The effects of multiple administrations of sevoflurane to cynomolgus monkeys: clinical pathologic, hematologic, and pathologic study.

The effect of multiple administrations of sevoflurane was evaluated by several measures of toxicity. Cynomolgus monkeys assigned to a control group and three treatment groups were anesthetized with sevoflurane at 1.0, 1.6, and 2.0 times the minimum alveolar anesthetic concentration (MAC) for 3 h/day, 3 days/wk for 8 wk. Reductions in total erythrocyte and leukocyte counts and increases in serum enzymes were the only changes noted. The increases in the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactic dehydrogenase (LDH), and creatinine kinase (CK), occurred at Week 1 at all three concentrations of sevoflurane. These increases were dose-related, and returned to baseline by Week 2 for 1.0 MAC. All serum enzyme concentrations had returned to baseline by the end of the study. There were no gross pathologic, histopathologic, or ultrastructural differences found in any of the four groups of monkeys. At 2.0 MAC, three deaths occurred. The multiple administrations of 1.0 and 1.6 MAC sevoflurane anesthesia were well tolerated by the monkeys. The techniques of this study did not detect adverse effects from the above enzyme changes.

Subchronic feeding study of four white mineral oils in dogs and rats.

Subchronic 90-day feeding studies were conducted on four highly refined white mineral oils to determine any potential for toxicity in Long-Evans rats (20 per sex per dose level) and beagle dogs (4 per sex per dose level). Each oil was fed at dietary dose levels of 300 ppm and 1500 ppm (w/w). No treatment-related effects of toxicological importance were detected in daily observations of general health or in periodic assessments of food consumption and body weight, hematology, serum clinical chemistry, and urinalysis. Observations in dogs suggested that the white oils produced mild laxative effects. Gross and histopathologic examinations, as well as measurements of organ weights, did not reveal any macroscopic or microscopic changes which could be due to treatment. In addition, special staining by Oil Red O of liver, mesenteric lymph nodes, spleen, gastrointestinal tract, stomach, and kidneys indicated no evidence of oil or lipid deposition. A special re-examination of tissues from female and male rats, in response to more recent conflicting data from the Fischer 344 strain, found no histopathologic signs of macrophage accumulation and/or microgranuloma formation in liver, spleen, or mesenteric lymph nodes. These data indicate that repeated exposure to relatively high levels of white mineral oils in the diets does not produce significant subchronic toxicity in Long-Evans rats or beagle dogs.

Subchronic inhalation toxicity of hexamethylenediamine in rats.

Four groups of 15 male and 15 female Sprague-Dawley-derived (CD) rats each were exposed to aqueous hexamethylenediamine (HMD) aerosols for 6 hr/day, 5 days/week for 13 weeks at mean analytical concentrations of 0, 12.8, or 51 mg/m3. Because of exposure-related deaths in a group of male and female rats similarly exposed to 215 mg/m3 HMD, this group was terminated during the seventh week of the study. Signs of respiratory and conjunctival irritation were observed in rats at both the 51 and 215 mg/m3 HMD test levels. Body weight gain was significantly reduced in both sexes exposed to 215 mg/m3 HMD. At the 5-week study interval, slight hemopoietic stimulation of peripheral blood parameters was observed in rats of both sexes exposed to 215 mg/m3 HMD. Treatment-related microscopic lesions were seen only in rats exposed to 215 mg/m3 MD and were confined to the trachea, nasal passages, and lungs. The no-effect level in this study is considered to be 12.8 mg/m3 HMD.

Toxicological evaluation of hydrochlorofluorocarbon 142b.

Groups of 110 rats of each sex were exposed by whole-body inhalation to 0, 1000, 10,000 or 20,000 ppm (v/v) of hydrochlorofluorocarbon 142b (CFC 142b or 1-chloro-1, 1-difluoroethane) for 6 hr/day, 5 days/wk for 104 wk (ten rats from each group were killed after 52 wk) in a combined chronic toxicity and oncogenicity study. Concurrently, ten male rats per group were exposed to the same concentrations for 13 wk in a bone-marrow cytogenicity study and another ten male rats per group were exposed for 15 wk in a dominant lethal study. No toxicologically significant compound-related effects were observed in behaviour, appearance, growth, clinical pathology, or gross and microscopic pathology. Respiratory infection and consequently higher than expected mortality during the first year did not compromise the studies or conclusions but may have contributed to the intergroup differences in the numbers of chromosome breaks and acentric fragments. No evidence for mutagenic potential was seen in either the dominant lethal or the cytogenetic assays. These data indicate the very low toxicity of CFC 142b with respect to chronic effects and genotoxic and oncogenic potential. The toxicological profile of CFC 142b is similar to that of other chlorofluorocarbons that have been assigned a threshold limit value (TLV) of 1000 ppm as a workplace 8-hr time-weighted average by the American Conference of Governmental Industrial Hygienists.

Chronic toxicity/carcinogenicity study of FD & C Blue No. 2 in mice.

Charles River CD-1 mice were fed FD & C Blue No. 2 in the diet levels of 0.5, 1.5 and 5.0% in a long-term toxicity/carcinogenicity study. Each group consisted of 60 males and 60 females. Two concurrent control groups each of 60 males and 60 females received the basal diet. Maximum exposure was 23 months. No consistent compound-related or statistically significant biologically adverse effects were noted.

Chronic toxicity/carcinogenicity study of FD & C Blue No. 2 in rats.

FD & C Blue No. 2 was fed to rats in the diet in a long-term toxicity/carcinogenicity study. The study included an in utero phase in which the compound was administered to groups of 60 male and 60 female Charles River CD albino rats at levels of 0.5, 1.0 and 2.0%. Two concurrent control groups, each containing 60 rats of each sex, received the basal diet. After random selection of the F1 animals, the long-term phase was initiated at the same dietary levels, with 70 rats of each sex in each dose group and in each of two control groups. Maximum exposure was 30 months. No consistent compound-related biologically adverse effects were noted. There were random statistically significant differences from the controls with respect to body weight, food consumption and clinical chemistry tests. Food consumption by the test groups showed a dose-related increase. This was probably due to the non-nutritive character of the colouring. A statistically significant increase in gliomas in the high-dose male rats was not found to be biologically significant, since none of the criteria for determining the neurocarcinogenic potential of chemical substances was met. The overall brain-tumour incidence in this study was within the range typical for 2-yr-old CD rats. Under the conditions of this study, FD & C Blue No. 2 did not produce evidence of any toxicity, including carcinogenicity.