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| Names | |||
|---|---|---|---|
| Preferred IUPAC name N,N-Dimethylnitrous amide | |||
| Identifiers | |||
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3D model (JSmol) | |||
| ChEBI | |||
| ChEMBL | |||
| ChemSpider |
| ||
| ECHA InfoCard | 100.000.500 | ||
| EC Number |
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| KEGG |
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| MeSH | Dimethylnitrosamine | ||
| RTECS number |
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| UNII | |||
| UN number | 3382 | ||
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| 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) | |||
| logP | −0.496 | ||
| Vapor pressure | 700 Pa (at 20 °C) | ||
Refractive index (nD) | 1.437 | ||
| Thermochemistry | |||
Std enthalpy of combustion(ΔcH⦵298) | 1.65 MJ/mol | ||
| Hazards | |||
| Occupational safety and health (OHS/OSH): | |||
Main hazards | Known carcinogen,[1] extremely toxic | ||
| GHS labelling: | |||
   | |||
| Danger | |||
| H300,H330,H350,H372,H411 | |||
| P260,P273,P284,P301+P310,P310 | |||
| NFPA 704 (fire diamond) | |||
| Flash point | 61.0 °C (141.8 °F; 334.1 K) | ||
| Lethal dose or concentration (LD, LC): | |||
LD50 (median dose) | 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 theirstandard state (at 25 °C [77 °F], 100 kPa). | |||
N-Nitrosodimethylamine (NDMA), also known asdimethylnitrosamine (DMN), is anorganic compound with the formula (CH3)2NNO. It is one of the simplest members of a large class ofnitrosamines. It is a volatile yellow oil. NDMA has attracted wide attention as being highlyhepatotoxic and a knowncarcinogen in laboratory animals.[2]
Of more general concern, NDMA can be produced bywater treatment bychlorination orchloramination. The question is the level at which it is produced. In the U.S. state of California, the allowable level is 10 nanograms/liter.[3] The Canadian province of Ontario set the standard at 9 ng/L. The potential problem is greater for recycled water that can containdimethylamine.[4] Further, NDMA can form or be leached during treatment of water byanion exchangeresins.[5]
Contamination of drinking water with NDMA is of particular concern due to the minute concentrations at which it is harmful and the difficulty in detecting it at these concentrations.
Relatively high levels ofUV radiation in the 200 to 260 nm range breaks the N–N bond. Thus, it can be used to degrade NDMA. Additionally,reverse osmosis removes approximately 50% of NDMA.[6]
NDMA is found at low levels in numerous items of human consumption, including cured meat, fish, beer, as well as during use of tobacco products and the inhalation of tobacco smoke.[5][7]
Unsymmetrical dimethylhydrazine, a rocket fuel, is a highly effective precursor to NDMA:
Groundwater near rocket launch sites often has high levels of NDMA.[6]
TheUnited States Environmental Protection Agency (EPA) determined that the maximal admissible concentration of NDMA indrinking water is 7 ng/L.[8] As of July 2020, the EPA has not set a regulatory maximal contaminant level (MCL) for drinking water. At high doses, it is a "potenthepatotoxin that can causefibrosis of theliver" in rats.[9] The induction of liver tumors in rats after chronic exposure to low doses is well documented.[10] Its toxic effects on humans are inferred from animal experiments, but not well-established experimentally.
It is classified as anextremely 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.[11]
In July 2020, theCommittee for Medicinal Products for Human Use (CHMP) of theEuropean 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.[12][13] 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.[12] Generally, people should not be exposed to a lifetime risk of cancer exceeding 1 in 100,000 from nitrosamines in their medicines.[12] 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.[12] A subsequent CHMP review ofsartan blood-pressure medicines in 2019, led to new requirements for the manufacture of sartans, while its 2020 review of ranitidine recommended an EU-wide suspension of ranitidine medicines.[12]
The C2N2O core of NDMA is planar, as established byX-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.[14]
NDMA forms from a variety of dimethylamine-containing compounds, e.g. hydrolysis ofdimethylformamide. Dimethylamine is susceptible to oxidation tounsymmetrical dimethylhydrazine, which air-oxidizes to NDMA.[15]
In the laboratory, NDMA can be synthesised by the reaction ofnitrous acid withdimethylamine:
The mechanism of its carcinogenicity involves metabolic activation steps resulting in the formation ofmethyldiazonium, analkylating agent.[2]
Several incidents in which NDMA was used intentionally to 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.[16][17] That same year,Steven Roy Harper spiked lemonade with NDMA at the Johnson family home inOmaha,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.[18]
In the 2013Fudan poisoning case, Huang Yang, a postgraduate medical student atFudan University, was the victim of a poisoning inShanghai,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.[19]
In 2018, NDMA was used in an attempted poisoning atQueen's University in Kingston, Canada.
In 2018, and then again in 2019, various brands ofvalsartan were recalled because of contamination with NDMA.[20][21] In 2019,ranitidine was recalled around the world due to contamination with NDMA.[22] In December 2019, the FDA began testing samples of the diabetes drugmetformin for NDMA.[23] The FDA announcement followed a recall of three versions of metformin in Singapore, and the European Medicines Agency's request that manufacturers test for NDMA.[24][25]
In September 2019,N-nitrosodimethylamine was discovered inranitidine products from a number of manufacturers, resulting in recalls.[26][27][28][29][30][31] In April 2020, ranitidine was withdrawn from the United States market, suspended in the European Union, and suspended in Australia due to concerns about NDMA.[28][32][33][34][35]
In August 2021, a class 2 medicines recall was issued for a batch of metformin hydrochloride 500 mg/5ml Oral Solution from Rosemont Pharmaceuticals Limited, which was first distributed in December 2020, due to the identification of higher than acceptable levels of NDMA.[36]
A study has shown that NDMA perturbs arginine biosynthesis, mitochondrial genome maintenance, and DNA damage repair in yeast.[37]
This article incorporates text from this source, which is in thepublic domain. This article incorporates text from this source, which is in thepublic domain.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 thepublic domain. This article incorporates text from this source, which is in thepublic domain.
