Effects of a thirteen-week inhalation exposure to ethyl tertiary butyl ether on fischer-344 rats and CD-1 mice

Abstract

The 1990 Clean Air Act Amendments require that oxygenates be added to automotive fuels to reduce emissions of carbon monoxide and hydrocarbons. One potential oxygenate is the aliphatic ether ethyl tertiary butyl ether (ETBE). Our objective was to provide data on the potential toxic effects of ETBE. Male and female Fisher 344 rats and CD-1 mice were exposed to 0 (control), 500, 1750, or 5000 ppm of ETBE for 6 h/day and 5 days/wk over a 13-week period. ETBE exposure had no effect on mortality and body weight with the exception of an increase in body weights of the female rats in the 5000-ppm group. No major changes in clinical pathology parameters were noted for either rats or mice exposed to ETBE for 6 (rats only) or 13 weeks. Liver weights increased with increasing ETBE-exposure concentration for both sexes of rats and mice. Increases in kidney, adrenal, and heart (females only) weights were noted in rats. Degenerative changes in testicular seminiferous tubules were observed in male rats exposed to 1750 and 5000 ppm but were not seen in mice. This testicular lesion has not been reported previously for aliphatic ethers. Increases in the incidence of regenerative foci, rates of renal cell proliferation, and alpha2u-globulin containing protein droplets were noted in the kidneys of all treated male rats. These lesions are associated with the male rat-specific syndrome of alpha2u-globulin nephropathy. Increases in the incidence of centrilobular hepatocyte hypertrophy and rates of hepatocyte cell proliferation were seen in the livers of male and female mice in the 5000-ppm group, consistent with a mitogenic response to ETBE. These two target organs for ETBE toxicity, mouse liver and male rat kidney, have also been reported for methyl tertiary butyl ether and unleaded gasoline.

No carcinogenicity of ethyl <i>tertiary</i>-butyl ether by 2-year oral administration in rats

“…In the 13-week preliminary study preceding the current 2-year study, a significant enhancement of the degree of hyaline droplet accumulation in the renal tubular epithelium was noted in the kidneys of male rats administered 10,000 ppm ETBE in their drinking water. In another study, an increased incidence of α2u-globulin containing protein droplets was reported in male F344 rats exposed to ETBE vapor by inhalation for 13 weeks (Medinsky et al, 1999). These results suggest that the urothelial hyperplasia of the pelvis and the mineral deposition in the renal papilla observed in male rats administered ETBE in the present study resulted from accumulation of α2u-globulin in the renal tubular epithelium.…”

Physiologically based pharmacokinetic model for ethyl tertiary‐butyl ether and tertiary‐butyl alcohol in rats: Contribution of binding to α2u–globulin in male rats and high‐exposure nonlinear kinetics to toxicity and cancer outcomes

“…Unlike MTBE, there is no direct evidence for ETBE binding to the male‐rat‐specific protein α2u–globulin. However, there is indirect evidence – including evidence that ETBE causes α2u–globulin accumulation in the male rat kidney following inhalation exposure to ETBE (Medinsky et al ., 1999), as well as the reported high male rat kidney/air PC (Kaneko et al ., 2000) – suggesting that, besides solubility in the male rat kidney, there is another process affecting the uptake of ETBE into the tissue. Based on this specific information on MTBE, which is structurally similar to ETBE, along with the fact that other chemicals such as methanol, ethanol, 2‐propanol and 2‐methyl‐2 propanol have similar PCs in the liver and kidney (Meulenberg & Viverberg, 2000), assigning the same value to the kidney/blood PC and the liver/blood PC is warranted.…”

“…There is evidence that TBA binds to α2u–globulin (Williams & Borghoff, 2001), but there is no direct evidence that ETBE binds to this protein. However, indirect evidence supports ETBE binding to α2u–globulin, from a study in which ETBE‐exposed male rats developed pathological features associated with α2u–globulin nephropathy (Medinsky et al ., 1999). α2u–Globulin nephropathy is a syndrome associated with chemical binding to α2u–globulin, which results in decreased catabolism of this protein and its accumulation in the kidney in the form of protein droplets.…”

“…In a 90 day inhalation toxicity study carried out in male and female F344 rats at ETBE concentrations up to 5000 ppm, there was an increase in the liver weights in both male and female rats; in male rats only, there was a time‐ and concentration‐dependent increase in renal cell proliferation, along with increased protein droplet accumulation in the kidneys, with evidence of α2u–globulin immunoreactivity (Medinsky et al ., 1999). TBA, a major metabolite of ETBE, has also been shown to cause α2u–globulin nephropathy following exposure in drinking water (NTP, 1995) and via inhalation (Borghoff et al ., 2001; NTP, 1997) and has been shown to bind reversibly to α2u–globulin (Williams & Borghoff, 2001).…”

Aldh2 Knockout Mice Were More Sensitive to DNA Damage in Leukocytes due to Ethyl Tertiary Butyl Ether Exposure

“…However, in mice lacking ALDH2 enzyme activity, the DNA damage was detectable even at the lowest dose of ETBE (500 ppm), suggesting that low ALDH2 activity due to genetic polymorphisms may greatly increase the risk of adverse health effects of ETBE. Previous experimental animal studies have shown that substantial damage in liver and kidney is caused by chronic exposure to ETBE at concentrations of 1,750 ppm or higher 10) . However, we suggest that the threshold of toxicity, should be lowered to 500 ppm.…”