- General information enquiries
- Call 00 800 6 7 8 9 10 11
- E-mail your questions
Directorate-General for Health and Food Safety
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.
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.
