N-Nitrosodimethylamine

N-Nitrosodimethylamine (NDMA), also known as dimethylnitrosamine (DMN), is an organic compound with the formula (CH3)2NNO. It is one of the simplest members of a large class of N-nitrosamines. It is a volatile yellow oil. NDMA has attracted wide attention as being highly hepatotoxic and a known carcinogen in lab animals.[2]

Not to be confused with MDMA, NMDA, or N-Nitrosodiethylamine.
N-Nitrosodimethylamine
Names
Preferred IUPAC name
N,N-Dimethylnitrous amide
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.000.500
EC Number
  • 200-549-8
KEGG
MeSH Dimethylnitrosamine
RTECS number
  • IQ0525000
UNII
UN number 3382
Properties
C2H6N2O
Molar mass 74.083 g·mol−1
Appearance Yellow oil[1]
Odor faint, characteristic[1]
Density 1.005 g/mL
Boiling point 153.1 °C; 307.5 °F; 426.2 K
290 mg/ml (at 20 °C)
log P −0.496
Vapor pressure 700 Pa (at 20 °C)
1.437
Thermochemistry
1.65 MJ/mol
Hazards
Main hazards Known carcinogen,[1] extremely toxic
GHS pictograms
GHS Signal word Danger
H301, H330, H350, H372, H411
P260, P273, P284, P301+310, P310
NFPA 704 (fire diamond)
Flammability code 2: Must be moderately heated or exposed to relatively high ambient temperature before ignition can occur. Flash point between 38 and 93 °C (100 and 200 °F). E.g. diesel fuelHealth code 4: Very short exposure could cause death or major residual injury. E.g. VX gasReactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
2
4
0
Flash point 61.0 °C (141.8 °F; 334.1 K)
Lethal dose or concentration (LD, LC):
37.0 mg/kg (oral, rat)
NIOSH (US health exposure limits):
PEL (Permissible)
 OSHA-Regulated Carcinogen[1]
REL (Recommended)
 Ca[1]
IDLH (Immediate danger)
 Ca [N.D.][1]
Related compounds
Related compounds
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YN ?)
Infobox references

Occurrence

Drinking water

Of more general concern, NDMA can be produced by water treatment by chlorination or chloramination. The question is the level at which it is produced. In the U.S. state of California, the allowable level is 10 nanograms/liter. The Canadian province of Ontario set the standard at 9 ng/L. The potential problem is greater for recycled water that can contain dimethylamine.[3] Further, NDMA can form or be leached during treatment of water by anion exchange resins.[4]

NDMA's contamination of drinking water is of particular concern due to the minute concentrations at which it is harmful, the difficulty in detecting it at these concentrations, and to the difficulty in removing it from drinking water. It does not readily biodegrade, adsorb, or volatilize. As such, it cannot be removed by activated carbon and travels easily through soils. Relatively high levels of UV radiation in the 200 to 260 nm range breaks the N–N bond and can thus be used to degrade NDMA. Additionally, reverse osmosis removes approximately 50% of NDMA.[5]

Cured meat

NDMA is found at low levels in numerous items of human consumption, including cured meat, fish, beer, and tobacco smoke.[4][6] The pathway for NDMA formation involves nitrous acid produced from sodium nitrite, which is used to cure meat. NDMA arises by the combination of nitrous acid and dimethylamine derived from the degradation of dietary protein in the lower gut.

Rocket fuel

Unsymmetrical dimethylhydrazine, a rocket fuel, is a highly effective precursor to NDMA:

(CH3)2NNH2 + 2 O → (CH3)2NNO + H2O

Groundwater near rocket launch sites often has high levels of NDMA.[5]

Regulation
See also: Ranitidine § impurities, Valsartan § recalls, Angiotensin II receptor blocker § recalls, and Metformin § impurities

United States

The United States Environmental Protection Agency (EPA) determined that the maximal admissible concentration of NDMA in drinking water is 7 ng/L.[7] The EPA has not yet set a regulatory maximal contaminant level (MCL) for drinking water. At high doses, it is a "potent hepatotoxin that can cause fibrosis of the liver" in rats.[8] The induction of liver tumors in rats after chronic exposure to low doses is well documented.[9] Its toxic effects on humans are inferred from animal experiments but not well-established experimentally.

It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002) and is subject to strict reporting requirements by facilities that produce, store, or use it in significant quantities.[10]

It was found as an impurity in valsartan and other angiotensin II receptor blockers (ARBs) used to treat high blood pressure and heart failure. The U.S. Food and Drug Administration (FDA) confirmed levels of NDMA and/or N-Nitrosodiethylamine (NDEA) exceeding the interim acceptable intake limits, and the affected medicines are being recalled as of November 2019.[11]

The FDA is also requesting makers of antacids that include ranitidine, such as Zantac, to recall their products because unacceptable levels of NDMA form in ranitidine over time, especially when these antacids are stored where it is warmer than room temperature.[12][13]

The FDA has further requested that the makers of metformin extended release (ER) recall their products due to unacceptable levels of NDMA.[14]

European Union

In July 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued an opinion requiring companies to take measures to limit the presence of nitrosamines in human medicines as far as possible and to ensure levels of these impurities do not exceed set limits.[15][16] Nitrosamines are classified as probable human carcinogens (substances that could cause cancer). The limits for nitrosamines in medicines have been set using internationally agreed standards (ICH M7(R1)) based on lifetime exposure.[15] People should generally not be exposed to a lifetime risk of cancer exceeding 1 in 100,000 from nitrosamines in their medicines.[15] EU regulators first became aware of nitrosamines in medicines in mid-2018, and took regulatory actions, including recalling medicines and stopping the use of active substances from certain manufacturers.[15] A subsequent CHMP review of sartan blood pressure medicines in 2019, led to new requirements for the manufacture of sartans, while its review of ranitidine recommended in 2020, an EU-wide suspension of ranitidine medicines.[15]

Chemistry

The C2N2O core of NDMA is planar, as established by X-ray crystallography. The central nitrogen is bound to two methyl groups and the NO group with bond angles of 120°. The N-N and N-O distances are 1.32 and 1.26 Å, respectively.[17]

NDMA forms from a variety of dimethylamine-containing compounds, e.g. hydrolysis of dimethylformamide. Dimethylamine is susceptible to oxidation to unsymmetrical dimethylhydrazine, which air-oxidizes to NDMA.[18]

In the laboratory, NDMA can be synthesised by the reaction of nitrous acid with dimethylamine:

HONO + (CH3)2NH → (CH3)2NNO + H2O

The mechanism of its carcinogenicity involves metabolic activation steps resulting in the formation of methyl diazonium, an alkylating agent.[2]

Metabolic activation of NDMA relevant to its cancer-causation.[2]

As a poison
See also: Forensic Files (season 3): "Without a Trace" for Steven Roy Harper case

Several incidents in which NDMA was used to intentionally poison another person have garnered media attention. In 1978, a teacher in Ulm, Germany, was sentenced to life in prison for trying to murder his wife by poisoning jam with NDMA and feeding it to her. Both the wife and the teacher later died from liver failure.[19][20] Also in 1978, Steven Roy Harper spiked lemonade with NDMA at the Johnson family home in Omaha, Nebraska. The incident resulted in the deaths of 30-year-old Duane Johnson and 11-month-old Chad Shelton. For his crime, Harper was sentenced to death, but committed suicide in prison before his execution could be carried out.[21]

In the 2013 Fudan poisoning case, Huang Yang, a postgraduate medical student at Fudan University, was the victim of a poisoning in Shanghai, China. Huang was poisoned by his roommate Lin Senhao, who had placed NDMA into the water cooler in their dormitory. Lin claimed that he only did this as an April Fool's joke. He received a death sentence, and was executed in 2015.[22] In 2018, NDMA was used in an attempted poisoning at Queen's University in Kingston, Canada.[23]

Drug contamination
See also: Ranitidine § impurities, Valsartan § recalls, Angiotensin II receptor blocker § recalls, and Metformin § impurities

In 2018, and then again in late 2019, various brands of valsartan were recalled because of contamination with N-nitrosodimethylamine.[24] In 2019, ranitidine was recalled across the world due to contamination with NDMA.[25] In December 2019, the FDA began testing samples of the diabetes drug metformin for the carcinogen N-nitrosodimethylamine (NDMA). The FDA's announcement followed a recall of three versions of metformin in Singapore, and the European Medicines Agency's request that manufacturers test for NDMA.[26][27]

In September 2019, the carcinogen N-nitrosodimethylamine (NDMA) was discovered in ranitidine products from a number of manufacturers, resulting in recalls.[28][12][13][29][30][31] In April 2020, it was withdrawn from the United States market and suspended in the European Union due to these concerns.[13][32][33]

References
  1. NIOSH Pocket Guide to Chemical Hazards. "#0461". National Institute for Occupational Safety and Health (NIOSH).
  2. Tricker, A.R.; Preussmann, R. (1991). "Carcinogenic N-nitrosamines in the Diet: Occurrence, Formation, Mechanisms and Carcinogenic Potential". Mutation Research/Genetic Toxicology. 259 (3–4): 277–289. doi:10.1016/0165-1218(91)90123-4. PMID 2017213.
  3. David L. Sedlak, Rula A. Deeb, Elisabeth L. Hawley, William A. Mitch, Timothy D. Durbin, Sam Mowbray and Steve Carr (2005). "Sources and Fate of Nitrosodimethylamine and Its Precursors in Municipal Wastewater Treatment Plants". Water Environment Research. 77 (1, Emerging Micropollutants in Treatment Systems (Jan.–Feb. 2005)): 32–39. doi:10.2175/106143005X41591. JSTOR 25045835. PMID 15765933.CS1 maint: uses authors parameter (link)
  4. Najm, I.; Trussell, R. R. (2001). "NDMA Formation in Water and Wastewater". Journal American Water Works Association. 93 (2): 92–99. doi:10.1002/j.1551-8833.2001.tb09129.x. ISSN 0003-150X.
  5. Mitch, W. A.; Sharp, J. O.; Trussell, R. R.; Valentine, R. L.; Alvarez-Cohen, L.; Sedlak, D. L. (2003). "N-Nitrosodimethylamine (NDMA) as a Drinking Water Contaminant: A Review". Environmental Engineering Science. 20 (5): 389–404. CiteSeerX 10.1.1.184.204. doi:10.1089/109287503768335896.
  6. Hecht, Stephen S. (1998). "Biochemistry, Biology, and Carcinogenicity of Tobacco-Specific N-Nitrosamines†". Chemical Research in Toxicology. 11 (6): 559–603. doi:10.1021/tx980005y. PMID 9625726.
  7. Andrzejewski, P.; Kasprzyk-Hordern, B.; Nawrocki, J. (2005). "The hazard of N-nitrosodimethylamine (NDMA) formation during water disinfection with strong oxidants". Desalination. 176 (1–3): 37–45. doi:10.1016/j.desal.2004.11.009.
  8. George, J.; Rao, K. R.; Stern, R.; Chandrakasan, G. (2001). "Dimethylnitrosamine-induced liver injury in rats: the early deposition of collagen". Toxicology. 156 (2–3): 129–138. doi:10.1016/S0300-483X(00)00352-8. PMID 11164615.
  9. Peto, R.; Gray, R.; Brantom, P.; Grasso, P. (1991). "Dose and Time Relationships for Tumor Induction in the Liver and Esophagus of 4080 Inbred Rats by Chronic Ingestion of N-Nitrosodiethylamine or N-Nitrosodimethylamine" (PDF). Cancer Research. 51 (23 Part 2): 6452–6469. PMID 1933907.
  10. "40 C.F.R.: Appendix A to Part 355—The List of Extremely Hazardous Substances and Their Threshold Planning Quantities" (PDF) (July 1, 2008 ed.). Government Printing Office. Archived from the original (PDF) on February 25, 2012. Retrieved October 29, 2011. Cite journal requires |journal= (help)
  11. "FDA Updates and Press Announcements on Angiotensin II Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan)". Drug Safety and Availability. U.S. Food and Drug Administration (FDA). November 7, 2019. Retrieved November 15, 2019.
  12. "Statement alerting patients and health care professionals of NDMA found in samples of ranitidine". U.S. Food and Drug Administration (FDA). 13 September 2019. Archived from the original on 26 September 2019. Retrieved 26 September 2019. This article incorporates text from this source, which is in the public domain.
  13. "Questions and Answers: NDMA impurities in ranitidine (commonly known as Zantac)". U.S. Food and Drug Administration (FDA). 11 October 2019. Archived from the original on 24 October 2019. Retrieved 23 October 2019. This article incorporates text from this source, which is in the public domain.
  14. "FDA Updates and Press Announcements on NDMA in Metformin". U.S. Food and Drug Administration (FDA). 2 July 2020. Retrieved 11 July 2020.
  15. "EMA finalises opinion on presence of nitrosamines in medicines". European Medicines Agency (EMA) (Press release). 9 July 2020. Retrieved 11 July 2020. This article incorporates text from this source, which is in the public domain.
  16. "Nitrosamine impurities". European Medicines Agency (EMA). Retrieved 11 July 2020.
  17. Krebs, Bernt; Mandt, Jürgen (1975). "Kristallstruktur des N-Nitrosodimethylamins". Chemische Berichte. 108 (4): 1130–1137. doi:10.1002/cber.19751080419.
  18. Mitch, William A.; Sedlak, David L. (2002). "Formation of N-Nitrosodimethylamine (NDMA) from Dimethylamine during Chlorination". Environmental Science & Technology. 36 (4): 588–595. Bibcode:2002EnST...36..588M. doi:10.1021/es010684q. PMID 11878371.
  19. Ein teuflischer Plan: Tod aus dem Marmeladeglas (in German).
  20. Karsten Strey: "Die Welt der Gifte", Lehmanns, 2. Edition p. 193 (in German).
  21. Roueche, Betron (January 25, 1982). "Annals of Medicine – The Prognosis for this Patient is Horrible". The New Yorker: 57–71.
  22. "15 days log in hospital". Archived from the original on 2014-01-09. Retrieved 2013-04-30.
  23. https://www.thewhig.com/news/local-news/man-admits-poisoning-fellow-researcher-in-kingston?
  24. EMA Staff (September 17, 2018). "EMA reviewing medicines containing valsartan from Zhejiang Huahai following detection of an impurity: some being recalled across the EU". European Medicines Agency. Retrieved December 3, 2019.
  25. BBC Staff (September 29, 2019). "Sale of heartburn drug suspended over cancer fears". BBC News. Retrieved December 3, 2019.
  26. Lauerman, John (December 4, 2019). "Diabetes Drugs Latest to Be Targeted for Carcinogen Scrutiny". Bloomberg Business. Retrieved January 5, 2020.
  27. Koenig, D. (December 6, 2019). "FDA Investigating Metformin for Possible Carcinogen". Medscape. Retrieved December 14, 2019.
  28. "Health Canada assessing NDMA in ranitidine". Health Canada. 13 September 2019. Archived from the original on 26 September 2019. Retrieved 26 September 2019.
  29. "EMA to provide guidance on avoiding nitrosamines in human medicines". European Medicines Agency (EMA) (Press release). 13 September 2019. Retrieved 19 September 2019. This article incorporates text from this source, which is in the public domain.
  30. "EMA to review ranitidine medicines following detection of NDMA". European Medicines Agency (EMA) (Press release). 13 September 2019. Retrieved 19 September 2019.
  31. "FDA updates and press announcements on NDMA in Zantac (ranitidine)". U.S. Food and Drug Administration (FDA). 28 October 2019. Archived from the original on 29 October 2019. Retrieved 28 October 2019. FDA observed the testing method used by a third-party laboratory uses higher temperatures. The higher temperatures generated very high levels of NDMA from ranitidine products because of the test procedure. FDA published the method for testing angiotensin II receptor blockers (ARBs) for nitrosamine impurities. That method is not suitable for testing ranitidine because heating the sample generates NDMA.
    FDA recommends using an LC-HRMS testing protocol to test samples of ranitidine. FDA's LC-HRMS testing method does not use elevated temperatures and has shown the presence of much lower levels of NDMA in ranitidine medicines than reported by the third-party laboratory. International regulators using similar LC-MS testing methods have also shown the presence of low levels of NDMA in ranitidine samples.     This article incorporates text from this source, which is in the public domain.
  32. "FDA Requests Removal of All Ranitidine Products (Zantac) from the Market". U.S. Food and Drug Administration (FDA) (Press release). 1 April 2020. Retrieved 1 April 2020. This article incorporates text from this source, which is in the public domain.
  33. "Suspension of ranitidine medicines in the EU". European Medicines Agency (Press release). 30 April 2020. Retrieved 2 June 2020. This article incorporates text from this source, which is in the public domain.
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