Toxicokinetics of inhaled 2-butoxyethanol and its major metabolite, 2-butoxyacetic acid, in F344 rats and B6C3F1 mice

2-Butoxyethanol (2BE) is used extensively in the production of cleaning age nts and solvents. It is primarily metabolized in the liver to 2-butoxyaceti c acid (2BAA), which is believed to be responsible for 2BE toxicities assoc iated with hemolysis of red blood cells. The objective of the study was to characterize the systemic disposition of 2BE and 2BAA in rats and mice duri ng 2-year 2BE inhalation toxicity studies. Male and female F344 rats and B6 C3F1 mice (6-7 weeks old) were exposed to target 2BE concentrations of 0, 3 1.2, 62.5, or 125 ppm (rats), or 0, 62.5, 125, or 250 ppm (mice), by whole- body inhalation for 6 h/day, 5 days/ week far up to 18 months. Postexposure blood samples were collected after 1 day, 2 weeks, and 3, 6, 12, and 18 mo nths of exposure. Postexposure 16-h urine samples were collected after 2 we eks and 3, 6, 12, and 18 months of exposure. A separate set of mice was kep t in the control chamber and exposed to 2BE for 3 weeks when they were appr oximately 19 months old. Postexposure blood samples were collected after 1 day and 3 weeks of exposure and 16-h urine samples were collected after 2 w eeks of exposure from these aged mice. Blood samples were analyzed for both 2BE and 2BAA and urine samples were analyzed for 2BAA using GC/MS, and the ir kinetic parameters were estimated through the curve-fitting method using SAS. Systemically absorbed 2BE was rapidly cleared from blood (t(1/2-RAT) < 10 min; t(1/2-MOUSE) < 5 min after the 1-day exposure) independent of exp osure concentration. proportional increases in AUC(2BE) relative to increas es in exposure concentration indicated linear 2BE kinetics. In contrast, th e rate of 2BAA elimination from blood decreased as the exposure concentrati on increased. Nonproportional increases in AUC(2BAA) also indicated that 2B AA is eliminated following dose-dependent, nonlinear kinetics. Overall, mic e eliminated both 2BE and 2BAA from blood faster than rats. Sex-related dif ferences in 2BAA elimination were most significant with rats, in that femal es were less efficient in clearing 2BAA from the blood. Differences in rena l excretion of 2BAA are possibly responsible for the sex-related difference in the 2BAA blood profiles in rats. As exposure continued, the rates of el imination for both 2BE and 2BAA decreased in both species, resulting in lon ger residence times in the blood. When 19-month-old naive mice were exposed to 125 ppm, 2BE was rapidly cleared from the systemic circulation, exhibit ing clearance profiles similar to young mice. However, old mice eliminated 2BAA from blood > 10 times slower than young mice after 1-day of exposure. This delayed elimination of 2BAA in old mice was less obvious after 3 weeks of exposure, suggesting that there might be other factors in addition to t he age of animals that could influence the apparent difference in 2BAA kine tics between old and young mice. It was concluded that the elimination kine tics of 2BE and 2BAA following repeated 2BE exposure appear to be dependent on species, sex, age, time of exposure, as well as the exposure concentrat ion. (C) 1998 Academic Press.