Blood pharmacokinetics of tertiary amyl methyl ether in male and female F344 rats and CD‐1 mice after nose‐only inhalation exposure

Abstract

Interest in understanding the biological behavior of aliphatic ethers has increased owing to their use as gasoline additives. The purpose of this study was to investigate the blood pharmacokinetics of the oxygenate tertiary amyl methyl ether (TAME), its major metabolite tertiary amyl alcohol (TAA) and acetone in rats and mice following inhalation exposure to TAME. Species differences in the area under the curve (AUC) for TAME were significant at each exposure concentration. For rats, the blood TAME AUC increased in proportion with an increase in exposure concentration. For mice, an increase in exposure concentration (100-500 ppm) resulted in a disproportional increase in the TAME AUC. Mice had greater (two- to threefold) blood concentrations of TAA compared with rats following exposure to 2500 or 500 ppm TAME. Mice had a disproportional increase in the TAA AUC with an increase in exposure concentration (100-500 ppm). This difference could result from saturation of a process (e.g. oxidation, glucuronide conjugation) that is involved in the further metabolism of TAA. For each species, gender and exposure concentration, acetone increased during exposure and returned to control values by 16 h following exposure. The source of acetone could be both as a metabolite of TAA or an effect on endogenous metabolism produced by exposure to TAME.

Species and gender differences in the metabolism and distribution of tertiary amyl methyl ether in male and female rats and mice after inhalation exposure or gavage administration

“…This may indicate a more rapid clearance of TAME during the inhalation exposure for mice, resulting in a higher and more rapid uptake. A longer half-life for TAME and TAA in blood of rats (TAME, 0.6 -1.4 h; TAA, 1-1.7 h) compared with mice (TAME, 0.3 -0.5 h; TAA, 0.2-0.8 h) is consistent with these measurements (Sumner et al, 2003b).…”

“…Details concerning the conduct of the nose-only inhalation exposure were reported previously (Sumner et al, 2003b). Rats used for metabolism and distribution studies and cannulated rats used for the time-course collection of blood were exposed on the same day.…”

“…At the end of each 6-h nose-only exposure, four additional rats and four additional mice were sacrificed immediately for determination of the total retained [ 14 C]TAME equivalents (Sumner et al, 2003a). In addition, following inhalation exposure and gavage administration of [ 14 C]TAME, four rats and four mice were transported to glass metabolism cages for the collection of urine (over dry ice, 0-8, 8-24 and 24-48 h), feces (0-24 and 24-48 h), exhaled volatile organics (two charcoal traps in series) and 14 CO 2 (0-1, 1-3, 3-6, 6-8, 8-24 and 24-48 h) after termination of exposure (Sumner et al, 2003b). Rats and mice were euthanized (by CO 2 ) 48 h after termination of exposure and necropsied for the collection of blood and tissues (abdominal fat, subcutaneous fat, blood, brain, femur, heart, kidney, large intestine, small intestine, liver, lung, muscle, skin, spleen, stomach, testes (male), ovaries and uterus (female) and residual carcass.…”

“…For both species and gender, blood radioactivity decreased by >90% between 0 and 48 h after termination of exposure. The sums of the concentrations of TAME and TAA measured 0, 4, 10 and 18 h after termination of exposures (Sumner et al, 2003b) were compared with the [ 14 C]TAME equivalents measured via scintillation counting (Table 3). For rats, TAME and TAA accounted for ≥85% of the [ 14 C]TAME equivalents in blood immediately following exposure to 2500 ppm TAME, whereas these compounds accounted for ≥62% of the radioactivity in mice.…”

“…Exhaled volatile [ 14 C] equivalents were extracted from the charcoal traps using N,N-dimethylformamide (DMF) and aliquots of the extracts were analyzed directly by liquid scintillation counting (LSC). The concentrations of TAME and TAA in the extracts were determined using gas chromatographic analysis (Sumner et al, 2003b). Previously HPLC was used to separate and isolate three peaks from urine obtained from male rats exposed to 2500 ppm [ 13 C/ 14 C]TAME (Sumner et al, 2003a).…”