Subchronic Oral Study Research Articles

Metabolic and toxicologic study of an artificial sweetener, oxime V.

Metabolic disposition and subchronic oral toxicologic studies were conducted on a new synthetic sweetener, Oxime V. Based on radioactivity assay, the compound was readily absorbed and metabolized. Excretion was nearly quantitative 48 hours after dosing the rat, dog, and rhesus monkey. The major metabolites were formed by oxidation and reduction of the cyclohexadiene ring, oxidation of the aldoxime and dimethyl ether moieties followed by conjugation with glycine, thiomethylation of the ring, and O-glucuronidation of the aldoxime. A two-month feeding study was conducted with male adult rats. The average consumption of Oxime V was 396.5 mg/kg per day by rats fed a diet containing 0.6% of the test compound. No treatment related histopathologic lesion was observed in the liver, kidney, spleen, and testes. The liver weight relative to the body weight and serum bilirubin level were increased.

2 Final Report on the Safety Assessment of Butylated Hydroxyanisole

Butylated hydroxyanisole (BHA) is used in cosmetic formulations as a chemical preservative and as an antioxidant. Both animal and human studies have shown that BHA is absorbed from the gastrointestinal tract and metabolized. Tissue storage may occur with BHA because of its lipid solubility. However, the amount stored is limited by rapid metabolism and excretion. Reported acute oral LD50 values for BHA in rats varied from 2.0 to > 5.0 g/kg. Formulations containing BHA elicited, at most, minimal or moderate skin and eye irritation in rabbits. An extensive number of subchronic and chronic oral studies have been conducted and are reviewed. BHA given orally or parenterally to mice and rats was shown to inhibit the carcinogenic effects of a broad range of chemical carcinogens. BHA has been shown to inhibit mutagenesis and was not a mutagenic agent in standard in vitro tests. No evidence of carcinogenicity was observed when BHA was administered to mice by subcutaneous injection, by intraperitoneal injection, or by topical application. No carcinogenesis was demonstrated following dietary administration of BHA to either rats or dogs. An increased incidence of forestomach papillomas and squamous cell carcinomas has been observed in rats fed BHA. Studies with pregnant rabbits, mice, rats, and hamsters receiving BHA during gestation by a variety of oral dosage regimens revealed no significant embryotoxic or teratogenic effects. Clinical data for BHA in cosmetic formulations indicated that they were generally nonsensitizing, nonphotosensitizing, and only minimally or mildly irritating. It is concluded that BHA is safe as a cosmetic ingredient in the present practices of use.

Safety aspects of midazolam.

The LD50 in the rat and the mouse is about 1600 mg/kg (oral administration) and 75 mg/kg (rat) and 50 mg/kg (mouse) on intravenous administration. Subchronic oral studies over 13 weeks in doses of 5, 15 and 45 mg/kg/day in the dog and 50, 100 and 200 mg/kg/day in the rat have demonstrated minimal toxicity for midazolam, as for other benzodiazepines. High doses produced increased liver weight in the rat and the expected increases in alkaline phosphatase in the dog (species-specific reaction). Detailed blood and urine analyses as well as histological examination of organs produced no indication of changes relevant for man. Subchronic parenteral studies (i.v. and i.m. for five weeks) using up to 6 mg/kg/day in dogs and rats showed the compound to be not only systemically, but also locally, extremely well tolerated. Reproduction toxicology studies have shown that midazolam is neither embryotoxic nor teratogenic and that it has no effect on the fertility and post-natal development of animals. In the AMES test and the fluctuation test, midazolam had no mutagenic effect.