Oncogenicity Testing of 2-Ethylhexanol in Fischer 344 Rats and B6C3F1 Mice

2-Ethylhexanol (2EH) is a weak nongenotoxic hepatic peroxisomeproliferator in the rat. It is a high-volume chemical intermediatein the preparation of the plasticizers bis-(2-ethylhexyl) adipate(DEHA), bis-(2-ethylhexyl) phthalate (DEHP), and tris-(2-ethylhexyl)phosphate (TEHP), which are weak hepatocellular tumorigens infemale mice. In consequence, the oncogenic potential of 2EHwas evaluated in male (M) and female (F) rats and mice (50 animals/sex/group).Oral gavage doses of 2EH in 0.005% aqueous Cremophor EL (polyoxyl-35castor oil) were given five 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 controlsand treatment groups. There were no differences of biologicalsignificance between data from vehicle and water control groups.In rats, there were no dose-related changes at 50 mg/kg. Therewas reduced body weight gain at 150 mg/kg (M, 16; F, 12%) and500 mg/kg (M, 33; F, 31%) and an increased incidence of lethargyand unkemptness. There were dose-related increases in relativeliver, stomach, brain, kidney, and testis weights at sacrifice.Female rat mortality was markedly increased at 500 mg/kg. Therewas marked aspiration-induced bronchopneumonia in rats at 500mg/kg; hematologic, gross, and microscopic changes, includingtumors, were otherwise comparable among all rat groups. In miceat 50 and 200 mg/kg there were no dose-related changes and essentiallyno time-dependent or time-independent adverse trends in livertumor incidence at the 5% significance level. At 750 mg/kg mousebody weight gain was reduced (M, 26; F, 24%), and mortalityincreased (M and F, 30%) versus vehicle controls. At 750 mg/kgthere was a slight increase in nonneoplastic focal hyperplasiain the forestomach of mice (M 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 basophilic foci and an18% incidence of hepatocellular carcinomas in male mice at 750mg/kg, not statistically significant compared with either controlby Fisher's exact test. There was a 12% incidence of hepaticbasophilic foci and a 10% incidence of hepatocellular carcinomasin female mice at 750 mg/kg, statistically significant (p <0.05) compared with vehicle but not with water controls by Fisher'sexact test. There were no metastases. Time-dependent and -independentstatistical analyses showed an adverse trend in the incidenceof hepatocellular carcinomas in male and female mice, correlatedwith toxicity (expressed as mortality) at 750 mg/kg. The time-adjustedincidence of hepatocellular carcinomas in male mice (18.8%)was within the historical normal range at the testing facility(0–22%), but that in females (13.1%) lay outside the normalrange (0–2%). Under the conditions of these studies 2EHwas not oncogenic in rats, but there were weak adverse trendsin hepatocellular carcinoma incidence in mice at high dose levelswhich may have been associated with toxicity. The major effectsof chronic dosing were mortality in female rats at 500 mg/kgand in male and female mice at 750 mg/kg, accompanied by reductionsin body weight gain in rats at 150 and 500 mg/kg and in miceat 750 mg/kg. Direct comparison of any tumorogenic effects of2EH given alone to female mice with those due to 2EH formedin vivo from DEHA, DEHP, or TEHP is limited by the high mortalitycaused by 2EH in female mice at equivalent doses of 2EH. While2EH may be a contributing factor in the hepatocellular carcinogenesisin female mice associated with the chronic administration ofDEHA and DEHP, it is unlikely to be the entire proximate carcinogen.     

Studies on the Prenatal Toxicity of 3-Methyl-1-butanol and 2-Methyl-1-propanol in Rats and Rabbits Following Inhalation Exposure

3-Methyl-1-butanol (MEB) and 2-methyl-1-propanol (MEP) weretested for their prenatal inhalation toxicity in pregnant Wistarrats or Himalayan rabbits. Twenty-five female rats and 15 femalerabbits per group were exposed to MEB and MEP vapors at concentrationsof 10, 2.5, or 0.5 mg/liter, 6 hr/day. The rats were exposedon Days 6–15 postcoitum (pc) and the rabbits were exposedon Days 7–19 postinsemination (pi). Control groups wereexposed to clean air. The body weights of the animals of eitherspecies were determined several times throughout the studies.All rats and all rabbits were killed on Day 20 pc and Day 29pi, respectively. The fetuses were removed from the uterus andexamined for compound-related effects. The high concentrationof 10 mg/liter caused a slight retardation of body weight gainin the dams of either species exposed to MEB and in the damsof rabbits exposed to MEP during the first days of the exposureperiod. Eye irritation was observed only in the MEB-treatedrabbits during the period of exposure to 10 mg/liter. The fetusesof either species exhibited no signs of embryo-/fetotoxicityor teratogenic effects caused by MEP or MEB. Under the experimentalconditions, 2.5 mg/liter was found to be a no-observable-adverse-effectlevel (NOAEL) for the dams of either species exposed to MEBand for the does exposed to MEP, whereas 10 mg/liter MEP wasthe NOAEL for the maternal rats. For both substances 10 mg/literwas defined as the NOAEL for the conceptuses of either species.     

Effect of fluoride treatment on remineralization of bleached enamel

summary The objective of the study was to evaluate the remineralizing capacity of different fluoride treatments on dental enamel bleached with carbamide peroxide (Opalescence®). Sixty bovine enamel slabs were subjected to four cycles comprising bleaching (12 h) and remineralization in artificial saliva (8 h). The samples were evenly distributed among four groups (A-D). During the first hour of the remineralization period the specimens in group A were covered with a fluoride varnish (Duraphat®; 2.23% F⁻). In group B the enamel slabs were stored in a fluoride solution (0.2% F⁻ as NaF) for 1 min prior to remineralization. Group C did not receive a fluoride treatment, and group D (control) was stored in distilled water instead of bleaching. Microhardness (VHN) was evaluated before the experimerits and after the second and fourth cycle, respectively. Final hardness was calculated as percentage of the initial hardness. Analysis of variance was applied to the data followed by pairwise comparisons with corrected level of significance ( P < 0.01). Hardness decreased significantly in groups A-C compared to the control group (D). The bleached and unfluoridated specimens (group C) showed a significantly higher hardness loss compared to the fluoridated specimens, whereas no significant difference was observed between the two fluoridated groups. It is concluded that remineralization of bleached enamel is improved by application of highly concentrated fluorides.