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In this 2-year study, the suitability of the Hsd:Sprague-Dawley SD (SD) as a replacement for the Crl:CD BR (CD) rat was assessed by comparing survival rates, palpable mass incidence, body weights, food consumption, clinical laboratory parameters, and necropsy and histopathology observations. At week 104, survival rates in the CD and SD males were 29 and 49%, respectively. Corresponding survival rates in females were 44 and 63%. The total numbers of animals with palpable masses and animals with neoplasms were similar in the CD and SD rats; however, the total numbers of palpable masses and neoplasms were higher in the CD rats. The incidence of corneal lesions was higher in the SD rats, whereas the incidence of lenticular opacities was higher in the CD rats. Body weights, food and water consumption, and organ weights were significantly lower in the SD rats. In contrast, food intake per kilogram of body weight was slightly higher in the SD rats. Numerous differences in clinical laboratory parameters between the CD and SD rats were observed. Some of these were consistent with the increased prevalence of kidney disease and secondary sequelae in the SD rats. Taken together, the better survival, smaller size, and lower food consumption of the SD rat may make it a better model for chronic bioassays. However, the increased propensity for spontaneous renal disease may limit the utility of the SD rat for studying nephrotoxic compounds.

Inhalation studies were conducted to determine the potential toxicity and/or potential neurotoxicity of cyclohexane. Groups of rats and mice were exposed to 0, 500, 2000, or 7000 ppm concentrations of cyclohexane vapor 6 hr/day, 5 days/week for 14 weeks. Subgroups of rats and mice were further observed during a 1-month recovery period. Functional observational battery (FOB) and motor activity (MA) behavioral tests were conducted on rats. These tests were conducted prior to the exposure series and during weeks 4, 8, and 13 on non-exposure days. Clinical pathology evaluations were conducted after approximately 7, 13, and 18 weeks. Approximately 14 and 18 weeks after study initiation, tissues from rats and mice were histologically processed and evaluated by light microscopy. During exposure to 2000 or 7000 ppm, rats and mice had a diminished response or an absent response to delivery of a punctate auditory alerting stimulus. Immediately following removal of rats from the inhalation chambers, 7000 ppm males and females and 2000 ppm females displayed a compound-related increase in the incidence of wet and/or stained fur (which occurred in the areas of the mouth, chin, and/or perineum). These signs were transient, were not observed during exposure or prior to exposure the following day, and were not associated with any behavioral or morphological changes. During exposure sessions, mice exposed to 7000 ppm exhibited clinical signs of toxicity which included hyperactivity, circling, jumping/hopping, excessive grooming, kicking of rear legs, standing on front legs, and occasional flipping behavior. Clinical signs of toxicity observed in 7000 ppm mice immediately after exposure included hyperactivity, hyperreactivity, ruffled fur (females only), gait abnormalities, spasms in both rear legs, and excessive grooming (males only). The clinical signs observed in mice during and immediately after exposure were transient, and were not present prior to the subsequent exposure. A few mice exposed to 2000 ppm appeared hyperactive during exposure in the latter portion of the study. There were no compound-related changes in mean body weights, body weight gains, food consumption, food efficiency, or mortality; and there were no ophthalmological abnormalities in rats or mice. In addition, there were no compound-related effects on 37 different behavioral parameters assessed during the FOB or during motor activity tests in rats. Male and female mice exposed to 7000 ppm had slight increases in measures of circulating erythrocyte mass (red blood cells, hemoglobin, hematocrit) and plasma protein concentration (males only). Male rats and male and female mice exposed to 7000 ppm had significantly increased relative liver weights, and 7000 ppm male mice also had significantly increased absolute liver weights at the end of the exposure period. At the end of the 1-month recovery period, absolute and relative liver weights of male and female mice were similar to control. However, relative liver weights of 7000 ppm male rats continued to be signifi...

To evaluate whether methyl isobutyl ketone (MIBK) affects reproductive performance, a two-generation reproduction study was conducted. MIBK was administered to 30 Sprague-Dawley rats/sex/group via whole-body inhalation at concentrations of 0, 500, 1000, or 2000 ppm, 6 h daily, for 70 days prior to mating. F(0) and F(1) females were exposed from mating through gestation day 20 and from postnatal day 5; F(2) litters were maintained through postnatal day 21. No treatment-related mortality of adult animals occurred. There was a dose-related increase in adult animals with no or a decreased response to a sound stimulus at 1000 and 2000 ppm; however, no adverse clinical signs occurred 1 h after exposure, suggesting this was a transient sedative effect. Clinical signs of central nervous system (CNS) depression in the pups were observed and one F(1) pup died after initial exposure to 2000 ppm on postnatal day 22; subsequently exposure was delayed until postnatal day 28. Decreased body weight gain and slight decreased food consumption were observed during the first 2 weeks of exposure in both generations at 2000 ppm. There were no adverse effects on male and female reproductive function or landmarks of sexual maturation. Increased F(0) and F(1) liver weights with associated centrilobular hypertrophy occurred in rats at 2000 ppm, indicative of an adaptive response. Increased male kidney weights at all exposure concentrations, associated with hyaline droplets, were indicative of male rat-specific nephropathy. Other than acute sedative effects, the no-observed-adverse-effect level (NOAEL) for parental systemic effects (excluding male rat kidney) was 1000 ppm, based on transient decreased body weight and food consumption; for reproductive effects, 2000 ppm, the highest concentration tested; and for neonatal toxicity, 1000 ppm (based on acute CNS depressive effects).

Published studies for reproductive and developmental toxicity conducted with isopropanol have been conducted by the inhalation and oral gavage routes of administration. Interpretation of the data from these studies has resulted in discussions regarding NOAELs and additional benchmark dose modeling publications. Unpublished reproductive and developmental toxicity studies administered in the drinking water were also conducted by BIBRA, and the results of those studies are presented here. In addition, all of the reproductive and developmental toxicity studies conducted with isopropanol are summarized and evaluated for concordance of effects and NOAELs. Endpoints of concern for regulatory agencies were decreases in male mating index and reductions in postnatal pup survival. Original study reports were evaluated and data collated to address these two endpoints, and the data summarized. Data are presented suggesting that there were technical problems in the study that implied a decrease in male mating index, and based on the results from the drinking water studies, the weight of evidence suggests that isopropanol does not affect male mating or fertility at dose levels of up to 1000 mg/kg/day. The weight of evidence suggests that isopropanol can cause decreases in postnatal pup survival following oral gavage administration of 1000-1200 mg/kg/day to the dams. The NOAEL for this endpoint with oral gavage administration was 700 mg/kg/day. Indications of maternal toxicity were also an important predictor for decreased postnatal survival. Decreased postnatal pup survival was also noted in the drinking water studies with isopropanol with a LOAEL of 2278 mg/kg/day and a NOAEL of 1947 mg/kg/day.

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