Review Article

Research on Nitrosamines in Cosmetics: A Review

Yingjie Zhu¹, Yuan Xia¹, Zhanghao Chen² and Liangliang Lin¹*

¹Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, China

²Guangdong Institute for Drug Control, NMPA Key Laboratory for Safety Risk Assessment of Cosmetics, China

Submission: December 19, 2022;Published: January 05, 2023

*Corresponding author: Liangliang Lin, Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, China

How to cite this article: Yingjie Z, Yuan X, Zhanghao C, Liangliang L. Research on Nitrosamines in Cosmetics: A Review. JOJ Dermatol & Cosmet. 2023; 5(2): 555656. DOI: 10.19080/JOJDC.2023.05.555656

Abstract

As a kind of toxic and strongly carcinogenic substance, nitrosamines are likely to be present in the raw materials of cosmetics, or during the preparation, storage, and transportation processes. This would result in the potential hazard to the health of consumers. This paper carries out the study on nitrosamines. Firstly, the physical and chemical properties of nitrosamines as well as their types in cosmetics are introduced. Then, the formation reasons and possible reaction mechanisms of nitrosamines in cosmetics are summarized. Next, various detection methods of nitrosamines are concluded and compared. The legislation, norms, and standards for nitrosamines in cosmetics around the world are listed. Finally, the development trends of detection, supervision, and management for nitrosoamines in cosmetics are predicted.

Keywords: Nitrosamines; Cosmetics; Toxic substances; Nitrosamine detection; Cosmetic hazards

Introduction

Economic development and the pursuit of beauty make the cosmetics market vigorous, and cosmetics are essential for the peoples in their daily life. Due to the strong purchasing power, China has become the second largest market of cosmetics in the world. It has been reported by National Bureau of Statistics that the total retail sales of cosmetics of China in 2021 reached 402.6 billion yuan, increasing by 18.41% in comparison with 340 billion yuan in 2020. Hence, the average annual rate is higher than that of other countries. Moreover, the number of licensed cosmetics manufacturers is 5,400, and the number of products with legal licenses reaches up to 1.6 million. Hence, the cosmetics have a wider develop space in China [1]. As is well known, cosmetics are a kind of mixture produced according to scientific formulations. During the processes of production, processing, storage and transportation, some harmful substances could be generated or brought into, thus posing a threat to the consumers’ health. Among them, nitrosamines are the common hazards with obvious carcinogenicity, as well as easily produced by the reaction between precursor secondary amine and nitrite. Simultaneously, the reaction can progress well under the natural conditions or in the human and animal bodies. They can enter our bodies via the respiratory tract, digestive tract, or skin. Moreover, not only can the long-term low dose cause cancer, but also a shock of higher dose can directly result in carcinogenesis [2]. Therefore, the nitrosamines harm has undoubtedly been paid close attention to. Moreover, it is of great research significance and application value to know the sources, influence factors, formation mechanisms and detection methods of nitrosamines in cosmetics to effectively inhibit the formation of nitrosamines.

Nitrosamines Profile

The nitrosamines have significant carcinogenicity, which is related to their chemical structures, physical and chemical properties, tissues and organs, metabolic process, etc. However, until now, the specific mechanism has still not been clear. The existing findings suggest that the increase of electron-withdrawing ability of hydrogen at α-C (R¹ and R²) attached to ammonia nitrogen decreases the electron cloud and density of α-C and N-nitroso-group and increases the number of static charges. This would make the hydrogens on the carbon atom more reactive, and easily oxidized, decomposed, isomerized to alkyldiazohydroxides in vivo. As a highly active carcinogen, this compound can block DNA replication and induce gene mutation [3]. Furthermore, some researchers have found that the carcinogenicity of nitrosamines might be related to the free radical activity. For example, Hirata et al. have shown that the N-nitrosamine compounds in the tobacco could induce the generation of reactive oxygen species, stimulate the Wnt signal path, and thus resulting in the lung cancer.

All the countries issue the standards for the contents of nitrosamines in cosmetics. However, there are still many cosmetics with a lower content of nitrosamines, and then they can’t be analyzed and detected at the present stage. Furthermore, due to the complex raw materials and limited detection means, the generation condition and formation mechanism are still unknown, which further increases the difficulty to effectively inhibit the content of nitrosamines in cosmetics. In this paper, the types of nitrosamines, generation causes, reaction mechanisms, detection means, regulations and standards in various countries are summarized, so as to provide the references for relevant manufacturers, consumers, supervisors, and researchers.

Types and Sources of Nitrosamines

Types of nitrosamines

There are many types of nitrosamines in cosmetics (Figure 1), of which the most common one is N-Nitrosodiethanolamine (NDELA). In 1997, the Food and Drug Administration (FDA) first reported that the detection rate of NDELA in cosmetics was up to 31% with the content of 1~130000 μg/kg [4,5]. In 1986, 2-isoctyl-4-(N-nitroso-N-methylamino) benzoic acid (NMPABAO) was detected in the sunscreens, as well as a familiar type of nitrosamine. Notably, with more attention to the cancer risk of nitrosamines and the progress of detection technology, more than 300 types of nitrosamines have been detected in cosmetics. The frequently detected ones are listed in Table 1.

Sources of Nitrosamines

Raw materials: Since nitrosamines were detected in cosmetics in 1977 for the first time, most researchers regard the raw materials as an import source of the nitrosamines. From 1980 to 1984, FDA detected 1 mg/kg of nitrosamines in about 30% cosmetics [25]. Joo et al. [26] detected NDELA in multiple raw materials of cosmetics (triethanolamine, trimethylamine, coconut fatty acid diethanolamide, fatty acid chain alkanolamide, and triethanolamine-dodecyl sulfate) with high-performance Liquid Chromatography-tandem Mass Spectrometry (HPLCMS- MS) method. Guo Huifang [27] analyzed the several typical nitrogen-containing surfactants in cosmetics, such as coconolic acid monoethanolamide (CMEA), cocoanut fatty acid n, n-diethanolamide (CDEA), and castor oil acylthreonine sodium, simultaneously, established an efficient and simple method to detect the NDELA in nitrogen-containing surfactants.

In 2014, the detection limit and quantification limit of volatile nitrosamines in ten types of cosmetics were determined in China [28]. However, the complex raw materials of cosmetics could result in the increase of the types of hazards introducing the nitrosamines. Cocoamidopropyl betaine (CAB) is common in cosmetics, and widely used in washing products such as shower gel, shampoo, and hand sanitizer. It has a quaternary ammonium group with strong electronic induction, which makes the carboxylic acid group attached to the quaternary nitrogen atom always present in a salt-like group, and thus showing amphoteric ions characteristics. Hence, CAB is a kind of better surfactant [29]. The synthesis of CAB includes three steps, that is, synthesis of cocamidopropyl dimethylamine, neutralization between chloroacetic acid aqueous solution and alkali, and synthesis of coir amide propyl betaine, as shown in Figure 2.

Both the raw materials for synthetizing CAB and intermediate products have the tertiary amine structure. Moreover, once the tertiary amine structure contacts with the nitrosation reagents such as nitrite and nitrate, the nitrification reaction would occur. Therefore, there would possibly form a tiny amount of nitrosamines during the synthesis process of CAB, resulting in the potential risk of nitrosamines in the products.

Preparation process: In addition to the raw materials, the preparation process of cosmetics is also an important source of nitrosamines. Under the effect of nitrosification reagents, the precursors (primary amine, secondary amine, and tertiary amine) can form nitrosamine compounds. Among them, the secondary amine is more prone to nitrosation reaction [30]. At present, there are many nitrosation reagents, i.e., HNO₂, NO, NO₂, N₂O₃, N₂O₄, NOX (X=Cl and Br), various nitrates, and nitrites. If the cosmetics contain diethanol amine DEA), triethanolamine (TEA), nitrosation agent, and fatty acid alkanolamide as the emulsifier or pH modifier, there would form nitrosoamines under certain conditions [31]. As such, the formation mechanism relates with pH. Under acidic conditions, HNO₂ can directly react with amines, or two HNO₂ molecules can react with each other to form N₂O₃ and H₂O. Then, N₂O₃ forms nitrosamine after one-step reaction. For example, the nitrosation reaction of N, N-dimethylaniline can progress under the acidic condition, and this reaction can be divided into two steps (Figure 3). Firstly, the nitrous acid forms the nitrosyl cation in an acidic environment. Subsequently, the nitrosyl cation attacks the nitrogen atoms as the electrophile, thus forming the nitroso cation intermediate of nitrogen. Then, according to the different classifications of amine, the substituents attached to nitrogen atom with positive charge of intermediate are different. When the hydrogen atoms are attached to nitrogen atoms of primary amine and secondary amine, they can be directly removed to form nitrosamine. On the contrary, there are no hydrogen atoms attached to the nitrogen atoms, so failing in dehydrogenation. However, the dimethylamino is an active group, and the nitroso cation can form C-Nitroso compound through the electrophilic substitution on the para-position of the benzene ring [31].

Nitrosamines are relatively stable under non-acidic conditions, whereas the resonant structure resulting from conjugated effect between lone pair electrons and nitroso could make the H attached to α-C easily oxidized. Moreover, as the electron withdrawing group is attached toα-C, the electron cloud densities of α-C and N-NO would be decreased. Simultaneously, the H attached to α-C would be more active and easily be oxidized. In 2002, CHOI et al. [32] have reported that NDMA could be formed in the waste water with chloramine, and simultaneously, they proposed the reaction mechanism (Figure 4). Notably, DMA can react with NO^2- to form NDMA under the catalysis effect of formaldehyde, trichloroacetaldehyde, and carbonyl compound such as acetaldehyde, acetone and trifluoroacetaldehyde [33]. Bromonitropropanol is the common preservative and fungicide in cosmetics with the content of 0.04%~0.1%. When pH is 8~12, Br-, NO^2- and formaldehyde could be released from bromonitropropanol after decomposition, and then catalyzes their reactions with DMA to form NDMA (Figure 5). Hence, our law requires that the content of bromonitropropanol should not exceed 0.1%.

Storage process: Generally, the preservatives and stabilizers are added to cosmetics for the long-term storage and good performance. The surfactant, viscosifier, pH regulator, emulsifier and antibacterial preservative with secondary amine can all catalyze the potential nitrosation reaction at temperatures above 35°C or at acidic pH [34]. In addition, the storage vat with the nitrite for anti-corrosion and some packaging materials with residual toxic solvent might result in the nitrosamines formation. The packaging materials of cosmetics are mainly based on plastic, and simultaneously, N, N-DMA is widely applied in the packaging materials due to high thermal stability, low corrosion, and low toxicity. Thus, the DMA in the plastic containers could volatilize and shift to the contents, resulting in polluting the cosmetics [35].

Detection Methods of Nistrosamines

It is greatly difficult to detect the nitrosoamines in cosmetics, attributed to more types, lower content, greater difference in the properties of nitrosamines, and possible false positive disturbance of new nitrosamine formed in the analysis process [36]. At present, the frequently-used detection methods include gas chromatography (GC), liquid chromatography (LC), gas chromatography-mass spectrography (GC-MS), UVVIS spectrophotometry, thin layer chromatography, micellar electrokinetic capillary chromatography (MECC), polarography, surface-enhanced Raman scattering method (SERS), etc. Furthermore, for the detection of volatile nitrosamines in water substrate, nitrogen phosphorous detection (NPD) and nitrogen chemiluminescence detection (NCD) methods are used as the mass spectra (MS) for cost reduction.

GC is a chromatographic separation and analysis method using gas as mobile phase, suitable for qualitative and quantitative analysis for volatile organic compounds. In principle, the gas sample is brought to the chromatographic column by carrier gas. The forces between stationary phase and sample components in column are different, so the components can be separated from each other due to their different outflow time from column. Similarly, the LC takes liquid as the mobile phase, and the components in mixture are separated in dependence on the difference in the affinity of each component for two phases. This method is characterized by high efficiency, high sensitivity, and simple operation.

As can be seen by comparison, the GC-MS has not only the separation capability of GC but also the highly sensitive identification capability of MS. GC-MS/MS is used to detect 14 nitrosamines in 44 types of drugs such as sartan and ranitidine. Compared with HPLC, LC-MS has a higher column efficiency and separation speed, withstands higher column pressure and faster flow rate. Thus, LC-MS has the higher peak capacity and separation effect. Small volatile nitrosamines such as NPMA has been detected in active pharmaceutical ingredient (API) by Vogel et al. [37] using LC-MS/MS (Figure 6). (b) Ion chromatograms of all the nitrosamines detected after adding 50 ng/ml aqueous reference solution. (c) Ion chromatograms of quantitative nitrosamines extracted with their own LOD value.

The thermal analysis technology (TEA) is usually used with GC or LC together. The nitrosamines mixture is firstly separated, and then the N-NO bond breaks after through the TEA cracking chamber. The released nitroso (NO) is oxidized by ozone to electronically excited NO₂. Accordingly, the decayed radiation intensity is in proportion to the concentration of NO [38]. Because of some advantages such as high sensitivity, high precision and rapid detection, so this method has been widely applied in many fields. The methods mentioned above can qualitatively and quantitatively detect the unknown samples, but they still have some disadvantages of tedious preprocessing process, high detection cost, long detection period, expensive instruments, etc.

In recent years, Luo et al. used Raman spectra detection based on the surface enhanced Raman scattering (SERS) of precious metals to detect the trace nitrite ions in aqueous solution of nitrosation (Figure 7). This technology can make the signal intensity increase by 10⁸~10¹² times, and effectively improve the sensitivity of traditional Raman detection in trace analysis. Moreover, it has advantages such as ease of operation, strong selectivity, freedom from interference of water molecules, and fingerprint spectrum, so with a better detection effect for illegal additives in cosmetics, i.e., nitrosoamines, Rhodamine B, hydroquinone, and crystal violet. Representative detection methods of nitrosamine are listed in Table 2.

Furthermore, there has been a difficulty in directly analyzing the target due to more types of cosmetics and complex components. It is necessary to select an appropriate pretreatment method according to the target to be quantified. The target should be detected after the enrichment of purified samples. At present, the pretreatment technologies of common cosmetic samples include the digestion method, liquid-liquid extraction method, solid phase extraction method, microextraction techonology, microwaveassisted extraction method, ultrasonic-assisted extraction method, etc. [41] added cerium dioxide into porous silicon dioxide (SBA-15). The nitrosoamines are extracted from cosmetic samples with solid-phase microextraction, and meanwhile, the stirring rod is used to improve the adsorption efficiency. This solid-phase microextraction-GC-MS method is very sensitive and efficient in the detection of trace nitrosamines in cosmetics with the stirring rod support base on Ce-SBA-15 development. Miralles et al. [17] detected seven kinds of trace prohibited N-nitrosoamines in cosmetics using reversed phase dispersionliquid- phase microextraction-LC. Accordingly, the results show that the enrichment factor is up to 65, detection limit is 1.8～50 ng/g, with a better repeatability (RSD < 9.8%). More importantly, this method is used to detect different samples of cosmetics, and then obtaining the equal relative recovery (80~113%).

Norms and Standards related to Nitrosoamines in Cosmetics

The GB/T 29669-2013 published in 2014 stipulates the detection methods, detection limits and quantitative limits of ten types of nitrosamines such as NDMA in cosmetics. The industry development, technology progress and cosmetics supervision demand prompt the State Food and Drug Administration to revise the Cosmetic Safety Code, and then the cosmetic safety technical specification (2015) was put forward. A total of 944 kinds of nitrosamines are listed in the prohibited substances table, such as N-nitroso dimethylamine, N-nitroso dipropylamine, and N-Nitrosodiethanolamine. In addition, the standards of the nitrosamines contents in cosmetics are introduced at abroad. For example, the International Organization for Standardization has issued the detection and analysis method for NDELA in cosmetics and proposed the Technical Guide Document. British Standards Institution has published the standard detection method of NDELA in cosmetics. Likewise, France has issued the standard determination method of NDELA in cosmetics. Table 3 lists the norms and standards related to nitrosamines in cosmetics.

Conclusion

With constant improvement of cosmetics performance, their components are more and more complex. Because of longterm contact with skin, the strongly carcinogenic substance in cosmetics such as nitrosoamines could result in greatly potential hazard to the human body. Although some nitrosamine compounds are prohibited in cosmetics in national standards, their coverage and completeness can’t meet the safety supervision demand of cosmetics. Moreover, the nitrosamines detection could be interfered by matrix components of cosmetics, and the existing detection means are insufficient. Therefore, more effort should be devoted to establishing rapid, large-scale, sensitive, accurate and low-cost detection methods for nitrosamines, as well as improving relevant standards and specifications in future. Simultaneously, much attention to the cosmetics’ safety and intensification of industrial supervision would make the studies on nitrosamines contamination in cosmetics develop toward the norms of cosmetics.

Acknowledgments

We would like to acknowledge the financial support from NMPA Key Laboratory of Cosmetic Safety Assessment, Guangdong Institute for Drug Control (KF2021014); Key Laboratory of Technological Innovation of Gungdong Medical Products Administration (2021ZDZ03); Key Laboratory of Green Cleaning Technology & Detergent of Zhejiang Province (Q202204), China Postdoctoral Science Foundation (2021M690068), and Central University Basic Research Fund of China (JUSRP221018, JUSPR622038).

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