Nitrosamine

Source: Wikipedia, the free encyclopedia.
Not to be confused with Nitroamine.
Structure of the nitrosamino group

In organic chemistry, nitrosamines (or more formally N-nitrosamines) are organic compounds with the chemical structure R2N−N=O, where R is usually an alkyl group.[1] They feature a nitroso group (NO+) 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]

Chemistry

NDMA converts it to the alkylating agent diazomethane[4]

The organic chemistry of nitrosamines is well developed with regard to their syntheses, their structures, and their reactions.

nitrosyl sources (e.g. N
2O
4, NOCl, RONO) have the same effect:[7]

HONO + R2NH → R2N-NO + H2O

The nitrous acid usually arises from protonation of a

Fischer-Hepp rearrangement.[8]

With regards to structure, the C2N2O core of nitrosamines is planar, as established by

dimethylnitrosamine,[9]
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

alkyldiazonium centers.[10][4]

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,

tumours in rats. Subsequent studies showed that approximately 90% of the 300 nitrosamines tested were carcinogenic in a wide variety of animals.[11]

Tobacco exposure

A common way ordinary consumers are exposed to nitrosamines is through tobacco use and cigarette smoke.

ppm for American dip snuff compared to 2.8 ppm in Swedish snuff or snus).[12]

Dietary exposure

This section is transcluded from Nitrosamine formation during digestion. (edit | history)

oesophageal cancer risk today.[14][15][16][17]

For example, during the 1970s, certain Norwegian farm animals began exhibiting elevated levels of liver cancer. These animals had been fed herring meal preserved with sodium nitrite. The sodium nitrite had reacted with dimethylamine in the fish and produced dimethylnitrosamine.[18]

The effects of nitroso compounds vary dramatically across the gastrointestinal tract, and with diet. Nitroso compounds present in stool do not induce nitrosamine formation, because stool has neutral

vitamin C (ascorbic acid) concentration (e.g. high-fruit diet).[21][22][23] However, when 10% of the meal is fat, the effect reverses, and ascorbic acid markedly increases nitrosamine formation.[24][25]

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 and others.

The US Food and Drug Administration published guidance about the control of nitrosamine impurities in medicines.[26][27] Health Canada published guidance about nitrosamine impurities in medications[28] and a list of established acceptable intake limits of nitrosamine impurities in medications.[29]

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[30]
 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;
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

Additional reading

  • Altkofer, Werner; Braune, Stefan; Ellendt, Kathi; Kettl-Grömminger, Margit; Steiner, Gabriele (2005). "Migration of nitrosamines from rubber products - are balloons and condoms harmful to the human health?". Molecular Nutrition & Food Research. 49 (3): 235–238.
    PMID 15672455
    .
  • Proctor, Robert N. (2012). Golden Holocaust: Origins of the Cigarette Catastrophe and the Case for Abolition. Berkeley: University of California Press.
    OCLC 784884555
    .

References

  1. PMID 33474939
    .
  2. ^ Yang, Chung S.; Yoo, Jeong-Sook H.; Ishizaki, Hiroyuki; Hong, Junyan (1990). "Cytochrome P450IIe1: Roles in Nitrosamine Metabolism and Mechanisms of Regulation". Drug Metabolism Reviews. 22 (2–3): 147–159.
    PMID 2272285
    .
  3. PMID 16865769
    .
  4. ^
    PMID 2017213
    .
  5. ISBN 0-8412-0503-5
    .
  6. ^ Vogel, A. I. (1962). Practical Organic Chemistry (3rd ed.). Impression. p. 1074.
  7. ISBN 978-0-471-72091-1
  8. ISBN 978-0-471-72091-1
  9. doi:10.1002/cber.19751080419
    .
  10. ^
    PMID 9625726
    .
  11. ISBN 978-0-12-407798-0
    .
  12. ^ Gregory N. Connolly; Howard Saxner (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". {{cite journal}}: Cite journal requires |journal= (help)
  13. PMID 22062097
    .
  14. PMID 17052997
    .
  15. S2CID 4951579
    .
  16. S2CID 13274953
    .
  17. PMID 16865769
    .
  18. ISBN 978-1-4614-1586-2
    .
  19. PMID 7285009
    .
  20. PMID 17761300
    .
  21. S2CID 26275960
    .
  22. S2CID 196379002
    .
  23. S2CID 41045030
    . Retrieved 2015-06-06. Evidence now exists that ascorbic acid is a limiting factor in nitrosation reactions in people.
  24. PMID 17785370
    .
  25. PMID 20026204
    .
  26. ^ "Control of Nitrosamine Impurities in Human Drugs". U.S. Food and Drug Administration (FDA). 24 February 2021.
  27. ^ https://www.fda.gov/media/141720/download
  28. ^ "Nitrosamine impurities in medications: Guidance". Health Canada. 4 April 2022. Retrieved 29 March 2024.
  29. ^ "Nitrosamine impurities in medications: Established acceptable intake limits". Health Canada. 15 March 2024. Retrieved 29 March 2024.
  30. ^ 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

External links

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