SCCNFP/586/02, final

THE SCIENTIFIC COMMITTEE ON COSMETIC PRODUCTS AND NON-FOOD PRODUCTS
INTENDED FOR CONSUMERS

OPINION
CONCERNING

THE DETERMINATION OF CERTAIN FORMALDEHYDE RELEASERS IN
COSMETIC PRODUCTS

Adopted by the SCCNFP during the 22nd plenary meetingof 17 December 2002

SCCNFP/586/02, final
Evaluation and opinion on : determination of certain formaldehyde releasers in cosmetic products_____________________________________________________________________________________________

1.

Background

The EU working party (WP) on Methods of Chemical Analysis of Cosmetic Products has
observed that certain formaldehyde releaser in aqueous/polar solvents release some or all of theformaldehyde they contain, and they do not remain as a single compound. The working party has
identified 4 such formaldehyde releasers, which are permitted to be used as preservatives incosmetic products, according to Directive 76/768/EC: imidazolidinyl urea, diazolidinyl urea,
sodium hydroxymethyl glycinate and benzylhemiformal (entries 27, 46, 51 and 55 respectively
in Annex VI, part 1 of the Directive). As these compounds did not remain intact during various
analytical conditions employed, WP concluded that it may not be possible to develop method(s)of analysis of these compounds. One of the approaches to overcome the analytical problem,suggested by working party, is that these 4 formaldehyde releasers may be regulated on the basisof their formaldehyde content.

2.

Request to the SCCNFP

With reference to above-mentioned background the SCCNFP was requested to answer following
questions :·Does the SCCNFP consider it possible to amend the above mentioned entries 27, 46, 51and
55 so that the maximum authorised concentration could be expressed as a concentration of
total formaldehyde without prejudicing the safety of cosmetic products?

·

If so, can the SCCNFP propose maximum authorised concentrations of these preservatives,
expressed as total formaldehyde, in cosmetic products?

3.

Legislation on formaldehyde content of cosmetic products

According to Annex VI of the Cosmetic Directive 76/768/EC, the maximum authorised
concentration of free formaldehyde is 0.2%. In addition, the provisions of Annex VI state that,All finished products containing formaldehyde or substances in this Annex and which releaseformaldehyde must be labelled with the warning “contains formaldehyde” where theconcentration of formaldehyde in the finished product exceeds 0.05%.
The legislation is thus dependent upon the ability of analytical methods to differentiate freeformaldehyde from the bound, inert form. The official EC method (1) for analysis determines thelevel of free formaldehyde in the presence of its donor compound.

4.

Analytical problem

According to the Cosmetic Directive, official EU methods should be used to check thecompliance of cosmetic products. The EU WP on Methods of Chemical Analysis of Cosmetic
Products developed and validated a method for the determination of free formaldehyde in thepresence of formaldehyde releasers (1). The method has been used since 1990 as the official EU
method for the determination of free formaldehyde. During the development of method(s) for the
analysis of formaldehyde releasers imadozolidinyl urea, diazolidinyl urea, sodium
2

SCCNFP/586/02, final
Evaluation and opinion on : determination of certain formaldehyde releasers in cosmetic products_____________________________________________________________________________________________hydroxymethyl glycinate and benzylhemiformal, it was observed that these compounds
decompose very rapidly to release formaldehyde when dissolved in aqueous/ polar solvents.
Therefore, identification and determination of these compounds in cosmetic products may not be
possible with the present state of knowledge. There is no information on the stability of thesecompounds in cosmetic products.
5.

The formaldehyde releasers

5.1

Imidazolidinyl urea : 3,3-Bis(1-hydroxymethyl-2,5-dioxoimidazolidin-4-yl)-1-1’methyldiurea

Empirical formula
MW
CAS Reg. No.

:::

C11H16N8O8
388
39236-46-9

Soluble in water, propylene glycol, glycerine
Maximum authorised concentration in cosmetic products : 0.6%

Imidazolidinyl urea is soluble only in polar solvents. In aqueous solution, it is decomposed torelease formaldehyde. The formaldehyde release from imidazolidinyl urea in an aqueous solution
increases with the increase in pH and temperature of the solution as well as with the increase instorage period (2). One molecule of imidazolidinyl urea can release 4 molecules of formaldehyde
under rigorous conditions. The total free formaldehyde content in a product containing 0.6%
imidazolidinyl urea will thus correspond to 0.186%.
A method for analysis imidazolidinyl urea in cosmetic products was published in 1994 (3). Thismethod employs determination of the compound by micellar electrokinetic chromatography(MEKC). However, it was not established that the chromatographic peak obtained by the
analysis of imidazolidinyl urea was in fact the intact compound. Furthermore, this method could
not be reproduced in another laboratory (4). The research in the later laboratory also indicatedthat it would not be possible by the MEKC to discriminate between imidazolidinyl urea anddiazolidinyl urea, even if this method worked properly. It is possible that a common
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SCCNFP/586/02, final
Evaluation and opinion on : determination of certain formaldehyde releasers in cosmetic products_____________________________________________________________________________________________

decomposition product (an allantoin derivative) of both imidazolidinyl urea and diazolidinyl urea
is seen as a single peak in MEKC. Further attempts to develop a method for the analysis of
imidazolidinyl urea failed (4), because it was not possible to verify the identity of the parent
compound under experimental conditions (as the compound degrades spontaneously in thesolution). It has been shown by high performance liquid chromatography (HPLC), capillary zone
electrophoresis (CZE) and nuclear magnetic resonance spectrometry (NMR) that the solution of
imidazolidinyl urea contains several entities (2,4). It has not been established whether all
molecules present in a solution of imidazolidinyl urea are decomposition products of the parent
compound or the parent compound itself is a mixture of isomers. In any case, several of thesemolecules will contain formaldehyde. It is also expected that such molecules exist in the aqueous
phase of water-containing cosmetics such as shampoos as well as in emulsion type cosmetics.
The latest Opinion on imidazolidinyl urea dates back to 1 July 1986. The Scientific Committee
on Cosmetology (SCC) in its Opinon of 1 July 1986 stated that, “The available informationsuggests the substance to be of relatively low toxicity. Details of the Ames test are required and achromosome aberration test in mammalian cells in vitro. However, the Committee sees noobjection to maintaining the use of this substance as a preservative in cosmetic products for thetime being at a maximum level of 0.6%”.
The SCC did not consider the release of formaldehyde from imidazolidinyl urea when the safetyof this compound was assessed. The toxic profile of decomposition product(s) of imidazolidinylurea may be different than that of parent compound, which appears to be a mixture of isomers.
However, it may be considered that the decomposition products of imidazolidinyl urea were
present in the test solutions used in experiments performed for the elucidation of toxicity of thecompound.
5.2

Diazolidinyl Urea :Empirical formula
MW
CAS Reg. No.

:::

N-[1,3-bis(hydroxymethyl)-2,5-dioxo-4-imidazolidinyl]-N,N’-bis(hydroxymethyl)urea
C8H14N4O7
278
78491-02-8

Soluble in water, insoluble in most organic solvents
Maximum authorised concentration in cosmetic products: 0.5%

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SCCNFP/586/02, final
Evaluation and opinion on : determination of certain formaldehyde releasers in cosmetic products_____________________________________________________________________________________________

In aqueous solution, diazolidinyl urea is decomposed to release formaldehyde. One molecule ofdiazolidinyl urea can release 4 molecules of formaldehyde under rigorous conditions. The total
free formaldehyde content in a product containing 0.5% diazolidinyl urea will thus correspond to
0.215%.
A HPLC method for the analysis of diazolidinyl urea in an experimental cream was published in
1997 (5). This method involves UV detection of the compound at 214 nm, while the lmax ofdiazolidinyl urea is 236nm. It was not established that the chromatographic peak obtained by the
analysis of diazolidinyl urea was in fact the intact compound. The applicability of the method
has not yet been demonstrated to any cosmetic product available in the market. Attempts todevelop a method for the analysis of diazolidinyl urea failed (4), because it was not possible toverify the identity of the parent compound under experimental conditions (as the compound
degrades spontaneously in the solution). HPLC, CZE and NMR studies have shown that
diazolidinyl urea solution contains several entities (4). It has not been established whether all
molecules present in a solution of diazolidinyl urea are decomposition products of the parent
compound or the parent compound itself is a mixture of isomers. In any case, several of thesemolecules will contain formaldehyde. It is also expected that such molecules exist in the aqueous
phase of water-containing cosmetics such as shampoos as well as in emulsion type cosmetics.
The latest Opinion on imidazolidinyl urea dates back to 10-11October 1990. The SCC in its
Opinon of 10-11October 1990 concluded that, “The Committee had requested a study using theoral route, since this would have provided much more information on the teratogenic potential ofGermal II (diazolidinyl urea) than the dermal study actually carried out. It is likely that (eg. fromphysicochemical considerations) the compound is poorly absorbed through the skin, although
there is little data on this aspect. The results do however indicate that compound is unlikely togive rise to any concern regarding teratogenic effect”.
The SCC did not consider the release of formaldehyde from diazolidinyl urea when the safety ofthis compound was assessed. The toxic profile of decomposition product(s) of diazolidinyl urea
may be different than that of parent compound, which appears to be a mixture of isomers.
However, it may be considered that the decomposition products of diazolidinyl urea were present
in the test solutions used in experiments performed for the elucidation of toxicity of thecompound
5.3

Sodium hydroxymethyl glycinate :Empirical formula
MW
CAS Reg. No.

:::

Sodium hydoxymethylamino acetate

C3H6NO3Na
127
70161-44-3

Highly soluble in water, soluble in methanol propylene glycol, glycerine, but insoluble in mostorganic solvents.
Maximum authorised concentration in cosmetic products: 0.5%5

SCCNFP/586/02, final
Evaluation and opinion on : determination of certain formaldehyde releasers in cosmetic products_____________________________________________________________________________________________In an aqueous solution, sodium hydroxymethyl glycinate is decomposed to releaseformaldehyde. One molecule of formaldehyde is formed by the decomposition of each moleculeof sodium hydroxymethyl glycinate, as described below.

The total free formaldehyde content in a product containing 0.5% sodium hydroxymethyl
glycinate corresponds to 0.118%.
Attempts to develop a method for the analysis of sodium hydroxymethyl glycinate failed because
the parent compound could not be identified under experimental conditions (6).
The latest Opinion on sodium hydroxymethyl glycinate is from 1995 (SPC/1254/95 Rev. 1). The
SCC concluded that, “According to the control that we have done on all reports to secure
validity of the previous assessment, and to the negative results obtained with the in vivo – invitro UDS assay, a safety margin of 70 is still applicable. Nevertheless, it is strongly
recommended to the industry to define accurately if Suttocide A (sodium hydroxymethyl
glycinate) is a powder or a 50% aqueous solution of the powder. No further assays appear to benecessary at the present time. Experimental data demonstrate that this compound is a potential
allergen according to the guinea pig maximisation test. At the current usage levels, there is noevidence of unacceptable risk of sensitisation to the consumers. However, any background ofsensitivity to the compound may be assessed at the later date if it becomes more widely used ascosmetic preservative”.
The SCC did not consider the release of formaldehyde from sodium hydroxymethyl glycinate,
when the safety of this compound was assessed. However, the decomposition product of sodiumhydroxymethyl glycinate, e.g. sodium glycinate cannot be considered harmful.
5.4

Benzylhemiformal

Empirical formula
MW
CAS Reg. No.

:::

153 for 1.5 mol/per mol of benzylhemiformal
14548-60-8

Soluble in organic solvents; solubility in water 25 g/L (at 20°C)
Maximum authorised concentration in cosmetic products: 0.15% in “rinse-off” products

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SCCNFP/586/02, final
Evaluation and opinion on : determination of certain formaldehyde releasers in cosmetic products_____________________________________________________________________________________________

Benzylhemiformal in an aqueous solution is decomposed to formaldehyde and benzyl alcohol.
The decomposition of benzylhemiformal releases all formaldehyde it contains, as described
below.

The total free formaldehyde content in a product containing 0.15% benzylhemiformal
corresponds to 0.044%
A method for the analysis of benzylhemiformal is not possible, because the parent compoundcannot be identified under experimental conditions (7).
The latest Opinion on benzylhemiformal is from 1998 (SCCNFP/0033/98)). The SCCNFP
concluded that, “Under the assumption of a complete release of HCHO out of the
Benzylhemiformal (P21) molecule and the given maximal product concentration of 0.15% a
HCHO content of less than 0.05% is to be expected.In real figures related to the use of
Benzylhemiformal as a preservative in “rinse-off”-cosmetic products with a maximum
concentration of 0.15% means that the maximum possible exposure of …….” Classification: 1 at
a maximum concentration of 0.15% in rinse-off products

6.

Summary

It is demonstrated that in aqueous solutions, imidazolidinyl urea, diazolidinyl urea sodiumhydroxymethyl glycinate and benzylhemiformal release some or all of the formaldehyde they
contain, and thus, they may not be available for analysis as parent compounds in cosmetic
products.
A MEKC method is published for the analysis of imidazolidinyl urea, in which it was notestablished that the chromatographic peak obtained by the analysis of imidazolidinyl urea was infact the intact compound. The method could not be reproduced in another testing laboratory.
Similarly, a HPLC method is published for the analysis of diazolidininyl, in which it was notestablished that the chromatographic peak obtained by the analysis of diazolidinyl urea wasinfact the intact compound. Furthermore, the applicability of the HPLC method validated for the
analysis of diazolidinyl urea in an experimental cream has not been demonstrated for the analysisof this compound in the marketed cosmetics. HPLC, CZE and NMR studies have indicated thatboth imidazolidinyl urea and diazolidinyl urea may be a mixture of isomers. It appears that it is
impossible, with present state of knowledge, to develop a method(s) for the analysis of
imidazolidinyl urea and diazolidinyl urea as parent compounds in cosmetic products.
Sodium hydroxymethyl glycinate and benzylhemiformal, present in a cosmetic product,
theoretically should release all of the formaldehyde they contain. Thus, an analytical method(s)for the identification and quantification of these preservatives in cosmetic products is notnecessary.

7

SCCNFP/586/02, final
Evaluation and opinion on : determination of certain formaldehyde releasers in cosmetic products_____________________________________________________________________________________________The maximum authorised concentrations of imidazolidinyl urea, diazolidinyl urea, sodiumhydroxymethyl glycinate and benzylhemiformal in cosmetic products are based on the Opinionsof SCC/SCCNFP. Only in the case of benzylhemiformal, SCCNFP considered complete
decomposition of the preservative releasing total formaldehyde of the compound as freeformaldehyde. The decomposition product of Sodium hydroxymethyl glycinate, e.g. sodium
glycinate cannot be considered harmful. As regards the decomposition products ofimidazolidinyl urea and diazolidinyl urea, it may be considered that they were present in the test
solutions used in the experiments performed for the elucidation of toxicity of the parent
compounds. And thus, the safety profile of the decomposition products has been elucidated
together with that of parent compounds.
A possibility to overcome the unavailability of the analytical method(s) for these 4 formaldehyde
releasers may be to determine total formaldehyde content in a product and relate this amount tothe amount of the formaldehyde releaser. But this approach can only be used when theformaldehyde releaser in a product can be unequivocally identified, and when it is guaranteedthat there is only one source of formaldehyde in the product. Both of these conditions appear to
be impractical.

7.

OpinionSCCNFP has reviewed the previous SCC/SCCNFP Opinions on imidazolidinyl urea,
diazolidinyl urea, sodium hydroxymethyl glycinate and benzylhemiformal (entries 27, 46, 51and
55 respectively in Annex VI of Cosmetic Directive) and analytical problems associated with thedetermination of these compounds. The SCCNFP does not recommend a general amendment ofthese entries, so that the maximum allowed concentration could be expressed as a concentrationof total formaldehyde.
In the absence of analytical methods to check the compliance of cosmetic products with respect
to the content of the four preservatives, consumer safety may be ascertained by adequately
assessing the presence of formaldehyde in the cosmetic products; the total content offormaldehyde in the finished cosmetic product must not exceed 0.2%

8.

References

1.
2.

Commission Directive 90/207/EEC. Off. J. Eur. Commun. L108, 92 (1990)
Engelhardt H and Klinkner R (1990) Determination of free formaldehyde in the presenceof donators in cosmetics by HPLC and post-column derivation. Chromatographia 20, 559566.
Michalakis GM and Barry EF (1994) Determination of imidurea in cosmetic products bycapillary zone electrophoresis and miscellar electrokinetic chromatography. J. Soc.
Cosmet. Chem. 45, 194-202
Schouten A, Van Osenbruggen WA, De Vries AJ and Verhoef A (1996) Methods ofdetermination of preservatives mentioned in the EC Council Directive regarding cosmetic
products. 122. Progress report on the “ Selection and development of methods for thedetermination of Germall 115, Germall II and hexetidine in cosmetic products”. TNO
report V.96.619, TNO Nutrition and Food Research Institute, Netherlands

3.
4.

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SCCNFP/586/02, final
Evaluation and opinion on : determination of certain formaldehyde releasers in cosmetic products_____________________________________________________________________________________________

5.
6.

7.

Williams RO, Mahaguna V and Sriwongjanya M (1997) Determination of diazolidinylurea in a topical cream by high performance liquid chromatography. J. chromatogr. B 696,
303-306.
Gevers EchTh (1994) Methods of determination of preservatives mentioned in the EC
Council Directive regarding cosmetic products. 114 determination of sodiumhydroxymethyl aminoacetate in cosmetic products. TNO report V.94.479, TNO Nutrition
and Food Research Institute, Netherland
EU Commission, Proposal Future Research DG Enterprise. Document 00/Enter/COS/18

Annex
Free formaldehyde equivalent to maximum authorised concentration of certain
formaldehyde releasers
Nr.

CompoundMaximum authorised
concentration
0.15%

VI,1,55 Benzylhemiformal,(containing 1.5 moleformaldehyde)
VI,1,51 Sodium
0.5%
Hydroxymethylglycinate
VI,1,46 Diazolidinyl Urea
0.5%
VI,1,27 Imidazolidinyl Urea
0.6%

Formaldehyde
equivalent
0.044%
0.118%
0.215%
0.186%

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