Nitrosamines in Cosmetics, Toiletries and Personal Care Products.

Date: July 2003


Prepared by John O'Donnell

Summary

The cosmetic industry was first made aware of the presence of nitrosamines in March 1977 with a presentation of a paper on the subject at an American Chemical Society meeting. Since that reported finding of trace levels of N-nitrosodiethanolamines, (NDELA), in commercial cosmetic products, the cosmetic industry has worked to define the problem, assess its magnitude and minimise NDELA in cosmetic products.

NDELA is a member of the class of compounds known as N-Nitrosamines. Some nitrosamines have been shown in laboratory tests with animals to be carcinogens when administered orally, although the toxicity when administered topically is still to be determined.

It is important to realise that nitrosamines can be present in cosmetic products as a result of impurities in raw materials, reaction during manufacture, as a result of storage, or by absorption of nitrosamine precursors from the environment, including packaging.

Nitrosamines are the reaction products of amines and nitrites or oxides of nitrogen, and that once formed, are very difficult to destroy.

The ASCC recommends that cosmetic product formulators carefully check all formulations containing alkyl-amines or alkanol-amines or derivatives to ensure that nitrosating agents are not also included in the formulation. Manufacturers or raw materials derived from/containing alkyl-amines or alkanol-amines should also have available information on nitrosamine levels in the raw material as well as the potential for nitrosamine formation in cosmetic formulations.

 Alkyl-amines or alkanol-amines derived raw materials represent a useful class of cosmetic ingredients and provided appropriate steps are taken by formulators and manufacturers these ingredients can continue to be used safely in cosmetic products.

Background

The cosmetic industry was first made aware of the presence of nitrosamines in March 1977 with a presentation of a paper on the subject at an American Chemical Society meeting. Since that reported finding of trace levels of N-nitrosodiethanolamines, (NDELA), in commercial cosmetic products, the cosmetic industry has worked to define the problem, assess it’s magnitude and minimise NDELA in cosmetic products. In addition to NDELA, nitrosodialkylamines may also be formed from alkyl amines.

The results of this work was called into question because the method of analysis, Gas Liquid Chromatography/Thermal Energy Analysis (GLC/TEA), because the presence of nitromusks would give false positive results for nitrosamines. Since this time further analysis and basic research has provided clear evidence that secondary alkanolamines and alkylamines are precursors of nitrosamine formation. This is in contrast to primary and tertiary alkanolamines/alkyl amines which are much less likely to form nitrosamines.

NDELA is a member of the class of compounds known as N-Nitrosamines. Some nitrosamines have been shown in laboratory tests with animals to be carcinogens when administered orally, although the toxicity when administered topically is still to be determined.

Many ingredients used in the formulation of Cosmetic and Personal care products contain nitrogen and thus there is a potential to form Nitrosamines. As previously stated the potential for nitrosamine formation is structurally related with secondary amines having the most potential to form nitrosamines.

Nitrosamines are the reaction products of amines and nitrites or oxides of nitrogen, and that once formed, are very difficult to destroy.

Formation 

There are 2 types of organic nitroso compounds, one in which the nitroso radical is bonded to the carbon (C-Nitroso) and the other in which it is bonded to the nitrogen (N-Nitroso):

They are readily formed by the reaction of amines with nitrites or nitrogen oxides.

Generally, C-Nitroso compounds have low toxicity and are weak carcinogens, probably because they isomerise or dimerise.

Primary amines can be nitrosated, but tend to be unstable because of rapid isomerisation:

Secondary amines are the most potent to form stable N-Nitrosamines:

They are nitrosated in aqueous environments and the reaction is most complete at pH 3.0 – 3.4, but trace amounts do occur at higher pH’s of 5 – 8.

Tertiary amines also form the corresponding N-Nitrosamine by reaction with dinitrogen trioxide:

All of the necessary raw materials for the production of N-Nitrosamines are abundant in nature (see Table 1)

Table 1: Naturally occurring nitrosating materials

Nitrosating Material

Source

Amines

Fish, cereal, tobacco, dyes and other organic materials.

Nitrates

Fertilisers; present in spinach.

Nitrites

Used as food additives for preservation of cured meats. Also found in human saliva.

Nitrogen Oxides

Abundant in the atmosphere.

Nitrosamines

Produced by normal metabolic processes.

Usually a mixture of nitrosating species is involved in the reaction depending on the acidity of the medium and, in emulsions, 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, H2O+NO. Thus, nitrosation by nitrate in aqueous solutions is enhanced in acidic pH’s having a maximum value around pH 3.4. In the presence of catalysts such as chloral or an aldehyde (formaldehyde), nitrosation proceeds readily up to a pH of 11.

Dinitrogen trioxide, N2O3, and dinitrogen tetroxide, N2O4, are reported to be rapid nitrosating agents basic solutions, actually nitrosating secondary amines more rapidly than acidified nitrites.

Much of the early work on nitrosamines focused on mono-, di- and trialkanolamines mainly due to the wide use of triethanolamine in formulations. Triethanolamine can contain up to 15% diethanolamine and the United States Pharmacopeia contains a monograph for Triethanolamine 85%, in which the remaining 15% is diethanolamine. In the course of these investigations, secondary alkyl amines were not extensively reviewed.

A review of alkyl amines showed that some nitrosodialkylamines were more carcinogenic than nitrosodialkanolamines:

Table 2: Summary of Carcinogenicity

Nitrosamine

StBM

GMMC

UDnS

MT

N-nitroso-diethanolamine

+/-

n.d.

n.d.

-

N-nitroso-methylamine

+

+

+

+

N-nitroso-diethylamine

+

+

n.d.

N-nitroso-diisopropanolamine

+

+

-

n.d


StBM = standard bacterial mutation

GMMC = gene mutation in mammalian cells

UDnS = unscheduled DNA synthesis

MT = Micronucleus test

While the data indicates nitrosamines formed from alkyl amines are potentially more harmful the reaction kinetics for nitrosamine formation must also be considered. Nitrosation reaction rates can vary by varying orders of magnitude and is strongly dependant on the basicity of the amine. Alkyl amines have the potential to form nitrosamines but reaction kinetics prevents nitrosamine formation and so raw materials and products containing alkyl amines are not considered to be at risk.

Prevention

There are various substances that compete with the amine for the nitrosating species, therefore, preventing the formation of N-Nitrosamine. Substances acting as inhibitors are:

  • Antioxidants
  • Chelating agents

The mechanism is by reducing the NO+ ion to NO. NO was thought to be inert with respect to nitrosation of amines so that nitrosamine formation would be avoided by addition of antioxidants such as alpha-tocopherol, ascorbic acid etc. The poor results of all attempts made in this direction have indicated that the NO formed is quickly re-oxidised to NO2 .

Use of anti-oxidants or chelating agent must be proven for individual systems.

Nitrosamines can be degraded by exposure to UV light, or reaction with urea or guanidine.

Nitrosamines in Cosmetic Products

"The risk of introducing contaminants into a product is always a concern in cosmetic manufacture, whether they are introduced through contaminated raw ingredients or form during the manufacturing process. Nitrosamines and dioxane are among those contaminants that may form during the manufacturing process and raise safety issues. Research also has raised safety questions about diethanolamine (DEA) and related ingredients that may contain residual levels of this substance.

Nitrosamines. Many nitrosamines have been determined to cause cancer in laboratory animals. They also have been shown to penetrate the skin."

FDA expressed its concern about the contamination of cosmetics with nitrosamines in a notice published in the Federal Register of April 10, 1979 (44 FR 21365). It stated that cosmetics containing nitrosamines may be considered adulterated and subject to enforcement action.

Cosmetics containing as ingredients amines or amino derivatives, particularly diethanolamine, or ingredients that are derived from diethanolamine or possibly contain diethanolamine as a contaminant, may form nitrosamines if they also contain an ingredient that acts as a nitrosating agent, such as 2-bromo-2-nitropropane-1,3-diol (Bronopol), 5-bromo-5-nitro-1,3-dioxane or tris(hydroxymethyl)nitromethane (Tris Nitro), or if they are contaminated with a nitrosating agent, e.g., sodium nitrite. Amines and their derivatives are mostly present in creams, cream lotions, hair shampoos, and cream hair conditioners. Nitrosamines are avoidable by proper formulation: by not using amines or amino derivatives in combination with a nitrosating agent and by testing the product under use conditions to make sure that nitrosamines do not form under customary conditions of use.”

Secondary amines are the most susceptible to nitrosamine formation, however for nitrosamines to form a nitrosating agent must be present. In cosmetic products, surfactants & emulsifiers which are ammonia or amine salts are common are potential sources of nitrosamines. Raw materials based on secondary amines, eg diethanolamine, have the highest potential for nitrosamine formation.

Anionic surfactants neutralised with ammonia, monoethanolamine, diethanolamine and triethanolamine do not show detectable levels of nitrosamines.

Derivatives of tertiary amines, such as alkyl betaines, alkyl amido betaines, alkyl trimethyl ammonium methosulfates, cocoamphoacetates and quaternary ammonium compounds, likewise, do not show detectable levels of nitrosamines.

Confirmation of the presence of nitrosamines has been found in amine oxides. However, modifications to raw manufacturing processes, by minimising the presence of secondary amines can eliminate the formation of nitrosamines. Nevertheless, amine oxides are potential precursors and final formulations as well as the raw material should be checked for the presence of nitrosamines.

Confirmation of the presence of nitrosamines has been found in fatty acid alkanolamides, in particular Cocamide DEA. The class of cosmetics based on dialkyl- and dialkanolamines and their salts that are of most concern.

Detection

Specialised analytical equipment is required for analysis of N-Nitrosamines and particular care has to be taken that N-Nitrosamines are not formed as a result of sample preparation and analysis. N-Nitrosamines can be quantitatively detected down to less than 10 ppb. Analysis is typically based on Gas Liquid Chromatography/Thermal Energy Analysis.

Summary

Table 3: Summary of Potential for Nitrosamine formation

Chemical
Potential
Comment
Secondary dialkanolamines
High
Prohibited for use in Europe
Fatty acid dialkanolamides
Moderate
Restricted use in Europe
Monoalkanolamines
Moderate
Restricted use in Europe
Trialkanolamines
Moderate
Restricted use in Europe
Dialkanolamine salts
Moderate
Proposed to be prohibited in Europe
Dialkylamine salts
Moderate
Proposed to be prohibited in Europe
Secondary alkylamines
High
Proposed to be prohibited in Europe
Alkyldimethyl-N-oxides
Low
No restrictions
Monoalkanolamine salts
Low
Proposed restrictions in Europe
Trialkanolamine salts
Low
Proposed restrictions in Europe
The proposed restrictions relate to a maximum secondary amine content of 0.5%, maximum nitrosamine concentration of 50ppb and storage in nitrite free containers.

Recommendation

The ASCC recommends:

  1. In line with the EU Cosmetic Directive 76/768/EEC, Annex III, the ASCC recommends:
  2. Secondary dialkanolamines, such as diethanolamine and diisopropanolamine not be used.
  3. Fatty acid dialkanolamides (Cocamide DEA) should not contain more than 5% m/m free dialkanolamine in the raw material and that the level of free dialkanolamine should not exceed 0.5% in the finished formulation.
  4. Mono- and trialkanolamines should:
    - have a purity of 99% minimum
    - contain a maximum of 0.5% dialkylanolamine
    - contain less than 50ppb N-nitrosodialkanolamine.
    - Alkylamines and alkanolamines raw materials and formulated products should not be preserved with formaldehyde
  5. Amine and Ammonia derivatives must not be combined with nitrosating agents.
  6. Cosmetics, toiletries and personal care products containing amine oxides should include analysis  for nitrosamines in product stability testing and the level of nitrosamines should not exceed 50ppb.
  7. Suitable inhibitors are recommended to counteract nitrosamine, and the suitability of any inhibitor must be proven in every single case.
  8. Raw materials and final formulations should be stored in nitrite free metal or plastic containers.

References

FDA Website: “Prohibited ingredients and related Safety Issues”

FDA Website: “Diethanolamine and Cosmetic Products”

Dunhill, RD “Nitrosamines”
Internal Albright & Wilson Document

Scientific Committee for Cosmetic Products and Non-food Products intended for Consumers – 17th plenary meeting of 12 June 2001.
EU Cosmetic Directive 76/768/EEC, ANNEX II
EU Cosmetic Directive 76/768/EEC, ANNEX III