The disposition kinetics of ethylene oxide, ethylene glycol, and 2-chloroethanol were studied following their intravenous administration to beagle dogs. Plasma concentration of ethylene oxide was found to decline exponentially with a mean rate constant of 0.024 +/- 0.008 min-1 (mean +/- SD) and total body clearance of 20.0 +/- 5.2 ml/kg X min. Ethylene oxide was found to be metabolized mainly to ethylene glycol, which had a mean plasma half-life of 221.0 +/- 77.7 min and a total body clearance of 2.13 +/- 0.58 ml/kg X min. Between 7 and 24% of intravenously administered ethylene oxide was eliminated in the urine as ethylene glycol within 24 h. The elimination half-life and clearance values for 2-chlorethanol were 40.8 +/- 5.7 min and 10.3 +/- 1.7 ml/kg X min, respectively. The pharmacokinetic data gathered in the present investigation suggest that ethylene glycol rather than 2-chloroethanol is the major metabolite of ethylene oxide in the dog.

The disposition kinetics of cyclohexanone, a commonly used industrial solvent, was studied in beagle dogs following intravenous administration of a 284 mg/kg dose at various rates for 18 or 21 days. The major metabolite of cyclohexanone was identified as cyclohexanol. Plasma and urine concentrations of the compound and the metabolite were determined using a newly developed gas chromatographic procedure. A two-compartment open model was used to analyze plasma concentration-time data of cyclohexanone. The distribution half-life, biological half-life, and clearance values for cyclohexanone were 6.6 ± 3.6 min, 81.0 ± 22.5 min, and 27.4 ± 4.3 ml/kg/min, respectively. Between 74 and 100% of the administered dose of cyclohexanone was converted to cyclohexanol and approximately 60% of the dose was excreted in the urine as the glucuronide conjugate of cyclohexanol. Peak cyclohexanol concentrations in plasma following intravenous bolus administrations of 284 mg/kg of cyclohexanone ranged from 140 to 220 μg/ml and occurred between 5 and 30 min after cyclohexanone administration. Apparent plasma elimination half-life of the metabolite was 99 min. Urinary excretion data suggested that less than 1% of the dose was excreted as cyclohexanol and cyclohexanone. Under the dosage schedule employed in the present study, there was neither any accumulation of cyclohexanone nor any evidence of enzyme induction on repeated administrations. The data gathered in the present investigation are useftul in calculations of cyclohexanone peak or steady-state levels during comparative toxicological studies involving different dosage regimens.

Polyurethane copolymers may contain aromatic diisocyanate. This reactive chemical substance can give rise to aromatic amine structures during processing. 4,4′-Diaminodiphenylmethane, commonly referred to as 4,4′-methylenedianiline (MDA), was identified in aqueous extracts of a polyurethane material developed for medical use. This study demonstrates the mutagenic potential of MDA using Salmonella typhimurium test strains.

Benzyl alcohol was injected into mice, rats, dogs, and monkeys and compared with ethyl alcohol to delineate its limits of tolerance. Intravenously, 1 ml/kg of 0.9% benzyl alcohol did not affect, in anesthetized and unanesthetized dogs and anesthetized monkeys, the blood pressure, heart rate, respiration, ECG or hematalogic parameters. The lethal iv dose of 0.9% benzyl alcohol in anesthetized, normovolemic dogs was 88–113 ml/kg (0.83–1.06 g/kg). Intracarotid and intrarenal injections of 0.9% benzyl alcohol did not cause any significant effects on ECG, blood pressure, heart rate, respiration or EEG of anesthetized dogs. Rapid iv injections of 0.9% benzyl alcohol were nonlethal in mice at 50 ml/kg (0.48 g/kg). Both 0.9% benzyl and ethyl alcohol could be given, iv, to rats, slowly, with no fatalities at 40 ml/kg. After rapid injection, the LD50 for 0.9% benzyl was 33.4 ml/kg while 37.5 ml/kg of the ethyl alcohol was nonlethal. Volumes of 22.5 ml/kg or less of 0.9% benzyl alcohol were nonlethal in rats. There is a calculated safety factor of 38 following a rapid injection of a 30-ml vial dose of 0.9% benzyl alcohol to a 50-kg adult. Intraarterially, 0.9% benzyl and ethyl alcohol were tolerated by rats at 44.5 ml/kg. Benzyl alcohol (94%) was 23 times more toxic in rats, iv, than ethyl alcohol (95%). Again, the calculated LD50 in mice for benzyl alcohol (94%) was less than 0.5 ml/kg (0.48 g/kg), and that for ethyl alcohol (95%) was 1.9 ml/kg (1.46 g/kg).