An understanding of pharmacokinetic factors can assist greatly in both dose-setting for toxicity studies and in the interpretation of the results. Selected chemicals on-test by the NTP are nominated for disposition studies. The absorption, both oral and dermal, distribution, metabolism, and excretion of these chemicals are studied in rats and other species as needed. The effect of dose on disposition is determined, as is the effect of the route of exposure. These studies help to predict the results obtained upon chronic exposure. Xenobiotics to be studied are radiolabeled with 14C or 3H by custom syntheses. Distribution and excretion are compared after iv, oral, and/or dermal exposures at several doses, the highest being 1/10th of the LD50. Disposition after an iv dose is examined at multiple time points after treatment. The excreta, expired air, and volatiles are analyzed for radioactivity which is resolved in parent compound and metabolites by organic solvent extraction and chromatography. Metabolites are then characterized by chemical and/or enzymatic means. Current work has focused on the disposition of citral (""""""""oil of lemon""""""""), a common flavoring and fragrance. It is completely absorbed after oral exposure, and well absorbed dermally, although volatilization makes dermal absorption incomplete. Urine is the major route of excretion although biliary elimination results in some enterohepatic circulation as well as some fecal excretion. Oxidative metabolism results in the production of substantial amounts of 14CO2. Citral is rapidly metabolized with little parent compound being detected in the blood within 10 minutes of administration. There are at least eight metabolites, some of which are common to urine and feces. Both glucuronides and sulphate conjugates appear to be produced. Studies are ongoing to further characterize the metabolites of citral.
