2-GENERATION REPRODUCTION TOXICITY STUDY WITH ISOPROPANOL IN RATS

A two generation reproduction toxicity study was conducted in rats wit h isopropanol. Thirty rats of each sex per group (P-1) were dosed once daily by oral gavage with 0, 100, 500 or 1000 mg isopropanol kg(-1) f or at least 10 weeks prior to mating. Parental animals were mated with in groups for up to 3 weeks. Parental females were dosed during mating , gestation and lactation; parental males were dosed during mating thr ough delivery of their last litter sired. The P-2 adults were selected from the F-1 litters and were dosed for 10-13 weeks before mating to produce a single litter. Findings in the parental animals included inc reased lactation body weight gain in the mid- and high-dose females, i ncreased liver and kidney weights in the mid- and high-dose groups of both sexes and centrilobular hepatocyte hypertrophy in some P-2 males. There was also accumulation of hyaline droplets and other microscopic findings in the kidneys from the mid- and high-dose P-1 males and fro m all treated groups of the P-2 males. Increased mortality was observe d in the high-dose F-1 offspring during the early postnatal period, al though no other clinical signs of toxicity were observed in the offspr ing of either generation. In addition, offspring body weight was reduc ed during the early postnatal period in the high-dose F-1 males and in the high-dose F-2 pups of both sexes. Eighteen out of 70 F-1 weanling s in the 1000 mg kg(-1) group died or were euthanized prior to P-2 sel ection. No treatment-related post-mortem findings were observed in the offspring from either generation. A statistically significant reducti on was observed in the male mating index of the high-dose P-2 males co mpared with that of the controls. However, no treatment-related micros copic changes in reproductive tissues or biologically meaningful diffe rences in other reproductive parameters were observed in adults of eit her generation. The no-observed effect-level (NOEL) for reproductive e ffects in this study, based on the reduced male mating index of the hi gh-dose P-2 males, is 500 mg kg(-1) day(-1).