Pharmacokinetics and disposition of methyl t-butyl ether in Fischer-344 rats.

Methyl t-butyl ether (MTBE) is a commonly used octane booster in gasoline. This study examines the pharmacokinetics and disposition of MTBE in Fischer-344 rats after i.v., oral, dermal and inhalation routes of administration. Groups of male and female rats were given single i.v. (40 mg kg-1), oral (40 and 400 mg kg-1) and dermal (40 and 400 mg kg-1 in occluded chambers) doses of [14C]MTBE. For inhalation studies, rats were exposed nose-only for 6 h to low (400 ppm), high (8000 ppm) and repeated daily 6-h low (400 ppm x 15 days) chamber concentrations of [14C]MTBE. Blood, expired air, and excreta (urine and feces) were collected at selected times up to 7 days post-dose and quantified for 14C content. Plasma concentrations of MTBE and t-butyl alcohol (TBA) were quantified and mean values used for pharmacokinetic analysis. The mean total recoveries of 14C ranged from 91 to 105%. Methyl t-butyl ether was rapidly and completely absorbed after oral and inhalation exposures; dermal absorption was low. After all routes, MTBE was rapidly eliminated from blood (ti = 0.5 h) by exhalation and metabolism to TBA. At the high doses, metabolism was saturated and the proportion of renal 14C excretion decreased relative to the pulmonary route. At 48 h post-exposure, virtually all of the 14C was eliminated. The major metabolites recovered in urine were 2-methyl-1,2-propanediol and alpha-hydroxyisobutyric acid. There were no significant gender or route-dependent differences in the pharmacokinetics and disposition of MTBE.

Two-generation reproductive toxicity study of methyl tertiary-butyl ether (MTBE) in rats.

A two-generation reproductive toxicity study of methyl tertiary-butyl ether (MTBE) was conducted in Sprague-Dawley rats. Twenty-five rats of each sex (F0) were exposed by inhalation to 0, 400, 3000 or 8000 ppm MTBE vapor, 6 h a day for 10 weeks prior to mating. Parental animals were then mated within groups for up to 3 weeks. Parental females were exposed during mating, gestation and lactation (starting on day 5); parental males were exposed during mating through delivery of their last litter sired. The F1 adults were selected from the F1 litters and were exposed beginning on postnatal day 28 for at least 8 weeks before mating to produce F2 litters. During exposures to 3000 and 8000 ppm MTBE, group observations included hypoactivity and lack of startle reflex in parental animals from both generations. Parental animals at 8000 ppm were also ataxic. During the pre-mating period, body weights of the 8000 ppm males from both generations and the F1 females were significantly reduced compared to control animals. Transient body weight reduction was also observed in the 3000 ppm F1 males and females during the pre-mating period. Lactational body weights were increased in the 8000 ppm females from both generations. In the F1 generation, increased liver weights were noted in the 3000 and 8000 ppm animals for both sexes, although histopathological examination revealed no treatment-related effects. There were no treatment-related reproductive effects noted in any of the parameters measured in this study. Offspring survival was equivalent among treated and control groups from both generations, and there were no remarkable post-mortem findings. There was, however, a significant increase in dead F2 pups in the 8000 ppm group on postnatal day 4. The F1 litters at 3000 and 8000 ppm had lowered body weights from postnatal days 14-21 and 14-28, respectively. The F2 generation of pups at 3000 and 8000 ppm also exhibited lowered body weights from postnatal days 14-28 and 7-28, respectively. Body weight gains in both the F1 and F2 litters were also reduced for the corresponding time intervals. Thus, exposure to MTBE vapor produced no reproductive toxicity to two generations of Sprague-Dawley rats even in the presence of parental toxicity at 3000 and 8000 ppm. Postnatal toxicity was observed in the offspring of both generations, but only in the presence of maternal toxicity. The no-observed-effect level (NOEL) for both parental and postnatal toxicity is 400 ppm, and the NOEL for reproductive toxicity is at least 8000 ppm.

Assessment of the in vivo mutagenic potential of methyl tertiary-butyl ether.

Methyl tertiary-butyl ether (MTBE) is one of the highest production volume chemicals in the USA. Previous results from in vitro genetic toxicity studies suggested that it was not mutagenic. However, chronic exposure at high levels resulted in liver tumors in female mice and kidney tumors in male rats. The current program assessed in vivo genotoxicity and also explored the possibility that a mutagenic mechanism was involved in the carcinogenic process. The specific tests used included the Drosophila sex-linked-recessive-lethal test, the rat bone marrow cytogenetics test, the mouse bone marrow micronucleus test and the in vivo-in vitro hepatocyte unscheduled DNA synthesis test in the mouse. All tests produced negative results, indicating that the potential for in vivo mutagenic activity was low. These data also suggest that the tumorigenic activity was probably the result of a non-genotoxic process.

Oncogenicity studies of inhaled methyl tertiary-butyl ether (MTBE) in CD-1 mice and F-344 rats.

Oncogenicity studies of methyl tertiary-butyl ether (MTBE) vapor were conducted in CD-1 mice and Fischer 344 rats. Fifty animals of each sex per species per group were exposed for 6 h a day, 5 days per week to 0 (control), 400, 3000 and 8000 ppm MTBE vapor in air for 18 months (mice) and 24 months (rats). Both species showed reversible central nervous system depression at 8000 ppm for the first week of exposure, which continued for mice for the study duration. For the 8000 ppm mice, reduced body weight gain and early mortality prior to terminal euthanasia were exposure related. In the males, these deaths appear to be due to exacerbation of uropathy or dysuria, which occurs spontaneously in this strain. Increases in absolute and relative liver (both sexes) and kidney weight (males only) were seen at 3000 and 8000 ppm and decreases in brain and spleen weights were also noted (the latter decreases were without microscopic lesions and occurred at 8000 ppm only). An increase in hepatocellular hypertrophy occurred in both sexes at the two highest concentrations. The only neoplastic lesion found in this study in mice was an increased incidence of hepatocellular adenomas in females at the 8000 ppm exposure. In a follow-up study, a statistically significant elevation of cell proliferation in female mouse liver has been shown to occur following 5 days, but not 28 days, of exposure to 8000 ppm MTBE, suggesting that MTBE induces mitogenesis. For male rats, early euthanasia was required at week 82 and week 97 for the 8000 and 3000 ppm groups, respectively, due to excessive mortality from a severe progressive nephrosis. The end stage of this process appeared earlier in the male rats of all MTBE exposure groups; the incidence of this lesion and mortality for exposed females was comparable to control females. No exposure-related changes in hematological parameters were observed for any group at any time point, but a decrease in corticosterone levels was seen for male rats from the 8000 ppm group. Absolute and relative kidney and liver weight increases occurred in 3000 and 8000 ppm exposure groups, but the liver weight change was not accompanied by histopathological change. At study termination, increases in the incidence and severity of a chronic nephropathy in males from all exposure groups and in females exposed to 3000 and 8000 ppm was associated with secondary lesions of hyperplasia of the parathyroid and mineralization of tissues. Renal tubular cell tumors were increased in male rats exposed to 3000 and 8000 ppm. This may be associated with an accumulation of protein (stainable by Mallory's Heidenhain) in kidney tubular epithelial cells after 4 weeks of exposure. An increased incidence of interstitial cell adenomas of the testes was seen in males exposed to 3000 and 8000 ppm but was believed to be an artefact of an unusually low control incidence and not considered to be exposure related. Based on the above effects, the no-observed-effect level (NOEL) for chronic toxicity is 400 ppm, and the NOEL for carcinogenic effects is 3000 ppm (mice) and 400 ppm (rats).

Evaluation of 13-week inhalation toxicity study on methyl t-butyl ether (MTBE) in Fischer 344 rats.

Methyl-t-butyl ether (MTBE) is widely used as an octane enhancing agent in gasoline. A 13-week inhalation study was conducted in Fischer 344 rats to provide information on potential target organs and toxicity of MTBE, and to ascertain a no-observed-adverse-effect level (NOAEL) for MTBE. Male and female Fischer 344 rats were exposed to target doses of MTBE vapor of 0, 800, 4000 and 8000 ppm for 6 h a day, 5 days per week for 13 weeks: MTBE produced no mortalities. At 8000 ppm, males and females showed a decrease in body weights compared to controls. The only notable effect on clinical observation was ataxia at 8000 ppm, which was apparent during the first 4 weeks of treatment. Mild hematological and clinical chemistry changes were observed in the 8000 ppm group. At 8000 ppm, animals showed increased serum levels of corticosteroids, which suggest some stress-like effect. At necropsy, there were no treatment-related gross lesions. Absolute and relative organ weights (liver, adrenals and kidneys) were increased in both sexes at 4000 and 8000 ppm, but there were no microscopic lesions in these tissues with the exception of the kidney. Microscopic examination of other tissues revealed no effects with the exception that at 8000 ppm, male rats showed: mild increased size of hyaline droplets within the kidney, mild increase in hemosiderosis in the spleen and higher incidence of hyperplasia in the lymph nodes. The highest NOAEL was judged at 800 ppm.

Neurotoxicological evaluation of methyl tertiary-butyl ether in rats.

Methyl tertiary-butyl ether (MTBE) is an oxygenate that is added to gasoline to boost octane and enhance combustion, thereby reducing carbon monoxide and hydrocarbon tailpipe emissions. The acute and subchronic neurotoxicity of MTBE were evaluated in rats using a functional observation battery (FOB), measures of motor activity (MA) and a neuropathological evaluation. In the acute study, rats were exposed once to 0, 800, 4000 or 8000 ppm MTBE by inhalation for 6 h and then evaluated three times over a 24-h period. In the FOB evaluations, treatment-related effects were seen at the 1-h session immediately following exposure and were indicative of transient central nervous system (CNS) depression. Effects were most apparent in the high-dose group (8000 ppm) but were also evident to a lesser extent in the mid-dose (4000 ppm) group. Labored respiration, ataxia, duck-walk gait and decreases in muscle tone, hind-limb grip strength and treadmill performance were the most frequently noted findings. No significant effects were observed in the FOB when testing was conducted at 6 h and 24 h post-exposure. The pattern of motor activity measured in the different dose groups following exposure was also in keeping with a reversible CNS-depressant effect of MTBE. In the subchronic study, rats were exposed to 0, 800, 4000 or 8000 ppm MTBE for 6 h a day, 5 days per week, for 13 weeks. No persistent or cumulative effects on neurobehavioral function were found. Body weights and absolute brain weights were reduced in the 8000 ppm group, however there were no differences among groups when brain weight was expressed relative to body weight. No histopathological changes were noted in the brains or peripheral nervous tissues of MTBE-exposed animals. In summary, MTBE produced signs of acute reversible CNS depression following exposure to 8000 ppm and, to a lesser extent, to 4000 ppm vapor. The no-observed-adverse-effect level for these effects was 800 ppm in the present study. No persistent or cumulative neurotoxic effects were observed following exposure to MTBE at concentrations up to 8000 ppm for 13 weeks.