Nitrosamine

File:Nitrosamine Formulae V.1.svg

Structure of the nitrosamino group

Nitrosamines (or more formally N-nitrosamines) are organic compounds produced by industrial processes.<ref>California Water Boards, State Water Resources Control Board, "Nitrosamines", 09 December 2024</ref>Template:Improve The chemical structure is Template:Chem2, where R is usually an alkyl group.<ref>Template:Cite journal</ref> Nitrosamines have a nitroso group (Template:Chem2) that are "probable human carcinogens",<ref>World Health Organization, Medical product alert, Note on Nitrosamine impurities, "Update on Nitrosamine impurities", 20 November 2019</ref> bonded to a deprotonated amine. Most nitrosamines are carcinogenic in animals.<ref>Template:Cite journal</ref> 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".<ref>Template:Cite journal</ref>

Chemistry

File:Ndma activ.svg

Metabolic activation of the nitrosamine NDMA converts it to the alkylating agent diazomethane<ref name=Tricker>Template:Cite journal</ref>

The organic chemistry of nitrosamines is well developed with regard to their syntheses, their structures, and their reactions.<ref>Template:Cite book</ref><ref>Template:Cite book</ref> They usually are produced by the reaction of nitrous acid (Template:Chem2) and secondary amines, although other nitrosyl sources (e.g. Template:Chem, Template:Chem, RONO) have the same effect:<ref>Template:March6th</ref>

Template:Chem2

The nitrous acid usually arises from protonation of a nitrite. This synthesis method is relevant to the generation of nitrosamines under some biological conditions.Template:Sfn The nitrosation is also reversible, particularly in acidic solutions of nucleophiles.<ref>Template:Cite book</ref> Aryl nitrosamines rearrange to give a para-nitroso aryl amine in the Fischer-Hepp rearrangement.<ref>Template:March6th</ref>

With regards to structure, the Template:Chem2 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,<ref>Template:Cite journal</ref> 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.<ref name=Hecht>Template:Cite journal</ref><ref name=Tricker/>

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.<ref name="nitrocancer">Template:Cite book</ref>

Tobacco exposure

A common way ordinary consumers are exposed to nitrosamines is through tobacco use and cigarette smoke.<ref name=Hecht/> 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).<ref>Template:Cite journal</ref>

Dietary exposure

Template:Transcluded sectionNitrosamine formation during digestion

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Health Canada published guidance about nitrosamine impurities in medications<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and a list of established acceptable intake limits of nitrosamine impurities in medications.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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<ref>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</ref>	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

See also

• Hydrazines derived from these nitrosamines, e.g. UDMH, are also carcinogenic.
• Possible health hazards of pickled vegetables
• Tobacco-specific nitrosamines

Additional reading

• Template:Cite journal
• Template:Cite book

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 Template:Webarchive