The percutaneous absorption and disposition of iodochlorhydroxyquin (5-chloro-7-iodo-8-quinolinol; I) from a 3% cream were studied in five dogs over a 28-d topical treatment period. Plasma levels, determined by HPLC, were 0.275-0.525 microgram/mL. The steady-state elimination rate of total I in urine was 2.4-3.0 mg/d. The apparent elimination rate constant and half-life were 0.25 +/- 0.05 d-1 and 3.1 +/- 0.5 d, respectively. Greater than 50% of topically applied I was absorbed over 16 h. Occlusion of the skin without the drug indicated that the skin acted as a reservoir for the drug. Feces analysis for iodochlorhydroxyquin from one dog showed that 27.1 +/- 8.5 mg/d was eliminated via this route. Tissue levels of I 15 d after the 28-d topical treatment were 0.7 microgram/g of liver, 0.2 microgram/g of kidney, and 0.8 microgram/g of mesenteric fat. The apparent rate constants of plasma level decline after a 100-mg iv bolus dose of I were alpha = 3.9 h-1 and beta = 0.6 h-1. The urinary elimination after intravenous administration was biphasic. The rate constant for the slow elimination phase was 0.4 +/- 0.1 d-1, and the half-life was 2.0 +/- 0.5 d. The primary neurological symptoms observed during topical treatment were ataxia and hind limb paralysis. Microscopic examination revealed liver necrosis. A weight loss of 15.3 +/- 2.7% was also observed over the 28-d topical treatment period. The results indicate that significant percutaneous absorption of I occurs, and that chronic high-dose topical treatment may lead to toxicity.