N-Nitrosodimethylamine


N-Nitrosodimethylamine, also known as dimethylnitrosamine, is an organic compound with the formula 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.

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. Further, NDMA can form or be leached during treatment of water by anion exchange resins.
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.

Cured meat

NDMA is found at low levels in numerous items of human consumption, including cured meat, fish, beer, and tobacco smoke. 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

, a rocket fuel, is a highly effective precursor to NDMA:
Groundwater near rocket launch sites often has high levels of NDMA.

Regulation

United States

The United States Environmental Protection Agency determined that the maximal admissible concentration of NDMA in drinking water is 7 ng/L. The EPA has not yet set a regulatory maximal contaminant level for drinking water. At high doses, it is a "potent hepatotoxin that can cause fibrosis of the liver" in rats. The induction of liver tumors in rats after chronic exposure to low doses is well documented. 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 and is subject to strict reporting requirements by facilities that produce, store, or use it in significant quantities.
It was found as an impurity in valsartan and other angiotensin II receptor blockers used to treat high blood pressure and heart failure. The U.S. Food and Drug Administration confirmed levels of NDMA and/or N-Nitrosodiethylamine exceeding the interim acceptable intake limits, and the affected medicines are being recalled as of November 2019.
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.
The FDA has further requested that the makers of metformin recall their products due to unacceptable levels of NDMA.

European Union

In July 2020, the Committee for Medicinal Products for Human Use of the European Medicines Agency 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. Nitrosamines are classified as probable human carcinogens. The limits for nitrosamines in medicines have been set using internationally agreed standards based on lifetime exposure. People should generally not be exposed to a lifetime risk of cancer exceeding 1 in 100,000 from nitrosamines in their medicines. 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. 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.

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.
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.
In the laboratory, NDMA can be synthesised by the reaction of nitrous acid with dimethylamine:
The mechanism of its carcinogenicity involves metabolic activation steps resulting in the formation of methyl diazonium, an alkylating agent.

As a poison

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. 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.
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. In 2018, NDMA was used in an attempted poisoning at Queen's University in Kingston, Canada.

Drug contamination

In 2018, and then again in late 2019, various brands of valsartan were recalled because of contamination with N-nitrosodimethylamine. In 2019, ranitidine was recalled across the world due to contamination with NDMA. In December 2019, the FDA began testing samples of the diabetes drug metformin for the carcinogen N-nitrosodimethylamine. 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.
In September 2019, the carcinogen N-nitrosodimethylamine was discovered in ranitidine products from a number of manufacturers, resulting in recalls. In April 2020, it was withdrawn from the United States market and suspended in the European Union due to these concerns.