Absorption and disposition of 14C-labelled Kathon biocide, a mixture of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one, following intravenous or dermal administration to male Sprague-Dawley rats.

Kathon biocide (KB), a 75:25 mixture of 5-chloro-2-methyl-4-isothiazolin-3-one (KI) and 2-methyl-4-isothiazolin-3-one (KII), is a broad-spectrum antimicrobial agent. The absorption and disposition of 14C label were studied in male Sprague-Dawley rats following iv or dermal administration of KB 14C labelled in the carbonyl carbon of either KI or KII. KI-labelled Kathon was distributed rapidly following an iv dose (0.8 mg/kg). Total 14C label in the plasma was rapidly eliminated, with the data best described by a three-compartment model. Total 14C label concentration in the blood, however, remained constant at 3 ppm from 6 to 96 hr after administration and represented 29% of the dose, indicating that KI-labelled Kathon and/or metabolites was sequestered by the cellular fraction of blood. Elimination of 14C label from the tissues examined was biphasic, with a terminal half-life of more than 4 days; by 96 hr, faeces, urine and CO2 accounted for 35, 31 and 4% of the dose, respectively. Following a single 24-hr dermal application of 0.2 ml of an aqueous solution containing 2000 ppm [14C]KB (400 micrograms), rats absorbed 94% of KI-labelled KB and 82% of KII-labelled KB. However, the systemic bioavailability of KB was substantially less than this, since approximately half of the absorbed KB was associated with the skin at the application site 24 hr after the application. Percutaneous absorption was not affected by concentration over the range 500-4000 ppm. As the concentration of KI-labelled KB in the applied solution increased from 500 to 4000 ppm, the relative amount of 14C label associated with the skin decreased, while that in the excreta increased, indicating greater systemic penetration at higher concentrations. Low amounts of 14C label were found in the testes (less than 2 ppb) and blood (24 ppb) 28 days after a single dermal application of KI-labelled KB. Four consecutive daily applications of KI-labelled KB did not influence the proportion of the dose absorbed from the skin. However, the proportion of the dose excreted was higher than after a single application of an equivalent amount of KB.

Toxicological and biochemical effects of repeated administration of benzene in mice.

Repeated dosing of mice with benzene led to a dose-related decrease in red cell production as measured by the incorporation of 59Fe into developing erythrocytes. Phenol, catechol, and hydroquinone were observed in the urine, largely conjugated with glucuronic acid and ethereal sulfate. During repeated dosing, toluene-soluble radioactivity derived from labeled benzene was found to accumulate in blood, liver fat, and, most significantly, bone marrow. Greater accumulation was observed when water-soluble metabolites of benzene were examined in these organs. Covalent binding of benzene metabolites was also observed in liver and marrow during repetitive treatment. Both covalently bound and soluble metabolites accumulated in bone marrow, liver, and kidney over a 24-h period after a single administration of benzene. The highest levels of covalent binding were seen in kidney and liver after 3 d of dosing at 880 mg/kg, two doses per day. Studies in vitro demonstrated the necessity for metabolic activation to produce covalent binding from benzene. These studies demonstrate that increasing benzene toxicity during repetitive treatment of mice is accompanied by increases in the levels of both water-soluble and covalently bound benzene metabolites.