ISOPROPANOL VAPOR INHALATION ONCOGENICITY STUDY IN FISCHER-344 RATS AND CD-1 MICE

The potential oncogenic effects of isopropanol, a widely used solvent, were investigated, Four groups of animals, each consisting of 75 CD-1 mice/sex and 75 Fischer 344 rats/sex, were exposed to isopropanol vap or (GAS No. 67-63-0) at target concentrations of 0 (filtered air contr ol), 500, 2500, or 5000 ppm. Animals assigned to the core group (55 mi ce/sex/group and 65 rats/sex/group) were exposed for 6 hr/day, 5 conse cutive days/week for at least 78 weeks for the mice or 104 weeks for t he rats. Ten mice/sex/group and 10 rats/sex/group were assigned to an interim euthanasia group and were terminated during Weeks 54 and 73, r espectively. In addition, 10 mice/sex/group were assigned to a recover y group and did not receive any further exposure following Week 53 but were retained until the core group of animals was euthanized. Transie nt signs of narcosis were observed for both mice and rats during expos ure to 2500 and 5000 ppm and following exposure for mice from the 5000 -ppm group, Increased mortality (100% versus 82% for controls) and a d ecreased mean survival time (577 days versus 631 days for controls) we re noted for male rats from the 5000-ppm group, Increases in body weig ht and/or body weight gain were typically observed for both sexes of m ice and rats from the 2500- and 5000-ppm groups throughout the study. Urinalysis and urine chemistry changes indicative of impaired kidney f unction (i.e., decreased osmolality and increased total protein, volum e, and glucose) were noted for male rats from the 2500-ppm group as we ll as for male and female rats from the 5000-ppm group, At the interim euthanasia, a concentration-related increase in testes weight (absolu te and relative as a percentage of body and brain weight) was observed for male rats. Concentration-related increases in absolute and relati ve liver weight (as a percentage of body weight) were observed for mal e and female mice. In addition, increased absolute and/or relative (as a percentage of body and brain weight) liver and kidney weights were observed for male and/or female rats from the 2500- and 5000-ppm group s, At necropsy, an increased incidence of seminal vesicle enlargement was observed grossly for male mice from the 2500- and 5000-ppm groups. Microscopically, some of the nonneoplastic lesions noted for mice inc luded an increased incidence of ectasia of the seminal vesicles for ma le mice from the 2500- and 5000-ppm groups, minimal renal tubular prot einosis for male and female mice from all isopropanol groups, and rena l tubular dilation for female mice from the 5000-ppm group. A number o f nonneoplastic lesions were observed for male and female rats from th e 2500- and 5000-ppm groups, with the most significant lesions being o bserved in the kidney and associated with chronic renal disease, The l esions noted with increased severity and/or frequency included mineral ization, tubular dilation, glomerulosclerosis, interstitial nephritis, interstitial fibrosis, hydronephrosis, and transitional cell hyperpla sia. The only tumor type increased in incidence during the study was i nterstitial cell adenomas of the testes in male rats, However, the inc rease in these adenomas was not believed to be exposure-related due to an unusually low incidence observed for the control group. There were no increased frequencies of neoplastic lesions noted for male or fema le mice or for female rats from any isopropanol exposure group. Chroni c renal disease was attributed to be the main cause of death for male and female rats from the 5000-ppm group and was also considered to acc ount for much of the mortality observed for male rats from the 2500-pp m group, In conclusion, the no-observed-effect level (NOEL) for toxic effects for both rats and mice was 500 ppm, The NOEL for oncogenicity effects for both mice and rats was determined to be greater than 5000 ppm. (C) 1997 Society of Toxicology.