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 agents and solvents. It is primarily metabolized in the liver to 2-butoxyacetic acid (2BAA), which is believed to be responsible for 2BE toxicities associated 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 during 2-year 2BE inhalation toxicity studies. Male and female F344 rats and B6C3F1 mice (6-7 weeks old) were exposed to target 2BE concentrations of 0, 31.2, 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 for up to 18 months. Postexposure blood samples were collected after 1 day, 2 weeks, and 3, 6, 12, and 18 months of exposure. Postexposure 16-h urine samples were collected after 2 weeks and 3, 6, 12, and 18 months of exposure. A separate set of mice was kept in the control chamber and exposed to 2BE for 3 weeks when they were approximately 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 weeks 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 their kinetic parameters were estimated through the curve-fitting method using SAS. Systemically absorbed 2BE was rapidly cleared from blood (t1/2-RAT < 10 min; t1/2-MOUSE < 5 min after the 1-day exposure) independent of exposure concentration. Proportional increases in AUC2BE relative to increases in exposure concentration indicated linear 2BE kinetics. In contrast, the rate of 2BAA elimination from blood decreased as the exposure concentration increased. Nonproportional increases in AUC2BAA also indicated that 2BAA is eliminated following dose-dependent, nonlinear kinetics. Overall, mice eliminated both 2BE and 2BAA from blood faster than rats. Sex-related differences in 2BAA elimination were most significant with rats, in that females were less efficient in clearing 2BAA from the blood. Differences in renal excretion of 2BAA are possibly responsible for the sex-related difference in the 2BAA blood profiles in rats. As exposure continued, the rates of elimination for both 2BE and 2BAA decreased in both species, resulting in longer residence times in the blood. When 19-month-old naive mice were exposed to 125 ppm, 2BE was rapidly cleared from the systemic circulation, exhibiting 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 the age of animals that could influence the apparent difference in 2BAA kinetics between old and young mice. It was concluded that the elimination kinetics of 2BE and 2BAA following repeated 2BE exposure appear to be dependent on species, sex, age, time of exposure, as well as the exposure concentration.
Dill
J A
JA
Preclinical Drug Development-Northwest Operations, Battelle, Richland, Washington, USA.
Lee
K M
KM
Bates
D J
DJ
Anderson
D J
DJ
Johnson
R E
RE
Chou
B J
BJ
Burka
L T
LT
Roycroft
J H
JH
D000280:Administration, Inhalation; D000367:Age Factors; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005026:Ethylene Glycols / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005260:Female; D006016:Glycolates / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D051381:Rats; D011916:Rats, Inbred F344; D012727:Sex Characteristics; D012997:Solvents / Q000493:pharmacokinetics*; D013045:Species Specificity; D013997:Time Factors
D005026:Ethylene Glycols; D006016:Glycolates; D012997:Solvents; C017095:n-butoxyacetic acid; C017096:n-butoxyethanol