N,N-Dimethylacetamide: Uses, Preparation and Toxicities

General Description

N,N-Dimethylacetamide is a synthetic organic compound that is produced from a reaction of dimethylamine and acetic acid or acetic anhydride. It is a colorless to yellow liquid with a faint odor resembling ammonia. N,N-Dimethylacetamide has similar density to water and is miscible with water and organic substances. This organic compound is commonly associated with many industrial uses, either as a starting material or an intermediate. N,N-Dimethylacetamide is a good solvent that is used in polymer dissolution, especially in the fiber industry. Historically, N,N-Dimethylacetamide was also tested as a possible antineoplastic agent in a phase 1 study involving 17 patients. However, liver and central nervous system (CNS) toxicity associated with N,N-Dimethylacetamide was observed and these patients had altered mental states, resulting in no further drug development.

Figure 1. Properties of N,N-Dimethylacetamide

Uses

N,N-Dimethylacetamide is a multipurpose reagent which delivers its own H, C, N and O atoms for the synthesis of a variety of compounds under a number of different experimental conditions. N,N-Dimethylacetamide is a water-miscible solvent, FDA approved as excipient and therefore widely used as drug-delivery vehicle. It has been shown that N,N-Dimethylacetamide is epigenetically active since it binds bromodomains and inhibits osteoclastogenesis and inflammation. N,N-Dimethylacetamide has a potential as an anti-osteoporotic agent via the inhibition of osteoclast mediated bone resorption and enhanced bone regeneration.¹

N,N-Dimethylacetamide is used as a polar solvent in organic synthesis as well as in reactions involving strong bases such as sodium hydroxide. N,N-Dimethylacetamide finds application as a reaction medium in the production of pharmaceuticals, agrochemicals, dyes and plasticizers. It is widely used in polymer industry due to its high solving power for high molecular-weight polymers and synthetic resins. It plays an important role as a catalyst in various reactions viz. cyclization, halogenation, cynidation, alkylation and dehydrogenation and increases the yield of main products. It is also used as an extracting agent for oil and gases, in paint removers, in the production of photo-resist stripping compounds and as booster solvent in coatings. Moreover, this aprotic dipolar solvent is also used in X-ray and photographic products and in the production of polyimide films. The polyimide films are produced for a variety of industries, including consumer electronics, solar photovoltaic and wind energy, aerospace, automotive, and industrial applications.²

Preparation

N,N-Dimethylacetamide is prepared commercially by the reaction of dimethylamine with acetic anhydride or acetic acid. Dehydration of the salt of dimethylamine and acetic acid also furnishes this compound:

CH₃CO₂H·HN(CH₃)₂ → H₂O + CH₃CON(CH₃)₂

Dimethylacetamide can also be produced by the reaction of dimethylamine with methyl acetate.

Figure 2. Preparation of N,N-Dimethylacetamide

The separation and purification of the product is carried out by multistage distillation in rectification columns. N,N-Dimethylacetamide is obtained with essentially quantitive (99%) yield referred to methyl acetate.³

Toxicity

Acute and Short-Term Toxicity

The acute oral toxicity of N,N-Dimethylacetamide is relatively low, with an LD50 ranging from 3000 to 6000 mg kg^-1 in rats. Similarly, the dermal LD50 values for rats and mice were 7500 and 9600 mg kg^-1 bw, respectively. Liver toxicity is generally associated with N,N-Dimethylacetamide toxicity. In an acute inhalational toxicity study, the lowest LC50 for rat was 8.81 mg L^-1 for 1 h exposure and 1.47 mg L^-1 for 3.5 h in mice. In both species, inhalational toxicity is associated with degeneration of liver. N,N-Dimethylacetamide is not classified as a skin or respiratory sensitizer, although it may cause mild skin irritation and irritation to the eye. The no observed adverse effect concentration (NOAECs) determined from repeated dose inhalation studies of between 14 days and 2 years in rats and mice were 25 ppm (0.09 mg L^-1) and higher. Histopathological changes observed were liver degeneration, irritation to the respiratory tract, and reduction in body weight gain.⁴

Chronic Toxicity

Inhalation of N,N-Dimethylacetamide (40 ppm) for 6 h day^-1 for 5 days week^-1over 6 months and N,N-Dimethylacetamide (50 ppm) for 30 weeks resulted in no liver damage (in dogs and rats) and no injuries (in rabbits and cats), respectively. Liver injury by N,N-Dimethylacetamide was prolonged at higher concentrations in the study, while the recovery with no residual effects occurred in 4–6 months and in repeated inhalation of the compound (100–200 ppm) in some rats and dogs. Repeated intraperitoneal injections of N,N-Dimethylacetamide also reduced significant weight in rats while administration of a near lethality dose to mice caused hepatocyte damage, necrotic pancreatitis, and very significant necrosis of splenic lymphocytes. Rats received the LD50 of N,N-Dimethylacetamide orally, resulting in generalized hemorrhage in several organs and necrosis in the liver and kidneys. Dermally, N,N-Dimethylacetamide at 2 g kg^-1 led to death in rabbits from acute hepatic necrosis and N,N-Dimethylacetamide at 4 g kg^-1 day^-1 for 5 days week
1 for 6 weeks exposed dermally also killed dogs after experiencing other effects such as weakness, ataxia, diarrhea, loss of weight, and jaundice. However, dogs treated with 1 g kg^-1 N,N-Dimethylacetamide survived for 6 months with only a pale coloration and fatty liver degeneration. At higher doses, N,N-Dimethylacetamide also caused toxic effects such as electroencephalographic changes, dysrhythmias, and electrographic seizures to the CNS of rabbits that were given 0.25–2 g kg^-1 N,N-Dimethylacetamide by different routes for 21 days or longer.⁵

Carcinogenicity

N,N-Dimethylacetamide is not classifiable as a human carcinogen. In a retrospective epidemiological cohort study undertaken on 571 workers in an acrylic fiber factory with simultaneous exposure to acrylonitrile and N,N-Dimethylacetamide, there was no relationship between mortality from tumors and N,N-Dimethylacetamide exposure. No dose– response relationship was established in a 2 year drinking water study in rats and the incidences of thymomas in female rats in the same study were also not thought to be related to the treatment. Similar results were also observed in an 18 month inhalation study in rats and mice, in which increases in squamous cell papilloma in the stomach of females rats and in lymphoma in female mice (at 350 ppm N,N-Dimethylacetamide) were not chemical-related effects and both were found to be within the range of controls.⁶

Genotoxicity

N,N-Dimethylacetamide is not found to be mutagenic in the in vitro screening assays, including Ames test, cytogenetic assay on human lymphocytes, and unscheduled DNA synthesis assay in human embryonic intestinal cells. Similarly, in vivo studies using Muta Mouse (lacZ) and the Big Blue (lacI) transgenic mouse mutation assays also demonstrated that N,N-Dimethylacetamide is not mutagenic. In addition, N,N-Dimethylacetamide was also found to be negative in the dominant lethal assays with rats (dermal and inhalation) and mouse (dermal, inhalation, and intraperitoneal). A cytogenetic assay on human lymphocytes from 20 workers who were in contact with N,N-Dimethylacetamide also did not show significant chromosome aberration.⁷

Toxicokinetics

Due to its physicochemical properties, N,N-Dimethylacetamide is easily absorbed by inhalation and ingestion and can penetrate the skin. It is rapidly absorbed through biological membranes in the body and largely accumulated in fat and muscles. N,N-Dimethylacetamide is sequentially N-demethylated (major metabolic pathway) and excreted in the urine as N-monomethylacetamide (MMAC), N-hydroxymethylacetamide, acetamide, and some residual N,N-Dimethylacetamide. Animal studies in rats employing ¹⁴C-labeled N,N-Dimethylacetamide given orally showed urinary metabolites of 60–70% MMAC, 7–10% N-hydroxymethylacetamide, and 7–10% acetamide, and less than 1% was hydrolyzed and removed as carbon dioxide. Similar metabolites were also found when the rats were exposed to N,N-Dimethylacetamide subcutaneously. It has been shown that N,N-Dimethylacetamideis metabolized by cytochrome P450, probably CYP2E1, resulting in a carbon-centered free radical intermediate. This reactive metabolite dose dependently attacks the heme prosthetic group of cytochrome P450, resulting in suicidal enzyme inactivation. This mechanism of action may be responsible for liver toxicity.⁸

References

1. ECHA, 2011. European Chemical Agency. Annex XV dossier for N,N-dimethylacetamide (DMAC). August 2011. 

2. Jung, S.J., Lee, C.Y., Kim, S.A., et al., 2007. Dimethylacetamide induced hepatic injuries among spandex fiber workers. Clin. Toxicol. 45, 435–439. 

3. Kennedy, G.L., 2012. Toxicology of dimethyl and monomethyl derivatives of acetamide and formamide: a second update. Crit. Rev. Toxicol. 42 (10), 793–826.

4. N,N-Dimethylacetamide Kennedy, G.M., 2012. Dimethylacetamide. In: Patty’s Toxicology, sixth ed. pp. 888–894.

5. Kim, S.N., 1988. Preclinical toxicology and pharmacology of dimethylacetamide, with clinical notes. Drug Metabol. Rev. 19 (3–4), 345–368.

6. Lide, D.R. (Ed.), 2000. CRC Handbook of Chemistry and Physics, eighty first ed. CRC Press, Boca Raton.

7. Nomiyama, T., Omae, K., Ishizuka, C., et al., 2000. Dermal absorption of N,N-dimethylacetamide in human volunteers. Int. Arch. Occup. Environ. Health 73 (2), 121–126.

8. Okuda, H., Takeuchi, T., Senoh, H., Arito, H., Nagano, K., Yamamoto, S., Matsushima, T., 2006. Developmental toxicity induced by inhalation exposure of pregnant rats to N,N-dimethylacetamide. J. Occup. Health 48 (3), 154–160.

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