Paracetamol was originally used therapeutically in the latter nineteenth century but did not receive much attention until after the 1940s when it was found to be a metabolite of phenacetin (Smith, 1958). It was given the approved name "Paracetamol " by the British Pharmacopoeia Commission in February, 1957, and was introduced into the 1963 edition of the British Pharmacopoeia. It has been considered as a possible substitute for phenacetin (e.g., Comely & Ritter, 1956) following reports of interstitial nephritis allegedly due to phenacetin (e.g., Editorial, 1965). We decided to study the toxicity of paracetamol following previous work in this laboratory on the acute oral toxicity of phenacetin (Boyd, 1959 and1960). The most interesting finding was that when death was delayed there was an associated necrosis of the liver.The initial objective was to compare the acute toxicity of paracetamol with that of phenacetin. Therefore the project was designed so that toxicity would be determined at the range of the LD50 given to albino rats by intragastric cannula. The oral LD50 of paracetamol has been reported somewhat lower than that of phenacetin in mice and higher in rats (Smith, 1958). In rats it has been found of the order of 3.0 to 4.5 g/kg (Renault, Rohrbach & Dugniolle, 1956;Smith, 1958).
METHODSThe experiments were performed upon young male CBL-Wistar albino rats of 100 to 200 g body weight fed Purina laboratory chow and water ad libitum. Sixteen hours before paracetamol administration each rat was placed in a metabolism cage, 1 rat per cage, and deprived of food but not water. Paracetamol (Eastman) was then administered by intragastric cannula as a freshly prepared suspension in distilled water. The suspension was stabilized by the addition of gum tragacanth powder to 0.2% (w/v) and the volume administered was maintained constant at 20.0 ml./kg since Ferguson (1962) has shown that drug toxicity can increase with increasing volume per kg of distilled water vehicle. Each of the following doses, expressed as g/kg, was given to 15 to 20 rats: 0.0, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 6.0, and 7.0. Following drug administration the rat was returned to its metabolism cage which contained a weighed amount of food (50 g) and a measured amount of water (100 ml.).Clinical measurements were made upon each rat at daily, or shorter if indicated, intervals for 5 days. Survivors were then returned to the animal boarding quarters and observed for one month.Clinical measurements included body weight in g, food consumption in g rat feed/kg body weight per 24 hr, water consumption in ml./kg per 24 hr, colonic temperature in°C, urinary volume in ml./kg per 24 hr, urinary glucose output in mg/kg per 24 hr, urinary pH of 24 hour sample, urinary protein output in mg/kg per 24 hr, and other clinical signs quantitated at 1 + to 4+. Colonic temperature was recorded by a Thermistemp Telethermometer (Yellow Springs Instrument
