications (2-4). The
Scientific Committee had not
adopted a position on a
regulatory recommendation
because the results of the
GLC/TEA (Gas Liquid
Chromatography/Thermal Energy
Analysis) analysis were
called into question by a
publication indicating also
that the presence of
nitromusks would cause
false-positive results in the
search for the presence of
nitrosamines (5).
Later,
during 1988-1992, an
ad hoc Working Group
on "Nitrosamines" had
evaluated a number of papers
from the scientific
literature and of specific
reports, including a final
report on the project "Study
of nitrosamine formation and
inhibition of N-Nitrosation
in cosmetic products"
conducted by the University
of Kaiserslautern, Department
of Food Chemistry and
Environmental Toxicology (6),
and two special ECETOC
Technical Reports
(7,8).
ed the
following proposal to be
transmitted to the Commission
(11).
Minimum requirements for
ingredients of cosmetics,
toiletries and personal
care products
1) Secondary
alkanolamines such as
diethanolamine and
diisopropanolamine must not
be used.
2) Fatty acid
dialkanolamides with the
lowest achievable
contamination by
dialkanolamines are to be
used. As a standard figure,
contamination should not
exceed 0.5% dialkanolamine
in the respective fatty
acid dialkanolamide.
3) Mono- and
trialkanolamines must not
be used with less than 99%
purity. Content of
secondary amine must not
exceed 0.5% and
contamination by
N-nitrosodialkanolamine is
limited to a maximal value
of 50 ppb*.
4) Non-rinse-off
formulations must not
contain more than 2.5% of
trialkanolamine.
5) Nitrosating agents
must be excluded in the
presence of nitrosatable
nitrogen compounds.
6) Suitable inhibitors
are recommended to
counteract nitrosamine
formation. The suitability
of a given inhibitor has to
be proven in every single
case.
7) Raw materials and
final formulations should
be stored in nitrite free
metal or plastic
containers.
____________________________
* Determination
according to Z. Lebensm.
Unters. Forsch. (1989) 189,
144-146
This
recommendation of the SCC has
been included in the
Fifteenth Commission
Directive 92/86/EC of 21
October 1992 adapting to
technical progress the
Annexes of the Cosmetics
Directive as follows:
Annex II
N° 411.
Secondary
dialkanolamines.
Annex III
Note: The
expression "secondary
dialkanolamines" in Annex II
is superfluous because
dialkanolamines are by
definition secondary
amines.
3.2. Salts versus free
bases
Dialkanolamines
are strong bases, having pK
values in the range 11-12.
This means that even at pH =
11 (strongly alkaline) about
50% occurs in ionic form, the
rest being undissociated
base. At pH values 9 (still
alkaline) or lower, nearly
100% occurs in the form of
salts.
The vast
majority of cosmetic products
belong to this last case. As
a matter of fact, the
''functions'' of all
alkanolamines and their salts
in cosmetic products are
buffering agents, or
emulsifiers, or
surfactants, i.e.
functions due just to the
properties of their salts.
Consequently, in all cosmetic
formulations containing
dialkanolamines, the finished
product contains them
exclusively in the form of
their salts, regardless if
they were added in the form
of free bases or salts to the
formulation. Therefore, there
is no doubt that all the
reports previously evaluated
by the SCC, concerning either
nitrosamine contents of
commercial cosmetic product,
or basic research on
mechanism(s) of nitrosamine
formation, apply directly to
dialkanolamine salts rather
than to free
dialkanolamines.
As a
matter of fact, the velocity
of nitrosation of amines is
influenced by a number of
conditions including the
nature of amine and
counteracting anionic species
in its salts, the pH, the
nature of the medium or of
the biphasic system
(emulsion), the prevailing
species of nitrosating agent,
the presence of catalysts,
etc.
Usually a
mixture of nitrosating
species is involved in the
reaction depending on the
acidity of the medium and, in
emulsions (e.g., cosmetic
products), the dielectric
constant of the oily layer
and nature of the anionic
surfactant. In all mechanisms
of nitrosamine formation, the
actual nitrosating agent is
the nitrosonium ion, NO
+ (in the oily
phase), or its hydrated form,
the nitrous acidium ion, H
2O
+NO (formed in the
aqueous phase by direct
protonation of the nitrous
acid, HNO
2). Thus,
nitrosation by nitrite in
aqueous solutions (simpler
case) is enhanced in acidic
pH's favouring the formation
of H
2O
+NO, having a
maximum value at pH around
3.4, the pK
a of nitrous acid.
In the presence of a catalyst
such as chloral or an
aldehyde, e.g. formaldehyde,
nitrosation actually proceeds
quite readily up to a pH of
11 (2-4,8).
On the
other hand, dinitrogen
trioxide or nitrous
anhydride, N
2O
3, and dinitrogen
tetroxide, N
2O
4 (the dimer of
nitrogen dioxide, NO
2), are reported
to be extremely rapid
nitrosating agents in basic
solutions, actually
nitrosating secondary amines
more rapidly that acidified
nitrites (2,3).
These two
nitrosating agents behave
like nitrosonium salts (NO
+...NO
2
- and NO
+...NO
3
- respectively)
especially in solvents of
high dielectric constants. In
biphasic systems, N
2O
3 and N
2O
4 are partitioned
in the oily layer where the
nucleophilic anionic
counterparts (e.g., RCOO
-) serve as
carriers of the nitrosonium
ion in the form of
nitrosonium salts (RCOO
-.. NO
+ ), which in
turn, react with the amine
(9). This occurs in the whole
range of pH values (acidic,
neutral, basic) and it is
just under these conditions
that secondary amines was
observed to be nitrosated,
i.e. the nitrosation of amine
salts in hydrophobic
environment (oily layer or
chloroform) was shown to be
much faster than nitrosation
of free (not neutralised)
secondary amines (9).
Nitrogen dioxide, NO
2, which by itself
is not a good nitrosating
agent, is easily converted to
a mixture of nitrite and
nitrate, of which nitrite may
produce N
2O
3 by dehydration
[2 HNO
2 = H
2O + N
2O
3], following
thereafter the above
mechanisms of nitrosating
amines (9). It should be
noted that alkanolamines have
an enormous capacity for
absorbing and holding NO
2 and its
dehydration and subsequent
transformation to N
2O
3 is extremely
favoured under the anhydrous
conditions of the film
remaining on the skin after
quick evaporation of the
moisture of the product (9).
On the other hand, NO2 is
quickly formed by oxidation
(by lipid peroxides or even
by air) of the nitric oxide,
NO, which in the past was
thought to be inert with
respect to nitrosation of
amines, so that nitrosamine
formation would be avoided by
using anti-oxidants, such as
a-tocopherol, ascorbic acid
etc. The poor results of all
attempts made to this
direction have indicated that
the NO formed as the final
product of reduction of all
other nitrogen oxides by
anti-oxidants, is quickly
re-oxidized to NO2 , while
using anti-oxidants in large
excesses did not avoid
completely the -slower
though- nitrosation
processes.
3.3. Alkyl- versus
alkanol-amines (mono-, di-,
tri-)
As already
mentioned, in the reports
evaluated in the past by SCC,
the properties of the mono-,
di- and tri-alkylamines share
quite similar properties with
their respective alkanolamine
analogs with respect to their
potential as precursors of
nitrosamine formation.
Therefore, the same
restrictions and limitations
should apply to both classes
of substances.
In 1992
the Scientific Committee had
inadequate information about
the use of secondary
alkylamines in cosmetic
products, which has been
revealed after the
publication of the cosmetics
Inventory. At that time
almost all pertinent reports
had been addressed to
problems connected with use
of alkanolamine derivatives,
mainly due to the very wide
use of triethanolamine highly
contaminated with
diethanolamine. This is a
most probable reason for the
fact that the old proposals
of the SCC had been referred
to alkanolamine derivatives
only. The present
re-evaluation of the subject
should be a good opportunity
for the SCCNFP to restore the
problem to its scientifically
correct dimensions.
It must be
emphasized that some
nitrosodialkylamines are more
potent carcinogens than
nitrosodialkanolamines. All
N-nitroso-dialkylamines
tested were found strongly
carcinogenic to all animal
species tested, and more
potent mutagens than NDELA.
NDEA induces tumors following
different routes of
administration, including
ingestion, inhalation and
skin painting. It is
carcinogenic in single dose
experiments and following
prenatal exposure. A summary
of selected test results on
mutagenicity and
carcinogenicity, taken from
the data described in full
detail in the ECETOC
Technical Report N
o 41 (7), is
outlined in the following
table.
*
StBM=Standard bacterial
mutation, GMMC=Gene mutation
in mammalian cells,
UDnS=Unscheduled DNA
synthesis, MT=Micronucleus
test,
NDELA=N-nitroso-diethanolamine,
NDMA=N-nitroso-methylamine,
NDEA=N-nitroso-diethylamine,
NDIPLA=N-nitroso-diisopropanolamine
It has to
be mentioned that a
comparison of the
toxicological risk of amines
and alkanolamines with regard
to their nitroso derivatives
should not only be based on
carcinogenic potency but, in
addition, should integrate
the kinetics of nitrosation
(13).
The ease
of nitrosation is strongly
dependent on the basicity of
the amines and varies over
several orders of magnitude
(12). Therefore, the
potential of secondary amines
as nitrosamines precursors is
given but the formation rate
is varying. Furthermore,
there are « safe
amines » which were
proposed to substitute the
known nitrosamine precursors
in the rubber industry. These
amines are substituted in
alpha-position with
tert.alkyl groups and were
selected since they are
hardly nitrosated and/or
yield non-carcinogenic
nitrosamines.
4. Opinion
The
toxicological effects of the
dialkanolamine salts, and, in
particular their readiness
for nitrosamines' formation
are similar to the respective
properties of the
dialkanolamines since there
is a pH-dependent equilibrium
between the salt and the
respective free base. In
addition, dialkylamines and
their salts have very similar
properties with the
respective dialkanolamines'
analogs with respect to
nitrosamines'
formation.
Therefore,
it is the opinion of the
SCCNFP that Entry N° 411 of
Annex II and Entries N° 60,
61 and 62 of Annex III must
be amended accordingly, as
indicated below.
Annex II
N° 411.
Dialkyl- and dialkanolamines
and their salts.
Annex III
5. Other
considerations
The SCCNFP
considers that, in principle,
secondary amines and
alkyldimethyl-N-oxides are
potential precursors of
nitrosamines (14). In
addition, nitrosamine
formation and contamination
has been observed in the case
of the UV-filter
2-Ethylhexyl-4-dimethylaminobenzoate
(15).
6. Minority opinions
/
7. References
1. EU
Official Document
SPC/142/90-EN (1990)
"Nitrosamines" (Progress
Report) .
2.
Anderson G.A (1979)
"Nitrosamines in Cosmetics",
Cosmetics & Toiletries,
94, 65-68.
3. Chalis
B.C. and Kyrtopoylos S.A.
(1976) "Rapid formation of
carcinogenic N-nitrosamines
in aqueous alkaline
solutions", Brit. J. Cancer,
35, 693-696.
4. Chalis
B.C. and Kyrtopoylos S.A.
(1979) "The Chemistry of
Nitroso-Compounds. Part II.
Nitrosation of amines by the
two-phase interaction of
amines in solution with
gaseous oxides of nitrogen",
in JCS Perkin 1,
299-304.
5. Sine
M.R. (1986) "Nitromusks:
False positives in the
analysis for nitrosamines",
L. Soc. Cosm. Chem.,
37, 266-267.
6.
Eisenbrand G. (1988)
"Nitrosamine formation in
cosmetic products, detergents
and cleansing agents and the
development of prevention
methods", submitted by the
FRG Government in support of
the respective Communication
of 6 June 1988 (XI/517/87)
proposing banning the use of
diethanolamine and
diisopropylamine and possibly
the entire group of secondary
amines in cosmetic products
by entering them in Annex II
of the Cosmetics Directice
76/768/EEC.
7. ECETOC
(1990) "Human exposure
to N-nitrosamines, their
effects, and a risk
assessment for
N-nitrosoethanolamine in
personal care products",
Technical Report N
o 41, August 1990
(ISSN-07773-8072-41).
8. ECETOC
(1991) "Critical
evaluation of methods for the
determination of
N-nitrosamines in personal
care and household products",
Technical Report N
o 42, February
1991
(ISSN-0773-8072-42).
9. Powell
J.B. (1987) "Minimizing
N-nitrosodiethanolamine
formation from nitrite and NO
2 in nonaqueous
triethanolamine systems", J.
Soc. Cosmet. Chem.
38, 29-42.
10. EU
Official Document SPC/019/92
on Nitrosamines in
cosmetics.
11. EU
Official Document SPC023/92
on Nitrosamines in
cosmetics.
12.
Mirvish (1975) Toxicol. Appl.
Pharmacol.
31, 325-351.
13.
Shepard et al. (1987) Food
Chem. Toxicol.,
25, 91-108.
14.
Eisenbrand G., Fuchs A. and
Koehl W. (1996) "N-nitroso
compounds in cosmetics,
household commodities and
cutting fluids" Eur. J.
Cancer Prevention,
5
(Suppl. 1),
41-46.
15. Dunkel
V.C. et al. (1992)
"Evaluation of the
mutagenicity of N-nitroso
contaminant of the sunscreen
Padimate O" Env.& Mol.
Mutag.,
20, 188-198.
| |
| | |
|
|
