In organic chemistry, nitrosamines (or more formally N-nitrosamines) are organic compounds with the chemical structure, where R is usually an alkyl group.[1] They feature a nitroso group bonded to a deprotonated amine. Most nitrosamines are carcinogenic in nonhuman animals.[2] A 2006 systematic review supports a "positive association between nitrite and nitrosamine intake and gastric cancer, between meat and processed meat intake and gastric cancer and oesophageal cancer, and between preserved fish, vegetable and smoked food intake and gastric cancer, but is not conclusive".[3]
The organic chemistry of nitrosamines is well developed with regard to their syntheses, their structures, and their reactions.[4] [5] They usually are produced by the reaction of nitrous acid and secondary amines, although other nitrosyl sources (e.g.,, RONO) have the same effect:
The nitrous acid usually arises from protonation of a nitrite. This synthesis method is relevant to the generation of nitrosamines under some biological conditions.June 2023. The nitrosation is also partially reversible; aryl nitrosamines rearrange to give a para-nitroso aryl amine in the Fischer-Hepp rearrangement.
With regards to structure, the core of nitrosamines is planar, as established by X-ray crystallography. The N-N and N-O distances are 132 and 126 pm, respectively in dimethylnitrosamine,[6] one of the simplest members of a large class of N-nitrosamines
Nitrosamines are not directly carcinogenic. Metabolic activation is required to convert them to the alkylating agents that modify bases in DNA, inducing mutations. The specific alkylating agents vary with the nitrosamine, but all are proposed to feature alkyldiazonium centers.[7]
In 1956, two British scientists, John Barnes and Peter Magee, reported that a simple member of the large class of N-nitrosamines, dimethylnitrosamine, produced liver tumours in rats. Subsequent studies showed that approximately 90% of the 300 nitrosamines tested were carcinogenic in a wide variety of animals.[8]
A common way ordinary consumers are exposed to nitrosamines is through tobacco use and cigarette smoke.[7] Tobacco-specific nitrosamines also can be found in American dip snuff, chewing tobacco, and to a much lesser degree, snus (127.9 ppm for American dip snuff compared to 2.8 ppm in Swedish snuff or snus).[9]
There have been recalls for various medications due to the presence of nitrosamine impurities. There have been recalls for angiotensin II receptor blockers, ranitidine, valsartan and others.
The US Food and Drug Administration published guidance about the control of nitrosamine impurities in medicines.[10] [11] Health Canada published guidance about nitrosamine impurities in medications[12] and a list of established acceptable intake limits of nitrosamine impurities in medications.[13]
| Substance name | CAS number | Synonyms | Molecular formula | Physical appearance | Carcinogenity category | |
|---|---|---|---|---|---|---|
| N-Nitrosonornicotine | 16543-55-8 | NNN | C9H11N3O | Light yellow low-melting solid | ||
| 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone[14] | 64091-91-4 | NNK, 4′-(nitrosomethylamino)-1-(3-pyridyl)-1-butanone | C10H15N3O2 | Light yellow oil | ||
| N-Nitrosodimethylamine | 62-75-9 | Dimethylnitrosamine, N,N-dimethylnitrosamine, NDMA, DMN | C2H6N2O | Yellow liquid | EPA-B2; IARC-2A; OSHA carcinogen; TLV-A3 | |
| N-Nitrosodiethylamine | 55-18-5 | Diethylnitrosamide, diethylnitrosamine, N,N-diethylnitrosamine, N-ethyl-N-nitrosoethanamine, diethylnitrosamine, DANA, DENA, DEN, NDEA | C4H10N2O | Yellow liquid | EPA-B2; IARC-2A | |
| 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol | 76014-81-8 | NNAL | ||||
| N-Nitrosoanabasine | 37620-20-5 | NAB | C10H13N3O | Yellow Oil | IARC-3 | |
| N-Nitrosoanatabine | 71267-22-6 | NAT | C10H11N3O | Clear yellow-to-orange oil | IARC-3 |