nitrosamine

File:Ndma activ.svg converts it to the alkylating agent diazomethane{{cite journal|doi=10.1016/0165-1218(91)90123-4|pmid=2017213|title=Carcinogenic N-Nitrosamines in the Diet: Occurrence, Formation, Mechanisms and Carcinogenic Potential|journal=Mutation Research/Genetic Toxicology|volume=259|issue=3–4|pages=277–289|year=1991|last1=Tricker|first1=A.R.|last2=Preussmann|first2=R.}}]]

The organic chemistry of nitrosamines is well developed with regard to their syntheses, their structures, and their reactions.{{cite book|doi=10.1021/bk-1979-0101.ch001|chapter=The Organic Chemistry of N-Nitrosamines: A Brief Review|title=N-Nitrosamines|volume=101|pages=1–12|series=ACS Symposium Series|year=1979|last1=Anselme|first1=Jean-Pierre|isbn=0-8412-0503-5}}{{cite book|last=Vogel |first=A. I. |title=Practical Organic Chemistry |edition=3rd |publisher=Impression |date=1962 |page=1074}} They usually are produced by the reaction of nitrous acid ({{chem2|HNO2}}) and secondary amines, although other nitrosyl sources (e.g. {{chem|N|2|O|4|link=dinitrogen tetroxide}}, {{chem|N|O|Cl|link=nitrosyl chloride}}, RONO) have the same effect:{{March6th|pages=846-847}}

:{{chem2| HONO + R2NH -> R2N\-NO + H2O }}

The nitrous acid usually arises from protonation of a nitrite. This synthesis method is relevant to the generation of nitrosamines under some biological conditions.{{sfn|Williams|1988|p=142}} The nitrosation is also reversible, particularly in acidic solutions of nucleophiles.{{cite book|title=Nitrosation|first=D. L. H.|last=Williams|publisher=Cambridge University|location=Cambridge, UK|year=1988|isbn=0-521-26796-X|url=https://archive.org/details/nitrosation0000will|url-access=registration|pages=128–139}} Aryl nitrosamines rearrange to give a para-nitroso aryl amine in the Fischer-Hepp rearrangement.{{March6th|page=739}}

With regards to structure, the {{chem2|C2N2O}} 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,{{cite journal|doi=10.1002/cber.19751080419|title=Kristallstruktur des N-Nitrosodimethylamins|journal=Chemische Berichte|volume=108|issue=4|pages=1130–1137|year=1975|last1=Krebs|first1=Bernt|last2=Mandt|first2=Jürgen}} 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.{{cite journal|doi=10.1021/tx980005y|pmid=9625726|title=Biochemistry, Biology, and Carcinogenicity of Tobacco-Specific N-Nitrosamines|journal=Chemical Research in Toxicology|volume=11|issue=6|pages=559–603|year=1998|last1=Hecht|first1=Stephen S.}}

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.{{cite book|title=Advances in Agronomy|url=https://books.google.com/books?id=lMrEEB3rhV8C&pg=PA159|date=2013-01-08|publisher=Academic Press|isbn=978-0-12-407798-0|page=159}}

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).{{Cite journal|author1=Gregory N. Connolly |author2=Howard Saxner |title=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 |date=August 21, 2001 }}

{{Transcluded section|source=Nitrosamine formation during digestion}}{{:Nitrosamine formation during digestion}}

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.{{cite web | title=Control of Nitrosamine Impurities in Human Drugs | website=U.S. Food and Drug Administration (FDA) | date=24 February 2021 | url=https://www.fda.gov/regulatory-information/search-fda-guidance-documents/control-nitrosamine-impurities-human-drugs | archive-url=https://web.archive.org/web/20200901235726/https://www.fda.gov/regulatory-information/search-fda-guidance-documents/control-nitrosamine-impurities-human-drugs | url-status=dead | archive-date=September 1, 2020 }}{{Cite web| title=Control of Nitrosamine Impurities in Human Drugs - Guidance for Industry | url=https://www.fda.gov/media/141720/download | archive-url=https://web.archive.org/web/20200902011837/https://www.fda.gov/media/141720/download | archive-date=2020-09-02}} Health Canada published guidance about nitrosamine impurities in medications{{cite web | title=Nitrosamine impurities in medications: Guidance | website=Health Canada | date=4 April 2022 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/information-health-product/drugs/nitrosamine-impurities/medications-guidance.html | access-date=29 March 2024}} and a list of established acceptable intake limits of nitrosamine impurities in medications.{{cite web | title=Nitrosamine impurities in medications: Established acceptable intake limits | website=Health Canada | date=15 March 2024 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/information-health-product/drugs/nitrosamine-impurities/established-acceptable-intake-limits.html | access-date=29 March 2024}}

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

• {{cite journal |doi=10.1002/mnfr.200400050 |pmid=15672455 |title=Migration of nitrosamines from rubber products - are balloons and condoms harmful to the human health? |journal=Molecular Nutrition & Food Research |volume=49 |issue=3 |pages=235–238 |year=2005 |last1=Altkofer |first1=Werner |last2=Braune |first2=Stefan |last3=Ellendt |first3=Kathi |last4=Kettl-Grömminger |first4=Margit |last5=Steiner |first5=Gabriele}}
• {{Cite book|title=Golden Holocaust: Origins of the Cigarette Catastrophe and the Case for Abolition|last=Proctor, Robert N.|date=2012|publisher=University of California Press|isbn=9780520950436|location=Berkeley|oclc=784884555}}

{{reflist}}

• [http://lpi.oregonstate.edu/f-w00/nitrosamine.html Oregon State University, Linus Pauling Institute article on Nitrosamines and cancer, including info on history of meat laws]
• [http://pathology2.jhu.edu/pancreas Risk factors in Pancreatic Cancer] {{Webarchive|url=https://web.archive.org/web/20100612113930/http://pathology2.jhu.edu/pancreas |date=2010-06-12 }}

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Category:Nitrogen cycle

Category:Functional groups

Category:Garde manger

Category:Carcinogens

Category:IARC Group 1 carcinogens