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Names | |||
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Preferred IUPAC name N,N-Dimethylnitrous amide | |||
Identifiers | |||
3D model (JSmol) | |||
ChEBI | |||
ChEMBL | |||
ChemSpider | |||
ECHA InfoCard | 100.000.500 | ||
EC Number |
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KEGG | |||
MeSH | Dimethylnitrosamine | ||
PubChem CID | |||
RTECS number |
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UNII | |||
UN number | 3382 | ||
CompTox Dashboard (EPA) | |||
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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) | |||
log P | −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: | |||
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Danger | |||
H301, 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 their standard state (at 25 °C [77 °F], 100 kPa). |
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 nitrosamines. It is a volatile yellow oil. NDMA has attracted wide attention as being highly hepatotoxic and a known carcinogen in laboratory animals. [2]
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. [3] The Canadian province of Ontario set the standard at 9 ng/L. The potential problem is greater for recycled water that can contain dimethylamine. [4] Further, NDMA can form or be leached during treatment of water by anion exchange resins. [5]
Contamination of drinking water with NDMA 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.[ citation needed ] 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. 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]
The United States Environmental Protection Agency (EPA) determined that the maximal admissible concentration of NDMA in drinking 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 "potent hepatotoxin that can cause fibrosis of the liver" 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 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. [11]
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. [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 of sartan 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 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. [14]
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. [15]
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 diazomethane, an alkylating 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]
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. [18]
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. [19]
In 2018, NDMA was used in an attempted poisoning at Queen's University in Kingston, Canada. [20]
In 2018, and then again in 2019, various brands of valsartan were recalled because of contamination with NDMA. [21] [22] In 2019, ranitidine was recalled around the world due to contamination with NDMA. [23] In December 2019, the FDA began testing samples of the diabetes drug metformin for NDMA. [24] 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. [25] [26]
In September 2019, N-nitrosodimethylamine was discovered in ranitidine products from a number of manufacturers, resulting in recalls. [27] [28] [29] [30] [31] [32] 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. [29] [33] [34] [35] [36]
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. [37]
A study has shown that NDMA perturbs arginine biosynthesis, mitochondrial genome maintenance, and DNA damage repair in yeast. [38]
Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid prescription. In many countries, OTC drugs are selected by a regulatory agency to ensure that they contain ingredients that are safe and effective when used without a physician's care. OTC drugs are usually regulated according to their active pharmaceutical ingredient (API) and strengths of final products.
Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. It is sometimes used as an off-label adjunct to lessen the risk of metabolic syndrome in people who take antipsychotics. Metformin is not associated with weight gain and is taken by mouth.
Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists, also known as angiotensin receptor blockers, angiotensin II receptor antagonists, or AT1 receptor antagonists, are a group of pharmaceuticals that bind to and inhibit the angiotensin II receptor type 1 (AT1) and thereby block the arteriolar contraction and sodium retention effects of renin–angiotensin system.
Irbesartan, sold under the brand name Aprovel among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth. Versions are available as the combination irbesartan/hydrochlorothiazide.
In organic chemistry, nitrosamines are organic compounds with the chemical structure R2N−N=O, where R is usually an alkyl group. They feature a nitroso group bonded to a deprotonated amine. Most nitrosamines are carcinogenic in nonhuman animals. 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".
Ranitidine, previously sold under the brand name Zantac among others, was a medication used to decrease stomach acid production. It was commonly used in treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndrome. It was given either by mouth, injection into a muscle, or injection into a vein.
Valsartan, sold under the brand name Diovan among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It belongs to a class of medications referred to as angiotensin II receptor blockers (ARBs). It is a reasonable initial treatment for high blood pressure. It is taken by mouth.
Rifapentine, sold under the brand name Priftin, is an antibiotic used in the treatment of tuberculosis. In active tuberculosis it is used together with other antituberculosis medications. In latent tuberculosis it is typically used with isoniazid. It is taken by mouth.
Torrent Pharmaceuticals Ltd is an Indian multinational pharmaceutical company, part of the Torrent Group and headquartered in Ahmedabad. It was promoted by U. N. Mehta, initially as Trinity Laboratories Ltd, and was later renamed Torrent Pharmaceuticals Ltd.
Dapagliflozin, sold under the brand names Farxiga (US) and Forxiga (EU) among others, is a medication used to treat type 2 diabetes. It is also used to treat adults with heart failure and chronic kidney disease. It reversibly inhibits sodium-glucose co-transporter 2 (SGLT-2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion.
N-Nitrosodiethylamine (NDEA) is an organic compound with the formula Et2NNO (Et = C2H5). A member of the nitrosamines, it is a light-sensitive, volatile, clear yellow oil that is soluble in water, lipids, and other organic solvents. It has an amine or aromatic odor. It is used as gasoline and lubricant additive, antioxidant, and stabilizer for industry materials. When heated to decomposition, N-nitrosodiethylamine emits toxic fumes of nitrogen oxides. N-Nitrosodiethylamine affects DNA integrity, probably by alkylation, and is used in experimental research to induce liver tumorigenesis. It is carcinogenic and mutagenic. NDEA has also been found to perturb amino acid biosynthesis including arginine, as well as DNA damage repair and mitochondrial genome maintenance in yeast.
Pasireotide, sold under the brand name Signifor, is an orphan drug approved in the United States and the European Union for the treatment of Cushing's disease in patients who fail or are ineligible for surgical therapy. It was developed by Novartis. Pasireotide is a somatostatin analog with a 40-fold increased affinity to somatostatin receptor 5 compared to other somatostatin analogs.
Aurobindo Pharma Limited is an Indian multinational pharmaceutical manufacturing company headquartered in HITEC City, Hyderabad. The company manufactures generic pharmaceuticals and active pharmaceutical ingredients. The company's area of activity includes six major therapeutic and product areas: antibiotics, anti-retrovirals, cardiovascular products, central nervous system products, gastroenterologicals, and anti-allergics. The company markets these products in over 125 countries. Its marketing partners include AstraZeneca and Pfizer.
Ertugliflozin, sold under the brand name Steglatro, is a medication for the treatment of type 2 diabetes.
Vildagliptin/metformin, sold under the brand name Eucreas among others, is a fixed-dose combination anti-diabetic medication for the treatment of type 2 diabetes. It was approved for use in the European Union in November 2007, and the approval was updated in 2008. It combines 50 mg vildagliptin with either 500, 850, or 1000 mg metformin.
Empagliflozin/metformin, sold under the brand name Synjardy among others, is a fixed-dose combination anti-diabetic medication used to treat type 2 diabetes. It contains empagliflozin and metformin hydrochloride. It is taken by mouth.
Dapagliflozin/saxagliptin/metformin, sold under the brand name Qternmet XR among others, is a fixed-dose combination anti-diabetic medication used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. It is a combination of dapagliflozin, saxagliptin, and metformin. It is taken by mouth. The drug is marketed by AstraZeneca.
Dapagliflozin/saxagliptin, sold under the brand name Qtern, is a fixed-dose combination anti-diabetic medication used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. It is a combination of dapagliflozin and saxagliptin. It is taken by mouth.
Canagliflozin/metformin, sold under the brand name Vokanamet among others, is a fixed-dose combination anti-diabetic medication used for the treatment of type 2 diabetes. It is used in combination with diet and exercise. It is taken by mouth.
Pioglitazone/glimepiride, sold under the brand name Duetact among others, is a fixed-dose combination anti-diabetic medication for the treatment of type 2 diabetes. It contains the thiazolidinedione pioglitazone and the sulfonylurea glimepiride. It is taken by mouth.
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.