A Study of the Acid Lability and Acute Toxicity of Dimethoxymethane in Rats

Abstract

The pH stability and acute oral toxicity of dimethoxymethane (DMM) in rats were studied. In in vitro studies, DMM was found to be stable in artificial gastric juice at pH 2.5 and above but readily hydrolyzed at pH 2 and below, with 1 mole of DMM producing approximately 1 mole of formaldehyde and 2 moles of methanol. DMM incubated in sealed, excised stomachs appeared to equilibrate with the external incubation fluid over a 24-hour period without significant hydrolysis. In the toxicity study, three groups of female rats ( n = 5) were administered, by gavage, phosphate-buffered saline (control), DMM (31 mmoles/kg body weight [bw]/day), or methanol (MeOH) (30 mmoles/kg bw/day), respectively, for 3 consecutive days and then sacrificed on day 5. Transient ataxia lasting about 30 minutes was observed in animals following DMM administration. Increased urine volume was observed in the DMM group at the end of days 4 and 5. Markedly elevated level of formic acid was present in the urine of the MeOH group at days 1, 2, and 3, but not in the DMM group. Urinary ascorbic acid levels were increased in the DMM group on days 1, 2 and 3, and returned to baseline level at days 4 and 5. Microscopic examination detected no abnormal histological changes in the liver and kidneys of MeOH-or DMM-treated animals. No treatment effects were observed on the following endpoints: organ weights (liver, heart, thymus, kidneys), serum corticosterone, serum chemistry profile, hematology, hepatic phase 1 and phase 2 mixed-function oxidase activities, hepatic and serum thiobarbituric acid, hepatic glutathione, urinary protein, and urinary N-acetylglucosaminidase activity. These observations suggested that hydrolysis of DMM in the stomach required a gastric acidity below pH 2.5. At higher pH, intact DMM readily penetrated the stomach and therefore likely reached the circulation and other body tissues. There was no significant hydrolysis of orally administered DMM, and the acute effects were limited to transient ataxia and biochemical responses in the liver.