Biological Effects of Acetamide, Formamide, and Their Monomethyl and Dimethyl Derivatives

Abstract

The industrial use of certain acetamides and formamides (particularly DMAC and DMF) for their solvent properties has resulted in rather extensive examination of their biological properties. Both DMAC and DMF are rapidly absorbed through biological membranes and are metabolized by demethylation first to monomethyl derivatives and then to the parent acetamide or formamide. Relatively high single doses to various species following oral, dermal, i.p., i.v., or inhalation exposures generally are required to produce mortality. The liver is the primary target following acute high level exposure, but massive doses can also produce damage to other organs and tissues. Repeated sublethal treatment by various routes also shows the liver to be the target organ with the degree of damage being proportional to the amount absorbed. With MMF, the potential usefulness as a cancer chemotherapeutic agent needs to be measured against the hepatotoxic effects produced in man. Acetamides and formamides are generally inactive in mutagenicity tests. Mammalian test systems do not appear to be genetically sensitive and DMF has been recommended for use as the vehicle in microbial assays designed to test for genetic activity of hard-to-dissolve chemicals. Embryotoxicity can be demonstrated at high doses; doses which generally show toxicity to the maternal animals. Structural abnormalities in sensitive species such as the rabbit are produced following exposure at near-lethal levels. The spectrum of abnormalities seen is broad and fails to show any time or site specificity in terms of developing organs/organ systems. Inhalation exposures to DMAC and DMF at levels producing some maternal toxicity in rats have produced no teratogenic response and only slight evidence of embryotoxicity. Long-term feeding of relatively high levels of acetamide produces liver cancer in rats. DMAC and DMF appear to be noncarcinogenic. The environmental toxicity of these chemicals is low. Liver damage can be produced by overexposure to these chemicals in man. Airborne concentrations need to be controlled and care should be taken to avoid excessive liquid contact as the chemicals are absorbed through the skin. A relationship exists between the amount of DMAC or DMF absorbed and the amount of MMAC or MMF excreted in the urine so that biomonitoring of the urinary metabolites can indicate situations in which total exposures, both dermal and inhalation, are excessive. An interaction between DMF and ethanol occurs such that signs, including severe facial flushing, appear when DMF-exposed individuals consume alcoholic beverages.

Recent density functional theory model calculations of drug metabolism by cytochrome P450

“…Amide compounds exist in insect repellents, industrial solvents and drugs, possessing important biological activities [104][105][106]. Many of these compounds undergo oxidative N-dealkylation mainly by P450 [107][108][109][110][111][112].…”

Liver injury in workers exposed to dimethylformamide.

“…Thus we are almost certain that dimethylformamide (or dimethylformamide in synergism with some other agent or agents) was the causative agent of the orig inal epidemic of toxic liver disease. This possibility is further supported by preexisting evidence in the literature of dimethylformamide hepatotoxicity in both humans and animals (14). Therefore, we recommend that this chemical, with its extensive use and significant skin absorption, be monitored closely in the future, especially since recent investigations suggest that, in addition to its hepatotoxic effects, dimethylformamide may also be a testicular carcinogen in humans (15,16).…”

Proposed Occupational Exposure Limits for Non-Carcinogenic Hanford Waste Tank Vapor Chemicals

“…Acetamide, dimethylacetamide, formamide, and dimethylformamide all cause progressive hepatotoxicity (Kennedy 1986). The hepatocellular carcinomas observed by Fleischman et al (1980) may have been due to hepatocellular cytotoxicity and concomitant compensatory cellular regeneration, which would have a threshold effect.…”