Nitrosamines (or more formally N-nitrosamines) are organic compounds produced by industrial processes.California Water Boards, State Water Resources Control Board, "Nitrosamines", 09 December 2024 The chemical structure is , where R is usually an alkyl group.
Nitrosamines have a nitroso group () that are "probable human carcinogens",World Health Organization, Medical product alert, Note on Nitrosamine impurities, "Update on Nitrosamine impurities", 20 November 2019 bonded to a deprotonated amine. Most nitrosamines are carcinogenic in animals. 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".
Chemistry
The organic chemistry of nitrosamines is well developed with regard to their syntheses, their structures, and their reactions. 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. The nitrosation is also reversible, particularly in acidic solutions of nucleophiles. 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, 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.
History and occurrence 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.
Tobacco exposure A common way ordinary consumers are exposed to nitrosamines is through tobacco use and cigarette smoke. 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).
Dietary exposure
Medication impurities There have been recalls for various medications due to the presence of nitrosamine impurities. Some of those medications that have been recalled include angiotensin II receptor blockers, ranitidine, valsartan, and duloxetine.
The US Food and Drug Administration published guidance about the control of nitrosamine impurities in medicines. Health Canada published guidance about nitrosamine impurities in medications and a list of established acceptable intake limits of nitrosamine impurities in medications.
Examples Substance nameCAS numberSynonymsMolecular formulaPhysical appearanceCarcinogenity categoryN-Nitrosonornicotine16543-55-8NNNC9H11N3OLight yellow low-melting solid 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanoneHecht, Steven S.; Borukhova, Anna; Carmella, Steven G. "Tobacco specific nitrosamines" Chapter 7; of "Nicotine safety and toxicity" Society for Research on Nicotine and Tobacco; 1998 - 203 pages64091-91-4NNK, 4′-(nitrosomethylamino)-1-(3-pyridyl)-1-butanoneC10H15N3O2Light yellow oilN-Nitrosodimethylamine62-75-9Dimethylnitrosamine, N,N-dimethylnitrosamine, NDMA, DMNC2H6N2OYellow liquidEPA-B2; IARC-2A; OSHA carcinogen; TLV-A3N-Nitrosodiethylamine55-18-5Diethylnitrosamide, diethylnitrosamine, N,N-diethylnitrosamine, N-ethyl-N-nitrosoethanamine, diethylnitrosamine, DANA, DENA, DEN, NDEAC4H10N2OYellow liquidEPA-B2; IARC-2A4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol76014-81-8NNALN-Nitrosoanabasine37620-20-5NABC10H13N3OYellow OilIARC-3N-Nitrosoanatabine71267-22-6NATC10H11N3OClear yellow-to-orange oilIARC-3
See also Hydrazines derived from these nitrosamines, e.g. UDMH, are also carcinogenic. Possible health hazards of pickled vegetables Tobacco-specific nitrosamines
Additional reading
References
External links Oregon State University, Linus Pauling Institute article on Nitrosamines and cancer, including info on history of meat laws Risk factors in Pancreatic Cancer