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

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

“…To determine exposure concentrations above which the kinetics of ETBE and TBA become nonlinear, the model was used to simulate ETBE blood AUC 0–∞ following either single oral gavage administration or 6 h inhalation exposure to ETBE at the concentrations used in two separate cancer bioassays (Saito et al ., 2013; Suzuki et al ., 2012); the results are presented in Fig. 11.…”

“…12, this model predicts that an inhalation exposure of 5000 ppm corresponds to an inhaled dose level of ~842–860 mg kg −1 bw day −1 . This dose level is ~1.5‐fold higher than the oral dose in the ETBE drinking‐water study in which no liver tumors were observed (Suzuki et al ., 2012), suggesting that tumors in the male rat develop an ETBE concentration at which the metabolism is saturated.…”

“…It was also negative in two in vivo micronucleus assays, with one assay finding no micronucleus formation in the bone marrow following ETBE exposure of rats and mice via drinking water (Noguchi et al ., 2013). However, two reliable ETBE cancer bioassays were conducted in male and female F344 rats via different routes of administration – inhalation (ETBE at 0, 400, 1500 and 5000 ppm, 6 h day −1 , 5 days week −1 for 104 weeks) (Saito et al ., 2013) and drinking‐water exposure (at estimated daily dose levels up to 560 mg kg −1 bodyweight (bw) day −1 ) (Suzuki et al ., 2012). At the highest inhalation exposure concentration of 5000 ppm, male rats exhibited an increased incidence of hepatocellular adenomas (only one rat had a hepatocellular carcinoma), as well as an increased incidence of eosinophilic and basophilic cell foci, both of which are considered pre‐neoplastic lesions.…”

“…At the highest inhalation exposure concentration of 5000 ppm, male rats exhibited an increased incidence of hepatocellular adenomas (only one rat had a hepatocellular carcinoma), as well as an increased incidence of eosinophilic and basophilic cell foci, both of which are considered pre‐neoplastic lesions. No neoplastic lesions were observed in the chronic drinking‐water study, which was conducted at ETBE concentrations that resulted in estimated daily dose levels up to 560 mg kg −1 bw day −1 (Suzuki et al ., 2012). In both the ETBE inhalation and drinking‐water chronic studies, there were increased severities of chronic progressive nephropathy in male and female rats, with an increase in urothelial hyperplasia of the renal pelvis and mineral deposition in the renal papilla in male rats exposed to the highest concentrations.…”

Lack of micronucleus induction activity of ethyl <i>tertiary</i>-butyl ether in the bone marrow of F344 rats by sub-chronic drinking-water treatment, inhalation exposure, or acute intraperitoneal injection

“…Maltoni et al (1999) administered ETBE to male and female SD rats by oral gavage for 104 weeks and found a significant dose-related increase of mouth and forestomach tumors, uterus malignant tumors and hemolymphoreticular neoplasms, and Hagiwara et al (2011) using a multi-organ carcinogenesis bioassay found that ETBE promoted tumorigenesis of the thyroid, forestomach, colon, liver, kidney and urinary bladder in male rats by oral gavage for 28 weeks. In contrast, Suzuki et al (2012) administered ETBE to male and female rats in the drinking water for 104 weeks and found that ETBE did not have any carcinogenic effect. Thus, the results of the carcinogenicity studies of ETBE are mixed.…”