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Nitrosamine

1=Organic compounds of the form >N–N=O

Structure of the nitrosamino group

Nitrosamines (or more formally N-nitrosamines) are organic compounds produced by industrial processes. The chemical structure is , where R is usually an alkyl group. Nitrosamines have a nitroso group () that are "probable human carcinogens", 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

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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.

Dietary exposure

Medication impurities

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, duloxetine, and others.

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 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	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

Additional reading

References

California Water Boards, State Water Resources Control Board, "Nitrosamines", 09 December 2024
(21 January 2021). "An Organic Chemist's Guide to ''N''-Nitrosamines: Their Structure, Reactivity, and Role as Contaminants". The Journal of Organic Chemistry.
World Health Organization, Medical product alert, Note on Nitrosamine impurities, "Update on Nitrosamine impurities", 20 November 2019
(1990). "Cytochrome P450IIe1: Roles in Nitrosamine Metabolism and Mechanisms of Regulation". Drug Metabolism Reviews.
(2006). "Nitrosamine and related food intake and gastric and oesophageal cancer risk: A systematic review of the epidemiological evidence". World Journal of Gastroenterology.
(1991). "Carcinogenic ''N''-Nitrosamines in the Diet: Occurrence, Formation, Mechanisms and Carcinogenic Potential". Mutation Research/Genetic Toxicology.
(1979). "''N''-Nitrosamines".
Vogel, A. I.. (1962). "Practical Organic Chemistry". Impression.
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Williams, D. L. H.. (1988). "Nitrosation". [[Cambridge University Press.
{{March6th
(1975). "Kristallstruktur des ''N''-Nitrosodimethylamins". Chemische Berichte.
(1998). "Biochemistry, Biology, and Carcinogenicity of Tobacco-Specific ''N''-Nitrosamines". Chemical Research in Toxicology.
(2013-01-08). "Advances in Agronomy". Academic Press.
(August 21, 2001). "Informational Update Research on Tobacco Specific Nitrosamines (TSNAs) in Oral Snuff and a Request to Tobacco Manufacturers to Voluntarily Set Tolerance Limits For TSNAs in Oral Snuff".
(24 February 2021). "Control of Nitrosamine Impurities in Human Drugs".
"Control of Nitrosamine Impurities in Human Drugs - Guidance for Industry".
(4 April 2022). "Nitrosamine impurities in medications: Guidance".
(15 March 2024). "Nitrosamine impurities in medications: Established acceptable intake limits".
Hecht, 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 pages

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nitrogen-cycle functional-groups nitrosamines garde-manger carcinogens iarc-group-1-carcinogens

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