N-NITROSODIMETHYLAMINE

Description

Nitrosamines are chemicals that possess the general structure R1N(R2)-N=O. These chemicals have been used in the manufacture of rocket fuel, cosmetics, pesticides, and polymers. Research studies dating back to the 1950s have demonstrated that most nitrosamines (>90%) possess some degree of toxicity.
Of particular interest is the nitrosamine N-nitrosodimethylamine (DMN). This semi-volatile organic compound is highly toxic and is a suspected human carcinogen. At higher doses, it has been shown to be a hepatotoxin that causes liver fibrosis and cancer in several animal species. Its toxic effects were first reported by British scientists John Barnes and Peter Magee in 1956 during their screening of chemicals that were being used as solvents in the dry cleaning industry. Since then, levels of DMN have been detected in food, drinking water, soil, and air.
The consumption of contaminated food and water accounts for the majority of the exposure to DMN. Most nonoccupational exposure to DMN is a result of chemical reactions between precursors that form DMN, rather than the industrial utilization of the chemical itself. For example, after DMN was discovered in beer in Europe in the 1970s, it was shown that the direct firedrying of the malt barley used was the DMN source. Modifications to the drying procedure were able to substantially reduce the levels of DMN found in beer today. Additionally, the formation of DMN was attributed to an outbreak of liver cancers and disorders in livestock that were fed herring meal in Norway in the 1970s. Subsequent studies showed that reaction of dimethylamine (naturally occurring in fish) with nitrosating reagents derived from sodium nitrite (a widely used preservative) formed the NMD responsible for the liver toxicities. These studies caused widespread concern over the use of sodium nitrite in many foods consumed by humans. To ameliorate the formation of DMN in food caused by sodium nitrite, manufactures now add antioxidants such as ascorbic acid (vitamin C), erythorbic acid (an isomer of ascorbic acid), and a-tocopherol (vitamin E).
DMN has been found in groundwater in many states. Major sources of DMN in groundwater include rocket fuel production, and water treatment via chlorination or chloroamination of wastewater. The removal of DMN from drinking water usually involves ultraviolet treatment or reverse osmosis.

Description

N-Nitrosodimethylamine (NDMA) is a highly toxic, potentially carcinogenic liquid. It is synthesized by the reaction of dimethylamine or one of its salts with sodium or potassium nitrite.
NDMA has several industrial uses; the most common is as a precursor to the rocket fuel 1,1-dimethylhydrazine (1,1-DMH). It is found in the waste products of some industrial syntheses, including that of 1,1-DMH; in cured meat and fish; and in chlorinated nitrogen-rich wastewater.
NDMA’s high solubility in water and other solvents has led to its use in intentional poisonings that date back to 1973. In the most recent occurrence (2018), a graduate student at Queen’s University (Kingston, ON) dissolved NDMA in ethanol and added it to the food of a fellow student.
The victim experienced several unpleasant symptoms (e.g., diarrhea and vomiting); but unlike most NDMA victims, he survived. He says that he will always live in fear of developing cancer from the poisoning.

Chemical properties

yellow liquid

Chemical properties

N-Nitrosodimethylamine is a yellow oily liquid. Faint, characteristic odor.

Physical properties

Yellow, oily liquid with a faint, characteristic odor

The Uses of N-NITROSODIMETHYLAMINE

N-Nitrosodimethylamine is a highly toxic semi-volatile organic compound and a suspected human carcinogen. It induces liver tumors in rats after chronic exposure to low doses (1,2). Drinking water contaminant candidate list 3 (CCL 3) compound as per United States Environmental Protection Agency (EPA). Environmental contaminants; Food contaminants.NDMA and NDEA were found as an impurity in generic versions of valsartan, losartan and irbesartan.

The Uses of N-NITROSODIMETHYLAMINE

A highly toxic semi-volatile organic compound and a suspected human carcinogen. It induces liver tumors in rats after chronic exposure to low doses.

The Uses of N-NITROSODIMETHYLAMINE

Formerly in the production of rocket fuels; antioxidant; additive for lubricants; softener of copolymers.

The Uses of N-NITROSODIMETHYLAMINE

No longer used industrially or commercially in the US; may occur as a by-product from the manufacture of pesticides, rubber tires, alkylamines, and dyes

Production Methods

Dimethylnitrosamine (DMN) is prepared by the addition of acetic acid and sodium nitrite to dimethylamine. It came into industrial prominence in the manufacture of 1,1- dimethylhydrazine, a rocket fuel component, probably in the 1940s in Germany and in the mid-1950s in the United States. DMN is no longer used except for research. OSHA identified DMN as a carcinogen in 1974. In 1976, the last plant to make DMN was closed. DMN was first considered by IARC in 1971. The current IARC classification of DMN is 2A: “The agent is probably carcinogenic to humans, based upon positive cancer findings in animal studies.” For this reason, DMN is discussed here as an example of one of a large group of nitrosamines generally regarded as carcinogenic. IARC Monographs 1 and 17 and other publications discuss the toxicology, biochemistry, environmental impact, and carcinogenicity of many nitrosamines.

Definition

ChEBI: N-nitrosodimethylamine is a nitrosamine. It has a role as a geroprotector and a mutagen.

General Description

Yellow oily liquid with a faint characteristic odor. Boiling point 151-153°C. Can reasonably be expected to be a carcinogen. Used as an antioxidant, as an additive for lubricants and as a softener of copolymers. An intermediate in 1,1-dimethylhydrazine production.

Air & Water Reactions

Water soluble.

Reactivity Profile

N-NITROSODIMETHYLAMINE is sensitive to exposure to light, especially ultraviolet light. Is stable at room temperature for more than 14 days in aqueous solution at neutral and alkaline pH in the absence of light. Slightly less stable at strongly acid pH at room temperature. Incompatible with strong oxidizing agents. Also incompatible with strong bases. Can be reduced by reducing agents. Incompatible with hydrogen bromide in acetic acid. Also photo chemically reactive.

Health Hazard

N-nitrosodimethylamine (DMN) is a liver toxin and is carcinogenic in many species of test animals.

Fire Hazard

When heated to decomposition, N-NITROSODIMETHYLAMINE emits toxic fumes of nitrogen oxides. Avoid exposure to ultraviolet light.

Potential Exposure

Nitrosodimethylamine was formerly used in the production of rocket fuels. Presently used as an antioxidant; as an additive for lubricants and as a softener of copolymers. It is used as an intermediate for 1,1-dimethylhydrazine.

Carcinogenicity

N-Nitrosodimethylamine is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.

Source

After 2 d, N-nitrodimethylamine was identified as a major metabolite of dimethylamine in an Arkport fine sandy loam (Varna, NY) and sandy soil (Lake George, NY) amended with sewage and nitrite-N. Mills and Alexander (1976) reported that N-nitrosodimethylamine also formed in soil, municipal sewage, and lake water supplemented with dimethylamine (ppm) and nitrite-N (100 ppm). They found that nitrosation occurred under nonenzymatic conditions at neutral pHs.
Glória et al. (1997) reported N-nitrodimethylamine was detected in 50% of domestic beers at concentrations ranging from 0.05 to 0.50 877 μg/kg with an average value of 0.07 μg/kg. In imported beers purchased in the U.S., N-nitrodimethylamine was detected in 63% of 78 beers analyzed at concentrations up to 0.55 μg/kg. The average N-nitrodimethylamine concentration was 0.09 μg/kg.

Environmental Fate

Biological. Two of seven microorganisms, Escherichia coli and Pseudomonas fluorescens, were capable of slowly degrading N-nitrosodimethylamine to dimethylamine (Mallik and Tesfai, 1981).
Photolytic. N-nitrosodimethylamine absorbs UV at 228 nm. An enhanced oxidation process equipped with UV lamps (195 to 240 nm), mineralized >99.9 % of N-nitrosodimethylamine in water to concentrations <0.25 μg/L (Smith, 1992). A Teflon bag containing air and N-nitrosodimethylamine was subjected to sunlight on two different days. On a cloudy day, half of the N-nitrosodimethylamine was photolyzed in 60 min. On a sunny day, half of the N-nitrosodimethylamine was photolyzed in 30 min. Photolysis products include nitric oxide, carbon monoxide, formaldehyde, and an unidentified compound (Hanst et al., 1977).
Chemical/Physical. N-Nitrosodimethylamine will not hydrolyze because it does not contain a hydrolyzable functional group (Kollig, 1993). Odziemkowski et al. (2000) studied the reduction mechanism of N-nitrosodimethylamine by granular iron using potentiostatic electrolysis and differential pulse voltammetry. In the electrochemical experiments, dimethylamine and nitrous oxide formed. The investigators reported that in an earlier experiment using batch and column experiments, nitrous oxide, characteristic of electrochemical reduction, was not detected. Rather, ammonia and dimethylamine were the products identified. The investigators proposed catalytic hydrogenation was the mechanism for N-nitrosodimethylamine reduction.

Shipping

UN2810 Toxic liquids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. PG I.

Purification Methods

Dry the nitrosamine over anhydrous K2CO3 or dissolve it in Et2O, dry it over solid KOH, filter, evaporate Et2O and distil the yellow oily residue through a 30cm fractionating column discarding the first fraction which may contain Me2N. Also dry over CaCl2 and distil it at atmospheric pressure. All operations should be done in an efficient fume cupboard as the vapors are TOXIC and CARCINOGENIC. [Fischer Chem Ber 8 1588 1875, Romberg Recl Trav Chim, Pays-Bas 5 248 1886, Hatt Org Synth Coll Vol II 211 1961, Krebs & Mandt Chem Ber 108 1130 1975.] 2,6-Dimethyl-2,4,6-octatriene see neo-alloocimene below.

Toxicity evaluation

DMN must undergo bioactivation to exert its toxic properties, and this process is thought to play an important role in determining tissue- and species-specific toxicity. Bioactivation of DMN involves oxidation of one of the N-methyl groups to a primary alcohol by various cytochrome P-450s, followed by expulsion of a formaldehyde molecule to give an unstable monomethylnitrosamine product. This then collapses to produce a highly reactive carbocation, which has been shown to react with biomolecules such as protein, DNA, and RNA. Single- and double-strand breaks in DNA and DNA fragmentation in the form of a ladder have been observed in cells and tissues.
The bioactivation of DMN is catalyzed by numerous cytochrome P-450 isoforms, mainly in the liver. Various isoforms of cytochrome P-450 possess differing affinities for DMN; the isoforms participating in DMN activation is dependent on DMN concentration. In humans, for example, P-450IIE1 has high affinity for DMN and a high turnover number in catalyzing the methylation and denitrozation of DMN. Its homologue is present in rats, rabbits, and other animals, and is inducible by a variety of substances, including acetone, ethanol, pyrazole, and isoniazid, as well as by physiological conditions such as fasting and diabetes. In contrast, human isoform P-450IIBI metabolizes DMN when it is present at high concentrations. Since animals and humans are rarely exposed to such high levels of DMN, it is believed that P-450IIE1 is the isoform responsible for the toxic effects of DMN.
DMN metabolism has been shown to be affected by the levels of micronutrients. For example, ascorbate deficiency can result in a net decrease in levels of cytochrome P-450 and cytochrome b5, and hence lower DMN bioactivation and toxicity. Interestingly though, excessive intake of ascorbate did not result in significant enrichment in levels of cytochromes P- 450 and b5.

Incompatibilities

Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong acids, especially peracids strong bases. Sensitive to UV light. Should be stored in dark bottles.

Waste Disposal

Pour over soda ash, neutralize with HCl, then flush to drain with large volumes of water. Consult with environmental regulatory agencies for guidance on acceptable disposal practices. Generators of waste containing this contaminant (≥100 kg/mo) must conform with EPA regulations governing storage, transportation, treatment, and waste disposal.