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The fertility of rats ranges from one to 18 months. In standard teratogenicity testing young, mature females are used which may not reflect the situation in women above 35 years old. Reproduction among different age groups of Wistar ats (strain Chbb: THOM) was compared at 3, 6, 9, 12, 15 and 18 months. At least 20 virgin females were inseminated per age group. The copulation rate did not differ between the groups. From the maternal age of 12 months, the pregnancy rate was significantly decreased, from the age of 9 months, the litter values were significantly lowered and the resorption rates were increased. Maternal age did not influence the incidence of fetal variations and malformations. Additionally, the chromosomal aberration rate in the bone marrow was evaluated in male and female rats. Twelve animals of each sex were scheduled per group, and studied at the age of 1, 3, 6, 12, 15, 18, 21 or 24 months. In males, the aberration rate increased continuously from 0.18 through 3%, while in females the increase continued from 0.33 to 2.29% at 15 months old when a plateau was reached. When testing new compounds for embryotoxicity or genotoxicity in female rats, the animals should be of comparable age to man in order to avoid a misinterpretation of spontaneous abnormalities. From these studies, however, it was concluded that the use of higher age groups of female rats in teratogenicity studies would not improve the risk assessment.

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A joint study was undertaken in three testing facilities to evaluate cumulative background data of Himalayan rabbits. All litters were derived from control does. The conception rate was high (84.0-95.1%) but the average numbers of corpora lutea (7.9-8.7), implantation sites (6.5-7.5) and viable fetuses (5.8-6.9) were somewhat lower than that of most other strains of rabbit. Altogether 90 malformed fetuses (1.12%) and 425 fetuses with variations (5.27%) occurred among 8,060 virable fetuses.

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Brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno [3,2-f]-1,2,4-triazolo[4,3-a]-1,4-diazepine, We 941, Lendormin), a new hypnotic, was submitted to a comprehensive range of safety assessment tests. Acute (single dose) toxicity was very low, while in subacute and chronic studies in rodents, signs of toxicity were first seen at doses of 400 mg/kg or more. Histopathological changes were only seen in the 1 1/2-year study. Ataxia, salivation, and diarrhea were observed in a 4-week intravenous study in dogs, and ataxia, increased feed intake, muscular spasms, increased liver weight, and lipid depletion of the adrenal cortex in two oral studies in monkeys. Reproductive studies in the rat and the rabbit revealed no disturbances in fertility, nor were any embryotoxic or teratogenic effects detected in doses of up to 30 mg/kg. Only at 400 mg/kg was litter mortality increased. Local tolerance tests in rabbits indicated good compatibility of brotizolam when administered intramuscularly, intra-arterially, or intravenously. No signs of any genotoxic action could be detected. A carcinogenicity study in mice showed no evidence of any oncogenic effect, while in rats, although the incidence of certain tumors appeared somewhat higher in the high-dose group, this could be explained by the range of biological variation within the strain, a possible modulating effect on the immune system due to the stress of a very high dose, and a functional effect on the thyroid. These studies thus demonstrate that brotizolam has a remarkably wide therapeutic range.(ABSTRACT TRUNCATED AT 250 WORDS)

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Acute studies. Following oral or intraperitoneal administration, toxicity was very low (LD50 in rodents greater than 10,000 and greater than 900 mg/kg, respectively). Subacute and chronic studies in rodents. Signs of toxicity were seen only at doses of 400 mg/kg or more. Histopathological changes were found only in the 78-week study. Subacute studies in dogs (intravenous) and primates (oral). In dogs, doses of 0.1 and 0.3 mg/kg produced ataxia, salivation, and diarrhoea. In monkeys doses of 7 mg/kg or higher produced ataxia, increased appetite, hyperreflexive muscular spasms, increase in liver weight, and lipid depletion of the adrenal cortex. Reproductive studies in the rat and rabbit. Repeated doses of up to 30 mg/kg were not associated with any disturbance in fertility; nor were any embryotoxic or teratogenic effects observed. When dams wer treated with 400 mg/kg, litter mortality was markedly increased. Mutagenicity studies. The four different tests performed gave no indication of any mutagenic effect. Local tolerance tests in the rabbit. Brotizolam was well tolerated when administered intramuscularly, intra-arterially, or intravenously. Carcinogenicity studies in rodents. The mouse study showed no evidence of a tumourigenic effect. The rat study is still being evaluated. The toxicological studies demonstrate that brotizolam has an unusually wide therapeutic range. Findings of toxicological significance, most of which were reversible, were first recorded at doses of 7-10 mg/kg, i.e. at more than 100-times the intended human therapeutic dose.

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During teratologic trials, routine investigations of 4261 brains from rabbit foetuses, fixed in Bouin's solution and sectioned by Wilson's free-hand razor blade technique, revealed cyst-like spaces in the brains of 164 foetuses (3.8%). The cyst-like spaces, characterised by the absence of an epithelial or endothelial lining, were usually solitary and occurred mainly in the massa intermedia of the thalamus. The spaces were found almost as ofter in control foetuses as in those from treated animals. On the basis of histologic examination and different fixation techniques, involving a further 1430 foetuses, these cyst-like spaces, previously interpreted as strain specific brain malformations, can be regarded as fixation artefacts.

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In investigations of the effect of the bronchospasmolytic (8r)-3alpha-e (ipratropiumbromide, Sch 1000, Atrovent) on the reproductive function in the mouse, rat and rabbit, no teratogenic effect was demonstrated following administration by either gavage or inhalation. Extremely high dose resulted in mortality in pregnant animals and reduction in foetal birthweight. Similarly, no evidence of impaired fertility or perinatal survival due to the substance was found. Postnatal development progressed normally.

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