ONCOGENICITY TESTING OF 2-ETHYLHEXANOL IN FISCHER-344 RATS AND B6C3F1MICE

2-Ethylhexanol (2EH) is a weak nongenotoxic hepatic peroxisome prolife rator in the rat. It is a high-volume chemical intermediate in the pre paration of the plasticizers bis-(2-ethylhexyl) adipate (DEHA), bis-(2 -ethylhexyl) phthalate (DEHP), and tris(2-ethylhexyl) phosphate (TEHP) , which are weak hepatocellular tumorigens in female mice. In conseque nce, the oncogenic potential of 2EH was evaluated in male (M) and fema le (F) rats and mice (50 animals/sex/group). Oral gavage doses of 2EH in 0.005% aqueous Cremophor EL (polyoxyl-35 castor oil) were given fiv e times a week to rats: 0 (water), 0 (vehicle), 50, 150, and 500 mg/kg for 24 months, and to mice: 0 (water), 0 (vehicle), 50, 200, and 750 mg/kg for 18 months. Statistical comparisons of data were made between vehicle controls and treatment groups. There were no differences of b iological significance between data from vehicle and water control gro ups. In rats, there were no dose-related changes at 50 mg/kg. There wa s reduced body weight gain at 150 mg/kg (M, 16; F, 12%) and 500 mg/kg (M, 33; F, 31%) and an increased incidence of lethargy and unkemptness . There were dose-related increases in relative liver, stomach, brain, kidney, and testis weights at sacrifice. Female rat mortality was mar kedly increased at 500 mg/kg. There was marked aspiration-induced bron chopneumonia in rats at 500 mg/kg; hematologic, gross, and microscopic changes, including tumors, were otherwise comparable among all rat gr oups. In mice at 50 and 200 mg/kg there were no dose-related changes a nd essentially no time-dependent or time-independent adverse trends in liver tumor incidence at the 5% significance level. At 750 mg/kg mous e body weight gain was reduced (M, 26; F, 24%), and mortality increase d (M and F, 30%) versus vehicle controls. At 750 mg/kg there was a sli ght increase in nonneoplastic focal hyperplasia in the forestomach of mice OSI 5/50, F 4/50) versus vehicle controls (M 1/50, F 1/50). There were increases in mouse relative liver (F, 21%) and stomach (M, 13%; F, 19%) weights at 750 mg/kg. There was a 12% incidence of hepatic bas ophilic foci and an 18% incidence of hepatocellular carcinomas in male mice at 750 mg/kg, not statistically significant compared with either control by Fisher's exact test. There was a 12% incidence of hepatic basophilic foci and a 10% incidence of hepatocellular carcinomas in fe male mice at 750 mg/kg, statistically significant (p < 0.05) compared with vehicle but not with water controls by Fisher's exact test. There were no metastases. Time-dependent and -independent statistical analy ses showed an adverse trend in the incidence of hepatocellular carcino mas in male and female mice, correlated with toxicity (expressed as mo rtality) at 750 mg/kg. The time-adjusted incidence of hepatocellular c arcinomas in male mice (18.8%) was within the historical normal range at the testing facility (0-22%), but that in females (13.1%) lay outsi de the normal range (0-2%). Under the conditions of these studies 2EH was not oncogenic in rats, but there were weak adverse trends in hepat ocellular carcinoma incidence in mice at high dose levels which may ha ve been associated with toxicity. The major effects of chronic dosing were mortality in female rats at 500 mg/kg and in male and female mice at 750 mg/kg, accompanied by reductions in body weight gain in rats a t 150 and 500 mg/kg and in mice at 750 mg/kg. Direct comparison of any tumorogenic effects of 2EH given alone to female mice with those due to 2EH formed in vivo from DEHA, DEHP, or TEHP is limited by the high mortality caused by 2EH in female mice at equivalent doses of 2EH. Whi le 2EH may be a contributing factor in the hepatocellular carcinogenes is in female mice associated with the chronic administration of DEHA a nd DEHP, it is unlikely to be the entire proximate carcinogen. (C) 199 6 Society of Toxicology