Biochemical and morphological studies on the percutaneous uptake of [14C] ethylenediamine in the rat.

Male Wistar rats were exposed to aqueous [14C]ethylenediamine (EDA) solutions (10, 25, or 50%) percutaneously over a 7 x 7 cm area on the back with occlusion for 24 h. For each rat dosed, three types of studies were conducted: (1) plasma kinetics, (2) material balance, and (3) histological evaluation, including autoradiography of the skin sample from the dosing area. Adequate kinetic measurements were obtained only from animals treated with 25 and 50% EDA, but not from the 10% treatment group, due to analytical limitations. The uptake of [14C]EDA percutaneously by the rat was relatively slow in comparison with uptake following peroral or endotracheal administration. The absorption of EDA by the animals was estimated to be greater than 61, 55, and 12%, respectively, for the 50, 25, and 10% treatment groups. A large portion (11-32%) of the dose was left on/in the dosing area. Urinary excretion was the predominant route for the disposition of EDA. The recovery of the administered dose was low (70-83%), possibly due to volatilization of EDA from the skin during dosing and holding. Histologic examination of skin sections (dosing areas) revealed a normal, intact epidermis in rats dosed with 10% EDA, but full-thickness epidermal necrosis in rats dosed with 25% or 50% EDA solutions. The damage of the epidermis apparently enhanced the penetration of EDA. Autoradiographic preparations revealed a concentration of the [14C]EDA radiolabel over the keratin layer and hair shafts.

The effects of ethylene oxide (EO) exposure on tissue glutathione levels in rats and mice.

Male Fischer 344 rats and male Swiss-Webster mice were exposed to different atmospheric concentrations of ethylene oxide (EO) for 4 hours. In mice sacrificed immediately after exposure to 100, 450 or 900 ppm EO, there was a concentration related decrease in the GSH levels of all tissues examined. Similar findings were obtained in rats immediately after exposure to 100, 600 or 1200 ppm EO except that blood GSH levels were not affected at any exposure concentration. In both species, lung and liver GSH levels were depressed at all exposure concentrations. Twenty-four hours after exposure to 1200 ppm EO, the GSH concentrations of rat bone marrow and testis had not returned to control levels. Only blood GSH levels remained depressed in mice 48 hours after exposure to 900 ppm EO. The results indicate a marked species difference between rats and mice regarding the effects of EO exposure on blood GSH levels which may have important toxicological implications.

Age-dependent pharmacokinetic changes of ethylenediamine in Fischer 344 rats parallel to a two-year chronic toxicity study.

As part of a 2-year chronic toxicity study, the pharmacokinetics of ethylenediamine (EDA) was studied in Fischer 344 rats of both sexes at day zero (naive animals), 6 months (controls and high level animals), and 18 months (controls and high level animals). The rats, which were randomized along with the rest of the animals on the toxicity study, were taken for pharmacokinetic experiments at the specified time. A single per os (po) dose of 50 mg [14C]EDA X 2HCl/kg was given to each rat and the plasma kinetics was followed for a 24-hr period. Five pharmacokinetic parameters (absorption rate constant, terminal half-life, area under the curve, volume of distribution, and 14CO2 production rate constant) were compared with respect to age, sex, and chronic dosing. There were no apparent age-, sex-, and/or chronic dosing-related differences in absorption rate constant and terminal half-life. However, age-related changes in area under the curve (AUC) were evident. The older rats had higher values (generally two- to threefold) for AUC than the younger rats. This age-related difference in AUC is closely associated with the volumes of distribution (Vd) of the animals of varying ages. On the basis of liters per kilogram, the Vd's of the older rats are approximately one-fourth to one-half of those for the younger (zero day) rats. The 14CO2 production rate constant was derived from the rate of formation of 14CO2 as a result of [14C]EDA X 2HCl dosing. The comparison of this constant under the various experimental conditions suggests sex-related differences.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and subchronic toxicity of ethylenediamine in laboratory animals.

As part of a comprehensive toxicology program on ethylenediamine (EDA), acute, short-term repeated and subchronic toxicity studies were conducted. Ethylenediamine dihydrochloride (EDA X 2HCl) was used in these studies. EDA X 2HCl was slightly to moderately toxic to laboratory rats, mice or rabbits in the following acute tests: Peroral intubation, percutaneous administration, primary skin irritation and eye injury. Following dietary inclusion of EDA X 2HCl for 7 days at up to 2.70 g/kg/day to Fischer 344 rats or B6C3F1 mice, body weight gain and some organ weights of the animals were depressed in both sexes at the highest dose level. When Fischer 344 rats were fed EDA X 2HCl at 0, 0.05, 0.25, 1.00 g/kg/day for 3 months, marked decreases in body weight gain were observed in both sexes at the highest dose level. Other dose-related effects observed in either or both sexes primarily at the highest dose level, and for some at the intermediate dose level, included organ weight changes and alterations in some clinical chemistry, hematology and urinalysis parameters. No deaths occurred during the exposure period, nor were there any significant gross lesions in any of the animals. Histologic findings indicate a dose-related increase in hepatocellular pleomorphism and mild hepatocellular degeneration.

Behavioral and neuropharmacological toxicology of the macrocyclic ether 18-crown-6.

18-CROWN-6 was assessed for neurologic effects in rats, mice, and rabbits by intravenous (IV) and intraperitoneal (IP) routes of administration. Male rats and mice exhibited no effects with IV doses to 20 mg/kg. Given IP doses of 20 to 160 mg/kg/day, rats and mice exhibited numerous signs, including aggression, tremors, muscle weakness and a degradation of some reflexes. All signs faded after four days when dosage levels were kept constant, but returned when the dose was doubled. All signs disappeared upon discontinuance of exposure. Treatment with PCPA (p-chlorophenylalanine) or dibenzyline caused most signs to disappear. Rabbits given 6.0 mg/kg/day IV displayed tremors, hyperactivity, unsteady gait and stereotypic behavior, with acclimation as in rats and mice. 18-CROWN-6 had no activity in isolated tissue preparations unless it was first incubated with tissues. PCPA and dibenzyline reversibly blocked the actions of incubated 18-CROWN-6 on isolated tissue. 18-CROWN-6 is hypothesized to be metabolized to a serotonergic agonist.