. 2016 Nov 24;37(5):621–640. doi: 10.1002/jat.3412

Table 1.

ETBE cancer study findings

Reference	Species/ strain	Exposure	Non‐neoplastic and neoplastic lesions
Suzuki et al. (2012)	Rats/F344	ETBE drinking water: 0, 625, 2500 or 10 000 ppm Males: 0, 28, 121, 542 mg kg⁻¹ bw day⁻¹ Females: 0, 46, 171, 560 mg kg⁻¹ bw day⁻¹ 7 days week⁻¹ for 104 weeks	Non‐neoplastic: Increase in severity of CPN at 10 000 ppm in male and female rats. Increased incidence of urothelial hyperplasia of the pelvis and mineral deposition in the renal papilla at ≥2500 ppm in male rats. Neoplastic: No increase in tumor incidence detected in any organ up to the highest daily dose, estimated to be 542–560 mg kg⁻¹ bw day⁻¹
Saito et al. (2013)	Rats/F344	ETBE inhalation: Males and females: 0, 500, 1500 or 5000 ppm Exposure 6 h day⁻¹, 5 day week⁻¹ Note: authors reported that exposure concentration of 5000 ppm corresponded to a daily uptake of 4222 mg kg⁻¹ bw day⁻¹ in rats, assuming a minute volume of 561 ml min⁻¹ and lung absorption at 100%. However, this is an overestimate and assumes no exhalation of parent ETBE.	Non‐neoplastic: Increased incidence of eosinophilic and basophilic cell foci in male rats at 5000 ppm. Increase in severity of CPN at 5000 ppm in male and female rats. Increased incidence of urothelial hyperplasia of the pelvis at ≥1500 ppm and mineral deposition in the renal papilla at 5000 ppm in male rats. Neoplastic: Increased incidence of hepatocellular adenomas in male rats at 5000 ppm.
Hagiwara et al. (2015)	Rats/Wistar	Oral gavage: EHEN: 2 weeks initiation ETBE: 19 weeks promotion (0, 100, 300, 500 or 1000 mg kg⁻¹ bw day⁻¹, 5 days week⁻¹	Neoplastic: Increased incidence of hepatocellular adenomas and combined hepatocellular adenomas and carcinomas promoted with 1000 mg kg⁻¹. Increased average number of atypical tubule hyperplasia (pre‐neoplastic lesion).
Cirvello et al. (1995); NTP (1995)	Rats/F344	TBA drinking water: Males: 0, 1.25, 2.5 or 5 mg ml⁻¹ (average daily doses 85, 195 or 420 mg kg⁻¹ bw day⁻¹) for 104 weeks. Females: 0, 2.5, 5 or 10 mg ml⁻¹ (average daily doses 180, 330 or 650 mg kg⁻¹ bw day⁻¹) for 104 weeks.	Neoplastic: Increased incidence of renal tubule adenoma and carcinoma combined after extended evaluation in male rats at 2.5, but not 5 mg ml⁻¹ concentration. Transitional epithelial hyperplasia (extended evaluation) of the kidney in male rats (25: 50, 32: 50, 36: 50, 40: 50 with increasing concentrations), with CPN severity ranging from 3.1 to 3.3, and in female rats (0: 50, 0: 50, 3: 50, 1: 50 with increasing concentrations), with CPN severity ranging from 1.6 to 2.9.

CPN, chronic progressive nephropathy; EHEN, N‐ethyl‐N‐(2‐hydroxyethyl)nitrosamine; ETBE, ethyl tertiary‐butyl ether; TBA, tertiary‐butyl alcohol.