Toxicokinetics of diethylene glycol (DEG) in the rat

Abstract

Oral doses of 1 and 5 ml/kg¹⁴C-diethylene glycol (DEG) given to rats were rapidly and almost completely absorbed, the invasion constants being 2.95 h⁻ and 4.24 h⁻¹. The kinetics of invasion were determined with the method of residuals (Rowland and Tozer 1989) and by reconstruction of the invasion curves according to Kübier (1970).¹⁴C-DEG was rapidly distributed from the blood into the organs and tissues in the order kidneys > brain > spleen > liver > muscle > fat, i.e. the same order as the blood flow. The relative volume of distribution, app. V_D, was determined at 298 ml, indicating distribution over the whole body. After oral doses of 1, 5, and 10 ml¹⁴C-DEG/kg 64, 87, and 91% of¹⁴C activity in rat blood disappeared in 12–16 h with a half-life of 3.4 h and the remaining 9, 5, and 4% with half-lives of 39 h, 45 h, and 49 h. A total of 73–96% of¹⁴C activity in blood was excreted with the urine and 0.7–2.2% with the faeces. From the cumulative urinary excretion kinetics half-lives of 6 h were determined for doses of 1 and 5 ml/kg and 10 h for the dose of 10 ml/kg. After doses of 5 ml/kg and 10 ml/kg¹⁴C-DEG semi-logarithmic plots of elimination rate versus time were constant for 5 and 9 h, respectively, indicating that DEG accelerated its renal elimination by inducing osmotic diuresis. Thereafter urinary excretion followed first order kinetics with elimination half-lives of 3.6 h. After oral doses of 5 ml/kg¹⁴C-DEG given to rats of 336 g body weight with an app. V_D of 297 ml, the total clearance of¹⁴C activity was determined at 63 ml/h, and the renal clearance of unmetabolized DEG was 66 ml/h. The ratio of Cl_DEG to Cl_inulin = 0.64 indicated that DEG and its metabolite 2-hydroxyethoxyacetate (2-HEAA) were reabsorbed from the tubuli into the blood capillaries. DEG produced metabolic acidosis, which was completely balanced after doses of 1 and 5 ml/kg, but doses greater than 10 ml/kg produced non-compensated metabolic acidosis, hydropic degeneration of the tubuli, oliguria, anuria, accumulation of urea-N, and death in uraemic coma.