Toxicology of dimethyl and monomethyl derivatives of acetamide and formamide: a second update

Abstract

Dimethylacetamide (DMAC) and dimethylformamide (DMF) continue to be important, widely used solvents involved in a wide variety of industrial applications. As liquids with relatively low vapor pressures, contact with both the integumentary and respiratory systems is the main source of human exposure. Although airborne control levels for the workplace have been established and industrial hygiene practices to limit dermal contact have been put in place, use of these chemicals has been associated with occupational illness, mainly in Asia where new and expanded uses have led to overexposures. Thus an update of the basic toxicology data including tables indicating the dose/exposure response characteristics of both DMAC and DMF is currently important. Both chemicals are similar from a toxicology perspective. Human experience has generally shown the materials to be without adverse effect except under conditions where airborne and dermal controls were not properly applied. The use of urinary metabolite monitoring has successfully been employed to measure integrated dermal and inhalation worker exposure. The chemicals are not particularly toxic following acute exposure but high doses can produce damage to the liver, the organ which is first affected by these two chemicals. Repeated dose/exposure studies have characterized both the targets of toxicity and the doses required to produce changes by various routes of exposure. Higher doses of these materials can produce changes in developing systems, infrequently in experiments at doses in which the maternal animal is unaffected, thus care needs to be taken when exposures are to women of child-bearing age. The chemicals appear to be low in genetic activity and inhalation exposures have not shown the materials to produce tumors in rodents except with DMF in a situation in which aerosol formation was encountered. This presentation extends the two previous reviews and, like those, includes updated information on acetamide and formamide and their monomethyl derivatives as well as the commercially important DMAC and DMF. Since a large portion of the newer information deals with effects in humans and biomonitoring, these sections are presented at the start of this review.

Hepatotoxicity in Rats Treated with Dimethylformamide or Toluene or Both

“…Intake of DMF may be mainly from inhalation of its vapor and by physical contact with skin, and occupational exposure to DMF may cause nausea, abdominal pain, and alcohol intolerance (2). Especially, DMF has been shown to induce hepatotoxicity and liver dysfunction in animals and humans by many investigators, and it is known that the primary target organ of DMF is the liver in animals and humans (3-5). DMF is hydroxylated at its methyl moieties by the cytochrome P-450 (CYP) to produce N-methyl-N-hydroxymethylformamide (DMF-OH), the generated DMF-OH being biotransformed to N-methylformamide (NMF) by a non-enzymatic or enzymatic reaction, undergoing further reactions that result in xenobiotic enzymes (6,7).…”

Toxicological and chemical studies of wastewater from hydraulic fracture and conventional shale gas wells

“…Several chemicals that were present in the samples analyzed in the present study have been shown to exhibit toxic properties after acute or repeated exposure to skin, liver, kidneys, the CNS, the gastrointestinal tract, blood, and lungs, including developmental toxicity, corrosivity, and skin sensitization (Middaugh et al 2002;Kennedy 2012;PubChem 2017;ChemicalBook 2017;USEPA 2017). Genotoxic and tumor-promoting substances were also present (Horton et al 1965;PubChem 2017).…”

“…2,2,4‐Trimethyl 1,3‐pentanediol is a developmental toxicant with acute dermal and respiratory toxicity (PubChem ). N ‐Methylthioformamide is a developmental toxicant with acute dermal, respiratory, and liver toxicity (Kennedy ). Tetramethylbutanedinitrile is acutely toxic by the oral, dermal, and inhalation routes (PubChem ).…”

Comparative Study on the EC50Value in Single and Mixtures of Dimethylformamide, Methyl Ethyl Ketone, and Toluene

“…Metabolic intermediates formed by xenobiotic metabolizing enzymes are known, in most cases, to have a larger effect on human toxicity than the original chemical itself. DMF, which is widely used in the industry (15) , is known to largely affect the liver (16) , where the metabolic intermediate N-methylforamide (NMF) is produced during metabolism with the xenobiotic metabolizing enzyme cytochrome P-450(CYP)2E1 acting as catalyst. NMF is reported to have greater toxicity than DMF (15) .…”